Analgesic efficacy of zoledronic acid and its effect on functional status of prostate cancer patients with metastasis

PubMed Central

Gálvez, Rafael; Ribera, Victoria; González-Escalada, José Ramón; Souto, Alicia; Cánovas, María Luz; Castro, Andrés; Herrero, Begoña; de los Ángeles Maqueda, María; Castilforte, Matilde; Marco-Martínez, José Javier; Pérez, Concepción; Vicente-Fatela, Lorenza; MD, Consuelo Nieto; Orduña, Maria José; Padrol, Anna; Reig, Enrique; Carballido, Joaquín; Cózar, José Manuel

2008-01-01

Objectives A multi-centered observational study evaluated the efficacy of zoledronic acid for improving pain and mobility, and preventing skeletal-related events (SRE) (fracture, spinal compression, pain-relieving radiotherapy), in patients with prostate cancer and bone metastasis. Materials and Methods Males (n = 218) with prostate cancer and bone metastasis undergoing oncologic therapy received zoledronic acid (4 mg iv/month) for 6 months. Parameters evaluated were: 1) pain and movement after 2 consecutive doses; 2) quality of life; 3) SRE incidence and time-to-appearance. Medication tolerance and treatment satisfaction were assessed using a questionnaire. Results A total of 170 that matched all the inclusion criteria (78%) out of 218 were evaluable for efficacy. There was a measurable statistically significant reduction in pain at rest and on movement as well as an improvement in the quality of life compared with baseline. Best results were obtained with early treatment. Overall incidence of bone events was 11.2%. Of the 212 patients (97.2%) evaluable for safety, 16% suffered adverse events and 66% expressed satisfaction with the treatment Discussion Zoledronic acid is effective for reducing pain, improving mobility, and increasing the quality of life in patients with prostate cancer with bone metastasis. Its easy administration and good tolerability make zoledronic acid one of the principal therapeutic tools in the management of patients with pain associated with bone metastasis from prostate cancer. PMID:19920966

Zoledronic acid overcomes chemoresistance and immunosuppression of malignant mesothelioma

PubMed Central

Kopecka, Joanna; Gazzano, Elena; Sara, Orecchia; Ghigo, Dario; Riganti, Chiara

2015-01-01

The human malignant mesothelioma (HMM) is characterized by a chemoresistant and immunosuppressive phenotype. An effective strategy to restore chemosensitivity and immune reactivity against HMM is lacking. We investigated whether the use of zoledronic acid is an effective chemo-immunosensitizing strategy. We compared primary HMM samples with non-transformed mesothelial cells. HMM cells had higher rate of cholesterol and isoprenoid synthesis, constitutive activation of Ras/extracellular signal-regulated kinase1/2 (ERK1/2)/hypoxia inducible factor-1α (HIF-1α) pathway and up-regulation of the drug efflux transporter P-glycoprotein (Pgp). By decreasing the isoprenoid supply, zoledronic acid down-regulated the Ras/ERK1/2/HIF-1α/Pgp axis and chemosensitized the HMM cells to Pgp substrates. The HMM cells also produced higher amounts of kynurenine, decreased the proliferation of T-lymphocytes and expanded the number of T-regulatory (Treg) cells. Kynurenine synthesis was due to the transcription of the indoleamine 1,2 dioxygenase (IDO) enzyme, consequent to the activation of the signal transducer and activator of transcription-3 (STAT3). By reducing the activity of the Ras/ERK1/2/STAT3/IDO axis, zoledronic acid lowered the kyurenine synthesis and the expansion of Treg cells, and increased the proliferation of T-lymphocytes. Thanks to its ability to decrease Ras/ERK1/2 activity, which is responsible for both Pgp-mediated chemoresistance and IDO-mediated immunosuppression, zoledronic acid is an effective chemo-immunosensitizing agent in HMM cells. PMID:25544757

Zoledronic Acid Treatment in Primary Bone Marrow Edema Syndrome.

PubMed

Flores-Robles, Bryan Josué; Sanz-Sanz, Jesus; Sanabria-Sanchinel, Adel Abel; Huntley-Pascual, Dixie; Andréu Sánchez, José Luis; Campos Esteban, José; Blanco, Ricardo; Merino-Argumanez, Carolina; Espinosa-Malpartida, Maria; Ramos-Giráldez, Maria Consuleo; Godoy-Tundidor, Hildegarde; Jiménez-Palop, Maria Mercedes; Barbadillo Mateos, Carmen; Villa-Alcázar, Luis Fernando; Isasi, Carlos Maria; Mulero, Juan Bartolome

2017-03-01

Primary bone marrow edema syndrome (BMES) is characterized by the combination of joint pain and distinctive magnetic resonance imaging changes. It has been suggested that the use of bisphosphonate drugs reduce symptom severity. Our objective was to review cases of patients diagnosed with BMES in the last 7 years who had been treated with zoledronic acid. Access to a pharmaceutical database was gained in order to obtain a list of zoledronic acid prescriptions. Based on clinical and MRI criteria for BMES, patients were selected. Baseline pain intensity was evaluated on a scale of 0 to 3 and was also assessed after 3 and 12 months. Functional recovery was evaluated by noting if a patient had returned to carrying out his or her normal daily activities. Out of 633 patients, 17 cases of BMES were identified (8 men), with a median age of 54 ± 14.1 years. The most frequently affected joint was the ankle (9), followed by the hip. Sixteen patients presented with moderate to severe pain initially. Of those patients, 13 had no pain after 12 months. Zoledronic acid is a option in the management of BMES, since 75% of patients treated with it presented with a complete response.

Cost-minimization study comparing annual infusion of zoledronic acid or weekly oral alendronate in women with low bone mineral density.

PubMed

Chávez-Valencia, Venice; Arce-Salinas, César Alejandro; Espinosa-Ortega, Fabricio

2014-01-01

Cost-minimization study to assess the annual direct costs of 2 antiresorptive strategies in postmenopausal women with low bone mineral densities (BMDs). Patients were randomly assigned to receive 70 mg of oral weekly alendronate or a 1-time 5mg of intravenous zoledronic acid. All medical and nonmedical direct costs were recorded for 1 yr. Student's t-test or the Chi-squared test was used. A total of 101 postmenopausal women were enrolled with a mean age of 58.3 ± 7.6 yr and a postmenopausal period of 13.5 ± 8.3 yr. A total of 50 patients completed 1 yr of alendronate and 51 patients received zoledronic acid. At baseline, no differences were seen between the 2 groups in anthropometric measures, comorbidities, and bone mineral density. The costs for medical attention for low bone mass were $81,532 (US Dollars) for the alendronate group and $69,251 for the zoledronic acid group; the cost per patient was $1631 in the alendronate group vs $1358 in the zoledronic acid group (p<0.0001). Therefore, zoledronic acid treatment provided an annual savings of 15% of the direct costs compared with oral alendronate treatment. Moreover, there was a significant increase in lumbar spine T-scores in the zoledronic acid group when compared with the alendronate group. Annual zoledronic acid infusion as an antiresorptive treatment in women with low BMD provides significant monetary savings when compared with weekly alendronate therapy for 1 yr. Zoledronic acid infusion is also linked to higher increase in BMD and compliance. Copyright © 2014 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.

The bisphosphonate zoledronic acid effectively targets lung cancer cells by inhibition of protein prenylation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xie, Fan; Li, Pengcheng; Gong, Jianhua

Aberrant activation of oncoproteins such as members of the Ras family is common in human lung cancers. The proper function of Ras largely depends on a post-translational modification termed prenylation. Bisphosphonates have been shown to inhibit prenylation in cancer cells. In this study, we show that zoledronic acid, a third generation bisphosphonate, is effective in targeting lung cancer cells. This is achieved by the induction of apoptosis and inhibition of proliferation, through suppressing the activation of downstream Ras and EGFR signalling by zoledronic acid. The combination of zoledronic acid and paclitaxel or cisplatin (commonly used chemotherapeutic drugs for lung cancer)more » augmented the activity of either drug alone in in vitro lung cancer cellular system and in vivo lung xenograft mouse model. Importantly, zoledronic acid inhibits protein prenylation as shown by the increased levels of unprenylated Ras and Rap1A. In addition, the effects of zoledronic acid were reversed in the presence of geranylgeraniol and farnesol, further confirming that mechanism of zoledroinc acid's action in lung cancer cells is through prenylation inhibition. Since zoledronic acid is already available for clinic use, these results suggest that it may be an effective addition to the armamentarium of drugs for the treatment of lung cancer. - Highlights: • Zoledronic acid (ZA) is effectively against lung cancer cells in vitro and in vivo. • ZA acts on lung cancer cells through inhibition of protein prenylation. • ZA suppresses global downstream phosphorylation of Ras signalling. • ZA enhances the effects of chemotherapeutic drugs in lung cancer cells.« less

Effect of zoledronic acid therapy on postmenopausal osteoporosis between the Uighur and Han population in Xinjiang: An open-label, long-term safety and efficacy study.

PubMed

Xu, W; Xiang, C; Wang, H; Yuan, H; Zhao, X; Xiao, X

2018-06-01

Postmenopausal osteoporosis is becoming an urgent health problem in China. A once-yearly infusion of zoledronic acid can be very effective for the treatment of postmenopausal osteoporosis in significantly reducing the risk of hip, vertebral and other fractures. This study aimed to investigate zoledronic acid treatment on postmenopausal osteoporosis in Uighur and Han patients in Xinjiang province, China. A self-controlled and prospective trial design was adopted. A total of 155 Uighur and 151 Han patients were enrolled. All subjects received an intravenous infusion of zoledronic acid (5 mg) at day 0 (baseline) and at 12 months. Patients were followed up for 24 months; the bone mineral density (BMD) of the left total hip and L1-L4 vertebrae was measured at day 0 and at 24 months. BMD was significantly higher after zoledronic acid treatment compared with baseline levels in all patients, as assessed at 24 months. Moreover, the BMD of left total hip increased with 2.7% in the Han group was significantly higher than that of the Uighur group with 1.4% (left total hip, 95% CI: 2.6% to 2.8% in Han group vs 1.2% to 1.4% in Uighur group). The BMD of L1-L4 vertebrae increased with 2.2% in the Han group was significantly higher than that of the Uighur group with 1.6% (L1-L4 vertebrae, 95% CI, 2.0% to 2.4% in Han group vs 1.4% to 1.7% in Uighur group); P < .001. There was no significant difference in drug-related adverse effects between the two groups (P > .05). Zoledronic acid appears to be more effective in postmenopausal osteoporosis in Han than in Uighur subjects. The reasons for this require further investigation. © 2017 John Wiley & Sons Ltd.

Zoledronic acid as compared with observation in multiple myeloma patients at biochemical relapse: results of the randomized AZABACHE Spanish trial

PubMed Central

García-Sanz, Ramón; Oriol, Albert; Moreno, María J.; de la Rubia, Javier; Payer, Angel R.; Hernández, Miguel T.; Palomera, Luis; Teruel, Ana I.; Blanchard, María J.; Gironella, Mercedes; Ribas, Paz; Bargay, Joan; Abellá, Eugenia; Granell, Miquel; Ocio, Enrique M.; Ribera, Josep M.; San Miguel, Jesús F.; Mateos, María V.

2015-01-01

This study analyzed the anti-myeloma effect of zoledronic acid monotherapy by investigating patients at the time of asymptomatic biochemical relapse. One hundred patients were randomized to receive either zoledronic acid (4 mg iv/4 weeks, 12 doses) (n=51) or not (n=49). Experimental and control groups were well balanced for disease and prognostic features. Zoledronic acid did not show an antitumor effect according to changes in M-component. However, there were fewer symptomatic progressions in the experimental group than in the control group (34 versus 41, respectively; P=0.05) resulting in a median time to symptoms of 16 versus 10 months (P=0.161). The median time to next therapy was also slightly longer for the treated group than the untreated, control group (13.4 versus 10.1 months), although the difference was not statistically significant (P=0.360). The pattern of relapses was different for treated versus control patients: progressive bone disease (8 versus 20), anemia (24 versus 18), renal dysfunction (1 versus 2), and plasmacytomas (1 versus 1, respectively). This concurred with fewer skeletal-related events in the treated group than in the control group (2 versus 14), with a projected 4-year event proportion of 6% versus 40% (P<0.001). In summary, zoledronic acid monotherapy does not show an antitumor effect on biochemical relapses in multiple myeloma, but does reduce the risk of progression with symptomatic bone disease and skeletal complications. This trial was registered in the ClinicalTrials.gov database with code NCT01087008 PMID:26069291

Self-assembling nanoparticles encapsulating zoledronic acid inhibit mesenchymal stromal cells differentiation, migration and secretion of proangiogenic factors and their interactions with prostate cancer cells

PubMed Central

Pivetta, Eliana; Colombatti, Alfonso; Boccellino, Mariarosaria; Amler, Evzen; Normanno, Nicola; Caraglia, Michele; De Rosa, Giuseppe; Aldinucci, Donatella

2017-01-01

Zoledronic Acid (ZA) rapidly concentrates into the bone and reduces skeletal-related events and pain in bone metastatic prostate cancer (PCa), but exerts only a limited or absent impact as anti-cancer activity. Recently, we developed self-assembling nanoparticles (NPS) encapsulating zoledronic acid (NZ) that allowed a higher intratumor delivery of the drug compared with free zoledronic acid (ZA) in in vivo cancer models of PCa. Increasing evidence suggests that Bone Marrow (BM) Mesenchymal stromal cells (BM-MSCs) are recruited into the stroma of developing tumors where they contribute to progression by enhancing tumor growth and metastasis. We demonstrated that treatment with NZ decreased migration and differentiation into adipocytes and osteoblasts of MSCs and inhibited osteoclastogenesis. Treatment with NZ reduced the capability of MSCs to promote the migration and the clonogenic growth of the prostate cancer cell lines PC3 and DU145. The levels of Interleukin-6 and of the pro-angiogenic factors VEGF and FGF-2 were significantly reduced in MSC-CM derived from MSCs treated with NZ, and CCL5 secretion was almost totally abolished. Moreover, treatment of MSCs with supernatants from PC3 cells, leading to tumor-educated MSCs (TE-MSCs), increased the secretion of IL-6, CCL5, VEGF and FGF-2 by MSCs and increased their capability to increase PC3 cells clonogenic growth. Treatment with NZ decreased cytokine secretion and the pro-tumorigenic effects also of TE-MSCS. In conclusion, demonstrating that NZ is capable to inhibit the cross talk between MSCs and PCa, this study provides a novel insight to explain the powerful anticancer activity of NZ on PCa. PMID:28477013

Melorheostosis and its treatment with intravenous zoledronic acid

PubMed Central

Hollick, Rosemary Jane; Black, Alison; Reid, David

2010-01-01

We report a case of melorheostosis, a rare bone disorder characterised by mesodermal dysplasia, and its successful and prolonged treatment with the intravenous bisphosphonate zoledronic acid. The middle-aged man presented with pain and swelling of his tibia, which was diagnosed by imaging and bone biopsy as being due to melorheostosis. There was early symptom control after a single infusion of intravenous zoledronic acid. Prolonged symptom relief was accompanied by long-term suppression of the bone resorption marker β cross-laps. We suggest that melorheostosis can be treated with intravenous zoledronic acid and that treatment can be monitored by the use of a specific bone resorption marker. PMID:22479293

The cost effectiveness of zoledronic acid 5 mg for the management of postmenopausal osteoporosis in women with prior fractures: evidence from Finland, Norway and the Netherlands.

PubMed

Akehurst, R; Brereton, N; Ariely, R; Lusa, T; Groot, M; Foss, P; Boonen, S

2011-01-01

This study was conducted to assess the cost effectiveness of zoledronic acid 5 mg as a first-line treatment for the secondary prevention of fragility fractures in women with postmenopausal osteoporosis in Finland, Norway and the Netherlands. A discrete-event, individual-patient computer-simulation model was used to compare the cost effectiveness of zoledronic acid with that of basic treatment (calcium and vitamin D) and commonly prescribed bisphosphonates in postmenopausal women aged 50-80 years who have experienced one previous fracture and have a bone mineral density T-score of -2.5. The cost per quality-adjusted life-year (QALY) gained with zoledronic acid compared with basic treatment ranged from being cost saving in all age groups in Norway, to costing approximately €19,000 in Finland and €22,300 in the Netherlands. Compared with the other branded bisphosphonates, zoledronic acid was cost saving in many scenarios, including all age groups in Finland. In Norway, zoledronic acid dominated branded risedronate and ibandronate in all age groups and dominated or had incremental cost-effectiveness ratios (ICERs) of up to NOK83,954 per QALY gained compared with branded alendronate. In the Netherlands, zoledronic acid dominated branded intravenous ibandronate in all age groups; compared with branded risedronate and oral ibandronate, zoledronic acid dominated or had ICERs of up to €4832 per QALY gained; compared with branded alendronate, it had ICERs of up to €48,383 per QALY gained. In all three countries, zoledronic acid may be cost effective compared with generic alendronate when patient compliance with drug therapy is taken into account. Sensitivity analyses showed that the model was robust to changes in key values. The main model limitations were the lack of real-life compliance and persistence data, and lack of country-specific data for some parameters. Using local or commonly used thresholds, this analysis suggests that zoledronic acid would be a cost-effective first-line option compared with other branded bisphosphonates and, in some scenarios, compared with generic alendronate, for the secondary prevention of fractures in women with postmenopausal osteoporosis in Finland, Norway and the Netherlands.

Cost-effectiveness of oral ibandronate compared with intravenous (i.v.) zoledronic acid or i.v. generic pamidronate in breast cancer patients with metastatic bone disease undergoing i.v. chemotherapy.

PubMed

De Cock, E; Hutton, J; Canney, P; Body, J J; Barrett-Lee, P; Neary, M P; Lewis, G

2005-12-01

Ibandronate is the first third-generation bisphosphonate to have both oral and intravenous (i.v.) efficacy. An incremental cost-effectiveness model compared oral ibandronate with i.v. zoledronic acid and i.v. generic pamidronate in female breast cancer patients with metastatic bone disease, undergoing i.v. chemotherapy. A global economic model was adapted to the UK National Health Service (NHS), with primary outcomes of direct healthcare costs and quality-adjusted life years (QALYs). Efficacy, measured as relative risk reduction of skeletal-related events (SREs), was obtained from clinical trials. Resource use data for i.v. bisphosphonates and the cost of managing SREs were obtained from published studies. Hospital management and SRE treatment costs were taken from unit cost databases. Monthly drug acquisition costs were obtained from the British National Formulary. Utility scores were applied to time with/without an SRE to adjust survival for quality of life. Model design and inputs were validated through expert UK clinician review. Total cost, including drug acquisition, was pound 386 less per patient with oral ibandronate vs. i.v. zoledronic acid and pound 224 less vs. i.v. generic pamidronate. Oral ibandronate gained 0.019 and 0.02 QALYs vs. i.v. zoledronic acid and i.v. pamidronate, respectively, making it the economically dominant option. At a threshold of pound 30,000 per QALY, oral ibandronate was cost-effective vs. zoledronic acid in 85% of simulations and vs. pamidronate in 79%. Oral ibandronate is a cost-effective treatment for metastatic bone disease from breast cancer due to reduced SREs, bone pain, and cost savings from avoidance of resource use commonly associated with bisphosphonate infusions.

Risk factors for symptomatic hypocalcaemia complicating treatment with zoledronic acid.

PubMed

Chennuru, S; Koduri, J; Baumann, M A

2008-08-01

The bisphosphonate zoledronic acid is commonly prescribed to prevent skeletal complications in patients with multiple myeloma or metastatic cancer. Although symptomatic hypocalcaemia is a potential risk of treatment, it has been thought to be uncommon. After seeing several episodes of symptomatic hypocalcaemia following zoledronic acid administration, we undertook a review to determine the incidence of this complication in our population and to attempt to identify risk factors. We reviewed the records of all patients receiving zoledronic acid in two teaching hospitals over a 2-year period. Findings collected included the indication for treatment, whether dosing was adjusted for creatinine clearance, coadministered medications, serum chemistries and clinical course. Of 120 patients who received a total of 546 zoledronic acid infusions, hypocalcaemia developed related to 55 infusions (10%) in 42 patients (35%). Symptomatic hypocalcaemia requiring i.v. supplementation occurred in 10 patients (8%), in spite of appropriate dose adjustment for creatinine clearance and despite prophylactic administration of oral calcium and vitamin D. More patients who became hypocalcaemic developed impairment of creatinine clearance during zoledronic acid treatment than in the group that remained normocalcaemic. Hypomagnesaemia was found in all patients who developed hypocalcaemia who had serum magnesium measured. Hypocalcaemia was common in our patient group following zoledronic acid treatment. Because of the prolonged elimination half-life of this agent (146 h), renal impairment occurring during a number of days after administration may increase risk. Hypomagnesaemia may further increase risk by blunting compensatory increase in parathyroid hormone secretion.

Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases

PubMed Central

Himelstein, Andrew L.; Foster, Jared C.; Khatcheressian, James L.; Roberts, John D.; Seisler, Drew K.; Novotny, Paul J.; Qin, Rui; Go, Ronald S.; Grubbs, Stephen S.; O’Connor, Tracey; Velasco, Mario R.; Weckstein, Douglas; O’Mara, Ann; Loprinzi, Charles L.; Shapiro, Charles L.

2017-01-01

IMPORTANCE Zoledronic acid, a third-generation aminobisphosphonate, reduces the incidence of skeletal-related events and pain in patients with bone metastases. The optimal dosing interval for zoledronic acid is uncertain. OBJECTIVE To determine whether zoledronic acid administered every 12 weeks is noninferior to zoledronic acid administered every 4 weeks. DESIGN, SETTING, PARTICIPANTS Randomized, open-label clinical trial conducted at 269 academic and community sites in the United States. Patients (n = 1822) with metastatic breast cancer, metastatic prostate cancer, or multiple myeloma who had at least 1 site of bone involvement were enrolled between May 2009 and April 2012; follow-up concluded in April 2014. INTERVENTIONS; Patients were randomized to receive zoledronic acid administered intravenously every 4 weeks (n = 911) vs every 12 weeks (n = 911) for 2 years. MAIN OUTCOMES AND MEASURES; The primary end point was the proportion of patients having at least 1 skeletal-related event (defined as clinical fracture, spinal cord compression, radiation to bone, or surgery involving bone) within 2 years after randomization and a between-group absolute difference of 7%as the noninferiority margin. Secondary end points included the proportion of patients with at least 1 skeletal-related event by disease type, pain as assessed by the Brief Pain Inventory (range, 0–10; higher scores indicate worse pain), Eastern Cooperative Oncology Group performance status (range, 0–4; higher scores indicate worse disability), incidence of osteonecrosis of the jaw, kidney dysfunction, skeletal morbidity rate (mean number of skeletal-related events per year), and, in a subset of 553 patients, suppression of bone turnover (assessed by C-terminal telopeptide levels). RESULTS Among 1822 patients who were randomized (median age, 65 years; 980 [53.8%] women; 855 with breast cancer, 689 with prostate cancer, and 278 with multiplemyeloma), 795 completed the study at 2 years. A total of 260 patients (29.5%) in the zoledronic acid every 4-week dosing group and 253 patients (28.6%) in the every 12-week dosing group experienced at least 1 skeletal-related event within 2 years of randomization (risk difference of −0.3%[1-sided 95%CI, −4% to ∞]; P < .001 for noninferiority). The proportions of skeletal-related events did not differ significantly between the every 4-week dosing group vs the every 12-week dosing group for patients with breast cancer, prostate cancer, or multiple myeloma. Pain scores, performance status scores, incidence of jaw osteonecrosis, and kidney dysfunction did not differ significantly between the treatment groups. Skeletal morbidity rates were numerically identical in both groups, but bone turnover was greater (C-terminal telopeptide levels were higher) among patients who received zoledronic acid every 12 weeks. CONCLUSIONS AND RELEVANCE Among patients with bone metastases due to breast cancer, prostate cancer, or multiplemyeloma, the use of zoledronic acid every 12 weeks compared with the standard dosing interval of every 4 weeks did not result in an increased risk of skeletal events over 2 years. This longer interval may be an acceptable treatment option. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00869206 PMID:28030702

Zoledronic Acid Injection

MedlinePlus

... acid (Reclast) is used to prevent or treat osteoporosis (condition in which the bones become thin and ... Zoledronic acid (Reclast) is also used to treat osteoporosis in men, and to prevent or treat osteoporosis ...

Effect of zoledronic acid on bone density and markers of bone turnover in a community clinic.

PubMed

Lim, Ria; Zailskas, Susan; Goldsby, Tashauna U; Lukens, Carrie; Muravev, Rostislav; Dulipsingh, Latha

2013-01-01

This study aims to document the efficacy of zoledronic acid by comparing bone densities and markers of bone turnover, in patients with osteoporosis. Bone mineral density (BMD) and urinary N-telopeptide, a marker of bone turnover, were compared before and after treatment with intravenous zoledronic acid. 52 participants had atleast two doses of zoledronic acid over 36 months. Significant increases in BMD were found in the spine (t=4.38, P<0.01) and decrease in bone turnover marker N-telopeptide (t=3.30, P=0.002). Small but significant correlations were determined between prior steroid use and change in BMD in the spine (r=0.35, P<0.05), and family history of osteoporosis and change in BMD in the right femur (r=0.38, P<0.05). Annual infusions of zoledronic acid for at least two years, revealed a significant increase in bone density at the spine and a decrease in urinary N-telopeptide in patients treated at our center.

Effect of zoledronic acid used in the root surface treatment of late replanted teeth: a study in rats.

PubMed

Mori, Graziela Garrido; Janjacomo, Daniela Maria de Mendonça; Nunes, Daniele Clapes; Castilho, Lithiene Ribeiro

2010-01-01

This study evaluated the use of zoledronic acid, a resorption inhibitor, as a medication for root resorption treatment of late replanted teeth. Twenty-four maxillary right central incisors of rats were avulsed and kept dry for 30 min. Then, the teeth were divided into 2 groups. In group I, root surface was treated with 2% sodium fluoride for 20 min; in group II, 10-6M zoledronic acid solution was used for 20 min. All root canals were filled with calcium hydroxide. Next, teeth were replanted in their respective sockets. After 15 and 60 days post-replantation, the animals were killed and the anatomic pieces were obtained and prepared for microscopic and morphometric analyses. The results showed that zoledronic acid was capable of limiting the occurrence of root resorption and preserving cementum resorption. Further research must be performed to confirm the use of zoledronic acid in root surface treatment of late replanted teeth.

A novel bisphosphonate inhibitor of squalene synthase combined with a statin or a nitrogenous bisphosphonate in vitro[S

PubMed Central

Wasko, Brian M.; Smits, Jacqueline P.; Shull, Larry W.; Wiemer, David F.; Hohl, Raymond J.

2011-01-01

Statins and nitrogenous bisphosphonates (NBP) inhibit 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (HMGCR) and farnesyl diphosphate synthase (FDPS), respectively, leading to depletion of farnesyl diphosphate (FPP) and disruption of protein prenylation. Squalene synthase (SQS) utilizes FPP in the first committed step from the mevalonate pathway toward cholesterol biosynthesis. Herein, we have identified novel bisphosphonates as potent and specific inhibitors of SQS, including the tetrasodium salt of 9-biphenyl-4,8-dimethyl-nona-3,7-dienyl-1,1-bisphosphonic acid (compound 5). Compound 5 reduced cholesterol biosynthesis and lead to a substantial intracellular accumulation of FPP without reducing cell viability in HepG2 cells. At high concentrations, lovastatin and zoledronate impaired protein prenylation and decreased cell viability, which limits their potential use for cholesterol depletion. When combined with lovastatin, compound 5 prevented lovastatin-induced FPP depletion and impairment of protein farnesylation. Compound 5 in combination with the NBP zoledronate completely prevented zoledronate-induced impairment of both protein farnesylation and geranylgeranylation. Cotreatment of cells with compound 5 and either lovastatin or zoledronate was able to significantly prevent the reduction of cell viability caused by lovastatin or zoledronate alone. The combination of an SQS inhibitor with an HMGCR or FDPS inhibitor provides a rational approach for reducing cholesterol synthesis while preventing nonsterol isoprenoid depletion. PMID:21903868

Bilateral retrobulbar optic neuropathy as the only sign of zoledronic acid toxicity.

PubMed

Lavado, Félix Manco; Prieto, Marta Para; Osorio, María Rosalba Ramoa; Gálvez, María Isabel López; Leal, Lucía Manzanas

2017-10-01

Bisphosphonates may rarely cause ocular adverse effects and retrobulbar optic neuropathy (RON) secondary to zoledronic acid is very rare. A 67-year-old man was referred because of progressive and painless decrease vision in the left eye. He had been treated with 7 cycles of zoledronic acid infusions because of metastatic prostate cancer. On examination, VA was 20/20 in the right eye (OD) and 20/50 in the left eye (OS). The optic nerve was unremarkable OU. Pattern visual evoked potentials (pVEP) and electroretinography were performed with the result of VEP responses abolished in OS, and the VEP waveform within the normal range amplitude and delayed peak latencies in OD. Due to the high suspicion of bilateral RON secondary to zoledronic acid, we decided to discontinue the treatment. Two months later, VA was 20/20 OD and hand motions OS, with relative afferent pupillary defect and a pallor of the optic disc in OS. The diagnosis of bilateral RON secondary to zoledronic acid infusions was confirmed, and it was only partially reversible. Zoledronic acid is a potent new generation bisphosphonate increasingly used in oncologic patients and it is usually well tolerated. Optic nerve toxicity is not a side effect recognised by either the Food and Drug Administration or the drug manufacturers, and to our knowledge, this is the first case of zoledronic acid-related bilateral RON with late onset. In conclusion, patients treated with bisphosphonates should be informed about the possibility of ocular side-effects, and ophthalmologists should be consider discontinuing the drug. Copyright © 2017 Elsevier Ltd. All rights reserved.

Zoledronic acid-encapsulating self-assembling nanoparticles and doxorubicin: a combinatorial approach to overcome simultaneously chemoresistance and immunoresistance in breast tumors

PubMed Central

Kopecka, Joanna; Porto, Stefania; Lusa, Sara; Gazzano, Elena; Salzano, Giuseppina; Pinzòn-Daza, Martha Leonor; Giordano, Antonio; Desiderio, Vincenzo; Ghigo, Dario; De Rosa, Giuseppe; Caraglia, Michele; Riganti, Chiara

2016-01-01

The resistance to chemotherapy and the tumor escape from host immunosurveillance are the main causes of the failure of anthracycline-based regimens in breast cancer, where an effective chemo-immunosensitizing strategy is lacking. The clinically used aminobisphosphonate zoledronic acid (ZA) reverses chemoresistance and immunoresistance in vitro. Previously we developed a nanoparticle-based zoledronic acid-containing formulation (NZ) that allowed a higher intratumor delivery of the drug compared with free ZA in vivo. We tested its efficacy in combination with doxorubicin in breast tumors refractory to chemotherapy and immune system recognition as a new combinatorial approach to produce chemo- and immunosensitization. NZ reduced the IC50 of doxorubicin in human and murine chemoresistant breast cancer cells and restored the doxorubicin efficacy against chemo-immunoresistant tumors implanted in immunocompetent mice. By reducing the metabolic flux through the mevalonate pathway, NZ lowered the activity of Ras/ERK1/2/HIF-1α axis and the expression of P-glycoprotein, decreased the glycolysis and the mitochondrial respiratory chain, induced a cytochrome c/caspase 9/caspase 3-dependent apoptosis, thus restoring the direct cytotoxic effects of doxorubicin on tumor cell. Moreover, NZ restored the doxorubicin-induced immunogenic cell death and reversed the tumor-induced immunosuppression due to the production of kynurenine, by inhibiting the STAT3/indoleamine 2,3 dioxygenase axis. These events increased the number of dendritic cells and decreased the number of immunosuppressive T-regulatory cells infiltrating the tumors. Our work proposes the use of nanoparticle encapsulating zoledronic acid as an effective tool overcoming at the same time chemoresistance and immunoresistance in breast tumors, thanks to the effects exerted on tumor cell and tumor-infiltrating immune cells. PMID:26980746

Bone effect of adjuvant tamoxifen, letrozole or letrozole plus zoledronic acid in early-stage breast cancer: the randomized phase 3 HOBOE study.

PubMed

Nuzzo, F; Gallo, C; Lastoria, S; Di Maio, M; Piccirillo, M C; Gravina, A; Landi, G; Rossi, E; Pacilio, C; Labonia, V; Di Rella, F; Bartiromo, A; Buonfanti, G; De Feo, G; Esposito, G; D'Aniello, R; Maiolino, P; Signoriello, S; De Maio, E; Tinessa, V; Colantuoni, G; De Laurentiis, M; D'Aiuto, M; Di Bonito, M; Botti, G; Giordano, P; Daniele, G; Morabito, A; Normanno, N; de Matteis, A; Perrone, F

2012-08-01

To measure bone mineral density (BMD) reduction produced by letrozole as compared with tamoxifen and the benefit of the addition of zoledronic acid. A phase 3 trial comparing tamoxifen, letrozole or letrozole+zoledronic acid in patients with hormone receptor-positive early breast cancer was conducted; triptorelin was given to premenopausal patients. Two comparisons were planned: letrozole versus tamoxifen and letrozole+zoledronic acid versus letrozole. Primary end point was the difference in 1-year change of T-score at lumbar spine (LTS) measured by dual energy X-ray absorptiometry scan. Out of 483 patients enrolled, 459 were available for primary analyses. Median age was 50 (range 28-80). The estimated mean difference (95% confidence interval [CI]) in 1-year change of LTS was equal to -0.30 (95% CI -0.44 to -0.17) in the letrozole versus tamoxifen comparison (P<0.0001) and to +0.60 (95% CI +0.46 to +0.77) in the letrozole+zoledronic acid versus letrozole comparison (P<0.0001). Bone damage by letrozole decreased with increasing baseline body mass index in premenopausal, but not postmenopausal, patients (interaction test P=0.004 and 0.47, respectively). In the HOBOE (HOrmonal BOne Effects) trial, the positive effect of zoledronic acid on BMD largely counteracts damage produced by letrozole as compared with tamoxifen. Letrozole effect is lower among overweight/obese premenopausal patients.

Medication-related osteonecrosis of the jaws from once per year intravenous zoledronic acid (Reclast): report of 4 cases.

PubMed

Lee, Cameron Y S; Suzuki, Jon B

2015-04-01

Osteonecrosis of the jaws is a commonly reported side effect with patients prescribed oral antiresorptive medications to treat osteoporosis and osteopenia. Oral antiresorptive agents are considered as the standard of care for the prevention and treatment of women with postmenopausal osteoporosis. Because of patient's noncompliance of the antiresorptive medications, which may require once-weekly or once-monthly oral ingestion, a new once a year intravenous (IV) infusion of zoledronic acid was recently introduced in the management of osteoporosis. Reports of medication-related osteonecrosis of the jaw (MRONJ) have been reported in patients with cancer treated with multiple doses of IV zoledronic acid. However, there is a paucity of reports occurring with the once-yearly infusion of zoledronic acid (Reclast) for the management of osteoporosis. In this article, we report 4 cases of patients who had a history of long-term oral antiresorptive therapy and now were taking the once-yearly IV zoledronic acid (Reclast) and soon developed MRONJ after completing surgery of the maxilla and mandible.

A 5-year retrospective longitudinal study on the incidence and the risk factors of osteonecrosis of the jaws in patients treated with zoledronic acid for bone metastases from solid tumors.

PubMed

Manfredi, M; Mergoni, G; Goldoni, M; Salvagni, S; Merigo, E; Meleti, M; Vescovi, P

2017-05-01

The aim of this study was to evaluate the incidence and the risk factors of osteonecrosis of the jaw (ONJ) in a group of patients treated with zoledronic acid (ZA) for bone metastases from solid tumors and enrolled in a preventive dental program. This 5-year retrospective longitudinal study included all consecutive oncological patients who underwent at least one infusion with ZA between 2004 and 2011 for bone metastases due to solid neoplasms. Of the 156 patients enrolled in the study, 17 developed ONJ (10.89%). At the multivariate analysis, severe periodontal disease (P=0.025), tooth extraction (P<0.0001) and starting the preventive dental program after the beginning of ZA therapy (P=0.02) were the only factors which showed a significant association with the occurrence of ONJ. This study demonstrated the importance of beginning dental prevention before zoledronic acid exposure in reducing ONJ occurrence, especially in the long term. The results of this research show that control of periodontal disease and an increase in the time between tooth extraction and the first ZA administration are recommended in order to reduce the risk of ONJ development.

Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study

PubMed Central

Fizazi, Karim; Carducci, Michael; Smith, Matthew; Damião, Ronaldo; Brown, Janet; Karsh, Lawrence; Milecki, Piotr; Shore, Neal; Rader, Michael; Wang, Huei; Jiang, Qi; Tadros, Sylvia; Dansey, Roger; Goessl, Carsten

2011-01-01

Summary Background Bone metastases are a major burden in men with advanced prostate cancer. We compared denosumab, a human monoclonal antibody against RANKL, with zoledronic acid for prevention of skeletal-related events in men with bone metastases from castration-resistant prostate cancer. Methods In this phase 3 study, men with castration-resistant prostate cancer and no previous exposure to intravenous bisphosphonate were enrolled from 342 centres in 39 countries. An interactive voice response system was used to assign patients (1:1 ratio), according to a computer-generated randomisation sequence, to receive 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cutoff date. Randomisation was stratified by previous skeletal-related event, prostate-specific antigen concentration, and chemotherapy for prostate cancer within 6 weeks before randomisation. Supplemental calcium and vitamin D were strongly recommended. Patients, study staff, and investigators were masked to treatment assignment. The primary endpoint was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary endpoint. Efficacy analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00321620, and has been completed. Findings 1904 patients were randomised, of whom 950 assigned to denosumab and 951 assigned to receive zoledronic acid were eligible for the efficacy analysis. Median duration on study at primary analysis cutoff date was 12·2 months (IQR 5·9–18·5) for patients on denosumab and 11·2 months (IQR 5·6–17·4) for those on zoledronic acid. Median time to first on-study skeletal-related event was 20·7 months (95% CI 18·8–24·9) with denosumab compared with 17·1 months (15·0–19·4) with zoledronic acid (hazard ratio 0·82, 95% CI 0·71–0·95; p=0·0002 for non-inferiority; p=0·008 for superiority). Adverse events were recorded in 916 patients (97%) on denosumab and 918 patients (97%) on zoledronic acid, and serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. More events of hypocalcaemia occurred in the denosumab group (121 [13%]) than in the zoledronic acid group (55 [6%]; p<0·0001). Osteonecrosis of the jaw occurred infrequently (22 [2%] vs 12 [1%]; p=0·09). Interpretation Denosumab was better than zoledronic acid for prevention of skeletal-related events, and potentially represents a novel treatment option in men with bone metastases from castration-resistant prostate cancer. Funding Amgen. PMID:21353695

Local effect of zoledronic acid on new bone formation in posterolateral spinal fusion with demineralized bone matrix in a murine model.

PubMed

Zwolak, Pawel; Farei-Campagna, Jan; Jentzsch, Thorsten; von Rechenberg, Brigitte; Werner, Clément M

2018-01-01

Posterolateral spinal fusion is a common orthopaedic surgery performed to treat degenerative and traumatic deformities of the spinal column. In posteriolateral spinal fusion, different osteoinductive demineralized bone matrix products have been previously investigated. We evaluated the effect of locally applied zoledronic acid in combination with commercially available demineralized bone matrix putty on new bone formation in posterolateral spinal fusion in a murine in vivo model. A posterolateral sacral spine fusion in murine model was used to evaluate the new bone formation. We used the sacral spine fusion model to model the clinical situation in which a bone graft or demineralized bone matrix is applied after dorsal instrumentation of the spine. In our study, group 1 received decortications only (n = 10), group 2 received decortication, and absorbable collagen sponge carrier, group 3 received decortication and absorbable collagen sponge carrier with zoledronic acid in dose 10 µg, group 4 received demineralized bone matrix putty (DBM putty) plus decortication (n = 10), and group 5 received DBM putty, decortication and locally applied zoledronic acid in dose 10 µg. Imaging was performed using MicroCT for new bone formation assessment. Also, murine spines were harvested for histopathological analysis 10 weeks after surgery. The surgery performed through midline posterior approach was reproducible. In group with decortication alone there was no new bone formation. Application of demineralized bone matrix putty alone produced new bone formation which bridged the S1-S4 laminae. Local application of zoledronic acid to demineralized bone matrix putty resulted in significant increase of new bone formation as compared to demineralized bone matrix putty group alone. A single local application of zoledronic acid with DBM putty during posterolateral fusion in sacral murine spine model increased significantly new bone formation in situ in our model. Therefore, our results justify further investigations to potentially use local application of zoledronic acid in future clinical studies.

Management of osteoporosis in the aging male: Focus on zoledronic acid

PubMed Central

Piper, Paul K; Gruntmanis, Ugis

2009-01-01

Osteoporosis in the aging male remains an important yet under-recognized and undertreated disease. Current US estimates indicate that over 14 million men have osteoporosis or low bone mass, and men suffer approximately 500,000 osteoporotic fractures each year. Men experience fewer osteoporotic fractures than women but have higher mortality after fracture. Bisphosphonates are potent antiresorptive agents that inhibit osteoclast activity, suppress in vivo markers of bone turnover, increase bone mineral density, decrease fractures, and improve survival in men with osteoporosis. Intravenous zoledronic acid may be a preferable alternative to oral bisphosphonate therapy in patients with cognitive dysfunction, the inability to sit upright, or significant gastrointestinal pathology. Zoledronic acid (Reclast) is approved in the US as an annual 5 mg intravenous infusion to treat osteoporosis in men. The zoledronic acid (Zometa) 4 mg intravenous dose has been studied in the prevention of bone loss associated with androgen deprivation therapy. PMID:19750231

Management of osteoporosis in the aging male: focus on zoledronic acid.

PubMed

Piper, Paul K; Gruntmanis, Ugis

2009-01-01

Osteoporosis in the aging male remains an important yet under-recognized and undertreated disease. Current US estimates indicate that over 14 million men have osteoporosis or low bone mass, and men suffer approximately 500,000 osteoporotic fractures each year. Men experience fewer osteoporotic fractures than women but have higher mortality after fracture. Bisphosphonates are potent antiresorptive agents that inhibit osteoclast activity, suppress in vivo markers of bone turnover, increase bone mineral density, decrease fractures, and improve survival in men with osteoporosis. Intravenous zoledronic acid may be a preferable alternative to oral bisphosphonate therapy in patients with cognitive dysfunction, the inability to sit upright, or significant gastrointestinal pathology. Zoledronic acid (Reclast) is approved in the US as an annual 5 mg intravenous infusion to treat osteoporosis in men. The zoledronic acid (Zometa) 4 mg intravenous dose has been studied in the prevention of bone loss associated with androgen deprivation therapy.

Addition of docetaxel and/or zoledronic acid to standard of care for hormone-naive prostate cancer: a cost-effectiveness analysis.

PubMed

Zhang, Pengfei; Wen, Feng; Fu, Ping; Yang, Yu; Li, Qiu

2017-07-31

The effectiveness of the addition of docetaxel and/or zoledronic acid to the standard of care (SOC) for hormone-naive prostate cancer has been evaluated in the STAMPEDE trial. The object of the present analysis was to evaluate the cost-effectiveness of these treatment options in the treatment of advanced hormone-naive prostate cancer in China. A cost-effectiveness analysis using a Markov model was carried out from the Chinese societal perspective. The efficacy data were obtained from the STAMPEDE trial and health utilities were derived from previous studies. Transition probabilities were calculated based on the survival in each group. The primary endpoint in the analysis was the incremental cost-effectiveness ratio (ICER), and model uncertainties were explored by 1-way sensitivity analysis and probabilistic sensitivity analysis. SOC alone generated an effectiveness of 2.65 quality-adjusted life years (QALYs) at a lifetime cost of $20,969.23. At a cost of $25,001.34, SOC plus zoledronic acid was associated with 2.69 QALYs, resulting in an ICER of $100,802.75/QALY compared with SOC alone. SOC plus docetaxel gained an effectiveness of 2.85 QALYs at a cost of $28,764.66, while the effectiveness and cost data in the SOC plus zoledronic acid/docetaxel group were 2.78 QALYs and $32,640.95. Based on the results of the analysis, SOC plus zoledronic acid, SOC plus docetaxel, and SOC plus zoledronic acid/docetaxel are unlikely to be cost-effective options in patients with advanced hormone-naive prostate cancer compared with SOC alone.

[Evidences of safety and tolerability of the zoledronic acid 5 mg yearly in the post-menopausal osteoporosis: the HORIZON project].

PubMed

Dalle Carbonare, L; Bertoldo, F; Lo Cascio, V

2009-01-01

Bisphosphonates are the most commonly prescribed medications for the treatment of osteoporosis. Despite evidence supporting the anti-fracture efficacy of aminobisphosphonates approximately 50% of patients do not follow their prescribed treatment regimen and/or discontinue treatment within the first year. Poor compliance is associated with negative outcomes, including increased fracture risk. Tolerability and safety are among the causes of poor compliance. Intravenous bisphosphonates avoids the gastrointestial intolerance and the complex dosing instruction of the oral route ensuring full compliance which may provide improved efficacy. However, there are some concerns regarding potent intravenous bisphosphonates as zoledronic acid with respect to tolerability, mainly the acute phase response and to safety, mainly a theoretical risk of over suppression of bone turnover, renal toxicity and osteonecrosis of the jaw. In the HORIZON study, 152 patients on active treatment (82) or placebo (70) underwent to a bone biopsy after double tetracycline labeling. Bone biopsies (iliac crest) were obtained at the final visit at month 36, 1 year after the last infusion. The biopsies were analyzed by histomorphometry on bone sections and by micro-CT (microCT) analysis. One hundred forthy-three biopsies (76 zoledronic acid, 67 placebo) had at least one microCT parameter measured and 111 were available for quantitative histomorphometry (59 zoledronic acid, 52 placebo). Micro-CT analysis of bone structure revealed higher trabecular bone volume (BV/TV), decreased trabecular separation (Tb.Sp), and a strong trend towards improvement in connectivity density in biopsies obtained from patients treated with zoledronic acid, indicating preservation of trabecular bone structure with respect to placebo. Histomorphometric analysis obtained from patients treated with zoledronic acid exhibited reduction of bone turnover, as suggested by decreased activation frequency (Ac.F) by 63%, mineralizing surface (MS/BS), bone formation rate (BFR/BV). In addition, mineral appositional rate (MAR), reflecting the bone-forming capacity of osteoblastic teams at the bone multicellular unit (BMU) level, was significantly higher in patients on active treatment. No sign of excessive suppression of bone turnover or mineralization impairment was detected, confirming the safety of the treatment with intravenous zoledronic acid once a year. These interesting findings are discussed in the article, particularly in terms of new histomorphometric results and clinical findings supporting the tolerability and safety of zoledronic acid.

EFFECTS OF ZOLEDRONIC ACID ON OOFORECTOMIZED RATS' TIBIAE: A PROSPECTIVE AND RANDOMIZED STUDY

PubMed Central

Alves Pereira, Fernando Roberto; Dutra, Ricardo César; Reis Olímpio, Thiago César; Müller, Sérgio Swain; Palacio, Evandro Pereira

2015-01-01

To investigate clinical, biomechanic and histomorphometric effects of zoledronic acid on osteoporotic rats’ tibiae after bilateral ooforectomy. Methods: 40 female Wistar (Rattus novergicus albinus) rats were prospectively studied. On the 60th day of life, the animals were randomized into two groups according to the surgical procedure: bilateral ooforectomy (O) (n=20) and sham surgery (“sham”) (P) (n=20). After 30 days, the animals were divided into four groups, according to the administration of zoledronic acid (ZA) 0.1mg/kg or distilled water (DW): OZA (n=10), ODW (n=10), PZA (n=10) and PDW (n=10). After 12 months, the animals were sacrificed, and had their tibiae assessed. In the clinical study, animals’ weight was considered; in the biomechanical study, compressive assays were applied and, in the histomorphometric analysis, the bone trabecular area was determined. Results: “O” groups showed a significantly greater weight gain than “P” groups (p=0.005). Groups OZA and PZA showed an insignificant weight gain when compared to ODW (p=0.47) and PDW (p=0.68). The groups receiving zoledronic acid and distilled water were able to bear maximum load, similar (p=0.2), at the moment of fracture. In the groups receiving zoledronic acid, an insignificant increase of the bone trabecular area was found when compared to the groups receiving distilled water (p=0.21). There was a positive correlation between trabecular area and maximum load (p=0.04; r=0.95). Conclusion: Zoledronic acid did not significantly influence animals’ weight. The results showed an insignificant increase both of the tibial shaft bone resistance and the bone trabecular area. PMID:26998455

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) associated with a once-yearly IV infusion of zoledronic acid (Reclast) 5 mg: two cases and review of the literature.

PubMed

Katz, Joseph; Ordoveza, Patrisha A

2014-09-01

The use of a once-yearly IV infusion of 5 mg zoledronic acid has become more common, as the drug is being reported as safe, with few to minimal adverse reactions. This one-time annual administration has a favorable outcome for patients with osteoporosis and spares the burden of taking daily oral bisphosphonates. The present literature search found 10 well-documented cases of bisphosphonate-related osteonecrosis of the jaw (BRONJ) associated with annual administration of 5 mg zoledronic acid for the treatment of osteoporosis. Two new cases are also described, with underlying risk factors similar to previous reports. These include prior dental surgical procedures, the presence of diabetes, autoimmune conditions, past use of bisphosphonate and steroids, and concomitant immunosuppression. Although the reported incidence of BRONJ related to once-a-year IV administered zoledronic acid is low, it may be plausible. Both medical and dental clinicians should be aware of its manifestation.

Effect of once-yearly zoledronic acid five milligrams on fracture risk and change in femoral neck bone mineral density.

PubMed

Eastell, Richard; Black, Dennis M; Boonen, Steven; Adami, Silvano; Felsenberg, Dieter; Lippuner, Kurt; Cummings, Steven R; Delmas, Pierre D; Palermo, Lisa; Mesenbrink, Peter; Cauley, Jane A

2009-09-01

In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly - Pivotal Fracture Trial (HORIZON-PFT), zoledronic acid (ZOL) 5 mg significantly reduced fracture risk. The aim of the study was to identify factors associated with greater efficacy during ZOL 5 mg treatment. We conducted a subgroup analysis (preplanned and post hoc) of a multicenter, double-blind, placebo-controlled, 36-month trial in 7765 women with postmenopausal osteoporosis. A single infusion of ZOL 5 mg or placebo was administered at baseline, 12, and 24 months. Primary endpoints were new vertebral fracture and hip fracture. Secondary endpoints were nonvertebral fracture and change in femoral neck bone mineral density (BMD). Baseline risk factor subgroups were age, BMD T-score and vertebral fracture status, total hip BMD, race, weight, geographical region, smoking, height loss, history of falls, physical activity, prior bisphosphonates, creatinine clearance, body mass index, and concomitant osteoporosis medications. Greater ZOL induced effects on vertebral fracture risk were seen with younger age (treatment-by-subgroup interaction, P = 0.05), normal creatinine clearance (P = 0.04), and body mass index >or= 25 kg/m(2) (P = 0.02). There were no significant treatment-factor interactions for hip or nonvertebral fracture or for change in BMD. ZOL appeared more effective in preventing vertebral fracture in younger women, overweight/obese women, and women with normal renal function. ZOL had similar effects irrespective of fracture risk factors or femoral neck BMD.

Denosumab Reduces Risk of Bone Side Effects in Advanced Prostate Cancer

Cancer.gov

The biological agent denosumab (Xgeva) is more effective than zoledronic acid at decreasing the risk of bone fractures and other skeletal-related events (SRE) in men with castration-resistant metastatic prostate cancer, according to results from a randomi

Acute bilateral uveitis and right macular edema induced by a single infusion of zoledronic acid for the treatment of postmenopausal osteoporosis as a substitution for oral alendronate: a case report.

PubMed

Tian, Yiming; Wang, Rui; Liu, Lianyuan; Ma, Chunming; Lu, Qiang; Yin, Fuzai

2016-02-11

Zoledronic acid-induced uveitis (ZAIU) is rare but severe, and has been recently considered part of an acute phase reaction. Only 15 cases have been reported since 2005. Here we describe a case with macular edema, which is the first reported case observed after long-term alendronate tolerance. A 63-year-old Asian woman received her first intravenous zoledronic acid treatment for the management of postmenopausal osteoporosis as a more convenient substitute for oral alendronate. Twenty-four hours later, bilateral eye irritations, periorbital swelling, blurred vision, and diplopia presented. The complete blood count and transaminase levels were normal, but the erythrocytic sedimentation, C-reactive protein, and serum C4 levels were elevated. On detailed ophthalmological examination, a diagnosis of bilateral acute uveitis and macular edema in the right eye was made. The ocular symptoms were not improved until administration of topical and oral steroids. Complete resolution was achieved. There was no rechallenge of bisphosphonates, and no recurrence at 6 months follow-up. Based on an extensive review, abnormal fundus is rarely reported, especially in cases of macular edema. Rechallenge with zoledronic acid in five cases induced no additional uveitis, and changing the medication to pamidronate in another patient was also tolerated. Interestingly, our patient suffered from uveitis soon after intravenous zoledronate exposure after a two-year tolerance to oral alendronate. This is the first report of zoledronic acid induced uveitis with macular edema after long-term alendronate tolerance. Prior oral alendronate may not entirely prevent ZAIU. Steroids are usually necessary in the treatment of ZAIU. Bisphosphonate rechallenge is not fully contraindicated, and prior steroid administration may be a more reasonable treatment choice according to the available evidence.

Effect of zoledronic acid on reducing femoral bone mineral density loss following total hip arthroplasty: A meta-analysis from randomized controlled trails.

PubMed

Gao, Jian; Gao, Chong; Li, Hui; Wang, Guo-Sheng; Xu, Chang; Ran, Jian

2017-11-01

This meta-analysis aimed to assess the efficiency of intravenous administration of zoledronic acid on reducing femoral periprosthetic bone mineral density loss in patients undergoing primary total hip arthroplasty (THA). A systematic search was performed in Medline (1966-2017.07.31), PubMed (1966-2017.07.31), Embase (1980-2017.07.31), ScienceDirect (1985-2017.07.31) and the Cochrane Library (1966-2017.07.31). Fixed/random effect model was used according to the heterogeneity tested by I 2 statistic. Sensitivity analysis was conducted and publication bias was assessed. Meta-analysis was performed using Stata 11.0 software. Four studies including 185 patients met the inclusion criteria. The present meta-analysis indicated that there were significant differences between groups in terms of periprosthetic bone mineral density in Gruen zone 1 (SMD = 0.752, 95% CI: 0.454 to 1.051, P = 0.000), 2 (SMD = 0.524, 95% CI: 0.230 to 0.819, P = 0.000), 4 (SMD = 0.400, 95% CI: 0.107 to 0.693, P = 0.008), 6 (SMD = 0.893, 95% CI: 0.588 to 1.198, P = 0.000) and 7 (SMD = 0.988, 95% CI: 0.677 to 1.300, P = 0.000). Intravenous administration of zoledronic acid could significantly reduce periprosthetic bone mineral density loss (Gruen zone 1, 2, 4, 6 and 7) after THA. In addition, no severe adverse events were identified. High-quality RCTs with large sample size were still required. Copyright © 2017 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

Real-world effectiveness of osteoporosis therapies for fracture reduction in post-menopausal women.

PubMed

Yusuf, Akeem A; Cummings, Steven R; Watts, Nelson B; Feudjo, Maurille Tepie; Sprafka, J Michael; Zhou, Jincheng; Guo, Haifeng; Balasubramanian, Akhila; Cooper, Cyrus

2018-03-21

Studies examining real-world effectiveness of osteoporosis therapies are beset by limitations due to confounding by indication. By evaluating longitudinal changes in fracture incidence, we demonstrated that osteoporosis therapies are effective in reducing fracture risk in real-world practice settings. Osteoporosis therapies have been shown to reduce incidence of vertebral and non-vertebral fractures in placebo-controlled randomized clinical trials. However, information on the real-world effectiveness of these therapies is limited. We examined fracture risk reduction in older, post-menopausal women treated with osteoporosis therapies. Using Medicare claims, we identified 1,278,296 women age ≥ 65 years treated with zoledronic acid, oral bisphosphonates, denosumab, teriparatide, or raloxifene. Fracture incidence rates before and after treatment initiation were described to understand patients' fracture risk profile, and fracture reduction effectiveness of each therapy was evaluated as a longitudinal change in incidence rates. Fracture incidence rates increased during the period leading up to treatment initiation and were highest in the 3-month period most proximal to treatment initiation. Fracture incidence rates following treatment initiation were significantly lower than before treatment initiation. Compared with the 12-month pre-index period, there were reductions in clinical vertebral fractures for denosumab (45%; 95% confidence interval [CI] 39-51%), zoledronic acid (50%; 95% CI 47-52%), oral bisphosphonates (24%; 95% CI 22-26%), and teriparatide (72%; 95% CI 69-75%) during the subsequent 12 months. Relative to the first 3 months after initiation, clinical vertebral fractures were reduced for denosumab (51%; 95% CI 42-59%), zoledronic acid (25%; 95% CI 17-32%), oral bisphosphonates (23%; 95% CI 20-26%), and teriparatide (64%; 95% CI 58-69%) during the subsequent 12 months. In summary, reductions in fracture incidence over time were observed in cohorts of patients treated with osteoporosis therapies.

Cost-effectiveness of denosumab versus zoledronic acid for preventing skeletal-related events in the Czech Republic.

PubMed

Cristino, Joaquim; Finek, Jíndřich; Jandova, Petra; Kolek, Martin; Pásztor, Bálint; Giannopoulou, Christina; Qian, Yi; Brezina, Tomas; Lothgren, Mickael

2017-08-01

This study assessed the cost-effectiveness of the subcutaneous RANKL inhibitor, denosumab, vs the intravenous bisphosphonate, zoledronic acid, for the prevention of skeletal-related events (SREs) in patients with prostate cancer, breast cancer, and other solid tumors (OST) in the Czech Republic. A lifetime Markov model was developed to compare the effects of denosumab and zoledronic acid on costs (including drug costs and administration, patient management, SREs, and adverse events), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios from a national payer perspective. Different discount rates, time horizons, SRE rates, distributions, and nature (asymptomatic vs all SREs), and the inclusion of treatment discontinuation were considered in scenario analyses. The robustness of the model was tested using deterministic and probabilistic sensitivity analyses. Across tumor types, denosumab was associated with fewer SREs, improved QALYs, and higher total costs over a lifetime. The incremental cost per QALY gained for denosumab vs zoledronic acid was 382,673 CZK for prostate cancer, 408,450 CZK for breast cancer, and 608,133 CZK for OST. Incremental costs per SRE avoided for the same tumor type were 54,007 CZK, 51,765 CZK, and 94,426 CZK, respectively. In scenario analyses, the results remained similar to baseline, when different discount rates and time horizons were considered. At a non-official willingness-to-pay threshold of 1.2 million CZK, the probabilities of denosumab being cost-effective vs zoledronic acid were 0.64, 0.67, and 0.49 for prostate cancer, breast cancer, and OST, respectively. The SRE rates used were obtained from clinical trials; studies suggest rates may be higher in clinical practice. Additional evidence on real-world SRE rates could further improve the accuracy of the modeling. Compared with zoledronic acid, denosumab provides a cost-effective treatment option for the prevention of SREs in patients with prostate cancer, breast cancer, and OST in the Czech Republic.

Clinical Practice. Postmenopausal Osteoporosis.

PubMed

Black, Dennis M; Rosen, Clifford J

2016-01-21

Key Clinical Points Postmenopausal Osteoporosis Fractures and osteoporosis are common, particularly among older women, and hip fractures can be devastating. Treatment is generally recommended in postmenopausal women who have a bone mineral density T score of -2.5 or less, a history of spine or hip fracture, or a Fracture Risk Assessment Tool (FRAX) score indicating increased fracture risk. Bisphosphonates (generic) and denosumab reduce the risk of hip, nonvertebral, and vertebral fractures; bisphosphonates are commonly used as first-line treatment in women who do not have contraindications. Teriparatide reduces the risk of nonvertebral and vertebral fractures. Osteonecrosis of the jaw and atypical femur fractures have been reported with treatment but are rare. The benefit-to-risk ratio for osteoporosis treatment is strongly positive for most women with osteoporosis. Because benefits are retained after discontinuation of alendronate or zoledronic acid, drug holidays after 5 years of alendronate therapy or 3 years of zoledronic acid therapy may be considered for patients at lower risk for fracture.

Effect of Once-Yearly Zoledronic Acid Five Milligrams on Fracture Risk and Change in Femoral Neck Bone Mineral Density

PubMed Central

Eastell, Richard; Black, Dennis M.; Boonen, Steven; Adami, Silvano; Felsenberg, Dieter; Lippuner, Kurt; Cummings, Steven R.; Delmas, Pierre D.; Palermo, Lisa; Mesenbrink, Peter; Cauley, Jane A.

2016-01-01

Context In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly – Pivotal Fracture Trial (HORIZON-PFT), zoledronic acid (ZOL) 5 mg significantly reduced fracture risk. Objective The aim of the study was to identify factors associated with greater efficacy during ZOL 5 mg treatment. Design, Setting, and Patients We conducted a subgroup analysis (preplanned and post hoc) of a multicenter, double-blind, placebo-controlled, 36-month trial in 7765 women with postmenopausal osteoporosis. Intervention A single infusion of ZOL 5 mg or placebo was administered at baseline, 12, and 24 months. Main Outcome Measures Primary endpoints were new vertebral fracture and hip fracture. Secondary endpoints were nonvertebral fracture and change in femoral neck bone mineral density (BMD). Baseline risk factor subgroups were age, BMD T-score and vertebral fracture status, total hip BMD, race, weight, geographical region, smoking, height loss, history of falls, physical activity, prior bisphosphonates, creatinine clearance, body mass index, and concomitant osteoporosis medications. Results Greater ZOL induced effects on vertebral fracture risk were seen with younger age (treatment-by-subgroup interaction, P =0.05), normal creatinine clearance (P =0.04), and body mass index ≥ 25 kg/m2 (P = 0.02). There were no significant treatment–factor interactions for hip or nonvertebral fracture or for change in BMD. Conclusions ZOL appeared more effective in preventing vertebral fracture in younger women, overweight/obese women, and women with normal renal function. ZOL had similar effects irrespective of fracture risk factors or femoral neck BMD. PMID:19567517

Early, middle, or late administration of zoledronate alleviates spontaneous nociceptive behavior and restores functional outcomes in a mouse model of CFA-induced arthritis.

PubMed

Morado-Urbina, Carlos Eduardo; Alvarado-Vázquez, Perla Abigail; Montiel-Ruiz, Rosa Mariana; Acosta-González, Rosa Issel; Castañeda-Corral, Gabriela; Jiménez-Andrade, Juan Miguel

2014-11-01

This study was performed to evaluate whether early, middle, or late treatment of zoledronate, an approved bisphosphonate that blocks bone resorption, can reduce nociceptive behaviors in a mouse arthritis model. Arthritis was produced by repeated intra-articular knee injections of complete Freund's adjuvant (CFA). A dose-response curve with zoledronate (3, 30, 100, and 300 μg/kg, i.p., day 4 to day 25, twice weekly for 3 weeks) was performed, and the most effective dose of zoledronate (100 μg/kg, i.p.) was initially administered at different times of disease progression: day 4 (early), day 15 (middle), or day 21 (late) and continued until day 25 after the first CFA injection. Flinching of the injected extremity (spontaneous nociceptive behavior), vertical rearings and horizontal activity (functional outcomes), and knee edema were assessed. Zoledronate improved both functional outcomes and reduced flinching behavior. At day 25, the effect of zoledronate on flinching behavior and vertical rearings was greater in magnitude when it was given early or middle rather than late in the treatment regimen. Chronic zoledronate did not reduce knee edema in CFA-injected mice nor functional outcomes in naïve mice by itself. These results suggest that zoledronate may have a positive effect on arthritis-induced nociception and functional disabilities. © 2014 Wiley Periodicals, Inc.

Zoledronic acid and alendronate sodium and the implications in orthodontic movement.

PubMed

Franzoni, J S; Soares, F M P; Zaniboni, E; Vedovello Filho, M; Santamaria, M P; Dos Santos, G M T; Esquisatto, M A M; Felonato, M; Mendonca, F A S; Franzini, C M; Santamaria, M

2017-08-01

To evaluate orthodontic tooth movement (OTM) in rats treated with two types of bisphosphonates (BPs), alendronate sodium (A) and zoledronic acid (Z). In all, 15 male Wistar rats were randomly divided into three groups. Group OTM+A: orthodontic tooth movement and subcutaneous administration of alendronate sodium (2.5 mg/kg); Group OTM+Z: orthodontic tooth movement and subcutaneous administration of zoledronic acid (0.02 mg/kg), and Group OTM: orthodontic tooth movement and subcutaneous injection of saline. The BPs were administered once a day during 25 days before OTM started and during 10 days of OTM. The left upper first molar was moved with a stainless-steel closed coil spring which delivered an initial force of 0.4N. OTM was measured with a digital caliper comparing the moved and the contralateral side. The histomorphometric analysis counted the number of osteoclasts, inflammatory cells, blood vessels and fibroblasts (n/10 4  m 2 ) in periodontal ligament (PDL) of the distobuccal root. A reduction of 58.3% of OTM was found in Group OTM+A and 99.6% in Group OTM+Z, when compared with Group OTM. There was a significant decrease of osteoclasts and inflammatory cells in BP-treated groups. Blood vessels and fibroblastic cells decreased mainly in Group OTM+Z. Alendronate sodium and zoledronic acid have similar effects on the periodontal tissue during orthodontic treatment in rats. Especially, zoledronic acid can affect orthodontic tooth movement. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

High incidence of hypocalcemia and serum creatinine increase in patients with bone metastases treated with zoledronic acid.

PubMed

Zuradelli, Monica; Masci, Giovanna; Biancofiore, Giuseppe; Gullo, Giuseppe; Scorsetti, Marta; Navarria, Pierina; Tancioni, Flavio; Berlusconi, Marco; Giordano, Laura; Santoro, Armando

2009-05-01

Zoledronic acid belongs to the new generation of bisphosphonates with demonstrated clinical benefit for the treatment of bone metastases from different kinds of neoplasms. Hypocalcemia and serum creatinine elevation are expected adverse events during this therapy. The monitoring of serum calcium and creatinine is therefore recommended. The primary aim of this study was to establish the actual incidence of hypocalcemia and serum creatinine elevation during treatment with zoledronic acid. Skeletal-related events and side effects were also assessed. Serum creatinine and calcium levels were evaluated in 240 consecutive patients (83 males, 157 females; mean age, 62 years) with metastatic bone lesions from different solid tumors treated with zoledronic acid. Overall, 93 of 240 patients (38.8%) developed hypocalcemia, which was grade (G)1 in 45 patients (48.4%), G2 in 37 patients (39.8%), G3 in 10 patients (10.8%), and G4 in one patient (1.1%). The median time to occurrence of hypocalcemia (any grade) was 2.3 months after the beginning of the treatment (range, 0-34.9 months). Increased serum creatinine was observed in 33 of 240 patients (13.7%), of whom 19 had G1 (57.6%), 11 had G2 (33.3%), and three had G3 (9.1%). The median time to serum creatinine increase (for any grade) was 4.7 months (range, 0-29.2 months). Our analysis shows a high incidence of hypocalcemia and increased serum creatinine level during treatment with zoledronic acid. These results strongly support the need for accurate monitoring of plasma calcium and creatinine levels.

Chondroprotective effects of zoledronic acid on articular cartilage in dogs with experimentally induced osteoarthritis.

PubMed

Dearmin, Michael G; Trumble, Troy N; García, Anapatricia; Chambers, Jon N; Budsberg, Steven C

2014-04-01

To assess effects of zoledronic acid on biomarkers, radiographic scores, and gross articular cartilage changes in dogs with induced osteoarthritis. 21 purpose-bred hound-type dogs. The left stifle joint of each dog was examined arthroscopically to determine initial articular cartilage status, which was followed by cranial cruciate ligament (CrCL) transection to induce osteoarthritis. Dogs were assigned to 3 groups (control group, low dose [10 μg of zoledronic acid/kg], or high dose [25 μg of zoledronic acid/kg). Treatments were administered SC every 3 months for 1 year beginning the day after CrCL transection. Serum and synovial fluid samples and radiographs were obtained 0, 1, 3, 6, 9, and 12 months after transection. At 12 months, each joint was scored for cartilage defects. Serum and synovial fluid biomarkers of bone and cartilage turnover (bone-specific alkaline phosphatase, type I and II collagen, carboxy-propeptide of type II collagen, and chondroitin sulfate 846) were analyzed with ELISAs. The high-dose group had fewer total articular defects and lower severity scores in CrCL-transected stifle joints than did the control group. In addition, the high-dose group had significantly less change in collagenase cleavage of type I or II collagen in the synovial fluid at 1 and 3 months after CrCL transection than did the control group and also had greater changes in bone-specific alkaline phosphatase in synovial fluid at 3 months after CrCL transection than did the control group. Zoledronic acid had a chondroprotective effect in dogs with a transected CrCL.

The effect of a single infusion of zoledronic acid on early implant migration in total hip arthroplasty. A randomized, double-blind, controlled trial.

PubMed

Friedl, Gerald; Radl, Roman; Stihsen, Christoph; Rehak, Peter; Aigner, Reingard; Windhager, Reinhard

2009-02-01

Aseptic loosening is the most frequent cause of implant failure in total hip arthroplasty. While a direct link between aseptic loosening and periprosthetic bone loss remains elusive, there is plentiful evidence for a close association with early implant migration. The present trial was primarily designed to evaluate whether a single infusion of 4 mg of zoledronic acid prevented early implant migration in patients with osteonecrosis of the femoral head. Fifty patients were consecutively enrolled to receive either zoledronic acid or saline solution after cementless total hip arthroplasty. Radiographs, biochemical parameters of bone turnover, and the Harris hip-rating score were determined preoperatively and at each follow-up examination at seven weeks, six months, one year, and yearly thereafter. The median follow-up period was 2.8 years. We found a significant subsidence of the stem of up to a mean (and standard deviation) of -1.2 +/- 0.6 mm at two years within the control group, and the cups had a mean medialization of 0.6 +/- 1.0 mm and a mean cranialization of 0.6 +/- 0.8 mm (p < 0.001). Treatment with zoledronic acid effectively minimized the migration of the cups in both the transverse and the vertical direction (mean, 0.15 +/- 0.6 mm and 0.06 +/- 0.6 mm, respectively; p < 0.05), while only a trend to decreased subsidence of the stem was detected. Finally, the Harris hip score rapidly increased over time in both treatment groups, although this increase was significantly more pronounced in the zoledronate-treated group than in the control group (analysis of variance, p = 0.008). A single infusion of zoledronic acid shows promise in improving initial fixation of a cementless implant, which may improve the clinical outcome of total hip arthroplasty in patients with osteonecrosis of the femoral head.

In vitro and in vivo investigation of bisphosphonate-loaded hydroxyapatite particles for peri-implant bone augmentation.

PubMed

Kettenberger, Ulrike; Luginbuehl, Vera; Procter, Philip; Pioletti, Dominique P

2017-07-01

Locally applied bisphosphonates, such as zoledronate, have been shown in several studies to inhibit peri-implant bone resorption and recently to enhance peri-implant bone formation. Studies have also demonstrated positive effects of hydroxyapatite (HA) particles on peri-implant bone regeneration and an enhancement of the anti-resorptive effect of bisphosphonates in the presence of calcium. In the present study, both hydroxyapatite nanoparticles (nHA) and zoledronate were combined to achieve a strong reinforcing effect on peri-implant bone. The nHA-zoledronate combination was first investigated in vitro with a pre-osteoclastic cell assay (RAW 264.7) and then in vivo in a rat model of postmenopausal osteoporosis. The in vitro study confirmed that the inhibitory effect of zoledronate on murine osteoclast precursor cells was enhanced by loading the drug on nHA. For the in vivo investigation, either zoledronate-loaded or pure nHA were integrated in hyaluronic acid hydrogel. The gels were injected in screw holes that had been predrilled in rat femoral condyles before the insertion of miniature screws. Micro-CT-based dynamic histomorphometry and histology revealed an unexpected rapid mineralization of the hydrogel in vivo through formation of granules, which served as scaffold for new bone formation. The delivery of zoledronate-loaded nHA further inhibited a degradation of the mineralized hydrogel as well as a resorption of the peri-implant bone as effectively as unbound zoledronate. Hyaluronic acid with zoledronate-loaded nHA, thanks to its dual effect on inducing a rapid mineralization and preventing resorption, is a promising versatile material for bone repair and augmentation. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

FES-Rowing versus Zoledronic Acid to Improve Bone Health in SCI

DTIC Science & Technology

2015-10-01

although the risk is high in this population of osteoporosis -related bone fracture. This study aims to learn if the severe osteoporosis in lower... Osteoporosis , FES-rowing, zoledronic acid, exercise, bone health 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a...9 Introduction Serious spinal cord injury (SCI) causes osteoporosis in the lower extremities, significantly increasing

Denosumab for the management of bone disease in patients with solid tumors.

PubMed

Body, Jean-Jacques

2012-03-01

Many patients with advanced cancer develop bone metastases, which reduces their quality of life. Bone metastases are associated with an increased risk of skeletal-related events, which can lead to increased morbidity and mortality. In patients with bone metastases, tumor cells disrupt the normal process of bone remodeling, leading to increased bone destruction. Denosumab is a fully human monoclonal antibody against receptor activator of NF-κB ligand (RANKL), a key regulatory factor in bone remodeling. By binding to RANKL, denosumab disrupts the cycle of bone destruction. In clinical studies in patients with prostate or breast cancer and bone metastases, denosumab was superior to the current standard of care, zoledronic acid, for delaying skeletal-related events, while in patients with other solid tumors or multiple myeloma, denosumab was noninferior to zoledronic acid. This article examines the pharmacokinetics, efficacy, and safety and tolerability of denosumab for the management of bone events in patients with cancer.

Role of zoledronic acid in the prevention and treatment of osteoporosis

PubMed Central

Räkel, Agnès; Boucher, Andrée; Ste-Marie, Louis-Georges

2011-01-01

Taken once a year, intravenous zoledronic acid (Zol) (Reclast® or Aclasta®) is a third-generation nitrogen-containing bisphosphonate that is effective compared with placebo in reducing the risk of fractures in patients with postmenopausal osteoporosis and recent low-trauma hip fracture. In glucocorticoid-induced osteoporosis, there is no significant difference between Zol and risedronate for new fractures. Improvements in bone mineral density and early reduction of bone remodeling markers are observed in postmenopausal osteoporosis, recent low-trauma hip fracture, and glucocorticoid-induced osteoporosis. Given that Zol is generally well tolerated and very convenient, it is an interesting therapeutic option for aging patients who take multiple oral drugs, who have adherence or gastrointestinal tolerance issues, and who have an indication for oral bisphosphonates. Zol is not recommended for patients with severe renal impairment. Vitamin D deficiency should be corrected before the administration of Zol. PMID:21594000

Role of zoledronic acid in the prevention and treatment of osteoporosis.

PubMed

Räkel, Agnès; Boucher, Andrée; Ste-Marie, Louis-Georges

2011-01-01

Taken once a year, intravenous zoledronic acid (Zol) (Reclast® or Aclasta®) is a third-generation nitrogen-containing bisphosphonate that is effective compared with placebo in reducing the risk of fractures in patients with postmenopausal osteoporosis and recent low-trauma hip fracture. In glucocorticoid-induced osteoporosis, there is no significant difference between Zol and risedronate for new fractures. Improvements in bone mineral density and early reduction of bone remodeling markers are observed in postmenopausal osteoporosis, recent low-trauma hip fracture, and glucocorticoid-induced osteoporosis. Given that Zol is generally well tolerated and very convenient, it is an interesting therapeutic option for aging patients who take multiple oral drugs, who have adherence or gastrointestinal tolerance issues, and who have an indication for oral bisphosphonates. Zol is not recommended for patients with severe renal impairment. Vitamin D deficiency should be corrected before the administration of Zol.

Zoledronic Acid Inhibits Aromatase Activity and Phosphorylation: Potential Mechanism for Additive Zoledronic Acid and Letrozole Drug Interaction

PubMed Central

Schech, Amanda J.; Nemieboka, Brandon E.; Brodie, Angela H.

2012-01-01

Zoledronic acid (ZA), a bisphosphonate originally indicated for use in osteoporosis, has been reported to exert a direct effect on breast cancer cells, although the mechanism of this effect is currently unknown. Data from the ABCSG-12 and ZO-FAST clinical trials suggest that treatment with the combination of ZA and aromatase inhibitors (AI) result in increased disease free survival in breast cancer patients over AI alone. To determine whether the mechanism of this combination involved inhibition of aromatase, AC-1 cells (MCF-7 human breast cancer cells transfected with an aromatase construct) were treated simultaneously with combinations of ZA and AI letrozole for 72 hours. This combination significantly increased inhibition of aromatase activity of AC-1 cells by compared to letrozole alone. Combination treatment of 1nM letrozole and 1μM and 10μM zoledronic acid resulted in an additive drug interaction on inhibiting cell viability, as measured by MTT assay. Treatment with ZA was found to inhibit phosphorylation of aromatase on serine 473. Zoledronic acid was also shown to be more effective in inhibiting cell viability in aromatase transfected AC-1 cells when compared to inhibition of cell viability observed in non-transfected MCF-7. Estradiol was able to partially rescue the effect of 1μM and 10μM ZA on cell viability following treatment for 72 hours, as shown by a shift to the right in the estradiol dose response curve. In conclusion, these results indicate that the combination of ZA and letrozole results in an additive inhibition of cell viability. Furthermore, ZA alone can inhibit aromatase activity through inhibition of serine phosphorylation events important for aromatase enzymatic activity and contributes to inhibition of cell viability. PMID:22659283

Hypocalcaemia in patients with metastatic bone disease treated with denosumab.

PubMed

Body, Jean-Jacques; Bone, Henry G; de Boer, Richard H; Stopeck, Alison; Van Poznak, Catherine; Damião, Ronaldo; Fizazi, Karim; Henry, David H; Ibrahim, Toni; Lipton, Allan; Saad, Fred; Shore, Neal; Takano, Toshimi; Shaywitz, Adam J; Wang, Huei; Bracco, Oswaldo L; Braun, Ada; Kostenuik, Paul J

2015-09-01

This analysis was performed to further characterise treatment-emergent hypocalcaemia in patients with bone metastases receiving denosumab. Laboratory abnormalities and adverse events of hypocalcaemia in patients with metastatic bone disease were analysed using data from three identically designed phase 3 trials of subcutaneous denosumab 120 mg (n = 2841) versus intravenous zoledronic acid 4 mg (n = 2836). The overall incidence of laboratory events of hypocalcaemia grade ⩾ 2 was higher with denosumab (12.4%) than with zoledronic acid (5.3%). Hypocalcaemia events were primarily grade 2 in severity and usually occurred within the first 6 months of treatment. Patients who reported taking calcium and/or vitamin D supplements had a lower incidence of hypocalcaemia. Prostate cancer or small-cell lung cancer, reduced creatinine clearance and higher baseline bone turnover markers of urinary N-telopeptide of type I collagen (uNTx; > 50 versus ⩽ 50 nmol/mmol) and bone-specific alkaline phosphatase (BSAP; > 20.77 μg/L [median] versus ⩽ 20.77 μg/L) values were important risk factors for developing hypocalcaemia. The risk associated with increased baseline BSAP levels was greater among patients who had > 2 bone metastases at baseline versus those with ⩽ 2 bone metastases at baseline. Hypocalcaemia was more frequent with denosumab versus zoledronic acid, consistent with denosumab's greater antiresorptive effect. Low serum calcium levels and potential vitamin D deficiency should be corrected before initiating treatment with a potent osteoclast inhibitor, and corrected serum calcium levels should be monitored during treatment. Adequate calcium and vitamin D intake appears to substantially reduce the risk of hypocalcaemia. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Dual-therapy with αvβ3-targeted Sn2 lipase-labile fumagillin-prodrug nanoparticles and zoledronic acid in the Vx2 rabbit tumor model.

PubMed

Esser, Alison K; Schmieder, Anne H; Ross, Michael H; Xiang, Jingyu; Su, Xinming; Cui, Grace; Zhang, Huiying; Yang, Xiaoxia; Allen, John S; Williams, Todd; Wickline, Samuel A; Pan, Dipanjan; Lanza, Gregory M; Weilbaecher, Katherine N

2016-01-01

Fumagillin, an unstable anti-angiogenesis mycotoxin, was synthesized into a stable lipase-labile prodrug and incorporated into integrin-targeted lipid-encapsulated nanoparticles (αvβ3-Fum-PD NP). Dual anti-angiogenic therapy combining αvβ3-Fum-PD NP with zoledronic acid (ZA), a long-acting osteoclast inhibitor with proposed anti-angiogenic effects, was evaluated. In vitro, αvβ3-Fum-PD NP reduced (P<0.05) endothelial cell viability without impacting macrophage viability. ZA suppressed (P<0.05) macrophage viability at high dosages but not endothelial cell proliferation. 3D MR neovascular imaging of rabbit Vx2 tumors showed no effect with ZA, whereas αvβ3-Fum-PD NP alone and with ZA decreased angiogenesis (P<0.05). Immunohistochemistry revealed decreased (P<0.05) microvascularity with αvβ3-Fum-PD NP and ZA and further microvascular reduction (P<0.05) with dual-therapy. In vivo, ZA did not decrease tumor macrophage numbers nor cancer cell proliferation, whereas αvβ3-Fum-PD-NPs reduced both measures. Dual-therapy with ZA and αvβ3-Fum-PD-NP may provide enhanced neo-adjuvant utility if macrophage ZA uptake is increased. From the Clinical Editor: Although anti-angiogenesis is one of the treatment modalities in the fight against cancer, many cancers become resistant to VEGF pathway inhibitors. In this article, the authors investigated the use of dual therapy using fumagillin, integrin-targeted lipid-encapsulated nanoparticles (αvβ3- Fum-PD NP) and zoledronic acid (ZA), in both in-vitro and in-vivo experiments. This combination approach may provide an insight to the design of future drugs against cancers. Copyright © 2015 Elsevier Inc. All rights reserved.

Effect of bisphosphonate use on risk of postmenopausal breast cancer: results from the randomized clinical trials of alendronate and zoledronic acid.

PubMed

Hue, Trisha F; Cummings, Steven R; Cauley, Jane A; Bauer, Douglas C; Ensrud, Kristine E; Barrett-Connor, Elizabeth; Black, Dennis M

2014-10-01

Studies have shown that bisphosphonates may have antitumor and antimetastatic properties. Recently, observational studies have suggested a possible protective effect of bisphosphonates on breast cancer, but the effect of bisphosphonate use on risk of breast cancer has not been tested in randomized trials. To assess the relationship of postmenopausal breast cancer incidence and bisphosphonate use using data from 2 randomized (1:1), double-blind, placebo-controlled trials. The Fracture Intervention Trial (FIT) randomly assigned 6459 women aged 55 to 81 years to alendronate or placebo for a mean follow-up of 3.8 years. The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) randomly assigned 7765 women aged 65 to 89 years to annual intravenous zoledronic acid or placebo for a mean follow-up of 2.8 years. Data were collected at clinical centers in the United States (FIT and HORIZON-PFT) and in Asia and the Pacific, Europe, North America, and South America (HORIZON-PFT). Women, in either study, with recurrent breast cancer or who reported a history of breast cancer were excluded from analyses. In each trial, a blinded review was conducted of each cancer adverse event report to verify incident invasive breast cancer cases. The primary analysis compared events in the active vs placebo group using a log-rank test. Alendronate vs placebo (FIT) or zoledronic acid vs placebo (HORIZON-PFT). Hazard ratio for incident breast cancer in the bisphosphonate treatment group compared to the placebo group. There was no significant difference in the rate of breast cancer in FIT: 1.5% (n = 46) in the placebo group and 1.8% (n = 57) in the alendronate group (hazard ratio [HR], 1.24 [95% CI, 0.84-1.83]). In HORIZON-PFT, there was also no significant difference: 0.8% (n = 29) in the placebo group and 0.9% (n = 33) in the zoledronic acid group (HR, 1.15 [95% CI, 0.70-1.89]). There was also no significant difference when the data from FIT and HORIZON-PFT were pooled (HR, 1.20 [95% CI, 0.89-1.63]). These 2 randomized clinical trials do not support the findings from observational research. Contrary to the results from observational studies, we found that 3 to 4 years of bisphosphonate treatment did not decrease the risk of invasive postmenopausal breast cancer. clinicaltrials.gov Identifier: NCT00049829 (HORIZON-PFT).

Economic evaluation of denosumab compared with zoledronic acid in hormone-refractory prostate cancer patients with bone metastases.

PubMed

Xie, Jipan; Namjoshi, Madhav; Wu, Eric Q; Parikh, Kejal; Diener, Melissa; Yu, Andrew P; Guo, Amy; Culver, Kenneth W

2011-10-01

Bone metastases are common in patients with hormone-refractory prostate cancer. In a study of autopsies of patients with prostate cancer, 65%-75% had bone metastases. Bone metastases place a substantial economic burden on payers with estimated total annual costs of $1.9 billion in the United States. Skeletal-related events (SREs), including pathologic fractures, spinal cord compression, surgery to bone, and radiation to bone, affect approximately 50% of patients with bone metastases. They are associated with a decreased quality of life and increased health care costs. Zoledronic acid is an effective treatment in preventing SREs in solid tumors and multiple myeloma. Recently, denosumab was FDA-approved for prevention of SREs in patients with bone metastases from solid tumors. A Phase 3 clinical trial (NCT00321620) demonstrated that denosumab had superior efficacy in delaying first and subsequent SREs compared with zoledronic acid. However, the economic value of denosumab has not been assessed in patients with hormone-refractory prostate cancer. To compare the cost-effectiveness of denosumab with zoledronic acid in the treatment of bone metastases in men with hormone-refractory prostate cancer. An Excel-based Markov model was developed to assess costs and effectiveness associated with the 2 treatments over a 1- and 3-year time horizon. Because the evaluation was conducted from the perspective of a U.S. third-party payer, only direct costs were included. Consistent with the primary outcome in the Phase 3 trial, effectiveness was assessed based on the number of SREs. The model consisted of 9 health states defined by SRE occurrence, SRE history, disease progression, and death. A hypothetical cohort of patients with hormone-refractory prostate cancer received either denosumab 120 mg or zoledronic acid 4 mg at the model entry and transitioned among the 9 health states at the beginning of each 13-week cycle. Transition probabilities associated with experiencing the first SRE, subsequent SREs, disease progression, and death were primarily derived from the results of the Phase 3 clinical trial and were supplemented with published literature. The model assumed that a maximum of 1 SRE could occur in each cycle. Drug costs included wholesale acquisition cost, health care professional costs associated with drug administration, and drug monitoring costs, if applicable. Nondrug costs included incremental costs associated with disease progression, costs associated with SREs, and terminal care costs, which were derived from the literature. Adverse event (AE) costs were estimated based on the incidence rates reported in the Phase 3 trial. Resource utilization associated with AEs was estimated based on consultation with a senior medical director employed by the study sponsor. All costs were presented in 2010 dollars. The base case estimated the incremental total cost per SRE avoided over a 1-year time horizon. Results for a 3-year time horizon were also estimated. One-way sensitivity analyses and probabilistic sensitivity analyses (PSA) were performed to test the robustness of the model. In the base case, the total per patient costs incurred over 1 year were estimated at $35,341 ($19,230 drug costs and $16,111 nondrug costs) for denosumab and $27,528 ($10,960 drug costs and $16,569 nondrug costs) for zoledronic acid, with an incremental total direct cost of $7,813 for denosumab. The estimated numbers of SREs per patient during the 1-year period were 0.49 for denosumab and 0.60 for zoledronic acid, resulting in an incremental number of SREs of -0.11 in the denosumab arm. The estimated incremental total direct costs per SRE avoided with the use of denosumab instead of zoledronic acid were $71,027 for 1 year and $51,319 for 3 years. The 1-way sensitivity analysis indicated that the results were sensitive to the drug costs, median time to first SRE, and increased risk of SRE associated with disease progression. Results of the PSA showed that based on willingness-to-pay thresholds of $70,000, $50,000, and $30,000 per SRE avoided, respectively, denosumab was cost-effective compared with zoledronic acid in 49.5%, 17.5%, and 0.3% of the cases at 1 year, respectively, and 79.0%, 49.8%, and 4.1% of the cases at 3 years, respectively. Although denosumab has demonstrated benefits over zoledronic acid in preventing or delaying SREs in a Phase 3 trial, it may be a costly alternative to zoledronic acid from a U.S. payer perspective.

Early onset acute tubular necrosis following single infusion of zoledronate.

PubMed

Yachoui, Ralph

2016-01-01

Zoledronate is a highly potent bisphosphonate widely used in the treatment of postmenopausal osteoporosis. We report the first occurrence of toxic acute tubular necrosis (ATN) following treatment with zoledronate in a patient with osteoporosis. A 63-year-old Caucasian female with rheumatoid arthritis on anti-immune agents received a single dose of zoledronic acid (reclast) for worsening osteoporosis. Twelve days later, she developed renal failure with a rise in serum creatinine from a baseline level of 1.1 mg/dL to 5.5 mg/dL. Renal biopsy showed toxic ATN. Zoledronate was discontinued and the patient had subsequent gradual improvement in renal function with final serum creatinine of 1.8 mg/dL at 1 month of follow up. Careful monitoring of serum creatinine and awareness of the potential nephrotoxicity may avert the development of acute renal failure in osteoporosis patients treated with this agent.

Early onset acute tubular necrosis following single infusion of zoledronate

PubMed Central

Yachoui, Ralph

2016-01-01

Summary Zoledronate is a highly potent bisphosphonate widely used in the treatment of postmenopausal osteoporosis. We report the first occurrence of toxic acute tubular necrosis (ATN) following treatment with zoledronate in a patient with osteoporosis. A 63-year-old Caucasian female with rheumatoid arthritis on anti-immune agents received a single dose of zoledronic acid (reclast) for worsening osteoporosis. Twelve days later, she developed renal failure with a rise in serum creatinine from a baseline level of 1.1 mg/dL to 5.5 mg/dL. Renal biopsy showed toxic ATN. Zoledronate was discontinued and the patient had subsequent gradual improvement in renal function with final serum creatinine of 1.8 mg/dL at 1 month of follow up. Careful monitoring of serum creatinine and awareness of the potential nephrotoxicity may avert the development of acute renal failure in osteoporosis patients treated with this agent. PMID:27920815

Zoledronic acid inhibits NFAT and IL-2 signaling pathways in regulatory T cells and diminishes their suppressive function in patients with metastatic cancer

PubMed Central

Murray, Shannon; Witt, Kristina; Seitz, Christina; Wallerius, Majken; Xie, Hanjing; Ullén, Anders; Harmenberg, Ulrika; Lidbrink, Elisabet; Rolny, Charlotte; Andersson, John

2017-01-01

ABSTRACT Regulatory T cells (Treg) suppress anti-tumor immune responses and their infiltration in the tumor microenvironment is associated with inferior prognosis in cancer patients. Thus, in order to enhance anti-tumor immune responses, selective depletion of Treg is highly desired. We found that treatment with zoledronic acid (ZA) resulted in a selective decrease in the frequency of Treg that was associated with a significant increase in proliferation of T cells and natural killer (NK) cells in peripheral blood of patients with metastatic cancer. In vitro, genome-wide transcriptomic analysis revealed alterations in calcium signaling pathways in Treg following treatment with ZA. Furthermore, co-localization of the nuclear factor of activated T cells (NFAT) and forkhead box P3 (FOXP3) was significantly reduced in Treg upon ZA-treatment. Consequently, reduced expression levels of CD25, STAT5 and TGFβ were observed. Functionally, ZA-treated Treg had reduced capacity to suppress T and NK cell proliferation and anti-tumor responses compared with untreated Treg in vitro. Treatment with ZA to selectively inhibit essential signaling pathways in Treg resulting in reduced capacity to suppress effector T and NK cell responses represents a novel approach to inhibit Treg activity in patients with cancer. PMID:28920001

[Efficacy of zoledronic acid combined with chemotherapy in treatment of skeletal metastases of non-small cell lung cancer and the bone metabolic markers].

PubMed

Hu, Xiao-ye; Zou, Qing-feng; Jin, Chuan; Li, Wei-dong; Chen, Wen-sheng; Ma, Lei

2010-06-01

To evaluate the clinical efficacy of zoledronic acid combined with chemotherapy in the management of skeletal metastasis of non-small cell lung cancer (NSCLC) and investigate the value in urine amino-terminal telopeptide of type I collagen (uNTX) and serum bone specific alkaline phosphatase (sBALP) in monitoring skeletal metastasis of NSCLC. From February, 2007 to January, 2009, 32 NSCLC patients with bone metastases received treatment with zoledronic acid at the dose of 4 mg given every 3 weeks and platinum-based chemotherapy (each cycle lasting for 3 weeks). Before and during the treatments, uNTX and sBALP were measured in these patients using ELISA and precipitation with wheat germ lectin, respectively. The patients were followed up for skeletal-related events (SREs) and status of survival. A significant decrease occurred in the pain scores and analgesic use in the patients after the therapy. SREs were not observed during the treatment. Serum creatinine and calcium levels underwent no significant variation during the treatment. Eleven patients reported 14 possible zoledronic acid-related adverse events. The concentration of uNTX and sBALP in patients with bone metastases was above the upper limit of the normal range. A positive correlation was observed between the levels of the markers and the extent of bone metastases. At the third month, uNTX and sBALP were significantly lowered, but radionuclide whole-body bone imaging showed no obvious changes. Of the 32 patients, 24 had elevated uNTX values, which became normal after the treatment in 15 patients and remained elevated in the other 9 patients. SREs occurred in these two subgroups at the rates of 53% and 89% (P=0.039), respectively. Twenty-six patients had elevated sBALP level, and 16 of them exhibited normal sBALP level after the treatment. The incidences of SREs in the patients with elevated and normal sBALP level were 50% and 90% (P=0.038), respectively. The levels of uNTX/Cr and sBALP were not correlated to the survival of the patients. Zoledronic acid combined with chemotherapy is an effective treatment for NSCLC with bone metastases. Zoledronic acid is safe and well tolerated. Urinary NTX and serum BALP have a high value in the diagnosis, therapeutic effect monitoring and SRE prediction of NSCLC with bone metastases.

Osteogenesis imperfecta type V: Genetic and clinical findings in eleven Chinese patients.

PubMed

Liu, Yi; Wang, Jiawei; Ma, Doudou; Lv, Fang; Xu, Xiaojie; Xia, Weibo; Jiang, Yan; Wang, Ou; Xing, Xiaoping; Zhou, Peiran; Wang, Jianyi; Yu, Wei; Li, Mei

2016-11-01

Osteogenesis imperfecta (OI) type V is a rare inherited disease characterized by multiple fractures, intraosseous membrane calcification, and hypercallus formation. We investigate the causative gene, phenotype and also observe the effects of zoledronic acid in Chinese OI type V patients. The clinical phenotype and causative gene mutation was investigated in eleven patients with type V OI. Patients were given a dose of zoledronic acid 5mg intravenously. Fracture incidence and Z-score of bone mineral density (BMD) were evaluated. Serum levels of biomarkers such as cross linked C-telopeptide of type I collagen (β-CTX) and safety parameters were assessed. The c.-14C>T mutation in the 5' untranslated region of IFITM5 was detected in all patients. The phenotype was largely variable, and no significant correlation of genotype and phenotype was found. After one dose of zoledronic acid infusion, fracture incidence significantly dropped from 2fractures/year before treatment to 0fracture/year after treatment (P=0.01). Z score of lumbar spine BMD elevated from -2.6 to -1.3 (P<0.001). Serum β-CTX level decreased by 50% (P<0.05). No serious adverse event was found. No obvious correlation was found between the genotype and phenotype. Zoledronic acid had significantly skeletal protective effects in OI of type V. Copyright © 2016 Elsevier B.V. All rights reserved.

Short-term effect of zoledronic acid upon fracture resistance of the mandibular condyle and femoral head in an animal model

PubMed Central

López-Jornet, Pía; Vicente-Hernández, Ascensión

2013-01-01

Objective: The aim of this study was to compare the effects in terms of resistance to fracture of the mandibular condyle and femoral head following different doses of zoledronic acid in an animal model. Study design: A total of 80 adult male Sprague-Dawley rats were included in a prospective randomized study. The animals were randomly divided into four groups of 20 rats each. Group 1 (control) received sterile saline solution, while groups 2, 3 and 4 received a accumulated dose of 0.2 mg, 0.4 mg and 0.6 mg of zoledronic acid, respectively. The animals were sacrificed 28 days after the last dose, and the right hemimandible and the right femur were removed. The fracture strength was measured (in Newtons) with a universal test machine using a 1 kN load connected to a metal rod with one end angled at 30 degrees. The cross-head speed was 1 mm/min. Later, the specimens were observed under a scanning electron microscope with backscattered electron imaging (SEM-BSE). At last, chemical analysis and elemental mapping of the mineral bone composition were generated using a microanalytical system based on energy-dispersive and X-ray spectrometry (EDX). Results: A total of 160 fracture tests were performed. The fracture resistance increased in mandible and femur with a higher accumulated dose of zoledronic acid. Statistically significant differences were recorded versus the controls with all the studies groups. The chemical analysis in mandible showed a significantly increased of calcium and phosphorous to compare the control with all of the study groups; however, in femur no statistically significant differences between the four study groups were observed. Conclusions: The administration of bisphosphonates increases the fracture resistance in mandible and femur. Key words:Zoledronic acid, bisphosphonates, animal experimentation, fracture test. PMID:23524420

Effective combination treatment of GD2-expressing neuroblastoma and Ewing's sarcoma using anti-GD2 ch14.18/CHO antibody with Vγ9Vδ2+ γδT cells.

PubMed

Fisher, Jonathan P H; Flutter, Barry; Wesemann, Florian; Frosch, Jennifer; Rossig, Claudia; Gustafsson, Kenth; Anderson, John

Gamma delta T lymphocytes (γδT cells) have pleiotropic properties including innate cytotoxicity, which make them attractive effectors for cancer immunotherapy. Combination treatment with zoledronic acid and IL-2 can activate and expand the most common subset of blood γδT, which express the Vγ9Vδ2 T cell receptor (TCR) (Vδ2 T cells). Vγ9Vδ2 T cells are equipped for antibody-dependent cell-mediated cytotoxicity (ADCC) through expression of the low-affinity FcγR CD16. GD2 is a highly ranked tumor associated antigen for immunotherapy due to bright expression on the cell surface, absent expression on normal tissues and availability of therapeutic antibodies with known efficacy in neuroblastoma. To explore the hypothesis that zoledronic acid, IL-2 and anti-GD2 antibodies will synergize in a therapeutic combination, we evaluated in vitro cytotoxicity and tumor growth inhibition in the GD2 expressing cancers neuroblastoma and Ewing's sarcoma. Vδ2 T cells exert ADCC against GD2-expressing Ewing's sarcoma and neuroblastoma cell lines, an effect which correlates with the brightness of GD2 expression. In an immunodeficient mouse model of small established GD2-expressing Ewing's sarcoma or neuroblastoma tumors, the combination of adoptively transferred Vδ2+ T cells, expanded in vitro with zoledronic acid and IL-2, with anti-GD2 antibody ch14.18/CHO, and with systemic zoledronic acid, significantly suppressed tumor growth compared to antibody or γδT cell-free controls. Combination treatment using ch14.18/CHO, zoledronic acid and IL-2 is more effective than their use in isolation. The already-established safety profiles of these agents make testing of the combination in GD2 positive cancers such as neuroblastoma or Ewing's sarcoma both rational and feasible.

Effective combination treatment of GD2-expressing neuroblastoma and Ewing's sarcoma using anti-GD2 ch14.18/CHO antibody with Vγ9Vδ2+ γδT cells

PubMed Central

Fisher, Jonathan P H; Flutter, Barry; Wesemann, Florian; Frosch, Jennifer; Rossig, Claudia; Gustafsson, Kenth; Anderson, John

2016-01-01

Gamma delta T lymphocytes (γδT cells) have pleiotropic properties including innate cytotoxicity, which make them attractive effectors for cancer immunotherapy. Combination treatment with zoledronic acid and IL-2 can activate and expand the most common subset of blood γδT, which express the Vγ9Vδ2 T cell receptor (TCR) (Vδ2 T cells). Vγ9Vδ2 T cells are equipped for antibody-dependent cell-mediated cytotoxicity (ADCC) through expression of the low-affinity FcγR CD16. GD2 is a highly ranked tumor associated antigen for immunotherapy due to bright expression on the cell surface, absent expression on normal tissues and availability of therapeutic antibodies with known efficacy in neuroblastoma. To explore the hypothesis that zoledronic acid, IL-2 and anti-GD2 antibodies will synergize in a therapeutic combination, we evaluated in vitro cytotoxicity and tumor growth inhibition in the GD2 expressing cancers neuroblastoma and Ewing's sarcoma. Vδ2 T cells exert ADCC against GD2-expressing Ewing's sarcoma and neuroblastoma cell lines, an effect which correlates with the brightness of GD2 expression. In an immunodeficient mouse model of small established GD2-expressing Ewing's sarcoma or neuroblastoma tumors, the combination of adoptively transferred Vδ2+ T cells, expanded in vitro with zoledronic acid and IL-2, with anti-GD2 antibody ch14.18/CHO, and with systemic zoledronic acid, significantly suppressed tumor growth compared to antibody or γδT cell-free controls. Combination treatment using ch14.18/CHO, zoledronic acid and IL-2 is more effective than their use in isolation. The already-established safety profiles of these agents make testing of the combination in GD2 positive cancers such as neuroblastoma or Ewing's sarcoma both rational and feasible. PMID:26942051

Prevention of Bone Loss after Acute SCI by Zoledronic Acid: Durability, Effect on Bone Strength, and Use of Biomarkers to Guide Therapy

DTIC Science & Technology

2016-10-01

6 and 12 months during the first year; participants are re-randomized after 12 months with subsequent data collection at 18 and 24 months. Currently...bone mass, bone strength, osteoporosis, zoledronic acid 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18 . NUMBER OF PAGES 19a. NAME...and bone markers will be obtained at baseline, 3 months, 6 months, 12 months, 18 months and 24 months. KEYWORDS: spinal cord

Zoledronic acid impairs stromal reactivity by inhibiting M2-macrophages polarization and prostate cancer-associated fibroblasts.

