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Sample records for receiving zoledronic acid

  1. Zoledronic Acid Injection

    MedlinePlus

    Zoledronic acid (Reclast) is used to prevent or treat osteoporosis (condition in which the bones become thin and weak ... of life,' end of regular menstrual periods). Zoledronic acid (Reclast) is also used to treat osteoporosis in ...

  2. Endocytotic Uptake of Zoledronic Acid by Tubular Cells May Explain Its Renal Effects in Cancer Patients Receiving High Doses of the Compound

    PubMed Central

    Verhulst, Anja; Sun, Shuting; McKenna, Charles E.; D’Haese, Patrick C.

    2015-01-01

    Zoledronic acid, a highly potent nitrogen-containing bisphosphonate used for the treatment of pathological bone loss, is excreted unmetabolized via the kidney if not bound to the bone. In cancer patients receiving high doses of the compound renal excretion may be associated with acute tubular necrosis. The question of how zoledronic acid is internalized by renal tubular cells has not been answered until now. In the current work, using a primary human tubular cell culture system, the pathway of cellular uptake of zoledronic acid (fluorescently/radiolabeled) and its cytotoxicity were investigated. Previous studies in our laboratory have shown that this primary cell culture model consistently mimics the physiological characteristics of molecular uptake/transport of the epithelium in vivo. Zoledronic acid was found to be taken up by tubular cells via fluid-phase-endocytosis (from apical and basolateral side) as evidenced by its co-localization with dextran. Cellular uptake and the resulting intracellular level was twice as high from the apical side compared to the basolateral side. Furthermore, the intracellular zoledronic acid level was found to be dependent on the administered concentration and not saturable. Cytotoxic effects however, were only seen at higher administration doses and/or after longer incubation times. Although zoledronic acid is taken up by tubular cells, no net tubular transport could be measured. It is concluded that fluid-phase-endocytosis of zoledronic acid and cellular accumulation at high doses may be responsible for the acute tubular necrosis observed in some cancer patients receiving high doses of the compound. PMID:25756736

  3. Spontaneous Acetabular Periprosthetic Fracture in a Patient Continuously Having Zoledronic Acid

    PubMed Central

    Tantavisut, Saran; Thanakit, Voranuch; Ngarmukos, Srihatach; Wilairatana, Vajara; Wangroongsub, Yongsak

    2014-01-01

    Zoledronic acid has been used for prevention of osteolytic and osteoblastic bone metastasis. This case report illustrates an undesirable consequence from prolonged usage of zoledronic acid in bone metastasis prevention. Periprosthetic acetabular fracture in a patient treated with zoledronic acid for 7 years was reported. The clinical presentation, radiographic and pathological results were described. This is a rare complication after total hip arthroplasty which should not be ignored especially in patients who received long term bisphosphonate. PMID:25177464

  4. Zoledronic Acid May Reduce Intraoperative Bleeding in Spinal Tumors: A Prospective Cohort Study

    PubMed Central

    Wu, Juan; Zheng, Wei; Tan, Yan; Hu, Xiao-Yuan; Huang, Quan; Fan, Kai-Hua; Ma, Jie; Xiao, Wen-Jing; Ren, Jian-Dong; Hou, Jun; Xiao, Jian-Ru

    2015-01-01

    Between June 2010 and June 2011, 176 patients were divided into 2 groups: a group with spinal metastasis of solid tumors (n = 157) and a group with multiple myeloma (n = 19). Both groups were further divided into 2 subgroups: a group receiving zoledronic acid before surgery and a control group. The zoledronic acid subgroup of the solid tumors group was group A (n = 81), the control subgroup of the solid tumors group was group B (n = 76), the zoledronic acid subgroup of the multiple myeloma group was group C (n = 10), and the control subgroup of the multiple myeloma group was group D (n = 9). The average intraoperative blood loss during spinal surgery was as follows: 1311 ± 691 mL in group A and 1752 ± 740 mL in group B (P = 0.000) and 1994 ± 810 mL in group C and 3134 ± 795 mL in group D (P = 0.000). Patients receiving zoledronic acid before surgery had significantly less intraoperative bleeding than those who did not receive it. Preoperative use of zoledronic acid can effectively reduce intraoperative bleeding during surgery for the treatment of spinal tumors. PMID:25685817

  5. 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:18427590

  6. Re-treatment of relapsed Paget's disease of bone with zoledronic acid: results from an open-label study.

    PubMed

    Reid, Ian R; Brown, Jacques P; Levitt, Naomi; Román Ivorra, José A; Bachiller-Corral, Javier; Ross, Ian L; Su, Guoqin; Antunez-Flores, Oscar; Aftring, R Paul

    2013-01-01

    Six patients from the phase 3 trials of zoledronic acid in Paget's disease, who had received zoledronic acid initially and had subsequently relapsed, were entered into an open re-treatment study. Following re-treatment, each patient reached similar absolute nadirs of serum alkaline phosphatase to those recorded after their first dose. No significant adverse events were reported. It is concluded that, while re-treatment of Paget's disease with zoledronic acid is rarely needed, it is safe and effective, with no evidence of treatment resistance based on this small cohort. PMID:24422139

  7. Comparative Effectiveness on Survival of Zoledronic Acid versus Pamidronate in Multiple Myeloma

    PubMed Central

    Sanfilippo, KM; Gage, B; Luo, S; Weilbaecher, K; Tomasson, M; Vij, R; Colditz, G; Carson, K

    2015-01-01

    Zoledronic acid and pamidronate are the two bisphosphonates approved to reduce multiple myeloma skeletal complications in the United States. Little prior evidence exists comparing survival outcomes between the two. We evaluated the incidence of skeletal related events and overall survival in myeloma patients treated with zoledronic acid versus pamidronate using a cohort of 1,018 United States Veterans. At median follow-up of 26.9 months, patients receiving zoledronic acid had a 22% reduction in risk of death compared to pamidronate (hazard ratio (HR) 0.78; 95% CI, 0.67–0.92). The benefit persisted after controlling for potential confounders. Adjusted Cox modeling with inverse probability weighting and propensity score matching supported these findings. Zoledronic acid was also associated with a 25% decrease in skeletal-related events. Zoledronic acid is associated with increased overall survival and decreased skeletal related events compared to pamidronate in patients with multiple myeloma and should become the preferred bisphosphonate. PMID:24844358

  8. Study of Adverse Effect Profile of Parenteral Zoledronic Acid in Female Patients with Osteoporosis

    PubMed Central

    Kotian, Prem; Sreenivasan, Sushanth

    2016-01-01

    Introduction Osteoporosis is still a under recognized entity in the population. Osteoporosis-related fractures can be prevented if people at risk can be screened, diagnosed and treated early. Bisphosphonates remain the mainstay of osteoporosis treatment as they have multimodal action. Oral bisphosphonate therapy has, significant gastrointestinal side effects leading to noncompliance. Of late parenteral Zoledronic Acid is being used as once or twice yearly infusion for the treatment of osteoporosis. Aim Our article studies the side effect profile and tolerability of parenteral Zoledronic Acid, one of the most potent bisphosphonate used in clinical practice in patients with osteoporosis. Materials and Methods This study was done in KMC hospitals where 49 patients diagnosed with osteoporosis were included for the study. After obtaining a written informed consent each patient received one infusion of 5 mg Zoledronic Acid as per standard treatment protocol. Patient was monitored for clinical improvement and development of any adverse effects. Conclusion In our study all subjects reported significant pain relief after infusion of Zoledronic Acid. Zoledronic Acid had very few serious adverse effects that can be prevented through pre-infusion screening, maintaining good hydration and careful patient monitoring. In our population the patients only experienced mild symptoms of pyrexia, arthralgia myalgia and influenza like symptoms which resolved with symptomatic treatment. PMID:26894105

  9. Correlation between zoledronic acid infusion and repeat vertebroplasty surgery in osteoporotic patients.

    PubMed

    Lin, Tung-Yi; Yang, Shih-Chieh; Tsai, Tsung-Ting; Lai, Po-Liang; Fu, Tsai-Sheng; Niu, Chi-Chien; Chen, Lih-Huei; Chen, Wen-Jer

    2016-05-01

    Objective The incidence of bone fractures rapidly increases as people age, mostly due to bone loss resulting from osteoporosis. The purpose of this study is to compare the rates of repeat vertebroplasty in osteoporotic patients treated with or without zoledronic acid (ZOL) infusion following initial vertebroplasty. Research design and methods We conducted a retrospective chart review of osteoporotic patients who underwent vertebroplasty from June 2009 to June 2012. Patients with existing vertebral fracture(s) were retrospectively divided into two groups according to whether or not they received zoledronic acid infusion after initial vertebroplasty. Zoledronic acid infusion was intravenously administered once a year for three consecutive years, as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. The primary efficacy variable was the number of patients requiring repeat vertebroplasty procedures after the initial surgery due to subsequent vertebral fractures. The Cox proportional hazards model was used to compare the risk ratios of repeat vertebroplasty between these two groups. Results A total of 1646 patients, including 456 males and 1190 females (age range: 65-89 years), were enrolled. Compared to the 1595 patients who did not receive osteoporosis medication, the 51 patients treated with zoledronic acid infusion demonstrated a significantly lower rate of repeat vertebroplasty. In the ZOL-treated group, only 4% of the patients (2/51) required a second vertebroplasty, compared to 13% (206/1595) in the non-ZOL-treated group (p = 0.032). Conclusions The results indicate that osteoporotic patients who undergo vertebroplasty are significantly less likely to require reoperation if treated with zoledronic acid infusion. However, since the number of male patients in the ZOL-treated group was limited, and since Taiwan's National Health System program does not cover the cost of receiving zoledronic acid infusions for male patients, the

  10. Mevalonates restore zoledronic acid-induced osteoclastogenesis inhibition.

    PubMed

    Nagaoka, Y; Kajiya, H; Ozeki, S; Ikebe, T; Okabe, K

    2015-04-01

    Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is likely to be caused by continuous imperfection of bone healing after surgical treatments in patients with long-term administration of nitrogen-containing bisphosphonates (NBPs). NBPs inhibit osteoclastic bone resorption by impairing the mevalonic acid sterol pathway in osteoclasts. Thus, we hypothesized that exogenous mevalonic acid metabolites restore the inhibitory effects of NBPs on osteoclastogenesis and bone remodeling. To clarify the effects of mevalonic acid metabolites, especially geranylgeranyl pyrophosphate (GGPP) and geranylgeranyl transferase substrate geranylgeranyl acid (GGOH), we examined the effects of zoledronic acid with or without GGOH or GGPP on osteoclast differentiation, multinucleation, and bone mineral deposition in tooth-extracted sockets. Zoledronic acid decreased the number of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells derived from mouse osteoclast precursors treated with receptor activator of nuclear factor-κB ligand and macrophage colony-stimulating factor. Zoledronic acid simultaneously suppressed not only the expressions of osteoclastic differentiation-related molecules such as TRAP, cathepsin K, calcitonin receptor, and vacuolar H-ATPase but also those of multinucleation-related molecules such as dendrocyte-expressed 7 transmembrane proteins and osteoclast stimulatory transmembrane protein. Treatment with GGOH or GGPP, but not farnesyl acid, restored the zoledronic acid-inhibited number of TRAP-positive multinuclear cells together with the expressions of these molecules. Although intraperitoneal administration of zoledronic acid and lipopolysaccharide into mice appeared to induce BRONJ-like lesions with empty bone lacunae and decreased mineral deposition in tooth-extracted socket, both GGOH and GGPP partially restored the inhibitory effects on zoledronic acid-related mineral deposition. These results suggest the potential of mevalonic acid

  11. Zoledronic Acid-Induced Interface Dermatitis.

    PubMed

    Succaria, Farah; Collier, Mary; Mahalingam, Meera

    2015-12-01

    Zoledronic acid (ZA) is a bisphosphonate given intravenously, most commonly for the treatment of postmenopausal osteoporosis. Increase in usage of ZA because it was FDA-approved has resulted in increasing reports of side effects. For the most part, these are systemic. Cutaneous side effects associated with ZA are infrequent and limited to 2 reports of dermatomyositis to date. In both, patients presented with clinical and laboratory stigmata of dermatomyositis soon after initiation of therapy. In this report, we describe a 62-year-old woman who presented with diffuse, erythematous scaly plaques over the right thigh after 12 hours of infusion of ZA. Histopathologic examination of a skin biopsy from the right thigh revealed patchy scale crust containing neutrophils and inspissated serum, interface change with scattered individually necrotic keratinocytes, and a mild, superficial perivascular lymphocytic infiltrate with scattered eosinophils and pigment incontinence-findings consistent with an interface dermatitis. Given that the patient had no other systemic manifestations or laboratory abnormalities, to the best of our knowledge, ours is the first report of interface dermatitis secondary to ZA with the caveat that longer follow-up is required to definitively exclude the development of drug-induced connective tissue disease. PMID:26588338

  12. Spontaneously recovered severe thrombocytopaenia following zoledronic acid infusion for osteoporosis.

    PubMed

    Kulkarni, Pooja; Cushman, Terra; Donthireddy, Vijayalakshmi; Rao, Sudhaker

    2016-01-01

    Zoledronic acid is widely used for the treatment of various skeletal disorders. While acute phase reactions are commonly seen, hypocalcaemia, femoral shaft fractures, osteonecrosis of the jaw and renal failure are rare. Two cases of fatal thrombocytopaenic purpura have been reported following zoledronic acid infusion. We report a case of non-fatal thrombocytopaenia with spontaneous recovery. A 70-year woman with osteoporosis participated in a research study. Complete blood and platelet counts prior to zoledronic acid infusion were normal (138 000/µL), but had declined slightly from 185 000/µL 2 years ago. One year after the first zoledronic acid infusion, her platelet count declined to 50 000/µL without any clinical manifestations, and rose slowly returning to normal (156 000/µL) over the next 1 year. Extensive evaluation did not reveal any specific abnormalities, and the pathogenesis of her transient severe thrombocytopaenia after two infusions of zoledronic acid remains unclear. PMID:26843222

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

    PubMed Central

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

    2015-01-01

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

  14. Atypical femoral fracture following zoledronic acid treatment.

    PubMed

    Ataoğlu, Baybars; Kaptan, Ahmet Yiğit; Eren, Toygun Kağan; Yapar, Ali Ekber; Berkay, Ahmet Fırat

    2016-04-01

    A 68-year-old female patient admitted to our clinic with right anterior thigh pain ongoing for six months and which increased in last two months. The patient had no trauma history. The patient had been followed-up for 15 years because of osteoporosis and administrated alendronate and ibandronate treatment for 10 years. Patient had three shots of zoledronate once a year during the last three years. Her pain was increasing when she was walking. Physical examination revealed pain in her right thigh. Radiogram showed thickened lateral cortex of the subtrochanteric area. Magnetic resonance imaging also showed thickening and edema of the same area. These images were correlated with atypical fracture in right femoral subthrochanteric zone. Dual energy X-ray absorptiometry revealed that T score was -3.3 in lumbar region and -2.5 in femoral neck. Zoledronate treatment was ended. Prophylactic surgical fixation was performed with titanium elastic nails. PMID:26874637

  15. Safety & Efficacy of Cyclic Zoledronic Acid Therapy on Pediatric Secondary Osteoporosis

    PubMed Central

    Al-Agha, Abdulmoein E.; Shaikhain, Talal A.; Ashour, Abdullah A.

    2016-01-01

    Background/Aim: Osteoporosis is a systemic disease characterized by decreased bone density and increased tendency to develop fractures. Osteoporosis in children and adolescents is a rare disease usually secondary to Medical conditions or medications given to children. The condition affects normal bone growth and development and carries with it multiple morbidities (physical and psychological) if not corrected promptly. This study aims to share our experience with Zoledronic Acid Therapy in Pediatric patients with secondary osteoporosis. Method: A retrospective study which included 46 patients aged 3 to 18 years. All patients received specific doses of Zoledronic acid and were followed up at King Abdulaziz University Hospital (KAUH) in Jeddah, Saudi Arabia. Clinical and laboratory data were collected for each patient from their files. Adverse events were also recorded. Results: The use of Zoledronic Acid in children and adolescents appears to be statically significant reduce fracture rate (p=0.005), bone turnover markers (Osteocalcin p= 0.003, CTX p= 0.008) and pain frequency in symptomatic individuals (p=0.000). Careful selection of cases is required to provide maximum benefits compared to risks associated with therapy. Conclusion: This study demonstrates that Zoledronic acid has positive effects on clinical outcome and bone marker level as well as quality of life for Pediatric patients with Osteoporosis and their families, with no long-term side effects.

  16. Zoledronic acid overcomes chemoresistance and immunosuppression of malignant mesothelioma

    PubMed Central

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

    2015-01-01

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

  17. Jaw osteonecrosis management around a dental implant inserted 2 years before starting treatment with zoledronic acid

    PubMed Central

    Marín-Fernández, Ana-Belén; García Medina, Blas; Aguilar-Salvatierra, Antonio; Jiménez-Burkhardt, Alberto

    2015-01-01

    Bisphosphonates (BP) are a type of drug known to inhibit bone resorption through complex interventions. Their primary mechanism of action is aimed at the cellular level, inhibiting osteoclast activity and so bone resorption. BPs are widely used, with many patients receiving continuous treatment for years. But it is well known that these drugs can produce osteonecrosis of the jaw (ONJ). Zoledronic acid (ZA) is an intravenous BP used in the treatment and prophylaxis of bone disease in patients with malignant tumors with bone implication. ZA is the most potent BP in clinical development. This report describes the case of a 62-year-old woman with breast cancer antecedents which relapsed, who had received a maxillary dental implant two years before the start of therapy with zoledronic acid. She later developed osteonecrosis of the jaw (ONJ), which began in the peri-implant area, and was treated for stage 3 ONJ by sub-total maxillectomy. Key words:Bisphosphonates, zoledronic acid, osteonecrosis of the jaw, peri-implantitis, maxillectomy. PMID:26330946

  18. Phase II trial of weekly Docetaxel, Zoledronic acid, and Celecoxib for castration-resistant prostate cancer.

    PubMed

    Kattan, Joseph; Bachour, Marwan; Farhat, Fadi; El Rassy, Elie; Assi, Tarek; Ghosn, Marwan

    2016-08-01

    Background Treatment options for patients with metastatic castration-resistance prostate cancer are unsatisfactory. Docetaxel monotherapy offers promising results with a tolerable toxicity profile. However, enhancing the clinical index of Docetaxel-based therapy remains the ultimate goal. Methods We conducted a phase II, open label, multinational prospective trial to evaluate the efficacy of weekly Docetaxel combined with Zoledronic acid and Celecoxib. Eligible patients received 25 mg/m(2) Docetaxel weekly for 3 consecutive weeks every 4 weeks, 4 mg Zoledronic acid every 4 weeks, and 200 mg oral Celecoxib twice daily. Enrollment was terminated prematurely upon the publication of reports of cardiac toxicity associated with cyclooxygenase (COX) 2 inhibitors. Results Our study enrolled 22 patients with a median of 4.7 cycles per patient. The median overall survival (OS) was 9.8 months (range 0.7 to 24.1 months) with 36 % and 4.5 % survival rates at 1 and 2 years, respectively. Our patients had a biologic response in 40.1 % of cases and a palliative response in 72.7 %. Among the eight patients with measurable disease, three had partial responses, two had stable disease, and three had progressive disease, leading to a response rate (RR) of 62.5 %. The observed toxicities were mild and limited to grade 3 events. Nine patients had anemia (40.1 %), 5 had sensory neuropathy (22.7 %) and 2 had stomatitis (9.1 %). Conclusion The combination of Docetaxel, Celecoxib, and Zoledronic acid failed to improve OS or to offer an acceptable biologic response. We do not believe that there is compelling evidence to include either Celecoxib or Zoledronic acid in further phase II/III trials. PMID:27159981

  19. 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. PMID:24613450

  20. Combined effects of zoledronic acid and doxorubicin on breast cancer cell invasion in vitro.

    PubMed

    Woodward, Julia K L; Neville-Webbe, Helen L; Coleman, Robert E; Holen, Ingunn

    2005-09-01

    The bisphosphonate zoledronic acid and the cytotoxic drug doxorubicin induce synergistic levels of apoptosis in breast cancer cells. As zoledronic acid and doxorubicin have been shown to reduce cell invasion and migration, we have investigated if these drugs also act synergistically on breast cancer invasion in vitro. MCF7 cells were treated with 0.05 microM doxorubicin/4 h followed by 1 or 10 microM zoledronic acid/24 h (or the reverse sequence). To study invasion, MCF7 cells were either grown on Transwell membranes coated with Matrigel or in a 24-well plate. Cells were treated sequentially using the above drug combinations, prior to starting the invasion assays for 48 h. Cell growth and death were also assessed under the same conditions. We found that invasion of MCF7 cells treated with zoledronic acid and doxorubicin was significantly reduced when compared with control, but the effect was dependent on drug sequence. At 1 microM, zoledronic acid significantly reduced invasion only if cells were pre-treated with doxorubicin, but cell growth was unaffected. For 10 microM zoledronic acid, invasion was reduced when administered before or after the doxorubicin, but this dose of zoledronic acid caused a significant reduction in MCF7 growth. Apoptosis was not induced by any of the drug doses and combinations. We conclude that pre-treatment with 0.05 microM doxorubicin followed by 1 microM zoledronic acid reduces invasion when cells were grown on Matrigel. For 10 microM zoledronic acid, pre- or post-doxorubicin also reduces invasion, but for this combination inhibition of cell growth may contribute to the reduction in invasion observed. PMID:16096432

  1. Randomized Controlled Trial of Early Zoledronic Acid in Men With Castration-Sensitive Prostate Cancer and Bone Metastases: Results of CALGB 90202 (Alliance)

    PubMed Central

    Smith, Matthew R.; Halabi, Susan; Ryan, Charles J.; Hussain, Arif; Vogelzang, Nicholas; Stadler, Walter; Hauke, Ralph J.; Monk, J. Paul; Saylor, Philip; Bhoopalam, Nirmala; Saad, Fred; Sanford, Ben; Kelly, W. Kevin; Morris, Michael; Small, Eric J.

    2014-01-01

    Purpose Zoledronic acid decreases the risk for skeletal-related events (SREs) in men with castration-resistant prostate cancer and bone metastases but its role earlier in the natural history of the disease is unknown. This phase III study evaluated the efficacy and safety of earlier treatment with zoledronic acid in men with castration-sensitive metastatic prostate cancer. Patients and Methods Men with castration-sensitive prostate cancer and bone metastases whose androgen-deprivation therapy was initiated within 6 months of study entry were randomly assigned in a blinded 1:1 ratio to receive zoledronic acid (4 mg intravenously every 4 weeks) or a placebo. After their disease progressed to castration-resistant status, all patients received open-label treatment with zoledronic acid. The primary end point was time to first SRE, defined as radiation to bone, clinical fracture, spinal cord compression, surgery to bone, or death as a result of prostate cancer. Target accrual was 680 patients. Primary analysis was planned after 470 SREs. The study was discontinued prematurely (645 patients; 299 SREs) after the corporate supporter withdrew study drug supply. Results Early zoledronic acid was not associated with increased time to first SRE. The median time to first SRE was 31.9 months in the zoledronic acid group (95% CI, 24.2 to 40.3) and 29.8 months in the placebo group (95% CI, 25.3 to 37.2; hazard ratio, 0.97; 95% CI, 0 to 1.17; one-sided stratified log-rank P = .39). Overall survival was similar between the groups (hazard ratio, 0.88; 95% CI, 0.70 to 1.12; P = .29). Rates of adverse events were similar between the groups. Conclusion In men with castration-sensitive prostate cancer and bone metastases, early treatment with zoledronic acid was not associated with lower risk for SREs. PMID:24590644

  2. Data from extension trials: denosumab and zoledronic acid.

    PubMed

    Dore, Robin K

    2012-03-01

    Osteoporosis and fractures that occur as a result of this condition pose a huge public health problem to society and result in morbidity and mortality to individuals. Because osteoporosis is often a result of aging, many people are not aware that therapies exist to reduce the risk of fracture. Until recently, the most common therapies used to treat osteoporosis, the oral bisphosphonates, had an inconvenient and cumbersome mode of administration. Within the last 4 years, two new parenteral antiresorptive drugs to treat osteoporosis were approved by the US Food and Drug Administration. As treatment of osteoporosis may extend for many years, the collection of long-term efficacy and safety data is warranted. This paper discusses data from the extension trials of denosumab and zoledronic acid. PMID:22086442

  3. [Sunitinib and zoledronic acid induced osteonecrosis of the jaw].

    PubMed

    Soós, Balázs; Vajta, László; Szalma, József

    2015-11-15

    The tendency for bisphosphonate and non-bisphosphonate (eg.: antiresorptive or anti-angiogenesis drugs) induced osteonecrosis is increasing. Treatment of these patients is a challenge both for dentists and for oral and maxillofacial surgeons. Cooperation with the drug prescribing general medicine colleagues to prevent osteonecrosis is extremely important. Furthermore, prevention should include dental focus elimination, oral hygienic instructions and education, dental follow-up and, in case of manifest necrosis, referral to maxillofacial departments. Authors outline the difficulties of conservative and surgical treatment of a patient with sunitinib and zoledronic acid induced osteonecrosis. The patient became symptomless and the operated area healed entirely six and twelve months postoperatively. A long term success further follow-up is necessary to verify long-term success. PMID:26548471

  4. Cathepsin K in treatment monitoring following intravenous zoledronic acid

    PubMed Central

    JAHN, OLIVER; WEX, THOMAS; KLOSE, SILKE; KROPF, SIEGFRIED; ADOLF, DANIELA; PIATEK, STEFAN

    2014-01-01

    Cathepsin K (CatK) is mainly expressed by osteoclasts and plays an important role in bone resorption. As CatK is expressed and secreted by osteoclasts during active bone resorption, it may be a useful and specific biochemical marker of osteoclastic activity. Therefore, CatK serum levels were studied for monitoring the treatment of females with postmenopausal osteoporosis by zoledronic acid. The serum CatK levels were determined in nine postmenopausal females before and after 3, 6 and 12 months of treatment. The levels were significantly reduced after 3 and 6 months (P<0.05), whereas they returned to baseline after 1 year. Taken together, the serum level of CatK may be suitable for monitoring anti-osteoporotic therapy in association with treatment response. PMID:25279169

  5. A Longitudinal Study of Skeletal Histomorphometry at 6 and 24 Months Across Four Bone Envelopes in Postmenopausal Women With Osteoporosis Receiving Teriparatide or Zoledronic Acid in the SHOTZ Trial.

    PubMed

    Dempster, David W; Zhou, Hua; Recker, Robert R; Brown, Jacques P; Bolognese, Michael A; Recknor, Christopher P; Kendler, David L; Lewiecki, E Michael; Hanley, David A; Rao, Sudhaker D; Miller, Paul D; Woodson, Grattan C; Lindsay, Robert; Binkley, Neil; Alam, Jahangir; Ruff, Valerie A; Gallagher, Eileen R; Taylor, Kathleen A

    2016-07-01

    Previously, we reported the effects of teriparatide (TPTD) and zoledronic acid (ZOL) on bone formation based on biochemical markers and bone histomorphometry of the cancellous envelope at month 6 in postmenopausal women with osteoporosis who participated in the 12-month primary Skeletal Histomorphometry in Subjects on Teriparatide or Zoledronic Acid Therapy (SHOTZ) study. Patients were eligible to enter a 12-month extension on their original treatment regimen: TPTD 20 μg/day (s.c. injection) or ZOL 5 mg/year (i.v. infusion). A second biopsy was performed at month 24. Here we report longitudinal changes between and within each treatment group in the cancellous, endocortical, intracortical, and periosteal bone envelopes in patients with evaluable biopsies at months 6 and 24 (paired data set: TPTD, n = 10; ZOL, n = 9). Between-group differences are also reported in the larger set of patients with evaluable biopsies at month 6 (TPTD, n = 28; ZOL, n = 30). Data from the cancellous envelope at month 6 or month 24 provided a reference to compare differences across envelopes within each treatment group. The 24-month results extend our earlier report that TPTD and ZOL possess different tissue-level mechanisms of action. Moreover, these differences persisted for at least 2 years in all four bone envelopes. Few longitudinal differences were observed within or across bone envelopes in ZOL-treated patients, suggesting that the low bone formation indices at month 6 persisted to month 24. Conversely, the magnitude of the effect of TPTD on bone formation varied across individual envelopes: median values for mineralizing surface (MS/BS) and bone formation rate (BFR/BS) at month 6 were approximately 3-fold to 5-fold higher in the endocortical and intracortical envelopes compared to the cancellous envelope. Although MS/BS and BFR/BS declined in these envelopes at month 24, median values continued to exceed, or were not significantly different from, those in the

  6. Assessment of the Impact of Zoledronic Acid on Ovariectomized Osteoporosis Model Using Micro-CT Scanning

    PubMed Central

    Shuai, Bo; Shen, Lin; Yang, Yanping; Ma, Chen; Zhu, Rui; Xu, Xiaojuan

    2015-01-01

    Purpose/Objective Prompted by preliminary findings, this study was conducted to investigate the impact of zoledronic acid on the cancellous bone microstructure and its effect on the level of β-catenin in a mouse model of postmenopausal osteoporosis. Methods and Materials 96 8-week-old specific-pathogen-free C57BL/6 mice were randomly divided into 4 groups (24 per group): a sham group, an ovariectomized osteoporosis model group, an estradiol-treated group, and a zoledronic acid-treated group. Five months after surgery, the third lumbar vertebra and left femur of the animals were dissected and scanned using micro-computed tomography (micro-CT) to acquire three-dimensional imagery of their cancellous bone microstructure. The impact of ovariectomy, the effect of estradiol, and the effect of zoledronic acid intervention on cancellous bone microstructure, as well as on the expression of β-catenin, were evaluated. Results The estradiol-treated and the zoledronic acid-treated group exhibited a significant increase in the bone volume fraction, trabecular number, trabecular thickness, bone surface to bone volume ratio (BS/BV), and β-catenin expression, when compared with those of the control group (P <0.01). In contrast, the structure model index, trabecular separation, and BS/BV were significantly lower compared with those of the model group (P <0.01). No differences were observed in the above parameters between animals of the zoledronic acid-treated and the estradiol-treated group. Conclusion These results suggest that increased β-catenin expression may be the mechanism underlying zoledronic acid-related improvement in the cancellous bone microstructure in ovariectomized mice. Our findings provide a scientific rationale for using zoledronic acid as a therapeutic intervention to prevent bone loss in post-menopausal women. PMID:26148020

  7. Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial

    PubMed Central

    Aft, Rebecca; Naughton, Michael; Trinkaus, Kathryn; Watson, Mark; Ylagan, Lourdes; Chavez-MacGregor, Mariana; Zhai, Jing; Kuo, Sacha; Shannon, William; Diemer, Kathryn; Herrmann, Virginia; Dietz, Jill; Ali, Amjad; Ellis, Matthew; Weiss, Peter; Eberlein, Timothy; Ma, Cynthia; Fracasso, Paula M; Zoberi, Imran; Taylor, Marie; Gillanders, William; Pluard, Timothy; Mortimer, Joanne; Weilbaecher, Katherine

    2013-01-01

    Summary Background Treatment with bisphosphonates decreases bone loss and can increase disease-free survival in patients with breast cancer. The aim of our study was to assess the effect of zoledronic acid on clearance of disseminated tumour cells (DTCs) from the bone marrow in women undergoing neoadjuvant chemotherapy for breast cancer. Methods Patients were recruited for this open-label, phase 2 randomised trial between March 17, 2003, and May 19, 2006, at a single centre. Eligible patients had clinical stage II–III (≥T2 and/or ≥N1) newly diagnosed breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, and normal cardiac, renal, and liver function. 120 women were randomly assigned, using allocation concealment, to receive 4 mg zoledronic acid intravenously every 3 weeks (n=60), or no zoledronic acid (n=60), for 1 year concomitant with four cycles of neoadjuvant epirubicin (75 mg/m²) plus docetaxel (75 mg/m²) and two cycles of adjuvant epirubicin plus docetaxel. The primary endpoint was the number of patients with detectable DTCs at 3 months. Final analysis was done 1 year after the last patient was enrolled. Analyses were done for all patients with available data at 3 months. This study is registered with ClinicalTrials.gov, number NCT00242203. Findings Of the 120 patients initially enrolled, one withdrew after signing consent and one patient’s baseline bone marrow was not available. Both of these patients were in the control group. At 3 months, 109 bone-marrow samples were available for analysis. In the zoledronic acid group, bone marrow was not collected from one patient because of disease progression, one patient was taken off study because of severe diarrhoea, and two patients had not consented at the time of surgery. In the control group, bone marrow was not collected from two patients because of disease progression, one patient withdrew consent, and three patients were not consented at the time of surgery. At baseline

  8. 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

  9. 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

  10. Effect of zoledronic acid on bone mineral density in patients of celiac disease: A prospective, randomized, pilot study

    PubMed Central

    Kumar, Mukul; Rastogi, Ashu; Bhadada, Sanjay Kumar; Bhansali, Anil; Vaiphei, Kim; Kochhar, Rakesh

    2013-01-01

    Background & objectives: The symptoms of celiac disease (CD) are varied and metabolic bone disease (MBD) is less recognized amongst all manifestations in CD patients. Bone disease in CD is attributed to secondary hyperparathyroidism, which in turn is associated with increased bone remodelling. Improvement in bone mineral density (BMD) with gluten free diet (GFD) is known, but the data on efficacy of bisphosphonates in CD patients are limited. Bisphosphonates being a potent inhibitor of bone resorption may be useful in patients with CD having low BMD. The aim of the present investigation was to study the effect of zoledronic acid on BMD in CD patients. Methods: A total of 28 CD patients were randomized to receive GFD, calcium and cholecalciferol (group A), and zoledronic acid (group B). Baseline biochemical tests and T-score by dual energy x-ray absorptiometer were done and repeated after 12 months. Results: The T-score showed improvement in the control arm (group A) from -3.31 ± 1.46 to -2.12 ± 1.44, a gain of 35.9 per cent (P<0.05) and in drug arm (group B) -2.82 ± 1.27 to -1.06 ± 1.84, registering a gain of 62.4 per cent (P<0.001). However, there was no difference in improvement of T-score in zoledronic acid group as compared to the control group. Interpretation & conclusions: Administration of zoledronic acid was not found to be better than GFD alone in increasing BMD in CD patients with low BMD in this pilot study. PMID:24521630

  11. Inhibition of breast cancer cell proliferation in repeated and non-repeated treatment with zoledronic acid

    PubMed Central

    2012-01-01

    Background Zoledronic acid is used to treat bone metastases and has been shown to reduce skeletal-related events and exert antitumor activity. The present in vitro study investigates the mechanism of action of Zoledronic Acid on breast cancer cell lines with different hormonal and HER2 patterns. Furthermore, we investigated the efficacy of repeated versus non-repeated treatments. Methods The study was performed on 4 breast cancer cell lines (BRC-230, SkBr3, MCF-7 and MDA-MB-231). Non-repeated treatment (single exposure of 168 hrs’ duration) with zoledronic acid was compared with repeated treatment (separate exposures, each of 48 hrs’ duration, for a total of 168 hrs) at different dosages. A dose–response profile was generated using sulforhodamine B assay. Apoptosis was evaluated by TUNEL assay and biomolecular characteristics were analyzed by western blot. Results Zoledronic acid produced a dose-dependent inhibition of proliferation in all cell lines. Anti-proliferative activity was enhanced with the repeated treatment, proving to be statistically significant in the triple-negative lines. In these lines repeated treatment showed a cytocidal effect, with apoptotic cell death caused by caspase 3, 8 and 9 activation and decreased RAS and pMAPK expression. Apoptosis was not observed in estrogen receptor-positive line: p21 overexpression suggested a slowing down of cell cycle. A decrease in RAS and pMAPK expression was seen in HER2-overexpressing line after treatment. Conclusions The study suggests that zoledronic acid has an antitumor activity in breast cancer cell lines. Its mechanism of action involves the decrease of RAS and RHO, as in osteoclasts. Repeated treatment enhances antitumor activity compared to non-repeated treatment. Repeated treatment has a killing effect on triple-negative lines due to apoptosis activation. Further research is warranted especially in the treatment of triple-negative breast cancer. PMID:23173568

  12. The effects of a systemic single dose of zoledronic acid on post-implantation bone remodelling and inflammation in an ovariectomised rat model.

