Bisphosphonates For Postmenopausal Osteoporosis Research Articles

Bisphosphonates for postmenopausal osteoporosis: a network meta-analysis

Bisphosphonates for postmenopausal osteoporosis: a network meta-analysis

Clinical utility of bone turnover markers in monitoring the withdrawal of treatment with oral bisphosphonates in postmenopausal osteoporosis.

Measurement of bone turnover markers (BTMs) may be useful to monitor offset of treatment with bisphosphonates (BP) in osteoporosis. We assessed the effect of withdrawal of BP treatment by comparing the changes in BTMs and total hip (TH) bone density (BMD). We studied postmenopausal osteoporotic women who had completed a randomised study of three oral BPs. After 2years of treatment, participants with BMD T-score > - 2.5 and in whom it was considered clinically appropriate to discontinue treatment, were invited to participate in a further 2-year observational study. Biochemical response was assessed using BTMs (CTX and PINP) with offset being defined by two criteria: (1) an increase greater than the least significant change (LSC) and (2) an increase above the reference mean value. Fifty women completed the study. At 48weeks after stopping BPs, CTX was greater than the LSC for 66% of women and PINP 72%; CTX was above the reference mean for 64% of women and PINP 42%. The decrease in THBMD was greater for women with the largest increase in BTM compared to those with continued suppression (mean difference for CTX was - 2.98%, 95%CI - 4.75 to - 1.22, P < 0.001, PINP - 2.25%, 95% CI - 4.46 to - 0.032, P = 0.046). The measurement of BTM after withdrawal of BPs is potentially useful to evaluate patients that are taking a pause from treatment. An increase in BTMs more than the LSC and/or reference mean reflects loss of treatment effect and identifies patients that are likely to have a decrease in BMD. Such changes could provide an indication for reintroduction of treatment.

A Review of the Cost Effectiveness of Bisphosphonates in the Treatment of Post-Menopausal Osteoporosis in Switzerland

The economic burden associated with osteoporosis is considerable. As such, cost-effectiveness analyses are important contributors to the diagnostic and therapeutic decision-making process. The aim of this study was to review the cost effectiveness of treating post-menopausal osteoporosis with bisphosphonates and identify the key factors that influence the cost effectiveness of such treatment in the Swiss setting. A systematic search of databases (MEDLINE, EMBASE and the Cochrane Library) was conducted to identify published literature on the cost effectiveness of bisphosphonates in post-menopausal osteoporosis in the Swiss setting. Outcomes were compared with similar studies in Western European countries. Three cost-effectiveness studies of bisphosphonates in this patient population were identified; all were from a healthcare payer perspective. Outcomes showed that, relative to no treatment, treatment with oral bisphosphonates was predicted to be cost saving for most women aged ≥70 years with osteoporosis or at least one risk factor for fracture, and cost effective for women aged ≥75 years without prior fracture when used as a component of a population-based screen-and-treat programme. Results were most sensitive to changes in fracture risk, cost of fractures, cost of treatment, nursing home admissions and adherence with treatment. Swiss results were generally comparable to those in other European settings. Assuming similar clinical efficacy, lowering treatment cost (through the use of price-reduced brand-name or generic drugs) and/or improving adherence should both contribute to further improving the cost effectiveness of bisphosphonates in women with post-menopausal osteoporosis. Published evidence indicates that bisphosphonates are estimated to be similarly cost effective or cost saving in most treatment scenarios of post-menopausal osteoporosis in Switzerland and in neighbouring European countries.

Bisphosphonates for postmenopausal osteoporosis

Bisphosphonates are effective in reducing bone turnover, increasing BMD and reducing fracture risk in postmenopausal women with osteoporosis. The licensed bisphosphonates exhibit some differences in potency and speed of onset and offset of action. These differences mean that different agents may be more advantageous in different situations. Uncertainties still exist around the optimum duration of treatment and treatment holidays, how best to use bisphosphonates with anabolic treatments, and the benefits of treatment in patients who do not have a BMD T-score below -2.5.

Bisphosphonates for post-menopausal osteoporosis: are they all the same?

