Reductions In Nonvertebral Fracture Risk Research Articles

Denosumab in the Treatment of Osteoporosis: 10Years Later: A Narrative Review.

The fully human monoclonal antibody denosumab was approved for treatment of osteoporosis in 2010 on the basis of its potent antiresorptive activity, which produces clinically meaningful increases in bone mineral density (BMD) and reduces fracture risk at key skeletal sites. At that time, questions remained regarding the long-term safety and efficacy of this receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor; and with clinical experience, new questions have arisen regarding its optimal use. Here, we examine these questions through the lens of data from the FREEDOM trial program and other studies to determine where denosumab fits in the osteoporosis treatment landscape. Clinical consensus and evidentiary support have grown for denosumab as a highly effective anti-osteoporosis therapy for patients at high risk of fracture. In the 10-year FREEDOM Extension study, denosumab treatment produced progressive incremental increases in BMD, sustained low rates of vertebral fracture, and further reduction in nonvertebral fracture risk without increased risk of infection, cancer, or immunogenicity. There was no evidence that suppression of bone turnover or mineralization was excessive, and rates of osteonecrosis of the jaw (ONJ) and atypical femoral fracture (AFF) were very low. It is now recognized, however, that transitioning to another anti-osteoporosis therapy after denosumab discontinuation is essential to mitigate a transient rebound of bone turnover causing rapid BMD loss and increased risk of multiple vertebral fractures (MVFs). Taken together, the available data show that denosumab has a favorable benefit/risk profile and is a versatile agent for preventing osteoporotic fractures in the short and long term. Video abstract: Denosumab in the Treatment of Osteoporosis—10 Years Later (MP4 62727 KB)Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01936-y.

Hip fracture rates and time trends in use of anti-osteoporosis medications in Denmark for the period 2005 to 2015: Missed opportunities in fracture prevention.

Declining use of bisphosphonates (BP) in the United States and Europe may lead to a widening of the treatment gap for osteoporosis and an increase in fracture rates. However, a shift to non-bisphosphonates and to hospital administered i.v. BPs could lead to overestimation of the treatment gap if analyses are based exclusively on BP prescriptions. When a healthcare system successfully narrows the treatment gap by making appropriate use of anti-osteoporosis drugs, we would expect to see declining rates of osteoporotic fractures with much of the decrease being statistically attributable to medication uptake. We analysed a best-case scenario where all use of BPs, denosumab, raloxifene and PTH analogues - including the oncology area - was contrasted with the trend in hip fracture rates. This scenario also considered users of raloxifene and teriparatide as covered by osteoporosis drugs though the primary RCT for raloxifene showed no risk reduction in nonvertebral fractures and the RCT for teriparatide risk reductions for non-vertebral fractures but not hip fracture specifically. Sensitivity analyses were also done. We used aggregate statistics on hip fracture events and total use of the above medications estimating the number of persons potentially covered. The reduction in hip fracture rates attributable to treatment was estimated using the absolute risk reduction (ARR) found in real-world users of oral alendronate in Denmark with the ARR in the FIT primary prevention arm as an alternative scenario. A plateau in use of osteoporosis medications occurred in 2014. Between 2005 and 2015, hip fracture rates declined by 30%. However, only up to 20% of the observed reduction in hip fracture rates was statistically attributable to treatment even in a best-case scenario. Sensitivity analyses where raloxifene and teriparatide were excluded did not impact on this finding. Anti-osteoporosis treatment in Denmark reached a plateau in 2014 even in a best-case scenario where all dispensations were assumed to be for osteoporosis. Future studies may be able to distinguish between the oncology area and the osteoporosis indication as well as provide a delineation of age and gender demographics among users of hospital administered osteoporosis medications. About 80% of the decline in hip fracture rates appears to be due to factors other than osteoporosis medication. The plateau in use of osteoporosis treatment at a level that is too low to make a meaningful impact on societal fracture burden is problematic given the predicted increased age-specific hip fracture rates.

Romosozumab FRAME Study: A Post Hoc Analysis of the Role of Regional Background Fracture Risk on Nonvertebral Fracture Outcome.

