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Zoledronic Acid (zoledronic + acid)
Kinds of Zoledronic Acid Selected AbstractsEfficacy and Safety of a Once-Yearly Intravenous Zoledronic Acid 5 mg for Fracture Prevention in Elderly Postmenopausal Women with Osteoporosis Aged 75 and OlderJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 2 2010Steven Boonen MD OBJECTIVES: To determine the efficacy of once-yearly intravenous zoledronic acid (ZOL) 5 mg in reducing risk of clinical vertebral, nonvertebral, and any clinical fractures in elderly osteoporotic postmenopausal women. DESIGN: A post hoc subgroup analysis of pooled data from the Health Outcome and Reduced Incidence with Zoledronic Acid One Yearly (HORIZON) Pivotal Fracture Trial and the HORIZON Recurrent Fracture Trial. SETTING: Multicenter, randomized, double-blind, placebo-controlled trials. PARTICIPANTS: Postmenopausal women (aged ,75) with documented osteoporosis (T -score ,,2.5 at femoral neck or ,1 prevalent vertebral or hip fracture) or a recent hip fracture. INTERVENTION: Patients were randomized to receive an intravenous infusion of ZOL 5 mg (n=1,961) or placebo (n=1,926) at baseline and 12 and 24 months. MEASUREMENTS: Primary endpoints were incidence of clinical vertebral and nonvertebral and any clinical fracture after treatment. RESULTS: At 3 years, incidence of any clinical, clinical vertebral, and nonvertebral fracture were significantly lower in the ZOL group than in the placebo group (10.8% vs 16.6%, 1.1% vs 3.7%, and 9.9% vs 13.7%, respectively) (hazard ratio (HR)=0.65, 95% confidence interval (CI)=0.54,0.78, P<.001; HR=0.34, 95% CI=0.21,0.55, P<.001; and HR=0.73, 95% CI=0.60,0.90, P=.002, respectively). The incidence of hip fracture was lower with ZOL but did not reach statistical significance. The incidence rate of postdose adverse events were higher with ZOL, although the rate of serious adverse events and deaths was comparable between the two groups. CONCLUSION: Once-yearly intravenous ZOL 5 mg was associated with a significant reduction in the risk of new clinical fractures (vertebral and nonvertebral) in elderly postmenopausal women with osteroporosis. [source] Long-Term Protective Effects of Zoledronic Acid on Cancellous and Cortical Bone in the Ovariectomized Rat,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 4 2008Jürg A Gasser PhD Abstract Current bisphosphonate therapies effectively prevent bone loss in postmenopausal women. We studied the effect of a single intravenous dose of ZOL in ovariectomized rats. Protection from bone loss was dose dependent, lasting for up to 32 weeks, supporting the rationale for an annual intravenous dosing regimen of ZOL for treatment of postmenopausal osteoporosis. Introduction: Once-yearly dosing with zoledronic acid (ZOL) 5 mg can increase BMD and reduce fracture rate in postmenopausal women with low BMD. The primary objective of this study was to determine the duration of bone protective effects of a single dose of ZOL in ovariectomized rats, an animal model of postmenopausal osteopenia. Secondary objectives were to determine the effects on bone turnover and mechanical properties. Materials and Methods: Female Wistar rats (10 per group) received single intravenous doses of ZOL 0.8, 4, 20, 100, or 500 ,g/kg, alendronate 200 ,g/kg, or isotonic saline 4 days before bilateral ovariectomy. Sham-operated controls were pretreated with saline. Mass and density of cancellous and cortical bone (pQCT) were measured at 4-wk intervals for 32 wk. Bone architecture (,CT), bone formation dynamics (fluorochrome label-based histomorphometry), and biomechanical strength in compression testing were also assessed at 32 wk. Results: Ovariectomy-associated BMD loss was significantly attenuated for 32 wk by ZOL ,4 ,g/kg for total BMD, ZOL ,20 ,g/kg for cortical BMD, and ZOL ,4 ,g/kg for cancellous BMD (p < 0.01 versus ovariectomized controls). Alendronate 200 ,g/kg was of equivalent potency to ZOL 20 ,g/kg. Ovariectomy-associated decreases in trabecular architectural parameters were dose-dependently attenuated by ZOL. Alendronate 200 ,g/kg was equivalent to ZOL 20 ,g/kg. The bone resorption marker TRACP5b indicated transient suppression of elevated osteoclast activity by ZOL relative to OVX-rats even at the lowest dose of 0.8 ,g/kg, whereas at 100,500 ,g/kg, the effect was significant relative to the OVX control for the entire duration of the study of 32 wk. Bone formation parameters were not significantly affected by ZOL 20 ,g/kg but were significantly reduced by ZOL 100,500 ,g/kg. Alendronate 200 ,g/kg was equivalent to ZOL 100 ,g/kg. ZOL produced dose-related improvements in bone strength parameters after ovariectomy. Alendronate 200 ,g/kg was of similar potency to ZOL 20 ,g/kg. Conclusions: The duration and magnitude of the bone-protecting effect of a single intravenous dose of ZOL in ovariectomized rats is dose dependent and lasts for up to 32 wk. Compared with alendronate, ZOL shows 10-fold higher potency in preventing bone loss. These data support the use of an annual intravenous ZOL dosing regimen for the treatment of osteoporosis. [source] Editorial: Positive Effects of Intravenous Zoledronic Acid on Bone Remodeling and Structure: Are Different Effects on Osteoblast Activity to Other Oral Bisphosphonates Responsible?,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2008Peter R Ebeling MD No Abstracts. [source] Pharmacologic profile of zoledronic acid: A highly potent inhibitor of bone resorptionDRUG DEVELOPMENT RESEARCH, Issue 4 2002Jonathan R. Green Abstract Bisphosphonates are effective in treating benign and malignant skeletal diseases characterized by enhanced osteoclastic bone resorption (i.e., osteoporosis, Paget's disease, tumor-induced osteolysis). The nitrogen-containing bisphosphonate pamidronate is currently the standard treatment for hypercalcemia of malignancy (HCM) and skeletal complications of bone metastases. Zoledronic acid, a novel nitrogen-containing bisphosphonate with an imidazole substituent, has demonstrated more potent inhibition of osteoclast-mediated bone resorption than all other bisphosphonates, including pamidronate, in both in vitro and in vivo preclinical models. Zoledronic acid inhibited ovariectomy-induced bone loss in adult monkeys and rats, and long-term treatment prevented skeletal turnover and subsequent bone loss, reduced cortical porosity, and increased mechanical strength. Zoledronic acid also significantly inhibited bone loss associated with arthritis, bone metastases, and prosthesis loosening. The increased potency of zoledronic acid vs. pamidronate has been demonstrated clinically: zoledronic acid (4 or 8 mg iv) was superior to pamidronate (90 mg iv) in normalizing corrected serum calcium in patients with HCM. In patients with bone metastases, low doses of zoledronic acid (, 2 mg) suppressed bone resorption markers , 50% below baseline, whereas pamidronate 90 mg yielded only 20 to 30% suppression. Importantly, the increased potency of zoledronic acid is not associated with an increased incidence of local (bone) or systemic adverse events. Zoledronic acid does not impair bone mineralization and, compared with pamidronate, has a greater renal and intestinal tolerability therapeutic index. Thus, based on preclinical assays and clinical data, zoledronic acid is the most potent bisphosphonate tested to date. Given its potency and excellent safety profile, zoledronic acid is now poised to become the new standard of treatment for HCM and metastatic bone disease. Drug Dev. Res. 55:210,224, 2002. © 2002 Wiley-Liss, Inc. [source] Zoledronic acid prevents bone loss after allogeneic haemopoietic stem cell transplantationINTERNAL MEDICINE JOURNAL, Issue 9 2006A. B. D'Souza Abstract Allogeneic haemopoietic stem cell transplant (alloHSCT) patients are at increased risk of osteoporosis. Zoledronic acid (ZA) is a potent i.v. bisphosphonate; however, there are few data on ZA use after alloHSCT. The aim of this study is to examine the effect of a single 4 mg ZA infusion in alloHSCT patients with either osteoporosis (T -score < ,2.5) or rapid bone loss post-alloHSCT. An uncontrolled, prospective study of 12 consecutive patients receiving ZA, predominantly within the first year post-HSCT. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry at the spine and proximal femur pretransplant, pre-ZA and post-ZA. The median annualized percentage change in total hip BMD between the pretransplant scan and the scan immediately before ZA was ,13% (range, ,51 to +3.6%). After ZA treatment, the total hip BMD increased by a median of +3.3% (range, ,20.4 to +14.8%) in 75% of patients. The median annualized percentage change in femoral neck BMD between the pretransplant scan and the scan immediately before ZA was ,13.2% (range, ,40 to +1.0%). Post-ZA, femoral neck BMD increased by a median of +1.4% (range, ,22.2 to +33.6%). Only one patient continued to lose bone from the femoral neck post-ZA infusion. The median annualized percentage change in spinal BMD pretransplant was ,12.5% (range, ,38 to +6.9%). Post-ZA, spinal BMD decreased by a median of ,2.8% (range, ,27.6 to +24.4%). Four patients continued to lose bone from the spine post-ZA. ZA reduces bone loss in most patients after alloHSCT. Our data require confirmation in a larger prospective, randomized study. [source] Bone turnover 18 months after a single intravenous dose of zoledronic acidINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 6 2007V. Z. C. Borba Summary Zoledronic acid inhibits bone resorption for up to 12 months. It is not known whether the duration of this antiresorptive effect extends beyond this period of time. The aim of this study was to evaluate the changes in bone turnover at 12 months (T12) and 18 months (T18) after a single injection of 4 mg of zoledronic acid. It is a prospective, longitudinal study, with a follow-up for 18 months. We studied male and female patients (60.5 ± 11.0 years old), with low bone mineral density (BMD) coming from the outpatient clinic in a metabolic bone unit of a tertiary care hospital. All patients received a single intravenous dose of 4 mg of zoledronic acid, bone turnover markers [serum carboxyterminal telopeptide of type I collagen (CTX-I), bone-specific alkaline phosphatase (BSAP)] and BMD [lumbar spine (LS) and total hip (TH)] were measured at baseline, and after 12 months (T12) and 18 months (T18). Median serum CTX-I and BSAP levels were suppressed at T12 in comparison with baseline values: 0.183 to 0.039 ng/ml for CTX-I (p = 0.0002) and 16.95 to 13.96 U/l for BSAP (p = 0.005). At T18, both CTX-I and BSAP continued to be suppressed below baseline at 0.108 ng/ml and 12.23 U/l (p = 0.009 and p = 0.02, vs. T0). Significant increases in BMD at T18 as compared with T12 were observed in patients (median increase 6.1% for LS and 2.0% for TH). Zoledronic acid inhibits bone turnover effectively for 12 months, with evidence for continued suppression and gains in BMD even after 18 months. [source] Zoledronic acid improves femoral head sphericity in a rat model of perthes diseaseJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 4 2005David G. Little Abstract We hypothesized that the bisphosphonate zoledronic acid (ZA) could improve femoral head sphericity in Perthes disease by changing the balance between bone resorption and new bone formation. This study tests the effect of ZA in an established model of Perthes disease, the spontaneously hypertensive rat (SHR). One hundred and twenty 4-week old SHR rats were divided into three groups of 40: saline monthly, 0.015 mg/kg ZA weekly, or 0.05 mg/kg ZA monthly. At 15 weeks DXA measurements documented that femoral head BMD was increased by 18% in ZA weekly and 21% in ZA monthly compared to controls (p < 0.01). Femoral head sphericity in animals with osteonecrosis was improved in ZA-treatment groups (p < 0.01) as measured by epiphyseal quotient (EQ). The proportion of "flat" heads (EQ ± 0.40) was significantly reduced from 32% in saline-treated animals to 12% in weekly ZA and 3% in monthly ZA (p < 0.01). Histologically there was a similar prevalence of osteonecrosis in all groups. The prevalence of ossification delay was significantly reduced by ZA treatment (p < 0.01). Zoledronic acid favorably altered femoral head shape in this spontaneous model of osteonecrosis in growing rats. Translation of these results to Perthes disease could mean that deformity of the femoral head may be modified in children, perhaps reducing the need for surgical intervention in childhood and adult life. © 2005 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved. [source] Zoledronic acid for the treatment of osteopenia in pediatric Crohn's diseasePEDIATRICS INTERNATIONAL, Issue 5 2010Anne Marie Sbrocchi Abstract Background:, Pediatric patients with Crohn's disease often have low bone mass (osteopenia) for age. No randomized, placebo-controlled trials using zoledronic acid have ever been performed in this population. The objective of this study was to assess the efficacy of zoledronic acid in children with Crohn's disease and osteopenia. Methods:, A double-blind, randomized, placebo-controlled design was used. Thirteen adolescents received either a single intravenous dose of zoledronic acid (0.066 mg/kg, max 4 mg, n= 7) or saline placebo (n= 6). The primary outcome was change in lumbar spine bone mineral density (LSBMD) z-score at 6 months. Secondary outcomes included bone markers and adverse events. Results:, At 6 months, the change in LSBMD z-score was significantly higher in the zoledronic acid group compared to placebo (0.7 vs 0.1, P < 0.001). Volumetrically adjusted LSBMD z-score also significantly increased in the treated group. This significant difference persisted until 12 months. With zoledronic acid, urinary C-telopeptide excretion decreased by 50% at 6 months and remained suppressed at 12 months (P= 0.02), but no changes were observed with placebo. Both groups had similar adverse events which included transient fever, arthralgias, and nausea (3/7 treated, 2/6 placebo, P= NS). Conclusions:, In this study, zoledronic acid demonstrated a significant increase in LSBMD at 6 and 12 months following a well-tolerated infusion. [source] Latest news and product developmentsPRESCRIBER, Issue 22 2007Article first published online: 28 DEC 200 Glitazones: benefits outweigh the risks Following a review of the safety of rosiglitazone and pioglitazone, the European Medicines Agency (EMEA) has concluded that their benefits outweigh their risks in the approved indications. The review was prompted by reports of an increased risk of fractures in women and, in patients taking rosiglitazone, ischaemic heart disease. The EMEA concluded that prescribing information for rosiglitazone should now include a warning that, in patients with ischaemic heart disease, it should only be used after careful evaluation of each patient's individual risk, and the combination of rosiglitazone and insulin should only be used in exceptional cases and under close supervision. No change was considered necessary to the prescribing information for pioglitazone. Modern dressings no better? A systematic review has found only weak evidence that modern dressings are better than saline gauze or paraffin gauze for healing acute and chronic wounds (Arch Dermatol 2007;143: 1297-304). The analysis, which included 99 studies, found that only hydrocolloids were demonstrably better than older dressings for healing chronic wounds, and alginates were superior to other modern dressings for debriding necrotic wounds. There was no evidence that modern dressings offered superior overall performance to the older alternatives. Hospital inflation twice primary care level The cost of drugs prescribed in secondary care but dispensed in the community increased by 6.4 per cent in 2006 - twice the rate of inflation in primary care - according to the latest statistics on hospital prescribing in England. The increase follows a reduction in costs in 2005 after the introduction of the new PPRS scheme. Data from The Information Centre (www.ic.nhs.uk) show that hospital medicines make up about 24 per cent of the NHS drugs budget. Secondary care has a consistently better record than primary care in prescribing lower-cost alternatives within therapeutic categories, eg simvastatin and pravastatin among the statins, omeprazole and lansoprazole among PPIs, and ACE inhibitors among drugs acting on the renin angiotensin system. The most expensive drug prescribed by hospital specialists and dispensed in the community is interferon beta. MHRA limits the use of fibrates The Medicines and Healthcare products Regulatory Agency (MHRA) has advised that fibrates should now be reserved for the treatment of isolated severe hypertriglyceridaemia. They should be considered for hypercholesterolaemia only when a statin or other treatment is contraindicated or not tolerated. In the latest Drug Safety Update, the MHRA says there is insufficient evidence of long-term benefits from fibrates, and first-line use is no longer justified because the evidence for the benefits of statins is robust. The MHRA also warns that some breastfeeding infants have increased susceptibility to the adverse effects of codeine taken by their mother, and that St John's wort may affect the hepatic metabolism of any anticonvulsant. Annual zoledronic acid infusion cuts mortality after hip fracture Once-yearly infusion of zoledronic acid (Aclasta) after hip fracture reduces deaths over a two-year period by 28 per cent compared with placebo, US investigators say (N Engl J Med 2007;357:1799-809). The HORIZON Recurrent Fracture Trial randomised 2127 men and women (mean age 75) within 90 days of surgery for hip fracture to zoledronic acid 5mg yearly or placebo. Mortality over 1.9 years of follow-up was 9.6 per cent with zoledronic acid and 13.3 