The primary goal of treatment for post-menopausal osteoporosis (PMO) is reduction in fracture risk. Therefore, clinicians must recommend therapies that are safe and have proven anti-fracture efficacy. Bisphosphonates have long been established as first-line therapy for osteoporosis and several of these drugs significantly reduce osteoporotic fracture risk. However, choosing among different bisphosphonates can represent a difficult clinical decision. This review outlines the pharmacology of various bisphosphonates, discusses how their pharmacological characteristics affect their efficacy, and summarizes clinical safety and efficacy data. Clinical trial data and the opinions of expert bodies suggest that alendronate, risedronate, ibandronate and zoledronic acid all provide fracture protection for patients with PMO. However, there are differences among these agents. For example, all four agents have demonstrated efficacy in preventing vertebral fractures, but only zoledronic acid and risedronate significantly reduce non-vertebral fracture risk in pivotal trials. Moreover, reduction in hip fracture risk has only been established for alendronate, risedronate and zoledronic acid. Current data suggest that ibandronate and zoledronic acid have the most persistent antifracture effect. Bisphosphonates have been associated with a number of side effects, the evidence for which is summarized in this review. The most pertinent of these when choosing a bisphosphonate for a particular patient are the well-documented associations between gastrointestinal adverse events and oral administration, and between acute phase reactions and intravenous administration. Ultimately, selection of a specific bisphosphonate for treatment of PMO should be based on efficacy, risk profile, cost-effectiveness and patient preference.

Intravenous bisphosphonates for post-menopausal osteoporosis: adherence to a network guideline

An evidence-based guideline on the use of intravenous (i.v.) bisphosphonates in post-menopausal osteoporosis was developed across a healthcare system and approved by clinical experts and Pharmacy and Therapeutics Committees. The objective of the study was to evaluate adherence to the guideline at hospitals in the healthcare system. Post-menopausal women who received i.v. zoledronic acid or i.v. ibandronate for osteoporosis between September 2007 and October 2008 were identified through a data repository that provides patient-level longitudinal information on diagnoses, medications and laboratory tests. Manual review of electronic medical records supplemented the data capture. The guideline recommends use of i.v. bisphosphonates in patients: (i) who have had a recent vertebral or hip fracture; (ii) who cannot stand or sit upright for 30-60 min; (iii) who have oesophageal dysmotility or varices; (iv) who have documented adherence issues or, (v) who failed to tolerate oral bisphosphonates after 12 months. In addition, specific monitoring tests are recommended prior to administration. Among the 220 women that received an i.v. bisphosphonate (hospitals A/B: n = 92 vs. hospital C: n = 128), 72% met the criteria for use. The results were similar when examined by institution (hospitals A/B 66% vs. hospital C 77%; P = 0·094). On review of the electronic medical records, an additional reason for using i.v. bisphosphonates was identified: persistent bone loss despite oral bisphosphonate therapy. When this criterion for use was included, the adherence rate increased to 80% (hospitals A/B 72% vs. hospital C 86%; P = 0·009). Serum calcium and 25-OH vitamin D were performed in 75% (hospitals A/B 77% vs. hospital C 73%; P = 0·53), and 86% (hospitals A/B 84% vs. hospital C 87%; P = 0·53) of patients respectively. Adherence to an i.v. bisphosphonates evidence-based guideline was adequate (defined as at least 80%) although room for improvement in meeting the criteria for use at one hospital and for conducting baseline serum calcium levels was noted. A future project is warranted to re-assesses adherence after the measures to improve guideline adherence are implemented.

Changes in bone mineral density after discontinuation of bisphosphonates in postmenopausal osteoporosis

Changes in bone mineral density after discontinuation of bisphosphonates in postmenopausal osteoporosis

Bisphosphonates for postmenopausal osteoporosis: Determining duration of treatment

Doctors who treat patients with osteoporosis are increasingly confronted with the question of how long to continue treatment with bisphosphonates (BPs), which have the unique characteristic of accumulating in the skeleton. Limited available long-term data suggest that such decisions should be made on a case-by-case approach and guided by an individual re-evaluation of clinical fracture risks and bone mineral density, efficacy, and safety issues. In patients who still have a high fracture risk after 5 years of treatment with BPs, continuing treatment could be considered, but stopping BPs could be appropriate in those with a low fracture risk after 5 years of treatment. Switching to recombinant human parathyroid hormone 1-34 or 1-84 is indicated when recurrent incident vertebral fractures occur despite adequate antiresorptive therapy for more than 1 year. However, the usefulness of more than 5 years of treatment with BPs needs to be proved with higher levels of evidence-based medicine.

