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.

Zoledronic Acid in Reducing Clinical Fracture and Mortality after Hip Fracture

PubMed Central

Lyles, Kenneth W.; Colón-Emeric, Cathleen S.; Magaziner, Jay S.; Adachi, Jonathan D.; Pieper, Carl F.; Mautalen, Carlos; Hyldstrup, Lars; Recknor, Chris; Nordsletten, Lars; Moore, Kathy A.; Lavecchia, Catherine; Zhang, Jie; Mesenbrink, Peter; Hodgson, Patricia K.; Abrams, Ken; Orloff, John J.; Horowitz, Zebulun; Eriksen, Erik Fink; Boonen, Steven

2008-01-01

BACKGROUND Mortality is increased after a hip fracture, and strategies that improve outcomes are needed. METHODS In this randomized, double-blind, placebo-controlled trial, 1065 patients were assigned to receive yearly intravenous zoledronic acid (at a dose of 5 mg), and 1062 patients were assigned to receive placebo. The infusions were first administered within 90 days after surgical repair of a hip fracture. All patients received supplemental vitamin D and calcium. The median follow-up was 1.9 years. The primary end point was a new clinical fracture. RESULTS The rates of any new clinical fracture were 8.6% in the zoledronic acid group and 13.9% in the placebo group, a 35% risk reduction (P = 0.001); the respective rates of a new clinical vertebral fracture were 1.7% and 3.8% (P = 0.02), and the respective rates of new nonvertebral fractures were 7.6% and 10.7% (P = 0.03). In the safety analysis, 101 of 1054 patients in the zoledronic acid group (9.6%) and 141 of 1057 patients in the placebo group (13.3%) died, a reduction of 28% in deaths from any cause in the zoledronic-acid group (P = 0.01). The most frequent adverse events in patients receiving zoledronic acid were pyrexia, myalgia, and bone and musculoskeletal pain. No cases of osteonecrosis of the jaw were reported, and no adverse effects on the healing of fractures were noted. The rates of renal and cardiovascular adverse events, including atrial fibrillation and stroke, were similar in the two groups. CONCLUSIONS An annual infusion of zoledronic acid within 90 days after repair of a low-trauma hip fracture was associated with a reduction in the rate of new clinical fractures and improved survival. (ClinicalTrials.gov number, NCT00046254.) PMID:17878149

Efficacy and Safety of Zoledronic Acid for Treatment of Postmenopausal Osteoporosis: A Meta-Analysis of Randomized Controlled Trials.

PubMed

Wang, Chao

We conducted a meta-analysis based on eligible studies to assess the efficacy and safety of zoledronic acid treatment for postmenopausal women with osteoporosis. PubMed, Web of Science, and Embase were searched for eligible studies that assessed the efficacy of zoledronic acid in the prevention of fractures among postmenopausal women with osteoporosis. The primary outcomes were new vertebral fracture, nonvertebral fracture, and hip fracture. Secondary outcomes were bone mineral density (BMD) and safety outcomes. A fixed-effect or random-effect model was used to pool the estimates according to the heterogeneity among the included studies. Eight randomized controlled trials, involving 13,335 patients, were included in this meta-analysis. Pooled results showed that treatment with zoledronic acid significantly reduced the incidences of nonvertebral fractures, vertebral fractures, and hip fractures, as compared with placebo. Zoledronic acid was also associated with significant improvement in BMD at lumbar spine, total hip, femoral neck, and trochanter. However, the incidence of any adverse events was higher in the zoledronic acid group than that in the control group, and serious adverse events were comparable between the 2 groups. This meta-analysis indicated that zoledronic acid could significantly reduce the fracture risk and increase BMD in postmenopausal women with osteoporosis. Furthermore, it would not result in serious adverse events. Zoledronic acid could be used as an effective and well-tolerated treatment for postmenopausal women with 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.

Modifying the osteoblastic niche with zoledronic acid in vivo—Potential implications for breast cancer bone metastasis

PubMed Central

Haider, Marie-Therese; Holen, Ingunn; Dear, T. Neil; Hunter, Keith; Brown, Hannah K.

2014-01-01

Introduction Bone metastasis is the most common complication of advanced breast cancer. The associated cancer-induced bone disease is treated with bone-sparing agents like zoledronic acid. Clinical trials have shown that zoledronic acid also reduces breast cancer recurrence in bone; potentially by modifying the bone microenvironment surrounding disseminated tumour cells. We have characterised the early effects of zoledronic acid on key cell types of the metastatic niche in vivo, and investigated how these modify the location of breast tumour cells homing to bone. Methods Female mice were treated with a single, clinically achievable dose of zoledronic acid (100 μg/kg) or PBS. Bone integrity, osteoclast and osteoblast activity and number/mm trabecular bone on 1, 3, 5 and 10 days after treatment were assessed using μCT, ELISA (TRAP, PINP) and bone histomorphometry, respectively. The effect of zoledronic acid on osteoblasts was validated in genetically engineered mice with GFP-positive osteoblastic cells. The effects on growth plate cartilage were visualised by toluidine blue staining. For tumour studies, mice were injected i.c. with DID-labelled MDA-MB-231-NW1-luc2 breast cancer cells 5 days after zoledronic acid treatment, followed by assessment of tumour cell homing to bone and soft tissues by multiphoton microscopy, flow cytometry and ex vivo cultures. Results As early as 3 days after treatment, animals receiving zoledronic acid had significantly increased trabecular bone volume vs. control. This rapid bone effect was reflected in a significant reduction in osteoclast and osteoblast number/mm trabecular bone and reduced bone marker serum levels (day 3–5). These results were confirmed in mice expressing GFP in osteoblastic linage cells. Pre-treatment with zoledronic acid caused accumulation of an extra-cellular matrix in the growth plate associated with a trend towards preferential [1] homing of tumour cells to osteoblast-rich areas of bone, but without

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.

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

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

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

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.

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

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.

Effect of zoledronic acid on serum calcium in Paget’s disease patients after educational strategies to improve calcium and vitamin D supplementation

PubMed Central

Bone, Henry G.; Su, Guoqin; Tan, Monique; Ozturk, Zafer E.; Aftring, Paul

2015-01-01

Objective: Bisphosphonates are the most effective therapeutic agents in patients with Paget’s disease of bone. As a result of their inhibition of osteoclastic activity, hypocalcemia of variable frequency and severity following intravenous bisphosphonate therapy has been reported. The present study assessed the effect of physician and patient education on adequate supplementation of calcium and vitamin D to reduce the potential risk of developing hypocalcemia following infusion of 5 mg zoledronic acid. Methods: This was an open-label, multicenter, controlled registry trial in which patients with Paget’s disease were treated with a single intravenous infusion of zoledronic acid. Physicians were provided with educational materials focusing on optimization of calcium and vitamin D supplementation following zoledronic infusion that they used to educate their patients. The primary safety variable was the percentage of patients with serum calcium level <2.07mmol/l 9–11 days after zoledronic acid infusion. Results: A total of 75 patients were evaluable in the post dose hypocalcemia safety analysis. Of these, only 1 patient had treatment-emergent hypocalcemia, with a serum calcium level of 1.92 mmol/l 4 days following therapy. Hypocalcemia-related symptoms were not reported in this patient and the serum calcium returned to normal range at 2.17 mmol/l within 1 week on oral calcium supplementation. Conclusions: These results suggest that, with optimization of calcium and vitamin D supplementation by physician and patient education, hypocalcemia is an infrequent occurrence following zoledronic acid infusion. PMID:26301065

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

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.

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.

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.

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

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.

Once-Yearly Zoledronic Acid and Days of Disability, Bed Rest, and Back Pain: Randomized, Controlled HORIZON Pivotal Fracture Trial

PubMed Central

Cauley, Jane A.; Black, Dennis; Boonen, Steven; Cummings, Steven R.; Mesenbrink, Peter; Palermo, Lisa; Man, Zulema; Hadji, Peyman; Reid, Ian R.

2016-01-01

The objective of this study was to determine the effect of once-yearly zoledronic acid on the number of days of back pain and the number of days of disability (ie, limited activity and bed rest) owing to back pain or fracture in postmenopausal women with osteoporosis. This was a multicenter, randomized, double-blind, placebo-controlled trial in 240 clinical centers in 27 countries. Participants included 7736 postmenopausal women with osteoporosis. Patients were randomized to receive either a single 15-minute intravenous infusion of zoledronic acid (5 mg) or placebo at baseline, 12 months, and 24 months. The main outcome measures were self-reported number of days with back pain and the number of days of limited activity and bed rest owing to back pain or a fracture, and this was assessed every 3 months over a 3-year period. Our results show that although the incidence of back pain was high in both randomized groups, women randomized to zoledronic acid experienced, on average, 18 fewer days of back pain compared with placebo over the course of the trial (p = .0092). The back pain among women randomized to zoledronic acid versus placebo resulted in 11 fewer days of limited activity (p = .0017). In Cox proportional-hazards models, women randomized to zoledronic acid were about 6% less likely to experience 7 or more days of back pain [relative risk (RR) = 0.94, 95% confidence interval (CI) 0.90–0.99] or limited activity owing to back pain (RR = 0.94, 95% CI 0.87–1.00). Women randomized to zoledronic acid were significantly less likely to experience 7 or more bed-rest days owing to a fracture (RR = 0.58, 95% CI 0.47–0.72) and 7 or more limited-activity days owing to a fracture (RR = 0.67, 95% CI 0.58–0.78). Reductions in back pain with zoledronic acid were independent of incident fracture. Our conclusion is that in women with postmenopausal osteoporosis, a once-yearly infusion with zoledronic acid over a 3-year period significantly reduced the number of days that

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.

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

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

Adjuvant Therapy With Zoledronic Acid in Patients With Breast Cancer: A Systematic Review and Meta-Analysis

PubMed Central

Polyzos, Nikolaos P.; Coleman, Robert E.; Gnant, Michael; Eidtmann, Holger; Brufsky, Adam M.; Aft, Rebecca; Tevaarwerk, Amye J.; Swenson, Karen; Lind, Pehr; Mauri, Davide

2013-01-01

Background. The purpose of the study was to estimate the impact on survival and fracture rates of the use of zoledronic acid versus no use (or delayed use) in the adjuvant treatment of patients with early-stage (stages I–III) breast cancer. Materials and Methods. We performed a systematic review and meta-analysis of randomized clinical trials. Trials were located through PubMed, ISI, Cochrane Library, and major cancer scientific meeting searches. All trials that randomized patients with primary breast cancer to undergo adjuvant treatment with zoledronic acid versus nonuse, placebo, or delayed use of zoledronic acid as treatment to individuals who develop osteoporosis were considered eligible. Standard meta-analytic procedures were used to analyze the study outcomes. Results. Fifteen studies were considered eligible and were further analyzed. The use of zoledronic acid resulted in a statistically significant better overall survival outcome (five studies, 6,414 patients; hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.70–0.94). No significant differences were found for the disease-free survival outcome (seven studies, 7,541 patients; HR, 0.86; 95% CI, 0.70–1.06) or incidence of bone metastases (seven studies, 7,543 patients; odds ratio [OR], 0.94; 95% CI, 0.64–1.37). Treatment with zoledronic acid led to a significantly lower overall fracture rate (OR, 0.78; 95% CI, 0.63–0.96). Finally, the rate of osteonecrosis of the jaw was 0.52%. Conclusion. Zoledronic acid as adjuvant therapy in breast cancer patients appears to not only reduce the fracture risk but also offer a survival benefit over placebo or no treatment. PMID:23404816

A Phase I Study of Zoledronic Acid and Low Dose Cyclophosphamide in Recurrent/Refractory Neuroblastoma: A New Approaches to Neuroblastoma Therapy (NANT) Study

PubMed Central

Russell, Heidi V.; Groshen, Susan G.; Ara, Tasnim; DeClerck, Yves A.; Hawkins, Randy; Jackson, Hollie A.; Daldrup-Link, Heike E.; Marachelian, Araz; Skerjanec, Andrej; Park, Julie R.; Katzenstein, Howard; Matthay, Katherine K.; Blaney, Susan M.; Villablanca, Judith G.

2010-01-01

Background Zoledronic acid, a bisphosphonate, delays progression of bone metastases in adult malignancies. Bone is a common metastatic site of advanced neuroblastoma. We previously reported efficacy of zoledronic acid in a murine model of neuroblastoma bone invasion prompting this Phase I trial of zoledronic acid with cyclophosphamide in children with neuroblastoma and bone metastases. The primary objective was to determine recommended dosing of zoledronic acid for future trials. Procedure Escalating doses of intravenous zoledronic acid were given every 28 days with oral metronomic cyclophosphamide (25 mg/m2/day). Toxicity, response, zoledronic acid pharmacokinetics, bone turnover markers, serum IL-6, and sIL-6R were evaluated. Results Twenty-one patients, median age 7.5 (range 0.8 - 25.6) years were treated with 2 mg/m2 (n=4), 3 mg/m2 (n=3), or 4 mg/m2 (n=14) zoledronic acid. Fourteen patients were evaluable for dose escalation. A median of one (range 1-18) courses was given. Two dose limiting toxicities (Grade 3 hypophosphatemia) occurred at 4 mg/m2 zoledronic acid. Other Grade 3-4 toxicities included hypocalcemia (n=2), elevated transaminases (n=1), neutropenia (n=2), anemia (n=1), lymphopenia (n=1), and hypokalemia (n=1). Osteosclerosis contributed to fractures in one patient after 18 courses. Responses in evaluable patients included 1 partial response, 9 stable disease (median 4.5 courses, range 3-18), and 10 progressions. Zoledronic acid pharmacokinetics were similar to adults. Markers of osteoclast activity and serum IL-6 levels decreased with therapy. Conclusions Zoledronic acid with metronomic cyclophosphamide is well tolerated with clinical and biologic responses in recurrent/refractory neuroblastoma. The recommended dose of zoledronic acid is 4 mg/m2 every 28 days. PMID:21671363

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

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 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.

Treatment with acetaminophen/paracetamol or ibuprofen alleviates post-dose symptoms related to intravenous infusion with zoledronic acid 5 mg.

PubMed

Wark, J D; Bensen, W; Recknor, C; Ryabitseva, O; Chiodo, J; Mesenbrink, P; de Villiers, T J

2012-02-01

Patients treated with intravenous zoledronic acid 5 mg for osteoporosis may experience post-dose influenza-like symptoms. Oral acetaminophen/paracetamol or ibuprofen administered 4 h post-infusion reduced the proportion of patients with increased oral temperature and worsening post-infusion symptom scores vs. placebo, thus providing an effective strategy for the treatment of such symptoms. Once-yearly intravenous zoledronic acid 5 mg is a safe and effective treatment for postmenopausal osteoporosis. This study assessed whether transient influenza-like post-dose symptoms associated with intravenous infusion of zoledronic acid can be reduced by post-dose administration of acetaminophen/paracetamol or ibuprofen. In an international, multicenter, randomized, double-blind, double-dummy parallel-group study, bisphosphonate-naïve postmenopausal women with osteopenia (n = 481) were randomized to receive zoledronic acid 5 mg + acetaminophen/paracetamol (n = 135), ibuprofen (n = 137) or placebo (n = 137), or placebo + placebo (n = 72). Acetaminophen/paracetamol and ibuprofen were administered every 6 h for 3 days beginning 4 h post-infusion. The proportion of patients with increased oral temperature (≥1°C above 37.5°C) and with worsening post-infusion symptom scores over 3 days was significantly lower in patients receiving ibuprofen (36.8% and 48.5%) or acetaminophen/paracetamol (37.3% and 46.3%) vs. those receiving placebo (63.5% and 75.9%, respectively; all p < 0.0001) compared with background rates of 11.1% and 16.7%, respectively, in the absence of any active treatment. Overall incidence of adverse events was comparable for patients receiving acetaminophen/paracetamol or ibuprofen. Oral acetaminophen/paracetamol or ibuprofen effectively managed the transient influenza-like symptoms associated with zoledronic acid 5 mg.

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.

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.

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

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.

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

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.

Multicenter Study on Observation of Acute-phase Responses After Infusion of Zoledronic Acid 5 mg in Chinese Women with Postmenopausal Osteoporosis.

PubMed

Ding, Yue; Zeng, Jian-Cheng; Yin, Fei; Zhang, Chun-Lin; Zhang, Yan; Li, Shi-Xun; Liu, Xun; Zhang, Chao; Xue, Qing-Yun; Lin, Hua; Pei, Fu-Xing

2017-08-01

It has been reported that acute-phase reactions (APR) after infusion of 5 mg zoledronic acid for the first time is common. This study surveyed the incidence and characteristics of APR in Chinese postmenopausal women receiving 5 mg zoledronic acid intravenously for osteoporosis and to evaluate the efficacy of non-steroidal anti-inflammatory drugs (NSAID) in preventing or alleviating APR following the first 5 mg zoledronic acid infusion. A total of 2601 patients with an average age of 68.14 ± 9.89 years and a mean body mass index of 22.90 ± 3.24 kg/m 2 from 62 centers in China were treated with 5 mg zoledronic acid intravenously for the first time. The incidence of fever and pain were observed in these patients, and the time of fever or pain onset and duration, and the intensity of fever and grade of pain were also recorded. The dosage, duration, and efficacy of NSAID and safety outcomes were also documented. At the end of the study, 18 patients are eliminated due to incomplete records of temperature. The incidence of fever was 28.65% (740/2583) within 7 days following zoledronic acid infusion; 98.34% (727/740) occurred at 1.03 ± 0.66 days after infusion and lasted 1.72 ± 0.93 days. A total of 456 (17.53%) patients had newly onset pain (312 of 1187, 26.28%) or experienced pain aggravation (144 of 1414, 10.18%), which mostly occurred within 3 days after zoledronic acid infusion. A total of 1246 (47.6%) patients had received NSAID for a median time of 2.63 ± 2.45 days. Using NSAID for at least 2 days could decrease body temperature by 0.54 ± 0.86°C, increase the percentage of pain-free patients by 6.17%, and reduce the percentage of patients with moderate to severe pain by 8.7%. Compared with Western populations, Chinese patients had a higher rate of fever and pain after their first zoledronic acid infusion. These symptoms were often mild to moderate in intensity and transient in duration. NSAID could effectively reduce the incidence and

[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

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

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

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.

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.

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

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

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

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

[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 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.

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

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

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

Incidence of osteonecrosis of the jaw in women with postmenopausal osteoporosis in the health outcomes and reduced incidence with zoledronic acid once yearly pivotal fracture trial.