PubMed

Comito, Giuseppina; Pons Segura, Coral; Taddei, Maria Letizia; Lanciotti, Michele; Serni, Sergio; Morandi, Andrea; Chiarugi, Paola; Giannoni, Elisa

2017-01-03

Zoledronic acid (ZA) is a biphosphonate used for osteoporosis treatment and also proved to be effective to reduce the pain induced by bone metastases when used as adjuvant therapy in solid cancers. However, it has been recently proposed that ZA could have direct anti-tumour effects, although the molecular mechanism is unknown. We herein unravel a novel anti-tumour activity of ZA in prostate cancer (PCa), by targeting the pro-tumorigenic properties of both stromal and immune cells. Particularly, we demonstrate that ZA impairs PCa-induced M2-macrophages polarization, reducing their pro-invasive effect on tumour cells and their pro-angiogenic features. Crucially, ZA administration reverts cancer associated fibroblasts (CAFs) activation by targeting the mevalonate pathway and RhoA geranyl-geranylation, thereby impairing smooth muscle actin-α fibers organization, a prerequisite of fibroblast activation. Moreover, ZA prevents the M2 macrophages-mediated activation of normal fibroblast, highlighting the broad efficacy of this drug on tumour microenvironment. These results are confirmed in a metastatic xenograft PCa mouse model in which ZA-induced stromal normalization impairs cancer-stromal cells crosstalk, resulting in a significant reduction of primary tumour growth and metastases. Overall these findings reinforce the efficacy of ZA as a potential therapeutic approach to reduce cancer aggressiveness, by abrogating the supportive role of tumour microenvironment.

Cost-Effectiveness Analysis of Monthly Zoledronic Acid, Zoledronic Acid Every 3 Months, and Monthly Denosumab in Women With Breast Cancer and Skeletal Metastases: CALGB 70604 (Alliance).

PubMed

Shapiro, Charles L; Moriarty, James P; Dusetzina, Stacie; Himelstein, Andrew L; Foster, Jared C; Grubbs, Stephen S; Novotny, Paul J; Borah, Bijan J

2017-12-10

Purpose Skeletal-related events (SREs) such as pathologic fracture, spinal cord compression, or the necessity for radiation or surgery to bone metastasis cause considerable morbidity, decrements in quality of life, and costs to the health care system. The results of a recent large randomized trial (Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology [CALGB/Alliance 70604]) showed that zoledronic acid (ZA) every 3 months was noninferior to monthly ZA in reducing the risks of SREs. We sought to determine the cost-effectiveness (CE) of monthly ZA, ZA every 3 months, and monthly denosumab in women with breast cancer and skeletal metastases. Methods Using a Markov model, costs per SRE avoided were calculated for the three treatments. Sensitivity analyses were performed where denosumab SRE probabilities were assumed to be 50%, 75%, and 90% lower than the ZA SRE probabilities. Quality-adjusted life-years were also calculated. The analysis was from the US payer perspective. Results The mean costs of the denosumab treatment strategy are nine-fold higher than generic ZA every 3 months. Quality-adjusted life-years were virtually identical in all the three treatment arms; hence, the optimal treatment would be ZA every 3 months because it was the least costly treatment. The sensitivity analyses showed that relative to ZA every 3 months, the incremental costs per mean SRE avoided for denosumab ranged from $162,918 to $347,655. Conclusion ZA every 3 months was more CE in reducing the risks of SRE than monthly denosumab. This analysis was one of the first to incorporate the costs of generic ZA and one of the first independent CE analyses not sponsored by either Novartis or Amgen, the makers of ZA and denosumab, respectively. ZA every 3 months is the more CE option and more reasonable alternative to monthly denosumab.

Efficacy and Safety of a Once-Yearly Intravenous Zoledronic Acid 5 mg for Fracture Prevention in Elderly Postmenopausal Women with Osteoporosis Aged 75 and Older

PubMed Central

Boonen, Steven; Black, Dennis M.; Colón-Emeric, Cathleen S.; Eastell, Richard; Magaziner, Jay S.; Eriksen, Erik Fink; Mesenbrink, Peter; Haentjens, Patrick; Lyles, Kenneth W.

2013-01-01

OBJECTIVES To determine the efficacy of once-yearly intravenous zoledronic acid (ZOL) 5 mg in reducing risk of clinical vertebral, nonvertebral, and any clinical fractures in elderly osteoporotic postmenopausal women. DESIGN A post hoc subgroup analysis of pooled data from the Health Outcome and Reduced Incidence with Zoledronic Acid One Yearly (HORIZON) Pivotal Fracture Trial and the HORIZON Recurrent Fracture Trial. SETTING Multicenter, randomized, double-blind, placebo-controlled trials. PARTICIPANTS Postmenopausal women (aged ≥75) with documented osteoporosis (T-score ≤ −2.5 at femoral neck or ≥1 prevalent vertebral or hip fracture) or a recent hip fracture. INTERVENTION Patients were randomized to receive an intravenous infusion of ZOL 5 mg (n =1,961) or placebo (n =1,926) at baseline and 12 and 24 months. MEASUREMENTS Primary endpoints were incidence of clinical vertebral and nonvertebral and any clinical fracture after treatment. RESULTS At 3 years, incidence of any clinical, clinical vertebral, and nonvertebral fracture were significantly lower in the ZOL group than in the placebo group (10.8% vs 16.6%, 1.1% vs 3.7%, and 9.9% vs 13.7%, respectively) (hazard ratio (HR) =0.65, 95% confidence interval (CI) =0.54–0.78, P<.001; HR =0.34, 95% CI =0.21–0.55, P<.001; and HR =0.73, 95% CI =0.60–0.90, P =.002, respectively). The incidence of hip fracture was lower with ZOL but did not reach statistical significance. The incidence rate of postdose adverse events were higher with ZOL, although the rate of serious adverse events and deaths was comparable between the two groups. CONCLUSION Once-yearly intravenous ZOL 5 mg was associated with a significant reduction in the risk of new clinical fractures (vertebral and nonvertebral) in elderly postmenopausal women with osteroporosis. PMID:20070415

Effect of zoledronic acid in an L6-L7 rabbit spine fusion model.

PubMed

Bransford, Rick; Goergens, Elisabeth; Briody, Julie; Amanat, Negin; Cree, Andrew; Little, David

2007-04-01

Previous studies have shown that zoledronic acid administration can increase mineral content and strength in distraction osteogenesis. Of the few studies that have examined the use of bisphosphonates in spinal arthrodesis, none have assessed the effect of single dose treatment. The objective of this study was to evaluate the feasibility of enhancing spinal fusion rate using single dose zoledronic acid (ZA) to increase fusion-mass size and mineral density. Forty-eight New Zealand white rabbits underwent an L6-L7 intertransverse process fusion. The L6-L7 model is more challenging than the more commonly used level of L5-L6. Animals were randomly allocated to one of three groups, one received iliac crest bone graft alone, one group received iliac crest bone graft with locally administered zoledronic acid, 20 microg, and one group received iliac crest bone graft with a single dose of systemically administered zoledronic acid, 0.1 mg/kg. ZA doses were administered at the time of surgery. Twenty-four rabbits were culled at 6 weeks and 24 rabbits were culled at 12 weeks. Success of spinal fusion was determined by manual palpation. Specimens were evaluated radiographically, underwent quantitative computerised tomography analysis and were tested biomechanically in flexion and extension. In the six-week group, only five of the 24 spines fused with no noticeable trend with respect to treatment. In the 12-week group there was a trend toward increased fusion in the systemically administered ZA group (63%) versus the other two groups (25%) but was not statistically significant (p = 0.15). Radiographically, the local ZA treatment group showed a delay in remodelling with the presence of unremodelled bone chips. The 12-week systemic ZA group exhibited an 86% increase in BMC, a 31% increase in vBMD and a 41% increase in the volume of the fusion-mass (p < 0.05). The 12-week local ZA group also showed significant increases in BMC (69%), vBMD (31%) and total fusion-mass volume (29%) (p < 0.05). Biomechanical testing showed that the range of motion in flexion decreased to 4.5 (+/-2.5) degrees and 4.8 (+/-4.7) degrees for the local and systemic groups respectively compared to 9.6 (+/-4.9) degrees for the control group (p < 0.05). This study has shown that zoledronic acid increased fusion-mass size and bone mineral content. Systemic ZA led to an increased fusion rate; however the fusion rate remained below 100%. We suggest that bisphosphonate treatment may require an anabolic conjunctive therapy to ensure enhanced successful fusion.

Downregulation of CXCR4 Expression and Functionality After Zoledronate Exposure in Canine Osteosarcoma.

PubMed

Byrum, M L; Pondenis, H C; Fredrickson, R L; Wycislo, K L; Fan, T M

2016-07-01

The establishment and progression of metastases remains the life-limiting factor for dogs diagnosed with osteosarcoma (OS). The pattern of metastases is likely regulated through interactions between chemokine receptors and chemokines, and perturbations in these signaling cascades responsible for cytoskeletal organization and directional migration have the potential to alter metastatic cell trafficking behaviors. Zoledronate will impair directional migration of OS cells through downregulation of chemokine (C-X-C motif) receptor 4 (CXCR4) expression and functionality. Nineteen archived tumor specimens and plasma from 20 dogs with OS. Prospectively, the expressions of CXCR4 were studied in OS cell lines and spontaneous tumor samples. The effect of zoledronate on CXCR4 expression and functionality was investigated by characterizing responses in 3 OS cell lines. In 19 OS specimens and 20 dogs with OS, changes in CXCR4 expression and circulating CXCR4 concentrations were characterized in response to zoledronate therapy respectively. All canine OS cells express CXCR4, and zoledronate reduces CXCR4 expression and functionality by 27.7% (P < .0001), through augmented proteasome degradation and reduced prenylation of heterotrimeric G-proteins in 33% of tumor cell lines evaluated. In OS-bearing dogs, zoledronate reduces CXCR4 expressions by 40% within the primary tumor compared to untreated controls (P = .03) and also decreases the circulating concentrations of CXCR4 in 18 of 20 dogs with OS. Zoledronate can alter CXCR4 expression and functionality in OS cells, and consequent perturbations in CXCR4 intracellular signaling cascades might influence patterns of metastases. Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Intravenous zoledronate for osteoporosis: less might be more

PubMed Central

Grey, Andrew

2016-01-01

Annual administration of 5 mg intravenous zoledronate is moderately effective in reducing fracture risk in older adults, decreasing the relative risk of clinical fracture by 33%. However, almost 10 years after its approval for use in clinical practice there remain very substantial uncertainties about the optimal treatment regimen, that is, the lowest dose and/or longest dosing interval that is efficacious. Several pieces of clinical research suggest that the current recommendation for annual administration of 5 mg zoledronate might represent overtreatment. Clinical trials to clarify the optimal use of zoledronate for reduction of fracture risk should be undertaken. PMID:27493690

Intravenous zoledronate for osteoporosis: less might be more.

PubMed

Grey, Andrew

2016-08-01

Annual administration of 5 mg intravenous zoledronate is moderately effective in reducing fracture risk in older adults, decreasing the relative risk of clinical fracture by 33%. However, almost 10 years after its approval for use in clinical practice there remain very substantial uncertainties about the optimal treatment regimen, that is, the lowest dose and/or longest dosing interval that is efficacious. Several pieces of clinical research suggest that the current recommendation for annual administration of 5 mg zoledronate might represent overtreatment. Clinical trials to clarify the optimal use of zoledronate for reduction of fracture risk should be undertaken.

Zoledronate and ion-releasing resins impair dentin collagen degradation.

PubMed

Tezvergil-Mutluay, A; Seseogullari-Dirihan, R; Feitosa, V P; Tay, F R; Watson, T F; Pashley, D H; Sauro, S

2014-10-01

This study analyzed the amounts of solubilized telopeptides cross-linked carboxyterminal telopeptide of type I collagen (ICTP) and C-terminal crosslinked telopeptide of type I collagen (CTX) derived from matrix-metalloproteinases (MMPs) and cysteine cathepsins (CTPs) subsequent to application of a filler-free (Res.A) or an ion-releasing resin (Res.B) to ethylenediaminetetraacetic acid (EDTA)-demineralized dentin with or without zoledronate-containing primer (Zol-primer) pre-treatment. The chemical modification induced following treatments and artificial saliva (AS) storage was also analyzed through attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR). Totally EDTA-demineralized specimens were infiltrated with Res.A or Res.B with or without Zol-primer pre-treatment, light-cured, and immersed in AS for up to 4 wk. ICTP release was reduced following infiltration with Res.B and further reduced when Res.B was used with Zol-primer; remarkable phosphate mineral uptake was attained after AS storage. CTX release was increased in Res.A- and Res.B-treated dentin. However, when Zol-primer was used with Res.A, the CTX release fell significantly compared to the other tested resin-infiltration methods. In conclusion, zoledronate offers an additional inhibitory effect to the ion-releasing resins in MMP-mediated collagen degradation. However, Zol-primer induces a modest reduction in CTX release only when used with resin-based systems containing no ion-releasing fillers. © International & American Associations for Dental Research.

Zoledronate and Ion-releasing Resins Impair Dentin Collagen Degradation

PubMed Central

Tezvergil-Mutluay, A.; Seseogullari-Dirihan, R.; Feitosa, V.P.; Tay, F.R.; Watson, T.F.; Pashley, D.H.; Sauro, S.

2014-01-01

This study analyzed the amounts of solubilized telopeptides cross-linked carboxyterminal telopeptide of type I collagen (ICTP) and C-terminal crosslinked telopeptide of type I collagen (CTX) derived from matrix-metalloproteinases (MMPs) and cysteine cathepsins (CTPs) subsequent to application of a filler-free (Res.A) or an ion-releasing resin (Res.B) to ethylenediaminetetraacetic acid (EDTA)-demineralized dentin with or without zoledronate-containing primer (Zol-primer) pre-treatment. The chemical modification induced following treatments and artificial saliva (AS) storage was also analyzed through attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR). Totally EDTA-demineralized specimens were infiltrated with Res.A or Res.B with or without Zol-primer pre-treatment, light-cured, and immersed in AS for up to 4 wk. ICTP release was reduced following infiltration with Res.B and further reduced when Res.B was used with Zol-primer; remarkable phosphate mineral uptake was attained after AS storage. CTX release was increased in Res.A- and Res.B-treated dentin. However, when Zol-primer was used with Res.A, the CTX release fell significantly compared to the other tested resin-infiltration methods. In conclusion, zoledronate offers an additional inhibitory effect to the ion-releasing resins in MMP-mediated collagen degradation. However, Zol-primer induces a modest reduction in CTX release only when used with resin-based systems containing no ion-releasing fillers. PMID:25074494

Efficacy and safety of once-yearly zoledronic acid in Japanese patients with primary osteoporosis: two-year results from a randomized placebo-controlled double-blind study (ZOledroNate treatment in Efficacy to osteoporosis; ZONE study).

PubMed

Nakamura, T; Fukunaga, M; Nakano, T; Kishimoto, H; Ito, M; Hagino, H; Sone, T; Taguchi, A; Tanaka, S; Ohashi, M; Ota, Y; Shiraki, M

2017-01-01

In a 2-year randomized, placebo-controlled study of 665 Japanese patients with primary osteoporosis, once-yearly administration of zoledronic acid (5 mg) reduced the risk of new morphometric vertebral fractures. The purpose of this study was to determine the efficacy and safety of once-yearly intravenous infusion of ZOL in Japanese patients with primary osteoporosis. This was a two-year multicenter, randomized, placebo-controlled, double-blind, parallel-group comparative study (ZONE Study). Subjects were 665 Japanese patients between the ages of 65 and 89 years who had prevalent vertebral fracture. Subjects were randomly assigned to receive once-yearly intravenous infusion of 5 mg of ZOL or placebo at baseline and 12 months. The 2-year incidence of new morphometric vertebral fracture was 3.0 % (10/330 subjects) in the ZOL group and 8.9 % (29/327) in the placebo group (p = 0.0016). The 24-month cumulative incidence of new morphometric vertebral fracture was 3.3 % in the ZOL group versus 9.7 % in the placebo group (log-rank test: p = 0.0029; hazard ratio: 0.35; 95 % confidence interval: 0.17-0.72). The cumulative incidence of any clinical fracture, clinical vertebral fracture, and non-vertebral fracture was significantly reduced in the ZOL group by 54, 70, and 45 %, respectively, compared to the placebo group. At 24 months, ZOL administration increased bone mineral density in the lumbar spine, femoral neck, and total hip (t test: p < 0.0001). No new adverse events or osteonecrosis of the jaw were observed in this study. Once-yearly administration of ZOL 5 mg to Japanese patients with primary osteoporosis reduced the risk of new morphometric vertebral fractures and was found to be safe.

Monitoring changes in quality of life in patients with lung cancer under treatment with chemotherapy and co administration of zoledronic acid by using specialized questionnaires.

PubMed

Tremmas, Ioannis; Petsatodis, George; Potoupnis, Michael; Laskou, Stella; Giannakidis, Dimitrios; Mantalovas, Stylianos; Koulouris, Charilaos; Katsaounis, Athanasios; Pavlidis, Efstathios; Amaniti, Aikaterini; Huang, Haidong; Bai, Chong; Shi, Dongchen; Dardas, Athanasios; Zarogoulidis, Paul; Sardeli, Chrisanthi; Konstantinou, Fotis; Katsikogiannis, Nikolaos; Zarogoulidis, Konstantinos; Karapantzos, Ilias; Karapantzou, Chrysanthi; Shen, Xiaping; Kesisoglou, Isaak; Sapalidis, Konstantinos

2018-01-01

Background: Due to the severity of the primary disease in patients with lung cancer, quality of life (QoL) is often overlooked. Factors that form QoL should be taken in consideration when planning the appropriate treatment and determining therapy targets, because of the increasing frequency of bone metastasis leading to high levels of pain. Purpose of this study is to assess quality of life in patients with lung cancer, before and after treatment combined with zoledronic acid. Methods and materials: QoL was assessed in 80 patients (49 males-31 females), of which 45 developed bone metastasis. Prior and post treatment (with co administration of zoledronic acid) seven reliable scales: Pittsburgh Sleep Quality index (PSQI), Epworth Sleeping Scale (ess), Dyspnea Scale (ds), Fatigue Severity Scale (FSS), Brief Pain Inventory (BPI), Fact-G scale for sleep quality and EQ-5D for general health condition. Results: Statistically positive correlations were verified between PSQI-DS, PSQI-FSS, BPI-ESS, DS-FSS, DS-BPI and BPI-FSS (p<0,005) prior and post treatment. Patients sleep quality was improved, pain levels decreased and betterment in quality of life was marked (p<0,001). Although significant decrease in fatigue levels was observed (p<0,001) there has been an increase in dyspnea symptoms (p<0,001). Conclusions: Significant improvement was apparent when zoledronic acid was co administered in any treatment in patients with lung cancer. Sleep quality, fatigue and pain parameters also improved, with no positive impact on the symptoms of dyspnea.

Could zoledronic acid prevent root resorption in replanted rat molar?

PubMed

Yoo, Jung Eun; Kim, Mi Sun; Kwon, Yong-Dae; Kim, Eun-Cheol; Kim, Kwang Chul; Choi, Sung Chul

2015-12-01

In this study, we evaluated whether zoledronate could suppress the progression of external root resorption in rat due to delayed replantation by inhibiting osteoclastic activity. Also, we estimated the optimal dosage of zoledronate in root treatment of the rat model for a maximum effect of zoledronate. Maxillary first molars in Sprague Dawley rats (N = 84) were extracted, dried for 60 min, and then replanted. The rats were divided into 6 groups (1 mM alendronate, and 1, 5, 10, 20, 40 μM zoledronate). At 4 and 8 weeks postreplantation, the animals were sacrificed and evaluated by radiographic and histological analysis. There were no significant differences at 4 weeks. However, at 8 weeks, 10, 20, and 40 μM ZOL showed more increased radiopaque and smaller periapical lesion in radiographic analysis. In histological analysis, all groups showed similar inflammatory root resorption rate at 4 weeks. However, at 8 weeks, 20 and 40 μM ZOL showed lower rate than those of other groups (P < 0.05). In concerning of replacement resorption, there were no significant differences statistically. In this animal experiment, zoledronate was capable of limiting the occurrence of root resorption in delayed replantation model. In particular, 20 μM dosage of zoledronate solution showed the most effective dose in long-term follow up and might be suitable for inhibition of root resorption in delayed tooth replantation. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Zoledronic acid modulates maturation of human monocyte-derived dendritic cells.

PubMed

Orsini, Giulia; Failli, Alessandra; Legitimo, Annalisa; Adinolfi, Barbara; Romanini, Antonella; Consolini, Rita

2011-12-01

Zoledronic acid (ZA) is a drug of the bisphosphonate class, which is widely used for the treatment of both osteoporosis and skeletal metastasis. Besides its main bone antiresorptive activity, ZA displays antitumor properties, by triggering the expansion and activation of γδ T-cells, which exert an antitumor effect through dendritic cells (DCs). Several studies have reported the interaction between ZA and γδ T-cells, but the potential immunoregulatory activity of this drug on DCs has scarcely been investigated. Therefore, in this paper, we evaluated the effects of a therapeutic dose of ZA on the in vitro generation and maturation of DCs derived from peripheral blood monocytes of healthy adult donors. We demonstrate that ZA treatment did not affect DC differentiation, but inhibited DC maturation on lipopolysaccharide activation, as shown by the impaired expression of maturation surface markers and reduced ability to induce allogeneic T-cell proliferation. Interestingly, IL-10 secretion by mature DCs was significantly lower in ZA-treated cells than in controls. We conclude that ZA exerts its immunological in vitro activity also by modulating the maturation of DCs.

Modulation of Tumor Cell Metabolism by Laser Photochemotherapy with Cisplatin or Zoledronic Acid In Vitro.

PubMed

Heymann, Paul Günther Baptist; Henkenius, Katharina Sabine Elisabeth; Ziebart, Thomas; Braun, Andreas; Hirthammer, Klara; Halling, Frank; Neff, Andreas; Mandic, Robert

2018-03-01

Laser photochemotherapy is a new approach in cancer treatment using low-level laser therapy (LLLT) to enhance the effect of chemotherapy. In order to evaluate the effect of LLLT on tumor cells, HeLa cells were treated with cisplatin or zoledronic acid (ZA) followed by LLLT. Cell viability was evaluated with 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide assay. Oxidative phosphorylation and glycolysis were measured using extracellular flux analysis. Immunocytochemistry of heat-shock protein 70 (HSP70) and western blot analysis were performed. LLLT alone increased viability and was associated with lower oxidative phosphorylation but higher glycolysis rates. Cisplatin and ZA alone lowered cell viability, glycolysis and oxidative phosphorylation. This effect was significantly enhanced in conjunction with LLLT and was accompanied by reduced oxidative phosphorylation and collapse of glycolysis. Our observations indicate that LLLT may raise the cytotoxicity of cisplatin and ZA by modulating cellular metabolism, pointing to a possible application in cancer treatment. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Zoledronic acid impairs stromal reactivity by inhibiting M2-macrophages polarization and prostate cancer-associated fibroblasts

PubMed Central

Comito, Giuseppina; Segura, Coral Pons; Taddei, Maria Letizia; Lanciotti, Michele; Serni, Sergio; Morandi, Andrea; Chiarugi, Paola; Giannoni, Elisa

2017-01-01

Zoledronic acid (ZA) is a biphosphonate used for osteoporosis treatment and also proved to be effective to reduce the pain induced by bone metastases when used as adjuvant therapy in solid cancers. However, it has been recently proposed that ZA could have direct anti-tumour effects, although the molecular mechanism is unknown. We herein unravel a novel anti-tumour activity of ZA in prostate cancer (PCa), by targeting the pro-tumorigenic properties of both stromal and immune cells. Particularly, we demonstrate that ZA impairs PCa-induced M2-macrophages polarization, reducing their pro-invasive effect on tumour cells and their pro-angiogenic features. Crucially, ZA administration reverts cancer associated fibroblasts (CAFs) activation by targeting the mevalonate pathway and RhoA geranyl-geranylation, thereby impairing smooth muscle actin-α fibers organization, a prerequisite of fibroblast activation. Moreover, ZA prevents the M2 macrophages-mediated activation of normal fibroblast, highlighting the broad efficacy of this drug on tumour microenvironment. These results are confirmed in a metastatic xenograft PCa mouse model in which ZA-induced stromal normalization impairs cancer-stromal cells crosstalk, resulting in a significant reduction of primary tumour growth and metastases. Overall these findings reinforce the efficacy of ZA as a potential therapeutic approach to reduce cancer aggressiveness, by abrogating the supportive role of tumour microenvironment. PMID:27223431

Role of the nurse in preserving patients' independence.

PubMed

Maxwell, Cathy

2007-01-01

Patients with metastatic bone disease may be treated with bisphosphonates to reduce or delay skeletal complications including pathologic fracture, radiotherapy to bone, and hypercalcemia of malignancy. Nurses can provide important education to patients and support or encourage the use of bisphosphonates throughout therapy. Literature and congress reports were reviewed for relevant efficacy information on bisphosphonates and adverse events that may occur during bisphosphonate therapy. Bisphosphonates can provide meaningful benefits to patients, and zoledronic acid is now approved for the treatment of bone metastases secondary to any solid tumor. To optimize care, nurses can monitor pain scores, changes in mobility, adverse events, and serum creatinine levels. A useful tool for recording these parameters is a patient diary. The nurse should fill out the diary at each patient visit and compare it with baseline information before treatment is administered. Patients should also be counseled on the importance of adequate hydration, good dental hygiene, the need for calcium and vitamin D supplements, and how to best manage potential side effects. Bisphosphonates are effective in reducing and delaying skeletal complications, and zoledronic acid has demonstrated significant efficacy in preventing skeletal complications across a wide range of solid tumors and multiple myeloma. Nurses play an important role in enabling patients to optimize bisphosphonate therapy and in supporting patients to continue treatment to preserve their functional independence.

Zoledronic acid in pediatric metabolic bone disorders.

PubMed

Bowden, Sasigarn A; Mahan, John D

2017-10-01

Zoledronic acid (ZA), a highly potent intravenous bisphosphonate (BP), has been increasingly used in children with primary and secondary osteoporosis due to its convenience of shorter infusion time and less frequent dosing compared to pamidronate. Many studies have also demonstrated beneficial effects of ZA in other conditions such as hypercalcemia of malignancy, fibrous dysplasia (FD), chemotherapy-related osteonecrosis (ON) and metastatic bone disease. This review summarizes pharmacologic properties, mechanism of action, dosing regimen, and therapeutic outcomes of ZA in a variety of metabolic bone disorders in children. Several potential novel uses of ZA are also discussed. Safety concerns and adverse effects are also highlighted.

Short-term effect of zoledronic acid upon fracture resistance of the mandibular condyle and femoral head in an animal model.

PubMed

Camacho-Alonso, Fabio; López-Jornet, Pía; Vicente-Hernández, Ascensión

2013-05-01

The aim of this study was to compare the effects in terms of resistance to fracture of the mandibular condyle and femoral head following different doses of zoledronic acid in an animal model. A total of 80 adult male Sprague-Dawley rats were included in a prospective randomized study. The animals were randomly divided into four groups of 20 rats each. Group 1 (control) received sterile saline solution, while groups 2, 3 and 4 received a accumulated dose of 0.2 mg, 0.4 mg and 0.6 mg of zoledronic acid, respectively. The animals were sacrificed 28 days after the last dose, and the right hemimandible and the right femur were removed. The fracture strength was measured (in Newtons) with a universal test machine using a 1 kN load connected to a metal rod with one end angled at 30 degrees. The cross-head speed was 1 mm/min. Later, the specimens were observed under a scanning electron microscope with backscattered electron imaging (SEM-BSE). At last, chemical analysis and elemental mapping of the mineral bone composition were generated using a microanalytical system based on energy-dispersive and X-ray spectrometry (EDX). A total of 160 fracture tests were performed. The fracture resistance increased in mandible and femur with a higher accumulated dose of zoledronic acid. Statistically significant differences were recorded versus the controls with all the studies groups. The chemical analysis in mandible showed a significantly increased of calcium and phosphorous to compare the control with all of the study groups; however, in femur no statistically significant differences between the four study groups were observed. The administration of bisphosphonates increases the fracture resistance in mandible and femur.

Zoledronic acid in pediatric metabolic bone disorders

PubMed Central

Mahan, John D.

2017-01-01

Zoledronic acid (ZA), a highly potent intravenous bisphosphonate (BP), has been increasingly used in children with primary and secondary osteoporosis due to its convenience of shorter infusion time and less frequent dosing compared to pamidronate. Many studies have also demonstrated beneficial effects of ZA in other conditions such as hypercalcemia of malignancy, fibrous dysplasia (FD), chemotherapy-related osteonecrosis (ON) and metastatic bone disease. This review summarizes pharmacologic properties, mechanism of action, dosing regimen, and therapeutic outcomes of ZA in a variety of metabolic bone disorders in children. Several potential novel uses of ZA are also discussed. Safety concerns and adverse effects are also highlighted. PMID:29184807

Zoledronic acid in children with osteogenesis imperfecta and Bruck syndrome: a 2-year prospective observational study.

PubMed

Otaify, G A; Aglan, M S; Ibrahim, M M; Elnashar, M; El Banna, R A S; Temtamy, S A

2016-01-01

Treatment with zoledronic acid (ZA) over 2 years, among 33 children with osteogenesis imperfecta (OI) and five Bruck syndrome cases, showed reduction in fracture rates, pain, and improvement in bone mineral density (BMD) and motor milestones of development. This is the first study reporting the use of bisphosphonates in patients with Bruck syndrome (BS). OI and BS are genetic disorders that result in bone fragility and reduced BMD. There is little literature describing the efficacy and safety of ZA in this population. In this study, we assess the response to treatment with ZA at six monthly intervals in Egyptian children with OI and BS for a period of 2 years. Thirty-three patients with OI and five patients with BS were treated with 0.1 mg/kg ZA intravenously every 6 months for 2 years during which they were followed up using different parameters. A clinical severity score (CSS) was applied to the patients before and 2 years after the start of therapy. Comparison of disease severity and response to ZA treatment between autosomal-dominant (AD) and autosomal-recessive (AR) OI patients was also done. After 6 months of treatment, OI and BS patients showed a significant increase in BMD Z-scores (P < 0.003 in the spine and P < 0.004 in the hip), together with a significant drop in fracture rate (P < 0.001), relief of pain (P < 0.001), and improvement in ambulation (P < 0.001). CSS was significantly reduced after 2 years of treatment in both OI and BS patients. AR-OI patients were more severely affected than AD-OI patients and showed more significant improvement. Zoledronic acid proved to be safe and effective in the treatment of OI and BS. The biannual infusion protocol was convenient to patients. There was a positive correlation between disease severity and benefits of the treatment. The use of the CSS proved to be of value in the assessment of the degree of severity in OI, and with some modifications, it was a valuable tool for the assessment of response to treatment.

Effect of zoledronic acid and amputation on bone invasion and lung metastasis of canine osteosarcoma in nude mice

PubMed Central

Wolfe, Tobie D.; Somanathan Pillai, Smitha Pankajavally; Hildreth, Blake Eason; Lanigan, Lisa G.; Martin, Chelsea K.; Werbeck, Jillian L.

2014-01-01

Osteosarcoma (OSA) is an aggressive, highly metastatic and lytic primary bone neoplasm commonly affecting the appendicular skeleton of dogs and children. Current treatment options include amputation of the afflicted limb, limb-sparing procedures, or palliative radiation with or without adjunct chemotherapy. Therapies that inhibit bone resorption, such as the bisphosphonates, may be an effective palliative therapy by limiting the local progression of OSA in those patients that are not viable candidates for amputation. We have developed a mouse model of canine skeletal OSA following intratibial inoculation of OSCA40 cells that spontaneously metastasized to the lungs. We demonstrated that therapy with a nitrogen-containing bisphosphonate, zoledronic acid (Zol), reduced OSA-induced bone lysis; however, Zol monotherapy or in combination with amputation was not effective at inhibiting pulmonary metastasis. While not reaching statistical significance, amputation of the tumor-bearing limb reduced the average incidence of lung metastases; however, this effect was nullified when Zol was added to the treatment protocol. In untreated mice, the magnitude of proximal tibial lysis was significantly correlated with the incidence of metastasis. The data support amputation alone for the management of appendicular OSA rather than combining amputation with Zol. However, in patients that are not viable candidates for amputation, Zol may be a useful palliative therapy for OSA by reducing the magnitude of lysis and therefore bone pain, despite the risk of increased pulmonary metastasis. PMID:21374084

Effect of Bisphosphonate Use on Risk of Postmenopausal Breast Cancer

PubMed Central

Hue, Trisha F.; Cummings, Steven R.; Cauley, Jane A.; Bauer, Douglas C.; Ensrud, Kristine E.; Barrett-Connor, Elizabeth; Black, Dennis M.

2015-01-01

IMPORTANCE Studies have shown that bisphosphonates may have antitumor and antimetastatic properties. Recently, observational studies have suggested a possible protective effect of bisphosphonates on breast cancer, but the effect of bisphosphonate use on risk of breast cancer has not been tested in randomized trials. OBJECTIVE To assess the relationship of postmenopausal breast cancer incidence and bisphosphonate use using data from 2 randomized (1:1), double-blind, placebo-controlled trials. DESIGN, SETTING, AND PARTICIPANTS The Fracture Intervention Trial (FIT) randomly assigned 6459 women aged 55 to 81 years to alendronate or placebo for a mean follow-up of 3.8 years. The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly–Pivotal Fracture Trial (HORIZON-PFT) randomly assigned 7765 women aged 65 to 89 years to annual intravenous zoledronic acid or placebo for a mean follow-up of 2.8 years. Data were collected at clinical centers in the United States (FIT and HORIZON-PFT) and in Asia and the Pacific, Europe, North America, and South America (HORIZON-PFT). Women, in either study, with recurrent breast cancer or who reported a history of breast cancer were excluded from analyses. In each trial, a blinded review was conducted of each cancer adverse event report to verify incident invasive breast cancer cases. The primary analysis compared events in the active vs placebo group using a log-rank test. INTERVENTION Alendronate vs placebo (FIT) or zoledronic acid vs placebo (HORIZON-PFT). MAIN OUTCOMES AND MEASURES Hazard ratio for incident breast cancer in the bisphosphonate treatment group compared to the placebo group. RESULTS There was no significant difference in the rate of breast cancer in FIT: 1.5% (n = 46) in the placebo group and 1.8% (n = 57) in the alendronate group (hazard ratio [HR], 1.24 [95% CI, 0.84–1.83]). In HORIZON-PFT, there was also no significant difference: 0.8% (n = 29) in the placebo group and 0.9% (n = 33) in the zoledronic acid group (HR, 1.15 [95% CI, 0.70–1.89]). There was also no significant difference when the data from FIT and HORIZON-PFT were pooled (HR, 1.20 [95% CI, 0.89–1.63]). CONCLUSIONS AND RELEVANCE These 2 randomized clinical trials do not support the findings from observational research. Contrary to the results from observational studies, we found that 3 to 4 years of bisphosphonate treatment did not decrease the risk of invasive postmenopausal breast cancer. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00049829 (HORIZON-PFT). PMID:25111880

Reactive oxygen species are required for zoledronic acid-induced apoptosis in osteoclast precursors and mature osteoclast-like cells

PubMed Central

Tai, Ta-Wei; Chen, Ching-Yu; Su, Fong-Chin; Tu, Yuan-Kun; Tsai, Tsung-Ting; Lin, Chiou-Feng; Jou, I.-Ming

2017-01-01

Inhibiting osteoclasts and osteoclast precursors to reduce bone resorption is an important strategy to treat osteoclast-related diseases, such as osteoporosis, inflammatory bone loss, and malignant bone metastasis. However, the mechanism by which apoptosis is induced in the osteoclasts and their precursors are not completely understood. Here, we used nitrogen-containing bisphosphonate zoledronic acid (ZA) to induce cell apoptosis in human and murine osteoclast precursors and mature osteoclast-like cells. Caspase-3-mediated cell apoptosis occurred following the ZA (100 μM) treatment. Reactive oxygen species (ROS) were also generated in a time-dependent manner. Following knock-down of the p47phox expression, which is required for ROS activation, or co-treatment with the ROS inhibitor, N-acetyl-L-cysteine, ZA-induced apoptosis was significantly suppressed in both osteoclast precursors and mature osteoclast-like cells. The ROS-activated mitogen-activated protein kinases pathways did not trigger cell apoptosis. However, a ROS-regulated Mcl-1 decrease simultaneously with glycogen synthase kinase (GSK)-3β promoted cell apoptosis. These findings show that ZA induces apoptosis in osteoclast precursors and mature osteoclast-like cells by triggering ROS- and GSK-3β-mediated Mcl-1 down-regulation. PMID:28281643

An individualised risk-adapted protocol of pre- and post transplant zoledronic acid reduces bone loss after allogeneic stem cell transplantation: results of a phase II prospective trial.

PubMed

Grigg, A; Butcher, B; Khodr, B; Bajel, A; Hertzberg, M; Patil, S; D'Souza, A B; Ganly, P; Ebeling, P; Wong, E

2017-09-01

Bone loss occurs frequently following allogeneic haematopoietic stem cell transplantation (alloSCT). The Australasian Leukaemia and Lymphoma Group conducted a prospective phase II study of pretransplant zoledronic acid (ZA) and individualised post-transplant ZA to prevent bone loss in alloSCT recipients. Patients received ZA 4 mg before conditioning. Administration of post-transplant ZA from days 100 to 365 post alloSCT was determined by a risk-adapted algorithm based on serial bone density assessments and glucocorticoid exposure. Of 82 patients enrolled, 70 were alive and without relapse at day 100. A single pretransplant dose of ZA prevented femoral neck bone loss at day 100 compared with baseline (mean change -2.6±4.6%). Using the risk-adapted protocol, 42 patients received ZA between days 100 and 365 post alloSCT, and this minimised bone loss at day 365 compared with pretransplant levels (mean change -2.9±5.3%). Femoral neck bone loss was significantly reduced in ZA-treated patients compared with historical untreated controls at days 100 and 365. This study demonstrates that a single dose of ZA pre-alloSCT prevents femoral neck bone loss at day 100 post alloSCT, and that a risk-adapted algorithm is able to guide ZA administration from days 100 to 365 post transplant and minimise further bone loss.

Zoledronic acid causes γδ T cells to target monocytes and down-modulate inflammatory homing

PubMed Central

Fowler, Daniel W; Copier, John; Dalgleish, Angus G; Bodman-Smith, Mark D

2014-01-01

Zoledronic acid (ZA) is a potential immunotherapy for cancer because it can induce potent γδ T-cell-mediated anti-tumour responses. Clinical trials are testing the efficacy of intravenous ZA in cancer patients; however, the effects of systemic ZA on the activation and migration of peripheral γδ T cells remain poorly understood. We found that γδ T cells within ZA-treated peripheral blood mononuclear cells were degranulating, as shown by up-regulated expression of CD107a/b. Degranulation was monocyte dependent because CD107a/b expression was markedly reduced in the absence of CD14+ cells. Consistent with monocyte-induced degranulation, we observed γδ T-cell-dependent induction of monocyte apoptosis, as shown by phosphatidylserine expression on monocytes and decreased percentages of monocytes in culture. Despite the prevailing paradigm that ZA promotes tumour homing in γδ T cells, we observed down-modulation of their tumour homing capacity, as shown by decreased expression of the inflammatory chemokine receptors CCR5 and CXCR3, and reduced migration towards the inflammatory chemokine CCL5. Taken together our data suggest that ZA causes γδ T cells to target monocytes and down-modulate the migratory programme required for inflammatory homing. This study provides novel insight into how γδ T cells interact with monocytes and the possible implications of systemic use of ZA in cancer. PMID:24912747

Zoledronic acid inhibits macrophage/microglia-assisted breast cancer cell invasion

PubMed Central

Rietkötter, Eva; Menck, Kerstin; Bleckmann, Annalen; Farhat, Katja; Schaffrinski, Meike; Schulz, Matthias; Hanisch, Uwe-Karsten; Binder, Claudia; Pukrop, Tobias

2013-01-01

The bisphosphonate zoledronic acid (ZA) significantly reduces complications of bone metastasis by inhibiting resident macrophages, the osteoclasts. Recent clinical trials indicate additional anti-metastatic effects of ZA outside the bone. However, which step of metastasis is influenced and whether this is due to direct toxicity on cancer cells or inhibition of the tumor promoting microenvironment, is unknown. In particular, tumor-associated and resident macrophages support each step of organ metastasis and could be a crucial target of ZA. Thus, we comparatively investigate the ZA effects on: i) different types of macrophages, ii) on breast cancer cells but also iii) on macrophage-induced invasion. We demonstrate that ZA concentrations reflecting the plasma level affected viability of human macrophages, murine bone marrow-derived macrophages as well as their resident brain equivalents, the microglia, while it did not influence the tested cancer cells. However, the effects on the macrophages subsequently reduced the macrophage/microglia-induced invasiveness of the cancer cells. In line with this, manipulation of microglia by ZA in organotypic brain slice cocultures reduced the tissue invasion by carcinoma cells. The characterization of human macrophages after ZA treatment revealed a phenotype/response shift, in particular after external stimulation. In conclusion, we show that therapeutic concentrations of ZA affect all types of macrophages but not the cancer cells. Thus, anti-metastatic effects of ZA are predominantly caused by modulating the microenvironment. Most importantly, our findings demonstrate that ZA reduced microglia-assisted invasion of cancer cells to the brain tissue, indicating a potential therapeutic role in the prevention of cerebral metastasis. PMID:24036536

Zoledronic Acid-Induced Expansion of γδ T Cells from Early-Stage Breast Cancer Patients: Effect of IL-18 on Helper NK Cells

PubMed Central

Sugie, Tomoharu; Murata-Hirai, Kaoru; Iwasaki, Masashi; Morita, Craig T.; Li, Wen; Okamura, Haruki; Minato, Nagahiro; Toi, Masakazu; Tanaka, Yoshimasa

2013-01-01

Human γδ T cells display potent cytotoxicity against various tumor cells pretreated with zoledronic acid (Zol). Zol has shown benefits when added to adjuvant endocrine therapy for patients with early-stage breast cancer or to standard chemotherapy for patients with multiple myeloma. Although γδ T cells may contribute to this additive effect, the responsiveness of γδ T cells from early-stage breast cancer patients has not been fully investigated. In this study, we determined the number, frequency, and responsiveness of Vγ2Vδ2 T cells from early- and late-stage breast cancer patients and examined the effect of IL-18 on their ex vivo expansion. The responsiveness of Vγ2Vδ2 T cells from patients with low frequencies of Vγ2Vδ2 T cells was significantly diminished. IL-18, however, enhanced ex vivo proliferative responses of Vγ2Vδ2 T cells and helper NK cells from patients with either low or high frequencies of Vγ2Vδ2 T cells. Treatment of breast cancer patients with Zol alone decreased the number of Vγ2Vδ2 T cells and reduced their ex vivo responsiveness. These results demonstrate that Zol can elicit immunological responses by γδ T cells from early-stage breast cancer patients but that frequent in vivo treatment reduces Vγ2Vδ2 T cell numbers and their responsiveness to stimulation. PMID:23151944

Adoptive transfer of ex vivo expanded Vγ9Vδ2 T cells in combination with zoledronic acid inhibits cancer growth and limits osteolysis in a murine model of osteolytic breast cancer.

PubMed

Zysk, Aneta; DeNichilo, Mark O; Panagopoulos, Vasilios; Zinonos, Irene; Liapis, Vasilios; Hay, Shelley; Ingman, Wendy; Ponomarev, Vladimir; Atkins, Gerald; Findlay, David; Zannettino, Andrew; Evdokiou, Andreas

2017-02-01

Bone metastases occur in over 75% of patients with advanced breast cancer and are responsible for high levels of morbidity and mortality. In this study, ex vivo expanded cytotoxic Vγ9Vδ2 T cells isolated from human peripheral blood were tested for their anti-cancer efficacy in combination with zoledronic acid (ZOL), using a mouse model of osteolytic breast cancer. In vitro, expanded Vγ9Vδ2 T cells were cytotoxic against a panel of human breast cancer cell lines, and ZOL pre-treatment further sensitised breast cancer cells to killing by Vγ9Vδ2 T cells. Vγ9Vδ2 T cells adoptively transferred into NOD/SCID mice localised to osteolytic breast cancer lesions in the bone, and multiple infusions of Vγ9Vδ2 T cells reduced tumour growth in the bone. ZOL pre-treatment potentiated the anti-cancer efficacy of Vγ9Vδ2 T cells, with mice showing further reductions in tumour burden. Mice treated with the combination also had reduced tumour burden of secondary pulmonary metastases, and decreased bone degradation. Our data suggests that adoptive transfer of Vγ9Vδ2 T cell in combination with ZOL may prove an effective immunotherapeutic approach for the treatment of breast cancer bone metastases. Copyright © 2016. Published by Elsevier Ireland Ltd.

Duration of antiresorptive activity of zoledronate in postmenopausal women with osteopenia: a randomized, controlled multidose trial

PubMed Central

Grey, Andrew; Bolland, Mark J.; Horne, Anne; Mihov, Borislav; Gamble, Greg; Reid, Ian R.

2017-01-01

BACKGROUND: Intravenous zoledronate 5 mg annually reduces fracture risk, and 5 mg every 2 years prevents bone loss, but the optimal dosing regimens for these indications are uncertain. METHODS: We conducted a 3-year open-label extension of a 2-year randomized, placebo-controlled, double-blind study. Late postmenopausal women with osteopenia were assigned to receive a single baseline dose of 1 mg, 2.5 mg or 5 mg of zoledronate or placebo. The primary outcome was change in spine bone mineral density (BMD). Secondary outcomes were changes in hip BMD and serum markers of bone turnover. RESULTS: The study involved 160 women. Zoledronate increased BMD and reduced markers of bone turnover in a dose-dependent manner. After 2 years, the 1-mg, 2.5-mg and 5-mg zoledronate doses increased spine BMD over placebo by 5.0% (95% confidence interval [CI] 3.0% to 7.0%), 5.7% (95% CI 3.7% to 7.7%) and 5.7% (95% CI 3.7% to 7.6%), respectively; after 5 years, the respective increases were 2.0% (95% CI −1.1% to 5.0%), 2.2% (95% CI −1.0% to 5.4%) and 5.1% (95% CI 2.2% to 8.1%). After 2 years, the 1-mg, 2.5-mg and 5-mg zoledronate doses increased total hip BMD over placebo by 2.6% (95% CI 1.3% to 3.9%), 4.1% (95% CI 2.9% to 5.4%) and 4.7% (95% CI 3.4% to 5.9%), respectively; after 5 years, the respective increases were 1.8% (95% CI −0.1% to 3.8%), 2.8% (95% CI 0.8% to 4.8%) and 5.4% (95% CI 3.5% to 7.3%). BMD remained above baseline values for 2–3 years in the 1-mg group, 3–4 years in the 2.5-mg group and at least 5 years in the 5-mg group. INTERPRETATION: The antiresorptive activity of single zoledronate doses of 1–5 mg persist for at least 3 years in postmenopausal women with osteopenia. Clinical trials would be justified to evaluate the effects on fracture risk of less frequent or lower doses of zoledronate than are currently recommended. Trial registration: www.anzctr.org.au, no. ACTRN12607000576426 PMID:28893875

Nephrotoxicity of ibandronate and zoledronate in Wistar rats with normal renal function and after unilateral nephrectomy.

PubMed

Bergner, R; Siegrist, B; Gretz, N; Pohlmeyer-Esch, G; Kränzlin, B

2015-09-01

A previous animal study compared the nephrotoxic effect of ibandronate (IBN) and zoledronate (ZOL), but interpretation of these study results was limited because of the model of minimal nephrotoxic dosage with a dosage ratio of 1:3. The present study investigated the nephrotoxicity of ibandronate and zoledronate in a 1.5:1 dose ratio, as used in clinical practice and compared the nephrotoxicity in rats with normal and with mildly to moderately impaired renal function. We compared rats with normal renal function (SHAM) and with impaired renal function after unilateral nephrectomy (UNX), treated either with ibandronate 1.5mg/kg, zoledronate 1mg/kg or placebo once (1×) or nine (9×) times. Renal function and markers of tubular toxicity were measured over a 27 week period. After last bisphosphonate treatment the rats were sacrificed and kidneys examined histologically. All bisphosphonate treated animals showed a significant tubular toxicity, which was temporary except in the ZOL-UNX-9×-group. Also the renal function was only transiently reduced except in the ZOL-UNX-9×-group. Histologically, bisphosphonate treatment led to cortical tubuloepithelial degeneration/necrosis and medullary tubuloepithelial swelling which were slightly more pronounced in ibandronate treated animals, when compared to zoledronate treated animals, especially with impaired renal function. In contrast to the previous study we found a similar nephrotoxicity of ibandronate and zoledronate in rats with normal renal function. In rats with impaired renal function the peak of toxicity had not even been fully reached until end of experiment in the zoledronate treated animals. The peak of toxicity seems to be more severe and delayed in rats with impaired renal function compared with rats with normal renal function. Copyright © 2015 Elsevier Ltd. All rights reserved.

Inhibiting the osteocyte-specific protein sclerostin increases bone mass and fracture resistance in multiple myeloma

PubMed Central

Mohanty, Sindhu T.; Seckinger, Anja; Terry, Rachael L.; Pettitt, Jessica A.; Simic, Marija K.; Le, Lawrence M. T.; Kramer, Ina; Falank, Carolyne; Fairfield, Heather; Ghobrial, Irene M.; Baldock, Paul A.; Little, David G.; Kneissel, Michaela; Vanderkerken, Karin; Bassett, J. H. Duncan; Williams, Graham R.; Oyajobi, Babatunde O.; Hose, Dirk

2017-01-01

Multiple myeloma (MM) is a plasma cell cancer that develops in the skeleton causing profound bone destruction and fractures. The bone disease is mediated by increased osteoclastic bone resorption and suppressed bone formation. Bisphosphonates used for treatment inhibit bone resorption and prevent bone loss but fail to influence bone formation and do not replace lost bone, so patients continue to fracture. Stimulating bone formation to increase bone mass and fracture resistance is a priority; however, targeting tumor-derived modulators of bone formation has had limited success. Sclerostin is an osteocyte-specific Wnt antagonist that inhibits bone formation. We hypothesized that inhibiting sclerostin would prevent development of bone disease and increase resistance to fracture in MM. Sclerostin was expressed in osteocytes from bones from naive and myeloma-bearing mice. In contrast, sclerostin was not expressed by plasma cells from 630 patients with myeloma or 54 myeloma cell lines. Mice injected with 5TGM1-eGFP, 5T2MM, or MM1.S myeloma cells demonstrated significant bone loss, which was associated with a decrease in fracture resistance in the vertebrae. Treatment with anti-sclerostin antibody increased osteoblast numbers and bone formation rate but did not inhibit bone resorption or reduce tumor burden. Treatment with anti-sclerostin antibody prevented myeloma-induced bone loss, reduced osteolytic bone lesions, and increased fracture resistance. Treatment with anti-sclerostin antibody and zoledronic acid combined increased bone mass and fracture resistance when compared with treatment with zoledronic acid alone. This study defines a therapeutic strategy superior to the current standard of care that will reduce fractures for patients with MM. PMID:28515094

Cost-effectiveness of zoledronic acid and strontium-89 as bone protecting treatments in addition to chemotherapy in patients with metastatic castrate-refractory prostate cancer: results from the TRAPEZE trial (ISRCTN 12808747).

PubMed

Andronis, Lazaros; Goranitis, Ilias; Pirrie, Sarah; Pope, Ann; Barton, Darren; Collins, Stuart; Daunton, Adam; McLaren, Duncan; O'Sullivan, Joe M; Parker, Chris; Porfiri, Emilio; Staffurth, John; Stanley, Andrew; Wylie, James; Beesley, Sharon; Birtle, Alison; Brown, Janet E; Chakraborti, Prabir; Hussain, Syed A; Russell, J Martin; Billingham, Lucinda J; James, Nicholas D

2017-04-01

To evaluate the cost-effectiveness of adding zoledronic acid or strontium-89 to standard docetaxel chemotherapy for patients with castrate-refractory prostate cancer (CRPC). Data on resource use and quality of life for 707 patients collected prospectively in the TRAPEZE 2 × 2 factorial randomised trial (ISRCTN 12808747) were used to assess the cost-effectiveness of i) zoledronic acid versus no zoledronic acid (ZA vs. no ZA), and ii) strontium-89 versus no strontium-89 (Sr89 vs. no Sr89). Costs were estimated from the perspective of the National Health Service in the UK and included expenditures for trial treatments, concomitant medications, and use of related hospital and primary care services. Quality-adjusted life-years (QALYs) were calculated according to patients' responses to the generic EuroQol EQ-5D-3L instrument, which evaluates health status. Results are expressed as incremental cost-effectiveness ratios (ICERs) and cost-effectiveness acceptability curves. The per-patient cost for ZA was £12 667, £251 higher than the equivalent cost in the no ZA group. Patients in the ZA group had on average 0.03 QALYs more than their counterparts in no ZA group. The ICER for this comparison was £8 005. Sr89 was associated with a cost of £13 230, £1365 higher than no Sr89, and a gain of 0.08 QALYs compared to no Sr89. The ICER for Sr89 was £16 884. The probabilities of ZA and Sr89 being cost-effective were 0.64 and 0.60, respectively. The addition of bone-targeting treatments to standard chemotherapy led to a small improvement in QALYs for a modest increase in cost (or cost-savings). ZA and Sr89 resulted in ICERs below conventional willingness-to-pay per QALY thresholds, suggesting that their addition to chemotherapy may represent a cost-effective use of resources. © 2016 The Authors BJU International published by John Wiley & Sons Ltd on behalf of BJU International.

Bone Marrow Biopsy: RNA Isolation with Expression Profiling in Men with Metastatic Castration-resistant Prostate Cancer—Factors Affecting Diagnostic Success

PubMed Central

Afonso, P. Diana; Vinson, Emily N.; Turnbull, James D.; Morris, Karla K.; Foye, Adam; Madden, John F.; Roy Choudhury, Kingshuk; Febbo, Phillip G.; George, Daniel J.

2013-01-01

Purpose To determine the rate at which computed tomographically guided pelvic percutaneous bone biopsy in men with metastatic castration-resistant prostate cancer (mCRPC) yields adequate tissue for genomic profiling and to identify issues likely to affect diagnostic yields. Materials and Methods This study was institutional review board approved, and written informed consent was obtained. In a phase II trial assessing response to everolimus, 31 men with mCRPC underwent 54 biopsy procedures (eight men before and 23 men both before and during treatment). Variables assessed were lesion location (iliac wing adjacent to sacroiliac joint, iliac wing anterior and/or superior to sacroiliac joint, sacrum, and remainder of pelvis), mean lesion attenuation, subjective lesion attenuation (purely sclerotic vs mixed), central versus peripheral lesion sampling, lesion size, core number, and use of zoledronic acid for more than 1 year. Results Of 54 biopsy procedures, 21 (39%) yielded adequate tissue for RNA isolation and genomic profiling. Three of four sacral biopsies were adequate. Biopsies of the ilium adjacent to the sacroiliac joints were more likely adequate than those from elsewhere in the ilium (48% vs 28%, respectively). All five biopsies performed in other pelvic locations yielded inadequate tissue for RNA isolation. Mean attenuation of lesions with inadequate tissue was 172 HU greater than those with adequate tissue (621.1 HU ± 166 vs 449 HU ± 221, respectively; P = .002). Use of zoledronic acid, peripheral sampling, core number, and lesion size affected yields, but the differences were not statistically significant. Histologic examination with hematoxylin-eosin staining showed that results of 36 (67%) biopsies were positive for cancer; only mean attenuation differences were significant (707 HU ± 144 vs 473 HU ± 191, negative vs positive, respectively; P < .001). Conclusion In men with mCRPC, percutaneous sampling of osseous metastases for genomic profiling is possible, but use of zoledronic acid for more than 1 year may reduce the yield of adequate tissue for RNA isolation. Sampling large low-attenuating lesions at their periphery maximizes yield. © RSNA, 2013 PMID:23925271

Zoledronic acid increases the circulating soluble RANKL level in mice, with a further increase in lymphocyte-derived soluble RANKL in zoledronic acid- and glucocorticoid-treated mice stimulated with bacterial lipopolysaccharide.

PubMed

Abe, Takahiro; Sato, Tsuyoshi; Kokabu, Shoichiro; Hori, Naoko; Shimamura, Yumiko; Sato, Tomoya; Yoda, Tetsuya

2016-07-01

The nitrogen-containing bisphosphonate (BP) zoledronic acid (ZA) is a potent antiresorptive drug used in conjunction with standard cancer therapy to treat osteolysis or hypercalcemia due to malignancy. However, it is unclear how ZA influences the circulating levels of bone remodeling factors. The aim of this study was to evaluate the effects of ZA on the serum levels of soluble receptor activator of NF-kB ligand (sRANKL) and osteoprotegerin (OPG). The following four groups of C57BL/6 mice were used (five mice per group): (1) the placebo+phosphate-buffered saline (PBS) group, in which placebo-treated mice were injected once weekly with PBS for 4weeks; (2) the placebo+ZA group, in which placebo-treated mice were injected once weekly with ZA for 4weeks; (3) the prednisolone (PSL)+PBS group, in which PSL-treated mice were injected once weekly with PBS for 4weeks; and (4) the PSL+ZA group, in which PSL-treated mice were injected once weekly with ZA for 4weeks. At the 3-week time point, all mice were subjected to oral inflammatory stimulation with bacterial lipopolysaccharide (LPS). The sera of these mice were obtained every week and the levels of sRANKL and OPG were measured using enzyme-linked immunosorbent assay. At the time of sacrifice, femurs were prepared for micro-computed tomography (micro-CT), histological, and histomorphometric analyses. Our data indicated that ZA administration remarkably reduced bone turnover and significantly increased the basal level of sRANKL. Interestingly, the PSL+ZA group showed a dramatically elevated sRANKL level after LPS stimulation. In contrast, the PSL+ZA group in nonobese diabetic mice with severe combined immunodeficiency disease (NOD-SCID mice), which are characterized by the absence of functional T- and B-lymphocytes, showed no increase in the sRANKL level. Our data suggest that, particularly with combination treatment of ZA and glucocorticoids, surviving lymphocytes might be the source of inflammation-induced sRANKL. Thus, circulating sRANKL levels might be modulated by ZA. Copyright © 2016 Elsevier Ltd. All rights reserved.

Zoledronic acid increases bone mineral density and improves health-related quality of life over two years of treatment in Chinese women with postmenopausal osteoporosis.

PubMed

Huang, Shushu; Lin, Hua; Zhu, Xiufen; Chen, Xin; Fan, Lu; Liu, Changchang

2014-01-01

Osteoporosis is characterised by decreased bone mass and weakened bones, with an increased risk of fractures. Osteoporotic fracture, the most serious complication of osteoporosis, is related not only to lower bone mineral density (BMD), but also falls. Osteoporosis and fractures are associated with a decreased health-related quality of life (HRQL). Zoledronic acid (ZOL) is an intravenous once-yearly bisphosphonate that has been shown to be effective and safe in improving BMD and reducing fracture risk in controlled clinical trials. In this self-controlled, prospective trial, 220 postmenopausal women with osteoporosis (mean age 67 years) received a single infusion of ZOL 5 mg at baseline and month 12. BMD, HRQL and Fall Index (FI) were measured at baseline, and months 12 and 24 (before each use of ZOL). The main outcome measures were the changes in lumbar spine and hip BMD and the changes in HRQL, the Short Form-36 questionnaire (SF-36). Additional comparisons were based on the FI. LSD multiple comparisons were used in the comparisons of BMD, SF-36 domain scores and FI. The patients had significantly higher L1-4, total hip, femoral neck and trochanter BMD (P < 0.05) with improved HRQL (P < 0.05) over two years of treatment of once-yearly ZOL 5mg. FI was reduced (P < 0.05) with oral daily elemental calcium and vitamin D in the treatment course. ZOL improves BMD and HRQL, especially in the physical aspects, over two years of treatment in women with postmenopausal osteoporosis, and can help improve balance ability.

Effect of once-yearly zoledronic acid on the spine and hip as measured by quantitative computed tomography: results of the HORIZON Pivotal Fracture Trial

PubMed Central

Lang, T.; Boonen, S.; Cummings, S.; Delmas, P. D.; Cauley, J. A.; Horowitz, Z.; Kerzberg, E.; Bianchi, G.; Kendler, D.; Leung, P.; Man, Z.; Mesenbrink, P.; Eriksen, E. F.; Black, D. M.

2016-01-01

Summary Changes in bone mineral density and bone strength following treatment with zoledronic acid (ZOL) were measured by quantitative computed analysis (QCT) or dual-energy X-ray absorptiometry (DXA). ZOL treatment increased spine and hip BMD vs placebo, assessed by QCT and DXA. Changes in trabecular bone resulted in increased bone strength. Introduction To investigate bone mineral density (BMD) changes in trabecular and cortical bone, estimated by quantitative computed analysis (QCT) or dual-energy X-ray absorptiometry (DXA), and whether zoledronic acid 5 mg (ZOL) affects bone strength. Methods In 233 women from a randomized, controlled trial of once-yearly ZOL, lumbar spine, total hip, femoral neck, and trochanter were assessed by DXA and QCT (baseline, Month 36). Mean percentage changes from baseline and between-treatment differences (ZOL vs placebo, t-test) were evaluated. Results Mean between-treatment differences for lumbar spine BMD were significant by DXA (7.0%, p<0.01) and QCT (5.7%, p<0.0001). Between-treatment differences were significant for trabecular spine (p=0.0017) [non-parametric test], trabecular trochanter (10.7%, p<0.0001), total hip (10.8%, p<0.0001), and compressive strength indices at femoral neck (8.6%, p=0.0001), and trochanter (14.1%, p<0.0001). Conclusions Once-yearly ZOL increased hip and spine BMD vs placebo, assessed by QCT vs DXA. Changes in trabecular bone resulted in increased indices of compressive strength. PMID:19802508

PRGF exerts a cytoprotective role in zoledronic acid-treated oral cells.

PubMed

Anitua, Eduardo; Zalduendo, Mar; Troya, María; Orive, Gorka

2016-04-01

Bisphosphonates-related osteonecrosis of the jaw (BRONJ) is a common problem in patients undergoing long-term administration of highly potent nitrogen-containing bisphosphonates (N-BPs). This pathology occurs via bone and soft tissue mechanism. Zoledronic acid (ZA) is the most potent intravenous N-BP used to prevent bone loss in patients with bone dysfunction. The objective of this in vitro study was to evaluate the role of different ZA concentrations on the cells from human oral cavity, as well as the potential of plasma rich in growth factors (PRGF) to overcome the negative effects of this BP. Primary human gingival fibroblasts and primary human alveolar osteoblasts were used. Cell proliferation was evaluated by means of a fluorescence-based method. A colorimetric assay to detect DNA fragmentation undergoing apoptosis was used to determine cell death, and the expression of both NF-κB and pNF-κB were quantified by Western blot analysis. ZA had a cytotoxic effect on both human gingival fibroblasts and human alveolar osteoblasts. This BP inhibits cell proliferation, stimulates apoptosis, and induces inflammation. However, the addition of PRGF suppresses all these negative effects of the ZA. PRGF shows a cytoprotective role against the negative effects of ZA on primary oral cells. At present, there is no definitive treatment for bisphosphonates-related osteonecrosis of the jaw (BRONJ), being mainly palliatives. Our results revealed that PRGF has a cytoprotective role in cells exposed to zoledronic acid, thus providing a reliable adjunctive therapy for the treatment of BRONJ pathology.

Enhancing adoptive cancer immunotherapy with Vγ2Vδ2 T cells through pulse zoledronate stimulation.

PubMed

Nada, Mohanad H; Wang, Hong; Workalemahu, Grefachew; Tanaka, Yoshimasa; Morita, Craig T

2017-01-01

Human γδ T cells expressing Vγ2Vδ2 T cell receptors monitor foreign- and self-prenyl pyrophosphate metabolites in isoprenoid biosynthesis to mediate immunity to microbes and tumors. Adoptive immunotherapy with Vγ2Vδ2 T cells has been used to treat cancer patients with partial and complete remissions. Most clinical trials and preclinical studies have used continuous zoledronate exposure to expand Vγ2Vδ2 cells where zoledronate is slowly diluted over the course of the culture. Zoledronate inhibits farnesyl diphosphate synthase (FDPS) in monocytes causing isopentenyl pyrophosphate to accumulate that then stimulates Vγ2Vδ2 cells. Because zoledronate inhibition of FDPS is also toxic for T cells, we hypothesized that a short period of exposure would reduce T cell toxicity but still be sufficient for monocytes uptake. Additionally, IL-15 increases the anti-tumor activity of murine αβ T cells in mice but its effect on the in vivo anti-tumor activity of human Vγ2Vδ2 cells has not been assessed. Human Vγ2Vδ2 T cells were expanded by pulse or continuous zoledronate stimulation with IL-2 or IL-15. Expanded Vγ2Vδ2 cells were tested for their expression of effector molecules and killing of tumor cells as well as their in vivo control of human prostate cancer tumors in immunodeficient NSG mice. Pulse zoledronate stimulation with either IL-2 or IL-15 resulted in more uniform expansion of Vγ2Vδ2 cells with higher purity and cell numbers as compared with continuous exposure. The Vγ2Vδ2 cells had higher levels of CD107a and perforin and increased tumor cytotoxicity. Adoptive immunotherapy with Vγ2Vδ2 cells derived by pulse stimulation controlled human PC-3 prostate cancer tumors in NSG mice significantly better than those derived by continuous stimulation, halting tumor growth. Although pulse zoledronate stimulation with IL-15 preserved early memory subsets, adoptive immunotherapy with IL-15-derived Vγ2Vδ2 cells equally inhibited PC-3 tumor growth as those derived with IL-2. Pulse zoledronate stimulation maximizes the purity, quantity, and quality of expanded Vγ2Vδ2 cells for adoptive immunotherapy but there is no advantage to using IL-15 over IL-2 in our humanized mouse model. Pulse zoledronate stimulation is a simple modification to existing protocols that will enhance the effectiveness of adoptively transferred Vγ2Vδ2 cells by increasing their numbers and anti-tumor activity.

Preventive dental management of osteonecrosis of the jaws related to zoledronic acid treatment.

PubMed

Coello-Suanzes, J A; Rollon-Ugalde, V; Castaño-Seiquer, A; Lledo-Villar, E; Herce-Lopez, J; Infante-Cossio, P; Rollon-Mayordomo, A

2018-02-07

To evaluate the effect of preventive dental management on reducing the incidence and delaying the onset of bisphosphonate-related osteonecrosis of the jaw (BRONJ) in patients treated with intravenous zoledronic acid (ZA). This single-center clinical study included 255 cancer patients monitored over a 6-year period. Patients received dental treatment prior (Group A) or after (Group B) the initiation of ZA therapy. Dental treatments performed, incidence proportion (IP) and incidence rate (IR) in both groups were analyzed using significance tests. BRONJ onset were estimated using the Kaplan-Meier estimator and log-rank test. Independent risk factors to develop BRONJ were evaluated using Cox regression analysis models. 37 patients suffered from BRONJ (IP=14.5%), 7.3% in group A and 36.5% in group B (p=0.000). The IR was 0.007 patients/month in group B and 0.004 in group A. BRONJ free survival at 3 years were 97% in group A and 66% in group B. Survival curves were significant (p=0.056) according to log-rank test. Multivariate Cox models showed that dental extractions (p=0.000) were significant. BRONJ occurred significantly in patients who underwent dental extractions after the initiation of ZA and did not accomplish a preventive dental program. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Zoledronic Acid in Aromatase Inhibitor Induced Musculoskeletal Symptoms

ClinicalTrials.gov

2017-10-05

Ductal Carcinoma in Situ; Estrogen Receptor-positive Breast Cancer; Progesterone Receptor-positive Breast Cancer; Stage I Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

Pharmacoeconomics of bisphosphonates for skeletal-related event prevention in metastatic non-breast solid tumours.

PubMed

Carter, John A; Joshi, Avani D; Kaura, Satyin; Botteman, Marc F

2012-05-01

Bisphosphonates reduce the risk of skeletal-related events (SREs; i.e. spinal cord compression, pathological fracture, radiation or surgery to the bone, and hypercalcaemia) in patients with metastatic cancer. A number of analyses have been conducted to assess the cost effectiveness of bisphosphonates in patients with bone metastases secondary to breast cancer, but few in other solid tumours. This is a review of cost-effectiveness analyses in patients with non-breast solid tumours and bone metastases. A literature search was conducted to identify cost-effectiveness analyses reporting the cost per QALY gained of bisphosphonates in patients with metastatic bone disease secondary to non-breast solid tumours. Four analyses met inclusion criteria. These included two in prostate cancer (one of which used a global perspective but expressed results in $US, and the other reported from a multiple country perspective: France, Germany, Portugal and the Netherlands). The remaining analyses were in lung cancer (in the UK, France, Germany, Portugal and the Netherlands), and renal cell carcinoma (in the UK, France and Germany). In each analysis, the cost effectiveness of zoledronic acid versus placebo was analysed. Zoledronic acid was found to be cost effective in all European countries across all three indications but not in the sole global prostate cancer analysis. Across countries and indications, assumptions regarding patient survival, drug cost and baseline utility (i.e. patient utility with metastatic disease but without an SRE) were the most robust drivers of modelled estimates. Assumptions of SRE-related costs were most often the second strongest cost driver. Further review indicated that particular attention should be paid to the inclusion or exclusion of nonsignificant survival benefits, whether health state utilities were elicited from community or patient samples or author assumptions, delineation between symptomatic and asymptomatic SREs, and the methods with which SRE disutility was modelled over time. While the field of cost-effectiveness analysis in solid tumours other than breast cancer is still evolving, outcomes will likely continue to be driven by drug cost and assumptions regarding treatment benefits. Although considerations such as adverse events and administration costs are important, they were not found to influence cost-effectiveness estimates greatly. As zoledronic acid will lose patent protection in 2013 and subsequently be greatly reduced in price, it is likely that the field of cost effectiveness will change with regard to SRE-limiting agents. Meanwhile, research should be conducted to improve our understanding of the impact on quality of life and medical costs of preventing SREs.

The Effect of 3 Versus 6 Years of Zoledronic Acid Treatment of Osteoporosis: A Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT)

PubMed Central

Black, Dennis M; Reid, Ian R; Boonen, Steven; Bucci-Rechtweg, Christina; Cauley, Jane A; Cosman, Felicia; Cummings, Steven R; Hue, Trisha F; Lippuner, Kurt; Lakatos, Peter; Leung, Ping Chung; Man, Zulema; Martinez, Ruvie Lou Maria; Tan, Monique; Ruzycky, Mary Ellen; Su, Guoqin; Eastell, Richard

2012-01-01

Zoledronic acid 5 mg (ZOL) annually for 3 years reduces fracture risk in postmenopausal women with osteoporosis. To investigate long-term effects of ZOL on bone mineral density (BMD) and fracture risk, the Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly–Pivotal Fracture Trial (HORIZON-PFT) was extended to 6 years. In this international, multicenter, double-blind, placebo-controlled extension trial, 1233 postmenopausal women who received ZOL for 3 years in the core study were randomized to 3 additional years of ZOL (Z6, n = 616) or placebo (Z3P3, n = 617). The primary endpoint was femoral neck (FN) BMD percentage change from year 3 to 6 in the intent-to-treat (ITT) population. Secondary endpoints included other BMD sites, fractures, biochemical bone turnover markers, and safety. In years 3 to 6, FN-BMD remained constant in Z6 and dropped slightly in Z3P3 (between-treatment difference = 1.04%; 95% confidence interval 0.4 to 1.7; p = 0.0009) but remained above pretreatment levels. Other BMD sites showed similar differences. Biochemical markers remained constant in Z6 but rose slightly in Z3P3, remaining well below pretreatment levels in both. New morphometric vertebral fractures were lower in the Z6 (n = 14) versus Z3P3 (n = 30) group (odds ratio = 0.51; p = 0.035), whereas other fractures were not different. Significantly more Z6 patients had a transient increase in serum creatinine >0.5 mg/dL (0.65% versus 2.94% in Z3P3). Nonsignificant increases in Z6 of atrial fibrillation serious adverse events (2.0% versus 1.1% in Z3P3; p = 0.26) and stroke (3.1% versus 1.5% in Z3P3; p = 0.06) were seen. Postdose symptoms were similar in both groups. Reports of hypertension were significantly lower in Z6 versus Z3P3 (7.8% versus 15.1%, p < 0.001). Small differences in bone density and markers in those who continued versus those who stopped treatment suggest residual effects, and therefore, after 3 years of annual ZOL, many patients may discontinue therapy up to 3 years. However, vertebral fracture reductions suggest that those at high fracture risk, particularly vertebral fracture, may benefit by continued treatment. (ClinicalTrials.gov identifier: NCT00145327). © 2012 American Society for Bone and Mineral Research. PMID:22161728

Biomarkers in Tissue Samples From Patients With Newly Diagnosed Breast Cancer Treated With Zoledronic Acid

ClinicalTrials.gov

2018-06-01

Estrogen Receptor-positive Breast Cancer; Invasive Ductal Breast Carcinoma; Progesterone Receptor-positive Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer

The effects of local administration of Zoledronate solution on the tooth movement and periodontal ligament.

PubMed

Liu, Chang; Sun, Xinhua; Chen, Yuanping; Hu, Min; Liang, Tang

2002-07-01

To investigate the effects of local administration of Zoledronate solution on the tooth movement and periodontal ligament. Orthodontic tooth movement of upper first molar was performed in 42 rats with coil spring. Zoledronate solution was injected into the palatal submucosal area adjacent to the left upper first molar in experimental group 3 days prior to the use of the appliance. In control group, same amount of 0.9% NaCl solution was injected into the palatal submucosal area adjacent to the left and right upper first molar. The injection was applied every third day. The application of mesial force lasted 0.3, 7, 14, 21 days respectively. After the rats were sacrificed, the distance of tooth movement was measured. Sections were stained and then observed with microscope. 1. The distance of tooth movement in the experimental group was significantly smaller than that in the control group. 2. The number of osteoclast on the pressure side in the experiment group was significantly smaller than that in the control group through the experimental period, but there was no distinct difference between experimental group and control group (except for 14 days) for the number of odontoclast in interradicular area. 3. The osteoclasts and odontoclasts were the main target cell of Zoledronate in periodontal tissue. Zoledronate may be a useful agent for anchorage control and reducing the number of osteoclast on pressure side of alveolar bone.

Changes in cortical bone channels network and osteocyte organization after the use of zoledronic acid.

PubMed

Rabelo, Gustavo Davi; Travençolo, Bruno Augusto Nassif; Oliveira, Marcio Augusto; Beletti, Marcelo Emílio; Gallottini, Marina; Silveira, Fernando Ricardo Xavier da

2015-12-01

The aim of this study was to evaluate the effects of zoledronic acid (ZA) on the cortical bone channels network (CBCN) and osteocyte organization in relation to the bone channels. Eighteen male Wistar rats were divided into control (CG) and test groups (TG). Twelve animals from TG received 3 ZA doses (7.5 µg/kg), and 6 animals from CG did not receive any medication. TG animals were euthanized at 14 (n = 6) and 75 (n = 6) dadys after drug injection. CBCN was analyzed in mandibles and tibias using computational routines. The osteocyte organization was qualitatively evaluated in tibias using a three-dimensional reconstruction of images from serial histological sections. Significant differences in CBCN of tibia were found between the treated and untreated rats, with a wider range of sizes and shapes of the channels after the use of ZA (channels area p = 0.0063, channels area SD p = 0.0276) and less bone matrix (bone volume p = 0.0388). The alterations in the channels' morphology were more evident at 75 days after the drug injection (channels perimeter p = 0.0286). No differences were found in mandibles CBCN. The osteocyte distribution revealed more variable patterns of cell distribution in ZA groups, with non-homogeneous distribution of cells in relation to the bone channels. Zoledronic acid induces structural changes in CBCN and modifies the osteocyte arrangement in cortical bone in the tibia; also, the variability in the morphology of bone channels became more evident after a certain time of the use of the drug.

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial

PubMed Central

James, Nicholas D; Sydes, Matthew R; Clarke, Noel W; Mason, Malcolm D; Dearnaley, David P; Spears, Melissa R; Ritchie, Alastair W S; Parker, Christopher C; Russell, J Martin; Attard, Gerhardt; de Bono, Johann; Cross, William; Jones, Rob J; Thalmann, George; Amos, Claire; Matheson, David; Millman, Robin; Alzouebi, Mymoona; Beesley, Sharon; Birtle, Alison J; Brock, Susannah; Cathomas, Richard; Chakraborti, Prabir; Chowdhury, Simon; Cook, Audrey; Elliott, Tony; Gale, Joanna; Gibbs, Stephanie; Graham, John D; Hetherington, John; Hughes, Robert; Laing, Robert; McKinna, Fiona; McLaren, Duncan B; O'Sullivan, Joe M; Parikh, Omi; Peedell, Clive; Protheroe, Andrew; Robinson, Angus J; Srihari, Narayanan; Srinivasan, Rajaguru; Staffurth, John; Sundar, Santhanam; Tolan, Shaun; Tsang, David; Wagstaff, John; Parmar, Mahesh K B

2016-01-01

Summary Background Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. Methods Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m2) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). Findings 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60–71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23–184). Median follow-up was 43 months (IQR 30–60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79–1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66–0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69–0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3–5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. Interpretation Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. Funding Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research. PMID:26719232

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial.

PubMed

James, Nicholas D; Sydes, Matthew R; Clarke, Noel W; Mason, Malcolm D; Dearnaley, David P; Spears, Melissa R; Ritchie, Alastair W S; Parker, Christopher C; Russell, J Martin; Attard, Gerhardt; de Bono, Johann; Cross, William; Jones, Rob J; Thalmann, George; Amos, Claire; Matheson, David; Millman, Robin; Alzouebi, Mymoona; Beesley, Sharon; Birtle, Alison J; Brock, Susannah; Cathomas, Richard; Chakraborti, Prabir; Chowdhury, Simon; Cook, Audrey; Elliott, Tony; Gale, Joanna; Gibbs, Stephanie; Graham, John D; Hetherington, John; Hughes, Robert; Laing, Robert; McKinna, Fiona; McLaren, Duncan B; O'Sullivan, Joe M; Parikh, Omi; Peedell, Clive; Protheroe, Andrew; Robinson, Angus J; Srihari, Narayanan; Srinivasan, Rajaguru; Staffurth, John; Sundar, Santhanam; Tolan, Shaun; Tsang, David; Wagstaff, John; Parmar, Mahesh K B

2016-03-19

Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research. Copyright © 2016 James et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.

Site Specific Effects of Zoledronic Acid during Tibial and Mandibular Fracture Repair

PubMed Central

Yu, Yan Yiu; Lieu, Shirley; Hu, Diane; Miclau, Theodore; Colnot, Céline

2012-01-01

Numerous factors can affect skeletal regeneration, including the extent of bone injury, mechanical loading, inflammation and exogenous molecules. Bisphosphonates are anticatabolic agents that have been widely used to treat a variety of metabolic bone diseases. Zoledronate (ZA), a nitrogen-containing bisphosphonate (N-BP), is the most potent bisphosphonate among the clinically approved bisphosphonates. Cases of bisphosphonate-induced osteonecrosis of the jaw have been reported in patients receiving long term N-BP treatment. Yet, osteonecrosis does not occur in long bones. The aim of this study was to compare the effects of zoledronate on long bone and cranial bone regeneration using a previously established model of non-stabilized tibial fractures and a new model of mandibular fracture repair. Contrary to tibial fractures, which heal mainly through endochondral ossification, mandibular fractures healed via endochondral and intramembranous ossification with a lesser degree of endochondral ossification compared to tibial fractures. In the tibia, ZA reduced callus and cartilage formation during the early stages of repair. In parallel, we found a delay in cartilage hypertrophy and a decrease in angiogenesis during the soft callus phase of repair. During later stages of repair, ZA delayed callus, cartilage and bone remodeling. In the mandible, ZA delayed callus, cartilage and bone remodeling in correlation with a decrease in osteoclast number during the soft and hard callus phases of repair. These results reveal a more profound impact of ZA on cartilage and bone remodeling in the mandible compared to the tibia. This may predispose mandible bone to adverse effects of ZA in disease conditions. These results also imply that therapeutic effects of ZA may need to be optimized using time and dose-specific treatments in cranial versus long bones. PMID:22359627

High-Dose Hypofractionated Radiation Therapy for Noncompressive Vertebral Metastases in Combination With Zoledronate: A Phase 1 Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pichon, Baptiste; Campion, Loïc; Delpon, Grégory

Introduction: Hypofractionated stereotactic radiation therapy (HSRT) for vertebral metastases gives good results in terms of local control but increases the risk of fracture in the treated volume. Preclinical and clinical studies have shown that zoledronate not only reduces the risk of fracture and stimulates osteoclastic remodeling but also increases the immune response and radiosensitivity. This study aimed to evaluate the tolerability and effectiveness of zoledronate in association with radiation therapy. Patients and Methods: We conducted a multicenter phase 1 study that combined HSRT (3 × 9 Gy) and zoledronate in patients with vertebral metastasis ( (NCT01219790)). The principal objective was the absence ofmore » spinal cord adverse reactions at 1 year. The secondary objectives were acute tolerability, the presentation of a bone event, local tumor control, pain control, progression-free survival, and overall survival. Results: Thirty patients (25 male, 5 female), median age 66 years, who were followed up for a median period of 19.2 months, received treatment for 49 vertebral metastases. A grade 3 acute mucosal adverse event occurred in 1 patient during the treatment and in 2 more at 1 month. No late neurologic adverse events were reported at 1 year. The mean pain scores diminished significantly at 1 month (1.35; P=.0125) and 3 months (0.77; P<.0001) compared with pain scores at study entry (2.49). Vertebral collapse in the irradiated zone occurred in 1 (2%) treated vertebra. Control of local disease was achieved in 94% of irradiated patients (3 local recurrences). Conclusion: The combination of zoledronate and HSRT in the treatment of vertebral metastasis is well tolerated and seems to reduce the rate of vertebral collapse, effectively relieve pain, and achieve good local tumor control with no late neurologic adverse effects.« less

Effect of Zoledronic Acid and Denosumab in Patients With Low Back Pain and Modic Change: A Proof-of-Principle Trial.

PubMed

Cai, Guoqi; Laslett, Laura L; Aitken, Dawn; Halliday, Andrew; Pan, Feng; Otahal, Petr; Speden, Deborah; Winzenberg, Tania M; Jones, Graeme

2018-05-01

The aim of this study was to evaluate the effect of zoledronic acid (ZA) and denosumab on low back pain (LBP) and Modic change (MC) over 6 months. Adults aged ≥40 years with significant LBP for at least 6 months duration and MC (type 1, 2, or mixed) were randomized to receive ZA (5 mg/100 mL), denosumab (60 mg), or placebo. LBP was measured monthly by visual analogue scale (VAS) and the LBP Rating Scale (RS). MC was measured from MRIs of T 12 -S 1 vertebrae at screening and 6 months. A total of 103 participants with moderate/severe LBP (mean VAS = 57 mm; mean RS = 18) and median total MC area 538 mm 2 were enrolled. Compared to placebo, LBP reduced significantly at 6 months in the ZA group for RS (-3.3; 95% CI, -5.9 to -0.7) but not VAS (-8.2; 95% CI, -18.8 to +2.4) with similar findings for denosumab (RS, -3.0; 95% CI, -5.7 to -0.3; VAS, -10.7; 95% CI, -21.7 to +0.2). There was little change in areal MC size overall and no difference between groups with the exception of denosumab in those with type 1 Modic change (-22.1 mm 2 ; 95% CI, -41.5 to -2.7). In post hoc analyses, both medications significantly reduced VAS LBP in participants with milder disc degeneration and non-neuropathic pain, and denosumab reduced VAS LBP in those with type 1 MC over 6 months, compared to placebo. Adverse events were more frequent in the ZA group. These results suggests a potential therapeutic role for ZA and denosumab in MC-associated LBP. © 2018 American Society for Bone and Mineral Research. © 2018 American Society for Bone and Mineral Research.

European Myeloma Network Guidelines for the Management of Multiple Myeloma-related Complications

PubMed Central

Terpos, Evangelos; Kleber, Martina; Engelhardt, Monika; Zweegman, Sonja; Gay, Francesca; Kastritis, Efstathios; van de Donk, Niels W.C.J.; Bruno, Benedetto; Sezer, Orhan; Broijl, Annemiek; Bringhen, Sara; Beksac, Meral; Larocca, Alessandra; Hajek, Roman; Musto, Pellegrino; Johnsen, Hans Erik; Morabito, Fortunato; Ludwig, Heinz; Cavo, Michele; Einsele, Hermann; Sonneveld, Pieter; Dimopoulos, Meletios A.; Palumbo, Antonio

2015-01-01

The European Myeloma Network provides recommendations for the management of the most common complications of multiple myeloma. Whole body low-dose computed tomography is more sensitive than conventional radiography in depicting osteolytic disease and thus we recommend it as the novel standard for the detection of lytic lesions in myeloma (grade 1A). Myeloma patients with adequate renal function and bone disease at diagnosis should be treated with zoledronic acid or pamidronate (grade 1A). Symptomatic patients without lytic lesions on conventional radiography can be treated with zoledronic acid (grade 1B), but its advantage is not clear for patients with no bone involvement on computed tomography or magnetic resonance imaging. In asymptomatic myeloma, bisphosphonates are not recommended (grade 1A). Zoledronic acid should be given continuously, but it is not clear if patients who achieve at least a very good partial response benefit from its continuous use (grade 1B). Treatment with erythropoietic-stimulating agents may be initiated in patients with persistent symptomatic anemia (hemoglobin <10g/dL) in whom other causes of anemia have been excluded (grade 1B). Erythropoietic agents should be stopped after 6–8 weeks if no adequate hemoglobin response is achieved. For renal impairment, bortezomib-based regimens are the current standard of care (grade 1A). For the management of treatment-induced peripheral neuropathy, drug modification is needed (grade 1C). Vaccination against influenza is recommended; vaccination against streptococcus pneumonia and hemophilus influenza is appropriate, but efficacy is not guaranteed due to suboptimal immune response (grade 1C). Prophylactic aciclovir (or valacyclovir) is recommended for patients receiving proteasome inhibitors, autologous or allogeneic transplantation (grade 1A). PMID:26432383

Endocrine effects of adjuvant letrozole compared with tamoxifen in hormone-responsive postmenopausal patients with early breast cancer: the HOBOE trial.

PubMed

Rossi, Emanuela; Morabito, Alessandro; Di Rella, Francesca; Esposito, Giuseppe; Gravina, Adriano; Labonia, Vincenzo; Landi, Gabriella; Nuzzo, Francesco; Pacilio, Carmen; De Maio, Ermelinda; Di Maio, Massimo; Piccirillo, Maria Carmela; De Feo, Gianfranco; D'Aiuto, Giuseppe; Botti, Gerardo; Chiodini, Paolo; Gallo, Ciro; Perrone, Francesco; de Matteis, Andrea

2009-07-01

PURPOSE We compared the endocrine effects of 6 and 12 months of adjuvant letrozole versus tamoxifen in postmenopausal patients with hormone-responsive early breast cancer within an ongoing phase III trial. PATIENTS AND METHODS Patients were randomly assigned to receive tamoxifen, letrozole, or letrozole plus zoledronic acid. Serum values of estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, dehydroepiandrosterone-sulphate (DHEA-S), progesterone, and cortisol were measured at baseline and after 6 and 12 months of treatment. For each hormone, changes from baseline at 6 and 12 months were compared between treatment groups, and differences over time for each group were analyzed. Results Hormonal data were available for 139 postmenopausal patients with a median age of 62 years, with 43 patients assigned to tamoxifen and 96 patients assigned to letrozole alone or combined with zoledronic acid. Baseline values were similar between the two groups for all hormones. Many significant changes were observed between drugs and for each drug over time. Namely, three hormones seemed significantly affected by one drug only: estradiol that decreased and progesterone that increased with letrozole and cortisol that increased with tamoxifen. Both drugs affected FSH (decreasing with tamoxifen and slightly increasing with letrozole), LH (decreasing more with tamoxifen than with letrozole), testosterone (slightly increasing with letrozole but not enough to differ from tamoxifen), and DHEA-S (increasing with both drugs but not differently between them). Zoledronic acid did not have significant impact on hormonal levels. CONCLUSION Adjuvant letrozole and tamoxifen result in significantly distinct endocrine effects. Such differences can explain the higher efficacy of letrozole as compared with tamoxifen.

FemZone trial: a randomized phase II trial comparing neoadjuvant letrozole and zoledronic acid with letrozole in primary breast cancer patients

PubMed Central

2014-01-01

Background The objective of this prospectively randomized phase II trial (Trial registration: EUCTR2004-004007-37-DE) was to compare the clinical response of primary breast cancer patients to neoadjuvant therapy with letrozole alone (LET) or letrozole and zoledronic acid (LET + ZOL). Methods Patients were randomly assigned to receive either LET 2.5 mg/day (n = 79) or the combination of LET 2.5 mg/day and a total of seven infusions of ZOL 4 mg every 4 weeks (n = 89) for 6 months. Primary endpoint was clinical response rate as assessed by mammogram readings. The study was terminated prematurely due to insufficient recruitment. We report here on an exploratory analysis of this data. Results Central assessment of tumor sizes during the treatment period was available for 131 patients (66 LET, 65 LET + ZOL). Clinical responses (complete or partial) were seen in 54.5% (95% CI: 41.8-66.9) of the patients in the LET arm and 69.2% (95% CI: 56.6-80.1) of those in the LET + ZOL arm (P = 0.106). A multivariate model showed an OR of 1.72 (95% CI: 0.83-3.59) for the experimental arm. Conclusion No increase in the clinical response rate was observed with the addition of ZOL to a neoadjuvant treatment regimen with LET. However a trend towards a better reponse in the LET + ZOL arm could be observed. This trend is consistent with previous studies that have investigated the addition of ZOL to chemotherapy, and it may support the evidence for a direct antitumor action of zoledronic acid. PMID:24499441

Osteonecrosis of the jaw: effect of bisphosphonate type, local concentration, and acidic milieu on the pathomechanism.

PubMed

Otto, Sven; Pautke, Christoph; Opelz, Christine; Westphal, Ines; Drosse, Inga; Schwager, Joanna; Bauss, Frieder; Ehrenfeld, Michael; Schieker, Matthias

2010-11-01

Osteonecrosis of the jaw has been reported in patients receiving high doses of intravenous nitrogen-containing bisphosphonates (N-BPs) because of malignant disease. The exact pathomechanisms have been elusive and questions of paramount importance remain unanswered. Recent studies have indicated toxic effects of bisphosphonates on different cell types, apart from osteoclast inhibition. Multipotent stem cells play an important role in the processes of wound healing and bone regeneration, which seem to be especially impaired in the jaws of patients receiving high doses of N-BPs. Therefore, the aim of the present study was to investigate the effects of different bisphosphonate derivatives and dose levels combined with varying pH levels on the mesenchymal stem cells in vitro. The effect of 2 N-BPs (zoledronate and ibandronate) and 1 non-N-BP (clodronate) on immortalized mesenchymal stem cells was tested at different concentrations, reflecting 1, 3, and 6 months and 1, 3, 5, and 10 years of exposure to standard oncology doses of the 2 N-BPs and equimolar concentrations of clodronate at different pH values (7.4, 7.0, 6.7, and 6.3). Cell viability and activity were analyzed using a WST assay. Cell motility was investigated using scratch wound assays and visualized using time-lapse microscopy. Both types of bisphosphonates revealed remarkable differences. Zoledronate and ibandronate showed a dose- and pH-dependent cellular toxicity. Increasing concentrations of both N-BPs and an acidic milieu led to a significant decrease in cell viability and activity (P < .01), with more pronounced effects for zoledronate. Equimolar concentrations of clodronate did not affect the cell survival or activity significantly, apart from the effect of pH reduction itself, which was also detectable in the patients in the control group who did not receive bisphosphonates. Our results have shown that high concentrations of N-BPs and a local acidic milieu, which is commonly present in infections of the jaw, might play a key role in the pathogenesis of osteonecrosis of the jaw in patients receiving high doses of N-BPs for malignant diseases. Also the potency of N-BPs might be different, suggesting a greater risk of osteonecrosis of the jaw with zoledronate. Copyright © 2010 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Zoledronic acid induces dose-dependent increase of antigen-specific CD8 T-cell responses in combination with peptide/poly-IC vaccine.

PubMed

Park, Hye-Mi; Cho, Hyun-Il; Shin, Chang-Ae; Shon, Hyun-Jung; Kim, Tai-Gyu

2016-03-04

Zoledronic acid (ZA) is used for treating osteoporosis and for preventing skeletal fractures in cancer patients suffering from myeloma and prostate cancer. It is also reported to directly induce cancer cell apoptosis and indirectly modulate T-cell immune response as an antitumor agent. In this study, the effect of ZA following peptide/polyinosinic-polycytidylic acid (poly-IC) vaccination was investigated in a murine tumor model. The combination of ZA with peptide/poly-IC vaccine showed a synergistic effect on the induction of antigen-specific CD8 T-cell response. Three consecutive intravenous administrations of ZA was defined to induce the highest CD8 T-cell response. Further, total splenocyte counts and antigen-specific CD8 T-cell response gradually increased depending on the dose of ZA. In tumor-bearing mice, ZA showed a dose-dependent decrease of growth and prolonged survival. Treatment with ZA only decreased the number of CD11b(+)Gr1(+) myeloid cells in blood. Our results demonstrate that the use of ZA could improve antitumor immune responses induced by the peptide/poly-IC vaccine. Copyright © 2016 Elsevier Ltd. All rights reserved.

Skeletal accumulation of fluorescently tagged zoledronate is higher in animals with early stage chronic kidney disease.

PubMed

Swallow, E A; Aref, M W; Chen, N; Byiringiro, I; Hammond, M A; McCarthy, B P; Territo, P R; Kamocka, M M; Winfree, S; Dunn, K W; Moe, S M; Allen, M R

2018-06-11

This work examines the skeletal accumulation of fluorescently tagged zoledronate in an animal model of chronic kidney disease. The results show higher accumulation in 24-h post-dose animals with lower kidney function due to greater amounts of binding at individual surfaces. Chronic kidney disease (CKD) patients suffer from increased rates of skeletal-related mortality from changes driven by biochemical abnormalities. Bisphosphonates are commonly used in reducing fracture risk in a variety of diseases, yet their use is not recommended in advanced stages of CKD. This study aimed to characterize the accumulation of a single dose of fluorescently tagged zoledronate (FAM-ZOL) in the setting of reduced kidney function. At 25 weeks of age, FAM-ZOL was administered to normal and CKD rats. Twenty-four hours later, multiple bones were collected and assessed using bulk fluorescence imaging, two-photon imaging, and dynamic histomorphometry. CKD animals had significantly higher levels of FAM-ZOL accumulation in the proximal tibia, radius, and ulna, but not in lumbar vertebral body or mandible, based on multiple measurement modalities. Although a majority of trabecular bone surfaces were covered with FAM-ZOL in both normal and CKD animals, the latter had significantly higher levels of fluorescence per unit bone surface in the proximal tibia. These results provide new data regarding how reduced kidney function affects drug accumulation in rat bone.

A randomized phase II trial evaluating different schedules of zoledronic acid on bone mineral density in patients with prostate cancer beginning androgen deprivation therapy.

PubMed

Lang, Joshua M; Wallace, Marianne; Becker, Jordan T; Eickhoff, Jens C; Buehring, Bjoern; Binkley, Neil; Staab, Mary Jane; Wilding, George; Liu, Glenn; Malkovsky, Miroslav; McNeel, Douglas G

2013-12-01

To assess the effects of timing and schedule of zoledronic acid (ZA) administration on bone mineral density (BMD) in patients beginning androgen deprivation therapy (ADT) for the treatment of recurrent prostate cancer. In this randomized, 3-arm trial, we evaluated changes in BMD after 3 different ZA administration schedules in men with recurrent prostate cancer who were beginning ADT. Forty-four patients were enrolled and randomized to receive a single dose of ZA given 1 week before beginning ADT (arm 1), a single dose of ZA given 6 months after beginning ADT (arm 2), or monthly administration of ZA starting 6 months after beginning ADT, for a total of 6 doses (arm 3). Patients who received ZA before ADT had a significant improvement in BMD at the total proximal femur and trochanter after 6 months compared with the other groups. In addition, only patients in the arm that received multiple doses improved lumbar spine BMD while on ADT, with these findings persisting to 24 months. However, this group also experienced more grade 1 adverse events. Analysis of these data suggests that ZA administration before initiation of ADT was superior to treatment 6 months after starting ADT in maintaining BMD. In addition, monthly ZA administration can increase BMD above baseline but is associated with more adverse events. Further study is needed to examine whether the timing and frequency of ZA therapy in patients on ADT can reduce fracture risk. Copyright © 2013 Elsevier Inc. All rights reserved.

The role of vitamin E in the prevention of zoledronic acid-induced nephrotoxicity in rats: a light and electron microscopy study.

PubMed

Sert, İbrahim Unal; Kilic, Ozcan; Akand, Murat; Saglik, Lutfi; Avunduk, Mustafa Cihat; Erdemli, Esra

2018-03-01

Bisphosphonates are widely used in metastatic cancer such as prostate and breast cancer, and their nephrotoxic effects have been established previously. In this study we aimed to evaluate both the nephrotoxic effects of zoledronic acid (ZA) and the protective effects of vitamin E (Vit-E) on this process under light and electron microscopy. A total of 30 male Sprague-Dawley rats were divided into 3 groups. The first group constituted the control group. The second group was given i.v. ZA of 3 mg/kg once every 3 weeks for 12 weeks from the tail vein. The third group received the same dosage of ZA with an additional i.m . injection of 15 mg Vit-E every week for 12 weeks. Tissues were taken 4 days after the last dose of ZA for histopathological and ultrastructural evaluation. Paller score, tubular epithelial thickness and basal membrane thickness were calculated for each group. For group 2, the p -values are all < 0.001 for Paller score, epitelial thickness, and basal membrane thickness. For group 3 (ZA + Vit. E), the p -values are < 0.001 for Paller score, 0.996 for epitelial thickness, and < 0.001 basal membrane thickness. Significant differences were also observed in ultrastructural changes for group 2. However, adding Vit-E to ZA administration reversed all the histopathological changes to some degree, with statistical significance. Administration of ZA had nephrotoxic effects on rat kidney observed under both light and electron microscopy. Concomitant administration of Vit-E significantly reduces toxic histopathological effects of ZA.

Osteoclasts but not osteoblasts are affected by a calcified surface treated with zoledronic acid in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schindeler, Aaron; Little, David G.; Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney

2005-12-16

Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption. Recent interest has centered on the effects of bisphosphonates on osteoblasts. Chronic dosing of osteoblasts with solubilized bisphosphonates has been reported to enhance osteogenesis and mineralization in vitro. However, this methodology poorly reflects the in vivo situation, where free bisphosphonate becomes rapidly bound to mineralized bone surfaces. To establish a more clinically relevant cell culture model, we cultured bone cells on calcium phosphate coated quartz discs pre-treated with the potent nitrogen-containing bisphosphonate, zoledronic acid (ZA). Binding studies utilizing [{sup 14}C]-labeled ZA confirmed that the bisphosphonate bound in a concentration-dependent manner over themore » 1-50 {mu}M dose range. When grown on ZA-treated discs, the viability of bone-marrow derived osteoclasts was greatly reduced, while the viability and mineralization of the osteoblastic MC3T3-E1 cell line were largely unaffected. This suggests that only bone resorbing cells are affected by bound bisphosphonate. However, this system does not account for transient exposure to unbound bisphosphonate in the hours following a clinical dosing. To model this event, we transiently treated osteoblasts with ZA in the absence of a calcified surface. Osteoblasts proved highly resistant to all transitory treatment regimes, even when utilizing ZA concentrations that prevented mineralization and/or induced cell death when dosed chronically. This study represents a pharmacologically more relevant approach to modeling bisphosphonate treatment on cultured bone cells and implies that bisphosphonate therapies may not directly affect osteoblasts at bone surfaces.« less

Favorable therapeutic response of osteoporosis patients to treatment with intravenous zoledronate compared with oral alendronate

PubMed Central

Al-Bogami, Mohammed M.; Alkhorayef, Mohammed A.; Bystrom, Jonas; Akanle, Olufunso A.; Al-Adhoubi, Nasra K.; Jawad, Ali S.; Mageed, Rizgar A.

2015-01-01

Objectives: To evaluate the efficacy of orally-administered alendronate compared with intravenously-administered zoledronate. Methods: This prospective study was carried out at Barts Health HNS Trust between April 2010 and March 2012. This study compares changes in bone mineral density (BMD) in 234 patients treated with 2 bisphosphonates: alendronate taken orally, and zoledronate administered intravenously. One hundred and eighteen patients received alendronate at 70 mg/week, while 116 patients received zoledronate once annually. Dual energy x-ray absorptiometry was used to measure BMD of the left hip and anterior-posterior spine (lumbar L1-L4) skeletal sites at baseline, and at one-, and 2-years post-treatment. Results: This study provides evidence that lumbar spine BMD increased by 3.6% in patients receiving alendronate, and 5.7% in patients receiving zoledronate after 2 years compared with baseline values (p=0.0001 for both). Total hip BMD decreased in patients treated with alendronate by 0.4% but increased in patients receiving zoledronate by 0.8% (p=0.0001). Conclusion: This study provides evidence that zoledronate is more effective than alendronate in treating patients with osteoporosis and with no gastrointestinal (GI) serious side effects. Furthermore, zoledronate appears to have the added advantage of a better safety profile in patients suffering from GI intolerance of oral bisphosphonates. PMID:26593163

Zoledronic acid inhibits vasculogenic mimicry in murine osteosarcoma cell line in vitro.