per cent with placebo. Zoledronic acid also significantly reduced the rate of any new clinical fractures (by 35 per cent) and new clinical vertebral fractures(by 45 per cent),but the lower rate of hip fracture (2.0 vs 3.5 per cent with placebo) was not statistically significant. Rivastigmine patch for mild to moderate AD Rivastigmine (Exelon) is now available as a transdermal patch for the treatment of mild to moderate Alzheimer's disease. Applied once daily, the patch delivers 9.5mg per 24 hours and, says manufacturer Novartis, is associated with a lower incidence of nausea and vomiting than a comparable oral dose. The patch is available in two strengths: 4.6mg per 24hr is equivalent to oral doses of 3 or 6mg per day, and the 9.5mg per 24hr patch is equivalent to 9 or 12mg per day orally. The recommended dose of the patch is 9.5mg per day; both strengths cost £83.84 for 30 patches. Women more aspirin resistant than men? The cardioprotective effect of low-dose aspirin may be lower in women than men, say Canadian investigators (BMC Medicine 2007;5:29 doi: 10.1186/1741-70155-29). Their meta-analysis of 23 randomised trials involving a total of 113 494 participants found that aspirin significantly reduced the risk of nonfatal but not fatal myocardial infarction (MI). About one-quarter of the variation in its effects on nonfatal MI was accounted for by the sex mix of the trial population. Separating the results by sex showed the reduction in risk with aspirin use was statistically significant in men (relative risk, RR, 0.62) but not in women (RR 0.87). Look after physical health of mentally ill GPs and other primary care workers should take more responsibility for the physical health of their mentally ill patients, say advocacy groups. Mind and Body: Preventing and Improving Physical Health Problems in Patients With Schizophrenia points out that the mental health needs of patients with schizophrenia are met in secondary care, but their physical health needs should be met in primary care. In particular, the metabolic effects of antipsychotics may lead to obesity, diabetes and cardiovascular disease, and weight gain in particular is a frequent reason for nonadherence to treatment. The Mind and Body Manifesto was developed by SANE, The Mental Health Nurses Association, The National Obesity Forum and The Disability Rights Commission and sponsored by Bristol-Myers Squibb Pharmaceuticals Limited and Otsuka Pharmaceuticals (UK) Ltd. Copies are available from elizabeth.green@ ogilvyhealthworld.com. Health eCard costs Some costs quoted in our article on the Health eCard (The Health eCard: the way ahead for medical records?,5 October issue, pages 28-9) have been revised: the card and initial download will cost patients £39.50, and GPs will be entitled to charge patients £10 per annum for subsequent downloads. NICE appraisals of cytokine inhibitors in RA NICE has endorsed the use of the anti-TNF agents adalimumab (Humira), etanercept (Enbrel) and infliximab (Remicade), normally in conjunction with methotrexate, for the treatment of active RA when methotrexate and another DMARD have failed (also see New from NICE below). NICE has provisionally concluded, subject to consultation, that abatacept (Orencia) should not be recommended for the treatment of RA. Boots and BMJ launch health advice site www.askbootshealth.com is a new website providing information about health and medicines for the public produced by Boots using information provided by the BMJ Publishing Group. The website covers many of the topics already available from NHSDirect, with perhaps more information about available treatments. Diabetes care shows small improvement The third National Diabetes Audit in England and Wales has found that more people with diabetes were achieving the targets set by NICE for cholesterol levels, glycaemic control and blood pressure in 2005/06 - but younger patients were doing less well. Overall, the HbA1C target of ,7.5 per cent was achieved in 60 per cent of people with diabetes compared with 58 per cent in 2004/05. However, HbA1C was >9.5 per cent in 30 per cent of children and young people, of whom 9 per cent experienced at least one episode of ketoacidosis. More topics for NICE New topics referred to NICE include clinical guidelines on ovarian cancer, coeliac disease and stable angina, public health guidance on preventing cardiovascular disease, and technology appraisals on insulin detemir (Levemir) for type 1 diabetes, several treatments for cancer and hepatic and haematological disorders, and biological therapies for juvenile arthritis. New from NICE NICE appraisal on anti-TNFs for RA Since NICE published its first appraisal of agents acting against tumour necrosis factor-alpha (anti-TNFs) for the treatment of RA in 2002, the product licences for etanercept (Enbrel) and infliximab (Remicade) have changed and a new agent, adalimumab (Humira), has been introduced. The anti-TNFs act in different ways. Infliximab is a chimeric monoclonal antibody that binds to TNF-alpha, neutralising its activity. Etanercept, a recombinant human TNF-alpha receptor fusion protein, and adalimumab, a human-sequence antibody, both bind to TNF-alpha and block its interaction with cell surface receptors. Adalimumab also modulates some biological responses induced or regulated by TNF-alpha. These agents are recommended for adults with severe active RA (defined as a disease activity score - DAS28 - greater than 5.1) who have already tried two disease-modifying drugs, including methotrexate (if not contraindicated). Prior treatment should have been of at least six months' duration, including two months at the standard dose (unless limited by toxicity). Anti-TNFs should normally be prescribed with methotrexate; when this is not appropriate, etanercept and adalimumab may be prescribed as monotherapy. Treatment with an anti-TNF should be continued beyond six months only if there is an adequate response (defined as an improvement in DAS28 of at least 1.2). Data from the British Rheumatology Society Biologics register show that, after six months, 67 per cent of patients met NICE criteria for an adequate response; this declined to 55 per cent at 18 months. The basic annual cost of treatment is £9295 for adalimumab 40mg on alternate weeks or etanercept 25mg twice weekly; infliximab costs £3777 for a loading dose, then £7553-£8812 depending on dose. Assuming no progression of disability, the incremental costs per QALY (compared with sequential DMARDs) were £30 200 for adalimumab, £24 600 for etanercept and £39 400 for infliximab. There are no direct comparative trials of the anti-TNFs, and their clinical trial findings are not directly comparable. Unless other factors determine treatment choice, NICE therefore recommends the least expensive. If the first anti-TNF is withdrawn within six months due to an adverse event, a second may be tried. [source] Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesionCANCER, Issue 1 2004Lee S. Rosen M.D. Abstract BACKGROUND Treatment with zoledronic acid (Zol) was compared with a dose of 90 mg of pamidronate (Pam) in breast carcinoma (BC) patients with at least 1 osteolytic lesion based on data from a Phase III, randomized trial. METHODS Overall, 1130 patients with breast carcinoma who had all types of bone metastases (osteolytic, mixed, or osteoblastic by radiology) were randomized to receive treatment with either 4 mg of Zol or 8 mg of Zol as a 15-minute infusion or 90 mg of Pam as a 2-hour infusion every 3,4 weeks for 12 months. A skeletal-related event (SRE) was defined as a pathologic fracture, spinal cord compression, radiotherapy, or surgery to bone. RESULTS Among all patients with BC, the proportion of those who had an SRE (primary endpoint) was comparable between treatment groups (43% of patients who received 4 mg of Zol vs. 45% of patients who received Pam). Among patients who had breast carcinoma with at least 1 osteolytic lesion (n = 528 patients), the proportion with an SRE was lower in the 4-mg Zol group compared with the Pam group (48% vs. 58%), but this did not reach statistical significance (P = 0.058). The time to first SRE was significantly longer in the 4-mg Zol group compared with the Pam group (median, 310 vs. 174 days; P = 0.013). Moreover, multiple-event analysis demonstrated significant further reductions in the risk of developing SREs over the reduction achieved with Pam (30% in the osteolytic subset [P = 0.010] and 20% for all patients with BC [P = 0.037]). CONCLUSIONS The current data indicate that treatment with 4 mg of Zol was more effective than 90 mg of Pam in reducing skeletal complications in a subset of patients with breast carcinoma who had at least 1 osteolytic lesion at study entry. Cancer 2004;100:36,43. © 2003 American Cancer Society. [source] Zoledronic acid delays the onset of skeletal-related events and progression of skeletal disease in patients with advanced renal