PubMed

Grbic, John T; Landesberg, Regina; Lin, Shou-Qing; Mesenbrink, Peter; Reid, Ian R; Leung, Ping-Chung; Casas, Noemi; Recknor, Christopher P; Hua, Ye; Delmas, Pierre D; Eriksen, Erik F

2008-01-01

The authors determined incidence of osteonecrosis of the jaw (ONJ) in a large, prospective three-year clinical trial of zoledronic acid in women with postmenopausal osteoporosis (PMO). A total of 7,714 women with PMO received intravenous zoledronic acid 5 mg or a placebo. No spontaneous reports of ONJ were received. An independent, blinded adjudication committee searched the trial's adverse event database by using 60 terms. On an ongoing basis, the committee reviewed the identified events, and it defined ONJ as exposed bone in the maxillofacial area with delayed healing for more than six weeks despite appropriate care. One participant who received a placebo and one participant who received zoledronic acid experienced delayed healing associated with infection. Both conditions resolved after antibiotic therapy, débridement or both. The occurrence of ONJ is rare in a PMO population, and delayed healing of lesions can occur with and without bisphosphonate use over three years. The low incidence of ONJ must be assessed in the context of the clinical benefit of zoledronic acid therapy in reducing hip, vertebral and nonvertebral fractures in this at-risk population. There is no evidence to suggest that healthy patients with osteoporosis who are receiving bisphosphonates require any special treatment beyond routine dental care or to support altering standard treatment practices.

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.

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.

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.

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.

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 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.

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.

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

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.

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.

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.

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

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.

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.

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.

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.

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.

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

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.

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

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.

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 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

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.

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.

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.

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

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

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.

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.

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 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.

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.

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

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

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.

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.

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

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

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.

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

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.

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.

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.

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.

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

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.

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.

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.

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.

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

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

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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

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

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.

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

%) 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

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.

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.

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.

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

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 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.

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

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

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

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.

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.

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

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.

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.

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.

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

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.

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

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.

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

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.

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.

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.

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.

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.

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.

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.

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

[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.

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

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.

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.

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

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

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

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

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

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.

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.

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.

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

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

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

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.

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

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.

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

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

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.

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

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

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.

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

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.

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.

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

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.

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

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.

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.

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.

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

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.

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

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.

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.

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.

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

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.

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.

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.

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

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.

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

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

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

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.

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.

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.

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

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

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

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.

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.

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

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.

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

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

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

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

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.

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.

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.

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.

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

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.

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

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

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.

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

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

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.

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 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.

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.

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.

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.

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

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

[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.

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.

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

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

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.

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

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

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

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.

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.

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

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 �

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.

Distillation Separation of Hydrofluoric Acid and Nitric Acid from Acid Waste Using the Salt Effect on Vapor-Liquid Equilibrium

NASA Astrophysics Data System (ADS)

Yamamoto, Hideki; Sumoge, Iwao

2011-03-01

This study presents the distillation separation of hydrofluoric acid with use of the salt effect on the vapor-liquid equilibrium for acid aqueous solutions and acid mixtures. The vapor-liquid equilibrium of hydrofluoric acid + salt systems (fluorite, potassium nitrate, cesium nitrate) was measured using an apparatus made of perfluoro alkylvinylether. Cesium nitrate showed a salting-out effect on the vapor-liquid equilibrium of the hydrofluoric acid-water system. Fluorite and potassium nitrate showed a salting-in effect on the hydrofluoric acid-water system. Separation of hydrofluoric acid from an acid mixture containing nitric acid and hydrofluoric acid was tested by the simple distillation treatment using the salt effect of cesium nitrate (45 mass%). An acid mixture of nitric acid (5.0 mol · dm-3) and hydrofluoric acid (5.0 mol · dm-3) was prepared as a sample solution for distillation tests. The concentration of nitric acid in the first distillate decreased from 5.0 mol · dm-3 to 1.13 mol · dm-3, and the concentration of hydrofluoric acid increased to 5.41 mol · dm-3. This first distillate was further distilled without the addition of salt. The concentrations of hydrofluoric acid and nitric acid in the second distillate were 7.21 mol · dm-3 and 0.46 mol · dm-3, respectively. It was thus found that the salt effect on vapor-liquid equilibrium of acid mixtures was effective for the recycling of acids from acid mixture wastes.

Effects of phosphoric acid on the lead-acid battery reactions

NASA Astrophysics Data System (ADS)

Ikeda, Osamu; Iwakura, Chiaki; Yoneyama, Hiroshi; Tamura, Hideo

1986-10-01

The addition of a small amount of phosphoric acid to 5 M H2SO4 (commercial electrolyte of lead-acid batteries) results in various positive effects on the lead-acid battery reactions: (1) depression of the corrosion rate of the lead substrate through a preferential formation of alpha-PbO2 on the substrate surface; (2) retardation of hard sulfate formation or of deactivation of active materials; and (3) change in the crystal morphology of PbSO2 formed on the discharge of PbO2. Most of these effects results from chemisorption of phosphoric acid on PbSO4 crystals produced in the discharge process of PbO2.

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.

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.

Effect of acetic acid on citric acid fermentation in an integrated citric acid-methane fermentation process.

PubMed

Xu, Jian; Chen, Yang-Qiu; Zhang, Hong-Jian; Tang, Lei; Wang, Ke; Zhang, Jian-Hua; Chen, Xu-Sheng; Mao, Zhong-Gui

2014-09-01

An integrated citric acid-methane fermentation process was proposed to solve the problem of extraction wastewater in citric acid fermentation process. Extraction wastewater was treated by anaerobic digestion and then recycled for the next batch of citric acid fermentation to eliminate wastewater discharge and reduce water resource consumption. Acetic acid as an intermediate product of methane fermentation was present in anaerobic digestion effluent. In this study, the effect of acetic acid on citric acid fermentation was investigated and results showed that lower concentration of acetic acid could promote Aspergillus niger growth and citric acid production. 5-Cyano-2,3-ditolyl tetrazolium chloride (CTC) staining was used to quantify the activity of A. niger cells, and the results suggested that when acetic acid concentration was above 8 mM at initial pH 4.5, the morphology of A. niger became uneven and the part of the cells' activity was significantly reduced, thereby resulting in deceasing of citric acid production. Effects of acetic acid on citric acid fermentation, as influenced by initial pH and cell number in inocula, were also examined. The result indicated that inhibition by acetic acid increased as initial pH declined and was rarely influenced by cell number in inocula.

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.

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.

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.

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

[Effect of Gram-negative bacteria on fatty acids].

PubMed

Vuillemin, N; Dupeyron, C; Leluan, G; Bory, J

1981-01-01

The gram-negative bacteria investigated exert various effects on fatty acids. P. aeruginosa and A. calcoaceticus catabolize any of the fatty acids tested. S. marcescens is effective upon all fatty acids excepting butyric acid. The long chain fatty acids only are degraded by E. coli, meanwhile the other fatty acids present a bacteriostatic or bactericidal activity on it. The authors propose a simple and original method for testing the capability of degradation of fatty acids by some bacterial species.

Differential effects of eicosapentaenoic acid and docosahexaenoic acid on human skin fibroblasts.

PubMed

Brown, E R; Subbaiah, P V

1994-12-01

To better understand the mode of action of omega 3 fatty acids in cell membranes, human foreskin fibroblasts were grown in serum-free medium supplemented with 50 microM oleic acid linoleic acid, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), and the effects on membrane composition, fluorescence polarization and enzyme activities were followed. The cells were enriched with EPA and DHA up to 7 and 13% of total lipids, respectively, of which > 95% was associated with phospholipids. In addition, the concentration of 22:5n-3 increased with both EPA and DHA to 7.5, and 2.1% of the total fatty acids, respectively. When compared to controls (oleic acid), cells treated with DHA showed a decrease in cholesterol, phospholipids, arachidonic acid (AA) and free cholesterol/phospholipid ratio (P < 0.05). In the presence of EPA, only decreases in AA and cholesterol were significant (P < 0.05). Membrane fluidity, assessed by fluorescence anisotropy, was increased 16% in cells enriched with DHA (P < 0.05), but showed no change with EPA or linoleic acid. There was an increase in membrane-associated 5'-nucleotidase (+27%) and adenylate cyclase (+19%) activities (P < 0.05), in DHA-enriched, but not in EPA-enriched cells, when compared with oleate controls. The studies show that incorporation of DHA, but not EPA, into cell membranes of fibroblasts alters membrane biophysical characteristics and function. We suggest that these two major n-3 fatty acids of fish oils have differential effects on cell membranes, and this may be related to the known differences in their physiological effects.

[Effects of low molecular weight organic acids on speciation of exogenous Cu in an acid soil].

PubMed

Huang, Guo-Yong; Fu, Qing-Ling; Zhu, Jun; Wan, Tian-Ying; Hu, Hong-Qing

2014-08-01

In order to ascertain the effect of LMWOA (citric acid, tartaric acid, oxalic acid) on Cu-contaminated soils and to investigate the change of Cu species, a red soil derived from quartz sandstone deposit was added by Cu (copper) in the form of CuSO4 x 5H2O so as to simulate soil Cu pollution, keeping the additional Cu concentrations were 0, 100, 200, 400 mg x kg(-1) respectively. After 9 months, different LMWOA was also added into the simulated soil, keeping the additional LMWOAs in soil were 0, 5, 10, 20 mmol x kg(-1) respectively. After 2 weeks incubation, the modified sequential extraction method on BCR (European Communities Bureau of Reference) was used to evaluate the effects of these LMWOAs on the changes of copper forms in soil. The result showed that the percentage of weak acid dissolved Cu, the most effective form in the soil increased with three organic acids increase in quantity in the simulated polluted soil. And there was a good activation effect on Cu in the soil when organic acid added. Activation effects on Cu increased with concentration of citric acid increasing, but it showed a rise trend before they are basically remained unchanged in the case of tartaric acid and oxalic acid added in the soil. On the contrary, the state of the reduction of copper which was regarded as a complement for effective state decreased with the increased concentration of organic acid in the soil, especially with citric acid. When 20 mmol x kg(-1) oxalic acid and citric acid were added into the soil, the activation effect was the best; whereas for tartaric, the concentration was 10 mmol x kg(-1). In general, the effect on the changes of Cu forms in the soil is citric acid > tartaric acid > oxalic acid.

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

Effects of dietary conjugated linoleic acid and linoleic:linolenic acid ratio on polyunsaturated fatty acid status in laying hens.

PubMed

Du, M; Ahn, D U; Sell, J L

2000-12-01

A study was conducted to determine the effects of dietary conjugated linoleic acid (CLA) and the ratio of linoleic:linolenic acid on long-chain polyunsaturated fatty acid status. Thirty-two 31-wk-old White Leghorn hens were randomly assigned to four diets containing 8.2% soy oil, 4.1% soy oil + 2.5% CLA (4.1% CLA source), 4.1% flax oil + 2.5% CLA, or 4.1% soy oil + 4.1% flax oil. Hens were fed the diets for 3 wk before eggs and tissues were collected for the study. Lipids were extracted from egg yolk and tissues, classes of egg yolk lipids were separated, and fatty acid concentrations of total lipids, triglyceride, phosphatidylethanolamine, and phosphatidylcholine were analyzed by gas chromatography. The concentrations of monounsaturated fatty acids and non-CLA polyunsaturated fatty acids were reduced after CLA feeding. The amount of arachidonic acid was decreased after CLA feeding in linoleic acid- and linolenic acid-rich diets, but amounts of eicosapentaenoic acid and docosahexaenoic acid were increased in the linolenic-rich diet, indicating that the synthesis or deposition of long-chain n-3 fatty acids was accelerated after CLA feeding. The increased docosahexaenoic acid and eicosapentaenoic acid contents in lipid may be compensation for the decreased arachidonic acid content. Dietary supplementation of linoleic acid increased n-6 fatty acid levels in lipids, whereas linolenic acid increased n-3 fatty acid levels. Results also suggest that CLA might not be elongated to synthesize long-chain fatty acids in significant amounts. The effect of CLA in reducing the level of n-6 fatty acids and promoting the level of n-3 fatty acids could be related to the biological effects of CLA.

The Cardioprotective Effects of Citric Acid and L-Malic Acid on Myocardial Ischemia/Reperfusion Injury

PubMed Central

Tang, Xilan; Liu, Jianxun; Dong, Wei; Li, Peng; Li, Lei; Lin, Chengren; Zheng, Yongqiu; Hou, Jincai; Li, Dan

2013-01-01

Organic acids in Chinese herbs, the long-neglected components, have been reported to possess antioxidant, anti-inflammatory, and antiplatelet aggregation activities; thus they may have potentially protective effect on ischemic heart disease. Therefore, this study aims to investigate the protective effects of two organic acids, that is, citric acid and L-malic acid, which are the main components of Fructus Choerospondiatis, on myocardial ischemia/reperfusion injury and the underlying mechanisms. In in vivo rat model of myocardial ischemia/reperfusion injury, we found that treatments with citric acid and L-malic acid significantly reduced myocardial infarct size, serum levels of TNF-α, and platelet aggregation. In vitro experiments revealed that both citric acid and L-malic acid significantly reduced LDH release, decreased apoptotic rate, downregulated the expression of cleaved caspase-3, and upregulated the expression of phosphorylated Akt in primary neonatal rat cardiomyocytes subjected to hypoxia/reoxygenation injury. These results suggest that both citric acid and L-malic acid have protective effects on myocardial ischemia/reperfusion injury; the underlying mechanism may be related to their anti-inflammatory, antiplatelet aggregation and direct cardiomyocyte protective effects. These results also demonstrate that organic acids, besides flavonoids, may also be the major active ingredient of Fructus Choerospondiatis responsible for its cardioprotective effects and should be attached great importance in the therapy of ischemic heart disease. PMID:23737849

Effect of baseline plasma fatty acids on eicosapentaenoic acid levels in individuals supplemented with alpha-linolenic acid.

PubMed

DeFilippis, Andrew P; Harper, Charles R; Cotsonis, George A; Jacobson, Terry A

2009-01-01

We previously reported a >50% increase in mean plasma eicosapentaenoic acid levels in a general medicine clinic population after supplementation with alpha-linolenic acid. In the current analysis, we evaluate the variability of changes in eicosapentaenoic acid levels among individuals supplemented with alpha-linolenic acid and evaluated the impact of baseline plasma fatty acids levels on changes in eicosapentaenoic acid levels in these individuals. Changes in eicosapentaenoic acid levels among individuals supplemented with alpha-linolenic acid ranged from a 55% decrease to a 967% increase. Baseline plasma fatty acids had no statistically significant effect on changes in eicosapentaenoic levels acid after alpha-linolenic acid supplementation. Changes in eicosapentaenoic acid levels varied considerably in a general internal medicine clinic population supplemented with alpha-linolenic acid. Factors that may impact changes in plasma eicosapentaenoic acid levels after alpha-linolenic acid supplementation warrant further study.

Interactive Effects of Jasmonic Acid, Salicylic Acid, and Gibberellin on Induction of Trichomes in Arabidopsis1

PubMed Central

Traw, M. Brian; Bergelson, Joy

2003-01-01

Leaf trichomes protect plants from attack by insect herbivores and are often induced following damage. Hormonal regulation of this plant induction response has not been previously studied. In a series of experiments, we addressed the effects of artificial damage, jasmonic acid, salicylic acid, and gibberellin on induction of trichomes in Arabidopsis. Artificial damage and jasmonic acid caused significant increases in trichome production of leaves. The jar1-1 mutant exhibited normal trichome induction following treatment with jasmonic acid, suggesting that adenylation of jasmonic acid is not necessary. Salicylic acid had a negative effect on trichome production and consistently reduced the effect of jasmonic acid, suggesting negative cross-talk between the jasmonate and salicylate-dependent defense pathways. Interestingly, the effect of salicylic acid persisted in the nim1-1 mutant, suggesting that the Npr1/Nim1 gene is not downstream of salicylic acid in the negative regulation of trichome production. Last, we found that gibberellin and jasmonic acid had a synergistic effect on the induction of trichomes, suggesting important interactions between these two compounds. PMID:14551332

Effects of alkali or acid treatment on the isomerization of amino acids.

PubMed

Ohmori, Taketo; Mutaguchi, Yuta; Doi, Katsumi; Ohshima, Toshihisa

2012-10-01

The effect of alkali treatment on the isomerization of amino acids was investigated. The 100×D/(D+L) values of amino acids from peptide increased with increase in the number of constituent amino acid residues. Furthermore, the N-terminal amino acid of a dipeptide was isomerized to a greater extent than the C-terminal residue. Copyright © 2012. Published by Elsevier B.V.

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 propionic acid on citric acid fermentation in an integrated citric acid-methane fermentation process.

PubMed

Xu, Jian; Bao, Jia-Wei; Su, Xian-Feng; Zhang, Hong-Jian; Zeng, Xin; Tang, Lei; Wang, Ke; Zhang, Jian-Hua; Chen, Xu-Sheng; Mao, Zhong-Gui

2016-03-01

In this study, an integrated citric acid-methane fermentation process was established to solve the problem of wastewater treatment in citric acid production. Citric acid wastewater was treated through anaerobic digestion and then the anaerobic digestion effluent (ADE) was further treated and recycled for the next batch citric acid fermentation. This process could eliminate wastewater discharge and reduce water resource consumption. Propionic acid was found in the ADE and its concentration continually increased in recycling. Effect of propionic acid on citric acid fermentation was investigated, and results indicated that influence of propionic acid on citric acid fermentation was contributed to the undissociated form. Citric acid fermentation was inhibited when the concentration of propionic acid was above 2, 4, and 6 mM in initial pH 4.0, 4.5 and, 5.0, respectively. However, low concentration of propionic acid could promote isomaltase activity which converted more isomaltose to available sugar, thereby increasing citric acid production. High concentration of propionic acid could influence the vitality of cell and prolong the lag phase, causing large amount of glucose still remaining in medium at the end of fermentation and decreasing citric acid production.

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

Combined effect of sesamin and α-lipoic acid on hepatic fatty acid metabolism in rats.