    PubMed

    Cardemil, Carina; Omar, Omar M; Norlindh, Birgitta; Wexell, Cecilia L; Thomsen, Peter

    2013-02-01

    Bisphosphonates reverse the negative effects of ovariectomy on bone, but they have also been associated with adverse processes in human jawbone. The molecular events determining bone regeneration and implant integration in osteoporotic conditions, with and without bisphosphonate treatment, are unclear. In this study, ovariectomised rats, to which a single dose of saline (NaCl) or zoledronic acid (Zol) was administered, received titanium alloy implants in their tibiae and mandibles. An enzyme-linked immunosorbent assay, gene expression analysis and histomorphometry were performed. The results show that ovariectomy, per se, upregulated the expression of genes denoting bone formation in the tibia, bone remodelling in the mandible and apoptosis in the tibia and mandible. Zoledronic acid administration resulted in lower levels of a remodelling marker in serum and downregulated gene expression for inflammation, bone formation, angiogenesis and apoptosis, mainly in the mandible, after 28 d of healing. Histomorphometry revealed improved bone-to-implant contact in the tibia, while the opposite was observed in the mandible. The present data show that a systemic single dose of zoledronic acid, in ovariectomised animals, results in site-specific differences in the regulation of genes involved in bone healing and regeneration in association with implant installation. These events occur in parallel with site-specific differences in the rate of osseointegration, indicating diverse tissue responses in the tibia and mandible after zoledronic acid treatment. The zoledronic acid effect on gene expression, during the late phase of healing in the mandible, suggests negative effects by the anti-resorptive agent on osseointegration at that particular site. PMID:23182921

  13. Ab initio investigation of the adsorption of zoledronic acid molecule on hydroxyapatite (001) surface: an atomistic insight of bone protection

    NASA Astrophysics Data System (ADS)

    Ri, Mun-Hyok; Yu, Chol-Jun; Jang, Yong-Man; Kim, Song-Un

    2016-03-01

    We report a computational study of the adsorption of zoledronic acid molecule on hydroxyapatite (001) surface within ab initio density functional theory. The systematic study has been performed, from hydroxyapatite bulk and surface, and zoledronic acid molecule to the adsorption of the molecule on the surface. The optimized bond lengths and bond angles were obtained and analyzed, giving an evidence of structural similarity between subjects under study. The formation energies of hydroxyapatite (001) surfaces with two kinds of terminations were computed as about 1.2 and 1.5 J/m^2 with detailed atomistic structural information. We determined the adsorption energies of zoledronic acid molecule on the surfaces, which are -260 kJ/mol at 0.25 ML and -400 kJ/mol at 0.5 ML. An atomistic insight of strong binding affinity of zoledronic acid to the hydroxyapatite surface was given and discussed.

  14. Phase II study of zoledronic acid combined with docetaxel for non-small-cell lung cancer: West Japan Oncology Group

    PubMed Central

    Murakami, Haruyasu; Yamanaka, Takeharu; Seto, Takashi; Sugio, Kenji; Okamoto, Isamu; Sawa, Toshiyuki; Hirashima, Tomonori; Takeda, Koji; Atagi, Shinji; Fukuoka, Masahiro; Nakanishi, Yoichi; Nakagawa, Kazuhiko; Yamamoto, Nobuyuki

    2014-01-01

    The aim of this open-label, multicenter, randomized phase II trial was to evaluate the efficacy and safety of zoledronic acid in combination with docetaxel in previously treated patients with non-small-cell lung cancer (NSCLC) and bone metastases. In this study, patients randomly received docetaxel (60 mg/m2) with (group DZ) or without (group D) zoledronic acid every 21 days. There were 50 patients in each group, and the primary endpoint was progression-free survival. In an efficacy analysis of 94 patients (DZ, 48; D, 46), the median progression-free survival was 2.7 months (95% confidence interval [CI], 1.5–3.5 months) for the DZ group and 2.6 months (95% CI, 1.5–3.4 months) for the D group (stratified log-rank test, P = 0.89). The median overall survival was 10.4 months (95% CI, 7.0–15.8 months) for the DZ group and 9.7 months (95% CI, 6.1–12.5 months) for the D group (stratified log-rank test, P = 0.62). There were no clinically relevant differences in the frequencies of grade 3 or 4 adverse events between the two groups. No treatment-related deaths occurred in the DZ group. Zoledronic acid combined with docetaxel was well tolerated but did not meet the primary endpoint of demonstrating a longer progression-free survival in advanced NSCLC patients with bone metastases compared with docetaxel alone. This trial was registered with the University Hospital Medical Information Network (UMIN000001098). PMID:24837137

  15. Severe resistant hypocalcemia in multiple myeloma after zoledronic acid administration: a case report

    PubMed Central

    2014-01-01

    Introduction Hypercalcemia is one of the most common metabolic abnormalities encountered in any form of malignancy. Hypocalcemia, however, is a rare manifestation, especially in cancers with bone involvement. Here we present a case of hypocalcemia in a patient with multiple myeloma that was refractory to treatment. Case presentation A 73-year-old African American woman recently diagnosed with multiple myeloma, presented with a 2-day history of fever, vomiting and hypocalcemia. Ten days prior to admission she received zoledronic acid, Velcade® (bortezomib), Revlimid® (lenalidomide) and dexamethasone. Treatment was started with intravenous antibiotics and calcium gluconate boluses. After 24 hours of treatment her calcium level became undetectable (<5mg/dL). Continuous intravenous calcium gluconate infusions in addition to boluses were started. She remained persistently hypocalcemic and eventually developed tonic–clonic seizures. Vitamin D levels were found to be low and intravenous paricalcitol was initiated, which improved her calcium level. Conclusions Underlying vitamin D deficiency can precipitate severe hypocalcemia in patients with multiple myeloma receiving bisphosphonates. This warrants baseline screening for vitamin D deficiency in these patients. PMID:25342294

  16. Self-assembling nanoparticles encapsulating zoledronic acid revert multidrug resistance in cancer cells

    PubMed Central

    Gazzano, Elena; Salzano, Giuseppina; Giordano, Antonio; Desiderio, Vincenzo; Ghigo, Dario; Caraglia, Michele; De Rosa, Giuseppe; Riganti, Chiara

    2015-01-01

    The overexpression of ATP binding cassette (ABC) transporters makes tumor cells simultaneously resistant to several cytotoxic drugs. Impairing the energy metabolism of multidrug resistant (MDR) cells is a promising chemosensitizing strategy, but many metabolic modifiers are too toxic in vivo. We previously observed that the aminobisphosphonate zoledronic acid inhibits the activity of hypoxia inducible factor-1α (HIF-1α), a master regulator of cancer cell metabolism. Free zoledronic acid, however, reaches low intratumor concentration. We synthesized nanoparticle formulations of the aminobisphosphonate that allow a higher intratumor delivery of the drug. We investigated whether they are effective metabolic modifiers and chemosensitizing agents against human MDR cancer cells in vitro and in vivo. At not toxic dosage, nanoparticles carrying zoledronic acid chemosensitized MDR cells to a broad spectrum of cytotoxic drugs, independently of the type of ABC transporters expressed. The nanoparticles inhibited the isoprenoid synthesis and the Ras/ERK1/2-driven activation of HIF-1α, decreased the transcription and activity of glycolytic enzymes, the glucose flux through the glycolysis and tricarboxylic acid cycle, the electron flux through the mitochondrial respiratory chain, the synthesis of ATP. So doing, they lowered the ATP-dependent activity of ABC transporters, increasing the chemotherapy efficacy in vitro and in vivo. These effects were more pronounced in MDR cells than in chemosensitive ones and were due to the inhibition of farnesyl pyrophosphate synthase (FPPS), as demonstrated in FPPS-silenced tumors. Our work proposes nanoparticle formulations of zoledronic acid as the first not toxic metabolic modifiers, effective against MDR tumors. PMID:26372812

  17. 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

  18. Gorham–Stout disease of the proximal fibula treated with radiotherapy and zoledronic acid

    PubMed Central

    Yerganyan, V.V.; Body, J.J.; De Saint Aubain, N.; Gebhart, M.

    2015-01-01

    Gorham–Stout disease is a rare disease characterized by anarchic lymphovascular proliferation causing resorption of bone sometimes leading to disastrous complications. Bone tissue is progressively replaced by angiomatic and lymphangiomatic tissue and finally by fibrous tissue. This disease is known to be ubiquitous and of complex etiology. We present a case of Gorham–Stout disease of the proximal fibula invading the proximal tibia and soft tissues of the popliteal space that was successfully treated with radiotherapy and zoledronic acid. PMID:26579487

  19. Disruption of a Nuclear NFATc2 Protein Stabilization Loop Confers Breast and Pancreatic Cancer Growth Suppression by Zoledronic Acid*

    PubMed Central

    Singh, Shiv K.; Baumgart, Sandra; Singh, Garima; König, Alexander O.; Reutlinger, Kristina; Hofbauer, Lorenz C.; Barth, Peter; Gress, Thomas M.; Lomberk, Gwen; Urrutia, Raul; Fernandez-Zapico, Martin E.; Ellenrieder, Volker

    2011-01-01

    The aminobisphosphonate zoledronic acid has elicited significant attention due to its remarkable anti-tumoral activity, although its detailed mechanism of action remains unclear. Here, we demonstrate the existence of a nuclear GSK-3β-NFATc2 stabilization pathway that promotes breast and pancreatic cancer growth in vitro and in vivo and serves as a bona fide target of zoledronic acid. Specifically, the serine/threonine kinase GSK-3β stabilizes nuclear NFATc2 through phosphorylation of the serine-rich SP2 domain, thus protecting the transcription factor from E3-ubiquitin ligase HDM2-mediated proteolysis. Zoledronic acid disrupts this NFATc2 stabilization pathway through two mechanisms, namely GSK-3β inhibition and induction of HDM2 activity. Upon nuclear accumulation, HDM2 targets unphosphorylated NFATc2 for ubiquitination at acceptor lysine residues Lys-684/Lys-897 and hence labels the factor for subsequent proteasomal degradation. Conversely, mutagenesis-induced constitutive serine phosphorylation (Ser-215, Ser-219, and Ser-223) of the SP2 domain prevents NFATc2 from HDM2-mediated ubiquitination and degradation and consequently rescues cancer cells from growth suppression by zoledronic acid. In conclusion, this study demonstrates a critical role of the GSK-3β-HDM2 signaling loop in the regulation of NFATc2 protein stability and growth promotion and suggests that double targeting of this pathway is responsible, at least to a significant part, for the potent and reliable anti-tumoral effects of zoledronic acid. PMID:21628454

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

    PubMed Central

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

    2015-01-01

    Introduction Our objective was to determine effects of zoledronic acid (ZA) on atrial electrophysiological parameters and electrocardiographic measurements. Methods and Results 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 two weeks in one 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 two 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. Conclusion ZA shortens left atrial APD and ERP and increases P wave dispersion. PMID:25684326

  1. Subgroup Variations in Bone Mineral Density Response to Zoledronic Acid After Hip Fracture

    PubMed Central

    Magaziner, Jay S; Orwig, Denise L; Lyles, Kenneth W; Nordsletten, Lars; Boonen, Steven; Adachi, Jonathan D; Recknor, Chris; Colón-Emeric, Cathleen S; Mesenbrink, Peter; Bucci-Rechtweg, Christina; Su, Guoqin; Johnson, Rasheeda; Pieper, Carl F

    2014-01-01

    Minimizing post-fracture bone loss is an important aspect of recovery from hip fracture, and determination of factors that affect bone mineral density (BMD) response to treatment after hip fracture may assist in the development of targeted therapeutic interventions. A post hoc analysis of the HORIZON Recurrent Fracture Trial was done to determine the effect of zoledronic acid (ZOL) on total hip (TH) and femoral neck (FN) BMD in subgroups with low-trauma hip fracture. A total of 2127 patients were randomized (1:1) to yearly infusions of ZOL 5 mg (n = 1065) or placebo (n = 1062) within 90 days of operation for low-trauma hip fracture. The 1486 patients with a baseline and at least one post-baseline BMD assessment at TH or FN (ZOL = 745, placebo = 741) were included in the analyses. Percentage change from baseline in TH and FN BMD was assessed at months 12 and 24 and compared across subgroups of hip fracture patients. Percentage change from baseline in TH and FN BMD at months 12 and 24 was greater (p < 0.05) in ZOL-treated patients compared with placebo in most subgroups. Treatment-by-subgroup interactions (p < 0.05) indicated that a greater effect on BMD was observed for TH BMD at month 12 in females, in patients in the lower tertile body mass index at baseline (≤22.6 kg/m2), and in patients with baseline FN BMD T-score of ≤ –2.5; for FN BMD in patients who received ZOL for >6 weeks post-surgery; and for TH and FN BMD in patients with a history of one or more prior fractures. All interactions were limited to the first 12 months after treatment with none observed for the 24-month comparisons. (Clinical trial registration number NCT00046254.) PMID:24839241

  2. Data in support of the bone analysis of NOD-SCID mice treated with zoledronic acid and prednisolone.

    PubMed

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

    2016-06-01

    This paper reports data on the bone, specifically the tibia and mandible, of nonobese diabetic mice with severe combined immunodeficiency disease (NOD-SCID mice) treated with zoledronic acid (ZA) and prednisolone (PSL). The data described here are related to the research article titled "Zoledronic acid basically increases circulating soluble RANKL level in mice, and in glucocorticoid-administrated mice, more increases lymphocytes derived sRANKL by bacterial endotoxic stimuli" [1]. The present data and the NOD-SCID mice experiments described contain insights into the role of bone-remodeling factors induced by ZA treatment. PMID:27182545

  3. Data in support of the bone analysis of NOD–SCID mice treated with zoledronic acid and prednisolone

    PubMed Central

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

    2016-01-01

    This paper reports data on the bone, specifically the tibia and mandible, of nonobese diabetic mice with severe combined immunodeficiency disease (NOD–SCID mice) treated with zoledronic acid (ZA) and prednisolone (PSL). The data described here are related to the research article titled “Zoledronic acid basically increases circulating soluble RANKL level in mice, and in glucocorticoid-administrated mice, more increases lymphocytes derived sRANKL by bacterial endotoxic stimuli” [1]. The present data and the NOD–SCID mice experiments described contain insights into the role of bone-remodeling factors induced by ZA treatment. PMID:27182545

  4. Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1-34)] in postmenopausal osteoporosis.

    PubMed

    Cosman, Felicia; Eriksen, Erik Fink; Recknor, Chris; Miller, Paul D; Guañabens, Núria; Kasperk, Christian; Papanastasiou, Philemon; Readie, Aimee; Rao, Hanumantha; Gasser, Jürg A; Bucci-Rechtweg, Christina; Boonen, Steven

    2011-03-01

    Clinical data suggest concomitant therapy with bisphosphonates and parathyroid hormone (PTH) may blunt the anabolic effect of PTH; rodent models suggest that infrequently administered bisphosphonates may interact differently. To evaluate the effects of combination therapy with an intravenous infusion of zoledronic acid 5 mg and daily subcutaneous recombinant human (rh)PTH(1-34) (teriparatide) 20 µg versus either agent alone on bone mineral density (BMD) and bone turnover markers, we conducted a 1-year multicenter, multinational, randomized, partial double-blinded, controlled trial. 412 postmenopausal women with osteoporosis (mean age 65 ± 9 years) were randomized to a single infusion of zoledronic acid 5 mg plus daily subcutaneous teriparatide 20 µg (n = 137), zoledronic acid alone (n = 137), or teriparatide alone (n = 138). The primary endpoint was percentage increase in lumbar spine BMD (assessed by dual-energy X-ray absorptiometry [DXA]) at 52 weeks versus baseline. Secondary endpoints included change in BMD at the spine at earlier time points and at the total hip, trochanter, and femoral neck at all time points. At week 52, lumbar spine BMD had increased 7.5%, 7.0%, and 4.4% in the combination, teriparatide, and zoledronic acid groups, respectively (p < .001 for combination and teriparatide versus zoledronic acid). In the combination group, spine BMD increased more rapidly than with either agent alone (p < .001 versus both teriparatide and zoledronic acid at 13 and 26 weeks). Combination therapy increased total-hip BMD more than teriparatide alone at all times (all p < .01) and more than zoledronic acid at 13 weeks (p < .05), with final 52-week increments of 2.3%, 1.1%, and 2.2% in the combination, teriparatide, and zoledronic acid groups, respectively. With combination therapy, bone formation (assessed by serum N-terminal propeptide of type I collagen [PINP]) increased from 0 to 4 weeks, declined minimally from 4 to 8 weeks, and then rose throughout

  5. Zoledronic acid in vivo increases in vitro proliferation of rat mesenchymal stromal cells.

    PubMed

    Heino, Terhi J; Alm, Jessica J; Halkosaari, Heikki J; Välimäki, Ville-Valtteri

    2016-08-01

    Background and purpose - Bisphosphonates are widely used in the treatment of bone loss, but they might also have positive effects on osteoblastic cells and bone formation. We evaluated the effect of in vivo zoledronic acid (ZA) treatment and possible concomitant effects of ZA and fracture on the ex vivo osteogenic capacity of rat mesenchymal stromal cells (MSCs). Methods - A closed femoral fracture model was used in adult female rats and ZA was administered as a single bolus or as weekly doses up to 8 weeks. Bone marrow MSCs were isolated and cultured for in vitro analyses. Fracture healing was evaluated by radiography, micro-computed tomography (μCT), and histology. Results - Both bolus and weekly ZA increased fracture-site bone mineral content and volume. MSCs from weekly ZA-treated animals showed increased ex vivo proliferative capacity, while no substantial effect on osteoblastic differentiation was observed. Fracture itself did not have any substantial effect on cell proliferation or differentiation at 8 weeks. Serum biochemical markers showed higher levels of bone formation in animals with fracture than in intact animals, while no difference in bone resorption was observed. Interestingly, ex vivo osteoblastic differentiation of MSCs was found to correlate with in vivo serum bone markers. Interpretation - Our data show that in vivo zoledronic acid treatment can influence ex vivo proliferation of MSCs, indicating that bisphosphonates can have sustainable effects on cells of the osteoblastic lineage. Further research is needed to investigate the mechanisms. PMID:27196705

  6. Detecting Early Biomechanical Effects of Zoledronic Acid on Femurs of Osteoporotic Female Rats

    PubMed Central

    Palacio, Evandro Pereira; Müller, Sérgio Swain; Sardenberg, Trajano; Mizobuchi, Roberto Ryuiti; Galbiatti, José Antônio; Durigan, Alcides; Savarese, Aniello; Ortolan, Érika Veruska Paiva

    2012-01-01

    Aim. To investigate the biomechanical effects of zoledronic acid (ZA) on femurs of female osteoporotic rats after follow-up periods of 9 and 12 months. Methods. Eighty female Wistar rats were prospectively assessed. At 60 days of age, the animals were randomly divided into two groups: bilateral oophorectomy (O) (n = 40) and sham surgery (S) (n = 40). At 90 days of age, groups O and S were randomly subdivided into four groups, according to whether 0.1 mg/kg of ZA or distilled water (DW) was intraperitoneally administered: OZA (n = 20), ODW (n = 20), SZA (n = 20), and SDW (n = 20). The animals were sacrificed at 9 and 12 months after the administration of the substances, and then their right femurs were removed and analyzed biomechanically. Axial compression tests that focused on determining the maximum load (N), yield point (N), and stiffness coefficient (N/mm) of the proximal femur were performed in the biomechanical study. Results. ZA significantly increased the maximum load and yield point, reducing the stiffness coefficient concerning the oophorectomy status and follow-up period. Conclusion. Zoledronic acid, at a dose of 0.1 mg/kg, significantly increased the maximum loads and yield points and reduced the stiffness coefficients in the femurs of female rats with osteoporosis caused by bilateral oophorectomy. PMID:23304634

  7. Evaluating results from the multiple myeloma patient subset treated with denosumab or zoledronic acid in a randomized phase 3 trial

    PubMed Central

    Raje, N; Vadhan-Raj, S; Willenbacher, W; Terpos, E; Hungria, V; Spencer, A; Alexeeva, Y; Facon, T; Stewart, A K; Feng, A; Braun, A; Balakumaran, A; Roodman, G D

    2016-01-01

    In a phase 3 trial of denosumab vs zoledronic acid in patients (n=1776) with bone metastases and solid tumors or multiple myeloma, denosumab was superior to zoledronic acid for the primary end point of prevention of skeletal-related events. There was no difference in overall survival between the two groups; however, an ad hoc overall survival analysis in the multiple myeloma subset of patients (n=180) favored zoledronic acid (hazard ratio (HR) 2.26; 95% confidence interval (CI) 1.13–4.50; P=0.014). In the present analysis, we found imbalances between the groups with respect to baseline risk characteristics. HRs with two-sided 95% CIs were estimated using the Cox model. After adjustment in a covariate analysis, the CI crossed unity (HR 1.86; 95% CI 0.90–3.84; P=0.0954). Furthermore, we found a higher rate of early withdrawals for the reasons of lost to follow-up and withdrawal of consent in the zoledronic acid group; after accounting for these, the HR was 1.31 (95% CI 0.80–2.15; P=0.278). In conclusion, the survival results in multiple myeloma patients in this trial were confounded and will eventually be resolved by an ongoing phase 3 trial. PMID:26745852

  8. A comparison of calcium to zoledronic acid for improvement of cortical bone in an animal model of CKD

    PubMed Central

    Moe, Sharon M.; Chen, Neal X.; Newman, Christopher L.; Gattone, Vincent H.; Organ, Jason M.; Chen, Xianming; Allen, Matthew R.

    2013-01-01

    Patients with chronic kidney disease (CKD) have increased risk of fractures, yet the optimal treatment is unknown. In secondary analyses of large randomized trials, bisphosphonates have been shown to improve bone mineral density and reduce fractures. However, bisphosphonates are currently not recommended in patients with advanced kidney disease due to concern about over-suppressing bone remodeling, which may increase the risk of developing arterial calcification. In the present study we used a naturally occurring rat model of CKD with secondary hyperparathyroidism, the Cy/+ rat, and compared the efficacy of treatment with zoledronic acid, calcium given in water to simulate a phosphate binder, and the combination of calcium and zoledronic acid. Animals were treated beginning at 25 weeks of age (approximately 30% of normal renal function) and followed for ten weeks. The results demonstrate that both zoledronic acid and calcium improved bone volume by microCT and both equally suppressed mineral apposition rate, bone formation rate, and mineralizing surface of trabecular bone. In contrast, only calcium treatment with or without zoledronic acid improved cortical porosity and cortical biomechanical properties (ultimate load and stiffness) and lowered parathyroid hormone (PTH). However, only calcium treatment led to the adverse effects of increased arterial calcification and fibroblast growth factor 23 (FGF23). These results suggest zoledronic acid may improve trabecular bone volume in CKD in the presence of secondary hyperparathyroidism, but does not benefit extraskeletal calcification or cortical biomechanical properties. Calcium effectively reduces PTH and benefits both cortical and trabecular bone yet increases the degree of extra skeletal calcification. PMID:24038306

  9. Synergistic anti-tumor effects of zoledronic acid and radiotherapy against metastatic hepatocellular carcinoma.

    PubMed

    Morii, Kazuhiko; Aoyama, Yuhki; Nakamura, Shinichiro; Okushin, Hiroaki

    2015-01-01

    A 72-year-old man with advanced hepatocellular carcinoma and decompensated hepatitis C virus-related cirrhosis suffered from a metastatic femoral fracture. After undergoing radiotherapy, he was only treated with supportive care, except for the administration of zoledronic acid (ZA). Thereafter, the initially elevated serum α-fetoprotein and des-gamma carboxyprothrombin levels declined to within the normal ranges. Hepatic and metastatic adrenal tumors, distant from the radiation field, exhibited a surprising regression. ZA is known to inhibit the activity of osteoclasts, bone-residential macrophages, and has been reported to have a direct anti-tumor effect. ZA may adjust the immunological milieu in tumor microenvironments by inhibiting the tumor-associated macrophages. Because radiotherapy can enhance the presentation of tumor-associated antigens, ZA and radiotherapy may exert synergistic anti-tumor effects. PMID:26466697

  10. Efficacy and Safety of Zoledronic Acid and Pamidronate Disodium in the Treatment of Malignant Skeletal Metastasis: A Meta-Analysis.

    PubMed

    Yang, Liqing; Du, Shuai

    2015-10-01

    Solid tumors frequently metastasize to bone. Two bisphosphonates have been investigated for bone metastases including pamidronate disodium and zoledronic acid.By searching the PubMed, Embase, Wanfang, and China National Knowledge Infrastructure (CNKI) databases, we conducted a meta-analysis to determine the efficacy and safety of zoledronic acid compared with pamidronate disodium in reducing pain in patients with bone metastases.Studies were pooled, and the relative risk (RR) and its corresponding 95 % confidence interval (CI) were calculated. Version 12.0 STATA software was used for statistical analysis. Twenty relevant articles were included for this meta-analysis study.The complete response rate in cancer patients treatment with zoledronic acid was significantly higher than that with pamidronate disodium (relative risk [RR] = 1.32 [95% confidence interval (CI), 1.00-1.75]; P = 0.987, I = 0%). However, there was no significant difference in the rate of partial response rate (RR = 1.04, 95% CI: 0.90-1.20; P = 0.942, I = 0%) and in the total effective rate (RR = 1.06, 95% CI: 1.00-1.12; P = 0.998, I = 0%). For adverse events (AE), the incidence of headache in cancer patients with zoledronic acid was significantly lower than that with pamidronate disodium (RR = 0.82, 95% CI: 0.70-0.96; P = 0.793, I = 0%). There was no significant difference in nausea or vomiting (RR = 1.00, 95% CI: 0.92-1.09; P = 0.494, I = 0%), fever (RR = 0.98, 95% CI: 0.85-1.14; P =0.633, I = 0%), fatigue (RR = 1.01, 95% CI: 0.91-1.11; P = 0.914, I = 0%) and anorexia (RR = 1.31, 95% CI: 0.91-1.87; P = 0.024, I = 64.4%).In conclusion, this meta-analysis indicates that treatment with zoledronic acid was more effective than pamidronate disodium in the complete response assessments and the incidence of headache, an AE, was significantly lower in cancer patients with zoledronic acid. PMID:26496320

  11. Multiple cranial neuropathies following zoledronic acid infusion: a relationship? Clinical features and pathogenic discussion concerning a case.

    PubMed

    Deshayes, S; Martin Silva, N; Cogez, J; Baldolli, A; Fedrizzi, S; Bienvenu, B; Aouba, A

    2016-08-01

    The widespread use of bisphosphonates, especially in osteoporosis, has led to a greater number of reports of side effects. We describe for the first time a case of a 75-year-old female patient with a history of indolent sicca syndrome who developed multiple cranial neuropathies after zoledronic acid infusion. In this case, the elimination of the main causes of multiple cranial neuropathies, the chronology with zoledronic acid infusion, the absence of secondary complications of the Sjögren's syndrome, reported cases of similar peripheral nerve injuries with interferon infusions, the spontaneous remission of this multiple cranial neuropathy in parallel with the induced flu-like syndrome, argue for its iatrogenic origin, probably by a great release of inflammatory mediators in this particular background of primary Sjögren's syndrome. PMID:26980457

  12. Long-term leukopenia in a lung transplanted patient with cystic fibrosis treated with zoledronic acid: a case report.

    PubMed

    Karahasanovic, A; Thorsteinsson, A-L; Bjarnason, N H; Eiken, P

    2016-08-01

    Cystic fibrosis (CF) is a serious autosomal recessive genetic disorder associated with chronic lung disease, malabsorption, malnutrition, pancreatic insufficiency and premature respiratory failure. Recent advances in medical science and technology have increased the lifespan of patients with CF, albeit with long-term consequences of the disease, such as osteoporosis, becoming of increasing significance. The medical treatment of osteoporosis in patients with CF or after organ transplantation is still being explored, and no clear guidelines regarding the best choice of bisphosphonate exist. We report a case of a young woman with CF, lung transplantation and low bone mass developing long-term leukopenia after treatment with zoledronic acid. The leukopenia, with a strong affection of the neutrocytes, lasted for 4 months and the condition only went into remission after granulocyte-colony stimulating factor (G-CSF) treatment. It is important to be aware of symptomatic leukopenia in immunosuppressive patients after treatment with zoledronic acid. PMID:27080707

  13. 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

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

    PubMed

    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

    2015-09-01

    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

  15. 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

  16. THE BISPHOSPHONATE ZOLEDRONIC ACID DECREASES TUMOR GROWTH IN BONE IN MICE WITH DEFECTIVE OSTEOCLASTS*

    PubMed Central

    Hirbe, Angela C.; Roelofs, Anke J.; Floyd, Desiree H.; Deng, Hongju; Becker, Stephanie N.; Lanigan, Lisa G.; Apicelli, Anthony J.; Xu, Zhiqiang; Prior, Julie L.; Eagleton, Mark C.; Piwnica-Worms, David; Rogers, Michael J.; Weilbaecher, Katherine

    2009-01-01

    Bisphosphonates (BPs), bone targeted drugs that disrupt osteoclast function, are routinely used to treat complications of bone metastasis. Studies in preclinical models of cancer have shown that BPs reduce skeletal tumor burden and increase survival. Similarly, we observed in the present study that administration of the Nitrogen-containing BP (N-BP), zoledronic acid (ZA) to osteolytic tumor-bearing Tax+ mice beginning at 6 months of age led to resolution of radiographic skeletal lesions. N-BPs inhibit farnesyl diphosphate (FPP) synthase, thereby inhibiting protein prenylation and causing cellular toxicity. We found that ZA decreased Tax+ tumor and B16 melanoma viability and caused the accumulation of unprenylated Rap1a proteins in vitro. However, it is presently unclear whether N-BPs exert anti-tumor effects in bone independent of inhibition of osteoclast (OC) function in vivo. Therefore, we evaluated the impact of treatment with ZA on B16 melanoma bone tumor burden in irradiated mice transplanted with splenic cells from src-/- mice, which have non-functioning OCs. OC-defective mice treated with ZA demonstrated a significant 88% decrease in tumor growth in bone compared to vehicle-treated OC-defective mice. These data support an osteoclast-independent role for N-BP therapy in bone metastasis. PMID:19442620

  17. 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

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

    PubMed Central

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

    2015-01-01

    Background 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. Material and Methods 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. Results 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. Conclusions 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. Key words: Micronucleus, toxicity, dental adhesive, zolendronic acid, radiation effects. PMID:26034923

  19. Potentiated suppression of Dickkopf-1 in breast cancer by combined administration of the mevalonate pathway inhibitors zoledronic acid and statins.