cell carcinomaCANCER, Issue 5 2003Allan Lipton M.D. Abstract BACKGROUND The objective of this study was to assess the efficacy and safety of zoledronic acid in patients with bone metastases secondary to renal cell carcinoma (RCC). METHODS A retrospective subset analysis of patients with RCC enrolled in a multicenter, randomized, placebo-controlled study of zoledronic acid was performed. Patients were randomized to receive zoledronic acid (4 or 8 mg as a 15-minute infusion) or placebo with concomitant antineoplastic therapy every 3 weeks for 9 months. The primary efficacy analysis was the proportion of patients with one or more skeletal-related events (SREs), which were defined as pathologic fracture, spinal cord compression, radiation therapy, or surgery to bone. Secondary analyses included time to first SRE, skeletal morbidity rate (events per year), disease progression, and multiple event analysis. RESULTS In this subset of 74 patients with RCC, zoledronic acid (4 mg) was found to significantly reduce the proportion of patients with an SRE (37% vs. 74% for placebo; P = 0.015). Similarly, zoledronic acid significantly reduced the mean skeletal morbidity rate (2.68 vs. 3.38 for placebo; P = 0.014) and extended the time to the first event (median not reached vs. 72 days for placebo; P = 0.006). A multiple event analysis demonstrated that the risk of developing an SRE was reduced by 61% compared with placebo (hazard ratio of 0.394; P = 0.008). The median time to progression of bone lesions was significantly longer for patients who were treated with zoledronic acid (P = 0.014 vs. placebo). Zoledronic acid appeared to be well tolerated; the most common adverse events in all treatment groups included bone pain, nausea, anemia, and emesis. CONCLUSIONS Zoledronic acid (4 mg as a 15-minute infusion) demonstrated significant clinical benefit in patients with bone metastases from RCC, suggesting that further investigation of zoledronic acid in this patient population is warranted. Cancer 2003;98:962,9. © 2003 American Cancer Society. DOI 10.1002/cncr.11571 [source] Pharmacologic profile of zoledronic acid: A highly potent inhibitor of bone resorptionDRUG DEVELOPMENT RESEARCH, Issue 4 2002Jonathan R. Green Abstract Bisphosphonates are effective in treating benign and malignant skeletal diseases characterized by enhanced osteoclastic bone resorption (i.e., osteoporosis, Paget's disease, tumor-induced osteolysis). The nitrogen-containing bisphosphonate pamidronate is currently the standard treatment for hypercalcemia of malignancy (HCM) and skeletal complications of bone metastases. Zoledronic acid, a novel nitrogen-containing bisphosphonate with an imidazole substituent, has demonstrated more potent inhibition of osteoclast-mediated bone resorption than all other bisphosphonates, including pamidronate, in both in vitro and in vivo preclinical models. Zoledronic acid inhibited ovariectomy-induced bone loss in adult monkeys and rats, and long-term treatment prevented skeletal turnover and subsequent bone loss, reduced cortical porosity, and increased mechanical strength. Zoledronic acid also significantly inhibited bone loss associated with arthritis, bone metastases, and prosthesis loosening. The increased potency of zoledronic acid vs. pamidronate has been demonstrated clinically: zoledronic acid (4 or 8 mg iv) was superior to pamidronate (90 mg iv) in normalizing corrected serum calcium in patients with HCM. In patients with bone metastases, low doses of zoledronic acid (, 2 mg) suppressed bone resorption markers , 50% below baseline, whereas pamidronate 90 mg yielded only 20 to 30% suppression. Importantly, the increased potency of zoledronic acid is not associated with an increased incidence of local (bone) or systemic adverse events. Zoledronic acid does not impair bone mineralization and, compared with pamidronate, has a greater renal and intestinal tolerability therapeutic index. Thus, based on preclinical assays and clinical data, zoledronic acid is the most potent bisphosphonate tested to date. Given its potency and excellent safety profile, zoledronic acid is now poised to become the new standard of treatment for HCM and metastatic bone disease. Drug Dev. Res. 55:210,224, 2002. © 2002 Wiley-Liss, Inc. [source] Relevance of a new rat model of osteoblastic metastases from prostate carcinoma for preclinical studies using zoledronic acidINTERNATIONAL JOURNAL OF CANCER, Issue 4 2008François Lamoureux Abstract Animal models that mimic osteoblastic metastases associated with prostate carcinoma are required to improve the therapeutic options in humans. A new model was then developed and characterized in immunocompetent rats. The bisphosphonate zoledronic acid (ZOL) was tested to validate this model as a therapeutic application. Rat AT6-1 prostate tumor cells were characterized in vitro at the transcriptional (bone and epithelial markers) and functional (induction of mineralized nodules) levels. The bone lesions induced after their direct injection into the femur bone marrow were characterized by radiography, microscanner and histology analyses. ZOL effects were studied in vivo on bone lesion development and in vitro on AT6-1 cell proliferation, apoptosis and cell cycle analysis. Apart from epithelial markers, AT6-1 cells express an osteoblast phenotype as they express osteoblastic markers and are able to induce mineralized nodule formation in vitro. A disorganization of the trabecular bone at the growth zone level was observed in vivo after intraosseous AT6-1 cell injection as well as cortical erosion. The tumor itself is associated with bone formation as revealed by SEM analysis and polarized light microscopy. ZOL prevents the development of such osteoblastic lesions, related to a direct inhibitory effect on tumor cell proliferation independent of caspase 3 activation, but associated with cell cycle arrest. A new rat model of osteoblastic bone metastases was validated in immunocompetent rats and used to show the relevance of using ZOL in such lesions, as this compound shows bifunctional effects on both bone remodelling and tumor cell proliferation. © 2007 Wiley-Liss, Inc. [source] Bone turnover 18 months after a single intravenous dose of zoledronic acidINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 6 2007V. Z. C. Borba Summary Zoledronic acid inhibits bone resorption for up to 12 months. It is not known whether the duration of this antiresorptive effect extends beyond this period of time. The aim of this study was to evaluate the changes in bone turnover at 12 months (T12) and 18 months (T18) after a single injection of 4 mg of zoledronic acid. It is a prospective, longitudinal study, with a follow-up for 18 months. We studied male and female patients (60.5 ± 11.0 years old), with low bone mineral density (BMD) coming from the outpatient clinic in a metabolic bone unit of a tertiary care hospital. All patients received a single intravenous dose of 4 mg of zoledronic acid, bone turnover markers [serum carboxyterminal telopeptide of type I collagen (CTX-I), bone-specific alkaline phosphatase (BSAP)] and BMD [lumbar spine (LS) and total hip (TH)] were measured at baseline, and after 12 months (T12) and 18 months (T18). Median serum CTX-I and BSAP levels were suppressed at T12 in comparison with baseline values: 0.183 to 0.039 ng/ml for CTX-I (p = 0.0002) and 16.95 to 13.96 U/l for BSAP (p = 0.005). At T18, both CTX-I and BSAP continued to be suppressed below baseline at 0.108 ng/ml and 12.23 U/l (p = 0.009 and p = 0.02, vs. T0). Significant increases in BMD at T18 as compared with T12 were observed in patients (median increase 6.1% for LS and 2.0% for TH). Zoledronic acid inhibits bone turnover effectively for 12 months, with evidence for continued suppression and gains in BMD even after 18 months. [source] Efficacy and Safety of a Once-Yearly Intravenous Zoledronic Acid 5 mg for Fracture Prevention in Elderly Postmenopausal Women with Osteoporosis Aged 75 and OlderJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 2 2010Steven Boonen MD OBJECTIVES: To determine the efficacy of once-yearly intravenous zoledronic acid (ZOL) 5 mg in reducing risk of clinical vertebral, nonvertebral, and any clinical fractures in elderly osteoporotic postmenopausal women. DESIGN: A post hoc subgroup analysis of pooled data from the Health Outcome and Reduced Incidence with Zoledronic Acid One Yearly (HORIZON) Pivotal Fracture Trial and the HORIZON Recurrent Fracture Trial. SETTING: Multicenter, randomized, double-blind, placebo-controlled trials. PARTICIPANTS: Postmenopausal women (aged ,75) with documented osteoporosis (T -score ,,2.5 at femoral neck or ,1 prevalent vertebral or hip fracture) or a recent hip fracture. INTERVENTION: Patients were randomized to receive an intravenous infusion of ZOL 5 mg (n=1,961) or placebo (n=1,926) at baseline and 12 and 24 months. MEASUREMENTS: Primary endpoints were incidence