PubMed

Ide, Takashi; Azechi, Ayana; Kitade, Sayaka; Kunimatsu, Yoko; Suzuki, Natsuko; Nakajima, Chihiro

2013-04-01

Dietary sesamin (1:1 mixture of sesamin and episesamin) decreases fatty acid synthesis but increases fatty acid oxidation in rat liver. Dietary α-lipoic acid lowers hepatic fatty acid synthesis. These changes can account for the serum lipid-lowering effect of sesamin and α-lipoic acid. It is expected that the combination of these compounds in the diet potentially ameliorates lipid metabolism more than the individual compounds. We therefore studied the combined effect of sesamin and α-lipoic acid on lipid metabolism in rats. Male Sprague-Dawley rats were fed diets supplemented with 0 or 2 g/kg sesamin and containing 0 or 2.5 g/kg α-lipoic acid for 22 days. Sesamin and α-lipoic acid decreased serum lipid concentrations and the combination of these compounds further decreased the parameters in an additive fashion. These compounds reduced the hepatic concentration of triacylglycerol, the lignan being less effective in decreasing this value. The combination failed to cause a stronger decrease in hepatic triacylglycerol concentration. The combination of sesamin and α-lipoic acid decreased the activity and mRNA levels of hepatic lipogenic enzymes in an additive fashion. Sesamin strongly increased the parameters of hepatic fatty acid oxidation enzymes. α-Lipoic acid antagonized the stimulating effect of sesamin of fatty acid oxidation through reductions in the activity of some fatty acid oxidation enzymes and carnitine concentration in the liver. This may account for the failure to observe strong reductions in hepatic triacylglycerol concentration in rats given a diet containing both sesamin and α-lipoic acid.

Comparative Effects of Retinoic Acid or Glycolic Acid Vehiculated in Different Topical Formulations

PubMed Central

Maia Campos, Patrícia Maria Berardo Gonçalves; Gaspar, Lorena Rigo; Gonçalves, Gisele Mara Silva; Pereira, Lúcia Helena Terenciane Rodrigues; Semprini, Marisa; Lopes, Ruberval Armando

2015-01-01

Retinoids and hydroxy acids have been widely used due to their effects in the regulation of growth and in the differentiation of epithelial cells. However, besides their similar indication, they have different mechanisms of action and thus they may have different effects on the skin; in addition, since the topical formulation efficiency depends on vehicle characteristics, the ingredients of the formulation could alter their effects. Thus the objective of this study was to compare the effects of retinoic acid (RA) and glycolic acid (GA) treatment on the hairless mouse epidermis thickness and horny layer renewal when added in gel, gel cream, or cream formulations. For this, gel, gel cream, and cream formulations (with or without 6% GA or 0.05% RA) were applied in the dorsum of hairless mice, once a day for seven days. After that, the skin was analyzed by histopathologic, morphometric, and stereologic techniques. It was observed that the effects of RA occurred independently from the vehicle, while GA had better results when added in the gel cream and cream. Retinoic acid was more effective when compared to glycolic acid, mainly in the cell renewal and the exfoliation process because it decreased the horny layer thickness. PMID:25632398

Effects of humic acids in vitro.

PubMed

Vašková, Janka; Veliká, Beáta; Pilátová, Martina; Kron, Ivan; Vaško, Ladislav

2011-06-01

Humic acids are known for their overall positive health and productivity effects in animal feeding trials and, controversially, as an aetiological factor of cancer. We tried to assess the in vitro effect of humic acids from a selected source in Slovakia when used at recommended prophylactic dosage. We investigated antioxidant properties, enzymatic and non-enzymatic antioxidant defence system in liver mitochondria and cultured cancer cell lines in vitro. We observed a significant decrease in superoxide dismutase activity after humic acids treatment irrespective of dissolving in dimethyl sulphoxide or direct addition to mitochondria suspension in a respiration medium. Activities of other antioxidant enzymes measured, such as glutathione peroxidase and glutathione reductase, showed no significant differences from the control as well as the reduced glutathione content. Percentage of inhibition by humic acids of superoxide radical indicated lower efficacy compared with that of hydroxyl radical. Survival of six different cancer cells lines indicated that only the acute T lymphoblastic leukaemia cell line was sensitive to the tested humic acids. Despite relatively low solubility in aqueous solutions, humic acids from the selected source participated in redox regulation. By recapturing the radicals, humic acids reloaded the antioxidant defensive mechanism. Results from in vitro study conducted with humic acids from the natural source showed potential of these substances as promising immunity enhancing agents.

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...

Reciprocal effects of 5-(tetradecyloxy)-2-furoic acid on fatty acid oxidation.

PubMed

Otto, D A; Chatzidakis, C; Kasziba, E; Cook, G A

1985-10-01

Under certain incubation conditions 5-(tetradecyloxy)-2-furoic acid (TOFA) stimulated the oxidation of palmitate by hepatocytes, as observed by others. A decrease in malonyl-CoA concentration accompanied the stimulation of oxidation. Under other conditions, however, TOFA inhibited fatty acid oxidation. The observed effects of TOFA depended on the TOFA and fatty acid concentrations, the cell concentration, the time of TOFA addition relative to the addition of fatty acid, and the nutritional state of the animal (fed or starved). The data indicate that only under limited incubation conditions may TOFA be used as an inhibitor of fatty acid synthesis without inhibition of fatty acid oxidation. When rat liver mitochondria were preincubated with TOFA, ketogenesis from palmitate was slightly inhibited (up to 20%) at TOFA concentrations that were less than that of CoA, but the inhibition became almost complete (up to 90%) when TOFA was greater than or equal to the CoA concentration. TOFA had only slight or no inhibitory effects on the oxidation of palmitoyl-CoA, palmitoyl(-)carnitine, or butyrate. Since TOFA can be converted to TOFyl-CoA, the data suggest that the inhibition of fatty acid oxidation from palmitate results from the decreased availability of CoA for extramitochondrial activation of fatty acids. These data, along with previous data of others, indicate that inhibition of fatty acid oxidation by CoA sequestration is a common mechanism of a group of carboxylic acid inhibitors. A general caution is appropriate with regard to the interpretation of results when using TOFA in studies of fatty acid oxidation.

Acidic Depositions: Effects on Wildlife and Habitats

USGS Publications Warehouse

1993-01-01

The phenomenon of 'acid rain' is not new; it was recognized in the mid-1800s in industrialized Europe. In the 1960s a synthesis of information about acidification began in Europe, along with predictions of ecological effects. In the U.S. studies of acidification began in the 1920s. By the late 1970s research efforts in the U.S. and Canada were better coordinated and in 1980 a 10-year research program was undertaken through the National Acid Precipitation Assessment Plan (NAPAP) to determine the causes and consequences of acidic depositions. Much of the bedrock in the northeastern U.S. and Canada contains total alkalinity of 20 kg/ha/yr of wet sulphate depositions and are vulnerable to acidifying processes. Acidic depositions contribute directly to acidifying processes of soil and soil water. Soils must have sufficient acid-neutralizing capacity or acidity of soil will increase. Natural soil-forming processes that lead to acidification can be accelerated by acidic depositions. Long-term effects of acidification are predicted, which will reduce soil productivity mainly through reduced availability of nutrients and mobilization of toxic metals. Severe effects may lead to major alteration of soil chemistry, soil biota, and even loss of vegetation. Several species of earthworms and several other taxa of soil-inhabiting invertebrates, which are important food of many vertebrate wildlife species, are affected by low pH in soil. Loss of canopy in declining sugar maples results in loss of insects fed on by certain neotropical migrant bird species. No definitive studies categorically link atmospheric acidic depositions with direct or indirect effects on wild mammals. Researchers have concentrated on vegetative and aquatic effects. Circumstantial evidence suggests that effects are probable for certain species of aquatic-dependent mammals (water shrew, mink, and otter) and that these species are at risk from the loss of foods or contamination of these foods by metals

Uric Acid and Antioxidant Effects of Wine

PubMed Central

Boban, Mladen; Modun, Darko

2010-01-01

The aim of this article is to review the role of uric acid in the context of antioxidant effects of wine and its potential implication to human health. We described and discussed the mechanisms of increase in plasma antioxidant capacity after consumption of moderate amounts of wine. Because this effect is largely contributed by acute elevation in plasma uric acid, we paid special attention to wine constituents and metabolic processes that are likely to be involved in uric acid elevation. PMID:20162741

Cellular Effects of Perfluorinated Fatty Acids.

DTIC Science & Technology

1985-01-01

perfluoro -n-de canoic acid ( PFDA ), fluoresce e -- I j ~recovery after photobleaching (FRAPB), cell culture ~ . 19. ABSTRACT (Continue an reverse if...necessmzejj dctiy by block number) --Tecompoubd perfluor i--ecan’oic’ acid ( PFDA ) was exposed to three tissue culturer cell lines, PTK2 (kidney),/BRL (buffalo...all cell systems. In particular, previous in vivo and in vitro studies on the similarities of the toxic effects of perfluoro -n-decanoic acid ( PFDA ) and

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

Anxiolytic-like effects of ursolic acid in mice.

PubMed

Colla, André R S; Rosa, Julia M; Cunha, Mauricio P; Rodrigues, Ana Lúcia S

2015-07-05

Ursolic acid is a pentacyclic triterpenoid that possesses several biological and neuropharmacological effects including antidepressant-like activity. Anxiety disorders represent common and disability psychiatric conditions that are often associated with depressive symptoms. This work investigated the anxiolytic-like effects of ursolic acid administration in different behavioral paradigms that evaluate anxiety in mice: open field test, elevated plus maze test, light/dark box test and marble burying test. To this end, mice were administered with ursolic acid (0.1, 1 and 10mg/kg, p.o.) or diazepam (2mg/kg, p.o.), positive control, and submitted to the behavioral tests. The results show that ursolic acid (10mg/kg) elicited an anxiolytic-like effect observed by the increased total time in the center and decreased number of rearings responses in the open field test and an increased percentage of entries and total time spent in the open arms of elevated plus maze, similarly to diazepam. No significant effects of ursolic acid were shown in the light/dark box and marble burying test. These data indicate that ursolic acid exhibits anxiolytic-like effects in the open field and elevated plus maze test, but not in the light/dark box and marble burying test, showing the relevance of testing several behavioral paradigms in the evaluation of anxiolytic-like actions. Of note, the results extend the understanding on the effects of ursolic acid in the central nervous system and suggest that it may be a novel approach for the management of anxiety-related disorders. Copyright © 2015. Published by Elsevier B.V.

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.

The antimicrobial effect of boric acid on Trichomonas vaginalis.

PubMed

Brittingham, Andrew; Wilson, Wayne A

2014-12-01

The treatment options for trichomoniasis are largely limited to nitroimidazole compounds (metronidazole and tinidazole). Few alternatives exist in cases of recalcitrant infections or in cases of nitroimidazole hypersensitivity. Recently, the intravaginal administration of boric acid has been advocated as an alternative treatment of trichomoniasis. However, no in vitro studies are available that directly assess the sensitivity of Trichomonas vaginalis to boric acid. We examined the sensitivity of common laboratory strains and recent clinical isolates of T. vaginalis to boric acid. The effect of increasing concentrations of boric acid on parasite growth and viability was determined, and a minimal lethal concentration was reported. The effect of pH on boric acid toxicity was assessed and compared with that of lactic and acetic acid. Boric acid is microbicidal to T. vaginalis, and its antitrichomonal activity is independent of environmental acidification. Unlike acetic acid and lactic acid, boric acid exposure results in growth suppression and lethality over a wide range of pH (5-7) and under conditions that are normally permissible for growth in vitro. The microbicidal effect of boric acid on T. vaginalis, coupled with its previous clinical use in treating vaginal candidiasis, supports the continued inclusion of boric acid in the therapeutic arsenal for treating trichomoniasis.

Enzymatic polymerization of natural anacardic acid and antibiofouling effects of polyanacardic acid coatings.

PubMed

Chelikani, Rahul; Kim, Yong Hwan; Yoon, Do-Young; Kim, Dong-Shik

2009-05-01

Anacardic acid, separated from cashew nut shell liquid, is well known for its strong antibiotic and antioxidant activities. Recent findings indicate that phenolic compounds from plant sources have an effect on Gram-negative bacteria biofilm formation. In this work, a polyphenolic coating was prepared from anacardic acid using enzymatic synthesis and tested for its effects on biofilm formation of both Gram-negative and Gram-positive bacteria. Natural anacardic acid was enzymatically polymerized using soybean peroxidase. Hydrogen peroxide and phenothiazine-10-propionic acid were used as an oxidizing agent and redox mediator, respectively. Nuclear magnetic resonance and Fourier transform infrared (FTIR) analyses showed the formation of oxyphenylene and phenylene units through the phenol rings. No linkage through the alkyl chain was observed, which proved a high chemo-selectivity of the enzyme. Aqueous solvents turned out to play an important role in the polymer production yield and molecular weight. With 2-propanol, the highest production yield (61%) of polymer (molecular weight = 3,900) was observed, and with methanol, higher-molecular-weight polymers (5,000) were produced with lower production yields (43%). The resulting polyanacardic acid was cross-linked on a solid surface to form a permanent natural polymer coating. The FTIR analysis indicates that the cross-linking between the polymers took place through the unsaturated alkyl side chains. The polyanacardic acid coating was then tested for its antibiofouling effect against Gram-negative and Gram-positive bacteria and compared with the antibiofouling effects of polycardanol coatings reported in the literature. The polyanacardic acid coating showed more reduction in biofilm formation on its surface than polycardanol coatings in the case of Gram-positive bacteria, while in the case of Gram-negative bacteria, it showed a similar reduction in biofilm formation as polycardanol.

Effect of aspartic acid and glutamate on metabolism and acid stress resistance of Acetobacter pasteurianus.

PubMed

Yin, Haisong; Zhang, Renkuan; Xia, Menglei; Bai, Xiaolei; Mou, Jun; Zheng, Yu; Wang, Min

2017-06-15

Acetic acid bacteria (AAB) are widely applied in food, bioengineering and medicine fields. However, the acid stress at low pH conditions limits acetic acid fermentation efficiency and high concentration of vinegar production with AAB. Therefore, how to enhance resistance ability of the AAB remains as the major challenge. Amino acids play an important role in cell growth and cell survival under severe environment. However, until now the effects of amino acids on acetic fermentation and acid stress resistance of AAB have not been fully studied. In the present work the effects of amino acids on metabolism and acid stress resistance of Acetobacter pasteurianus were investigated. Cell growth, culturable cell counts, acetic acid production, acetic acid production rate and specific production rate of acetic acid of A. pasteurianus revealed an increase of 1.04, 5.43, 1.45, 3.30 and 0.79-folds by adding aspartic acid (Asp), and cell growth, culturable cell counts, acetic acid production and acetic acid production rate revealed an increase of 0.51, 0.72, 0.60 and 0.94-folds by adding glutamate (Glu), respectively. For a fully understanding of the biological mechanism, proteomic technology was carried out. The results showed that the strengthening mechanism mainly came from the following four aspects: (1) Enhancing the generation of pentose phosphates and NADPH for the synthesis of nucleic acid, fatty acids and glutathione (GSH) throughout pentose phosphate pathway. And GSH could protect bacteria from low pH, halide, oxidative stress and osmotic stress by maintaining the viability of cells through intracellular redox equilibrium; (2) Reinforcing deamination of amino acids to increase intracellular ammonia concentration to maintain stability of intracellular pH; (3) Enhancing nucleic acid synthesis and reparation of impaired DNA caused by acid stress damage; (4) Promoting unsaturated fatty acids synthesis and lipid transport, which resulted in the improvement of cytomembrane

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.

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.

Molecular Mechanisms for Sweet-suppressing Effect of Gymnemic Acids*

PubMed Central

Sanematsu, Keisuke; Kusakabe, Yuko; Shigemura, Noriatsu; Hirokawa, Takatsugu; Nakamura, Seiji; Imoto, Toshiaki; Ninomiya, Yuzo

2014-01-01

Gymnemic acids are triterpene glycosides that selectively suppress taste responses to various sweet substances in humans but not in mice. This sweet-suppressing effect of gymnemic acids is diminished by rinsing the tongue with γ-cyclodextrin (γ-CD). However, little is known about the molecular mechanisms underlying the sweet-suppressing effect of gymnemic acids and the interaction between gymnemic acids versus sweet taste receptor and/or γ-CD. To investigate whether gymnemic acids directly interact with human (h) sweet receptor hT1R2 + hT1R3, we used the sweet receptor T1R2 + T1R3 assay in transiently transfected HEK293 cells. Similar to previous studies in humans and mice, gymnemic acids (100 μg/ml) inhibited the [Ca2+]i responses to sweet compounds in HEK293 cells heterologously expressing hT1R2 + hT1R3 but not in those expressing the mouse (m) sweet receptor mT1R2 + mT1R3. The effect of gymnemic acids rapidly disappeared after rinsing the HEK293 cells with γ-CD. Using mixed species pairings of human and mouse sweet receptor subunits and chimeras, we determined that the transmembrane domain of hT1R3 was mainly required for the sweet-suppressing effect of gymnemic acids. Directed mutagenesis in the transmembrane domain of hT1R3 revealed that the interaction site for gymnemic acids shared the amino acid residues that determined the sensitivity to another sweet antagonist, lactisole. Glucuronic acid, which is the common structure of gymnemic acids, also reduced sensitivity to sweet compounds. In our models, gymnemic acids were predicted to dock to a binding pocket within the transmembrane domain of hT1R3. PMID:25056955

The effects of boric acid and phosphoric acid on the compressive strength of glass-ionomer cements.

PubMed

Prentice, Leon H; Tyas, Martin J; Burrow, Michael F

2006-01-01

Both boric acid (H3BO3) and phosphoric acid (H3PO4) are components of dental cements, commonly incorporated into glass (as ingredients in the melt) and occasionally added to the powder or liquid components. This study investigated the effect of boric acid addition to an experimental glass-ionomer powder and the effect of phosphoric acid addition to a glass-ionomer liquid on the 24-h compressive strength. Boric acid powder was added in various concentrations to an experimental glass-ionomer powder and, separately, phosphoric acid was added to an experimental glass-ionomer liquid. Powders and liquids were dosed into capsules at various powder:liquid ratios and cements thus formed were assessed for 24-h compressive strength. Incorporation of boric acid in glass-ionomer powder resulted in a pronounced decrease (p < 0.05 at 1% boric acid) in compressive strength. Addition of phosphoric acid produced initially stronger cements (up to 13% increase at 1% phosphoric acid) before also declining. The incorporation of less than 2% w/w phosphoric acid in glass-ionomer liquids may improve cement strengths without compromising clinical usefulness. The incorporation of boric acid in glass-ionomer cements is contraindicated.

Effects of acid rain on grapevines

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

Forsline, P.L.; Musselman, R.C.; Dee, R.J.