PubMed

Fu, Dehao; He, Xianfeng; Yang, Shuhua; Xu, Weihua; Lin, Tao; Feng, Xiaobo

2011-06-30

To study the effects of zoledronic acid (ZA) on the vasculogenic mimicry of osteosarcoma cells in vitro. A Three-dimensional culture of LM8 osteosarcoma cells on a type I collagen matrix was used to investigate whether osteosarcoma cells can develop vasculogenic mimicry, and to determine the effects of ZA on this process. In addition, the cellular ultrastructural changes were observed using scanning electron microscopy and laser confocal microscopy. The effects of ZA on the translocation of RhoA protein from the cytosol to the membrane in LM8 cells were measured via immunoblotting. ZA inhibited the development of vasculogenic mimicry by the LM8 osteosarcoma cells, decreased microvilli formation on the cell surface, and disrupted the F-actin cytoskeleton. ZA prevented translocation of RhoA protein from the cytosol to the membrane in LM8 cells. ZA can impair RhoA membrane localization in LM8 cells, causing obvious changes in the ultrastructure of osteosarcoma cells and induce cell apoptosis, which may be one of the underlying mechanisms by which the agent inhibits the development of vasculogenic mimicry by the LM8 cells.

The IL-6 receptor super-antagonist Sant7 enhances antiproliferative and apoptotic effects induced by dexamethasone and zoledronic acid on multiple myeloma cells.

PubMed

Tassone, Pierfrancesco; Galea, Eulalia; Forciniti, Samantha; Tagliaferri, Pierosandro; Venuta, Salvatore

2002-10-01

Interleukin-6 (IL-6) is the major growth and survival factor for multiple myeloma (MM), and has been shown to protect MM cells from apoptosis induced by a variety of agents. IL-6 receptor antagonists, which prevent the assembly of functional IL-6 receptor complexes, inhibit cell proliferation and induce apoptosis in MM cells. We have investigated whether the IL-6 receptor super-antagonist Sant7 might enhance the antiproliferative and apoptotic effects induced by the combination of dexamethasone (Dex) and zoledronic acid (Zln) on human MM cell lines and primary cells from MM patients. Here we show that each of these compounds individually induced detectable antiproliferative effects on MM cells. Sant7 significantly enhanced growth inhibition and apoptosis induced by Dex and Zln on both MM cell lines and primary MM cells. These results indicate that overcoming IL-6 mediated cell resistance by Sant7 potentiates the effect of glucocorticoides and bisphosphonates on MM cell growth and survival, providing a rationale for therapies including IL-6 antagonists in MM.

The anti-tumour effects of zoledronic acid

PubMed Central

Zekri, Jamal; Mansour, Maged; Karim, Syed Mustafa

2014-01-01

Bone is the most common site for metastasis in patients with solid tumours. Bisphosphonates are an effective treatment for preventing skeletal related events and preserving quality of life in these patients. Zoledronic acid (ZA) is the most potent osteoclast inhibitor and is licensed for the treatment of bone metastases. Clodronate and pamidronate are also licensed for this indication. In addition, ZA has been demonstrated to exhibit antitumour effect. Direct and indirect mechanisms of anti-tumour effect have been postulated and at many times proven. Evidence exists that ZA antitumour effect is mediated through inhibition of tumour cells proliferation, induction of apoptosis, synergistic/additive to inhibitory effect of cytotoxic agents, inhibition of angiogenesis, decrease tumour cells adhesion to bone, decrease tumour cells invasion and migration, disorganization of cell cytoskeleton and activation of specific cellular antitumour immune response. There is also clinical evidence from clinical trials that ZA improved long term survival outcome in cancer patients with and without bone metastases. In this review we highlight the preclinical and clinical studies investigating the antitumour effect of bisphosphonates with particular reference to ZA. PMID:26909294

Pregnancy and Lactation-Associated Osteoporosis: Bone Histomorphometric Analysis and Response to Treatment with Zoledronic Acid.

PubMed

Grizzo, Felipe Merchan Ferraz; da Silva Martins, Janaina; Pinheiro, Marcelo M; Jorgetti, Vanda; Carvalho, Maria Dalva Barros; Pelloso, Sandra Marisa

2015-10-01

Pregnancy and lactation-associated osteoporosis (PAO) is a rare condition with little known pathophysiology. Most cases are diagnosed in the third trimester of pregnancy or in the first weeks postpartum, particularly in first pregnancies. Vertebral fractures are most commonly observed and characterised by prolonged severe pain, functional limitations and a loss of height. Measurements of bone mineral density and biochemical markers of bone remodelling are the clinical methods most commonly used for the management of these patients. However, a bone biopsy with histomorphometric analysis has been considered to be the gold-standard. Few studies have evaluated the histomorphometry in patients with this clinical condition and none of them performed the procedure at the beginning of the clinical assessment. In this study, we report a case of PAO in a 31-year-old postpartum patient who had undergone a twin pregnancy. We describe the clinical, laboratory tests and imaging features. Bone histomorphometry showed a high resorption rate and excellent evolution after 1 year of treatment with intravenous zoledronic acid. Our data suggest that osteoclastogenesis plays a central role in the pathophysiological processes of this disease.

Local delivery of zoledronate from a poly (D,L-lactide)-Coating increases fixation of press-fit implants.

PubMed

Jakobsen, Thomas; Bechtold, Joan E; Søballe, Kjeld; Jensen, Thomas; Greiner, Stefan; Vestermark, Marianne T; Baas, Jørgen

2016-01-01

Early secure fixation of total joint replacements is crucial for long-term survival. Antiresorptive agents such as bisphosphonates have been shown to increase implant fixation. We investigated whether local delivery of zoledronate from poly-D, L-lactide (PDLLA)-coated implants could improve implant fixation and osseointegration. Experimental titanium implants were bilaterally inserted press-fit into the proximal tibiae of 10 dogs. On one side the implant was coated with PDLLA containing zoledronate. The contralateral implant was uncoated and used as control. Observation period was 12 weeks. Implant fixation was evaluated with histomorphometry and biomechanical push-out test. We found an approximately twofold increase in all biomechanical parameters when comparing data from the zoledronate group with their respective controls. Histomorphometry showed increased amount of preserved bone and increased bone formation around the zoledronate implants. This study indicates that local delivery of zoledronate from a PDDLA coating has the potential to increase implant fixation. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

The impact of zoledronic acid on regenerate and native bone after consolidation and removal of the external fixator: an animal model study.

PubMed

Saghieh, Said; Khoury, Nabil J; Tawil, Ayman; Masrouha, Karim Z; Musallam, Khaled M; Khalaf, Kinda; Dosh, Laura; Jaouhari, Rosemarie Reich; Birjawi, Ghina; El-Hajj-Fuleihan, Ghada

2010-02-01

We investigated the role of zoledronic acid on the regenerate and native bone after consolidation and removal of the external fixator in a rabbit model of distraction osteogenesis using 28 New Zealand white rabbits. The rabbits were randomly distributed into two groups. The first group received three doses of zoledronic acid (ZA) 0.1 mg/kg subcutaneously at weekly intervals while the second group received injections of sterile saline. Distraction started on day 7 at a rate of 0.8 mm/day for 12 days. At week 3 the average lengthening, regenerate density, and regenerate continuity were comparable between the two groups. At week 11 the regenerate in the treated group had a significant increase in Bone Mineral Density (BMD) and Bone Mineral Content (BMC) compared to the placebo group. On axial compression, the regenerate showed an increase in the peak load and a higher modulus of elasticity in the treated group. At 6 months, radiographs demonstrated signs of osteopenia of the proximal metaphysis in the control group, and failure of new bone formation around the pin sites in the treated group. BMC and BMD value differences between the two groups were not statistically significant. Histologically, there was persistence of more bone trabeculae in the medullary canal of the regenerate with the persistence of the pin-holes in the treated group. Mechanically, the regenerates in the treated group remain stronger in resisting the axial compression. The proximal fragment in the treated group exhibited a statistically significant decrease in the peak load, toughness and efail %. In conclusion, bisphosphonate-treated rabbits have a stronger regenerate during distraction, and directly after removal of the fixator. They do not develop disuse osteopenia in their lengthened tibia. This treatment may shorten the time in the external fixator and prevent fragility fractures in the treated extremity. However, its long-term safety has not yet been established. (c) 2009 Elsevier Inc. All rights reserved.

Effect of Zoledronate on Oral Wound Healing in Rats

PubMed Central

Yamashita, Junro; Koi, Kiyono; Yang, Dong-Ye; McCauley, Laurie K.

2010-01-01

Purpose Osteonecrosis of the jaw (ONJ) is a growing concern in patients who receive bisphosphonates which target osteoclasts. Since osteoclasts play multifunctional roles in the bone marrow, their suppression likely affects bone homeostasis and alters wound healing of the jaw. The objective was to delineate the impact of osteoclast suppression in the bone marrow and wound healing of the jaw. Experimental Design Zoledronate was administered to senile rats for 14 weeks. A portion of the gingiva was removed to denude the palatal bone. Gene expression in the bone marrow was assessed and histologic sections analyzed to determine the wound healing status. Results Angiogenesis-related genes, CD31 and VEGF-A, were not altered by zoledronate. VEGF-C, which plays a role in lymphangiogenesis, was suppressed. There was a decrease in gene expression of Tcirg1 and MMP-13. Bone denudation caused extensive osteocyte death indicative of bone necrosis. In zoledronate-treated rats, the necrotic bone was retained in the wound while, in controls, osteoclastic resorption of the necrotic bone was prominent. Even though large necrotic bone areas existed in zoledronate-treated rats, overlaying soft tissue healed clinically. Immunohistochemical staining showed rich vascularity in the overlaying soft tissue. Conclusions Zoledronate therapy impacts bone marrow by suppressing genes associated with lymphoangiogenesis and tissue remodeling, such as VEGF-C and MMP-13. Zoledronate was associated with impaired osseous wound healing but had no effect on angiogenic markers in the bone marrow or soft tissue wound healing. Zoledronate selectively blunts healing in bone but does not effect soft tissue healing in the oral cavity. PMID:21149614

Zoledronate promotes bone formation by blocking osteocyte-osteoblast communication during bone defect healing.

PubMed

Cui, Pingping; Liu, Hongrui; Sun, Jing; Amizuka, Norio; Sun, Qinfeng; Li, Minqi

2018-01-01

Nitrogen-containing bisphosphonates (N-BPs) are potent antiresorptive drugs and their actions on osteoclasts have been studied extensively. Recent studies have suggested that N-BPs also target bone-forming cells. However, the precise mechanism of N-BPs in osteoblasts is paradoxical, and the specific role of osteocytes is worthy of in-depth study. Here, we investigated the cellular mechanisms of N-BPs regulating bone defect healing by zoledronate (ZA). Bone histomorphometry confirmed an increase in new bone formation by systemic ZA administration. ZA induced more alkaline phosphatase-positive osteoblasts and tartrate-resistant acid phosphatase-positive osteoclasts residing on the bone surface. Inexplicably, ZA increased SOST expression in osteocytes embedded in the bone matrix, which was not compatible with the intense osteoblast activity on the bone surface. ZA induced heterogeneous osteocytes and disturbed the distribution of the osteocytic-canalicular system (OLCS). Furthermore, according to the degree of OLCS regularity, dentin matrix protein 1 reactivity had accumulated around osteocytes in the ZA group, but it was distributed evenly in the OLCS of the control group. The control group showed a dense array of the gap junction protein connexin 43. However, connexin 43 was extremely sparse after ZA administration. In summary, ZA treatment reduces gap junction connections and blocks cellular communication between osteocytes and osteoblasts. Retaining SOST expression in osteocytes leads to activation of the Wnt signaling pathway and subsequent bone formation.

Sclerostin Blockade and Zoledronic Acid Improve Bone Mass and Strength in Male Mice With Exogenous Hyperthyroidism.

PubMed

Tsourdi, Elena; Lademann, Franziska; Ominsky, Michael S; Rijntjes, Eddy; Köhrle, Josef; Misof, Barbara M; Roschger, Paul; Klaushofer, Klaus; Hofbauer, Lorenz C; Rauner, Martina

2017-11-01

Hyperthyroidism in mice is associated with low bone mass, high bone turnover, and high concentrations of sclerostin, a potent Wnt inhibitor. Here, we explored the effects of either increasing bone formation with sclerostin antibodies (Scl-Ab) or reducing bone turnover with bisphosphonates on bone mass and strength in hyperthyroid mice. Twelve-week-old C57BL/6 male mice were rendered hyperthyroid using l-thyroxine (T4; 1.2 µg/mL added to the drinking water) and treated with 20 mg/kg Scl-Ab twice weekly or 100 µg/kg zoledronic acid (ZOL) once weekly or phosphate-buffered saline for 4 weeks. Hyperthyroid mice displayed a lower trabecular bone volume at the spine (-42%, P < 0.05) and the distal femur (-55%, P < 0.05) compared with euthyroid controls. Scl-Ab and ZOL treatment of hyperthyroid mice increased trabecular bone volume at the spine by threefold and twofold, respectively. Serum bone formation and resorption markers were increased in hyperthyroid mice and suppressed by treatment with ZOL but not Scl-Ab. Trabecular bone stiffness at the lumbar vertebra was 63% lower in hyperthyroid mice (P < 0.05) and was increased fourfold by Sci-Ab (P < 0.001) and threefold by ZOL treatment (P < 0.01). Bone strength based on ultimate load, which was 10% lower in hyperthyroidism, was increased by Scl-Ab by 71% and ZOL by 22% (both P < 0.001). Increased proportion of low mineralized bone seen in hyperthyroid mice was restored by treatment with Scl-Ab and ZOL. Thus, bone-forming and antiresorptive drugs prevent bone loss in hyperthyroid mice via different mechanisms. Copyright © 2017 Endocrine Society.

Toxicity of a dental adhesive compared with ionizing radiation and zoledronic acid.

PubMed

Alcaraz, Miguel; Olivares, Amparo; Achel, Daniel-Giyngiri; García-Cruz, Emilio; Fondevilla-Soler, Adriana; Canteras-Jordana, Manuel

2015-07-01

To determine the toxicity of aqueous dilutions of a universal self-priming dental adhesive (DA) and comparing these with those elicited by exposure to ionizing radiation (IR), Zoledronic acid (Z) treatment and the synergic effects of the combined treatment with IR+Z. The genotoxic effect of DA was determined by the increase in the frequency of micronuclei in cytokinesis-blocked in cultured human lymphocytes before and after exposure to 2Gy of X-rays. The cytotoxic effect was studied by using the MTT cell viability test in normal prostate cell lines (PNT2) after exposure to different X-ray doses (0Gy-20Gy). The cell lines divided into different groups and treated with different test substances: DA in presence of O2, DA in absence of O2, Z-treated and control. An in vitro dose-dependent and time-dependent cytotoxic effect of DA, Z and IR on PNT2 cells (p>0.001) was demonstrated. DA without-O2, following the recommendations of manufacturers, had a more pronounced effect of increasing cell death than DA with-O2 (p<0.001). In the genotoxicity assay, DA at 25% of its original concentration significantly increased chromosome damage (p<0.001). The samples studied were found to be toxic, and the samples photo-polymerized in absence of O2 showed a bigger cytotoxic effect comparable to the additive toxic effect showed by the combined treatment of IR+Z. Additional effort should be carried out to develop adhesives, which would reduce the release of hazardous substances; since toxic effects are similar to that reported by other agents whose clinical use is controlled by the health authorities.

Zoledronic acid at subtoxic dose extends osteoblastic stage span of primary human osteoblasts.

PubMed

Zara, Susi; De Colli, Marianna; di Giacomo, Viviana; Zizzari, Vincenzo Luca; Di Nisio, Chiara; Di Tore, Umberto; Salini, Vincenzo; Gallorini, Marialucia; Tetè, Stefano; Cataldi, Amelia

2015-04-01

This study aimed to check the effect of zoledronic acid (ZA) at subtoxic dose on human osteoblasts (HOs) in terms of cell viability, apoptosis occurrence, and differentiation induction. ZA belongs to the family of bisphosphonates (BPs), largely used in the clinical practice for the treatment of bone diseases, often associated with jaw osteonecrosis onset. Their pharmacological action consists in the direct block of the osteoclast-mediated bone resorption along with indirect action on osteoblasts. HOs were treated choosing the highest limit concentration (10(-5) M) which does not induce toxic effects. Live/dead staining, flow cytometry, mitochondrial membrane potential assay, osteocalcin western blotting, gp38 RT-PCR, collagen type I, PGE2, and IL-6 ELISA assays were performed. Similar viability level between control and ZA-treated samples is found along with no significant increase of apoptotic and necrotic cells in ZA-treated sample. To establish if an early apoptotic pathway was triggered, Bax expression and mitochondrial membrane potential were evaluated finding a higher protein expression in control sample and a good integrity of mitochondrial membrane in both experimental points. Type I collagen secretion and alkaline phosphatase (ALP) activity appear increased in ZA-treated sample, osteocalcin expression level is reduced in ZA-treated cells, whereas no modifications of gp38 mRNA level are evidenced. No statistical differences are identified in PGE2 secretion level whereas IL-6 secretion is lower in ZA-treated HOs with respect to control ones. These results highlight that ZA, delaying the osteoblastic differentiation process versus the osteocytic lineage, strengthens its pharmacological activity enhancing bone density. The knowledge of ZA effects on osteoblasts at subtoxic dose allows to improve therapeutic protocols in order to strengthen drug pharmacological activity through a combined action on both osteoclastic and osteoblastic cells.

Zoledronic acid in metastatic osteosarcoma: encouraging progression free survival in four consecutive patients.

PubMed

Conry, Robert M; Rodriguez, Michael G; Pressey, Joseph G

2016-01-01

Zoledronic acid (ZA) is a third-generation bisphosphonate in widespread clinical use to reduce pain and skeletal events in patients from a variety of malignancies with bone metastases. Pre-clinical studies indicate that ZA inhibits osteosarcoma through direct anti-proliferative effects, immune activation and anti-angiogenic activity. The purpose of this study was to evaluate the antitumor efficacy of ZA at standard dose until progression in patients with stage IV osteosarcoma lacking a standard of care treatment option proven to influence survival. Researchers retrospectively reviewed medical records of all patients at our institution with high-grade osteosarcoma presumed to be incurable due to metastases progressive after primary combination chemotherapy who received single agent ZA in an effort to delay progression. In our four-patient cohort following initiation of ZA, the median progression-free survival was 19 months, and median overall survival was 56+ months. Two of four patients have remained progression-free since starting ZA. The other two initially progressed after 18-20 months on ZA followed by metastasectomy of lung or dural metastases and further stability for over a year following resumption of ZA. After a 20-month progression-free interval on ZA alone, one patient had partial response following addition of pazopanib to ZA that likely contributed to long term disease control. The four patients experienced no significant toxicities despite protracted dosing of ZA for up to 5 years, and none have required chemotherapy since beginning ZA. Single agent ZA was associated with encouraging progression-free survival in four consecutive patients with metastatic osteosarcoma. Prospective trials of single agent ZA are warranted as protracted maintenance therapy in surgically incurable osteosarcoma relapsed or refractory to first line combination chemotherapy with radiographically measurable metastases.

Zoledronic acid prevents the tumor-promoting effects of mesenchymal stem cells via MCP-1 dependent recruitment of macrophages.

PubMed

Jia, Xiao-Hua; Du, Yang; Mao, Duo; Wang, Zhong-Liang; He, Zhen-Qiang; Qiu, Jing-Dan; Ma, Xi-Bo; Shang, Wen-Ting; Ding, Dan; Tian, Jie

2015-09-22

Zoledronic acid (ZA) has been tested in clinical trials as an additive therapy for early-stage breast cancer. However, the mechanism by which ZA exerts its antitumor activity is still unclear. The aim of this study is to investigate whether the prevention of tumor growth by ZA is through regulating the mesenchymal stem cells (MSC)-monocyte chemotactic protein 1 (MCP-1)-macrophages axis in the tumor microenvironment. To address this issue, MDA-MB-231-FLUC human breast cancer cells were cultured and injected either alone, or coupled with MSC into the mammary fat pads of nude mice. MSC were treated with either ZA or untreated. Tumor growth was determined by using an in vivo bioluminescence imaging (BLI) and the tumor-associated macrophages (TAMs) in tumor tissues were immunohistochemically analyzed by using CD206 antibody. The effects of ZA on the cytokine related gene expression of MSC were assessed by using real-time PCR. In this study, we found that ZA-treated mice showed a significant delay in tumor growth. In addition, our data revealed that ZA weakened the ability of MSC to promote tumor growth by impairing TAMs recruitment and tumor vascularization. Furthermore, it was found that ZA decreased MCP-1 expression of MSC, and therefore reduced the recruitment of TAMs to the tumor sites and hence inhibited the tumor growth. Altogether, our study demonstrated ZA can prevent the tumor-promoting effects of MSC. The antitumor effects of ZA were caused by decreasing the MCP-1 expression of MSC, which further decreased the infiltration of TAMs into tumor sites, and therefore inhibited the tumor growth.

Zoledronic acid induces micronuclei formation, mitochondrial-mediated apoptosis and cytostasis in kidney cells.

PubMed

Singireesu, Soma Shiva Nageswara Rao; Mondal, Sujan Kumar; Yerramsetty, Suresh; Misra, Sunil

2018-06-15

Zoledronic acid (ZA), a FDA approved drug has used widely in the treatment of bone metastasis complications, has been linked to renal toxicity with unclear mechanism. The present study is aimed at investigating the genotoxic and cytotoxic effects of ZA in renal epithelial cells. The genotoxic effect of ZA in Vero and MDCK cells determined by cytokinesis block micronucleus (CBMN) assay. The cytotoxic effect assessed by analysing cell cycle profile, cell death and mitochondrial membrane potential by flow cytometry using propidium iodide, AnnexinV-FITC/PI and JC1 dye staining, respectively, BAX and Bcl-2 expression by Western blotting and caspase activity by spectrofluorimetry. The cytotoxic effect of ZA based on MTT assay revealed variable sensitivities of Vero and MDCK cells, with IC 50 values of 7.41 and 109.58 μM, respectively. The CBMN assay has shown prominent dose-dependent (IC 10-50 ) induction of micronuclei formation in both cells, indicating ZA's clastogenic and aneugenic potential. Further, the ZA treatment led the cells to apoptosis, evident from dose-dependent increase in the percentage of cells in subG1 phase and display of membranous phosphatidylserine translocation. Studies also confirmed apoptosis through mitochondria, evident from the prominent increase in BAX/Bcl-2 ratio, mitochondrial membrane depolarization and caspase-3/7 activity. In addition, ZA reduces cytokinetic activity of renal cells, evident from dose-wise lowered replicative indices. The study depict ZA's potential genotoxic effect along with cytotoxic effect in renal epithelial cells, could be key factors for the development of renal complications associated with it, which prompts renal safety measures in lieu with ZA usage. Copyright © 2018 Elsevier Inc. All rights reserved.

78 FR 54842 - Medicare and Medicaid Programs: Hospital Outpatient Prospective Payment and Ambulatory Surgical...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-06

..., ado- K2 $29.40 trastuzumab emtansine, 1 mg. C9736 Laparoscopy, G2 2,010.57 surgical, radiofrequency... Injection, K2 545.44 Doxorubicin Hydrochloride, Liposomal, Not Otherwise Specified, 10 mg. Q2051 Injection, K2 196.42 Zoledronic Acid, Not Otherwise Specified, 1 mg. * Note: HCPCS code Q2050 replaced code...

Geranylgeranyl diphosphate synthase inhibition induces apoptosis that is dependent upon GGPP depletion, ERK phosphorylation and caspase activation.

PubMed

Agabiti, Sherry S; Li, Jin; Wiemer, Andrew J

2017-03-16

Bisphosphonates are diphosphate analogs that inhibit the intermediate enzymes of the mevalonate pathway. Here, we compared the effects of a farnesyl diphosphate synthase inhibitor, zoledronate, and a geranylgeranyl diphosphate synthase (GGDPS) inhibitor, digeranyl bisphosphonate (DGBP), on lymphocytic leukemia cell proliferation and apoptosis. Both zoledronate and DGBP inhibited proliferation with DGBP doing so more potently. DGBP was markedly less toxic than zoledronate toward the viability of healthy human peripheral blood mononuclear cells. Addition of GGPP, but not farnesyl diphosphate (FPP), prevented the anti-proliferative effects of DGBP. Both GGPP and FPP partially rescued the effects of zoledronate. Co-treatment with DGBP and zoledronate was antagonistic. To further assess the effects of the bisphosphonates, we analyzed annexin V and propidium iodide staining via flow cytometry and found that DGBP induced apoptosis more potently than zoledronate. Western blots show that DGBP treatment altered expression and membrane affinity of some but not all geranylgeranylated small GTPases, activated caspases and increased ERK phosphorylation. Importantly, the anti-proliferative effects of DGBP were blocked by treatment with a caspase inhibitor and by treatment with a MEK inhibitor. Together, our findings indicate that DGBP is a more potent and selective compound than zoledronate in inducing apoptosis mediated through pathways that include caspases and MEK/ERK. These findings support the further development of GGDPS inhibitors as anticancer therapeutics.

Established role of bisphosphonate therapy for prevention of skeletal complications from myeloma bone disease.

PubMed

Terpos, Evangelos; Dimopoulos, Meletios A; Berenson, James

2011-02-01

Patients with advanced multiple myeloma (MM) often have increased osteolytic activity of osteoclasts and impaired osteogenesis by osteoblasts, resulting in osteolytic bone lesions that increase the risk of skeletal-related events (SREs) including pathologic fracture, the need for radiotherapy or surgery to bone, and spinal cord compression. Such SREs are potentially life-limiting, and can reduce patients' functional independence and quality of life. Bisphosphonates (e.g., oral clodronate and intravenous pamidronate and zoledronic acid) can inhibit osteoclast-mediated osteolysis, thereby reducing the risk of SREs, ameliorating bone pain, and potentially prolonging survival in patients with MM. Extensive clinical experience demonstrates that bisphosphonates are generally well tolerated, and common adverse events are typically mild and manageable. Studies are ongoing to optimize the timing and duration of bisphosphonate therapy in patients with bone lesions from MM. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

FES-Rowing versus Zoledronic Acid to Improve Bone Health in SCI

DTIC Science & Technology

2013-10-01

bone density (total hip and femoral neck) according to the World Health Organization (WHO) definitions of normal (T-score >-1), osteopenia (T-score...0.694 ± 0.22 0.759 ± 0.19 0.748 ± 0.21 0.982 ± 0.08 Osteoporosis status • Normal • Osteopenia • Osteoporosis/BMD lower than expected for age

The apoptotic effect of Zoledronic acid on the nasopharyngeal carcinoma cells via ROS mediated chloride channel activation.

PubMed

Wang, Liang; Gao, Hong; Yang, Xiaoya; Liang, Xiechou; Tan, Qiuchan; Chen, Zhanru; Zhao, Chan; Gu, Zhuoyu; Yu, Meisheng; Zheng, Yanfang; Huang, Yanqing; Zhu, Linyan; Jacob, Tim J C; Wang, Liwei; Chen, Lixin

2018-06-08

Zoledronic acid (ZA), a third-generation bisphosphonate, has been applied for treatment of bone metastases caused by malignant tumors. Recent studies have found its anti-cancer effects on various tumor cells. One of the mechanisms of anti-cancer effects of ZA is induction of apoptosis. However, the mechanisms of ZA-induced apoptosis in tumor cells have not been clarified clearly. In this study, we investigated the roles of chloride channels in ZA-induced apoptosis in nasopharyngeal carcinoma CNE-2Z cells. Apoptosis and chloride current were induced by ZA and suppressed by chloride channel blockers. After the knockdown of ClC-3 expression by ClC-3 siRNA, ZA-induced chloride current and apoptosis were significantly suppressed, indicating that the chloride channel participated in ZA-induced apoptosis may be ClC-3. When reactive oxygen species (ROS) generation was inhibited by the antioxidant N-acetyl-L-cysteine (L-NAC), ZA-induced apoptosis and chloride current were blocked accordingly, suggesting that ZA induces apoptosis through promoting ROS production and subsequently activating chloride channel. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Absorbed dose assessment of 177Lu-zoledronate and 177Lu-EDTMP for human based on biodistribution data in rats

PubMed Central

Yousefnia, Hassan; Zolghadri, Samaneh; Jalilian, Amir Reza

2015-01-01

Over the past few decades, several bone-seeking radiopharmaceuticals including various bisphosphonate ligands and β-emitting radionuclides have been developed for bone pain palliation. Recently, 177Lu was successfully labeled with zoledronic acid (177Lu-ZLD) as a new generation potential bisphosphonate and demonstrated significant accumulation in bone tissue. In this work, the absorbed dose to each organ of human for 177Lu-ZLD and 177Lu-ethylenediaminetetramethylene phosphonic acid (177Lu-EDTMP;as the only clinically bone pain palliation agent) was investigated based on biodistribution data in rats by medical internal radiation dosimetry (MIRD) method. 177Lu-ZLD and 177Lu-EDTMP were prepared in high radiochemical purity (>99%, instant thin layer chromatography (ITLC)) at the optimized condition. The biodistribution of the complexes demonstrated fast blood clearance and major accumulation in the bone tissue. The highest absorbed dose for both 177Lu-ZLD and 177Lu-EDTMP is observed in trabecular bone surface with 12.173 and 10.019 mSv/MBq, respectively. The results showed that 177Lu-ZLD has better characteristics compared to 177Lu-EDTMP and can be a good candidate for bone pain palliation. PMID:26170557

RNA-transfection of γ/δ T cells with a chimeric antigen receptor or an α/β T-cell receptor: a safer alternative to genetically engineered α/β T cells for the immunotherapy of melanoma.

PubMed

Harrer, Dennis C; Simon, Bianca; Fujii, Shin-Ichiro; Shimizu, Kanako; Uslu, Ugur; Schuler, Gerold; Gerer, Kerstin F; Hoyer, Stefanie; Dörrie, Jan; Schaft, Niels

2017-08-17

Adoptive T-cell therapy relying on conventional T cells transduced with T-cell receptors (TCRs) or chimeric antigen receptors (CARs) has caused substantial tumor regression in several clinical trials. However, genetically engineered T cells have been associated with serious side-effects due to off-target toxicities and massive cytokine release. To obviate these concerns, we established a protocol adaptable to GMP to expand and transiently transfect γ/δ T cells with mRNA. PBMC from healthy donors were stimulated using zoledronic-acid or OKT3 to expand γ/δ T cells and bulk T cells, respectively. Additionally, CD8 + T cells and γ/δ T cells were MACS-isolated from PBMC and expanded with OKT3. Next, these four populations were electroporated with RNA encoding a gp100/HLA-A2-specific TCR or a CAR specific for MCSP. Thereafter, receptor expression, antigen-specific cytokine secretion, specific cytotoxicity, and killing of the endogenous γ/δ T cell-target Daudi were analyzed. Using zoledronic-acid in average 6 million of γ/δ T cells with a purity of 85% were generated from one million PBMC. MACS-isolation and OKT3-mediated expansion of γ/δ T cells yielded approximately ten times less cells. OKT3-expanded and CD8 + MACS-isolated conventional T cells behaved correspondingly similar. All employed T cells were efficiently transfected with the TCR or the CAR. Upon respective stimulation, γ/δ T cells produced IFNγ and TNF, but little IL-2 and the zoledronic-acid expanded T cells exceeded MACS-γ/δ T cells in antigen-specific cytokine secretion. While the cytokine production of γ/δ T cells was in general lower than that of conventional T cells, specific cytotoxicity against melanoma cell lines was similar. In contrast to OKT3-expanded and MACS-CD8 + T cells, mock-electroporated γ/δ T cells also lysed tumor cells reflecting the γ/δ T cell-intrinsic anti-tumor activity. After transfection, γ/δ T cells were still able to kill MHC-deficient Daudi cells. We present a protocol adaptable to GMP for the expansion of γ/δ T cells and their subsequent RNA-transfection with tumor-specific TCRs or CARs. Given the transient receptor expression, the reduced cytokine release, and the equivalent cytotoxicity, these γ/δ T cells may represent a safer complementation to genetically engineered conventional T cells in the immunotherapy of melanoma (Exper Dermatol 26: 157, 2017, J Investig Dermatol 136: A173, 2016).

Osteoprotegerin reduces the development of pain behaviour and joint pathology in a model of osteoarthritis

PubMed Central

Sagar, Devi Rani; Ashraf, Sadaf; Xu, Luting; Burston, James J; Menhinick, Matthew R; Poulter, Caroline L; Bennett, Andrew J; Walsh, David A; Chapman, Victoria

2014-01-01

Background Increased subchondral bone turnover may contribute to pain in osteoarthritis (OA). Objectives To investigate the analgesic potential of a modified version of osteoprotegerin (osteoprotegerin-Fc (OPG-Fc)) in the monosodium iodoacetate (MIA) model of OA pain. Methods Male Sprague Dawley rats (140–260 g) were treated with either OPG-Fc (3 mg/kg, subcutaneously) or vehicle (phosphate-buffered saline) between days 1 and 27 (pre-emptive treatment) or days 21 and 27 (therapeutic treatment) after an intra-articular injection of MIA (1 mg/50 µl) or saline. A separate cohort of rats received the bisphosphonate zoledronate (100 µg/kg, subcutaneously) between days 1 and 25 post-MIA injection. Incapacitance testing and von Frey (1–15 g) hind paw withdrawal thresholds were used to assess pain behaviour. At the end of the study, rats were killed and the knee joints and spinal cord removed for analysis. Immunohistochemical studies using Iba-1 and GFAP quantified levels of activation of spinal microglia and astrocytes, respectively. Joint sections were stained with haematoxylin and eosin or Safranin-O fast green and scored for matrix proteoglycan and overall joint morphology. The numbers of tartrate-resistant acid phosphatase-positive osteoclasts were quantified. N=10 rats/group. Results Pre-emptive treatment with OPG-Fc significantly attenuated the development of MIA-induced changes in weightbearing, but not allodynia. OPG-Fc decreased osteoclast number, inhibited the formation of osteophytes and improved structural pathology within the joint similarly to the decrease seen after pretreatment with the bisphosphonate, zoledronate. Therapeutic treatment with OPG-Fc decreased pain behaviour, but did not improve pathology in rats with established joint damage. Conclusions Our data suggest that early targeting of osteoclasts may reduce pain associated with OA. PMID:23723320

OPG-Fc but Not Zoledronic Acid Discontinuation Reverses Osteonecrosis of the Jaws (ONJ) in Mice

PubMed Central

de Molon, Rafael Scaf; Shimamoto, Hiroaki; Bezouglaia, Olga; Pirih, Flavia Q; Dry, Sarah M; Kostenuik, Paul; Boyce, Rogely W; Dwyer, Denise; Aghaloo, Tara L; Tetradis, Sotirios

2016-01-01

Osteonecrosis of the jaws (ONJ) is a significant complication of antiresorptive medications, such as bisphosphonates and denosumab. Antiresorptive discontinuation to promote healing of ONJ lesions remains highly controversial and understudied. Here, we investigated whether antiresorptive discontinuation alters ONJ features in mice, employing the potent bisphosphonate zoledronic acid (ZA) or the receptor activator of NF-κB ligand (RANKL) inhibitor OPG-Fc, utilizing previously published ONJ animal models. Mice were treated with vehicle (veh), ZA, or OPG-Fc for 11 weeks to induce ONJ, and antiresorptives were discontinued for 6 or 10 weeks. Maxillae and mandibles were examined by µCT imaging and histologically. ONJ features in ZA and OPG-Fc groups included periosteal bone deposition, empty osteocyte lacunae, osteonecrotic areas, and bone exposure, each of which substantially resolved 10 weeks after discontinuing OPG-Fc but not ZA. Full recovery of tartrate-resistant acid phosphatase-positive (TRAP+) osteoclast numbers occurred after discontinuing OPG-Fc but not ZA. Our data provide the first experimental evidence demonstrating that discontinuation of a RANKL inhibitor, but not a bisphosphonate, reverses features of osteonecrosis in mice. It remains unclear whether antiresorptive discontinuation increases the risk of skeletal-related events in patients with bone metastases or fracture risk in osteoporosis patients, but these preclinical data may nonetheless help to inform discussions on the rationale for a “drug holiday” in managing the ONJ patient. PMID:25727550

Quantitation of zoledronic acid in murine bone by liquid chromatography coupled with tandem mass spectrometry.

PubMed

Raccor, Brianne S; Sun, Jianxun; Lawrence, Ross F; Li, Lei; Zhang, Hai; Somerman, Martha J; Totah, Rheem A

2013-09-15

An in vitro method for extraction and quantification of zoledronic acid (ZA) from murine bone was developed. Whole mouse bones were incubated in ZA solutions with predetermined concentrations and bound ZA was subsequently extracted from bone with phosphoric acid and derivatized using trimethylsilyl diazomethane (TMS-DAM). ZA tetra-methyl phosphonate was quantified by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS). This resulted in a sensitive, accurate, and precise method that was linear over three orders of magnitude (0.0250-50.0μg/mL ZA). For quality control (QC) samples, intra-and inter-day coefficients of variance were calculated and were less than 10%. This method was then applied to an in vivo model to quantitate ZA from the femur and mandible of three mice treated with ZA for two weeks. The mean ZA extracted from the mandible was four fold higher than that extracted from the femur (3.06±0.52 vs. 0.76±0.09ng/mg, respectively) indicating that ZA did not distribute equally in the skeleton and had a preference to the mandible. In conclusion, a highly sensitive method to measure ZA from mouse skeleton was developed, which can be easily adapted to multiple mammalian models including humans receiving ZA treatment. Copyright © 2013 Elsevier B.V. All rights reserved.

Local treatment of cancellous bone grafts with BMP-7 and zoledronate increases both the bone formation rate and bone density

PubMed Central

2011-01-01

Background and purpose The remodeling of morselized bone grafts in revision surgery can be enhanced by an anabolic substance such as a bone morphogenetic protein (BMP). On the other hand, BMPs boost catabolism and might cause a premature resorption, both of the graft and of the new-formed bone. Bisphosphonates inactivate osteoclasts and can be used to control the resorption. We studied a combination of both drugs as a local admix to a cancellous allograft. Methods Cancellous bone allografts were harvested and freeze-dried. Either saline, BMP-7, the bisphosphonate zoledronate, or a combination of BMP-7 and zoledronate were added in solution. The grafts were placed in bone conduction chambers and implanted in the proximal tibia of 34 rats. The grafts were harvested after 6 weeks and evaluated by histomorphometry. Results Bone volume/total volume (BV/TV) was 50% in the grafts treated with the combination of BMP-7 and zoledronate and 16% in the saline controls (p < 0.001). In the zoledronate group BV/TV was 56%, and in the BMP group it was 14%. The ingrowth distance of new bone into the graft was 3.5 mm for the combination of BMP-7 and zoledronate and 2.6 mm in the saline control (p = 0.002). The net amount of retained remodeled bone was more than 4 times higher when BMP-7 and zoledronate were combined than in the controls. Interpretation An anabolic drug like BMP-7 can be combined with an anti-catabolic bisphosphonate as local bone graft adjunct, and the combination increases the amount of remaining bone after remodeling is complete. PMID:21434769

Evaluation of the interaction between hydroxyapatite and bisphosphonate by nonlinear capillary electrochromatography.

PubMed

Kong, Deying; Chen, Zilin

2017-05-01

Bisphosphonates are a class of chemical compounds used to treat diseases caused by increased bone resorption. Zoledronate is a third-generation bisphosphonate drug. Hydroxyapatite is main mineral constituent of bones, which can be bound by bisphosphonates in vivo. In this work, we report a method of nonlinear capillary electrochromatography for study on the interaction between hydroxyapatite and bisphosphonate. Hydroxyapatite was modified on the inner wall of capillary by a biomimetic-mineralization method. Then nonlinear chromatography was used to fit and analyze the interaction between zoledronate and hydroxyapatite. The association rate constants of zoledronate in hydroxyapatite-modified capillary and bare capillary are 642.3 and 195/M/min, respectively. This indicates that there is strong binding interactions and affinity between zoledronate and hydroxyapatite. Besides, the interaction between zoledronate and hydroxyapatite was confirmed further by ultraviolet spectroscopy. The method of nonlinear capillary electrochromatography provides a fast and effect approach for studying of bone metabolism disease by evaluation of interaction between hydroxyapatite and bisphosphonates. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effects of antiresorptive therapies on glucose metabolism: results from the FIT, HORIZON-PFT, and FREEDOM trials.

PubMed

Schwartz, Ann V; Schafer, Anne L; Grey, Andrew; Vittinghoff, Eric; Palermo, Lisa; Lui, Li-Yung L; Wallace, Robert B; Cummings, Steven R; Black, Dennis M; Bauer, Douglas C; Reid, Ian R

2013-06-01

In rodent models, undercarboxylated osteocalcin (ucOC) acts as a hormone that promotes insulin sensitivity and secretion. If ucOC plays a similar role in humans, then antiresorptive therapies, which reduce ucOC levels, may increase the risk of insulin resistance and diabetes. We tested whether antiresorptive therapies result in higher fasting glucose, increased weight, or greater diabetes incidence in post hoc analyses of three randomized, placebo-controlled trials in postmenopausal women: Fracture Intervention Trial (FIT) (N = 6151) of alendronate (4 years), Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial (HORIZON-PFT) (N = 7113) of zoledronic acid (3 years), and Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial (N = 7076) of denosumab (3 years). Fasting glucose was measured annually in FIT and HORIZON in a subset of women, and every 6 months in FREEDOM in all participants. Weight was measured annually in all trials. Incident diabetes was identified from adverse event reports, initiation of diabetes medication, or elevated fasting glucose. Differences in fasting glucose changes from randomization to trial conclusion between treatment and placebo groups were not statistically significant: -0.47 mg/dL in FIT, 0.20 mg/dL in HORIZON-PFT, and 0.09 mg/dL in FREEDOM, all p > 0.6. Weight change differed between treatment and placebo groups in FIT (0.32 kg, p = 0.003) and FREEDOM (0.31 kg, p = 0.023) but not in HORIZON-PFT (0.15 kg, p = 0.132). In the three trials combined, diabetes occurred in 203 and 225 women assigned to treatment or placebo, respectively. Diabetes incidence was not increased in any of the treatment groups or in the pooled estimate (pooled relative risk [RR] = 0.90; 95% confidence interval [CI] 0.74-1.10). Antiresorptive therapy does not have a clinically important effect on fasting glucose, weight, or diabetes risk in postmenopausal women. Contrary to predictions from mouse models, reduced bone turnover does not appear to play a significant role in glucose metabolism in humans. Copyright © 2013 American Society for Bone and Mineral Research.

FES-Rowing versus Zoledronic Acid to Improve Bone Health in SCI

DTIC Science & Technology

2014-10-01

may FES rowing improves tibial stress distribution. This image demonstrates the change in stress distribution in response to the same axial force...kN/mm). This indicates improved bone strength and better stress distribution. improve fracture risk prediction and detection of response to...osteoporosis-related bone fracture . This study aims to learn if the severe osteoporosis in lower extremities caused by spinal cord injuries can be slowed or

FES-Rowing versus Zoledronic Acid to Improve Bone Health in SCI

DTIC Science & Technology

2012-10-01

density (total hip and femoral neck) according to the World Health Organization (WHO) definitions of normal (T-score >-1), osteopenia (T-score <-1 and...0.846 ± 0.23 0.993 ± 0.08 0.714 ± 0.22 0.705 ± 0.20 0.796 ± 0.20 0.777 ± 0.22 0.994 ± 0.09 Osteoporosis status • Normal • Osteopenia

FES-Rowing versus Zoledronic Acid to Improve BoneHealth in SCI

DTIC Science & Technology

2016-12-01

SUPPLEMENTARY NOTES 14. ABSTRACT There is no established treatment to prevent bone loss or to induce new bone formation following SCI, although the... no established treatment to prevent bone loss or to induce new bone formation following SCI. The goal of this clinical trial -- FES-Rowing versus...Army position, policy or decision unless so designated by other documentation. REPORT DOCUMENTATION PAGE Form Approved OMB No . 0704-0188 Public

Microscopic Evaluation of the Effect of Oral Microbiota on the Development of Bisphosphonate-Related Osteonecrosis of the Jaws in Rats

PubMed Central

Silveira, Felipe M.; Etges, Adriana; Correa, Marcos B.

2016-01-01

ABSTRACT Objectives Osteonecrosis of the jaws is a side effect associated with the use of bisphosphonates. Using histologic analysis, this study aimed to evaluate the influence of microbial colonies in the development of osteonecrosis in the jaws of rats subjected to nitrogenous and non-nitrogenous bisphosphonates, undergoing surgical procedures. Material and Methods Thirty-four rats (Rattus norvegicus, Wistar strain) were allocated randomly into three groups: 12 animals treated with zoledronic acid; 12 animals treated with clodronate; and 10 animals treated with saline. Sixty days after the start of treatment, the animals underwent three extractions of the upper right molars. After 120 days of drug administration, the rats were killed. Histologic analysis was performed on specimens stained with hematoxylin and eosin by the technique of manual counting points using Image-Pro Plus software on images of the right hemimaxilla. Results Osteonecrosis was induced in the test groups. There was no statistically significant association between the presence of microbial colonies and the presence of non-vital bone (Kruskal-Wallis, P > 0.05). Conclusions Use of zoledronic acid was associated with non-vital bone and the results suggested that the presence of microbial colonies does not lead to osteonecrosis. PMID:28154747

Zoledronic acid enhances antitumor efficacy of liposomal doxorubicin.

PubMed

Hattori, Yoshiyuki; Shibuya, Kazuhiko; Kojima, Kaori; Miatmoko, Andang; Kawano, Kumi; Ozaki, Kei-Ichi; Yonemochi, Etsuo

2015-07-01

Previously, we found that the injection of zoledronic acid (ZOL) into mice bearing tumor induced changes of the vascular structure in the tumor. In this study, we examined whether ZOL treatment could decrease interstitial fluid pressure (IFP) via change of tumor vasculature, and enhance the antitumor efficacy of liposomal doxorubicin (Doxil®). When ZOL solution was injected at 40 µg/mouse per day for three consecutive days into mice bearing murine Lewis lung carcinoma LLC tumor, depletion of macrophages in tumor tissue and decreased density of tumor vasculature were observed. Furthermore, ZOL treatments induced inflammatory cytokines such as interleukin (IL)-10 and -12, granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF)-α in serum of LLC tumor-bearing mice, but not in normal mice, indicating that ZOL treatments might induce an inflammatory response in tumor tissue. Furthermore, ZOL treatments increased antitumor activity by Doxil in mice bearing a subcutaneous LLC tumor, although they did not significantly increase the tumor accumulation of doxorubicin (DXR). These results suggest that ZOL treatments might increase the therapeutic efficacy of Doxil via improvement of DXR distribution in a tumor by changing the tumor vasculature. ZOL treatment can be an alternative approach to increase the antitumor effect of liposomal drugs.

Paget’s Disease in an Omani: Long-term Improvement Following a Single Injection of Zoledronic Acid

PubMed Central

Elshafie, Omayma; Alsaffi, Nooralddin; Hussain, Samir; Woodhouse, Nicholas

2016-01-01

Paget’s disease of bone is a patchy skeletal disorder characterized by an increase in bone resorption and formation in the affected areas. It affects up to 3% of individuals of Anglo-Saxon origin over the age of 40 years but is rare in Arabs. Although most patients are asymptomatic, a variety of symptoms and complications may develop directly from bone involvement or secondarily to compression by bone expansion and increased blood flow. The disease can be treated by using medications that inhibit bone resorption, such as calcitonin and the bisphosphonates. Here we describe the case of an Omani patient with the disease, involving the skull, spine, pelvis, and tibia. He presented to the endocrine clinic in Sultan Qaboos University Hospital with a six-year history of headache, bone pain, progressive skull enlargement, and left-sided deafness. His alkaline phosphatase (ALP) level was 1500 U/L. His disease responded gradually to six months of subcutaneous and nasal calcitonin followed by a single 5 mg intravenous injection of zoledronic acid. This resulted in a further progressive reduction of his bone pain, skull size, and improvement in his hearing, as well as normalization of his serum ALP levels after one-year. This effect has been sustained for 3 years. PMID:27168927

Zoledronic acid induces a significant decrease of circulating endothelial cells and circulating endothelial precursor cells in the early prostate cancer neoadjuvant setting.

PubMed

Santini, Daniele; Zoccoli, Alice; Gregorj, Chiara; Di Cerbo, Melania; Iuliani, Michele; Pantano, Francesco; Zamarchi, Rita; Sergi, Federico; Flammia, Gerardo; Buscarini, Maurizio; Rizzo, Sergio; Cicero, Giuseppe; Russo, Antonio; Vincenzi, Bruno; Avvisati, Giuseppe; Tonini, Giuseppe

2013-01-01

Published data demonstrated that zoledronic acid (ZOL) exhibits antiangiogenetic effects. A promising tool for monitoring antiangiogenic therapies is the measurement of circulating endothelial cells (CECs) and circulating endothelial precursor cells (CEPs) in the peripheral blood of patients. Our aim was to investigate the effects of ZOL on levels of CECs and CEPs in localized prostate cancer. Ten consecutive patients with a histologic diagnosis of low-risk prostate adenocarcinoma were enrolled and received an intravenous infusion of ZOL at baseline (T0), 28 days (T28) and 56 days (T56). Blood samples were collected at the following times: T0 (before the first infusion of ZOL), T3 (72 h after the first dose), T28, T56 (both just before the ZOL infusion) and T84 (28 days after the last infusion of ZOL) and CEC/CEP levels were directly quantified by flow cytometry at all these time points. Our analyses highlighted a significant reduction of mean percentage of CECs and CEPs after initiation of ZOL treatment [p = 0.014 (at day 3) and p = 0.012 (at day 84), respectively]. These preliminary results demonstrate that ZOL could exert an antiangiogenic effect in early prostate cancer through CEP and CEC modulation.

Effect of low-level laser therapy on tissue repair after dental extraction in rats administered zoledronic acid and dexamethasone

NASA Astrophysics Data System (ADS)

Weber, João Batista Blessmann; Camilotti, Renata Stifelman; Jasper, Juliana; Casagrande, Liliane Cristina Onofre; Maito, Fábio Luiz Dal Moro

2017-05-01

Bisphosphonates (BPs) are being increasingly used for the treatment of metabolic and oncological pathologies involving the skeletal system. Because of the severity of the BP associated osteonecrosis of the jaws, the difficulties of treatment, and patient discomfort, additional support methods for their management are needed. Laser therapy has an easy handling, photobiostimulator effect on tissues healing, so it can be considered a preferred therapy. The aim of this study was to evaluate the influence of low-level laser therapy in the 685- and 830-nm wavelength in the healing process of the bone and soft tissues in rats under BP therapy [zoledronic acid (ZA)] and dexamethasone concomitantly that underwent a surgery for the extraction of upper molars. There were statistically significant differences in the clinical evaluation of the wound and the weight of the animals. Regarding the histological evaluation, it was possible to observe the different maturations of the healing stage between groups. The effect of drug therapy with ZA and dexamethasone in the bone tissue repair process induces osteonecrosis of the jaw in rats and slows down the healing process. In the laser groups, at the stipulated dosimetry, a positive influence on the bone and soft tissue repair process was observed.

A Case of Severe, Prolonged, Refractory Hypophosphatemia After Zoledronic Acid Administration.

PubMed

Clark, Sarah L; Nystrom, Erin M

2016-04-01

Zoledronic acid (ZA) administration has been associated with electrolyte abnormalities, including hypocalcemia, hypomagnesemia, hypokalemia, and hypophosphatemia. We describe a case of severe, refractory hypophosphatemia in a patient who received ZA for hypercalcemia of malignancy (HCM). Little data are available that describe the incidence or degree of severity of hypophosphatemia that can occur following ZA administration. In addition, no formal recommendations exist to guide monitoring for or management of electrolyte derangements in the setting of bisphosphonate use. Our patient required daily, high-dose phosphorus replacement beginning day 4 following ZA administration. The average daily dose of phosphorus, including both intravenous and enteral administration, was highest in the first 2 weeks after ZA, averaging 77 mmol/d days 4 through 15, and does not include sources of phosphorus from the patient's nutrition support. Despite this high amount of supplementation, which was well beyond what meets normal daily requirements and the amount expected to treat "usual" hypophosphatemia, the patient did not achieve sustained normal serum phosphorus levels for over 30 days after ZA. ZA is a favorable option for treating HCM because of its longer duration of action, potent serum calcium-lowering effects, and favorable safety profile. The risk of hypophosphatemia with ZA use is reviewed. © The Author(s) 2016.

Replacing zoledronic acid with denosumab is a risk factor for developing osteonecrosis of the jaw.

PubMed

Higuchi, Tomoko; Soga, Yoshihiko; Muro, Misato; Kajizono, Makoto; Kitamura, Yoshihisa; Sendo, Toshiaki; Sasaki, Akira

2018-06-01

Intravenous zoledronic acid (ZA) is often replaced with subcutaneous denosumab in patients with bone metastatic cancer. Despite their different pharmacologic mechanisms of action, both denosumab and ZA are effective in bone metastasis but cause osteonecrosis of the jaw (ONJ) as a side effect. ZA persists in the body almost indefinitely, whereas denosumab does not persist for long periods. This study evaluated the risks of developing ONJ when replacing ZA with denosumab. In total, 161 Japanese patients administered ZA for bone metastatic cancer were enrolled in this single-center, retrospective, observational study. The risk of developing ONJ was evaluated by logistic regression analysis using the following factors: age, gender, cancer type, angiogenesis inhibitors, steroids, and replacement of ZA with denosumab. Seventeen patients (10.6%) developed ONJ. Multiple regression analysis indicated a significant difference in rate of ONJ associated with replacement of ZA with denosumab (odds ratio = 3.81; 95% confidence interval 1.04-13.97; P = .043). Replacing ZA with denosumab is a risk factor for the development of ONJ. Both binding of bisphosphonate to bone and receptor activator of nuclear factor-κ B ligand inhibition could additively increase the risk of ONJ. We bring the replacement of ZA with denosumab to the attention of clinical oncologists. Copyright © 2018 Elsevier Inc. All rights reserved.

Once-yearly zoledronic acid in hip fracture prevention

PubMed Central

Demontiero, Oddom; Duque, Gustavo

2009-01-01

Osteoporosis is an escalating global problem. Hip fractures, the most catastrophic complication of osteoporosis, continue to cause significant mortality and morbidity despite increasing availability of effective preventative agents. Among these agents, oral bisphosphonates have been the first choice for the treatment and prevention of osteoporotic fractures. However, the use of oral bisphosphonates, especially in the older population, has been limited by their side effects and method of administration thus compromising their persistent use. The resultant low adherence by patients has undermined their full potential and has been associated with an increase in the incidence of fragility fractures. Recently, annual intravenous zoledronic acid (ZOL) has been approved for osteoporosis. Randomized controlled trials have demonstrated ZOL to be safe, have good tolerability and produce significant effect on bone mass and microarchitecture. Adherence has also been shown to be better with ZOL. Furthermore two large trials firmly demonstrated significant anti-osteoporotic effect (∼59% relative risk reduction of hip fractures) and mortality benefit (28% reduction in mortality) of ZOL in older persons with recent hip fractures. In this review, we report the current evidence on the use of ZOL for the prevention of hip fractures in the elderly. We also report the pharmacological characteristics and the advantages and disadvantages of ZOL in this particular group. PMID:19503777

Integrated approach to pain management for a patient with multiple bone metastases of uterine cervical cancer.

PubMed

Qin, De-An; Song, Jie-Fu; Song, Li-Ping; Feng, Gui-Sheng

2018-05-01

Background Pain management for multiple bone metastases is complex and often requires multidisciplinary treatment. We herein describe patient-centered multidisciplinary pain management for metastatic cancer. A 61-year-old woman with multiple bone metastases of uterine cervical cancer developed intractable low back pain. After external beam radiotherapy failed, we performed lumbar spinal intralesional curettage, pedicle screw fixation, and nerve decompression. However, the neuralgia persisted. We then percutaneously injected epirubicin into the intervertebral foramina under computed tomography guidance for L5 dorsal root ganglion destruction. Osteoplasty was performed under C-arm X-ray guidance; however, the sacrum was mistaken for the ilium, and treatment was ineffective. We administered zoledronic acid and strontium-89. The last resort was outpatient implantation of an epidural bupivacaine-morphine infusion system. A visual analog scale (VAS) was used for pain evaluation. Lumbar spinal intralesional curettage and fixation, epirubicin-induced ganglion destruction, and administration of zoledronic acid and strontium-89 decreased her VAS pain score from 7-8 to 3-4. Radiotherapy and nerve decompression and release were ineffective, as was osteoplasty because of the location error. The epidural infusion system decreased the VAS score from 7-8 to 2-3 and was highly efficient. Conclusions Multidisciplinary integrated treatment for metastatic cancer can be effective.

Protocol for a randomised control trial of bisphosphonate (zoledronic acid) treatment in childhood femoral head avascular necrosis due to Perthes disease

PubMed Central

Zacharin, Margaret; Foster, Bruce; Donald, Geoffrey; Hassall, Timothy; Siafarikas, Aris; Johnson, Michael; Tham, Elaine; Whitewood, Colin; Gebski, Val; Cowell, Chris T; Little, David Graham; Munns, Craig Frank

2017-01-01

Introduction Perthes disease (PD) is an idiopathic disorder presenting with avascular necrosis to the femoral head, which frequently results in flattening. Long-term function is directly related to the subsequent femoral head sphericity. Current treatment includes mechanical modalities and surgical procedures, which are therapeutic but are not uniformly able to prevent collapse. The use of the nitrogen-containing bisphosphonate zoledronic acid (ZA) to inhibit osteoclastic bone resorption is aimed at preserving femoral head strength, reducing collapse and thus maintaining shape. The proposed multicentre, prospective, randomised controlled trial intends to evaluate the efficacy of ZA treatment in PD. Methods and analysis An open-label randomised control trial recruiting 100 children (50 each treatment arm) 5 to 16 years old with unilateral PD. Subjects are randomly assigned to either (a) ZA and standard care or (b) Standard care. The primary outcome measure is deformity index (DI), a radiographic parameter of femoral head roundness assessed at 24 months, following 12 months of ZA treatment (3-monthly doses of ZA 0.025 mg/kg at baseline, 3, 6, 9 and 12 months) plus 12 months observation (group A) or 24 months of observation (group B). Secondary outcome measures are femoral head subluxation, Faces Pain scale, Harris hip score and quality of life. Assessments are made at baseline, 3 monthly during the first year of follow-up and then 6 monthly, until the 24th month. Ethics and dissemination The study commenced following the written approval from the Human Research Ethics Committee. Safety considerations regarding the effects of ZA are monitored which include the subject’s symptomatology, mineral status, bone mass and turnover activity, and metaphyseal modelling. Data handling plan requires that all documents, clinical information, biological samples and investigation results will be held in strict confidence by study investigators to preserve its safety and confidentiality. Trial registration number Australian and New Zealand Clinical Trials ACTRN12610000407099, pre-results. PMID:29637122

Synergistic suppression of human breast cancer cells by combination of plumbagin and zoledronic acid In vitro.

PubMed

Qiao, Han; Wang, Ting-yu; Yan, Wei; Qin, An; Fan, Qi-ming; Han, Xiu-guo; Wang, Yu-gang; Tang, Ting-ting

2015-09-01

Zoledronic acid (ZA), a bisphosphonate, is currently used in combination with chemotherapeutic agents to suppress breast cancer cell proliferation or breast cancer-induced osteolysis. The aim of this study was to investigate the effects of ZA combined with a natural anticancer compound plumbagin (PL) against human breast cancer cells in vitro. Human breast cancer MDA-MB-231SArfp cells were treated with ZA, PL or a combination of ZA and PL. The cell growth, apoptosis and migration were evaluated using CCK-8 assay, flow cytometry and transwell assay, respectively. The expression of apoptosis-related proteins was measured using real-time PCR and Western blotting. Synergism was evaluated using Compusyn software, and the combination index (CI) and drug reduction index (DRI) values were determined. PL or ZA alone caused mild cytotoxicity (the IC50 value at 24 h was 12.18 and above 100 μmol/L, respectively). However, the combination of ZA and PL caused a synergistic cytotoxicity (CI=0.26). The DRI values also showed a synergistic effect between PL and ZA, with actual values of 5.52 and 3.59, respectively. Furthermore, PL and ZA synergistically induced apoptosis and inhibited migration of the breast cancer cells. Moreover, the combination of ZA and PL decreased the expression of Notch-1, cleaved PARP, Bcl-2 and Bcl-xl, and increased the expression of cleaved caspase-3, CDKN1A and ID1. When the breast cancer cells were transfected with specific siRNA against Notch-1, the combination of ZA and PL markedly increased the expression of Bcl-2. Combination of ZA and PL synergistically suppresses human breast cancer MDA-MB-231SArfp cells in vitro. PL can inhibit ZA-induced activation of the Notch-1 signaling pathway and subsequently reduce the expression of Bcl-2, thus potentiating cancer cell apoptosis.

Local vs. systemic administration of bisphosphonates in rat cleft bone graft: A comparative study

PubMed Central

Lin, Lawrence; Olson, Jeffrey; Kwon, Taewoo; Bezouglaia, Olga; Tran, Jaime; Hoang, Michael; Bui, Kimberly; Kim, Reuben H.; Tetradis, Sotirios

2018-01-01

A majority of patients with orofacial cleft deformity requires cleft repair through a bone graft. However, elevated amount of bone resorption and subsequent bone graft failure remains a significant clinical challenge. Bisphosphonates (BPs), a class of anti-resorptive drugs, may offer great promise in enhancing the clinical success of bone grafting. In this study, we compared the effects of systemic and local delivery of BPs in an intraoral bone graft model in rats. We randomly divided 34 female 20-week-old Fischer F344 Inbred rats into four groups to repair an intraoral critical-sized defect (CSD): (1) Control: CSD without graft (n = 4); (2) Graft/Saline: bone graft with systemic administration of saline 1 week post-operatively (n = 10); (3) Graft/Systemic: bone graft with systemic administration of zoledronic acid 1 week post-operatively (n = 10); and (4) Graft/Local: bone graft pre-treated with zoledronic acid (n = 10). At 6-weeks post-operatively, microCT volumetric analysis showed a significant increase in bone fraction volume (BV/TV) in the Graft/Systemic (62.99 ±14.31%) and Graft/Local (69.35 ±13.18%) groups compared to the Graft/Saline (39.18±10.18%). Similarly, histological analysis demonstrated a significant increase in bone volume in the Graft/Systemic (78.76 ±18.00%) and Graft/Local (89.95 ±4.93%) groups compared to the Graft/Saline (19.74±18.89%). The local delivery approach resulted in the clinical success of bone grafts, with reduced graft resorption and enhanced osteogenesis and bony integration with defect margins while avoiding the effects of BPs on peripheral osteoclastic function. In addition, local delivery of BPs may be superior to systemic delivery with its ease of procedure as it involves simple soaking of bone graft materials in BP solution prior to graft placement into the defect. This new approach may provide convenient and promising clinical applications towards effectively managing cleft patients. PMID:29304080

Retrospective evaluation of the clinical benefit of long-term continuous use of zoledronic acid in patients with lung cancer and bone metastases.

PubMed

Henk, Henry J; Kaura, Satyin; Teitelbaum, April

2012-01-01

For patients with bone metastases, skeletal-related events including fracture are common, can cause considerable morbidity, and may reduce overall survival (OS). This retrospective analysis assessed the effect of Zometa (zoledronic acid, ZOL), an intravenous bisphosphonate (IV-BP), on fracture risk and OS in patients with bone metastases from lung cancer (LC). (Zometa is a registered trademark of Novartis Pharmaceuticals Corporation, USA.) A claims-based analysis using commercial and Medicare Advantage data from >45 US managed-care plans was used to evaluate the association between fracture risk and treatment persistency (31-90, 91-180, 181-365, and ≥366 days) and follow-up duration in LC patients diagnosed with bone metastases between 01/01/2001 and 12/31/2006 and treated with ZOL or without (no IV-BP). Persistency was defined as the absence of a >45-day gap between ZOL treatments. Analysis of variance tests were used to compare follow-up duration, a proxy for OS, between ZOL persistency groups. The effect of time to treatment with ZOL was also assessed. In 9874 LC patients with bone metastases (n = 1090 ZOL; n = 8784 no IV-BP) the unadjusted relative fracture risk was reduced by 40% with ZOL vs no IV-BP; fracture risk decreased consistently with increasing duration of ZOL treatment. Even short-term (31-90 days) ZOL significantly reduced fracture risk (47%) vs no IV-BP (p = 0.005) with adjustment for differences in demographic and clinical characteristics. Delaying ZOL until after bone metastases were diagnosed significantly increased fracture risk (p = 0.0017). For a sub-set of patients included in a survival analysis (n = 550 ZOL; n = 4512 no IV-BP), mortality was significantly lower (mean, 38.6 vs 46.8 deaths/100 person-years; p = 0.038) in those treated with ZOL vs no IV-BP. Interpretation of this claims-based analysis must be tempered by the inherent limitations of observational data, such as limited clinical information and the ability to control for prognostic factors. This retrospective analysis demonstrates that LC patients with bone metastases receiving ZOL had significantly reduced risk of fracture (p = 0.005) and death (p < 0.038) vs patients receiving no IV-BP. Longer ZOL persistency consistently yielded better outcomes, with ≥12 months' treatment producing the greatest benefit.

Two novel metal–organic coordination polymers based on diphosphonate and oxalate: Synthesis, structures and properties

DOE Office of Scientific and Technical Information (OSTI.GOV)

Niu, Qing-Jun; Zheng, Yue-Qing, E-mail: yqzhengmc@163.com; Zhou, Lin-Xia

2015-07-15

Two 2-(1-imidazole)-1-hydroxyl-1,1'-ethylidenediphosphonato and oxalic acid bridged coordination polymers (H{sub 2}en)[Co{sub 3}(H{sub 2}zdn){sub 2}(ox)(H{sub 2}O){sub 2}] (1) and Cd{sub 2}(H{sub 2}zdn)(ox){sub 0.5}(H{sub 2}O) (2) (2-(1-imidazole)-1-hydroxyl-1,1'-ethylidenediphosphonic acid=H{sub 5}zdn; oxalic acid=H{sub 2}ox) were synthesized under hydrothermal conditions and characterized by the infrared (IR), thermogravimetric analyses (TGA), elemental analyses (EA) and X-ray diffraction (XRD). Compound 1 is bridged by phosphonate anions to 1D chain, and further linked by oxalate anions to 2D layer. Compound 2 is bridged by O–P–O units of H{sub 5}zdn to the layer, and then pillared by oxalate anions to generate 3D frameworks. Compound 1 shows anti-ferromagnetic behaviors analyzed with themore » temperature-dependent zero-field ac magnetic susceptibilities, while compound 2 exhibits an influence on the luminescent property. - Graphical abstract: Linked by oxalate, two zoledronate-based metal–organic frameworks are synthesized, which exhibits the different frameworks. Magnetism and luminescent properties have been studied. The weak antiferromagnetic coupling is conducted in 1. - Highlights: • Compound 1 and 2 are first linked by oxalate anion based on zoledronic acid. • Compound 1 generates a classic “dia Diamond” (6{sup 6}) topology. • Compound 2 exhibits a (4{sup 4}·6{sup 2})(4{sup 4}·6{sup 6}) topology. • Magnetism and luminescent properties of 1 and 2 have been studied, respectively.« less

Effect of zoledronic acid on lumbar spinal fusion in osteoporotic patients.

PubMed

Ding, Qirui; Chen, Jian; Fan, Jin; Li, Qingqing; Yin, Guoyong; Yu, Lipeng

2017-11-01

To investigate the effect of zoledronic acid (ZA) on lumbar spinal fusion in patients with osteoporosis. This retrospective study includes 94 osteoporotic patients suffering from lumbar degenerative diseases or lumbar fracture who underwent lumbar spinal fusion in our institution from January 2013 to August 2014. They were divided into ZA group and control group according to whether the patient received ZA infusion or not. The patients in ZA group were given 5 mg intravenous ZA at the 3rd-5th days after operation. All patients took daily oral supplement of 600 mg calcium carbonate and 800 IU vitamin D during the follow-up after operation. The Visual Analogue Scale (VAS), Oswestry Disability Index (ODI), and Short Form 36 (SF-36) scores were recorded preoperatively and post-operatively to evaluate the clinic outcomes; the spinal fusion was assessed by X-ray or CT Scan. 64 patients finished the final follow-up, including 30 patients in ZA group and 34 patients in control group. No significant difference was observed in gender, age, and preoperative BMI VAS, ODI, and SF-36 scores between the two groups (P > 0.05). The post-operative VAS and ODI scores decreased rapidly at 3 and 6 months, but rose back slightly at 12 and 24 months in both groups. On the contrary, post-operative SF-36 scores increased rapidly at 3 and 6 months, while fell back slightly at 12 and 24 months, with a statistically significant difference between the two groups at 12 months, but not at 3 and 6 month post-operation. The spinal fusion rate in ZA group was 90% at 6 months, 92% at 12 months, while it was 75% at 6 months, 92.86% at 12 months in control group, significantly different between the two groups at 12 months, but not at 6 months. In the whole follow-up period, adjacent vertebral compressing fracture occurred in five patients in control group, none in ZA group. No pedicle screw loosening was observed in ZA group, with six in control group. Zoledronic acid accelerates spinal fusion, shortens the time of fusion without changing fusion rate, and also decreases the risk of adjacent vertebral compressing fracture and the rate of pedicle screw loosening, resulting in the improvement of clinical outcomes and quality of life.

Zoledronate induces apoptosis in cells from fibro-cellular membrane of unicameral bone cyst (UBC).

PubMed

Yu, John; Chang, Seong-Sil; Suratwala, Sanjeev; Chung, Woo-Sik; Abdelmessieh, Peter; Lee, Hahn-Jun; Yang, Jay; Lee, Francis Young-In

2005-09-01

Unicameral bone cyst (UBC) is a benign cystic lesion in children which is prone to fracture. Various treatments are available, but recurrence after different types of percutaneous injection therapy can cause bone destruction and pathologic fracture. The potential therapeutic effects of anti-resorptive agents, such as bisphosphonates, have not been investigated for UBC. The objective of this study was to characterize the cells from the fibro-cellular membrane of unicameral bone cyst (UBC cells) and to determine whether zoledronate, a nitrogen-containing bisphosphonate, could induce apoptosis in UBC cells. Flow cytometry and immunoblotting were performed in order to determine whether zoledronate induced apoptosis. Cells derived from normal human trabecular bones were used as controls against UBC cells to compare the effect of zoledronate in inducing apoptosis. Immunohisto/cytochemistry (IHC/ICC) and mini-array analyses were performed on tissues and cultured cells. Isolated peripheral blood mononuclear cells were incubated with conditioned media from the UBC cells to determine whether they are capable of inducing osteoclastogenesis. UBC membrane is composed of cells staining positively with CD68, SDF-1, STRO-1 and RANKL, but in vitro cells showed no staining with antibodies to CD68 and STRO-1, suggesting that there was a clonal selection of stromal cells during cell culture. UBC cells also express RUNX2 (runt-related transcription factor-2, core binding factor-1), a key transcription factor for osteoblastic differentiation. In addition, media collected from UBC cells induced a generation of multi-nucleated osteoclast-like cells of peripheral blood mononuclear cells. Zoledronate induced apoptosis of UBC cells in a dose-dependent manner. Apoptosis was evidenced by induction of the active cleaved form of caspase-3. The baseline apoptotic fractions were similar in UBC cells and trabecular bone cells. However, in the overall apoptotic fractions in this study, trabecular bone cells showed 17.2% of apoptosis, significantly lower than 24.2% of UBC cells (p-value=0.007). With the various zoledronate concentrations, mean apoptotic fractions of trabecular bone cells was 19.2%, significantly lower than 27.8% of UBC cells (p-value=0.040). With GGOH co-treatment in various zoledronate concentrations, 15.1% apoptosis was shown in trabecular bone cells, which was not significantly lower than 20.6% of UBC cells (p-value=0.076). This data suggests that zoledronate causes apoptosis in both UBC and trabecular bone cells by inhibition of the mevalonate pathway. In addition to the known anti-osteoclastogenic effect of bisphosphonates, the GGOH inhibitory effects of zoledronate were more prominent in UBC cells than trabecular bone cells, indicating their potential therapeutic role in UBC.

Medical treatment of orthotopic glioblastoma with transferrin-conjugated nanoparticles encapsulating zoledronic acid.

PubMed

Porru, Manuela; Zappavigna, Silvia; Salzano, Giuseppina; Luce, Amalia; Stoppacciaro, Antonella; Balestrieri, Maria Luisa; Artuso, Simona; Lusa, Sara; De Rosa, Giuseppe; Leonetti, Carlo; Caraglia, Michele

2014-11-15

Glioblastomas are highly aggressive adult brain tumors with poor clinical outcome. In the central nervous system (CNS) the blood-brain barrier (BBB) is the most important limiting factor for both development of new drugs and drug delivery. Here, we propose a new strategy to treat glioblastoma based on transferrin (Tf)-targeted self-assembled nanoparticles (NPs) incorporating zoledronic acid (ZOL) (NPs-ZOL-Tf). NPs-ZOL-Tf have been assessed on the glioblastoma cell line U373MG-LUC that showed a refractoriness in vitro to temozolomide (TMZ) and fotemustine (FTM). NPs-ZOL-Tf treatment resulted in higher in vitro cytotoxic activity than free ZOL. However, the potentiation of anti-proliferative activity of NPs-ZOL-Tf was superimposable to that one induced by NPs-ZOL (not armed with Tf). On the other hand, NPs-ZOL-Tf showed a higher antitumor efficacy if compared with that one caused by NPs-ZOL in immunosuppressed mice intramuscularly bearing U373MG-LUC xenografts, inducing a significant tumor weight inhibition (TWI). The experiments performed on mice with intracranial U373MG-LUC xenografts confirmed the efficacy of NPs-ZOL-Tf. These effects were paralleled by a higher intratumour localization of fluorescently-labeled-NPs-Tf both in intramuscular and intracranial xenografts. In conclusion, our results demonstrate that the encapsulation of ZOL increases the antitumor efficacy of this drug in glioblastoma through the acquisition of ability to cross the BBB.

Effects of green tea and bisphosphonate association on dental socket repair of rats.

PubMed

Mada, Edson Yoshihiro; Santos, Alana Claro Cunha; Fonseca, Angelica Cristina; Biguetti, Claudia Cristina; Neves, Fernando Tozze Alves; Saraiva, Patrícia Pinto; Matsumoto, Mariza Akemi

2017-03-01

To evaluate the effects of green tea intake and zoledronic acid intravenous therapy on teeth socket repair. Sixty male albinus Wistar rats were divided into 4 groups: C-Control, intravenous (IV) 0.9% saline solution (SS), GT-1% green tea in drinking water and IV SS, BP-IV zoledronic acid (BP), and BP+GT-IV BP and 1% green tea. 0.035mg/kg of BP was administered every two weeks. After ten weeks, right upper molars were extracted and the green tea started to be offered for GT and BP+GT. After 7, 14, and 28days the animals were euthanized. Histopathology analysis revealed lack of socket repair in BP and BP+GT groups, which presented significant increased number of polimorphonuclear leukocytes at day 28, in comparison with C (p<0.05). No significant differences were detected between C and the experimental groups at the same period (p<0.05) when considering mononuclear leukocytes. Immunolabeling revealed that the association of BP and GT caused a slight disturbance in OPG/RANKL system and retarded Runx-2 labeling. Although strong TRAP labeling was observed, most of the positive cells in BP and BP+GT groups were not located on bone surface. Socket healing of rats treated with BP and regular drinking green tea presented no relevant differences in comparison to those treated with BP alone. Copyright © 2016 Elsevier Ltd. All rights reserved.

Medical treatment of orthotopic glioblastoma with transferrin-conjugated nanoparticles encapsulating zoledronic acid

PubMed Central

Porru, Manuela; Zappavigna, Silvia; Salzano, Giuseppina; Luce, Amalia; Stoppacciaro, Antonella; Balestrieri, Maria Luisa; Artuso, Simona; Lusa, Sara; De Rosa, Giuseppe; Leonetti, Carlo; Caraglia, Michele

2014-01-01

Glioblastomas are highly aggressive adult brain tumors with poor clinical outcome. In the central nervous system (CNS) the blood-brain barrier (BBB) is the most important limiting factor for both development of new drugs and drug delivery. Here, we propose a new strategy to treat glioblastoma based on transferrin (Tf)-targeted self-assembled nanoparticles (NPs) incorporating zoledronic acid (ZOL) (NPs-ZOL-Tf). NPs-ZOL-Tf have been assessed on the glioblastoma cell line U373MG-LUC that showed a refractoriness in vitro to temozolomide (TMZ) and fotemustine (FTM). NPs-ZOL-Tf treatment resulted in higher in vitro cytotoxic activity than free ZOL. However, the potentiation of anti-proliferative activity of NPs-ZOL-Tf was superimposable to that one induced by NPs-ZOL (not armed with Tf). On the other hand, NPs-ZOL-Tf showed a higher antitumor efficacy if compared with that one caused by NPs-ZOL in immunosuppressed mice intramuscularly bearing U373MG-LUC xenografts, inducing a significant tumor weight inhibition (TWI). The experiments performed on mice with intracranial U373MG-LUC xenografts confirmed the efficacy of NPs-ZOL-Tf. These effects were paralleled by a higher intratumour localization of fluorescently-labeled-NPs-Tf both in intramuscular and intracranial xenografts. In conclusion, our results demonstrate that the encapsulation of ZOL increases the antitumor efficacy of this drug in glioblastoma through the acquisition of ability to cross the BBB. PMID:25431953

Reaction of 3-Amino-1,2,4-Triazole with Diethyl Phosphite and Triethyl Orthoformate: Acid-Base Properties and Antiosteoporotic Activities of the Products.

PubMed

Miszczyk, Patrycja; Wieczorek, Dorota; Gałęzowska, Joanna; Dziuk, Błażej; Wietrzyk, Joanna; Chmielewska, Ewa

2017-02-08

The reaction of diethyl phosphite with triethyl orthoformate and a primary amine followed by hydrolysis is presented, and the reaction was suitable for the preparation of (aminomethylene)bisphosphonates. 3-Amino-1,2,4-triazole was chosen as an interesting substrate for this reaction because it possesses multiple groups that can serve as the amino component in the reaction-namely, the side-chain and triazole amines. This substrate readily forms 1,2,4-triazolyl-3-yl-aminomethylenebisphosphonic acid (compound 1 ) as a major product, along with N -ethylated bisphosphonates as side products. The in vitro antiproliferative effects of the synthesized aminomethylenebisphosphonic acids against J774E macrophages were determined. These compounds exhibit similar activity to zoledronic acid and higher activity than incadronic acid.

Fractures and mortality in relation to different osteoporosis treatments.

PubMed

Yun, Huifeng; Delzell, Elizabeth; Saag, Kenneth G; Kilgore, Meredith L; Morrisey, Michael A; Muntner, Paul; Matthews, Robert; Guo, Lingli; Wright, Nicole; Smith, Wilson; Colón-Emeric, Cathleen; O'Connor, Christopher M; Lyles, Kenneth W; Curtis, Jeffrey R

2015-01-01

Few studies have assessed the effectiveness of different drugs for osteoporosis (OP). We aimed to determine if fracture and mortality rates vary among patients initiating different OP medications. We used the Medicare 5% sample to identify new users of intravenous (IV) zoledronic acid (n=1.674), oral bisphosphonates (n=32.626), IV ibandronate (n=492), calcitonin (n=2.606), raloxifene (n=1.950), or parathyroid hormone (n=549). We included beneficiaries who were ≥65 years of age, were continuously enrolled in fee-for-service Medicare and initiated therapy during 2007-2009. Outcomes were hip fracture, clinical vertebral fracture, and all-cause mortality, identified using inpatient and physician diagnosis codes for fracture, procedure codes for fracture repair, and vital status information. Cox regression models compared users of each medication to users of IV zoledronic acid, adjusting for multiple confounders. During follow-up (median, 0.8-1.5 years depending on the drug), 787 subjects had hip fractures, 986 had clinical vertebral fractures, and 2.999 died. Positive associations included IV ibandronate with hip fracture (adjusted hazard ratio (HR), 2.37; 95% confidence interval (CI) 1.25-4.51), calcitonin with vertebral fracture (HR=1.59, 95%CI 1.04-2.43), and calcitonin with mortality (HR=1.31; 95%CI 1.02-1.68). Adjusted HRs for other drug-outcome comparisons were not statistically significant. IV ibandronate and calcitonin were associated with higher rates of some types of fracture when compared to IV zolendronic acid. The relatively high mortality associated with use of calcitonin may reflect the poorer health of users of this agent.

Osteoprotegerin reduces the development of pain behaviour and joint pathology in a model of osteoarthritis.

PubMed

Sagar, Devi Rani; Ashraf, Sadaf; Xu, Luting; Burston, James J; Menhinick, Matthew R; Poulter, Caroline L; Bennett, Andrew J; Walsh, David A; Chapman, Victoria

2014-08-01

Increased subchondral bone turnover may contribute to pain in osteoarthritis (OA). To investigate the analgesic potential of a modified version of osteoprotegerin (osteoprotegerin-Fc (OPG-Fc)) in the monosodium iodoacetate (MIA) model of OA pain. Male Sprague Dawley rats (140-260 g) were treated with either OPG-Fc (3 mg/kg, subcutaneously) or vehicle (phosphate-buffered saline) between days 1 and 27 (pre-emptive treatment) or days 21 and 27 (therapeutic treatment) after an intra-articular injection of MIA (1 mg/50 µl) or saline. A separate cohort of rats received the bisphosphonate zoledronate (100 µg/kg, subcutaneously) between days 1 and 25 post-MIA injection. Incapacitance testing and von Frey (1-15 g) hind paw withdrawal thresholds were used to assess pain behaviour. At the end of the study, rats were killed and the knee joints and spinal cord removed for analysis. Immunohistochemical studies using Iba-1 and GFAP quantified levels of activation of spinal microglia and astrocytes, respectively. Joint sections were stained with haematoxylin and eosin or Safranin-O fast green and scored for matrix proteoglycan and overall joint morphology. The numbers of tartrate-resistant acid phosphatase-positive osteoclasts were quantified. N=10 rats/group. Pre-emptive treatment with OPG-Fc significantly attenuated the development of MIA-induced changes in weightbearing, but not allodynia. OPG-Fc decreased osteoclast number, inhibited the formation of osteophytes and improved structural pathology within the joint similarly to the decrease seen after pretreatment with the bisphosphonate, zoledronate. Therapeutic treatment with OPG-Fc decreased pain behaviour, but did not improve pathology in rats with established joint damage. Our data suggest that early targeting of osteoclasts may reduce pain associated with OA. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Topical bisphosphonate augments fixation of bone-grafted hydroxyapatite coated implants, BMP-2 causes resorption-based decrease in bone.

PubMed

Baas, Jorgen; Vestermark, Marianne; Jensen, Thomas; Bechtold, Joan; Soballe, Kjeld; Jakobsen, Thomas

2017-04-01

Bone allograft is used in total joint arthroplasties in order to enhance implant fixation. BMPs are known to stimulate new bone formation within allograft, but also known to accelerate graft resorption. Bisphosphonates are strong inhibitor of bone resorption. The aim of this study was to investigate whether the bisphosphonate zoledronate was able to counteract the accelerated graft resorption without interfering with the BMP induced bone formation. In the present study the two drugs alone and in combination were studied in our canine model of impaction bone grafting. We included 10 dogs in this study. Cancellous allograft bone grafts were soaked in either saline or zoledronate solution (0.005mg/mL) and then vehicle or BMP2 (0.15mg rhBMP2) was added. This produced four treatment groups: A) control, B) BMP2, C) zoledronate and D) BMP2+zoledronate. The allograft treated with A, B, C or D was impacted into a circumferential defect of 2.5mm around HA-coated porous Ti implants. Each dog received all four treatment groups with two implants in the distal part of each femur. The group with allograft soaked in zoledronate (C) showed better biomechanical fixation than all other groups (p<0.05). It had less allograft resorption compared to all other groups (p<0.005) without any statistically significant change in new bone formation. The addition of BMP2 to the allograft did not increase new bone formation significantly, but did accelerate allograft resorption. This was also the case where the allograft was treated with BMP2 and zoledronate in combination (D). This caused a decrease in mechanical implant fixation in both these groups compared to the control group, however only statistically significant for the BMP2 group compared to control. The study shows that topical zoledronate can be a valuable tool for augmenting bone grafts when administered optimally. The use of BMP2 in bone grafting procedures seems associated with a high risk of bone resorption and mechanical weakening. Copyright © 2017 Elsevier Inc. All rights reserved.

Topical Bisphosphonate Augments Fixation of Bone-grafted Hydroxyapatite coated Implants, BMP-2 causes Resorption-based decrease in Bone

PubMed Central

Baas, Jorgen; Vestermark, Marianne; Jensen, Thomas; Bechtold, Joan; Soballe, Kjeld; Jakobsen, Thomas

2017-01-01

Bone allograft is used in total joint artroplasties in order to enhance implant fixation. BMPs are known to stimulate new bone formation within allograft, but also known to accelerate graft resorption. Bisphosphonates are strong inhibitor of bone resorption. The aim of this study was to investigate whether the bisphosphonate zoledronate was able to counteract the accelerated graft resorption without interfering with the BMP induced bone formation. In the present study the two drugs alone and in combination were studied in our canine model of impaction bone grafting. We included 10 dogs in this study. Cancellous allograft bone grafts were soaked in either saline or zoledronate solution (0.005 mg/mL) and then vehicle or BMP2 (0.15 mg rhBMP2) was added. This produced four treatment groups: A) control B) BMP2 C) zoledronate and D) BMP2+ zoledronate. The allograft treated with A,B,C or D was impacted into a circumferential defect of 2.5 mm around HA-coated porous Ti implants. Each dog received all four treatment groups with two implants in the distal part of each femur. The group with allograft soaked in zoledronate (C) showed better biomechanical fixation than all other groups (p<0.05). It had less allograft resorption compared to all other groups (p<0.005) without any statistically significant change in new bone formation. The addition of BMP2 to the allograft did not increase new bone formation significantly, but did accelerate allograft resorption. This was also the case where the allograft was treated with BMP2 and zoledronate in combination (D). This caused a decrease in mechanical implant fixation in both these groups compared to the control group, however only statistically significant for the BMP2 group compared to control. The study shows that topical zoledronate can be a valuable tool for augmenting bone grafts when administered optimally. The use of BMP2 in bone grafting procedures seems associated with a high risk of bone resorption and mechanical weakening. PMID:28082076

Mechanisms of Radiation-Induced Bone Loss and Effects on Prostate Cancer Bone Metastases

DTIC Science & Technology

2013-06-01

and in vivo bone imaging [months 6-10]. b. Determine apoptosis of bone cells (OT, OB & OC) by quantifying TUNEL staining [months 6-10]. Animal...Zoledronic acid will be used as positive control for inhibition of apoptosis and also inhibition of resorption [month 10]. c. Perform in vivo bone imaging ...described and presented in Task 3. Task 5: Image calvarial osteocytes in real-time after single dose exposure of 2 Gy [months 6-12] A single dose of

Rac1/Pak1/p38/MMP-2 axis regulates angiogenesis in ovarian cancer

PubMed Central

Gonzalez-Villasana, Vianey; Fuentes-Mattei, Enrique; Ivan, Cristina; Dalton, Heather J.; Rodriguez-Aguayo, Cristian; Fernandez-de Thomas, Ricardo J.; Aslan, Burcu; Monroig, Paloma del C.; Velazquez-Torres, Guermarie; Previs, Rebecca A.; Pradeep, Sunila; Kahraman, Nermin; Wang, Huamin; Kanlikilicer, Pinar; Ozpolat, Bulent; Calin, George; Sood, Anil K.; Lopez-Berestein, Gabriel

2015-01-01

Purpose Zoledronic acid (ZA) is being increasingly recognized for its anti-tumor properties, but the underlying functions are not well understood. In this study, we hypothesized that ZA inhibits ovarian cancer (OC) angiogenesis preventing Rac1 activation. Experimental Design The biological effects of ZA were examined using a series of in vitro (cell invasion, cytokine production, Rac1 activation, reverse-phase protein array and in vivo (orthotopic mouse models) experiments. Results There was significant inhibition of OC (HeyA8-MDR and OVCAR-5) cell invasion as well as reduced production of pro-angiogenic cytokines in response to ZA treatment. Furthermore, ZA inactivated Rac1 and decreased the levels of Pak1/p-38/matrix metalloproteinase-2 in OC cells. In vivo, ZA reduced tumor growth, angiogenesis and cell proliferation and inactivated Rac1 in both HeyA8-MDR and OVCAR-5 models. These in vivo antitumor effects were enhanced in both models when ZA was combined with nab-paclitaxel. Conclusion ZA has robust anti-tumor and anti-angiogenic activity and merits further clinical development as OC treatment. PMID:25595279

Teriparatide and the treatment of bisphosphonate-related osteonecrosis of the jaw: a rat model.

PubMed

Ersan, N; van Ruijven, L J; Bronckers, A L J J; Olgaç, V; Ilgüy, D; Everts, V

2014-01-01

The objectives of this study were to establish a bisphosphonate-related osteonecrosis of the jaw (BRONJ) rat model and to analyse the effects of teriparatide (TP) on this model. Sprague-Dawley rats were divided into three groups: I-zoledronic acid (ZA, n = 10); II-ZA and teriparatide (ZA + TP, n = 10); III-control (n = 10). Osteonecrosis was induced by administering zoledronic acid to groups ZA and ZA + TP. A week after the injections, rats underwent extraction of the first left mandibular molar. Following a four week period, TP was administered to the ZA + TP group for 28 days. Upon killing, extraction sockets were examined clinically, radiologically and histopathologically. Clinical examination revealed necrotic bone exposure in none of the animals. MicroCT (µCT) examination showed that bone mineral density of the newly formed bone in the extraction socket was lower in the ZA group than in the ZA + TP group (p < 0.05). Histopathological examination revealed that only the ZA and ZA + TP groups developed osteonecrosis, and the osteonecrotic bone area in the ZA group was larger than that in the ZA + TP group (p < 0.05). Tartrate-resistant acid phosphatase (TRAcP) enzyme histochemistry revealed that the number of detached and large osteoclasts were higher in the ZA group than in other groups, whereas the number of apoptotic osteoclasts in both ZA and ZA + TP groups were higher than in the control group (p < 0.05). Our data indicate that bisphosphonate-related osteonecrosis of the jaw model used in the present study is an attractive model to investigate treatment modalities and that TP might be an effective treatment in BRONJ.

Diminished Progression of Periapical Lesions with Zoledronic Acid in Ovariectomized Rats.

PubMed

Wayama, Marcelo Tadahiro; Yoshimura, Hitoshi; Ohba, Seigo; Yoshida, Hisato; Matsuda, Shinpei; Kobayashi, Junichi; Kobayashi, Motohiro; Gomes Filho, João Eduardo; Sano, Kazuo

2015-12-01

The aim of this study was to investigate the effects of systemically administered zoledronic acid (ZOL) on the progression of periapical lesions in estrogen-deficient rats. Female Wistar rats were divided into the following groups: SHAM-veh, sham surgery treated with vehicle (physiological saline); OVX-veh, ovariectomy treated with vehicle; SHAM-ZOL, sham surgery treated with ZOL; and OVX-ZOL, ovariectomy treated with ZOL. Vehicle or ZOL was administered intravenously once a week for 4 weeks. The pulp of the mandibular first molar of all rats was exposed to the oral environment to induce a periapical lesion, and the lesions were analyzed after 7 and 30 days. The mandibles were examined by micro-computed tomographic imaging and histopathologic, histometric, and immunohistochemical analyses. Histopathologically, the OVX-veh group had more severe inflammation and bone loss and a larger number of cells that were positive for tartrate-resistant acid phosphatase compared with the SHAM-veh and OVX-ZOL groups; the SHAM-veh and OVX-ZOL groups were similar to each other. The SHAM-ZOL group had the lowest magnitude of these conditions. Tomographically, the OVX-veh group had greater bone loss than the other groups at both time points. The SHAM-veh, SHAM-ZOL, and OVX-ZOL groups had similar bone loss at both time points. In the sagittal section on day 30, the SHAM-ZOL group had lower bone loss compared with the SHAM-veh and OVX-ZOL groups. The hypoestrogenic condition aggravates the progression of periapical lesions. ZOL therapy may help contain bone destruction of periapical lesions. Copyright © 2015 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Biostimulatory effects of low-level laser therapy on epithelial cells and gingival fibroblasts treated with zoledronic acid

NASA Astrophysics Data System (ADS)

Basso, F. G.; Pansani, T. N.; Turrioni, A. P. S.; Kurachi, C.; Bagnato, V. S.; Hebling, J.; de Souza Costa, C. A.

2013-05-01

Low-level laser therapy (LLLT) has been considered as an adjuvant treatment for bisphosphonate-related osteonecrosis, presenting positive clinical outcomes. However, there are no data regarding the effect of LLLT on oral tissue cells exposed to bisphosphonates. This study aimed to evaluate the effects of LLLT on epithelial cells and gingival fibroblasts exposed to a nitrogen-containing bisphosphonate—zoledronic acid (ZA). Cells were seeded in wells of 24-well plates, incubated for 48 h and then exposed to ZA at 5 μM for an additional 48 h. LLLT was performed with a diode laser prototype—LaserTABLE (InGaAsP—780 nm ± 3 nm, 25 mW), at selected energy doses of 0.5, 1.5, 3, 5, and 7 J cm-2 in three irradiation sessions, every 24 h. Cell metabolism, total protein production, gene expression of vascular endothelial growth factor (VEGF) and collagen type I (Col-I), and cell morphology were evaluated 24 h after the last irradiation. Data were statistically analyzed by Kruskal-Wallis and Mann-Whitney tests at 5% significance. Selected LLLT parameters increased the functions of epithelial cells and gingival fibroblasts treated with ZA. Gene expression of VEGF and Col-I was also increased. Specific parameters of LLLT biostimulated fibroblasts and epithelial cells treated with ZA. Analysis of these in vitro data may explain the positive in vivo effects of LLLT applied to osteonecrosis lesions.

High serum ALP level is associated with increased risk of denosumab-related hypocalcemia in patients with bone metastases from solid tumors.

PubMed

Kinoshita, Yuka; Arai, Makoto; Ito, Nobuaki; Takashi, Yuichi; Makita, Noriko; Nangaku, Masaomi; Shinoda, Yusuke; Fukumoto, Seiji

2016-05-31

Metastatic bone disease is one of the most common complications of advanced cancers. Pathological fractures, spinal cord compression, and radiotherapy or surgery to the bone are collectively called skeletal-related events (SREs), which cause severe pain, increase hospitalization rates, and impair the quality of life (QOL) of patients with bone metastases. The receptor activator of nuclear factor-kB ligand (RANKL)/RANK pathway is critical in the progression of bone metastases. Previous studies have demonstrated that an anti-RANKL antibody (denosumab) was superior to zoledronic acid in prolonging time to first SRE in patients with bone metastases from prostate and breast cancers. However, severe hypocalcemic events occur more frequently after treatment with denosumab compared with zoledronic acid. In this study, 368 administrations of denosumab in 219 patients with metastatic bone disease from solid tumors were analyzed to clarify the risk factors for developing hypocalcemia. The results showed that grade 2/3 hypocalcemia was observed in 10.4% of the total number of denosumab administrations. Patients with higher baseline serum ALP, higher performance status (PS), or gastric cancer were at higher risk for developing hypocalcemia. The cut-off value for ALP to predict denosumab-related hypocalcemia was 587 U/L with a sensitivity of 0.77 and a specificity of 0.81. Close monitoring of serum calcium, especially after the first treatment with denosumab, is strongly recommended in these patients.

In vitro comparison of new bisphosphonic acids and zoledronate effects on human gingival fibroblasts viability, inflammation and matrix turnover.

PubMed

De Colli, Marianna; Tortorella, Paolo; Marconi, Guya Diletta; Agamennone, Mariangela; Campestre, Cristina; Tauro, Marilena; Cataldi, Amelia; Zara, Susi

2016-11-01

Bisphosphonates (BPs) are drugs clinically used in resorptive diseases. It was already proved that some clinically relevant BPs can inhibit a class of enzymes called matrix metalloproteinases (MMPs), required during tissue remodelling. Combining the arylsulfonamide function with the bisphosphonic group, several compounds were synthesized to obtain selective inhibitors of MMPs. The aim of the present study was to compare the effect of zoledronic acid (ZA), the most potent bisphosphonate available as therapy, with new sulfonamide containing BPs in an in vitro model of human gingival fibroblasts (HGFs). Western blot was used to measure procollagen I, β1 integrin MMP-8 and MMP-9, phase contrast and MTT for cell viability; L-lactate-dehydrogenase (LDH) measurement was performed for toxicity evaluation and ELISA for prostaglandin E 2 (PGE 2 ) secretion assessment. When compared with ZA, the treatment with the newly synthesized compounds shows increasing viability, procollagen I expression and decreased expression of β1 integrin in HGFs. Higher levels of released LDH, PGE 2 and MMP-9 expression are recorded in ZA-treated HGFs. Increased levels of MMP-8 are recorded in newly synthesized compounds-treated samples. These findings allowed to conclude that new tested BPs did not affect HGFs viability and adhesion, did not induce cellular toxicity, were not responsible for inflammatory event induction and could preserve the physiological matrix turnover. It could be hypothesized that the new molecules were better tolerated by soft tissues, resulting in lesser side effects.

Cytoprotective effects of melatonin on zoledronic acid-treated human mesenchymal stem cells in vitro.

PubMed

Rodríguez-Lozano, Francisco Javier; García-Bernal, David; Ros-Roca, Maria de Los Ángeles; Algueró, Maria del Carmen; Oñate-Sánchez, Ricardo Elías; Camacho-Alonso, Fabio; Moraleda, Jose María

2015-07-01

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a common clinical complication in patients receiving bisphosphonate therapy. Furthermore, melatonin has been proposed as a therapeutic drug for the oral cavity due to its antioxidant properties. This study aimed to evaluate the cytoprotective effects of melatonin on zoledronic acid (ZA)-treated human mesenchymal stem cells from periodontal ligament (PDLSCs) and bone marrow (BMMSCs). PDLSCs and BMMSCs were exposed to ZA, melatonin or ZA + melatonin for 72 h. Cell proliferation was measured by a colorimetric assay, whereas their mesenchymal phenotype was analyzed by flow cytometry. Proliferation assays showed that BMMSCs presented higher ZA resistance than PDLSCs, as well as a difference in response to the simultaneous treatment of ZA + melatonin. Using PDLSCs, high doses of melatonin significantly increased their proliferation, whereas lower concentrations were enough to enhance ZA-treated BMMSC proliferation. Moreover, PDLSCs displayed a CD90/CD105 downregulation and CD73 upregulation in response to ZA, which was more pronounced in response to melatonin. Furthermore, ZA or ZA + low doses of melatonin induced a decrease of expression of CD90/CD105/CD73 on BMMSCs, while a higher concentration recovered CD73 levels. These results suggest that melatonin has a cytoprotective effect on ZA-treated PDLSCs and BMMSCs. Thus, it could be used for BRONJ prevention. Copyright © 2015 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

Zoledronic acid induces cytogenetic toxicity in male germline cells of Swiss albino mice.

PubMed

Dasari, Ramakrishna; Misra, Sunil

2018-04-12

This study mainly focuses on the cytogenetic toxicity induction by zoledronic acid (ZA), a nitrogen containing bisphosphonate (N-BPs) in the male germline cells of Swiss albino mice. A single intraperitoneal exposure with three different doses of ZA (2, 4, and 8 mg/kg body weight), toxicity was assessed by analyzing spermatogonial metaphase chromosome aberrations at 24 h, aberrant primary spermatocytes at week 4, and abnormal spermatozoa at week 8 posttreatment. Cyclophosphamide (40 mg/kg) and 0.9% NaCl were used as positive and vehicle controls respectively in the study. The results showed that there was a significant induction in the number of chromosomal aberrations especially at two doses of ZA (4 and 8 mg/kg) after 24 h in the spermatogonial cells (p < 0.001) compared to vehicle control. The transmission genetic damages were noticed as aberrant spermatocytes with atypical bivalents (X-Y/autosomal asynapsis) at 4 mg/kg of ZA (p < 0.01) and at 8 mg/kg of ZA (p < 0.001) at week 4 posttreatment. A statistically significant higher number of abnormal spermatozoa (sperm) were also noticed at week 8 posttreatment of both at 4 and 8 mg/kg of ZA (p < 0.001). Hence, from these genotoxicity studies, it can be concluded that ZA is genotoxic in male germline cells and has the potential of transmitting the genotoxic effects from spermatogonial cells to sperm in male Swiss mice.

Survival benefit of zoledronic Acid in postmenopausal breast cancer patients receiving aromatase inhibitors.

PubMed

Ahn, Sung Gwe; Kim, Sung Hyun; Lee, Hak Min; Lee, Seung Ah; Jeong, Joon

2014-12-01

A growing body of evidence indicates that zoledronic acid (ZA) can improve the clinical outcome in patients with breast cancer and low estrogen levels. In the present study, we aimed to investigate the survival benefit of ZA administration in postmenopausal Korean women with breast cancer who were also receiving aromatase inhibitors. Between January 2004 and December 2010, 235 postmenopausal breast cancer patients undergoing aromatase inhibitor therapy were investigated. All patients were postmenopausal, as confirmed by laboratory tests. Of these patients, 77 received adjuvant upfront ZA for at least 1 year in addition to conventional adjuvant treatment. The remaining 158 patients never received ZA and were treated according to the St. Gallen guidelines. The baseline characteristics for ZA treatment were not different between the two groups. The median follow-up time was 62 months, and the patients who received ZA in addition to aromatase inhibitors showed a better recurrence-free survival compared to those who received aromatase inhibitors alone (p=0.035). On multivariate analysis, the patients who received ZA showed a better recurrence-free survival independent of the tumor size, nodal status, progesterone receptor, and histological grade. For this model, Harrell c index was 0.743. The hazard ratio of ZA use for recurrence-free survival was 0.12 (95% confidence interval, 0.01-0.99). Our findings suggest that upfront use of ZA as part of adjuvant treatment can offer a survival benefit to postmenopausal breast cancer patients receiving aromatase inhibitor treatment.