    PubMed

    Göbel, Andy; Browne, Andrew J; Thiele, Stefanie; Rauner, Martina; Hofbauer, Lorenz C; Rachner, Tilman D

    2015-12-01

    The Wnt-inhibitor dickkopf-1 (DKK-1) promotes cancer-induced osteolytic bone lesions by direct inhibition of osteoblast differentiation and indirect activation of osteoclasts. DKK-1 is highly expressed in human breast cancer cells and can be suppressed by inhibitors of the mevalonate pathway such as statins and amino-bisphosphonates. However, supraphysiological concentrations are required to suppress DKK-1. We show that a sequential mevalonate pathway blockade using statins and amino-bisphosphonates suppresses DKK-1 more significantly than the individual agents alone. Thus, the reduction of the DKK-1 expression and secretion in the human osteotropic tumor cell lines MDA-MB-231, MDA-MET, and MDA-BONE by zoledronic acid was potentiated by the combination with low concentrations of statins (atorvastatin, simvastatin, and rosuvastatin) by up to 75% (p < 0.05). The specific rescue of prenylation using farnesyl pyrophosphate or geranylgeranyl pyrophosphate revealed that these effects were mediated by suppressed geranylgeranylation rather than by suppressed farnesylation. Moreover, combining low concentrations of statins (1 µM atorvastatin or 0.25 µM simvastatin) and zoledronic acid at low concentrations resulted in an at least 50% reversal of breast cancer-derived DKK-1-mediated inhibition of osteogenic markers in C2C12 cells (p < 0.05). Finally, the intratumoral injection of atorvastatin and zoledronic acid in as subcutaneous MDA-MB-231 mouse model reduced the serum level of human DKK-1 by 25% compared to untreated mice. Hence our study reveals that a sequential mevalonate pathway blockade allows for the combined use of low concentration of statins and amino-bisphosphonates. This combination still significantly suppresses breast cancer-derived DKK-1 to levels where it can no longer inhibit Wnt-mediated osteoblast differentiation. PMID:26515701

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

    SciTech Connect

    Schindeler, Aaron . E-mail: AaronS@chw.edu.au; Little, David G.

    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 the 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.

  1. Enhanced antimelanoma activity of methotrexate and zoledronic acid within polymeric sandwiches.

    PubMed

    Schilrreff, Priscila; Cervini, Gabriela; Romero, Eder Lilia; Morilla, Maria Jose

    2014-10-01

    New therapies are urgently needed against melanoma, one of the most aggressive tumors. Melanoma cells are resistant to the antifolate methotrexate (MTX), since MTX is taken up by the folate receptor-α (FRα), sequestered in melanosomes and exported out of the cell. The bisphosphonate zoledronic acid (ZOL) is active in several non-skeletal tumors; however, its antitumoral activity is hampered by its long-term accumulation in bones and low cellular permeability. Recently, we showed that core-shell tecto-dendrimers made of amine-terminated polyamidoamine generation 5 dendrimer (G5) as core and carboxyl-terminated G2.5 dendrimer as shell (G5G2.5) had selective cytotoxicity to melanoma cells. We hypothesized here that the activity of MTX and ZOL on melanoma cells could be enhanced when loaded within G5G2.5. MTX and ZOL were loaded within G5 cores, which were coated by a covalently bound shell of G2.5 dendrimers (drug-sandwiches). 12nm mean diameter and -12mV Z potential drug-sandwiches incorporating 6 and 31 molecules of MTX and ZOL, respectively, per G5G2.5, showed higher cytotoxicity (by MTT and apoptosis/necrosis assays) to melanoma (Sk-Mel-28) cells than free drugs and G5G2.5. Only MTX-sandwich was cytotoxic to Sk-Mel-28 cells and harmless to keratinocytes (HaCaT cells). The intracellular pathway of G5G2.5 was followed using chemical inhibitors of endocytosis. The increased cytotoxicity of MTX-sandwich could be due to its uptake by macropinocytosis instead of by FRα, avoiding MTX exocytosis. The increased cytotoxicity of ZOL-sandwich could be due to an increased intracellular accumulation of ZOL, owed by its endocytic uptake instead of diffusing as free drug. PMID:25016541

  2. Mono- and Combined Therapy of Metastasizing Breast Carcinoma 4T1 with Zoledronic Acid and Doxorubicin.

    PubMed

    Baklaushev, V P; Grinenko, N F; Yusubalieva, G M; Gubskii, I L; Burenkov, M S; Rabinovich, E Z; Ivanova, N V; Chekhonin, V P

    2016-08-01

    The efficiency of monotherapy with zoledronic acid (Resorba), doxorubicin, and their combination was studied on the model of metastasizing breast carcinoma in BALB/c mice. Doxorubicin monotherapy was accompanied by a significant increase in median survival up to 57 days (vs. 34 and 35 days in control groups); 27% animals survived for 90 days (duration of the study). Bioluminescence area of the primary tumor significantly decreased on days 21 and 28; the total number of visceral metastases also decreased according to magnetic-resonance imaging data. Resorba monotherapy produced no general toxic effect, the median survival increased to 64 days, and 90-day survival was 33%. Imaging techniques (magnetic-resonance imaging, microtomography, bioluminescent analysis) showed that Resorba delayed the development of the primary tumor (regression of luminescence area on days 21 and 28, regression of standardized bioluminescence intensity on day 28) and significantly reduced the number of visceral metastases in comparison with the control. Combination therapy was less effective than monotherapy with the same medications. Median survival was 55 days, 90-day survival was 13%, but magnetic-resonance imaging and bioluminescence analysis after combination therapy also showed delayed growth of the primary tumor and reduced number of visceral metastases. Microtomography revealed bone metastases in ~30% animals of the control group; in experimental groups, no bone metastases were found. The experiment with periosteal (distal epiphysis of the femur) injection of 4T1-Luc2 tumor cells demonstrated pronounced selective effectiveness of Resorba in relation to bone metastases. Monotherapy with Resorba can prevent the development of not only bone, but also visceral metastases of breast cancer. PMID:27590765

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

    PubMed Central

    KOMATSU, YUKO; IBI, MIHO; CHOSA, NAOYUKI; KYAKUMOTO, SEIKO; KAMO, MASAHARU; SHIBATA, TOSHIYUKI; SUGIYAMA, YOSHIKI; ISHISAKI, AKIRA

    2016-01-01

    Bisphosphonates (BPs) are analogues of pyro-phosphate 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. PMID:27176567

  4. Influence of early zoledronic acid administration on bone marrow fat in ovariectomized rats.

    PubMed

    Li, Guan-Wu; Xu, Zheng; Chang, Shi-Xin; Zhou, Lei; Wang, Xiao-Yan; Nian, Hua; Shi, Xiao

    2014-12-01

    Although the primary target cell of bisphosphonates is the osteoclast, increasing attention is being given to other effector cells influenced by bisphosphonates, such as osteoblasts and marrow adipocytes. Early zoledronic acid (ZA) treatment to ovariectomized (OVX) rats has been found to fully preserve bone microarchitecture over time. However, little is known regarding the influence of ZA on marrow adipogenesis. The purpose of this study was to monitor the ability of early administration of ZA in restoring marrow adiposity in an estrogen-deficient rat model. Thirty female Sprague-Dawley rats were randomly divided into sham-operated (SHAM), OVX + vehicle, and OVX + ZA groups (n=10/group). Dual-energy x-ray absorptiometry and water/fat magnetic resonance imaging were performed at baseline, 6 weeks, and 12 weeks after treatment to assess bone mineral density and marrow fat fraction. Serum biochemical markers, bone remodeling, and marrow adipocyte parameters were analyzed using biochemistry, histomorphometry, and histopathology, respectively. The expression levels of osteoblast, adipocyte, and osteoclast-related genes in bone marrow were assessed using RT-PCR. The OVX rats showed marked bone loss, first detected at 12 weeks, but estrogen deficiency resulted in a remarked increase in marrow fat fraction, first detected at 6 weeks compared with the SHAM rats (all P < .001). Similarly, the OVX rats had a substantially larger percent adipocyte area (+163.0%), mean diameter (+29.5%), and higher density (+57.3%) relative to the SHAM rats. Bone histomorphometry, levels of osteoclast-related gene expression, and a serum resorption marker confirmed that ZA significantly suppressed bone resorption activities. Furthermore, ZA treatment returned adipocyte-related gene expression and marrow adipocyte parameters toward SHAM levels. These data suggest that a single dose of early ZA treatment acts to reverse marrow adipogenesis occurring during estrogen deficiency, which may

  5. Clusterin inhibition using OGX-011 synergistically enhances zoledronic acid activity in osteosarcoma

    PubMed Central

    Lamoureux, Francois; Baud'huin, Marc; Ory, Benjamin; Guiho, Romain; Zoubeidi, Amina; Gleave, Martin; Heymann, Dominique; Rédini, Françoise

    2014-01-01

    Purpose Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants new strategies still needed to improve overall patient survival. Among new therapeutic approaches, zoledronic acid (ZOL) represents a promising adjuvant molecule to chemotherapy to limit the osteolytic component of bone tumors. However, ZOL triggers the elevation of heat shock proteins (Hsp), including Hsp27 and clusterin (CLU), which could enhance tumor cell survival and treatment resistance. We hypothesized that targeting CLU using siRNA or the antisense drug, OGX-011, will suppress treatment-induced CLU induction and enhance ZOL-induced cell death in osteosarcoma (OS) cells. Methods The combined effects of OGX-011 and ZOL were investigated in vitro on cell growth, viability, apoptosis and cell cycle repartition of ZOL-sensitive or -resistant human OS cell lines (SaOS2, U2OS, MG63 and MNNG/HOS). Results In OS cell lines, ZOL increased levels of HSPs, especially CLU, in a dose- and time-dependent manner by mechanism including increased HSF1 transcription activity. The OS resistant cells to ZOL exhibited higher CLU expression level than the sensitive cells. Moreover, CLU overexpression protects OS sensitive cells to ZOL-induced cell death by modulating the MDR1 and farnesyl diphosphate synthase expression. OGX-011 suppressed treatment-induced increases in CLU and synergistically enhanced the activity of ZOL on cell growth and apoptosis. These biologic events were accompanied by decreased expression of HSPs, MDR1 and HSF1 transcriptional activity. In vivo, OGX-011, administered 3 times a week (IP, 20mg/kg), potentiated the effect of ZOL (s.c; 50μg/kg), significantly inhibiting tumor growth by 50% and prolonging survival in MNNG/HOS xenograft model compared to ZOL alone. Conclusion These results indicate that ZOL-mediated induction of CLU can be attenuated by OGX-011, with synergistic effects on delaying progression of

  6. Transferrin-Targeted Nanoparticles Containing Zoledronic Acid as a Potential Tool to Inhibit Glioblastoma Growth.

    PubMed

    Salzano, G; Zappavigna, S; Luce, A; D'Onofrio, N; Balestrieri, M L; Grimaldi, A; Lusa, S; Ingrosso, D; Artuso, S; Porru, M; Leonetti, C; Caraglia, M; De Rosa, G

    2016-04-01

    The treatment of glioblastoma (GBM) is a challenge for the biomedical research since cures remain elusive. Its current therapy, consisted on surgery, radiotherapy, and concomitant chemotherapy with temozolomide (TMZ), is often uneffective. Here, we proposed the use of zoledronic acid (ZOL) as a potential agent for the treatment of GBM. Our group previously developed self-assembling nanoparticles, also named PLCaPZ NPs, to use ZOL in the treatment of prostate cancer. Here, we updated the previously developed nanoparticles (NPs) by designing transferrin (Tf)-targeted self-assembling NPs, also named Tf-PLCaPZ NPs, to use ZOL in the treatment of brain tumors, e.g., GBM. The efficacy of Tf-PLCaPZ NPs was evaluated in different GBM cell lines and in an animal model of GBM, in comparison with PLCaPZ NPs and free ZOL. Tf-PLCaPZ NPs were characterized by a narrow size distribution and a high incorporation efficiency of ZOL. Moreover, the presence of Tf significantly reduced the hemolytic activity of the formulation. In vitro, in LN229 cells, a significant uptake and cell growth inhibition after treatment with Tf-PLCaPZ NPs was achieved. Moreover, the sequential therapy of TMZ and Tf-PLCaPZ NPs lead to a superior therapeutic activity compared to their single administration. The results obtained in mice xenografted with U373MG, revealed a significant anticancer activity of Tf-PLCaPZ NPs, while the tumors remained unaffected with free TMZ. These promising results introduce a novel type of easy-to-obtain NPs for the delivery of ZOL in the treatment of GBM tumors. PMID:27301207

  7. Cancellous bone healing around strontium-doped hydroxyapatite in osteoporotic rats previously treated with zoledronic acid.

    PubMed

    Li, Yunfeng; Shui, Xueping; Zhang, Li; Hu, Jing

    2016-04-01

    Bisphosphonates (BPs) are potent anti-osteoporotic agents. Strontium-doped hydroxyapatite (HA) (SrHA) has been reported to increase bone density and improve trabecular microarchitecture in osteoporotic animals. But information about the effect of SrHA on the surrounding bone tissue in osteoporotic animals previously on BPs treatment is limited. We hypothesize that SrHA will induce increased bone density in the vicinity of the material when compared to HA, even in osteoporotic animals previously treated with BPs. HA and 10%SrHA (HA with 10 mol % calcium substituted by strontium) implants were prepared and characterized by scanning electronic microscopy (SEM), X-ray photoemission spectroscopy (XPS), and X-ray diffraction (XRD). Osteoporotic animal model was established by bilateral ovariectomy. Twelve weeks later, all OVX rats accepted subcutaneous injection of zoledronic acid (ZOL) at the dose of 1.5 μg/kg weekly for another twelve weeks. Subsequently, rod-shaped HA and SrHA implants were inserted in the distal femur of the OVX animals previously treated with ZOL. Eight weeks after implantation, specimens were harvested for histological and micro-computed tomography (micro-CT) analysis. Compared to HA, 10%SrHA raised the percent bone volume by 32.7%, the mean trabecular thickness by 36.5%, the mean trabecular number by 34.3%, the mean connectivity density by 38.4%, while the mean trabecular separation showed no significant difference. 10%SrHA also increased the bone area density by 36.3% in histological analysis. Results from this study indicated that 10%SrHA increased bone density and improved trabecular microarchitecture around implants in osteoporotic animals previously treated with ZOL when compared to HA. PMID:25891947

  8. Denosumab or Zoledronic Acid in Postmenopausal Women With Osteoporosis Previously Treated With Oral Bisphosphonates

    PubMed Central

    Pannacciulli, N.; Brown, J. P.; Czerwinski, E.; Nedergaard, B. S.; Bolognese, M. A.; Malouf, J.; Bone, H. G.; Reginster, J.-Y.; Singer, A.; Wang, C.; Wagman, R. B.; Cummings, S. R.

    2016-01-01

    Context: Denosumab and zoledronic acid (ZOL) are parenteral treatments for patients with osteoporosis. Objective: The objective of the study was to compare the effect of transitioning from oral bisphosphonates to denosumab or ZOL on bone mineral density (BMD) and bone turnover. Design and Setting: This was an international, multicenter, randomized, double-blind trial. Participants: A total of 643 postmenopausal women with osteoporosis previously treated with oral bisphosphonates participated in the study. Interventions: Subjects were randomized 1:1 to sc denosumab 60 mg every 6 months plus iv placebo once or ZOL 5 mg iv once plus sc placebo every 6 months for 12 months. Main Outcome Measures: Changes in BMD and bone turnover markers were measured. Results: BMD change from baseline at month 12 was significantly greater with denosumab compared with ZOL at the lumbar spine (primary end point; 3.2% vs 1.1%; P < .0001), total hip (1.9% vs 0.6%; P < .0001), femoral neck (1.2% vs −0.1%; P < .0001), and one-third radius (0.6% vs 0.0%; P < .05). The median decrease from baseline was greater with denosumab than ZOL for serum C-telopeptide of type 1 collagen at all time points after day 10 and for serum procollagen type 1 N-terminal propeptide at month 1 and at all time points after month 3 (all P < .05). Median percentage changes from baseline in serum intact PTH were significantly greater at months 3 and 9 with denosumab compared with ZOL (all P < .05). Adverse events were similar between groups. Three events consistent with the definition of atypical femoral fracture were observed (two denosumab and one ZOL). Conclusions: In postmenopausal women with osteoporosis previously treated with oral bisphosphonates, denosumab was associated with greater BMD increases at all measured skeletal sites and greater inhibition of bone remodeling compared with ZOL. PMID:27270237

  9. A successful treatment of hypercalcemia with zoledronic acid in a 15-year-old boy with acute lymphoblastic leukemia

    PubMed Central

    Park, Hye-Jin; Choi, Eun-Jin

    2016-01-01

    Severe hypercalcemia in children is a rare medical emergency. We present a case of a 15-year-old boy with hypercalcemia (total calcium level, 14.2 mg/dL) with a normal complete blood count, no circulating blasts in the peripheral blood film, and no other signs of acute lymphoblastic leukemia (ALL), including no signs of lymphadenopathy or hepatosplenomegaly. The hypercalcemia was successfully treated with zoledronic acid. As hypercalcemia can be the only presenting symptom of ALL in children, the diagnosis is often delayed. In children presenting with hypercalcemia, malignancies must be considered in the differential diagnosis. PMID:27462588

  10. 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

  11. The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT).

    PubMed

    Black, Dennis M; Reid, Ian R; Cauley, Jane A; Cosman, Felicia; Leung, Ping Chung; Lakatos, Peter; Lippuner, Kurt; Cummings, Steven R; Hue, Trisha F; Mukhopadhyay, Amitava; Tan, Monique; Aftring, R Paul; Eastell, Richard

    2015-05-01

    While bisphosphonates reduce fracture risk over 3 to 5 years, the optimal duration of treatment is uncertain. In a randomized extension study (E1) of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT), zoledronic acid (ZOL) 5 mg annually for 6 years showed maintenance of bone mineral density (BMD), decrease in morphometric vertebral fractures, and a modest reduction in bone turnover markers (BTMs) compared with discontinuation after 3 years. To investigate the longer-term efficacy and safety of ZOL, a second extension (E2) was conducted to 9 years in which women on ZOL for 6 years in E1 were randomized to either ZOL (Z9) or placebo (Z6P3) for 3 additional years. In this multicenter, randomized, double-blind study, 190 women were randomized to Z9 (n = 95) and Z6P3 (n = 95). The primary endpoint was change in total hip BMD at year 9 vs. year 6 in Z9 compared with Z6P3. Other secondary endpoints included fractures, BTMs, and safety. From year 6 to 9, the mean change in total hip BMD was -0.54% in Z9 vs. -1.31% in Z6P3 (difference 0.78%; 95% confidence interval [CI]: -0.37%, 1.93%; p = 0.183). BTMs showed small, non-significant increases in those who discontinued after 6 years compared with those who continued for 9 years. The number of fractures was low and did not significantly differ by treatment. While generally safe, there was a small increase in cardiac arrhythmias (combined serious and non-serious) in the Z9 group but no significant imbalance in other safety parameters. The results suggest almost all patients who have received six annual ZOL infusions can stop medication for up to 3 years with apparent maintenance of benefits. PMID:25545380

  12. 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. PMID:27176567

  13. A Randomised Controlled Trial of Intravenous Zoledronic Acid in Malignant Pleural Disease: A Proof of Principle Pilot Study

    PubMed Central

    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

    Introduction 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. Methods 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. Results 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. Conclusions 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. Trial Registration UK Clinical

  14. [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

  15. Effect of zoledronate acid treatment on osseointegration and fixation of implants in autologous iliac bone grafts in ovariectomized rabbits.

    PubMed

    Qi, Mengchun; Hu, Jing; Li, Jianping; Li, Jinyuan; Dong, Wei; Feng, Xiaojie; Yu, Jing

    2012-01-01

    One main problem associated with alveolar bone augmentation in implant dentistry is resorption of grafted bone, which may be further compromised by systemic skeletal disorders such as osteoporosis. Zoledronate acid (ZOL) is the most potent bisphosphonate to treat osteoporosis and therefore it is hypothesized to be able to invert the negative effect of osteoporosis on osseointegration and fixation of dental implants in autologous bone grafts. In this study, 56 rabbits received bilateral ovariectomy (OVX) (40 rabbits) or sham operation (16 rabbits). Three months later, 8 animals from each group were sacrificed for bone mineral density (BMD) examination. Then the remaining animals underwent bilateral autologous iliac bone grafting with simultaneous implantation of titanium implants in tibiae and were divided into 5 groups (n=8): Sham, OVX, Loc-ZOL (local treatment), Sys-ZOL (systemic treatment) and Loc+Sys-ZOL (local plus systemic) group. At 3 months after implantation, all animals were sacrificed and specimens were harvested for examinations. Both BMD and histological examinations of femurs showed osteoporotic changes after ovariectomy, while systemic treatment with ZOL restored mineralized bone. Micro-CT examination demonstrated that OVX group showed significant decrease of mineralized bone and implant-bone contact when compared with sham control, whereas both systemic and local treatments of ZOL significantly increased mineralized bone and implant-bone contact in ovariectomized animals. However, the best effects were observed in Loc+Sys-ZOL group (combined use of ZOL) and most of bone indices were similar to (IBCR, p>0.05) or higher than (BV/TV, Conn.D and Tb.N) (p<0.01) those of the sham group, except Tb.Th, which was still significantly lower (p<0.01), and Tb.Sp, which was further decreased (p<0.01). The aforementioned effects were also confirmed by histomorphometric analysis of bone indices on implant-bone contact and mineralized bone. In addition, biomechanical

  16. Efficacy and Safety of Single Dose Zoledronic Acid for Osteoporosis in Frail Seniors: A Randomized Clinical Trial

    PubMed Central

    Greenspan, Susan L.; Perera, Subashan; Ferchak, Mary Anne; Nace, David A.; Resnick, Neil M.

    2016-01-01

    Importance 85% of institutionalized elderly have osteoporosis, with fracture rates 8–9 fold higher than observed among community-dwelling elderly. Yet most are untreated and excluded from pivotal osteoporosis trials. Objective Determine the efficacy and safety of zoledronic acid in frail elderly women. Design 2-year, randomized, placebo-controlled, double-blinded study conducted between December 2007 and March 2012. Setting Nursing home and assisted living facilities. Participants 181 women ≥ age 65 with osteoporosis including those with cognitive impairment, immobility, and multimorbidity. Intervention One 5 mg dose of zoledronic acid or placebo IV and daily calcium and vitamin D. Main Outcomes (1) Hip and spine bone mineral density (BMD) at 12 and 24 months and (2) adverse events. Results There were no baseline differences in age (mean=85.4±0.6 years), BMD, or functional or cognitive status, but the treatment group included more subjects with frailty, falls history, diabetes, and anticonvulsant use. BMD was available for 87% of participants at 12 months and 73% at 24 months. BMD changes were greater in the treatment group (p< 0.01): 3.2 ± 0.7 and 3.9 ± 0.7 percentage point differences (mean ± SE) in the total hip at 12 and 24 months respectively, and 1.8 ± 0.7 and 3.6 ± 0.7 at the spine (p<0.01); adjusted analyses were similar. The treatment and placebo groups’ fracture rates were 20% and 16%, respectively (OR=1.30; 95% CI=0.61–2.78); mortality rates were 16% and 13% (OR=1.24; 95% CI=0.54–2.86). Groups did not differ in the proportion of single fallers (28% vs. 24%; OR=1.24; 95% CI=0.64–2.42; p=0.52) but more subjects in the treatment group had multiple falls (49% vs. 35%; OR=1.83; 95% CI=1.01–3.33; p=0.047); this was no longer significant when adjusted for baseline frailty. Conclusions and Relevance In this group of frail, osteoporotic women, one dose of zoledronic acid improved BMD over 2 years. The clinical importance of nonsignificant

  17. Randomized Controlled Trial of Zoledronic Acid plus Chemotherapy versus Chemotherapy Alone as Neoadjuvant Treatment of HER2-Negative Primary Breast Cancer (JONIE Study)

    PubMed Central

    Hasegawa, Yoshie; Tanino, Hirokazu; Horiguchi, Jun; Miura, Daishu; Ishikawa, Takashi; Hayashi, Mitsuhiro; Takao, Shintaro; Kim, Seung Jin; Yamagami, Kazuhiko; Miyashita, Masaru; Konishi, Muneharu; Shigeoka, Yasushi; Suzuki, Masato; Taguchi, Tetsuya; Kubota, Tomoyuki; Akazawa, Kouhei; Kohno, Norio

    2015-01-01

    Purpose Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate that induces osteoclast apoptosis and inhibits bone resorption by inhibiting the mevalonate pathway. Its benefit for the prevention of skeletal complications due to bone metastases has been established. However, the antitumor efficacy of ZOL, although suggested by multiple preclinical and clinical studies, has not yet been clinically proven. We performed the present randomized Phase 2 trial to investigate the antitumor effect of ZOL with chemotherapy (CT). Methods Asian patients with HER2-negative invasive breast cancer were randomly assigned to either the CT or CT+ZOL (CTZ) group. One hundred and eighty-eight patients were randomized to either the CT group (n = 95) or the CTZ group (n = 93) from March 2010 to April 2012, and 180 patients were assessed. All patients received four cycles of FEC100 (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2), followed by 12 cycles of paclitaxel at 80 mg/m2 weekly. ZOL (4 mg) was administered three to four times weekly for 7 weeks to the patients in the CTZ group. The primary endpoint was the pathological complete response (pCR) rate, which was defined as no invasive cancer in the breast tissue specimen. Safety was assessed in all patients who received at least one dose of the study drug. Results This randomized controlled trial indicated that the rates of pCR in CTZ group (14.8%) was doubled to CT group (7.7%), respectively (one-sided chi-square test, p = 0.068), though the additional efficacy of zoledronic acid was not demonstrated statistically. The pCR rate in postmenopausal patients was 18.4% and 5.1% in the CTZ and CT groups, respectively (one-sided Fisher’s exact test, p = 0.071), and that in patients with triple-negative breast cancer was 35.3% and 11.8% in the CTZ and CT groups, respectively (one-sided Fisher’s exact test, p = 0.112). Thus the addition of ZOL to neoadjuvant CT has potential anticancer benefits in

  18. 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

  19. Differential Effects of Teriparatide and Zoledronic Acid on Bone Mineralization Density Distribution at 6 and 24 Months in the SHOTZ Study.

    PubMed

    Dempster, David W; Roschger, Paul; Misof, Barbara M; Zhou, Hua; Paschalis, Eleftherios P; Alam, Jahangir; Ruff, Valerie A; Klaushofer, Klaus; Taylor, Kathleen A

    2016-08-01

    The Skeletal Histomorphometry in Patients on Teriparatide or Zoledronic Acid Therapy (SHOTZ) study assessed the progressive effects of teriparatide (TPTD) and zoledronic acid (ZOL) on bone remodeling and material properties in postmenopausal women with osteoporosis. Previously, we reported that biochemical and histomorphometric bone formation indices were significantly higher in patients receiving TPTD versus ZOL. Here we report bone mineralization density distribution (BMDD) results based on quantitative backscattered electron imaging (qBEI). The 12-month primary study was randomized and double blind until the month 6 biopsy, then open label. Patients (TPTD, n = 28; ZOL, n = 31) were then eligible to enter a 12-month open-label extension with their original treatment: TPTD 20 μg/d (subcutaneous injection) or ZOL 5 mg/yr (intravenous infusion). A second biopsy was collected from the contralateral side at month 24 (TPTD, n = 10; ZOL, n = 10). In cancellous bone, ZOL treatment was associated at 6 and 24 months with significantly higher average degree of mineralization (CaMEAN, +2.2%, p = 0.018; +3.9%, p = 0.009, respectively) and with lower percentage of low mineralized areas (CaLOW , -34.6%, p = 0.029; -33.7%, p = 0.025, respectively) and heterogeneity of mineralization CaWIDTH (-12.3%, p = 0.003; -9.9%, p = 0.012, respectively), indicating higher mineralization density and more homogeneous mineral content versus TPTD. Within the ZOL group, significant changes were found in all parameters from month 6 to 24, indicating a progressive increase in mineralization density. In sharp contrast, mineralization density did not increase over time with TPTD, reflecting ongoing deposition of new bone. Similar results were observed in cortical bone. In this study, TPTD stimulated new bone formation, producing a mineralized bone matrix that remained relatively heterogeneous with a stable mean mineral content. ZOL slowed bone turnover

  20. 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

  1. 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

  2. The clinical response on bone metastasis from breast and lung cancer during treatment with zoledronic acid is inversely correlated to skeletal related events (SRE).

    PubMed

    Facchini, G; Caraglia, M; Santini, D; Nasti, G; Ottaiano, A; Striano, S; Maiolino, P; Ruberto, M; Fiore, F; Tonini, G; Budillon, A; Iaffaioli, R V; Zeppetella, G L

    2007-09-01

    Current management of bone metastases involves a multimodal approach. Aminobisphosphonates (BPs) are a valid weapon in the treatment of skeletal localization of tumour disease. Patients with bone metastases from breast and lung cancer were enrolled in order to evaluate the impact of the addition of bisphosphonates therapy to standard treatments in terms of (i) pain control, (ii) quality of life (QoL) and (iii) toxicity and to evaluate (iv) any relations between clinical activity and the occurrence of SREs. A total of 60 patients were included in the study. Median age was 76 years (range 40-83). The majority of patients were treated with chemotherapy or hormonal therapy. All patients received zoledronic acid (ZOL) (4 mg) every 3-4 weeks for at least 3 cycles. No significant improvement in Performance Status of patients after 12 cycles of ZOL (p = 0.1672) was recorded. A statistically significant early and long-lasting amelioration of both pain, narcotic scores and QoL was found. Twenty-one patients (48%) experienced at least one SRE during the study. The most common SRE was radiation to bone (30% of patients). An inverse correlation between bone tumour response and SREs was also found (p = 0.019). ZOL addition induces a clinical benefit and improves QoL of patients with bone metastases. Moreover, the occurrence of bone clinical response is related to a reduced risk of SREs. PMID:17987788

  3. 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

  4. Synergistic Antiproliferative Effects of Zoledronic Acid and Fluvastatin on Human Pancreatic Cancer Cell Lines: An in Vitro Study.

    PubMed

    Elsayed, Mahitab; Kobayashi, Daisuke; Kubota, Toshio; Matsunaga, Naoya; Murata, Ryusei; Yoshizawa, Yuko; Watanabe, Natsuki; Matsuura, Tohru; Tsurudome, Yuya; Ogino, Takashi; Ohdo, Shigehiro; Shimazoe, Takao

    2016-08-01

    Bisphosphonates and statins are known to have antitumor activities against different types of cancer cell lines. In the present study, we investigated the antiproliferative effects of the combination of zoledronic acid (ZOL), a bisphophosphonate, and fluvastatin (FLU), a statin, in vitro on two types of human pancreatic cancer cell lines, Mia PaCa-2 and Suit-2. The pancreatic cancer cell lines were treated with ZOL and FLU both individually and in combination to evaluate their antiproliferative effects using WST-8 cell proliferation assay. In this study, we demonstrated a potent synergistic antiproliferative effect of both drugs when used in combination in both cell lines. Moreover, we studied the molecular mechanism behind this synergistic effect, which was inhibited by the addition of the mevalonate pathway products, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Furthermore, we aimed to determine the effect of ZOL and FLU combination on RhoA and Ras guanosine 5'-triphosphate (GTP)-proteins. The combination induced a marked accumulation in RhoA and unprenylated Ras. GGPP and FPP reversed the increase in the amount of both proteins. These results indicated that the combination treatment impaired RhoA and Ras signaling pathway by the inhibition of geranylgeranylation and/or farnesylation. This study provides a potentially effective approach for the treatment of pancreatic cancer using a combination treatment of ZOL and FLU. PMID:27181081

  5. 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

  6. Zoledronic acid suppresses metastasis of esophageal squamous cell carcinoma cells through upregulating the tight junction protein occludin.

    PubMed

    Lin, Canfeng; Xin, Shubo; Qin, Xin; Li, Haijun; Lin, Lianxing; You, Yanjie

    2016-08-01

    We have previously demonstrated the radio-sensitizing effect of zoledronic acid (ZOL), a third generation bisphosphonate, on human esophageal squamous cell carcinoma (ESCC) cells. Here we show that ZOL suppresses metastatic progression of ESCC cells mainly through up-regulating the tight junction protein occludin. Exposure to ZOL at lower concentrations dramatically reduced migration and invasion of ESCC cells. In addition, ZOL treatment decreased the expression of mesenchymal markers, vimentin and N-cadherin, while increased the expression of the tight junction protein occludin. Moreover, ectopic expression of Slug, a well-known transcriptional repressor of occludin, partially but significantly abrogated the effect of ZOL on occludin expression and subsequently rescued the malignant metastatic phenotype, suggesting that Slug is one of the mediators underlying the anti-metastatic effect of ZOL. The present study is the first to report the significance of ZOL on ESCC metastasis. These data are promising for the future application of this drug regimen in patients with ESCC. PMID:26204820

  7. 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.

  8. 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. PMID:25950681

  9. 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

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

    PubMed

    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

    2016-04-12

    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

  11. 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

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

    PubMed

    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

  13. 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

  14. The ZOTECT study: Effect of zoledronic acid on bone metabolism in patients with bone metastases from prostate or breast cancer

    PubMed Central

    Hadji, Peyman; Ziller, May; Maurer, Tobias; Autenrieth, Michael; Muth, Mathias; Ruebel, Amelie; May, Christoph; Birkholz, Katrin; Diebel, Erhardt; Gleissner, Jochen; Rothe, Peter; Gschwend, Juergen E.

    2012-01-01

    Purpose The ZOTECT study assesses the effect of zoledronic acid (ZOL) on bone-marker levels and potential correlations with disease outcomes in bisphosphonate-naive patients. Methods This prospective, single-arm, open-label study in bisphosphonate-naive (≥6 months) patients with bone metastases from prostate cancer (PC; n=301) or breast cancer (BC; n=99) enrolled at 98 German sites (May 2006 to July 2008) investigated the effect of ZOL (4 mg intravenously every 4 weeks×4 months, with a final follow-up at 12 months) on bone-marker levels. Secondary assessments: skeletal-related event (SRE) rate, pain, quality of life (QoL), and prostate-specific antigen levels. Endpoints were assessed using summary statistics by visit/tumor type and Kaplan–Meier analyses. Results ZOL treatment significantly decreased bone-marker levels (amino-terminal propeptide of type I collagen [P1NP], C-terminal cross-linking telopeptide of type I collagen [CTX]; P<0.0001), and this decrease was maintained through the final 1-year follow-up visit. Baseline P1NP and CTX levels correlated with extent of bone disease (P<0.0001, each) and on-treatment decreases in marker levels. Skeletal disease burden and bone-marker levels were similar between PC and BC patients, and ZOL did not significantly influence osteoprotegerin/receptor activator of nuclear factor-κB ligand levels. Only 13 SREs occurred in 11 patients, supporting the known ZOL-mediated reduction in SREs. On-treatment bone-marker level changes did not correlate with SRE rate, pain scores, or QoL. Generally, ZOL was well tolerated and adverse events were consistent with its known safety profile. Conclusions This study confirms that ZOL therapy significantly reduces bone turnover (measured as P1NP and CTX levels) in patients with bone metastases from PC or BC. PMID:26909262

  15. The effect of zoledronic acid on serum dickkopf-1, osteoprotegerin, and RANKL in patients with Paget's disease of bone.