1983-01-01

Mature vineyard-growing Concord grapevines were sprayed with simulated acid rain solutions ranging from pH 2.5 to 5.5 both as acute treatments at anthesis and chronically throughout the season in 1980 and 1981. In 1981, 8 additional varieties were also treated with simulated acid rain solutions at pH 2.75 and 3.25. With Concord in 1981, few foliar lesions on leaves were visible at pH 2.75. In contrast, many leaf lesions with decreased fruit soluble solids were observed at pH 2.5 in 1980. The relationship between acid-rain and oxidant stipple, chlorosis, and soluble solids in the absence of acid rain leaf lesionsmore » at pH>2.5 remains unclear. Acute sprays (pH2.75) at anthesis reduced pollen germination in four grape cultivars. However, fruit set was reduced in only one of these. Grape yields were not influenced by acid rain treatments. There was no evidence that acid-rain at ambient pH levels had negative effects on grape production or fruit quality.« less

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.

Acid rain effects on aluminum mobilization clarified by inclusion of strong organic acids.

PubMed

Lawrence, G B; Sutherland, J W; Boylen, C W; Nierzwicki-Bauer, S W; Momen, B; Baldigo, B P; Simonin, H A

2007-01-01

Assessments of acidic deposition effects on aquatic ecosystems have often been hindered by complications from naturally occurring organic acidity. Measurements of pH and ANCG, the most commonly used indicators of chemical effects, can be substantially influenced by the presence of organic acids. Relationships between pH and inorganic Al, which is toxic to many forms of aquatic biota, are also altered by organic acids. However, when inorganic Al concentrations are plotted against ANC (the sum of Ca2+, Mg2+, Na+, and K+, minus S042-, N03-, and Cl-), a distinct threshold for Al mobilization becomes apparent. If the concentration of strong organic anions is included as a negative component of ANC, the threshold occurs at an ANC value of approximately zero, the value expected from theoretical charge balance constraints. This adjusted ANC is termed the base-cation surplus. The threshold relationship between the base-cation surplus and Al was shown with data from approximately 200 streams in the Adirondack region of New York, during periods with low and high dissolved organic carbon concentrations, and for an additional stream from the Catskill region of New York. These results indicate that (1) strong organic anions can contribute to the mobilization of inorganic Al in combination with SO42- and N03-, and (2) the presence of inorganic Al in surface waters is an unambiguous indication of acidic deposition effects.

[The matrix effects of organic acid compounds in ICP-MS].

PubMed

Nie, Xi-Du; He, Xiao-Mei; Li, Li-Bo; Xie, Hua-Lin

2007-07-01

The matrix effects arising from oxalic acid, lactic acid, tartaric acid and citric acid in inductively coupled plasma mass spectrometry (ICP-MS) were investigated. It has been proved that the sensitivity of analytes can be significantly enhanced by adding small amounts of organic acid compounds with adjusted nebulizer gas flow-rate, especially for the elements with ionization potential between 9 and 11 eV. The tartaric acid has higher enhancement effect on the signal intensity of the hard-to-ionize elements than oxalic acid, lactic acid and citric acid. The mechanism of the enhancement was investigated. The method has been used to determine Be, Zn, As, Se, Sb and Hg in water standard reference materials (SRM). The analytical results are very close to the certified values.

Interaction of solid organic acids with carbon nanotube field effect transistors

NASA Astrophysics Data System (ADS)

Klinke, Christian; Afzali, Ali; Avouris, Phaedon

2006-10-01

A series of solid organic acids were used to p-dope carbon nanotubes. The extent of doping is shown to be dependent on the pKa value of the acids. Highly fluorinated carboxylic acids and sulfonic acids are very effective in shifting the threshold voltage and making carbon nanotube field effect transistors to be more p-type devices. Weaker acids like phosphonic or hydroxamic acids had less effect. The doping of the devices was accompanied by a reduction of the hysteresis in the transfer characteristics. In-solution doping survives standard fabrication processes and renders p-doped carbon nanotube field effect transistors with good transport characteristics.

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.

Effect of salt addition on acid resistance response of Escherichia coli O157:H7 against acetic acid.

PubMed

Bae, Young-Min; Lee, Sun-Young

2017-08-01

A combination of salt and acid is commonly used in the production of many foods, such as pickles and fermented foods. However, in our previous studies, addition of salt significantly reduced the inhibitory effect of acetic acid against E. coli O157:H7 in laboratory media and pickled cucumbers. Therefore, this study was conducted to determine the effect of salt addition on the acid resistance (AR) response of E. coli O157:H7 after treatment with acetic acid. The combined effect of acetic acid and salt showed different results depending on media tested. Organic compounds such as yeast extract and tryptone were required to observe the antagonistic effect of salt and acetic acid in combination. However, use of an rpoS mutant or addition of chloramphenicol resulted in no changes in the antagonistic effect of acetic acid and salt. The addition of glutamate to phosphate buffer significantly increased the survival levels of E. coli O157:H7 after the acetic acid treatment; however, the survival levels were lower than those after the treatment with acetic acid alone. Thus, the addition of salt may increase the AR response of E. coli O157:H7; however, these survival mechanisms were not proven clearly. Therefore, further studies need to be performed to better understand the antagonism of acetic acid salt against E. coli O157:H7. Copyright © 2017 Elsevier Ltd. 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.

Comparison the effectiveness of pyruvic acid 50% and salicylic acid 30% in the treatment of acne.

PubMed

Jaffary, Fariba; Faghihi, Gita; Saraeian, Sara; Hosseini, Sayed Mohsen

2016-01-01

Acne vulgaris is a chronic inflammatory disease of the pilosebaceous follicles and one of the most common skin diseases. The peeling method has been recently found to be effective for acne treatment. This study aimed to compare the efficacy of pyruvic acid 50% and salicylic acid 30% peeling in the treatment of mild to moderate acne. In a prospective single-blinded clinical trial, 86 patients with acne were randomly assigned into two groups. In both groups, the routine treatment of acne (topical solution of erythromycin 4%, triclorocarban soap, and sunscreen) were used twice a day for 8 weeks. In addition, salicylic acid 30% for the control group and pyruvic acid 50% for the case group were used. In both groups, acne severity index (ASI) was calculated before and at week 2, 4, 6, and 8 of the treatment. Patient satisfaction was assessed at the end of the treatment. Side effects were recorded using a checklist. In both groups, the reduction in the number of comedones, papules, and ASI were statistically significant ( P < 0.001) in the course of treatment. However, it was not significant regarding the number of pustules ( P = 0.09). None of the number of comedone, papules, pustules, and ASI was statistically different between study groups. Both treatment groups had similar side effects except for scaling in the fifth session, which was significantly lower in salicylic acid - treated patients ( P = 0.015). Both pyruvic acid 50% and salicylic acid 30% are effective in the improvement of mild to moderate acne with no significant difference in efficacy and side effects.

Acid rain effects on aluminum mobilization clarified by inclusion of strong organic acids

USGS Publications Warehouse

Lawrence, G.B.; Sutherland, J.W.; Boylen, C.W.; Nierzwicki-Bauer, S. W.; Momen, B.; Baldigo, Barry P.; Simonin, H.A.

2007-01-01

Assessments of acidic deposition effects on aquatic ecosystems have often been hindered by complications from naturally occurring organic acidity. Measurements of pH and ANCG, the most commonly used indicators of chemical effects, can be substantially influenced by the presence of organic acids. Relationships between pH and inorganic Al, which is toxic to many forms of aquatic biota, are also altered by organic acids. However, when inorganic Al concentrations are plotted against ANC (the sum of Ca2+, Mg 2+, Na+, and K+, minus SO42-, NO3-, and Cl-), a distinct threshold for Al mobilization becomes apparent. If the concentration of strong organic anions is included as a negative component of ANC, the threshold occurs at an ANC value of approximately zero, the value expected from theoretical charge balance constraints. This adjusted ANC is termed the base-cation surplus. The threshold relationship between the base-cation surplus and Al was shown with data from approximately 200 streams in the Adirondack region of New York, during periods with low and high dissolved organic carbon concentrations, and for an additional stream from the Catskill region of New York. These results indicate that (1) strong organic anions can contribute to the mobilization of inorganic Al in combination with SO42- and NO 3-, and (2) the presence of inorganic Al in surface waters is an unambiguous indication of acidic deposition effects. ?? 2007 American Chemical Society.

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.

Effect of Hydrochloric Acid Concentration on the Conversion of Sugarcane Bagasse to Levulinic Acid

NASA Astrophysics Data System (ADS)

Anggorowati, Heni; Jamilatun, Siti; Cahyono, Rochim B.; Budiman, Arief

2018-01-01

Levulinic acid is a new green platform chemical used to the synthesis of a variety of materials for numerous applications such as fuel additives, polymers and resins. It can be produced using renewable resources such as biomass like sugarcane bagasse which are cheap and widely available as waste in Indonesia. In this study, sugarcane bagasse was hydrolyzed using hydrochloric acid with a solid liquid ratio 1:10. The effects of hydrochloric acid concentration at temperature of 180 °C and reaction time of 30 min were studied. The presence of levulinic acid in product of hydrolysis was measured with gas chromatography (GC). It was found that the highest concentration of levulinic acid was obtained at 1 M hydrochloric acid in 25.56 yield%.

Effects of acid-mine wastes on aquatic ecosystems

Treesearch

John David Parsons

1976-01-01

The Cedar Creek Basin (39th N parallel 92nd W meridian) was studied for the period June 1952 through August 1954 to observe the effects of both continuous and periodic acid effluent flows on aquatic communities. The acid strip-mine effluent contained ferric and ferrous iron, copper, lead, zinc, aluminum, magnesium, titratable acid, and elevated hydrogen ion...

Effects of aerosol formulation to amino acids and fatty acids contents in Haruan extract.

PubMed

Febriyenti; Bai-Baie, Saringat Bin; Laila, Lia

2012-01-01

Haruan (Channa striatus) extract was formulated to aerosol for wound and burn treatment. Haruan extract is containing amino acids and fatty acids that important for wound healing process. The purpose of this study is to observe the effect of formulation and other excipients in the formula to amino acids and fatty acids content in Haruan extract before and after formulated into aerosol. Precolumn derivatization with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) method is used for amino acids analysis. Fatty acids in Haruan extract were esterified using transesterification method to form FAMEs before analyzed using GC. Boron trifluoride-methanol reagent is used for transesterification. Tyrosine and methionine concentrations were different after formulated. The concentrations were decrease. There are six fatty acids have amount that significantly different after formulated into concentrate and aerosol. Contents of these fatty acids were increase. Generally, fatty acids which had content increased after formulated were the long-chain fatty acids. This might be happen because of chain extension process. Saponification and decarboxylation would give the chain extended product. Therefore contents of long-chain fatty acids were increase. Generally, the aerosol formulation did not affect the amino acids concentrations in Haruan extract while some long-chain fatty acids concentrations were increase after formulated into concentrate and aerosol.

Effects of oral eicosapentaenoic acid versus docosahexaenoic acid on human peripheral blood mononuclear cell gene expression

USDA-ARS?s Scientific Manuscript database

Objective: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have beneficial effects on inflammation and cardiovascular disease (CVD). Our aim was to assess the effect of a six-week supplementation with either olive oil, EPA, or DHA on gene expression in peripheral blood mononuclear cells (...

Utilization of acidic α-amino acids as acyl donors: an effective stereo-controllable synthesis of aryl-keto α-amino acids and their derivatives.

PubMed

Wang, Lei; Murai, Yuta; Yoshida, Takuma; Okamoto, Masashi; Tachrim, Zetryana Puteri; Hashidoko, Yasuyuki; Hashimoto, Makoto

2014-05-16

Aryl-keto-containing α-amino acids are of great importance in organic chemistry and biochemistry. They are valuable intermediates for the construction of hydroxyl α-amino acids, nonproteinogenic α-amino acids, as well as other biofunctional components. Friedel-Crafts acylation is an effective method to prepare aryl-keto derivatives. In this review, we summarize the preparation of aryl-keto containing α-amino acids by Friedel-Crafts acylation using acidic α-amino acids as acyl-donors and Lewis acids or Brönsted acids as catalysts.

Comparison the effectiveness of pyruvic acid 50% and salicylic acid 30% in the treatment of acne

PubMed Central

Jaffary, Fariba; Faghihi, Gita; Saraeian, Sara; Hosseini, Sayed Mohsen

2016-01-01

Background: Acne vulgaris is a chronic inflammatory disease of the pilosebaceous follicles and one of the most common skin diseases. The peeling method has been recently found to be effective for acne treatment. This study aimed to compare the efficacy of pyruvic acid 50% and salicylic acid 30% peeling in the treatment of mild to moderate acne. Materials and Methods: In a prospective single-blinded clinical trial, 86 patients with acne were randomly assigned into two groups. In both groups, the routine treatment of acne (topical solution of erythromycin 4%, triclorocarban soap, and sunscreen) were used twice a day for 8 weeks. In addition, salicylic acid 30% for the control group and pyruvic acid 50% for the case group were used. In both groups, acne severity index (ASI) was calculated before and at week 2, 4, 6, and 8 of the treatment. Patient satisfaction was assessed at the end of the treatment. Side effects were recorded using a checklist. Results: In both groups, the reduction in the number of comedones, papules, and ASI were statistically significant (P < 0.001) in the course of treatment. However, it was not significant regarding the number of pustules (P = 0.09). None of the number of comedone, papules, pustules, and ASI was statistically different between study groups. Both treatment groups had similar side effects except for scaling in the fifth session, which was significantly lower in salicylic acid – treated patients (P = 0.015). Conclusion: Both pyruvic acid 50% and salicylic acid 30% are effective in the improvement of mild to moderate acne with no significant difference in efficacy and side effects. PMID:27904577

Individual bile acids have differential effects on bile acid signaling in mice

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

Song, Peizhen, E-mail: songacad@gmail.com; Rockwell, Cheryl E., E-mail: rockwelc@msu.edu; Cui, Julia Yue, E-mail: juliacui@uw.edu

2015-02-15

Bile acids (BAs) are known to regulate BA synthesis and transport by the farnesoid X receptor in the liver (FXR-SHP) and intestine (FXR-Fgf15). However, the relative importance of individual BAs in regulating these processes is not known. Therefore, mice were fed various doses of five individual BAs, including cholic acid (CA), chenodeoxycholic acid (CDCA), deoxoycholic acid (DCA), lithocholic acid (LCA), and ursodeoxycholic acid (UDCA) in their diets at various concentrations for one week to increase the concentration of one BA in the enterohepatic circulation. The mRNA of BA synthesis and transporting genes in liver and ileum were quantified. In themore » liver, the mRNA of SHP, which is the prototypical target gene of FXR, increased in mice fed all concentrations of BAs. In the ileum, the mRNA of the intestinal FXR target gene Fgf15 was increased at lower doses and to a higher extent by CA and DCA than by CDCA and LCA. Cyp7a1, the rate-limiting enzyme in BA synthesis, was decreased more by CA and DCA than CDCA and LCA. Cyp8b1, the enzyme that 12-hydroxylates BAs and is thus responsible for the synthesis of CA, was decreased much more by CA and DCA than CDCA and LCA. Surprisingly, neither a decrease in the conjugated BA uptake transporter (Ntcp) nor increase in BA efflux transporter (Bsep) was observed by FXR activation, but an increase in the cholesterol efflux transporter (Abcg5/Abcg8) was observed with FXR activation. Thus in conclusion, CA and DCA are more potent FXR activators than CDCA and LCA when fed to mice, and thus they are more effective in decreasing the expression of the rate limiting gene in BA synthesis Cyp7a1 and the 12-hydroxylation of BAs Cyp8b1, and are also more effective in increasing the expression of Abcg5/Abcg8, which is responsible for biliary cholesterol excretion. However, feeding BAs do not alter the mRNA or protein levels of Ntcp or Bsep, suggesting that the uptake or efflux of BAs is not regulated by FXR at physiological and

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

Raw data of the effects of Chlorogenic acid in 3-Nitropropionic acid induced toxicity and genotoxicity.

PubMed

Norberto, Alarcón-Herrera; Saúl, Flores-Maya; Belén, Bellido; García-Bores Ana, M; Ernesto, Mendoza; Guillermo, Ávila-Acevedo; Elizabeth, Hernández-Echeagaray

2017-10-01

The raw data showed in this article comes from the published research article entitled "Protective effects of Chlorogenic acid in 3-Nitropropionic acid induced toxicity and genotoxicity" Food Chem Toxicol. 2017 May 3. pii: S0278-6915(17)30226-0. DOI:10.1016/j.fct.2017.04.048. [1]. Data illustrates antitoxic and antigenotoxic effects of Chlorogenic acid (CGA) on toxicity and genotoxicity produced by the in vivo treatment with mitochondria toxin 3-Nitropropionic acid (3-NP) in mice. Toxicity and genotoxicity was evaluated in erythrocytes of peripheral blood through the micronuclei assay. Data was share at the Elsevier repository under the reference number FCT9033.

[Combined effect of benzylpenicillin, furagin and bile acids on staphylococci].

PubMed

Sytnik, I A; Tkachuk, N I

1982-11-01

The results of the study of the effect of benzylpenicillin or furagin in combination with bile acids, such as cholic, glycocholic and desoxycholic on the collection cultures of staphylococci are presented. The study showed that the subbacteriostatic doses of the bile acids increased the bacteriostatic and bactericidal effects of benzylpenicillin and furagin by tens and hundreds times. The highest potentiation effect was attained with the use of the furagin combination and desoxycholic acid.

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.

Effects of Oxalic Acid on Apis mellifera (Hymenoptera: Apidae)

PubMed Central

Rademacher, Eva; Harz, Marika; Schneider, Saskia

2017-01-01

Oxalic acid dihydrate is used to treat varroosis of Apis mellifera. This study investigates lethal and sublethal effects of oxalic acid dihydrate on individually treated honeybees kept in cages under laboratory conditions as well as the distribution in the colony. After oral application, bee mortality occurred at relatively low concentrations (No Observed Adverse Effect Level (NOAEL) 50 µg/bee; Lowest Observed Adverse Effect Level (LOAEL) 75 µg/bee) compared to the dermal treatment (NOAEL 212.5 µg/bee; LOAEL 250 µg/bee). The dosage used in regular treatment via dermal application (circa 175 µg/bee) is below the LOAEL, referring to mortality derived in the laboratory. However, the treatment with oxalic acid dihydrate caused sublethal effects: This could be demonstrated in an increased responsiveness to water, decreased longevity and a reduction in pH-values in the digestive system and the hemolymph. The shift towards stronger acidity after treatment confirms that damage to the epithelial tissue and organs is likely to be caused by hyperacidity. The distribution of oxalic acid dihydrate within a colony was shown by macro-computed tomography; it was rapid and consistent. The increased density of the individual bee was continuous for at least 14 days after the treatment indicating the presence of oxalic acid dihydrate in the hive even long after a treatment. PMID:28783129

Harmful effects of usnic acid on hepatic metabolism.