A Biphasic Calcium Sulphate/Hydroxyapatite Carrier Containing Bone Morphogenic Protein-2 and Zoledronic Acid Generates Bone

PubMed Central

Raina, Deepak Bushan; Isaksson, Hanna; Hettwer, Werner; Kumar, Ashok; Lidgren, Lars; Tägil, Magnus

2016-01-01

In orthopedic surgery, large amount of diseased or injured bone routinely needs to be replaced. Autografts are mainly used but their availability is limited. Commercially available bone substitutes allow bone ingrowth but lack the capacity to induce bone formation. Thus, off-the-shelf osteoinductive bone substitutes that can replace bone grafts are required. We tested the carrier properties of a biphasic, calcium sulphate and hydroxyapatite ceramic material, containing a combination of recombinant human bone morphogenic protein-2 (rhBMP-2) to induce bone, and zoledronic acid (ZA) to delay early resorption. In-vitro, the biphasic material released 90% of rhBMP-2 and 10% of ZA in the first week. No major changes were found in the surface structure using scanning electron microscopy (SEM) or in the mechanical properties after adding rhBMP-2 or ZA. In-vivo bone formation was studied in an abdominal muscle pouch model in rats (n = 6/group). The mineralized volume was significantly higher when the biphasic material was combined with both rhBMP-2 and ZA (21.4 ± 5.5 mm3) as compared to rhBMP-2 alone (10.9 ± 2.1 mm3) when analyzed using micro computed tomography (μ-CT) (p < 0.01). In the clinical setting, the biphasic material combined with both rhBMP-2 and ZA can potentially regenerate large volumes of bone. PMID:27189411

Selective efficacy of zoledronic acid on metastasis in a patient-derived orthotopic xenograph (PDOX) nude-mouse model of human pancreatic cancer.

PubMed

Hiroshima, Yukihiko; Maawy, Ali A; Katz, Matthew H G; Fleming, Jason B; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M

2015-03-01

Patient-derived orthotopic xenograft (PDOX) nude-mouse models replicate the behavior of clinical cancer, including metastasis. The objective of the study was to determine the efficacy of zoledronic acid (ZA) on metastasis of a patient-derived orthotopic xenograft (PDOX) nude-mouse model of pancreatic cancer. In the present study, we examined the efficacy of ZA on pancreatic cancer growth and metastasis in a PDOX nude-mouse model. ZA monotherapy did not significantly suppress primary tumor growth. However, the primary tumor weight of gemcitabine (GEM) and combination GEM + ZA-treated mice was significantly decreased compared to the control group (GEM: P = 0.003; GEM + ZA: P = 0.002). The primary tumor weight of GEM + ZA-treated mice was significantly decreased compared to GEM-treated mice (P = 0.016). The metastasis weight decreased in ZA- or GEM-treated mice compared to the control group (ZA: P = 0.009; GEM: P = 0.007. No metastasis was detected in combination GEM + ZA-treated mice compared to the control group (GEM + ZA; P = 0.005). The results of the present study indicate that ZA can selectively target metastasis in a pancreatic cancer PDOX model and that the combination of ZA and GEM should be evaluated clinically in the near future for this highly treatment-resistant disease. © 2014 Wiley Periodicals, Inc.

Addition of zoledronic acid to neoadjuvant chemotherapy does not enhance tumor response in patients with HER2-negative stage II/III breast cancer: the NEOZOTAC trial (BOOG 2010-01).

PubMed

Charehbili, A; van de Ven, S; Smit, V T H B M; Meershoek-Klein Kranenbarg, E; Hamdy, N A T; Putter, H; Heijns, J B; van Warmerdam, L J C; Kessels, L; Dercksen, M; Pepels, M J; Maartense, E; van Laarhoven, H W M; Vriens, B; Wasser, M N; van Leeuwen-Stok, A E; Liefers, G J; van de Velde, C J H; Nortier, J W R; Kroep, J R

2014-05-01

The role of zoledronic acid (ZA) when added to the neoadjuvant treatment of breast cancer (BC) in enhancing the clinical and pathological response of tumors is unclear. The effect of ZA on the antitumor effect of neoadjuvant chemotherapy has not prospectively been studied before. NEOZOTAC is a national, multicenter, randomized study comparing the efficacy of TAC (docetaxel, adriamycin and cyclophosphamide i.v.) followed by granulocyte colony-stimulating factor on day 2 with or without ZA 4 mg i.v. q 3 weeks inpatients withstage II/III, HER2-negative BC. We present data on the pathological complete response (pCR in breast and axilla), on clinical response using MRI, and toxicity. Post hoc subgroup analyses were undertaken to address the predictive value of menopausal status. Addition of ZA to chemotherapy did not improve pCR rates (13.2% for TAC+ZA versus 13.3% for TAC). Postmenopausal women (N = 96) had a numerical benefit from ZA treatment (pCR 14.0% for TAC+ZA versus 8.7% for TAC, P = 0.42). Clinical objective response did not differ between treatment arms (72.9% versus 73.7%). There was no difference in grade III/IV toxicity between treatment arms. Addition of ZA to neoadjuvant chemotherapy did not improve pathological or clinical response to chemotherapy. Further investigations are warranted in postmenopausal women with BC, since this subgroup might benefit from ZA treatment.

Role of zoledronic acid in oncolytic virotherapy: Promotion of antitumor effect and prevention of bone destruction.

PubMed

Yamakawa, Yasuaki; Tazawa, Hiroshi; Hasei, Joe; Osaki, Shuhei; Omori, Toshinori; Sugiu, Kazuhisa; Komatsubara, Tadashi; Uotani, Kouji; Fujiwara, Tomohiro; Yoshida, Aki; Kunisada, Toshiyuki; Urata, Yasuo; Kagawa, Shunsuke; Ozaki, Toshifumi; Fujiwara, Toshiyoshi

2017-09-01

Osteosarcoma is an aggressive malignant bone tumor that causes bone destruction. Although tumor-specific replicating oncolytic adenovirus OBP-301 induces an antitumor effect in an osteosarcoma tumor, it cannot prevent bone destruction. Zoledronic acid (ZOL) is a clinically available agent that inhibits bone destruction. In this study, we investigated the potential of combination therapy with OBP-301 and ZOL against osteosarcomas with bone destruction. The antitumor activity of OBP-301 and ZOL in monotherapy or combination therapy was assessed using three human osteosarcoma cell lines (143B, MNNG/HOS, SaOS-2). The cytotoxic effect of OBP-301 and/or ZOL was measured by assay of cell apoptosis. The effect of OBP-301 and ZOL on osteoclast activation was investigated. The potential of combination therapy against tumor growth and bone destruction was analyzed using an orthotopic 143B osteosarcoma xenograft tumor model. OBP-301 and ZOL decreased the viability of human osteosarcoma cells. Combination therapy with OBP-301 and ZOL displayed a synergistic antitumor effect, in which OBP-301 promoted apoptosis through suppression of anti-apoptotic myeloid cell leukemia 1 (MCL1). Combination therapy significantly inhibited tumor-mediated osteoclast activation, tumor growth and bone destruction compared to monotherapy. These results suggest that combination therapy of OBP-301 and ZOL suppresses osteosarcoma progression via suppression of MCL1 and osteoclast activation. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Zoledronate Effects on Systemic and Jaw Osteopenias in Ovariectomized Periostin-Deficient Mice

PubMed Central

Bonnet, Nicolas; Lesclous, Philippe; Saffar, Jean Louis; Ferrari, Serge

2013-01-01

Osteoporosis and periodontal disease (PD) are frequently associated in the elderly, both concurring to the loss of jaw alveolar bone and finally of teeth. Bisphosphonates improve alveolar bone loss but have also been associated with osteonecrosis of the jaw (ONJ), particularly using oncological doses of zoledronate. The effects and therapeutic margin of zoledronate on jaw bone therefore remain uncertain. We reappraised the efficacy and safety of Zoledronate (Zol) in ovariectomized (OVX) periostin (Postn)-deficient mice, a unique genetic model of systemic and jaw osteopenia. Compared to vehicle, Zol 1M (100 µg/kg/month) and Zol 1W (100 µg/kg/week) for 3 months both significantly improved femur BMD, trabecular bone volume on tissue volume (BV/TV) and cortical bone volume in both OVX Postn+/+ and Postn−/− (all p<0.01). Zol 1M and Zol 1W also improved jaw alveolar and basal BV/TV, although the highest dose (Zol 1W) was less efficient, particularly in Postn−/−. Zol decreased osteoclast number and bone formation indices, i.e. MAR, MPm/BPm and BFR, independently in Postn−/− and Postn+/+, both in the long bones and in deep jaw alveolar bone, without differences between Zol doses. Zol 1M and Zol 1W did not reactivate inflammation nor increase fibrous tissue in the bone marrow of the jaw, whereas the distance between the root and the enamel of the incisor (DRI) remained high in Postn−/− vs Postn+/+ confirming latent inflammation and lack of crestal alveolar bone. Zol 1W and Zol 1M decreased osteocyte numbers in Postn−/− and Postn+/+ mandible, and Zol 1W increased the number of empty lacunae in Postn−/−, however no areas of necrotic bone were observed. These results demonstrate that zoledronate improves jaw osteopenia and suggest that in Postn−/− mice, zoledronate is not sufficient to induce bone necrosis. PMID:23505553

GRAND-4: the German retrospective analysis of long-term persistence in women with osteoporosis treated with bisphosphonates or denosumab.

PubMed

Hadji, P; Kyvernitakis, I; Kann, P H; Niedhart, C; Hofbauer, L C; Schwarz, H; Kurth, A A; Thomasius, F; Schulte, M; Intorcia, M; Psachoulia, E; Schmid, T

2016-10-01

This retrospective database study assessed 2-year persistence with bisphosphonates or denosumab in a large German cohort of women with a first-time prescription for osteoporosis treatment. Compared with intravenous or oral bisphosphonates, 2-year persistence was 1.5-2 times higher and risk of discontinuation was significantly lower (P < 0.0001) with denosumab. Persistence with osteoporosis therapies is critical for fracture risk reduction. Detailed data on long-term persistence (≥2 years) with bisphosphonates and denosumab are sparse. From the German IMS® database, we included women aged 40 years or older with a first-time prescription for bisphosphonates or denosumab between July 2010 and August 2014; patients were followed up until December 2014. The main outcome was treatment discontinuation, with a 60-day permissible gap between filled prescriptions. Two-year persistence was estimated using Kaplan-Meier survival curves, with treatment discontinuation as the failure event. Denosumab was compared with intravenous (i.v.) and oral bisphosphonates separately. Cox proportional hazard ratios (HRs) for the 2-year risk of discontinuation were calculated, with adjustment for age, physician specialty, health insurance status, and previous medication use. Two-year persistence with denosumab was significantly higher than with i.v. or oral bisphosphonates (39.8 % [n = 21,154] vs 20.9 % [i.v. ibandronate; n = 20,472] and 24.8 % [i.v. zoledronic acid; n = 3966] and 16.7-17.5 % [oral bisphosphonates; n = 114,401]; all P < 0.001). Patients receiving i.v. ibandronate, i.v. zoledronic acid, or oral bisphosphonates had a significantly increased risk of treatment discontinuation than did those receiving denosumab (HR = 1.65, 1.28, and 1.96-2.02, respectively; all P < 0.0001). Two-year persistence with denosumab was 1.5-2 times higher than with i.v. or oral bisphosphonates, and risk of discontinuation was significantly lower with denosumab than with bisphosphonates. A more detailed understanding of factors affecting medication-taking behavior may improve persistence and thereby reduce rates of fracture.

Treatment- and Disease-Related Complications of Prostate Cancer

PubMed Central

Simoneau, Anne R

2006-01-01

One of the highlights of the 16th International Prostate Cancer Update was a session on treatment- and disease-related complications of prostate disease. It began with presentation of a challenging case of rising prostate-specific antigen levels after radical prostatectomy, followed by an overview of the use of zoledronic acid in prostate cancer, a review of side effects of complementary medicines, an overview of complications of cryotherapy, an assessment of complications of brachytherapy and external beam radiation therapy, and a comparison of laparoscopy versus open prostatectomy. PMID:17021643

Effect of Nd:YAG laser light on post-extractive socket healing in rats treated with zoledronic acid and dexamethasone

NASA Astrophysics Data System (ADS)

Mergoni, Giovanni; Merigo, Elisabetta; Passerini, Pietro; Corradi, Domenico; Maestri, Roberta; Bussolati, Ovidio; Bianchi, Massimiliano; Sala, Roberto; Govoni, Paolo; Namour, Samir; Vescovi, Paolo

2016-03-01

Introduction The effect of low level laser therapy (LLLT) on the healing process could be useful for the prevention of post-extractive Bisphosphonate-related Osteonecrosis of the Jaws (BRONJ). The aim of the study was to investigate the effect of LLLT on the post-extractive socket healing in rats treated with zoledronic acid and dexamethasone. Material and Methods Thirty male Sprague-Dawley rats were divided in 4 groups: control group (C, n = 5), laser group (L, n = 5), treatment group (T, n = 10) and treatment plus laser group (T+L, n = 10). Rats of group T and T+L received zoledronate 0,1 mg/Kg and dexamethasone 1 mg/Kg every 2 days for 10 weeks. Rats of group C and L were infused with vehicle. After 9 weeks the first maxillary molars were extracted in all rats. Rats of groups L and T+L received laser therapy (Nd:YAG, 1064 nm, 1.25W, 15Hz, 5 min, 14.37 J/cm2) in the socket area at days 0, 2, 4 and 6 after surgery. At 8 days from extraction, the sockets were clinically assessed with a grading score and the wound area was measured with a dedicate software. Histomorphometric evaluation and western blot analysis of osteopontin and osteocalcin expression were performed. Results Group T+L showed a trend toward a better clinical grading score compared to group T (grade I 22% Vs 28 % - grade II 56% Vs 28% - grade III 22% Vs 44%, respectively). The average wound area was similar among the groups. Inhibition of osteoclastic alveolar bone resorption was found in groups T and T+L (P<0.001). Rats of groups L and T+L showed a significant higher expression of osteocalcin compared to rats of groups C and T (C=0.3993; L=1.394; T=0.2922; T+L=1.156; P=0.0001). The expression of osteopontin did not show significant differences in the groups treated with Nd:YAG compared to the ones that did not receive laser irradiation. Conclusion Our findings suggest that laser irradiation after tooth extraction can promote osteoblast differentiation, as demonstrated by the higher expression of osteocalcin. Thus, laser irradiation could be considered a way to improve socket healing in conditions at risk for MRONJ development.

An analysis of current pharmaceutical industry practices for making clinical trial results publicly accessible.

PubMed

Viereck, Christopher; Boudes, Pol

2009-07-01

We compared the clinical trial transparency practices of US/European pharma by analyzing the publicly-accessible clinical trial results databases of major drugs (doripenem, varenicline, lapatinib, zoledronic acid, adalimumab, insulin glargine, raltegravir, gefitinib). We evaluated their accessibility and utility from the perspective of the lay public. We included databases on company websites, http://www.clinicalstudyresults.org, http://www.clinicaltrials.gov and http://clinicaltrials.ifpma.org. Only 2 of 8 company homepages provide a direct link to the results. While the use of common terms on company search engines led to results for 5 of the 8 drugs following 2-4 clicks, no logical pathway was identified. The number of clinical trials in the databases was inconsistent: 0 for doripenem to 45 for insulin glargine. Results from all phases of clinical development were provided for 2 (insulin glargine and gefitinib) of the 8 drugs. Analyses of phase III reports revealed that most critical elements of the International Conference of Harmonization E3 Structure and Content of Synopses for Clinical Trial Reports were provided for 2 (varenicline, lapatinib) of the 8 drugs. For adalimumab and zoledronic acid, only citations were provided, which the lay public would be unable to access. None of the clinical trial reports was written in lay language. User-friendly support, when provided, was of marginal benefit. Only 1 of the databases (gefitinib) permitted the user to find the most recently updated reports. None of the glossaries included explanations for adverse events or statistical methodology. In conclusion, our study indicates that the public faces significant hurdles in finding and understanding clinical trial results databases.

Comparison of the efficacy, adverse effects, and cost of zoledronic acid and denosumab in the treatment of osteoporosis.

PubMed

Sheedy, Kellen C; Camara, Maria I; Camacho, Pauline M

2015-03-01

Injectable osteoporosis drugs are increasing in popularity due to their efficacy and convenient administration. In this retrospective comparison of the two available treatments, denosumab (Prolia®) and zoledronic acid (ZA, Reclast®), we aimed to determine and compare the efficacy and tolerability of denosumab and ZA. The charts of patients who received denosumab and ZA at Loyola Hospital were reviewed, and adverse events were noted. Of primary interest were myalgias, flu-like symptoms, back pain, and fractures. A questionnaire regarding the efficacy, tolerability, and treatment cost supplemented this chart review in a subset of study participants. Bone mineral density (BMD) changes, bone turnover markers, and questionnaire results were also compared. The study cohort consisted of 107 patients (51 denosumab, 56 ZA). The denosumab group had a greater mean increase in spine BMD at 1 year (0.060 g/cm2) than the ZA group (0.021 g/cm2; P = .04). The change in femur and spine BMD at 1 year were not significantly different between the 2 groups. The ZA group had a significantly greater incidence of mild flu-like symptoms (29% ZA group vs. 0% denosumab group; P = .04). The denosumab group had a higher mean increase in spine BMD, and the ZA group had a higher incidence of flu-like symptoms, but the study groups were statistically similar in terms of patient satisfaction. As denosumab is still a relatively new therapy, there were a limited number of patients with posttreatment data available for comparison. As more posttherapy data become available, it can be further investigated.

Activation of p38 MAPK-regulated Bcl-xL signaling increases survival against zoledronic acid-induced apoptosis in osteoclast precursors.

PubMed

Tai, Ta-Wei; Su, Fong-Chin; Chen, Ching-Yu; Jou, I-Ming; Lin, Chiou-Feng

2014-10-01

The nitrogen-containing bisphosphonate zoledronic acid (ZA) induces apoptosis in osteoclasts and inhibits osteoclast-mediated bone resorption. It is widely used to treat osteoporosis. However, some patients are less responsive to ZA treatment, and the mechanisms of resistance are still unclear. Here, we identified that murine osteoclast precursors may develop resistance to ZA-induced apoptosis. These resistant cells survived the apoptotic effect of ZA following an increase in anti-apoptotic Bcl-xL. Pharmacologically inhibiting Bcl-xL facilitated ZA-induced apoptosis. Treatment with ZA activated p38 MAPK, increasing Bcl-xL expression and cell survival. Nuclear import of β-catenin regulated by p38 MAPK determined Bcl-xL mRNA expression and cell survival in response to ZA. ZA also inactivated glycogen synthase kinase (GSK)-3β, a negative upstream regulator of β-catenin, in a p38 MAPK-mediated manner. Synergistic pharmacological inhibition of p38 MAPK with ZA attenuated receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation and facilitated ZA-induced apoptosis. These results demonstrate that elevated Bcl-xL expression mediated by p38 MAPK-regulated GSK-3β/β-catenin signaling is required for cell survival of ZA-induced apoptosis in both osteoclast precursors and osteoclasts. Finally, we demonstrated that inhibiting p38 MAPK-mediated pathway enhanced ZA effect on increasing the bone mineral density of ovariectomized mice. This result suggests that targeting these pathways may represent a potential therapeutic strategy. Copyright © 2014 Elsevier Inc. All rights reserved.

Combination Therapy with Zoledronic Acid and Parathyroid Hormone Improves Bone Architecture and Strength following a Clinically-Relevant Dose of Stereotactic Radiation Therapy for the Local Treatment of Canine Osteosarcoma in Athymic Rats

PubMed Central

Curtis, Ryan C.; Custis, James T.; Ehrhart, Nicole P.; Ehrhart, E. J.; Condon, Keith W.; Gookin, Sara E.; Donahue, Seth W.

2016-01-01

Clinical studies using definitive-intent stereotactic radiation therapy (SRT) for the local treatment of canine osteosarcoma (OSA) have shown canine patients achieving similar median survival times as the current standard of care (amputation and adjuvant chemotherapy). Despite this, there remains an unacceptable high risk of pathologic fracture following radiation treatment. Zoledronic acid (ZA) and parathyroid hormone (PTH) are therapeutic candidates for decreasing this fracture risk post-irradiation. Due to differing mechanisms, we hypothesized that the combined treatment with ZA and PTH would significantly improve bone healing more than ZA or PTH treatment alone. Using an orthotopic model of canine osteosarcoma in athymic rats, we evaluated bone healing following clinically-relevant doses of radiation therapy (12 Gy x 3 fractions, 36 Gy total). Groups included 36 Gy SRT only, 36 Gy SRT plus ZA, 36 Gy SRT plus ZA and PTH, 36 Gy SRT plus PTH, and 36 Gy SRT plus localized PTH treatment. Our study showed significant increases in bone volume and increased polar moments of inertia (in the distal femoral metaphysis) 8 weeks after radiation in the combined (ZA/PTH) treatment group as compared to radiation treatment alone. Histomorphometric analysis revealed evidence of active mineralization at the study endpoint as well as successful tumor-cell kill across all treatment groups. This work provides further evidence for the expanding potential indications for ZA and PTH therapy, including post-irradiated bone disease due to osteosarcoma. PMID:27332712

Combination sclerostin antibody and zoledronic acid treatment outperforms either treatment alone in a mouse model of osteogenesis imperfecta.

PubMed

Little, David G; Peacock, Lauren; Mikulec, Kathy; Kneissel, Michaela; Kramer, Ina; Cheng, Tegan L; Schindeler, Aaron; Munns, Craig

2017-08-01

In this study, we examined the therapeutic potential of anti-Sclerostin Antibody (Scl-Ab) and bisphosphonate treatments for the bone fragility disorder Osteogenesis Imperfecta (OI). Mice with the Amish OI mutation (Col1a2 G610C mice) and control wild type littermates (WT) were treated from week 5 to week 9 of life with (1) saline (control), (2) zoledronic acid given 0.025mg/kg s.c. weekly (ZA), (3) Scl-Ab given 50mg/kg IV weekly (Scl-Ab), or (4) a combination of both (Scl-Ab/ZA). Functional outcomes were prioritized and included bone mineral density (BMD), bone microarchitecture, long bone bending strength, and vertebral compression strength. By dual-energy absorptiometry, Scl-Ab treatment alone had no effect on tibial BMD, while ZA and Scl-Ab/ZA significantly enhanced BMD by week 4 (+16% and +27% respectively, P<0.05). Scl-Ab/ZA treatment also led to increases in cortical thickness and tissue mineral density, and restored the tibial 4-point bending strength to that of control WT mice. In the spine, all treatments increased compression strength over controls, but only the combined group reached the strength of WT controls. Scl-Ab showed greater anabolic effects in the trabecular bone than in cortical bone. In summary, the Scl-Ab/ZA intervention was superior to either treatment alone in this OI mouse model, however further studies are required to establish its efficacy in other preclinical and clinical scenarios. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

Combination Therapy with Zoledronic Acid and Parathyroid Hormone Improves Bone Architecture and Strength following a Clinically-Relevant Dose of Stereotactic Radiation Therapy for the Local Treatment of Canine Osteosarcoma in Athymic Rats.

PubMed

Curtis, Ryan C; Custis, James T; Ehrhart, Nicole P; Ehrhart, E J; Condon, Keith W; Gookin, Sara E; Donahue, Seth W

2016-01-01

Clinical studies using definitive-intent stereotactic radiation therapy (SRT) for the local treatment of canine osteosarcoma (OSA) have shown canine patients achieving similar median survival times as the current standard of care (amputation and adjuvant chemotherapy). Despite this, there remains an unacceptable high risk of pathologic fracture following radiation treatment. Zoledronic acid (ZA) and parathyroid hormone (PTH) are therapeutic candidates for decreasing this fracture risk post-irradiation. Due to differing mechanisms, we hypothesized that the combined treatment with ZA and PTH would significantly improve bone healing more than ZA or PTH treatment alone. Using an orthotopic model of canine osteosarcoma in athymic rats, we evaluated bone healing following clinically-relevant doses of radiation therapy (12 Gy x 3 fractions, 36 Gy total). Groups included 36 Gy SRT only, 36 Gy SRT plus ZA, 36 Gy SRT plus ZA and PTH, 36 Gy SRT plus PTH, and 36 Gy SRT plus localized PTH treatment. Our study showed significant increases in bone volume and increased polar moments of inertia (in the distal femoral metaphysis) 8 weeks after radiation in the combined (ZA/PTH) treatment group as compared to radiation treatment alone. Histomorphometric analysis revealed evidence of active mineralization at the study endpoint as well as successful tumor-cell kill across all treatment groups. This work provides further evidence for the expanding potential indications for ZA and PTH therapy, including post-irradiated bone disease due to osteosarcoma.

Effect of bisphosphonates on root resorption after tooth replantation - a systematic review.

PubMed

Najeeb, Shariq; Siddiqui, Fahad; Khurshid, Zohaib; Zohaib, Sana; Zafar, Muhammad Sohail; Ansari, Shazia Akbar

2017-04-01

Replantation of avulsed teeth may lead to root resorption. Bisphosphonates (BPs), a class of drugs of used to treat resorptive diseases of the bone such as osteoporosis and Paget's disease, have been observed to exert an antiresorptive effect on periodontal bone as well. The antiresorptive properties of BPs could prove them useful in preventing root resorption of replanted avulsed teeth. The aim of this systematic review was to analyze and summarize the currently available literature concerning the use of BPs in preventing root resorption of avulsed teeth. PubMed/MEDLINE, Google Scholar, ISI Web of Knowledge, and Embase databases were searched using keywords 'bisphosphonate', 'replantation', and 'tooth'. Quality assessment of each study was carried out. In addition, general characteristics and outcomes of each study were summarized. After exclusion of 116 irrelevant articles, 10 animal studies were included in this review. The majority of the studies suggest that surface application of zoledronate or alendronate reduces root resorption of replanted teeth in animal models. Surface treatment with etidronate had no significant effect on root resorption, and intracanal etidronate accelerated resorption. Surface application of zoledronate and alendronate reduces root resorption of replanted teeth in animal models. However, the efficacy of intracanal usage of BPs is still debatable. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

[gammadelta T cells stimulated by zoledronate kill osteosarcoma cells].

PubMed

Jiang, Hui; Xu, Qiang; Yang, Chao; Cao, Zhen-Guo; Li, Zhao-Xu; Ye, Zhao-Ming

2010-12-01

To investigate the cytotoxicity of human γδT cells from PBMCs stimulated by zoledronate against osteosarcoma cell line HOS in vitro and in vivo and evaluate the relavent pathways. The peripheral blood mononuclear cells (PBMCs)of healthy donors were stimulated by single dose zoledronate and cultured in the present of IL-2 for two weeks, analysising the percentage of γδT cells on a FACSCalibur cytometer.Study the cytotoxicity of γδT cells against the osteosarcoma line HOS using LDH release assay kit. Pre-treatment of γδT cells with anti-human γδTCR antibody, anti-human NKG2D antibody and concanamycin A to bolck the relavent pathways for evaluating the mechenisms of its cytotoxicity. In vivo, BALB/c mice were inoculated subcutaneously osteosarcoma cell HOS for developing hypodermal tumors. And they were randomized into two groups: unteated group, γδT cell therapy group. Tumor volume and weight of the two groups were compared. After two weeks of culture, γδT cells from zoledronate-stimulated PBMCs could reach (95±3)%. When the E:T as 6:1, 12:1, 25:1, 50:1, the percentage of osteosarcoma cell HOS killed by γδT cells was 26.8%, 31.5%, 37.8%, 40.9%, respectively.When anti-huma γδTCR antibody, anti-human NKG2D antibody and concanamycin A blocked the relavent pathways, the percentage was 32.3%, 4.7%, 16.7% ( E:T as 25:1), respectively. In vivo, the tumor inhibition rate of the group of γδT cell therapy was 42.78%. γδT cells derived from PBMCs stimulated by zoledronate can acquired pure γδT cells. And they show strong cytoxicity against osteosarcoma cell line HOS in vitro and in vivo.

Successful treatment of pain in melorheostosis with zoledronate, with improvement on bone scintigraphy.

PubMed

Slimani, Samy; Nezzar, Adlen; Makhloufi, Hachemi

2013-06-21

Melorheostosis is a very rare sclerosing bone disorder that involves frequently one limb. It may be asymptomatic, but pain and limb deformity may occur and can be very debilitating. Different reports have indicated efficacy of bisphosphonates (pamidronate and etidronate) on symptoms. We report an adult patient with a very painful melorheostosis, who  improved after treatment with zoledronate, either on symptoms or on bone scans.

Expression of Dlx-5 and Msx-1 in Craniofacial Skeletons and Ilia of Rats Treated With Zoledronate.

PubMed

Xuan, Bin; Yang, Pan; Wu, Shichao; Li, Lin; Zhang, Jian; Zhang, Wenyi

2017-05-01

Because of the different embryologic origins of the craniofacial skeleton and ilium, differences in gene expression patterns have been observed between the jaw bones and ilium. Distal-less homeobox (Dlx) genes and Msh homeobox genes, particularly Dlx-5 and Msx-1, play major roles in cell differentiation and osteogenesis. The purpose of this study was to investigate the effects of zoledronate (ZOL) on the craniofacial skeleton and ilium by detecting changes in Dlx-5 and Msx-1 expression at both the protein and messenger RNA levels. A total of 24 female Sprague-Dawley rats were randomly divided into 2 groups: ZOL group (n = 12), in which the rats were injected intraperitoneally with zoledronic acid for 12 weeks, and control group (n = 12), in which the rats were injected with saline solution for 12 weeks. By use of immunohistochemistry, Western blotting, and real-time reverse transcription polymerase chain reaction, the expression levels of Dlx-5 and Msx-1 in the craniofacial skeleton (including the maxilla, mandible, and parietal bone) and ilium were examined. Dlx-5 expression in the maxilla and mandible was increased at the protein and messenger RNA levels in the ZOL group compared with the control group (P < .01). In addition, Msx-1 expression in the maxilla and mandible was decreased in the ZOL group (P < .01). Furthermore, Dlx-5 and Msx-1 expression in the ilium was decreased in the ZOL group (P < .05). However, no significant difference in Dlx-5 or Msx-1 expression in the parietal bone was observed between the 2 groups (P > .05). Site-specific differences in the effects of ZOL on the craniofacial skeleton and ilium could be explained by differently altered tendencies in Dlx-5 and Msx-1 expression. The jaw bones were more susceptible to the effects of ZOL than the parietal bone and ilium. Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

The effect of zoledronic acid on type and volume of Modic changes among patients with low back pain.

PubMed

Koivisto, Katri; Järvinen, Jyri; Karppinen, Jaro; Haapea, Marianne; Paananen, Markus; Kyllönen, Eero; Tervonen, Osmo; Niinimäki, Jaakko

2017-06-23

Modic changes (MC) are associated with low back pain (LBP). In this study, we compared changes in size and type of MC, after a single intravenous infusion of 5 mg zoledronic acid (ZA) or placebo, among chronic LBP patients with MC on magnetic resonance imaging (MRI), and evaluated whether the MRI changes correlate with symptoms. All patients (N = 19 in ZA, 20 in placebo) had MRI at baseline (0.23-1.5 T) and at one year (1.5-3 T). We evaluated the level, type and volume of all the MC. The MC were classified into M1 (M1 (100%)), predominating M1 (M1/2 (65:35%)) or predominating M2 (M1/2 (35:65%)), and M2 (M2 (100%)). The first two were considered M1-dominant, and the latter two M2-dominant. Volumes of M1 and M2 were calculated separately for the primary MC, which was assumed to cause the symptoms, and the other MC. We analysed the one-year treatment differences in M1 and M2 volumes using analysis of covariance with adjustments for age, sex, body mass index, and smoking. The correlations between the MRI changes and the changes in LBP symptoms were analysed using Pearson correlations. In the ZA group, 84.2% of patients had M1-dominant primary MC at baseline, compared to 50% in the placebo group (p = 0.041). The primary MC in the ZA group converted more likely to M2-dominant (42.1% ZA, 15% placebo; p = 0.0119). The other MC (15 ZA, 8 placebo) were on average 42% smaller and remained largely M2-dominant. The M1 volume of the primary MC decreased in the ZA group, but increased in the placebo group (-0.83 cm 3 vs 0.91 cm 3 ; p = 0.21). The adjusted treatment difference for M1 volume was -1.9 cm 3 (95% CI -5.0 to 1.2; p = 0.22) and for M2 volume 0.23 cm 3 (p = 0.86). In the MC that remained M1-dominant, volume change correlated positively with increased symptoms in the placebo group, whereas the correlations were negative and weak in the ZA group. Zoledronic acid tended to speed up the conversion of M1-dominant into M2-dominant MC and decrease the volume of M1-dominant MC, although statistical significance was not demonstrated. The registration number in ClinicalTrials.gov is NCT01330238 and the date of registration February 11, 2011.

Successful treatment of pain in melorheostosis with zoledronate, with improvement on bone scintigraphy

PubMed Central

Slimani, Samy; Nezzar, Adlen; Makhloufi, Hachemi

2013-01-01

Melorheostosis is a very rare sclerosing bone disorder that involves frequently one limb. It may be asymptomatic, but pain and limb deformity may occur and can be very debilitating. Different reports have indicated efficacy of bisphosphonates (pamidronate and etidronate) on symptoms. We report an adult patient with a very painful melorheostosis, who  improved after treatment with zoledronate, either on symptoms or on bone scans. PMID:23813581

Structural simulation of adenosine phosphate via plumbagin and zoledronic acid competitively targets JNK/Erk to synergistically attenuate osteoclastogenesis in a breast cancer model

PubMed Central

Qiao, H; Wang, T-y; Yu, Z-f; Han, X-g; Liu, X-q; Wang, Y-g; Fan, Q-m; Qin, A; Tang, T-t

2016-01-01

The treatment of breast cancer-induced osteolysis remains a challenge in clinical settings. Here, we explored the effect and mechanism of combined treatment with zoledronic acid (ZA) and plumbagin (PL), a widely investigated component derived from Plumbago zeylanica, against breast cancer-induced osteoclastogenesis. We found that the combined treatment with PL and ZA suppressed cell viability of precursor osteoclasts and synergistically inhibited MDA-MB-231-induced osteoclast formation (combination index=0.28) with the abrogation of recombinant mouse receptor activator of nuclear factor-κB ligand (RANKL)-induced activation of NF-κB/MAPK (nuclear factor-κB/mitogen-activated protein kinase) pathways. Molecular docking suggested a putative binding area within c-Jun N-terminal kinase/extracellular signal-regulated kinase (JNK/Erk) protease active sites through the structural mimicking of adenosine phosphate (ANP) by the spatial combination of PL with ZA. A homogeneous time-resolved fluorescence assay further illustrated the direct competitiveness of the dual drugs against ANP docking to phosphorylated JNK/Erk, contributing to the inhibited downstream expression of c-Jun/c-Fos/NFATc-1 (nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1). Then, in vivo testing demonstrated that the combined administration of PL and ZA attenuated breast cancer growth in the bone microenvironment. Additionally, these molecules prevented the destruction of proximal tibia, with significant reduction of tartrate-resistant acid phosphatase (TRAcP)-positive osteoclast cells and potentiation of apoptotic cancer cells, to a greater extent when combined than when the drugs were applied independently. Altogether, the combination treatment with PL and ZA could significantly and synergistically suppress osteoclastogenesis and inhibit tumorigenesis both in vitro and in vivo by simulating the spatial structure of ANP to inhibit competitively phosphorylation of c-Jun N-terminal kinase/extracellular signal-regulated kinase (JNK/Erk). PMID:26866274

Effects of Local and Systemic Zoledronic Acid Application on Titanium Implant Osseointegration: An Experimental Study Conducted on Two Surface Types.

PubMed

Dundar, Serkan; Yaman, Ferhan; Gecor, Orhan; Cakmak, Omer; Kirtay, Mustafa; Yildirim, Tuba Talo; Karaman, Tahir; Benlidayi, Mehmet Emre

2017-06-01

The aim of this study was to evaluate the effects of local and systemic zoledronic acid (ZA) applications on titaniumoksit ceramic blasted (TiO-CB)- and sandblasted large acid-grit (SLA)-surfaced titanium implant osseointegration. Twelve New Zealand White rabbits were used in the study, divided into 6 groups: the TiO-CB (TiO-CB-CNT) (n = 2) and SLA (SLA-CNT) (n = 2) control groups in which TiO-CB- and SLA-surfaced titanium implants were surgically inserted into rabbit tibias but no treatment was applied; the TiO-CB (TiO-CB-LZA) (n = 2) and SLA (SLA-LZA) (n = 2) local ZA groups in which 1 mL of normal saline solution containing 2 mg of ZA was injected into sockets and after this the implants were integrated; and the TiO-CB (TiO-CB-SZA) (n = 2) and SLA (SLA-SZA) (n = 2) systemic ZA groups in which a single infusion of 0.1 mg/kg of ZA was administered during surgical implant insertion. Following a period of osseointegration, bone implant contact (BIC) was recorded as a proportion of the total implant surface length in direct contact with the bone. Results of this study indicate that BIC was greater in the systemic ZA application groups than in the local ZA application groups, and BIC was greater in the local ZA groups than in the controls. Statistically significant differences in BIC were not detected between the TiO-CB- and SLA-surfaced implants in all the groups. Furthermore, this study did not reveal significant differences between the 2 types of surfaces due to similar average roughness values. Overall, systemic ZA application was found to be more effective in increasing BIC than local ZA application based on the results obtained by testing 2 implant surfaces.

A promising approach for treatment of tumor-induced bone diseases: utilizing bisphosphonate derivatives of nucleoside antimetabolites.

PubMed

Reinholz, Monica M; Zinnen, Shawn P; Dueck, Amylou C; Dingli, David; Reinholz, Gregory G; Jonart, Leslie A; Kitzmann, Kathleen A; Bruzek, Amy K; Negron, Vivian; Abdalla, Abdalla K; Arendt, Bonnie K; Croatt, Anthony J; Sanchez-Perez, Luis; Sebesta, David P; Lönnberg, Harri; Yoneda, Toshiyuki; Nath, Karl A; Jelinek, Diane F; Russell, Stephen J; Ingle, James N; Spelsberg, Thomas C; Dixon, Henry B F Hal; Karpeisky, Alexander; Lingle, Wilma L

2010-07-01

Despite palliative treatments, tumor-induced bone disease (TIBD) remains highly debilitating for many cancer patients and progression typically results in death within two years. Therefore, more effective therapies with enhanced anti-resorptive and cytotoxic characteristics are needed. We developed bisphosphonate-chemotherapeutic conjugates designed to bind bone and hydrolyze, releasing both compounds, thereby targeting both osteoclasts and tumor cells. This study examined the effects of our lead compound, MBC-11 (the anhydride formed between arabinocytidine (AraC)-5'-phosphate and etidronate), on bone tumor burden, bone volume, femur bone mineral density (BMD), and overall survival using two distinct mouse models of TIBD, the 4T1/luc breast cancer and the KAS-6/1-MIP1alpha multiple myeloma models. In mice orthotopically inoculated with 4T1/luc mouse mammary cells, MBC-11 (0.04 microg/day; s.c.) reduced the incidence of bone metastases to 40% (4/10), compared to 90% (9/10; p=0.057) and 100% (5/5; p=0.04) of PBS- or similarly-dosed, zoledronate-treated mice, respectively. MBC-11 also significantly decreased bone tumor burden compared to PBS- or zoledronate-treated mice (p=0.021, p=0.017, respectively). MBC-11 and zoledronate (0.04 microg/day) significantly increased bone volume by two- and four-fold, respectively, compared to PBS-treated mice (p=0.005, p<0.001, respectively). In mice systemically injected with human multiple myeloma KAS-6/1-MIP1alpha cells, 0.04 and 4.0 microg/day MBC-11 improved femur BMD by 13% and 16%, respectively, compared to PBS (p=0.025, p=0.017, respectively) at 10 weeks post-tumor cell injection and increased mean survival to 95 days compared to 77 days in mice treated with PBS (p=0.047). Similar doses of zoledronate also improved femur BMD (p< or =0.01 vs PBS) and increased mean survival to 86 days, but this was not significantly different than in PBS-treated mice (p=0.53). These results demonstrate that MBC-11 decreases bone tumor burden, maintains bone structure, and may increase overall survival, warranting further investigation as a treatment for TIBD. 2010 Elsevier Inc. All rights reserved.

The effects of topical application of bisphosphonates on replanted rat molars.

PubMed

Choi, Sung Chul; Kwon, Yong-Dae; Kim, Kwang Chul; Kim, Gue-Tae

2010-12-01

The purpose of this study was to evaluate the potential usefulness of two bisphosphonates (BPs) (etidronate and zoledronate), compared with that of alendronate, which is a well-known drug for delayed replantation, in decreasing or preventing inflammatory root resorption and replacement root resorption in replanted teeth. Eighty-four Sprague Dawley rat maxillary first molars were extracted, dried for 60 min and then replanted after root treatment. The rats were divided into four groups (control, alendronate, etidronate, zoledronate) as following treatments of avulsed root before replantation. At 7, 14, and 28 days postreplantation, the animals were sacrificed and the samples obtained and process for microscopic analysis. The data were statistically analyzed with the SPSS procedure, anova test and each test was complemented by the Tukey's post hoc test. The result indicated that topical application of alendronate and zoledronate, both nitrogen containing BPs, prevented inflammatory root resorption and inflammatory cell response in the delayed replantation model. Both drugs were demonstrated similar effects in the delayed tooth replantation model (P = 0.9). Etidronate did not prevent inflammatory root resorption and inflammation in the delayed replantation (P < 0.05). No significant differences in replacement root resorption were observed among all drugs. These results suggest that when teeth are dried and not replanted immediately, zoledronate, like alendronate, may prevent root resorption and facilitates the regeneration of periodontal tissues after replantation. © 2010 John Wiley & Sons A/S.

Zoledronic acid overcomes chemoresistance by sensitizing cancer stem cells to apoptosis.

PubMed

Rouhrazi, H; Turgan, N; Oktem, G

2018-01-01

Unlike low tumorigenic bulk tumor cells (non-CSCs), cancer stem cells (CSCs) are a subset of tumor cells that can self-renew and differentiate into different cancer subtypes. CSCs are considered responsible for tumor recurrence, distant metastasis, angiogenesis, and drug or radiation resistance. CSCs also are resistant to apoptosis. Zoledronic acid (ZA) is a third generation bisphosphonate that reduces cell proliferation and exhibits anti-tumor effects by inducing cell death in some malignancies; however, the effects of ZA on CSCs are unclear. We investigated the anti-cancer effects of ZA on two epithelial cancer cell lines, prostate DU-145 and breast MCF7, focusing primarily on induction and activation of apoptosis. Cluster of differentiation (CD) 133 + /CD44 + prostate CSCs and CD 44 + /CD24 breast CSCs were isolated from the DU-145 human prostate cancer and MCF-7 human breast cancer cell lines, respectively, using FACSAria flow cytometry cell sorting. CSCs and non-CSCs were exposed to increasing concentrations of ZA for 24, 48 and 72 h to determine the IC 50 dose. Annexin-V assay for detecting cell death and cell cycle was performed using the Muse™ Cell Analyzer. Prostate CSCs and non-CSCs were assayed by quantitative reverse transcription PCR (qRT-PCR) array for detecting 84 key apoptosis related genes. Gene regulation at the protein level was investigated by immunofluorescence. ZA caused a dose- and time-dependent decrease in cell viability. Treatment with ZA resulted in a concomitant increase in apoptosis and cell cycle arrest at S-phase in CSCs. Significant over/under-expressions were detected in seven of the genes of ZA-treated DU-145 CSCs cells. Expressions of CASP9, CASP4, BAX and BAD genes increased, while the expressions of BIRC3, BIRC2 and BCL2 genes decreased. In the DU-145 non-CSCs, five genes exhibited changes in gene expression after ZA treatment, two exhibited increased expression (CASP7 and BAD) and three exhibited decreased expression (BIRC3, BIRC2 and BCL2). ZA caused cell death of drug resistant breast MCF-7 and prostate DU-145 cancer stem cells by activating apoptosis. ZA can facilitate the intrinsic pathway of apoptosis in human prostate CSCs by down-regulating anti-apoptotic genes and up-regulating pro-apoptotic genes. ZA may be an effective therapeutic agent for targeting chemoresistance in CSCs.

Prospective observational study of treatment pattern, effectiveness and safety of zoledronic acid therapy beyond 24 months in patients with multiple myeloma or bone metastases from solid tumors.

PubMed

Van den Wyngaert, T; Delforge, M; Doyen, C; Duck, L; Wouters, K; Delabaye, I; Wouters, C; Wildiers, H

2013-12-01

To study the treatment patterns, effectiveness and safety of zoledronic acid (ZOL) beyond 2 years of therapy, given the paucity of data on long-term treatment in daily clinical practice. Patients with multiple myeloma (MM) or solid tumor bone metastases (STM) and at least 24 months of regular q3-4w ZOL therapy were followed prospectively for an additional 18 months beyond the 24 months required for study entry. End-points included ZOL exposure, incidence of skeletal related events (SRE), and safety. In all, 298 evaluable patients were enrolled. The mean continuation rate of ZOL was 90.6%. Exposure to ZOL decreased with time in all patients, but was lower (50.0% vs. 67.6%; p<0.001) and with higher discontinuation rates (incidence rate ratio [IRR]=1.95; p=0.002) in MM compared to the STM group. ZOL suppressed the rate of SREs similarly during the study as compared to before inclusion (0.12 vs. 0.13 events per person-year; p=0.7). At 18 months, 84.5% remained SRE-free. In STM patients, persistent ZOL therapy was associated with lower SRE risk (hazard ratio [HR]=0.42; p=0.01), but not in MM. Renal deterioration occurred in 3.7% and osteonecrosis of the jaw (ONJ) developed in 6.0%, with dental trauma increasing ONJ risk (HR=4.67; p=0.002). Beyond 2 years of therapy, treatment patterns of ZOL were heterogeneous and SRE rates were low. The safety profile of ZOL was acceptable, and interrupting ZOL in patients with solid tumors was associated with a higher risk of SREs.

Zoledronic acid has differential antitumor activity in the pre- and postmenopausal bone microenvironment in vivo.

PubMed

Ottewell, Penelope D; Wang, Ning; Brown, Hannah K; Reeves, Kimberly J; Fowles, C Anne; Croucher, Peter I; Eaton, Colby L; Holen, Ingunn

2014-06-01

Clinical trials in early breast cancer have suggested that benefits of adjuvant bone-targeted treatments are restricted to women with established menopause. We developed models that mimic pre- and postmenopausal status to investigate effects of altered bone turnover on growth of disseminated breast tumor cells. Here, we report a differential antitumor effect of zoledronic acid (ZOL) in these two settings. Twleve-week-old female Balb/c-nude mice with disseminated MDA-MB-231 breast tumor cells in bone underwent sham operation or ovariectomy (OVX), mimicking the pre- and postmenopausal bone microenvironment, respectively. To determine the effects of bone-targeted therapy, sham/OVX animals received saline or 100 μg/kg ZOL weekly. Tumor growth was assessed by in vivo imaging and effects on bone by real-time PCR, micro-CT, histomorphometry, and measurements of bone markers. Disseminated tumor cells were detected by two-photon microscopy. OVX increased bone resorption and induced growth of disseminated tumor cells in bone. Tumors were detected in 83% of animals following OVX (postmenopausal model) compared with 17% following sham operation (premenopausal model). OVX had no effect on tumors outside of bone. OVX-induced tumor growth was completely prevented by ZOL, despite the presence of disseminated tumor cells. ZOL did not affect tumor growth in bone in the sham-operated animals. ZOL increased bone volume in both groups. This is the first demonstration that tumor growth is driven by osteoclast-mediated mechanisms in models that mimic post- but not premenopausal bone, providing a biologic rationale for the differential antitumor effects of ZOL reported in these settings. Clin Cancer Res; 20(11); 2922-32. ©2014 AACR. ©2014 American Association for Cancer Research.

Differential Effect of Zoledronic Acid on Human Vascular Smooth Muscle Cells

PubMed Central

Albadawi, Hassan; Haurani, Mounir J.; Oklu, Rahmi; Trubiano, Jordan P.; Laub, Peter J.; Yoo, Hyung-Jin; Watkins, Michael T.

2012-01-01

Introduction The activation of human vascular smooth muscle cell proliferation, adhesion and migration is essential for intimal hyperplasia formation. These experiments were designed to test whether Zoledronic Acid (ZA) would modulate indices of human smooth muscle cell activation, exert differential effects on proliferating vs. quiescent cells and determine whether these effects were dependent on GTPase binding proteins prenylation. ZA was chosen for testing in these experiments because it is clinically used in humans with cancer, and has been shown to modulate rat smooth muscle cell proliferation and migration. Methods Human aortic smooth muscle cells (HASMC) were cultured under either proliferating or growth arrest (quiescent) conditions in the presence or absence of ZA for 48 hours, whereupon the effect of ZA on HASMC proliferation, cellular viability, metabolic activity and membrane integrity were compared. In addition, the effect of ZA on adhesion and migration were assessed in proliferating cells. The effect of increased concentration of ZA on the mevalonate pathway and genomic/cellular stress related poly ADP Ribose polymerase (PARP) enzyme activity were assessed using the relative prenylation of Rap-1A/B protein and the formation of poly ADP- ribosylated proteins (PAR) respectively. Results There was a dose dependent inhibition of cellular proliferation, adhesion and migration following ZA treatment. ZA treatment decreased indices of cellular viability and significantly increased membrane injury in proliferating vs. quiescent cells. This was correlated with the appearance of unprenylated Rap-1A protein and dose dependent down regulation of PARP activity. Conclusions These data suggest that ZA is effective in inhibiting HASMC proliferation, adhesion and migration which coincide with the appearance of unprenylated RAP-1A/B protein, thereby suggesting that the mevalonate pathway may play a role in the inhibition of HASMC activation. PMID:23164362

Zoledronic acid inhibits pulmonary metastasis dissemination in a preclinical model of Ewing’s sarcoma via inhibition of cell migration

PubMed Central

2014-01-01

Background Ewing’s sarcoma (ES) is the second most frequent primitive malignant bone tumor in adolescents with a very poor prognosis for high risk patients, mainly when lung metastases are detected (overall survival <15% at 5 years). Zoledronic acid (ZA) is a potent inhibitor of bone resorption which induces osteoclast apoptosis. Our previous studies showed a strong therapeutic potential of ZA as it inhibits ES cell growth in vitro and ES primary tumor growth in vivo in a mouse model developed in bone site. However, no data are available on lung metastasis. Therefore, the aim of this study was to determine the effect of ZA on ES cell invasion and metastatic properties. Methods Invasion assays were performed in vitro in Boyden’s chambers covered with Matrigel. Matrix Metalloproteinase (MMP) activity was analyzed by zymography in ES cell culture supernatant. In vivo, a relevant model of spontaneous lung metastases which disseminate from primary ES tumor was induced by the orthotopic injection of 106 human ES cells in the tibia medullar cavity of nude mice. The effect of ZA (50 μg/kg, 3x/week) was studied over a 4-week period. Lung metastases were observed macroscopically at autopsy and analysed by histology. Results ZA induced a strong inhibition of ES cell invasion, probably due to down regulation of MMP-2 and −9 activities as analyzed by zymography. In vivo, ZA inhibits the dissemination of spontaneous lung metastases from a primary ES tumor but had no effect on the growth of established lung metastases. Conclusion These results suggest that ZA could be used early in the treatment of ES to inhibit bone tumor growth but also to prevent the early metastatic events to the lungs. PMID:24612486

Enhanced Anti-Tumor Effect of Zoledronic Acid Combined with Temozolomide against Human Malignant Glioma Cell Expressing O6-Methylguanine DNA Methyltransferase

PubMed Central

Fukai, Junya; Koizumi, Fumiaki; Nakao, Naoyuki

2014-01-01

Temozolomide (TMZ), a DNA methylating agent, is widely used in the adjuvant treatment of malignant gliomas. O6-methylguanine-DNA methyltranferase (MGMT), a DNA repair enzyme, is frequently discussed as the main factor that limits the efficacy of TMZ. Zoledronic acid (ZOL), which is clinically applied to treat cancer-induced bone diseases, appears to possess direct anti-tumor activity through apoptosis induction by inhibiting mevalonate pathway and prenylation of intracellular small G proteins. In this study, we evaluated whether ZOL can be effectively used as an adjuvant to TMZ in human malignant glioma cells that express MGMT. Malignant glioma cell lines, in which the expression of MGMT was detected, did not exhibit growth inhibition by TMZ even at a longer exposure. However, combination experiment of TMZ plus ZOL revealed that a supra-additive effect resulted in a significant decrease in cell growth. In combined TMZ/ZOL treatment, an increased apoptotic rate was apparent and significant activation of caspase-3 and cleavage of poly-(ADP-ribose) polymerase were observed compared with each single drug exposure. There were decreased amounts of Ras-GTP, MAPK and Akt phosphorylation and MGMT expression in the ZOL-treated cells. Subcutanous xenograft models showed significant decrease of tumor growth with combined TMZ/ZOL treatment. These results suggest that ZOL efficaciously inhibits activity of Ras in malignant glioma cells and potentiates TMZ-mediated cytotoxicity, inducing growth inhibition and apoptosis of malignant glioma cells that express MGMT and resistant to TMZ. Based on this work, combination of TMZ with ZOL might be a potential therapy in malignant gliomas that receive less therapeutic effects of TMZ due to cell resistance. PMID:25111384

Clinical study evaluating the effect of bevacizumab on the severity of zoledronic acid-related osteonecrosis of the jaw in cancer patients.

PubMed

Lescaille, Géraldine; Coudert, Amélie E; Baaroun, Vanessa; Ostertag, Agnès; Charpentier, Emmanuel; Javelot, Marie-José; Tolédo, Rafael; Goudot, Patrick; Azérad, Jean; Berdal, Ariane; Spano, Jean-Philippe; Ruhin, Blandine; Descroix, Vianney

2014-01-01

This study aimed to evaluate the effect of bevacizumab (BVZ) on the severity of osteonecrosis of the jaw (ONJ) in a cohort of cancer patients treated with intravenous zoledronic acid (ZA). We reviewed 42 oncologic patients with ONJ between 2007 and 2010. Only patients with solids tumors and who had received ZA were included. Data analyses included age, sex, underlying disease, ZA and BVZ dosages, dental history and ONJ characteristics. Of the 42 ONJ patients treated with ZA, 10 also received BVZ. In the 10 ZA/BVZ patients, the mean duration of ZA treatment at the time of ONJ diagnosis was 12.4 months (±6.8), compared to 22.9 months (±4.8) in the 32 patients who received ZA only (p<0.05). Cox's model analysis of the delay to ONJ diagnosis confirmed the impact of BVZ on ONJ diagnosis. In the ZA/BVZ-treated group, 7 (70%) patients developed spontaneous osteonecrosis. Multiple logistic regression analysis showed that ZA/BVZ is associated with increased risk of developing spontaneous ONJ (OR 6.07; 95% CI, [1.3-28.2], p<0.05). And finally, the number of ONJ lesions was increased in the ZA/BVZ-treated group compared to the ZA group (p<0.01). Other clinical conditions as type of tumor (prostate, breast…), cancer severity or other chemotherapy drugs also could be involved in ONJ evolution. However, this study demonstrates for the first time the potential negative influence of BVZ on the incidence and severity of ONJ in patients receiving ZA. Within the study limits, our results suggest that combination ZA/BVZ treatment may possibly predispose to the development of spontaneous and earlier ONJ. © 2013.

Precision cancer immunotherapy: optimizing dendritic cell-based strategies to induce tumor antigen-specific T-cell responses against individual patient tumors.

PubMed

Osada, Takuya; Nagaoka, Koji; Takahara, Masashi; Yang, Xiao Yi; Liu, Cong-Xiao; Guo, Hongtao; Roy Choudhury, Kingshuk; Hobeika, Amy; Hartman, Zachary; Morse, Michael A; Lyerly, H Kim

2015-05-01

Most dendritic cell (DC)-based vaccines have loaded the DC with defined antigens, but loading with autologos tumor-derived antigens would generate DCs that activate personalized tumor-specific T-cell responses. We hypothesized that DC matured with an optimized combination of reagents and loaded with tumor-derived antigens using a clinically feasible electroporation strategy would induce potent antitumor immunity. We first studied the effects on DC maturation and antigen presentation of the addition of picibanil (OK432) to a combination of zoledronic acid, tumor necrosis factor-α, and prostaglandin E2. Using DC matured with the optimized combination, we tested 2 clinically feasible sources of autologous antigen for electroloading, total tumor mRNA or total tumor lysate, to determine which stimulated more potent antigen-specific T cells in vitro and activated more potent antitumor immunity in vivo. The combination of tumor necrosis factor-α/prostaglandin E2/zoledronic acid/OK432 generated DC with high expression of maturation markers and antigen-specific T-cell stimulatory function in vitro. Mature DC electroloaded with tumor-derived mRNA [mRNA electroporated dendritic cell (EPDC)] induced greater expansion of antigen-specific T cells in vitro than DC electroloaded with tumor lysate (lysate EPDC). In a therapeutic model of MC38-carcinoembryonic antigen colon cancer-bearing mice, vaccination with mRNA EPDC induced the most efficient anti-carcinoembryonic antigen cellular immune response, which significantly suppressed tumor growth. In conclusion, mature DC electroloaded with tumor-derived mRNA are a potent cancer vaccine, especially useful when specific tumor antigens for vaccination have not been identified, allowing autologous tumor, and if unavailable, allogeneic cell lines to be used as an unbiased source of antigen. Our data support clinical testing of this strategy.

Toward a noncytotoxic glioblastoma therapy: blocking MCP-1 with the MTZ Regimen

PubMed Central

Salacz, Michael E; Kast, Richard E; Saki, Najmaldin; Brüning, Ansgar; Karpel-Massler, Georg; Halatsch, Marc-Eric

2016-01-01

To improve the prognosis of glioblastoma, we developed an adjuvant treatment directed to a neglected aspect of glioblastoma growth, the contribution of nonmalignant monocyte lineage cells (MLCs) (monocyte, macrophage, microglia, dendritic cells) that infiltrated a main tumor mass. These nonmalignant cells contribute to glioblastoma growth and tumor homeostasis. MLCs comprise of approximately 10%–30% of glioblastoma by volume. After integration into the tumor mass, these become polarized toward an M2 immunosuppressive, pro-angiogenic phenotype that promotes continued tumor growth. Glioblastoma cells initiate and promote this process by synthesizing 13 kDa MCP-1 that attracts circulating monocytes to the tumor. Infiltrating monocytes, after polarizing toward an M2 phenotype, synthesize more MCP-1, forming an amplification loop. Three noncytotoxic drugs, an antibiotic – minocycline, an antihypertensive drug – telmisartan, and a bisphosphonate – zoledronic acid, have ancillary attributes of MCP-1 synthesis inhibition and could be re-purposed, singly or in combination, to inhibit or reverse MLC-mediated immunosuppression, angiogenesis, and other growth-enhancing aspects. Minocycline, telmisartan, and zoledronic acid – the MTZ Regimen – have low-toxicity profiles and could be added to standard radiotherapy and temozolomide. Re-purposing older drugs has advantages of established safety and low drug cost. Four core observations support this approach: 1) malignant glioblastoma cells require a reciprocal trophic relationship with nonmalignant macrophages or microglia to thrive; 2) glioblastoma cells secrete MCP-1 to start the cycle, attracting MLCs, which subsequently also secrete MCP-1 perpetuating the recruitment cycle; 3) increasing cytokine levels in the tumor environment generate further immunosuppression and tumor growth; and 4) MTZ regimen may impede MCP-1-driven processes, thereby interfering with glioblastoma growth. PMID:27175087

Estradiol impairs the antiproliferative and proapoptotic effect of Zoledronic acid in hormone sensitive breast cancer cells in vitro

PubMed Central

Weingartshofer, Sigrid; Grunt, Thomas W.; Mairhofer, Mario; Tan, Yen; Gamper, Jutta; Singer, Christian F.

2017-01-01

Background Zoledronic acid (ZA) has antiresorptive effects and protects from bone metastasis in women with early breast cancer. In addition, in postmenopausal women with endocrine responsive breast cancer ZA prolongs DFS. The exact mechanism is still unclear. We have therefore investigated the effect of increasing concentrations of ZA in breast cancer cell lines in the absence or presence of estradiol to mimic the hormonal environment in vitro. Materials and methods Using assays for cell proliferation (EZ4U, BrdU) and cell death (Annexin/PI), we have analyzed the dose-dependent antiproliferative and pro-apoptotic effects of ZA in two hormone sensitive cell lines (MCF-7 and T47D) and a hormone insensitive, triple negative cell line (MDA-MB-231) in the presence of 0, 1 and 10 nM estradiol. Results In the absence of estradiol, ZA exerts dose-dependent antiproliferative and pro-apoptotic antitumor effects in both, hormone sensitive (MCF-7, T47D) and -insensitive (MDA-MB-231) breast cancer cell lines (p<0.0001). In the presence of estradiol, the antitumoral effect of ZA was significantly decreased only in the hormone sensitive MCF-7 and T47D cell lines (p = 0.0008 and p = 0.0008, respectively). Conclusion We have demonstrated that estradiol impairs the antiproliferative and proapoptotic effect of ZA in hormone sensitive, but not in hormone insensitive breast cancer cell lines. Our findings provide a possible explanation for the differential effect of ZA on DFS in pre- and postmenopausal patients with hormone sensitive early breast cancer, which has been demonstrated clinically. We further hypothesize that endocrine insensitive tumors such as triple negative breast cancer (TNBC) should benefit from ZA irrespective of their menopausal status. PMID:28945801

Is administration of trastuzumab an independent risk factor for developing osteonecrosis of the jaw among metastatic breast cancer patients under zoledronic acid treatment?

PubMed

Pilanci, Kezban Nur; Alco, Gul; Ordu, Cetin; Sarsenov, Dauren; Celebi, Filiz; Erdogan, Zeynep; Agacayak, Filiz; Ilgun, Serkan; Tecimer, Coskun; Demir, Gokhan; Eralp, Yesim; Okkan, Sait; Ozmen, Vahit

2015-05-01

One of the most important adverse effects of zoledronic acid (ZA) is osteonecrosis of the jaw (ONJ). In previous literature, several risk factors have been identified in the development of ONJ. In this study, we aimed to determine the role of trastuzumab, an antiangiogenic agent, as an independent risk factor for the development of this serious side effect.Our study included 97 patients (mean age: 54 ± 10 years) with breast cancer, recorded in the archives of the Istanbul Florence Nightingale Breast Study Group, who received ZA therapy due to bone metastases between March 2006 and December 2013. We recorded the patients' ages, weights, duration of treatment with ZA, number of ZA infusions, dental procedures, anticancer treatments (chemotherapy, aromatase inhibitor, trastuzumab), the presence of diabetes mellitus or renal dysfunction, and smoking habits.Thirteen patients (13.40%) had developed ONJ. Among the patients with ONJ, the mean time of exposure to ZA was 41 months (range: 13-82) and the mean number of ZA infusions was 38 (range: 15-56). The duration of treatment with ZA and the use of trastuzumab were observed to be 2 factors that influenced the development of ONJ (P = 0.049 and P = 0.028, respectively).The development of ONJ under ZA treatment may be associated solely with the duration of ZA treatment and the concurrent administration of trastuzumab. These findings show that patients who are administered trastuzumab for metastatic breast cancer while undergoing ZA treatment are prone to developing ONJ. Therefore, we recommend intense clinical observation to avoid this particular condition in patients receiving ZA and trastuzumab.

Influence of Zoledronic Acid on Atrial Electrophysiological Parameters and Electrocardiographic Measurements.

PubMed

Tisdale, James E; Allen, Matthew R; Overholser, Brian R; Jaynes, Heather A; Kovacs, Richard J

2015-06-01

Our objective was to determine effects of zoledronic acid (ZA) on atrial electrophysiological parameters and electrocardiographic measurements. Ex vivo perfusion study: Isolated guinea pig hearts were perfused with modified Krebs-Henseleit (K-H) buffer with or without ZA 0.07 mg/kg/L (each n = 6). In ZA-perfused hearts, atrial action potential at 90% repolarization (APD90 ) decreased more from baseline than in controls (-23.2% ± -5.1% vs. -2.1% ± -8.1%, P < 0 .0001), as did APD30 (-28.8% ± -3.8% vs. -2.1% ± -2.1%, P < 0.0001). In vivo dose-response study: Guinea pigs underwent intraperitoneal injections every 2 weeks in 1 of 4 groups (each n = 8): ZA 0.007 mg/kg (low-dose), ZA 0.07 mg/kg (medium-dose), ZA 0.7 mg/kg (high-dose), or placebo. Hearts were excised at 8 weeks and perfused with modified K-H. Atrial effective refractory period (ERP) was lower with medium- and high-dose ZA versus placebo (P = 0.004). Atrial APD30 was lower with high-dose ZA versus placebo, low and medium doses (P < 0.001). Canine ECG study: Mature female beagles received intravenous ZA 0.067 mg/kg or saline (placebo; each n = 6) every 2 weeks for 12 weeks. P wave dispersion was greater in the ZA group (7.7 ± 3.7 vs. 3.4 ± 2.6 ms, P = 0.04). There were no significant differences in P wave index, maximum or minimum P wave duration, or PR interval. ZA shortens left atrial APD and ERP and increases P wave dispersion. © 2015 Wiley Periodicals, Inc.

Short-Term Safety of Zoledronic Acid in Young Patients With Bone Disorders: An Extensive Institutional Experience.

PubMed

George, Sobenna; Weber, David R; Kaplan, Paige; Hummel, Kelly; Monk, Heather M; Levine, Michael A

2015-11-01

Zoledronic acid (ZA) is increasingly used in young patients with bone disorders. However, data related to the safety of ZA administration in this population are limited. The study aimed to characterize the short-term safety profile of ZA and identify risk factors for ZA-related adverse events (AEs) in young patients. This was a retrospective chart review of inpatients and outpatients less than 21 years old who received at least one ZA infusion between July 2010 and January 2014 at The Children's Hospital of Philadelphia. Eighty-one patients (56% male; median age, 12 y; age at first infusion, 0.5 to 20 y) with diverse skeletal disorders received a total of 204 infusions. The most common indications were osteoporosis (33% of cohort) and osteogenesis imperfecta (27.2%). The median ZA dose was 0.025 mg/kg (interquartile range, 0.025-0.05); the median dosing interval was 6 months (range, 1 to 25.6 mo). AEs were mild and more common after the first ZA infusion in patients with no previous bisphosphonate exposure: hypophosphatemia (25.2% of infusions), acute phase reactions (19.1%), and hypocalcemia (16.4%). Symptomatic hypocalcemia requiring iv calcium occurred after two infusions. ZA dose was significantly associated with hypophosphatemia, but not other AEs. Hypocalcemia was more common in patients with high bone turnover as assessed by preinfusion alkaline phosphatase levels. AEs were not associated with diagnosis, baseline serum calcium, or calcium/calcitriol supplementation. Acute AEs related to ZA infusion in youths are common, occur principally after the first ZA infusion in bisphosphonate-naive patients, and are typically mild and easily managed. Future prospective studies are needed to determine the potential long-term risks, as well as benefits, of ZA therapy in the pediatric population.

Estradiol impairs the antiproliferative and proapoptotic effect of Zoledronic acid in hormone sensitive breast cancer cells in vitro.

PubMed

Gschwantler-Kaulich, Daphne; Weingartshofer, Sigrid; Grunt, Thomas W; Mairhofer, Mario; Tan, Yen; Gamper, Jutta; Singer, Christian F

2017-01-01

Zoledronic acid (ZA) has antiresorptive effects and protects from bone metastasis in women with early breast cancer. In addition, in postmenopausal women with endocrine responsive breast cancer ZA prolongs DFS. The exact mechanism is still unclear. We have therefore investigated the effect of increasing concentrations of ZA in breast cancer cell lines in the absence or presence of estradiol to mimic the hormonal environment in vitro. Using assays for cell proliferation (EZ4U, BrdU) and cell death (Annexin/PI), we have analyzed the dose-dependent antiproliferative and pro-apoptotic effects of ZA in two hormone sensitive cell lines (MCF-7 and T47D) and a hormone insensitive, triple negative cell line (MDA-MB-231) in the presence of 0, 1 and 10 nM estradiol. In the absence of estradiol, ZA exerts dose-dependent antiproliferative and pro-apoptotic antitumor effects in both, hormone sensitive (MCF-7, T47D) and -insensitive (MDA-MB-231) breast cancer cell lines (p<0.0001). In the presence of estradiol, the antitumoral effect of ZA was significantly decreased only in the hormone sensitive MCF-7 and T47D cell lines (p = 0.0008 and p = 0.0008, respectively). We have demonstrated that estradiol impairs the antiproliferative and proapoptotic effect of ZA in hormone sensitive, but not in hormone insensitive breast cancer cell lines. Our findings provide a possible explanation for the differential effect of ZA on DFS in pre- and postmenopausal patients with hormone sensitive early breast cancer, which has been demonstrated clinically. We further hypothesize that endocrine insensitive tumors such as triple negative breast cancer (TNBC) should benefit from ZA irrespective of their menopausal status.

Increased risk of SSEs in bone-only metastatic breast cancer patients treated with zoledronic acid.

PubMed

Yanae, Masashi; Fujimoto, Shinichiro; Tane, Kaori; Tanioka, Maki; Fujiwara, Kimiko; Tsubaki, Masanobu; Yamazoe, Yuzuru; Morishima, Yoshiyuki; Chiba, Yasutaka; Takao, Shintaro; Komoike, Yoshifumi; Tsurutani, Junji; Nakagawa, Kazuhiko; Nishida, Shozo

2017-09-01

Bone represents one of the most common sites to which breast cancer cells metastasize. Patients experience skeletal related adverse events (pathological fractures, spinal cord compressions, and irradiation for deteriorated pain on bone) even during treatment with zoledronic acid (ZA). Therefore, we conducted a retrospective cohort study to investigate the predictive factors for symptomatic skeletal events (SSEs) in bone-metastasized breast cancer (b-MBC) patients. We retrospectively collected data on b-MBC patients treated with ZA. Patient characteristics, including age, subtype, the presence of non-bone lesions, the presence of multiple bone metastases at the commencement of ZA therapy, duration of ZA therapy, the time interval between breast cancer diagnosis and the initiation of ZA therapy, and type of systemic therapy, presence of previous SSE were analyzed using multivariable logistic regression analysis. The medical records of 183 patients were reviewed and 176 eligible patients were analyzed. The median age was 59 (range, 30-87) years. Eighty-seven patients were aged ≥60 years and 89 patients were aged < 60 years. The proportions of patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-positive disease were 81.8%, 63.1%, and 17.6%, respectively. Fifty-three patients had bone-only MBC at the commencement of ZA therapy. SSEs were observed in 42 patients. In the multivariable logistic regression analysis, bone-only MBC but not a breast cancer subtype was an independent risk factor for an SSE during ZA therapy (odds ratio: 3.878, 95% confidence interval: 1.647-9.481; p = 0.002). Bone-only MBC patients are more likely to experience an SSE even after treatment with ZA.

Effect of different doses of zoledronic acid in establishing of bisphosphonate-related osteonecrosis.

PubMed

Silva, Paulo Goberlânio de Barros; Ferreira Junior, Antonio Ernando Carlos; Teófilo, Carolina Rodrigues; Barbosa, Maritza Cavalcante; Lima Júnior, Roberto César Pereira; Sousa, Fabrício Bitú; Mota, Mário Rogério Lima; Ribeiro, Ronaldo de Albuquerque; Alves, Ana Paula Negreiros Nunes

2015-09-01

To establish osteonecrosis of the jaws in rats treated with different doses of zoledronic acid (ZA). Male Wistar rats (n=6-7) received three consecutive weekly intravenous ZA infusions at doses of 0.04, 0.20 or 1.00mg/kg ZA or saline (control). Four weeks after the last administration, the animals were submitted to simple extraction of the lower left first molar. An additional dose of ZA was administered seven days later, and the animals were sacrificed 28 days after exodontia. Weight was measured and blood was collected weekly for analysis. The jaw was radiographically and microscopically examined along with the liver, spleen, kidney and stomach. All ZA doses showed a higher radiolucent area than the control (p<0.0001), but the dose of 0.04mg/kg did not show BRONJ. Doses of 0.20 and 1.00mg/kg ZA showed histological evidence of bone necrosis (p=0.0004). Anaemia (p<0.0001, r(2)=0.8073) and leucocytosis (p<0.0001, r(2)=0.9699) are seen with an increase of lymphocytes (p<0.0001, r(2)=0.6431) and neutrophils and monocytes (p=0.0218, r(2)=0.8724) in all the animals treated with an increasing dose of ZA. Haemorrhage and ectasia were observed in the spleen (p=0.0004) and stomach (p=0.0168) in a dose-dependent manner, and the animals treated with ZA showed a lower rate of weight gain (p<0.0001). We designed a bisphosphonate-related osteonecrosis of the jaw model that reproduces radiographic and histological parameters and mimics clinical alterations such as leucocytosis, anaemia and idiosyncratic inflammatory post infusion reactions. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effects of neoadjuvant chemotherapy with or without zoledronic acid on pathological response: A meta-analysis of randomised trials.

PubMed

Kroep, J R; Charehbili, A; Coleman, R E; Aft, R L; Hasegawa, Y; Winter, M C; Weilbaecher, K; Akazawa, K; Hinsley, S; Putter, H; Liefers, G J; Nortier, J W R; Kohno, N

2016-02-01

The addition of bisphosphonates to adjuvant therapy improves survival in postmenopausal breast cancer (BC) patients. We report a meta-analysis of four randomised trials of neoadjuvant chemotherapy (CT) +/- zoledronic acid (ZA) in stage II/III BC to investigate the potential for enhancing the pathological response. Individual patient data from four prospective randomised clinical trials reporting the effect of the addition of ZA on the pathological response after neoadjuvant CT were pooled. Primary outcomes were pathological complete response in the breast (pCRb) and in the breast and lymph nodes (pCR). Trial-level and individual patient data meta-analyses were done. Predefined subgroup-analyses were performed for postmenopausal women and patients with triple-negative BC. pCRb and pCR data were available in 735 and 552 patients respectively. In the total study population ZA addition to neoadjuvant CT did not increase pCRb or pCR rates. However, in postmenopausal patients, the addition of ZA resulted in a significant, near doubling of the pCRb rate (10.8% for CT only versus 17.7% with CT+ZA; odds ratio [OR] 2.14, 95% confidence interval [CI] 1.01-4.55) and a non-significant benefit of the pCR rate (7.8% for CT only versus 14.6% with CT+ZA; OR 2.62, 95% CI 0.90-7.62). In patients with triple-negative BC a trend was observed favouring CT+ZA. This meta-analysis shows no impact from the addition of ZA to neoadjuvant CT on pCR. However, as has been seen in the adjuvant setting, the addition of ZA to neoadjuvant CT may augment the effects of CT in postmenopausal patients with BC. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Effects of zoledronic acid and geranylgeraniol on the cellular behaviour and gene expression of primary human alveolar osteoblasts.

PubMed

Zafar, S; Coates, D E; Cullinan, M P; Drummond, B K; Milne, T; Seymour, G J

2016-11-01

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious complication of bisphosphonate therapy. The mechanism underlying BRONJ pathogenesis is poorly understood. To determine the effects of zoledronic acid (ZA) and geranylgeraniol (GGOH) on the mevalonate pathway (MVP) in osteoblasts generated from the human mandibular alveolar bone in terms of cell viability/proliferation, migration, apoptosis and gene expression. Primary human osteoblasts (HOBs) isolated from the mandibular alveolar bone were phenotyped. HOBs were cultured with or without ZA and GGOH for up to 72 h. Cellular behaviour was examined using a CellTiter-Blue® viability assay, an Ibidi culture-insert migration assay, an Apo-ONE® Homogeneous Caspase-3/7 apoptosis assay and transmission electron microscopy (TEM). Quantitative real-time reverse transcriptase polymerase chain reaction (qRT 2 -PCR) was used to determine the simultaneous expression of 168 osteogenic and angiogenic genes modulated in the presence of ZA and GGOH. ZA decreased cell viability and migration and induced apoptosis in HOBs. TEM revealed signs of apoptosis in ZA-treated HOBs. However, the co-addition of GGOH ameliorated the effect of ZA and partially restored the cells to the control state. Twenty-eight genes in the osteogenic array and 27 genes in the angiogenic array were significantly regulated in the presence of ZA compared with those in the controls at one or more time points. The cytotoxic effect of ZA on HOBs and its reversal by the addition of GGOH suggests that the effect of ZA on HOBs is mediated via the MVP. The results suggest that GGOH could be used as a possible therapeutic/preventive strategy for BRONJ.

Immune modulation of CD4+CD25+ regulatory T cells by zoledronic acid.

PubMed

Liu, Hsien; Wang, Shih-Han; Chen, Shin-Cheh; Chen, Ching-Ying; Lo, Jo-Lin; Lin, Tsun-Mei

2016-11-25

CD4 + CD25 + regulatory T (Treg) cells suppress tumor immunity by inhibiting immune cells. Manipulation of Treg cells represents a new strategy for cancer treatment. Zoledronic acid (ZA), a nitrogen-containing bisphosphonate, inhibits the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) on osteoblasts to inhibit osteoclastogenesis. In a mouse model of bisphosphonate-related osteonecrosis of the jaw, administration of ZA suppressed Treg-cell activity and activated inflammatory Th17 cells. However, the interaction between ZA and Treg cells remained unclear. This study investigated the immune modulation of Treg cells by ZA. Flow cytometry was used to analyze the phenotypic and immunosuppressive characteristics of Treg cells treated with ZA. Chemotactic migration was evaluated using transwell assays. Quantitative real-time PCR (qRT-PCR) was used to investigate the effect of ZA on the expression of suppressive molecules by Treg cells. Proliferation of isolated Treg cells in culture was inhibited by ZA, although ZA did not induce apoptosis. qRT-PCR and flow cytometry showed that ZA significantly downregulated the expression of CCR4, CTLA4, PD-1 and RANKL on Treg cells. Chemotactic migration and immunosuppressive functions were also significantly attenuated in Treg cells pretreated with ZA, and these effects were dose-dependent. Co-culture with Treg cells significantly increased the migration rate of breast cancer cells, while pretreatment of Treg cells with ZA attenuated this effect. Our findings demonstrated that ZA acted as an immune modulator by significantly inhibiting the expansion, migration, immunosuppressive function and pro-metastatic ability of Treg cells. Immunomodulation of Treg cells by ZA represents a new strategy for cancer therapy.

L-MTP-PE and zoledronic acid combination in osteosarcoma: preclinical evidence of positive therapeutic combination for clinical transfer

PubMed Central

Biteau, Kevin; Guiho, Romain; Chatelais, Mathias; Taurelle, Julien; Chesneau, Julie; Corradini, Nadège; Heymann, Dominique; Redini, Françoise

2016-01-01

Osteosarcoma, the most frequent malignant primary bone tumor in pediatric patients is characterized by osteolysis promoting tumor growth. Lung metastasis is the major bad prognosis factor of this disease. Zoledronic Acid (ZA), a potent inhibitor of bone resorption is currently evaluated in phase III randomized studies in Europe for the treatment of osteosarcoma and Ewing sarcoma. The beneficial effect of the liposomal form of Muramyl-TriPeptide-Phosphatidyl Ethanolamine (L-mifamurtide, MEPACT®), an activator of macrophage populations has been demonstrated to eradicate lung metastatic foci in osteosarcoma. The objective of this study was to evaluate the potential therapeutic benefit and the safety of the ZA and L-mifamurtide combination in preclinical models of osteosarcoma, as a prerequisite before translation to patients. The effects of ZA (100 μg/kg) and L-mifamurtide (1 mg/kg) were investigated in vivo in xenogeneic and syngeneic mice models of osteosarcoma, at clinical (tumor proliferation, spontaneous lung metastases development), radiological (bone microarchitecture by microCT analysis), biological and histological levels. No interference between the two drugs could be observed on ZA-induced bone protection and on L-mifamurtide-induced inhibition of lung metastasis development. Unexpectedly, ZA and L-mifamurtide association induced an additional and in some cases synergistic inhibition of primary tumor progression. L-mifamurtide has no effect on tumor proliferation in vitro or in vivo, and macrophage population was not affected at the tumor site whatever the treatment. This study evidenced for the first time a significant inhibition of primary osteosarcoma progression when both drugs are combined. This result constitutes a first proof-of-principle for clinical application in osteosarcoma patients. PMID:27152244

Nanoparticles for the delivery of zoledronic acid to prostate cancer cells: A comparative analysis through time lapse video-microscopy technique

PubMed Central

Schiraldi, Chiara; Zappavigna, Silvia; D' Agostino, Antonella; Porto, Stefania; Gaito, Ornella; Lusa, Sara; Lamberti, Monica; De Rosa, Mario; De Rosa, Giuseppe; Caraglia, Michele

2014-01-01

Time-lapse live cell imaging is a powerful tool for studying the responses of cells to drugs. Zoledronic acid (ZOL) is the most potent aminobiphosphonate able to induce cell growth inhibition at very low concentrations. The lack of clear evidence of ZOL-induced anti-cancer effects is likely due to its unfavorable pharmacokinetic profile. The use of nanotechnology-based formulations allows overcoming these limitations in ZOL pharmaco-distribution. Recently, stealth liposomes (LIPOs) and new self-assembly PEGylated nanoparticles (NPs) encapsulating ZOL were developed. Both the delivery systems showed promising anticancer activity in vitro and in vivo. In this work, we investigated the cytostatic effect of these novel formulations (LIPOs and NPs) compared with free ZOL on 2 different prostate cancer cell lines, PC 3 and DU 145 and on prostate epithelial primary cells EPN using time lapse video-microscopy (TLVM). In PC3 cells, free ZOL showed a significant anti-proliferative effect but this effect was lower than that induced by LIPOs and NPs encapsulating ZOL; moreover, LIPO-ZOL was more potent in inducing growth inhibition than NP-ZOL. On the other hand, LIPO-ZOL slightly enhanced the free ZOL activity on growth inhibition of DU 145, while the anti-proliferative effect of NP-ZOL was not statistically relevant. These novel formulations did not induce anti-proliferative effects on EPN cells. Finally, we evaluated cytotoxic effects on DU145 where, LIPO-ZOL induced the highest cytotoxicity compared with NP-ZOL and free ZOL. In conclusion, ZOL can be transformed in a powerful anticancer agent, if administered with nanotechnology-based formulations without damaging the healthy tissues. PMID:25482949

Effect of zoledronic acid on fracture healing in osteoporotic patients with intertrochanteric fractures.

PubMed

Hayer, Prabhnoor Singh; Deane, Anit Kumar Samuel; Agrawal, Atul; Maheshwari, Rajesh; Juyal, Anil

2017-01-01

To assess the effect of zoledronic acid (ZOL) on fracture healing in osteoporotic patients with intertrochanteric fracture based on radiological evaluation and to study the correlations between severity of osteoporosis, age, gender, and time taken to fracture union. An open label study was conducted on 43 patients at a tertiary care center. The osteoporosis status of all the included patients was documented using a double-energy X-ray absorptiometry scan. A single dose of injection ZOL 5 mg was administered intravenously to all the patients after fixation during their hospital stay. Follow-up of the patients was done at 1, 3, and 6 months after surgery until union was seen radiologically. Data were entered into Microsoft Office Excel version 2007, and interpretation and analysis of obtained data were done using summary statistics. Pearson correlation between age, gender, bone mineral density (BMD), and time taken to fracture union was done using the IBM SPSS Version 22.0 (IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp.). The average age of the patients included in the study was 71.27 ± 11.48 and the average BMD was -4.58±1.42. All the fractures united by the 6 th month of follow-up, which was similar to the union rate in comparison with the literature. The correlations between the gender, BMD, age, and time to union were calculated, and all the r values obtained showed very low correlation and the P values in all the variables were not significant. The bisphosphonate therapy did not adversely affect radiologically determined fracture union, and no correlations between severity of osteoporosis, age, gender, and time taken to fracture union were found to be significant.

Effect of local injection of Zolena, zoledronic acid made in Iran, on orthodontic tooth movement and root and bone resorption in rats.

PubMed

Seifi, Massoud; Asefi, Sohrab; Hatamifard, Ghazal; Lotfi, Ali

2017-01-01

Background. Anchorage control is an essential part of orthodontic treatment planning, especially in adult patients who demand a more convenient treatment. Zoledronic acid (ZA) is an effective choice to address this problem. It is the most potent member of the bisphosphonates family that has an inhibitory effect on bone resorption by suppressing osteoclast function. Therefore, ZA might be a good option for orthodontic anchorage control. The current study evaluated the effect of local administration of Zolena (ZA made in Iran) on orthodontic tooth movement (OTM) and root and bone resorption. Methods. The experimental group consisted of 30 rats in 3 subgroups (n=10). Anesthesia was induced, and one closed NiTi coil spring was installed between the first molar and central incisor unilaterally, except for the negative control group. The positive control group received vestibular injection of 0.01 mL of saline next to the maxillary first molar, and 0.01 mL of the solution was injected at the same site in the ZA group. After 21 days, the rats were sacrificed and the distance between the first and second molars was measured with a leaf gauge. Histological analysis was conducted by a blind pathologist for the number of Howship's lacunae, blood vessels, osteoclast-like cells and root resorption lacunae. Data were analyzed with ANOVA, Tukey test and t-test. Results. There were no significant differences in OTM between the force-applied groups. ZA significantly inhibited bone/root resorption and angiogenesis compared to the positive control group. Conclusion. Zolena did not decrease OTM but significantly inhibited bone and root resorption. Zolena might be less potent than its foreign counterparts.

Is Administration of Trastuzumab an Independent Risk Factor for Developing Osteonecrosis of the Jaw Among Metastatic Breast Cancer Patients Under Zoledronic Acid Treatment?

PubMed Central

Pilanci, Kezban Nur; Alco, Gul; Ordu, Cetin; Sarsenov, Dauren; Celebi, Filiz; Erdogan, Zeynep; Agacayak, Filiz; Ilgun, Serkan; Tecimer, Coskun; Demir, Gokhan; Eralp, Yesim; Okkan, Sait; Ozmen, Vahit

2015-01-01

Abstract One of the most important adverse effects of zoledronic acid (ZA) is osteonecrosis of the jaw (ONJ). In previous literature, several risk factors have been identified in the development of ONJ. In this study, we aimed to determine the role of trastuzumab, an antiangiogenic agent, as an independent risk factor for the development of this serious side effect. Our study included 97 patients (mean age: 54 ± 10 years) with breast cancer, recorded in the archives of the Istanbul Florence Nightingale Breast Study Group, who received ZA therapy due to bone metastases between March 2006 and December 2013. We recorded the patients’ ages, weights, duration of treatment with ZA, number of ZA infusions, dental procedures, anticancer treatments (chemotherapy, aromatase inhibitor, trastuzumab), the presence of diabetes mellitus or renal dysfunction, and smoking habits. Thirteen patients (13.40%) had developed ONJ. Among the patients with ONJ, the mean time of exposure to ZA was 41 months (range: 13–82) and the mean number of ZA infusions was 38 (range: 15–56). The duration of treatment with ZA and the use of trastuzumab were observed to be 2 factors that influenced the development of ONJ (P = 0.049 and P = 0.028, respectively). The development of ONJ under ZA treatment may be associated solely with the duration of ZA treatment and the concurrent administration of trastuzumab. These findings show that patients who are administered trastuzumab for metastatic breast cancer while undergoing ZA treatment are prone to developing ONJ. Therefore, we recommend intense clinical observation to avoid this particular condition in patients receiving ZA and trastuzumab. PMID:25950681

Update on long-term treatment with bisphosphonates for postmenopausal osteoporosis: a systematic review.

PubMed

Eriksen, Erik F; Díez-Pérez, Adolfo; Boonen, Steven

2014-01-01

Osteoporosis is a progressive skeletal disorder that requires long-term treatment. However, there is little guidance regarding optimal treatment duration and what the treatment discontinuation and retreatment criteria should be. Given that bisphosphonates are the most commonly prescribed class of agent for the treatment of osteoporosis, we reviewed the long-term data relating to these therapies and discussed the considerations for using bisphosphonates in postmenopausal women with osteoporosis. A PubMed search, using the search terms 'bisphosphonate', 'postmenopausal osteoporosis' and 'long term' and/or 'extension' was conducted in January 2013. Results from nine controlled studies that prospectively assessed alendronate, risedronate, ibandronate or zoledronic acid in women with postmenopausal osteoporosis were reviewed. Clinical studies in postmenopausal women with osteoporosis showed that long-term use of bisphosphonates resulted in persistent antifracture and bone mineral density (BMD) increasing effects beyond 3 years of treatment. No unexpected adverse events were identified in these studies and the long-term tolerability profiles of bisphosphonates remain favorable. Data from the withdrawal extension studies of alendronate and zoledronic acid also showed that residual fracture benefits were seen in patients who discontinued treatment for 3 to 5 years after an initial 3- to 5-year treatment period. BMD monitoring and fracture risk assessments should be conducted regularly to determine whether treatment could be stopped or should be reinitiated. Patients exhibiting T-scores<-2.5 or who have suffered a new fracture while on treatment should continue treatment, while patients with T-scores>-2.5 could be considered for discontinuation of active treatment while undergoing continued monitoring of their bone health. The duration and potential discontinuation of treatment should be personalized for individual patients based on their response to treatment, fracture risk and comorbidities. © 2013. Published by Elsevier Inc. All rights reserved.

Extracellular Ca(2+)-dependent enhancement of cytocidal potency of zoledronic acid in human oral cancer cells.

PubMed

Inoue, Sayaka; Arai, Naoya; Tomihara, Kei; Takashina, Michinori; Hattori, Yuichi; Noguchi, Makoto

2015-08-15

Direct antitumor effects of bisphosphonates (BPs) have been demonstrated in various cancer cells in vitro. However, the effective concentrations of BPs are typically much higher than their clinically relevant concentrations. Oral cancers frequently invade jawbone and may lead to the release of Ca(2+) in primary lesions. We investigated the effects of the combined application of zoledronic acid (ZA) and Ca(2+) on proliferation and apoptosis of oral cancer cells. Human oral cancer cells, breast cancer cells, and colon cancer cells were treated with ZA at a wide range of concentrations in different Ca(2+) concentration environments. Under a standard Ca(2+) concentration (0.6mM), micromolar concentrations of ZA were required to inhibit oral cancer cell proliferation. Increasing extracellular Ca(2+) concentrations greatly enhanced the potency of the ZA cytocidal effect. The ability of Ca(2+) to enhance the cytocidal effects of ZA was negated by the Ca(2+)-selective chelator EGTA. In contrast, the cytocidal effect of ZA was less pronounced in breast and colon cancer cells regardless of whether extracellular Ca(2+) was elevated. In oral cancer cells incubated with 1.6mM Ca(2+), ZA up-regulated mitochondrial Bax expression and increased mitochondrial Ca(2+) uptake. This was associated with decreased mitochondrial membrane potential and increased release of cytochrome c. We suggest that ZA can specifically produce potent cytocidal activity in oral cancer cells in an extracellular Ca(2+)-dependent manner, implying that BPs may be useful for treatment of oral squamous cell carcinoma with jawbone invasion leading to the hypercalcemic state. Copyright © 2015 Elsevier B.V. All rights reserved.

Two isomorphous Co(ii) coordination polymers based on new α,α-disubstituted derivatives of zoledronic acid: synthesis, structures and properties.

PubMed

Rojek, Tomasz; Goldeman, Waldemar; Slepokura, Katarzyna; Duczmal, Marek; Wojciechowska, Agnieszka; Matczak-Jon, Ewa

2017-05-30

Two novel α,α-disubstituted derivatives of zoledronic acid, namely 1-hydroxy-2-(1H-imidazol-1-yl)-2-methylpropylidene-1,1-diphosphonic acid (H 4 L1) and 1-hydroxy-2-[1-(1H-imidazol-1-yl)cyclopropyl]ethylidene-1,1-diphosphonic acid (H 4 L2) were synthesized and structurally characterized by single-crystal X-ray diffraction. The reaction of cobalt acetate with H 4 L1 and H 4 L2 carried out under hydrothermal conditions afforded two isomorphous Co 3 (HL1) 2 (H 2 O) 6 ·6H 2 O (1a) and Co 3 (HL2) 2 (H 2 O) 6 ·6H 2 O (2a) complexes. Both compounds are characterized by means of X-ray crystallography, IR and NIR-Vis-UV spectroscopic methods. Furthermore, their magnetic properties and thermal stabilities are reported. The crystals of 1a and 2a feature infinite 1D polymeric chains built from alternately arranged dinuclear [Co2(HL1/HL2)(H 2 O) 2 ] 2 units and {Co1O 6 } octahedra running along the [1[combining macron]10] crystallographic direction. In both compounds, crystallographically distinct Co1 and Co2 atoms are six-coordinated. As is reflected in T values (T - index of tetragonality), the coordination environment of Co1 generates a slightly elongated octahedron (T = 0.94), whereas a slightly compressed octahedron (T = 1.06 for 1a and 1.05 for 2a) is formed around Co2. An assumption that the d-d type absorption is mainly attributed to the inversion related Co2 centers, whose population is two times higher than that of Co1, afforded a good correlation between calculated transition energies and experimental NIR-Vis-UV spectra. The magnetic susceptibility measurements analyzed in terms of a spin-3/2 Heisenberg trimer chain revealed that Co1Co2 interactions within the trimer are antiferromagnetic whereas Co2Co2 intertrimer interactions are ferromagnetic.

Large-scale expansion of γδ T cells and peptide-specific cytotoxic T cells using zoledronate for adoptive immunotherapy.

PubMed

Yoshikawa, Toshiaki; Takahara, Masashi; Tomiyama, Mai; Nieda, Mie; Maekawa, Ryuji; Nakatsura, Tetsuya

2014-11-01

Specific cellular immunotherapy for cancer requires efficient generation and expansion of cytotoxic T lymphocytes (CTLs) that recognize tumor-associated antigens. However, it is difficult to isolate and expand functionally active T-cells ex vivo. In this study, we investigated the efficacy of a new method to induce expansion of antigen-specific CTLs for adoptive immunotherapy. We used tumor-associated antigen glypican-3 (GPC3)-derived peptide and cytomegalovirus (CMV)-derived peptide as antigens. Treatment of human peripheral blood mononuclear cells (PBMCs) with zoledronate is a method that enables large-scale γδ T-cell expansion. To induce expansion of γδ T cells and antigen-specific CTLs, the PBMCs of healthy volunteers or patients vaccinated with GPC3 peptide were cultured with both peptide and zoledronate for 14 days. The expansion of γδ T cells and peptide-specific CTLs from a few PBMCs using zoledronate yields cell numbers sufficient for adoptive transfer. The rate of increase of GPC3‑specific CTLs was approximately 24- to 170,000-fold. These CD8(+) cells, including CTLs, showed GPC3-specific cytotoxicity against SK-Hep-1/hGPC3 and T2 pulsed with GPC3 peptide, but not against SK-Hep-1/vec and T2 pulsed with human immunodeficiency virus peptide. On the other hand, CD8(-) cells, including γδ T cells, showed cytotoxicity against SK-Hep-1/hGPC3 and SK-Hep-1/vec, but did not show GPC3 specificity. Furthermore, adoptive cell transfer of CD8(+) cells, CD8(-) cells, and total cells after expansion significantly inhibited tumor growth in an NOD/SCID mouse model. This study indicates that simultaneous expansion of γδ T cells and peptide-specific CTLs using zoledronate is useful for adoptive immunotherapy.

Exploring methods for comparing the real-world effectiveness of treatments for osteoporosis: adjusted direct comparisons versus using patients as their own control.

PubMed

Karlsson, Linda; Mesterton, Johan; Tepie, Maurille Feudjo; Intorcia, Michele; Overbeek, Jetty; Ström, Oskar

2017-09-21

Using Swedish and Dutch registry data for women initiating bisphosphonates, we evaluated two methods of comparing the real-world effectiveness of osteoporosis treatments that attempt to adjust for differences in patient baseline characteristics. Each method has advantages and disadvantages; both are potential complements to clinical trial analyses. We evaluated methods of comparing the real-world effectiveness of osteoporosis treatments that attempt to adjust for both observed and unobserved confounding. Swedish and Dutch registry data for women initiating zoledronate or oral bisphosphonates (OBPs; alendronate/risedronate) were used; the primary outcome was fracture. In adjusted direct comparisons (ADCs), regression and matching techniques were used to account for baseline differences in known risk factors for fracture (e.g., age, previous fracture, comorbidities). In an own-control analysis (OCA), for each treatment, fracture incidence in the first 90 days following treatment initiation (the baseline risk period) was compared with fracture incidence in the 1-year period starting 91 days after treatment initiation (the treatment exposure period). In total, 1196 and 149 women initiating zoledronate and 14,764 and 25,058 initiating OBPs were eligible in the Swedish and Dutch registries, respectively. Owing to the small Dutch zoledronate sample, only the Swedish data were used to compare fracture incidences between treatment groups. ADCs showed a numerically higher fracture incidence in the zoledronate than in the OBPs group (hazard ratio 1.09-1.21; not statistically significant, p > 0.05). For both treatment groups, OCA showed a higher fracture incidence in the baseline risk period than in the treatment exposure period, indicating a treatment effect. OCA showed a similar or greater effect in the zoledronate group compared with the OBPs group. ADC and OCA each possesses advantages and disadvantages. Combining both methods may provide an estimate of real-world treatment efficacy that could potentially complement clinical trial findings.

Infra Red Dye and Endostar Loaded Poly Lactic Acid Nano Particles as a Novel Theranostic Nanomedicine for Breast Cancer.

PubMed

Zhang, Qian; Du, Yang; Jing, Lijia; Liang, Xiaolong; Li, Yaqian; Li, Xiaofeng; Dai, Zhifei; Tian, Jie

2016-03-01

Endostar, a novel recombinant human endostatin, has been proven to inhibit tumor angiogenesis and is utilized as an anticancer drug. While free drugs can display limited efficacy, nanoscaled anticancer drugs have been fabricated and proven to possess superior therapeutic effects. Poly(lactic acid) (PLA) is a FDA-approved biomaterial displaying excellent biocompatibility and low toxicity. In this study, Endostar-loaded PLA nanoparticles (EPNPs) were first prepared, and a near-infrared (NIR) dye, IRDye 800CW, was conjugated to the surface for detecting nanoparticle biodistribution through fluorescence molecular imaging (FMI) using an orthotopic breast tumor mouse model. The antitumor efficacy of EPNPs was examined using bioluminescence imaging (BLI) and immunohistology. To further improve the antitumor effects, we combined EPNPs with zoledronic acid monohydrate (ZA), which is known to decrease the tumor-associated macrophages (TAM) and inhibit tumor progression. We found that EPNPs decreased human umbilical vein endothelial cell (HUVEC) viability by inhibiting tumor growth gene expression more significantly than free Endostar in vitro. In vivo, EPNPs displayed better tumor growth inhibitory effects compared with free Endostar, and the combination of EPNPs with ZA exhibited more significant antitumor effects. As confirmed by CD31 and CD11b immunohistochemistry, the combination of EPNPs and ZA showed synergistic effects in reducing tumor angiogenesis and TAM accumulation in tumor regions. Taken together, this study presents a novel and effective form of nanoscaled Endostar for the treatment of breast cancer that displays synergistic antitumor effects in combination with ZA.

Developments in the pharmacotherapeutic management of osteoporosis.

PubMed

Close, Pierre; Neuprez, Audrey; Reginster, Jean-Yves

2006-08-01

During the last two decades, several medications have been granted a marketing authorisation for the management of osteoporosis. Bisphosphonates are the most widely prescribed drugs in this area, worldwide. Alendronate and risedronate are given daily or weekly and have demonstrated their ability to reduce fracture rates at the spine and hip. Ibandronate has demonstrated spine antifracture efficacy with intervals between dosings greater than weekly. New developments in this class include intravenous administration of ibandronate or zoledronate, once every three months or once yearly. Raloxifene, a selective estrogen-receptor modulator, reduces spine fractures and, in post-hoc analyses, non-spine fractures in high-risk subjects. New selective estrogen-receptor modulators, including lasofoxifene, bazedoxifene and arzoxifene, are expected to demonstrate antifracture efficacy at the hip level, whilst retaining the extra-skeletal benefits (such as in the breast) that are obtained with raloxifene. The peptides from the parathyroid hormone family are potent stimulators of bone formation. Teriparatide (1 - 34 amino acid fragment of the parathyroid hormone) reduces spine and non-spine fractures, an effect that is sustained for up to 30 months after the withdrawal of treatment. The intact hormone (1 - 84 amino acids) showed similar results on spine fractures, and more data are requested to evaluate its effect on non-spine or hip fractures. Strontium ranelate is suggested to be the first medication to uncouple bone formation from bone resorption. It has shown antifracture efficacy at all sites in a large number of postmenopausal women. New developments include: denosumab, an antibody against receptor activator of NF-kappaB ligand (RANKL); a cytokine that is responsible for osteoclastogenesis; and inhibitors of cathepsin K, a cysteine protease that is involved in the cleavage of collagen.

Drug Repositioning for Effective Prostate Cancer Treatment.

PubMed

Turanli, Beste; Grøtli, Morten; Boren, Jan; Nielsen, Jens; Uhlen, Mathias; Arga, Kazim Y; Mardinoglu, Adil

2018-01-01

Drug repositioning has gained attention from both academia and pharmaceutical companies as an auxiliary process to conventional drug discovery. Chemotherapeutic agents have notorious adverse effects that drastically reduce the life quality of cancer patients so drug repositioning is a promising strategy to identify non-cancer drugs which have anti-cancer activity as well as tolerable adverse effects for human health. There are various strategies for discovery and validation of repurposed drugs. In this review, 25 repurposed drug candidates are presented as result of different strategies, 15 of which are already under clinical investigation for treatment of prostate cancer (PCa). To date, zoledronic acid is the only repurposed, clinically used, and approved non-cancer drug for PCa. Anti-cancer activities of existing drugs presented in this review cover diverse and also known mechanisms such as inhibition of mTOR and VEGFR2 signaling, inhibition of PI3K/Akt signaling, COX and selective COX-2 inhibition, NF-κB inhibition, Wnt/β-Catenin pathway inhibition, DNMT1 inhibition, and GSK-3β inhibition. In addition to monotherapy option, combination therapy with current anti-cancer drugs may also increase drug efficacy and reduce adverse effects. Thus, drug repositioning may become a key approach for drug discovery in terms of time- and cost-efficiency comparing to conventional drug discovery and development process.