    PubMed

    Polyzos, S A; Anastasilakis, A D; Efstathiadou, Z; Kita, M; Litsas, I; Avramidis, A; Arsos, G; Moralidis, E; Gerou, S; Pavlidou, V; Papatheodorou, A; Terpos, E

    2009-11-01

    Overexpression of dickkopf (DKK)-1 in pagetic osteoblast cultures resulted in stimulation of osteoclast proliferation and inhibition of osteoblast growth. The aim of this study was to evaluate for the first time in Paget's disease of bone (PDB): 1) the serum levels of DKK1; 2) the association of DKK-1 with receptor activator of nuclear factor kappa B (RANKL) and osteoprotegerin (OPG); and 3) the effect of zoledronic acid (ZOL) on serum DKK-1, RANKL, and OPG. The study was conducted as a prospective open-label cohort study. Eleven patients with PDB (median age 60 years) were recruited. Twelve age- gender- and body mass index (BMI)-matched healthy individuals were used as controls at baseline. Blood samples were obtained before treatment (baseline) and after 3, 6, 12, and 18 months following ZOL infusion in patients with PDB. Patients with PDB had significantly higher RANKL (p=0.002), OPG (p=0.001), and bone markers (total alkaline phosphatase and C-terminal cross-linking telopeptide of type I collagen) compared with controls at baseline. There was no difference between groups in DKK-1 at baseline. Bone markers were both significantly decreased after therapy. Serum OPG, RANKL, RANKL:OPG ratio, and DKK-1 remained unaffected throughout the study. No correlations were found between OPG, RANKL, RANKL:OPG ratio, and DKK-1 at baseline nor between their changes during the study. Although both OPG and RANKL were increased in patients with PDB, ZOL had no effect on their serum levels. Serum DKK-1 was neither increased in patients with PDB nor related to OPG and RANKL, and was unaffected by ZOL. PMID:19670154

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

    PubMed

    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 mm(3)) as compared to rhBMP-2 alone (10.9 ± 2.1 mm(3)) 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

  17. Oncologic Doses of Zoledronic Acid Induce Osteonecrosis of the Jaw-Like Lesions in Rice Rats (Oryzomys Palustris) with Periodontitis

    PubMed Central

    Aguirre, J. I.; Akhter, M. P.; Kimmel, D. B.; Pingel, J. E.; Williams, A.; Jorgensen, M.; Kesavalu, L.; Wronski, T. J.

    2012-01-01

    Though osteonecrosis of the jaw (ONJ) is temporally-associated with the use of nitrogen-containing bisphosphonates (N-BPs), a cause/effect relationship has not yet been established. We hypothesize that ONJ is a two-stage process in which: a) risk factors initiate pathologic processes in the oral cavity that lead to a supranormal rate of hard tissue necrosis, and b) powerful anti-resorptives reduce the rate of removal of necrotic bone sufficiently to allow its net accumulation in the jaw. To test this hypothesis, we used the rice rat model of periodontitis. At age 28 days, rats (n=15/group) were placed on a high sucrose and casein diet to exacerbate the development of periodontitis. Animals were injected SC biweekly with vehicle or alendronate (ALN, 15μg/kg), or IV once monthly with vehicle, a low dose (LD), or a high dose (HD) of zoledronic acid (ZOL) and sacrificed after 6, 12, 18, and 24 wks. Mandibles and maxillae were analyzed to determine the effects on the: a) progression of periodontitis, b) integrity of alveolar bone, c) status of bone resorption and formation, d) vascularity, and e) osteocyte viability. We found that only HD-ZOL induced ONJ-like lesions in mandibles of rice rats after 18 and 24 wks of treatment. These lesions were characterized by areas of exposed necrotic alveolar bone, osteolysis, a honey comb-like appearance of the alveolar bone, presence of bacterial colonies, and periodontal tissue destruction. In addition, inhibition of bone formation, a paradoxical abolition of the antiresorptive effect of only HD-ZOL, increased osteocyte necrosis/apoptosis, and decreased blood vessel number were found after 18 and/or 24 wks. Our study suggests that only HD-ZOL exacerbates the inflammatory response and periodontal tissue damage in rice rats, inducing bone lesions that resemble ONJ. PMID:22623376

  18. Solvent effect on molecular structure, IR spectra, thermodynamic properties and chemical stability of zoledronic acid: DFT study.

    PubMed

    Liu, Qingzhu; Qiu, Ling; Wang, Yang; Lv, Gaochao; Liu, Guiqing; Wang, Shanshan; Lin, Jianguo

    2016-04-01

    Zoledronic acid (ZL) has been used widely for treating skeletal diseases because of its high potency in inhibiting bone resorption. A detailed understanding of its physicochemical characteristics may be of great significance in both medicinal chemistry and structural biology for the design of novel bisphosphonates with higher activity. In the present work, the monoclinic (IM) and triclinic (IT) polymorphs of ZL in the gas phase and the aqueous phase were studied by density functional theory (DFT) method at the B3LYP/6-311++G** level. The polarizable continuum model (PCM) was employed to study the solvent effect on structures and properties. The optimized IM and IT conformations in both phases are in reasonable agreement with the experimental structures with the overall mean absolute percent deviation (MAPD%) less than 3.1 %. The presence of intramolecular hydrogen bond within both conformations was identified in the solvent. The IR spectra were simulated and assigned in detail, which agreed well with the experimental data. The intramolecular hydrogen bonding interactions resulted in the shift of vibrational frequencies of hydroxyl to the low band by 12-22 cm(-1) and 24-26 cm(-1) for IM and IT conformations, respectively. Their thermodynamic properties were also calculated based on the harmonic vibrational analysis, including standard heat capacity (C (°) p,m), entropy (S (°) m), and enthalpy (H (°) m). The molecular stability, hydrogen bonding interaction and other electronic properties have been further analyzed by the natural bond orbital (NBO), atoms in molecules (AIM), molecular electrostatic potential (MEP) and frontier molecular orbital (FMO) analysis. Graphical abstract FMOs of IM and IT conformations in the gas phase and in the water. PMID:26994018

  19. 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

  20. 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

  1. Combined inhibition of the mevalonate pathway with statins and zoledronic acid potentiates their anti-tumor effects in human breast cancer cells.

    PubMed

    Göbel, Andy; Thiele, Stefanie; Browne, Andrew J; Rauner, Martina; Zinna, Valentina M; Hofbauer, Lorenz C; Rachner, Tilman D

    2016-05-28

    Amino-bisphosphonates are antiresorptive drugs for the treatment of osteolytic bone metastases, which are frequently caused by breast and other solid tumors. Like statins, amino-bisphosphonates inhibit the mevalonate pathway. Direct anti-tumor effects of amino-bisphosphonates and statins have been proposed, although high concentrations are required to achieve these effects. Here, we demonstrate that the treatment of different human breast cancer cell lines (MDA-MB-231, MDA-Bone, and MDA-Met) by combined inhibition of the mevalonate pathway using statins and zoledronic acid at the same time significantly reduces the concentrations required to achieve a meaningful anti-tumor effect over a single agent approach (50% reduction of cell vitality and 4-fold increase of apoptosis; p < 0.05). The effects were mediated by suppressed protein geranylation that caused an accumulation of GTP-bound RhoA and CDC42. Importantly, the knockdown of both proteins prior to mevalonate pathway inhibition reduced apoptosis by up to 65% (p < 0.01), indicating the accumulation of the GTP-bound GTPases as the mediator of apoptosis. Our results point to effective anti-tumor effects in breast cancer by the combination of statins and zoledronic acid and warrant further validation in preclinical settings. PMID:26968247

  2. Efficacy of zoledronic acid for chronic low back pain associated with Modic changes in magnetic resonance imaging

    PubMed Central

    2014-01-01

    Background Modic changes (MC) are associated with low back pain (LBP), but effective treatments are lacking. The aim of this randomized, placebo-controlled, double-blinded trial was to evaluate the efficacy of zoledronic acid (ZA) for chronic LBP among patients with MC in magnetic resonance imaging (MRI). Methods Inclusion criteria were LBP lasting ≥3 months, with an intensity of ≥6 on a 10-cm VAS or an Oswestry Disability Index (ODI) of ≥30%, and MC in MRI. Patients were randomized into single intravenous infusion of ZA 5 mg (n = 20), or placebo (n = 20) groups. The primary outcome was LBP intensity, secondary outcomes leg pain intensity, ODI, health-related quality of life (RAND-36), lumbar flexibility, sick leaves and use of pain medication. The treatment differences at one month and one year were analysed using ANCOVA with adjustment for the baseline score. Results The mean difference (MD) between the groups in the primary outcome, intensity of LBP, was 1.4 (95% confidence intervals (CI) 0.01 to 2.9) in favour of ZA at one month. We observed no significant between-group difference in the intensity of LBP at one year (MD 0.7; 95% CI −1.0 to 2.4) or in secondary outcomes at any time point except that 20% of patients in the ZA group used non-steroidal anti-inflammatory drugs at one year compared to 60% in the placebo group (P = 0.022). Acute phase reactions (fever, flu-like symptoms, arthralgia) emerged in 95% of the patients in the ZA group, compared to 35% in the placebo group. Conclusions ZA was effective in reducing the intensity of LBP in the short term and in reducing the use of NSAIDs within the time span of one year among patients with chronic LBP and MC confirmed in MRI. Although the results seem encouraging, larger studies are required to analyse the effectiveness and safety of ZA for patients with MC. Trial registration ClinicalTrial.gov identifier NCT01330238. PMID:24588905

  3. Zoledronic Acid Injection

    MedlinePlus

    ... It works by slowing bone breakdown, increasing bone density (thickness), and decreasing the amount of calcium released ... sure to drink at least 2 glasses of water or another liquid within a few hours before ...

  4. Rare Form of Erdheim-Chester Disease Presenting with Isolated Central Skeletal Lesions Treated with a Combination of Alfa-Interferon and Zoledronic Acid

    PubMed Central

    Bulycheva, E. N.; Baykov, V. V.; Zaraĭskiĭ, M. I.; Salogub, G. N.

    2015-01-01

    Erdheim-Chester disease (ECD) represents a clonal non-Langerhans histiocytosis, which manifests under an extensive variety of clinical symptoms. This creates a challenge for the physician, who is required to recognize and diagnose the disease in the early stages. Despite this considerable challenge, in the last decade there has been a dramatic increase in ECD diagnoses, in most part due to an increasing awareness of this rare disorder. Involvement of the axial skeleton is exclusively uncommon with no official recommendations for the treatment of the bone lesions. Here, we present a case report of a young male patient with isolated lesions of the spine, ribs, and pelvis, who was successfully treated with a combination therapy of alfa-interferon and zoledronic acid. PMID:25949835

  5. Effects of Zoledronate on Mortality and Morbidity after Surgical Treatment of Hip Fractures

    PubMed Central

    Cengiz, Ömer; Polat, Gökhan; Karademir, Gökhan; Tunç, Oytun Derya; Erdil, Mehmet; Tuncay, İbrahim; Şen, Cengiz

    2016-01-01

    We aimed to evaluate the effects of intertrochanteric femoral fractures on mortality, morbidity, and cost of zoledronate treatment in elderly patients treated by osteosynthesis. Based on Evans classification, 114 patients with unstable intertrochanteric femoral fractures were treated with osteosynthesis. After the surgical treatment of intertrochanteric fractures, the treatment group (M/F, 24/32; mean age, 76.7 ± SD years) received zoledronate infusion, and the control group (M/F, 20/38; mean age, 80.2 ± SD years) received placebo. Postoperative control visits were performed at 6-week, 3-month, 6-month, and 12-month time points. Functional level of patients was evaluated by the modified Harris hip score and Merle d'Aubigné hip score. By 12 months, the mean HHS in treatment and control groups was 81.93 and 72.9, respectively. For time of death of the patients, mortality was found to be 57.1% (16/28) on the first 3 months and 92.9% (26/28) on the first six months. The mortality rate in the treatment and control groups was 14.3% (8/56) and 34.5% (20/58), respectively. The use of zoledronic acid after surgical treatment of intertrochanteric femoral fractures in osteoporotic elderly patients is a safe treatment modality which helps to reduce mortality, improves functional outcomes, and has less side effects with single dose use per year. PMID:27092280

  6. Annexin A1 is involved in the acquisition and maintenance of a stem cell-like/aggressive phenotype in prostate cancer cells with acquired resistance to zoledronic acid.

    PubMed

    Bizzarro, Valentina; Belvedere, Raffaella; Milone, Maria Rita; Pucci, Biagio; Lombardi, Rita; Bruzzese, Francesca; Popolo, Ada; Parente, Luca; Budillon, Alfredo; Petrella, Antonello

    2015-09-22

    In this study, we have characterized the role of annexin A1 (ANXA1) in the acquisition and maintenance of stem-like/aggressive features in prostate cancer (PCa) cells comparing zoledronic acid (ZA)-resistant DU145R80 with their parental DU145 cells. ANXA1 is over-expressed in DU145R80 cells and its down-regulation abolishes their resistance to ZA. Moreover, ANXA1 induces DU145 and DU145R80 invasiveness acting through formyl peptide receptors (FPRs). Also, ANXA1 knockdown is able to inhibit epithelial to mesenchymal transition (EMT) and to reduce focal adhesion kinase (FAK) and metalloproteases (MMP)-2/9 expression in PCa cells. DU145R80 show a cancer stem cell (CSC)-like signature with a high expression of CSC markers including CD44, CD133, NANOG, Snail, Oct4 and ALDH7A1 and CSC-related genes as STAT3. Interestingly, ANXA1 knockdown induces these cells to revert from a putative prostate CSC to a more differentiated phenotype resembling DU145 PCa cell signature. Similar results are obtained concerning some drug resistance-related genes such as ATP Binding Cassette G2 (ABCG2) and Lung Resistant Protein (LRP). Our study provides new insights on the role of ANXA1 protein in PCa onset and progression. PMID:26312765

  7. Annexin A1 is involved in the acquisition and maintenance of a stem cell-like/aggressive phenotype in prostate cancer cells with acquired resistance to zoledronic acid

    PubMed Central

    Bizzarro, Valentina; Belvedere, Raffaella; Milone, Maria Rita; Pucci, Biagio; Lombardi, Rita; Bruzzese, Francesca; Popolo, Ada; Parente, Luca; Budillon, Alfredo; Petrella, Antonello

    2015-01-01

    In this study, we have characterized the role of annexin A1 (ANXA1) in the acquisition and maintenance of stem-like/aggressive features in prostate cancer (PCa) cells comparing zoledronic acid (ZA)-resistant DU145R80 with their parental DU145 cells. ANXA1 is over-expressed in DU145R80 cells and its down-regulation abolishes their resistance to ZA. Moreover, ANXA1 induces DU145 and DU145R80 invasiveness acting through formyl peptide receptors (FPRs). Also, ANXA1 knockdown is able to inhibit epithelial to mesenchymal transition (EMT) and to reduce focal adhesion kinase (FAK) and metalloproteases (MMP)-2/9 expression in PCa cells. DU145R80 show a cancer stem cell (CSC)-like signature with a high expression of CSC markers including CD44, CD133, NANOG, Snail, Oct4 and ALDH7A1 and CSC-related genes as STAT3. Interestingly, ANXA1 knockdown induces these cells to revert from a putative prostate CSC to a more differentiated phenotype resembling DU145 PCa cell signature. Similar results are obtained concerning some drug resistance-related genes such as ATP Binding Cassette G2 (ABCG2) and Lung Resistant Protein (LRP). Our study provides new insights on the role of ANXA1 protein in PCa onset and progression.

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

    PubMed

    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

  9. 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

  10. 5-year Follow-up of a Randomized Controlled Trial of Immediate versus Delayed Zoledronic Acid for Prevention of Bone Loss in Postmenopausal Women with Breast Cancer Starting Letrozole after Tamoxifen: N03CC (Alliance)

    PubMed Central

    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.

    2015-01-01

    Background Postmenopausal women with breast cancer (BC) receiving aromatase inhibitors are at increased risk for bone loss. The current study was undertaken to determine whether upfront versus delayed treatment with zoledronic acid (ZA) impacted bone loss. This report describes the 5-year follow-up results. Methods 551 postmenopausal women with BC completing tamoxifen and undergoing daily letrozole treatment were randomized to upfront (274) or delayed (277) ZA 4 mg IV every 6 months. In the delayed arm, ZA was initiated for post-baseline bone mineral density (BMD) T-score < -2.0 or fracture. Results The incidence of a 5% decrease in total lumbar spine BMD at 5 years was 10.2% in the upfront arm versus 41.2% in the delayed arm, p < 0.0001. 41 patients in the delayed arm were eventually started on ZA. With the exception of increased grade 1/2 elevated creatinine and fever in the upfront arm and cerebrovascular ischemia in the delayed arm, there were no significant differences between arms with respect to the most common adverse events of arthralgia and back pain. Osteoporosis occurred less frequently in the upfront arm (2 versus 8 cumulative cases) though this difference was not statistically significant. Bone fractures occurred in 24 patients in the upfront arm versus 25 patients in the delayed arm. Conclusions Immediate treatment with ZA prevented bone loss compared with delayed treatment in postmenopausal women on letrozole and these differences were maintained at 5 years. The incidence of osteoporosis or fractures was not different between arms. PMID:25930719

  11. Panobinostat synergizes with zoledronic acid in prostate cancer and multiple myeloma models by increasing ROS and modulating mevalonate and p38-MAPK pathways

    PubMed Central

    Bruzzese, F; Pucci, B; Milone, M R; Ciardiello, C; Franco, R; Chianese, M I; Rocco, M; Di Gennaro, E; Leone, A; Luciano, A; Arra, C; Santini, D; Caraglia, M; Budillon, A

    2013-01-01

    Patients with advanced prostate cancer (PCa) and multiple myeloma (MM) have limited long-term responses to available therapies. The histone deacetylase inhibitor panobinostat has shown significant preclinical and clinical anticancer activity in both hematological and solid malignancies and is currently in phase III trials for relapsed MM. Bisphosphonates (BPs), such as zoledronic acid (ZOL), inhibit osteoclast-mediated bone resorption and are indicated for the treatment of bone metastasis. BPs, including ZOL, have also shown anticancer activity in several preclinical and clinical studies. In the present report, we found a potent synergistic antiproliferative effect of panobinostat/ZOL treatment in three PCa and three MM cell lines as well as in a PCa ZOL-resistant subline, independently of p53/KRAS status, androgen dependency, or the schedule of administration. The synergistic effect was also observed in an anchorage-independent agar assay in both ZOL-sensitive and ZOL-resistant cells and was confirmed in vivo in a PCa xenograft model. The co-administration of the antioxidant N-acetyl-L-cysteine blocked the increased reactive oxygen species generation and apoptosis observed in the combination setting compared with control or single-agent treatments, suggesting that oxidative injury plays a functional role in the synergism. Proapoptotic synergy was also partially antagonized by the addition of geranyl-geraniol, which bypasses the inhibition of farnesylpyrophosphate synthase by ZOL in the mevalonate pathway, supporting the involvement of this pathway in the synergy. Finally, at the molecular level, the inhibition of basal and ZOL-induced activation of p38-MAPK by panobinostat in sensitive and ZOL-resistant cells and in tumor xenografts could explain, at least in part, the observed synergism. PMID:24157872

  12. Zoledronic acid therapy impacts risk and frequency of skeletal complications and follow-up duration in prostate cancer patients with bone metastasis

    PubMed Central

    Hatoum, Hind T.; Lin, Swu-Jane; Guo, Amy; Lipton, Allan; Smith, Matthew R.

    2011-01-01

    Purpose To evaluate the effects of timing and length of zoledronic acid (ZA) treatment on outcomes for patients with prostate cancer in clinical practice. Materials and methods Patients with prostate cancer and first bone metastasis diagnosed from January 2003 to October 2006 were included. Patients were considered ‘untreated’ if no ZA was given, ‘early ZA-treated’ if ZA was initiated before skeletal complication (SC) occurrence or ‘late ZA-treated’ if one or more SC was documented before or at ZA initiation. Patients were classified with short (≤90 days), medium (91–180 days) or long (>180 days) treatment persistence. Assessments included follow-up duration (FUP) and risk of developing one or more SC. Results Among eligible patients, 847 were untreated, 243 were early ZA-treated and 218 were late ZA-treated. For untreated versus early ZA-treated groups, median FUP was 263 versus 357 days (p<0.0001), respectively, and time to first SC was 199 versus 273 days (p<0.0001), respectively. ZA treatment was associated with significantly longer FUP and lower SC risk. The early ZA-treated group had significantly longer FUP versus the late ZA-treated group (median days, 357 vs. 299.5); the late ZA-treated group experienced significantly higher SC risk vs. the early ZA-treated group (odds ratio, 1.51). Compared with the long-persistence group, FUP was 56% and 40% shorter in the short and medium groups, respectively (p<0.0001). Conclusion Treatment with and early initiation of ZA for patients with prostate cancer and bone metastasis significantly prolonged time to and reduced risk of developing SC, while extending FUP. PMID:21083514

  13. Panobinostat synergizes with zoledronic acid in prostate cancer and multiple myeloma models by increasing ROS and modulating mevalonate and p38-MAPK pathways.

    PubMed

    Bruzzese, F; Pucci, B; Milone, M R; Ciardiello, C; Franco, R; Chianese, M I; Rocco, M; Di Gennaro, E; Leone, A; Luciano, A; Arra, C; Santini, D; Caraglia, M; Budillon, A

    2013-01-01

    Patients with advanced prostate cancer (PCa) and multiple myeloma (MM) have limited long-term responses to available therapies. The histone deacetylase inhibitor panobinostat has shown significant preclinical and clinical anticancer activity in both hematological and solid malignancies and is currently in phase III trials for relapsed MM. Bisphosphonates (BPs), such as zoledronic acid (ZOL), inhibit osteoclast-mediated bone resorption and are indicated for the treatment of bone metastasis. BPs, including ZOL, have also shown anticancer activity in several preclinical and clinical studies. In the present report, we found a potent synergistic antiproliferative effect of panobinostat/ZOL treatment in three PCa and three MM cell lines as well as in a PCa ZOL-resistant subline, independently of p53/KRAS status, androgen dependency, or the schedule of administration. The synergistic effect was also observed in an anchorage-independent agar assay in both ZOL-sensitive and ZOL-resistant cells and was confirmed in vivo in a PCa xenograft model. The co-administration of the antioxidant N-acetyl-L-cysteine blocked the increased reactive oxygen species generation and apoptosis observed in the combination setting compared with control or single-agent treatments, suggesting that oxidative injury plays a functional role in the synergism. Proapoptotic synergy was also partially antagonized by the addition of geranyl-geraniol, which bypasses the inhibition of farnesylpyrophosphate synthase by ZOL in the mevalonate pathway, supporting the involvement of this pathway in the synergy. Finally, at the molecular level, the inhibition of basal and ZOL-induced activation of p38-MAPK by panobinostat in sensitive and ZOL-resistant cells and in tumor xenografts could explain, at least in part, the observed synergism. PMID:24157872

  14. Acquired resistance to zoledronic acid and the parallel acquisition of an aggressive phenotype are mediated by p38-MAP kinase activation in prostate cancer cells

    PubMed Central

    Milone, M R; Pucci, B; Bruzzese, F; Carbone, C; Piro, G; Costantini, S; Capone, F; Leone, A; Di Gennaro, E; Caraglia, M; Budillon, A

    2013-01-01

    The nitrogen-containing bisphosphonates (N-BP) zoledronic acid (ZOL) inhibits osteoclast-mediated bone resorption, and it is used to prevent skeletal complications from bone metastases. ZOL has also demonstrated anticancer activities in preclinical models and, recently, in cancer patients, highlighting the interest in determining eventual mechanisms of resistance against this agent. In our study, we selected and characterised a resistant subline of prostate cancer (PCa) cells to better understand the mechanisms, by which tumour cells can escape the antitumour effect of ZOL. DU145R80-resistant cells were selected in about 5 months using stepwise increasing concentrations of ZOL from DU145 parental cells. DU145R80 cells showed a resistance index value of 5.5 and cross-resistance to another N-BP, pamidronate, but not to the non-nitrogen containing BP clodronate. Notably, compared with DU145 parental cells, DU145R80 developed resistance to apoptosis and anoikis, as well as overexpressed the anti-apoptotic protein Bcl-2 and oncoprotein c-Myc. Moreover, DU145R80 cells underwent epithelial to mesenchymal transition (EMT) and showed increased expression of the metalloproteases MMP-2/9, as well as increased invading capability. Interestingly, compared with DU145, DU145R80 cells also increased the gene expression and protein secretion of VEGF and the cytokines Eotaxin-1 and IL-12. At the molecular level, DU145R80 cells showed strong activation of the p38-MAPK-dependent survival pathway compared with parental sensitive cells. Moreover, using the p38-inhibitor SB203580, we completely reversed the resistance to ZOL, as well as EMT marker expression and invasion. Furthermore, SB203580 treatment reduced the expression of VEGF, Eotaxin-1, IL-12, MMP-9, Bcl-2 and c-Myc. Thus, for the first time, we demonstrate that the p38-MAPK pathway can be activated under continuous extensive exposure to ZOL in PCa cells and that the p38-MAPK pathway has a critical role in the induction of

  15. 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. PMID:27168397

  16. Zoledronate Inhibits Ischemia-Induced Neovascularization by Impairing the Mobilization and Function of Endothelial Progenitor Cells

    PubMed Central

    Tsai, Shih-Hung; Huang, Po-Hsun; Chang, Wei-Chou; Tsai, Hsiao-Ya; Lin, Chih-Pei; Leu, Hsin-Bang; Wu, Tao-Cheng; Chen, Jaw-Wen; Lin, Shing-Jong

    2012-01-01

    Background Bisphosphonates are a class of pharmacologic compounds that are commonly used to treat postmenopausal osteoporosis and malignant osteolytic processes. Studies have shown that bone marrow-derived endothelial progenitor cells (EPCs) play a significant role in postnatal neovascularization. Whether the nitrogen-containing bisphosphonate zoledronate inhibits ischemia-induced neovascularization by modulating EPC functions remains unclear. Methodology/Principal Findings Unilateral hindlimb ischemia was surgically induced in wild-type mice after 2 weeks of treatment with vehicle or zoledronate (low-dose: 30 μg/kg; high-dose: 100 μg/kg). Doppler perfusion imaging demonstrated that the ischemic limb/normal side blood perfusion ratio was significantly lower in wild-type mice treated with low-dose zoledronate and in mice treated with high-dose zoledronate than in controls 4 weeks after ischemic surgery (control vs. low-dose vs. high-dose: 87±7% vs. *61±18% vs. **49±17%, *p<0.01, **p<0.005 compared to control). Capillary densities were also significantly lower in mice treated with low-dose zoledronate and in mice treated with high-dose zoledronate than in control mice. Flow cytometry analysis showed impaired mobilization of EPC-like cells (Sca-1+/Flk-1+) after surgical induction of ischemia in mice treated with zoledronate but normal levels of mobilization in mice treated with vehicle. In addition, ischemic tissue from mice that received zoledronate treatment exhibited significantly lower levels of the active form of MMP-9, lower levels of VEGF, and lower levels of phosphorylated eNOS and phosphorylated Akt than ischemic tissue from mice that received vehicle. Results of the in vitro studies showed that incubation with zoledronate inhibited the viability, migration, and tube-forming capacities of EPC. Conclusions/Significance Zoledronate inhibited ischemia-induced neovascularization by impairing EPC mobilization and angiogenic functions. These findings suggest

  17. 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. PMID:27332712

  18. 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

  19. Zoledronic Acid–Induced Interface Dermatitis

    PubMed Central

    Succaria, Farah; Collier, Mary

    2015-01-01

    Abstract: Zoledronic acid (ZA) is a bisphosphonate given intravenously, most commonly for the treatment of postmenopausal osteoporosis. Increase in usage of ZA because it was FDA-approved has resulted in increasing reports of side effects. For the most part, these are systemic. Cutaneous side effects associated with ZA are infrequent and limited to 2 reports of dermatomyositis to date. In both, patients presented with clinical and laboratory stigmata of dermatomyositis soon after initiation of therapy. In this report, we describe a 62-year-old woman who presented with diffuse, erythematous scaly plaques over the right thigh after 12 hours of infusion of ZA. Histopathologic examination of a skin biopsy from the right thigh revealed patchy scale crust containing neutrophils and inspissated serum, interface change with scattered individually necrotic keratinocytes, and a mild, superficial perivascular lymphocytic infiltrate with scattered eosinophils and pigment incontinence—findings consistent with an interface dermatitis. Given that the patient had no other systemic manifestations or laboratory abnormalities, to the best of our knowledge, ours is the first report of interface dermatitis secondary to ZA with the caveat that longer follow-up is required to definitively exclude the development of drug-induced connective tissue disease. PMID:26588338

  20. Sulfate Reduction in Freshwater Sediments Receiving Acid Mine Drainage

    PubMed Central

    Herlihy, Alan T.; Mills, Aaron L.

    1985-01-01

    One arm of Lake Anna, Va., receives acid mine drainage (AMD) from Contrary Creek (SO42− concentration = 2 to 20 mM, pH = 2.5 to 3.5). Acid-volatile sulfide concentrations, SO42− reduction rates, and interstitial SO42− concentrations were measured at various depths in the sediment at four stations in four seasons to assess the effects of the AMD-added SO42− on bacterial SO42− reduction. Acid-volatile sulfide concentrations were always an order of magnitude higher at the stations receiving AMD than at a control station in another arm of the lake that received no AMD. Summer SO42− reduction rates were also an order of magnitude higher at stations that received AMD than at the control station (226 versus 13.5 mmol m−2 day−1), but winter values were inconclusive, probably due to low sediment temperature (6°C). Profiles of interstitial SO42− concentrations at the AMD stations showed a rapid decrease with depth (from 1,270 to 6 μM in the top 6 cm) due to rapid SO42− reduction. Bottom-water SO42− concentrations in the AMD-receiving arm were highest in winter and lowest in summer. These data support the conclusion that there is a significant enhancement of SO42− reduction in sediments receiving high SO42− inputs from AMD. PMID:16346696

  1. Sulfate reduction in freshwater sediments receiving Acid mine drainage.

    PubMed

    Herlihy, A T; Mills, A L

    1985-01-01

    One arm of Lake Anna, Va., receives acid mine drainage (AMD) from Contrary Creek (SO(4) concentration = 2 to 20 mM, pH = 2.5 to 3.5). Acid-volatile sulfide concentrations, SO(4) reduction rates, and interstitial SO(4) concentrations were measured at various depths in the sediment at four stations in four seasons to assess the effects of the AMD-added SO(4) on bacterial SO(4) reduction. Acid-volatile sulfide concentrations were always an order of magnitude higher at the stations receiving AMD than at a control station in another arm of the lake that received no AMD. Summer SO(4) reduction rates were also an order of magnitude higher at stations that received AMD than at the control station (226 versus 13.5 mmol m day), but winter values were inconclusive, probably due to low sediment temperature (6 degrees C). Profiles of interstitial SO(4) concentrations at the AMD stations showed a rapid decrease with depth (from 1,270 to 6 muM in the top 6 cm) due to rapid SO(4) reduction. Bottom-water SO(4) concentrations in the AMD-receiving arm were highest in winter and lowest in summer. These data support the conclusion that there is a significant enhancement of SO(4) reduction in sediments receiving high SO(4) inputs from AMD. PMID:16346696

  2. 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 Central

    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

    2016-01-01

    BACKGROUND: 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. METHODS: 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. RESULTS: PATIENTS: 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

  3. HANDBOOK FOR CONSTRUCTED WETLANDS RECEIVING ACID MINE DRAINAGE

    EPA Science Inventory

    In the summer of 1987, a pilot constructed wetland was built at the Big Five Tunnel in Idaho Springs, Colorado. his report details the theory, design and construction of wetlands receiving acid mine drainages, based on the second and third year of operation of this wetland, which...

  4. HANDBOOK FOR CONSTRUCTED WETLANDS RECEIVING ACID MINE DRAINAGE

    EPA Science Inventory

    In the summer of 1987, a pilot constructed wetland was built at the Big Five Tunnel in Idaho Springs, Colorado. This report details the theory, design and construction of wetlands receiving acid mine drainages, based on the second and third year of operation of this wetland, whic...

  5. Sulfate reduction in freshwater sediments receiving acid mine drainage

    SciTech Connect

    Herlihy, A.T.; Mills, A.L.

    1985-01-01

    One arm of Lake Anna, Va., receives acid mine drainage (AMD) from Contrary Creek (SO/sub 4//sup 2 -/ concentration = 2 to 20 mM, pH = 2.5 to 3.5). Acid-volatile sulfide concentrations, SO/sub 4//sup 2 -/ reduction rates, and interstitial SO/sub 4//sup 2 -/ concentrations were measured at various depths in the sediment at four stations in four seasons to assess the effects of the AMD-added SO/sub 4//sup 2 -/ on bacterial SO/sub 4//sup 2 -/ reduction. Acid-volatile sulfide concentrations were always an order of magnitude higher at the stations receiving AMD than at a control station in another arm of the lake that received no AMD. Summer SO/sub 4//sup 2 -/ reduction rates were also an order of magnitude higher at stations that received AMD than at the control station (226 versus 13.5 mmol m/sup -2/ day/sup -1/), but winter values were inconclusive, probably due to low sediment temperature (6/sup 0/C). Profiles of interstitial SO/sub 4//sup 2 -/ concentrations at the AMD stations showed a rapid decrease with depth (from 1270 to 6 ..mu..M in the top 6 cm) due to rapid SO/sub 4//sup 2 -/ reduction. Bottom-water SO/sub 4//sup 2 -/ concentrations in the AMD-receiving arm were highest in winter and lowest in summer. These data support the conclusion that there is a significant enhancement of SO/sub 4//sup 2 -/ reduction in sediments receiving high SO/sub 4//sup 2 -/ inputs from AMD.