PubMed

Moreira, Caroline T; Oliveira, Andrea L; Comar, Jurandir F; Peralta, Rosane M; Bracht, A

2013-04-25

Usnic acid is a naturally occurring dibenzofuran derivative found in several lichen species. The compound has been marketed as an ingredient of food supplements for weight reduction. There is evidence that the compound acts as an uncoupler of mitochondrial oxidative phosphorylation and it is also clear that consumption of the drug can lead to severe hepatotoxicity depending on the doses. Based on these and other ideas the objective of the present work was to investigate the possible effects of usnic acid on liver metabolism. Livers of male Wistar rats were perfused in a non-recirculating system. Usnic acid stimulated oxygen consumption at low concentrations, diminished the cellular ATP levels, increased the cytosolic but diminished the mitochondrial NADH/NAD(+) ratio, strongly inhibited gluconeogenesis from three different substrates (IC(50) between 1.33 and 3.61 μM), stimulated glycolysis, fructolysis, glycogenolysis and ammoniagenesis and inhibited ureogenesis. The (14)CO(2) production from [1-(14)C]octanoate and [1-(14)C]oleate was increased by usnic acid, but ketogenesis from octanoate was diminished and that from oleate was not affected. It may be concluded that the effects of usnic acid up to 2.5 μM reflect predominantly its activity as an uncoupler. At higher concentrations, however, several other effects may become significant, including inhibition of mitochondrial electron flow and inhibition of medium-chain fatty acid oxidation. In metabolic terms, toxicity of usnic acid can be predicted to be especially dangerous in the fasted state due to the combination of several deleterius events such as diminished hepatic glucose and ketone bodies output to the brain and increased ammonia production. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Effects of organic acids, amino acids and ethanol on the radio-degradation of patulin in an aqueous model system

NASA Astrophysics Data System (ADS)

Yun, Hyejeong; Lim, Sangyong; Jo, Cheorun; Chung, Jinwoo; Kim, Soohyun; Kwon, Joong-Ho; Kim, Dongho

2008-06-01

The effects of organic acids, amino acids, and ethanol on the radio-degradation of patulin by gamma irradiation in an aqueous model system were investigated. The patulin, dissolved in distilled water at a concentration of 50 ppm, was practically degraded by the gamma irradiation at the dose of 1.0 kGy, while 33% of the patulin remained in apple juice. In the aqueous model system, the radio-degradation of patulin was partially inhibited by the addition of organic acids, amino acids, and ethanol. The proportions of remaining patulin after irradiation with the dose of 1.0 kGy in the 1% solution of malic acid, citric acid, lactic acid, acetic acid, ascorbic acid, and ethanol were 31.4%, 2.3%, 31.2%, 6.1%, 50.8%, and 12.5%, respectively. During 30 days of storage, the remaining patulin was reduced gradually in the solution of ascorbic acid and malic acid compared to being stable in other samples. The amino acids, serine, threonine, and histidine, inhibited the radio-degradation of patulin. In conclusion, it was suggested that 1 kGy of gamma irradiation (recommended radiation doses for radicidation and/or quarantine in fruits) is effective for the reduction of patulin, but the nutritional elements should be considered because the radio-degradation effects are environment dependent.

Effects of acidic precipitation on host-parasite interactions

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

Shriner, D.S.

1974-01-01

During the past decade, the average acidity of rain and snow increased by 1-2 pH units in many parts of Europe and North America. Little is known of the effects of acid rain resulting from dissolution of sulfur dioxide on biological systems. The effects of simulated sulfuric acid rain on four host-pathogen system were studied. Plants were exposed in greenhouse and field to simulated rain of pH 3.2 or pH 6.0 in amounts and intervals common to weather patterns of the eastern United States. Simulated acid rain resulted in: (1) an 86% inhibition in telia production of Cronartium fusiforme onmore » willow oak (Quercus phellos); (2) a 66% inhibition in the production of root-knot nematodes (Meloidogyne hapla) on field grown kidney beans (Phaseolus vulgaris Red Kidney); (3) a 20% decrease in the severity of Uromyces phaseoli infection of field grown kidney beans; and (4) either stimulated or inhibited development of halo blight on kidney bean (caused by Pseudomonas phaseolicola) depending upon the segment of the disease cycle in which the stress occurred: (a) simulated acid rain before inoculation stimulated disease development; (b) suspension of inoculum in acid rain decreased inoculum potential; and (c) acid rain after infection inhibited disease development. Results suggest that the pH of rain is a new environmental parameter of concern to plant pathologists.« less

Combined effects of organic acids and salt depending on type of acids and pathogens in laboratory media and acidified pickle.

PubMed

Bae, Y-M; Lee, S-Y

2015-08-01

In this study, the effectiveness of combining each of seven types of acids with 3% salt as a treatment against pathogens was investigated in laboratory media and acidified food. When 0.5% malic, 0.5% tartaric, 0.5% citric or 0.25% phosphoric acid was combined with 3% salt, there was a higher reduction in Gram-negative bacteria (Escherichia coli O157:H7 and Salmonella Typhimurium) compared to when using acid alone. However, when 0.5% acetic, 0.5% propionic or 0.25% lactic acid was combined with 3% salt, the salt provided protection against the acid treatment. However, the antagonistic effects of acetic, propionic and lactic acid seen with Gram-negative bacteria were not observed in Listeria monocytogenes. Antagonistic effects were similarly observed when E. coli O157:H7 was treated with acetic acid and salt in food. These results show that the addition of salt increases the resistance of Gram-negative bacteria to acid treatments when using acetic, propionic and lactic acid. This study shows that antagonistic effects were observed when Gram-negative bacteria were treated with organic acids of simple structure. It may provide useful information for understanding the acid resistance mechanism of Gram-negative bacteria and developing methods for preserving acidified food. © 2015 The Society for Applied Microbiology.

THE EFFECTS OF PANTOTHENIC ACID ON RESPIRATORY ACTIVITY.

PubMed

Pratt, E F; Williams, R J

1939-05-20

Experiments using the Warburg-Barcroft apparatus led to the following results and conclusions: (1) Two yeasts in three different media were strikingly stimulated in their respiration by minute amounts of pantothenic acid. (2) Nine other compounds (vitamins and other biologically important substances) were tested and found in all cases to have on the deficient G.M. yeast, lesser and in some cases no appreciable stimulative effect. Thiamin was the most effective of these compounds. Its action was shown to be different and in some ways antagonistic to that of pantothenic acid. (3) Liver extract (Lilly's Number 343) contains substances capable of speeding up respiration (and growth) to a much higher level than seems possible with known compounds. (4) Pantothenic acid was found to have a definite stimulative effect on fermentation by dialyzed maceration juice from yeast. (5) It likewise stimulated respiration of apple and potato tissue and indications of a similar effect on certain animal tissues were obtained.

Toxic and signalling effects of oxalic acid

PubMed Central

Lehner, Arnaud; Meimoun, Patrice; Errakhi, Rafik; Madiona, Karine; Barakate, Mustapha

2008-01-01

Oxalic acid is thought to be a key factor of the early pathogenic stage in a wide range of necrotrophic fungi. We have recently published that oxalic acid induces Programmed Cell Death (PCD) in Arabidopsis thaliana cells. This cell death results from an early anionic efflux which is a prerequisite for the synthesis of ethylene and the PCD. Complementary experiments have been carried out by using seedlings of A. thaliana. The effects of millimolar concentrations of oxalic acid were analysed on A. thaliana seedlings. A treatment with a 3 mM oxalic acid solution does not alter the development of the plants but induces the transcription of defence related genes which are anion channel dependant. Moreover, our results suggest that a pre-treatment of the seedlings with oxalic acid is able to confer the resistance of A. thaliana against Sclerotium rolfsii. Regarding our results, we suggest that oxalic acid plays two distinct roles, depending on the concentration: a high concentration of oxalic acid induces a large PCD and then contribute to the progression of the fungi. However, at low concentration it is able to induce the establishment of a resistance of the plant against the fungi. PMID:19704845

Potential adverse effects of omega-3 Fatty acids in dogs and cats.

PubMed

Lenox, C E; Bauer, J E

2013-01-01

Fish oil omega-3 fatty acids, mainly eicosapentaenoic acid and docosahexaenoic acid, are used in the management of several diseases in companion animal medicine, many of which are inflammatory in nature. This review describes metabolic differences among omega-3 fatty acids and outlines potential adverse effects that may occur with their supplementation in dogs and cats with a special focus on omega-3 fatty acids from fish oil. Important potential adverse effects of omega-3 fatty acid supplementation include altered platelet function, gastrointestinal adverse effects, detrimental effects on wound healing, lipid peroxidation, potential for nutrient excess and toxin exposure, weight gain, altered immune function, effects on glycemic control and insulin sensitivity, and nutrient-drug interactions. Copyright © 2013 by the American College of Veterinary Internal Medicine.

Biochemical Characterization of Ferulic Acid and Caffeic Acid Which Effectively Inhibit Melanin Synthesis via Different Mechanisms in B16 Melanoma Cells.

PubMed

Maruyama, Hiroko; Kawakami, Fumitaka; Lwin, Thet-Thet; Imai, Motoki; Shamsa, Fazel

2018-01-01

In this study, we examined the inhibitory effects of ferulic acid and caffeic acid on melanin production using a murine B16 melanoma cell line. The mechanisms by which the two acids inhibit melanin production were investigated by evaluating their effects on the activity of tyrosinase, which is involved is the first step of melanin biosynthesis. Ferulic acid showed no toxicity against the melanoma cells at any dose, whereas caffeic acid exerted cellular toxicity at concentrations higher than 0.35 mM. Both ferulic and caffeic acids effectively inhibited melanin production in the B16 melanoma cells. Ferulic acid reduced tyrosinase activity by directly binding to the enzyme, whereas no binding was observed between caffeic acid and tyrosinase. Both ferulic acid and caffeic acid inhibited casein kinase 2 (CK2)-induced phosphorylation of tyrosinase in a dose-dependent manner in vitro. Ferulic acid was found to be a more effective inhibitor of melanin production than caffeic acid; this difference in the inhibitory efficacy between the two substances could be attributable to the difference in their tyrosine-binding activity. Our analysis revealed that both substances also inhibited the CK2-mediated phosphorylation of tyrosinase.

Effects of diet on titratable acid-base excretion in grasshoppers.

PubMed

Frazier, M R; Harrison, J F; Behmer, S T

2000-01-01

Despite the potential for diet to affect organismal acid-base status, especially in herbivores, little is known about the effects of diet on acid-base loading and excretion. We tested the effects of diet on acid-base loading and excretion in grasshoppers by (a) comparing the fecal acid-base content of 15 grasshopper species collected from the field and (b) comparing fecal acid-base excretion rates of Schistocerca americana grasshoppers fed vegetable diets that differed in their ashed and raw acid-base contents. The field experiments indicated that grass-feeding species excrete fairly neutral fecal pellets, while forb/mixed-feeding species vary widely in their fecal acid-base contents. In the laboratory experiment, acid-base excretion rates were positively correlated with dietary ashed base intake rates but were not correlated with the acid-base content of raw, unashed diet or feeding rate. These experiments suggest that some diets could strongly challenge the acid-base homeostasis of herbivores; in some grasshoppers, dietary acid-base loads could produce certainly lethal 1-unit changes in average body pH within 6 h if they were not excreted.

Physiological effects of γ-linolenic acid and sesamin on hepatic fatty acid synthesis and oxidation.

PubMed

Ide, Takashi; Iwase, Haruka; Amano, Saaya; Sunahara, Saki; Tachihara, Ayuka; Yagi, Minako; Watanabe, Tsuyoshi

2017-03-01

Interrelated effects of γ-linolenic acid (GLA) and sesamin, a sesame lignan, on hepatic fatty acid synthesis and oxidation were examined. Rats were fed experimental diets supplemented with 0 or 2 g/kg sesamin (1:1 mixture of sesamin and episesamin) and containing 100 g/kg of palm oil (saturated fat), safflower oil rich in linoleic acid, or oil of evening primrose origin containing 43% GLA (GLA oil) for 18 days. In rats fed sesamin-free diets, GLA oil, compared with other oils, increased the activity and mRNA levels of various enzymes involved in fatty acid oxidation, except for some instances. Sesamin greatly increased these parameters, and the enhancing effects of sesamin on peroxisomal fatty acid oxidation rate and acyl-CoA oxidase, enoyl-CoA hydratase and acyl-CoA thioesterase activities were more exaggerated in rats fed GLA oil than in the animals fed other oils. The combination of sesamin and GLA oil also synergistically increased the mRNA levels of some peroxisomal fatty acid oxidation enzymes and of several enzymes involved in fatty acid metabolism located in other cell organelles. In the groups fed sesamin-free diets, GLA oil, compared with other oils, markedly reduced the activity and mRNA levels of various lipogenic enzymes. Sesamin reduced all these parameters, except for malic enzyme, in rats fed palm and safflower oils, but the effects were attenuated in the animals fed GLA oil. These changes by sesamin and fat type accompanied profound alterations in serum lipid levels. This may be ascribable to the changes in apolipoprotein-B-containing lipoproteins. Copyright © 2016 Elsevier Inc. All rights reserved.

Bile Acids Improve the Antimicrobial Effect of Rifaximin▿ †

PubMed Central

Darkoh, Charles; Lichtenberger, Lenard M.; Ajami, Nadim; Dial, Elizabeth J.; Jiang, Zhi-Dong; DuPont, Herbert L.

2010-01-01

Diarrhea is one of the most common infirmities affecting international travelers, occurring in 20 to 50% of persons from industrialized countries visiting developing regions. Enterotoxigenic Escherichia coli (ETEC) is the most common causative agent and is isolated from approximately half of the cases of traveler's diarrhea. Rifaximin, a largely water-insoluble, nonabsorbable (<0.4%) antibiotic that inhibits bacterial RNA synthesis, is approved for use for the treatment of traveler's diarrhea caused by diarrheagenic E. coli. However, the drug has minimal effect on the bacterial flora or the infecting E. coli strain in the aqueous environment of the colon. The purpose of the present study was to evaluate the antimicrobial effect and bioavailability of rifaximin in aqueous solution in the presence and absence of physiologic concentrations of bile acids. The methods used included growth measurement of ETEC (strain H10407), rifaximin solubility measurements, total bacterial protein determination, and assessment of the functional activity of rifaximin by monitoring inhibition of bacterial β-galactosidase expression. Solubility studies showed rifaximin to be 70- to 120-fold more soluble in bile acids (approximately 30% in 4 mM bile acids) than in aqueous solution. Addition of both purified bile acids and human bile to rifaximin at subinhibitory and inhibitory concentrations significantly improved the drug's anti-ETEC effect by 71% and 73%, respectively, after 4 h. This observation was confirmed by showing a decrease in the overall amount of total bacterial protein expressed during incubation of rifaximin plus bile acids. Rifaximin-treated samples containing bile acids inhibited the expression of ETEC β-galactosidase at a higher magnitude than samples that did not contain bile acids. The study provides data showing that bile acids solubilize rifaximin on a dose-response basis, increasing the drug's bioavailability and antimicrobial effect. These observations suggest

EFFECTIVE ACIDITY CONSTANT BEHAVIOR NEAR ZERO CHARGE CONDITIONS

EPA Science Inventory

Surface site (>SOH group) acidity reactions require expressions of the form: Ka = [>SOHn-1(z-1)]aH+EXP(-DG/RT)/[>SOHnz] (where all variables have their usual meaning). One can rearrange this expression to generate an effective acidity constant historically defined as: Qa = Ka...

Potential effects of chlorogenic acids on platelet activiation

USDA-ARS?s Scientific Manuscript database

Coffee (Coffea sp) is a most consumed beverage world-wide. Chlorogenic acids (CHAs) are naturally occurring phenolic acid esters abundantly found in coffee. They are reported to have potential health effects on several chronic diseases such as obesity, diabetes and cardiovascular diseases (CVD). At...

Effect of Eicosapentaenoic Acid and Docosahexaenoic Acid on Myogenesis and Mitochondrial Biosynthesis during Murine Skeletal Muscle Cell Differentiation.

PubMed

Hsueh, Tun-Yun; Baum, Jamie I; Huang, Yan

2018-01-01

Polyunsaturated fatty acids are important nutrients for human health, especially omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which have been found to play positive roles in the prevention of various diseases. However, previous studies have reported that excessive omega-3 fatty acids supplement during pregnancy caused side effects such as slower neural transmission times and postnatal growth restriction. In this study, we investigated the effect of EPA and DHA on mitochondrial function and gene expression in C2C12 myoblasts during skeletal muscle differentiation. C2C12 myoblasts were cultured to confluency and then treated with differentiation medium that contained fatty acids (50-µM EPA and DHA). After 72 h of myogenic differentiation, mRNA was collected, and gene expression was analyzed by real-time PCR. Microscopy was used to examine cell morphology following treatment with fatty acids. The effect of EPA and DHA on cellular oxygen consumption was measured using a Seahorse XF24 Analyzer. Cells treated with fatty acids had fewer myotubes formed ( P ≤ 0.05) compared with control cells. The expression of the genes related to myogenesis was significantly lower ( P ≤ 0.05) in cells treated with fatty acids, compared with control cells. Genes associated with adipogenesis had higher ( P ≤ 0.05) expression after treatment with fatty acids. Also, the mitochondrial biogenesis decreased with lower ( P ≤ 0.05) gene expression and lower ( P ≤ 0.05) mtDNA/nDNA ratio in cells treated with fatty acids compared with control cells. However, the expression of genes related to peroxisome biosynthesis was higher ( P ≤ 0.05) in cells treated with fatty acids. Moreover, fatty-acid treatment reduced ( P ≤ 0.05) oxygen consumption rate under oligomycin-inhibited (reflecting proton leak) and uncoupled conditions. Our data imply that fatty acids might reduce myogenesis and increase adipogenesis in myotube formation. Fatty acids

Effects of caffeic and chlorogenic acids on the rat skeletal system.