Recent developments in the management of postmenopausal osteoporosis with bisphosphonates: enhanced efficacy by enhanced compliance

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.

Glucocorticoid-induced osteoporosis: a systematic review and cost-utility analysis

To determine whether strategies can be devised for the assessment and treatment of glucocorticoid-induced osteoporosis (GIO). Electronic databases were searched up to October 2002. A systematic review of interventions was undertaken of all randomised controlled trials in which fracture was measured as an outcome. Effectiveness was compared with effectiveness in postmenopausal osteoporosis. The risk of osteoporotic fractures at any given T-score for bone mineral density (BMD) was determined from published meta-analyses of the relationship between BMD and fracture risk. The risk of an osteoporotic fracture in the presence of a prior osteoporotic fracture was computed from a published meta-analysis of the relationship between the prior occurrence of fracture of each type and the risk of a future fracture of each type. The additional risk due to exposure to glucocorticoids was determined by meta-analysis of prospectively studied population-based cohorts. The consequences of fracture on mortality were assessed for each fracture type. Costs and utilities were determined for osteoporosis in the UK by updating systematic reviews of the literature. A model was prepared that comprised an individual patient-based approach that simulated whether or not events occurred in each subsequent year for each patient. Effectiveness was populated from a systematic review of interventions in GIO and postmenopausal osteoporosis. Treatments were given for 5 years using a 5-year offset time (in this context, offset time is the duration for which an effect on fracture persists after the treatment stops). The analytic framework was set at 10 years. Because of the many uncertainties, extensive sensitivity analysis was undertaken. Evidence of anti-fracture efficacy was confined to a minority of agents used in the management of GIO. Only risedronate (a bisphosphonate) and calcidiol (vitamin D) were shown to have significant effects on vertebral fracture risk, but neither had significant effects on non-vertebral fracture risk. In further meta-analyses, the effects of bisphosphonates in GIO were compared with effects combining all available data for bisphosphonates in GIO and in postmenopausal osteoporosis. Since calcidiol is not licensed for use in the UK, cost-effectiveness analysis was confined to risedronate and to a pooled bisphosphonate effect. Analysis of cost-effectiveness of risedronate using the empirical data in GIO showed better cost-effectiveness with increasing age, but at no age did cost-effectiveness ratios fall below the threshold value of 30,000 pounds per quality-adjusted life-year gained. When account was taken of BMD, cost-effectiveness was confined to less than 10% of patients with very low T-scores for BMD. Assuming that bisphosphonate efficacy on fracture risk was comparable to that observed with bisphosphonates in postmenopausal osteoporosis, cost-effectiveness was shown in patients with a prior fracture. In patients with no prior fracture, cost-effectiveness was observed in individuals aged 75 years or more. In younger patients without a prior fracture, cost-effective scenarios were found contingent upon a T-score for BMD that was 2.0 SD or less. Cost-effective scenarios for risedronate in the management of GIO were identified, but only at the extremes of age and T-score, such that less than 10% of patients aged 50 years or more would be eligible for treatment. Greater cost-effectiveness was observed assuming that the effects of bisphosphonate in GIO were similar to those observed in postmenopausal osteoporosis, an assumption tested by meta-analysis. An assessment algorithm is proposed based on age, the presence of a prior fragility fracture and BMD tests in individuals aged 50 years or more with no fracture. The conclusions derived are conservative, mainly because of the assumptions that were made in the absence of sufficient data. Thus, conclusions that treatment scenarios are cost-effective are reasonably secure. By contrast, scenarios shown not to be cost-effective are less secure. As information in these areas becomes available, the implications for cost-effectiveness of interventions should be reappraised. Health economic assessment based on probability of fracture is an important area for further research. Other areas for further research arise from gaps in empirical knowledge on utilities and side-effects that are amenable to primary research. Further secondary research is recommended to evaluate more closely the impact of all vertebral fractures (rather than clinically overt vertebral fractures) on cost-effectiveness and methods of monitoring treatment.