Gelatin- hydroxyapatite- calcium sulphate based biomaterial for long term sustained delivery of bone morphogenic protein-2 and zoledronic acid for increased bone formation: In-vitro and in-vivo carrier properties.

PubMed

Raina, Deepak Bushan; Larsson, David; Mrkonjic, Filip; Isaksson, Hanna; Kumar, Ashok; Lidgren, Lars; Tägil, Magnus

2018-02-28

In this study, a novel macroporous composite biomaterial consisting of gelatin-hydroxyapatite-calcium sulphate for delivery of bone morphogenic protein-2 (rhBMP-2) and zoledronic acid (ZA) has been developed. The biomaterial scaffold has a porous structure and functionalization of the scaffold with rhBMP-2 induces osteogenic differentiation of MC3T3-e1 cells seen by a significant increase in biochemical and genetic markers of osteoblastic differentiation. In-vivo muscle pouch experiments showed higher mineralization using scaffold+rhBMP-2 when compared to an approved absorbable collagen sponge (ACS)+rhBMP-2 as verified by micro-CT. Co-delivery of rhBMP-2+ZA via the novel scaffold enabled a reduction in the effective rhBMP-2 doses. The presence of tartrate resistant acid phosphatase staining in the rhBMP-2 group indicates osteoclastic resorption, which could be stalled by adding ZA, which by speculation could explain the net increase in mineralization. The new scaffold allowed for slow release of rhBMP-2 in-vitro (3.3±0.1%) after 4weeks. Using single photon emission computed tomography (SPECT), the release kinetics of 125 I-rhBMP-2 in-vivo was followed for 4weeks and a total of 65.3±15.2% 125 I-rhBMP-2 was released from the scaffolds. In-vitro 14 C-ZA release curve shows an initial burst release on day 1 (8.8±0.7%) followed by a slow release during the following 4weeks (13±0.1%). In-vivo, an initial release of 43.2±7.6% of 14 C-ZA was detected after 1day, after which the scaffold retained the remaining ZA during 4-weeks. Taken together, our results show that the developed biomaterial is an efficient carrier for spatio-temporal delivery of rhBMP-2 and ZA leading to increased bone formation compared to commercially available carrier for rhBMP-2. Copyright © 2018 Elsevier B.V. All rights reserved.

Dental extraction following zoledronate, induces osteonecrosis in rat's jaw.

PubMed

Vidal-Gutiérrez, X; Gómez-Clavel, J-F; Gaitán-Cepeda, L-A

2017-03-01

Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) is clinically characterized by the presence of exposed bone in the oral cavity that persists for more than eight weeks. Previous attempts to establish an animal model have not sufficiently considered disease features. Our aim was to establish an inexpensive and replicable animal model that develops BRONJ in a short time. Thirty-two male Wistar rats were randomly divided into two groups: control and experimental. In the experimental group, we administered 0.06mg/kg intraperitoneal dose of zoledronic acid (ZA) 7 and 14 days prior to maxillary second molar extraction. At two, four and six weeks after tooth extraction, the animals were euthanized, and we dissected the maxilla following histological procedures. We stained serial slides with hematoxylin and eosin and Masson's trichrome. The samples were harvested for macroscopic, radiologic and histological evaluation of bone changes. At two weeks postextraction, we observed exposed necrotic bone in dental socket areas in experimental groups. Radiological analysis revealed osteolytic lesions accompanied by extensive destruction and sequestrum formation in the same group. Histological examination confirmed the absence of necrotic bone in control groups in contrast with the experimental groups. The percentage of empty lacunae and the number of osteoclasts and the necrotic bone area were significantly increased (p<0.05) in the experimental groups. The animal model using ZA administration to prior dental extraction successfully mimicked human BRONJ lesions. Also, the model was easily replicated, inexpensive and showed different features than other previous BRONJ models.

Cost-effectiveness of zoledronic acid in the prevention of skeletal-related events in patients with bone metastases secondary to advanced renal cell carcinoma: application to France, Germany, and the United Kingdom.

PubMed

Botteman, M F; Meijboom, M; Foley, I; Stephens, J M; Chen, Y M; Kaura, S

2011-12-01

The use of zoledronic acid (ZOL) has recently been shown to significantly reduce the risk of new skeletal-related events (SREs) in renal cell carcinoma (RCC) patients with bone metastases. The present exploratory study assessed the cost-effectiveness of ZOL in this population, adopting a French, German, and United Kingdom (UK) government payer perspective. This cost-effectiveness model was based on a post hoc retrospective analysis of a subset of patients with RCC who were included in a larger randomized clinical trial of patients with bone metastases secondary to a variety of cancers. In the trial, patients were randomized to receive ZOL (n = 27) or placebo (n = 19) with concomitant antineoplastic therapy every 3 weeks for 9 months (core study) plus 12 months during a study extension. Since the trial did not collect costs or data on the quality-adjusted life years (QALYs) of the patients, these outcomes had to be assumed via modeling exercises. The costs of SREs were estimated using hospital DRG tariffs. These estimates were supplemented with literature-based costs where possible. Drug, administration, and supply costs were obtained from published and internet sources. Consistent with similar economic analyses, patients were assumed to experience quality of life decrements lasting 1 month for each SRE. Uncertainty surrounding outcomes was addressed via multivariate sensitivity analyses. Patients receiving ZOL experienced 1.07 fewer SREs than patients on placebo. Patients on ZOL experienced a gain in discounted QALYs of approximately 0.1563 in France and Germany and 0.1575 in the UK. Discounted SRE-related costs were substantially lower among ZOL than placebo patients (-€ 4,196 in France, - € 3,880 in Germany, and -€ 3,355 in the UK). After taking into consideration the drug therapy costs, ZOL saved € 1,358, € 1,223, and € 719 in France, Germany, and the UK, respectively. In the multivariate sensitivity analyses, therapy with ZOL saved costs in 67-77% of simulations, depending on the country. The cost per QALY gained for ZOL versus placebo was below € 30,000 per QALY gained threshold in approximately 93-94% of multivariate sensitivity analyses simulations. The present analysis suggests that ZOL saves costs and increases QALYs compared to placebo in French, German, and UK RCC patients with bone metastases. Additional prospective research may be needed to confirm these results in a larger sample of patients.

The prevention of fragility fractures in patients with non-metastatic prostate cancer: a position statement by the international osteoporosis foundation

PubMed Central

Cianferotti, Luisella; Bertoldo, Francesco; Carini, Marco; Kanis, John A.; Lapini, Alberto; Longo, Nicola; Martorana, Giuseppe; Mirone, Vincenzo; Reginster, Jean-Yves; Rizzoli, Rene; Brandi, Maria Luisa

2017-01-01

Androgen deprivation therapy is commonly employed for the treatment of non-metastatic prostate cancer as primary or adjuvant treatment. The skeleton is greatly compromised in men with prostate cancer during androgen deprivation therapy because of the lack of androgens and estrogens, which are trophic factors for bone. Men receiving androgen deprivation therapy sustain variable degrees of bone loss with an increased risk of fragility fractures. Several bone antiresorptive agents have been tested in randomized controlled trials in these patients. Oral bisphosphonates, such as alendronate and risedronate, and intravenous bisphosphonates, such as pamidronate and zoledronic acid, have been shown to increase bone density and decrease the risk of fractures in men receiving androgen deprivation therapy. Denosumab, a fully monoclonal antibody that inhibits osteoclastic-mediated bone resorption, is also effective in increasing bone mineral density and reducing fracture rates in these patients. The assessment of fracture risk, T-score and/or the evaluation of prevalent fragility fractures are mandatory for the selection of patients who will benefit from antiresorptive therapy. In the future, new agents modulating bone turnover and skeletal muscle metabolism will be available for testing in these subjects. PMID:29088899

The prevention of fragility fractures in patients with non-metastatic prostate cancer: a position statement by the international osteoporosis foundation.

PubMed

Cianferotti, Luisella; Bertoldo, Francesco; Carini, Marco; Kanis, John A; Lapini, Alberto; Longo, Nicola; Martorana, Giuseppe; Mirone, Vincenzo; Reginster, Jean-Yves; Rizzoli, Rene; Brandi, Maria Luisa

2017-09-26

Androgen deprivation therapy is commonly employed for the treatment of non-metastatic prostate cancer as primary or adjuvant treatment. The skeleton is greatly compromised in men with prostate cancer during androgen deprivation therapy because of the lack of androgens and estrogens, which are trophic factors for bone. Men receiving androgen deprivation therapy sustain variable degrees of bone loss with an increased risk of fragility fractures. Several bone antiresorptive agents have been tested in randomized controlled trials in these patients. Oral bisphosphonates, such as alendronate and risedronate, and intravenous bisphosphonates, such as pamidronate and zoledronic acid, have been shown to increase bone density and decrease the risk of fractures in men receiving androgen deprivation therapy. Denosumab, a fully monoclonal antibody that inhibits osteoclastic-mediated bone resorption, is also effective in increasing bone mineral density and reducing fracture rates in these patients. The assessment of fracture risk, T-score and/or the evaluation of prevalent fragility fractures are mandatory for the selection of patients who will benefit from antiresorptive therapy. In the future, new agents modulating bone turnover and skeletal muscle metabolism will be available for testing in these subjects.

Dose-dependent inhibitory effects of zoledronic acid on osteoblast viability and function in vitro

PubMed Central

HUANG, XIN; HUANG, SHILONG; GUO, FENGJIN; XU, FEI; CHENG, PENG; YE, YAPING; DONG, YONGHUI; XIANG, WEI; CHEN, ANMIN

2016-01-01

Zoledronic acid (ZA), which is one of the most potent and efficacious bisphosphonates, has been commonly used in clinical practice for the treatment of various bone disorders. The extensive use of ZA has been associated with increasing occurrence of jaw complications, now known as bisphosphonate-associated osteonecrosis of the jaw (BRONJ). However, the mechanism underlying BRONJ remains to be fully elucidated. The aim of the present study was to investigate the effects of different concentrations of ZA on the MC3T3-E1 murine preosteoblast cell line cells and examine the possible pathogenesis of BRONJ. In the present study, the effect of ZA on the viability, apoptosis, differentiation and maturation of MC3T3-E1 cells, as well as its relevant molecular mechanism, were examined The results of a Cell Counting Kit 8 assay, a flow cytometric Annexin-V/propidium iodide assay and western blot analysis demonstrated that ZA exhibited a significant inhibition of cell viability and induction of apoptosis at concentrations >10 µM. Subsequently, the effect of ZA on cell differentiation at concentrations <1 µM were investigated. In this condition, ZA inhibited bone nodule formation and decreased the activity of alkaline phosphatase. The results of reverse transcription-quantitative polymerase chain reaction and western blot analyses indicated that ZA downregulated the expression levels of the marker genes and proteins associated with osteogenic differentiation. Further investigation revealed that the suppression of differentiation by ZA was associated with decreased expression of bone morphogenetic protein-2 (BMP-2) and downregulation of the phosphorylation levels in the downstream extracellular signal-regulated kinase 1/2 and p38 pathways. These adverse effects of ZA were observed to be concentration-dependent. The results from the present study suggested that ZA at higher concentrations induces cytotoxicity towards osteoblasts, and ZA at lower concentrations suppresses osteoblast differentiation by downregulation of BMP-2. These results assist in further understanding the mechanisms of BRONJ. PMID:26648136

Successful treatment with denosumab in a patient with sacral giant cell tumor of bone refractory to combination therapy with arterial embolization and zoledronic acid: A case report

PubMed Central

Nishimura, Shunji; Hashimoto, Kazuhiko; Tan, Akihiro; Yagyu, Yukinobu; Akagi, Masao

2017-01-01

Giant cell tumor of bone (GCTB) is commonly treated with surgery; however, surgery of GCTB in the sacrum may be challenging due to the associated risk. A conservative approach may be selective arterial embolization or zoledronic acid (ZOL) treatment; however, there are currently no studies investigating the efficacy of combining these two treatments. Denosumab may also be used; however, to the best of our knowledge, there are no reports of a stepwise approach for the use of all three treatments in a single patient. We herein present such a case. A 32-year-old woman diagnosed with sacral GCTB was treated with selective arterial embolization for 3 months. No improvement was observed, and monthly infusions of ZOL were added (administered 2 weeks after each arterial embolization treatment). Ten months after the initiation of ZOL, there was still no improvement. The therapy was changed to denosumab 120 mg, injected subcutaneously once a month. By the third dose, the buttock pain had decreased and the patient became ambulatory. At 5 and 10 months, computed tomography scans revealed bone sclerosis gradually appearing around the sacrum. By 1 year, needle biopsy detected no neoplastic cells. At that point, the patient discontinued treatment, as there was hepatic function impairment due to a history of hepatitis B. Despite treatment discontinuation, the patient exhibited no further symptoms, there were no signs of progression on radiography, and surgery was not required. Our patient experienced treatment failure with selective arterial embolization. The combination of ZOL with selective arterial embolization also did not improve the patient's condition. Denosumab was found to be superior to both treatments, achieving tumor remission. The patient remains symptom- and disease-free. Further studies are required, but our results suggest that patients with unresectable GCTB who fail to respond to selective arterial embolization may benefit from denosumab treatment, but not from combination therapy with selective arterial embolization and ZOL. PMID:28451403

Zoledronic acid infusion for lumbar interbody fusion in osteoporosis.

PubMed

Tu, Chao-Wei; Huang, Kuo-Feng; Hsu, Hsien-Ta; Li, Hung-Yu; Yang, Stephen Shei-Dei; Chen, Yi-Chu

2014-11-01

Clinical outcomes of intravenous (IV) infusion of zoledronic acid (ZOL) for lumbar interbody fusion surgery (LIFS) remain unknown. We investigated the efficacy of IV ZOL on clinical outcome and bone fusion after LIFS. We retrospectively analyzed 64 patients with both degenerative lumbar spondylolisthesis and osteoporosis who underwent LIFS from January 2007 to April 2010. All patients were followed up for 2 y. Thirty-two were treated with an IV infusion of ZOL 3 d after surgery and a second injection 1 y later, and the other 32 patients did not receive ZOL. Preoperatively and every 3 mo postoperatively, oswestry disability index questionnaire and visual analog scale (VAS) scores for back and leg were compared. Preoperative and final postoperative follow-up to evaluate for subsequent compression fractures were also performed. Pedicle screw loosening, cage subsidence, and fusion rate were documented 2 y after surgery. At 2-y follow-up, a solid fusion was achieved in 75% of the ZOL group and only 56% of the control group. At final follow up, the incidence of final subsequent vertebral compression fractures (19% of the ZOL group and 51% of the control group, P = 0.006), pedicle screw loosening (18% of the ZOL group and 45% of the control group, P = 0.03), and cage subsidence >2 mm (28% of the ZOL group and only 54% of the control group, P = 0.04) were significantly lower in the ZOL group than in the control group. The ZOL group demonstrated improvement in VAS (for leg pain VAS, 2/10 for the ZOL group and 5/10 for the control group; for back pain VAS, 2/10 for the ZOL group and 6/10 for the control group) and oswestry disability index scores (7/25 for the ZOL group and 16/25 for the control group). ZOL treatment has beneficial effects on instrumented LIFS both radiographic and clinically. Thus, ZOL treatment can be recommended for osteoporosis patients undergoing LIFS. Copyright © 2014 Elsevier Inc. All rights reserved.

5-year follow-up of a randomized controlled trial of immediate versus delayed zoledronic acid for the prevention of bone loss in postmenopausal women with breast cancer starting letrozole after tamoxifen: N03CC (Alliance) trial.

PubMed

Wagner-Johnston, Nina D; Sloan, Jeff A; Liu, Heshan; Kearns, Ann E; Hines, Stephanie L; Puttabasavaiah, Suneetha; Dakhil, Shaker R; Lafky, Jacqueline M; Perez, Edith A; Loprinzi, Charles L

2015-08-01

Postmenopausal women with breast cancer receiving aromatase inhibitors are at an increased risk of bone loss. The current study was undertaken to determine whether upfront versus delayed treatment with zoledronic acid (ZA) impacted bone loss. This report described the 5-year follow-up results. A total of 551 postmenopausal women with breast cancer who completed tamoxifen treatment and were undergoing daily letrozole treatment were randomized to either upfront (274 patients) or delayed (277 patients) ZA at a dose of 4 mg intravenously every 6 months. In the patients on the delayed treatment arm, ZA was initiated for a postbaseline bone mineral density T-score of <-2.0 or fracture. The incidence of a 5% decrease in the total lumbar spine bone mineral density at 5 years was 10.2% in the upfront treatment arm versus 41.2% in the delayed treatment arm (P<.0001). A total of 41 patients in the delayed treatment arm were eventually started on ZA. With the exception of increased NCI Common Toxicity Criteria (CTC) grade 1/2 elevated creatinine and fever in the patients treated on the upfront arm and cerebrovascular ischemia among those in the delayed treatment arm, there were no significant differences observed between arms with respect to the most common adverse events of arthralgia and back pain. Osteoporosis occurred less frequently in the upfront treatment arm (2 vs 8 cumulative cases), although this difference was not found to be statistically significant. Bone fractures occurred in 24 patients in the upfront treatment arm versus 25 patients in the delayed treatment arm. Immediate treatment with ZA prevented bone loss compared with delayed treatment in postmenopausal women receiving letrozole and these differences were maintained at 5 years. The incidence of osteoporosis or fractures was not found to be significantly different between treatment arms. © 2015 American Cancer Society.

Cost per patient and potential budget implications of denosumab compared with zoledronic acid in adults with bone metastases from solid tumours who are at risk of skeletal-related events: an analysis for Austria, Sweden and Switzerland

PubMed Central

Lothgren, Mickael; Ribnicsek, Erna; Schmidt, Louise; Habacher, Wolfgang; Lundkvist, Jonas; Pfeil, Alena M; Biteeva, Irina; Vrouchou, Polina; Bracco, Andrea

2013-01-01

Objectives To assess cost implications per patient, per year, and to predict the potential annual budget impact when patients with bone metastases secondary to solid tumours at risk of skeletal-related events (SREs) transition from zoledronic acid (ZA; 4 mg every 3–4 weeks) to denosumab (120 mg every 4 weeks) in Austria, Sweden and Switzerland. Methods Country specific costs for medication and administration, patient management and SREs (defined as pathologic fracture, radiation to bone, surgery to bone and spinal cord compression) were assessed over a 1-year time horizon. Drug administration and patient management costs were taken from available public sources. SRE costs were based on local unit costs applied to country specific healthcare resources obtained from a multinational retrospective chart review study. Due to lack of real world data for the included countries, SRE rates were derived from phase III clinical trials in patients with advanced cancer and bone metastases. These trials demonstrated that denosumab was superior to ZA in the reduction of SREs. Results Estimated total annual cost savings for each patient transitioned from ZA to denosumab varied by country and cancer type, ranging from €1583 to €2375 in Austria, from €1980 to €2319 in Sweden (9.1 SEK/€) and from €3408 to €3857 in Switzerland (1.2 CHF/€). Cost savings were mainly driven by the lower SRE related costs and lower administration costs of denosumab compared with ZA. Conclusions Denosumab offers superior efficacy compared with ZA in patients with solid tumours and bone metastases. Cost savings are predicted in the Austrian, Swedish and Swiss healthcare systems following treatment transition from ZA to denosumab. PMID:23888248

Zoledronic acid renders human M1 and M2 macrophages susceptible to Vδ2+ γδ T cell cytotoxicity in a perforin-dependent manner.

PubMed

Fowler, Daniel W; Copier, John; Dalgleish, Angus G; Bodman-Smith, Mark D

2017-09-01

Vδ2 + T cells are a subpopulation of γδ T cells in humans that are cytotoxic towards cells which accumulate isopentenyl pyrophosphate. The nitrogen-containing bisphosphonate, zoledronic acid (ZA), can induce tumour cell lines to accumulate isopentenyl pyrophosphate, thus rendering them more susceptible to Vδ2 + T cell cytotoxicity. However, little is known about whether ZA renders other, non-malignant cell types susceptible. In this study we focussed on macrophages (Mϕs), as these cells have been shown to take up ZA. We differentiated peripheral blood monocytes from healthy donors into Mϕs and then treated them with IFN-γ or IL-4 to generate M1 and M2 Mϕs, respectively. We characterised these Mϕs based on their phenotype and cytokine production and then tested whether ZA rendered them susceptible to Vδ2 + T cell cytotoxicity. Consistent with the literature, IFN-γ-treated Mϕs expressed higher levels of the M1 markers CD64 and IL-12p70, whereas IL-4-treated Mϕs expressed higher levels of the M2 markers CD206 and chemokine (C-C motif) ligand 18. When treated with ZA, both M1 and M2 Mϕs became susceptible to Vδ2 + T cell cytotoxicity. Vδ2 + T cells expressed perforin and degranulated in response to ZA-treated Mϕs as shown by mobilisation of CD107a and CD107b to the cell surface. Furthermore, cytotoxicity towards ZA-treated Mϕs was sensitive-at least in part-to the perforin inhibitor concanamycin A. These findings suggest that ZA can render M1 and M2 Mϕs susceptible to Vδ2 + T cell cytotoxicity in a perforin-dependent manner, which has important implications regarding the use of ZA in cancer immunotherapy.

The miR-21/PTEN/Akt signaling pathway is involved in the anti-tumoral effects of zoledronic acid in human breast cancer cell lines.

PubMed

Fragni, M; Bonini, S A; Bettinsoli, P; Bodei, S; Generali, D; Bottini, A; Spano, P F; Memo, M; Sigala, S

2016-05-01

Preclinical data indicate a direct anti-tumor effect of zoledronic acid (ZA) outside the skeleton, but its molecular mechanism is still not completely clarified. The aim of this study was to investigate the anti-cancer effects of ZA in human breast cancer cell lines, suggesting that they may in part be mediated via the miR-21/PTEN/Akt signaling pathway. The effect of ZA on cell viability was measured by MTT assay, and cell death induction was analyzed using either a double AO/EtBr staining and M30 ELISA assay. A Proteome Profiler Human Apoptosis Array was executed to evaluate the molecular basis of ZA-induced apoptosis. Cell cycle analysis was executed by flow cytometry. The effect of ZA on miR-21 expression was quantified by qRT-PCR, and the amount of PTEN protein and its targets were analyzed by Western blot. ZA inhibited cell growth in a concentration- and time-dependent manner, through the activation of cell death pathways and arrest of cell cycle progression. ZA downregulated the expression of miR-21, resulting in dephosphorilation of Akt and Bad and in a significant increase of p21 and p27 proteins expression. These results were observed also in MDA-MB-231 cells, commonly used as an experimental model of bone metastasis of breast cancer. This study revealed, for the first time, an involvement of the miR-21/PTEN/Akt signaling pathway in the mechanism of ZA anti-cancer actions in breast cancer cells. We would like to underline that this pathway is present both in the hormone responsive BC cell line (MCF-7) as well as in a triple negative cell line (MDA-MB-231). Taken together these results reinforce the use of ZA in clinical practice, suggesting the role of miR-21 as a possible mediator of its therapeutic efficacy.

Effects of combined teriparatide and zoledronic acid on posterior lumbar vertebral fusion in an aged ovariectomized rat model of osteopenia.

PubMed

Yishake, Mumingjiang; Yasen, Miersalijiang; Jiang, Libo; Liu, Wangmi; Xing, Rong; Chen, Qian; Lin, Hong; Dong, Jian

2018-03-01

There has been no study regarding the effect of a combination of teriparatide (TPTD) and zoledronic acid (ZA) on vertebral fusion. In this study, we investigate the effect of single and combined TPTD and ZA treatment on lumbar vertebral fusion in aged ovariectomized (OVX) rats. Sixty two-month-old female Sprague-Dawley rats were ovariectomized and underwent bilateral L4-L5 posterolateral intertransverse fusion after 10 months. The OVX rats received vehicle (control) treatment, or ZA (100 µg/kg, once), or TPTD (60 µg/kg/2 d for 42 d), or ZA + TPTD until they were euthanized at 6 weeks following lumbar vertebral fusion. The lumbar spine was harvested. Bone mineral density (BMD), bone fusion, bone volume (BV), and bone formation rate (BFR)were analyzed by dual-energy X-ray absorptiometry (DXA), radiography, micro-computed tomography, and histomorphometry. Compared with vehicle (control) treatment, ZA and TPTD monotherapy increased bone volume (BV) at fusion site, and ZA + TPTD combined therapy had an additive effect. Treatment with TPTD and ZA + TPTD increased the bone fusion rate when compared with the control group. ZA monotherapy did not alter the rate of bone fusion. The TPTD and ZA + TPTD treatment groups had increased mineral apposition rate (MAR), mineralizing surfaces/bone surface ((MS/BS), and BFR/BS compared with the OVX group. Our experiment confirm that the monotherapy with TPTD and combination therapy with ZA + TPTD in an OVX rat model of osteopenia following lumbar vertebral fusion surgery increased bone fusion mass and bone fusion rate, and ZA + TPTD combined therapy had an additive effect on bone fusion mass. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:937-944, 2018. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Zoledronic acid suppresses transforming growth factor-β-induced fibrogenesis by human gingival fibroblasts.

PubMed

Komatsu, Yuko; Ibi, Miho; Chosa, Naoyuki; Kyakumoto, Seiko; Kamo, Masaharu; Shibata, Toshiyuki; Sugiyama, Yoshiki; Ishisaki, Akira

2016-07-01

Bisphosphonates (BPs) are analogues of pyrophosphate that are known to prevent bone resorption by inhibiting osteoclast activity. Nitrogen-containing BPs, such as zoledronic acid (ZA), are widely used in the treatment of osteoporosis and bone metastasis. However, despite having benefits, ZA has been reported to induce BP-related osteonecrosis of the jaw (BRONJ) in cancer patients. The molecular pathological mechanisms responsible for the development of BRONJ, including necrotic bone exposure after tooth extraction, remain to be elucidated. In this study, we examined the effects of ZA on the transforming growth factor-β (TGF‑β)-induced myofibroblast (MF) differentiation of human gingival fibroblasts (hGFs) and the migratory activity of hGFs, which are important for wound closure by fibrous tissue formation. The ZA maximum concentration in serum (Cmax) was found to be approximately 1.47 µM, which clinically, is found after the intravenous administration of 4 mg ZA, and ZA at this dose is considered appropriate for the treatment of cancer bone metastasis or bone diseases, such as Erdheim-Chester disease. At Cmax, ZA significantly suppressed i) the TGF‑β-induced promotion of cell viability, ii) the TGF‑β-induced expression of MF markers such as α-smooth muscle actin (α-SMA) and type I collagen, iii) the TGF‑β-induced migratory activity of hGFs and iv) the expression level of TGF‑β type I receptor on the surfaces of hGFs, as well as the TGF‑β-induced phosphorylation of Smad2/3. Thus, ZA suppresses TGF‑β-induced fibrous tissue formation by hGFs, possibly through the inhibition of Smad‑dependent signal transduction. Our findings partly elucidate the molecular mechanisms underlying BRONJ and may prove to be beneficial to the identification of drug targets for the treatment of this symptom at the molecular level.

Effect of intravenous zoledronic acid infusion on electrocardiographic parameters in patients with osteoporosis.

PubMed

Aktas, I; Nazikoglu, C; Kepez, A; Ozkan, F U; Kaysin, M Y; Akpinar, P; Dogan, Z; Ileri, C; Saymaz, S; Erdogan, O

2016-12-01

We evaluated the effects of zoledronic acid (ZA) therapy on electrocardiographic (ECG) parameters for the first time in the literature. Measurements were performed on ECGs obtained before and after ZA infusion on the same day as well as 1 month after the infusion. ZA infusion did not have any short- or long-term effect on any parameter that might be associated with the tendency for atrial fibrillation or ventricular arrhythmias. The aim of the present study was to evaluate the early and late effects of ZA therapy on ECG parameters which might be associated with the tendency for atrial and ventricular arrhythmias. Consecutive patients with osteoporosis who were admitted to our clinic between December 2013 and December 2014 and who were scheduled to receive ZA infusion constituted our study population. Twelve-lead surface ECGs were obtained from all patients before and after ZA infusion on the same day as well as 1 month after the infusion. All ECG parameters were measured and compared with each other for each patient. Data of 100 patients were used in the analysis (9 male; 70.5 ± 11.6 years of age). There were no significant differences between repeated measurements regarding pmax, pmin, and p dispersion values. QT max and QT min values were significantly increased after infusion; however, there were no significant changes in QT dispersion, Tp-e interval, and Tp-e dispersion values. ZA infusion did not affect P wave dispersion both at the immediate post-infusion period and 1 month after infusion. QT values were significantly increased early after ZA infusion; however, there were no significant differences in parameters reflecting disparity of ventricular recovery times and transmural dispersion of ventricular repolarization. Based on these observations, it may be suggested that ZA infusion did not have any short- or long-term effect on any parameter that might be associated with the tendency for atrial fibrillation or ventricular arrhythmias.

Guided bone regeneration with local zoledronic acid and titanium barrier: An experimental study.

PubMed

Dundar, Serkan; Ozgur, Cem; Yaman, Ferhan; Cakmak, Omer; Saybak, Arif; Ozercan, Ibrahim Hanifi; Alan, Hilal; Artas, Gokhan; Nacakgedigi, Onur

2016-10-01

The aim of this study was to evaluate the effects on new bone formation of autogenous blood alone or in combination with zoledronic acid (ZA), a β-tricalcium phosphate (β-TCP) graft or ZA plus a β-TCP graft placed under titanium barriers. For this purpose, eight adult male New Zealand white rabbits were used in the study, each with four titanium barriers fixed around four sets of nine holes drilled in the calvarial bones. The study included four groups, each containing 2 rabbits. In the autogenous blood (AB group), only autogeneous blood was placed under the titanium barriers. The three experimental groups were the AB+ZA group, with autogenous blood plus ZA, the AB+β-TCP group, with autogeneous blood plus a β-TCP graft, and the AB+β-TCP+ZA group, with autogeneous blood plus a β-TCP graft and ZA mixture under the titanium barriers. The animals were sacrificed after 3 months. The amounts of new bone formation identified histomorphometrically were found to be higher after 3 months than at the time of surgery in all groups. The differences between the groups were examined with histomorphometric analysis, and statistically significant differences were identified at the end of the 3 months. The bone formation rate in the AB+β-TCP+ZA group was determined to be significantly higher than that in the other groups (P<0.05). In the AB+ZA and AB+β-TCP groups, the bone formation rate was determined to be significantly higher than that in the AB group (P<0.05). No statistically significant difference in bone formation rate was observed between the AB+β-TCP and AB+ZA groups. Local ZA used with autogeneous blood and/or graft material appears to be a more effective method than the use of autogeneous blood or graft alone in bone augmentation executed with a titanium barrier.

Dose-dependent inhibitory effects of zoledronic acid on osteoblast viability and function in vitro.

PubMed

Huang, Xin; Huang, Shilong; Guo, Fengjin; Xu, Fei; Cheng, Peng; Ye, Yaping; Dong, Yonghui; Xiang, Wei; Chen, Anmin

2016-01-01

Zoledronic acid (ZA), which is one of the most potent and efficacious bisphosphonates, has been commonly used in clinical practice for the treatment of various bone disorders. The extensive use of ZA has been associated with increasing occurrence of jaw complications, now known as bisphosphonate‑associated osteonecrosis of the jaw (BRONJ). However, the mechanism underlying BRONJ remains to be fully elucidated. The aim of the present study was to investigate the effects of different concentrations of ZA on the MC3T3‑E1 murine preosteoblast cell line cells and examine the possible pathogenesis of BRONJ. In the present study, the effect of ZA on the viability, apoptosis, differentiation and maturation of MC3T3‑E1 cells, as well as its relevant molecular mechanism, were examined The results of a Cell Counting Kit 8 assay, a flow cytometric Annexin‑V/propidium iodide assay and western blot analysis demonstrated that ZA exhibited a significant inhibition of cell viability and induction of apoptosis at concentrations >10 µM. Subsequently, the effect of ZA on cell differentiation at concentrations <1 µM were investigated. In this condition, ZA inhibited bone nodule formation and decreased the activity of alkaline phosphatase. The results of reverse transcription-quantitative polymerase chain reaction and western blot analyses indicated that ZA downregulated the expression levels of the marker genes and proteins associated with osteogenic differentiation. Further investigation revealed that the suppression of differentiation by ZA was associated with decreased expression of bone morphogenetic protein‑2 (BMP‑2) and downregulation of the phosphorylation levels in the downstream extracellular signal‑regulated kinase 1/2 and p38 pathways. These adverse effects of ZA were observed to be concentration‑dependent. The results from the present study suggested that ZA at higher concentrations induces cytotoxicity towards osteoblasts, and ZA at lower concentrations suppresses osteoblast differentiation by downregulation of BMP-2. These results assist in further understanding the mechanisms of BRONJ.

Short-Term Safety of Zoledronic Acid in Young Patients With Bone Disorders: An Extensive Institutional Experience

PubMed Central

George, Sobenna; Weber, David R.; Kaplan, Paige; Hummel, Kelly; Monk, Heather M.

2015-01-01

Context: Zoledronic acid (ZA) is increasingly used in young patients with bone disorders. However, data related to the safety of ZA administration in this population are limited. Objective: The study aimed to characterize the short-term safety profile of ZA and identify risk factors for ZA-related adverse events (AEs) in young patients. Design, Setting, and Participants: This was a retrospective chart review of inpatients and outpatients less than 21 years old who received at least one ZA infusion between July 2010 and January 2014 at The Children's Hospital of Philadelphia. Results: Eighty-one patients (56% male; median age, 12 y; age at first infusion, 0.5 to 20 y) with diverse skeletal disorders received a total of 204 infusions. The most common indications were osteoporosis (33% of cohort) and osteogenesis imperfecta (27.2%). The median ZA dose was 0.025 mg/kg (interquartile range, 0.025–0.05); the median dosing interval was 6 months (range, 1 to 25.6 mo). AEs were mild and more common after the first ZA infusion in patients with no previous bisphosphonate exposure: hypophosphatemia (25.2% of infusions), acute phase reactions (19.1%), and hypocalcemia (16.4%). Symptomatic hypocalcemia requiring iv calcium occurred after two infusions. ZA dose was significantly associated with hypophosphatemia, but not other AEs. Hypocalcemia was more common in patients with high bone turnover as assessed by preinfusion alkaline phosphatase levels. AEs were not associated with diagnosis, baseline serum calcium, or calcium/calcitriol supplementation. Conclusion: Acute AEs related to ZA infusion in youths are common, occur principally after the first ZA infusion in bisphosphonate-naive patients, and are typically mild and easily managed. Future prospective studies are needed to determine the potential long-term risks, as well as benefits, of ZA therapy in the pediatric population. PMID:26308295

Home-based zoledronic acid infusion therapy in patients with solid tumours: compliance and patient-nurse satisfaction.

PubMed

Lebret, Thierry; Mouysset, Jean-Loup; Lortholary, Alain; El Kouri, Claude; Bastit, Laurent; Ktiouet, Meryem; Slimane, Khemaies; Murraciole, Xavier; Guérif, Stéphane

2013-06-01

This study aimed to explore patient and nurse satisfaction, compliance with best practice, technical feasibility and safety of home infusion of the bisphosphonate zoledronic acid (ZOL). This was a prospective 1-year survey of home ZOL therapy (4 mg Zometa, 15-min i.v., every 3-4 weeks) in patients with bone metastases secondary to a solid malignancy. A physician questionnaire, nurse satisfaction/feasibility questionnaire and patient satisfaction questionnaire were administered at several time-points. Physician participation rate was 56.5% (87/154). Physicians enrolled 818 patients visited by 381 predominantly community nurses. Of the 788 case report forms received, 763 met inclusion criteria. Patient characteristics were as follows: median age, 68 years (30-95); M/F, 40/60; ECOG-PS 0 or 1, 78.6%; and primary tumour site, breast (55.2%), prostate (28.4%), lung (7.2%) or other (9.4%). Nurse satisfaction rates were high: organisation of home ZOL therapy, 90.9%; ease of infusion, 96.7%; patient-nurse relationship, 97.5%; and relationship with hospital staff, 73%. Patient satisfaction was also very high (95.3%). The main reasons were quality of the nurse-patient relationship (57.6%), less travel/waiting (68.8%), home environment (52.9%) and less disruption to daily routine (36.6%). ZOL therapy was well tolerated, the discontinuation rate due to adverse events (including deaths whether related to diseases progression or not) was 33.6%. The incidence of osteonecrosis of the jaw was 0.6% and of fractures, 0.2%. Practitioner compliance with best practice was 76.7-83.7% for recommended and/or tolerated dosage, 73% for dental hygiene checks at inclusion and 48-56% thereafter, 66% for pre-infusion hydration, and often undocumented for calcium/vitamin D supplementation. Home ZOL therapy was well tolerated. Both patient and nurse satisfaction were very high. However, better compliance with best practice should be encouraged.

Systematic review and meta-analysis of the efficacy and safety of alendronate and zoledronate for the treatment of postmenopausal osteoporosis.

PubMed

Serrano, Ana Julissa; Begoña, Leire; Anitua, Eduardo; Cobos, Raquel; Orive, Gorka

2013-12-01

The aim of this meta-analysis was to evaluate the efficacy and safety of two bisphosphonates (alendronate and zoledronate) in the treatment of postmenopausal osteoporosis. The incidence of fractures was considered as primary endpoint. Only randomized trials with a follow-up period of 1 year or more were included in this systematic review and meta-analysis. We excluded studies that included patients with secondary osteoporosis especially in relation to therapy with corticosteroids or other drugs or diseases known to affect bone mineral density. Studies published as subgroup analysis, extension studies, economic evaluations, and comparisons with active control were excluded. The methodological quality of controlled clinical trials that met these inclusion criteria was evaluated. No studies were excluded from analysis due to lack of quality. The risk ratio of hip, vertebral and wrist fractures for alendronate were 0.61 [95% confidence interval (CI) 0.40-0.93], 0.54 (95% CI 0.44-0.66) and 0.65 (95% CI 0.33-1.25), respectively. Zoledronate risk ratio was 0.62 (95% CI 0.46-0.82) and 0.38 (95% CI 0.22-0.67) for hip and vertebral fractures, respectively.

Zoledronate, ibandronate and clodronate enhance osteoblast differentiation in a dose dependent manner--a quantitative in vitro gene expression analysis of Dlx5, Runx2, OCN, MSX1 and MSX2.

PubMed

Koch, Felix Peter; Merkel, Christina; Al-Nawas, Bilal; Smeets, Ralf; Ziebart, Thomas; Walter, Christian; Wagner, Wilfried

2011-12-01

Bisphosphonates are widely used in the clinical treatment of bone diseases with increased bone resorption. In terms of side effects, they are known to be associated with osteonecrosis of the jaw (BONJ). There are two groups of bisphosphonates: the nitrogen-containing bisphosphonates, e.g. zoledronate and ibandronate, and the non-nitrogen-containing bisphosphonates, e.g. clodronate. Their impact on bone metabolism seems to differ. The objective of this study was to compare the osteogenic differentiation potency of these two pharmacologic groups. Human osteoblasts were stimulated with zoledronate and ibandronate at concentrations of 5×10(-5) M, 5×10(-6) M and 5×10(-7) M over the experimental periods of 1, 2, 5, 10 and 14 days. Clodronate was applied with concentrations of 5×10(-3), 5×10(-5) M and 5×10(-6) M. At each time point, the cells were dissolved, the mRNA extracted, and the gene expression level of the osteoblast specific differentiation markers of the homeobox transcription factors MSX1 and MSX2, the distal-less homeobox 5 (Dlx5), the Runt-related transcription factor 2 (Runx2/CBF1a) and osteocalcin (OCN) were quantified by Real-Time PCR. The gene expression was compared to an unstimulated osteoblast cell culture as control. The results showed a significant difference between the nitrogen-containing and the non-nitrogen-containing bisphosphonates. Zoledronate and ibandronate at concentrations of 5×10(-5) M enhanced the gene expression of all differentiation markers by several hundred folds compared to unstimulated control after 10 days, whereas clodronate had less influence on gene expression, even at higher concentrations of 5×10(-3) M. Lower concentrations of zoledronate and ibandronate, however, led to a decreased gene expression. These data confirm the results of other studies which have shown the osteogenic stimulus on osteoblasts in a dose dependent manner. The nitrogen-containing bisphosphonates appear to enhance bone density by stimulation of osteoblast differentiation. Non-nitrogen-containing bisphosphonates seem to have less influence on osteoblast differentiation. Copyright © 2010 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

Oral Squamous Cell Carcinoma Arising in a Patient after Hematopoietic Stem Cell Transplantation with Bisphosphonate-Related Osteonecrosis of the Jaws

PubMed Central

Scully, Crispian; Chiusa, Luigi; Broccoletti, Roberto

2015-01-01

A 55-year-old man with a history of acute myeloid leukaemia treated with hematopoietic stem cell transplantation and with a 5-year history of bisphosphonate-related osteonecrosis of the jaws, following 12 cycles of intravenous zoledronic acid therapy, presented in December 2009 with a history of increasingly severe unilateral lower jaw pain. Oral examination revealed, as previously, exposed bone in the left mandible, but also a new exophytic mass on the lower-left buccal mucosa. Biopsy confirmed a diagnosis of oral squamous cell carcinoma. To the best of our knowledge, this is the first report of an oral squamous cell carcinoma that appeared adjacent to an area of osteochemonecrosis. PMID:25973278

Oral squamous cell carcinoma arising in a patient after hematopoietic stem cell transplantation with bisphosphonate-related osteonecrosis of the jaws.

PubMed

Arduino, Paolo G; Scully, Crispian; Chiusa, Luigi; Broccoletti, Roberto

2015-01-01

A 55-year-old man with a history of acute myeloid leukaemia treated with hematopoietic stem cell transplantation and with a 5-year history of bisphosphonate-related osteonecrosis of the jaws, following 12 cycles of intravenous zoledronic acid therapy, presented in December 2009 with a history of increasingly severe unilateral lower jaw pain. Oral examination revealed, as previously, exposed bone in the left mandible, but also a new exophytic mass on the lower-left buccal mucosa. Biopsy confirmed a diagnosis of oral squamous cell carcinoma. To the best of our knowledge, this is the first report of an oral squamous cell carcinoma that appeared adjacent to an area of osteochemonecrosis.

Dental extraction following zoledronate, induces osteonecrosis in rat´s jaw

PubMed Central

Gómez-Clavel, José-Francisco; Gaitán-Cepeda, Luis-Alberto

2017-01-01

Background Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) is clinically characterized by the presence of exposed bone in the oral cavity that persists for more than eight weeks. Previous attempts to establish an animal model have not sufficiently considered disease features. Our aim was to establish an inexpensive and replicable animal model that develops BRONJ in a short time. Material and Methods Thirty-two male Wistar rats were randomly divided into two groups: control and experimental. In the experimental group, we administered 0.06mg/kg intraperitoneal dose of zoledronic acid (ZA) 7 and 14 days prior to maxillary second molar extraction. At two, four and six weeks after tooth extraction, the animals were euthanized, and we dissected the maxilla following histological procedures. We stained serial slides with hematoxylin and eosin and Masson’s trichrome. The samples were harvested for macroscopic, radiologic and histological evaluation of bone changes. Results At two weeks postextraction, we observed exposed necrotic bone in dental socket areas in experimental groups. Radiological analysis revealed osteolytic lesions accompanied by extensive destruction and sequestrum formation in the same group. Histological examination confirmed the absence of necrotic bone in control groups in contrast with the experimental groups. The percentage of empty lacunae and the number of osteoclasts and the necrotic bone area were significantly increased (p<0.05) in the experimental groups. Conclusions The animal model using ZA administration to prior dental extraction successfully mimicked human BRONJ lesions. Also, the model was easily replicated, inexpensive and showed different features than other previous BRONJ models. Key words:Bisphosphonates, osteonecrosis, dental extractions, animal model, BRONJ. PMID:28160593

Bone metastases and non-small cell lung cancer: from bisphosphonates to targeted therapy.

PubMed

Rossi, A; Gridelli, C; Ricciardi, S; de Marinis, F

2012-01-01

About 30-40% of patients affected by non-small cell lung cancer (NSCLC) develop, during the course of their disease, bone metastases. The prognosis of these patients is poor with a median survival of less than 1 year. The therapeutic approach includes: palliative radiotherapy, and systemic therapy. In clinical practice, zoledronate is the most commonly used bisphosphonate to prevent, reduce the incidence and delay the onset of skeletal-related events in patients with metastatic NSCLC. However, an Italian Association of Thoracic Oncology (AIOT) survey, conducted to evaluate how bisphosphonates were used in clinical practice for the treatment of lung cancer bone metastases in Italy, showed that the bisphosphonates treatment is still not routine and varies in duration. Denosumab is a fully human monoclonal antibody directed against the receptor activator of nuclear factor kappa-B (RANK)-Ligand inhibiting the maturation of pre-osteoclasts into osteoclasts and is the first example of targeted therapy for bone metastases. An exploratory analysis showed that denosumab was associated with improved overall survival compared with zoledronate in patients with bone metastases from lung cancer. Biochemical markers of bone turnover to predict what patients are at greatest risk of developing skeletal-related events, and to direct treatment of bone metastases with either bisphosphonates or denosumab, are under investigation. This review is focused on the systemic management of bone metastases from NSCLC.

Bone targeting compounds for radiotherapy and imaging: *Me(III)-DOTA conjugates of bisphosphonic acid, pamidronic acid and zoledronic acid.

PubMed

Meckel, M; Bergmann, R; Miederer, M; Roesch, F

2017-01-01

Bisphosphonates have a high adsorption on calcified tissues and are commonly used in the treatment of bone disorder diseases. Conjugates of bisphosphonates with macrocyclic chelators open new possibilities in bone targeted radionuclide imaging and therapy. Subsequent to positron emission tomography (PET) examinations utilizing 68 Ga-labelled analogues, endoradiotheraphy with 177 Lu-labelled macrocyclic bisphosphonates may have a great potential in the treatment of painful skeletal metastases. Based on the established pharmaceuticals pamidronate and zoledronate two new DOTA-α-OH-bisphosphonates, DOTA PAM and DOTA ZOL (MM1.MZ) were successfully synthesized. The ligands were labelled with the positron emitting nuclide 68 Ga and the β - emitting nuclide 177 Lu and compared in in vitro studies and in ex vivo biodistribution studies together with small animal PET and single photon emission computed tomography (SPECT) studies against [ 18 F]NaF and a known DOTA-α-H-bisphosphonate conjugate (BPAPD) in healthy Wistar rats. The new DOTA-bisphosphonates can be labelled in high yield of 80 to 95 % in 15 min with post-processed 68 Ga and >98 % with 177 Lu. The tracers showed very low uptake in soft tissue, a fast renal clearance and a high accumulation on bone. The best compound was [ 68 Ga]DOTA ZOL (SUV Femur  = 5.4 ± 0.6) followed by [ 18 F]NaF (SUV Femur  = 4.8 ± 0.2), [ 68 Ga]DOTA PAM (SUV Femur  = 4.5 ± 0.2) and [ 68 Ga]BPAPD (SUV Femur  = 3.2 ± 0.3). [ 177 Lu]DOTA ZOL showed a similar distribution as the diagnostic 68 Ga complex. The 68 Ga labelled compounds showed a promising pharmacokinetics, with similar uptake profile and distribution kinetics. Bone accumulation was highest for [ 68 Ga]DOTA ZOL , which makes this compound probably an interesting bone targeting agent for a therapeutic approach with 177 Lu. The therapeutic compound [ 177 Lu]DOTA ZOL showed a high target-to-background ratio. SPECT experiments showed concordance to the PET scans in healthy rats. [ 68 Ga/ 177 Lu]DOTA ZOL appears to be a potential theranostic combination in the management of disseminated bone metastases.

TCRαβ+/CD19+ Depleted Haploidentical HSCT + Zoledronate

ClinicalTrials.gov

2018-05-09

Acute Myeloid Leukemia; Acute Lymphoblastic Leukemia; Hodgkin Lymphoma; Non-Hodgkin Lymphoma; Myelodysplastic Syndrome; Myeloproliferative Syndrome; Rhabdomyosarcoma; Ewing Sarcoma; Primitive Neuroectodermal Tumor; Osteosarcoma; Neuroblastoma

Early effects of zoledronic acid and teriparatide on bone microarchitecture, remodeling and collagen crosslinks: comparison between iliac crest and lumbar vertebra in ewes.

PubMed

Portero-Muzy, N R; Chavassieux, P M; Bouxsein, M L; Gineyts, E; Garnero, P; Chapurlat, R D

2012-10-01

Iliac crest bone biopsies are used to assess the mechanism of action of drug treatments, yet there are little data comparing this site to sites prone to fracture. The purpose of this study was to compare the delay and the amplitude of responses to treatment in two different bone sites. The short-term effects of zoledronic acid and teriparatide on microarchitecture, collagen crosslinks and bone remodeling were evaluated in iliac crest and lumbar vertebrae. Aged ewes (n=8/gr) received either vehicle (CTRL) or a single injection of zoledronic acid (ZOL, 10mg) or daily injections of teriparatide (TPTD, 20 μg/d) for 3 months. Blood samples were collected monthly for assessing bone turnover markers. At the end of the study, a transiliac bone biopsy (IC) and L1 lumbar vertebrae (LV1) were collected to assess bone microarchitecture; pyridinoline (PYD), deoxypyridinoline (DPD), pentosidine (PEN) content, static and dynamic parameters of bone remodeling. In CTRL, Tb-BV/TV was significantly higher in LV1 than IC (p<0.0001). This was associated with a trend of higher Tb.N, Tb.Th, DA, an inferior Conn.D and a lower bone turnover as shown by the decreases of osteoid parameters, MS/BS, Ac.f in LV1 when compared to IC. In addition, the ratio PYD/DPD was 4 times higher in LV1 than IC. After 3 months, significant decreases of sALP (p<0.001) and sCTX (p<0.001) were observed in the ZOL-group whereas in TPTD-group, after transient increases, they returned to baseline values. When compared to their respective CTRL, ZOL induced significant increases in Tb.BV/TV, Conn.D, Tb.N and Tb.Sp, in IC but not in LV1. Regardless of the site, ZOL markedly depressed the bone turnover: The static parameters of bone formation significantly decreased and the diminution of MS/BS, BFR/BS and Ac.f varied from -94 to -98% vs CTRL (p<0.01 to 0.001). It was associated with a diminution of the DPD content and the PYD/DPD ratio mainly in IC cortices. In contrast, after 3 months, TPTD did not modify the 3D structure and microarchitecture in IC and LV1, except a trend of higher Conn.D in IC, compared to IC-CTRL. TPTD treatment induced a significant increase in cortical porosity in LV1 (p<0.05) when compared to LV1-CTRL. Static parameters of bone formation and resorption were augmented in both sites, significantly only in LV1 (p<0.05) with a trend of increases in MS/BS and BFR/BS, compared to LV1-CTRL. In conclusion, in adult ewes, the bone mass, microarchitecture, remodeling and collagen crosslink content differ according to the bone site (iliac crest and vertebra). Furthermore, after 3 months, the responses to ZOL and TPTD were of different magnitude and delay between the two bone sites. The distinction of bone sites to study the early effects of anti-osteoporotic therapies appears meaningful in order to approach their site-specific anti-fracture efficacy. Copyright © 2012 Elsevier Inc. All rights reserved.

Clinical Outcomes and Survival Following Treatment of Metastatic Castrate-Refractory Prostate Cancer With Docetaxel Alone or With Strontium-89, Zoledronic Acid, or Both: The TRAPEZE Randomized Clinical Trial.

PubMed

James, Nicholas D; Pirrie, Sarah J; Pope, Ann M; Barton, Darren; Andronis, Lazaros; Goranitis, Ilias; Collins, Stuart; Daunton, Adam; McLaren, Duncan; O'Sullivan, Joe; Parker, Christopher; Porfiri, Emilio; Staffurth, John; Stanley, Andrew; Wylie, James; Beesley, Sharon; Birtle, Alison; Brown, Janet; Chakraborti, Prabir; Hussain, Syed; Russell, Martin; Billingham, Lucinda J

2016-04-01

Bony metastatic castrate-refractory prostate cancer (CRPC) has a poor prognosis and high morbidity. Zoledronic acid (ZA) is commonly combined with docetaxel in practice but lacks evidence that combining is effective, and strontium-89 (Sr89) is generally used palliatively in patients unfit for chemotherapy. Phase 2 analysis of the TRAPEZE trial confirmed combining the agents was safe and feasible, and the objectives of phase 3 include assessment of the treatments on survival. To determine clinical effectiveness and cost-effectiveness of combining docetaxel, ZA, and Sr89, all having palliative benefits and used in bony metastatic CRPC to control bone symptoms and, for docetaxel, to prolong survival. The TRAPEZE trial is a 2 × 2 factorial trial comparing docetaxel alone or with ZA, Sr89, or both. A cohort of 757 participants were recruited between February 2005 and February 2012 from hospitals in the United Kingdom. Overall, 169 participants (45%) had received palliative radiotherapy, and the median (IQR) prostate-specific antigen level was 146 (51-354). Follow-ups were performed for at least 12 months. Up to 10 cycles of docetaxel alone; docetaxel with ZA; docetaxel with a single Sr89 dose after 6 cycles; or docetaxel with both ZA and Sr89. Primary outcomes included clinical progression-free survival (CPFS) (pain progression, skeletal-related events [SREs], or death) and cost-effectiveness. Secondary outcomes included SRE-free interval, pain progression-free interval, total SREs, and overall survival (OS). Overall, of 757 participants, 349 (46%) completed docetaxel treatment. Median (IQR) age was 68 (63-73) years. Clinical progression-free survival did not reach statistical significance for either Sr89 or ZA. Cox regression analysis adjusted for all stratification variables showed benefit of Sr89 on CPFS (hazard ratio [HR], 0.85; 95% CI, 0.73-0.99; P = .03) and confirmed no effect of ZA (HR, 0.98; 95% CI, 0.85-1.14; P = .81); ZA had a significant effect on SRE-free interval (HR, 0.78; 95% CI, 0.65-0.95; P = .01). For OS, there was no effect of either Sr89 (HR, 0.92; 95% CI, 0.79-1.08; P = 0.34) or ZA (HR, 0.99; 95% CI, 0.84-1.16; P = 0.91). Strontium-89 combined with docetaxel improved CPFS but did not improve OS, SRE-free interval, or total SREs; ZA did not improve CPFS or OS but did significantly improve median SRE-free interval and reduced total SREs by around one-third, suggesting a role as postchemotherapy maintenance therapy. isrctn.com Identifier: ISRCTN12808747.

Protective effect of zoledronic acid on articular cartilage and subchondral bone of rabbits with experimental knee osteoarthritis

PubMed Central

She, Guorong; Zhou, Ziqi; Zha, Zhengang; Wang, Fei; Pan, Xiaoting

2017-01-01

Subchondral bone reabsorption and remodeling are responsible for the initiation and progression of osteoarthritis (OA). Zoledronic acid (ZOL), a third-generation bisphosphonate (BIS), is an inhibitor of bone reabsorption. However, the intervention effect of ZOL on OA has not been fully characterized and remains to be directly demonstrated in animal experiments. The present study examined the microscopic and macroscopic changes in the anterior cruciate ligament transection (ACLT) model of OA in rabbits and evaluated the effects of ZOL on cartilage degeneration and subchondral bone loss. A total of 32 New Zealand white rabbits were randomly divided into four groups: High-, medium- and low-dose ZOL groups, which received an intravenous injection of 250, 50 and 10 µg/kg ZOL, respectively, after modeling, as well as an untreated group. The bone mineral density (BMD) of the knee joint was evaluated by dual-energy X-ray absorptiometry scanning immediately after modeling and at 4 and 8 weeks. At week 8, quantitative measurement of cartilage was performed by a specialized magnetic resonance imaging (MRI) technique, including three-dimensional fat-suppressed spoil gradient-recalled sequence and T2 mapping. The rabbits were sacrificed by air embolism after anesthesia and both knee joints were harvested and evaluated by general and histological observation. Toluidine blue and hematoxylin and eosin staining were used to assess histological changes in the articular cartilage. Quantitative analysis of cartilage histopathology was performed according to the Mankin scoring system. The BMD of ACLT joints dropped after modeling, which was effectively suppressed by ZOL at the high and medium dose but not the low dose. MRI scans demonstrated that in the untreated group, articular cartilages on ACLT knees were thinner than those on normal knees. The high dose of ZOL preserved the cartilage tissue thickness more efficiently than the medium and low doses. Observation of specimens and pathological slices revealed that the articular cartilage degeneration in the high-dose ZOL group was lightest, while that in the medium- and low-dose ZOL group was moderate, and the untreated group exhibited the most severe defect. The untreated group had the highest Mankin score, whereas the high-dose ZOL group had the lowest score. In conclusion, ZOL increased the subchondral bone density, improved the microstructure and reduced the degeneration of articular cartilage in OA according to morphological as well as quantitative observation. ZOL exerted significant chondroprotective effects in a dose-dependent manner. A favorable chondroprotective effect was induced at the dose of 250 µg/kg. ZOL may represent a novel promising drug to complement the treatment of OA. PMID:29201194

Bisphosphonate-related osteonecrosis of the jaw: historical, ethical, and legal issues associated with prescribing.

PubMed

Faiman, Beth; Pillai, Aiswarya Lekshmi Pillai Chandran; Benghiac, Ana Gabriela

2013-01-01

The long-term effects of many drugs are unknown. Established risks are communicated to patients who participate in clinical trials during the informed consent process. However, unknown and unanticipated side effects of medications may occur years after treatment. Patients with metastatic bone cancer experience an imbalance between tumor cells and the bone marrow microenvironment. Increased cytokine release, osteoclastic activity, and uncoupled osteoblastic activity lead to weakened bone structure and osteolytic lesions. The bisphosphonates are a class of drugs available in IV and oral formulations to treat and prevent bone loss and decrease the risk of skeletal-related events. Intravenous bisphosphonates such as zoledronic acid and pamidronate disodium are approved by the US Food and Drug Administration for the treatment of bone pain and hypercalcemia of malignancy and the prevention of painful bone fractures in patients with metastatic bone cancer. Oral bisphosphonates such as alendronate, risedronate, and etidronate are used to reduce the risk of skeletal fractures in patients with osteoporosis and in breast cancer. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a rare but painful complication of treatment characterized by infection, exposed bone, and poor wound healing. In this article, we discuss BRONJ and identify past, present, and future ethical and legal issues surrounding bisphosphonate administration.

Longitudinal Effects of Teriparatide or Zoledronic Acid on Bone Modeling- and Remodeling-Based Formation in the SHOTZ Study.

PubMed

Dempster, David W; Zhou, Hua; Ruff, Valerie A; Melby, Thomas E; Alam, Jahangir; Taylor, Kathleen A

2018-04-01

Previously, we reported on bone histomorphometry, biochemical markers, and bone mineral density distribution after 6 and 24 months of treatment with teriparatide (TPTD) or zoledronic acid (ZOL) in the SHOTZ study. The study included a 12-month primary study period, with treatment (TPTD 20 μg/d by subcutaneous injection or ZOL 5 mg/yr by intravenous infusion) randomized and double-blind until the month 6 biopsy (TPTD, n = 28; ZOL, n = 30 evaluable), then open-label, with an optional 12-month extension receiving the original treatment. A second biopsy (TPTD, n = 10; ZOL, n = 9) was collected from the contralateral side at month 24. Here we present data on remodeling-based bone formation (RBF), modeling-based bone formation (MBF), and overflow modeling-based bone formation (oMBF, modeling overflow adjacent to RBF sites) in the cancellous, endocortical, and periosteal envelopes. RBF was significantly greater after TPTD versus ZOL in all envelopes at 6 and 24 months, except the periosteal envelope at 24 months. MBF was significantly greater with TPTD in all envelopes at 6 months but not at 24 months. oMBF was significantly greater at 6 months in the cancellous and endocortical envelopes with TPTD, with no significant differences at 24 months. At 6 months, total bone formation surface was also significantly greater in each envelope with TPTD treatment (all p < 0.001). For within-group comparisons from 6 to 24 months, no statistically significant changes were observed in RBF, MBF, or oMBF in any envelope for either the TPTD or ZOL treatment groups. Overall, TPTD treatment was associated with greater bone formation than ZOL. Taken together the data support the view that ZOL is a traditional antiremodeling agent, wheareas TPTD is a proremodeling anabolic agent that increases bone formation, especially that associated with bone remodeling, including related overflow modeling, with substantial modeling-based bone formation early in the course of treatment. © 2017 American Society for Bone and Mineral Research. © 2017 American Society for Bone and Mineral Research.

Adding Celecoxib With or Without Zoledronic Acid for Hormone-Naïve Prostate Cancer: Long-Term Survival Results From an Adaptive, Multiarm, Multistage, Platform, Randomized Controlled Trial

PubMed Central

Mason, Malcolm D.; Clarke, Noel W.; James, Nicholas D.; Dearnaley, David P.; Spears, Melissa R.; Ritchie, Alastair W.S.; Attard, Gerhardt; Cross, William; Jones, Rob J.; Parker, Christopher C.; Russell, J. Martin; Thalmann, George N.; Schiavone, Francesca; Cassoly, Estelle; Matheson, David; Millman, Robin; Rentsch, Cyrill A.; Barber, Jim; Gilson, Clare; Ibrahim, Azman; Logue, John; Lydon, Anna; Nikapota, Ashok D.; O’Sullivan, Joe M.; Porfiri, Emilio; Protheroe, Andrew; Srihari, Narayanan Nair; Tsang, David; Wagstaff, John; Wallace, Jan; Walmsley, Catherine; Parmar, Mahesh K.B.; Sydes, Matthew R.

2017-01-01

Purpose Systemic Therapy for Advanced or Metastatic Prostate Cancer: Evaluation of Drug Efficacy is a randomized controlled trial using a multiarm, multistage, platform design. It recruits men with high-risk, locally advanced or metastatic prostate cancer who were initiating long-term hormone therapy. We report survival data for two celecoxib (Cel)-containing comparisons, which stopped accrual early at interim analysis on the basis of failure-free survival. Patients and Methods Standard of care (SOC) was hormone therapy continuously (metastatic) or for ≥ 2 years (nonmetastatic); prostate (± pelvic node) radiotherapy was encouraged for men without metastases. Cel 400 mg was administered twice a day for 1 year. Zoledronic acid (ZA) 4 mg was administered for six 3-weekly cycles, then 4-weekly for 2 years. Stratified random assignment allocated patients 2:1:1 to SOC (control), SOC + Cel, or SOC + ZA + Cel. The primary outcome measure was all-cause mortality. Results were analyzed with Cox proportional hazards and flexible parametric models adjusted for stratification factors. Results A total of 1,245 men were randomly assigned (Oct 2005 to April 2011). Groups were balanced: median age, 65 years; 61% metastatic, 14% N+/X M0, 25% N0M0; 94% newly diagnosed; median prostate-specific antigen, 66 ng/mL. Median follow-up was 69 months. Grade 3 to 5 adverse events were seen in 36% SOC-only, 33% SOC + Cel, and 32% SOC + ZA + Cel patients. There were 303 control arm deaths (83% prostate cancer), and median survival was 66 months. Compared with SOC, the adjusted hazard ratio was 0.98 (95% CI, 0.80 to 1.20; P = .847; median survival, 70 months) for SOC + Cel and 0.86 (95% CI, 0.70 to 1.05; P =.130; median survival, 76 months) for SOC + ZA + Cel. Preplanned subgroup analyses in men with metastatic disease showed a hazard ratio of 0.78 (95% CI, 0.62 to 0.98; P = .033) for SOC + ZA + Cel. Conclusion These data show no overall evidence of improved survival with Cel. Preplanned subgroup analyses provide hypotheses for future studies. PMID:28300506

Adding Celecoxib With or Without Zoledronic Acid for Hormone-Naïve Prostate Cancer: Long-Term Survival Results From an Adaptive, Multiarm, Multistage, Platform, Randomized Controlled Trial.

PubMed

Mason, Malcolm D; Clarke, Noel W; James, Nicholas D; Dearnaley, David P; Spears, Melissa R; Ritchie, Alastair W S; Attard, Gerhardt; Cross, William; Jones, Rob J; Parker, Christopher C; Russell, J Martin; Thalmann, George N; Schiavone, Francesca; Cassoly, Estelle; Matheson, David; Millman, Robin; Rentsch, Cyrill A; Barber, Jim; Gilson, Clare; Ibrahim, Azman; Logue, John; Lydon, Anna; Nikapota, Ashok D; O'Sullivan, Joe M; Porfiri, Emilio; Protheroe, Andrew; Srihari, Narayanan Nair; Tsang, David; Wagstaff, John; Wallace, Jan; Walmsley, Catherine; Parmar, Mahesh K B; Sydes, Matthew R

2017-05-10

Purpose Systemic Therapy for Advanced or Metastatic Prostate Cancer: Evaluation of Drug Efficacy is a randomized controlled trial using a multiarm, multistage, platform design. It recruits men with high-risk, locally advanced or metastatic prostate cancer who were initiating long-term hormone therapy. We report survival data for two celecoxib (Cel)-containing comparisons, which stopped accrual early at interim analysis on the basis of failure-free survival. Patients and Methods Standard of care (SOC) was hormone therapy continuously (metastatic) or for ≥ 2 years (nonmetastatic); prostate (± pelvic node) radiotherapy was encouraged for men without metastases. Cel 400 mg was administered twice a day for 1 year. Zoledronic acid (ZA) 4 mg was administered for six 3-weekly cycles, then 4-weekly for 2 years. Stratified random assignment allocated patients 2:1:1 to SOC (control), SOC + Cel, or SOC + ZA + Cel. The primary outcome measure was all-cause mortality. Results were analyzed with Cox proportional hazards and flexible parametric models adjusted for stratification factors. Results A total of 1,245 men were randomly assigned (Oct 2005 to April 2011). Groups were balanced: median age, 65 years; 61% metastatic, 14% N+/X M0, 25% N0M0; 94% newly diagnosed; median prostate-specific antigen, 66 ng/mL. Median follow-up was 69 months. Grade 3 to 5 adverse events were seen in 36% SOC-only, 33% SOC + Cel, and 32% SOC + ZA + Cel patients. There were 303 control arm deaths (83% prostate cancer), and median survival was 66 months. Compared with SOC, the adjusted hazard ratio was 0.98 (95% CI, 0.80 to 1.20; P = .847; median survival, 70 months) for SOC + Cel and 0.86 (95% CI, 0.70 to 1.05; P =.130; median survival, 76 months) for SOC + ZA + Cel. Preplanned subgroup analyses in men with metastatic disease showed a hazard ratio of 0.78 (95% CI, 0.62 to 0.98; P = .033) for SOC + ZA + Cel. Conclusion These data show no overall evidence of improved survival with Cel. Preplanned subgroup analyses provide hypotheses for future studies.

A randomised controlled trial of intravenous zoledronic acid in malignant pleural disease: a proof of principle pilot study.

PubMed

Clive, Amelia O; Hooper, Clare E; Edey, Anthony J; Morley, Anna J; Zahan-Evans, Natalie; Hall, David; Lyburn, Iain; White, Paul; Braybrooke, Jeremy P; Sequeiros, Iara; Lyen, Stephen M; Milton, Tim; Kahan, Brennan C; Maskell, Nick A

2015-01-01

Animal studies have shown Zoledronic Acid (ZA) may diminish pleural fluid accumulation and tumour bulk in malignant pleural disease (MPD). We performed a pilot study to evaluate its effects in humans. We undertook a single centre, double-blind, placebo-controlled trial in adults with MPD. Patients were randomised (1:1) to receive 2 doses of intravenous ZA or placebo, 3 weeks apart and were followed-up for 6 weeks. The co-primary outcomes were change in Visual Analogue Scale (VAS) score measured breathlessness during trial follow-up and change in the initial area under the curve (iAUC) on thoracic Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) from randomisation to week 5. Multiple secondary endpoints were also evaluated. Between January 2010 and May 2013, 30 patients were enrolled, 24 randomised and 4 withdrew after randomisation (1 withdrew consent; 3 had a clinical decline). At baseline, the ZA group were more breathless, had more advanced disease on radiology and worse quality of life than the placebo group. There was no significant difference between the groups with regards change in breathlessness (Adjusted mean difference (AMD) 4.16 (95%CI -4.7 to 13.0)) or change in DCE-MRI iAUC (AMD -15.4 (95%CI -58.1 to 27.3). Two of nine (22%) in the ZA arm had a >10% improvement by modified RECIST (vs 0/11 who received placebo). There was no significant difference in quality of life measured by the QLQ-C30 score (global QOL: AMD -4.1 (-13.0 to 4.9)), side effects or serious adverse event rates. This is the first human study to evaluate ZA in MPD. The study is limited by small numbers and imbalanced baseline characteristics. Although no convincing treatment effect was identified, potential benefits for specific subgroups of patients cannot be excluded. This study provides important information regarding the feasibility of future trials to evaluate the effects of ZA further. UK Clinical Research Network ID 8877 ISRCTN17030426 www.isrctn.com.

Zoledronic Acid Induces Site-Specific Structural Changes and Decreases Vascular Area in the Alveolar Bone.

PubMed

Soares, Mariana Quirino Silveira; Van Dessel, Jeroen; Jacobs, Reinhilde; da Silva Santos, Paulo Sérgio; Cestari, Tania Mary; Garlet, Gustavo Pompermaier; Duarte, Marco Antonio Hungaro; Imada, Thaís Sumie Nozu; Lambrichts, Ivo; Rubira-Bullen, Izabel Regina Fischer

2018-03-15

The aim was to assess the effect of a relevant regimen of zoledronic acid (ZA) treatment for the study of bisphosphonate-related osteonecrosis of the jaw on alveolar bone microstructure and vasculature. A sub-objective was to use 3-dimensional imaging to describe site-specific changes induced by ZA in the alveolar bone. Five Wistar rats received ZA (0.6 mg/kg) and five (controls) received saline solution in the same volume. The compounds were administered intraperitoneally in 5 doses every 28 days. The rats were euthanized 150 days after therapy onset. The mandibles were scanned using high-resolution (14-μm) micro-computed tomography (micro-CT), decalcified, cut into slices for histologic analysis (5 μm), and stained with hematoxylin-eosin. Bone quality parameters were calculated using CT-Analyser software (Bruker, Kontich, Belgium) in 2 different volumes of interest (VOIs): the region between the first molar roots (VOI-1) and the periapical region under the first and second molars' apex (VOI-2). Blood vessel density and bone histomorphometric parameters were calculated only for the region between the roots of the first molar using AxioVision Imaging software (version 4.8; Carl Zeiss, Gottingen, Germany). ZA-treated rats showed a significant increase in percentage of bone volume and density (P < .05), with thicker and more connected trabeculae. Furthermore, the ZA group showed a significant decrease in the size of the marrow spaces and nutritive canals and in blood vessel density (P < .05). In the micro-CT evaluation, VOI-2 showed better outcomes in measuring the effect of ZA on alveolar bone. ZA treatment induced bone corticalization and decreased alveolar bone vascularization. VOI-2 should be preferred for micro-CT evaluation of the effect of bisphosphonates on alveolar bone. This analysis allowed the effect of ZA on alveolar bone and its vascularization to be characterized. The results of this analysis may add further knowledge to the understanding of the physiopathology of osteonecrosis of the jaw. Copyright © 2018 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Doses effects of zoledronic acid on mineral apatite and collagen quality of newly-formed bone in the rat's calvaria defect.

PubMed

Olejnik, Cécile; Falgayrac, Guillaume; During, Alexandrine; Cortet, Bernard; Penel, Guillaume

2016-08-01

Due to their inhibitory effects on resorption, bisphosphonates are widely used in the treatment of diseases associated to an extensive bone loss. Yet, little is known about bisphosphonates effects on newly-formed bone quality. In the present study, adult male Sprague-Dawley rats (n=80) with a bone defect calvaria area were used and short-term effects of zoledronic acid (ZA) were studied on the healing bone area. Three ZA treatments were tested by using either: 1°) a low single dose (120μgZA/kg, n=10; equivalent to human osteoporosis treatment), 2°) a low fractionated doses (20μgZA/kg daily for 6days either a total of 120μg/kg, n=15), and 3°) a high fractionated doses, (100μgZA/kg weekly for 6weeks, n=15; equivalent to 6months of human bone metastasis treatment). For each treatment, a control "vehicle" treatment was performed (with an identical number of rats). After ZA administration, the intrinsic bone material properties were evaluated by quantitative backscattered electron imaging (qBEI) and Raman microspectroscopy. Neither single nor fractionated low ZA doses modify the intrinsic bone material properties of the newly-formed bone compared to their respective control animals. On the opposite, the high ZA treatment resulted in a significant decrease of the crystallinity (-25%, P< 0.05) and of the hydroxyproline-to-proline ratio (-30%, P<0.05) in newly-formed bones. Moreover, with the high ZA treatment, the crystallinity was positively correlated with the hydroxyproline-to-proline ratio (ρ=0.78, P<0.0001). The present data highlight new properties for ZA on bone formation in a craniofacial defect model. As such, ZA at high doses disrupted the apatite crystal organization. In addition, we report here for the first time that high ZA doses decreased the hydroxyproline-to-proline ratio suggesting that ZA may affect the early collagen organization during the bone healing. Copyright © 2016 Elsevier Inc. All rights reserved.

Associations Between Serum Bone Biomarkers in Early Breast Cancer and Development of Bone Metastasis: Results From the AZURE (BIG01/04) Trial.

PubMed

Brown, Janet; Rathbone, Emma; Hinsley, Samantha; Gregory, Walter; Gossiel, Fatma; Marshall, Helen; Burkinshaw, Roger; Shulver, Helen; Thandar, Hasina; Bertelli, Gianfilippo; Maccon, Keane; Bowman, Angela; Hanby, Andrew; Bell, Richard; Cameron, David; Coleman, Robert

2018-02-07

Adjuvant therapies can prevent/delay bone metastasis development in breast cancer. We investigated whether serum bone turnover markers in early disease have clinical utility in identifying patients with a high risk of developing bone metastasis. Markers of bone formation (N-terminal propeptide of type-1 collagen [P1NP]) and bone resorption (C-telopeptide of type-1 collagen [CTX], pyridinoline cross-linked carboxy-terminal telopeptide of type-1 collagen [1-CTP]) were measured in baseline (pretreatment blood samples from 872 patients from a large randomized trial of adjuvant zoledronic acid (AZURE-ISRCTN79831382) in early breast cancer. Cox proportional hazards regression and cumulative incidence functions (adjusted for factors having a statistically significant effect on outcome) were used to investigate prognostic and predictive associations between recurrence events, bone marker levels, and clinical variables. All statistical tests were two-sided. When considered as continuous variables (log transformed), P1NP, CTX, and 1-CTP were each prognostic for future bone recurrence at any time (P = .006, P = .009, P = .008, respectively). Harrell's c-indices were a P1NP of 0.57 (95% confidence interval [CI] = 0.51 to 0.63), CTX of 0.57 (95% CI = 0.51 to 0.62), and 1-CTP of 0.57 (95% CI = 0.52 to 0.63). In categorical analyses based on the normal range, high baseline P1NP (>70 ng/mL) and CTX (>0.299 ng/mL), but not 1-CTP (>4.2 ng/mL), were also prognostic for future bone recurrence (P = .03, P = .03, P = .10, respectively). None of the markers were prognostic for overall distant recurrence; that is, they were bone metastasis specific, and none of the markers were predictive of treatment benefit from zoledronic acid. Serum P1NP, CTX, and 1-CTP are clinically useful, easily measured markers that show good prognostic ability (though low-to-moderate discrimination) for bone-specific recurrence and are worthy of further study. © The Author(s) 2018. Published by Oxford University Press.

Evaluation of the combined use of metronomic zoledronic acid and Coriolus versicolor in intratibial breast cancer mouse model.

PubMed

Ko, Chun-Hay; Yue, Grace Gar-Lee; Gao, Si; Luo, Ke-Wang; Siu, Wing-Sum; Shum, Wai-Ting; Shiu, Hoi-Ting; Lee, Julia Kin-Ming; Li, Gang; Leung, Ping-Chung; Evdokiou, Andreas; Lau, Clara Bik-San

2017-05-23

Coriolus versicolor (CV) is a mushroom traditionally used for strengthening the immune system and nowadays used as immunomodulatory adjuvant in anticancer therapy. Breast cancer usually metastasizes to the skeleton, interrupts the normal bone remodeling process and causes osteolytic bone lesions. The aims of the present study were to evaluate its herb-drug interaction with metronomic zoledronate in preventing cancer propagation, metastasis and bone destruction. Mice inoculated with human breast cancer cells tagged with a luciferase (MDA-MB-231-TXSA) in tibia were treated with CV aqueous extract, mZOL, or the combination of both for 4 weeks. Alteration of the luciferase signals in tibia, liver and lung were quantified using the IVIS imaging system. The skeletal response was evaluated using micro-computed tomography (micro-CT). In vitro experiments were carried out to confirm the in vivo findings. Results showed that combination of CV and mZOL diminished tumor growth without increasing the incidence of lung and liver metastasis in intratibial breast tumor model. The combination therapy also reserved the integrity of bones. In vitro studies demonstrated that combined use of CV and mZOL inhibited cancer cell proliferation and osteoclastogenesis. These findings suggested that combination treatment of CV and mZOL attenuated breast tumor propagation, protected against osteolytic bone lesion without significant metastases. This study provides scientific evidences on the beneficial outcome of using CV together with mZOL in the management of breast cancer and metastasis, which may lead to the development of CV as adjuvant health supplement for the control of breast cancer. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Mesenchymal Stem Cells Promote the Osteogenesis in Collagen-Induced Arthritic Mice through the Inhibition of TNF-α

PubMed Central

Liu, Chang; Tang, Xiaojun; Feng, Ruihai; Yao, Genhong; Chen, Weiwei; Li, Wenchao; Liang, Jun; Feng, Xuebing

2018-01-01

Objective To investigate the effects of umbilical cord mesenchymal stem cell (UC-MSC) transplantation on joint damage and osteoporosis in collagen-induced arthritis (CIA) mice and to explore the mechanisms by which UC-MSCs modulate the osteogenic differentiation. Methods CIA mice were divided into the following treated groups: UC-MSC transplantation group, antitumor necrosis factor- (TNF-) α group, and zoledronic acid (ZA) group. Microcomputed tomography (micro-CT) was used to analyze the bone morphology parameters. Osteogenic differentiation of treated CIA mice was determined. Bone marrow mesenchymal stem cells (BM-MSCs) from CIA mice were treated with TNF-α in vitro to explore their effects on osteogenesis. Results The arthritis score was significantly reduced in the UC-MSC transplantation and anti-TNF-α-treated CIA groups, compared with control mice (P < 0.001). Micro-CT showed that CIA mice developed osteoporosis at 12 weeks after immunization. The bone morphology parameters were partially improved in UC-MSC-treated CIA mice. Impaired osteogenic differentiation functions were indicated by decreased ALP activity (P < 0.001) and reduced mRNA and protein levels of osteogenic marker genes (P < 0.05) in CIA mice compared with DBA/1 mice. UC-MSC treatment significantly upregulated the impaired osteogenic differentiation ability in CIA mice. Meanwhile, the serum TNF-α level was decreased significantly in the UC-MSC group. The osteogenesis was reduced with the addition of TNF-α in vitro. Conclusion This study demonstrated that UC-MSC transplantation not only significantly improved the joint damage but also played a beneficial role in osteoporosis in CIA mice. Mechanistically, the improved osteogenic differentiation of CIA under UC-MSC treatment may be achieved by inhibition of TNF-α. PMID:29853911

Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy.

PubMed

Pol, Jonathan; Vacchelli, Erika; Aranda, Fernando; Castoldi, Francesca; Eggermont, Alexander; Cremer, Isabelle; Sautès-Fridman, Catherine; Fucikova, Jitka; Galon, Jérôme; Spisek, Radek; Tartour, Eric; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

2015-04-01

The term "immunogenic cell death" (ICD) is now employed to indicate a functionally peculiar form of apoptosis that is sufficient for immunocompetent hosts to mount an adaptive immune response against dead cell-associated antigens. Several drugs have been ascribed with the ability to provoke ICD when employed as standalone therapeutic interventions. These include various chemotherapeutics routinely employed in the clinic (e.g., doxorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, bortezomib, cyclophosphamide and oxaliplatin) as well as some anticancer agents that are still under preclinical or clinical development (e.g., some microtubular inhibitors of the epothilone family). In addition, a few drugs are able to convert otherwise non-immunogenic instances of cell death into bona fide ICD, and may therefore be employed as chemotherapeutic adjuvants within combinatorial regimens. This is the case of cardiac glycosides, like digoxin and digitoxin, and zoledronic acid. Here, we discuss recent developments on anticancer chemotherapy based on ICD inducers.

Postmenopausal osteoporosis.

PubMed

Diab, Dima L; Watts, Nelson B

2013-12-01

The aim of this study is to provide a thorough updated review of the diagnosis and treatment of postmenopausal osteoporosis. There have been several important findings in the field of postmenopausal osteoporosis over the past 1-2 years. Fewer morphometric vertebral fractures were found in women treated for 6 years with zoledronic acid compared with those who stopped treatment after 3 years. Longer duration of bisphosphonate therapy is associated with a higher risk of atypical femur fractures. Combination therapy with teriparatide and denosumab appears to increase bone mineral density to a greater extent than either therapy alone in postmenopausal women at high risk for fracture. There are several novel therapies under investigation for the treatment of osteoporosis, which are in various stages of development. Nonadherence to osteoporosis therapies continues to be a major problem in clinical practice. There are numerous effective pharmacologic treatment options for postmenopausal osteoporosis. Bisphosphonate drug holidays continue to be an area of significant debate.

Zoledronate Attenuates Accumulation of DNA Damage in Mesenchymal Stem Cells and Protects Their Function

PubMed Central

Misra, Juhi; Mohanty, Sindhu T.; Madan, Sanjeev; Fernandes, James A.; Hal Ebetino, F.; Russell, R. Graham G.

2015-01-01

Abstract Mesenchymal stem cells (MSCs) undergo a decline in function following ex vivo expansion and exposure to irradiation. This has been associated with accumulation of DNA damage and has important implications for tissue engineering approaches or in patients receiving radiotherapy. Therefore, interventions, which limit accumulation of DNA damage in MSC, are of clinical significance. We were intrigued by findings showing that zoledronate (ZOL), an anti‐resorptive nitrogen containing bisphosphonate, significantly extended survival in patients affected by osteoporosis. The effect was too large to be simply due to the prevention of fractures. Moreover, in combination with statins, it extended the lifespan in a mouse model of Hutchinson Gilford Progeria Syndrome. Therefore, we asked whether ZOL was able to extend the lifespan of human MSC and whether this was due to reduced accumulation of DNA damage, one of the important mechanisms of aging. Here, we show that this was the case both following expansion and irradiation, preserving their ability to proliferate and differentiate in vitro. In addition, administration of ZOL before irradiation protected the survival of mesenchymal progenitors in mice. Through mechanistic studies, we were able to show that inhibition of mTOR signaling, a pathway involved in longevity and cancer, was responsible for these effects. Our data open up new opportunities to protect MSC from the side effects of radiotherapy in cancer patients and during ex vivo expansion for regenerative medicine approaches. Given that ZOL is already in clinical use with a good safety profile, these opportunities can be readily translated for patient benefit. Stem Cells 2016;34:756–767 PMID:26679354

Zoledronate Attenuates Accumulation of DNA Damage in Mesenchymal Stem Cells and Protects Their Function.

PubMed

Misra, Juhi; Mohanty, Sindhu T; Madan, Sanjeev; Fernandes, James A; Hal Ebetino, F; Russell, R Graham G; Bellantuono, Ilaria

2016-03-01

Mesenchymal stem cells (MSCs) undergo a decline in function following ex vivo expansion and exposure to irradiation. This has been associated with accumulation of DNA damage and has important implications for tissue engineering approaches or in patients receiving radiotherapy. Therefore, interventions, which limit accumulation of DNA damage in MSC, are of clinical significance. We were intrigued by findings showing that zoledronate (ZOL), an anti-resorptive nitrogen containing bisphosphonate, significantly extended survival in patients affected by osteoporosis. The effect was too large to be simply due to the prevention of fractures. Moreover, in combination with statins, it extended the lifespan in a mouse model of Hutchinson Gilford Progeria Syndrome. Therefore, we asked whether ZOL was able to extend the lifespan of human MSC and whether this was due to reduced accumulation of DNA damage, one of the important mechanisms of aging. Here, we show that this was the case both following expansion and irradiation, preserving their ability to proliferate and differentiate in vitro. In addition, administration of ZOL before irradiation protected the survival of mesenchymal progenitors in mice. Through mechanistic studies, we were able to show that inhibition of mTOR signaling, a pathway involved in longevity and cancer, was responsible for these effects. Our data open up new opportunities to protect MSC from the side effects of radiotherapy in cancer patients and during ex vivo expansion for regenerative medicine approaches. Given that ZOL is already in clinical use with a good safety profile, these opportunities can be readily translated for patient benefit. © 2015 AlphaMed Press.

Bisphosphonates significantly increase the activity of doxorubicin or vincristine against canine malignant histiocytosis cells.

PubMed

Hafeman, S D; Varland, D; Dow, S W

2012-03-01

Canine malignant histiocytosis (MH) is an aggressive neoplasm of macrophages and dendritic cells. It carries a poor prognosis because of the development of widespread metastasis and poor sensitivity to chemotherapy. Thus, there is a large need for new treatments for MH. We hypothesized that bisphosphonates might be useful to increase the effectiveness of cytotoxic chemotherapy against MH. To address this question, we conducted in vitro screening studies using MH cell lines and a panel of 6 chemotherapy and 5 bisphosphonate drugs. The combination of clodronate with vincristine was found to elicit synergistic killing which was associated with a significant increase in cell cycle arrest. Second, zoledronate combined with doxorubicin also significantly increased cell killing. Zoledronate significantly increased the uptake of doxorubicin by MH cells. On the basis of these findings, we conclude that certain bisphosphonate drugs may increase the overall effectiveness of chemotherapy for MH in dogs. © 2011 Blackwell Publishing Ltd.

Bisphosphonates Significantly Increase the Activity of Doxorubicin or Vincristine Against Canine Malignant Histiocytosis Cells

PubMed Central

Hafeman, S.D.; Varland, D.; Dow, S.W.

2011-01-01

Canine malignant histiocytosis (MH) is an aggressive neoplasm of macrophages and dendritic cells. It carries a poor prognosis due to the development of widespread metastasis and poor sensitivity to chemotherapy. Thus, there is a large need for new treatments for MH. We hypothesized that bisphosphonates might be useful to increase the effectiveness of cytotoxic chemotherapy against MH. To address this question, we conducted in vitro screening studies using MH cell lines and a panel of 6 chemotherapy and 5 bisphosphonate drugs. The combination of clodronate with vincristine was found to elicit synergistic killing which was associated with a significant increase in cell cycle arrest. Second, zoledronate combined with doxorubicin also significantly increased cell killing. Zoledronate significantly increased the uptake of doxorubicin by MH cells. Based on these findings, we conclude that certain bisphosphonate drugs may increase the overall effectiveness of chemotherapy for MH in dogs. PMID:22236140

Calcium ions and osteoclastogenesis initiate the induction of bone formation by coral-derived macroporous constructs

PubMed Central

Klar, Roland M; Duarte, Raquel; Dix-Peek, Therese; Dickens, Caroline; Ferretti, Carlo; Ripamonti, Ugo

2013-01-01

Coral-derived calcium carbonate/hydroxyapatite macroporous constructs of the genus Goniopora with limited hydrothermal conversion to hydroxyapatite (7% HA/CC) initiate the induction of bone formation. Which are the molecular signals that initiate pattern formation and the induction of bone formation? To evaluate the role of released calcium ions and osteoclastogenesis, 7% HA/CC was pre-loaded with either 500 μg of the calcium channel blocker, verapamil hydrochloride, or 240 μg of the osteoclast inhibitor, biphosphonate zoledronate, and implanted in the rectus abdominis muscle of six adult Chacma baboons Papio ursinus. Generated tissues on days 15, 60 and 90 were analysed by histomorphometry and qRT-PCR. On day 15, up-regulation of type IV collagen characterized all the implanted constructs correlating with vascular invasion. Zoledronate-treated specimens showed an important delay in tissue patterning and morphogenesis with limited bone formation. Osteoclastic inhibition yielded minimal, if any, bone formation by induction. 7% HA/CC pre-loaded with the Ca++ channel blocker verapamil hydrochloride strongly inhibited the induction of bone formation. Down-regulation of bone morphogenetic protein-2 (BMP-2) together with up-regulation of Noggin genes correlated with limited bone formation in 7% HA/CC pre-loaded with either verapamil or zoledronate, indicating that the induction of bone formation by coral-derived macroporous constructs is via the BMPs pathway. The spontaneous induction of bone formation is initiated by a local peak of Ca++ activating stem cell differentiation and the induction of bone formation. PMID:24106923

Zoledronate Triggers Vδ2 T Cells to Destroy and Kill Spheroids of Colon Carcinoma: Quantitative Image Analysis of Three-Dimensional Cultures.

PubMed

Varesano, Serena; Zocchi, Maria Raffaella; Poggi, Alessandro

2018-01-01

New successful anti-cancer strategies are based on the stimulation of immune reaction against tumors: however, preclinical testing of such treatments is still a challenge. To improve the screening of anti-cancer drugs, three-dimensional (3D) culture systems, including spheroids, have been validated as preclinical models. We propose the spheroid 3D system to test anti-tumor drug-induced immune responses. We show that colorectal carcinoma (CRC) spheroids, generated with the epithelial growth factor (EGF), can be co-cultured with Vδ2 T cells to evaluate the anti-tumor activity of these effector lymphocytes. By computerized image analysis, the precise and unbiased measure of perimeters and areas of tumor spheroids is achievable, beside the calculation of their volume. CRC spheroid size is related to ATP content and cell number, as parameters for cell metabolism and proliferation; in turn, crystal violet staining can check the viability of cells inside the spheroids to detect tumor killing by Vδ2 T cells. In this 3D cultures, we tested (a) zoledronate that is known to activate Vδ2 T cells and (b) the therapeutic anti-EGF receptor humanized antibody cetuximab that can elicit the antibody-dependent cytotoxicity of tumor cells by effector lymphocytes. Zoledronate triggers Vδ2 T cells to kill and degrade CRC spheroids; we detected the T-cell receptor dependency of zoledronate effect, conceivably due to the recognition of phosphoantigens produced as a drug effect on target cell metabolism. In addition, cetuximab triggered Vδ2 T lymphocytes to exert the antibody-dependent cellular cytotoxicity of CRC spheroids. Finally, the system reveals differences in the sensitivity of CRC cell lines to the action of Vδ2 T lymphocytes and in the efficiency of anti-tumor effectors from distinct donors. A limitation of this model is the absence of cells, including fibroblasts, that compose tumor microenvironment and influence drug response. Nevertheless, the system can be improved by setting mixed spheroids, made of stromal and cancer cells. We conclude that this type of spheroid 3D culture is a feasible and reliable system to evaluate and measure anti-tumor drug-induced immune responses beside direct anti-cancer drug effect.

Assessment of zoledronic acid treatment patterns and clinical outcomes in patients with bone metastases from genitourinary cancers.

PubMed

Henk, Henry J; Kaura, Satyin

2012-01-01

Patients with bone metastases secondary to genitourinary (GU) cancer are at risk for skeletal-related events (SREs), including bone pain requiring palliative radiotherapy, fractures or surgery to bone, spinal cord compression, and hypercalcemia of malignancy. These SREs can be debilitating and potentially life-limiting. This study examined treatment practices and the association of treatment patterns with Zometa (zoledronic acid, ZOL), an intravenous bisphosphonate (IV-BP), with SREs and fractures. (Zometa is a registered trademark of Novartis Pharmaceuticals Corporation, USA.) Retrospective analysis of commercial and Medicare Advantage enrollment and medical claims data was performed to evaluate IV-BP use and SRE patterns in adult patients with GU cancers. Criteria included diagnosis of ≥1 bone metastasis and prostate cancer (PC), renal cell carcinoma (RCC), or bladder cancer (BlC) between January 2001 and December 2006; continuous healthcare plan enrollment for ≥6 months before the index date; and no evidence of prior IV-BP use. Patients were followed until disenrollment from the healthcare plan or December 2007. Of 6347 patients (PC, n = 4976; RCC, n = 941; BlC, n = 430; mean [standard deviation] age: 68.9 [11.1] years), only approximately 23% received ZOL. The mean time between diagnosis of bone metastasis and ZOL initiation was approximately 108 days. Among patients with PC, fracture risk was significantly smaller for ZOL vs no IV-BP (incidence rate ratio = 0.70; p < 0.001), and 2-year survival was significantly longer for ZOL-treated vs no IV-BP patients (p = 0.007). Patients with longer persistency on ZOL had a smaller fracture risk than patients with shorter persistency. Sub-set analyses were not performed for RCC and BIC because the proportion of patients treated was too low. Interpretation of this claims-based analysis must be tempered by the inherent limitations of observational data, such as limited and accurate available information, and unavailable information including clinical or disease-specific parameters. Intravenous BP therapy is not always received in patients with bone metastases secondary to GU cancers, and, when used, there are typically long time periods before treatment initiation. Without IV-BPs, PC patients have significantly larger risks of fracture and death compared with ZOL-treated patients, and benefits appear to be larger with increasing persistency on ZOL.

Early inhibitory effects of zoledronic acid in tooth extraction sockets in dogs are negated by recombinant human bone morphogenetic protein.

PubMed

Gerard, David A; Carlson, Eric R; Gotcher, Jack E; Pickett, David O

2014-01-01

This study was conducted with 2 purposes. The first was to determine the effect of a single dose of zoledronic acid (ZA) on the healing of a tooth extraction socket in dogs. The second was to determine if placement of recombinant human bone morphogenetic protein-2 (rhBMP-2)/absorbable collagen sponge (ACS) - INFUSE, (Medtronic, Memphis, TN) into these extraction sockets would inhibit the inhibition on bone healing and remodeling by ZA. Nine adult female beagle dogs (2 to 3 yr old) were placed into 3 groups of 3 dogs each. Group I received 15 mL of sterile saline intravenously; group II received 2.5 mg of ZA intravenously; and group III received 5 mg of ZA intravenously. Forty-five days after treatment, all dogs underwent extraction of noncontiguous right and left mandibular first molars and second premolars. In group I, the right mandibular extraction sockets had nothing placed in them, whereas the left mandibular sockets had only ACS placed in them. In groups II and III, the right mandibular sockets had rhBMP-2/ACS placed in them, whereas the left mandibular sockets had only ACS placed. All extraction sockets were surgically closed. Tetracycline was given intravenously 5 and 12 days later, and all animals were euthanized 15 days after tooth extraction. The extraction sockets and rib and femur samples were harvested immediately after euthanasia, processed, and studied microscopically. A single dose of ZA significantly inhibited healing and bone remodeling in the area of the tooth extractions. The combination of rhBMP-2/ACS appeared to over-ride some of the bone remodeling inhibition of the ZA and increased bone fill in the extraction sites, and remodeling activity in the area was noted. The effects of rhBMP-2/ACS were confined to the area of the extraction sockets because bone activity at distant sites was not influenced. A single dose of ZA administered intravenously inhibits early healing of tooth extraction sockets and bone remodeling in this animal model. The combination of rhBMP-2/ACS significantly increased bone fill and bone remodeling in these areas, negating much of the effect of the ZA. Copyright © 2014 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Bone turnover and periprosthetic bone loss after cementless total hip arthroplasty can be restored by zoledronic acid: a prospective, randomized, open-label, controlled trial.

PubMed

Huang, Tsan-Wen; Wang, Chao-Jan; Shih, Hsin-Nung; Chang, Yuhan; Huang, Kuo-Chin; Peng, Kuo-Ti; Lee, Mel S

2017-05-22

Although the loss of bone mineral density (BMD) after total hip arthroplasty (THA) is a known problem, it remains unresolved. This study prospectively examined the effect of zoledronic acid (ZA) on bone turnover and BMD after cementless THA. Between January 2010 and August 2011, 60 patients who underwent cementless THA were randomly assigned to receive either ZA infusion or placebo (0.9% normal saline only) postoperatively. ZA was administered at 2 day and 1 year postoperatively. Periprosthetic BMD in seven Gruen zones was assessed preoperatively and at given time points for 2 years. Serum markers of bone turnover, functional scales, and adverse events were recorded. Each group contained 27 patients for the final analysis. The loss of BMD across all Gruen zones (significantly in zones 1 and 7) up to 2 years postoperatively was noted in the placebo group. BMD was significantly higher in the ZA group than in the placebo group in Gruen zones 1, 2, 6, and 7 at 1 year and in Gruen zones 1, 6, and 7 at 2 years (p < 0.05). Compared with baseline measures of BMD, the ZA group had increased BMD in zones 1, 2, 4, 5, 6, and 7 at 1 year and in zones 1, 4, 6, and 7 at 2 years (p < 0.05). Serum bone-specific alkaline phosphatase and N-telopeptide of procollagen I levels were significantly increased at 6 weeks in the placebo group and decreased after 3 months in the ZA group. A transient decrease in osteocalcin level was found at 6 months in the ZA group. Functional scales and adverse events were not different between the two groups. The loss of periprosthetic BMD, especially in the proximal femur (zones 1 and 7), after cementless THA could be effectively reverted using ZA. In addition, bone turnover markers were suppressed until 2 years postoperatively following ZA administration. Chang Gung Memorial Hospital Protocol Record 98-1150A3, Prevention of Periprosthetic Bone Loss After Total Hip Replacement by Annual Bisphosphonate Therapy, has been reviewed and will be made public on ClinicalTrials.gov. NCT02838121 . Registered on 19 July, 2016.

Pharmacological interventions for the prevention of insufficiency fractures and avascular necrosis associated with pelvic radiotherapy in adults.

PubMed

van den Blink, Qurrat U; Garcez, Kate; Henson, Caroline C; Davidson, Susan E; Higham, Claire E

2018-04-23

Pelvic radiotherapy is a treatment delivered to an estimated 150,000 to 300,000 people annually across high-income countries. Fractures due to normal stresses on weakened bone due to radiotherapy are termed insufficiency fractures. Pelvic radiotherapy-related interruption of the blood supply to the hip is termed avascular necrosis and is another recognised complication. The reported incidences of insufficiency fractures are 2.7% to 89% and risk of developing avascular necrosis is 0.5%. These complications lead to significant morbidity in terms of pain, immobility and consequently risk of infections, pressure sores and mortality. To assess the effects of pharmacological interventions for preventing insufficiency fractures and avascular necrosis in adults over 18 years of age undergoing pelvic radiotherapy. We performed electronic literature searches in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and DARE to 19 April 2017. We also searched trial registries. Further relevant studies were identified through handsearching of citation lists of included studies. Randomised controlled trials (RCTs) or non RCTs with concurrent comparison groups including quasi-RCTs, cluster RCTs, prospective cohort studies and case series of 30 or more participants were screened. We included studies assessing the effect of pharmacological interventions in adults over 18 years of age undergoing radical pelvic radiotherapy as part of anticancer treatment for a primary pelvic malignancy. We excluded studies involving radiotherapy for bone metastases. We assessed use of pharmacological interventions at any stage before or during pelvic radiotherapy. Interventions included calcium or vitamin D (or both) supplementation, bisphosphonates, selective oestrogen receptor modulators, hormone replacement therapy (oestrogen or testosterone), denosumab and calcitonin. Two review authors independently assessed trial quality and extracted data. We contacted study authors to obtain missing data. Data were to be pooled using the random-effects model if study comparisons were similar, otherwise results were to be reported narratively. We included two RCTs (1167 participants). The first RCT compared zoledronic acid with placebo in 96 men undergoing pelvic radiotherapy for non-metastatic prostate cancer.The second RCT had four treatment arms, two of which evaluated zoledronic acid plus adjuvant androgen suppression compared with androgen suppression only in 1071 men undergoing pelvic radiotherapy for non-metastatic prostate cancer.Both studies were at a moderate to high risk of bias and all evidence was judged to be of very low certainty.The studies provided no evidence on the primary outcomes of the review and provided limited data in relation to secondary outcomes, such that meta-analyses were not possible. Both studies focused on interventions to improve bone health in relation to androgen deprivation rather than radiation-related insufficiency fractures and avascular necrosis. Few fractures were described in each study and those described were not specific to insufficiency fractures secondary to radiotherapy. Both studies reported that zoledronic acid in addition to androgen deprivation and pelvic radiotherapy led to improvements in BMD; however, the changes in BMD were measured and reported differently. There was no available evidence regarding adverse effects. The evidence relating to interventions to prevent insufficiency fractures and avascular necrosis associated with pelvic radiotherapy in adults is of very low certainty. This review highlights the need for prospective clinical trials using interventions prior to and during radiotherapy to prevent radiation-related bone morbidity, insufficiency fractures and avascular necrosis. Future trials could involve prospective assessment of bone health including BMD and bone turnover markers prior to pelvic radiotherapy. The interventions for investigation could begin as radiotherapy commences and remain ongoing for 12 to 24 months. Bone turnover markers and BMD could be used as surrogate markers for bone health in addition to radiographic imaging to report on presence of insufficiency fractures and development of avascular necrosis. Clinical assessments and patient reported outcomes would help to identify any associated adverse effects of treatment and quality of life outcomes.

Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial

PubMed Central

James, Nicholas D; Sydes, Matthew R; Mason, Malcolm D; Clarke, Noel W; Anderson, John; Dearnaley, David P; Dwyer, John; Jovic, Gordana; Ritchie, Alastair WS; Russell, J Martin; Sanders, Karen; Thalmann, George N; Bertelli, Gianfilippo; Birtle, Alison J; O'Sullivan, Joe M; Protheroe, Andrew; Sheehan, Denise; Srihari, Narayanan; Parmar, Mahesh KB

2012-01-01

Summary Background Long-term hormone therapy alone is standard care for metastatic or high-risk, non-metastatic prostate cancer. STAMPEDE—an international, open-label, randomised controlled trial—uses a novel multiarm, multistage design to assess whether the early additional use of one or two drugs (docetaxel, zoledronic acid, celecoxib, zoledronic acid and docetaxel, or zoledronic acid and celecoxib) improves survival in men starting first-line, long-term hormone therapy. Here, we report the preplanned, second intermediate analysis comparing hormone therapy plus celecoxib (arm D) with hormone therapy alone (control arm A). Methods Eligible patients were men with newly diagnosed or rapidly relapsing prostate cancer who were starting long-term hormone therapy for the first time. Hormone therapy was given as standard care in all trial arms, with local radiotherapy encouraged for newly diagnosed patients without distant metastasis. Randomisation was done using minimisation with a random element across seven stratification factors. Patients randomly allocated to arm D received celecoxib 400 mg twice daily, given orally, until 1 year or disease progression (including prostate-specific antigen [PSA] failure). The intermediate outcome was failure-free survival (FFS) in three activity stages; the primary outcome was overall survival in a subsequent efficacy stage. Research arms were compared pairwise against the control arm on an intention-to-treat basis. Accrual of further patients was discontinued in any research arm showing safety concerns or insufficient evidence of activity (lack of benefit) compared with the control arm. The minimum targeted activity at the second intermediate activity stage was a hazard ratio (HR) of 0·92. This trial is registered with ClinicalTrials.gov, number NCT00268476, and with Current Controlled Trials, number ISRCTN78818544. Findings 2043 patients were enrolled in the trial from Oct 17, 2005, to Jan 31, 2011, of whom 584 were randomly allocated to receive hormone therapy alone (control group; arm A) and 291 to receive hormone therapy plus celecoxib (arm D). At the preplanned analysis of the second intermediate activity stage, with 305 FFS events (209 in arm A, 96 in arm D), there was no evidence of an advantage for hormone therapy plus celecoxib over hormone therapy alone: HR 0·98 (95% CI 0·90–1·06). 2-year FFS was 51% (95% CI 46–56) in arm A and 51% (95% CI 43–58) in arm D. There was no evidence of differences in the incidence of adverse events between groups (events of grade 3 or higher were noted at any time in 123 [23%, 95% CI 20–27] patients in arm A and 64 [25%, 19–30] in arm D). The most common grade 3–5 events adverse effects in both groups were endocrine disorders (55 [11%] of patients in arm A vs 19 [7%] in arm D) and musculoskeletal disorders (30 [6%] of patients in arm A vs 15 [6%] in arm D). The independent data monitoring committee recommended stopping accrual to both celecoxib-containing arms on grounds of lack of benefit and discontinuing celecoxib for patients currently on treatment, which was endorsed by the trial steering committee. Interpretation Celecoxib 400 mg twice daily for up to 1 year is insufficiently active in patients starting hormone therapy for high-risk prostate cancer, and we do not recommend its use in this setting. Accrual continues seamlessly to the other research arms and follow-up of all arms will continue to assess effects on overall survival. Funding Cancer Research UK, Pfizer, Novartis, Sanofi-Aventis, Medical Research Council (London, UK). PMID:22452894

Gateways to clinical trials.

PubMed

Bayés, M; Rabasseda, X; Prous, J R

2007-12-01

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prous Science Intergrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 249553, 2-Methoxyestradiol; Abatacept, Adalimumab, Adefovir dipivoxil, Agalsidase beta, Albinterferon alfa-2b, Aliskiren fumarate, Alovudine, Amdoxovir, Amlodipine besylate/atorvastatin calcium, Amrubicin hydrochloride, Anakinra, AQ-13, Aripiprazole, AS-1404, Asoprisnil, Atacicept, Atrasentan; Belimumab, Bevacizumab, Bortezomib, Bosentan, Botulinum toxin type B, Brivaracetam; Catumaxomab, Cediranib, Cetuximab, cG250, Ciclesonide, Cinacalcet hydrochloride, Curcumin, Cypher; Darbepoetin alfa, Denosumab, Dihydrexidine; Eicosapentaenoic acid/docosahexaenoic acid, Entecavir, Erlotinib hydrochloride, Escitalopram oxalate, Etoricoxib, Everolimus, Ezetimibe; Febuxostat, Fenspiride hydrochloride, Fondaparinux sodium; Gefitinib, Ghrelin (human), GSK-1562902A; HSV-tk/GCV; Iclaprim, Imatinib mesylate, Imexon, Indacaterol, Insulinotropin, ISIS-112989; L-Alanosine, Lapatinib ditosylate, Laropiprant; Methoxy polyethylene glycol-epoetin-beta, Mipomersen sodium, Motexafin gadolinium; Natalizumab, Nimotuzumab; OSC, Ozarelix; PACAP-38, Paclitaxel nanoparticles, Parathyroid Hormone-Related Protein-(1-36), Pasireotide, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Pemetrexed disodium, Pertuzumab, Picoplatin, Pimecrolimus, Pitavastatin calcium, Plitidepsin; Ranelic acid distrontium salt, Ranolazine, Recombinant human relaxin H2, Regadenoson, RFB4(dsFv)-PE38, RO-3300074, Rosuvastatin calcium; SIR-Spheres, Solifenacin succinate, Sorafenib, Sunitinib malate; Tadalafil, Talabostat, Taribavirin hydrochloride, Taxus, Temsirolimus, Teriparatide, Tiotropium bromide, Tipifarnib, Tirapazamine, Tocilizumab; UCN-01, Ularitide, Uracil, Ustekinumab; V-260, Vandetanib, Vatalanib succinate, Vernakalant hydrochloride, Vorinostat; YM-155; Zileuton, Zoledronic acid monohydrate.

Addition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: a systematic review and meta-analyses of aggregate data

PubMed Central

Vale, Claire L; Burdett, Sarah; Rydzewska, Larysa H M; Albiges, Laurence; Clarke, Noel W; Fisher, David; Fizazi, Karim; Gravis, Gwenaelle; James, Nicholas D; Mason, Malcolm D; Parmar, Mahesh K B; Sweeney, Christopher J; Sydes, Matthew R; Tombal, Bertrand; Tierney, Jayne F

2016-01-01

Summary Background Results from large randomised controlled trials combining docetaxel or bisphosphonates with standard of care in hormone-sensitive prostate cancer have emerged. In order to investigate the effects of these therapies and to respond to emerging evidence, we aimed to systematically review all relevant trials using a framework for adaptive meta-analysis. Methods For this systematic review and meta-analysis, we searched MEDLINE, Embase, LILACS, and the Cochrane Central Register of Controlled Trials, trial registers, conference proceedings, review articles, and reference lists of trial publications for all relevant randomised controlled trials (published, unpublished, and ongoing) comparing either standard of care with or without docetaxel or standard of care with or without bisphosphonates for men with high-risk localised or metastatic hormone-sensitive prostate cancer. For each trial, we extracted hazard ratios (HRs) of the effects of docetaxel or bisphosphonates on survival (time from randomisation until death from any cause) and failure-free survival (time from randomisation to biochemical or clinical failure or death from any cause) from published trial reports or presentations or obtained them directly from trial investigators. HRs were combined using the fixed-effect model (Mantel-Haenzsel). Findings We identified five eligible randomised controlled trials of docetaxel in men with metastatic (M1) disease. Results from three (CHAARTED, GETUG-15, STAMPEDE) of these trials (2992 [93%] of 3206 men randomised) showed that the addition of docetaxel to standard of care improved survival. The HR of 0·77 (95% CI 0·68–0·87; p<0·0001) translates to an absolute improvement in 4-year survival of 9% (95% CI 5–14). Docetaxel in addition to standard of care also improved failure-free survival, with the HR of 0·64 (0·58–0·70; p<0·0001) translating into a reduction in absolute 4-year failure rates of 16% (95% CI 12–19). We identified 11 trials of docetaxel for men with locally advanced disease (M0). Survival results from three (GETUG-12, RTOG 0521, STAMPEDE) of these trials (2121 [53%] of 3978 men) showed no evidence of a benefit from the addition of docetaxel (HR 0·87 [95% CI 0·69–1·09]; p=0·218), whereas failure-free survival data from four (GETUG-12, RTOG 0521, STAMPEDE, TAX 3501) of these trials (2348 [59%] of 3978 men) showed that docetaxel improved failure-free survival (0·70 [0·61–0·81]; p<0·0001), which translates into a reduced absolute 4-year failure rate of 8% (5–10). We identified seven eligible randomised controlled trials of bisphosphonates for men with M1 disease. Survival results from three of these trials (2740 [88%] of 3109 men) showed that addition of bisphosphonates improved survival (0·88 [0·79–0·98]; p=0·025), which translates to 5% (1–8) absolute improvement, but this result was influenced by the positive result of one trial of sodium clodronate, and we found no evidence of a benefit from the addition of zoledronic acid (0·94 [0·83–1·07]; p=0·323), which translates to an absolute improvement in survival of 2% (−3 to 7). Of 17 trials of bisphosphonates for men with M0 disease, survival results from four trials (4079 [66%] of 6220 men) showed no evidence of benefit from the addition of bisphosphonates (1·03 [0·89–1·18]; p=0·724) or zoledronic acid (0·98 [0·82–1·16]; p=0·782). Failure-free survival definitions were too inconsistent for formal meta-analyses for the bisphosphonate trials. Interpretation The addition of docetaxel to standard of care should be considered standard care for men with M1 hormone-sensitive prostate cancer who are starting treatment for the first time. More evidence on the effects of docetaxel on survival is needed in the M0 disease setting. No evidence exists to suggest that zoledronic acid improves survival in men with M1 or M0 disease, and any potential benefit is probably small. Funding Medical Research Council UK. PMID:26718929

Anti-fibrotic characteristics of Vγ9+ γδ T cells in systemic sclerosis.

PubMed

Markovits, Noa; Bendersky, Anna; Loebstein, Ronen; Brusel, Marina; Kessler, Efrat; Bank, Ilan

2016-01-01

γδ T cells of the Vγ9Vδ2 subtype secrete anti-fibrotic cytokines upon isopentenyl pyrophosphate (IPP) stimulation. In this study, we sought to compare IPP and Zoledronate, an up-regulator of IPP, effects on proliferation and cytokine secretion of Vγ9+ T cells from systemic sclerosis (SSc) patients and healthy controls (HCs). We also examined the effect of IPP-triggered peripheral blood mononuclear cells (PBMC) on fibroblast procolla- gen secretion. PBMC from SSc patients and HCs were stimulated by increasing concentrations of Zoledronate, with or without IPP, and Vγ9+ T cell percentages were calculated using FACScan analysis. Subsequently, PBMC were cultured with IPP or toxic shock syndrome toxin-1 (TSST-1), and contents of the anti-fibrotic cytokines tumour necrosis factor (TNF)-α and interferon (IFN)-γ were measured by ELISA kits. Finally, supernatants of IPP-triggered Vγ9+ T cells from SSc patients were added to fibroblast cultures, and relative intensities of procollagen α1 chains were determined by densinometry. Higher concentrations of Zoledronate were required for maximal proliferation of Vγ9+ T cells in 9 SSc patients compared to 9 HCs, irrespective of exogenous IPP. When compared to stimulation by TSST-1, a non-Vγ9+ selective reagent, secretion of the anti-fibrotic cytokines TNF-α and IFN-γ in response to IPP was relatively diminished in SSc but not in HCs. Reduction of procollagen secretion by fibroblasts cultured with supernatants of IPP-stimulated PBMC was observed only in some SSc patients. Activated Vγ9+ T cells could act as anti-fibrotic mediators in SSc, although decreased responsiveness to IPP may play a role in the pathological fibrosis of this disease.

Bisphosphonate therapy for osteogenesis imperfecta.

PubMed

Dwan, Kerry; Phillipi, Carrie A; Steiner, Robert D; Basel, Donald

2016-10-19

Osteogenesis imperfecta is caused by a genetic defect resulting in an abnormal type I collagen bone matrix which typically results in multiple fractures with little or no trauma. Bisphosphonates are used in an attempt to increase bone mineral density and reduce these fractures in people with osteogenesis imperfecta. This is an update of a previously published Cochrane Review. To assess the effectiveness and safety of bisphosphonates in increasing bone mineral density, reducing fractures and improving clinical function in people with osteogenesis imperfecta. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Inborn Errors of Metabolism Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of journals and conference proceedings. We additionally searched PubMed and major conference proceedings.Date of the most recent search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Register: 28 April 2016. Randomised and quasi-randomised controlled trials comparing bisphosphonates to placebo, no treatment, or comparator interventions in all types of osteogenesis imperfecta. Two authors independently extracted data and assessed the risk of bias of the included trials. Fourteen trials (819 participants) were included. Overall, the trials were mainly at a low risk of bias, although selective reporting was an issue in several of the trials. Data for oral bisphosphonates versus placebo could not be aggregated; a statistically significant difference favouring oral bisphosphonates in fracture risk reduction and number of fractures was noted in two trials. No differences were reported in the remaining three trials which commented on fracture incidence. Five trials reported data for spine bone mineral density; all found statistically significant increased lumbar spine density z scores for at least one time point studied. For intravenous bisphosphonates versus placebo, aggregated data from two trials showed no statistically significant difference for the number of participants with at least one fracture, risk ratio 0.56 (95% confidence interval 0.30 to 1.06). In the remaining trial no statistically significant difference was noted in fracture incidence. For spine bone mineral density, no statistically significant difference was noted in the aggregated data from two trials, mean difference 9.96 (95% confidence interval -2.51 to 22.43). In the remaining trial a statistically significant difference in mean per cent change in spine bone mineral density z score favoured intravenous bisphosphonates at six and 12 months. Data describing growth, bone pain, and functional outcomes after oral or intravenous bisphosphonate therapy, or both, as compared to placebo were incomplete among all studies, but do not show consistent improvements in these outcomes. Two studies compared different doses of bisphosphonates. No differences were found between doses when bone mineral density, fractures, and height or length z score were assessed. One trial compared oral versus intravenous bisphosphonates and found no differences in primary outcomes. Two studies compared the intravenous bisphosphonates zoledronic acid and pamidronate. There were no significant differences in primary outcome. However, the studies were at odds as to the relative benefit of zoledronic acid over pamidronate for lumbosacral bone mineral density at 12 months. Bisphophonates are commonly prescribed to individuals with osteogenesis imperfecta. Current evidence, albeit limited, demonstrates oral or intravenous bisphosphonates increase bone mineral density in children and adults with this condition. These were not shown to be different in their ability to increase bone mineral density. It is unclear whether oral or intravenous bisphosphonate treatment consistently decreases fractures, though multiple studies report this independently and no studies report an increased fracture rate with treatment. The studies included here do not show bisphosphonates conclusively improve clinical status (reduce pain; improve growth and functional mobility) in people with osteogenesis imperfecta. Given their current widespread and expected continued use, the optimal method, duration of therapy and long-term safety of bisphosphonate therapy require further investigation. In addition, attention should be given to long-term fracture reduction and improvement in quality of life indicators.

Bisphosphonate therapy for osteogenesis imperfecta.

PubMed

Dwan, Kerry; Phillipi, Carrie A; Steiner, Robert D; Basel, Donald

2014-07-23

Osteogenesis imperfecta is caused by a genetic defect resulting in an abnormal type I collagen bone matrix which typically results in multiple fractures with little or no trauma. Bisphosphonates are used in an attempt to increase bone mineral density and reduce these fractures in people with osteogenesis imperfecta. To assess the effectiveness and safety of bisphosphonates in increasing bone mineral density, reducing fractures and improving clinical function in people with osteogenesis imperfecta. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Inborn Errors of Metabolism Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of journals and conference proceedings. We additionally searched PubMed and major conference proceedings.Date of the most recent search: 07 April 2014. Randomised and quasi-randomised controlled trials comparing bisphosphonates to placebo, no treatment, or comparator interventions in all types of osteogenesis imperfecta. Two authors independently extracted data and assessed the risk of bias of the included trials. Fourteen trials (819 participants) were included. Overall, the trials were mainly at a low risk of bias, although selective reporting was an issue in several of the trials. Data for oral bisphosphonates versus placebo could not be aggregated; a statistically significant difference favouring oral bisphosphonates in fracture risk reduction and number of fractures was noted in two trials. No differences were reported in the remaining three trials which commented on fracture incidence. Five trials reported data for spine bone mineral density; all found statistically significant increased lumbar spine density z scores for at least one time point studied. For intravenous bisphosphonates versus placebo, aggregated data from two trials showed no statistically significant difference for the number of participants with at least one fracture, risk ratio 0.56 (95% confidence interval 0.30 to 1.06). In the remaining trial no statistically significant difference was noted in fracture incidence. For spine bone mineral density, no statistically significant difference was noted in the aggregated data from two trials, mean difference 9.96 (95% confidence interval -2.51 to 22.43). In the remaining trial a statistically significant difference in mean per cent change in spine bone mineral density z score favoured intravenous bisphosphonates at six and 12 months. Data describing growth, bone pain, and functional outcomes after oral or intravenous bisphosphonate therapy, or both, as compared to placebo were incomplete among all studies, but do not show consistent improvements in these outcomes. Two studies compared different doses of bisphosphonates. No differences were found between doses when bone mineral density, fractures, and height or length z score were assessed. One study compared oral versus intravenous bisphosphonates and found no differences in primary outcomes. Two studies compared the intravenous bisphosphonates zoledronic acid and pamidronate. There were no significant differences in primary outcome. However, the studies were at odds as to the relative benefit of zoledronic acid over pamidronate for lumbosacral bone mineral density at 12 months. Bisphophonates are commonly prescribed to individuals with osteogenesis imperfecta. Current evidence, albeit limited, demonstrates oral or intravenous bisphosphonates increase bone mineral density in children and adults with this condition. These were not shown to be different in their ability to increase bone mineral density. It is unclear whether oral or intravenous bisphosphonate treatment consistently decreases fractures, though multiple studies report this independently and no studies report an increased fracture rate with treatment. The studies included here do not show bisphosphonates conclusively improve clinical status (reduce pain; improve growth and functional mobility) in people with osteogenesis imperfecta. Given their current widespread and expected continued use, the optimal method, duration of therapy and long-term safety of bisphosphonate therapy require further investigation. In addition, attention should be given to long-term fracture reduction and improvement in quality of life indicators.

Aquabis[1-hydroxy-2-(imidazol-3-ium-1-yl)-1,1′-ethylidenediphophonato-κ2 O,O′]zinc(II) dihydrate

PubMed Central

Freire, Eleonora; Vega, Daniel R.

2009-01-01

In the title complex, [Zn(C5H9NO7P2)2(H2O)]·2H2O, the zinc atom is coordinated by two zoledronate anions [zoledronate = (2-(1-imidazole)-1-hydr­oxy-1,1′-ethyl­idenediphophonate)] and one water mol­ecule. The coordination number is 5. There is one half-mol­ecule in the asymmetric unit, the zinc atom being located on a twofold rotation axis passing through the metal centre and the coordinating water O atom. The anion exists as a zwitterion with an overall charge of −1; the protonated nitro­gen in the ring has a positive charge and the two phospho­nates groups each have a single negative charge. Inter­molecular O—H⋯O hydrogen bonds link the mol­ecules. An N—H⋯O inter­action is also present. PMID:21578165

Nonuremic calciphylaxis precipitated by teriparatide [rhPTH(1-34)] therapy in the setting of chronic warfarin and glucocorticoid treatment.

PubMed

Spanakis, E K; Sellmeyer, D E

2014-04-01

Calciphylaxis occurs rarely in the absence of end stage renal disease. Predisposing factors for nonuremic calciphylaxis (NUC) include hyperparathyroidism, coagulopathies, connective tissue disease, liver disease, glucocorticoid use, and malignancy. Warfarin can facilitate vascular calcification by reducing vitamin K-dependent carboxylation of matrix-Gla proteins. An 86-year-old Caucasian woman with a history of polymyalgia rheumatica, two spontaneous deep venous thromboses (DVTs) and multiple fractures was treated with calcium, vitamin D, prednisone, and warfarin. The patient's low bone density was treated initially with estrogen, then oral bisphosphonate, which was discontinued due to upper gastrointestinal symptoms. Nasal calcitonin was initiated. After 10 years of calcitonin treatment, she was changed to teriparatide. Two months after initiating teriparatide, she developed lower extremity edema and painful erythematous nodular lesions on her calves bilaterally, that progressed to necrotic ulcers despite antibiotic therapy. Biopsy of the lesions showed calcification in the media of small blood vessels and subcutaneous fat with fat necrosis, consistent with calciphylaxis. Teriparatide was discontinued. Aggressive wound care, antibiotics, and intravenous zoledronic acid were initiated. With cessation of teriparatide therapy and intensive wound care, the patient's lesions resolved over 8 months. We report the first case of NUC precipitated by teriparatide therapy. Our patient had multiple underlying predisposing factors including a connective tissue disorder, glucocorticoid therapy, warfarin use, and possible underlying coagulopathy given her history of multiple DVTs. In such patients, alternative osteoporosis therapies may be preferred.

Effects of Zoledronate and Mechanical Loading during Simulated Weightlessness on Bone Structure and Mechanical Properties

NASA Technical Reports Server (NTRS)

Scott, R. T.; Nalavadi, M. O.; Shirazi-Fard, Y.; Castillo, A. B.; Alwood, J. S.

2016-01-01

Space flight modulates bone remodeling to favor bone resorption. Current countermeasures include an anti-resorptive drug class, bisphosphonates (BP), and high-force loading regimens. Does the combination of anti-resorptives and high-force exercise during weightlessness have negative effects on the mechanical and structural properties of bone? In this study, we implemented an integrated model to mimic mechanical strain of exercise via cyclical loading (CL) in mice treated with the BP Zoledronate (ZOL) combined with hindlimb unloading (HU). Our working hypothesis is that CL combined with ZOL in the HU model induces additive structural and mechanical changes. Thirty-two C57BL6 mice (male,16 weeks old, n8group) were exposed to 3 weeks of either HU or normal ambulation (NA). Cohorts of mice received one subcutaneous injection of ZOL (45gkg), or saline vehicle, prior to experiment. The right tibia was axially loaded in vivo, 60xday to 9N in compression, repeated 3xweek during HU. During the application of compression, secant stiffness (SEC), a linear estimate of slope of the force displacement curve from rest (0.5N) to max load (9.0N), was calculated for each cycle once per week. Ex vivo CT was conducted on all subjects. For ex vivo mechanical properties, non-CL left femurs underwent 3-point bending. In the proximal tibial metaphysis, HU decreased, CL increased, and ZOL increased the cancellous bone volume to total volume ratio by -26, +21, and +33, respectively. Similar trends held for trabecular thickness and number. Ex vivo left femur mechanical properties revealed HU decreased stiffness (-37),and ZOL mitigated the HU stiffness losses (+78). Data on the ex vivo Ultimate Force followed similar trends. After 3 weeks, HU decreased in vivo SEC (-16). The combination of CL+HU appeared additive in bone structure and mechanical properties. However, when HU + CL + ZOL were combined, ZOL had no additional effect (p0.05) on in vivo SEC. Structural data followed this trend with ZOL not modulating trabecular thickness in CL + NAHU mice. In summary, our integrated model simulates the combination of weightlessness, exercise-induced mechanical strain, and anti-resorptive treatment that astronauts experience during space missions. Based on these results, we conclude that, at the structural and stiffness level, zoledronate treatment during simulated spaceflight does not impede the skeletal response to axial compression. In contrast to our hypothesis, our data show that zoledronate confers no additional mechanical or structural benefit beyond those gained from cyclical loading.

The A to Z of pharmaceutical cocrystals: a decade of fast-moving new science and patents.

PubMed

Almarsson, Örn; Peterson, Matthew L; Zaworotko, Michael

2012-07-01

From aspirin to zoledronic acid, pharmaceutical cocrystals emerged in the past decade as a promising new weapon in the arsenal of drug development. Resurgence of interest in multicomponent crystal compositions has led to significant advances in the science of cocrystal design and discovery. These advances have built upon crystal engineering, which provides a deep understanding of supramolecular interactions between molecules that govern crystal packing and physicochemical properties of crystalline materials. Concomitantly, the patent landscape of pharmaceutical cocrystals developed rapidly in the last decade. This review presents a broad survey of patents issued in the area of pharmaceutical cocrystals. In addition, the review contains analyses of key patents in the area involving compositions and methodologies. Along the way, the main events of the past decade representing a renaissance of cocrystals of pharmaceutical materials are chronicled. Future directions in the area are discussed in light of key pending patent applications and recent publications of seminal interest.

Management of patients with Paget's disease: a consensus document of the Belgian Bone Club.

PubMed

Devogelaer, J-P; Bergmann, P; Body, J-J; Boutsen, Y; Goemaere, S; Kaufman, J-M; Reginster, J-Y; Rozenberg, S; Boonen, S

2008-08-01

Paget's disease of bone (PDB) is a potentially crippling condition. Pain, fracture, spinal stenosis, nerve entrapment, vascular steal syndrome, secondary osteoarthritis, bone deformity, dental problems, deafness, excessive bleeding during orthopaedic surgery, rare sarcomatous degeneration, and hypercalcaemia constitute complications that may impair the quality of life. The therapeutic approach varies from symptomatic (analgesics, anti-inflammatory drugs) to more specific drugs such as increasingly potent bisphosphonates. Studies such as the PRISM study should in the future help to determine the superiority or not of aggressive treatment over symptomatic treatment in the prevention of complications. Various oral and/or intravenous (i.v.) bisphosphonates have been tested and are currently on the market. The most recently available nitrogen-containing bisphosphonate, i.v. zoledronic acid, is the most potent therapy available for the treatment of PDB. Its therapeutic efficacy, its long-term effect on biologic activity and its good tolerance currently supports its use as a first-line therapeutic option in patients suffering from PDB.

Anti-osteoporotic treatments in France: initiation, persistence and switches over 6 years of follow-up.

PubMed

Belhassen, M; Confavreux, C B; Cortet, B; Lamezec, L; Ginoux, M; Van Ganse, E

2017-03-01

Limited information is available on anti-osteoporotic treatment initiation patterns in France. In 2006-2013, the most frequently prescribed first-line treatment class for osteoporosis was represented by bisphosphonates (alendronic acid and risedronic acid), followed by strontium ranelate. Persistence with anti-osteoporotic treatment was low, with high proportions of treatment discontinuations and switches. This epidemiological, longitudinal study described first-line treatment initiation, persistence, switches to second-line treatment, and medical care consumption in osteoporotic patients in France during the 2007-2013 period. Patients aged ≥50 years, who were recorded in a French claims database and did not die during the observation period, were included if they met ≥1 inclusion criteria for osteoporosis in 2007 (≥1 reimbursement for anti-osteoporotic treatment, hospitalisation for osteoporotic fracture (spine, hip, femur, forearm bones, humerus, wrist), or ≥1 reimbursement for long-term osteoporosis-associated status). We collected data on consumption of anti-osteoporotic treatment (alendronic acid, ibandronic acid, risedronic acid, zoledronic acid, raloxifene, strontium ranelate, teriparatide) and of osteoporosis-related medical care after the date of first reimbursement for anti-osteoporotic treatment. We obtained 2219 patients with a 6-year follow-up and 1387 who initiated an anti-osteoporotic treatment in 2007 and who can be selected for the treatment regimen analysis. The most frequently used first-line treatments were alendronic acid (32.7 %), risedronic acid (22.4 %), strontium ranelate (19.3 %), ibandronic acid (13.1 %) and raloxifene (12.2 %). Among patients who received these treatments, the highest persistence after 6 years was observed for raloxifene (37.3 %), alendronic acid (35.1 %) and risedronic acid (32.3 %). Treatment discontinuations were reported for 35.5 % (raloxifene) to 53.4 % (strontium ranelate) and treatment switches for 27.4 % (alendronic acid) to 56.6 % (ibandronic acid) of these patients. This study showed that persistence with anti-osteoporotic treatment was relatively low in France, with high proportions of treatment discontinuations and switches, and that patients with osteoporosis were insufficiently monitored by bone specialists.

Bisphosphonates inhibit pain, bone loss, and inflammation in a rat tibia fracture model of complex regional pain syndrome

PubMed Central

Wang, Liping; Guo, Tian-Zhi; Wei, Tzuping; Li, Wen-wu; Shi, Xiaoyou; Clark, J David; Kingery, Wade S

2016-01-01

BACKGROUND Bisphosphonates are used to prevent the bone loss and fractures associated with osteoporosis, bone metastases, multiple myeloma, and osteogenis deformans. Distal limb fractures cause regional bone loss with cutaneous inflammation and pain in the injured limb that can develop into complex regional pain syndrome (CRPS). Clinical trials have reported that anti-resorptive bisphosphonates can prevent fracture-induced bone loss, inhibit serum inflammatory cytokine levels, and alleviate CRPS pain. Previously we observed that the inhibition of inflammatory cytokines or adaptive immune responses attenuated the development of pain behavior in a rat fracture model of CRPS and we hypothesized that bisphosphonates could prevent pain behavior, trabecular bone loss, post-fracture cutaneous cytokine up-regulation, and adaptive immune responses in this CRPS model. METHODS Rats underwent tibia fracture and cast immobilization for 4 weeks and were chronically administered either subcutaneously perfused alendronate or oral zoledronate. Behavioral measurements included hindpaw von Frey allodynia, unweighting, warmth, and edema. Bone microarchitecture was measured by uCT and bone cellular activity was evaluated by static and dynamic histomorphometry. Spinal cord Fos immunostaining was performed and skin cytokine (TNF, IL-1, IL-6) and nerve growth factor (NGF) levels were determined by EIA. Skin and sciatic nerve immunoglobulin levels were determined by EIA. RESULTS Tibia fracture rats developed hindpaw allodynia, unweighting, warmth, and edema, increased spinal Fos expression, trabecular bone loss in the lumbar vertebra and bilateral distal femurs as measured by uCT, increased trabecular bone resorption and osteoclast surface with decreased bone formation rates, increased cutaneous inflammatory cytokine and NGF expression and elevated immunocomplex deposition in skin and nerve. Alendronate (60 μg/kg/day s.c.) or zoledronate (3 mg/kg/day p.o.) treatment for 28 days, started at the time of fracture, completely inhibited the development of hindpaw allodynia and reduced hindpaw unweighting by 44 ± 13% and 58 ± 5%, respectively. Orally administered zoledronate (3 mg/kg/day for 21 days) treatment also completely reversed established allodynia and unweighting when started at 4-weeks post-fracture. Histomorphometric and uCT analysis demonstrated that both the 3 and 60 μg/kg/day alendronate treatments reversed trabecular bone loss (a 88 ± 25% and 188 ± 39% increase in the ipsilateral distal femur BV/TV, respectively) and blocked the increase in osteoclast numbers and erosion surface observed in bilateral distal femurs and in L5 vertebra of the fracture rats. Alendronate treatment inhibited fracture-induced increases in hindpaw inflammatory mediators, reducing post-fracture levels of TNF by 43 ± 9%, IL-1 by 60 ± 9%, IL-6 by 56 ± 14%, and NGF by 37 ± 14%, but had no effect on increased spinal cord Fos expression, or skin and sciatic nerve immunocomplex deposition. CONCLUSIONS Collectively, these results indicate that bisphosphonate therapy inhibits pain, osteoclast activation, trabecular bone loss, and cutaneous inflammation in the rat fracture model of CRPS, data supporting the hypothesis that bisphosphonate therapy can provide effective multimodal treatment for CRPS. PMID:27636578

Pharmacological blocking of the osteoclastic biocorrosion of surgical stainless steel in vitro.

PubMed

Lionetto, S; Little, A; Moriceau, G; Heymann, D; Decurtins, M; Plecko, M; Filgueira, L; Cadosch, D

2013-04-01

In vitro studies suggest that human osteoclasts (OC) are able to corrode surgical stainless steel 316L (SS). The aim of this study was to investigate whether osteoclastic biocorrosion can be blocked pharmacologically. Human OCs were generated in vitro from peripheral blood monocytic cells (PBMCs) in the presence of OC differentiation cytokines. The osteoclastic viability, differentiation, and resorptive function (on both bone and SS) were assessed using standard colorimetric cell viability assay 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenil)-2H-tetrazolium, inner salt (MTS), fluorescence microscopy, tartrate-resistant acid phosphatase expression (flow cytometry), and scanning electron microscopy. OCs cultured on SS were exposed to nontoxic concentrations of bafilomycin A1, amiloride hydrochloride, or zoledronic acid. The extent of biocorrosion was quantified using atomic emission spectrometry (to measure the concentration of metal ions released into the supernatant) and scanning electron microscopy. PBMCs differentiated into mature and functional OC in the presence of all the drugs used. Osteoclastic resorption of SS was noted with differences in the resorption pattern for all drug treatments. Under the drug treatments, single areas of osteoclastic resorption were larger in size but less abundant when compared with positive controls. None of the drugs used were able to inhibit osteoclastic biocorrosion of SS. Copyright © 2012 Wiley Periodicals, Inc.

Diaqua­bis[1-hydroxy-2-(imidazol-3-ium-1-yl)-1,1′-ethyl­idenediphophonato-κ2 O,O′]zinc(II)

PubMed Central

Freire, Eleonora; Vega, Daniel R.

2009-01-01

In the title complex, [Zn(C5H9NO7P2)2(H2O)2], the zinc atom is coordinated by two bidentate zoledronate [zoledronate = (2-(1-imidazole)-1-hydr­oxy-1,1′-ethyl­idenediphophonate)] ligands and two water mol­ecules. The coordination number is 6. There is one half-mol­ecule in the asymmetric unit with the zinc atom located on a crystallographic inversion centre. The anion exists as a zwitterion with an overall charge of −1; the protonated nitro­gen in the ring has a positive charge and the two phospho­nates groups each have a single negative charge. There are two intra­molecular O—H⋯O hydrogen bonds. The mol­ecules are linked into a chain by inter­molecular O—H⋯O hydrogen bonds. Adjacent chains are further linked by O—H⋯O hydrogen bonds involving the aqua ligands. An N—H⋯O inter­action is also observed. PMID:21578164

Efficacy and safety of medical therapy for low bone mineral density in patients with Crohn disease

PubMed Central

Zhao, Xiaojing; Zhou, Changcheng; Chen, Han; Ma, Jingjing; Zhu, Yunjuan; Wang, Peixue; Zhang, Yi; Ma, Haiqin; Zhang, Hongjie

2017-01-01

Abstract Background: Low bone mineral density (BMD) is a frequent complication of inflammatory bowel disease (IBD), particularly in patients with Crohn disease (CD). The aim of our study is to determine the efficacy and safety of different drugs used to treat low BMD in patients with CD. Methods: PUBMED/MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were searched for eligible studies. A random-effects model within a Bayesian framework was applied to compare treatment effects as standardized mean difference (SMD) with their corresponding 95% credible interval (CrI), while odds ratio (OR) was applied to compare adverse events with 95% CrI. The surface under the cumulative ranking area (SUCRA) was calculated to make the ranking of the treatments for outcomes. Results: Twelve randomized controlled trials (RCTs) were eligible. Compared with placebo, zoledronate (SMDs 2.74, 95% CrI 1.36–4.11) and sodium-fluoride (SMDs 1.23, 95% CrI 0.19–2.26) revealed statistical significance in increasing lumbar spine BMD (LSBMD). According to SUCRA ranking, zoledronate (SUCRA = 2.5%) might have the highest probability to be the best treatment for increasing LSBMD in CD patients among all agents, followed by sodium-fluoride (27%). For safety assessment, the incidence of adverse events (AEs) demonstrated no statistical difference between agents and placebo. The corresponding SUCRA values indicated that risedronate (SUCRA = 77%) might be the most safe medicine for low BMD in CD patients and alendronate ranked the worst (SUCRA = 16%). Conclusions: Zoledronate might have the highest probability to be the best therapeutic strategy for increasing LSBMD. For the safety assessment, risedronate showed the greatest trend to decrease the risk of AEs. In the future, more RCTs with higher qualities are needed to make head-to-head comparison between 2 or more treatments. PMID:28296781

Bone mineralization and vascularization in bisphosphonate-related osteonecrosis of the jaw: an experimental study in the rat.

PubMed

Kün-Darbois, Jean-Daniel; Libouban, Hélène; Mabilleau, Guillaume; Pascaretti-Grizon, Florence; Chappard, Daniel

2018-02-16

Pathogenesis of bisphosphonate-related osteonecrosis of the jaws (BRONJ) is not fully explained. An antiangiogenic effect of bisphosphonates (BPs) or an altered bone quality have been advocated. The aims of the present study were to analyze alveolar mandibular vascularization and bone quality in rats with BRONJ. Thirty-eight Sprague-Dawley rats were randomized into two groups: zoledronic acid (ZA), n = 27, and control (CTRL) n = 11. The ZA group received a weekly IV injection of ZA (100 μg/kg) during 10 weeks. The CTRL group received saline. After 6 weeks, extraction of the right mandibular molars was performed. Rats were sacrificed after 14 weeks. Microtomography characterized bone lesions and vascularization after injection of a radio-opaque material. Raman microspectroscopy evaluated bone mineralization. Fifty-five percent of ZA rats presented bone exposure and signs of BRONJ. None sign was found at the left hemimandible in the ZA group and in the CTRL group. Vascular density appeared significantly increased in the right hemimandibles of the CTRL group compared to the left hemimandibles. Vascularization was reduced in the ZA group. A significantly increased of the mineral-to-amide ratio was found in the alveolar bone of ZA rats by Raman microspectroscopy. In a rat model of BRONJ, microtomography evidenced osteonecrosis in BRONJ. Raman spectroscopy showed an increased mineralization. Vascularization after tooth extraction was impaired by ZA. Prolonged BP administration caused an increase in the mineralization and a quantitative reduction of the vascularization in the alveolar bone; both factors might be involved concomitantly in the BRONJ pathophysiology.

Rheumatoid arthritis exacerbates the severity of osteonecrosis of the jaws (ONJ) in mice. A randomized, prospective, controlled animal study

PubMed Central

de Molon, Rafael Scaf; Hsu, Chingyun; Bezouglaia, Olga; Dry, Sarah M.; Pirih, Flavia Q.; Soundia, Akrivoula; Cunha, Fernando Queiroz; Cirelli, Joni Augusto; Aghaloo, Tara L.; Tetradis, Sotirios

2016-01-01

Rheumatoid arthritis (RA), an autoimmune inflammatory disorder, results in persistent synovitis with severe bone and cartilage destruction. Bisphosphonates (BPs) are often utilized in RA patients to reduce bone destruction and manage osteoporosis. However, BPs, especially at high doses, are associated with osteonecrosis of the jaw (ONJ). Here, utilizing previously published ONJ animal models, we are exploring interactions between RA and ONJ incidence and severity. DBA1/J-mice were divided in 4 groups: control, zoledronic acid (ZA), collagen induced arthritis (CIA), and CIA-ZA. Animals were pre-treated with vehicle or ZA. Bovine collagen II emulsified in Freund’s adjuvant was injected to induce arthritis (CIA) and the mandibular molar crowns were drilled to induce periapical disease. Vehicle or ZA treatment continued for 8-weeks. ONJ indices were measured by micro-CT and histological examination of maxillae and mandibles. Arthritis development was assessed by visual scoring of paw swelling, and by micro-CT and histology of interphalangeal and knee joints. Maxillae and mandibles of control and CIA mice showed bone loss, PDL space widening, lamina dura loss and cortex thinning. ZA prevented theses changes in both ZA and CIA-ZA groups. Epithelial to alveolar crest distance was increased in the control and CIA mice. This distance was preserved in ZA and CIA-ZA animals. Empty osteocytic lacunae and areas of osteonecrosis were present in ZA and CIA-ZA but more extensively in CIA-ZA animals, indicating more severe ONJ. CIA and CIA-ZA groups developed severe arthritis in the paws and knees. Interphalangeal and knee joints of CIA mice showed advanced bone destruction with cortical erosions and trabecular bone loss, and ZA treatment reduced these effects. Importantly, no osteonecrosis was noted adjacent to areas of articular inflammation in CIA-ZA mice. Our data suggest that ONJ burden was more pronounced in ZA treated CIA mice and that RA could be a risk factor for ONJ development. PMID:26950411

Complete response of a recurrent-metastatic liposarcoma with dedifferentiated histological features following the administration of trabectedin and review of literature.

PubMed

Kus, Tulay; Aktas, Gokmen; Kalender, Mehmet Emin; Tutar, Ediz; Ulker, Esra; Camci, Celaletdin

2015-01-01

The present case report defines a rare case of a liposarcoma with bone metastasis resulting in a complete remission (CR) following trabectedin treatment. The patient was referred with abdominal swelling and pain. A retroperitoneal mass was detected and described as dedifferentiated liposarcoma (DDLS). The mass was surgically removed and consequently adjuvant chemotherapy was administered. Three months after the completion of chemotherapy, patient presented with bone metastasis in thoracic and lumbar vertebrae. Vertebroplasty and radiotherapy (RT) was performed. After these therapies, bone pain persisted and bone scintigraphy showed increased activity in L4, T11, and T12 vertebrae. Zoledronic acid was added to trabectedin treatment. CR has been detected on bone scintigraphy and positron emission tomography-computed tomography (PET-CT) after 18 weeks. Previous cases about liposarcoma treated with trabectedin were mostly about the myxoid/round cell type (former name, currently known as myxoid liposarcoma (MLS)) and mostly reported partial responses. In this study, trabectedin was used for the treatment of a metastatic retroperitoneal DDLS and a CR was achieved.

The ATP-binding cassette transporter A1 regulates phosphoantigen release and Vγ9Vδ2 T cell activation by dendritic cells

PubMed Central

Castella, Barbara; Kopecka, Joanna; Sciancalepore, Patrizia; Mandili, Giorgia; Foglietta, Myriam; Mitro, Nico; Caruso, Donatella; Novelli, Francesco; Riganti, Chiara; Massaia, Massimo

2017-01-01

Vγ9Vδ2 T cells are activated by phosphoantigens, such as isopentenyl pyrophosphate (IPP), which is generated in the mevalonate pathway of antigen-presenting cells. IPP is released in the extracellular microenvironment via unknown mechanisms. Here we show that the ATP-binding cassette transporter A1 (ABCA1) mediates extracellular IPP release from dendritic cells (DC) in cooperation with apolipoprotein A-I (apoA-I) and butyrophilin-3A1. IPP concentrations in the supernatants are sufficient to induce Vγ9Vδ2 T cell proliferation after DC mevalonate pathway inhibition with zoledronic acid (ZA). ZA treatment increases ABCA1 and apoA-I expression via IPP-dependent LXRα nuclear translocation and PI3K/Akt/mTOR pathway inhibition. These results close the mechanistic gap in our understanding of extracellular IPP release from DC and provide a framework to fine-tune Vγ9Vδ2 T cell activation via mevalonate and PI3K/Akt/mTOR pathway modulation. PMID:28580927

Simple 3,4-Dihydroxy-L-Phenylalanine Surface Modification Enhances Titanium Implant Osseointegration in Ovariectomized Rats.

PubMed

Ma, Ting; Ge, Xi-Yuan; Hao, Ke-Yi; Zhang, Bi-Ru; Jiang, Xi; Lin, Ye; Zhang, Yu

2017-12-19

Osteoporosis presents a challenge to the long-term success of osseointegration of endosseous implants. The bio-inspired 3,4-dihydroxy-L-phenylalanine (Dopa) coating is widely used as a basic layer to bind osteogenetic molecules that may improve osseointegration. To date, little attention has focused on application of Dopa alone or binding inhibitors of bone resorption in osteoporosis. Local use of a bisphosphonate such as zoledronic acid (ZA), an inhibitor of osteoclast-mediated bone resorption, has been proven to improve implant osseointegration. In this study, ovariectomized rats were divided into four groups and implanted with implants with different surface modifications: sandblasted and acid-etched (SLA), SLA modified with Dopa (SLA-Dopa), SLA modified with ZA (SLA-ZA), and SLA modified with Dopa and ZA (SLA-Dopa + ZA). Measurement of removal torque, micro-computed tomography and histology revealed a greater extent of bone formation around the three surface-modified implants than SLA-controls. No synergistic effect was observed for combined Dopa + ZA coating. Microarray analysis showed the Dopa coating inhibited expression of genes associated with osteoclast differentiation, similarly to the mechanism of action of ZA. Simple Dopa modification resulted in a similar improvement in osseointegration compared to ZA. Thus, our data suggest simple Dopa coating is promising strategy to promote osseointegration of implants in patients with osteoporosis.

Gateways to clinical trials.

PubMed

Tomillero, A; Moral, M A

2009-04-01

(+)-Dapoxetine hydrochloride, [(123)I]-BZA, 9-Aminocamptothecin; Abacavir sulfate/lamivudine, Adalimumab, Adefovir dipivoxil, Alemtuzumab, Alvocidib hydrochloride, Ambrisentan, Amsilarotene, Anacetrapib, Anakinra, Apricitabine, Aripiprazole, Arsenic trioxide, Atazanavir sulfate, Atazanavir/ritonavir, Atrasentan, Azacitidine; Banoxantrone, Bazedoxifene acetate, Bevacizumab, Bexarotene, Biphasic insulin aspart, Bortezomib, Bosentan, Bromfenac; Cachectin, Calcipotriol/betamethasone dipropionate, Canakinumab, Carfilzomib, CAT-354, CCX-282, Certolizumab pegol, Cetuximab, Choline fenofibrate, Clevudine, Clofarabine, CNTO-328, Corifollitropin alfa, Crofelemer; Daptomycin, Darbepoetin alfa, Darunavir, Dasatinib, Decitabine, Deferasirox, Denosumab, Duloxetine hydrochloride, Dutasteride; Emtricitabine, Enfuvirtide, Entecavir, Epoetin zeta, Erlotinib hydrochloride, Escitalopram oxalate, Eslicarbazepine acetate, Eszopiclone, Etravirine, Everolimus, Exenatide, Ezetimibe, Ezetimibe/simvastatin; Farglitazar, Febuxostat, Fosamprenavir calcium, FX-06; Gabapentin enacarbil, Gefitinib; HIVIS DNA; Imatinib mesylate, INCB- 18424, Indacaterol, Inotuzumab ozogamicin, Insulin detemir; JNJ-26854165; Lacosamide, Landiolol, Laromustine, Lenalidomide, Liposomal doxorubicin, L-NAME, Lopinavir, Lopinavir/ritonavir, Lumiracoxib; Maraviroc, Mepolizumab, Methoxy polyethylene glycol- epoetin-beta, Miglustat, MK-0493, MVA-CMDR, Mycophenolic acid sodium salt; Natalizumab, Nepafenac, Neratinib, Neridronic acid, Nesiritide, Nilotinib hydrochloride monohydrate; Olmesartan medoxomil, Omacetaxine mepesuccinate, Omalizumab; Paclitaxel poliglumex, Palifermin, Patupilone, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Peginterferon alfa-2b/ ribavirin, Pemetrexed disodium, PHA-848125, Pitavastatin calcium, Posaconazole, Povidone-iodine liposome complex, Prasugrel, Pregabalin, Prucalopride; Raltegravir potassium, Retigabine, Revaprazan hydrochloride, rhFSH, Rilpivirine, Rivaroxaban, Romidepsin, Rosuvastatin calcium, RWJ-676070; SAR-109659, Sitagliptin phosphate monohydrate, Sorafenib, Stavudine/Lamivudine/Nevirapine, Sunitinib malate; Tadalafil, Telaprevir, Telbivudine, Tenofovir disoproxil fumarate, Tenofovir disoproxil fumarate/emtricitabine, Tenofovir disoproxil fumarate/emtricitabine/efavirenz, Teriparatide, Tigecycline, Tiotropium bromide, Tipifarnib, Tipranavir, Tocilizumab, Trifluridine/TPI; UP-780; Vandetanib, Vardenafil hydrochloride hydrate, Vatalanib succinate, Vitespen, Vorinostat; Yttrium 90 (90Y) ibritumomab tiuxetan; Zoledronic acid monohydrate. Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.

Biochemical Bone Turnover Markers and Osteoporosis in Older Men: Where Are We?

PubMed Central

Szulc, Pawel

2011-01-01

In men aged less than 60, the association of serum and urinary levels of biochemical bone turnover markers (BTMs) and bone mineral density (BMD) is weak or not significant. After this age, higher BTM levels are correlated weakly, but significantly, with lower BMD and faster bone loss. Limited data from the cohort studies suggest that BTM measurement does not improve the prediction of fragility fractures in older men in comparison with age, BMD, history of falls and fragility fractures. Testosterone replacement therapy (TRT) decreases bone resorption. During TRT, bone formation markers slightly increase (direct effect on osteoblasts), then decrease (slowdown of bone turnover). Bisphosphonates (alendronate, risedronate, ibandronate, zoledronate) induce a rapid decrease in bone resorption followed by a milder decrease in bone formation. In men receiving antiresorptive therapy for prostate cancer, zoledronate, denosumab and toremifene decrease significantly levels of bone resorption and bone formation markers. Teriparatide induced a rapid increase in serum concentrations of bone formation markers followed by an increase in bone resorption. We need more studies on the utility of BTM measurement for the improvement of the persistence and adherence to the anti-osteoporotic treatment in men. PMID:22220284

[Amplification of γδ T cells in PBMCs of healthy donors and osteosarcoma patients stimulated by zoledronate].

PubMed

Li, Zhao-xu; Sun, Ling-ling; Cheng, Rui-lin; Sun, Zheng-wang; Ye, Zhao-ming

2012-08-01

To investigate the amplification and cytotoxicity of γδ T cells in peripheral blood mononuclear cells (PBMCs) of healthy donors and osteosarcoma patients stimulated by zoledronate (Zol) and IL-2. PBMCs from healthy donors and osteosarcoma patients were stimulated with IL-2 and Zol+IL-2, respectively. After 14-day culture, the purity of γδ T cells was assessed by flow cytometry. The cytotoxicity of γδ T cells against target cells was analyzed using a standard lactate dehydrogenase release assay with γδ T lymphocyte-sensitive Daudi cells, γδ T lymphocyte-resistant Raji cells and human osteoblast cell line, hFOB, as the target cells. After 2-week culture ex vivo of PBMCs from healthy donors and osteosarcoma patients, compared with stimulation of IL-2, Zol+IL-2 significantly promoted the amplification of γδ T cells. In addition, γδ T cells showed the higher cytotoxicity against Daudi cells, but no cytotoxic effect on normal cells like hFOB. γδ T cells of high purity and high cytotoxicity can be obtained by the stimulation of Zol combined with IL-2 on PBMCs from healthy donors and osteosarcoma patients.

The Effect of Interferon-γ and Zoledronate Treatment on Alpha-Tricalcium Phosphate/Collagen Sponge-Mediated Bone-Tissue Engineering

PubMed Central

Li, Peiqi; Hashimoto, Yoshiya; Honda, Yoshitomo; Arima, Yoshiyuki; Matsumoto, Naoyuki

2015-01-01

Inflammatory responses are frequently associated with the expression of inflammatory cytokines and severe osteoclastogenesis, which significantly affect the efficacy of biomaterials. Recent findings have suggested that interferon (IFN)-γ and zoledronate (Zol) are effective inhibitors of osteoclastogenesis. However, little is known regarding the utility of IFN-γ and Zol in bone tissue engineering. In this study, we generated rat models by generating critically sized defects in calvarias implanted with an alpha-tricalcium phosphate/collagen sponge (α-TCP/CS). At four weeks post-implantation, the rats were divided into IFN-γ, Zol, and control (no treatment) groups. Compared with the control group, the IFN-γ and Zol groups showed remarkable attenuation of severe osteoclastogenesis, leading to a significant enhancement in bone mass. Histomorphometric data and mRNA expression patterns in IFN-γ and Zol-injected rats reflected high bone-turnover with increased bone formation, a reduction in osteoclast numbers, and tumor necrosis factor-α expression. Our results demonstrated that the administration of IFN-γ and Zol enhanced bone regeneration of α-TCP/CS implants by enhancing bone formation, while hampering excess bone resorption. PMID:26516841

RNA Disruption and Drug Response in Breast Cancer Primary Systemic Therapy.

PubMed

Pritzker, Kenneth; Pritzker, Laura; Generali, Daniele; Bottini, Alberto; Cappelletti, Maria Rosa; Guo, Baoqing; Parissenti, Amadeo; Trudeau, Maureen

2015-05-01

As there is now evidence that switching clinical nonresponders early in primary systemic therapy to alternate treatment regimens can enhance survival in some breast cancer patients, the need for a robust intermediate endpoint that can guide treatment response across all tumor subtypes is urgent. Recently, chemotherapy drugs have been shown to induce a decrease in RNA quality in tumor cells from breast cancer biopsies in some patients at midtherapy, and that this has been associated with subsequent achievement of pathological complete response (pCR). The decrease in RNA quality has been shown to be associated with RNA disruption; aberrant RNA bands visualized by RNA electrophoresis have been associated with subsequent tumor cell death. The objectives of these studies are to show that a new assay based on induction of RNA disruption in tumor cells by chemotherapy can stratify at midtherapy, pCR responders from non-pCR responders irrespective of clinical response and to present early evidence that clinically useful RNA disruption can be detected as early as 14 days after initiation of treatment. RNA disruption in tumor cells was quantified by analysis of the RNA electrophoresis banding pattern and expressed as an RNA disruption index (RDI). To develop the RNA disruption assay (RDA), RDI was correlated with clinical outcome (pCR) from the NCIC-CTG MA.22 breast cancer clinical trial (ClinicalTrials.gov NCT00066443). RDA Zones were established by stratifying patients using RDI values into Zone 1, Zone 2, and Zone 3. Zone 3 included seven out of eight pCR responders, whereas Zone 1 contained no pCR responders. An intermediate zone (Zone 2) was established which contained one pCR. Subsequently, to determine early drug response, RNA disruption was examined by RDI after 14 days exposure to trastuzumab, zoledronic acid, or letrozole + cyclophosphamide ± sorafenib therapy. In MA.22, RDA stratified 23 of 85 patients in Zone 1 as pCR nonresponders, 24 patients in Zone 2, an intermediate zone, and 38 patients in Zone 3, pCR responders and non-pCR patients who share RDI comparable to those achieving pCR. In the early response studies, after 14 days exposure to chemotherapy, some RNA disruption as measured by RDI elevation could be detected in 3/12 trastuzumab, 7/15 zoledronic acid, 5/29 letrozole + cyclophosphamide, and 5/23 letrozole + cyclophosphamide + sorafenib patients. RDA is a novel intermediate endpoint that has promise for clinical utility for breast cancers early in response-guided primary systemic therapy. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Adjuvant bisphosphonates in early breast cancer: consensus guidance for clinical practice from a European Panel.

PubMed

Hadji, P; Coleman, R E; Wilson, C; Powles, T J; Clézardin, P; Aapro, M; Costa, L; Body, J-J; Markopoulos, C; Santini, D; Diel, I; Di Leo, A; Cameron, D; Dodwell, D; Smith, I; Gnant, M; Gray, R; Harbeck, N; Thurlimann, B; Untch, M; Cortes, J; Martin, M; Albert, U-S; Conte, P-F; Ejlertsen, B; Bergh, J; Kaufmann, M; Holen, I

2016-03-01

Bisphosphonates have been studied in randomised trials in early breast cancer to investigate their ability to prevent cancer treatment-induced bone loss (CTIBL) and reduce the risk of disease recurrence and metastasis. Treatment benefits have been reported but bisphosphonates do not currently have regulatory approval for either of these potential indications. This consensus paper provides a review of the evidence and offers guidance to breast cancer clinicians on the use of bisphosphonates in early breast cancer. Using the nominal group methodology for consensus, a systematic review of the literature was augmented by a workshop held in October 2014 for breast cancer and bone specialists to present and debate the available pre-clinical and clinical evidence for the use of adjuvant bisphosphonates. This was followed by a questionnaire to all members of the writing committee to identify areas of consensus. The panel recommended that bisphosphonates should be considered as part of routine clinical practice for the prevention of CTIBL in all patients with a T score of <-2.0 or ≥2 clinical risk factors for fracture. Compelling evidence from a meta-analysis of trial data of >18,000 patients supports clinically significant benefits of bisphosphonates on the development of bone metastases and breast cancer mortality in post-menopausal women or those receiving ovarian suppression therapy. Therefore, the panel recommends that bisphosphonates (either intravenous zoledronic acid or oral clodronate) are considered as part of the adjuvant breast cancer treatment in this population and the potential benefits and risks discussed with relevant patients. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

A systematic review of dosing frequency with bone-targeted agents for patients with bone metastases from breast cancer

PubMed Central

Hutton, Brian; Addison, Christina L.; Campbell, Kaitryn; Fergusson, Dean; Mazarello, Sasha; Clemons, Mark

2013-01-01

Background Bone-targeted agents are usually administered to breast cancer patients with bone metastases every 3–4 weeks. Less frequent (‘de-escalated’) treatment may provide similar benefits with improved safety and reduced cost. Methods To systematically review randomised trials comparing de-escalated treatment with bone-targeted agents (i.e. every 12–16 weeks) to standard treatment (i.e. every 3–4 weeks), a formal systematic review of the literature was performed. Two individuals independently screened citations and full text articles. Random effects meta-analyses of clinically important outcomes were planned provided homogeneous studies were identified. Results Five relevant studies (n=1287 patients) were identified. Sample size ranged from 38 to 425. Information on outcomes including occurrence of SREs, bone pain, urinary N-telopeptide concentrations, serum C-telopeptide concentrations, pain medication use and safety outcomes was not consistently available. Two trials were non-inferiority studies, two dose-response evaluations and one was a pilot study. Bone-targeted agents use varied between studies, as did duration of prior therapy. Patient populations were considered heterogeneous in several ways, and thus no meta-analyses were performed. Observations from the included studies suggest there is potential that 3 month de-escalated treatment may provide similar benefits compared to 3–4 weekly treatment and that lower doses of zoledronic acid and denosumab might be equally effective. Conclusions Studies comparing standard and de-escalated treatment with bone-targeted agents in breast cancer are rare. The benefits of standard treatment compared to de-escalated therapy on important clinical outcomes remain unclear. Future pragmatic studies must be conducted to determine the merits of this approach. PMID:26909282

Pleiotropic effects of bisphosphonates on osteosarcoma.

PubMed

Ohba, Tetsuro; Cates, Justin M M; Cole, Heather A; Slosky, David A; Haro, Hirotaka; Ichikawa, Jiro; Ando, Takashi; Schwartz, Herbert S; Schoenecker, Jonathan G

2014-06-01

Osteosarcoma is the most common primary malignant tumor of bone and accounts for half of all primary skeletal malignancies in children and teenagers. The prognosis for patients who fail or progress on first-line chemotherapy protocols is poor, therefore, additional adjuvant therapeutic strategies are needed. A recent feasibility study has demonstrated that the nitrogen-containing bisphosphonate zoledronic acid (ZOL) can be combined safely with conventional chemotherapy. However, the pharmacodynamics of bisphosphonate therapy is not well characterized. Osteosarcoma is a highly angiogenic tumor. Recent reports of the anti-angiogenic effects of bisphosphonates prompted us to determine whether nitrogen-containing bisphosphonate (ZOL and alendronate) treatment attenuates osteosarcoma growth by inhibition of osteoclast activity, tumor-mediated angiogenesis, or direct inhibitory effects on osteosarcoma. Here, we demonstrate that bisphosphonates directly inhibit VEGFR2 expression in endothelial cells, as well as endothelial cell proliferation and migration. Additionally, bisphosphonates also decrease VEGF-A expression in osteosarcoma (K7M3) cells, resulting in reduced stimulation of endothelial cell migration in co-culture assays. ZOL also decreases VEGFR1 expression in aggressive osteosarcoma cell lines (K7M3, 143B) and induces apoptosis of these cells, but has negligible effects on less aggressive osteosarcoma cell lines (K12 and TE85). In vivo ZOL treatment results in significant reduction in osteosarcoma-initiated angiogenesis and tumor growth in a murine model of osteosarcoma. In conclusion, bisphosphonates have diverse growth inhibitory effects on osteosarcoma through: (1) activation of apoptosis and inhibition of cell proliferation, (2) inhibition of VEGF-A and VEGFR1 expression by tumor cells, (3) inhibition of tumor-induced angiogenesis, and (4) direct inhibitory actions on endothelial cells. Published by Elsevier Inc.

Effects of dexamethasone and nimesulide on bisphosphonate-related osteonecrosis of the jaw: An experimental study.

PubMed

Oliveira, Camila Carvalho de; Barros Silva, Paulo Goberlânio de; Ferreira, Antonio Ernando Carlos; Gonçalves, Romélia Pinheiro; Sousa, Fabrício Bitu de; Mota, Mário Rogério Lima; Alves, Ana Paula Negreiros Nunes

2017-11-01

To evaluate the effects of dexamethasone (DEX) and nimesulide (NIM) on Bisphosphonate-related Osteonecrosis of the Jaw (BRONJ) in rats. BRONJ was induced by zoledronic acid (ZA) infusion (0.2mg/kg) in Wistar rats (n=8), followed by extraction of the left lower first molar (BRONJ groups). Control groups (n=40) received saline (IV). For eight weeks, DEX (0.04, 0.4, 4mg/kg) or saline (SAL) were administered by gavage 24h before each infusion of ZA or saline (IV), or NIM (10.3mg/kg) was administered 24h and 12h before each infusion of ZA or saline (IV). The haematological analyses were conducted weekly. After euthanasia (day 70), the jaws were submitted to radiographic and microscopic analysis. Kidney, liver, spleen and stomach were analysed histopathologically. The BRONJ groups showed a higher radiolucent area compared with the control groups (p<0.05). Histomorphometric analysis revealed healing and new bone formation in the control groups, while the BRONJ groups exhibited devitalized bone with bacterial colonies and inflammatory infiltrate. The BRONJ-DEX 0.4 and 4mg/kg groups had a greater number of bacterial colonies (p<0.05) and an increased polymorphonuclear cell count compared to the saline-BRONJ group, while the BRONJ-NIM group had a lower polymorphonuclear count (p<0.05). The BRONJ groups had leucocytosis, which was reduced by DEX administration. Treatments with DEX with or without ZA caused white pulp atrophy. Thus, DEX or NIM therapy was not effective in preventing radiographic and histopathologic events associated with BRONJ. Treatment with DEX attenuated leucocytosis post-infusion with ZA. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Clinical Study on Administration of Opioid Antagonists in Terminal Cancer Patients: 7 Patients Receiving Opioid Antagonists Following Opioids among 2443 Terminal Cancer Patients Receiving Opioids.

PubMed

Uekuzu, Yoshihiro; Higashiguchi, Takashi; Futamura, Akihiko; Ito, Akihiro; Mori, Naoharu; Murai, Miyo; Ohara, Hiroshi; Awa, Hiroko; Chihara, Takeshi

2017-03-01

There have been few detailed reports on respiratory depression due to overdoses of opioids in terminal cancer patients. We investigated the situation of treatment with opioid antagonists for respiratory depression that occurred after administration of opioid at optimal doses in terminal cancer patients, to clarify pathological changes as well as causative factors. In 2443 terminal cancer patients receiving opioids, 7 patients (0.3%) received opioid antagonists: 6, morphine (hydrochloride, 5; sulfate, 1); 1, oxycodone. The median dosage of opioids was 13.3 mg/d, as converted to morphine injection. Respiratory depression occurred on this daily dose in 4 patients and after changed dose and route in 3 patients. Opioids were given through the vein in 6 patients and by the enteral route in 1 patient. Concomitant drugs included nonsteroidal anti-inflammatory drugs in 3 patients and zoledronic acid in 2 patients. In morphine-receiving patients, renal functions were significantly worsened at the time of administration of an opioid antagonist than the day before the start of opioid administration. These findings indicate that the proper use of opioids was safe and acceptable in almost all terminal cancer patients. In rare cases, however, a risk toward respiratory depression onset is indicated because morphine and morphine-6-glucuronide become relatively excessive owing to systemic debility due to disease progression, especially respiratory and renal dysfunctions. At the onset of respiratory depression, appropriate administration of an opioid antagonist mitigated the symptoms. Thereafter, opioid switching or continuous administration at reduced dosages of the same opioids prevented the occurrence of serious adverse events.

Low-intensity continuous ultrasound triggers effective bisphosphonate anticancer activity in breast cancer.

PubMed

Tardoski, Sophie; Ngo, Jacqueline; Gineyts, Evelyne; Roux, Jean-Paul; Clézardin, Philippe; Melodelima, David

2015-11-18

Ultrasound (US) is a non-ionizing pressure wave that can produce mechanical and thermal effects. Bisphosphonates have demonstrated clinical utility in bone metastases treatment. Preclinical studies suggest that bisphosphonates have anticancer activity. However, bisphosphonates exhibit a high affinity for bone mineral, which reduces their bioavailability for tumor cells. Ultrasound has been shown to be effective for drug delivery but in interaction with gas bubbles or encapsulated drugs. We examined the effects of a clinically relevant dose of bisphosphonate zoledronate (ZOL) in combination with US. In a bone metastasis model, mice treated with ZOL+US had osteolytic lesions that were 58% smaller than those of ZOL-treated animals as well as a reduced skeletal tumor burden. In a model of primary tumors, ZOL+US treatment reduced by 42% the tumor volume, compared with ZOL-treated animals. Using a fluorescent bisphosphonate, we demonstrated that US forced the release of bisphosphonate from the bone surface, enabling a continuous impregnation of the bone marrow. Additionally, US forced the penetration of ZOL within tumors, as demonstrated by the intratumoral accumulation of unprenylated Rap1A, a surrogate marker of ZOL antitumor activity. Our findings made US a promising modality to trigger bisphosphonate anticancer activity in bone metastases and in primary tumors.

Low-intensity continuous ultrasound triggers effective bisphosphonate anticancer activity in breast cancer

NASA Astrophysics Data System (ADS)

Tardoski, Sophie; Ngo, Jacqueline; Gineyts, Evelyne; Roux, Jean-Paul; Clézardin, Philippe; Melodelima, David

2015-11-01

Ultrasound (US) is a non-ionizing pressure wave that can produce mechanical and thermal effects. Bisphosphonates have demonstrated clinical utility in bone metastases treatment. Preclinical studies suggest that bisphosphonates have anticancer activity. However, bisphosphonates exhibit a high affinity for bone mineral, which reduces their bioavailibity for tumor cells. Ultrasound has been shown to be effective for drug delivery but in interaction with gas bubbles or encapsulated drugs. We examined the effects of a clinically relevant dose of bisphosphonate zoledronate (ZOL) in combination with US. In a bone metastasis model, mice treated with ZOL+US had osteolytic lesions that were 58% smaller than those of ZOL-treated animals as well as a reduced skeletal tumor burden. In a model of primary tumors, ZOL+US treatment reduced by 42% the tumor volume, compared with ZOL-treated animals. Using a fluorescent bisphosphonate, we demonstrated that US forced the release of bisphosphonate from the bone surface, enabling a continuous impregnation of the bone marrow. Additionally, US forced the penetration of ZOL within tumors, as demonstrated by the intratumoral accumulation of unprenylated Rap1A, a surrogate marker of ZOL antitumor activity. Our findings made US a promising modality to trigger bisphosphonate anticancer activity in bone metastases and in primary tumors.

Bisphosphonates enhance bacterial adhesion and biofilm formation on bone hydroxyapatite.

PubMed

Kos, Marcin; Junka, Adam; Smutnicka, Danuta; Szymczyk, Patrycja; Gluza, Karolina; Bartoszewicz, Marzenna

2015-07-01

Because of the suspicion that bisphosphonates enhance bacterial colonization, this study evaluated adhesion and biofilm formation by Streptococcus mutans 25175, Staphylococcus aureus 6538, and Pseudomonas aeruginosa 14454 reference strains on hydroxyapatite coated with clodronate, pamidronate, or zoledronate. Bacterial strains were cultured on bisphosphonate-coated and noncoated hydroxyapatite discs. After incubation, nonadhered bacteria were removed by centrifugation. Biofilm formation was confirmed by scanning electron microscopy. Bacterial colonization was estimated using quantitative cultures compared by means with Kruskal-Wallis and post-hoc Student-Newman-Keuls tests. Modeling of the interactions between bisphosphonates and hydroxyapatite was performed using the Density Functional Theory method. Bacterial colonization of the hydroxyapatite discs was significantly higher for all tested strains in the presence of bisphosphonates vs. Adherence in the presence of pamidronate was higher than with other bisphosphonates. Density Functional Theory analysis showed that the protonated amine group of pamidronate, which are not present in clodronate or zoledronate, forms two additional hydrogen bonds with hydroxyapatite. Moreover, the reactive cationic amino group of pamidronate may attract bacteria by direct electrostatic interaction. Increased bacterial adhesion and biofilm formation can promote osteomyelitis, cause failure of dental implants or bisphosphonate-coated joint prostheses, and complicate bone surgery in patients on bisphosphonates. Copyright © 2015 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

Ab initio design of drug carriers for zoledronate guest molecule using phosphonated and sulfonated calix[4]arene and calix[4]resorcinarene host molecules

NASA Astrophysics Data System (ADS)

Jang, Yong-Man; Yu, Chol-Jun; Kim, Jin-Song; Kim, Song-Un

2018-04-01

Monomolecular drug carriers based on calix[n]-arenes and -resorcinarenes containing the interior cavity can enhance the affinity and specificity of the osteoporosis inhibitor drug zoledronate (ZOD). In this work we investigate the suitability of nine different calix[4]-arenes and -resorcinarenes based macrocycles as hosts for the ZOD guest molecule by conducting {\\it ab initio} density functional theory calculations for structures and energetics of eighteen different host-guest complexes. For the optimized molecular structures of the free, phosphonated, sulfonated calix[4]-arenes and -resorcinarenes, the geometric sizes of their interior cavities are measured and compared with those of the host-guest complexes in order to check the appropriateness for host-guest complex formation. Our calculations of binding energies indicate that in gaseous states some of the complexes might be unstable but in aqueous states almost all of the complexes can be formed spontaneously. Of the two different docking ways, the insertion of ZOD with the \\ce{P-C-P} branch into the cavity of host is easier than that with the nitrogen containing heterocycle of ZOD. The work will open a way for developing effective drug delivering systems for the ZOD drug and promote experimentalists to synthesize them.

Technetium-99 conjugated with methylene diphosphonate ameliorates ovariectomy-induced osteoporotic phenotype without causing osteonecrosis in the jaw.

PubMed

Zhao, Yinghua; Wang, Lei; Liu, Yi; Akiyama, Kentaro; Chen, Chider; Atsuta, Ikiru; Zhou, Tao; Duan, Xiaohong; Jin, Yan; Shi, Songtao

2012-12-01

Technetium-99 conjugated with methylene diphosphonate ((99)Tc-MDP) is a novel bisphosphonate derivative without radioactivity and has been successfully used to treat arthritis in China for years. Since bisphosphonate therapy has the potential to induce bisphosphonate-related osteonecrosis of the jaw (BRONJ), we examined whether (99)Tc-MDP represents a new class of bisphosphonate for antiresorptive therapy to ameliorate estrogen deficiency-induced bone resorption with less risk of causing BRONJ. We showed that (99)Tc-MDP-treated, ovariectomized (OVX) mice had significantly improved bone mineral density and trabecular bone volume in comparison to the untreated OVX group by inhibiting osteoclasts and enhancing osteogenic differentiation of bone marrow mesenchymal stem cells. To determine the potential of inducing BRONJ, (99)Tc-MDP/dexamethasone (Dex) or zoledronate/Dex was administered into C57BL/6J mice via the tail vein, followed by extraction of maxillary first molars. Interestingly, (99)Tc-MDP treatment showed less risk to induce osteonecrosis in the maxillary bones compared to zoledronate treatment group, partially because (99)Tc-MDP neither suppressed adaptive regulatory T cells nor activated the inflammatory T-helper-producing interleukin-17 cells. Taken together, our findings demonstrate that (99)Tc-MDP therapy may be a promising approach in the treatment of osteoporosis with less risk of causing BRONJ.

A systematic review and economic evaluation of bisphosphonates for the prevention of fragility fractures.

PubMed

Davis, Sarah; Martyn-St James, Marrissa; Sanderson, Jean; Stevens, John; Goka, Edward; Rawdin, Andrew; Sadler, Susi; Wong, Ruth; Campbell, Fiona; Stevenson, Matt; Strong, Mark; Selby, Peter; Gittoes, Neil

2016-10-01

Fragility fractures are fractures that result from mechanical forces that would not ordinarily result in fracture. To evaluate the clinical effectiveness and safety of bisphosphonates [alendronic acid (Fosamax ® and Fosamax ® Once Weekly, Merck Sharp & Dohme Ltd), risedronic acid (Actonel ® and Actonel Once a Week ® , Warner Chilcott UK Ltd), ibandronic acid (Bonviva ® , Roche Products Ltd) and zoledronic acid (Aclasta ® , Novartis Pharmaceuticals UK Ltd)] for the prevention of fragility fracture and to assess their cost-effectiveness at varying levels of fracture risk. For the clinical effectiveness review, six electronic databases and two trial registries were searched: MEDLINE, EMBASE, The Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Web of Science and BIOSIS Previews, Clinicaltrials.gov and World Health Organization International Clinical Trials Registry Platform. Searches were limited by date from 2008 until September 2014. A systematic review and network meta-analysis (NMA) of effectiveness studies were conducted. A review of published economic analyses was undertaken and a de novo health economic model was constructed. Discrete event simulation was used to estimate lifetime costs and quality-adjusted life-years (QALYs) for each bisphosphonate treatment strategy and a strategy of no treatment for a simulated cohort of patients with heterogeneous characteristics. The model was populated with effectiveness evidence from the systematic review and NMA. All other parameters were estimated from published sources. A NHS and Personal Social Services perspective was taken, and costs and benefits were discounted at 3.5% per annum. Fracture risk was estimated from patient characteristics using the QFracture ® (QFracture-2012 open source revision 38, Clinrisk Ltd, Leeds, UK) and FRAX ® (web version 3.9, University of Sheffield, Sheffield, UK) tools. The relationship between fracture risk and incremental net benefit (INB) was estimated using non-parametric regression. Probabilistic sensitivity analysis (PSA) and scenario analyses were used to assess uncertainty. Forty-six randomised controlled trials (RCTs) were included in the clinical effectiveness systematic review, with 27 RCTs providing data for the fracture NMA and 35 RCTs providing data for the femoral neck bone mineral density (BMD) NMA. All treatments had beneficial effects on fractures versus placebo, with hazard ratios varying from 0.41 to 0.92 depending on treatment and fracture type. The effects on vertebral fractures and percentage change in BMD were statistically significant for all treatments. There was no evidence of a difference in effect on fractures between bisphosphonates. A statistically significant difference in the incidence of influenza-like symptoms was identified from the RCTs for zoledronic acid compared with placebo. Reviews of observational studies suggest that upper gastrointestinal symptoms are frequently reported in the first month of oral bisphosphonate treatment, but pooled analyses of placebo-controlled trials found no statistically significant difference. A strategy of no treatment was estimated to have the maximum INB for patients with a 10-year QFracture risk under 1.5%, whereas oral bisphosphonates provided maximum INB at higher levels of risk. However, the PSA suggested that there is considerable uncertainty regarding whether or not no treatment is the optimal strategy until the QFracture score is around 5.5%. In the model using FRAX, the mean INBs were positive for all oral bisphosphonate treatments across all risk categories. Intravenous bisphosphonates were estimated to have lower INBs than oral bisphosphonates across all levels of fracture risk when estimated using either QFracture or FRAX. We assumed that all treatment strategies are viable alternatives across the whole population. Bisphosphonates are effective in preventing fragility fractures. However, the benefit-to-risk ratio in the lowest-risk patients may be debatable given the low absolute QALY gains and the potential for adverse events. We plan to extend the analysis to include non-bisphosphonate therapies. This study is registered as PROSPERO CRD42013006883. The National Institute for Health Research Health Technology Assessment programme.

Cost effectiveness of bisphosphonates in the management of breast cancer patients with bone metastases.

PubMed

Botteman, M; Barghout, V; Stephens, J; Hay, J; Brandman, J; Aapro, M

2006-07-01

Bisphosphonates are recommended to prevent skeletal related events (SREs) in patients with breast cancer and bone metastases (BCBM). However, their clinical and economic profiles vary from one agent to the other. Using modeling techniques, we simulated from the perspective of the UK's National Health Service (NHS) the cost and quality adjusted survival (QALY) associated with five commonly-used bisphosphonates or no therapy in this patient population. The simulation followed patients into several health states (i.e. alive or dead, experiencing an SRE or no SRE, and receiving first or second line therapy). Drugs costs, infusion costs, SREs costs, and utility values were estimated from published sources. Utilities were applied to time with and without SREs to capture the impact on quality of life. Compared to no therapy, all bisphosphonates are either cost saving or highly cost-effective (with a cost per QALY < or = 6126 pounds sterlings). Within this evaluation, zoledronic acid was more effective and less expensive than all other options. Based on our model, the use of bisphosphonates in breast cancer patients with bone metastases should lead to improved patient outcomes and cost savings to the NHS and possibly other similar entities.

Drug repurposing in malignant pleural mesothelioma: a breath of fresh air?

PubMed

Boyer, Arnaud; Pasquier, Eddy; Tomasini, Pascale; Ciccolini, Joseph; Greillier, Laurent; Andre, Nicolas; Barlesi, Fabrice; Mascaux, Celine

2018-03-31

Drug repurposing is the use of known drugs for new indications. Malignant pleural mesothelioma (MPM) is a rare cancer with a poor prognosis. So far, few treatments have been approved in this disease. However, its incidence is expected to increase significantly, particularly in developing countries. Consequently, drug repurposing appears as an attractive strategy for drug development in MPM, since the known pharmacology and safety profile based on previous approvals of repurposed drugs allows for faster time-to-market for patients and lower treatment cost. This is critical in low- and middle-income countries where access to expensive drugs is limited. This review assesses the published preclinical and clinical data about drug repurposing in MPM.In this review, we identified 11 therapeutic classes that could be repositioned in mesothelioma. Most of these treatments have been evaluated in vitro , half have been evaluated in vivo in animal models of MPM and only three ( i.e. valproate, thalidomide and zoledronic acid) have been investigated in clinical trials, with limited benefits so far. Efforts could be coordinated to pursue further investigations and test promising drugs identified in preclinical experiments in appropriately designed clinical trials. Copyright ©ERS 2018.

Efficacy and tolerability of medical ozone gas insufflations in patients with osteonecrosis of the jaw treated with bisphosphonates-Preliminary data: Medical ozone gas insufflation in treating ONJ lesions.

PubMed

Ripamonti, C I; Maniezzo, M; Boldini, S; Pessi, M A; Mariani, L; Cislaghi, E

2012-12-01

Osteonecrosis of the Jaw (ONJ) is an adverse event reported especially in patients receiving cancer treatments regimen, bisphosphonates (BPs), and denosumab. We performed an open-label, prospective study in patients treated with zoledronic acid who developed ONJ lesions >2.5 cm, and had no benefit after the treatment with the standard therapy, to evaluate the efficacy and tolerability of medical ozone (O3) treatment delivered as gas insufflations on each ONJ lesions. Twenty-four patients (mean age 62.5, range 41-80; 12 female) with bone metastases due to breast (11), prostate (4)and lung (4)cancers, myeloma (2), or osteoporosis (3), previously treated with zoledronic acid and not underwent dental preventive measures and with ONJ lesions >2.5 cm, were observed and treated with topical O3 gas insufflation every third day for a minimum of 10 for each pathological area or till necrotic bone sequestrum or surgery. We used a special insufflation bell-shaped device adjusted to the specific characteristics of the patient, capable of eliminating any residue of O3 diffusion by degrading it and releasing O2 into the air. Azithromicin 500 mg/day was administered for 10 days in all patients before the first three gas insufflation although they had previously received various cycles of antibiotics. Ten patients required more than 10 O3 gas insufflations due to multiple lesions and/or purulent sovrainfections; one patient received two further O3 insufflations while waiting the day of surgery. Six of 24 patients interrupted the O3 gas therapy for oncological disease progression (five patients) and for fear of an experimental therapy (one patient). Six patients had the sequestrum and complete or partial (one patient) spontaneous expulsion of the necrotic bone followed by oral mucosa re-epithelization after a range of 4-27 of O3 gas insufflations. No patient reported adverse events. In 12 patients with the largest and deeper ONJ lesions, O3 gas therapy produced the sequestrum of the necrotic bone after 10 to 38 insufflations; surgery was necessary to remove it (11 patients). Of interest, removal was possible without the resection of healthy mandible edge because of the presence of bone sequestrum. All together the response rate was 75.0% (95% CI, 53.3-90.2%) in ITT analysis and 100% (95% CI, 81.5-100%) in the PP analysis. In all patients treated with O3 gas ± surgery, no ONJ relapse appeared (follow-up mean 18 months, range 1-3 years). Medical O3 gas insufflations is an effective and safe treatment for patients treated with BPs who developed ONJ lesions >2.5 cm. Short abstract: ONJ is an adverse event reported in patients receiving cancer treatments regimen, bisphosphonates and denosumab. We performed an open-label, prospective study in 24 patients with solid tumours, myeloma or osteoporosis due to hormonal therapy, treated with zoledronic acid without previuos preventive dental screening, who developed ONJ lesions >2.5 cm, and had no benefit after standard therapy, to evaluate the efficacy and tolerability of medical ozone (O3) treatment delivered as gas insufflations on each ONJ lesions. The patients were treated with O3 every third day for a minimum of 10 for each pathological area or till necrotic bone sequestrum or surgery. Eleven patients required more than ten O3 gas insufflations. Six of 24 patients interrupted the therapy for oncological disease progression. Six patients had the sequestrum and complete or partial (one patient) spontaneous expulsion of the necrotic bone followed by oral mucosa re-epithelization after a range of 4 to 27 of O3 gas insufflations. No patient reported adverse events. In 12 patients with the largest and deeper ONJ lesions, O3 gas therapy produced the sequestrum of the necrotic bone after 10 to 38 insufflations; surgery was necessary to remove it (11 patients). Of interest, removal was possible without the resection of healthy mandible edge because of the presence of bone sequestrum. All together the response rate was 75.0% (95% CI, 53.3-90.2%) in ITT analysis and 100% (95% CI, 81.5-100%) in the PP analysis. In all patients treated with O3 gas ± surgery, no ONJ relapse appeared (follow-up mean 18 months, range 1-3 years).

Induction of gamma delta T cells using zoledronate plus interleukin-2 in patients with metastatic cancer.

PubMed

Nagamine, Ichiro; Yamaguchi, Yoshiyuki; Ohara, Masahiro; Ikeda, Takuhiro; Okada, Morihito

2009-03-01

A loss of human leukocyte antigen (HLA) expression in clinical tumors is one of their escape mechanisms from immune attack by HLA-restricted effector cells. In this study, the induction of HLA-unrestricted effector cells, gamma delta T cells, using zoledronate (ZOL) and interleukin (IL)-2 in vitro was investigated in patients with metastatic cancer. Peripheral blood mononuclear cells (PBMCs) from 10 cancer patients (8 colorectal and 2 esophageal) with multiple metastases and ascites lymphocytes from 3 cancer patients (1 gastric and 2 colorectal) were stimulated with varied concentrations of ZOL plus 100 U/ml IL-2 for 48 hr followed by culturing with IL-2 alone for 12 days. Lymphocyte proliferative responses were determined using 3H-TdR uptakes and interferon (IFN)-gamma production was evaluated using enzyme-linked immunosorbent assay. Surface phenotyping was performed using flow cytometry. Cytotoxic activity of effector cells was determined using 51Cr-releasing assay. It was found that proliferative responses of PBMCs were significantly stimulated with ZOL plus IL-2 when compared with IL-2 alone, showing 200 to 500-fold expansions for 2 weeks, although ZOL alone induced no response. The optimal concentration of ZOL was 1-5 microM. Ascites lymphocytes could also be stimulated with ZOL plus IL-2. The proliferative responses were remarkable in patients whose PBMCs could produce high levels of IFN-gamma during an initial 48-hr stimulation using ZOL plus IL-2. Removal of an adherent cell fraction before the induction augmented the proliferative responses in patients who otherwise had low-grade proliferative responses. Generated cells comprising approximately 90 or 20% in PBMCs from healthy donors or cancer patients, respectively, expressed gamma delta-type T-cell receptor. Gamma delta T cells showed high cytotoxic activity against CD166-positive TE12 and TE13 cancer cells but not against CD166-negative MKN45 cells. The cytotoxic activity against TE13 cells was augmented when target cells were pre-treated overnight with ZOL. These results suggest that ZOL in the presence of IL-2 can efficiently stimulate the proliferation of gamma delta T cells, which have cytotoxic properties against cancer cells. The use of zoledronate-activated killer (ZAK) cells should be encouraged in possible adoptive immunotherapy trials for patients with incurable cancer.

Distinctive Tooth-Extraction Socket Healing: Bisphosphonate Versus Parathyroid Hormone Therapy

PubMed Central

Kuroshima, Shinichiro; Mecano, Rodan B.; Tanoue, Ryuichiro; Koi, Kiyono; Yamashita, Junro

2014-01-01

Background Patients with osteoporosis who receive tooth extractions are typically on either oral bisphosphonate or parathyroid hormone (PTH) therapy. Currently, the consequence of these therapies on hard- and soft-tissue healing in the oral cavity is not clearly defined. The aim of this study is to determine the differences in the therapeutic effect on tooth-extraction wound healing between bisphosphonate and PTH therapies. Methods Maxillary second molars were extracted in Sprague Dawley rats (n = 30), and either bisphosphonate (zoledronate [Zol]), PTH, or saline (vehicle control [VC]) was administered for 10 days (n = 10 per group). Hard-tissue healing was evaluated by microcomputed tomography and histomorphometric analyses. Collagen, blood vessels, inflammatory cell infiltration, and cathepsin K expression were assessed in soft tissue using immunohistochemistry, quantitative polymerase chain reaction, and immunoblotting. Results Both therapies significantly increased bone fill and suppressed vertical bone loss. However, considerably more devital bone was observed in the sockets of rats on Zol versus VC. Although Zol increased the numbers of blood vessels, the total blood vessel area in soft tissue was significantly smaller than in VC. PTH therapy increased osteoblastic bone formation and suppressed osteoclasts. PTH therapy promoted soft-tissue maturation by suppressing inflammation and stimulating collagen deposition. Conclusion Zoledronate therapy deters whereas PTH therapy promotes hard- and soft-tissue healing in the oral cavity, and both therapies prevent vertical bone loss. PMID:23688101

Endocrine effects of adjuvant letrozole + triptorelin compared with tamoxifen + triptorelin in premenopausal patients with early breast cancer.

PubMed

Rossi, Emanuela; Morabito, Alessandro; De Maio, Ermelinda; Di Rella, Francesca; Esposito, Giuseppe; Gravina, Adriano; Labonia, Vincenzo; Landi, Gabriella; Nuzzo, Francesco; Pacilio, Carmen; Piccirillo, Maria Carmela; D'Aiuto, Giuseppe; D'Aiuto, Massimiliano; Rinaldo, Massimo; Botti, Gerardo; Gallo, Ciro; Perrone, Francesco; de Matteis, Andrea

2008-01-10

To compare the endocrine effects of 6 months of adjuvant treatment with letrozole + triptorelin or tamoxifen + triptorelin in premenopausal patients with early breast cancer within an ongoing phase 3 trial (Hormonal Adjuvant Treatment Bone Effects study). Prospectively collected hormonal data were available for 81 premenopausal women, of whom 30 were assigned to receive tamoxifen + triptorelin and 51 were assigned letrozole + triptorelin +/- zoledronate. Serum 17-beta-estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), Delta4-androstenedione, testosterone, dehydroepiandrosterone-sulfate, progesterone, adrenocorticotropic hormone (ACTH), and cortisol were measured at baseline and after 6 months of treatment. For each hormone, 6-month values were compared between treatment groups by the Wilcoxon-Mann-Whitney exact test. Median age was 44 years for both groups of patients. Letrozole + triptorelin (+/- zoledronate) induced a stronger suppression of median E2 serum levels (P = .0008), LH levels (P = .0005), and cortisol serum levels (P < .0001) compared with tamoxifen + triptorelin. Median FSH serum levels were suppressed in both groups, but such suppression was lower among patients receiving letrozole, who showed significantly higher median FSH serum levels (P < .0001). No significant differences were observed for testosterone, progesterone, ACTH, androstenedione, and dehydroepiandrosterone between the two groups of patients. Letrozole in combination with triptorelin induces a more intense estrogen suppression than tamoxifen + triptorelin in premenopausal patients with early breast cancer.

Effect of bisphosphonates on macrophagic THP-1 cell survival in bisphosphonate-related osteonecrosis of the jaw (BRONJ).

PubMed

Hoefert, Sebastian; Sade Hoefert, Claudia; Munz, Adelheid; Schmitz, Inge; Grimm, Martin; Yuan, Anna; Northoff, Hinnak; Reinert, Siegmar; Alexander, Dorothea

2016-03-01

Immune deficiency and bacterial infection have been suggested to play a role in the pathophysiology of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Zoledronate was previously found to promote THP-1 cell death. To examine this hypothesis with all commonly prescribed bisphosphonates, we tested the effect of (nitrogen-containing) ibandronate, risedronate, alendronate, pamidronate, and (non-nitrogen-containing) clodronate on macrophagic THP-1 cells. Activated THP-1 cells were exposed to .5 to 50 μM of nitrogen-containing bisphosphonates and .5 to 500 μM of clodronate. Cell adherence and survival were assessed in vitro using the xCELLigence real-time monitoring system. Results were confirmed histologically and verified with Live/Dead staining. All bisphosphonates inhibited THP-1 cell adherence and survival dose and time dependently, significant for zoledronate, alendronate, pamidronate, and clodronate in high concentrations (50 μM and 500 μM; P < .05). Low concentrations (0.5 μM) of risedronate, alendronate, and pamidronate prolonged the inflexion points of THP-1 cell survival compared with controls (P < .05). THP-1 cells exhibited no cytomorphologic changes at all concentrations. Commonly prescribed bisphosphonates inhibit the survival of macrophagic THP-1 cells dose-dependently without altering morphology. This may suggest a local immune dysfunction reflective of individual bisphosphonate potency leading to the pathogenesis of BRONJ. Copyright © 2016 Elsevier Inc. All rights reserved.

Rheumatoid Arthritis Exacerbates the Severity of Osteonecrosis of the Jaws (ONJ) in Mice. A Randomized, Prospective, Controlled Animal Study.

PubMed

de Molon, Rafael Scaf; Hsu, Chingyun; Bezouglaia, Olga; Dry, Sarah M; Pirih, Flavia Q; Soundia, Akrivoula; Cunha, Fernando Queiroz; Cirelli, Joni Augusto; Aghaloo, Tara L; Tetradis, Sotirios

2016-08-01

Rheumatoid arthritis (RA), an autoimmune inflammatory disorder, results in persistent synovitis with severe bone and cartilage destruction. Bisphosphonates (BPs) are often utilized in RA patients to reduce bone destruction and manage osteoporosis. However, BPs, especially at high doses, are associated with osteonecrosis of the jaw (ONJ). Here, utilizing previously published ONJ animal models, we are exploring interactions between RA and ONJ incidence and severity. DBA1/J mice were divided into four groups: control, zoledronic acid (ZA), collagen-induced arthritis (CIA), and CIA-ZA. Animals were pretreated with vehicle or ZA. Bovine collagen II emulsified in Freund's adjuvant was injected to induce arthritis (CIA) and the mandibular molar crowns were drilled to induce periapical disease. Vehicle or ZA treatment continued for 8 weeks. ONJ indices were measured by micro-CT (µCT) and histological examination of maxillae and mandibles. Arthritis development was assessed by visual scoring of paw swelling, and by µCT and histology of interphalangeal and knee joints. Maxillae and mandibles of control and CIA mice showed bone loss, periodontal ligament (PDL) space widening, lamina dura loss, and cortex thinning. ZA prevented these changes in both ZA and CIA-ZA groups. Epithelial to alveolar crest distance was increased in the control and CIA mice. This distance was preserved in ZA and CIA-ZA animals. Empty osteocytic lacunae and areas of osteonecrosis were present in ZA and CIA-ZA but more extensively in CIA-ZA animals, indicating more severe ONJ. CIA and CIA-ZA groups developed severe arthritis in the paws and knees. Interphalangeal and knee joints of CIA mice showed advanced bone destruction with cortical erosions and trabecular bone loss, and ZA treatment reduced these effects. Importantly, no osteonecrosis was noted adjacent to areas of articular inflammation in CIA-ZA mice. Our data suggest that ONJ burden was more pronounced in ZA treated CIA mice and that RA could be a risk factor for ONJ development. © 2016 American Society for Bone and Mineral Research. © 2016 American Society for Bone and Mineral Research.

TRAPEZE: a randomised controlled trial of the clinical effectiveness and cost-effectiveness of chemotherapy with zoledronic acid, strontium-89, or both, in men with bony metastatic castration-refractory prostate cancer.

PubMed

James, Nicholas; Pirrie, Sarah; Pope, Ann; Barton, Darren; Andronis, Lazaros; Goranitis, Ilias; Collins, Stuart; McLaren, Duncan; O'Sullivan, Joe; Parker, Chris; Porfiri, Emilio; Staffurth, John; Stanley, Andrew; Wylie, James; Beesley, Sharon; Birtle, Alison; Brown, Janet; Chakraborti, Prabir; Russell, Martin; Billingham, Lucinda

2016-07-01

Bony metastatic castration-refractory prostate cancer is associated with a poor prognosis and high morbidity. TRAPEZE was a two-by-two factorial randomised controlled trial of zoledronic acid (ZA) and strontium-89 (Sr-89), each combined with docetaxel. All have palliative benefits, are used to control bone symptoms and are used with docetaxel to prolong survival. ZA, approved on the basis of reducing skeletal-related events (SREs), is commonly combined with docetaxel in practice, although evidence of efficacy and cost-effectiveness is lacking. Sr-89, approved for controlling metastatic pain and reducing need for subsequent bone treatments, is generally palliatively used in patients unfit for chemotherapy. Phase II analysis confirmed the safety and feasibility of combining these agents. TRAPEZE aimed to determine the clinical effectiveness and cost-effectiveness of each agent. Patients were randomised to receive six cycles of docetaxel plus prednisolone: alone, with ZA, with a single Sr-89 dose after cycle 6, or with both. Primary outcomes were clinical progression-free survival (CPFS: time to pain progression, SRE or death) and cost-effectiveness. Secondary outcomes were SRE-free interval (SREFI), total SREs, overall survival (OS) and quality of life (QoL). Log-rank test and Cox regression modelling were used to determine clinical effectiveness. Cost-effectiveness was assessed from the NHS perspective and expressed as cost per additional quality-adjusted life-year (QALY). An additional analysis was carried out for ZA to reflect the availability of generic ZA. 757 randomised (median age 68.7 years; Eastern Cooperative Oncology Group scale score 0, 40%; 1, 52%; 2, 8%; prior radiotherapy, 45%); median prostate-specific antigen 143.78 ng/ml (interquartile range 50.8-353.9 ng/ml). Stratified log-rank analysis of CPFS was statistically non-significant for either agent (Sr-89, p = 0.11; ZA, p = 0.45). Cox regression analysis adjusted for stratification variables showed CPFS benefit for Sr-89 [hazard ratio (HR) 0.845, 95% confidence interval (CI) 0.72 to 0.99; p = 0.036] and confirmed no effect of ZA (p = 0.46). ZA showed a significant SREFI effect (HR 0.76; 95% CI 0.63 to 0.93; p = 0.008). Neither agent affected OS (Sr-89, p = 0.74; ZA, p = 0.91), but both increased total cost (vs. no ZA and no Sr-89, respectively); decreased post-trial therapies partly offset costs [net difference: Sr-89 £1341; proprietary ZA (Zometa(®), East Hanover, NJ, USA) £1319; generic ZA £251]. QoL was maintained in all trial arms; Sr-89 (0.08 additional QALYs) and ZA (0.03 additional QALYs) showed slight improvements. The resulting incremental cost-effectiveness ratio (ICER) for Sr-89 was £16,590, with £42,047 per QALY for Zometa and £8005 per QALY for generic ZA. Strontium-89 improved CPFS, but not OS. ZA did not improve CPFS or OS but significantly improved SREFI, mostly post progression, suggesting a role as post-chemotherapy maintenance therapy. QoL was well maintained in all treatment arms, with differing patterns of care resulting from the effects of Sr-89 on time to progression and ZA on SREFI and total SREs. The addition of Sr-89 resulted in additional cost and a small positive increase in QALYs, with an ICER below the £20,000 ceiling per QALY. The additional costs and small positive QALY changes in favour of ZA resulted in ICERs of £42,047 (Zometa) and £8005 for the generic alternative; thus, generic ZA represents a cost-effective option. Additional analyses on the basis of data from the Hospital Episode Statistics data set would allow corroborating the findings of this study. Further research into the use of ZA (and other bone-targeting therapies) with newer prostate cancer therapies would be desirable. Current Controlled Trials ISRCTN12808747. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 53. See the NIHR Journals Library website for further project information.

Prevention and treatment of bone fragility in cancer patient

PubMed Central

Ottanelli, Silva

2015-01-01

Summary It is well known that fractures increase the risk of morbidity and mortality. The various mechanisms responsible for bone loss in cancer patients may have a different impact depending on the characteristics of the clinical case and correlates with the therapies used, or caused by the therapies used against cancer. Some hormonal treatments cause hypogonadism, event which contributes to the progressive loss of bone mass. This is detectable in patients with breast cancer receiving determines that estrogen-deprivation and in men with prostate cancer with therapies that determine androgen deprivation. Chemotherapy treatments used in cancer patients have reduced bone mass. In addition, low bone mass is detectable in patients with lymphoma treated with corticosteroids or radiation or alkylating agents. In premenopausal patients suffering from breast cancer, treatment with cytotoxic therapy or ablation of ovarian function, can lead to an 8% reduction in bone mineral density at the spine and 4% in the femur. With a chemotherapy regimen in CMF, the reduction of BMD is 6.5%; this bone loss is not recovered after discontinuation of therapy. Tamoxifen given for five years reduces bone remodeling and cause a 32% increase in the risk of osteoporotic fractures when used in premenopausal. After menopause, tamoxifen has a protective effect on bone mass, with a reduced risk of new fractures. Aromatase inhibitors in post-menopausal women, depending on the formulation can cause different effects on the reduction of BMD and fracture risk. We have in fact steroids, exemestane and nonsteroidal, letrozole and anastrozole. Patients at increased risk of fragility fractures should undergo preventive therapies as soon as possible after tests performed for the study of bone health. They can be used DEXA and the FRAX algorithm, which can define a secondary osteoporosis. Prevention and treatment of the increased risk of osteoporotic fracture is to maintain adequate levels of calcium and vitamin D. Bisphosphonates and denosumab are used for the management of bone remodeling and bone loss induced by cancer treatments. Bisphosphonates also have anti-tumor effects per se, which are expressed in potentially prevent the development of bone metastases. In men with metastatic prostate cancer and which is induced androgen deprivation, it is usefully used denosumab 120 mg monthly or zoledronic acid 4 mg monthly. PMID:26604936

Effects of Bisphosphonates and Calcium plus Vitamin-D Supplements on Cognitive Function in Postmenopausal Osteoporosis§.

PubMed

Safer, Umut; Safer, Vildan Binay; Demir, Sibel Ozbudak; Yanikoglu, Inci

2016-01-01

Postmenopausal osteoporosis has been linked to accelerated cognitive decline; however, little is known about the effects of medical treatment on cognitive functions. In this prospective study, we evaluated the effects of bisphosphonate treatment and calcium plus vitamin D supplementation on cognitive functions in 45 women with postmenopausal osteoporosis who were started on medical treatment. The medications included alendronate, zoledronic acid, risedronate, or ibandronic acid along with a low or high dose of calcium plus vitamin D supplements. The cognitive function was assessed by the mini-mental state examination (MMSE) test. All subjects underwent bone mineral density (BMD) measurement via dual-energy X-ray absorptiometry at baseline and at study completion. The mean T-score improved significantly at 1 year, except for neck of the femur area. The mean MMSE score did not change significantly at 12 months (26.40 ± 2.07 vs. 26.48 ± 2.07; p = 0.513), with no difference among bisphosphonates combined with calcium plus vitamin D. Higher dose (1200 mg/800 U/day) of calcium plus vitamin D supplementation tended to have a greater improvement as compared with lower dose (600 mg/400 U/day) (Δ MMSE: 0.11 ± 0.72 vs. -0.14 ± 0.69). Cognitive functions in the women remained unaltered, whereas bone BMD T-scores were significantly improved at the 12(th) month after the administration of bisphosphonates and calcium plus vitamin D supplements. Higher doses of calcium plus vitamin D supplements were likely to have better cognitive effects as compared with lower doses.

Fracture during intravenous bisphosphonate treatment in a child with osteogenesis imperfecta: an argument for a more frequent, low-dose treatment regimen.

PubMed

Biggin, Andrew; Briody, Julie N; Ormshaw, Elizabeth; Wong, Karen K Y; Bennetts, Bruce H; Munns, Craig F

2014-01-01

Intravenous bisphosphonate therapy is the mainstay of medical treatment in osteogenesis imperfecta (OI) and has been shown to increase bone mass, decrease bone pain, improve mobility, and reduce the incidence of fractures. Sclerotic metaphyseal lines parallel to the growth plate are seen on long bone radiographs following cyclical intravenous therapy. These areas create stress risers within the bone that may act as foci for subsequent fractures as exemplified in this clinical case. An 8-year-old girl with OI sustained a distal radial fracture following 3 years of treatment with 6-monthly intravenous zoledronate. Her diagnosis, response to treatment, and subsequent fracture at a sclerotic metaphyseal line is described. Peripheral quantitative computer tomography was used to characterise the presence of multiple stress risers at the distal forearm. Trabecular bone mineral density fluctuated from 34 to 126% compared to neighbouring 2-mm regions. There remain many unanswered questions about optimal bisphosphonate treatment regimens in children with OI. The formation of stress risers following intravenous bisphosphonate treatment raises the hypothesis that a more frequent and low-dose bisphosphonate regimen would provide more uniform dosing of bone in the growing child and reduce the likelihood of fractures compared to current treatment practices.

[Bone diseases].

PubMed

Uebelhart, Brigitte; Rizzoli, René

2016-01-13

Calcium intake shows a small impact on bone mineral density and fracture risk. Denosumab is a more potent inhibitor of bone resorption than zoledronate. Abaloparatide, PTHrP analog, increases bone mineral density and decreases fracture incidence. Teriparatide could be delivered via a transdermic device. Romosozumab and odanacatib improve calculated bone strength. Sequential or combined treatments with denosumab and teriparatide could be of interest, but not denosumab followed by teriparatide. Fibrous dysplasia, Paget disease and hypophosphatasia are updated, as well as atypical femoral fracture and osteonecrosis of the jaw.