PubMed

Folwarczna, J; Pytlik, M; Zych, M; Cegieła, U; Nowinska, B; Kaczmarczyk-Sedlak, I; Sliwinski, L; Trzeciak, H; Trzeciak, H I

2015-02-01

Caffeic acid, predominantly as esters linked to quinic acid (chlorogenic acids), is a phenolic acid present at high levels in coffee. The aim of the study was to investigate effects of caffeic and chlorogenic acids on the skeletal system of female rats with normal estrogen levels and estrogen-deficient. Caffeic acid (5 and 50 mg/kg p.o. daily) and chlorogenic acid (100 mg/kg p.o. daily) were administered for 4 weeks to non-ovariectomized and bilaterally ovariectomized mature Wistar rats, and their effects were compared with appropriate controls. Moreover, estradiol (0.2 mg/kg p.o. daily) was administered to ovariectomized rats. Bone turnover markers, mass, mineralization and mechanical properties were examined. Although caffeic acid at a low dose exerted some unfavorable effects on the skeletal system, at high doses, caffeic and chlorogenic acids slightly increased mineralization in the tibia and improved mechanical properties of the femoral diaphysis (compact bone). Unlike estradiol, they did not counteract the worsening of the tibial metaphysis bone strength (cancellous bone) and increases in osteocalcin concentration induced by estrogen deficiency. High doses of the phenolic acids slightly favorably affected the rat skeletal system independently of the estrogen status.

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.

Physiological effect and therapeutic application of alpha lipoic acid.

PubMed

Park, Sungmi; Karunakaran, Udayakumar; Jeoung, Nam Ho; Jeon, Jae-Han; Lee, In-Kyu

2014-01-01

Reactive oxygen species and reactive nitrogen species promote endothelial dysfunction in old age and contribute to the development of cardiovascular diseases such as atherosclerosis, diabetes, and hypertension. α-Lipoic acid was identified as a catalytic agent for oxidative decarboxylation of pyruvate and α-ketoglutarate in 1951, and it has been studied intensively by chemists, biologists, and clinicians who have been interested in its role in energetic metabolism and protection from reactive oxygen species-induced mitochondrial dysfunction. Consequently, many biological effects of α-lipoic acid supplementation can be attributed to the potent antioxidant properties of α-lipoic acid and dihydro α-lipoic acid. The reducing environments inside the cell help to protect from oxidative damage and the reduction-oxidation status of α-lipoic acid is dependent upon the degree to which the cellular components are found in the oxidized state. Although healthy young humans can synthesize enough α-lipoic acid to scavenge reactive oxygen species and enhance endogenous antioxidants like glutathione and vitamins C and E, the level of α-lipoic acid significantly declines with age and this may lead to endothelial dysfunction. Furthermore, many studies have reported α-lipoic acid can regulate the transcription of genes associated with anti-oxidant and anti-inflammatory pathways. In this review, we will discuss recent clinical studies that have investigated the beneficial effects of α-lipoic acid on endothelial dysfunction and propose possible mechanisms involved.

Effects of sodium citrate, citric acid and lactic acid on human blood coagulation.

PubMed

Scaravilli, Vittorio; Di Girolamo, Luca; Scotti, Eleonora; Busana, Mattia; Biancolilli, Osvaldo; Leonardi, Patrizia; Carlin, Andrea; Lonati, Caterina; Panigada, Mauro; Pesenti, Antonio; Zanella, Alberto

2018-05-01

Citric acid infusion in extracorporeal blood may allow concurrent regional anticoagulation and enhancement of extracorporeal CO 2 removal. Effects of citric acid on human blood thromboelastography and aggregometry have never been tested before. In this in vitro study, citric acid, sodium citrate and lactic acid were added to venous blood from seven healthy donors, obtaining concentrations of 9 mEq/L, 12 mEq/L and 15 mEq/L. We measured gas analyses, ionized calcium (iCa ++ ) concentration, activated clotting time (ACT), thromboelastography and multiplate aggregometry. Repeated measure analysis of variance was used to compare the acidifying and anticoagulant properties of the three compounds. Sodium citrate did not affect the blood gas analysis. Increasing doses of citric and lactic acid progressively reduced pH and HCO 3 - and increased pCO 2 (p<0.001). Sodium citrate and citric acid similarly reduced iCa ++ , from 0.39 (0.36-0.39) and 0.35 (0.33-0.36) mmol/L, respectively, at 9 mEq/L to 0.20 (0.20-0.21) and 0.21 (0.20-0.23) mmol/L at 15 mEq/L (p<0.001). Lactic acid did not affect iCa ++ (p=0.07). Sodium citrate and citric acid similarly incremented the ACT, from 234 (208-296) and 202 (178-238) sec, respectively, at 9 mEq/L, to >600 sec at 15 mEq/L (p<0.001). Lactic acid did not affect the ACT values (p=0.486). Sodium citrate and citric acid similarly incremented R-time and reduced α-angle and maximum amplitude (MA) (p<0.001), leading to flat-line thromboelastograms at 15 mEq/L. Platelet aggregometry was not altered by any of the three compounds. Citric acid infusions determine acidification and anticoagulation of blood similar to lactic acid and sodium citrate, respectively.

Cox-2 inhibitory effects of naturally occurring and modified fatty acids.

PubMed

Ringbom, T; Huss, U; Stenholm , A; Flock, S; Skattebøl, L; Perera, P; Bohlin, L

2001-06-01

In the search for new cyclooxygenase-2 (COX-2) selective inhibitors, the inhibitory effects of naturally occurring fatty acids and some of their structural derivatives on COX-2-catalyzed prostaglandin biosynthesis were investigated. Among these fatty acids, linoleic acid (LA), alpha-linolenic acid (alpha-LNA), myristic acid, and palmitic acid were isolated from a CH(2)Cl(2) extract of the plant Plantago major by bioassay-guided fractionation. Inhibitory effects of other natural, structurally related fatty acids were also investigated: stearic acid, oleic acid, pentadecanoic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Further, the inhibitory effects of these compounds on COX-2- and COX-1-catalyzed prostaglandin biosynthesis was compared with the inhibition of some synthesized analogues of EPA and DHA with ether or thioether functions. The most potent COX-2-catalyzed prostaglandin biosynthesis inhibitor was all-(Z)-5-thia-8,11,14,17-eicosatetraenoic acid (2), followed by EPA, DHA, alpha-LNA, LA, (7E,11Z,14Z,17Z)-5-thiaeicosa-7,11,14,17-tetraenoic acid, all-(Z)-3-thia-6,9,12,15-octadecatetraenoic acid, and (5E,9Z,12Z,15Z,18Z)-3-oxaheneicosa-5,9,12,15,18-pentaenoic acid, with IC(50) values ranging from 3.9 to180 microM. The modified compound 2 and alpha-LNA were most selective toward COX-2, with COX-2/COX-1 ratios of 0.2 and 0.1, respectively. This study shows that several of the natural fatty acids as well as all of the semisynthetic thioether-containing fatty acids inhibited COX-2-catalyzed prostaglandin biosynthesis, where alpha-LNA and compound 2 showed selectivity toward COX-2.

Experimental study on the estrogen-like effect of boric Acid.

PubMed

Wang, Yadong; Zhao, Yingzheng; Chen, Xiaoyu

2008-02-01

There are now considerable evidences that boric acid has reproductive and developmental toxicity, but it is uncertain whether such toxicity is caused by estrogen-like effect. Our objective is to determine the estrogen-like effect of boric acid. Proliferation assay of MCF-7 human breast cancer cells, uterotrophic assay, measure assay of the estradiol (E2), proliferation assay of mucous membrane cells, and assay of estrogen receptor were conducted in this study. Boric acid could increase the weight of uterus of ovariectomized SD rats and the height of epithelium cells of mucous membrane, enhance the expression of the proliferating cell nucleus antigen, and reduce the density of estrogen receptors. However, boric acid could not affect the level of estradiol in serum and stimulate the proliferation of MCF-7 human breast cancer cells. In this study, boric acid exhibited the estrogen-like effect in vivo.

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 Conjugated Linoleic Acid Feeding on the Growth Performance and Meat Fatty Acid Profiles in Broiler: Meta-analysis

PubMed Central

Cho, Sangbuem; Ryu, Chaehwa; Yang, Jinho; Mbiriri, David Tinotenda; Choi, Chang-Weon; Chae, Jung-Il; Kim, Young-Hoon; Shim, Kwan-Seob; Kim, Young Jun; Choi, Nag-Jin

2013-01-01

The effect of conjugated linoleic acid (CLA) feeding on growth performance and fatty acid profiles in thigh meat of broiler chicken was investigated using meta-analysis with a total of 9 studies. Overall effects were calculated by standardized mean differences between treatment (CLA fed) and control using Hedges’s adjusted g from fixed and random effect models. Meta-regression was conducted to evaluate the effect of CLA levels. Subgroups in the same study were designated according to used levels of CLA, CP levels or substituted oils in diets. The effects on final body weight, weight gain, feed intake and feed conversion ratio were investigated as growth parameters. Total saturated and unsaturated fatty acid concentrations and C16:0, C18:0, C18:2 and C18:3 concentrations in thigh meat of broiler chicken were used as fatty acid profile parameters. The overall effect of CLA feeding on final weight was negative and it was only significant in fixed effect model (p<0.01). Significantly lower weight gain, feed intake and higher feed conversion ratio compared to control were found (p<0.05). CLA feeding on the overall increased total saturated fatty acid concentration in broilers compared to the control diet (p<0.01). Total unsaturated fatty acid concentration was significantly decreased by CLA feeding (p<0.01). As for individual fatty acid profiles, C16:0, C18:0 and C18:3 were increased and C18:2 was significantly decreased by CLA feeding (p<0.01). In conclusion, CLA was proved not to be beneficial for improving growth performance, whereas it might be supposed that CLA is effective modulating n-6/n-3 fatty acids ratio in thigh meat. However, the economical compensation of the loss from suppressed growth performance and increased saturated fatty acids with the benefit from enhanced n-6/n-3 ratio should be investigated in further studies in order to propose an appropriate use of dietary CLA in the broiler industry. PMID:25049878

Adsorption of phthalic acid and salicylic acid and their effect on exchangeable Al capacity of variable-charge soils.

PubMed

Li, Jiuyu; Xu, Renkou

2007-02-01

Low-molecular-weight (LMW) organic acids may be adsorbed by soils and the adsorption could affect their biodegradation and efficiency in many soil processes. In the present study, the adsorption of phthalic acid and salicylic acid and their effect on the exchangeable Al capacity of variable-charge soils were investigated. The results indicated that phthalic acid and salicylic acid were adsorbed by four variable-charge soils to some extent, oxisols showed a greater adsorption capacity for organic acids than ultisols, and the ability of the four variable-charge soils to adsorb the organic acids at different pH generally followed the order Kunming oxisol > Xuwen oxisol > Jinxian ultisol > Lechang ultisol, which was closely related to their content of free iron oxides and amorphous iron and aluminum oxides. The adsorption of organic acids induced a decrease in the zeta potentials of soils and oxides. Goethite has greater adsorption capacity for organic acid than Xuwen oxisol and the adsorption of organic acids resulted in a bigger decrease in the zeta potential of goethite suspensions. After free iron oxides were removed, less organic acid was adsorbed by Xuwen oxisol and no change was observed in zeta potential for the soil suspension after organic acid was added. The presence of phthalic acid increased the capacity of exchangeable Al and the increment in the four variable-charge soils also followed the order Kunming oxisol > Xuwen oxisol > Lechang ultisol and Jinxian ultisol. The presence of salicylic acid increased the capacity of exchangeable Al in Kunming oxisol, Xuwen oxisol, and Jinxian ultisol, but decreased it in Lechang ultisol due to less adsorption of the acid and formation of soluble Al-salicylate complexes in solution. After free iron oxides were removed, less effect of organic acid on exchangeable Al was observed for Xuwen oxisol, which further confirmed that the iron oxides played a significant role in organic acid adsorption and had a consequent effect

Effect of lipoic acid combined with paclitaxel on breast cancer cells.

PubMed

Li, B J; Hao, X Y; Ren, G H; Gong, Y

2015-12-22

Breast cancer is the most common gynecologic tumor globally that threatens women's health. Lipoic acid is a type of antioxidant that can alleviate oxidative stress damage. Studies showed that lipoic acid could inhibit the proliferation of tumor cells in cervical cancer and colon cancer. This paper intends to explore the combined effect of lipoic acid and paclitaxel on breast cancer cells. Breast cancer MCF-7 cells were divided into four groups: control group, lipoic acid group, paclitaxel group, and a combination group. MTT was applied to detect the drugs' influence on breast cancer cell proliferation. A colony formation test was used to determine the effects on breast cancer cell clone formation rate. Western blot was performed to detect the effects on nuclear factor (NF)-κB. Lipoic acid alone can inhibit tumor cell proliferation and clone formation with time dependence. Compared with the control, paclitaxel alone can significantly suppress tumor cell proliferation and clone formation (P < 0.05). Lipoic acid and paclitaxel in combination obviously strengthened their individual inhibitory effects on tumor cells (P < 0.05). Compared with the paclitaxel alone group, the combination group exhibited more remarkable inhibitory effect (P < 0.05). Lipoic acid alone or combined with paclitaxel can inhibit NF-κB expression and inhibit breast cancer cell proliferation.

Health effects of acid aerosols formed by atmospheric mixtures.

PubMed Central

Kleinman, M T; Phalen, R F; Mautz, W J; Mannix, R C; McClure, T R; Crocker, T T

1989-01-01

Under ambient conditions, sulfur and nitrogen oxides can react with photochemical products and airborne particles to form acidic vapors and aerosols. Inhalation toxicological studies were conducted, exposing laboratory animals, at rest and during exercise, to multicomponent atmospheric mixtures under conditions favorable to the formation of acidic reaction products. Effects of acid and ozone mixtures on early and late clearance of insoluble radioactive particles in the lungs of rats appeared to be dominated by the oxidant component (i.e., the mixture did cause effects that were significantly different from those of ozone alone). Histopathological evaluations showed that sulfuric acid particles alone did not cause inflammatory responses in centriacinar units of rat lung parenchyma (expressed in terms of percent lesion area) but did cause significant damage (cell killing followed by a wave of cell replication) in nasal respiratory epithelium, as measured by uptake of tritiated thymidine in the DNA of replicating cells. Mixtures of ozone and nitrogen dioxide, which form nitric acid, caused significant inflammatory responses in lung parenchyma (in excess of effects seen in rats exposed to ozone alone), but did not damage nasal epithelium. Mixtures containing acidic sulfate particles, ozone, and nitrogen dioxide damaged both lung parenchyma and nasal epithelia. In rats exposed at rest, the response of the lung appeared to be dominated by the oxidant gas-phase components, while responses in the nose were dominated by the acidic particles. In rats exposed at exercise, however, mixtures of ozone and sulfuric acid particles significantly (2.5-fold) elevated the degree of lung lesion formation over that seen in rats exposed to ozone alone under an identical exercise protocol. PMID:2707193

Effects of acid rain on grapevines

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

Forsline, P.L.; Musselman, R.C.; Dee, R.J.

1983-01-01

Mature vineyard-growing Concord grapevines (Vitis labrusca, Bailey) were sprayed with simulated acid rain solutions ranging from pH 2.5 to pH 5.5 both as acute treatments at anthesis and chronically throughout the season in 1980 and 1981. In 1981, eight additional varieties were also treated with simulated acid rain solutions at pH 2.75 and pH 3.25. With Concord in 1981, few foliar lesions on leaves were visible at pH 2.75. In contrast, many leaf lesions with decreased fruit soluble solids in the absence of acid rain leaf lesions at pH>2.5 remains unclear. Acute sprays (pH 2.75) at anthesis reduced pollen germinationmore » in four grape cultivars. However, fruit set was reduced in only one of these. Only the cultivars de Chaunac and Ives had reduced berry soluble solids with chronic weekly sprays at pH 2.75. Reduction in soluble solids was not associated with increased oxidant stipple (ozone injury) in Concord and de Chaunac cultivars, but this association was observed in Ives. There was no evidence that acid rain in combination with ozone increased oxidant stipple as occurs when ozone and SO/sub 2/ are combined. Grape yields were not influenced by acid rain treatments. There was no evidence that acid rain at ambient pH levels had negative effects on grape production or fruit quality.« less

Acidic deposition: A review of biological effects

USGS Publications Warehouse

Sparling, Donald W.; Hoffman, David J.; Rattner, Barnett A.; Burton, G. Allen; Cairns, John

1995-01-01

The problem of acidic deposition and its possible effects on habitats, organisms, materials, and human health has been recognized for centuries. Earliest accounts date to Cicero (about 100 B.C.), who linked structural damage to buildings and statues in Rome to the smokey rains of wood and charcoal burning.3 Based on estimated of human demographics and centers of population, problems caused by acidic deposition may extend back to 400 to 500 B.C., but were not fully manifested until the mid-1800s with the rise of the Industrial revolution. the term "acid rain" was apparently first coined by R.A. Smith in 1972.4

Effects of clofibric acid on the activity and activity state of the hepatic branched-chain 2-oxo acid dehydrogenase complex.