Drug Insight: bisphosphonates for postmenopausal osteoporosis

Bisphosphonates are potent antiresorptive agents, which have largely been used for the treatment of postmenopausal osteoporosis during the past 10 years. When embedded in bone matrix, bisphosphonates are taken up by osteoclasts engaged in bone resorption, leading--mainly by inhibition of farnesyl diphosphate synthase, a key enzyme of the mevalonate pathway--to osteoclast apoptosis. Bone resorption decreases, with consequent improvement in the mechanical properties of bone and a reduced risk of fracture. Alendronate and risedronate are oral nitrogen-containing bisphosphonates. Several randomized, placebo-controlled trials have shown the ability of these bisphosphonates to halve the risk of vertebral fracture when taken daily for 3 years. Nonvertebral fracture risk, including that at the hip, was also significantly decreased. Weekly regimens have simplified the administration of bisphosphonates and, probably, improved adherence to treatment. A significant reduction in the risk of vertebral fracture has also been demonstrated with an intermittent regimen of ibandronate, which is a new, potent, nitrogen-containing bisphosphonate. Ibandronate was recently marketed for use in an oral, once-monthly dose of 150 mg, with the goal of improving compliance. Bisphosphonates are usually well tolerated in the long term. Intravenous administration of bisphosphonates in women with osteoporosis, which is currently under investigation, might be an interesting future option for women who cannot tolerate oral regimens, and for enhancing compliance.

Once-monthly dosing: An effective step forward

To improve upon the currently suboptimal level of therapeutic adherence with bisphosphonates in postmenopausal osteoporosis, there is a need to examine less-frequently dosed regimens that offer patients greater convenience than weekly dosing. Ibandronate is a potent, nitrogen-containing bisphosphonate specifically developed for administration with long between-dose intervals. It has proven antifracture efficacy when administered orally, daily or intermittently (>2 months dose-free interval) and a safety profile comparable with placebo. A dose-ranging study evaluating a simplified once-monthly ibandronate dosing schedule confirmed the feasibility of the regimen. Significant decreases from baseline in the biochemical markers of bone turnover, serum and urinary C-telopeptide of the α-chain of type 1 collagen (CTX) were observed for all once-monthly doses assessed. An analysis of the area under the effect curve for these two parameters confirmed a dose–response relationship. The MOBILE study was a large ( n = 1609), randomized, double-blind, non-inferiority study comparing three doses of monthly oral ibandronate (50 + 50 mg, 100 mg and 150 mg) with daily oral ibandronate (2.5 mg) in women with postmenopausal osteoporosis. Analyses have been completed at the end of 1 and 2 years of treatment. With substantial increases in lumbar spine bone mineral density (BMD; 5.3–6.6%), all of the once-monthly regimens were non-inferior, and, in addition, the 150 mg regimen was superior ( P ≤ 0.002) to the daily regimen. Corresponding increases in BMD were also observed at all hip sites. The greatest gains in lumbar spine, and hip BMD were consistently seen with the 150 mg regimen. Considerable reductions in serum CTX were seen with all regimens from 3 months onwards (50.0–66.4%); these reductions were maintained throughout the 2-year period (2 years: 56.1–67.7%). The safety profile of the once-monthly regimens was comparable with the daily regimen throughout the 2 years. Once-monthly ibandronate is an effective and well-tolerated treatment for patients with postmenopausal osteoporosis. Given the recently reported strong patient preference for once-monthly regimens and the impact of patient preference on therapeutic adherence, it is anticipated that once-monthly ibandronate will offer patients an alternative convenient regimen that may improve adherence over weekly bisphosphonates and should enhance outcomes.