of clinical vertebral and nonvertebral and any clinical fracture after treatment. RESULTS: At 3 years, incidence of any clinical, clinical vertebral, and nonvertebral fracture were significantly lower in the ZOL group than in the placebo group (10.8% vs 16.6%, 1.1% vs 3.7%, and 9.9% vs 13.7%, respectively) (hazard ratio (HR)=0.65, 95% confidence interval (CI)=0.54,0.78, P<.001; HR=0.34, 95% CI=0.21,0.55, P<.001; and HR=0.73, 95% CI=0.60,0.90, P=.002, respectively). The incidence of hip fracture was lower with ZOL but did not reach statistical significance. The incidence rate of postdose adverse events were higher with ZOL, although the rate of serious adverse events and deaths was comparable between the two groups. CONCLUSION: Once-yearly intravenous ZOL 5 mg was associated with a significant reduction in the risk of new clinical fractures (vertebral and nonvertebral) in elderly postmenopausal women with osteroporosis. [source] Atrial fibrillation and bisphosphonate therapyJOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2010Michael Pazianas Abstract Bisphosphonates are the most commonly used treatment for osteoporosis and have proven efficacy in the reduction of vertebral and nonvertebral fractures. Recently, concerns have been raised about a possible association between bisphosphonate therapy and atrial fibrillation (AF) following the report of a significant increase in risk of serious AF in women treated with zoledronic acid in the HORIZON study. Subsequent studies have produced conflicting results but have not excluded the possibility of such an association. Currently there is no direct evidence that bisphosphonates exert either acute or chronic effects on cardiac electrophysiology. Nevertheless, altered intracellular electrolyte homeostasis and proinflammatory, profibrotic, and antiangiogenic effects provide potential mechanisms by which atrial conduction could be affected in patients treated with bisphosphonates. In studies in which an increase in risk of AF has been identified, there is no evidence that this translates into increased mortality or increased risk of stroke, and the risk-benefit balance of bisphosphonate therapy in patients with osteoporosis and other forms of metabolic bone disease remains strongly positive. © 2010 American Society for Bone and Mineral Research [source] Antifracture Efficacy and Reduction of Mortality in Relation to Timing of the First Dose of Zoledronic Acid After Hip Fracture,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2009Erik Fink Eriksen Abstract Annual infusions of zoledronic acid (5 mg) significantly reduced the risk of vertebral, hip, and nonvertebral fractures in a study of postmenopausal women with osteoporosis and significantly reduced clinical fractures and all-cause mortality in another study of women and men who had recently undergone surgical repair of hip fracture. In this analysis, we examined whether timing of the first infusion of zoledronic acid study drug after hip fracture repair influenced the antifracture efficacy and mortality benefit observed in the study. A total of 2127 patients (1065 on active treatment and 1062 on placebo; mean age, 75 yr; 76% women and 24% men) were administered zoledronic acid or placebo within 90 days after surgical repair of an osteoporotic hip fracture and annually thereafter, with a median follow-up time of 1.9 yr. Median time to first dose after the incident hip fracture surgery was ,6 wk. Posthoc analyses were performed by dividing the study population into 2-wk intervals (calculated from time of first infusion in relation to surgical repair) to examine effects on BMD, fracture, and mortality. Analysis by 2-wk intervals showed a significant total hip BMD response and a consistent reduction of overall clinical fractures and mortality in patients receiving the first dose 2-wk or later after surgical repair. Clinical fracture subgroups (vertebral, nonvertebral, and hip) were also reduced, albeit with more variation and 95% CIs crossing 1 at most time points. We concluded that administration of zoledronic acid to patients suffering a low-trauma hip fracture 2 wk or later after surgical repair increases hip BMD, induces significant reductions in the risk of subsequent clinical vertebral, nonvertebral, and hip fractures, and reduces mortality. [source] Long-Term Protective Effects of Zoledronic Acid on Cancellous and Cortical Bone in the Ovariectomized Rat,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 4 2008Jürg A Gasser PhD Abstract Current bisphosphonate therapies effectively prevent bone loss in postmenopausal women. We studied the effect of a single intravenous dose of ZOL in ovariectomized rats. Protection from bone loss was dose dependent, lasting for up to 32 weeks, supporting the rationale for an annual intravenous dosing regimen of ZOL for treatment of postmenopausal osteoporosis. Introduction: Once-yearly dosing with zoledronic acid (ZOL) 5 mg can increase BMD and reduce fracture rate in postmenopausal women with low BMD. The primary objective of this study was to determine the duration of bone protective effects of a single dose of ZOL in ovariectomized rats, an animal model of postmenopausal osteopenia. Secondary objectives were to determine the effects on bone turnover and mechanical properties. Materials and Methods: Female Wistar rats (10 per group) received single intravenous doses of ZOL 0.8, 4, 20, 100, or 500 ,g/kg, alendronate 200 ,g/kg, or isotonic saline 4 days before bilateral ovariectomy. Sham-operated controls were pretreated with saline. Mass and density of cancellous and cortical bone (pQCT) were measured at 4-wk intervals for 32 wk. Bone architecture (,CT), bone formation dynamics (fluorochrome label-based histomorphometry), and biomechanical strength in compression testing were also assessed at 32 wk. Results: Ovariectomy-associated BMD loss was significantly attenuated for 32 wk by ZOL ,4 ,g/kg for total BMD, ZOL ,20 ,g/kg for cortical BMD, and ZOL ,4 ,g/kg for cancellous BMD (p < 0.01 versus ovariectomized controls). Alendronate 200 ,g/kg was of equivalent potency to ZOL 20 ,g/kg. Ovariectomy-associated decreases in trabecular architectural parameters were dose-dependently attenuated by ZOL. Alendronate 200 ,g/kg was equivalent to ZOL 20 ,g/kg. The bone resorption marker TRACP5b indicated transient suppression of elevated osteoclast activity by ZOL relative to OVX-rats even at the lowest dose of 0.8 ,g/kg, whereas at 100,500 ,g/kg, the effect was significant relative to the OVX control for the entire duration of the study of 32 wk. Bone formation parameters were not significantly affected by ZOL 20 ,g/kg but were significantly reduced by ZOL 100,500 ,g/kg. Alendronate 200 ,g/kg was equivalent to ZOL 100 ,g/kg. ZOL produced dose-related improvements in bone strength parameters after ovariectomy. Alendronate 200 ,g/kg was of similar potency to ZOL 20 ,g/kg. Conclusions: The duration and magnitude of the bone-protecting effect of a single intravenous dose of ZOL in ovariectomized rats is dose dependent and lasts for up to 32 wk. Compared with alendronate, ZOL shows 10-fold higher potency in preventing bone loss. These data support the use of an annual intravenous ZOL dosing regimen for the treatment of osteoporosis. [source] Early Detection of Bone Metastases in a Murine Model Using Fluorescent Human Breast Cancer Cells: Application to the Use of the Bisphosphonate Zoledronic Acid in the Treatment of Osteolytic LesionsJOURNAL OF BONE AND MINERAL RESEARCH, Issue 11 2001Olivier Peyruchaud Abstract A very common metastatic site for human breast cancer is bone. The traditional bone metastasis model requires human MDA-MB-231 breast carcinoma cell inoculation into the left heart ventricle of nude mice. MDA-MB-231 cells usually develop osteolytic lesions 3,4 weeks after intracardiac inoculation in these animals. Here, we report a new approach to study the formation of bone metastasis in animals using breast carcinoma cells expressing the bioluminescent jellyfish protein (green fluorescent protein [GFP]). We first established a subclone of MDA-MB-231 cells by repeated in vivo passages in bone using the heart injection model. On stable transfection of this subclone with an expression vector for GFP and subsequent inoculation of GFP-expressing tumor cells (B02/GFP.2) in the mouse tail vein, B02/GFP.2 cells displayed a unique predilection for dissemination to bone. Externally fluorescence imaging of live animals allowed the detection of fluorescent bone metastases approximately 1 week before the occurrence of radiologically distinctive osteolytic lesions. The number, size, and intensity of fluorescent bone metastases increased progressively with time and was indicative of breast cancer cell progression within bone. Histological examination of fluorescent long bones from B02/GFP.2-bearing mice revealed the occurrence of profound bone destruction. Treatment of B02/GFP.2-bearing