PubMed Central

Zhao, Y; Jaskiewicz, J; Harris, R A

1992-01-01

Feeding clofibric acid to rats caused little or no change in total activity of the liver branched-chain 2-oxo acid dehydrogenase complex (BCODC). No change in mass of liver BCODC was detected by immunoblot analysis in response to dietary clofibric acid. No changes in abundance of mRNAs for the BCODC E1 alpha, E1 beta and E2 subunits were detected by Northern-blot analysis. Likewise, dietary clofibric acid had no effect on the activity state of liver BCODC (percentage of enzyme in the dephosphorylated, active, form) of rats fed on a chow diet. However, dietary clofibric acid greatly increased the activity state of liver BCODC of rats fed on a diet deficient in protein. No stable change in liver BCODC kinase activity was found in response to clofibric acid in either chow-fed or low-protein-fed rats. Clofibric acid had a biphasic effect on flux through BCODC in hepatocytes prepared from low-protein-fed rats. Stimulation of BCODC flux at low concentrations was due to clofibric acid inhibition of BCODC kinase, which in turn allowed activation of BCODC by BCODC phosphatase. Inhibition of BCODC flux at high concentrations was due to direct inhibition of BCODC by clofibric acid. The results suggest that the effects of clofibric acid in vivo on branched-chain amino acid metabolism can be explained by the inhibitory effects of this drug on BCODC kinase. Images Fig. 2. Fig. 3. PMID:1637295

Anti-inflammatory effects of polyunsaturated fatty acids in THP-1 cells

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

Zhao Guixiang; Etherton, Terry D.; Department of Dairy and Animal Science, Pennsylvania State University, University Park, PA

2005-10-28

The effects of linoleic acid (LA), {alpha}-linolenic acid (ALA), and docosahexaenoic acid (DHA) were compared to that of palmitic acid (PA), on inflammatory responses in human monocytic THP-1 cells. When cells were pre-incubated with fatty acids for 2-h and then stimulated with lipopolysaccharide for 24-h in the presence of fatty acids, secretion of interleukin (IL)-6, IL-1{beta}, and tumor necrosis factor-{alpha} (TNF{alpha}) was significantly decreased after treatment with LA, ALA, and DHA versus PA (P < 0.01 for all); ALA and DHA elicited more favorable effects. These effects were comparable to those for 15-deoxy-{delta}{sup 12,14}-prostaglandin J2 (15d-PGJ2) and were dose-dependent. Inmore » addition, LA, ALA, and DHA decreased IL-6, IL-1{beta}, and TNF{alpha} gene expression (P < 0.05 for all) and nuclear factor (NF)-{kappa}B DNA-binding activity, whereas peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) DNA-binding activity was increased. The results indicate that the anti-inflammatory effects of polyunsaturated fatty acids may be, in part, due to the inhibition of NF-{kappa}B activation via activation of PPAR{gamma}.« less

Effect of Eicosapentaenoic Acid and Docosahexaenoic Acid on Myogenesis and Mitochondrial Biosynthesis during Murine Skeletal Muscle Cell Differentiation

PubMed Central

Hsueh, Tun-Yun; Baum, Jamie I.; Huang, Yan

2018-01-01

Polyunsaturated fatty acids are important nutrients for human health, especially omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which have been found to play positive roles in the prevention of various diseases. However, previous studies have reported that excessive omega-3 fatty acids supplement during pregnancy caused side effects such as slower neural transmission times and postnatal growth restriction. In this study, we investigated the effect of EPA and DHA on mitochondrial function and gene expression in C2C12 myoblasts during skeletal muscle differentiation. C2C12 myoblasts were cultured to confluency and then treated with differentiation medium that contained fatty acids (50-µM EPA and DHA). After 72 h of myogenic differentiation, mRNA was collected, and gene expression was analyzed by real-time PCR. Microscopy was used to examine cell morphology following treatment with fatty acids. The effect of EPA and DHA on cellular oxygen consumption was measured using a Seahorse XF24 Analyzer. Cells treated with fatty acids had fewer myotubes formed (P ≤ 0.05) compared with control cells. The expression of the genes related to myogenesis was significantly lower (P ≤ 0.05) in cells treated with fatty acids, compared with control cells. Genes associated with adipogenesis had higher (P ≤ 0.05) expression after treatment with fatty acids. Also, the mitochondrial biogenesis decreased with lower (P ≤ 0.05) gene expression and lower (P ≤ 0.05) mtDNA/nDNA ratio in cells treated with fatty acids compared with control cells. However, the expression of genes related to peroxisome biosynthesis was higher (P ≤ 0.05) in cells treated with fatty acids. Moreover, fatty-acid treatment reduced (P ≤ 0.05) oxygen consumption rate under oligomycin-inhibited (reflecting proton leak) and uncoupled conditions. Our data imply that fatty acids might reduce myogenesis and increase adipogenesis in myotube formation. Fatty acids may also

The amelioration effect of tranexamic acid in wrinkles induced by skin dryness.

PubMed

Hiramoto, Keiichi; Sugiyama, Daijiro; Takahashi, Yumi; Mafune, Eiichi

2016-05-01

Tranexamic acid (trans-4-aminomethylcyclohexanecarboxylic acid) is a medical amino acid widely used as an anti-inflammatory and a whitening agent. This study examined the effect of tranexamic acid administration in wrinkle formation following skin dryness. We administered tranexamic acid (750mg/kg/day) orally for 20 consecutive days to Naruto Research Institute Otsuka Atrichia (NOA) mice, which naturally develop skin dryness. In these NOA mice, deterioration of transepidermal water loss (TEWL), generation of wrinkles, decrease of collagen type I, and increases in mast cell proliferation and tryptase and matrix metalloproteinase (MMP-1) release were observed. However, these symptoms were improved by tranexamic acid treatment. Moreover, the increase in the β-endorphin level in the blood and the expression of μ-opioid receptor on the surface of fibroblasts increased by tranexamic acid treatment. In addition, when the fibroblasts induced by tranexamic acid treatment were removed, the amelioration effect by tranexamic acid treatment was halved. On the other hand, tranexamic acid treated NOA mice and mast cell removal in tranexamic acid treated NOA mice did not result in changes in the wrinkle amelioration effect. Additionally, the amelioration effect of mast cell deficient NOA mice was half that of tranexamic acid treated NOA mice. These results indicate that tranexamic acid decreased the proliferation of mast cells and increases the proliferation of fibroblasts, subsequently improving wrinkles caused by skin dryness. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Effect of alpha lipoic acid on leukotriene A4 hydrolase.

PubMed

Torres, María José; Fierro, Angélica; Pessoa-Mahana, C David; Romero-Parra, Javier; Cabrera, Gonzalo; Faúndez, Mario

2017-03-15

Leukotriene A 4 hydrolase is a soluble enzyme with epoxide hydrolase and aminopeptidase activities catalysing the conversion of leukotriene A 4 to leukotriene B 4 and the hydrolysis of the peptide proline-glycine-proline. Imbalances in leukotriene B 4 synthesis are related to several pathologic conditions. Currently there are no available drugs capable to modulate the synthesis of leukotriene B 4 or to block its receptors. Here we show the inhibitory profile of alpha lipoic acid on the activity of leukotriene A 4 Hydrolase. Alpha lipoic acid inhibited both activities of the enzyme at concentrations lower than 10μM. The 5-lipoxygenase inhibitor zileuton, or the 5-lipoxygenase activating protein inhibitor MK-886, were unable to inhibit the activity of the enzyme. Acute promyelocytic leukaemia HL-60 cells were differentiated to leukotriene A 4 hydrolase expressing neutrophil-like cells. Alpha lipoic acid inhibited the aminopeptidase activity of the cytosolic fraction from neutrophil-like cells but had no effect on the cytosolic fraction from undifferentiated cells. Docking and molecular dynamic approximations revealed that alpha lipoic acid participates in electrostatic interactions with K-565 and R-563, which are key residues for the carboxylate group recognition of endogenous substrates by the enzyme. Alpha lipoic acid is a compound widely used in clinical practice, most of its therapeutic effects are associated with its antioxidants properties, however, antioxidant effect alone is unable to explain all clinical effects observed with alpha lipoic acid. Our results invite to evaluate the significance of the inhibitory effect of alpha lipoic acid on the catalytic activity of leukotriene A 4 hydrolase using in vivo models. Copyright © 2017 Elsevier B.V. All rights reserved.

Biological and therapeutic effects of ortho-silicic acid and some ortho-silicic acid-releasing compounds: New perspectives for therapy.

PubMed

Jurkić, Lela Munjas; Cepanec, Ivica; Pavelić, Sandra Kraljević; Pavelić, Krešimir

2013-01-08

Silicon (Si) is the most abundant element present in the Earth's crust besides oxygen. However, the exact biological roles of silicon remain unknown. Moreover, the ortho-silicic acid (H4SiO4), as a major form of bioavailable silicon for both humans and animals, has not been given adequate attention so far. Silicon has already been associated with bone mineralization, collagen synthesis, skin, hair and nails health atherosclerosis, Alzheimer disease, immune system enhancement, and with some other disorders or pharmacological effects. Beside the ortho-silicic acid and its stabilized formulations such as choline chloride-stabilized ortho-silicic acid and sodium or potassium silicates (e.g. M2SiO3; M= Na,K), the most important sources that release ortho-silicic acid as a bioavailable form of silicon are: colloidal silicic acid (hydrated silica gel), silica gel (amorphous silicon dioxide), and zeolites. Although all these compounds are characterized by substantial water insolubility, they release small, but significant, equilibrium concentration of ortho-silicic acid (H4SiO4) in contact with water and physiological fluids. Even though certain pharmacological effects of these compounds might be attributed to specific structural characteristics that result in profound adsorption and absorption properties, they all exhibit similar pharmacological profiles readily comparable to ortho-silicic acid effects. The most unusual ortho-silicic acid-releasing agents are certain types of zeolites, a class of aluminosilicates with well described ion(cation)-exchange properties. Numerous biological activities of some types of zeolites documented so far might probably be attributable to the ortho-silicic acid-releasing property. In this review, we therefore discuss biological and potential therapeutic effects of ortho-silicic acid and ortho-silicic acid -releasing silicon compounds as its major natural sources.

Opposing effects of bile acids deoxycholic acid and ursodeoxycholic acid on signal transduction pathways in oesophageal cancer cells.

PubMed

Abdel-Latif, Mohamed M; Inoue, Hiroyasu; Reynolds, John V

2016-09-01

Ursodeoxycholic acid (UDCA) was reported to reduce bile acid toxicity, but the mechanisms underlying its cytoprotective effects are not fully understood. The aim of the present study was to examine the effects of UDCA on the modulation of deoxycholic acid (DCA)-induced signal transduction in oesophageal cancer cells. Nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) activity was assessed using a gel shift assay. NF-κB activation and translocation was performed using an ELISA-based assay and immunofluorescence analysis. COX-2 expression was analysed by western blotting and COX-2 promoter activity was assessed by luciferase assay. DCA induced NF-κB and AP-1 DNA-binding activities in SKGT-4 and OE33 cells. UDCA pretreatment inhibited DCA-induced NF-κB and AP-1 activation and NF-κB translocation. This inhibitory effect was coupled with a blockade of IκB-α degradation and inhibition of phosphorylation of IKK-α/β and ERK1/2. Moreover, UDCA pretreatment inhibited COX-2 upregulation. Using transient transfection of the COX-2 promoter, UDCA pretreatment abrogated DCA-induced COX-2 promoter activation. In addition, UDCA protected oesophageal cells from the apoptotic effects of deoxycholate. Our findings indicate that UDCA inhibits DCA-induced signalling pathways in oesophageal cancer cells. These data indicate a possible mechanistic role for the chemopreventive actions of UDCA in oesophageal carcinogenesis.

[Effects of simulated acid rain on water physiological characteristics of Myrica rubra seedlings].

PubMed

Yaho, Zhao-bin; Jiang, Hong; Yu, Shu-quan; Lu, Mei-juan

2011-08-01

Taking the seedlings of typical subtropical economic tree species Myrica rubra in Zhejiang Province as test materials, a pot experiment was conducted to study their water physiological characteristics under effects of simulated acid rain (pH 2.5 and pH 4.0), with water (pH 5.6) as the control. Season, year, and acid rain all had significant effects on the photosynthetic rate (Pn). Among the treatments, the Pn had a greater difference in summer than in spring and autumn, and was higher in treatment acid rain (pH 4.0). Season, year, acid rain, and the interactions of season and year and of the three factors had significant effects on the stomata conductance (Gs), and also, the Gs had a greater difference among the treatments in summer than in spring and autumn. Acid rain had inhibitory effect on Gs. Season, year, acid rain, and the interactions of season and year and of season and acid rain affected the transpiration rate (Tr) significantly. Same as Pn and Gs, the Tr had a greater difference among the treatments in summer than in spring and autumn. Acid rain (pH 2.5) had the strongest inhibitory effect on Tr. Acid rain and the interactions of season and year and of season and acid rain had significant effects on the water use efficiency (WUE), and acid rain (pH 2.5) had definitely positive effect on the WUE.

Protective Effect of Unsaturated Fatty Acids on Palmitic Acid-Induced Toxicity in Skeletal Muscle Cells is not Mediated by PPARδ Activation.

PubMed

Tumova, Jana; Malisova, Lucia; Andel, Michal; Trnka, Jan

2015-10-01

Unsaturated free fatty acids (FFA) are able to prevent deleterious effects of saturated FFA in skeletal muscle cells although the mechanisms involved are still not completely understood. FFA act as endogenous ligands of peroxisome proliferator-activated receptors (PPAR), transcription factors regulating the expression of genes involved in lipid metabolism. The aim of this study was to determine whether activation of PPARδ, the most common PPAR subtype in skeletal muscle, plays a role in mediating the protective effect of unsaturated FFA on saturated FFA-induced damage in skeletal muscle cells and to examine an impact on mitochondrial respiration. Mouse C2C12 myotubes were treated for 24 h with different concentrations of saturated FFA (palmitic acid), unsaturated FFA (oleic, linoleic and α-linolenic acid), and their combinations. PPARδ agonist GW501516 and antagonist GSK0660 were also used. Both mono- and polyunsaturated FFA, but not GW501516, prevented palmitic acid-induced cell death. Mono- and polyunsaturated FFA proved to be effective activators of PPARδ compared to saturated palmitic acid; however, in combination with palmitic acid their effect on PPARδ activation was blocked and stayed at the levels observed for palmitic acid alone. Unsaturated FFA at moderate physiological concentrations as well as GW501516, but not palmitic acid, mildly uncoupled mitochondrial respiration. Our results indicate that although unsaturated FFA are effective activators of PPARδ, their protective effect on palmitic acid-induced toxicity is not mediated by PPARδ activation and subsequent induction of lipid regulatory genes in skeletal muscle cells. Other mechanisms, such as mitochondrial uncoupling, may underlie their effect.

Acid rain and its environmental effects: Recent scientific advances

NASA Astrophysics Data System (ADS)

Burns, Douglas A.; Aherne, Julian; Gay, David A.; Lehmann, Christopher M. B.

2016-12-01

The term 'acid rain' refers to atmospheric deposition of acidic constituents that impact the earth as rain, snow, particulates, gases, and vapor. Acid rain was first recognized by Ducros (1845) and subsequently described by the English chemist Robert Angus Smith (Smith, 1852) whose pioneering studies linked the sources to industrial emissions and included early observations of deleterious environmental effects (Smith, 1872). Smith's work was largely forgotten until the mid-20th century when observations began to link air pollution to the deposition of atmospheric sulfate (SO42-) and other chemical constituents, first near the metal smelter at Sudbury, Ontario, Canada, and later at locations in Europe, North America, and Australia (Gorham, 1961). Our modern understanding of acid rain as an environmental problem caused largely by regional emissions of sulfur dioxide (SO2) and nitrogen oxides (NOx) stems from observations in the 1960s and early 1970s in Sweden by Svante Odén (Odén, 1976), and in North America by Gene Likens and colleagues (Likens and Bormann, 1974). These scientists and many who followed showed the link to emissions from coal-fired power plants and other industrial sources, and documented the environmental effects of acid rain such as the acidification of surface waters and toxic effects on vegetation, fish, and other biota.

[Trans-fatty acids--effects on coronary heart disease].

PubMed

Karbowska, Joanna; Kochan, Zdzisław

2011-07-01

Trans-fatty acids (TFA) are formed during the industrial process of hydrogenation of vegetable oils. The consumption of hydrogenated fats has increased significantly over the last few decades. In Poland, the average daily intake of TFA for adults was estimated to be 2.8 to 6.9 g; which greatly exceeds the recommended daily maximum of 2 g/day (less than 1% of total energy intake). Increasing trans-fatty acid intake has detrimental effects on the lipid profile: TFA raise total cholesterol, LDL-cholesterol and triglyceride concentrations, and decrease HDL-cholesterol levels. Moreover, dietary trans-fatty acids may increase plasma levels of lipoprotein (a) and biomarkers of inflammation and endothelial dysfunction. Several studies have demonstrated that a high intake of TFA is associated with an increased risk of coronary heart disease. In addition, TFA consumption has been implicated as an independent risk factor for sudden cardiac arrest. It is therefore necessary to reduce the intake of hydrogenated fats rich in trans-fatty acids in order to minimize the adverse effects of TFA on health.

Lipotoxicity: Effects of Dietary Saturated and Transfatty Acids

PubMed Central

Estadella, Débora; da Penha Oller do Nascimento, Claudia M.; Oyama, Lila M.; Ribeiro, Eliane B.; Dâmaso, Ana R.; de Piano, Aline

2013-01-01

The ingestion of excessive amounts of saturated fatty acids (SFAs) and transfatty acids (TFAs) is considered to be a risk factor for cardiovascular diseases, insulin resistance, dyslipidemia, and obesity. The focus of this paper was to elucidate the influence of dietary SFA and TFA intake on the promotion of lipotoxicity to the liver and cardiovascular, endothelial, and gut microbiota systems, as well as on insulin resistance and endoplasmic reticulum stress. The saturated and transfatty acids favor a proinflammatory state leading to insulin resistance. These fatty acids can be involved in several inflammatory pathways, contributing to disease progression in chronic inflammation, autoimmunity, allergy, cancer, atherosclerosis, hypertension, and heart hypertrophy as well as other metabolic and degenerative diseases. As a consequence, lipotoxicity may occur in several target organs by direct effects, represented by inflammation pathways, and through indirect effects, including an important alteration in the gut microbiota associated with endotoxemia. Interactions between these pathways may perpetuate a feedback process that exacerbates an inflammatory state. The importance of lifestyle modification, including an improved diet, is recommended as a strategy for treatment of these diseases. PMID:23509418

Dose-dependent antiinflammatory effect of ursodeoxycholic acid in experimental colitis.

PubMed

Martínez-Moya, Patricia; Romero-Calvo, Isabel; Requena, Pilar; Hernández-Chirlaque, Cristina; Aranda, Carlos J; González, Raquel; Zarzuelo, Antonio; Suárez, María Dolores; Martínez-Augustin, Olga; Marín, José Juan G; de Medina, Fermín Sánchez

2013-02-01

The denomination of inflammatory bowel disease comprises a group of chronic inflammatory diseases of the digestive tract, ulcerative colitis and Crohn's disease being the most important conditions. Bile acids may play a role both in etiology and pharmacology of this disease. Thus, although deoxycholic acid is regarded as a proinflammatory agent ursodeoxycholic acid, which is currently being used to treat certain types of cholestasis and primary biliary cirrhosis, because of their choleretic, cytoprotective and immunomodulatory effects, it has been reported to exert an anti-inflammatory activity. We aim to confirm and characterize the intestinal antiinflammatory activity of ursodeoxycholic acid. The experimental model trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats has been used. Animal status was characterized by a number of macroscopic and biochemical parameters. Oral administration of ursodeoxycholic acid was able to ameliorate experimental colonic inflammation. This occurred only at a relatively high dose (50 mg/kg day), whereas ursodeoxycholic acid was without significant effect at doses of 10 and 25 mg/kg day. The therapeutic effect was evidenced, among others, by a higher body weight recovery, a diminished affected to total mucosal area and lower alkaline phosphatase activity in treated vs. control (TNBS treated) animals. These results indicate that, at the appropriate dose, ursodeoxycholic acid is a potentially useful drug to reduce intestinal inflammation and could be envisaged to be incorporated in the treatment of inflammatory bowel diseases. Copyright © 2012 Elsevier B.V. All rights reserved.

Relativistic effects on acidities and basicities of Brønsted acids and bases containing gold.