  6. Handbook for constructed wetlands receiving acid mine drainage

    SciTech Connect

    Wildeman, T.; Dietz, J.; Gusek, J.; Morea, S.

    1993-09-01

    In the summer of 1987, a pilot constructed wetland was built at the Big Five Tunnel in Idaho Springs, Colorado. The report details the theory, design and construction of wetlands receiving acid mine drainages, based on the second and third year of operation of this wetland, which was funded by the U.S. Environmental Protection Agency under the SITE Emerging Technologies Program. The text is divided into two broad sections: Part A - Theoretical Development, and Part B - Design Consideration. In the latter sections of Part A and through all of Part B the focus is on removal of metals by precipitation of sulfides through the activity of sulfate reducing bacteria.

  7. Receivers

    NASA Astrophysics Data System (ADS)

    Donnelly, H.

    1983-07-01

    Before discussing Deep Space Network receivers, a brief description of the functions of receivers and how they interface with other elements of the Network is presented. Different types of receivers are used in the Network for various purposes. The principal receiver type is used for telemetry and tracking. This receiver provides the capability, with other elements of the Network, to track the space probe utilizing Doppler and range measurements, and to receive telemetry, including both scientific data from the onboard experiments and engineering data pertaining to the health of the probe. Another type of receiver is used for radio science applications. This receiver measures phase perturbations on the carrier signal to obtain information on the composition of solar and planetary atmospheres and interplanetary space. A third type of receiver utilizes very long baseline interferometry (VLBI) techniques for both radio science and spacecraft navigation data. Only the telemetry receiver is described in detail in this document. The integration of the Receiver-Exciter subsystem with other portions of the Deep Space Network is described.

  8. Receivers

    NASA Technical Reports Server (NTRS)

    Donnelly, H.

    1983-01-01

    Before discussing Deep Space Network receivers, a brief description of the functions of receivers and how they interface with other elements of the Network is presented. Different types of receivers are used in the Network for various purposes. The principal receiver type is used for telemetry and tracking. This receiver provides the capability, with other elements of the Network, to track the space probe utilizing Doppler and range measurements, and to receive telemetry, including both scientific data from the onboard experiments and engineering data pertaining to the health of the probe. Another type of receiver is used for radio science applications. This receiver measures phase perturbations on the carrier signal to obtain information on the composition of solar and planetary atmospheres and interplanetary space. A third type of receiver utilizes very long baseline interferometry (VLBI) techniques for both radio science and spacecraft navigation data. Only the telemetry receiver is described in detail in this document. The integration of the Receiver-Exciter subsystem with other portions of the Deep Space Network is described.

  9. Sulfur dynamics in an impoundment receiving acid mine drainage

    SciTech Connect

    Herlihy, A.T.

    1987-01-01

    To quantify the importance of bacterial sulfate reduction (SR) in an acidified system, a sulfate influx-efflux budget was constructed for Lake Anna, an impoundment receiving acid mine drainage. Forty eight percent of the entering sulfate was removed from the water column within the 2 km arm of the lake that receives the pollution. Directly measured SR equaled 200% of the sulfate removal calculated in the budget. Thus, sulfide oxidation must be an important process in these sediments. The calculated alkalinity generated by sulfate removal was more than twice that necessary to account for the observed pH increase in the impoundment. Inorganic sulfur concentrations in the sediments of the impacted arm of Lake Anna were significantly greater than those in unpolluted sections of the lake. Label experiments showed that FeS and elemental sulfur (S{degree}) were the major products of SR in the impacted sediments. Inorganic sulfur (FeS, S{degree}, and pyrite) made up to 60% to 100% of the total sediment sulfur concentration. Pyrite concentrations were high and decreased exponentially with distance from the AMD source, indicating that the pyrite is stream detrius. FeS and S{degree} concentrations were highest at a station 1 km away from the AMD inflow, indicating in situ formation. There was no evidence for the formation of organic sulfur species.

  10. 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

  11. 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. PMID:25074494

  12. 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

  13. Controlled Delivery of Zoledronate Improved Bone Formation Locally In Vivo

    PubMed Central

    Peng, Jiang; Lu, Qiang; Wang, Yu; Wang, Aiyuan; Guo, Quanyi; Gao, Xupeng; Xu, Wenjing; Lu, Shibi

    2014-01-01

    Bisphosphonates (BPs) have been widely used in clinical treatment of bone diseases with increased bone resorption because of their strong affinity for bone and their inhibition of bone resorption. Recently, there has been growing interest in their improvement of bone formation. However, the effect of local controlled delivery of BPs is unclear. We used polylactide acid-glycolic acid copolymer (PLGA) as a drug carrier to deliver various doses of the bisphosphonate zoledronate (Zol) into the distal femur of 8-week-old Sprague-Dawley rats. After 6 weeks, samples were harvested and analyzed by micro-CT and histology. The average bone mineral density and mineralized bone volume fraction were higher with medium- and high-dose PLGA-Zol (30 and 300 µg Zol, respectively) than control and low-dose Zol (3 µg PLGA-Zol; p<0.05). Local controlled delivery of Zol decreased the numbers of osteoclast and increased the numbers of osteoblast. Moreover, local controlled delivery of medium- and high-dose Zol accelerated the expression of bone-formation markers. PLGA used as a drug carrier for controlled delivery of Zol may promote local bone formation. PMID:24618585

  14. Acid neutralization within limestone sand reactors receiving coal mine drainage

    USGS Publications Warehouse

    Watten, B.J.; Sibrell, P.L.; Schwartz, M.F.

    2005-01-01

    Pulsed bed treatment of acid mine drainage (AMD) uses CO2 to accelerate limestone dissolution and intermittent fluidization to abrade and carry away metal hydrolysis products. Tests conducted with a prototype of 60 L/min capacity showed effective removal of H+ acidity over the range 196-584 mg/L (CaCO3) while concurrently generating surplus acid neutralization capacity. Effluent alkalinity (mg/L CaCO3) rose with increases in CO2 (DC, mg/L) according to the model Alkalinity = 31.22 + 2.97(DC)0.5, where DC was varied from 11-726 mg/L. Altering fluidization and contraction periods from 30 s/30 s to 10 s/50 s did not influence alkalinity but did increase energy dissipation and bed expansion ratios. Field trials with three AMD sources demonstrated the process is capable of raising AMD pH above that required for hydrolysis and precipitation of Fe3+ and Al3+ but not Fe2+ and Mn2+. Numerical modeling showed CO2 requirements are reduced as AMD acidity increases and when DC is recycled from system effluent. ?? 2005 Elsevier Ltd. All rights reserved.

  15. 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

  16. Evidence of improved serum fatty acid profile of postmenopausal women receiving atorvastatin and raloxifene.

    PubMed

    Piperi, C; Zisaki, K; Skenderi, K; Kalofoutis, C; Kalofoutis, A

    2005-07-01

    Raloxifene and atorvastatin have been shown to reduce the risk of cardiovascular disease associated with postmenopausal status and it has been postulated that their effects may be partly mediated by favourable changes in serum lipids and fatty acid composition. In the present study, individual administration of either raloxifene (Group A) or atorvastatin (Group B) or both (Group C) was compared for a period of 3 months and their effects on total lipids and fatty acids composition was evaluated. Postmenopausal women receiving both raloxifene and atorvastatin showed significant changes in the majority of serum lipids with important reductions in total cholesterol (p < 0.001), triglycerides (p < 0.001), LDL-C (p < 0.001) and Apo B levels (p < 0.001). Phospholipids concentrations (p < 0.01) as well as Apo A-I were also significantly raised (p < 0.001). Furthermore, oleic acid (18:1) and linoleic acid (18:2) levels were significantly increased (p < 0.01 and p < 0.001 respectively) followed by a marked reduction in palmitic acid (16:0) and arachidonic acid (20:4) concentrations (p < 0.01 and p < 0.001 respectively). The results of the study indicate that the serum lipid and fatty acid composition in postmenopausal women is influenced by the combined treatment of raloxifene and atorvastatin and a further attempt to evaluate the significance of these results is discussed. PMID:16183584

  17. Assessment of the microbial community in a constructed wetland that receives acid coal mine drainage

    SciTech Connect

    Nicomrat, D.; Dick, W.A.; Tuovinen, O.H.

    2006-01-15

    Constructed wetlands are used to treat acid drainage from surface or underground coal mines. However, little is known about the microbial communities in the receiving wetland cells. The purpose of this work was to characterize the microbial population present in a wetland that was receiving acid coal mine drainage (AMD). Samples were collected from the oxic sediment zone of a constructed wetland cell in southeastern Ohio that was treating acid drainage from an underground coal mine seep. Samples comprised Fe(Ill) precipitates and were pretreated with ammonium oxalate to remove interfering iron, and the DNA was extracted and purified by agarose gel electrophoresis prior to amplification of portions of the 16S rRNA gene. Amplified products were separated by denaturing gradient gel electrophoresis and DNA from seven distinct bands was excised from the gel and sequenced. The sequences were matched to sequences in the GenBank bacterial 16S rDNA database. The DNA in two of the bands yielded matches with Acidithiobacillus ferrooxidans and the DNA in each of the remaining five bands was consistent with one of the following microorganisms: Acidithiobacillus thiooxidans, strain TRA3-20 (a eubacterium), strain BEN-4 (an arsenite-oxidizing bacterium), an Alcaligenes sp., and a Bordetella sp. Low bacterial diversity in these samples reflects the highly inorganic nature of the oxic sediment layer where high abundance of iron- and sulfur-oxidizing bacteria would be expected. The results we obtained by molecular methods supported our findings, obtained using culture methods, that the dominant microbial species in an acid receiving, oxic wetland are A. thiooxidans and A. ferrooxidans.

  18. Pharmacokinetic and therapeutic efficacy of intrapulmonary administration of zoledronate for the prevention of bone destruction in rheumatoid arthritis.

    PubMed

    Katsumi, Hidemasa; Mozume, Takunori; Yanagi, Shin-Ichiro; Hasei, Tomohiro; Watanabe, Tetsushi; Sakane, Toshiyasu; Yamamoto, Akira

    2016-07-01

    Zoledronate, a third-generation nitrogen-containing bisphosphonate, is a new therapeutic agent for the prevention of joint destruction in rheumatoid arthritis (RA). Due to the poor oral absorption of zoledronate, the intravenous route has been the preferred method of administration. To evaluate whether the lung is a promising alternative route of zoledronate administration for the prevention of joint destruction in RA, we examined the pharmacokinetics, safety and therapeutic potential of zoledronate after intrapulmonary administration. The bioavailability of zoledronate was 55% after intrapulmonary administration in rats. In a collagen-induced RA mouse model, an intrapulmonary administration of zoledronate given 7 d before the 2nd collagen immunization effectively suppressed bone loss and joint destruction to a level similar to that achieved with intravenous injection at 21 d after the 2nd collagen immunization. Zoledronate only slightly affected lactate dehydrogenase activity in bronchoalveolar lavage fluid 4 h after intrapulmonary administration of the therapeutic dose in rats. Moreover, zoledronate only slightly changed the plasma level of creatinine after intrapulmonary administration while creatinine significantly increased after intravenous injection of zoledronate in mice. These results indicate that the lung is a promising alternative route of zoledronate administration for the treatment and prevention of joint destruction in RA. PMID:26508267

  19. Zoledronic Acid in Aromatase Inhibitor Induced Musculoskeletal Symptoms

    ClinicalTrials.gov

    2014-05-12

    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

  20. Zoledronate upregulates MMP-9 and -13 in rat vascular smooth muscle cells by inducing oxidative stress

    PubMed Central

    Arun, Mehmet Zuhuri; Reel, Buket; Sala-Newby, Graciela B; Bond, Mark; Tsaousi, Aikaterini; Maskell, Perry; Newby, Andrew C

    2016-01-01

    Background Bisphosphonates, including zoledronate, target osteoclasts and are widely used in the treatment of osteoporosis and other bone resorption diseases, despite side effects that include damaging the stomach epithelium. Beneficial and adverse effects on other organ systems, including the cardiovascular system, have also been described and could impact on the use of bisphosphonates as therapeutic agents. Vascular smooth muscle cells (VSMCs) are major constituents of the normal vascular wall and have a key role in intimal thickening and atherosclerosis, in part by secreting MMPs that remodel the extracellular matrix and cleave cell surface proteins or secreted mediators. In this study, we investigated the effects of zoledronate on MMP expression. Methods Rat VSMCs were stimulated by PDGF (50 ng/mL) plus TNF-α (10 ng/mL) or left unstimulated for a further 24 hours in serum-free medium. In other series of experiments, cells were pre-treated either with SC-514 (50 μM) or with apocynin (20 nM) for 2 hours, then zoledronate (100 μM) was added into 2% fetal calf serum containing medium for 24 hours. Results and discussion Using isolated rat VSMCs in culture, zoledronate (100 μM) increased MMP-9 and -13 mRNA expressions but inhibited MMP-2 expression. MMP-9 and MMP-13 up-regulation was shown to depend on the NF-κB pathway; and this was activated by zoledronate. Furthermore, zoledronate elevated the levels of reactive oxygen species detected by either dichlorofluorescein in isolated VSMCs or lucigenin enhanced chemiluminescence in rat aortic rings in vitro. Apocynin, an inhibitor of NADPH oxidase, reversed NF-κB activation and MMP-9 and MMP-13 up-regulation by zoledronate. Conclusion We conclude that zoledronate increases MMP-9 and MMP-13 expressions in rat VSMCs dependent upon stimulation of the NF-κB pathway by reactive oxygen species. Effects on MMP expression may contribute to the pharmacologic profile of bisphosphonates. PMID:27143852

  1. Enhancing the natural removal of As in a reactive fluvial confluence receiving acid drainage

    NASA Astrophysics Data System (ADS)

    Abarca, M. I.; Arce, G.; Montecinos, M.; Guerra, P. A.; Pasten, P.

    2014-12-01

    Fluvial confluences are natural reactors that can determine the fate of contaminants in watersheds receiving acid drainage. Hydrological, hydrodynamic and chemical factors determine distinct conditions for the formation of suspended particles of iron and aluminum oxyhydroxides. The chemical and physical properties of these particle assemblages (e.g. particle size, chemical composition) can vary according to inflow mixing ratios, hydrodynamic velocity profiles, and chemical composition of the flows mixing at the confluence. Due to their capacity to sorb metals, it is important to identify the optimal conditions for removing metals from the aqueous phase, particularly arsenic, a contaminant frequently found in acid drainage. We studied a river confluence in the Lluta watershed, located in the arid Chilean Altiplano. We performed field measurements and laboratory studies to find optimal mixing ratio for arsenic sorption onto oxyhydroxide particles at the confluence between the Azufre (pH=2, As=2 mg/L) and the Caracarani river (pH=8, As<0.1 mg/L). As the contribution of the acidic stream increased, the concentration of Fe and Al in the solid phase reached a peak at different pHs. Although the optimal pH for As sorption was ~3, the overall maximum removal of As at the confluence, ocurred for pH~4. This is produced because optimal As sorption does not occur necessarily for the highest concentrations of particles being formed. We propose that fluvial confluences could be engineered to enhance the natural attenuation of contaminants. An analogy between confluences and coagulation-flocculation-sedimentation drinking water plants could be used to engineer such intervention.Acknowledgements: Proyecto Fondecyt 1130936 and Proyecto CONICYT FONDAP 15110020

  2. Population Pharmacokinetics and Dose Optimization of Mycophenolic Acid in HCT Recipients Receiving Oral Mycophenolate Mofetil

    PubMed Central

    Li, H; Mager, D E; Sandmaier, B M; Maloney, D G; Bemer, M J; McCune, J S

    2012-01-01

    We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. 4,496 MPA concentration-time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two-compartment model with first-order elimination and a time-lagged first-order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance and volume of the central compartment were 24.2 L/hr and 36.4 L, respectively, for a 70 kg patient receiving tacrolimus with a serum albumin of 3.4 g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA clearance by 33.8%. The optimal LSS was immediately before and at 0.25, 1.25, 2, and 4hr after oral MMF administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five-sample LSS and maximum a posteriori Bayesian estimation. PMID:23382105

  3. Population pharmacokinetics and dose optimization of mycophenolic acid in HCT recipients receiving oral mycophenolate mofetil.

    PubMed

    Li, H; Mager, D E; Sandmaier, B M; Maloney, D G; Bemer, M J; McCune, J S

    2013-04-01

    We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. Four thousand four hundred ninety-six MPA concentration-time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two-compartment model with first-order elimination and a time-lagged first-order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance (CL) and volume of the central compartment were 24.2 L/hour and 36.4 L, respectively, for a 70 kg patient receiving tacrolimus with a serum albumin of 3.4 g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA CL by 33.8%. The optimal LSS was immediately before and at 0.25 hours, 1.25 hours, 2 hours, and 4 hours after oral mycophenolate mofetil administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five-sample LSS and maximum a posteriori Bayesian estimation. PMID:23382105

  4. 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. PMID:26177742

  5. Intraperitoneal injection of in vitro expanded Vγ9Vδ2 T cells together with zoledronate for the treatment of malignant ascites due to gastric cancer

    PubMed Central

    Wada, Ikuo; Matsushita, Hirokazu; Noji, Shuichi; Mori, Kazuhiko; Yamashita, Hiroharu; Nomura, Sachiyo; Shimizu, Nobuyuki; Seto, Yasuyuki; Kakimi, Kazuhiro

    2014-01-01

    Malignant ascites caused by peritoneal dissemination of gastric cancer is chemotherapy-resistant and associated with poor prognosis. We conducted a pilot study to evaluate the safety of weekly intraperitoneal injections of in vitro expanded Vγ9Vδ2 T cells together with zoledronate for the treatment of such malignant ascites. Patient peripheral blood mononuclear cells were stimulated with zoledronate (5 μmol/L) and interleukin-2 (1000 IU/mL). After 14 days culture, Vγ9Vδ2 T-cells were harvested and administered intraperitoneally in four weekly infusions. The day before T-cell injection, patients received zoledronate (1 mg) to sensitize their tumor cells to Vγ9Vδ2 T-cell recognition. Seven patients were enrolled in this study. The number of Vγ9Vδ2 T-cells in each injection ranged from 0.6 to 69.8 × 108 (median 59.0 × 108). There were no severe adverse events related to the therapy. Intraperitoneal injection of Vγ9Vδ2 T cells allows them access to the tumor cells in the peritoneal cavity. The number of tumor cells in the ascites was significantly reduced even after the first round of therapy and remained substantially lower over the course of treatment. IFN-γ was detected in the ascites on treatment. Computed tomography revealed a significant reduction in volume of ascites in two of seven patients. Thus, injection of these antitumor Vγ9Vδ2 T-cells can result in local control of malignant ascites in patients for whom no standard therapy apart from paracentesis is available. Adoptively transferred Vγ9Vδ2 T-cells do indeed recognize tumor cells and exert antitumor effector activity in vivo, when they access to the tumor cells. PMID:24515916

  6. Strontium and zoledronate hydroxyapatites graded composite coatings for bone prostheses.

    PubMed

    Boanini, Elisa; Torricelli, Paola; Sima, Felix; Axente, Emanuel; Fini, Milena; Mihailescu, Ion N; Bigi, Adriana

    2015-06-15

    Both strontium and zoledronate (ZOL) are known to be useful for the treatment of bone diseases associated to the loss of bone substance. In this work, we applied an innovative technique, Combinatorial Matrix-Assisted Pulsed Laser Evaporation (C-MAPLE), to deposit gradient thin films with variable compositions of Sr-substituted hydroxyapatite (SrHA) and ZOL modified hydroxyapatite (ZOLHA) on Titanium substrates. Compositional gradients were obtained by simultaneous laser vaporization of the two distinct material targets. The coatings display good crystallinity and granular morphology, which do not vary with composition. Osteoblast-like MG63 cells and human osteoclasts were co-cultured on the thin films up to 21 days. The results show that Sr counteracts the negative effect of relatively high concentration of ZOL on osteoblast viability, whereas both Sr and ZOL enhance extracellular matrix deposition. In particular, ZOL promotes type I collagen production, whereas Sr increases the production of alkaline phosphatase. Moreover, ZOL exerts a greater effect than Sr on osteoprotegerin/RANKL ratio and, as a consequence, on the reduction of osteoclast proliferation and activity. The deposition method allows to modulate the composition of the thin films and hence the promotion of bone growth and the inhibition of bone resorption. PMID:25706198

  7. Vitamin D status and parathyroid hormone concentrations influence the skeletal response to zoledronate and denosumab.

    PubMed

    Mosali, P; Bernard, L; Wajed, J; Mohamed, Z; Ewang, M; Moore, A; Fogelman, I; Hampson, G

    2014-05-01

    Studies suggest that optimal vitamin D status is required for the maximal effect of antiresorptive agents. We investigated the relationship between vitamin D status, serum parathyroid hormone (PTH) concentrations, and change in bone mineral density (BMD) following iv zoledronate and denosumab. We carried out a retrospective analysis of 111 patients, mean age 70 (SD 13) years, 89 women and 22 men, prescribed zoledronate and 43 postmenopausal women treated with denosumab for osteoporosis. We measured BMD at the lumbar spine (LS) and total hip (TH), serum 25 (OH) vitamin D, PTH, and bone turnover markers (plasma CTX, P1NP) at 1 year. In patients on zoledronate, BMD increased at the LS and TH (mean LS change [SEM] = 2.6 % [0.5 %], mean TH change = 1.05 % [0.5 %], p < 0.05). A significant increase in BMD was seen at the LS only in the denosumab group (p = 0.001). Significant decreases in CTX and P1NP were observed at 12 months in both treatment groups. At baseline and at 12 months, 34 % and 23 % of the patients on zoledronate had a serum vitamin D of <50 nmol/L, respectively. The mean PTH concentration in patients with 25 (OH) vitamin D <50 nmol/L was 44 ng/L (SEM 16.6). Patients with PTH concentration <44 ng/L had significantly higher increases in TH BMD compared to those with PTH >44 ng/L (zoledronate 1.9 [0.83] vs. -0.43 [0.81], p = 0.04; denosumab 4.1 [0.054] vs. -1.7 [0.04], p = 0.004). Optimal vitamin D status and PTH concentrations improve the skeletal response to zoledronate and denosumab. PMID:24509506

  8. 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

  9. A Model for Osteonecrosis of the Jaw with Zoledronate Treatment following Repeated Major Trauma

    PubMed Central

    Howie, R. Nicole; Borke, James L.; Kurago, Zoya; Daoudi, Asma; Cray, James; Zakhary, Ibrahim E.; Brown, Tara L.; Raley, J. Nathan; Tran, Loan T.; Messer, Regina; Medani, Fardous; Elsalanty, Mohammed E.

    2015-01-01

    This study aims to develop a reproducible rat model for post-traumatic bisphosphonate-related osteonecrosis of the jaw (BRONJ). In our previous studies using dental extraction as an inducing factor, only 30% - 60% of zoledronate-treated animals fulfilled the definition of clinical BRONJ. We modified the zoledronate regimen and introduced repeated surgical extraction to illicit quantifiable BRONJ in all animals. Eighty retired-breeder female Sprague-Dawley rats were divided between the treatment (IV zoledronate; 80 μg/kg/week for 13 weeks) and control (saline) groups. On week 13, the left mandibular first molar was surgically extracted, followed by the second molar a week later. Animals were euthanized at 1-week, 2-weeks, and 8-weeks following extraction. The occurrence and severity of BRONJ were scored in each animal based on gross and MicroCT analysis. Parameters of bone formation and osteoclast functions at the extraction site were compared between groups. All zoledronate-treated animals developed a severe case of BRONJ that fulfilled the clinical definition of the condition in humans. Osteoclast attachment continued to be defective eight weeks after stopping the treatment. There were no signs of kidney or liver toxicity. Our data confirmed that repeated surgical extraction (major trauma) by itself consistently precipitated massive bone necrosis in ZA-treated animals, eliminating the need to induce pre-existing infection or comorbidity. These results will be the basis for further studies examining the in-vivo pathogenesis and prevention of BRONJ. PMID:26186665

  10. Macrophage Depletion by Free Bisphosphonates and Zoledronate-Loaded Red Blood Cells

    PubMed Central

    Sabatino, Raffaella; Antonelli, Antonella; Battistelli, Serafina; Schwendener, Reto; Magnani, Mauro; Rossi, Luigia

    2014-01-01

    Bisphosphonates, besides being important drugs for the treatment of various bone diseases, could also be used to induce apoptosis in macrophage-like and cancer cells. However, their activity in vivo is limited by a short plasma half-life and rapid uptake within bone. Therefore, several delivery systems have been proposed to modify their pharmacokinetic profile and biodistribution. Among these, red blood cells (RBCs) represent one of the most promising biological carriers. The aim of this study was to select the best performing compound among Clodronate, Pamidronate, Ibandronate and Zoledronate in killing macrophages and to investigate RBCs as innovative carrier system to selectively target bisphosphonates to macrophages. To this end, the encapsulation of the selected bisphosphonates in autologous RBCs as well as the effect on macrophages, both in vitro and in vivo were studied. This work shows that, among the tested bisphosphonates, Zoledronate has proven to be the most active molecule. Human and murine RBCs have been successfully loaded with Zoledronate by a procedure of hypotonic dialysis and isotonic resealing, obtaining a dose-dependent drug entrapment with a maximal loading of 7.96±2.03, 6.95±3.9 and 7.0±1.89 µmoles of Zoledronate/ml of packed RBCs for human, Swiss and Balb/C murine RBCs, respectively. Engineered RBCs were able to detach human and murine macrophages in vitro, leading to a detachment of 66±8%, 67±8% and 60.5±3.5% for human, Swiss and Balb/C RBCs, respectively. The in vivo efficacy of loaded RBCs was tested in Balb/C mice administering 59 µg/mouse of RBC-encapsulated Zoledronate. By a single administration, depletion of 29.0±16.38% hepatic macrophages and of 67.84±5.48% spleen macrophages was obtained, confirming the ability of encapsulated Zoledronate to deplete macrophages in vivo. In conclusion, RBCs loaded with Zoledronate should be considered a suitable system for targeted delivery to macrophages, both in vitro and in vivo. PMID

  11. Preclinical Evaluation of Zoledronate to Maintain Bone Allograft and Improve Implant Fixation in Revision Joint Replacement

    PubMed Central

    Sørensen, Mette; Barckman, Jeppe; Bechtold, Joan E.; Søballe, Kjeld; Baas, Jørgen

    2013-01-01

    Background: Revision arthroplasty surgery is often complicated by loss of bone stock that can be managed by the use of bone allograft. The allograft provides immediate stability for the revision implant but may be resorbed, impairing subsequent implant stability. Bisphosphonates can delay allograft resorption. We hypothesized that zoledronate-impregnated allograft impacted around revision implants would improve implant fixation as characterized by mechanical push-out testing and histomorphometry. Methods: Twenty-four axially pistoning micromotion devices were inserted bilaterally into the knees of twelve dogs according to our revision protocol. This produced a standardized revision cavity with a loose implant, fibrous tissue, and a sclerotic bone rim. Revision surgery was performed eight weeks later; after stable titanium revision components were implanted, saline solution-soaked allograft was impacted around the component on the control side and allograft soaked in 0.005 mg/mL zoledronate was impacted on the intervention side. The results were evaluated after four weeks. Results: The zoledronate treatment resulted in a 30% increase in ultimate shear strength (p = 0.023), a 54% increase in apparent shear stiffness (p = 0.002), and a 12% increase in total energy absorption (p = 0.444). The quantity of allograft in the gap was three times greater in the zoledronate group compared with the control group (p < 0.001). The volume fraction of new bone in the zoledronate group (25%; 95% confidence interval [CI], 22% to 28%) was similar to that in the control group (23%; 95% CI, 19% to 26%) (p = 0.311). Conclusions: The data obtained in this canine model suggest that pretreating allograft with zoledronate may be beneficial for early stability of grafted revision arthroplasty implants, without any adverse effect on bone formation. Clinical studies are warranted. Clinical Relevance: The zoledronate treatment is simple to apply in the clinical setting. The treatment could

  12. Modification of Docosahexaenoic Acid Composition of Milk from Nursing Women Who Received Alpha Linolenic Acid from Chia Oil during Gestation and Nursing

    PubMed Central

    Valenzuela, Rodrigo; Bascuñán, Karla A.; Chamorro, Rodrigo; Barrera, Cynthia; Sandoval, Jorge; Puigrredon, Claudia; Parraguez, Gloria; Orellana, Paula; Gonzalez, Valeria; Valenzuela, Alfonso

    2015-01-01

    α-Linolenic acid (ALA) is the precursor of docosahexaenoic acid (DHA) in humans, which is fundamental for brain and visual function. Western diet provides low ALA and DHA, which is reflected in low DHA in maternal milk. Chia oil extracted from chia (Salvia hispanica L.), a plant native to some Latin American countries, is high in ALA (up to 60%) and thereby is an alternative to provide ALA with the aim to reduce DHA deficits. We evaluated the modification of the fatty acid profile of milk obtained from Chilean mothers who received chia oil during gestation and nursing. Forty healthy pregnant women (22–35 years old) tabulated for food consumption, were randomly separated into two groups: a control group with normal feeding (n = 21) and a chia group (n = 19), which received 16 mL chia oil daily from the third trimester of pregnancy until the first six months of nursing. The fatty acid profile of erythrocyte phospholipids, measured at six months of pregnancy, at time of delivery and at six months of nursing, and the fatty acid profile of the milk collected during the first six months of nursing were assessed by gas-chromatography. The chia group, compared to the control group, showed (i) a significant increase in ALA ingestion and a significant reduction of linoleic acid (LA) ingestion, no showing modification of arachidonic acid (AA), eicosapentaenoic acid (EPA) and DHA; (ii) a significant increase of erythrocyte ALA and EPA and a reduction of LA. AA and DHA were not modified; (iii) a increased milk content of ALA during the six months of nursing, whereas LA showed a decrease. AA and EPA were not modified, however DHA increased only during the first three months of nursing. Consumption of chia oil during the last trimester of pregnancy and the first three months of nursing transiently increases the milk content of DHA. PMID:26247968

  13. Effect of acidity and elevated PCO2 on acid. Neutralization within pulsed limestone bed reactors receiving coal mine drainage

    USGS Publications Warehouse

    Watten, B.J.; Sibrell, P.L.; Schwartz, M.F.

    2004-01-01

    Limestone has potential for reducing reagent costs and sludge volume associated with the treatment of acid mine drainage (AMD), but its use has been restricted by slow dissolution rates and sensitivity to scale forming reactions that retard transport of H+ at the solid-liquid interface. We evaluated a pulsed limestone bed (PLB) remediation process designed to circumvent these problems through use of intermittently fluidized beds of granular limestone and elevated carbon dioxide pressure. PLB limestone dissolution (LD, mg/L), and effluent alkalinity (Alk, mg/L) were correlated with reactor pressure (PCO2, kPa), influent acidity (Acy, mg/L) and reactor bed height (H, cm) using a prototype capable of processing 10 L/min. The PLB process effectively neutralized sulfuric acid acidity over the range of 6-1033 mg/L (as CaCO3) while generating high concentrations of alkalinity (36-1086 mg/L) despite a hydraulic residence time of just 4.2-5.0 min. Alk and LD (mg/L CaCO3) rose with increases in influent acidity and PCO2 (p < 0.001) according to the models: Alk = 58 + 38.4 (PCO2)0.5 + 0.080 (Acy) - 0.0059(PCO2) 0.5 (Acy); LD = 55 + 38.3 (PCO2)0.5 + 1.08 (Acy) - 0.0059 (PCO2)0.5 (Acy). Alkalinity decreased at an increasing rate with reductions in H over the range of 27.3-77.5 cm (p < 0.001). Carbon dioxide requirements (Q(avg)CO2, L/min) increased with PCO2 (p < 0.001) following the model Q(avg)CO2 = 0.858 (PCO2)0.620, resulting in a greater degree of pH buffering (depression) within the reactors, a rise in limestone solubility and an increase in limestone dissolution related to carbonic acid attack. Corresponding elevated concentrations of effluent alkalinity allow for sidestream treatment with blending. Numerical modeling demonstrated that carbon dioxide requirements are reduced as influent acidity rises and when carbon dioxide is recovered from system effluent and recycled. Field trials demonstrated that the PLB process is capable of raising the pH of AMD above that

  14. The Importance of Sediment Sulfate Reduction to the Sulfate Budget of an Impoundment Receiving Acid Mine Drainage

    NASA Astrophysics Data System (ADS)

    Herlihy, Alan T.; Mills, Aaron L.; Hornberger, George M.; Bruckner, Amy E.

    1987-02-01

    Alkalinity generation by bacterial sulfate reduction (SR) has been shown to be an important neutralizing agent for acid mine drainage and acid precipitation in lakes and reservoirs. In order to quantify the importance of SR in an acidified system, a sulfate influx-efflux budget was constructed for Lake Anna, an impoundment in central Virginia that receives acid mine drainage. For the 1983 and 1984 water years, 48% (namely, 8.0 × 105 kg) of the sulfate entering the impoundment was removed from the water column within the first 2 km of the arm of the lake receiving the pollution. SR rates measured using 35S-labeled sulfate were extrapolated across the surface area of this arm of the lake; this calculated amount of sulfate removed was equal to 200% of the sulfate removed from the lake as calculated in the budget. The calculated alkalinity generated by this sulfate removal was more than twice that necessary to account for the observed pH increase in the impoundment. The magnitude of the sulfate removal and alkalinity generation demonstrates the quantitative importance of SR as an ecosystem level buffering mechanism.

  15. Using a mass balance to understand the geology and geochemistry of a reservoir receiving and discharging acid mine drainage

    SciTech Connect

    Turney, D.C.; Edwards, K.