mice with the bisphosphonate zoledronic acid markedly inhibited the progression of established osteolytic lesions and the expansion of breast cancer cells within bone. Overall, this new bone metastasis model of breast cancer combining both fluorescence imaging and radiography should provide an invaluable tool to study the effectiveness of pharmaceutical agents that could suppress cancer colonization in bone. [source] Recent developments in the management of postmenopausal osteoporosis with bisphosphonates: enhanced efficacy by enhanced complianceJOURNAL OF INTERNAL MEDICINE, Issue 4 2008S. Boonen Abstract. Bisphosphonates are the current mainstay of treatment for postmenopausal osteoporosis. Although daily oral dosing is effective, it is associated with poor compliance, partly because of the pre and postdose fasting and posture requirements. This negatively impacts treatment outcomes, leading to a reduced clinical benefit. Improved, yet still suboptimal adherence has been noticed with less frequent bisphosphonate dosing e.g. once-weekly and once-monthly oral regimens. The recently approved quarterly intravenous (i.v.) injection regimen of ibandronate and yearly i.v. infusion of zoledronic acid are attractive options in the management of postmenopausal osteoporosis. These regimens may assure quarterly and year long compliance. [source] Addition of bisphosphonate to antibiotic and anti-inflammatory treatment reduces bone resorption in experimental Staphylococcus aureus -induced arthritisJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 3 2007Margareta Verdrengh Abstract Bacterial arthritis is a disease with high morbidity leading to rapidly progressive bone resorption. We have shown earlier that treatment with antibiotics in combination with corticosteroids decreases joint inflammation and mortality but does not significantly affect bone/cartilage destruction of the joints. This study was performed to assess the effect of treatment with bisphosphonate [zoledronic acid (ZA)] in combination with antibiotics and corticosteroids, on the course and outcome of Staphlococcus aureus -induced arthritis. Three days after intravenous inoculation with S. aureus, mice were treated with antibiotics alone, ZA alone, ZA and antibiotics, or ZA combined with antibiotics and corticosteroids, respectively. One group served as controls and received PBS. Clinical assessment of arthritis was performed as well as histological analysis of bone and cartilage destruction in the joints. One femur from each mouse was collected for bone mineral density (BMD) analysis. In addition, serum levels of type I collagen fragments (RatLaps), and osteocalcin, markers for osteoclastic and osteoblastic activity, respectively, were analyzed. Mice treated with ZA and antibiotics or with ZA in combination with antibiotics and corticosteroids lost significantly less in trabecular bone density compared to infected control mice. Furthermore, the addition of corticosteroids to animals treated with ZA and antibiotics, significantly decreased serum levels of RatLaps and osteocalcin, compared to animals treated with ZA and antibiotics or ZA alone. Treatment with bisphosphonates in combination with antimicrobial agents and corticosteroids significantly decreases the activity of osteoclasts in septic arthritis, thereby reducing the risk of skeletal destruction. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res [source] Anticancer effects of zoledronic acid against human osteosarcoma cellsJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 6 2006B. Kubista Abstract Based on neoadjuvant chemotherapy, the prognosis of osteosarcoma patients has improved dramatically. However, due to therapy resistance in patient subgroups, the development of new treatment strategies is still of utmost importance. The aim of our study was to test the effects of the nitrogen-containing bisphosphonate zoledronic acid (ZOL) on osteosarcoma cell lines (N,=,9). Exposure to ZOL at low micromolar concentrations induced a dose- and time-dependent block of DNA synthesis and cell cycle progression followed by microfilament breakdown and apoptosis induction. The ZOL-induced cell cycle accumulation in S phase was accompanied by significant changes in the expression of cyclins and cyclin-dependent kinase inhibitors with a prominent loss of cyclin E and D1. ZOL not only inhibited growth but also migration of osteosarcoma cells. The mevalonate pathway intermediary geranyl-geraniol (GGOH) but not farnesol (FOH) significantly inhibited the anticancer effects of ZOL against osteosarcoma cells. Correspondingly, ZOL sensitivity correlated with the blockade of protein geranylgeranylation indicated by unprenylated Rap1. Overexpression of even high levels of P-glycoprotein, as frequently present in therapy-resistant osteosarcomas, did not impair the anticancer activity of ZOL. Summarizing, our data suggest that ZOL, which selectively accumulates in the bone, represents a promising agent to improve osteosarcoma therapy. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res [source] Zoledronic acid improves femoral head sphericity in a rat model of perthes diseaseJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 4 2005David G. Little Abstract We hypothesized that the bisphosphonate zoledronic acid (ZA) could improve femoral head sphericity in Perthes disease by changing the balance between bone resorption and new bone formation. This study tests the effect of ZA in an established model of Perthes disease, the spontaneously hypertensive rat (SHR). One hundred and twenty 4-week old SHR rats were divided into three groups of 40: saline monthly, 0.015 mg/kg ZA weekly, or 0.05 mg/kg ZA monthly. At 15 weeks DXA measurements documented that femoral head BMD was increased by 18% in ZA weekly and 21% in ZA monthly compared to controls (p < 0.01). Femoral head sphericity in animals with osteonecrosis was improved in ZA-treatment groups (p < 0.01) as measured by epiphyseal quotient (EQ). The proportion of "flat" heads (EQ ± 0.40) was significantly reduced from 32% in saline-treated animals to 12% in weekly ZA and 3% in monthly ZA (p < 0.01). Histologically there was a similar prevalence of osteonecrosis in all groups. The prevalence of ossification delay was significantly reduced by ZA treatment (p < 0.01). Zoledronic acid favorably altered femoral head shape in this spontaneous model of osteonecrosis in growing rats. Translation of these results to Perthes disease could mean that deformity of the femoral head may be modified in children, perhaps reducing the need for surgical intervention in childhood and adult life. © 2005 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved. [source] Updates on bisphosphonates and potential pathobiology of bisphosphonate-induced jaw osteonecrosisORAL DISEASES, Issue 3 2008J Sarin Osteonecrosis of the jaws is a major complication associated with long-term use of bisphosphonates. While osteonecrosis can arise from other precipitating conditions, bisphosphonate-induced jaw osteonecrosis (BJON) is highly associated with long-term administration of pamidronate (Aredia®) and zoledronic acid (Zometa®), which are two intravenous bisphosphonate formulations. The underlying pathogenesis of BJON and its site-specific presentation still remain to be fully elucidated. This review will discuss clinically available bisphosphonates, current opinions, pathogenesis, and management guidelines for bisphosphonate-induced jaw osteonecrosis. [source] Ovariectomy stimulates and bisphosphonates inhibit intracortical remodeling in the mouse mandibleORTHODONTICS & CRANIOFACIAL RESEARCH, Issue 4 2010DJ Kubek To cite this article: Kubek DJ, Burr DB, Allen MR: Ovariectomy stimulates and bisphosphonates inhibit intracortical remodeling in the mouse mandible Orthod Craniofac Res 2010;13:214,222 Structured Abstract Authors,,, Kubek DJ, Burr DB, Allen MR Objective,,, The pathophysiology of osteonecrosis of the jaw (ONJ) is thought to be linked to suppression of intracortical remodeling. The aim of this study was to determine whether mice, which normally do not undergo appreciable amounts of intracortical remodeling, could be stimulated by ovariectomy to remodel within the cortex of the mandible and if bisphosphonates (BPs) would suppress this intracortical remodeling. Material and Methods,,, Skeletally mature female C3H mice were either ovariectomized (OVX) or SHAM operated and treated with two intravenous doses of zoledronic acid (ZOL, 0.06 mg/kg body weight) or vehicle (VEH). This ZOL dose corresponds to the dose given to patients with cancer on a mg/kg basis, adjusted for body weight. Calcein was administered prior to sacrifice to label active formation sites. Dynamic histomorphometry of the mandible and femur was performed. Results,,, Vehicle-treated OVX animals had significantly higher (eightfold) intracortical remodeling of the alveolar portion of the mandible