PubMed

Koppel, Ilmar A; Burk, Peeter; Kasemets, Kalev; Koppel, Ivar

2013-11-07

It is usually believed that relativistic effects as described by the Dirac-Schrödinger equation (relative to the classical or time-independent Schrödinger equation) are of little importance in chemistry. A closer look, however, reveals that some important and widely known properties (e.g., gold is yellow, mercury is liquid at room temperature) stem from relativistic effects. So far the influence of relativistic effects on the acid-base properties has been mostly ignored. Here we show that at least for compounds of gold such omission is completely erroneous and would lead to too high basicity and too low acidity values with errors in the range of 25-55 kcal mol(-1) (or 20 to 44 powers of ten in pK(a) units) in the gas-phase. These findings have important implications for the design of new superstrong acids and bases, and for the understanding of gold-catalysed reactions.

Neuroprotective Effects of Glutamate Antagonists and Extracellular Acidity

NASA Astrophysics Data System (ADS)

Kaku, David A.; Giffard, Rona G.; Choi, Dennis W.

1993-06-01

Glutamate antagonists protect neurons from hypoxic injury both in vivo and in vitro, but in vitro studies have not been done under the acidic conditions typical of hypoxia-ischemia in vivo. Consistent with glutamate receptor antagonism, extracellular acidity reduced neuronal death in murine cortical cultures that were deprived of oxygen and glucose. Under these acid conditions, N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isox-azolepropionate-kainate antagonists further reduced neuronal death, such that some neurons tolerated prolonged oxygen and glucose deprivation almost as well as did astrocytes. Neuroprotection induced by this combination exceeded that induced by glutamate antagonists alone, suggesting that extracellular acidity has beneficial effects beyond the attenuation of ionotropic glutamate receptor activation.

Antagonist effects of veratric acid against UVB-induced cell damages.

PubMed

Shin, Seoung Woo; Jung, Eunsun; Kim, Seungbeom; Lee, Kyung-Eun; Youm, Jong-Kyung; Park, Deokhoon

2013-05-10

Ultraviolet (UV) radiation induces DNA damage, oxidative stress, and inflammatory processes in human epidermis, resulting in inflammation, photoaging, and photocarcinogenesis. Adequate protection of skin against the harmful effect of UV irradiation is essential. In recent years naturally occurring herbal compounds such as phenolic acids, flavonoids, and high molecular weight polyphenols have gained considerable attention as beneficial protective agents. The simple phenolic veratric acid (VA, 3,4-dimethoxybenzoic acid) is one of the major benzoic acid derivatives from vegetables and fruits and it also occurs naturally in medicinal mushrooms which have been reported to have anti-inflammatory and anti-oxidant activities. However, it has rarely been applied in skin care. This study, therefore, aimed to explore the possible roles of veratric acid in protection against UVB-induced damage in HaCaT cells. Results showed that veratric acid can attenuate cyclobutane pyrimidine dimers (CPDs) formation, glutathione (GSH) depletion and apoptosis induced by UVB. Furthermore, veratric acid had inhibitory effects on the UVB-induced release of the inflammatory mediators such as IL-6 and prostaglandin-E2. We also confirmed the safety and clinical efficacy of veratric acid on human skin. Overall, results demonstrated significant benefits of veratric acid on the protection of keratinocyte against UVB-induced injuries and suggested its potential use in skin photoprotection.

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 glutamic acid analogues on identifiable giant neurones, sensitive to beta-hydroxy-L-glutamic acid, of an African giant snail (Achatina fulica Férussac).

PubMed Central

Nakajima, T.; Nomoto, K.; Ohfune, Y.; Shiratori, Y.; Takemoto, T.; Takeuchi, H.; Watanabe, K.

1985-01-01

The effects of the seven glutamic acid analogues, alpha-kainic acid, alpha-allo-kainic acid, domoic acid, erythro-L-tricholomic acid, DL-ibotenic acid, L-quisqualic acid and allo-gamma-hydroxy-L-glutamic acid were examined on six identifiable giant neurones of an African giant snail (Achatina fulica Férussac). The neurones studied were: PON (periodically oscillating neurone), d-RPLN (dorsal-right parietal large neurone), VIN (visceral intermittently firing neurone), RAPN (right anterior pallial neurone), FAN (frequently autoactive neurone) and v-RCDN (ventral-right cerebral distinct neurone). Of these, d-RPLN and RAPN were excited by the two isomers (erythro- and threo-) of beta-hydroxy-L-glutamic acid (L-BHGA), whereas PON, VIN, FAN and v-RCDN were inhibited. L-Glutamic acid (L-Glu) had virtually no effect on these neurones. alpha-Kainic acid and domoic acid showed marked excitatory effects, similar to those of L-BHGA, on d-RPLN and RAPN. Their effective potency quotients (EPQs), relative to the more effective isomer of L-BHGA were: 0.3 for both substances on d-RPLN, and 1 for alpha-kainic acid and 3-1 for domoic acid on RAPN. alpha-Kainic acid also had excitatory effects on FAN and v-RCDN (EPQ for both: 0.3), which were inhibited by L-BHGA but excited by gamma-aminobutyric acid (GABA). Erythro-L-tricholomic acid showed marked effects, similar to those of L-BHGA, on VIN (EPQ: 0.3) and RAPN (EPQ: 3-1), but produced weaker effects on PON and d-RPLN (EPQ: 0.1). DL-Ibotenic acid produced marked effects, similar to those of L-BHGA, on PON, VIN (EPQ for both: 1) and RAPN (EPQ: 1-0.3), but had weak effects on d-RPLN (EPQ: less than 0.1) and FAN (EPQ: 0.1). It had excitatory effects on v-RCDN (EPQ: 0.1). This neurone was inhibited by L-BHGA but excited by GABA. L-Quisqualic acid showed the same effects as L-BHGA on all of the neurones examined (EPQ range 30-0.1). It was the most potent of the compounds tested on RAPN (EPQ: 30-10), FAN (EPQ: 30) and v-RCDN (EPQ: 3). alpha

Hypotensive effect of alpha-lipoic acid after a single administration in rats.

PubMed

Dudek, Magdalena; Razny, Katarzyna; Bilska-Wilkosz, Anna; Iciek, Malgorzata; Sapa, Jacek; Wlodek, Lidia; Filipek, Barbara

2016-05-01

The effect of alpha-lipoic acid on blood pressure was investigated many times in chronic studies, but there are no studies on the effect of this compound after a single administration. Alpha-lipoic acid is a drug used in diabetic neuropathy, often in obese patients, to treat hypertension. Therefore, knowledge of the potential antihypertensive effect of alpha-lipoic acid even after a single dose and possibly too much pressure reduction is interesting and useful. The mechanism of the hypotensive effect of alpha-lipoic acid was examined in normotensive rats in vivo after a single intraperitoneal administration, blood pressure in the left carotid artery of the rats was measured prior to the administration of the compounds (alpha- lipoic acid and/or glibenclamide) and 80 min thereafter. Alpha-lipoic acid at a dosage of 50 mg/kg b.w. i.p. significantly decreased the blood pressure from the 50th min after drug administration. This cardiovascular effect of this compound was reversed by glibenclamide, a selective KATP blocker. Glibenclamide alone at this dose did not significantly affect the blood pressure. Statistical significance was evaluated using two-way ANOVA. This suggests that alpha-lipoic acid affects ATP-dependent potassium channels. It is possible that this is an indirect effect of hydrogen sulfide because alpha-lipoic acid can increase its concentration. The results obtained in this study are very important because the patients taking alpha-lipoic acid may be treated for co-existing hypertension. Therefore, the possibility of blood pressure lowering by alpha-lipoic acid should be taken into account, although it does not lead to excessive orthostatic hypotension.

Effect of sugar fatty acid esters on rumen fermentation in vitro.

PubMed

Wakita, M; Hoshino, S

1987-11-01

1. The effect of sugar fatty acid esters (SFEs; currently used as food additives for human consumption) on rumen volatile fatty acids (VFA) and gas production was studied with sheep rumen contents in vitro. 2. Some SFEs having monoester contents of more than 70% increased the molar proportion of propionate in conjunction with reduction in the acetate:propionate ratio when the individual SFE was added to rumen contents in a final concentration of 4 g/l. Laurate sugar ester was the most potent propionate enhancer and rumen gas depressor, the effective dose being as low as 1 g/l in a final concentration. Fatty acid esters other than SFEs had little, if any, effect on rumen VFA production and their molar proportions. 3. Approximately 50% of laurate sugar ester was hydrolysed by in vitro incubation with rumen fluid for 2 h. The addition of fatty acids and sucrose was also effective in the alterations of rumen VFA and gas production. However, the effect of SFEs on in vitro rumen fermentation was significantly greater than that of their constituent fatty acids or sucrose, or both. Accordingly, the effect appeared to be ascribed to the complex action of SFE itself and to its constituents, free fatty acids and sucrose. 4. SFEs, at the level of 4 g/l, reduced substantially the froth formation (ingesta volume increase) and seemed to be effective for the prevention of bloat.

Effect of omega-3 fatty acids on the modification of erythrocyte membrane fatty acid content including oleic acid in peritoneal dialysis patients.

PubMed

An, W S; Lee, S M; Son, Y K; Kim, S E; Kim, K H; Han, J Y; Bae, H R; Park, Y

2012-01-01

Erythrocyte membrane fatty acids (FA), such as oleic acid, are related to acute coronary syndrome. There is no report about the effect of omega-3 FA on oleic acid in peritoneal dialysis (PD) patients. We hypothesized that omega-3 FA can modify erythrocyte membrane FA, including oleic acid, in PD patients. In a double-blind, randomized, placebo-controlled study, 18 patients who were treated with PD for at least 6 months were randomized to treatment for 12 weeks with omega-3 FA or placebo. Erythrocyte membrane FA content was measured by gas chromatography at baseline and after 12 weeks. The erythrocyte membrane content of eicosapentaenoic acid and docosahexaenoic acid was significantly increased and saturated FA and oleic acid were significantly decreased in the omega-3 FA supplementation group after 12 weeks compared to baseline. In conclusion, erythrocyte membrane FA content, including oleic acid, was significantly modified by omega-3 FA supplementation for 12 weeks in PD patients. Copyright © 2011 Elsevier Ltd. All rights reserved.

Effects of imposed acid-base derangement on the cardiovascular effects and pharmacokinetics of bupivacaine and thiopental.

PubMed

Mather, Laurence E; Ladd, Leigh A; Copeland, Susan E; Chang, Dennis H-T

2004-06-01

By changing physicochemical properties such as effective lipophilicity, changes in blood pH could alter the distribution, elimination, and effects of weakly ionizing drugs. The authors examined the outcome of imposed acid-base derangement on cardiovascular effects and myocardial and whole body pharmacokinetics of bupivacaine, a weak base, and thiopental, a weak acid. Intravenous infusions of rac-bupivacaine HCl (37.5 mg) or rac-thiopental sodium (250 mg, subanesthetic dose) were administered over 3 min to previously instrumented conscious ewes with normal blood pH, acidemia imposed by lactic acid infusion, or alkalemia imposed by bicarbonate infusion. Hemodynamic and electrocardiographic effects were recorded; arterial and coronary sinus drug blood concentrations were analyzed by chiral high-performance liquid chromatography. Bupivacaine decreased myocardial contractility, coronary perfusion, heart rate, and cardiac output; however, cardiac output and stroke volume were not as affected by bupivacaine with acidemia. Thiopental decreased myocardial contractility and stroke volume and increased heart rate; acidemia enhanced the tachycardia and produced a greater decrease in stroke volume than with alkalemia. Taken as a whole, the cardiovascular changes were not systematically modified by acid-base derangement. Overall, the tissue distribution of bupivacaine was favored by alkalemia, but thiopental pharmacokinetics were essentially unaffected by acid-base derangement. Acid-base derangement did not influence the kinetics of either drug enantioselectively. At the doses used, the hemodynamic and electrocardiographic effects of bupivacaine and thiopental were not systematically modified by acid-base derangement, nor were there changes in regional or whole body pharmacokinetics of either drug that were clearly related to acid-base status.

Effects of acetic acid on the viability of Ascaris lumbricoides eggs

PubMed Central

Beyhan, Yunus E.; Yilmaz, Hasan; Hokelek, Murat

2016-01-01

Objectives: To investigate the effects of acetic acid on durable Ascaris lumbricoides (A. lumbricoides) eggs to determine the effective concentration of vinegar and the implementation period to render the consumption of raw vegetables more reliable. Methods: This experimental study was performed in May 2015 in the Parasitology Laboratory, Faculty of Medicine, Yuzuncu Yil University, Van, Turkey. The A. lumbricoides eggs were divided into 2 groups. Eggs in the study group were treated with 1, 3, 5, and 10% acetic acid concentrations, and eggs in the control group were treated with Eosin. The eggs’ viability was observed at the following points in time during the experiment: 0, 10, 15, 20, 30, 45, and 60 minutes. Results: The 1% acetic acid was determined insufficient on the viability of Ascaris eggs. At the 30th minute, 3% acetic acid demonstrated 95% effectiveness, and at 5% concentration, all eggs lost their viability. Treatment of acetic acid at the ratio of 4.8% in 30 minutes, or a ratio of 4.3% in 60 minutes is required for full success of tretment. Conclusion: Since Ascaris eggs have 3 layers and are very resistant, the acetic acid concentration, which can be effective on these eggs are thought to be effective also on many other parasitic agents. In order to attain an active protection, after washing the vegetables, direct treatment with a vinegar containing 5% acetic acid for 30 minutes is essential. PMID:26905351

Parsing the life-shortening effects of dietary protein: effects of individual amino acids

PubMed Central

Bouchebti, Sofia; Bazazi, Sepideh; Le Hesran, Sophie; Puga, Camille; Latil, Gérard; Simpson, Stephen J.

2017-01-01

High-protein diets shorten lifespan in many organisms. Is it because protein digestion is energetically costly or because the final products (the amino acids) are harmful? To answer this question while circumventing the life-history trade-off between reproduction and longevity, we fed sterile ant workers on diets based on whole proteins or free amino acids. We found that (i) free amino acids shortened lifespan even more than proteins; (ii) the higher the amino acid-to-carbohydrate ratio, the shorter ants lived and the lower their lipid reserves; (iii) for the same amino acid-to-carbohydrate ratio, ants eating free amino acids had more lipid reserves than those eating whole proteins; and (iv) on whole protein diets, ants seem to regulate food intake by prioritizing sugar, while on free amino acid diets, they seem to prioritize amino acids. To test the effect of the amino acid profile, we tested diets containing proportions of each amino acid that matched the ant's exome; surprisingly, longevity was unaffected by this change. We further tested diets with all amino acids under-represented except one, finding that methionine, serine, threonine and phenylalanine are especially harmful. All together, our results show certain amino acids are key elements behind the high-protein diet reduction in lifespan. PMID:28053059

Parsing the life-shortening effects of dietary protein: effects of individual amino acids.

PubMed

Arganda, Sara; Bouchebti, Sofia; Bazazi, Sepideh; Le Hesran, Sophie; Puga, Camille; Latil, Gérard; Simpson, Stephen J; Dussutour, Audrey

2017-01-11

High-protein diets shorten lifespan in many organisms. Is it because protein digestion is energetically costly or because the final products (the amino acids) are harmful? To answer this question while circumventing the life-history trade-off between reproduction and longevity, we fed sterile ant workers on diets based on whole proteins or free amino acids. We found that (i) free amino acids shortened lifespan even more than proteins; (ii) the higher the amino acid-to-carbohydrate ratio, the shorter ants lived and the lower their lipid reserves; (iii) for the same amino acid-to-carbohydrate ratio, ants eating free amino acids had more lipid reserves than those eating whole proteins; and (iv) on whole protein diets, ants seem to regulate food intake by prioritizing sugar, while on free amino acid diets, they seem to prioritize amino acids. To test the effect of the amino acid profile, we tested diets containing proportions of each amino acid that matched the ant's exome; surprisingly, longevity was unaffected by this change. We further tested diets with all amino acids under-represented except one, finding that methionine, serine, threonine and phenylalanine are especially harmful. All together, our results show certain amino acids are key elements behind the high-protein diet reduction in lifespan. © 2017 The Author(s).

Diverse physiological effects of long-chain saturated fatty acids: implications for cardiovascular disease.

PubMed

Flock, Michael R; Kris-Etherton, Penny M

2013-03-01

The purpose of this review is to discuss the metabolism of long-chain saturated fatty acids and the ensuing effects on an array of metabolic events. Individual long-chain saturated fatty acids exhibit unique biological properties. Dietary saturated fat absorption varies depending on chain-length and the associated food matrix. The in-vivo metabolism of saturated fatty acids varies depending on the individual fatty acid and the nutritional state of the individual. A variety of fatty acid metabolites are formed, each with their own unique structure and properties that warrant further research. Replacing saturated fatty acids with unsaturated fatty acids improves the blood lipid profile and reduces cardiovascular disease risk, although the benefits depend on the specific saturated fatty acid(s) being replaced. Acknowledging the complexity of saturated fatty acid metabolism and associated metabolic events is important when assessing their effects on cardiovascular disease risk. Investigating the biological effects of saturated fatty acids will advance our understanding of how they affect cardiovascular disease risk.

Non-linear direct effects of acid rain on leaf photosynthetic rate of terrestrial plants.

PubMed

Dong, Dan; Du, Enzai; Sun, Zhengzhong; Zeng, Xuetong; de Vries, Wim

2017-12-01

Anthropogenic emissions of acid precursors have enhanced global occurrence of acid rain, especially in East Asia. Acid rain directly suppresses leaf function by eroding surface waxes and cuticle and leaching base cations from mesophyll cells, while the simultaneous foliar uptake of nitrates in rainwater may directly benefit leaf photosynthesis and plant growth, suggesting a non-linear direct effect of acid rain. By synthesizing data from literature on acid rain exposure experiments, we assessed the direct effects of acid rain on leaf photosynthesis across 49 terrestrial plants in China. Our results show a non-linear direct effect of acid rain on leaf photosynthetic rate, including a neutral to positive effect above pH 5.0 and a negative effect below that pH level. The acid rain sensitivity of leaf photosynthesis showed no significant difference between herbs and woody species below pH 5.0, but the impacts above that pH level were strongly different, resulting in a significant increase in leaf photosynthetic rate of woody species and an insignificant effect on herbs. Our analysis also indicates a positive effect of the molar ratio of nitric versus sulfuric acid in the acid solution on leaf photosynthetic rate. These findings imply that rainwater acidity and the composition of acids both affect the response of leaf photosynthesis and therefore result in a non-linear direct effect. Copyright © 2017 Elsevier Ltd. All rights reserved.