    1996-11-01

    Howard-Williams Lake is a 14.5 acre reservoir located in an abandoned coal mine in Perry County, Ohio. With a pH of 3.0 and acidity values of 300--400 mg/L, the reservoir has no plants or fish currently surviving in the lake. Reclamation of spoil piles adjacent to the lake to the north in the late 1980s was not successful in reducing the acidity of the lake. Currently, papermill sludge is being used on the reclaimed area to the north to promote vegetation, but the reservoir has shown no signs of improving. The goal of this project is to transform the lake into a fishable and swimmable one. The reservoir is receiving about 175 gallons per minute of acid mine drainage, not including seepage into the lake, from eight different sources. Three of the sources account for about 165 gallons per minute of the surface water that enters the lake. These inflows have relatively low acidity readings, which range from 66 mg/L to 568 mg/L. The other five sources of acid mine drainage have much lower flowrates, but have acidity values as high as 3,000 mg/L. Samples of all of the surface inflows and the outflow of the lake were taken and sent to a laboratory and tested for the following parameters: total acidity as CaCO{sub 3}, total alkalinity as CaCO{sub 2}, specific conductivity, total suspended solids, sulfate, chloride calcium, magnesium, sodium, potassium, total iron, total manganese, aluminum, and hardness. During sampling of the surface inflows, volumetric flowrates were measured for each inflow. Once the flowrates and the concentrations of the various parameters were known, a mass balance could be constructed which would show how much of each parameter was entering the lake each day. These data were then used to gain an understanding of the geochemistry and geology of the site.

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

    PubMed

    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

  17. Leaching behavior of heavy metals and transformation of their speciation in polluted soil receiving simulated acid rain.

    PubMed

    Zheng, Shun-an; Zheng, Xiangqun; Chen, Chun

    2012-01-01

    Heavy metals that leach from contaminated soils under acid rain are of increasing concern. In this study, simulated acid rain (SAR) was pumped through columns of artificially contaminated purple soil. Column leaching tests and sequential extraction were conducted for the heavy metals Cu, Pb, Cd, and Zn to determine the extent of their leaching as well as to examine the transformation of their speciation in the artificially contaminated soil columns. Results showed that the maximum leachate concentrations of Cu, Pb, Cd, and Zn were less than those specified in the Chinese Quality Standards for Groundwater (Grade IV), thereby suggesting that the heavy metals that leached from the polluted purple soil receiving acid rain may not pose as risks to water quality. Most of the Pb and Cd leachate concentrations were below their detection limits. By contrast, higher Cu and Zn leachate concentrations were found because they were released by the soil in larger amounts as compared with those of Pb and Cd. The differences in the Cu and Zn leachate concentrations between the controls (SAR at pH 5.6) and the treatments (SAR at pH 3.0 and 4.5) were significant. Similar trends were observed in the total leached amounts of Cu and Zn. The proportions of Cu, Pb, Cd, and Zn in the EXC and OX fractions were generally increased after the leaching experiment at three pH levels, whereas those of the RES, OM, and CAR fractions were slightly decreased. Acid rain favors the leaching of heavy metals from the contaminated purple soil and makes the heavy metal fractions become more labile. Moreover, a pH decrease from 5.6 to 3.0 significantly enhanced such effects. PMID:23185399

  18. Leaching Behavior of Heavy Metals and Transformation of Their Speciation in Polluted Soil Receiving Simulated Acid Rain

    PubMed Central

    Zheng, Shun-an; Zheng, Xiangqun; Chen, Chun

    2012-01-01

    Heavy metals that leach from contaminated soils under acid rain are of increasing concern. In this study, simulated acid rain (SAR) was pumped through columns of artificially contaminated purple soil. Column leaching tests and sequential extraction were conducted for the heavy metals Cu, Pb, Cd, and Zn to determine the extent of their leaching as well as to examine the transformation of their speciation in the artificially contaminated soil columns. Results showed that the maximum leachate concentrations of Cu, Pb, Cd, and Zn were less than those specified in the Chinese Quality Standards for Groundwater (Grade IV), thereby suggesting that the heavy metals that leached from the polluted purple soil receiving acid rain may not pose as risks to water quality. Most of the Pb and Cd leachate concentrations were below their detection limits. By contrast, higher Cu and Zn leachate concentrations were found because they were released by the soil in larger amounts as compared with those of Pb and Cd. The differences in the Cu and Zn leachate concentrations between the controls (SAR at pH 5.6) and the treatments (SAR at pH 3.0 and 4.5) were significant. Similar trends were observed in the total leached amounts of Cu and Zn. The proportions of Cu, Pb, Cd, and Zn in the EXC and OX fractions were generally increased after the leaching experiment at three pH levels, whereas those of the RES, OM, and CAR fractions were slightly decreased. Acid rain favors the leaching of heavy metals from the contaminated purple soil and makes the heavy metal fractions become more labile. Moreover, a pH decrease from 5.6 to 3.0 significantly enhanced such effects. PMID:23185399

  19. Increase in the Bmax of gamma-aminobutyric acid-A recognition sites in brain regions of mice receiving diazepam.

    PubMed Central

    Ferrero, P; Guidotti, A; Costa, E

    1984-01-01

    gamma-Aminobutyric acid (GABA) receptors were characterized in vivo by studying ex vivo the binding of [3H]muscimol to cerebellum, cortex, hippocampus, and corpus striatum of mice receiving intravenous injections of tracer doses of high-specific-activity (approximately equal to 30 Ci/mmol) [3H]muscimol. This ligand binds with high affinity (apparent Kd, 2-3 X 10(-9) M) to a single population of binding sites (apparent Bmax, 250-180 fmol per 10 mg of protein). Pharmacological studies using drugs that selectively bind to GABAA or GABAB receptors suggest that [3H]muscimol specifically labels a GABAA recognition site. Moreover, diazepam (1.5 mumol/kg, i.p.) increases the Bmax but fails to change the affinity of [3H]muscimol binding to different brain areas. This diazepam-elicited increase in Bmax is blocked in mice receiving the diazepam antagonist Ro 15-1788 (ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a]-[1,4] benzodiazepine-3-carboxylate). Since the diazepam-induced increase of [3H]muscimol binding is paralleled by a significant potentiation of the inhibitory effect of muscimol on locomotor activity, it is proposed that the facilitatory action on GABAergic transmission elicited in vivo by diazepam is mediated by an increase in the Bmax of the binding sites of GABAA receptors. Images PMID:6326115

  20. Association of LEPR and ANKK1 Gene Polymorphisms with Weight Gain in Epilepsy Patients Receiving Valproic Acid

    PubMed Central

    Li, Hongliang; Wang, Xueding; Zhou, Yafang; Ni, Guanzhong; Su, Qibiao; Chen, Ziyi; Chen, Zhuojia; Li, Jiali; Chen, Xinmeng; Hou, Xiangyu; Xie, Wen; Xin, Shuang; Zhou, Liemin

    2015-01-01

    Background: Weight gain is the most frequent adverse effect of valproic acid (VPA) treatment, resulting in poor compliance and many endocrine disturbances. Similarities in the weight change of monozygotic twins receiving VPA strongly suggests that genetic factors are involved in this effect. However, few studies have been conducted to identify the relevant genetic polymorphisms. Additionally, the causal relationship between the VPA concentration and weight gain has been controversial. Thus, we investigated the effects of single nucleotide polymorphisms (SNPs) in several appetite stimulation and energy homeostasis genes and the steady state plasma concentrations (Css) of VPA on the occurrence of weight gain in patients. Methods: A total of 212 epilepsy patients receiving VPA were enrolled. Nineteen SNPs in 11 genes were detected using the Sequenom MassArray iPlex platform, and VPA Css was determined by high-performance liquid chromatography (HPLC). Results: After 6 months of treatment, 20.28% of patients were found to gain a significant amount of weight (weight gained ≥7%). Three SNPs in the leptin receptor (LEPR), ankyrin repeat kinase domain containing 1 (ANKK1), and α catalytic subunit of adenosine monophosphate-activated protein kinase (AMPK) showed significant associations with VPA-induced weight gain (p < 0.001, p = 0.017 and p = 0.020, respectively). After Bonferroni correction for multiple tests, the genotypic association of LEPR rs1137101, the allelic association of LEPR rs1137101, and ANKK1 rs1800497 with weight gain remained significant. However, the VPA Css in patents who gained weight were not significantly different from those who did not gain weight (p = 0.121). Conclusions: LEPR and ANKK1 genetic polymorphisms may have value in predicting VPA-induced weight gain. PMID:25740917

  1. Risk factors associated with postoperative seizures in patients undergoing cardiac surgery who received tranexamic acid: a case-control study.

    PubMed

    Montes, Felix R; Pardo, Daniel F; Carreño, Marisol; Arciniegas, Catalina; Dennis, Rodolfo J; Umaña, Juan P

    2012-01-01

    Antifibrinolytic agents are used during cardiac surgery to minimize bleeding and reduce exposure to blood products. Several reports suggest that tranexamic acid (TA) can induce seizure activity in the postoperative period. To examine factors associated with postoperative seizures in patients undergoing cardiac surgery who received TA. University-affiliated hospital. Case-control study. Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) between January 2008 and December 2009 were identified. During this time, all patients undergoing heart surgery with CPB received TA. Cases were defined as patients who developed seizures that required initiation of anticonvulsive therapy within 48 h of surgery. Exclusion criteria included subjects with preexisting epilepsy and patients in whom the convulsive episode was secondary to a new ischemic lesion on brain imaging. Controls who did not develop seizures were randomly selected from the initial cohort. From an initial cohort of 903 patients, we identified 32 patients with postoperative seizures. Four patients were excluded. Twenty-eight cases and 112 controls were analyzed. Cases were more likely to have a history of renal impairment and higher preoperative creatinine values compared with controls (1.39 ± 1.1 vs. 0.98 ± 0.02 mg/dL, P = 0.02). Significant differences in the intensive care unit, postoperative and total lengths of stay were observed. An association between high preoperative creatinine value and postoperative seizure was identified. TA may be associated with the development of postoperative seizures in patients with renal dysfunction. Doses of TA should be reduced or even avoided in this population. PMID:22234015

  2. Early tissue responses to zoledronate, locally delivered by bone screw, into a compromised cancellous bone site: a pilot study

    PubMed Central

    2014-01-01

    Background In fracture treatment, adequate fixation of implants is crucial to long-term clinical performance. Bisphosphonates (BP), potent inhibitors of osteoclastic bone resorption, are known to increase peri-implant bone mass and accelerate primary fixation. However, adverse effects are associated with systemic use of BPs. Thus, Zoledronic acid (ZOL) a potent BP was loaded on bone screws and evaluated in a local delivery model. Whilst mid- to long-term effects are already reported, early cellular events occurring at the implant/bone interface are not well described. The present study investigated early tissue responses to ZOL locally delivered, by bone screw, into a compromised cancellous bone site. Methods ZOL was immobilized on fibrinogen coated titanium screws. Using a bilateral approach, ZOL loaded test and non-loaded control screws were implanted into femoral condyle bone defects, created by an overdrilling technique. Histological analyses of the local tissue effects such as new bone formation and osteointegration were performed at days 1, 5 and 10. Results Histological evaluation of the five day ZOL group, demonstrated a higher osseous differentiation trend. At ten days an early influx of mesenchymal and osteoprogenitor cells was seen and a higher level of cellular proliferation and differentiation (p < 5%). In the ZOL group bone-to-screw contact and bone volume values within the defect tended to increase. Local drug release did not induce any adverse cellular effects. Conclusion This study indicates that local ZOL delivery into a compromised cancellous bone site actively supports peri-implant osteogenesis, positively affecting mesenchymal cells, at earlier time points than previously reported in the literature. PMID:24656151

  3. Combined effect of strontium and zoledronate on hydroxyapatite structure and bone cell responses.

    PubMed

    Boanini, Elisa; Torricelli, Paola; Gazzano, Massimo; Della Bella, Elena; Fini, Milena; Bigi, Adriana

    2014-07-01

    The influence of the simultaneous presence of the two inhibitors of bone degradation, strontium and zoledronate, on the direct synthesis of hydroxyapatite was explored in the range of Sr concentration up to 50 atom% at two different bisphosphonate concentrations (ZOL7 and ZOL14). The results of structural analysis indicated that HA can be obtained as a single crystalline phase up to a Sr concentration in solution of 20 and 10 atom% within the ZOL7 and ZOL14 series respectively. Both Sr substitution and ZOL incorporation affect the length of the coherently scattering crystalline domains and the dimensions of HA nanocrystals. At greater Sr content, XRD full profile fitting data indicate that zoledronate provokes the segregation of Sr in two crystalline apatitic phases, at different strontium content. Co-cultures of osteoblast-like MG63 cells and human osteoclast show that ZOL displays a greater inhibitory influence than Sr on osteoclast proliferation and activity. On the other hand, the results obtained on osteoblast surnatant and on gene expression indicate that Sr exerts a greater promotion on osteoblast proliferation and differentiation. The co-presence of Sr and ZOL has a combined effect on the differentiation markers, so that HA containing about 4 wt% ZOL and 4 Sr atom%, and even more HA containing about 4 wt% ZOL and 8 Sr atom%, result the best compromise for osteoblast promotion and osteoclast inhibition. PMID:24731709

  4. Osteonecrosis of the Jaw in Patients Receiving Bone-Targeted Therapies: An Overview--Part I.

    PubMed

    Turner, Bruce; Drudge-Coates, Lawrence; Ali, Sacha; Pati, Jhumur; Nargund, Vinod; Ali, Enamul; Cheng, Leo; Wells, Paula

    2016-01-01

    Urologic patients receiving bone-targeted therapies are at risk of developing osteonecrosis of the jaw (ONJ). ONJ has historically been associated with bisphosphonate therapy. More recently, RANK-Ligand inhibitors (denosumab) have also been used to reduce the risk of skeletal-related events in patients who have advanced cancers with bone metastases. More than 65% of men with metastatic prostate cancer and nearly 75% of women with metastatic breast cancer are affected by bone metastases. The literature has described ONJ associated with bisphosphonate therapy as bisphosphonate-related osteonecrosis of the jaw (BRONJ). However, with evidence also linking the use of RANK-Ligand inhibitors with osteonecrosis of the jaw, we advocate use of the term "anti-bone resorption therapy-related osteonecrosis of the jaw" (ABRT-ONJ). The term "medication-related osteonecrosis of the jaw" (MRONJ) is now becoming more widespread. There is not a universally accepted definition of ABRT-ONJ, which may have hindered recognition and reporting of the condition. In Part I of this article, a review of current knowledge around the etiology of ABRT-ONJ and incidence data are provided. In Part II, we provide an audit of ONJ in a nurse consultant-led bone support clinic. In the article, we refer to zoledronic acid because this is the bisphosphonate of choice for use in men with prostate cancer in the United Kingdom. PMID:27501591

  5. Effect of exercise on the content of lipids, cholesterol and on the composition of fatty acids in the adrenals of rats receiving rapeseed oil in diet.

    PubMed

    Kucharczyk, B; Ziemlański, S

    1981-01-01

    The effect of different levels of high-erucic acid rapeseed oil in diet and exposure to graded exercise on the contents of total lipids and total cholesterol, and the composition of fatty acids, in total lipids and cholesterol ester fractions in the adrenals of Wistar rats was investigated. Presence of erucic acid in the diet produced greater changes in the characteristic composition of fatty acids in the fraction of cholesterol esters than in the total lipids in the adrenals. The intensity of changes in the composition of fatty acids was greater with higher amounts of rapeseed oil in the diet and longer administration of the diet. Exercise decreased the changes in fatty acid composition in the fraction of cholesterol esters in rats receiving 50% of calories from rapeseed oil. In the group receiving 30% of calories from rapeseed oil the trained rats accumulated more rapidly cholesterol in the adrenals than the untrained rats. Exercise load had no effect on the total lipid level in the adrenals. PMID:7304197

  6. Applying low-intensity pulsed ultrasounds (LIPUS) to a zoledronate-associated atypical femoral shaft fracture without cessation of zoledronate therapy for 3 years follow up: a case report

    PubMed Central

    Arakawa, Shoutaro; Saito, Mitsuru; Kubota, Makoto; Suzuki, Hidehiko; Tsuchida, Shigeki; Hashimoto, Kurando; Marumo, Keishi

    2015-01-01

    Summary Reports are increasing regarding atypical femoral fractures (AFFs) caused by minor trauma in patients using bisphosphonates (BPs) for long periods. Patients with malignant skeletal metastases potentially are at greater risk for these AFFs, especially considering the high dose and the duration of treatment with BPs. We evaluated a case of atypical femoral shaft fracture treated with an intramedullary nail in a patient treated for five years with zoledronate who had breast cancer with metastases to bone. Although bone union was achieved without cessation of zoledronate therapy by applying low-intensity pulsed ultrasounds (LIPUS), the remodeling phase of the fracture healing process was delayed. For BPs-associated AFFs, LIPUS is an alternative to parathyroid hormone (PTH) analogs such as teriparatide that are contraindicated in patients with malignant skeletal metastases. LIPUS is an effective treatment for fracture healing and may avoid the necessity to discontinue BP therapy. PMID:26811711

  7. Supplemental branched-chain amino acids improve performance and immune response of newly-received feedlot calves

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Supplemental branched-chain AA (BCAA) improved N balance of steers during a simulated pathogen challenge. The objective of this study was to determine the effect of supplemental BCAA on growth and health of newly-received feedlot steers. Steers (n = 120; initial BW = 376 ± 5 kg) were blocked by BW a...

  8. Selected resin acids in effluent and receiving waters derived from a bleached and unbleached kraft pulp and paper mill

    USGS Publications Warehouse

    Quinn, B.P.; Booth, M.M.; Delfino, J.J.; Holm, S.E.; Gross, T.S.

    2003-01-01

    Water samples were collected on three dates at 24 sites influenced by effluent from Georgia-Pacific's Palatka Pulp and Paper Mill Operation, a bleached and unbleached kraft mill near Palatka, Florida, USA. The sampling sites were located within the mill retention ponds, Rice Creek, and the St. John's River. Samples were analyzed by gas chromatography-mass spectrometry for abietic, dehydroabietic, and isopimaric acids, all of which are potentially toxic by-products of pulp production. Isopimaric acid concentrations greater than 12 mg/L were measured at the mill's effluent outfall but were less than 20 ??g/L at the end of Rice Creek. This result indicates that the waters of Rice Creek provide dilution or conditions conducive for degradation or sorption of these compounds. Large differences in resin acid concentrations were observed between sampling events. In two sampling events, the maximum observed concentrations were less than 2 mg/L for each analyte. In a third sampling event, all of the compounds were detected at concentrations greater than 10 mg/L. Data from the three sample dates showed that resin acid concentrations were below 20 ??g/L before the confluence of Rice Creek and the St. John's River in all cases.

  9. CALUTRON RECEIVER

    DOEpatents

    Barnes, S.W.

    1959-06-16

    An improved receiver and receiver mount for calutrons are described. The receiver can be manipulated from outside the tank by a single control to position it with respect to the beam. A door can be operated exteriorly also to prevent undesired portions of the beam from entering the receiver. The receiver has an improved pocket which is more selective in the ions collected. (T.R.H.)

  10. Effect of α -Lipoic Acid on Oxidative Stress in End-Stage Renal Disease Patients Receiving Intravenous Iron.

    PubMed

    Showkat, Arif; Bastnagel, William R; Hudson, Joanna Q

    2014-01-01

    Oxidative stress is associated with increased risk of cardiovascular disease in end-stage renal disease (ESRD) patients. Intravenous (IV) iron has been shown to increase oxidative stress. The aim of the study was to evaluate changes in oxidative stress markers following administration of IV sodium ferric gluconate (SFG) to ESRD patients with and without administration of the antioxidant, α -lipoic acid. This is an open-label, crossover study. 125 mg of IV SFG was administered during control (C) and intervention (I) visits. During the I visit, 600 mg of α -lipoic acid was given orally prior to IV SFG. Blood samples were collected at defined time periods for F2-isoprostane (FIP), lipid hydroperoxide (LHP), malondialdehyde (MDA), and iron indices. We recruited ten African-American ESRD subjects: 50% male; mean age 45 ± 9 years; mean hemoglobin 13 ± 1 g/dL; ferritin 449 ± 145 ng/mL; transferrin saturation 27 ± 4%. There were no significant differences in iron indices between the two visits after IV SFG. MDA, FIP, and LHP increased significantly for both C and I visits with a greater increase in the I group. Administration of IV SFG results in an acute rise in oxidative stress in ESRD patients. In contrast to previous studies, administration of α -lipoic acid was associated with a greater increase in oxidative stress. PMID:24967245

  11. Effect of α-Lipoic Acid on Oxidative Stress in End-Stage Renal Disease Patients Receiving Intravenous Iron

    PubMed Central

    Showkat, Arif; Bastnagel, William R.; Hudson, Joanna Q.

    2014-01-01

    Oxidative stress is associated with increased risk of cardiovascular disease in end-stage renal disease (ESRD) patients. Intravenous (IV) iron has been shown to increase oxidative stress. The aim of the study was to evaluate changes in oxidative stress markers following administration of IV sodium ferric gluconate (SFG) to ESRD patients with and without administration of the antioxidant, α-lipoic acid. This is an open-label, crossover study. 125 mg of IV SFG was administered during control (C) and intervention (I) visits. During the I visit, 600 mg of α-lipoic acid was given orally prior to IV SFG. Blood samples were collected at defined time periods for F2-isoprostane (FIP), lipid hydroperoxide (LHP), malondialdehyde (MDA), and iron indices. We recruited ten African-American ESRD subjects: 50% male; mean age 45 ± 9 years; mean hemoglobin 13 ± 1 g/dL; ferritin 449 ± 145 ng/mL; transferrin saturation 27 ± 4%. There were no significant differences in iron indices between the two visits after IV SFG. MDA, FIP, and LHP increased significantly for both C and I visits with a greater increase in the I group. Administration of IV SFG results in an acute rise in oxidative stress in ESRD patients. In contrast to previous studies, administration of α-lipoic acid was associated with a greater increase in oxidative stress. PMID:24967245

  12. Acidic pharmaceuticals in domestic wastewater and receiving water from hyper-urbanization city of China (Shanghai): environmental release and ecological risk.

    PubMed

    Duan, Yan-Ping; Meng, Xiang-Zhou; Wen, Zhi-Hao; Chen, Ling

    2013-01-01

    The occurrence, behavior, and release of five acidic pharmaceuticals, including ibuprofen (IBP), naproxen (NPX), ketoprofen (KEP), diclofenac (DFC), and clofibric acid (CA), have been investigated along the different units in a tertiary-level domestic wastewater treatment plant (WWTP) in hyper-urbanization city of China (Shanghai). IBP was the most abundant chemicals among the measured in raw wastewater. The loads of the acidic pharmaceuticals in the WWTP influent ranged from 7.5 to 414 mg/day/1,000 inh, which were lower than those reported in the developed countries suggesting a less per capita consumption of pharmaceuticals in Shanghai. IBP obtained by highest removal (87 %); NPX and KEP were also significantly removed (69-76 %). However, DFC and CA were only moderately removed by 37-53 %, respectively. Biodegradation seemed to play a key role in the elimination of the studied pharmaceuticals except for DFC and CA. An annual release of acidic pharmaceuticals was estimated at 1,499 and 61.7 kg/year through wastewater and sludge, respectively, from Shanghai. Highest pharmaceuticals concentrations were detected in the effluent discharge point of the WWTP, indicating that WWTP effluent is the main source of the acidic pharmaceuticals to its receiving river. Preliminary results indicated that only DFC in river had a high risk to aquatic organisms. Nevertheless, the joint toxicity effects of these chemicals are needed to further investigate. PMID:22669562

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

    ClinicalTrials.gov

    2016-07-12

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

  14. The effect of nitrogen containing bisphosphonates, zoledronate and alendronate, on the production of pro-angiogenic factors by osteoblastic cells.

    PubMed

    Ishtiaq, S; Edwards, S; Sankaralingam, A; Evans, B A J; Elford, C; Frost, M L; Fogelman, I; Hampson, G

    2015-02-01

    Bisphosphonates (BPs) have been shown to influence angiogenesis. This may contribute to BP-associated side-effects such as osteonecrosis of the jaw (ONJ) or atypical femoral fractures (AFF). The effect of BPs on the production of angiogenic factors by osteoblasts is unclear. The aims were to investigate the effect of (1) alendronate on circulating angiogenic factors; vascular endothelial growth factor (VEGF) and angiopoietin-1 (ANG-1) in vivo and (2) zoledronate and alendronate on the production of VEGF and ANG-1 by osteoblasts in vitro. We studied 18 post-menopausal women with T score⩽-2 randomized to calcium/vitamin D only (control arm, n=8) or calcium/vitamin D and alendronate 70mg weekly (treatment arm, n=10). Circulating concentrations of VEGF and ANG-1 were measured at baseline, 3, 6 and 12months. Two human osteoblastic cell lines (MG-63 and HCC1) and a murine osteocytic cell line (MLO-Y4) were treated with zoledronate or alendronate at concentrations of 10(-12)-10(-6)M. VEGF and ANG-1 were measured in the cell culture supernatant. We observed a trend towards a decline in VEGF and ANG-1 at 6 and 12months following treatment with alendronate (p=0.08). Production of VEGF and ANG-1 by the MG-63 and HCC1 cells decreased significantly by 34-39% (p<0.01) following treatment with zoledronate (10(-9)-10(-6)M). Treatment of the MG-63 cells with alendronate (10(-7) and 10(-6)) led to a smaller decrease (25-28%) in VEGF (p<0.05). Zoledronate (10(-10)-10(-)(6)M) suppressed the production of ANG-1 by MG-63 cells with a decrease of 43-49% (p<0.01). Co-treatment with calcitriol (10(-8)M) partially reversed this zoledronate-induced inhibition. BPs suppress osteoblastic production of angiogenic factors. This may explain, in part, the pathogenesis of the BP-associated side-effects. PMID:25461393

  15. CALUTRON RECEIVER

    DOEpatents

    Brunk, W.O.

    1959-09-29

    A description is given for an improved calutron receiver having a face plate lying at an angle to the direction of the entering ion beams but having an opening, the plane of which is substantially perpendicular to that of the entering ion beams. By so positioning the opening in the receiver, the effective area through which the desired material may enter the receiver is increased, and at the same time the effective area through which containattng material may enter the receiver is reduced.

  16. Predictors of treatment response in young people at ultra-high risk for psychosis who received long-chain omega-3 fatty acids

    PubMed Central

    Amminger, G P; Mechelli, A; Rice, S; Kim, S-W; Klier, C M; McNamara, R K; Berk, M; McGorry, P D; Schäfer, M R

    2015-01-01

    Previous efforts in the prospective evaluation of individuals who experience attenuated psychotic symptoms have attempted to isolate mechanisms underlying the onset of full-threshold psychotic illness. In contrast, there has been little research investigating specific predictors of positive outcomes. In this study, we sought to determine biological and clinical factors associated with treatment response, here indexed by functional improvement in a pre–post examination of a 12-week randomized controlled intervention in individuals at ultra-high risk (UHR) for psychosis. Participants received either long-chain omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) or placebo. To allow the determination of factors specifically relevant to each intervention, and to be able to contrast them, both treatment groups were investigated in parallel. Univariate linear regression analysis indicated that higher levels of erythrocyte membrane α-linolenic acid (ALA; the parent fatty acid of the ω-3 family) and more severe negative symptoms at baseline predicted subsequent functional improvement in the treatment group, whereas less severe positive symptoms and lower functioning at baseline were predictive in the placebo group. A multivariate machine learning analysis, known as Gaussian Process Classification (GPC), confirmed that baseline fatty acids predicted response to treatment in the ω-3 PUFA group with high levels of sensitivity, specificity and accuracy. In addition, GPC revealed that baseline fatty acids were predictive in the placebo group. In conclusion, our investigation indicates that UHR patients with higher levels of ALA may specifically benefit from ω-3 PUFA supplementation. In addition, multivariate machine learning analysis suggests that fatty acids could potentially be used to inform prognostic evaluations and treatment decisions at the level of the individual. Notably, multiple statistical analyses were conducted in a relatively small sample, limiting the

  17. CALUTRON RECEIVER

    DOEpatents

    York, H.F.

    1959-07-01

    A receiver construction is presented for calutrons having two or more ion sources and an individual receiver unit for each source. Design requirements dictate that the face plate defining the receiver entrance slots be placed at an angle to the approaching beam, which means that ions striking the face plate are likely to be scattcred into the entrance slots of other receivers. According to the present invention, the face plate has a surface provided with parallel ridges so disposed that one side only of each ridge's exposed directly to the ion beam. The scattered ions are directed away from adjacent receivers by the ridges on the lace plate.

  18. Stratification of Metal and Sulphate Loads in Acid Mine Drainage Receiving Water Dams - Variables Regionalization by Cluster Analysis.

    PubMed

    Grande, J A; de la Torre, M L; Valente, T; Fernández, J P; Borrego, J; Santisteban, M; Cerón, J C; Sánchez-Rodas, D

    2015-07-01

    The Sancho Reservoir (Iberian Pyrite Belt, SW Spain) is nourished by the waters of the river Meca, which is affected by acid mine drainage (AMD) processes from the abandoned Tharsis mine. The aim of the present work is to study the hydrochemical variations in this reservoir, in order to define potential stratification processes in metal load and sulphates. A stratified sampling from the surface, with one meter deep intervals to the bottom of the dam, was performed. The results show a clear stratification of temperature, pH, electric conductivity, dissolved oxygen, metal and sulphate loads associated with depth. There is an increase of metal loads at the bottom of the reservoir, though previous studies only detect iron. The proximity between pH and aluminium suggests that water chemistry is strongly influenced by aluminium precipitation processes. This indicates the buffer effect that aluminium exercises, which precipitates as amorphous or low crystalline phases, introducing hydrogen ions to the system, while alkalinity input tends to raise pH. PMID:26163498

  19. Radio receivers

    NASA Astrophysics Data System (ADS)

    Bankov, V. N.; Barulin, L. G.; Zhodzishskii, M. I.; Malyshev, I. V.; Petrusinskii, V. V.

    The book is concerned with the design of microelectronic radio receivers and their components based on semiconductor and hybrid integrated circuits. Topics discussed include the hierarchical structure of radio receivers, the synthesis of structural schemes, the design of the principal functional units, and the design of radio receiver systems with digital signal processing. The discussion also covers the integrated circuits of multifunctional amplifiers, analog multipliers, charge-transfer devices, frequency filters, piezoelectronic devices, and microwave amplifiers, filters, and mixers.

  20. CALUTRON RECEIVERS

    DOEpatents

    Lofgren, E.J.

    1958-09-01

    Improvements are described in isotope separation devices of the calutron type and, in particular, deals with a novel caiutron receiver which passes the optimum portions of the ion beam to a collecting chamber. In broad aspects the receiver provides means for pass delimited pontion of the beam and an elongated collecting pocket disposed to receive ions passed by the beam delimiting means. The collecting pocket is transversely partitioned into a plurality of ion receiving compartments respectively defined by a corresponding plurality of separately removable liner elements.

  1. CALUTRON RECEIVERS

    DOEpatents

    Schmidt, F.H.; Stone, K.F.

    1958-09-01

    S>This patent relates to improvements in calutron devices and, more specifically, describes a receiver fer collecting the ion curreot after it is formed into a beam of non-homogeneous isotropic cross-section. The invention embodies a calutron receiver having an ion receiving pocket for separately collecting and retaining ions traveling in a selected portion of the ion beam and anelectrode for intercepting ions traveling in another selected pontion of the ion beam. The electrode is disposed so as to fix the limit of one side of the pontion of the ion beam admitted iato the ion receiving pocket.

  2. CALUTRON RECEIVERS

    DOEpatents

    MacKenzie, K.R.

    1958-09-16

    A novel calutron receiver is described for collecting the constituent material of two closely adjacent selected portions of an ion beam in separate compartments. The receiver is so conntructed that ion scatter and intermixing of the closely adjacent beam portions do nnt occur when the ions strike the receiver structure, and the beam is sharply separated Into the two compartments. In essence, these desirable results are achieved by inclining the adjoining wall of one compartment with respect to the approaching ions to reduce possible rebounding of ions from the compartment into the adjacent compartment.