compared to sham , this was significantly suppressed by ZOL treatment. At all skeletal sites, overall bone formation rate was lower with ZOL treatment compared to the corresponding VEH group. Conclusions,,, Under normal conditions, the level of intracortical remodeling in the mouse mandible is minimal but in C3H mice it can be stimulated to appreciable levels with ovariectomy. Based on this, if the suppression of intracortical remodeling is found to be part of the pathophysiology of ONJ, the ovariectomized C3H mouse could serve as a useful tool for studying this condition. [source] Zoledronic acid for the treatment of osteopenia in pediatric Crohn's diseasePEDIATRICS INTERNATIONAL, Issue 5 2010Anne Marie Sbrocchi Abstract Background:, Pediatric patients with Crohn's disease often have low bone mass (osteopenia) for age. No randomized, placebo-controlled trials using zoledronic acid have ever been performed in this population. The objective of this study was to assess the efficacy of zoledronic acid in children with Crohn's disease and osteopenia. Methods:, A double-blind, randomized, placebo-controlled design was used. Thirteen adolescents received either a single intravenous dose of zoledronic acid (0.066 mg/kg, max 4 mg, n= 7) or saline placebo (n= 6). The primary outcome was change in lumbar spine bone mineral density (LSBMD) z-score at 6 months. Secondary outcomes included bone markers and adverse events. Results:, At 6 months, the change in LSBMD z-score was significantly higher in the zoledronic acid group compared to placebo (0.7 vs 0.1, P < 0.001). Volumetrically adjusted LSBMD z-score also significantly increased in the treated group. This significant difference persisted until 12 months. With zoledronic acid, urinary C-telopeptide excretion decreased by 50% at 6 months and remained suppressed at 12 months (P= 0.02), but no changes were observed with placebo. Both groups had similar adverse events which included transient fever, arthralgias, and nausea (3/7 treated, 2/6 placebo, P= NS). Conclusions:, In this study, zoledronic acid demonstrated a significant increase in LSBMD at 6 and 12 months following a well-tolerated infusion. [source] Latest news and product developmentsPRESCRIBER, Issue 22 2007Article first published online: 28 DEC 200 Glitazones: benefits outweigh the risks Following a review of the safety of rosiglitazone and pioglitazone, the European Medicines Agency (EMEA) has concluded that their benefits outweigh their risks in the approved indications. The review was prompted by reports of an increased risk of fractures in women and, in patients taking rosiglitazone, ischaemic heart disease. The EMEA concluded that prescribing information for rosiglitazone should now include a warning that, in patients with ischaemic heart disease, it should only be used after careful evaluation of each patient's individual risk, and the combination of rosiglitazone and insulin should only be used in exceptional cases and under close supervision. No change was considered necessary to the prescribing information for pioglitazone. Modern dressings no better? A systematic review has found only weak evidence that modern dressings are better than saline gauze or paraffin gauze for healing acute and chronic wounds (Arch Dermatol 2007;143: 1297-304). The analysis, which included 99 studies, found that only hydrocolloids were demonstrably better than older dressings for healing chronic wounds, and alginates were superior to other modern dressings for debriding necrotic wounds. There was no evidence that modern dressings offered superior overall performance to the older alternatives. Hospital inflation twice primary care level The cost of drugs prescribed in secondary care but dispensed in the community increased by 6.4 per cent in 2006 - twice the rate of inflation in primary care - according to the latest statistics on hospital prescribing in England. The increase follows a reduction in costs in 2005 after the introduction of the new PPRS scheme. Data from The Information Centre (www.ic.nhs.uk) show that hospital medicines make up about 24 per cent of the NHS drugs budget. Secondary care has a consistently better record than primary care in prescribing lower-cost alternatives within therapeutic categories, eg simvastatin and pravastatin among the statins, omeprazole and lansoprazole among PPIs, and ACE inhibitors among drugs acting on the renin angiotensin system. The most expensive drug prescribed by hospital specialists and dispensed in the community is interferon beta. MHRA limits the use of fibrates The Medicines and Healthcare products Regulatory Agency (MHRA) has advised that fibrates should now be reserved for the treatment of isolated severe hypertriglyceridaemia. They should be considered for hypercholesterolaemia only when a statin or other treatment is contraindicated or not tolerated. In the latest Drug Safety Update, the MHRA says there is insufficient evidence of long-term benefits from fibrates, and first-line use is no longer justified because the evidence for the benefits of statins is robust. The MHRA also warns that some breastfeeding infants have increased susceptibility to the adverse effects of codeine taken by their mother, and that St John's wort may affect the hepatic metabolism of any anticonvulsant. Annual zoledronic acid infusion cuts mortality after hip fracture Once-yearly infusion of zoledronic acid (Aclasta) after hip fracture reduces deaths over a two-year period by 28 per cent compared with placebo, US investigators say (N Engl J Med 2007;357:1799-809). The HORIZON Recurrent Fracture Trial randomised 2127 men and women (mean age 75) within 90 days of surgery for hip fracture to zoledronic acid 5mg yearly or placebo. Mortality over 1.9 years of follow-up was 9.6 per cent with zoledronic acid and 13.3 per cent with placebo. Zoledronic acid also significantly reduced the rate of any new clinical fractures (by 35 per cent) and new clinical vertebral fractures(by 45 per cent),but the lower rate of hip fracture (2.0 vs 3.5 per cent with placebo) was not statistically significant. Rivastigmine patch for mild to moderate AD Rivastigmine (Exelon) is now available as a transdermal patch for the treatment of mild to moderate Alzheimer's disease. Applied once daily, the patch delivers 9.5mg per 24 hours and, says manufacturer Novartis, is associated with a lower incidence of nausea and vomiting than a comparable oral dose. The patch is available in two strengths: 4.6mg per 24hr is equivalent to oral doses of 3 or 6mg per day, and the 9.5mg per 24hr patch is equivalent to 9 or 12mg per day orally. The recommended dose of the patch is 9.5mg per day; both strengths cost £83.84 for 30 patches. Women more aspirin resistant than men? The cardioprotective effect of low-dose aspirin may be lower in women than men, say Canadian investigators (BMC Medicine 2007;5:29 doi: 10.1186/1741-70155-29). Their meta-analysis of 23 randomised trials involving a total of 113 494 participants found that aspirin significantly reduced the risk of nonfatal but not fatal myocardial infarction (MI). About one-quarter of the variation in its effects on nonfatal MI was accounted for by the sex mix of the trial population. Separating the results by sex showed the reduction in risk with aspirin use was statistically significant in men (relative risk, RR, 0.62) but not in women (RR 0.87). Look after physical health of mentally ill GPs and other primary care workers should take more responsibility for the physical health of their mentally ill patients, say advocacy groups. Mind and Body: Preventing and Improving Physical Health Problems in Patients With Schizophrenia points out that the mental health needs of patients with schizophrenia are met in secondary care, but their physical health needs should be met in primary care. In particular, the metabolic effects of antipsychotics may lead to obesity, diabetes and cardiovascular disease, and weight gain in particular is a frequent reason for nonadherence to treatment. The Mind and Body Manifesto was developed by SANE, The Mental Health Nurses Association, The National Obesity Forum and The Disability Rights Commission and sponsored by Bristol-Myers Squibb Pharmaceuticals Limited and Otsuka Pharmaceuticals (UK) Ltd. Copies are available from elizabeth.green@ ogilvyhealthworld.com. Health eCard costs Some costs quoted in our article on the Health eCard (The Health eCard: the way ahead for medical records?,5 October issue, pages 28-9) have been revised: the card and initial download will cost patients £39.50, and GPs will be entitled to charge patients £10 per annum for subsequent downloads. NICE appraisals of cytokine inhibitors in RA NICE has endorsed the use of the anti-TNF agents adalimumab (Humira), etanercept (Enbrel) and infliximab (Remicade), normally in conjunction with methotrexate, for the treatment of active RA when methotrexate and another DMARD have failed (also see New from NICE below). NICE has provisionally concluded, subject to consultation, that abatacept (Orencia) should not be recommended for the treatment of RA. Boots and BMJ launch health advice site www.askbootshealth.com is a new website providing information about health and medicines for the public produced by Boots using information provided by the BMJ Publishing Group. The website covers many of the topics already available from NHSDirect, with perhaps more information about available treatments. Diabetes care shows small improvement The third National Diabetes Audit in England and Wales has found that more people with diabetes were achieving the targets set by NICE for cholesterol levels, glycaemic control and blood pressure in 2005/06 - but younger patients were doing less well. Overall, the HbA1C target of ,7.5 per cent was achieved in 60 per cent of people with diabetes compared with 58 per cent in 2004/05. However, HbA1C was >9.5 per cent in 30 per cent of children and young people, of whom 9 per cent experienced at least one episode of ketoacidosis. More topics for NICE New topics referred to NICE include clinical guidelines on ovarian cancer, coeliac disease and stable angina, public health guidance on preventing cardiovascular disease, and technology appraisals on insulin detemir (Levemir) for type 1 diabetes, several treatments for cancer and hepatic and haematological disorders, and biological therapies for juvenile arthritis. New from NICE NICE appraisal on anti-TNFs for RA Since NICE published its first appraisal of agents acting against tumour necrosis factor-alpha (anti-TNFs) for the treatment of RA in 2002, the product licences for etanercept (Enbrel) and infliximab (Remicade) have changed and a new agent, adalimumab (Humira), has been introduced. The anti-TNFs act in different ways. Infliximab is a chimeric monoclonal antibody that binds to TNF-alpha, neutralising its activity. Etanercept, a recombinant human TNF-alpha receptor fusion protein, and adalimumab, a human-sequence antibody, both bind to TNF-alpha and block its interaction with cell surface receptors. Adalimumab also modulates some biological responses induced or regulated by TNF-alpha. These agents are recommended for adults with severe active RA (defined as a disease activity score - DAS28 - greater than 5.1) who have already tried two disease-modifying drugs, including methotrexate (if not contraindicated). Prior treatment should have been of at least six months' duration, including two months at the standard dose (unless limited by toxicity). Anti-TNFs should normally be prescribed with methotrexate; when this is not appropriate, etanercept and adalimumab may be prescribed as monotherapy. Treatment with an anti-TNF should be continued beyond six months only if there is an adequate response (defined as an improvement in DAS28 of at least 1.2). Data from the British Rheumatology Society Biologics register show that, after six months, 67 per cent of patients met NICE criteria for an adequate response; this declined to 55 per cent at 18 months. The basic annual cost of treatment is £9295 for adalimumab 40mg on alternate weeks or etanercept 25mg twice weekly; infliximab costs £3777 for a loading dose, then £7553-£8812 depending on dose. Assuming no progression of disability, the incremental costs per QALY (compared with sequential DMARDs) were £30 200 for adalimumab, £24 600 for etanercept and £39 400 for infliximab. There are no direct comparative trials of the anti-TNFs, and their clinical trial findings are not directly comparable. Unless other factors determine treatment choice, NICE therefore recommends the least expensive. If the first anti-TNF is withdrawn within six months due to an adverse event, a second may be tried. [source] Bisphosphonate-related osteonecrosis of the jaw and its associated risk factors: A belgian case seriesTHE LARYNGOSCOPE, Issue 2 2009Sven Saussez MD Abstract Objectives: Bisphosphonate-related osteonecrosis of the jaw (BROJ) is a serious oral complication of bisphosphonate (BP) treatment involving the exposure of necrotic maxillary or mandibular bone. Our purpose is to describe the clinical presentation of 34 cases of BROJ and to identify potential risk factors. Study Design: A retrospective study was performed in four Belgian institutions. Methods: Complete medical histories were recorded and analyzed. These data include age, gender, initial disease requiring BP, type and duration of BP treatment, symptomatology and location of BROJ, prior dental procedures, treatment of the BROJ and treatment outcome, and radiographic, histological, and microbiological data. Results: Bisphosphonates (BP) were used in the management of disseminated cancers in 30 patients (88.5% of total studied), while four patients received BP due to osteoporosis (11.5%). The most frequently used BP was zoledronic acid in 29 patients (83%). Microbiological data obtained in 25 patients demonstrated that 72% of these patients were infected or colonized by an actinomyces. Eight of the 14 patients (57%) who received only medical treatment were cured. Of the 20 patients who underwent surgical treatments, only four were completely cured (20%). BROJ lesions smaller than 1 cm are associated with better prognosis in terms of treatment outcomes (P = .0009). Local treatments combined with long-term antibiotics are also correlated with better prognosis (P = .02). Conclusions: Lesions smaller than 1 cm and lesions that were subject to medical treatments are associated with a better outcome. Surgical treatments appear to be non-beneficial for BROJ. Laryngoscope, 119:323,329, 2009 [source] Bone microenvironment-related growth factors modulate differentially the anticancer actions of zoledronic acid and doxorubicin on PC-3 prostate cancer cellsTHE PROSTATE, Issue 2 2004Roxane Tenta Abstract OBJECTIVES We analyzed the actions of zoledronic acid (10,250 ,M) and doxorubicin (10,250 nM) on PC-3 prostate cancer cells using both continuous (48,96 hr) and pulsatile exposures (15 min/day for up to three consecutive days). RESULTS The proliferation of PC-3 cells was inhibited by either continuous or pulsatile exposures of zoledronic acid in a dose-dependent manner. In contrast, pulsatile exposures of doxorubicin failed to inhibit the growth of PC-3 cells. In addition, the inhibition of PC-3 cells by zoledronic acid was partially neutralized by exogenous administration of geranylgeranyl pyrophosphate (GGPP), however, not by farnesyl pyrophosphate (FPP). Furthermore, exogenous administration of transforming growth factor beta 1 (TGF-,1), interleukin 6 (IL-6), basic fibroblast growth factor (bFGF), and more potently, insulin-like growth factor 1 (IGF-1) inhibited the doxorubicin-induced apoptosis of PC-3 cells. Under identical experimental conditions, these growth factors failed to alter the cytotoxicity of PC-3 cells induced by zoledronic acid. CONCLUSIONS These data suggest that (i) repetitive and pulsatile (15 min/day) exposure to zoledronic acid inhibited the growth of PC-3 cells, (ii) this anticancer action of zoledronic acid was partially mediated by the attenuation of GGPP production, and (iii) bone microenvironment-related growth factors do not alter the anticancer actions of zoledronic acid on PC-3 cells. © 2004 Wileey-Liss, Inc. [source] Prophylactic Bisphosphonate Treatment Prevents Bone Fractures After Liver TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2007M. Bodingbauer A randomized controlled prospective open-label single center trial was performed. At the time of transplantation patients were randomly assigned to one of two treatment arms: The study group of 47 patients received zoledronic acid (ZOL, 8 infusions at 4 mg during the first 12 months after LT), calcium (1000 mg/d) and vitamin D (800 IE/d). The control group consisted of 49 patients who received calcium and vitamin D at same doses (CON). The incidence of bone fractures or death was predefined as the primary endpoint. Secondary endpoints included bone mineral density (BMD), serum biochemical markers of bone metabolism, parameters of trabecular bone histomorphometry and mineralization density distribution (BMDD). Patients were followed up for 24 months. Analysis was performed on an intention-to-treat basis. The primary endpoint fracture or death was reached in 26% of patients in the ZOL group and 46% in the CON group (p = 0.047, log rank test). Densitometry results were different between the groups at the femoral neck at 6 months after LT (mean+/-SD BMD ZOL: 0.80 ± 0.19 g/cm2 vs. CON: 0.73 ± 0.14 g/cm2, p = 0.036). Mixed linear models of biochemical bone markers showed less increase of osteocalcin in the ZOL group and histomorphometry and BMDD indicated a reduction in bone turnover. Prophylactic treatment with the bisphosphonate zoledronic acid reduces bone turnover and fractures after liver transplantation. [source] | ||||||||||||||||||||||||||||