Clinical Pharmacology of Potent New Bisphosphonates for Postmenopausal Osteoporosis

Bisphosphonates are potent inhibitors of bone resorption, used in most bone diseases associated with high bone resorption levels. Several bisphosphonates, developed to prevent and treat postmenopausal osteoporosis, increase bone mineral density and decrease biochemical markers of bone turnover, and more importantly, reduce fracture risk. Alendronate and risedronate have proven their efficacy to reduce vertebral and hip fracture risk among postmenopausal osteoporotic women, using daily regimens. Weekly intermittent schedules, however, are now most commonly prescribed, because they have shown pharmacologic equivalence to the daily regimen. Ibandronate has been the first bisphosphonate to demonstrate vertebral fracture risk reduction using an intermittent regimen. Studies using ibandronate as intravenous injections every 3 months are under way. Zoledronic acid may also be an attractive option for the treatment of postmenopausal osteoporosis if a large ongoing trial proves that a single annual injection of this compound allows osteoporotic fracture risk reduction.

Efficacy and safety of long-term bisphosphonates in postmenopausal osteoporosis

Efficacy and safety of long-term bisphosphonates in postmenopausal osteoporosis

Long-Term Tolerability of the Bisphosphonates in Postmenopausal Osteoporosis

Osteoporosis in postmenopausal women is a growing health concern for society. Bisphosphonates have become the mainstay of prevention and treatment with the mounting evidence of their efficacy over the past two decades. This review article examines the use of the etidronate, alendronate and risedronate. The pivotal trials are reviewed for long-term tolerability, evidence regarding histological safety and gastrointestinal tolerance. Etidronate, alendronate and risedronate have also been examined in meta-analyses, which reviewed methodologically sound trials. Length of treatment, adverse events and medication discontinuation and patients lost to follow-up were evaluated. Etidronate trials and the recent meta-analysis support the safe clinical use of cyclical etidronate with no signs of osteomalacia or other skeletal pathology over 2 to 3 years. In addition to increased bone mineral density (BMD) and vertebral fracture risk reduction, patients tolerated cyclical etidronate well up to 4 years in randomised studies. Non-randomised data has shown safety up to 7 years with clinical and bone biopsy data. Alendronate studies demonstrated similar overall adverse event rates, study discontinuation rates and loss to follow-up rates between placebo and treatment arms, in addition to consistent improvements in BMD, vertebral and non-vertebral fracture risk reductions over 3 to 4 years. Histological safety has been demonstrated up to 3 years. Longer-term therapy in non-randomised trials up to 7 years showed similar clinical safety between alendronate and placebo. Risedronate trials and the meta-analysis also showed similar adverse event profiles between placebo and treatment arms, as well as improvements in BMD, vertebral and non-vertebral fracture risk reductions up to 3 years. Rates of discontinuation due to gastrointestinal events were similar between groups. Histological safety has also been demonstrated for risedronate up to 3 years. Each of these bisphosphonates have been shown to have comparable safety with placebo up to 3 to 4 years, with the most rigourous trials carried out for alendronate and risedronate. Long-term comparative studies are awaited.

Current bone mineral density data on bisphosphonates in postmenopausal osteoporosis

Current bone mineral density data on bisphosphonates in postmenopausal osteoporosis

Current bone mineral density data on bisphosphonates in postmenopausal osteoporosis.

Osteoporosis is a disorder of skeletal fragility characterized by an imbalance in bone turnover such that bone resorption exceeds bone formation. Accelerated bone resorption is the principal physiological derangement responsible for both postmenopausal and age-related bone loss. Furthermore, increased bone turnover is itself a risk factor for fracture, independent of bone mineral density. Thus, there is a strong rationale for the use of potent antiresorptive drugs for the treatment of postmenopausal osteoporosis. Bisphosphonates are a class of drugs that inhibit osteoclast activity and bone resorption. Recent studies with etidronate, pamidronate, and alendronate demonstrate the ability of these drugs to suppress bone turnover and to preserve or increase bone mass. In large studies with alendronate, in long-term studies with clodronate, and in patients at high fracture risk treated with etidronate, decreased fracture occurrence is observed. Except for upper gastrointestinal intolerance with aminobisphosphonates, these drugs are very well tolerated. Bisphosphonates are promising alternatives to estrogen for the treatment of patients with decreased bone mass and, particularly, those with severe osteoporosis. Further studies are needed to define the optimal long-term dosing regimen and to establish whether more potent members of this drug class are more effective or can be administered by different routes. The effectiveness of bisphosphonates in combination with estrogen or bone growth stimulators also requires evaluation, and the extended long-term safety of these drugs must be determined.