  3. Urine Liver-Type Fatty Acid-Binding Protein and Kidney Injury Molecule-1 in HIV-Infected Patients Receiving Combined Antiretroviral Treatment Based on Tenofovir

    PubMed Central

    Wójcik, Kamila; Piekarska, Anna

    2014-01-01

    Abstract The aim of this study was to determine the presence of kidney tubular damage in the absence of overt evidence of glomerular dysfunction (GFR>60 ml/min without proteinuria) in HIV-infected patients receiving antiretroviral therapy. Urine kidney injury molecule-1 (KIM-1) and liver-type fatty acid-binding protein (L-FABP) levels were measured by ELISA and expressed as a ratio to creatinine. Sixty-six patients (median age 38 years) and 10 healthy controls (median age 35.5 years) were included in the study. Patients with chronic diseases such as diabetes, hypertension, heart disease, or kidney disease were excluded from the study. All patients received tenofovir/emtricitabine combined with one of three other components, namely efavirenz, atazanavir/norvir, or lopinavir/norvir. A lower concentration of L-FABP/creatinine was observed in HIV-infected as compared to healthy individuals (p=0.0353); KIM-1/creatinine was also lower in comparison with healthy controls but not statistically significantly. Patients receiving efavirenz had higher levels of L-FABP/creatinine in comparison to healthy controls (p=0.0039). Patients with anti-HCV had higher concentrations of L-FABP/creatinine as compared to the HIV-monoinfected individuals (not statistically significant) and to healthy subjects (p=0.0356). All four patients with L-FABP>17.5 μg/g creatinine were HIV/HCV coinfected. On multivariate logistic regression urine L-FABP above 5.5 μg/g creatinine was independently associated with body weight (OR=0.93 p=0.039). This study suggests that HIV/HCV-coinfected patients with lower body weight treated with tenofovir may be at an increased risk of tubular dysfunction and should be monitored more closely. The use of protease inhibitors was not associated with an increased risk of tubular disorders. PMID:24164392

  4. Systemic but No Local Effects of Combined Zoledronate and Parathyroid Hormone Treatment in Experimental Autoimmune Arthritis

    PubMed Central

    Keller, Kresten Krarup; Thomsen, Jesper Skovhus; Stengaard-Pedersen, Kristian; Hauge, Ellen-Margrethe

    2014-01-01

    Introduction Local bone erosions and osteoporosis in rheumatoid arthritis (RA) are the result of a more pronounced bone resorption than bone formation. Present treatment strategies for RA inhibit inflammation, but do not directly target bone erosions. The aim of the study was in experimental arthritis to investigate the juxtaarticular and systemic effects of simultaneous osteoclast inhibition with zoledronate (ZLN) and osteoblast stimulation with parathyroid hormone (PTH). Methods Arthritis was induced in 36 SKG mice. The mice were randomized to three treatment groups and an untreated group: ZLN, PTH, PTH+ZLN, and untreated. Arthritis score and ankle width measurements were performed. Histological sections were cut from the right hind paw, and design-based stereological estimators were used to quantify histological variables of bone volume and bone formation and resorption. The femora were DXA- and μCT-scanned, and the bone strength was determined at the femoral neck and mid-diaphysis. Results Locally, we found no differences in arthritis score or ankle width throughout the study. Similarly, none of the treatments inhibited bone erosions or stimulated bone formation in the paw. Systemically, all treatments improved bone mineral density, strength of the femoral neck and mid-diaphysis, and μCT parameters of both cortical and trabecular bone. In addition, there was an additive effect of combination treatment compared with single treatments for most trabecular parameters including bone mineral density and bone volume fraction. Conclusions No local effect on bone was found by the combined action of inhibiting bone resorption and stimulating bone formation. However, a clear systemic effect of the combination treatment was demonstrated. PMID:24637846

  5. Effects of local delivery of BMP2, zoledronate and their combination on bone microarchitecture, biomechanics and bone turnover in osteoporotic rabbits.

    PubMed

    Jing, Da; Hao, Xuguang; Xu, Fang; Liu, Jian; Xu, Fei; Luo, Erping; Meng, Guolin

    2016-01-01

    The hip fracture is one major clinical challenge associated with osteoporosis, resulting in heavy socioeconomic burdens and high mortality. Systemic therapies of anti-osteoporosis drugs are expensive, time-consuming and also evoke substantial side effects, which fails to provide early protection from fractures. Accumulating evidence demonstrates the high bioavailability and therapeutic efficacy of local drug delivery in accelerating facture healing and bone defect repair. This study aims at investigating the effects of local delivery of BMP2 and zoledronate (two promising anabolic/anti-catobolic reagents) encapsulated by fibrin sealants into femoral necks on regulating bone quality and remodeling in osteoporotic rabbits subjected to combined ovariectomy and glucocorticoid injection. We show that 6-week BMP2 delivery exhibited more prominent effect on mitigating trabecular bone microarchitecture deterioration and mechanical strength reduction of femoral necks than local zoledronate treatment. BMP2 plus zoledronate showed more significant improvement of bone microstructure, mechanical strength and bone formation rate at 12 weeks post injection than single BMP2 or zoledronate delivery via μCT, biomechanical, histomorphometric and serum biochemical analyses. This study enriches our knowledge for understanding the availability of local drug delivery for improving bone quantity and quality, which may lead to earlier, safer and more efficient protection from osteoporosis-induced fractures in clinics. PMID:27329730

  6. Effects of local delivery of BMP2, zoledronate and their combination on bone microarchitecture, biomechanics and bone turnover in osteoporotic rabbits

    PubMed Central

    Jing, Da; Hao, Xuguang; Xu, Fang; Liu, Jian; Xu, Fei; Luo, Erping; Meng, Guolin

    2016-01-01

    The hip fracture is one major clinical challenge associated with osteoporosis, resulting in heavy socioeconomic burdens and high mortality. Systemic therapies of anti-osteoporosis drugs are expensive, time-consuming and also evoke substantial side effects, which fails to provide early protection from fractures. Accumulating evidence demonstrates the high bioavailability and therapeutic efficacy of local drug delivery in accelerating facture healing and bone defect repair. This study aims at investigating the effects of local delivery of BMP2 and zoledronate (two promising anabolic/anti-catobolic reagents) encapsulated by fibrin sealants into femoral necks on regulating bone quality and remodeling in osteoporotic rabbits subjected to combined ovariectomy and glucocorticoid injection. We show that 6-week BMP2 delivery exhibited more prominent effect on mitigating trabecular bone microarchitecture deterioration and mechanical strength reduction of femoral necks than local zoledronate treatment. BMP2 plus zoledronate showed more significant improvement of bone microstructure, mechanical strength and bone formation rate at 12 weeks post injection than single BMP2 or zoledronate delivery via μCT, biomechanical, histomorphometric and serum biochemical analyses. This study enriches our knowledge for understanding the availability of local drug delivery for improving bone quantity and quality, which may lead to earlier, safer and more efficient protection from osteoporosis-induced fractures in clinics. PMID:27329730

  7. Pathogen translocation and histopathological lesions in an experimental model of Salmonella Dublin infection in calves receiving lactic acid bacteria and lactose supplements.

    PubMed

    Frizzo, Laureano S; Zbrun, María V; Soto, Lorena P; Bertozzi, Ezequiel; Sequeira, Gabriel J; Marti, Luis E; Signorini, Marcelo L; Armesto, Roberto Rodríguez; Rosmini, Marcelo R

    2012-09-01

    The purpose of this study was to evaluate the capacity of a lactic acid bacteria (LAB) inoculum to protect calves with or without lactose supplements against Salmonella Dublin infection by evaluating histopathological lesions and pathogen translocation. Fifteen calves were divided into three groups [control group (C-G), a group inoculated with LAB (LAB-G), and a group inoculated with LAB and given lactose supplements (L-LAB-G)] with five, six, and four animals, respectively. The inoculum, composed of Lactobacillus (L.) casei DSPV 318T, L. salivarius DSPV 315T, and Pediococcus acidilactici DSPV 006T, was administered with milk replacer. The LAB-G and L-LAB-G received a daily dose of 10(9) CFU/kg body weight of each strain throughout the experiment. Lactose was provided to the L-LAB-G in doses of 100 g/day. Salmonella Dublin (2 × 10(10) CFU) was orally administered to all animals on day 11 of the experiment. The microscopic lesion index values in target organs were 83%, 70%, and 64.3% (p < 0.05) for the C-G, LAB-G, and L-LAB-G, respectively. Administration of the probiotic inoculum was not fully effective against infection caused by Salmonella. Although probiotic treatment was unable to delay the arrival of pathogen to target organs, it was evident that the inoculum altered the response of animals against pathogen infection. PMID:23000583

  8. Pathogen translocation and histopathological lesions in an experimental model of Salmonella Dublin infection in calves receiving lactic acid bacteria and lactose supplements

    PubMed Central

    Zbrun, María V.; Soto, Lorena P.; Bertozzi, Ezequiel; Sequeira, Gabriel J.; Marti, Luis E.; Signorini, Marcelo L.; Armesto, Roberto Rodríguez; Rosmini, Marcelo R.

    2012-01-01

    The purpose of this study was to evaluate the capacity of a lactic acid bacteria (LAB) inoculum to protect calves with or without lactose supplements against Salmonella Dublin infection by evaluating histopathological lesions and pathogen translocation. Fifteen calves were divided into three groups [control group (C-G), a group inoculated with LAB (LAB-G), and a group inoculated with LAB and given lactose supplements (L-LAB-G)] with five, six, and four animals, respectively. The inoculum, composed of Lactobacillus (L.) casei DSPV 318T, L. salivarius DSPV 315T, and Pediococcus acidilactici DSPV 006T, was administered with milk replacer. The LAB-G and L-LAB-G received a daily dose of 109 CFU/kg body weight of each strain throughout the experiment. Lactose was provided to the L-LAB-G in doses of 100 g/day. Salmonella Dublin (2 × 1010 CFU) was orally administered to all animals on day 11 of the experiment. The microscopic lesion index values in target organs were 83%, 70%, and 64.3% (p < 0.05) for the C-G, LAB-G, and L-LAB-G, respectively. Administration of the probiotic inoculum was not fully effective against infection caused by Salmonella. Although probiotic treatment was unable to delay the arrival of pathogen to target organs, it was evident that the inoculum altered the response of animals against pathogen infection. PMID:23000583

  9. CALUTRON RECEIVER

    DOEpatents

    Barnes, S.W.

    1959-08-25

    An improvement in a calutron receiver for collecting the isotopes ts described. The electromagnetic separation of the isotopes produces a mass spectrum of closely adjacent beams of ions at the foci regions, and a dividing wall between the two pockets is arranged at an angle. Substantially all of the tons of the less abundant isotope enter one of the pockets and strike one side of the wall directly, while substantially none of the tons entering the other pocket strikes the wall directly.

  10. Zoledronate blocks geranylgeranylation not farnesylation to suppress human osteosarcoma U2OS cells metastasis by EMT via Rho A activation and FAK-inhibited JNK and p38 pathways.

    PubMed

    Cheng, Hsin-Lin; Lin, Chiao-Wen; Yang, Jia-Sin; Hsieh, Ming-Ju; Yang, Shun-Fa; Lu, Ko-Hsiu

    2016-03-01

    Zoledronate is a standard treatment for preventing skeletal complications of osteoporosis and some types of cancer associated with bone metastases, but we little know whether the effect of zoledronate on metastasis of osteosarcoma. Here, we investigated the inhibitory effects of zoledronate on cell viability, motility, migration and invasion of 4 osteosarcoma cell lines (Saos2, MG-63, HOS and U2OS) by affecting cell morphology, epithelial-mesenchymal transition (EMT) and cytoskeletal organization as well as induction of E-cadherin and reduction of N-cadherin with activation of transcription factors Slug and Twist, especially in U2OS cells. Zoledronate decreased JNK and p38 phosphorylation and upper streams of focal adhesion kinase (FAK) and Src to suppress the motility, invasiveness and migration of U2OS cells. In addition to zoledronate-inhibited Rho A and Cdc42 membrane translocation and GTPγS activities, the anti-metastatic effects in U2OS cells including inhibition of adhesion were reversed by geranylgeraniol, but not farnesol. In conclusion, Zoledronate blocks geranylgeranylation not farnesylation to suppress human osteosarcoma U2OS cell-matrix and cell-cell interactions, migration potential, the invasive activity, and the adhesive ability by EMT via Rho A activation and FAK-inhibited JNK and p38 pathways. PMID:26848867

  11. Zoledronate blocks geranylgeranylation not farnesylation to suppress human osteosarcoma U2OS cells metastasis by EMT via Rho A activation and FAK-inhibited JNK and p38 pathways

    PubMed Central

    Cheng, Hsin-Lin; Lin, Chiao-Wen; Yang, Jia-Sin; Hsieh, Ming-Ju; Yang, Shun-Fa; Lu, Ko-Hsiu

    2016-01-01

    Zoledronate is a standard treatment for preventing skeletal complications of osteoporosis and some types of cancer associated with bone metastases, but we little know whether the effect of zoledronate on metastasis of osteosarcoma. Here, we investigated the inhibitory effects of zoledronate on cell viability, motility, migration and invasion of 4 osteosarcoma cell lines (Saos2, MG-63, HOS and U2OS) by affecting cell morphology, epithelial-mesenchymal transition (EMT) and cytoskeletal organization as well as induction of E-cadherin and reduction of N-cadherin with activation of transcription factors Slug and Twist, especially in U2OS cells. Zoledronate decreased JNK and p38 phosphorylation and upper streams of focal adhesion kinase (FAK) and Src to suppress the motility, invasiveness and migration of U2OS cells. In addition to zoledronate-inhibited Rho A and Cdc42 membrane translocation and GTPγS activities, the anti-metastatic effects in U2OS cells including inhibition of adhesion were reversed by geranylgeraniol, but not farnesol. In conclusion, Zoledronate blocks geranylgeranylation not farnesylation to suppress human osteosarcoma U2OS cell-matrix and cell-cell interactions, migration potential, the invasive activity, and the adhesive ability by EMT via Rho A activation and FAK-inhibited JNK and p38 pathways. PMID:26848867

  12. Radiation receiver

    DOEpatents

    Hunt, A.J.

    1983-09-13

    The apparatus for collecting radiant energy and converting same to alternate energy form includes a housing having an interior space and a radiation transparent window allowing, for example, solar radiation to be received in the interior space of the housing. Means are provided for passing a stream of fluid past said window and for injecting radiation absorbent particles in said fluid stream. The particles absorb the radiation and because of their very large surface area, quickly release the heat to the surrounding fluid stream. The fluid stream particle mixture is heated until the particles vaporize. The fluid stream is then allowed to expand in, for example, a gas turbine to produce mechanical energy. In an aspect of the present invention properly sized particles need not be vaporized prior to the entrance of the fluid stream into the turbine, as the particles will not damage the turbine blades. In yet another aspect of the invention, conventional fuel injectors are provided to inject fuel into the fluid stream to maintain the proper temperature and pressure of the fluid stream should the source of radiant energy be interrupted. In yet another aspect of the invention, an apparatus is provided which includes means for providing a hot fluid stream having hot particles disbursed therein which can radiate energy, means for providing a cooler fluid stream having cooler particles disbursed therein, which particles can absorb radiant energy and means for passing the hot fluid stream adjacent the cooler fluid stream to warm the cooler fluid and cooler particles by the radiation from the hot fluid and hot particles. 5 figs.

  13. Radiation receiver

    DOEpatents

    Hunt, Arlon J.

    1983-01-01

    The apparatus for collecting radiant energy and converting same to alternate energy form includes a housing having an interior space and a radiation transparent window allowing, for example, solar radiation to be received in the interior space of the housing. Means are provided for passing a stream of fluid past said window and for injecting radiation absorbent particles in said fluid stream. The particles absorb the radiation and because of their very large surface area, quickly release the heat to the surrounding fluid stream. The fluid stream particle mixture is heated until the particles vaporize. The fluid stream is then allowed to expand in, for example, a gas turbine to produce mechanical energy. In an aspect of the present invention properly sized particles need not be vaporized prior to the entrance of the fluid stream into the turbine, as the particles will not damage the turbine blades. In yet another aspect of the invention, conventional fuel injectors are provided to inject fuel into the fluid stream to maintain the proper temperature and pressure of the fluid stream should the source of radiant energy be interrupted. In yet another aspect of the invention, an apparatus is provided which includes means for providing a hot fluid stream having hot particles disbursed therein which can radiate energy, means for providing a cooler fluid stream having cooler particles disbursed therein, which particles can absorb radiant energy and means for passing the hot fluid stream adjacent the cooler fluid stream to warm the cooler fluid and cooler particles by the radiation from the hot fluid and hot particles.

  14. Zoledronate inhibits receptor activator of nuclear factor kappa-B ligand-induced osteoclast differentiation via suppression of expression of nuclear factor of activated T-cell c1 and carbonic anhydrase 2.

    PubMed

    Nakagawa, Takayuki; Ohta, Kouji; Kubozono, Kazumi; Ishida, Yoko; Naruse, Takako; Takechi, Masaaki; Kamata, Nobuyuki

    2015-04-01

    Bisphosphonates (BPs) are widely used in the prevention of skeletal-related events (SRE), including osteoporosis, skeletal metastases of malignant tumours, and multiple myeloma. Osteonecrosis of the jaw (ONJ) is frequently reported as a major adverse effect induced by BP treatment. The receptor activator of the nuclear factor kappa-B ligand (RANKL) inhibitor, denosumab, has recently been used to prevent SRE, but the frequency of ONJ induced by denosumab is similar to that by BPs. This finding suggests that the inhibition of RANKL-mediated osteoclastogenesis may have a close relationship with the occurrence of ONJ. We therefore investigated the expression status of RANKL-inducible genes in zoledronate-treated mouse osteoclast precursor cells. The molecular targets of zoledronate in the RANKL signal pathway and additional factors associated with osteoclastogenesis were analysed by genome-wide screening. Microarray analysis identified that among 31 genes on 44 entities of RANKL-inducible genes, the mRNA expression level of two genes, i.e., nuclear factor of activated T-cells c1 (NFATc1) and carbonic anhydrase 2 (CAII), was decreased in zoledronate-treated cells. Subsequent analyses verified that these two genes were significantly silenced by zoledronate treatment and that their expression was restored following inhibition of zoledronate action by geranylgeraniol. Zoledronate inhibited RANKL-induced osteoclast differentiation by suppression of NFATc1 and CAII gene expression. Our results suggest that these genes might be common targets for zoledronate and denosumab in the mechanism underlying RANKL-induced osteoclast differentiation. A clear understanding of the common molecular mechanisms of bone-remodelling agents is thus essential for prevention of ONJ. PMID:25601046

  15. Systemic zoledronate treatment both prevents resorption of allograft bone and increases the retention of new formed bone during revascularization and remodelling. A bone chamber study in rats

    PubMed Central

    Åstrand, Jörgen; Harding, Anna Kajsa; Aspenberg, Per; Tägil, Magnus

    2006-01-01

    Background In osteonecrosis the vascular supply of the bone is interrupted and the living cells die. The inorganic mineral network remains intact until ingrowing blood vessels invade the graft. Accompanying osteoclasts start to resorb the bone trabeculae and gradually replace the bone. If the osteonecrosis occurs in mechanically loaded parts, like in the subchondral bone of a loaded joint, the remodelling might lead to a weakening of the bone and, in consequence to a joint collapse. Systemic bisphosphonate treatment can reduce the resorption of necrotic bone. In the present study we investigate if zoledronate, the most potent of the commercially available bisphosphonates, can be used to reduce the amount or speed of bone graft remodeling. Methods Bone grafts were harvested and placed in a bone chamber inserted into the tibia of a rat. Host tissue could grow into the graft through openings in the chamber. Weekly injections with 1.05 μg zoledronate or saline were given subcutaneously until the rats were harvested after 6 weeks. The specimens were fixed, cut and stained with haematoxylin/eosin and used for histologic and histomorphometric analyses. Results By histology, the control specimens were almost totally resorbed in the remodeled area and the graft replaced by bone marrow. In the zoledronate treated specimens, both the old graft and new-formed bone remained and the graft trabeculas were lined with new bone. By histomorphometry, the total amount of bone (graft+ new bone) within the remodelled area was 35 % (SD 13) in the zoledronate treated grafts and 19 % (SD 12) in the controls (p = 0.001). Also the amount of new bone was increased in the treated specimens (22 %, SD 7) compared to the controls (14 %, SD 9, p = 0.032). Conclusion We show that zoledronate can be used to decrease the resorption of both old graft and new-formed bone during bone graft remodelling. This might be useful in bone grafting procedure but also in other orthopedic conditions, both where

  16. Zoledronate and Molecular Iodine Cause Synergistic Cell Death in Triple Negative Breast Cancer through Endoplasmic Reticulum Stress.

    PubMed

    Tripathi, Ranu; Singh, Preeti; Singh, Aru; Chagtoo, Megha; Khan, Sajid; Tiwari, Swasti; Agarwal, Gaurav; Meeran, Syed Musthapa; Godbole, Madan M

    2016-01-01

    Women consuming molecular iodine (I2) through seaweeds suffer the least from breast cancers. Zoledronate (Zol) is in clinical use for alleviation of bone pain in cancer patients. Triple negative breast cancers exhibit high mortality due to lack of neoadjuvant chemotherapy. I2 and Zol independently cause weak antiproliferative and apoptotic effect. So far, their combined effects have not been tested. We analyzed the effect of combination of I2 with Zol as a potent adjuvant therapeutic agent for triple negative breast cancer cells (MDA-MBA-231) and in the mice model of breast cancer. Cell viability, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, Western blotting, real-time PCR, flow cytometry, and other assays were performed for assessing cell death, calcium levels, and migration potential, respectively, in treated cells. The increased caspase 8, increased [Ca(2+)]c levels, and endoplasmic reticulum (ER) stress resulted in apoptosis. Real time and fluorescence-based analysis demonstrated that the combination treatment targets ER Ca(2+) homeostasis chaperons leading to apoptosis. Combination therapy reduces metalloproteinases 2 and 9, inhibits invasion/migration of cells, and prevents growth of tumor in mice. I2 + Zol combination treatment induces synergistic increase in ER-mediated apoptosis, reduces invasion/migration potential of MDA-MB-231 cells, and exhibits antiproliferative property in vivo demonstrating its potential as combination therapy. PMID:27116040

  17. 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. PMID:26676633

  18. Role of acid sphingomyelinase in the age-dependent dysregulation of sphingolipids turnover in the tissues of rats.

    PubMed

    Babenko, Nataliya A; Garkavenko, Vladimir V; Storozhenko, Galina V; Timofiychuk, Olga A

    2016-04-01

    Old age-associated pathologies usually coincide with altered sphingolipid metabolism. In the present article, the role of acid sphingomyelinase (ASMase) in the age-dependent changes of sphingomyelin (SM) and ceramide contents in the tissues has been investigated by means of ASMase inhibitors, imipramine and zoledronic acid. It has been determined that ceramide content and ceramide/SM ratio increased, while SM level decreased in the heart, liver, blood serum and skeletal muscles of 24-month old rats in contrast to 3-month old animals. Injections of imipramine or zoledronic acid to 24-month old rats resulted in significant downregulation of ASMase in the liver and skeletal and heart muscles. The both inhibitors decreased the ceramide content and ceramide/SM ratio and increased the SM content in all tissues studied, except the heart, of old rats to the levels close to those observed in the young animals. Long-term treatment of rats by inhibitors, which have different mechanisms of action on ASMase, exerts the similar, but not equal effects on enzyme activity and SM turnover. In summary, the data above strongly suggest that the age-dependent up-regulation of ASMase plays an important role in the modulation of ceramide and SM contents in rat tissues and that imipramine and zoledronic acid are useful tools for SM turnover manipulation at old age. PMID:26830134

  19. [Acid-soluble collagen in the skin of rats who received a tryptophan load and were kept on a protein-free diet].

    PubMed

    Pechenova, T N; Gulyĭ, M F; Volodina, T T; Solodova, E V; Popova, N N

    1983-01-01

    Crystalline preparations of acid-soluble collagen of rat skin in norm and with tryptophan load against a background of the protein-free diet were fractionated by differential salting out using NaCl in concentrations corresponding to precipitation zones of collagen 1,3 and 4. Amino acid composition, electrophoretic mobility in polyacrylamide gel, profiles of elution from CM-cellulose, content of the carbohydrate component and--S--S-bonds were studied in proteins of the mentioned fractions and in the precipitate insoluble after the pepsin action. Essential differences as compared to the normal level in the amino acid composition and elution profiles were detected in the fraction corresponding to collagen I. Quantitative changes in the carbohydrate component and--S--S-bonds occur due to the fraction inaccessible to the persin action. PMID:6829075

  20. [Corrigendum] Cisplatin in combination with zoledronic acid: A synergistic effect in triple-negative breast cancer cell lines.

    PubMed

    Ibrahim, Toni; Liverani, Chiara; Mercatali, Laura; Sacanna, Emanuele; Zanoni, Michele; Fabbri, Francesco; Zoli, Wainer; Amadori, Dino

    2016-09-01

    Following the publication of the above article, an interested reader drew an anomaly associated with the presentation of Fig. 7 to our attention. Essentially, the panel showing the Cis 0.001 data at T0 for the BRC-230 cell line was the same as that showing the Cis 0.01 data. After having re-examined our data, we realized that an error must have occurred when preparing Fig. 7. A duplication of the photo corresponding to BRC-230 Cis 0.001 T0 was incorrectly placed in the position corresponding to BRC-230 Cis 0.01 T0, while the correct BRC-230 Cis 0.01 T0 figure was erroneously positioned in the BRC-230 Cis 0.01 T1 slot. Fortunately, we had retained all of the data on our computer and were able to find the correct photos representing the conditions of BRC-230 Cis 0.01 T0 and T1. The findings and conclusions of this paper are still supported by our experimental data and are not affected by this error. We sincerely apologize for this oversight and thank the reader for drawing this matter to our attention. We regret any inconvenience caused by our mistake. [the original article was published in the International Journal of Oncology 42: 1263-1270, 2013; DOI: 10.3892/ijo.2013.1809]. PMID:27573164

  1. Time course of bone screw fixation following a local delivery of Zoledronate in a rat femoral model - a micro-finite element analysis.

    PubMed

    Kettenberger, Ulrike; Latypova, Adeliya; Terrier, Alexandre; Pioletti, Dominique P

    2015-05-01

    A good fixation of osteosynthesis implants is crucial for a successful bone healing but often difficult to achieve in osteoporotic patients. One possible solution to this issue is the local delivery of bisphosphonates in direct proximity to the implants, A critical aspect of this method, that has not yet been well investigated, is the time course of the implant fixation following the drug release. Usual destructive mechanical tests require large numbers of animals to produce meaningful results. Therefore, a micro-finite element (microFE) approach was chosen to analyze implant fixation. In vivo micro computed tomography (microCT) scans were obtained, first weekly and later bi-weekly, after implantation of polymeric screws in the femoral condyles of ovariectomized rats. In one half of the animals, Zoledronate was released from a hydrogel matrix directly in the peri-implant bone stock, the other animals were implanted only with screws as control. The time course of the implant fixation was investigated with linear elastic microFE models that were created based on in vivo microCT scans. The numerical models were validated against experimental pullout-tests measurements in an additional cadaver study. The microFE analysis revealed a significant increase in force at yield of the Zoledronate treated group compared to the control group. The force of the treated group was 28% higher after 17 days of screw implantation, 42% higher after 31 days. The significant difference persisted until the end of the in vivo study at day 58 (p<0.01). The early onset and prolonged duration of the implant anchorage improvement that was found in this study indicates the great potential of Zoledronate-loaded hydrogel for an enhancement of osteosynthesis implant fixation in impaired bone. PMID:25679481

  2. 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. PMID:27021151

  3. Combined electron microscopy and spectroscopy characterization of as-received, acid purified, and oxidized HiPCO single-wall carbon nanotubes

    SciTech Connect

    Rosario-Castro, Belinda I.; Contes, Enid J.; Lebron-Colon, Marisabel; Meador, Michael A.; Sanchez-Pomales, Germarie; Cabrera, Carlos R.

    2009-12-15

    Single-wall carbon nanotubes (SWCNTs) are very important materials due to their combination of unique structure, dimension, strength, chemical stability, and electronic properties. Nevertheless, SWCNTs from commercial sources usually contain several impurities, which are usually removed by a purification process that includes reflux in acids and strong oxidation. This strong chemical procedure may alter the nanotube properties and it is thus important to control the extent of functionalization and oxidation during the purification procedure. In this report, we provide a comprehensive study of the structure and physical composition of SWCNTs during each step of the purification process. Techniques such as Raman spectroscopy, transmission electron microscopy, scanning electron microscopy, thermogravimetric analysis, X-ray photoelectron spectroscopy and Infrared spectroscopy were used to track the SWCNTs structure, in terms of length and diameter distribution, and surface chemical modifications during each purification stage.

  4. The Effect of Omega-3 Fatty Acids in Patients With Active Rheumatoid Arthritis Receiving DMARDs Therapy: Double-Blind Randomized Controlled Trial

    PubMed Central

    Rajaei, Elham; Mowla, Karim; Ghorbani, Ali; Bahadoram, Sara; Bahadoram, Mohammad; Dargahi-Malamir, Mehrdad

    2016-01-01

    Background: Rheumatoid arthritis is a symmetric peripheral polyarthritis of unknown etiology that, untreated or if unresponsive the therapy, typically leads to deformity and destruction of joints due to erosion of cartilage and bone. Omega-3 fatty acids have been shown to reduce morning stiffness, the number of tender joints and swollen joints in patients with rheumatoid arthritis. This study is designed for evaluation of omega-3 effects on disease activity and remission of rheumatoid arthritis in DMARDs treated patients and on weight changes and reduction of analgesic drugs consumption versus placebo. Methods: Sixty patients with active rheumatoid arthritis (49 female and 11 male) underwent rheumatologist examination and disease activity score were calculated. Then patients were enrolled in this 12 week, double blind, randomized, placebo- controlled study. The patients in both groups continued their pre study standard treatment. The patients were visited every 4 weeks, 4 times and data were recorded. Results: Significant improvement in the patient’s global evaluation and in the physician’s assessment of disease was observed in those taking omega-3. The proportions of patients who improved and of those who were able to reduce their concomitant analgesic medication were significantly greater with omega-3 consumption. There were no weight changes. Conclusion: Daily supplementation with omega-3 results has significant clinical benefit and may reduce the need for concomitant analgesic consumption without weight changes. PMID:26925896

  5. Tocopherols and tocotrienols in serum and liver of dairy cows receiving conjugated linoleic acids or a control fat supplement during early lactation.

    PubMed

    Sadri, H; Dänicke, S; Meyer, Ulrich; Rehage, J; Frank, J; Sauerwein, H

    2015-10-01

    The fat-soluble vitamin E comprises the 8 structurally related compounds (congeners) α-, β-, γ-, and δ-tocopherol (with a saturated side chain) and α-, β-, γ-, and δ-tocotrienol (with a 3-fold unsaturated side chain). Little is known regarding the blood and liver concentrations of the 8 vitamin E congeners during the transition from pregnancy to lactation in dairy cows. We thus quantified tocopherols (T) and tocotrienols (T3) in serum and liver and hepatic expression of genes involved in vitamin E metabolism in pluriparous German Holstein cows during late gestation and early lactation and investigated whether dietary supplementation (from d 1 in milk) with conjugated linoleic acids (CLA; 100g/d; each 12% of trans-10,cis-12 and cis-9,trans-11 CLA; n=11) altered these compared with control-fat supplemented cows (CTR; n=10). Blood samples and liver biopsies were collected on d -21, 1, 21, 70, and 105 (liver only) relative to calving. In both groups, the serum concentrations of αT, γT, βT3, and δT3 increased from d -21 to d 21 and remained unchanged between d 21 and 70, but were unaffected by CLA. The concentrations of the different congeners of vitamin E in liver did not differ between the CTR and the CLA groups. In both groups, the concentrations of the vitamin E forms in liver changed during the course of the study. The hepatic mRNA abundance of genes controlling vitamin E status did not differ between groups, but α-tocopherol transfer protein and tocopherol-associated protein mRNA increased with time of lactation in both. In conclusion, the concentrations of vitamin E congeners and the expression of genes related to vitamin E status follow characteristic time-related changes during the transition from late gestation to early lactation but are unaffected by CLA supplementation at the dosage used. PMID:26210275

  6. Hepatocellular carcinoma cell sensitivity to Vγ9Vδ2 T lymphocyte-mediated killing is increased by zoledronate

    PubMed Central

    SUGAI, SHIORI; YOSHIKAWA, TOSHIAKI; IWAMA, TATSUAKI; TSUCHIYA, NOBUHIRO; UEDA, NORIHIRO; FUJINAMI, NORIHIRO; SHIMOMURA, MANAMI; ZHANG, RONG; KANEKO, SHIN; UEMURA, YASUSHI; NAKATSURA, TETSUYA

    2016-01-01

    The limited efficacy of vaccines in hepatocellular carcinoma (HCC), due to the low frequency of tumor-infiltrating cytotoxic T lymphocytes (CTLs), indicates the importance of innate immune surveillance, which assists acquired immunity by directly recognizing and eliminating HCC. Innate Vγ9Vδ2 T cells have major histocompatibility complex-unrestricted antitumor activity and are activated by phosphoantigens, which are upregulated in cancer cells by the nitrogen-containing bisphosphonate, zoledronate (Zol). A better understanding of HCC susceptibility to Zol and downstream γδ T cell-mediated killing is essential to optimize γδ T cell-mediated immunotherapy. This study systematically examined the interactions between γδ T cells and Zol-treated HCC cell lines (HepG2, HLE, HLF, HuH-1, JHH5, JHH7, and Li-7) in vitro. All HCC cell lines expressed the DNAX accessory molecule-1 ligands, poliovirus receptor, and Nectin-2, and γδ T cell-mediated killing of these cells was significantly enhanced by Zol. Small interfering RNA-mediated knockdown of these ligands did not affect the susceptibility to γδ T cell lysis. This killing activity was partly inhibited by mevastatin, an inhibitor of the mevalonate pathway, and markedly reduced by a monoclonal antibody to γ- and δ-chain T cell receptor, indicating that this is crucial for Zol-induced HCC killing. In addition, Zol-treated HCC cell lines triggered γδ T cell proliferation and induced production of Th1 and Th2, but not Th17, cytokines. The Zol concentration that enhanced HCC cell susceptibility to γδ T cell killing was lower than that required to directly inhibit HCC proliferation. Thus, γδ T cells may be important effector cells in the presence of Zol, especially where there are insufficient number of cancer antigen-specific CTLs to eliminate HCC. Our in vitro data support the proposal that Zol-treatment, combined with adaptive γδ T cell immunotherapy, may provide a feasible and effective approach for

  7. Hepatocellular carcinoma cell sensitivity to Vγ9Vδ2 T lymphocyte-mediated killing is increased by zoledronate.

    PubMed

    Sugai, Shiori; Yoshikawa, Toshiaki; Iwama, Tatsuaki; Tsuchiya, Nobuhiro; Ueda, Norihiro; Fujinami, Norihiro; Shimomura, Manami; Zhang, Rong; Kaneko, Shin; Uemura, Yasushi; Nakatsura, Tetsuya

    2016-05-01

    The limited efficacy of vaccines in hepatocellular carcinoma (HCC), due to the low frequency of tumor-infiltrating cytotoxic T lymphocytes (CTLs), indicates the importance of innate immune surveillance, which assists acquired immunity by directly recognizing and eliminating HCC. Innate Vγ9Vδ2 T cells have major histocompatibility complex-unrestricted antitumor activity and are activated by phosphoantigens, which are upregulated in cancer cells by the nitrogen-containing bisphosphonate, zoledronate (Zol). A better understanding of HCC susceptibility to Zol and downstream γδ T cell-mediated killing is essential to optimize γδ T cell-mediated immunotherapy. This study systematically examined the interactions between γδ T cells and Zol-treated HCC cell lines (HepG2, HLE, HLF, HuH-1, JHH5, JHH7, and Li-7) in vitro. All HCC cell lines expressed the DNAX accessory molecule-1 ligands, poliovirus receptor, and Nectin-2, and γδ T cell-mediated killing of these cells was significantly enhanced by Zol. Small interfering RNA-mediated knockdown of these ligands did not affect the susceptibility to γδ T cell lysis. This killing activity was partly inhibited by mevastatin, an inhibitor of the mevalonate pathway, and markedly reduced by a monoclonal antibody to γ- and δ-chain T cell receptor, indicating that this is crucial for Zol-induced HCC killing. In addition, Zol-treated HCC cell lines triggered γδ T cell proliferation and induced production of Th1 and Th2, but not Th17, cytokines. The Zol concentration that enhanced HCC cell susceptibility to γδ T cell killing was lower than that required to directly inhibit HCC proliferation. Thus, γδ T cells may be important effector cells in the presence of Zol, especially where there are insufficient number of cancer antigen-specific CTLs to eliminate HCC. Our in vitro data support the proposal that Zol-treatment, combined with adaptive γδ T cell immunotherapy, may provide a feasible and effective

  8. Pharmacokinetics of para-Aminosalicylic Acid in HIV-Uninfected and HIV-Coinfected Tuberculosis Patients Receiving Antiretroviral Therapy, Managed for Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis

    PubMed Central

    de Kock, Lizanne; Sy, Sherwin K. B.; Diacon, Andreas H.; Prescott, Kim; Hernandez, Kenneth R.; Yu, Mingming; Derendorf, Hartmut; Donald, Peter R.