Aromatase Inhibitors and Bone Loss

PubMed Central

PEREZ, EDITH A.; M., Serene; Durling, Frances C.; WEILBAECHER, KATHERINE

2009-01-01

The aromatase inhibitors (AIs) anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are significantly more effective than the selective estrogen-receptor modulator (SERM) tamoxifen in preventing recurrence in estrogen receptor–positive early breast cancer. Aromatase inhibitors are likely to replace SERMs as first-line adjuvant therapy for many patients. However, AIs are associated with significantly more osteoporotic fractures and greater bone mineral loss. As antiresorptive agents, oral and intravenous bisphosphonates such as alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), pamidronate (Aredia), and zoledronic acid (Zometa) have efficacy in preventing postmenopausal osteoporosis, cancer treatment–related bone loss, or skeletal complications of metastatic disease. Clinical practice guidelines recommend baseline and annual follow-up bone density monitoring for all patients initiating AI therapy. Bisphosphonate therapy should be prescribed for patients with osteoporosis (T score < −2.5) and considered on an individual basis for those with osteopenia (T score < −1). Modifiable lifestyle behaviors including adequate calcium and vitamin D intake, weight-bearing exercise, and smoking cessation should be addressed. Adverse events associated with bisphosphonates include gastrointestinal toxicity, renal toxicity, and osteonecrosis of the jaw. These safety concerns should be balanced with the potential of bisphosphonates to minimize or prevent the debilitating effects of AI-associated bone loss in patients with early, hormone receptor–positive breast cancer. PMID:16986348

HTLV-1 Tax transgenic mice develop spontaneous osteolytic bone metastases prevented by osteoclast inhibition

PubMed Central

Gao, Ling; Deng, Hongju; Zhao, Haibo; Hirbe, Angela; Harding, John; Ratner, Lee; Weilbaecher, Katherine

2005-01-01

One in 20 carriers of human T-cell leukemia virus type 1 (HTLV-1) will develop adult T-cell leukemia/lymphoma (ATL), a disease frequently associated with hypercalcemia, bone destruction, and a fatal course refractory to current therapies. Overexpression of the HTLV-1–encoded Tax oncoprotein under the human granzyme B promoter causes large granular lymphocytic leukemia/lymphomas in mice. We found that Tax+ mice spontaneously developed hypercalcemia, high-frequency osteolytic bone metastases, and enhanced osteoclast activity. We evaluated Tax tumors for the production of osteoclast-activating factors. Purification of Tax+ tumor cells and nonmalignant tumor-infiltrating lymphocytes demonstrated that each of these populations expressed transcripts for distinct osteoclast-activating factors. We then evaluated the effect of osteoclast inhibition on tumor formation. Mice doubly transgenic for Tax and the osteoclast inhibitory factor, osteoprotegerin, were protected from osteolytic bone disease and developed fewer soft-tissue tumors. Likewise, osteoclast inhibition with bone-targeted zoledronic acid protected Tax+ mice from bone and soft-tissue tumors and prolonged survival. Tax+ mice represent the first animal model of high-penetrance spontaneous osteolytic bone metastasis and underscore the critical role of nonmalignant host cells recruited by tumor cells in the process of cancer progression and metastasis. PMID:16118323

Synergistic Phytochemicals Fail to Protect Against Ovariectomy Induced Bone Loss in Rats.

PubMed

Ambati, Suresh; Miller, Colette N; Bass, Erica F; Hohos, Natalie M; Hartzell, Diane L; Kelso, Emily W; Trunnell, Emily R; Yang, Jeong-Yeh; Della-Fera, Mary Anne; Baile, Clifton A; Rayalam, Srujana

2018-05-24

Menopause induces a loss of bone as a result of estrogen deficiency. Despite pharmaceutical options for the treatment of osteopenia and osteoporosis, many aging women use dietary supplements with estrogenic activity to prevent bone loss and other menopausal-related symptoms. Such supplements are yet to be tested for efficacy against a Food and Drug Administration (FDA) approved medication for menopausal bone loss such as zoledronic acid (ZA). The postmenopausal rat model was used to investigate the efficacy of various synergistic phytochemical blends mixed into the diet for 16 weeks. Retired-breeder, Fischer 344 rats were randomly assigned to sham or ovariectomy surgery and 4 treatment groups: ZA; genistein supplementation; and a low dose and high dose blend of genistein, resveratrol, and quercetin. Ovariectomy resulted in a loss of both trabecular and cortical bone which was prevented with ZA. The phytochemical blends tested were unable to reverse these losses. Despite the lack of effectiveness in preventing bone loss, a significant dose-response trend was observed in the phytochemical-rich diets in bone adipocyte number compared to ovariectomized control rats. Data from this study indicate that estrogenic phytochemicals are not as efficacious as ZA in preventing menopausal-related bone loss but may have beneficial effects on bone marrow adiposity in rats.

Clinical outcome for patients of solitary bone only metastasis.

PubMed

Hosaka, Seiichi; Katagiri, Hirohisa; Honda, Yosuke; Wasa, Junji; Murata, Hideki; Takahashi, Mitsuru

2016-03-01

Solitary bone only metastasis (SBOM) is a rare condition in which metastasis is limited to a single skeletal lesion originating from a previously treated or controllable primary lesion. The study objective was to evaluate the clinical features and survival regarding this rare condition and to clarify its treatment strategy. A total of 1453 patients with bone metastasis registered in our hospital database were enrolled. To assess the primary and/or metastatic lesion we used plain X-ray images, CT, MRI and FDG-PET scans as well as bone scans. Among the patients, only 27 (1.8%) had SBOM. The primary cancers responsible for SBOM were lung in seven patients, breast in five, kidney in four, prostate in two, uterus in two and other types in seven. Treatment of SBOM involved resection in four patients, radiotherapy only in 17, radiotherapy in combination with zoledronate in six and chemotherapy with zoledronate in one. Local recurrence did not develop in the four cases treated with resection. However, in-field recurrence was found in 4 of 22 (18%) patients who underwent radiotherapy. All three patients who received >40 Gy did not develop in-field recurrence. The overall and event free survival rates at 5 years were 63% and 41%, respectively. Solitary bone only metastasis should be treated with wide resection or long-course radiotherapy at doses 40-50 Gy to achieve long lasting local tumor control. Copyright © 2015 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.

Vγ9Vδ2 T cells and zoledronate mediate antitumor activity in an orthotopic mouse model of human chondrosarcoma.

PubMed

Sun, L; Li, Y; Jiang, Z; Zhang, J; Li, H; Li, B; Ye, Z

2016-06-01

Chondrosarcoma (CS) is a cartilaginous malignant neoplasm characterized by resistance to conventional adjuvant therapy. The prognosis of unresectable or metastatic CS is poor. Therefore, it is imperative to explore novel therapeutic approaches to improve the treatment efficacy for those CS patients. Emerging data has implicated the synergistic antitumor activity of zoledronate (ZOL) and Vγ9Vδ2 T cells. However, whether ZOL-stimulated Vγ9Vδ2 T cells could infiltrate bone sarcoma and inhibit tumor growth has not been thoroughly answered yet. In this study, Vγ9Vδ2 T cells from healthy donors and CS patients were expanded in the presence of ZOL (1 μM) and IL-2 (400 IU/ml). The antitumor activity of Vγ9Vδ2 T cells to ZOL-pretreated human CS was examined both in vitro and in vivo. ZOL pretreatment substantially enhanced the cytotoxicity of Vγ9Vδ2 T cells to SW1353 and primary CS cells. ZOL potentiated the migration and cytotoxicity of Vγ9Vδ2 T cells to SW1353 in dose- and time-dependent manner. Moreover, weekly intravenous ZOL followed by Vγ9Vδ2 T cells inhibited subcutaneous xenograft growth. Thus, Vγ9Vδ2 T cells were able to infiltrate bone tumor and significantly suppressed the development of orthotopic SW1353 xenografts. Altogether, the study raises the possibility of combining ZOL with Vγ9Vδ2 T cells for CS treatment.

The long-term effects of switching from active intravenous bisphosphonate treatment to low-dose maintenance therapy in children with osteogenesis imperfecta.

PubMed

Biggin, Andrew; Zheng, Linda; Briody, Julie N; Coorey, Craig P; Munns, Craig F

2015-01-01

Intravenous bisphosphonate therapy is the first-line treatment in moderate-to-severe osteogenesis imperfecta (OI), but there are varied treatment protocols with little data on long-term efficacy. This study evaluates the clinical outcomes when transitioning from active bisphosphonate treatment to maintenance therapy. A retrospective review was conducted on 17 patients before treatment, following active treatment (zoledronate 0.05 mg/kg 6-monthly or pamidronate 6-9 mg/kg/year) and after establishment on maintenance treatment for more than 2 years (zoledronate 0.025 mg/kg 6-monthly or pamidronate <4 mg/kg/year). There was a significant reduction in mean fracture rate from 1.5 ± 1.1 fractures/year at baseline to 0.7 ± 0.7 fractures/year on active treatment. Z-scores for lumbar spine bone mineral density, bone mineral content, volumetric bone mineral density and bone mineral content for lean tissue mass increased during active treatment. These improvements were maintained during the period of maintenance treatment. Vertebral height improved in fractured thoracic vertebrae from pre-treatment to active therapy and improved further during maintenance treatment. Metacarpal cortical thickness and relative cortical area also increased over the treatment periods. Maintenance intravenous bisphosphonate therapy preserved the beneficial effects of active treatment at the doses stated above. Further studies are required to determine the optimal bisphosphonate treatment regimen in the management of children with OI. © 2015 S. Karger AG, Basel.

Bisphosphonate induced hypocalcaemia - report of six cases and review of the literature.

PubMed

Kreutle, Veronika; Blum, Claudine; Meier, Christian; Past, Miriam; Müller, Beat; Schütz, Philipp; Borm, Katrin

2014-01-01

Intravenous bisphosphonates are widely used to treat osteoporosis and bone metastasis in cancer patients The risk of hypocalcaemia is a rare but underestimated side effect of anti-resorptive treatment. Clinically apparent hypocalcaemia is mostly related to high-dose treatment with zoledronate and denosumab in cancer patients Particular caution is mandatory in all malnourished patients and patients with renal failure who are treated for either bone metastases or osteoporosis. To avoid serious hypocalcaemia, pre-treatment calcium and vitamin D status should be assessed and corrected if appropriate.

Radiation dose escalation or longer androgen suppression for locally advanced prostate cancer? Data from the TROG 03.04 RADAR trial.

PubMed

Denham, James W; Steigler, Allison; Joseph, David; Lamb, David S; Spry, Nigel A; Duchesne, Gillian; Atkinson, Chris; Matthews, John; Turner, Sandra; Kenny, Lizbeth; Tai, Keen-Hun; Gogna, Nirdosh Kumar; Gill, Suki; Tan, Hendrick; Kearvell, Rachel; Murray, Judy; Ebert, Martin; Haworth, Annette; Kennedy, Angel; Delahunt, Brett; Oldmeadow, Christopher; Holliday, Elizabeth G; Attia, John

2015-06-01

The relative effects of radiation dose escalation (RDE) and androgen suppression (AS) duration on local prostatic progression (LP) remain unclear. We addressed this in the TROG 03.04 RADAR trial by incorporating a RDE programme by stratification at randomisation. Men were allocated 6 or 18 months AS±18 months zoledronate (Z). The main endpoint was a composite of clinically diagnosed LP or PSA progression with a PSA doubling time ⩾6 months. Fine and Gray competing risk modelling with adjustment for site clustering produced cumulative incidence estimates at 6.5 years for each RDE group. Composite LP declined coherently in the 66, 70 and 74 Gy external beam dosing groups and was lowest in the high dose rate brachytherapy boost (HDRB) group. At 6.5 years, adjusted cumulative incidences were 22%, 15%, 13% and 7% respectively. Compared to 6 months AS, 18 months AS also significantly reduced LP (p<0.001). Post-radiation urethral strictures were documented in 45 subjects and increased incrementally in the dosing groups. Crude incidences were 0.8%, 0.9%, 3.8% and 12.7% respectively. RDE and increasing AS independently reduce LP and increase urethral strictures. The risks and benefits to the individual must be balanced when selecting radiation dose and AS duration. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Gateways to clinical trials.

PubMed

Tomillero, A; Moral, M A

2010-06-01

[¹¹C]RAC; (18)F-Fluoromisonidazole; 89-12; 9-[¹⁸F]Fluoropropyl-(+)-dihydrotetrabenazine; Adalimumab, Adecatumumab, ADMVA, ADXS-11-001, Aflibercept, Agatolimod sodium, AGS-004, Alglucosidase alfa, Aliskiren fumarate, Alvocidib hydrochloride, AMG-108, AMG-853, Apixaban, Aripiprazole, Armodafinil, Atazanavir sulfate, Atomoxetine hydrochloride; Bevacizumab, BioMatrix Flex drug eluting stent, Biphasic insulin aspart, Bortezomib, Bosentan; Caspofungin acetate, Cediranib, Cetuximab, ChimeriVax-Dengue, Choriogonadotropin alfa, Cinacalcet hydrochloride, Cizolirtine citrate, Clofarabine, Cocaine conjugate vaccine, CX-717; Darbepoetin alfa, Dasatinib, Decitabine, Denosumab, Desvenlafaxine succinate, Dexamethasone sodium phosphate, Dienogest, Diphencyprone, Doripenem, DTaP-HepB-IPV, Dutasteride; E-7010, Ecallantide, Ecstasy, Eicosapentaenoic acid/docosahexaenoic acid, Emtricitabine, Enfuvirtide, Erlotinib hydrochloride, Eszopiclone, Etonogestrel/ethinyl estradiol, Etoricoxib, Everolimus, Everolimus-eluting coronary stent EVT-201, Ezetimibe, Ezetimibe/simvastatin; Ferumoxytol, Fesoterodine fumavate, Figitumumab, Filgrastim, Fingolimod hydrochloride, Fluticasone furoate, Fluval P, Fluzone, Fondaparinux sodium, Fulvestrant, Fungichromin; Gamma-hydroxybutyrate sodium, Gefitinib, GHB-01L1, GLY-230, GSK-1349572; Hib-MenCY-TT, Hib-TT, HPV-6/11/16/18, Hydrocodone bitartrate; IC-51, Icatibant acetate, Imatinib mesylate, Immunoglobulin intravenous (human), Indetanib, Influenza A (H1N1) 2009 Monovalent Vaccine, Inhalable human insulin, Insulin glargine, Insulin glulisine, Interferon-beta, Ispinesib mesylate, Ixabepilone; Laromustine, Latanoprost/timolol maleate, L-Citrulline, Lenalidomide, Lexatumumab, Linezolid, Lopinavir/ritonavir, Lutropin alfa; Mapatumumab, MDX-066, MDX-1388, Mepolizumab, Methoxy polyethylene glycol-epoetin-beta, Metreleptin, Micafungin sodium, Mometasone furoate/oxymetazoline hydrochloride, Mx-dnG1, Mycophenolic acid sodium salt; Nabiximols, Natalizumab, Nemonoxacin, Norelgestromin/ethinyl estradiol; Oblimersen sodium, Ocriplasmin, Olmesartan medoxomil, Omacetaxine mepesuccinate; Paclitaxel-eluting stent, Pagoclone, Paliperidone, Panitumumab, Pazopanib hydrochloride, PCV7, Pegaptanib octasodium, Peginterferon alfa-2a, Peginterferon alfa-2b/ ribavirin, Pegvisomant, Pemetrexed disodium, Perifosine, Pimecrolimus, Pitavastatin calcium, Plerixafor hydrochloride, Plitidepsin, Posaconazole, Pregabalin, Progesterone capriate; Raltegravir potassium, Ramucirumab, Ranelic acid distrontium salt, Rasburicase, Recombinant Bet V1, Recombinant human insulin, rhFSH, Rolofylline, Romidepsin, Romiplostim, Rosuvastatin calcium; Sapacitabine, Sevelamer carbonate, Sinecatechins, Sirolimus-eluting stent, Sitagliptin phosphate monohydrate, SN-29244, Sorafenib, Sugammadex sodium, Sunitinib malate; Tadalafil, Tafenoquine, Talnetant, Tanezumab, Tapentadol hydrochloride, Tasocitinib citrate, Technosphere/Insulin, Telcagepant, Tenofovir disoproxil fumarate, Teriparatide, Ticagrelor, Tigecycline, Tiotropium bromide, Tipifarnib, Tocilizumab, TS-041; Ulipristal acetate, Urtoxazumab, Ustekinumab; Vandetanib, Varenicline tartrate, Vicriviroc, Voriconazole, Vorinostat, VRC-HIVADV014-00-VP, VRC-HIVDNA016-00-VP; Zoledronic acid monohydrate. Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

Characterizing the composition of bone formed during fracture healing using scanning electron microscopy techniques.

PubMed

Perdikouri, Christina; Tägil, Magnus; Isaksson, Hanna

2015-01-01

About 5-10% of all bone fractures suffer from delayed healing, which may lead to non-union. Bone morphogenetic proteins (BMPs) can be used to induce differentiation of osteoblasts and enhance the formation of the bony callus, and bisphosphonates help to retain the newly formed callus. The aim of this study was to investigate if scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS) can identify differences in the mineral composition of the newly formed bone compared to cortical bone from a non-fractured control. Moreover, we investigate whether the use of BMPs and bisphosphonates-alone or combined-may have an effect on bone mineralization and composition. Twelve male Sprague-Dawley rats at 9 weeks of age were randomly divided into four groups and treated with (A) saline, (B) BMP-7, (C) bisphosphonates (Zoledronate), and (D) BMP-7 + Zoledronate. The rats were sacrificed after 6 weeks. All samples were imaged using SEM and chemically analyzed with EDS to quantify the amount of C, N, Ca, P, O, Na, and Mg. The Ca/P ratio was the primary outcome. In the fractured samples, two areas of interest were chosen for chemical analysis with EDS: the callus and the cortical bone. In the non-fractured samples, only the cortex was analyzed. Our results showed that the element composition varied to a small extent between the callus and the cortical bone in the fractured bones. However, the Ca/P ratio did not differ significantly, suggesting that the mineralization at all sites is similar 6 weeks post-fracture in this rat model.

Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update From the American College of Physicians.

PubMed

Qaseem, Amir; Forciea, Mary Ann; McLean, Robert M; Denberg, Thomas D

2017-06-06

This guideline updates the 2008 American College of Physicians (ACP) recommendations on treatment of low bone density and osteoporosis to prevent fractures in men and women. This guideline is endorsed by the American Academy of Family Physicians. The ACP Clinical Guidelines Committee based these recommendations on a systematic review of randomized controlled trials; systematic reviews; large observational studies (for adverse events); and case reports (for rare events) that were published between 2 January 2005 and 3 June 2011. The review was updated to July 2016 by using a machine-learning method, and a limited update to October 2016 was done. Clinical outcomes evaluated were fractures and adverse events. This guideline focuses on the comparative benefits and risks of short- and long-term pharmacologic treatments for low bone density, including pharmaceutical prescriptions, calcium, vitamin D, and estrogen. Evidence was graded according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. The target audience for this guideline includes all clinicians. The target patient population includes men and women with low bone density and osteoporosis. ACP recommends that clinicians offer pharmacologic treatment with alendronate, risedronate, zoledronic acid, or denosumab to reduce the risk for hip and vertebral fractures in women who have known osteoporosis. (Grade: strong recommendation; high-quality evidence). ACP recommends that clinicians treat osteoporotic women with pharmacologic therapy for 5 years. (Grade: weak recommendation; low-quality evidence). ACP recommends that clinicians offer pharmacologic treatment with bisphosphonates to reduce the risk for vertebral fracture in men who have clinically recognized osteoporosis. (Grade: weak recommendation; low-quality evidence). ACP recommends against bone density monitoring during the 5-year pharmacologic treatment period for osteoporosis in women. (Grade: weak recommendation; low-quality evidence). ACP recommends against using menopausal estrogen therapy or menopausal estrogen plus progestogen therapy or raloxifene for the treatment of osteoporosis in women. (Grade: strong recommendation; moderate-quality evidence). ACP recommends that clinicians should make the decision whether to treat osteopenic women 65 years of age or older who are at a high risk for fracture based on a discussion of patient preferences, fracture risk profile, and benefits, harms, and costs of medications. (Grade: weak recommendation; low-quality evidence).

Osteoclast inhibition impairs chondrosarcoma growth and bone destruction.

PubMed

Otero, Jesse E; Stevens, Jeff W; Malandra, Allison E; Fredericks, Douglas C; Odgren, Paul R; Buckwalter, Joseph A; Morcuende, Jose

2014-12-01

Because Chondrosarcoma is resistant to available chemotherapy and radiation regimens, wide resection is the mainstay in treatment, which frequently results in high morbidity and which may not prevent local recurrence. There is a clear need for improved adjuvant treatment of this malignancy. We have observed the presence of osteoclasts in the microenvironment of chondrosarcoma in human pathological specimens. We utilized the Swarm rat chondrosarcoma (SRC) model to test the hypothesis that osteoclasts affect chondrosarcoma pathogenesis. We implanted SRC tumors in tibia of Sprague-Dawley rats and analyzed bone histologically and radiographically for bone destruction and tumor growth. At three weeks, tumors invaded local bone causing cortical disruption and trabecular resorption. Bone destruction was accompanied by increased osteoclast number and resorbed bone surface. Treatment of rats with the zoledronic acid prevented cortical destruction, inhibited trabecular resorption, and resulted in decreased tumor volume in bone. To confirm that inhibition of osteoclasts per se, and not off-target effects of drug, was responsible for the prevention of tumor growth and bone destruction, we implanted SRC into osteopetrotic rat tibia. SRC-induced bone destruction and tumor growth were impaired in osteopetrotic bone compared with control bone. The results from our animal model demonstrate that osteoclasts contribute to chondrosarcoma-mediated bone destruction and tumor growth and may represent a therapeutic target in particular chondrosarcoma patients. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Medication-related osteonecrosis of the jaw. Introduction of a new modified experimental model.

PubMed

Curra, Cláudia; Cardoso, Camila Lopes; Ferreira, Osny; Curi, Marcos Martins; Matsumoto, Mariza Akemi; Cavenago, Bruno Cavalini; Santos, Pâmela Letícia Dos; Santiago, Joel Ferreira

2016-05-01

To evaluate a modified experimental model for medication-related osteonecrosis of the jaw (MRONJ) through the upper right central incisor extraction followed by intravenous bisphosphonate administration. Forty five rats underwent the upper right central incisor tooth extraction were divided in 2 groups: Group I - experimental group, 30 rats received an intravenous administration protocol of zoledronic acid 35μg/kg into the tail vein every two weeks, totalizing four administrations, during eight weeks of administration, previously the extraction, and Group II - control group, 15 rats didn't received any medication before extraction. The groups were subdivided in postoperative periods: 14/28/42 days. Clinical analysis and microtomography were performed to verify the presence of osteonecrosis. In addition, descritive histological analysis of hematoxylin-eosin stained sections was performed to evaluate the presence of osteonecrosis or necrotic foci. Twelve (40%) rats, from experimental group, showed clinical signs of MRONJ (p=0.005), however, all samples showed imaginologic findings like osteolysis and loss of integrity of the cellular walls (p≤0.001). Microscopic evaluation revealed osteonecrosis areas with microbial colonies and inflammatory infiltrate (p≤0.001). In the control group, all animals presented the chronology of a normal wound healing. The presence of medication-related osteonecrosis of the jaw after maxillary central incisor extraction in rats. This new experimental model may be considered an option for the study of MRONJ.

How rebates, copayments, and administration costs affect the cost-effectiveness of osteoporosis therapies.

PubMed

Ferko, Nicole C; Borisova, Natalie; Airia, Parisa; Grima, Daniel T; Thompson, Melissa F

2012-11-01

Because of rising drug expenditures, cost considerations have become essential, necessitating the requirement for cost-effectiveness analyses for managed care organizations (MCOs). The study objective is to examine the impact of various drug-cost components, in addition to wholesale acquisition cost (WAC), on the cost-effectiveness of osteoporosis therapies. A Markov model of osteoporosis was used to exemplify different drug cost scenarios. We examined the effect of varying rebates for oral bisphosphonates--risedronate and ibandronate--as well as considering the impact of varying copayments and administration costs for intravenous zoledronate. The population modeled was 1,000 American women, > or = 50 years with osteoporosis. Patients were followed for 1 year to reflect an annual budget review of formularies by MCOs. The cost of therapy was based on an adjusted WAC, and is referred to as net drug cost. The total annual cost incurred by an MCO for each drug regimen was calculated using the net drug cost and fracture cost. We estimated cost on a quality adjusted life year (QALY) basis. When considering different rebates, results for risedronate versus ibandronate vary from cost-savings (i.e., costs less and more effective) to approximately $70,000 per QALY. With no risedronate rebate, an ibandronate rebate of approximately 65% is required before cost per QALY surpasses $50,000. With rebates greater than 25% for risedronate, irrespective of ibandronate rebates, results become cost-saving. Results also showed the magnitude of cost savings to the MCO varied by as much as 65% when considering no administration cost and the highest coinsurance rate for zoledronate. Our study showed that cost-effectiveness varies considerably when factors in addition to the WAC are considered. This paper provides recommendations for pharmaceutical manufacturers and MCOs when developing and interpreting such analyses.

Zoledronate prevents lactation induced bone loss and results in additional post-lactation bone mass in mice.

PubMed

Wendelboe, Mette Høegh; Thomsen, Jesper Skovhus; Henriksen, Kim; Vegger, Jens Bay; Brüel, Annemarie

2016-06-01

In rodents, lactation is associated with a considerable and very rapid bone loss, which almost completely recovers after weaning. The aim of the present study was to investigate whether the bisphosphonate Zoledronate (Zln) can inhibit lactation induced bone loss, and if Zln interferes with recovery of bone mass after lactation has ceased. Seventy-six 10-weeks-old NMRI mice were divided into the following groups: Baseline, Pregnant, Lactation, Lactation+Zln, Recovery, Recovery+Zln, and Virgin Control (age-matched). The lactation period was 12days, then the pups were removed, and thereafter recovery took place for 28days. Zln, 100μg/kg, was given s.c. on the day of delivery, and again 4 and 8days later. Mechanical testing, μCT, and dynamic histomorphometry were performed. At L4, lactation resulted in a substantial loss of bone strength (-55% vs. Pregnant, p<0.01), BV/TV (-40% vs. Pregnant, p<0.01), and trabecular thickness (Tb.Th) (-29% vs. Pregnant, p<0.001). Treatment with Zln completely prevented lactation induced loss of bone strength, BV/TV, and Tb.Th at L4. Full recovery of micro-architectural and mechanical properties was found 28days after weaning in vehicle-treated mice. Interestingly, the recovery group treated with Zln during the lactation period had higher BV/TV (+45%, p<0.01) and Tb.Th (+16%, p<0.05) compared with virgin controls. Similar results were found at the proximal tibia and femur. This indicates that Zln did not interfere with the bone formation taking place after weaning. On this background, we conclude that post-lactation bone formation is not dependent on a preceding lactation induced bone loss. Copyright © 2016 Elsevier Inc. All rights reserved.

The effect of zoledronate-containing primer on dentin bonding of a universal adhesive.

PubMed

Zenobi, Walter; Feitosa, Victor Pinheiro; Moura, Maria Elisa Martins; D'arcangelo, Camillo; Rodrigues, Lidiany Karla de Azevedo; Sauro, Salvatore

2018-01-01

To evaluate the bonding ability and nanoleakage of a universal adhesive applied to dentin pre-treated using a zoledronate-containing primer (zol-primer) before and after mechanical load cycling. Flat dentin surfaces obtained from human molars were assigned to one of the following adhesion procedures (n=6): 1-Single Bond Universal (SBU) applied in etch-and-rinse mode; 2- SBU applied as etch-and-rinse after the application of zol-primer; 3- SBU applied in self-etch strategy; 4- SBU applied as self-etch after the use of zol-primer. Half of the specimens were processed for microtensile bond strength test after 24h, while the other half part was submitted to 200,000 mechanical cycles. Further specimens were silver-impregnated and assessed for interface nanoleakage by SEM. Data were analyzed with two-way ANOVA and Tukey's test (p<0.05). At 24h evaluation, the four groups presented similar bond strengths, whilst both groups bonded with etch-and-rinse technique showed significant bond strength reduction after mechanical load (p<0.05), with the highest drop in bond strength for the specimens pre-treated with the zol-primer. No negative effects were found for self-etch strategy (p>0.05) in microtensile test. Lower nanoleakage expression was observed for etch-and-rinse specimens treated with zol-primer. However, noteworthy reduction of adhesive layer thickness was observed when combining the zol-primer with the self-etch bonding approach. It can be concluded that zol-primer should not be used along with a universal adhesive in etch-and-rinse mode, but its application before self-etch application may provide less degradation of the resin-dentin interface. Copyright © 2017 Elsevier Ltd. All rights reserved.

Efficacy of osteoporosis pharmacotherapies in preventing fracture among oral glucocorticoid users: a network meta-analysis.

PubMed

Amiche, M A; Albaum, J M; Tadrous, M; Pechlivanoglou, P; Lévesque, L E; Adachi, J D; Cadarette, S M

2016-06-01

Efficacy of osteoporosis medication is not well-established among patients taking oral glucocorticoids. We assessed the efficacy of approved osteoporosis pharmacotherapies in preventing fracture by combining data from randomized controlled trials. Teriparatide, risedronate, and etidronate were associated with decreased vertebral fracture risk. Several osteoporosis drugs are approved for the prevention and treatment of glucocorticoid (GC)-induced osteoporosis. However, the efficacy of these treatments among oral GC users is still limited. We aimed to examine the comparative efficacy of osteoporosis treatments among oral GC users. We updated a systematic review through to March 2015 to identify all double-blinded randomized controlled trials (RCTs) that examined osteoporosis treatment among oral GC users. We used a network meta-analysis with informative priors to derive comparative risk ratios (RRs) and 95 % credible intervals (95 % CrI) for vertebral and non-vertebral fracture and mean differences in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD). Treatment ranking was estimated using the surface under the cumulative ranking curve (SUCRA) statistic. A meta-regression was completed to assess a subgroup effect between patients with prior GC exposures and GC initiators. We identified 27 eligible RCTs examining nine active comparators. Etidronate (RR, 0.41; 95%CrI = 0.17-0.90), risedronate (RR = 0.30, 95%CrI = 0.14-0.61), and teriparatide (RR = 0.07, 95%CrI = 0.001-0.48) showed greater efficacy than placebo in preventing vertebral fractures; yet, no treatment effects were statistically significant in reducing non-vertebral fractures. Alendronate, risedronate, and etidronate increased LS BMD while alendronate and raloxifene increased FN BMD. In preventing vertebral fractures, teriparatide was ranked as the best treatment (SUCRA: 77 %), followed by risedronate (77 %) and zoledronic acid (76 %). For non-vertebral fractures, teriparatide also had the highest SUCRA (69 %), followed by risedronate (64 %). No subgroup effect was identified with regards to prior GC exposure. Despite weak trial evidence available for fracture prevention among GC users, we identified several drugs that are likely to prevent osteoporotic fracture. Teriparatide, risedronate, and etidronate were associated with decreased vertebral fracture risk.

Treatment of primary osteoporosis in men

PubMed Central

Giusti, Andrea; Bianchi, Gerolamo

2015-01-01

With the aging of the population worldwide, osteoporosis and osteoporotic fractures are becoming a serious health care issue in the Western world. Although less frequent than in women, osteoporosis in men is a relatively common problem. Hip and vertebral fractures are particularly relevant, being associated with significant mortality and disability. Since bone loss and fragility fractures in men have been recognized as serious medical conditions, several randomized controlled trials (RCTs) have been undertaken in males with osteoporosis to investigate the anti-fracture efficacy of the pharmacological agents commonly used to treat postmenopausal osteoporosis. Overall, treatments for osteoporosis in men are less defined than in women, mainly due to the fact that there are fewer RCTs performed in male populations, to the relatively smaller sample sizes, and to the lack of long-term extension studies. However, the key question is whether men are expected to respond differently to osteoporosis therapies than women. The pharmacological properties of bisphosphonates, teriparatide, denosumab, and strontium ranelate make such differentiation unlikely, and available clinical data support their efficacy in men with primary osteoporosis as well as in women. In a series of well-designed RCTs, alendronate, risedronate, zoledronic acid, and teriparatide were demonstrated to reduce the risk of new vertebral fractures in men presenting with primary osteoporosis (including osteoporosis associated with low testosterone levels) and to improve the bone mineral density (BMD). In preliminary studies, ibandronate, denosumab, and strontium ranelate also showed their beneficial effects on surrogate outcomes (BMD and markers of bone turnover) in men with osteoporosis. Although direct evidence about their non-vertebral anti-fracture efficacy are lacking, the effects of bisphosphonates, denosumab, teriparatide, and strontium ranelate on surrogate outcomes (BMD and markers of bone turnover) were similar to those reported in pivotal RCTs undertaken in postmenopausal women, in which vertebral and non-vertebral anti-fracture efficacy have been clearly demonstrated. In conclusion, sufficient data exist to support the use of these pharmacological agents in men with primary osteoporosis. Further RCTs are warranted to establish their long-term efficacy and safety. PMID:25565793

The efficacy of bisphosphonates in preventing aromatase inhibitor induced bone loss for postmenopausal women with early breast cancer: a systematic review and meta-analysis.

PubMed

Anagha, Pooleriveetil Padikkal; Sen, Suchandra

2014-01-01

Objectives. We aim to determine the efficacy of bisphosphonates in preventing aromatase inhibitor induced bone loss (AIBL) in postmenopausal women with early breast cancer. The secondary objective was to determine the safety of bisphosphonates. Materials and Methods. We searched electronic databases in a time period of 1995 January to 2013 June. Random effects meta-analytical models were used; between study heterogeneity and publication bias was assessed. Results. A total of six eligible studies reported the BMD T score of LS at 12 months and from that 3 trials of Zoledronic acid compared the change in BMD in immediate ZOL versus delayed ZOL done with subgroups like patients with normal BMD at baseline (OR = 5.402, 95% CI = 1.329-21.959, P value = 0.018) and osteopenic BMD at baseline (OR = 4.008, 95% CI = 2.249-7.143, P value = 0.0002). Both had a significant decrease in BMD that favoured the delayed ZOL; 3 trials of risedronate and ibandronate also had a significant decrease in BMD in AIs alone group. Immediate ZOL versus delayed ZOL also showed increased risk of getting an ADR in immediate group. Conclusion. Third generation bisphosphonates has an effect on BMD of patients who are on treatment of AIs in breast cancer. Furthermore, the patients treated with immediate ZOL had a significantly high risk of musculoskeletal ADR's than patients with delayed ZOL.

Tumor-targeting Salmonella typhimurium A1-R inhibits human prostate cancer experimental bone metastasis in mouse models.

PubMed

Toneri, Makoto; Miwa, Shinji; Zhang, Yong; Hu, Cameron; Yano, Shuya; Matsumoto, Yasunori; Bouvet, Michael; Nakanishi, Hayao; Hoffman, Robert M; Zhao, Ming

2015-10-13

Bone metastasis is a frequent occurrence in prostate cancer patients and often is lethal. Zoledronic acid (ZOL) is often used for bone metastasis with limited efficacy. More effective models and treatment methods are required to improve the outcome of prostate cancer patients. In the present study, the effects of tumor-targeting Salmonella typhimurium A1-R were analyzed in vitro and in vivo on prostate cancer cells and experimental bone metastasis. Both ZOL and S. typhimurium A1-R inhibited the growth of PC-3 cells expressing red fluorescent protien in vitro. To investigate the efficacy of S. typhimurium A1-R on prostate cancer experimental bone metastasis, we established models of both early and advanced stage bone metastasis. The mice were treated with ZOL, S. typhimurium A1-R, and combination therapy of both ZOL and S. typhimurium A1-R. ZOL and S. typhimurium A1-R inhibited the growth of solitary bone metastases. S. typhimurium A1-R treatment significantly decreased bone metastasis and delayed the appearance of PC-3 bone metastases of multiple mouse models. Additionally, S. typhimurium A1-R treatment significantly improved the overall survival of the mice with multiple bone metastases. The results of the present study indicate that S. typhimurium A1-R is useful to prevent and inhibit prostate cancer bone metastasis and has potential for future clinical use in the adjuvant setting.

Distinct effect of zoledronate and clodronate on circulating levels of DKK1 and sclerostin in women with postmenopausal osteoporosis.

PubMed

Gatti, Davide; Viapiana, Ombretta; Idolazzi, Luca; Fracassi, Elena; Ionescu, Claudio; Dartizio, Carmela; Troplini, Sonila; Kunnathully, Vidya; Adami, Silvano; Rossini, Maurizio

2014-10-01

The coupling of bone formation to bone resorption during treatment of postmenopausal osteoporosis with antiresorbers might be related to changes in Wnt/b-catenin signaling. We compared the effects of two bisphosphonate treatments on two Wnt-inhibitors Sclerostin (SOST) and Dickkopf-related protein 1 (DKK1). The study population included 74 women with postmenopausal osteoporosis participating simultaneously in two multicenter, placebo controlled trials. The patients were randomized to: intramuscular clodronate 100mg/week (CLO) (N=36), and yearly intravenous therapy with 5mg zoledronate (ZOL) (N=18) and placebo (N=20). Bone turnover markers (intact N-propeptide of type I collagen [P1NP], C-terminal telopeptide of type I collagen [CTX]) remained unchanged in the placebo group while they significantly decreased during treatment with the two bisphosphonates, versus both placebo and baseline. In CLO treated patients serum DKK1 remained stable over the entire period of observation while serum SOST levels increased significantly after 12months of treatment both versus placebo group (p<0,005), baseline (p<0,001) and ZOL treated group. In the ZOL group, DKK1 levels increased significantly within one month and for the following 6months and it fell back to baseline values at 12months. The second ZOL infusion was again associated with an increase in DKK1 a month later, although to a lesser extent. In conclusion, in this study we have found that the treatment of postmenopausal osteoporosis with intermittent yearly ZOL is associated with transient and declining increases in DKK1 while continuous treatment with CLO, results in a late increase in serum SOST. These preliminary results and further ad hoc studies might contribute to shed light on our understanding of the bone coupling effects taking place during treatment of osteoporosis with different anti-resorbers or with different treatment regimens. Copyright © 2014 Elsevier Inc. All rights reserved.

Influence of Japanese Regulatory Action on Denosumab-Related Hypocalcemia Using Japanese Adverse Drug Event Report Database.

PubMed

Takeyama, Mayu; Sai, Kimie; Imatoh, Takuya; Segawa, Katsunori; Hirasawa, Noriyasu; Saito, Yoshiro

2017-01-01

The anti-receptor activator of nuclear factor kappa-B ligand (RANKL) antibody, Denosumab (DEN), was approved in April 2012 in Japan, but a Dear Healthcare Professional Letter of Rapid Safety Communication was released in September, 2012 by the regulatory authority because of the severe hypocalcemia risks. Currently, the effectiveness of this regulatory action has not been evaluated and, therefore, this study aimed to assess its impact on DEN-induced hypocalcemia using the Japanese Adverse Drug Event Report database (JADER). The case reports from April 2012 to September 2014 were collected from the JADER, which included 151642 adverse events for the primary suspected drugs. The reporting odds ratio (ROR) of hypocalcemia as a signal of the target adverse event was analyzed for DEN and zoledronic acid (ZOL, a reference drug). Changes in RORs were compared between the pre- (Pre, April 2012 to September 2012) and post- (Post 1, October 2012 to September 2013 and Post 2, October 2013 to September 2014) periods of the regulatory action. A decrease in the hypocalcemia ROR was observed for DEN in the post-periods, especially Post 2. Multivariate logistic regression analysis showed a significant decrease in hypocalcemia signal in Post 1 (p=0.0306 vs. Pre) and Post 2 (p=0.0054 vs. Pre). ZOL caused no significant changes in ROR of hypocalcemia, and none of the drugs caused ROR changes in jaw osteonecrosis (a reference adverse event). This study suggests that the regulatory action against hypocalcemia in DEN effectively decreased hypocalcemia signal. Further studies using medical information databases are needed to confirm this result.

Retreatment with teriparatide: our experience in three patients with severe secondary osteoporosis.

PubMed

Mana, D L; Zanchetta, M B; Zanchetta, J R

2017-04-01

Teriparatide is a drug for the treatment of osteoporosis which is licensed for use for up to 24 months. There is little experience with retreatment. The aim of this study was to evaluate, in three patients with severe secondary osteoporosis, the response to a second cycle of teriparatide regarding bone mineral density (BMD) and osteocalcin. Case 1 : A 62-year-old woman with multiple vertebral fractures has received corticoids for a long time. After starting teriparatide, her BMD and osteocalcin increased. She then received ibandronate for 3 years but her BMD declined. After a second treatment with teriparatide, her BMD increased again (18%). Case 2 : A 60-year-old woman with severe osteoporosis in lumbar spine (LS) (T-score - 4.5) had received corticoids for a long time and had celiac disease. After starting teriparatide, her BMD improved by 11.7%. She then received zoledronic acid for 15 months, but bone density decreased, so she was retreated with teriparatide. BMD had a slightly higher increase than after the first cycle (12.6%). Case 3 : A 60-year-old woman consulted for osteoporosis (LS T-score - 5.3), several fractures, and hyperthyroidism. She started teriparatide with improvement in BMD (39%). After 24 months, she received ibandronate for 1 year, but as her BMD declined, she was retreated with teriparatide. BMD showed an increase of 15%. The indication of a second cycle of treatment with teriparatide in three patients was effective in increasing BMD. Additional studies are needed to further identify the benefits and safety of retreatment with teriparatide.

Recurrence Factors in Giant Cell Tumors of the Spine.

PubMed

Ouyang, Han-Qiang; Jiang, Liang; Liu, Xiao-Guang; Wei, Feng; Yang, Shao-Min; Meng, Na; Jiang, Ping; Yu, Miao; Wu, Feng-Liang; Dang, Lei; Zhou, Hua; Zhang, Hua; Liu, Zhong-Jun

2017-07-05

Giant cell tumors (GCTs) are benign, locally aggressive tumors. We examined the rate of local recurrence of spinal GCTs and sought to identify recurrence factors in patients who underwent surgery. Between 1995 and 2014, 94 mobile spine GCT patients were treated at our hospital, comprising 43 male and 51 female patients with an average age of 33.4 years. Piecemeal intralesional spondylectomy and total en bloc spondylectomy (TES) were performed. Radiotherapy was suggested for recurrent or residual GCT cases. Since denosumab was not available before 2014 in our country, only interferon and/or zoledronic acid was suggested. Of the 94 patients, four underwent conservative treatment and 90 underwent operations. Seventy-five patients (79.8%) were followed up for a minimum of 24 months or until death. The median follow-up duration was 75.3 months. The overall recurrence rate was 37.3%. Ten patients (13.3%) died before the last follow-up (median: 18.5 months). Two patients (2.6%) developed osteogenic sarcoma. The local recurrence rate was 80.0% (24/30) in patients who underwent intralesional curettage, 8.8% (3/34) in patients who underwent extracapsular piecemeal spondylectomy, and 0 (0/9) in patients who underwent TES. The risk factors for local recurrence were lesions located in the cervical spine (P = 0.049), intralesional curettage (P < 0.001), repeated surgeries (P = 0.014), and malignancy (P < 0.001). Malignant transformation was a significant risk factor for death (P < 0.001). Cervical spinal tumors, curettage, and nonintact tumors were risk factors for local recurrence. Intralesional curettage and malignancy were the most important significant factors for local recurrence and death, respectively.

Exercise and pharmacological countermeasures for bone loss during long-duration space flight.

PubMed

Cavanagh, Peter R; Licata, Angelo A; Rice, Andrea J

2005-06-01

Bone loss in the lower extremities and lumbar spine is an established consequence of long-duration human space flight. Astronauts typically lose as much bone mass in the proximal femur in 1 month as postmenopausal women on Earth lose in 1 year. Pharmacological interventions have not been routinely used in space, and countermeasure programs have depended solely upon exercise. However, it is clear that the osteogenic stimulus from exercise has been inadequate to maintain bone mass, due to insufficient load or duration. Attention has therefore been focused on several pharmacological interventions that have been successful in preventing or attenuating osteoporosis on Earth. Anti-resorptives are the class of drugs most commonly used to treat osteoporosis in postmenopausal women, notably alendronate sodium, risedronate sodium, zoledronic acid, and selective estrogen receptor modulators, such as raloxifene. There has also been considerable recent interest in anabolic agents such as parathyroid hormone (PTH) and teriparatide (rhPTH [1-34]). Vitamin D and calcium supplementation have also been used. Recent studies of kindreds with abnormally high bone mineral density have provided insight into the genetic regulation of bone mass. This has led to potential therapeutic interventions based on the LRP5, Wnt and BMP2 pathways. Another target is the RANK-L/osteoprotegerin signaling pathway, which influences bone turnover by regulating osteoclast formation and maturation. Trials using such therapies in space are being planned. Among the factors to be considered are dose-response relationships, bone quality, post-use recovery, and combination therapies--all of which may have unique characteristics when the drugs are used in space.

* Composite Biomaterial as a Carrier for Bone-Active Substances for Metaphyseal Tibial Bone Defect Reconstruction in Rats.

PubMed

Horstmann, Peter Frederik; Raina, Deepak Bushan; Isaksson, Hanna; Hettwer, Werner; Lidgren, Lars; Petersen, Michael Mørk; Tägil, Magnus

2017-12-01

Restoring lost bone is a major challenge in orthopedic surgery. Currently available treatment strategies have shortcomings, such as risk of infection, nonunion, and excessive resorption. Our primary aim was to study if a commercially available gentamicin-containing composite calcium sulfate/hydroxyapatite biomaterial (GBM) could serve as a carrier for local delivery of bone morphogenic protein-2 (BMP-2) and zoledronic acid (ZA) in a tibia defect model in rats. Empty and allograft-filled defects were used as controls. A 3 × 4-mm metaphyseal bone defect was created in the proximal tibia, and the rats were grouped according to defect filling: (1) Empty, (2) Allograft, (3) GBM, (4) GBM + ZA, and (5) GBM + ZA + BMP-2. In vivo microcomputed tomography (micro-CT) images at 4 weeks showed significantly higher mineralized tissue volume (MV) in the intramedullary defect region and the neocortical/callus region in all GBM-treated groups. After euthanization at 8 weeks, ex vivo micro-CT showed that addition of ZA (GBM + ZA) and BMP-2 (GBM + ZA + BMP-2) mainly increased the neocortical and callus formation, with the highest MV in the combined ZA and BMP-2-treated group. Qualitative histological analysis, verifying the increased neocortical/callus thickness and finding of trabecular bone in all GBM-treated groups, supported that the differences in MV measured with micro-CT in fact represented bone tissue. In conclusion, GBM can serve as a carrier for ZA and BMP-2 leading to increased MV in the neocortex and callus of a metaphyseal bone defect in rats.

Exercise and pharmacological countermeasures for bone loss during long-duration space flight

NASA Technical Reports Server (NTRS)

Cavanagh, Peter R.; Licata, Angelo A.; Rice, Andrea J.

2005-01-01

Bone loss in the lower extremities and lumbar spine is an established consequence of long-duration human space flight. Astronauts typically lose as much bone mass in the proximal femur in 1 month as postmenopausal women on Earth lose in 1 year. Pharmacological interventions have not been routinely used in space, and countermeasure programs have depended solely upon exercise. However, it is clear that the osteogenic stimulus from exercise has been inadequate to maintain bone mass, due to insufficient load or duration. Attention has therefore been focused on several pharmacological interventions that have been successful in preventing or attenuating osteoporosis on Earth. Anti-resorptives are the class of drugs most commonly used to treat osteoporosis in postmenopausal women, notably alendronate sodium, risedronate sodium, zoledronic acid, and selective estrogen receptor modulators, such as raloxifene. There has also been considerable recent interest in anabolic agents such as parathyroid hormone (PTH) and teriparatide (rhPTH [1-34]). Vitamin D and calcium supplementation have also been used. Recent studies of kindreds with abnormally high bone mineral density have provided insight into the genetic regulation of bone mass. This has led to potential therapeutic interventions based on the LRP5, Wnt and BMP2 pathways. Another target is the RANK-L/osteoprotegerin signaling pathway, which influences bone turnover by regulating osteoclast formation and maturation. Trials using such therapies in space are being planned. Among the factors to be considered are dose-response relationships, bone quality, post-use recovery, and combination therapies--all of which may have unique characteristics when the drugs are used in space.

Evaluation of Mandibular Bone After Dental Extraction in Rats Treated With Antiresorptive Drugs.

PubMed

Poubel, Victor Lousan do Nascimento; Capella, Diogo Lenzi; Santos, Adair Roberto Soares; Correa, Márcio; Ruhland, Letícia; Rivero, Elena Riet Correa

2018-03-01

Zoledronic acid (ZOL) and denosumab (Dmab) are commonly used to treat bone pathologies. Because these drugs suppress bone metabolism, this study sought to compare their effect on bone repair after tooth extraction. Four-week-old male Wistar rats were randomly assigned to 1 of 3 groups: ZOL 0.125 mg/kg, Dmab 0.25 mg/kg, or saline solution 10 mL/kg (control). After 1 week of treatment, the first left molar was extracted; the rats were euthanized at 28 days. The jaws were removed and photographed for macroscopic analysis of wound healing and then subjected to tomographic and histologic analyses. Immunohistochemistry was carried out against the receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG). No difference in wound healing, presence of inflammatory infiltrate and bone sequestration, or osteocyte expression of RANKL and OPG was found among groups. Tomographic analysis showed that the ZOL group had less alveolar resorption and more complete alveolar repair compared with the other groups. There was a statistically significant difference in the OPG marker in the control (P = .008) and ZOL (P = .05) groups when comparing the extracted and non-extracted sides. Systemic use of ZOL can improve alveolar bone healing; however, the potential risk for the development of osteonecrosis should be considered. Higher expression of OPG seems to be associated with the control of osteoclastogenesis during bone repair. Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Osteoporosis medication dispensing for older Australian women from 2002 to 2010: influences of publications, guidelines, marketing activities and policy.

PubMed

Peeters, Geeske; Tett, Susan E; Duncan, Emma L; Mishra, Gita D; Dobson, Annette J

2014-12-01

Developments in anti-osteoporosis medications (AOMs) have led to changes in guidelines and policy, which, along with media and marketing strategies, have had an impact upon the prescribing of AOM. The aim was to examine patterns of AOM dispensing in older women (aged 76-81 years at baseline) from 2002 to 2010. Administrative claims data were used to describe AOM dispensing in 4649 participants (born in 1921-1926 and still alive in 2011) in the Australian Longitudinal Study on Women's Health. The patterns were interpreted in the context of changes in guidelines, indications for subsidy, publications (scholarly and general media), and marketing activities. Total use of AOM increased from 134 DDD/1000/day in 2002 to 216 DDD/1000/day in 2007 but then decreased to 184 DDD/1000/day in 2010. Alendronate was the most commonly dispensed AOM but decreased from 2007, while use of risedronate (2002 onward), strontium ranelate (2007 onward) and zoledronic acid (2008 onward) increased. Etidronate and hormone replacement therapy (HRT) prescriptions gradually decreased over time. The decline in alendronate dispensing coincided with increases of other bisphosphonates and publicity about potential adverse effects of bisphosphonates, despite relaxing indications for bone density testing and subsidy for AOM. Overall dispense of AOM from 2002 reached a peak in 2007 and thereafter declined despite increases in therapeutic options and improved subsidised access. The recent decline in overall AOM dispensing seems to be explained largely by negative publicity rather than specific changes in guidelines and policy. Copyright © 2014 John Wiley & Sons, Ltd.

21 CFR 146.148 - Reduced acid frozen concentrated orange juice.

Code of Federal Regulations, 2014 CFR

2014-04-01

... that the ratio of the Brix reading to the grams of acid, expressed as anhydrous citric acid, per 100... 21 Food and Drugs 2 2014-04-01 2014-04-01 false Reduced acid frozen concentrated orange juice. 146... Canned Fruit Juices and Beverages § 146.148 Reduced acid frozen concentrated orange juice. (a) Reduced...

21 CFR 146.148 - Reduced acid frozen concentrated orange juice.

Code of Federal Regulations, 2012 CFR

2012-04-01

... that the ratio of the Brix reading to the grams of acid, expressed as anhydrous citric acid, per 100... 21 Food and Drugs 2 2012-04-01 2012-04-01 false Reduced acid frozen concentrated orange juice. 146... Canned Fruit Juices and Beverages § 146.148 Reduced acid frozen concentrated orange juice. (a) Reduced...

21 CFR 146.148 - Reduced acid frozen concentrated orange juice.

Code of Federal Regulations, 2011 CFR

2011-04-01

... that the ratio of the Brix reading to the grams of acid, expressed as anhydrous citric acid, per 100... 21 Food and Drugs 2 2011-04-01 2011-04-01 false Reduced acid frozen concentrated orange juice. 146... Canned Fruit Juices and Beverages § 146.148 Reduced acid frozen concentrated orange juice. (a) Reduced...

21 CFR 146.148 - Reduced acid frozen concentrated orange juice.

Code of Federal Regulations, 2013 CFR

2013-04-01

... that the ratio of the Brix reading to the grams of acid, expressed as anhydrous citric acid, per 100... 21 Food and Drugs 2 2013-04-01 2013-04-01 false Reduced acid frozen concentrated orange juice. 146... Canned Fruit Juices and Beverages § 146.148 Reduced acid frozen concentrated orange juice. (a) Reduced...

Influence of the teaching program on the learning in knowledge and practice of osteonecrosis of the jaws produced by antireasorptives in dental students of the Principality of Asturias (Spain)

PubMed Central

Escobedo, Matias-Ferrán; García-Consuegra, Luis; Gay, Silvia; Álvarez, Lorena; Olay, Sonsoles; Ascani, Giuliano

2017-01-01

Background This study aims to evaluate the influence of changes in the teaching contents on medication-related osteonecrosis of the jaw may have on the knowledge and the capacity for practical case resolution about this pathology. Material and Methods A cross-sectional descriptive study was conducted through a survey divided into four sections: degree of means of knowledge acquisition, habitual practice and ability to solve clinical cases. The total number of respondents (n = 225) was divided into two groups: Group A (Year 2015-2016) and Group B (Year 2016-2017). The students in Group B received more teaching content on the subject than group A. Results A total of 175 survey responses were collected. The internet was the preferred tool for continuing education in both groups. The best known bisphosphonates (BPs) were Alendronate (Fosamax®: 56.9% Group A, 67.5% Group B) and Zoledronic Acid (Zometa®: 56.9% Group A, 51.8% Group B). A low percentage of students (37.9% Group A, 43.4% Group B) acknowledged the existence of other drugs that could also cause osteonecrosis of the jaws. Regarding the correct resolution of practical cases, the respondents of Group B reached a significantly higher score (5.67) than the score observed in Group A (4.04). Conclusions Training on medication-related osteonecrosis among dental students is susceptible to improvement. Introducing minor changes in the teachings allows this goal to be successfully achieved. Key words:Osteonecrosis of the jaw (ONJ), bisphosphonate-related osteonecrosis of the jaws (BRONJ), medication-related osteonecrosis of the jaw (MRONJ), dental education. PMID:29410755

The role of bisphosphonates or denosumab in light of the availability of new therapies for prostate cancer.

PubMed

Saad, Fred; Sternberg, Cora N; Mulders, Peter F A; Niepel, Daniela; Tombal, Bertrand F

2018-05-03

Most men with advanced prostate cancer will develop bone metastases, which have a substantial impact on quality of life. Bone metastases can lead to skeletal-related events (SREs), which place a burden on patients and healthcare systems. For men with castration-resistant prostate cancer (CRPC) and bone metastases, the treatment landscape has evolved rapidly over the past few years. The relatively recent approvals of the hormonal agents abiraterone acetate and enzalutamide, second-line chemotherapy cabazitaxel, and the radiopharmaceutical radium-223 dichloride (radium-223), have provided clinicians with a greater choice of treatments. These compounds have benefits in terms of overall survival based on the results of pivotal phase 3 studies. The bisphosphonate zoledronic acid and the RANK ligand inhibitor denosumab are indicated for the prevention of SREs in men with metastatic CRPC but studies of these compounds have not demonstrated a survival benefit. The important question of the role of bisphosphonates or denosumab in combination with these new agents has thus materialised. Current and emerging evidence from clinical studies of abiraterone acetate, enzalutamide and radium-223, suggest that addition of bisphosphonates or denosumab to these new therapies may provide further clinical benefits for patients with prostate cancer and bone metastases. This evidence may help to shape clinical practice but are based largely on post hoc analyses of clinical trial data. It is therefore apparent that further data are required from both clinical studies and real-world settings to enable physicians to understand the efficacy and safety of combination therapy with the new agents plus bisphosphonates or denosumab. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Natural History of Malignant Bone Disease in Gastric Cancer: Final Results of a Multicenter Bone Metastasis Survey

PubMed Central

Silvestris, Nicola; Pantano, Francesco; Ibrahim, Toni; Gamucci, Teresa; De Vita, Fernando; Di Palma, Teresa; Pedrazzoli, Paolo; Barni, Sandro; Bernardo, Antonio; Febbraro, Antonio; Satolli, Maria Antonietta; Bertocchi, Paola; Catalano, Vincenzo; Giommoni, Elisa; Comandone, Alessandro; Maiello, Evaristo; Riccardi, Ferdinando; Ferrara, Raimondo; Trogu, Antonio; Berardi, Rossana; Leo, Silvana; Bertolini, Alessandro; Angelini, Francesco; Cinieri, Saverio; Russo, Antonio; Pisconti, Salvatore; Brunetti, Anna Elisabetta; Azzariti, Amalia; Santini, Daniele

2013-01-01

Background Bone metastasis represents an increasing clinical problem in advanced gastric cancer (GC) as disease-related survival improves. In literature, few data on the natural history of bone disease in GC are available. Patients and Methods Data on clinicopathology, skeletal outcomes, skeletal-related events (SREs), and bone-directed therapies for 208 deceased GC patients with evidence of bone metastasis were statistically analyzed. Results Median time to bone metastasis was 8 months (CI 95%, 6.125–9.875 months) considering all included patients. Median number of SREs/patient was one. Less than half of the patients (31%) experienced at least one and only 4 and 2% experienced at least two and three events, respectively. Median times to first and second SRE were 2 and 4 months, respectively. Median survival was 6 months after bone metastasis diagnosis and 3 months after first SRE. Median survival in patients who did not experience SREs was 5 months. Among patients who received zoledronic acid before the first SRE, the median time to appearance of first SRE was significantly prolonged compared to control (7 months vs 4 months for control; P: 0.0005). Conclusions To our knowledge, this retrospective analysis is the largest multicenter study to demonstrate that bone metastases from GC are not so rare, are commonly aggressive and result in relatively early onset of SREs in the majority of patients. Indeed, our large study, which included 90 patients treated with ZOL, showed, for the first time in literature, a significant extension of time to first SRE and increase in the median survival time after diagnosis of bone metastasis. Taken together, these data may support the beneficial effects of ZOL in GC patients. PMID:24204569

Calcium Sulphate/Hydroxyapatite Carrier for Bone Formation in the Femoral Neck of Osteoporotic Rats.

PubMed

Sirka, Aurimas; Raina, Deepak Bushan; Isaksson, Hanna; Tanner, K Elizabeth; Smailys, Alfredas; Kumar, Ashok; Tarasevicius, Sarunas; Tägil, Magnus; Lidgren, Lars

2018-06-01

We investigated bone regeneration in the femoral neck canal of osteoporotic rats using a novel animal model. We used a calcium sulphate (CS)/ Hydroxyapatite (HA) carrier to locally deliver a bisphosphonate, zoledronic acid (ZA), with or without added recombinant human bone morphogenic protein-2 (rhBMP-2). Ovariectomized Sprague-Dawley rats of 28 weeks age were used. A 1 mm diameter and 8 mm long defect was created in the femoral neck by drilling from the lateral cortex in the axis of the femoral neck leaving the surrounding cortex intact. Three treatment groups and one control group were used 1) CS/HA alone, 2) CS/HA+ ZA (10 μg) 3) CS/HA+ZA (10 μg)+rhBMP-2 (4 μg) and 4) Empty defect. The bone formation was assessed at 4 weeks post-surgery using in vivo micro computed tomography (micro-CT). At 8 weeks post-surgery, the animals were sacrificed and both defect and contralateral femurs were subjected to micro-CT, mechanical testing and histology. Micro-CT results showed that the combination of CS/HA with ZA or ZA+rhBMP-2 increased the bone formation in the defect when compared to the other groups and to the contralateral hips. Evidence of new dense bone formation in CS/HA+ZA and CS/HA+ZA+rhBMP-2 groups was seen histologically. Mechanical testing results showed no differences in the load to fracture between the treatments in either of the treated or contralateral legs. The CS/HA biomaterial can be used as a carrier for ZA and rhBMP-2 to regenerate bone in the femoral neck canal of osteoporotic rats.

Bisphosphonates inhibit bone remodeling in the jaw bones of rats and delay healing following tooth extractions.

PubMed

Jabbour, Zaher; El-Hakim, Michel; Henderson, Janet E; de Albuquerque, Rubens F

2014-05-01

This study aimed to evaluate the impact of concurrent administration of clinically relevant doses of zoledronic acid (ZA) and dexamethasone (DX) on bone healing after tooth extraction (EXO). Forty-four Sprague-Dawley rats (6-8 month old) were randomized into five groups: ZA + DX = weekly injection of ZA with DX for 7 weeks; WD = ZA with DX for 3 weeks then DX alone for 4 weeks; C = control saline for 7 weeks; ZA = ZA alone for 7 weeks and DX = DX alone for 7 weeks. ZA was administered at 0.13 mg/kg/week and DX at 3.8 mg/kg/week and body weights recorded at the time of injection. All rats underwent extraction (EXO) of the mandibular and maxillary first molars at 3 weeks and were euthanized at 7 weeks. The extracted and non-extracted sides of both jaws were harvested for micro-CT analyses. All rats, particularly those injected with ZA, exhibited weight gain till EXO followed by decline then recovery. ZA + DX group demonstrated highest fractional bone to tissue volume (BV/TV) in the non-extracted side. ZA + DX rats exhibited also highest volume and surface of sequestra. Only sequestra volume was statistically higher in the WD group compared to C group. Combined treatment with ZA and DX over a prolonged period inhibits bone remodeling and increased sequestra formation to a greater extent than either drug alone. Trauma caused by these sequestra cutting through the mucosa could play a key role in the development of BRONJ by potentially facilitating infection. ZA withdrawal may promote bone-remodeling reactivation following EXO. Copyright © 2014 Elsevier Ltd. All rights reserved.

Differential effects of biologic versus bisphosphonate inhibition of wear debris-induced osteolysis assessed by longitudinal micro-CT.

PubMed

Tsutsumi, Ryosuke; Hock, Colleen; Bechtold, C Dustin; Proulx, Steven T; Bukata, Susan V; Ito, Hiromu; Awad, Hani A; Nakamura, Takashi; O'Keefe, Regis J; Schwarz, Edward M

2008-10-01

Aseptic loosening of total joint replacements is caused by wear debris-induced osteoclastic bone resorption, for which bisphosphonates (BPs) and RANK antagonists have been developed. Although BPs are effective in preventing metabolic bone loss, they are less effective for inflammatory bone loss. Because this difference has been attributed to the antiapoptotic inflammatory signals that protect osteoclasts from BP-induced apoptosis, but not RANK antagonists, we tested the hypothesis that osteoprotegerin (OPG) is more effective in preventing wear debris-induced osteolysis than zoledronic acid (ZA) or alendronate (Aln) in the murine calvaria model using in vivo micro-CT and traditional histology. Although micro-CT proved to be incompatible with titanium (Ti) particles, we were able to demonstrate a 3.2-fold increase in osteolytic volume over 10 days induced by polyethylene (PE) particles versus sham controls (0.49 +/- 0.23 mm(3) versus 0.15 +/- 0.067 mm(3); p < 0.01). Although OPG and high-dose ZA completely inhibited this PE-induced osteolysis (p < 0.001), pharmacological doses of ZA and Aln were less effective but still reached statistical significance (p < 0.05). Traditional histomorphometry of the sagital suture area of calvaria from both Ti and PE-treated mice confirmed the remarkable suppression of resorption by OPG (p < 0.001) versus the lack of effect by physiological BPs. The differences in drug effects on osteolysis were largely explained by the significant difference in osteoclast numbers observed between OPG versus BPs in both Ti- and PE-treated calvaria; and linear regression analyses that demonstrated a highly significant correlation between osteolysis volume and sagittal suture area versus osteoclast numbers (p < 0.001). (c) 2008 Orthopaedic Research Society.

Updated Recommendations for the Diagnosis and Management of Osteoporosis: A Local Perspective

PubMed Central

Raef, Hussein; Al-Bugami, Munira; Balharith, Sakra; Moawad, Mahmoud; El-Shaker, Mohammad; Hussain, Aneela; Al-Shaikh, Ahmad; Al-Badawi, Ismail

2011-01-01

Postmenopausal osteoporosis and osteoporosis in elderly men are major health problems, with a significant medical and economic burden. Although osteopenia and osteoporosis are more common locally than in the West, fracture rates are generally less than in Western countries. Vitamin D deficiency is common in the region and contributes adversely to bone health. Vitamin D deficiency should be suspected and treated in all subjects with ostopenia or osteoporosis. The use of risk factors to determine fracture risk has been adopted by the World Health Organization and many international societies. Absolute fracture risk methodology improves the use of resources by targeting subjects at higher risk of fractures for screening and management. The King Faisal Specialist Hospital Osteoporosis Working Group recommends screening for women 65 years and older and for men 70 years and older. Younger subjects with clinical risk factors and persons with clinical evidence of osteoporosis or diseases leading to osteoporosis should also be screened. These guidelines provide recommendations for treatment for postmenopausal women and men older than 50 years presenting with osteoporotic fractures for persons having osteoporosis—after excluding secondary causes—or for persons having low bone mass and a high risk for fracture. The Working Group has suggested an algorithm to use at King Faisal Specialist Hospital that is based on the availability, cost, and level of evidence of various therapeutic modalities. Adequate calcium and vitamin D supplement are recommended for all. Weekly alendronate (in the absence of contraindications) is recommended as first-line therapy. Alternatives to alendronate are raloxifene or strontium ranelate. Second-line therapies are zoledronic acid intravenously once yearly, when oral therapy is not feasible or complicated by side effects, or teriparatide in established osteoporosis with fractures. PMID:21403406

International Myeloma Working Group Recommendations for the Treatment of Multiple Myeloma–Related Bone Disease

PubMed Central

Terpos, Evangelos; Morgan, Gareth; Dimopoulos, Meletios A.; Drake, Matthew T.; Lentzsch, Suzanne; Raje, Noopur; Sezer, Orhan; García-Sanz, Ramón; Shimizu, Kazuyuki; Turesson, Ingemar; Reiman, Tony; Jurczyszyn, Artur; Merlini, Giampaolo; Spencer, Andrew; Leleu, Xavier; Cavo, Michele; Munshi, Nikhil; Rajkumar, S. Vincent; Durie, Brian G.M.; Roodman, G. David

2013-01-01

Purpose The aim of the International Myeloma Working Group was to develop practice recommendations for the management of multiple myeloma (MM) –related bone disease. Methodology An interdisciplinary panel of clinical experts on MM and myeloma bone disease developed recommendations based on published data through August 2012. Expert consensus was used to propose additional recommendations in situations where there were insufficient published data. Levels of evidence and grades of recommendations were assigned and approved by panel members. Recommendations Bisphosphonates (BPs) should be considered in all patients with MM receiving first-line antimyeloma therapy, regardless of presence of osteolytic bone lesions on conventional radiography. However, it is unknown if BPs offer any advantage in patients with no bone disease assessed by magnetic resonance imaging or positron emission tomography/computed tomography. Intravenous (IV) zoledronic acid (ZOL) or pamidronate (PAM) is recommended for preventing skeletal-related events in patients with MM. ZOL is preferred over oral clodronate in newly diagnosed patients with MM because of its potential antimyeloma effects and survival benefits. BPs should be administered every 3 to 4 weeks IV during initial therapy. ZOL or PAM should be continued in patients with active disease and should be resumed after disease relapse, if discontinued in patients achieving complete or very good partial response. BPs are well tolerated, but preventive strategies must be instituted to avoid renal toxicity or osteonecrosis of the jaw. Kyphoplasty should be considered for symptomatic vertebral compression fractures. Low-dose radiation therapy can be used for palliation of uncontrolled pain, impending pathologic fracture, or spinal cord compression. Orthopedic consultation should be sought for long-bone fractures, spinal cord compression, and vertebral column instability. PMID:23690408

BONE TURNOVER IN OSTEOPOROTIC WOMEN DURING LONG-TERM ORAL BISPHOSPHONATES TREATMENT: IMPLICATIONS FOR TREATMENT FAILURE AND "DRUG HOLIDAY" IN THE REAL WORLD.

PubMed

Liel, Yair; Plakht, Ygal; Tailakh, Muhammad Abu

2017-07-01

Little data exist to support concerns over bone turnover suppression during prolonged oral bisphosphonate treatment and on consequences of the recommended "drug holiday." This study was performed to assess bone resorption rates in postmenopausal osteoporotic women on prolonged oral bisphosphonate treatment and in response to switching to "drug holiday" intravenous bisphosphonate, or continuation of oral bisphosphonates. The frequency distribution of the bone resorption marker urinary deoxypyridinoline crosslinks (uDPD), was obtained retrospectively from 211 osteoporotic women attended at an academic hospital endocrine clinic, treated for >2 years with oral bisphosphonates. In some patients, uDPD was re-assessed following modification or continuation of treatment. The mean duration of oral bisphosphonates treatment was 7.2 ± 3.1 years. uDPD was within reference range for premenopausal women in 61.6% of the patients, below in 7.6% of the patients, and above upper limit in 30.8%. uDPD decreased significantly following intravenous zoledronic acid, increased significantly during "drug holiday," and slightly decreased in those continued on oral bisphosphonate treatment. In this real-world study, the majority of women on prolonged oral bisphosphonates maintained bone resorption rates within the normal reference range for premenopausal women. The likelihood for inadequate suppression was considerably greater than that of over-suppression. Implementing a "drug holiday" resulted in a marked increase in bone resorption rates. Additional studies should explore the potential role of bone turnover markers in the evaluation of patients on prolonged oral bisphosphonates and during "drug holiday" in different settings and using additional markers. BMD = bone mineral density; IQR = interquartile range; uDPD = urinary deoxypyridinoline crosslinks.

Development of Hypercalcemia in a Patient Receiving Peginterferon alfa-2a Therapy for Polycythemia Vera.

PubMed

Karne, Sheetal; Mainor, Candace B; Baer, Maria R

2016-06-01

Peginterferon alfa-2a (PEG-IFN alfa-2a) is commonly used to treat hepatitis C virus infection and is also being used increasingly to treat myeloproliferative neoplasms including polycythemia vera. Sarcoidosis associated with IFN therapy for treatment of hepatitis C is well described, with hypercalcemia occurring as a rare manifestation. We describe a 25-year-old man with polycythemia vera who became resistant to hydroxyurea after 6 years of treatment, requiring therapeutic phlebotomy procedures with increasing frequency for elevated hemoglobin and hematocrit levels. PEG-IFN alfa-2a was then initiated at 90 μg subcutaneously once/week and was progressively increased to 180 μg/week over the next 11 months, with normalization of his hemoglobin and hematocrit. The patient then developed hypercalcemia with low parathyroid hormone, parathyroid hormone-related protein, and 25-hydroxyvitamin D levels, and high 1,25-dihydroxyvitamin D and angiotensin-converting enzyme levels, without other evidence of sarcoidosis. PEG-IFN alfa-2a was discontinued, treatment with intravenous fluids and zoledronic acid was initiated, and the hypercalcemia resolved 10 weeks later. Use of the Naranjo Adverse Drug Reaction Probability Scale indicated a probable relationship (score of 7) between the patient's development of hypercalcemia and PEG-IFN alfa-2a therapy; the relationship could not be considered as definite because the patient was not rechallenged with the drug. To our knowledge, this is the first case report of IFN-induced hypercalcemia without other manifestations of sarcoidosis. Practitioners should be aware of hypercalcemia as a potential complication of PEG-IFN alfa-2a therapy, as well as its protracted time course, in patients with myeloproliferative neoplasms. © 2016 Pharmacotherapy Publications, Inc.

Additive effect of PTH (1-34) and zoledronate in the prevention of disuse osteopenia in rats.

PubMed

Vegger, Jens Bay; Nielsen, Esben Sommer; Brüel, Annemarie; Thomsen, Jesper Skovhus

2014-09-01

Immobilization is known to cause a rapid bone loss due to increased osteoclastic bone resorption and decreased osteoblastic bone formation. Zoledronate (Zln) is a potent anti-resorptive pharmaceutical, while intermittent PTH is a potent bone anabolic agent. The aim of the present study was to investigate whether PTH or Zln alone or in combination could prevent immobilization-induced osteopenia. Immobilization was achieved by injecting 4IU Botox (BTX) into the right hind limb musculature. Seventy-two 16-week-old female Wistar rats were randomized into 6 groups; baseline (Base), control (Ctrl), BTX, BTX+PTH, BTX+Zln, and BTX+PTH+Zln. PTH (1-34) (80μg/kg) was given 5days/week and Zln (100μg/kg) was given once at study start. The animals were killed after 4weeks of treatment. The bone properties were evaluated using DEXA, μCT, dynamic bone histomorphometry, and mechanical testing. BTX resulted in lower femoral trabecular bone volume fraction (BV/TV) (-25%, p<0.05), lower tibial trabecular bone formation rate (BFR/BS) (-29%, p<0.05), and lower bone strength (Fmax) at the distal femur (-19%, p<0.001) compared with Ctrl. BTX+PTH resulted in higher femoral BV/TV (+31%, p<0.05), higher tibial trabecular BFR/BS (+297%, p<0.05), and higher Fmax at the distal femur (+11%, p<0.05) compared with BTX. BTX+Zln resulted in higher femoral BV/TV (+36%, p<0.05), lower tibial trabecular BFR/BS (-93%, p<0.05), and higher Fmax at the distal femur (+10%, p<0.05) compared with BTX. BTX+PTH+Zln resulted in higher femoral BV/TV (+70%, p<0.001), higher tibial trabecular BFR/BS (+59%, p<0.05), and higher Fmax at the distal femur (+32%, p<0.001) compared with BTX. In conclusion, BTX-induced immobilization led to lower BV/TV, BFR/BS, and Fmax. In general, PTH or Zln alone prevented the BTX-induced osteopenia, whereas PTH and Zln given in combination not only prevented, but also increased BV/TV and BFR/BS, and maintained Fmax at the distal femoral metaphysis compared with Ctrl. Copyright © 2014 Elsevier Inc. All rights reserved.

Citric Acid Production by Aspergillus niger Cultivated on Parkia biglobosa Fruit Pulp

PubMed Central

Abidoye, Khadijat Toyin; Tahir, Hauwa; Ibrahim, Aliyu Dabai; Aransiola, Sesan Abiodun

2014-01-01

The study was conducted to investigate the potential of Parkia biglobosa fruit pulp as substrate for citric acid production by Aspergillus niger. Reducing sugar was estimated by 3,5-dinitrosalicylic acid and citric acid was estimated spectrophotometrically using pyridine-acetic anhydride methods. The studies revealed that production parameters (pH, inoculum size, substrate concentration, incubation temperature, and fermentation period) had profound effect on the amount of citric acid produced. The maximum yield was obtained at the pH of 2 with citric acid of 1.15 g/L and reducing sugar content of 0.541 mMol−1, 3% vegetative inoculum size with citric acid yield of 0.53 g/L and reducing sugar content of 8.87 mMol−1, 2% of the substrate concentration with citric acid yield of 0.83 g/L and reducing sugar content of 9.36 mMol−1, incubation temperature of 55°C with citric acid yield of 0.62 g/L and reducing sugar content of 8.37 mMol−1, and fermentation period of 5 days with citric acid yield of 0.61 g/L and reducing sugar content of 3.70 mMol−1. The results of this study are encouraging and suggest that Parkia biglobosa pulp can be harnessed at low concentration for large scale citric acid production. PMID:27433535

Effects of tempering (annealing), acid hydrolysis, low-citric acid substitution on chemical and physicochemical properties of starches of four yam (Dioscorea spp.) cultivars.

PubMed

Falade, Kolawole O; Ayetigbo, Oluwatoyin E

2017-05-01

The effects of tempering (annealing), acid hydrolysis and low-citric acid substitution on chemical and physicochemical properties of starches of four Nigerian yam cultivars were investigated. Crude fat and protein contents of the native starches decreased significantly after the modifications, while nitrogen-free extract increased significantly with acid hydrolysis and citric acid substitution. Acid hydrolysis and low-citric acid substitution reduced the least concentration for gel formation of the starches from 4 to 2% w/v, but tempering had no effect. Swelling power of the starches reduced significantly, and water solubility increased significantly at 75 and 85 °C, especially with acid hydrolysis and low-citric acid substitution. However, tempering significantly reduced starch solubility in the four cultivars. Paste clarity of starches of white (29.17%), water (18.90%), yellow (30.90%) and bitter (10.57%) yams reduced significantly with tempering to 14.43, 11.83, 16.93 and 7.27%, but increased significantly with acid hydrolysis to 41.40, 35.37, 28.77 and 32.33%, and low-citric acid substitution to 36.60, 44.17, 50.67 and 14.33%, respectively. Pasting properties such as peak, trough, breakdown, final, and setback viscosities and peak time of native starches reduced significantly with acid hydrolysis and low-citric acid substitution, however, tempering significantly increased their pasting temperature, peak time, setback and final viscosities.

Efficacy of FDA-Approved Hemostatic Drugs to Improve Survival and Reduce Bleeding in Rat Models of Uncontrolled Hemorrhage

DTIC Science & Technology

2005-07-01

drugs are used to reduce surgical bleeding. This series of studies tested whether these drugs (aprotinin, desmopressin, tranexamic acid , e- aminocaproic ...desmopressin, tranexamic acid , 8- aminocaproic acid ) could reduce bleeding due to traumatic injuries in two models of uncontrolled hemorrhage in rats... acid ) could reduce bleeding due to traumatic injuries in two models of uncontrolled hemorrhage in rats. In the first phase of each study, a lethal

Application of a Sex Pheromone, Pheromone Analogs, and Verticillium lecanii for Management of Heterodera glycines

PubMed Central

Meyer, S. L. F.; Huettel, R. N.

1996-01-01

A mutant strain of the fungus Verticillium lecanii and selected bioregulators of Heterodera glycines were evaluated for their potential to reduce population densities of the nematode on soybean under greenhouse conditions. The bioregulators tested were the H. glycines sex pheromone vanillic acid and the pheromone analogs syringic acid, isovanillic acid, ferulic acid, 4-hydroxy-3-methoxybenzonitrile, and methyl vanillate. A V. lecanii-vanillic acid combination and a V. lecanii-syringic acid combination were also applied as treatments. Syringic acid, 4-hydroxy-3-methoxybenzonitrile, V. lecanii, V. lecanii-vanillic acid, and V. lecanii-syringic acid significantly reduced nematode population densities in the greenhouse tests. Results with vanillic acid, isovanillic acid, and ferulic acid treatments were variable. Methyl vanillate did not significantly reduce cyst nematode population densities in the greenhouse tests. PMID:19277343

n-3 fatty acids reduce plasma 20-hydroxyeicosatetraenoic acid and blood pressure in patients with chronic kidney disease.

PubMed

Barden, Anne E; Burke, Valerie; Mas, Emilie; Beilin, Lawrence J; Puddey, Ian B; Watts, Gerald F; Irish, Ashley B; Mori, Trevor A

2015-09-01

Metabolism of arachidonic acid by cytochrome P450 ω-hydroxylase leads to the formation of 20-hydroxyeicosatetraenoic acid (20-HETE) that regulates vascular function, sodium homeostasis and blood pressure (BP). Supplementation with n-3 fatty acids is known to alter arachidonic acid metabolism and reduce the formation of the lipid peroxidation products F2-isoprostanes, but the effect of n-3 fatty acids on 20-HETE has not been studied. We previously reported a significant effect of n-3 fatty acids but not coenzyme Q10 (CoQ) to reduce BP in a double-blind, placebo-controlled intervention, wherein patients with chronic kidney disease (CKD) were randomized to n-3 fatty acids (4 g), CoQ (200 mg), both supplements or control (4 g olive oil), daily for 8 weeks. This study examined the effect of n-3 fatty acids on plasma and urinary 20-HETE in the same study, as well as plasma and urinary F2-isoprostanes, and relate these to changes in BP. Seventy-four patients completed the 8-week intervention. n-3 fatty acids but not CoQ significantly reduced plasma 20-HETE (P = 0.001) and F2-isoprostanes (P < 0.001). In regression models adjusted for BP at baseline, postintervention plasma 20-HETE was a significant predictor of the fall in SBP (P < 0.0001) and DBP (P < 0.0001) after n-3 fatty acids. This is the first report that n-3 fatty acid supplementation reduces plasma 20-HETE in humans and that this associates with reduced BP. These results provide a plausible mechanism for the reduction in BP observed in patients with CKD following n-3 fatty acid supplementation.

Tranexamic acid reduces intraoperative occult blood loss and tourniquet time in obese knee osteoarthritis patients undergoing total knee arthroplasty: a prospective cohort study.

PubMed

Meng, Yutong; Li, Zhirui; Gong, Ke; An, Xiao; Dong, Jiyuan; Tang, Peifu

2018-01-01

Obesity can result in increased blood loss, which is correlated with poor prognosis in total knee arthroplasty (TKA). Clinical application of tranexamic acid is effective in reducing blood loss in TKA. However, most previous studies focused on the effect of tranexamic acid in the whole population, neglecting patients with specific health conditions, such as obesity. We hypothesized that tranexamic acid would reduce blood loss to a greater extent in obese patients than in those of normal weight. A total of 304 patients with knee osteoarthritis treated with TKA from October 2013 to March 2015 were separated into tranexamic, non-tranexamic, obese, and non-obese groups. The demographic characteristics, surgical indices, and hematological indices were all recorded. We first investigated the ability of intravenous tranexamic acid to reduce intraoperative blood loss in knee osteoarthritis patients undergoing unilateral TKA. Second, we performed subgroup analysis to compare the effects of tranexamic acid between obese and non-obese patients separately. Of the 304 patients, 146 (52.0%) received tranexamic acid and 130 (42.8%) were obese. In the analysis of the whole group, both the actual and occult blood loss volume were lower in the tranexamic acid group (both P < 0.05). Tourniquet time was shorter in the tranexamic acid group ( P < 0.05). In subgroup analysis, tranexamic acid was shown to reduce theoretical and actual blood loss in both the obese and non-obese groups ( P < 0.05). Tranexamic acid reduced occult blood loss and tourniquet time in the obese group ( P < 0.05), while no such effects were observed in the non-obese group ( P > 0.05). Tranexamic acid can reduce occult blood loss and tourniquet time in obese patients to a greater extent than in patients of normal weight. Therefore, obese knee osteoarthritis patients undergoing TKA can benefit more from tranexamic acid.

Tranexamic acid reduces intraoperative occult blood loss and tourniquet time in obese knee osteoarthritis patients undergoing total knee arthroplasty: a prospective cohort study

PubMed Central

Gong, Ke; An, Xiao; Dong, Jiyuan; Tang, Peifu

2018-01-01

Purpose Obesity can result in increased blood loss, which is correlated with poor prognosis in total knee arthroplasty (TKA). Clinical application of tranexamic acid is effective in reducing blood loss in TKA. However, most previous studies focused on the effect of tranexamic acid in the whole population, neglecting patients with specific health conditions, such as obesity. We hypothesized that tranexamic acid would reduce blood loss to a greater extent in obese patients than in those of normal weight. Patients and methods A total of 304 patients with knee osteoarthritis treated with TKA from October 2013 to March 2015 were separated into tranexamic, non-tranexamic, obese, and non-obese groups. The demographic characteristics, surgical indices, and hematological indices were all recorded. We first investigated the ability of intravenous tranexamic acid to reduce intraoperative blood loss in knee osteoarthritis patients undergoing unilateral TKA. Second, we performed subgroup analysis to compare the effects of tranexamic acid between obese and non-obese patients separately. Results Of the 304 patients, 146 (52.0%) received tranexamic acid and 130 (42.8%) were obese. In the analysis of the whole group, both the actual and occult blood loss volume were lower in the tranexamic acid group (both P < 0.05). Tourniquet time was shorter in the tranexamic acid group (P < 0.05). In subgroup analysis, tranexamic acid was shown to reduce theoretical and actual blood loss in both the obese and non-obese groups (P < 0.05). Tranexamic acid reduced occult blood loss and tourniquet time in the obese group (P < 0.05), while no such effects were observed in the non-obese group (P > 0.05). Conclusion Tranexamic acid can reduce occult blood loss and tourniquet time in obese patients to a greater extent than in patients of normal weight. Therefore, obese knee osteoarthritis patients undergoing TKA can benefit more from tranexamic acid. PMID:29695912

Effect of reducing system on capacitive behavior of reduced graphene oxide film: Application for supercapacitor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Akbi, Hamdane; Yu, Lei; Wang, Bin

2015-01-15

To determine the best chemical reduction of graphene oxide film with hydriodic acid that gives maximum energy and power density, we studied the effect of two reducing systems, hydriodic acid/water and hydriodic acid/acetic acid, on the morphology and electrochemical features of reduced graphene oxide film. Using acetic acid as solvent results in high electrical conductivity (5195 S m{sup −1}), excellent specific capacitance (384 F g{sup −1}) and good cyclic stability (about 98% of its initial response after 4000 cycles). Using water as a solvent, results in an ideal capacitive behavior and excellent cyclic stability (about 6% increase of its initialmore » response after 2100 cycles). - Graphical abstract: The choice of reducing system determines the morphology and structure of the chemically reduced graphene film and, as a result, affects largely the capacitive behavior. - Highlights: • The structure of the graphene film has a pronounced effect on capacitive behavior. • The use of water/HI as reducing system results in an ideal capacitive behavior. • The use of acetic acid/HI as reducing system results in a high specific capacitance.« less

Seamustard (Undaria pinnatifida) Improves Growth, Immunity, Fatty Acid Profile and Reduces Cholesterol in Hanwoo Steers

PubMed Central

Hwang, J. A.; Islam, M. M.; Ahmed, S. T.; Mun, H. S.; Kim, G. M.; Kim, Y. J.; Yang, C. J.

2014-01-01

The study was designed to evaluate the effect of 2% seamustard (Undaria pinnatifida) by-product (SW) on growth performance, immunity, carcass characteristics, cholesterol content and fatty acid profile in Hanwoo steers. A total of 20 Hanwoo steers (ave. 22 months old; 619 kg body weight) were randomly assigned to control (basal diet) and 2% SW supplemented diet. Dietary SW supplementation significantly (p<0.05) improved average daily gain and gain:feed ratio as well as serum immunoglobulin G concentration. Chemical composition and quality grade of meat and carcass yield grades evaluated at the end of the trial were found to be unaffected by SW supplementation. Dietary SW significantly reduced meat cholesterol concentration (p<0.05). Dietary SW supplementation significantly reduced the myristic acid (C14:0) and palmitoleic acid (C16:ln-7) concentration, while SW increased the concentration of stearic acid (C18:0) and linolenic acid (C18:3n-3) compared to control (p<0.05). Dietary SW supplementation had no effect on saturated fatty acids (SFA), unsaturated fatty acids, poly unsaturated fatty acid (PUFA) or mono unsaturated fatty acid content in muscles. A reduced ratio of PUFA/SFA and n-6/n-3 were found in SW supplemented group (p<0.05). In conclusion, 2% SW supplementation was found to improve growth, immunity and fatty acid profile with significantly reduced cholesterol of beef. PMID:25083105

40 CFR 72.43 - Phase I reduced utilization plans.

Code of Federal Regulations, 2011 CFR

2011-07-01

... (CONTINUED) PERMITS REGULATION Acid Rain Compliance Plan and Compliance Options § 72.43 Phase I reduced... any Acid Rain emissions limitation or emissions reduction requirements during Phase I; and (ii) Meets... this section shall include in the Acid Rain permit application for the unit a reduced utilization plan...

40 CFR 72.43 - Phase I reduced utilization plans.

Code of Federal Regulations, 2013 CFR

2013-07-01

... (CONTINUED) PERMITS REGULATION Acid Rain Compliance Plan and Compliance Options § 72.43 Phase I reduced... any Acid Rain emissions limitation or emissions reduction requirements during Phase I; and (ii) Meets... this section shall include in the Acid Rain permit application for the unit a reduced utilization plan...

40 CFR 72.43 - Phase I reduced utilization plans.

Code of Federal Regulations, 2014 CFR

2014-07-01

... (CONTINUED) PERMITS REGULATION Acid Rain Compliance Plan and Compliance Options § 72.43 Phase I reduced... any Acid Rain emissions limitation or emissions reduction requirements during Phase I; and (ii) Meets... this section shall include in the Acid Rain permit application for the unit a reduced utilization plan...

40 CFR 72.43 - Phase I reduced utilization plans.

Code of Federal Regulations, 2012 CFR

2012-07-01

... (CONTINUED) PERMITS REGULATION Acid Rain Compliance Plan and Compliance Options § 72.43 Phase I reduced... any Acid Rain emissions limitation or emissions reduction requirements during Phase I; and (ii) Meets... this section shall include in the Acid Rain permit application for the unit a reduced utilization plan...

40 CFR 72.43 - Phase I reduced utilization plans.

Code of Federal Regulations, 2010 CFR

2010-07-01

... (CONTINUED) PERMITS REGULATION Acid Rain Compliance Plan and Compliance Options § 72.43 Phase I reduced... any Acid Rain emissions limitation or emissions reduction requirements during Phase I; and (ii) Meets... this section shall include in the Acid Rain permit application for the unit a reduced utilization plan...

Some structural features of the teichuronic acid of Bacillus licheniformis N.C.T.C. 6346 cell walls

PubMed Central

Hughes, R. C.; Thurman, P. F.

1970-01-01

A teichuronic acid, containing glucuronic acid and N-acetylgalactosamine, was purified from acid extracts of Bacillus licheniformis 6346 cell walls as described by Janczura, Perkins & Rogers (1961). After reduction of the carboxyl function of glucuronic acid residues in the polysaccharide the reduced polymer contains equimolar amounts of N-acetylgalactosamine and glucose. Methylation of the reduced polysaccharide by the Hakamori (1964) technique showed the glucose residues to be substituted on C-4. A disaccharide, 3-O-glucuronosylgalactosamine, was isolated from partial acid hydrolysates of teichuronic acid. After N-acetylation the disaccharide produces chromogen readily on heating at pH7, in agreement with C-3 substitution of the reducing N-acetylamino sugar. Teichuronic acid also produces chromogen under the same conditions, with concurrent elimination of a modified polysaccharide from C-3 of reducing terminal N-acetylgalactosamine residues of the teichuronic acid chains. The number-average chain lengths of several preparations of teichuronic acid were estimated from the amounts of chromogen produced in comparison with the N-acetylated disaccharide. The values obtained are in good agreement with the weight-average molecular weight determined by ultracentrifugal analysis. The reducing terminals of teichuronic acid are shown to be exclusively N-acetylgalactosamine by reduction with sodium boro[3H]hydride. The number-average chain lengths of the teichuronic acid preparations were estimated by the extent of in corporation of tritium and are in agreement with values obtained by the other methods. PMID:5419741

Gallic acid attenuates calcium calmodulin-dependent kinase II-induced apoptosis in spontaneously hypertensive rats.

PubMed

Jin, Li; Piao, Zhe Hao; Liu, Chun Ping; Sun, Simei; Liu, Bin; Kim, Gwi Ran; Choi, Sin Young; Ryu, Yuhee; Kee, Hae Jin; Jeong, Myung Ho

2018-03-01

Hypertension causes cardiac hypertrophy and leads to heart failure. Apoptotic cells are common in hypertensive hearts. Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is associated with apoptosis. We recently demonstrated that gallic acid reduces nitric oxide synthase inhibition-induced hypertension. Gallic acid is a trihydroxybenzoic acid and has been shown to have beneficial effects, such as anti-cancer, anti-calcification and anti-oxidant activity. The purpose of this study was to determine whether gallic acid regulates cardiac hypertrophy and apoptosis in essential hypertension. Gallic acid significantly lowered systolic and diastolic blood pressure in spontaneously hypertensive rats (SHRs). Wheat germ agglutinin (WGA) and H&E staining revealed that gallic acid reduced cardiac enlargement in SHRs. Gallic acid treatment decreased cardiac hypertrophy marker genes, including atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), in SHRs. The four isoforms, α, β, δ and γ, of CaMKII were increased in SHRs and were significantly reduced by gallic acid administration. Gallic acid reduced cleaved caspase-3 protein as well as bax, p53 and p300 mRNA levels in SHRs. CaMKII δ overexpression induced bax and p53 expression, which was attenuated by gallic acid treatment in H9c2 cells. Gallic acid treatment reduced DNA fragmentation and the TUNEL positive cells induced by angiotensin II. Taken together, gallic acid could be a novel therapeutic for the treatment of hypertension through suppression of CaMKII δ-induced apoptosis. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Topical Application of Tranexamic Acid to Reduce Blood Loss During Complex Combat Related Spine Trauma Surgery

DTIC Science & Technology

2015-10-01

AWARD NUMBER: W81XWH-14-2-0177 TITLE: Topical Application of Tranexamic Acid to Reduce Blood Loss During Complex Combat-Related Spine Trauma...COVERED (From - To) 30 Sep 2014 - 29 Sep 2015 4. TITLE AND SUBTITLE Topical Application of Tranexamic Acid to Reduce Blood Loss During Complex...application will be submitted shortly and successfully. 15. SUBJECT TERMS Spine; Tranexamic Acid ; Perioperative blood loss; Trauma; Antifibrinolytic

Prediction of bioavailability of selected bisphosphonates using in silico methods towards categorization into a biopharmaceutical classification system.

PubMed

Biernacka, Joanna; Betlejewska-Kielak, Katarzyna; Kłosińska-Szmurło, Ewa; Pluciński, Franciszek A; Mazurek, Aleksander P

2013-01-01

The physicochemical properties relevant to biological activity of selected bisphosphonates such as clodronate disodium salt, etidronate disodium salt, pamidronate disodium salt, alendronate sodium salt, ibandronate sodium salt, risedronate sodium salt and zoledronate disodium salt were determined using in silico methods. The main aim of our research was to investigate and propose molecular determinants thataffect bioavailability of above mentioned compounds. These determinants are: stabilization energy (deltaE), free energy of solvation (deltaG(solv)), electrostatic potential, dipole moment, as well as partition and distribution coefficients estimated by the log P and log D values. Presented values indicate that selected bisphosphonates a recharacterized by high solubility and low permeability. The calculated parameters describing both solubility and permeability through biological membranes seem to be a good bioavailability indicators of bisphosphonates examined and can be a useful tool to include into Biopharmaceutical Classification System (BCS) development.

Reduction of an E. coli O157:H7 and Salmonella composite on fresh strawberries by varying antimicrobial washes and vacuum perfusion.

PubMed

Gurtler, Joshua B; Bailey, Rebecca B; Jin, Tony Z; Fan, Xuetong

2014-10-17

A 2011 outbreak of hemorrhagic colitis, which resulted in the death of two individuals, was associated with contaminated strawberries. A study was conducted to identify antimicrobial washes effective at reducing E. coli O157:H7 and Salmonella enterica from the surface of fresh whole strawberries during two-minute immersion washes. Twenty-seven antimicrobial treatments were tested. Vacuum perfusion was applied to strawberries during chlorine and peracetic acid treatments to promote infiltration of sanitizer into porous strawberry tissue. Strawberries were inoculated to 7.1logCFU/strawberry with a seven-strain bacterial composite, consisting of three strains of E. coli O157:H7 and four serovars of Salmonella enterica. Berries were air-dried for 2h and immersed in circulating antimicrobial solutions for 120s at 22°C. Four treatments reduced ≥3.0logCFU/strawberry, including (a) 1% acetic acid+1% H2O2, (b) 30% ethanol+1% H2O2, (c) 90ppm peracetic acid, and (d) 1% lactic acid+1% H2O2. Two additional treatments that reduced 2.8logCFU/strawberry were (a) 40% ethanol, and (b) 1% each of phosphoric+fumaric acids. Eight treatments reduced 2.0-2.6logCFU/strawberry. Five treatments reduced <1.45CFU/strawberry, including (a) 1% citric acid, (b) 1% lactic acid, (c) 1% acetic acid, (d) 0.5% each of acetic+citric acids and (e) 0.5% each of acetic+lactic acids. The use of vacuum perfusion with 200ppm chlorine or 90ppm peracetic acid did not reduce greater populations of pathogens than did the same treatments without vacuum perfusion. Fourteen treatments reduced no more pathogens (p<0.05) than did sterile deionized water. Results from this study provide some options for end-point decontamination of strawberries for retail operations just prior to serving to customers. Published by Elsevier B.V.

Effect of replacing maize silage with red clover silage in the diet on milk fatty acid composition in cows.

PubMed

Schulz, Franziska; Westreicher-Kristen, Edwin; Molkentin, Joachim; Knappstein, Karin; Susenbeth, Andreas

2018-05-16

This study aimed to evaluate the effect of replacing maize silage plus soybean meal with red clover silage (RCS) plus wheat on the fatty acid (FA) profile in the milk fat of cows. Forty-four lactating German Holstein cows were used in a 4 × 4 Latin square design with 21-d periods composed of 13 d of adaptation to diets followed by an 8-d sampling phase. Experimental diets offered as total mixed ration consisted of a constant forage-to-concentrate ratio (75:25) with target proportions of RCS to maize silage of 15:60 (RCS 15 ), 30:45 (RCS 30 ), 45:30 (RCS 45 ), and 60:15 (RCS 60 ) on a dry matter basis. Increasing the level of RCS in the diet was accompanied by a reduction of linoleic acid content in the diet and decreased linearly the proportions of linoleic acid in the milk up to 4%. Proportions of α-linolenic acid in milk increased 2-fold with RCS 60 compared with RCS 15 , which resulted from the linear increase in α-linolenic acid intake with incremental levels of RCS. Vaccenic acid in the milk fat was reduced by 24%. Rumenic acid, a conjugated linoleic acid (cis-9,trans-11 conjugated linoleic acid) considered to be a human health promoter, was also decreased by 22%. Reduced rumenic acid in the milk fat was probably due to a reduced amount of vaccenic acid produced in the rumen and, consequently, to the low amount of vaccenic acid to be desaturated to rumenic acid in the mammary gland by Δ 9 -desaturase. Oleic acid was enriched in the milk fat, although the dietary concentration of oleic acid decreased. Stearic acid proportions remained constant with increasing levels of RCS. The proportions of total polyunsaturated FA were increased by 12%, and the long-chain FA proportions increased linearly with increasing levels of RCS. Myristic acid was reduced linearly, but palmitic acid remained constant. Saturated FA was reduced linearly by 2%. Branched-chain FA, which are presumed to possess anticarcinogenic properties, were reduced to a small extent only (quadratic effect). We conclude that replacing maize silage with RCS appears to alter milk FA composition by reducing linoleic acid intake and ruminal biohydrogenation. Feeding RCS represents a strategy to increase intake of α-linolenic acid in dairy cows. However, because changes in the FA profile show positive as well as negative effects, no distinct conclusions can be drawn with regard to human health benefits. Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Humic Acid Reduction by Propionibacterium freudenreichii and Other Fermenting Bacteria

PubMed Central

Benz, Marcus; Schink, Bernhard; Brune, Andreas

1998-01-01

Iron-reducing bacteria have been reported to reduce humic acids and low-molecular-weight quinones with electrons from acetate or hydrogen oxidation. Due to the rapid chemical reaction of amorphous ferric iron with the reduced reaction products, humic acids and low-molecular-weight redox mediators may play an important role in biological iron reduction. Since many anaerobic bacteria that are not able to reduce amorphous ferric iron directly are known to transfer electrons to other external acceptors, such as ferricyanide, 2,6-anthraquinone disulfonate (AQDS), or molecular oxygen, we tested several physiologically different species of fermenting bacteria to determine their abilities to reduce humic acids. Propionibacterium freudenreichii, Lactococcus lactis, and Enterococcus cecorum all shifted their fermentation patterns towards more oxidized products when humic acids were present; P. freudenreichii even oxidized propionate to acetate under these conditions. When amorphous ferric iron was added to reoxidize the electron acceptor, humic acids were found to be equally effective when they were added in substoichiometric amounts. These findings indicate that in addition to iron-reducing bacteria, fermenting bacteria are also capable of channeling electrons from anaerobic oxidations via humic acids towards iron reduction. This information needs to be considered in future studies of electron flow in soils and sediments. PMID:9797315

Enhanced lignin monomer production caused by cinnamic Acid and its hydroxylated derivatives inhibits soybean root growth.

PubMed

Lima, Rogério Barbosa; Salvador, Victor Hugo; dos Santos, Wanderley Dantas; Bubna, Gisele Adriana; Finger-Teixeira, Aline; Soares, Anderson Ricardo; Marchiosi, Rogério; Ferrarese, Maria de Lourdes Lucio; Ferrarese-Filho, Osvaldo

2013-01-01

Cinnamic acid and its hydroxylated derivatives (p-coumaric, caffeic, ferulic and sinapic acids) are known allelochemicals that affect the seed germination and root growth of many plant species. Recent studies have indicated that the reduction of root growth by these allelochemicals is associated with premature cell wall lignification. We hypothesized that an influx of these compounds into the phenylpropanoid pathway increases the lignin monomer content and reduces the root growth. To confirm this hypothesis, we evaluated the effects of cinnamic, p-coumaric, caffeic, ferulic and sinapic acids on soybean root growth, lignin and the composition of p-hydroxyphenyl (H), guaiacyl (G) and syringyl (S) monomers. To this end, three-day-old seedlings were cultivated in nutrient solution with or without allelochemical (or selective enzymatic inhibitors of the phenylpropanoid pathway) in a growth chamber for 24 h. In general, the results showed that 1) cinnamic, p-coumaric, caffeic and ferulic acids reduced root growth and increased lignin content; 2) cinnamic and p-coumaric acids increased p-hydroxyphenyl (H) monomer content, whereas p-coumaric, caffeic and ferulic acids increased guaiacyl (G) content, and sinapic acid increased sinapyl (S) content; 3) when applied in conjunction with piperonylic acid (PIP, an inhibitor of the cinnamate 4-hydroxylase, C4H), cinnamic acid reduced H, G and S contents; and 4) when applied in conjunction with 3,4-(methylenedioxy)cinnamic acid (MDCA, an inhibitor of the 4-coumarate:CoA ligase, 4CL), p-coumaric acid reduced H, G and S contents, whereas caffeic, ferulic and sinapic acids reduced G and S contents. These results confirm our hypothesis that exogenously applied allelochemicals are channeled into the phenylpropanoid pathway causing excessive production of lignin and its main monomers. By consequence, an enhanced stiffening of the cell wall restricts soybean root growth.