    2014-01-01

    The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis prompted the reintroduction of para-aminosalicylic acid (PAS) to protect companion anti-tuberculosis drugs from additional acquired resistance. In sub-Saharan Africa, MDR/XDR tuberculosis with HIV coinfection is common, and concurrent treatment of HIV infection and MDR/XDR tuberculosis is required. Out of necessity, patients receive multiple drugs, and PAS therapy is frequent; however, neither potential drug interactions nor the effects of HIV infection are known. Potential drug-drug interaction with PAS and the effect of HIV infection was examined in 73 pulmonary tuberculosis patients; 22 (30.1%) were HIV coinfected. Forty-one pulmonary MDR or XDR tuberculosis patients received 4 g PAS twice daily, and in a second crossover study, another 32 patients were randomized, receiving 4 g PAS twice daily or 8 g PAS once daily. A PAS population pharmacokinetic model in two dosing regimens was developed; potential covariates affecting its pharmacokinetics were examined, and Monte Carlo simulations were conducted evaluating the pharmacokinetic-pharmacodynamic index. The probability of target attainment (PTA) to maintain PAS levels above MIC during the dosing interval was estimated by simulation of once-, twice-, and thrice-daily dosing regimens not exceeding 12 g daily. Concurrent efavirenz (EFV) medication resulted in a 52% increase in PAS clearance and a corresponding >30% reduction in mean PAS area under the concentration curve in 19 of 22 HIV-M. tuberculosis-coinfected patients. Current practice recommends maintenance of PAS concentrations at ≥1 μg/ml (the MIC of M. tuberculosis), but the model predicts that at only a minimum dose of 4 g twice daily can this PTA be achieved in at least 90% of the population, whether or not EFV is concomitantly administered. Once-daily dosing of 12 g PAS will not provide PAS concentrations exceeding the MIC over the entire dosing

  9. Spaceborne receivers: Basic principles

    NASA Technical Reports Server (NTRS)

    Stacey, J. M.

    1984-01-01

    The underlying principles of operation of microwave receivers for space observations of planetary surfaces were examined. The design philosophy of the receiver as it is applied to operate functionally as an efficient receiving system, the principle of operation of the key components of the receiver, and the important differences among receiver types are explained. The operating performance and the sensitivity expectations for both the modulated and total power receiver configurations are outlined. The expressions are derived from first principles and are developed through the important intermediate stages to form practicle and easily applied equations. The transfer of thermodynamic energy from point to point within the receiver is illustrated. The language of microwave receivers is applied statistics.

  10. Solar heat receiver

    DOEpatents

    Hunt, A.J.; Hansen, L.J.; Evans, D.B.

    1982-09-29

    A receiver is described for converting solar energy to heat a gas to temperatures from 700 to 900/sup 0/C. The receiver is formed to minimize impingement of radiation on the walls and to provide maximum heating at and near the entry of the gas exit. Also, the receiver is formed to provide controlled movement of the gas to be heated to minimize wall temperatures. The receiver is designed for use with gas containing fine heat absorbing particles, such as carbon particles.

  11. Optical superheterodyne receiver.

    NASA Technical Reports Server (NTRS)

    Duval, K.; Lang, K.; Lucy, R. F.; Peters, C. J.

    1967-01-01

    Optical communication experiments to compare coherent and noncoherent optical detection fading characteristics in different weather conditions, using laser transmitter and optical superheterodyne receiver

  12. Hybrid receiver study

    NASA Technical Reports Server (NTRS)

    Stone, M. S.; Mcadam, P. L.; Saunders, O. W.

    1977-01-01

    The results are presented of a 4 month study to design a hybrid analog/digital receiver for outer planet mission probe communication links. The scope of this study includes functional design of the receiver; comparisons between analog and digital processing; hardware tradeoffs for key components including frequency generators, A/D converters, and digital processors; development and simulation of the processing algorithms for acquisition, tracking, and demodulation; and detailed design of the receiver in order to determine its size, weight, power, reliability, and radiation hardness. In addition, an evaluation was made of the receiver's capabilities to perform accurate measurement of signal strength and frequency for radio science missions.

  13. Data-fusion receiver

    DOEpatents

    Gabelmann, Jeffrey M.; Kattner, J. Stephen; Houston, Robert A.

    2006-12-19

    This invention is an ultra-low frequency electromagnetic telemetry receiver which fuses multiple input receive sources to synthesize a decodable message packet from a noise corrupted telemetry message string. Each block of telemetry data to be sent to the surface receiver from a borehole tool is digitally encoded into a data packet prior to transmission. The data packet is modulated onto the ULF EM carrier wave and transmitted from the borehole to the surface and then are simultaneously detected by multiple receive sensors disbursed within the rig environment. The receive sensors include, but are not limited to, electric field and magnetic field sensors. The spacing of the surface receive elements is such that noise generators are unequally coupled to each receive element due to proximity and/or noise generator type (i.e. electric or magnetic field generators). The receiver utilizes a suite of decision metrics to reconstruct the original, non noise-corrupted data packet from the observation matrix via the estimation of individual data frames. The receiver will continue this estimation process until: 1) the message validates, or 2) a preset "confidence threshold" is reached whereby frames within the observation matrix are no longer "trusted".

  14. Right to Receive.

    ERIC Educational Resources Information Center

    Oborn, Richard

    The concept of a United States citizen's right to receive information is acquiring increased judicial recognition. This report traces the evolution of that right from its philosophical basis in the United States Consitution, through its interpretation by the Supreme Court, up to the current concern that the public receive certain economic…

  15. CALUTRON RECEIVER STRUCTURE

    DOEpatents

    Roush, J.L.

    1959-09-01

    A receiver is described for collecting isotopes in a calutron The receiver has several compartments, formed by a sertes of parallel metal plates and an open front. Each plate has flanges which space it from the other plates and a flexible extension pressing against a common supporting red to maintain the plate in assembled relation when all but the last rod is removed. The plates may be removed individualy from the front of the receiver, cleaned ard replaced without disturbing the alignment of the other plates.

  16. Ultrasonic pulser-receiver

    SciTech Connect

    Taylor, Steven C.

    2006-09-12

    Ultrasonic pulser-receiver circuitry, for use with an ultrasonic transducer, the circuitry comprising a circuit board; ultrasonic pulser circuitry supported by the circuit board and configured to be coupled to an ultrasonic transducer and to cause the ultrasonic transducer to emit an ultrasonic output pulse; receiver circuitry supported by the circuit board, coupled to the pulser circuitry, including protection circuitry configured to protect against the ultrasonic pulse and including amplifier circuitry configured to amplify an echo, received back by the transducer, of the output pulse; and a connector configured to couple the ultrasonic transducer directly to the circuit board, to the pulser circuitry and receiver circuitry, wherein impedance mismatches that would result if the transducer was coupled to the circuit board via a cable can be avoided.

  17. Ceramic Solar Receiver

    NASA Technical Reports Server (NTRS)

    Robertson, C., Jr.

    1984-01-01

    Solar receiver uses ceramic honeycomb matrix to absorb heat from Sun and transfer it to working fluid at temperatures of 1,095 degrees and 1,650 degrees C. Drives gas turbine engine or provides heat for industrial processes.

  18. Solar energy receiver

    DOEpatents

    Schwartz, Jacob

    1978-01-01

    An improved long-life design for solar energy receivers provides for greatly reduced thermally induced stress and permits the utilization of less expensive heat exchanger materials while maintaining receiver efficiencies in excess of 85% without undue expenditure of energy to circulate the working fluid. In one embodiment, the flow index for the receiver is first set as close as practical to a value such that the Graetz number yields the optimal heat transfer coefficient per unit of pumping energy, in this case, 6. The convective index for the receiver is then set as closely as practical to two times the flow index so as to obtain optimal efficiency per unit mass of material.

  19. Receiver Gain Modulation Circuit

    NASA Technical Reports Server (NTRS)

    Jones, Hollis; Racette, Paul; Walker, David; Gu, Dazhen

    2011-01-01

    A receiver gain modulation circuit (RGMC) was developed that modulates the power gain of the output of a radiometer receiver with a test signal. As the radiometer receiver switches between calibration noise references, the test signal is mixed with the calibrated noise and thus produces an ensemble set of measurements from which ensemble statistical analysis can be used to extract statistical information about the test signal. The RGMC is an enabling technology of the ensemble detector. As a key component for achieving ensemble detection and analysis, the RGMC has broad aeronautical and space applications. The RGMC can be used to test and develop new calibration algorithms, for example, to detect gain anomalies, and/or correct for slow drifts that affect climate-quality measurements over an accelerated time scale. A generalized approach to analyzing radiometer system designs yields a mathematical treatment of noise reference measurements in calibration algorithms. By treating the measurements from the different noise references as ensemble samples of the receiver state, i.e. receiver gain, a quantitative description of the non-stationary properties of the underlying receiver fluctuations can be derived. Excellent agreement has been obtained between model calculations and radiometric measurements. The mathematical formulation is equivalent to modulating the gain of a stable receiver with an externally generated signal and is the basis for ensemble detection and analysis (EDA). The concept of generating ensemble data sets using an ensemble detector is similar to the ensemble data sets generated as part of ensemble empirical mode decomposition (EEMD) with exception of a key distinguishing factor. EEMD adds noise to the signal under study whereas EDA mixes the signal with calibrated noise. It is mixing with calibrated noise that permits the measurement of temporal-functional variability of uncertainty in the underlying process. The RGMC permits the evaluation of EDA by

  20. 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

  1. Highly directional acoustic receivers.

    PubMed

    Cray, Benjamin A; Evora, Victor M; Nuttall, Albert H

    2003-03-01

    The theoretical directivity of a single combined acoustic receiver, a device that can measure many quantities of an acoustic field at a collocated point, is presented here. The formulation is developed using a Taylor series expansion of acoustic pressure about the origin of a Cartesian coordinate system. For example, the quantities measured by a second-order combined receiver, denoted a dyadic sensor, are acoustic pressure, the three orthogonal components of acoustic particle velocity, and the nine spatial gradients of the velocity vector. The power series expansion, which can be of any order, is cast into an expression that defines the directivity of a single receiving element. It is shown that a single highly directional dyadic sensor can have a directivity index of up to 9.5 dB. However, there is a price to pay with highly directive sensors; these sensors can be significantly more sensitive to nonacoustic noise sources. PMID:12656387

  2. Central solar energy receiver

    DOEpatents

    Drost, M. Kevin

    1983-01-01

    An improved tower-mounted central solar energy receiver for heating air drawn through the receiver by an induced draft fan. A number of vertically oriented, energy absorbing, fin-shaped slats are radially arranged in a number of concentric cylindrical arrays on top of the tower coaxially surrounding a pipe having air holes through which the fan draws air which is heated by the slats which receive the solar radiation from a heliostat field. A number of vertically oriented and wedge-shaped columns are radially arranged in a number of concentric cylindrical clusters surrounding the slat arrays. The columns have two mirror-reflecting sides to reflect radiation into the slat arrays and one energy absorbing side to reduce reradiation and reflection from the slat arrays.

  3. Submillimeter wave heterodyne receiver

    NASA Technical Reports Server (NTRS)

    Chattopadhyay, Goutam (Inventor); Manohara, Harish (Inventor); Siegel, Peter H. (Inventor); Ward, John (Inventor)

    2011-01-01

    In an embodiment, a submillimeter wave heterodyne receiver includes a finline ortho-mode transducer comprising thin tapered metallic fins deposited on a thin dielectric substrate to separate a vertically polarized electromagnetic mode from a horizontally polarized electromagnetic mode. Other embodiments are described and claimed.

  4. Olympus beacon receiver

    NASA Technical Reports Server (NTRS)

    Ostergaard, Jens

    1988-01-01

    A medium-size Beacon Receiving System for reception and processing of the B1 (20 GHz) and B2 (30 GHz) beacons from Olympus has been developed. Integration of B1 and B2 receiving equipment into one system using one antenna and a common computer for control and data processing provides the advantages of a compact configuration and synchronization of the two receiver chains. Range for co-polar signal attenuation meaurement is about 30 dB for both beacons, increasing to 40 dB for B2 if the receivers are synchronized to B1. The accuracy is better than 0.5 dB. Cross-polarization discriminations of the order of 10 to 30 dB may be determined with an accuracy of 1 to 2 dB. A number of radiometers for complementary measurements of atmospheric attenuation of 13 to 30 GHz has also been constructed. A small multi-frequency system for operation around 22 GHz and 31 GHz is presently under development.

  5. Simplified OMEGA receivers

    NASA Technical Reports Server (NTRS)

    Burhans, R. W.

    1974-01-01

    The details are presented of methods for providing OMEGA navigational information including the receiver problem at the antenna and informational display and housekeeping systems based on some 4 bit data processing concepts. Topics discussed include the problem of limiters, zero crossing detectors, signal envelopes, internal timing circuits, phase counters, lane position displays, signal integrators, and software mapping problems.

  6. A digital beacon receiver

    NASA Technical Reports Server (NTRS)

    Ransome, Peter D.

    1988-01-01

    A digital satellite beacon receiver is described which provides measurement information down to a carrier/noise density ratio approximately 15 dB below that required by a conventional (phase locked loop) design. When the beacon signal fades, accuracy degrades gracefully, and is restored immediately (without hysteresis) on signal recovery, even if the signal has faded into the noise. Benefits of the digital processing approach used include the minimization of operator adjustments, stability of the phase measuring circuits with time, repeatability between units, and compatibility with equipment not specifically designed for propagation measuring. The receiver has been developed for the European Olympus satellite which has continuous wave (CW) beacons at 12.5 and 29.7 GHz, and a switched polarization beacon at 19.8 GHz approximately, but the system can be reconfigured for CW and polarization-switched beacons at other frequencies.

  7. Galileo probe relay receiver

    NASA Technical Reports Server (NTRS)

    Prouty, D. A.; Von Der Embse, U. A.

    1982-01-01

    For the Jovian mission, the data link from the Galileo probe to the orbiter uses suppressed-carrier Manchester encoded BPSK modulation and is protected with R = 1/2, K = 7 convolutional coding. The receiver closes the link by acquiring, tracking, and demodulating the data. It has to operate in a highly stressed environment with severe frequency offset, frequency rate, wind gust, and antenna spin conditions. Salient features are described and breadboard test data presented.

  8. Multichannel homodyne receiver

    DOEpatents

    Landt, Jeremy A.

    1982-01-01

    A homodyne radar transmitter/receiver device which produces a single combined output which contains modulated backscatter information for all phase conditions of both modulated and unmodulated backscatter signals. The device utilizes taps along coaxial transmission lines, strip transmission line, and waveguides which are spaced by 1/8 wavelength or 1/6 wavelength, etc. This greatly reduces costs by eliminating separate transmission and reception antennas and an expensive arrangement of power splitters and mixers utilized in the prior art.

  9. Multichannel homodyne receiver

    DOEpatents

    Landt, J.A.

    1981-01-19

    A homodyne radar transmitter/receiver device which produces a single combined output which contains modulated backscatter information for all phase conditions of both modulated and unmodulated backscatter signals is described. The device utilizes taps along coaxial transmission lines, strip transmission line, and waveguides which are spaced by 1/8 wavelength or 1/6 wavelength, etc. This greatly reduces costs by eliminating separate transmission and reception antennas and an expensive arrangement of power splitters and mixers utilized in the prior art.

  10. Low-level laser therapy supported teeth extractions of two patients receiving IV zolendronate.

    PubMed

    Kan, Bahadir; Altay, Mehmet Ali; Taşar, Ferda; Akova, Murat

    2011-09-01

    BRONJ (bisphosphonate-related osteonecrosis of jaws) is a frequently encountered disease, particularly in the maxillofacial region, and a consequence of bisphosphonate use. Treatment of BRONJ remains controversial, as efficiency of medical and surgical approaches as well as a combination of these methods with supportive treatments have not been clearly demonstrated in the literature. In recent years, laser usage alone or in combination with the main therapy methods, has become popular for the treatment of bisphosphonate-related osteo-necrosis of jaws. In this article, we present the successful management of two dental patients who had high potentials for BRONJ development as a result of chemo and radiotherapy combined with IV zoledronic acid application. Multiple consecutive teeth extractions followed with primary wound closure and LLLT applications were performed under high doses of antibiotics prophylaxis. Satisfactory wound healing in both the surrounding soft and hard tissues was achieved. LLLT application combined with atraumatic surgical interventions under antibiotics prophylaxis is a preferable approach in patients with a risk of BRONJ development. Adjunctive effect of LLLT in addition to careful infection control on preventing BRONJ was reported and concluded. PMID:20669038

  11. LANL receiver system development

    SciTech Connect

    Laubscher, B.; Cooke, B.; Cafferty, M.; Olivas, N.

    1997-08-01

    The CALIOPE receiver system development at LANL is the story of two technologies. The first of these technologies consists of off-the-shelf mercury-cadmium-telluride (MCT) detectors and amplifiers. The vendor for this system is Kolmar Technologies. This system was fielded in the Tan Trailer I (TTI) in 1995 and will be referred to in this paper as GEN I. The second system consists of a MCT detector procured from Santa Barbara Research Center (SBRC) and an amplifier designed and built by LANL. This system was fielded in the Tan Trailer II (TTII) system at the NTS tests in 1996 and will be referred to as GEN II. The LANL CALIOPE experimental plan for 1996 was to improve the lidar system by progressing to a higher rep rate laser to perform many shots in a much shorter period of time. In keeping with this plan, the receiver team set a goal of developing a detector system that was background limited for the projected 100 nanosecond (ns) laser pulse. A set of detailed simulations of the DIAL lidar experiment was performed. From these runs, parameters such as optimal detector size, field of view of the receiver system, nominal laser return power, etc. were extracted. With this information, detector physics and amplifier electronic models were developed to obtain the required specifications for each of these components. These derived specs indicated that a substantial improvement over commercially available, off-the-shelf, amplifier and detector technologies would be needed to obtain the goals. To determine if the original GEN I detector was usable, the authors performed tests on a 100 micron square detector at cryogenic temperatures. The results of this test and others convinced them that an advanced detector was required. Eventually, a suitable detector was identified and a number of these single element detectors were procured from SBRC. These single element detectors were witness for the detector arrays built for another DOE project.

  12. Garcinia Cambogia–Induced Acute Hepatitis; Varenicline-Induced Parkinsonism; Resistant Hypocalcemia After Zoledronic Acid Administration; Zonisamide-Induced Acute Kidney Injury; Psychosis Associated with Guanfacine;

    PubMed Central

    Mancano, Michael A.

    2015-01-01

    The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration’s (FDA’s) Med Watch program (800-FDA-1088). If you have reported an interesting, preventable ADR to Med Watch, please consider sharing the account with our readers. Write to Dr. Mancano at ISMP, 200 Lakeside Drive, Suite 200, Horsham, PA 19044 (phone: 215-707-4936; e-mail: mmancano@temple.edu). Your report will be published anonymously unless otherwise requested. This feature is provided by the Institute for Safe Medication Practices (ISMP) in cooperation with the FDA’s Med Watch program and Temple University School of Pharmacy. ISMP is an FDA Med Watch partner. PMID:26448666

  13. Garcinia Cambogia-Induced Acute Hepatitis; Varenicline-Induced Parkinsonism; Resistant Hypocalcemia After Zoledronic Acid Administration; Zonisamide-Induced Acute Kidney Injury; Psychosis Associated with Guanfacine.

    PubMed

    Mancano, Michael A

    2015-07-01

    The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration's (FDA's) Med Watch program (800-FDA-1088). If you have reported an interesting, preventable ADR to Med Watch, please consider sharing the account with our readers. Write to Dr. Mancano at ISMP, 200 Lakeside Drive, Suite 200, Horsham, PA 19044 (phone: 215-707-4936; e-mail: mmancano@temple.edu). Your report will be published anonymously unless otherwise requested. This feature is provided by the Institute for Safe Medication Practices (ISMP) in cooperation with the FDA's Med Watch program and Temple University School of Pharmacy. ISMP is an FDA Med Watch partner. PMID:26448666

  14. Ultra-wideband receiver

    DOEpatents

    McEwan, Thomas E.

    1994-01-01

    An ultra-wideband (UWB) receiver utilizes a strobed input line with a sampler connected to an amplifier. In a differential configuration, .+-.UWB inputs are connected to separate antennas or to two halves of a dipole antenna. The two input lines include samplers which are commonly strobed by a gating pulse with a very low duty cycle. In a single ended configuration, only a single strobed input line and sampler is utilized. The samplers integrate, or average, up to 10,000 pulses to achieve high sensitivity and good rejection of uncorrelated signals.

  15. Ultra-wideband receiver

    DOEpatents

    McEwan, Thomas E.

    1996-01-01

    An ultra-wideband (UWB) receiver utilizes a strobed input line with a sampler connected to an amplifier. In a differential configuration, .+-.UWB inputs are connected to separate antennas or to two halves of a dipole antenna. The two input lines include samplers which are commonly strobed by a gating pulse with a very low duty cycle. In a single ended configuration, only a single strobed input line and sampler is utilized. The samplers integrate, or average, up to 10,000 pulses to achieve high sensitivity and good rejection of uncorrelated signals.

  16. Ultra-wideband receiver

    DOEpatents

    McEwan, T.E.

    1996-06-04

    An ultra-wideband (UWB) receiver utilizes a strobed input line with a sampler connected to an amplifier. In a differential configuration, {+-}UWB inputs are connected to separate antennas or to two halves of a dipole antenna. The two input lines include samplers which are commonly strobed by a gating pulse with a very low duty cycle. In a single ended configuration, only a single strobed input line and sampler is utilized. The samplers integrate, or average, up to 10,000 pulses to achieve high sensitivity and good rejection of uncorrelated signals. 21 figs.

  17. Ultra-wideband receiver

    DOEpatents

    McEwan, T.E.

    1994-09-06

    An ultra-wideband (UWB) receiver utilizes a strobed input line with a sampler connected to an amplifier. In a differential configuration, [+-] UWB inputs are connected to separate antennas or to two halves of a dipole antenna. The two input lines include samplers which are commonly strobed by a gating pulse with a very low duty cycle. In a single ended configuration, only a single strobed input line and sampler is utilized. The samplers integrate, or average, up to 10,000 pulses to achieve high sensitivity and good rejection of uncorrelated signals. 16 figs.

  18. Weather Data Receiver

    NASA Technical Reports Server (NTRS)

    1982-01-01

    Northern Video Graphics, Inc. developed a low-cost satellite receiving system for users such as independent meteorologists, agribusiness firms, small airports or flying clubs, marine vessels and small TV stations. Called Video Fax, it is designed for use with certain satellites; the GOES (Geostationary Operational Environmental Satellite) spacecraft operated by the National Oceanic and Atmospheric Administration, the European Space Agency's Meteosat and Japan's Geostationary Meteorological Satellite. By dictum of the World Meteorological Organization, signals from satellites are available to anyone without cost so the Video Fax user can acquire signals directly from the satellite and cut out the middle man, enabling savings. Unit sells for about one-fifth the cost of the equipment used by TV stations. It consists of a two-meter antenna; a receiver; a microprocessor-controlled display computer; and a video monitor. Computer stores data from the satellites and converts it to an image which is displayed on the monitor. Weather map can be preserved as signal data on tape, or it can be stored in a video cassette as a permanent image.

  19. Digital Receiver Phase Meter

    NASA Technical Reports Server (NTRS)

    Marcin, Martin; Abramovici, Alexander

    2008-01-01

    The software of a commercially available digital radio receiver has been modified to make the receiver function as a two-channel low-noise phase meter. This phase meter is a prototype in the continuing development of a phase meter for a system in which radiofrequency (RF) signals in the two channels would be outputs of a spaceborne heterodyne laser interferometer for detecting gravitational waves. The frequencies of the signals could include a common Doppler-shift component of as much as 15 MHz. The phase meter is required to measure the relative phases of the signals in the two channels at a sampling rate of 10 Hz at a root power spectral density <5 microcycle/(Hz)1/2 and to be capable of determining the power spectral density of the phase difference over the frequency range from 1 mHz to 1 Hz. Such a phase meter could also be used on Earth to perform similar measurements in laser metrology of moving bodies. To illustrate part of the principle of operation of the phase meter, the figure includes a simplified block diagram of a basic singlechannel digital receiver. The input RF signal is first fed to the input terminal of an analog-to-digital converter (ADC). To prevent aliasing errors in the ADC, the sampling rate must be at least twice the input signal frequency. The sampling rate of the ADC is governed by a sampling clock, which also drives a digital local oscillator (DLO), which is a direct digital frequency synthesizer. The DLO produces samples of sine and cosine signals at a programmed tuning frequency. The sine and cosine samples are mixed with (that is, multiplied by) the samples from the ADC, then low-pass filtered to obtain in-phase (I) and quadrature (Q) signal components. A digital signal processor (DSP) computes the ratio between the Q and I components, computes the phase of the RF signal (relative to that of the DLO signal) as the arctangent of this ratio, and then averages successive such phase values over a time interval specified by the user.

  20. Solar thermal energy receiver

    NASA Technical Reports Server (NTRS)

    Baker, Karl W. (Inventor); Dustin, Miles O. (Inventor)

    1992-01-01

    A plurality of heat pipes in a shell receive concentrated solar energy and transfer the energy to a heat activated system. To provide for even distribution of the energy despite uneven impingement of solar energy on the heat pipes, absence of solar energy at times, or failure of one or more of the heat pipes, energy storage means are disposed on the heat pipes which extend through a heat pipe thermal coupling means into the heat activated device. To enhance energy transfer to the heat activated device, the heat pipe coupling cavity means may be provided with extensions into the device. For use with a Stirling engine having passages for working gas, heat transfer members may be positioned to contact the gas and the heat pipes. The shell may be divided into sections by transverse walls. To prevent cavity working fluid from collecting in the extensions, a porous body is positioned in the cavity.

  1. Advanced space solar dynamic receivers

    NASA Technical Reports Server (NTRS)

    Strumpf, Hal J.; Coombs, Murray G.; Lacy, Dovie E.

    1988-01-01

    A study has been conducted to generate and evaluate advanced solar heat receiver concepts suitable for orbital application with Brayton and Stirling engine cycles in the 7-kW size range. The generated receiver designs have thermal storage capability (to enable power production during the substantial eclipse period which accompanies typical orbits) and are lighter and smaller than state-of-the-art systems, such as the Brayton solar receiver being designed and developed by AiResearch for the NASA Space Station. Two receiver concepts have been developed in detail: a packed bed receiver and a heat pipe receiver. The packed bed receiver is appropriate for a Brayton engine; the heat pipe receiver is applicable for either a Brayton or Stirling engine. The thermal storage for both concepts is provided by the melting and freezing of a salt. Both receiver concepts offer substantial improvements in size and weight compared to baseline receivers.

  2. Anchorage Receives Record Snowfall

    NASA Technical Reports Server (NTRS)

    2002-01-01

    The forecast called for flurries, but the snow accumulated on the ground in Anchorage, Alaska, at the rate of 2 inches per hour (5 cm per hour) for much of Saturday, March 16, 2002. By the time the winter storm passed on Sunday afternoon, Anchorage had received 28.6 inches (72.6 cm) of snow, surpassing by far the previous record of 15.6 inches (39.6 cm) set on December 29, 1955. Flights were canceled and schools were closed as a result of the storm. This true-color image of Alaska was acquired by the Sea-viewing Wide Field-of-view Sensor (SeaWiFS), flying aboard the OrbView-2 satellite, on March 18. It appears another large, low-pressure system is heading toward the Anchorage region, which could bring substantially more snowfall. The low-pressure system can be identified by the characteristic spiral pattern of clouds located off Alaska's southwestern coast in this scene.

  3. ADMX Receiver and Analysis

    NASA Astrophysics Data System (ADS)

    Malagon, Ana; ADMX Collaboration

    2016-03-01

    ADMX looks for the excess radiation deposited into a cavity from the conversion of a dark matter axion into a microwave photon. The sensitivity of the experiment increases by reducing the background thermal noise and minimizing the electronic noise of the readout system. The axion masses that the experiment can detect are determined by the resonant frequency of the cavity mode of interest, which is tuned using a two rod configuration. One can also increase the search rate by measuring the output from two cavity modes at once, which requires two separate readout schemes. I will discuss the ADMX dual-channel receiver which has been upgraded to have near quantum-limited sensitivity on both channels, and describe how the correct modes are verified, using simulations, in the presence of dense electromagnetic structure. I conclude by describing upgrades to the ADMX analysis which allow for real-time exclusion limits. Supported by DOE Grants DE-FG02-97ER41029, DE-FG02-96ER40956, DE- AC52-07NA27344, DE-AC03-76SF00098, and the Livermore LDRD program.

  4. Real-time software receiver

    NASA Technical Reports Server (NTRS)

    Ledvina, Brent M. (Inventor); Psiaki, Mark L. (Inventor); Powell, Steven P. (Inventor); Kintner, Jr., Paul M. (Inventor)

    2007-01-01

    A real-time software receiver that executes on a general purpose processor. The software receiver includes data acquisition and correlator modules that perform, in place of hardware correlation, baseband mixing and PRN code correlation using bit-wise parallelism.

  5. Real-time software receiver

    NASA Technical Reports Server (NTRS)

    Ledvina, Brent M. (Inventor); Psiaki, Mark L. (Inventor); Powell, Steven P. (Inventor); Kintner, Jr., Paul M. (Inventor)

    2006-01-01

    A real-time software receiver that executes on a general purpose processor. The software receiver includes data acquisition and correlator modules that perform, in place of hardware correlation, baseband mixing and PRN code correlation using bit-wise parallelism.

  6. High temperature solar thermal receiver

    NASA Technical Reports Server (NTRS)

    1979-01-01

    A design concept for a high temperature solar thermal receiver to operate at 3 atmospheres pressure and 2500 F outlet was developed. The performance and complexity of windowed matrix, tube-header, and extended surface receivers were evaluated. The windowed matrix receiver proved to offer substantial cost and performance benefits. An efficient and cost effective hardware design was evaluated for a receiver which can be readily interfaced to fuel and chemical processes or to heat engines for power generation.

  7. High-temperature ceramic receivers

    SciTech Connect

    Jarvinen, P. O.

    1980-01-01

    An advanced ceramic dome cavity receiver is discussed which heats pressurized gas to temperatures above 1800/sup 0/F (1000/sup 0/C) for use in solar Brayton power systems of the dispersed receiver/dish or central receiver type. Optical, heat transfer, structural, and ceramic material design aspects of the receiver are reported and the development and experimental demonstration of a high-temperature seal between the pressurized gas and the high-temperature silicon carbide dome material is described.

  8. Receiving signals of any polarization

    NASA Technical Reports Server (NTRS)

    Ohlson, J. E.; Seidel, B. L.; Stelzried, C. H.

    1981-01-01

    Two-channel detection accomodates linear, circular, and elliptical polarization in one receiving unit. Receiver employs orthomode transducer which breaks any type signal into one left and one right circular component. These are processed in separate receiver channels with equal time-delay, and then recombined for data extraction. System eliminates losses due to polarization mismatch.

  9. Reflux solar receiver design considerations

    NASA Astrophysics Data System (ADS)

    Diver, R. B.

    Reflux heat-pipe and pool-boiler receivers are being developed to improve upon the performance and life of directly-illuminated tube receiver technology used in previous successful demonstrations of dish-Stirling systems. The design of a reflux receiver involves engineering tradeoffs. In this paper, on-sun performance measurements of the Sandia pool-boiler receiver are compared with results from the reflux receiver thermal analysis model, AEETES. Flux and performance implications of various design options are analyzed and discussed.

  10. Advanced solar thermal receiver technology

    NASA Technical Reports Server (NTRS)

    Kudirka, A. A.; Leibowitz, L. P.

    1980-01-01

    Development of advanced receiver technology for solar thermal receivers designed for electric power generation or for industrial applications, such as fuels and chemical production or industrial process heat, is described. The development of this technology is focused on receivers that operate from 1000 F to 3000 F and above. Development strategy is mapped in terms of application requirements, and the related system and technical requirements. Receiver performance requirements and current development efforts are covered for five classes of receiver applications: high temperature, advanced Brayton, Stirling, and Rankine cycle engines, and fuels and chemicals.