Treatment of menorrhagia during menstruation: randomised controlled trial of ethamsylate, mefenamic acid, and tranexamic acid.

PubMed Central

Bonnar, J.; Sheppard, B. L.

1996-01-01

OBJECTIVE: To compare the efficacy and acceptability of ethamsylate, mefenamic acid, and tranexamic acid for treating menorrhagia. DESIGN: Randomised controlled trial. SETTING: A university department of obstetrics and gynaecology. SUBJECTS: 76 women with dysfunctional uterine bleeding. INTERVENTIONS: Treatment for five days from day 1 of menses during three consecutive menstrual periods. 27 patients were randomised to take ethamsylate 500 mg six hourly, 23 patients to take mefenamic acid 500 mg eight hourly, and 26 patients to take tranexamic acid 1 g six hourly. MAIN OUTCOMES MEASURES: Menstrual loss measured by the alkaline haematin method in three control menstrual periods and three menstrual periods during treatment; duration of bleeding; patient's estimation of blood loss; sanitary towel usage; the occurrence of dysmenorrhoea; and unwanted events. RESULTS: Ethamsylate did not reduce mean menstrual blood loss whereas mefenamic acid reduced blood loss by 20% (mean blood loss 186 ml before treatment, 148 ml during treatment) and tranexamic acid reduced blood loss by 54% (mean blood loss 164 ml before treatment, 75 ml during treatment). Sanitary towel usage was significantly reduced in patients treated with mefenamic acid and tranexamic acid. CONCLUSIONS: Tranexamic acid given during menstruation is a safe and highly effective treatment for excessive bleeding. Patients with dysfunctional uterine bleeding should be offered medical treatment with tranexamic acid before a decision is made about surgery. PMID:8806245

Ascorbic acid glucoside reduces neurotoxicity and glutathione depletion in mouse brain induced by nitrotriazole radiosensitazer.

PubMed

Cherdyntseva, Nadezda V; Ivanova, Anna A; Ivanov, Vladimir V; Cherdyntsev, Evgeny; Nair, Cherupally Krishnan Krishnan; Kagiya, Tsutomu V

2013-01-01

To investigate the potential of the anti-oxidant ascorbic acid glucoside (AA-2G) to modulate neurotoxicity induced by high doses of nitrotriazole radiosensitizer. Male and female C56Bl/6xCBA hybrid mice aged 8-14 weeks (weight 18-24 g) were used. Nitrotriazole drug radiosensitizer sanazole at a high dose of 2, 1 g/kg was per os administered to induce neurotoxicity at mice. Ascorbic acid glucoside was given 30 min before the sanazole administration. Serum ascorbic acid, brain glutathione level, as well as behavioral performance using open field apparatus were measured. Administration of high (non-therapeutic) doses of the nitrotriazole drug sanazole results in neurotoxicity in mice as evidenced from behavioral performance, emotional activity and depletion of the cellular antioxidant, glutathione, in the brain. The serum levels of ascorbic acid was also found reduced in high dose sanazole treated animals. Per os administration of ascorbic acid glucoside significantly reduced the neurotoxicity. This effect was associated with the prevention of glutathione depletion in mouse brain and restoring the ascorbic acid level in serum. Administration of ascorbic acid glucoside, but not ascorbic acid, before sanazole administration protected from sanazole-induced neurotoxicity by preventing the decrease in the brain reduced glutathione level and providing high level of ascorbic acid in plasma.

A double-blind, placebo-controlled trial of epsilon-aminocaproic acid for reducing blood loss in coronary artery bypass grafting surgery.

PubMed

Kikura, Mutsuhito; Levy, Jerrold H; Tanaka, Kenichi A; Ramsay, James G

2006-02-01

Epsilon-aminocaproic acid is a plasmin inhibitor that potentially reduces perioperative bleeding when administered prophylactically to cardiac surgery patients. To evaluate the efficacy of epsilon-aminocaproic acid, a prospective placebo-controlled trial was conducted in patients undergoing primary coronary artery bypass grafting surgery. One hundred patients were randomly assigned to receive either epsilon-aminocaproic acid (100 mg/kg before skin incision followed by 1 g/hour continuous infusion until chest closure, 10 g in cardiopulmonary bypass circuit) or placebo, and the efficacy of epsilon-aminocaproic acid was evaluated by the reduction in postoperative thoracic-drainage volume and in donor-blood transfusion up to postoperative day 12. Postoperative thoracic-drainage volume was significantly lower in the epsilon-aminocaproic acid group compared with the placebo group (epsilon-aminocaproic acid, 649 +/- 261 mL; versus placebo, 940 +/- 626 mL; p=0.003). There were no significant differences between the epsilon-aminocaproic acid and placebo groups in the percentage of patients requiring donor red blood cell transfusions (epsilon-aminocaproic acid, 24%; versus placebo, 18%; p=0.62) or in the number of units of donor red blood cells transfused (epsilon-aminocaproic acid, 2.2 +/- 0.8 U; versus placebo, 1.9 +/- 0.8 U; p=0.29). Epsilon-aminocaproic acid did not reduce the risk of donor red blood cell transfusions compared with placebo (odds ratio: 1.2, 95% confidence interval; 0.4 to 3.2, p=0.63). Prophylactic administration of epsilon-aminocaproic acid reduces postoperative thoracic-drainage volume by 30%, but it may not be potent enough to reduce the requirement and the risk for donor blood transfusion in cardiac surgery patients. This information is useful for deciding on a therapy for hemostasis in cardiac surgery.

Acid-reducing vagotomy is associated with reduced risk of subsequent ischemic heart disease in complicated peptic ulcer: An Asian population study.

PubMed

Wu, Shih-Chi; Fang, Chu-Wen; Chen, William Tzu-Liang; Muo, Chih-Hsin

2016-12-01

Persistent exacerbation of a peptic ulcer may lead to a complicated peptic ulcer (perforation or/and bleeding). The management of complicated peptic ulcers has shifted from acid-reducing vagotomy, drainage, and gastrectomy to simple local suture or non-operative (endoscopic/angiographic) hemostasis. We were interested in the long-term effects of this trend change. In this study, complicated peptic ulcer patients who received acid-reducing vagotomy were compared with those who received simple suture/hemostasis to determine the risk of ischemic heart disease (IHD).This retrospective cohort study analyzed 335,680 peptic ulcer patients recorded from 2000 to 2006 versus 335,680 age-, sex-, comorbidity-, and index-year matched comparisons. Patients with Helicobacter pylori (HP) infection were excluded. In order to identify the effect of vagus nerve severance, patients who received gastrectomy or antrectomy were also excluded. The incidence of IHD in both cohorts, and in the complicated peptic ulcer patients who received acid-reducing vagotomy versus those who received simple suture or hemostasis was evaluated.The overall incidence of IHD was higher in patients with peptic ulcer than those without peptic ulcer (17.00 vs 12.06 per 1000 person-years), with an adjusted hazard ratio (aHR) of 1.46 based on multivariable Cox proportional hazards regression analysis controlling for age, sex, Charlson's comorbidity index, and death (competing risk). While comparing peptic ulcer patients with acid-reducing vagotomy to those with simple suture/hemostasis or those without surgical treatment, the aHR (0.58) was the lowest in the acid-reducing vagotomy group.Patients with peptic ulcer have an elevated risk of IHD. However, complicated peptic ulcer patients who received acid-reducing vagotomy were associated with reduced risk of developing IHD.

Acid-reducing vagotomy is associated with reduced risk of subsequent ischemic heart disease in complicated peptic ulcer

PubMed Central

Wu, Shih-Chi; Fang, Chu-Wen; Chen, William Tzu-Liang; Muo, Chih-Hsin

2016-01-01

Abstract Persistent exacerbation of a peptic ulcer may lead to a complicated peptic ulcer (perforation or/and bleeding). The management of complicated peptic ulcers has shifted from acid-reducing vagotomy, drainage, and gastrectomy to simple local suture or non-operative (endoscopic/angiographic) hemostasis. We were interested in the long-term effects of this trend change. In this study, complicated peptic ulcer patients who received acid-reducing vagotomy were compared with those who received simple suture/hemostasis to determine the risk of ischemic heart disease (IHD). This retrospective cohort study analyzed 335,680 peptic ulcer patients recorded from 2000 to 2006 versus 335,680 age-, sex-, comorbidity-, and index-year matched comparisons. Patients with Helicobacter pylori (HP) infection were excluded. In order to identify the effect of vagus nerve severance, patients who received gastrectomy or antrectomy were also excluded. The incidence of IHD in both cohorts, and in the complicated peptic ulcer patients who received acid-reducing vagotomy versus those who received simple suture or hemostasis was evaluated. The overall incidence of IHD was higher in patients with peptic ulcer than those without peptic ulcer (17.00 vs 12.06 per 1000 person-years), with an adjusted hazard ratio (aHR) of 1.46 based on multivariable Cox proportional hazards regression analysis controlling for age, sex, Charlson's comorbidity index, and death (competing risk). While comparing peptic ulcer patients with acid-reducing vagotomy to those with simple suture/hemostasis or those without surgical treatment, the aHR (0.58) was the lowest in the acid-reducing vagotomy group. Patients with peptic ulcer have an elevated risk of IHD. However, complicated peptic ulcer patients who received acid-reducing vagotomy were associated with reduced risk of developing IHD. PMID:27977613

Effect of azithromycin on acid reflux, hiatus hernia and proximal acid pocket in the postprandial period.

PubMed

Rohof, W O; Bennink, R J; de Ruigh, A A; Hirsch, D P; Zwinderman, A H; Boeckxstaens, G E

2012-12-01

The risk for acidic reflux is mainly determined by the position of the gastric acid pocket. It was hypothesised that compounds affecting proximal stomach tone might reduce gastro-oesophageal reflux by changing the acid pocket position. To study the effect of azithromycin (Azi) on acid pocket position and acid exposure in patients with gastro-oesophageal reflux disease (GORD). Nineteen patients with GORD were included, of whom seven had a large hiatal hernia (≥3 cm) (L-HH) and 12 had a small or no hiatal hernia (S-HH). Patients were randomised to Azi 250 mg/day or placebo during 3 days in a crossover manner. On each study day, reflux episodes were detected using concurrent high-resolution manometry and pH-impedance monitoring after a standardised meal. The acid pocket was visualised using scintigraphy, and its position was determined relative to the diaphragm. Azi reduced the number of acid reflux events (placebo 8.0±2.2 vs Azi 5.6±1.8, p<0.01) and postprandial acid exposure (placebo 10.5±3.8% vs Azi 5.9±2.5%, p<0.05) in all patients without affecting the total number of reflux episodes. Acid reflux occurred mainly when the acid pocket was located above, or at the level of, the diaphragm, rather than below the diaphragm. Treatment with Azi reduced hiatal hernia size and resulted in a more distal position of the acid pocket compared with placebo (below the diaphragm 39% vs 29%, p=0.03). Azi reduced the rate of acid reflux episodes in patients with S-HH (38% to 17%) to a greater extent than in patients with L-HH (69% to 62%, p=0.04). Azi reduces acid reflux episodes and oesophageal acid exposure. This effect was associated with a smaller hiatal hernia size and a more distal position of the acid pocket, further indicating the importance of the acid pocket in the pathogenesis of GORD. http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1970 NTR1970.

Investigation of the Prebiotic Synthesis of Amino Acids and RNA Bases from CO2 Using FeS/H2S As a Reducing Agent

NASA Technical Reports Server (NTRS)

Keefe, Anthony D.; Miller, Stanley L.; McDonald, Gene; Bada, Jeffrey

1995-01-01

An autotrophic theory of the origin of metabolism and life has been proposed in which carbon dioxide is reduced by ferrous sulfide and hydrogen sulfide by means of a reversed citric acid cycle, leading to the production of amino acids. Similar processes have been proposed for purine synthesis. Ferrous sulfide is a strong reducing agent in the presence of hydrogen sulfide and can produce hydrogen as well as reduce alkenes, alkynes, and thiols to saturated hydrocarbons and reduce ketones to thiols. However, the reduction of carbon dioxide has not been demonstrated. We show here that no amino acids, purities, or pyrimidines are produced from carbon dioxide with the ferrous sulfide and hydrogen sulfide system. Furthermore, this system does not produce amino acids from carboxylic acids by reductive amination and carboxylation. Thus, the proposed autotrophic theory, using carbon dioxide, ferrous sulfide, and hydrogen sulfide, lacks the robustness needed to be a geological process and is, therefore, unlikely to have played a role In the origin of metabolism or the origin of life.

Investigation of the Prebiotic Synthesis of Amino Acids and RNA Bases from CO2 using FeS/H2S as a Reducing Agent

NASA Technical Reports Server (NTRS)

Keefe, Anthony D.; Miller, Stanley L.; McDonald, Gene; Bada, Jeffrey

1995-01-01

An autotrophic theory of the origin of metabolism and life has been proposed in which carbon dioxide is reduced by ferrous sulfide and hydrogen sulfide by means of a reversed citric acid cycle, leading to the production of amino acids. Similar processes have been proposed for purine synthesis. Ferrous sulfide is a strong reducing agent in the presence of hydrogen sulfide and can produce hydrogen as well as reduce alkenes, alkynes, and thiols to saturated hydrocarbons and reduce ketones to thiols. However, the reduction of carbon dioxide has not been demonstrated. We show here that no amino acids, purines, or pyrimidines are produced from carbon dioxide with the ferrous sulfide and hydrogen sulfide system. Furthermore, this system does not produce amino acids from carboxylic acids by reductive amination and carboxylation. Thus, the proposed autotrophic theory, using carbon dioxide, ferrous sulfide, and hydrogen sulfide, lacks the robustness needed to be a geological process and is, therefore, unlikely to have played a role in the origin of metabolism or the origin of life.

Does daily folic acid supplementation reduce methotrexate efficacy?

PubMed

Cline, A; Jorizzo, J L

2017-11-15

Methotrexate is a mainstay treatment for autoimmune and inflammatory conditions in the field of Dermatology. However, in some patients, its use is associated with significant side effects and toxicity. Folate supplementation with either folic acid or folinic acid often mitigates side effects and reduces the incidence of systemic toxicity related to methotrexate. Although the value of methotrexate is clear, debate remains about folate supplementation. There is little agreement about the proper dosing or frequency of folate supplementation as many believe that daily folate supplementation can reduce methotrexate efficacy. Although daily use of folic acid does not appear to affect methotrexate efficacy, dosing of folinic acid close to methotrexate administration may hinder methotrexate efficacy. Therefore, folic acid should be used daily with methotrexate to ameliorate side effects, whereas folinic acid should only be used for methotrexate toxicity.

Effect of gallic and protocatechuic acids on the metabolism of ethyl carbamate in Chinese yellow rice wine brewing.

PubMed

Zhou, Wanyi; Fang, Ruosi; Chen, Qihe

2017-10-15

It was studied that gallic and protocatechuic acids played important roles in ethyl carbamate (EC) forming. Gallic and protocatechuic acids can reduce the arginine consumption through inhibiting the arginine deiminase enzyme. Therefore, they are generally added to regulate EC catabolism in the course of yellow rice wine leavening at the third day. In this work, gallic and protocatechuic acids made little influence on the growth of Saccharomyces cerevisiae. Besides, the addition of 200mg/L gallic or protocatechuic acid could prevent the transformation from urea/citrulline to EC. Gallic acid showed better inhibiting effect that the content of EC could be reduced by 91.9% at most. Furthermore, the production of amino acids and volatile flavor compounds are not markedly affected by phenolic compounds. The discoveries reveal that EC can be reduced by supplying gallic acid or protocatechuic acid while yellow rice wine leavening. Copyright © 2017 Elsevier Ltd. All rights reserved.

Saturated Fatty Acids and Cardiovascular Disease: Replacements for Saturated Fat to Reduce Cardiovascular Risk

PubMed Central

Briggs, Michelle A.; Petersen, Kristina S.; Kris-Etherton, Penny M.

2017-01-01

Dietary recommendations to decrease the risk of cardiovascular disease (CVD) have focused on reducing intake of saturated fatty acids (SFA) for more than 50 years. While the 2015–2020 Dietary Guidelines for Americans advise substituting both monounsaturated and polyunsaturated fatty acids for SFA, evidence supports other nutrient substitutions that will also reduce CVD risk. For example, replacing SFA with whole grains, but not refined carbohydrates, reduces CVD risk. Replacing SFA with protein, especially plant protein, may also reduce CVD risk. While dairy fat (milk, cheese) is associated with a slightly lower CVD risk compared to meat, dairy fat results in a significantly greater CVD risk relative to unsaturated fatty acids. As research continues, we will refine our understanding of dietary patterns associated with lower CVD risk. PMID:28635680

The xanthine oxidase inhibitor Febuxostat reduces tissue uric acid content and inhibits injury-induced inflammation in the liver and lung

PubMed Central

Kataoka, Hiroshi; Yang, Ke; Rock, Kenneth L.

2014-01-01

Necrotic cell death in vivo induces a robust neutrophilic inflammatory response and the resulting inflammation can cause further tissue damage and disease. Dying cells induce this inflammation by releasing pro-inflammatory intracellular components, one of which is uric acid. Cells contain high levels of intracellular uric acid, which is produced when purines are oxidized by the enzyme xanthine oxidase. Here we test whether a non-nucleoside xanthine oxidase inhibitor, Febuxostat (FBX), can reduce intracellular uric acid levels and inhibit cell death-induced inflammation in two different murine tissue injury models; acid-induced acute lung injury and acetaminophen liver injury. Infiltration of inflammatory cells induced by acid injection into lungs or peritoneal administration of acetaminophen was evaluated by quantification with flow cytometry and tissue myeloperoxidase activity in the presence or absence of FBX treatment. Uric acid levels in serum and tissue were measured before giving the stimuli and during inflammation. The impact of FBX treatment on the peritoneal inflammation caused by the microbial stimulus, zymosan, was also analyzed to see whether FBX had a broad anti-inflammatory effect. We found that FBX reduced uric acid levels in acid-injured lung tissue and inhibited acute pulmonary inflammation triggered by lung injury. Similarly, FBX reduced uric acid levels in the liver and inhibited inflammation in response to acetaminophen-induced hepatic injury. In contrast, FBX did not reduce inflammation to zymosan, and therefore is not acting as a general anti-inflammatory agent. These results point to the potential of using agents like FBX to treat cell death-induced inflammation. PMID:25449036

[Trance(s)--music and more].

PubMed

Stahl, Ziva; Grotto, Itamar; Moran, Dany; Ginsberg, Avidor

2013-12-01

The recent amendment, of the Israeli regulation for nutrition labeling on the packaged food label, as published in the government registry, mandates the labeling of trans fatty acids. The relationship between the types of fatty acids and the risk of developing heart disease is well known and has been researched for many years. As part of efforts of the health authorities around the world and in Israel to reduce morbidity and mortality from chronic diseases, the authorities act to reduce consumption of trans fatty acids and saturated fatty acids. This article reviews the major changes that have taken place in reducing the consumption of trans fatty acids in recent years. This includes the evidence which pointed to the negative effects of their use, the Latest recommendations of several leading health leading organization regarding optimal consumption of fats in particular and regarding nutrition in general. It also entails trends in the world food industry towards the reduction in trans fatty acids use, and policies countries are implementing in order to reduce the world's consumption of trans fatty acids, including the updating of nutritional labeling regulations in Israel.

Reduction of Campylobacter jejuni on chicken wings by chemical treatments.

PubMed

Zhao, Tong; Doyle, Michael P

2006-04-01

Eight chemicals, including glycerol monolaurate, hydrogen peroxide, acetic acid, lactic acid, sodium benzoate, sodium chlorate, sodium carbonate, and sodium hydroxide, were tested individually or in combination for their ability to inactivate Campylobacter jejuni at 4 degrees C in suspension. Results showed that treatment for up to 20 min with 0.01% glycerol monolaurate, 0.1% sodium benzoate, 50 or 100 mM sodium chlorate, or 1% lactic acid did not substantially (< or = 0.5 log CFU/ml) reduce C. jejuni populations but that 0.1 and 0.2% hydrogen peroxide for 20 min reduced C. jejuni populations by ca. 2.0 and 4.5 log CFU/ml, respectively. By contrast, treatments with 0.5, 1.0, 1.5, and 2.0% acetic acid, 25, 50, and 100 mM sodium carbonate, and 0.05 and 0.1 N sodium hydroxide reduced C. jejuni populations by >5 log CFU/ml within 2 min. A combination of 0.5% acetic acid plus 0.05% potassium sorbate or 0.5% acetic acid plus 0.05% sodium benzoate reduced C. jejuni populations by >5 log CFU/ml within 1 min; however, substituting 0.5% lactic acid for 0.5% acetic acid was not effective, with a reduction of C. jejuni of <0.5 log CFU/ml. A combination of acidic calcium sulfate, lactic acid, ethanol, sodium dodecyl sulfate, and polypropylene glycol (ACS-LA) also reduced C. jejuni in suspension by >5 log CFU/ml within 1 min. All chemicals or chemical combinations for which there was a >5-log/ml reduction of C. jejuni in suspension were further evaluated for C. jejuni inactivation on chicken wings. Treatments at 4 degrees C of 2% acetic acid, 100 mM sodium carbonate, or 0.1 N sodium hydroxide for up to 45 s reduced C. jejuni populations by ca. 1.4, 1.6, or 3.5 log CFU/g, respectively. Treatment with ACS-LA at 4 degrees C for 15 s reduced C. jejuni by >5 log CFU/g to an undetectable level. The ACS-LA treatment was highly effective in chilled water at killing C. jejuni on chicken and, if recycled, may be a useful treatment in chill water tanks for poultry processors to reduce campylobacters on poultry skin after slaughter.

Strategies for emission reduction of air pollutants produced from a chemical plant.

PubMed

Lee, Byeong-Kyu; Cho, Sung-Woong

2003-01-01

Various air pollution control (APC) techniques were employed in order to reduce emissions of air pollutants produced from chemical plants, which have many different chemical production facilities. For an emission reduction of acid gases, this study employed a method to improve solubility of pollutants by decreasing the operating temperature of the scrubbers, increasing the surface area for effective contact of gas and liquid, and modifying processes in the acid scrubbers. To reduce emission of both amines and acid gases, pollutant gas components were first separated, then condensation and/or acid scrubbing, depending on the chemical and physical properties of pollutant components, were used. To reduce emission of solvents, condensation and activated carbon adsorption were employed. To reduce emission of a mixture gases containing acid gases and solvents, the mixed gases were passed into the first condenser, the acid scrubber, the second condenser, and the activated carbon adsorption tower in sequence. As a strategy to reduce emission of pollutants at the source, this study also employed the simple pollution prevention concept of modification of the previously operating APC control device. Finally, air emissions of pollutants produced from the chemical plants were much more reduced by applying proper APC methods, depending upon the types (physical or chemical properties) and the specific emission situations of pollutants.

PseKRAAC: a flexible web server for generating pseudo K-tuple reduced amino acids composition.

PubMed

Zuo, Yongchun; Li, Yuan; Chen, Yingli; Li, Guangpeng; Yan, Zhenhe; Yang, Lei

2017-01-01

The reduced amino acids perform powerful ability for both simplifying protein complexity and identifying functional conserved regions. However, dealing with different protein problems may need different kinds of cluster methods. Encouraged by the success of pseudo-amino acid composition algorithm, we developed a freely available web server, called PseKRAAC (the pseudo K-tuple reduced amino acids composition). By implementing reduced amino acid alphabets, the protein complexity can be significantly simplified, which leads to decrease chance of overfitting, lower computational handicap and reduce information redundancy. PseKRAAC delivers more capability for protein research by incorporating three crucial parameters that describes protein composition. Users can easily generate many different modes of PseKRAAC tailored to their needs by selecting various reduced amino acids alphabets and other characteristic parameters. It is anticipated that the PseKRAAC web server will become a very useful tool in computational proteomics and protein sequence analysis. Freely available on the web at http://bigdata.imu.edu.cn/psekraac CONTACTS: yczuo@imu.edu.cn or imu.hema@foxmail.com or yanglei_hmu@163.comSupplementary information: Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Ascorbic acid reduces noise-induced nitric oxide production in the guinea pig ear.

PubMed

Heinrich, Ulf-Rüdiger; Fischer, Ilka; Brieger, Jürgen; Rümelin, Andreas; Schmidtmann, Irene; Li, Huige; Mann, Wolf J; Helling, Kai

2008-05-01

Noise-induced hearing loss can be caused, among other causes, by increased nitric oxide (NO) production in the inner ear leading to nitroactive stress and cell destruction. Some studies in the literature suggest that the degree of hearing loss (HL) could be reduced in an animal model through ascorbic acid supplementation. To identify the effect of ascorbic acid on tissue-dependent NO content in the inner ear of the guinea pig, we determined the local NO production in the organ of Corti and the lateral wall separately 6 hours after noise exposure. Prospective animal study in guinea pigs. Over a period of 7 days, male guinea pigs were supplied with minimum (25 mg/kg body weight/day) and maximum (525 mg/kg body weight/day) ascorbic acid doses, and afterwards exposed to noise (90 dB sound pressure level for 1 hour). The acoustic-evoked potentials were recorded before and after noise exposure. The organ of Corti and the lateral wall were incubated differently for 6 hours in culture medium, and the degree of NO production was determined by chemiluminescence. Ascorbic acid treatment reduced the hearing threshold shift after noise exposure depending on concentration. When the maximum ascorbic acid dose was substituted, NO production was significantly reduced in the lateral wall after noise exposure and slightly reduced in the organ of Corti. Oral supplementation of the natural radical scavenger ascorbic acid reduces the NO-production rate in the inner ear in noisy conditions. This finding supports the concept of inner ear protection by ascorbic acid supplementation.

Enhanced Lignin Monomer Production Caused by Cinnamic Acid and Its Hydroxylated Derivatives Inhibits Soybean Root Growth

PubMed Central

Lima, Rogério Barbosa; Salvador, Victor Hugo; dos Santos, Wanderley Dantas; Bubna, Gisele Adriana; Finger-Teixeira, Aline; Soares, Anderson Ricardo; Marchiosi, Rogério; Ferrarese, Maria de Lourdes Lucio; Ferrarese-Filho, Osvaldo

2013-01-01

Cinnamic acid and its hydroxylated derivatives (p-coumaric, caffeic, ferulic and sinapic acids) are known allelochemicals that affect the seed germination and root growth of many plant species. Recent studies have indicated that the reduction of root growth by these allelochemicals is associated with premature cell wall lignification. We hypothesized that an influx of these compounds into the phenylpropanoid pathway increases the lignin monomer content and reduces the root growth. To confirm this hypothesis, we evaluated the effects of cinnamic, p-coumaric, caffeic, ferulic and sinapic acids on soybean root growth, lignin and the composition of p-hydroxyphenyl (H), guaiacyl (G) and syringyl (S) monomers. To this end, three-day-old seedlings were cultivated in nutrient solution with or without allelochemical (or selective enzymatic inhibitors of the phenylpropanoid pathway) in a growth chamber for 24 h. In general, the results showed that 1) cinnamic, p-coumaric, caffeic and ferulic acids reduced root growth and increased lignin content; 2) cinnamic and p-coumaric acids increased p-hydroxyphenyl (H) monomer content, whereas p-coumaric, caffeic and ferulic acids increased guaiacyl (G) content, and sinapic acid increased sinapyl (S) content; 3) when applied in conjunction with piperonylic acid (PIP, an inhibitor of the cinnamate 4-hydroxylase, C4H), cinnamic acid reduced H, G and S contents; and 4) when applied in conjunction with 3,4-(methylenedioxy)cinnamic acid (MDCA, an inhibitor of the 4-coumarate:CoA ligase, 4CL), p-coumaric acid reduced H, G and S contents, whereas caffeic, ferulic and sinapic acids reduced G and S contents. These results confirm our hypothesis that exogenously applied allelochemicals are channeled into the phenylpropanoid pathway causing excessive production of lignin and its main monomers. By consequence, an enhanced stiffening of the cell wall restricts soybean root growth. PMID:24312480

Cranberry Juice and Combinations of Its Organic Acids Are Effective against Experimental Urinary Tract Infection.

PubMed

Jensen, Heidi D; Struve, Carsten; Christensen, Søren B; Krogfelt, Karen A

2017-01-01

The antibacterial effect of cranberry juice and the organic acids therein on infection by uropathogenic Escherichia coli was studied in an experimental mouse model of urinary tract infection (UTI). Reduced bacterial counts were found in the bladder ( P < 0.01) of mice drinking fresh cranberry juice. Commercially available cranberry juice cocktail also significantly reduced ( P < 0.01) bacterial populations in the bladder, as did the hydrophilic fraction of cranberry juice ( P < 0.05). Quinic, malic, shikimic, and citric acid, the preponderant organic acids in cranberry juice, were tested in combination and individually. The four organic acids also decreased bacterial levels in the bladder when administered together ( P < 0.001), and so did the combination of malic plus citric acid ( P < 0.01) and malic plus quinic acid ( P < 0.05). The other tested combinations of the organic acids, and the acids administered singly, did not have any effect in the UTI model. Apparently, the antibacterial effect of the organic acids from cranberry juice on UTI can be obtained by administering a combination of malic acid and either citric or quinic acid. This study show for the first time that cranberry juice reduce E. coli colonization of the bladder in an experimental mouse model of urinary tract infection and that the organic acids are active agents.

Growth Conditions To Reduce Oxalic Acid Content of Spinach

NASA Technical Reports Server (NTRS)

Johnson-Rutzke, Corinne

2003-01-01

A controlled-environment agricultural (CEA) technique to increase the nutritive value of spinach has been developed. This technique makes it possible to reduce the concentration of oxalic acid in spinach leaves. It is desirable to reduce the oxalic acid content because oxalic acid acts as an anti-nutritive calcium-binding component. More than 30 years ago, an enzyme (an oxidase) that breaks down oxalic acid into CO2 and H2O2 was discovered and found to be naturally present in spinach leaves. However, nitrate, which can also be present because of the use of common nitratebased fertilizers, inactivates the enzyme. In the CEA technique, one cuts off the supply of nitrate and keeps the spinach plants cool while providing sufficient oxygen. This technique provides the precise environment that enables the enzyme to naturally break down oxalate. The result of application of this technique is that the oxalate content is reduced by 2/3 in one week.

A sulfate-reducing bacterium with unusual growing capacity in moderately acidic conditions.

PubMed

Rampinelli, L R; Azevedo, R D; Teixeira, M C; Guerra-Sá, R; Leão, V A

2008-09-01

The use of sulfate-reducing bacteria (SRB) is a cost-effective route to treat sulfate- contaminated waters and precipitate metals. The isolation and characterization of a SRB strain from an AMD in a Brazilian tropical region site was carried out. With a moderately acidic pH (5.5), the C.1 strain began its growth and with continued growth, modified the pH accordingly. The strain under these conditions reduced sulfate at the same rate as an experiment performed using an initial pH of 7.0. The dsrB gene-based molecular approach was used for the characterization of this strain and its phylogenetic affiliation was similar to genus Desulfovibrio sp. The results show an SRB isolate with unexpected sulfate reducing capacity in moderately acidic conditions, bringing new possibilities for the treatment of AMD, as acid water would be neutralized to a mildly acidic condition.

[Intragastric utilization of antacids following meals in relation to stomach emptying].

PubMed

Lux, G; Hartog, C; Ruppin, H; Lederer, P; Schmitt, W

1983-03-01

Gastric acid secretion and gastric emptying rate was measured using double marker method and continuous titration of a liquid peptone test meal. Titration rate was significantly reduced by 30 ml of an aluminiumhydroxide- and magnesiumhydroxide containing antacid compound (Maalox). Acidity of gastric contents was reduced over a period of 48.4 +/- 9.1 min (mean +/- SD; endpoint of titration pH 5.5) and 77.6 +/- 2.0 min (pH 3.5) (p less than 0.05). The histamine H2-receptor blocker Ranitidine (0.25 mg/kg b.w.) and the antimuscarinic agent Pirenzepine reduced titrable gastric acid secretion in a similar range, as far as the observation period of 90 min is concerned. Biosorbin MCT, a formula diet, stimulated gastric acid secretion half the amount of gastric acid secretion stimulated by the peptone meal. Gastric emptying rate was significantly reduced by formula diet, but not by either of the other compounds.

NASA and ESA Collaboration on Alternative to Nitric Acid Passivation: Parameter Optimization of Citric Acid Passivation for Stainless Steel Alloys

NASA Technical Reports Server (NTRS)

Kessel, Kurt R.

2016-01-01

National Aeronautics and Space Administration (NASA) Headquarters chartered the Technology Evaluation for Environmental Risk Mitigation Principal Center (TEERM) to coordinate agency activities affecting pollution prevention issues identified during system and component acquisition and sustainment processes. The primary objectives of NASA TEERM are to: Reduce or eliminate the use of hazardous materials or hazardous processes at manufacturing, remanufacturing, and sustainment locations. Avoid duplication of effort in actions required to reduce or eliminate hazardous materials through joint center cooperation and technology sharing. Corrosion is an extensive problem that affects the National Aeronautics and Space Administration (NASA) and the European Space Agency (ESA). The damaging effects of corrosion result in steep costs, asset downtime affecting mission readiness, and safety risks to personnel. Consequently, it is vital to reduce corrosion costs and risks in a sustainable manner. NASA and ESA have numerous structures and equipment that are fabricated from stainless steel. The standard practice for protection of stainless steel is a process called passivation. Passivation is defined by The American Heritage Dictionary of the English Language as to treat or coat (a metal) in order to reduce the chemical reactivity of its surface. Passivation works by forming a shielding outer (metal oxide) layer that reduces the impact of destructive environmental factors such as air or water. Consequently, this process necessitates a final product that is very clean and free of iron and other contaminants. Typical passivation procedures call for the use of nitric acid; however, there are a number of environmental, worker safety, and operational issues associated with its use. Citric acid is an alternative to nitric acid for the passivation of stainless steels. Citric acid offers a variety of benefits including increased safety for personnel, reduced environmental impact, and reduced operational cost. The primary objective of this effort is to qualify citric acid as an environmentally-preferable alternative to nitric acid for the passivation of stainless steel alloys. While citric acid use has become more prominent in industry, there is little evidence that citric acid is a technically sound passivation agent, especially for the unique and critical applications encountered by NASA and ESA.

Suitable Concentrations of Uric Acid Can Reduce Cell Death in Models of OGD and Cerebral Ischemia-Reperfusion Injury.

PubMed

Zhang, Bin; Yang, Ning; Lin, Shao-Peng; Zhang, Feng

2017-07-01

Cerebral infarction (CI) is a common clinical cerebrovascular disease, and to explore the pathophysiological mechanisms and seek effective treatment means are the hotspot and difficult point in medical research nowadays. Numerous studies have confirmed that uric acid plays an important role in CI, but the mechanism has not yet been clarified. When treating HT22 and BV-2 cells with different concentrations of uric acid, uric acid below 450 μM does not have significant effect on cell viability, but uric acid more than 500 μM can significantly inhibit cell viability. After establishing models of OGD (oxygen-glucose deprivation) with HT22 and BV-2 cells, uric acid at a low concentration (50 μM) cannot improve cell viability and apoptosis, and Reactive oxygen species (ROS) levels during OGD/reoxygenation; a suitable concentration (300 μM) of uric acid can significantly improve cell viability and apoptosis, and reduce ROS production during OGD/reoxygenation; but a high concentration (1000 μM) of uric acid can further reduce cell viability and enhance ROS production. After establishing middle cerebral artery occlusion of male rats with suture method, damage and increase of ROS production in brain tissue could be seen, and after adding suitable concentration of uric acid, the degree of brain damage and ROS production was reduced. Therefore, different concentrations of uric acid should have different effect, and suitable concentrations of uric acid have neuroprotective effect, and this finding may provide guidance for study on the clinical curative effect of uric acid.

Efficacy of anti-osteoporotic medications in patients with type 1 and 2 diabetes mellitus: a systematic review.

PubMed

Anagnostis, Panagiotis; Paschou, Stavroula A; Gkekas, Nifon N; Artzouchaltzi, Aikaterini-Maria; Christou, Konstantinos; Stogiannou, Dimitrios; Vryonidou, Andromachi; Potoupnis, Michael; Goulis, Dimitrios G

2018-06-01

Both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) have been associated with bone fragility and increased fracture risk. However, little is known regarding the effect of anti-osteoporotic treatment on bone mineral density (BMD) and/or fracture risk in these patients. We aimed to systematically investigate the efficacy of anti-osteoporotic medications in patients with diabetes in comparison with non-diabetic subjects. MEDLINE and Scopus databases were searched (up to 31st October 2017). Nine studies fulfilled the pre-defined inclusion criteria [patients with T2DM (n = 8) or either T1DM or T2DM (n = 1)]. Regarding fracture risk, five studies were identified. Alendronate demonstrated comparable vertebral anti-fracture efficacy in patients with and without diabetes (n = 2), whereas non-vertebral fracture risk was either the same (n = 1) or higher in diabetic patients (n = 1). Raloxifene also demonstrated comparable vertebral anti-fracture efficacy in both groups (n = 2), without any effect on non-vertebral fractures in either group. In one study, diabetic patients exposed to raloxifene demonstrated the same vertebral and non-vertebral fracture risk with non-diabetic patients. Teriparatide (n = 1) demonstrated the same non-vertebral fracture rates in both patients with and without T2DM. Regarding BMD, equal increases in spine BMD were observed with alendronate (n = 4), risedronate (n = 1), and teriparatide (n = 1). With respect to hip BMD, similar increases were observed with teriparatide (n = 1), whereas data regarding alendronate were controversial (n = 3). No eligible study was found for zoledronic acid, ibandronate, strontium ranelate, denosumab, or bazedoxifene. The presence of diabetes does not alter anti-osteoporotic treatment response, regarding BMD increase and vertebral fracture risk reduction.

Acute Kidney Injury and Bisphosphonate Use in Cancer: A Report From the Research on Adverse Drug Events and Reports (RADAR) Project

PubMed Central

Edwards, Beatrice J.; Usmani, Sarah; Raisch, Dennis W.; McKoy, June M.; Samaras, Athena T.; Belknap, Steven M.; Trifilio, Steven M.; Hahr, Allison; Bunta, Andrew D.; Abu-Alfa, Ali; Langman, Craig B.; Rosen, Steve T.; West, Dennis P.

2013-01-01

Purpose: To determine whether acute kidney injury (AKI) is identified within the US Food and Drug Administration's Adverse Events and Reporting System (FDA AERS) as an adverse event resulting from bisphosphonate (BP) use in cancer therapy. Methods: A search of the FDA AERS records from January 1998 through June 2009 was performed; search terms were “renal problems” and all drug names for BPs. The search resulted in 2,091 reports. We analyzed for signals of disproportional association by calculating the proportional reporting ratio for zoledronic acid (ZOL) and pamidronate. Literature review of BP-associated renal injury within the cancer setting was conducted. Results: Four hundred eighty cases of BP-associated acute kidney injury (AKI) were identified in patients with cancer. Two hundred ninety-eight patients (56%) were female; mean age was 66 ± 10 years. Multiple myeloma (n = 220, 46%), breast cancer (n = 98, 20%), and prostate cancer (n = 24, 5%) were identified. Agents included ZOL (n = 411, 87.5%), pamidronate (n = 8, 17%), and alendronate (n = 36, 2%). Outcomes included hospitalization (n = 304, 63.3%) and death (n = 68, 14%). The proportional reporting ratio for ZOL was 1.22 (95% CI, 1.13 to 1.32) and for pamidronate was 1.55 (95% CI, 1.25 to 1.65), reflecting a nonsignificant safety signal for both drugs. Conclusion: AKI was identified in BP cancer clinical trials, although a safety signal for BPs and AKI within the FDA AERS was not detected. Our findings may be attributed, in part, to clinicians who believe that AKI occurs infrequently; ascribe the AKI to underlying premorbid disease, therapy, or cancer progression; or consider that AKI is a known adverse drug reaction of BPs and thus under-report AKI to the AERS. PMID:23814519

Existing data sources for clinical epidemiology: Scandinavian Cohort for osteonecrosis of the jaw – work in progress and challenges

PubMed Central

Schiodt, Morten; Larsson Wexell, Cecilia; Herlofson, Bente Brokstad; Giltvedt, Karen Marie; Norholt, Sven Erik; Ehrenstein, Vera

2015-01-01

Osteonecrosis of the jaw (ONJ) is a severe side effect associated with antiresorptive treatment. Monitoring of ONJ using routine databases in Scandinavian countries is a challenge owing to lack of valid algorithms and to heterogeneous referral practices. The aim of this paper is to describe the process of establishing a Scandinavian ONJ Cohort enrolling all ONJ cases related to antiresorptive treatment arising in Denmark, Norway, and Sweden between 2011 and 2019. The initial purpose of the cohort is to support an ongoing pharmacovigilance study of denosumab and zoledronic acid in Denmark, Norway, and Sweden. The three countries, with their 199 clinics, departments, and units of oral and maxillofacial surgery, both hospital-based and freestanding, differ somewhat in referral practices of the ONJ patients. By directly contacting all providers of care to ONJ patients in the three countries, we established a network for reporting incident cases to each country’s research database directly or through a member of the Scandinavian ONJ task force as a liaison. The task force includes a Scandinavian coordinator and three national coordinators collaborating directly with the clinics. A uniform ONJ registration form has been developed, and the relevant medical community has been informed either directly or through presentations at professional meetings. A website with study information is published in each country, and data entry is ongoing. This large-scale systematic uniform registration of ONJ cases in Denmark, Norway, and Sweden, with an underlying total population of more than 20 million people, merged into the Scandinavian ONJ Cohort, will contribute to better knowledge and understanding of this challenging group of patients, and ultimately, help improve patient care. The Scandinavian ONJ Cohort as a whole and its component national ONJ research databases may offer the potential for large-scale multinational intervention and safety studies in the future. PMID:25657594

New agents for prostate cancer.

PubMed

Agarwal, N; Di Lorenzo, G; Sonpavde, G; Bellmunt, J

2014-09-01

The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has been revolutionized by the arrival of multiple novel agents in the past 2 years. Immunotherapy in the form of sipuleucel-T, androgen axis inhibitors, including abiraterone acetate and enzalutamide, a chemotherapeutic agent, cabazitaxel, and a radiopharmaceutical, radium-223, have all yielded incremental extensions of survival and have been recently approved. A number of other agents appear promising in early studies, suggesting that the armamentarium against castrate-resistant prostate cancer is likely to continue to expand. Emerging androgen pathway inhibitors include androgen synthesis inhibitors (TAK700), androgen receptor inhibitors (ARN-509, ODM-201), AR DNA binding domain inhibitors (EPI-001), selective AR downregulators or SARDs (AZD-3514), and agents that inhibit both androgen synthesis and receptor binding (TOK-001/galeterone). Promising immunotherapeutic agents include poxvirus vaccines and CTLA-4 inhibitor (ipilimumab). Biologic agents targeting the molecular drivers of disease are also being investigated as single agents, including cabozantinib (Met and VEGFR2 inhibitor) and tasquinimod (angiogenesis and immune modulatory agent). Despite the disappointing results seen from studies evaluating docetaxel in combination with other agents, including GVAX, anti-angiogentic agents (bevacizumab, aflibercept, lenalinomide), a SRC kinase inhibitor (dasatinib), endothelin receptor antagonists (atrasentan, zibotentan), and high-dose calcitriol (DN-101), the results from the trial evaluating docetaxel in combination with the clusterin antagonist, custirsen, are eagerly awaited. New therapeutic hurdles consist of discovering new targets, understanding resistance mechanisms, the optimal sequencing and combinations of available agents, as well as biomarkers predictive for benefit. Novel agents targeting bone metastases are being developed following the success of zoledronic acid and denosumab. Finally, all of these modalities do not appear curative, suggesting that clinical trial enrollment and a better understanding of biology remain of paramount importance. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Preventive Effect of Phosphodiesterase Inhibitor Pentoxifylline Against Medication-Related Osteonecrosis of the Jaw: An Animal Study.

PubMed

Yalcin-Ulker, Gül Merve; Cumbul, Alev; Duygu-Capar, Gonca; Uslu, Ünal; Sencift, Kemal

2017-11-01

The aim of this experimental study was to investigate the prophylactic effect of pentoxifylline (PTX) on medication-related osteonecrosis of the jaw (MRONJ). Female Sprague-Dawley rats (n = 33) received zoledronic acid (ZA) for 8 weeks to create an osteonecrosis model. The left mandibular second molars were extracted and the recovery period lasted 8 weeks before sacrifice. PTX was intraperitoneally administered to prevent MRONJ. The specimens were histopathologically and histomorphometrically evaluated. Histomorphometrically, between the control and ZA groups, there was no statistically significant difference in total bone volume (P = .999), but there was a statistically significant difference in bone ratio in the extraction sockets (P < .001). A comparison of the bone ratio of the ZA group with the ZA/PTX group (PTX administered after extraction) showed no statistically significant difference (P = .69), but there was a statistically significant difference with the ZA/PTX/PTX group (PTX administered before and after extraction; P = .008). Histopathologically, between the control and ZA groups, there were statistically significant differences for inflammation (P = .013), vascularization (P = .022), hemorrhage (P = .025), and regeneration (P = .008). Between the ZA and ZA/PTX groups, there were no statistically significant differences for inflammation (P = .536), vascularization (P = .642), hemorrhage (P = .765), and regeneration (P = .127). Between the ZA and ZA/PTX/PTX groups, there were statistically significant differences for inflammation (P = .017), vascularization (P = .04), hemorrhage (P = .044), and regeneration (P = .04). In this experimental model of MRONJ, it might be concluded that although PTX, given after tooth extraction, improves new bone formation that positively affects bone healing, it is not prophylactic. However, PTX given before tooth extraction is prophylactic. Therefore, PTX might affect healing in a positive way by optimizing the inflammatory response. Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Isoliquiritigenin, a flavonoid from licorice, blocks M2 macrophage polarization in colitis-associated tumorigenesis through downregulating PGE{sub 2} and IL-6

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhao, Haixia; Zhang, Xinhua; Chen, Xuewei

M2 macrophage polarization is implicated in colorectal cancer development. Isoliquiritigenin (ISL), a flavonoid from licorice, has been reported to prevent azoxymethane (AOM) induced colon carcinogenesis in animal models. Here, in a mouse model of colitis-associated tumorigenesis induced by AOM/dextran sodium sulfate (DSS), we investigated the chemopreventive effects of ISL and its mechanisms of action. Mice were treated with AOM/DSS and randomized to receive either vehicle or ISL (3, 15 and 75 mg/kg). Tumor load, histology, immunohistochemistry, and gene and protein expressions were determined. Intragastric administration of ISL for 12 weeks significantly decreased colon cancer incidence, multiplicity and tumor size bymore » 60%, 55.4% and 42.6%, respectively. Moreover, ISL inhibited M2 macrophage polarization. Such changes were accompanied by downregulation of PGE{sub 2} and IL-6 signaling. Importantly, depletion of macrophages by clodronate (Clod) or zoledronic acid (ZA) reversed the effects of ISL. In parallel, in vitro studies also demonstrated that ISL limited the M2 polarization of RAW264.7 cells and mouse peritoneal macrophages with concomitant inactivation of PGE{sub 2}/PPARδ and IL-6/STAT3 signaling. Conversely, exogenous addition of PGE{sub 2} or IL-6, or overexpression of constitutively active STAT3 reversed ISL-mediated inhibition of M2 macrophage polarization. In summary, dietary flavonoid ISL effectively inhibits colitis-associated tumorigenesis through hampering M2 macrophage polarization mediated by the interplay between PGE{sub 2} and IL-6. Thus, inhibition of M2 macrophage polarization is likely to represent a promising strategy for chemoprevention of colorectal cancer. - Highlights: • Isoliquiritigenin (ISL) prevents colitis-associated tumorigenesis. • ISL inhibits M2 macrophage polarization in vivo and in vitro. • ISL inhibits PGE{sub 2} and IL-6 signaling in colitis-associated tumorigenesis. • ISL may be an attractive candidate agent for chemoprevention of colorectal cancer.« less

Variation in the days supply field for osteoporosis medications in Ontario.

PubMed

Burden, Andrea M; Huang, Anjie; Tadrous, Mina; Cadarette, Suzanne M

2013-01-01

We examined pharmacy claims for osteoporosis medications dispensed in the community (78 %) and long-term care (LTC) to determine if days supply values matched expected dosing intervals. Results identify potential reporting errors that can have implications for drug exposure misclassification, particularly in LTC where only 59 % of reported values matched expected values. The days supply field is commonly used to examine patterns of drug utilization and classify drug exposure, yet its accuracy has received little attention. We sought to describe the days supply reported for osteoporosis drugs and examine if values matched expected therapeutic dosing intervals. We examined days supply values for osteoporosis medications submitted to the Ontario Drug Benefits program for seniors, 1997-2011. Days supply values were evaluated by dosing regimen and setting (community or long-term care [LTC]) and compared to pre-defined expected values. We defined expected days supply by the therapeutic dosing interval: daily in 7- or 30-day intervals, or as 100 days; weekly in 7- or 30-day intervals; monthly and daily nasal spray in 28- or 30-day intervals; and cyclical etidronate as a 90-day supply. We identified 17,615,404 osteoporosis prescriptions, with 78 % dispensed in the community. Most daily oral prescriptions were dispensed by an expected therapeutic dosing interval (97 %). Annual IV zoledronic acid was most commonly dispensed as a 1-day supply (62 %). Distinct differences in agreement were observed for other regimens, with the expected days supply more commonly reported in community versus LTC: cyclical etidronate (86 % vs. 40 %), weekly (91 % vs. 60 %), monthly (94 % vs. 35 %), and nasal spray (84 % vs. 40 %). Results suggest that inaccuracies in the days supply field exist, particularly among prescriptions dispensed in LTC. Inaccurate reporting may have significant implications for osteoporosis drug exposure misclassification.

Cranial base pathology in pediatric osteogenesis imperfecta patients treated with bisphosphonates.

PubMed

Arponen, Heidi; Vuorimies, Ilkka; Haukka, Jari; Valta, Helena; Waltimo-Sirén, Janna; Mäkitie, Outi

2015-03-01

Cranial base pathology is a serious complication of osteogenesis imperfecta (OI). Our aim was to analyze whether bisphosphonate treatment, used to improve bone strength, could also prevent the development of craniocervical junction pathology (basilar impression, basilar invagination, or platybasia) in children with OI. In this single-center retrospective study the authors analyzed the skull base morphology from lateral skull radiographs and midsagittal MR images (total of 94 images), obtained between the ages of 0 and 25 years in 39 bisphosphonate-treated OI patients. The results were compared with age-matched normative values and with findings in 70 OI patients who were not treated with bisphosphonates. In addition to cross-sectional data, longitudinal data were available from 22 patients with an average follow-up period of 7.6 years. The patients, who had OI types I, III, IV, VI, and VII, had been treated with zoledronic acid, pamidronate, or risedronate for 3.2 years on average. Altogether 33% of the 39 bisphosphonate-treated patients had at least 1 cranial base anomaly, platybasia being the most prevalent diagnosis (28%). Logistic regression analysis suggested a higher risk of basilar impression or invagination in patients with severe OI (OR 22.04) and/or older age at initiation of bisphosphonate treatment (OR 1.45), whereas a decreased risk was associated with longer duration of treatment (OR 0.28). No significant associations between age, height, or cumulative bisphosphonate dose and the risk for cranial base anomaly were detected. In longitudinal evaluation, Kaplan-Meier curves suggested delayed development of cranial base pathology in patients treated with bisphosphonates but the differences from the untreated group were not statistically significant. These findings indicate that cranial base pathology may develop despite bisphosphonate treatment. Early initiation of bisphosphonate treatment may delay development of craniocervical junction pathology. Careful followup of cranial base morphology is warranted, particularly in patients with severe OI.

Dopamine induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages in rat C6 glioma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qin, Tian; Wang, Chenlong; Chen, Xuewei

Dopamine (DA), a monoamine catecholamine neurotransmitter with antiangiogenic activity, stabilizes tumor vessels in colon, prostate and ovarian cancers, thus increases chemotherapeutic efficacy. Here, in the rat C6 glioma models, we investigated the vascular normalization effects of DA and its mechanisms of action. DA (25, 50 mg/kg) inhibited tumor growth, while a precursor of DA (levodopa) prolonged the survival time of rats bearing orthotopic C6 glioma. DA improved tumor perfusion, with significant effects from day 3, and a higher level at days 5 to 7. In addition, DA decreased microvessel density and hypoxia-inducible factor-1α expression in tumor tissues, while increasing themore » coverage of pericyte. Conversely, an antagonist of dopamine receptor 2 (DR2) (eticlopride) but not DR1 (butaclamol) abrogated DA-induced tumor regression and vascular normalization. Furthermore, DA improved the delivery and efficacy of temozolomide therapy. Importantly, DA increased representative M1 markers (iNOS, CXCL9, etc.), while decreasing M2 markers (CD206, arginase-1, etc.). Depletion of macrophages by clodronate or zoledronic acid attenuated the effects of DA. Notably, DA treatment induced M2-to-M1 polarization in RAW264.7 cells and mouse peritoneal macrophages, and enhanced the migration of pericyte-like cells (10T1/2), which was reversed by eticlopride or DR2-siRNA. Such changes were accompanied by the downregulation of VEGF/VEGFR2 signaling. In summary, DA induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages. Thus, targeting the tumor microvasculature by DA represents a promising strategy for human glioma therapy. - Highlights: • Dopamine induces tumor growth inhibition and vascular normalization in rat C6 glioma. • Dopamine switches macrophage phenotype from M2 to M1. • Dopamine-induced vascular normalization is mediated by macrophage polarization. • Dopamine is a promising agent targeting the microvasculature in tumor microenvironment.« less

Managing Osteoporosis Patients after Long-Term Bisphosphonate Treatment

PubMed Central

Adler, Robert A.; Fuleihan, Ghada El-Hajj; Bauer, Douglas C.; Camacho, Pauline M.; Clarke, Bart L.; Clines, Gregory A.; Compston, Juliet E.; Drake, Matthew T.; Edwards, Beatrice J.; Favus, Murray J.; Greenspan, Susan L.; McKinney, Ross; Pignolo, Robert J.; Sellmeyer, Deborah E.

2016-01-01

Bisphosphonates (BPs) are the most commonly used medications for osteoporosis, but optimal duration of therapy is unknown. This ASBMR report provides guidance on BP therapy duration with a risk benefit perspective. Two trials provided evidence for long-term BP use. In the Fracture Intervention Trial Long-term Extension (FLEX), postmenopausal women receiving alendronate for 10 years had fewer clinical vertebral fractures than those switched to placebo after 5 years. In the HORIZON extension, women who received 6 annual infusions of zoledronic acid had fewer morphometric vertebral fractures compared with those switched to placebo after 3 years. Low hip T-score between −2 and −2.5 in FLEX and below −2.5 in HORIZON extension predicted a beneficial response to continued therapy. Hence, the Task Force suggests that after 5 years of oral BP or 3 years of intravenous BP, women should be reassessed. Women with previous major osteoporotic fracture, those who fracture on therapy, or others at high risk should generally continue therapy for up to 10 years (oral) or 6 years (intravenous), with periodic risk-benefit evaluation. Older women, those with a low hip T-score or high fracture risk score are considered high risk. The risk of osteonecrosis of the jaw and atypical femoral fracture increases with BP therapy duration, but such rare events are far outweighed by fracture risk reduction with BPs in high risk patients. For women not at high fracture risk after 3–5 years of BP treatment, a drug holiday of 2–3 years can be considered, with periodic reassessment. The algorithm provided for long term BP use is based on limited evidence in mostly Caucasian postmenopausal women and only for vertebral fracture reduction. It is probably applicable to men and patients with glucocorticoid-induced osteoporosis, with some adaptations. It is unlikely that future osteoporosis trials will provide data for formulating definitive recommendations. PMID:26350171

Remediation of Acid Mine Drainage with Sulfate Reducing Bacteria

ERIC Educational Resources Information Center

Hauri, James F.; Schaider, Laurel A.

2009-01-01

Sulfate reducing bacteria have been shown to be effective at treating acid mine drainage through sulfide production and subsequent precipitation of metal sulfides. In this laboratory experiment for undergraduate environmental chemistry courses, students design and implement a set of bioreactors to remediate acid mine drainage and explain observed…

Hybrid drug combination: Combination of ferulic acid and metformin as anti-diabetic therapy.

PubMed

Nankar, Rakesh; Prabhakar, P K; Doble, Mukesh

2017-12-15

Ferulic acid, an anti-oxidant phytochemical present in several dietary components, is known to produce wide range of pharmacological effects. It is approved for use in food industry as a preservative and in sports food. Previous reports from our lab have shown synergistic interaction of ferulic acid with metformin in cell lines and diabetic rats. The purpose of this review is to compile information about anti-diabetic activity of ferulic acid in in vitro and in vivo models with special emphasis on activity of ferulic acid when combined with metformin. The mechanism of synergistic interaction between ferulic acid and metformin is also proposed after carefully studying effects of these compounds on molecules involved in glucose metabolism. Scientific literature for the purpose of this review was collected using online search engines and databases such as ScienceDirect, Scopus, PubMed and Google scholar. Ferulic acid forms resonance stabilized phenoxyl radical which scavenges free radicals and reduce oxidative stress. It improves glucose and lipid profile in diabetic rats by enhancing activities of antioxidant enzymes, superoxide dismutase and catalase in the pancreatic tissue. Combining ferulic acid with metformin improves both, in vitro glucose uptake activity and in vivo hypoglycemic activity of the latter. It is possible to reduce the dose of metformin by four folds (from 50 to 12.5 mg/kg body weight) by combining it with 10 mg of ferulic acid/kg body weight in diabetic rats. Ferulic acid improves glucose uptake through PI3-K pathway whereas metformin activates AMPK pathway to improve glucose uptake. The synergistic interaction of ferulic acid and metformin is due their action on parallel pathways which are involved in glucose uptake. Due to synergistic nature of their interaction, it is possible to reduce the dose of metformin (by combining with ferulic acid) required to achieve normoglycemia. Since the dose of metformin is reduced, the dose associated side effects of metformin therapy can be reduced. Copyright © 2017 Elsevier GmbH. All rights reserved.

Amino acid homeostasis and signalling in mammalian cells and organisms

PubMed Central

Bröer, Angelika

2017-01-01

Cells have a constant turnover of proteins that recycle most amino acids over time. Net loss is mainly due to amino acid oxidation. Homeostasis is achieved through exchange of essential amino acids with non-essential amino acids and the transfer of amino groups from oxidised amino acids to amino acid biosynthesis. This homeostatic condition is maintained through an active mTORC1 complex. Under amino acid depletion, mTORC1 is inactivated. This increases the breakdown of cellular proteins through autophagy and reduces protein biosynthesis. The general control non-derepressable 2/ATF4 pathway may be activated in addition, resulting in transcription of genes involved in amino acid transport and biosynthesis of non-essential amino acids. Metabolism is autoregulated to minimise oxidation of amino acids. Systemic amino acid levels are also tightly regulated. Food intake briefly increases plasma amino acid levels, which stimulates insulin release and mTOR-dependent protein synthesis in muscle. Excess amino acids are oxidised, resulting in increased urea production. Short-term fasting does not result in depletion of plasma amino acids due to reduced protein synthesis and the onset of autophagy. Owing to the fact that half of all amino acids are essential, reduction in protein synthesis and amino acid oxidation are the only two measures to reduce amino acid demand. Long-term malnutrition causes depletion of plasma amino acids. The CNS appears to generate a protein-specific response upon amino acid depletion, resulting in avoidance of an inadequate diet. High protein levels, in contrast, contribute together with other nutrients to a reduction in food intake. PMID:28546457

Reducing capacity, chlorogenic acid content and biological activity in a collection of scarlet (Solanum aethiopicum) and Gboma (S. macrocarpon) eggplants.

PubMed

Plazas, Mariola; Prohens, Jaime; Cuñat, Amparo Noelia; Vilanova, Santiago; Gramazio, Pietro; Herraiz, Francisco Javier; Andújar, Isabel

2014-09-26

Scarlet (Solanum aethiopicum) and gboma (S. macrocarpon) eggplants are important vegetables in Sub-Saharan Africa. Few studies have been made on these crops regarding the diversity of phenolic content and their biological activity. We have studied the reducing activity, the chlorogenic acid and other phenolic acid contents in a collection of 56 accessions of scarlet eggplant, including the four cultivated groups (Aculeatum, Gilo, Kumba, Shum) and the weedy intermediate S. aethiopicum-S. anguivi types, as well as in eight accessions of gboma eggplant, including the cultivated S. macrocarpon and its wild ancestor, S. dasyphyllum. A sample of the accessions evaluated in this collection has been tested for inhibition of nitric oxide (NO) using macrophage cell cultures. The results show that there is a great diversity in both crops for reducing activity, chlorogenic acid content and chlorogenic acid peak area (% of total phenolic acids). Heritability (H2) for these traits was intermediate to high in both crops. In all samples, chlorogenic acid was the major phenolic acid and accounted for more than 50% of the chromatogram peak area. Considerable differences were found among and within groups for these traits, but the greatest values for total phenolics and chlorogenic acid content were found in S. dasyphyllum. In most groups, reducing activity was positively correlated (with values of up to 0.904 in the Aculeatum group) with chlorogenic acid content. Inhibition of NO was greatest in samples having a high chlorogenic acid content. The results show that both crops are a relevant source of chlorogenic acid and other phenolic acids. The high diversity found also indicates that there are good prospects for breeding new scarlet and gboma eggplant cultivars with improved content in phenolics and bioactive properties.

Reducing Capacity, Chlorogenic Acid Content and Biological Activity in a Collection of Scarlet (Solanum aethiopicum) and Gboma (S. macrocarpon) Eggplants

PubMed Central

Plazas, Mariola; Prohens, Jaime; Cuñat, Amparo Noelia; Vilanova, Santiago; Gramazio, Pietro; Herraiz, Francisco Javier; Andújar, Isabel

2014-01-01

Scarlet (Solanum aethiopicum) and gboma (S. macrocarpon) eggplants are important vegetables in Sub-Saharan Africa. Few studies have been made on these crops regarding the diversity of phenolic content and their biological activity. We have studied the reducing activity, the chlorogenic acid and other phenolic acid contents in a collection of 56 accessions of scarlet eggplant, including the four cultivated groups (Aculeatum, Gilo, Kumba, Shum) and the weedy intermediate S. aethiopicum-S. anguivi types, as well as in eight accessions of gboma eggplant, including the cultivated S. macrocarpon and its wild ancestor, S. dasyphyllum. A sample of the accessions evaluated in this collection has been tested for inhibition of nitric oxide (NO) using macrophage cell cultures. The results show that there is a great diversity in both crops for reducing activity, chlorogenic acid content and chlorogenic acid peak area (% of total phenolic acids). Heritability (H2) for these traits was intermediate to high in both crops. In all samples, chlorogenic acid was the major phenolic acid and accounted for more than 50% of the chromatogram peak area. Considerable differences were found among and within groups for these traits, but the greatest values for total phenolics and chlorogenic acid content were found in S. dasyphyllum. In most groups, reducing activity was positively correlated (with values of up to 0.904 in the Aculeatum group) with chlorogenic acid content. Inhibition of NO was greatest in samples having a high chlorogenic acid content. The results show that both crops are a relevant source of chlorogenic acid and other phenolic acids. The high diversity found also indicates that there are good prospects for breeding new scarlet and gboma eggplant cultivars with improved content in phenolics and bioactive properties. PMID:25264739

Does lead affect microbial metabolism in aquifer sediments under different terminal electron accepting conditions?

USGS Publications Warehouse

Bradley, P.M.; Chapelle, F.H.; Vroblesky, D.A.

1993-01-01

In groundwater from a petroleum hydrocarbon-contaminated aquifer. Substantial accumulation of aliphatic organic acids occurred only in methanogenic microcosms, and only trace amounts of acetic acid were detected in sulfate-reducing microcosms. This pattern parallels field observations in which high organic acid concentrations were detected in methanogenic zones, but only low concentrations of acetic acid were detected in sulfate-reducing zones. -from Authors

Effects of UV radiation and diet on polyunsaturated fatty acids in the skin, ocular tissue and dorsal muscle of Atlantic salmon (Salmo salar) held in outdoor rearing tanks.

PubMed

Arts, Michael T; Browman, Howard I; Jokinen, Ilmari E; Skiftesvik, Anne Berit

2010-01-01

The effect of UV radiation (UVR) on juvenile Atlantic salmon (Salmo salar) was assessed by measuring the fatty acid (FA) profiles of muscle, dorsal and ventral skin, and ocular tissues following 4-month long exposures to four different UVR treatments in outdoor rearing tanks. Fish were fed two different diets (Anchovy- and Herring-oil based) that differed in polyunsaturated fatty acid (PUFA) concentrations. Anchovy-fed salmon had higher concentrations of ALA (alpha-linoleic acid; 18:3n-3), EPA (eicosapentaenoic acid; 20:5n-3) and DPA (docosapentaenoic acid, 22:5n-3) in their muscle tissues than fish fed the Herring feed. Fish subjected to enhanced UVB levels had higher concentrations of LIN (linolenic acid, 18:2n-6) and ALA, total omega-6 FA and SAFA (saturated fatty acids) in their tissues compared with fish in reduced UV treatments. Concentrations of ALA, LIN, GLA (gamma-linolenic acid; 18:3n-6), EPA, PUFA and total FA were higher in ventral skin of fish exposed to enhanced UVB compared with fish in reduced UV treatments. Salmon exposed to reduced UV weighed more per-unit-length than fish exposed to ambient sunlight. The FA profiles suggest that fish exposed to UV radiation were more quiescent than fish in the reduced UV treatments resulting in a buildup of catabolic substrates.

Spectroscopic studies on the antioxidant activity of p-coumaric acid

NASA Astrophysics Data System (ADS)

Kiliç, Ismail; Yeşiloğlu, Yeşim

2013-11-01

p-coumaric acid (4-hydroxycinnamic acid), a phenolic acid, is a hydroxyl derivative of cinnamic acid. It decreases low density lipoprotein (LDL) peroxidation and reduces the risk of stomach cancer. In vitro radical scavenging and antioxidant capacity of p-coumaric acid were clarified using different analytical methodologies such as total antioxidant activity determination by ferric thiocyanate, hydrogen peroxide scavenging, 1,1-diphenyl-2-picryl-hydrazyl free radical (DPPH) scavenging, 2,2‧-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) radical scavenging activity and superoxide anion radical scavenging, ferrous ions (Fe2+) chelating activity and ferric ions (Fe3+) reducing ability. p-Coumaric acid inhibited 71.2% lipid peroxidation of a linoleic acid emulsion at 45 μg/mL concentration. On the other hand, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), α-tocopherol and ascorbic acid displayed 66.8%, 69.8%, 64.5% and 59.7% inhibition on the peroxidation of linoleic acid emulsion at the same concentration, respectively. In addition, p-coumaric acid had an effective DPPHrad scavenging, ABTSrad + scavenging, superoxide anion radical scavenging, hydrogen peroxide scavenging, ferric ions (Fe3+) reducing power and ferrous ions (Fe2+) chelating activities. Also, those various antioxidant activities were compared to BHA, BHT, α-tocopherol and ascorbic acid as references antioxidant compounds. These results suggested that p-coumaric acid can be used in the pharmacological and food industry because of these properties.

Amplification of trace amounts of nucleic acids

DOEpatents

Church, George M [Brookline, MA; Zhang, Kun [Brighton, MA

2008-06-17

Methods of reducing background during amplification of small amounts of nucleic acids employ careful analysis of sources of low level contamination. Ultraviolet light can be used to reduce nucleic acid contaminants in reagents and equipment. "Primer-dimer" background can be reduced by judicious design of primers. We have shown clean signal-to-noise with as little as starting material as one single human cell (.about.6 picogram), E. coli cell (.about.5 femtogram) or Prochlorococcus cell (.about.3 femtogram).

Lactic acid-producing yeast cells having nonfunctional L- or D-lactate:ferricytochrome C oxidoreductase cells

DOEpatents

Miller, Matthew [Boston, MA; Suominen, Pirkko [Maple Grove, MN; Aristidou, Aristos [Highland Ranch, CO; Hause, Benjamin Matthew [Currie, MN; Van Hoek, Pim [Camarillo, CA; Dundon, Catherine Asleson [Minneapolis, MN

2012-03-20

Yeast cells having an exogenous lactate dehydrogenase gene ae modified by reducing L- or D-lactate:ferricytochrome c oxidoreductase activity in the cell. This leads to reduced consumption of lactate by the cell and can increase overall lactate yields in a fermentation process. Cells having the reduced L- or D-lactate:ferricytochrome c oxidoreductase activity can be screened for by resistance to organic acids such as lactic or glycolic acid.

High folic acid intake reduces natural killer cell cytotoxicity in aged mice

USDA-ARS?s Scientific Manuscript database

Presence of unmetabolized folic acid in plasma, which is indicative of folic acid intake beyond the metabolic capacity of the body, is associated with reduced natural killer (NK) cell cytotoxicity in post-menopausal women >/= 50 years. NK cells are cytotoxic lymphocytes that are part of the innate i...

New alleles of FATB-1A to reduce palmitic acid levels in soybean

USDA-ARS?s Scientific Manuscript database

In wild-type soybeans, palmitic acid typically constitutes 10% of the total seed oil. Palmitic acid is a saturated fat linked to increased cholesterol levels, and reducing levels of saturated fats in soybean oil has been a breeding target. To identify novel and useful variation that could help in re...

Effect of pulp preconditioning on acidification, proteolysis, sugars and free fatty acids concentration during fermentation of cocoa (Theobroma cacao) beans.

PubMed

Afoakwa, Emmanuel Ohene; Quao, Jennifer; Budu, Agnes Simpson; Takrama, Jemmy; Saalia, Firibu Kwesi

2011-11-01

Changes in acidification, proteolysis, sugars and free fatty acids (FFAs) concentrations of Ghanaian cocoa beans as affected by pulp preconditioning (pod storage or PS) and fermentation were investigated. Non-volatile acidity, pH, proteolysis, sugars (total, reducing and non-reducing) and FFAs concentrations were analysed using standard methods. Increasing PS consistently decreased the non-volatile acidity with concomitant increase in pH during fermentation of the beans. Fermentation decreased the pH of the unstored beans from 6.7 to 4.9 within the first 4 days and then increased slightly again to 5.3 by the sixth day. Protein, total sugars and non-reducing sugars decreased significantly (p < 0.05) during fermentation, whereas reducing sugars and FFA increased. PS increased the FFA levels, reduced the protein content but did not have any effect on the sugars. The rate of total and non-reducing sugars degeneration with concomitant generation of reducing sugars in the cocoa beans was largely affected by fermentation than by PS.

PROCESS OF SECURING PLUTONIUM IN NITRIC ACID SOLUTIONS IN ITS TRIVALENT OXIDATION STATE

DOEpatents

Thomas, J.R.

1958-08-26

>Various processes for the recovery of plutonium require that the plutonium be obtalned and maintained in the reduced or trivalent state in solution. Ferrous ions are commonly used as the reducing agent for this purpose, but it is difficult to maintain the plutonium in a reduced state in nitric acid solutions due to the oxidizing effects of the acid. It has been found that the addition of a stabilizing or holding reductant to such solution prevents reoxidation of the plutonium. Sulfamate ions have been found to be ideally suitable as such a stabilizer even in the presence of nitric acid.

Cranberry Juice and Combinations of Its Organic Acids Are Effective against Experimental Urinary Tract Infection

PubMed Central

Jensen, Heidi D.; Struve, Carsten; Christensen, Søren B.; Krogfelt, Karen A.

2017-01-01

The antibacterial effect of cranberry juice and the organic acids therein on infection by uropathogenic Escherichia coli was studied in an experimental mouse model of urinary tract infection (UTI). Reduced bacterial counts were found in the bladder (P < 0.01) of mice drinking fresh cranberry juice. Commercially available cranberry juice cocktail also significantly reduced (P < 0.01) bacterial populations in the bladder, as did the hydrophilic fraction of cranberry juice (P < 0.05). Quinic, malic, shikimic, and citric acid, the preponderant organic acids in cranberry juice, were tested in combination and individually. The four organic acids also decreased bacterial levels in the bladder when administered together (P < 0.001), and so did the combination of malic plus citric acid (P < 0.01) and malic plus quinic acid (P < 0.05). The other tested combinations of the organic acids, and the acids administered singly, did not have any effect in the UTI model. Apparently, the antibacterial effect of the organic acids from cranberry juice on UTI can be obtained by administering a combination of malic acid and either citric or quinic acid. This study show for the first time that cranberry juice reduce E. coli colonization of the bladder in an experimental mouse model of urinary tract infection and that the organic acids are active agents. PMID:28421045

Role of Omega-3 Fatty Acids on Lipid Profile in Diabetic Dyslipidaemia: Single Blind, Randomised Clinical Trial.

PubMed

Chauhan, Shaylika; Kodali, Hanish; Noor, Jawad; Ramteke, Karuna; Gawai, Vidisha

2017-03-01

Diabetic dyslipidaemia is characterised by hypertriglyceridaemia, low High Density Lipoprotein (HDL), postprandial lipimea, small and dense LDL particles is considered to be a major predisposing factor for various macrovascular complications. Omega-3 fatty acids are fish oil derivative introduced in the market for dyslipidaemia associated with increased triglyceride level. To study the effect of omega-3 fatty acids on lipid profile in Type II diabetes patients. This study was prospective, single blind, randomized comparative trial. Hundred patients were randomized into three groups. Group I received metformin 500 mg twice daily and placebo, Group II received metformin 500 mg twice daily and omega-3 fatty acids (1 gram) once daily and the Group III received metformin 500 mg twice daily and omega-3 fatty acids (1 gram) twice daily. ANOVA test was applied for analysis. Group II was effective in reducing the triglyceride level from 144.59±14.18 mg/dl to 101±13.31 mg/dl which was significant as compared to Group I from 147.67±18.57 mg/dl to 145.8±19.86 mg/dl respectively. Group III containing 1 g of omega-3 fatty acids twice daily showed decrease from 144.83±22.17 mg/dl to 86±17.46 mg/dl and was more effective in reducing triglyceride levels than Group II containing 1 gram of omega-3 fatty acids once daily. Omega-3 fatty acids can be given in conjunction with metformin to reduce triglyceride levels in diabetic dyslipidaemia without any adverse drug reactions or any drug interaction. Omega-3 fatty acids were effective in reducing the triglyceride level significantly as compared to placebo. Two grams of omega-3 fatty acids were more effective than 1 gram of omega-3 fatty acids in reducing triglyceride levels.

Why do proton conducting polybenzimidazole phosphoric acid membranes perform well in high-temperature PEM fuel cells?

PubMed

Melchior, Jan-Patrick; Majer, Günter; Kreuer, Klaus-Dieter

2016-12-21

Transport properties and hydration behavior of phosphoric acid/(benz)imidazole mixtures are investigated by diverse NMR techniques, thermogravimetric analysis (TGA) and conductivity measurements. The monomeric systems can serve as models for phosphoric acid/poly-benzimidazole membranes which are known for their exceptional performance in high temperature PEM fuel cells. 1 H- and 31 P-NMR data show benzimidazole acting as a strong Brønsted base with respect to neat phosphoric acid. Since benzimidazole's nitrogens are fully protonated with a low rate for proton exchange with phosphate species, proton diffusion and conduction processes must take place within the hydrogen bond network of phosphoric acid only. The proton exchange dynamics between phosphate and benzimidazole species pass through the intermediate exchange regime (with respect to NMR line separations) with exchange times being close to typical diffusion times chosen in PFG-NMR diffusion measurements (ms regime). The resulting effects, as described by the Kärger equation, are included into the evaluation of PFG-NMR data for obtaining precise proton diffusion coefficients. The highly reduced proton diffusion coefficient within the phosphoric acid part of the model systems compared to neat phosphoric acid is suggested to be the immediate consequence of proton subtraction from phosphoric acid. This reduces hydrogen bond network frustration (imbalance of the number of proton donors and acceptors) and therefore also the rate of structural proton diffusion, phosphoric acid's acidity and hygroscopicity. Reduced water uptake, shown by TGA, goes along with reduced electroosmotic water drag which is suggested to be the reason for PBI-phosphoric acid membranes performing better in fuel cells than other phosphoric-acid-containing electrolytes with higher protonic conductivity.

Evaluation of sanitizing efficacy of acetic acid on Piper betle leaves and its effect on antioxidant properties.

PubMed

Singla, Richu; Ganguli, Abhijit; Ghosh, Moushumi; Sohal, Sapna

2009-01-01

The sanitizing efficacy of acetic acid and its effect on health beneficial properties of Piper betle leaves were determined. Betel leaves artificially inoculated with Aeromonas, Salmonella and Yersinia were subjected to organic acid (citric acid, acetic acid and lactic acid) treatment. Pathogen populations reduced by 4 log upon individual inoculation and up to 2 log in a mixed cocktail following treatment with 2% acetic acid during storage up to 20 h at 28 degrees C, indicating a residual antimicrobial effect on pathogen during storage. Antioxidant potential ethanolic extracts of both raw and treated P. betle leaves were assayed for free radical scavenging activities against 2,2-diphenyl-1-picryhydrazyl. Polyphenols, flavonoids and the reducing power of treated and untreated P. betle were also compared. No significant (P>0.05) changes were observed in antioxidant status; flavonoids, polyphenols and reducing power of treated betel leaves. Results indicate the feasibility of a simple intervention strategy for inactivating pathogens in edible leaves of P. betle.

Biodegradation of potato slops from a rural distillery by thermophilic aerobic bacteria.

PubMed

Cibis, Edmund; Kent, Christopher A; Krzywonos, Malgorzata; Garncarek, Zbigniew; Garncarek, Barbara; Miśkiewicz, Tadeusz

2002-10-01

A study has been made of thermophilic aerobic biodegradation of the liquid fraction of potato slops (distillation residue) from a rural distillery. The COD of this fraction ranged from 49 to 104 g O2/l, the main contributions to the COD coming from organic acids, reducing substances, and glycerol. It was found that biodegradation could be divided into the following stages: organic acids were removed first, followed by reducing substances and glycerol. The extent of removal varied according to the process temperature. At 50 degrees C, acetic and malic acids were removed completely, but the amount of isobutyric acid increased. At 60 degrees C, organic acid removal ranged from 51.2% (isobutyric acid) to 99.6% (lactic acid). Removals of glycerol and reducing substances were 86.2% and 87.4%, respectively. COD reduction was also temperature dependent, the highest removal efficiency (76.7%) being achieved at 60 degrees C. Dissolved oxygen may have limited the biodegradation process, as indicated by the DOT-versus-time profile.

Mechanism of fat taste perception: Association with diet and obesity.

PubMed

Liu, Dongli; Archer, Nicholas; Duesing, Konsta; Hannan, Garry; Keast, Russell

2016-07-01

Energy homeostasis plays a significant role in food consumption and body weight regulation with fat intake being an area of particular interest due to its palatability and high energy density. Increasing evidence from humans and animal studies indicate the existence of a taste modality responsive to fat via its breakdown product fatty acids. These studies implicate multiple candidate receptors and ion channels for fatty acid taste detection, indicating a complex peripheral physiology that is currently not well understood. Additionally, a limited number of studies suggest a reduced ability to detect fatty acids is associated with obesity and a diet high in fat reduces an individual's ability to detect fatty acids. To support this, genetic variants within candidate fatty acid receptors are also associated with obesity reduced ability to detect fatty acids. Understanding oral peripheral fatty acid transduction mechanisms and the association with fat consumption may provide the basis of novel approaches to control development of obesity. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Treatment of Irradiated Mice with High-Dose Ascorbic Acid Reduced Lethality

PubMed Central

Sato, Tomohito; Kinoshita, Manabu; Yamamoto, Tetsuo; Ito, Masataka; Nishida, Takafumi; Takeuchi, Masaru; Saitoh, Daizoh; Seki, Shuhji; Mukai, Yasuo

2015-01-01

Ascorbic acid is an effective antioxidant and free radical scavenger. Therefore, it is expected that ascorbic acid should act as a radioprotectant. We investigated the effects of post-radiation treatment with ascorbic acid on mouse survival. Mice received whole body irradiation (WBI) followed by intraperitoneal administration of ascorbic acid. Administration of 3 g/kg of ascorbic acid immediately after exposure significantly increased mouse survival after WBI at 7 to 8 Gy. However, administration of less than 3 g/kg of ascorbic acid was ineffective, and 4 or more g/kg was harmful to the mice. Post-exposure treatment with 3 g/kg of ascorbic acid reduced radiation-induced apoptosis in bone marrow cells and restored hematopoietic function. Treatment with ascorbic acid (3 g/kg) up to 24 h (1, 6, 12, or 24 h) after WBI at 7.5 Gy effectively improved mouse survival; however, treatments beyond 36 h were ineffective. Two treatments with ascorbic acid (1.5 g/kg × 2, immediately and 24 h after radiation, 3 g/kg in total) also improved mouse survival after WBI at 7.5 Gy, accompanied with suppression of radiation-induced free radical metabolites. In conclusion, administration of high-dose ascorbic acid might reduce radiation lethality in mice even after exposure. PMID:25651298

Bile acids modulate glucocorticoid metabolism and the hypothalamic–pituitary–adrenal axis in obstructive jaundice☆

PubMed Central

McNeilly, Alison D.; Macfarlane, David P.; O’Flaherty, Emmett; Livingstone, Dawn E.; Mitić, Tijana; McConnell, Kirsty M.; McKenzie, Scott M.; Davies, Eleanor; Reynolds, Rebecca M.; Thiesson, Helle C.; Skøtt, Ole; Walker, Brian R.; Andrew, Ruth

2010-01-01

Background & Aims Suppression of the hypothalamic–pituitary–adrenal axis occurs in cirrhosis and cholestasis and is associated with increased concentrations of bile acids. We investigated whether this was mediated through bile acids acting to impair steroid clearance by inhibiting glucocorticoid metabolism by 5β-reductase. Methods The effect of bile acids on glucocorticoid metabolism was studied in vitro in hepatic subcellular fractions and hepatoma cells, allowing quantitation of the kinetics and transcript abundance of 5β-reductase. Metabolism was subsequently examined in vivo in rats following dietary manipulation or bile duct ligation. Finally, glucocorticoid metabolism was assessed in humans with obstructive jaundice. Results In rat hepatic cytosol, chenodeoxycholic acid competitively inhibited 5β-reductase (Ki 9.19 ± 0.40 μM) and reduced its transcript abundance (in H4iiE cells) and promoter activity (reporter system, HepG2 cells). In Wistar rats, dietary chenodeoxycholic acid (1% w/w chow) inhibited hepatic 5β-reductase activity, reduced urinary excretion of 3α,5β-tetrahydrocorticosterone and reduced adrenal weight. Conversely, a fat-free diet suppressed bile acid levels and increased hepatic 5β-reductase activity, supplementation of the fat-free diet with CDCA reduced 5β-reductase activity, and urinary 3α,5β-reduced corticosterone. Cholestasis in rats suppressed hepatic 5β-reductase activity and transcript abundance. In eight women with obstructive jaundice, relative urinary excretion of 3α,5β-tetrahydrocortisol was significantly lower than in healthy controls. Conclusion These data suggest a novel role for bile acids in inhibiting hepatic glucocorticoid clearance, of sufficient magnitude to suppress hypothalamic–pituitary–adrenal axis activity. Elevated hepatic bile acids may account for adrenal insufficiency in liver disease. PMID:20347173

The effect of aprotinin, tranexamic acid, and aminocaproic acid on blood loss and use of blood products in major pediatric surgery: a meta-analysis.

PubMed

Schouten, Esther S; van de Pol, Alma C; Schouten, Anton N J; Turner, Nigel M; Jansen, Nicolaas J G; Bollen, Casper W

2009-03-01

Aprotinin reduces the blood loss and transfusion of blood products in children undergoing major surgery. Aprotinin has been associated with severe side effects in adults, and tranexamic acid and aminocaproic acid have been found to be safer alternatives in adults. This systematic review addresses the question of whether tranexamic acid and aminocaproic acid are equally effective as aprotinin for reducing blood loss and transfusion in children undergoing major surgery. A systematic review of the literature was conducted to identify all randomized controlled trials of aprotinin, tranexamic acid, and aminocaproic acid involving children undergoing cardiac or scoliosis surgery. Twenty-three cardiac studies, totaling 1893 patients, met the inclusion criteria. None of the studies directly compared aprotinin to an alternative antifibrinolytic. Five scoliosis studies, totaling 207 patients, met the inclusion criteria. Data on blood loss and use of blood products in the first 24 postoperative hours were extracted. Only homogenously distributed outcomes were pooled. Tranexamic acid showed a homogeneously distributed reduction of blood loss by 11 mL/kg (95% confidence interval [CI] 9-13 mL/kg). Outcomes of blood loss reduction by aprotinin and aminocaproic acid were too heterogeneously distributed to be pooled, so the effect on blood loss could not be evaluated. Both aprotinin and tranexamic acid significantly reduced packed red cell transfusion (4 mL/kg, 95% CI 2-7 mL/kg and 7 mL/kg, 95% CI 5-10 mL/kg, respectively). Type of antifibrinolytic was not a determining factor that explained differences in outcome among trials in a meta-regression analysis. In the scoliosis studies, aprotinin and tranexamic acid significantly reduced blood loss compared with placebo (385 mL, 95% CI 727-42 mL and 682 mL, 95% CI 1149-214 mL, respectively). There is no evidence that suggests that, compared with aprotinin, alternative antifibrinolytics such as tranexamic acid were less effective in reducing blood loss in major pediatric surgery.

A new low linolenic acid allele of GmFAD3A gene in soybean PE1690

USDA-ARS?s Scientific Manuscript database

Relative fatty acid content of soybean oil is about 12 % palmitic acid, 4 % stearic acid, 23 % oleic acid, 54 % linoleic acid, and 8 % linolenic acid. To improve oxidative stability and quality of oil, breeding programs have mainly focused on reducing saturated fatty acids, increasing oleic acid, an...

Efficacy of topical azelaic acid gel in the treatment of mild-moderate acne vulgaris.

PubMed

Iraji, Fariba; Sadeghinia, Ali; Shahmoradi, Zabiholahi; Siadat, Amir Hossein; Jooya, Abolfazl

2007-01-01

Twenty percent azelaic acid gel is recommended as a topical treatment for acne due to its favorable profile. Our objective in this study was to evaluate the efficacy of 20% azelaic acid gel in the treatment of mild to moderate acne vulgaris. This was a double blind, randomized clinical trial. Sixty patients with mild to moderate acne vulgaris were selected randomly to receive either azelaic acid gel or the vehicle gel alone. Patients were followed up every 15 days for a period of 45 days. The number of lesions and the acne severity index (ASI) were recorded and compared using Student's t-test. Total lesion count was reduced by 60.6% and 19.9% by azelaic acid gel and the placebo respectively (P = 0.002). ASI was reduced by 65.2% and 21.3% by azelaic acid gel and the placebo respectively (P = 0.001), i.e, azelaic acid gel was 3.06 times more effective than the placebo in reducing ASI. Azelaic acid gel can be used as an effective treatment in mild to moderate acne vulgaris.

Acid rain and its ecological consequences.

PubMed

Singh, Anita; Agrawal, Madhoolika

2008-01-01

Acidification of rain-water is identified as one of the most serious environmental problems of transboundary nature. Acid rain is mainly a mixture of sulphuric and nitric acids depending upon the relative quantities of oxides of sulphur and nitrogen emissions. Due to the interaction of these acids with other constituents of the atmosphere, protons are released causing increase in the soil acidity Lowering of soil pH mobilizes and leaches away nutrient cations and increases availability of toxic heavy metals. Such changes in the soil chemical characteristics reduce the soil fertility which ultimately causes the negative impact on growth and productivity of forest trees and crop plants. Acidification of water bodies causes large scale negative impact on aquatic organisms including fishes. Acidification has some indirect effects on human health also. Acid rain affects each and every components of ecosystem. Acid rain also damages man-made materials and structures. By reducing the emission of the precursors of acid rain and to some extent by liming, the problem of acidification of terrestrial and aquatic ecosystem has been reduced during last two decades.

Differential regulation of placental amino acid transport by saturated and unsaturated fatty acids.

PubMed

Lager, Susanne; Jansson, Thomas; Powell, Theresa L

2014-10-15

Fatty acids are critical for normal fetal development but may also influence placental function. We have previously reported that oleic acid (OA) stimulates amino acid transport in primary human trophoblasts (PHTs). In other tissues, saturated and unsaturated fatty acids have distinct effects on cellular signaling, for instance, palmitic acid (PA) but not OA reduces IκBα expression. We hypothesized that saturated and unsaturated fatty acids differentially affect trophoblast amino acid transport and cellular signaling. To test this hypothesis, PHTs were cultured in docosahexaenoic acid (DHA; 50 μM), OA (100 μM), or PA (100 μM). DHA and OA were also combined to test whether DHA could counteract the OA stimulatory effect on amino acid transport. The effects of fatty acids were compared against a vehicle control. Amino acid transport was measured by isotope-labeled tracers. Activation of inflammatory-related signaling pathways and the mechanistic target of rapamycin (mTOR) pathway were determined by Western blot analysis. Exposure of PHTs to DHA for 24 h reduced amino acid transport and phosphorylation of p38 MAPK, STAT3, mTOR, eukaryotic initiation factor 4E-binding protein 1, and ribosomal protein (rp)S6. In contrast, OA increased amino acid transport and phosphorylation of ERK, mTOR, S6 kinase 1, and rpS6. The combination of DHA with OA increased amino acid transport and rpS6 phosphorylation. PA did not affect amino acid transport but reduced IκBα expression. In conclusion, these fatty acids differentially regulated placental amino acid transport and cellular signaling. Taken together, these findings suggest that dietary fatty acids could alter the intrauterine environment by modifying placental function, thereby having long-lasting effects on the developing fetus. Copyright © 2014 the American Physiological Society.

The butyrophilin 3A1 intracellular domain undergoes a conformational change involving the juxtamembrane region.

PubMed

Nguyen, Khiem; Li, Jin; Puthenveetil, Robbins; Lin, Xiaochen; Poe, Michael M; Hsiao, Chia-Hung Christine; Vinogradova, Olga; Wiemer, Andrew J

2017-11-01

Small isoprenoid diphosphates, such as ( E )-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP), are ligands of the internal domain of BTN3A1. Ligand binding in target cells promotes activation of Vγ9Vδ2 T cells. We demonstrate by small-angle X-ray scattering (SAXS) that HMBPP binding to the internal domain of BTN3A1 induces a conformational change in the position of the B30.2 domain relative to the juxtamembrane (JM) region. To better understand the molecular details of this conformational rearrangement, NMR spectroscopy was used to discover that the JM region interacts with HMBPP, specifically at the diphosphate. The spectral location of the affected amide peaks, partial NMR assignments, and JM mutants (ST 296 AA or T 304 A) investigated, confirm that the backbone amide of at least one Thr (Thr 304 ), adjacent to conserved Ser, comes close to the HMBPP diphosphate, whereas double mutation of nonconserved residues (Ser/Thr 296/297 ) may perturb the local fold. Cellular mutation of either of the identified Thr residues reduces the activation of Vγ9Vδ2 T cells by HMBPP, zoledronate, and POM 2 -C-HMBP, but not by a partial agonist BTN3 antibody. Taken together, our results show that ligand binding to BTN3A1 induces a conformational change within the intracellular domain that involves the JM region and is required for full activation.-Nguyen, K., Li, J., Puthenveetil, R., Lin, X., Poe, M. M., Hsiao, C.-H. C., Vinogradova, O., Wiemer, A. J. The butyrophilin 3A1 intracellular domain undergoes a conformational change involving the juxtamembrane region. © FASEB.

Inhibition of rotavirus replication by downregulation of fatty acid synthesis.

PubMed

Gaunt, Eleanor R; Cheung, Winsome; Richards, James E; Lever, Andrew; Desselberger, Ulrich

2013-06-01

Recently the recruitment of lipid droplets (LDs) to sites of rotavirus (RV) replication was reported. LDs are polymorphic organelles that store triacylglycerols, cholesterol and cholesterol esters. The neutral fats are derived from palmitoyl-CoA, synthesized via the fatty acid biosynthetic pathway. RV-infected cells were treated with chemical inhibitors of the fatty acid biosynthetic pathway, and the effects on viral replication kinetics were assessed. Treatment with compound C75, an inhibitor of the fatty acid synthase enzyme complex (FASN), reduced RV infectivity 3.2-fold (P = 0.07) and modestly reduced viral RNA synthesis (1.2-fold). Acting earlier in the fatty acid synthesis pathway, TOFA [5-(Tetradecyloxy)-2-furoic acid] inhibits the enzyme acetyl-CoA carboxylase 1 (ACC1). TOFA reduced the infectivity of progeny RV 31-fold and viral RNA production 6-fold. The effect of TOFA on RV infectivity and RNA replication was dose-dependent, and infectivity was reduced by administering TOFA up to 4 h post-infection. Co-treatment of RV-infected cells with C75 and TOFA synergistically reduced viral infectivity. Knockdown by siRNA of FASN and ACC1 produced findings similar to those observed by inhibiting these proteins with the chemical compounds. Inhibition of fatty acid synthesis using a range of approaches uniformly had a more marked impact on viral infectivity than on viral RNA yield, inferring a role for LDs in virus assembly and/or egress. Specific inhibitors of fatty acid metabolism may help pinpoint the critical structural and biochemical features of LDs that are essential for RV replication, and facilitate the development of antiviral therapies.

The chemistry of sour taste and the strategy to reduce the sour taste of beer.

PubMed

Li, Hong; Liu, Fang

2015-10-15

The contributions of free hydrogen ions, undissociated hydrogen ions in protonated acid species, and anionic acid species to sour taste were studied through sensory experiments. According to tasting results, it can be inferred that the basic substance producing a sour taste is the hydrogen ion, including free hydrogen ions and undissociated hydrogen ions. The intensity of a sour taste is determined by the total concentration of free hydrogen ions and undissociated hydrogen ions. The anionic acid species (without hydrogen ions) does not produce a sour taste but can intensify or weaken the intensity of a sour taste. It seems that hydroxyl or conjugated groups in anionic acid species can intensify the sour taste produced by hydrogen ions. The following strategy to reduce the sensory sourness is advanced: not only reduce free hydrogen ions, namely elevate pH value, but also reduce the undissociated hydrogen ions contained in protonated acid species. Copyright © 2015 Elsevier Ltd. All rights reserved.

Caprylic acid reduces enteric Campylobacter colonization in market-aged broiler chickens but does not appear to alter cecal microbial populations

USDA-ARS?s Scientific Manuscript database

Campylobacter is one of the leading causes of food-borne illness in the United States, and epidemiological evidence indicates poultry and poultry products to be a significant source of human Campylobacter infections. Caprylic acid, an 8-carbon medium chain fatty acid, can reduce Campylobacter colon...

Renal Response to Acid Load after Phenformin

PubMed Central

Rooth, Gösta; Bandman, Ulf

1973-01-01

Normally the kidneys respond to an acid load by increased ammonia production. In six patients with adult-type diabetes this response was reduced by a mean 50% after a therapeutic dose of phenformin. The reduced ability to compensate for acid loads may be one factor leading to metabolic acidosis and lactoacidosis sometimes associated with phenformin therapy. PMID:4753235

Spectroscopic studies on the antioxidant activity of p-coumaric acid.

PubMed

Kiliç, Ismail; Yeşiloğlu, Yeşim

2013-11-01

p-coumaric acid (4-hydroxycinnamic acid), a phenolic acid, is a hydroxyl derivative of cinnamic acid. It decreases low density lipoprotein (LDL) peroxidation and reduces the risk of stomach cancer. In vitro radical scavenging and antioxidant capacity of p-coumaric acid were clarified using different analytical methodologies such as total antioxidant activity determination by ferric thiocyanate, hydrogen peroxide scavenging, 1,1-diphenyl-2-picryl-hydrazyl free radical (DPPH) scavenging, 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) radical scavenging activity and superoxide anion radical scavenging, ferrous ions (Fe(2+)) chelating activity and ferric ions (Fe(3+)) reducing ability. p-Coumaric acid inhibited 71.2% lipid peroxidation of a linoleic acid emulsion at 45μg/mL concentration. On the other hand, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), α-tocopherol and ascorbic acid displayed 66.8%, 69.8%, 64.5% and 59.7% inhibition on the peroxidation of linoleic acid emulsion at the same concentration, respectively. In addition, p-coumaric acid had an effective DPPH scavenging, ABTS(+) scavenging, superoxide anion radical scavenging, hydrogen peroxide scavenging, ferric ions (Fe(3+)) reducing power and ferrous ions (Fe(2+)) chelating activities. Also, those various antioxidant activities were compared to BHA, BHT, α-tocopherol and ascorbic acid as references antioxidant compounds. These results suggested that p-coumaric acid can be used in the pharmacological and food industry because of these properties. Copyright © 2013 Elsevier B.V. All rights reserved.

Effects of dietary fats on egg quality and lipid parameters in serum and yolks of Shan Partridge Duck.

PubMed

Du, Xue; Liu, Yali; Lu, Lizhi; Wang, Weiqun; Zeng, Tao; Tian, Yong; Xu, Xiaoqin; Shen, Jianliang; Niu, Dong; Lu, Yingru

2017-05-01

The effects of different dietary fats with variable levels of polyunsaturated fatty acids (PUFAs) on egg quality of Shan Partridge Duck, serum, and yolk lipid parameters were examined in this study. A flock of 585 optimal produced ducks were selected and diets enriched with 0.5%, 1%, or 2% fish oil (F)/flaxseed oil (FL)/rapeseed oil (R)/tallow (T) plus basal diet were supplied through a 28-d period. Supplemental fat source and fat level had no effects on egg qualities. Proportions of yolk total cholesterol (TC), saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs) were reduced (P < 0.001), while polyunsaturated fatty acids (PUFAs), ω-6 polyunsaturated fatty acids (n-6 PUFAs), ω-3 polyunsaturated fatty acids (n-3 PUFAs), Docosahexaenoic Acid (DHA), and Eicosapentaenoic Acid (EPA) were increased by fish oil, flaxseed oil, or rapeseed oil. Effects of supplementation increasing DHA and EPA were detected in F, FL, and R. Compared with C, fish oil significantly increased low-density lipoprotein cholesterol (LDL-C) in serum, flaxseed oil significantly reduced TC and increased very low-density lipoprotein cholesterol (VLDL-C), rapeseed oil significantly reduced TC and LDL-C in serum and increased VLDL-C, tallow significantly increased LDL-C. It is concluded that unsaturated fatty acids rich diets (fish oil, flaxseed oil, and rapeseed oil) might increase yolk PUFAs, reduce yolk cholesterol, and change serum lipid parameters without evident effect on egg qualities. © 2016 Poultry Science Association Inc.

Interim glycol flowsheet reduction/oxidation (redox) model for the Defense Waste Processing Facility (DWPF)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jantzen, C. M.; Williams, M. S.; Zamecnik, J. R.

Control of the REDuction/OXidation (REDOX) state of glasses containing high concentrations of transition metals, such as High Level Waste (HLW) glasses, is critical in order to eliminate processing difficulties caused by overly reduced or overly oxidized melts. Operation of a HLW melter at Fe +2/ΣFe ratios of between 0.09 and 0.33, a range which is not overly oxidizing or overly reducing, helps retain radionuclides in the melt, i.e. long-lived radioactive 99Tc species in the less volatile reduced Tc 4+ state, 104Ru in the melt as reduced Ru +4 state as insoluble RuO 2, and hazardous volatile Cr 6+ in themore » less soluble and less volatile Cr +3 state in the glass. The melter REDOX control balances the oxidants and reductants from the feed and from processing additives such as antifoam. Currently, the Defense Waste Processing Facility (DWPF) is running a formic acid-nitric acid (FN) flowsheet where formic acid is the main reductant and nitric acid is the main oxidant. During decomposition formate and formic acid releases H 2 gas which requires close control of the melter vapor space flammability. A switch to a nitric acid-glycolic acid (GN) flowsheet is desired as the glycolic acid flowsheet releases considerably less H 2 gas upon decomposition. This would greatly simplify DWPF processing. Development of an EE term for glycolic acid in the GN flowsheet is documented in this study.« less

Implementation of flowsheet change to minimize hydrogen and ammonia generation during chemical processing of high level waste in the Defense Waste Processing Facility

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lambert, Dan P.; Woodham, Wesley H.; Williams, Matthew S.

Testing was completed to develop a chemical processing flowsheet for the Defense Waste Processing Facility (DWPF), designed to vitrify and stabilize high level radioactive waste. DWPF processing uses a reducing acid (formic acid) and an oxidizing acid (nitric acid) to rheologically thin the slurry and complete the necessary acid base and reduction reactions (primarily mercury and manganese). Formic acid reduces mercuric oxide to elemental mercury, allowing the mercury to be removed during the boiling phase of processing through steam stripping. In runs with active catalysts, formic acid can decompose to hydrogen and nitrate can be reduced to ammonia, both flammablemore » gases, due to rhodium and ruthenium catalysis. Replacement of formic acid with glycolic acid eliminates the generation of rhodium- and ruthenium-catalyzed hydrogen and ammonia. In addition, mercury reduction is still effective with glycolic acid. Hydrogen, ammonia and mercury are discussed in the body of the report. Ten abbreviated tests were completed to develop the operating window for implementation of the flowsheet and determine the impact of changes in acid stoichiometry and the blend of nitric and glycolic acid as it impacts various processing variables over a wide processing region. Three full-length 4-L lab-scale simulations demonstrated the viability of the flowsheet under planned operating conditions. The flowsheet is planned for implementation in early 2017.« less