In the pivotal Fracture Study in Postmenopausal Women with Osteoporosis (FRAME; NCT01575834), 1 year of the bone-forming agent romosozumab significantly reduced new vertebral and clinical fracture risk versus placebo. Nonvertebral fracture risk was not significantly reduced in the overall population, influenced by a low placebo-group fracture rate, observed particularly in the highest-enrolling region of Latin America. In year 1 of FRAME, postmenopausal women with a T-score of -2.5 to -3.5 at the total hip or femoral neck were randomized to subcutaneous romosozumab 210 mg or placebo once monthly for 12 months. Of 7180 randomized women, 43% were from Latin America, largely Colombia and Brazil. Prespecified analyses assessed fracture risk reductions by geographic regions. A significant treatment-by-geographic region interaction for the clinical (p = 0.029) and nonvertebral fracture (p = 0.042) endpoints led to further characterization of the Latin American population and comparison with the remaining study population, grouped post hoc as rest-of-world. Nonvertebral fracture efficacy in the overall population was also assessed by baseline fracture risk using the Fracture Risk Assessment Tool (FRAX). Romosozumab significantly and consistently reduced new vertebral fracture risk in Latin America (70% reduction; p = 0.014) and rest-of-world (74% reduction; p < 0.001). For nonvertebral fracture, risk reductions were observed in rest-of-world (42% reduction; p = 0.012), with no treatment effect observed in Latin America, where background nonvertebral fracture risk was low (1.2% in the placebo group). Consistent with this finding, in the overall population, greater reductions in nonvertebral fracture risk were observed among women with higher FRAX scores. These findings suggest that fracture risk assessment should consider regional factors in addition to classical risk factors, such as bone mineral density. In women at high risk for fracture, romosozumab reduced nonvertebral fracture risk within 1 year. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

Efficacy of bisphosphonates against osteoporosis in adult men: a meta-analysis of randomized controlled trials.

This meta-analysis of published randomized controlled trials (RCTs) aimed to analyze the efficacy of administration of bisphosphonates in men with osteoporosis. Compared with placebo, bisphosphonates could reduce the risk of vertebral and non-vertebral fractures, reduce bone-specific alkaline phosphatase (BSAP) and C-terminal telopeptide of type I collagen (CTX), and increase bone mineral density (BMD). Bisphosphonates are well-investigated antiresorptive medications, approved as first-line drugs for osteoporosis in postmenopausal women. However, there is a paucity of high-quality evidence regarding the efficacy of bisphosphonates administered for osteoporosis in adult men. The aim of this meta-analysis was to analyse the efficacy of administration of bisphosphonates in men based on published RCTs. PubMed, Embase, MEDLINE, and the Cochrane library were searched, and mean differences were calculated to evaluate the efficacy of bisphosphonates on reducing the risk of vertebral and non-vertebral fracture, reducing bone-turnover biomarkers, and increasing BMD. Nine RCTs were included and the total number of participants was 2464. Compared with placebo, the efficacy of bisphosphonates on vertebral and non-vertebral fracture risk reduction was confirmed [for vertebral fracture, RR (95% CI) 0.36 (0.24, 0.56), P < 0.01; for non-vertebral fracture, RR (95% CI) 0.52 (0.32, 0.84), P < 0.01)] and heterogeneity was insignificant. The efficacy of bisphosphonates on reducing BSAP [MD (95% CI) -24.41 (-26.19, -22.62), P < 0.01) and CTX [MD (95% CI) -34.51 (-41.03, -27.98), P < 0.01)] was significant. A sensitivity analysis was applied to explain the origination of heterogeneity in analysis of decreasing of BSAP. BMD was increased in the bisphosphonates group compared with the control group at lumbar spine, femoral neck, and total hip (P < 0.01), and the heterogeneity of all comparisons was significant. Compared with placebo, bisphosphonates could decrease the risk of vertebral and non-vertebral fractures, reduce BSAP and CTX, and increase BMD in men with osteoporosis.

Selektive Östrogen-Rezeptormodulatoren (SERMs) zur Prävention und Therapie der postmenopausalen Osteoporose

The three modern Selective Estrogen Receptor Modulators (SERMs) Raloxifene, Lasoxifene and Bazedoxifene registered in Europe reduce in postmenopausal women with a high risk for osteoporosis the incidence of vertebral fractures by 30 - 50 %, depending on the subgroup they belong to. Solid prospective fracture data for risk reduction in non-vertebral fractures, including the hip, are missing for Raloxifene and Bazedoxifene. However, a post hoc analysis suggests that the risk for non-vertebral fractures is significantly reduced by Raloxfene in women with severe osteoporosis. The simultaneous decrease of the incidence of ER-positive invasive breast cancer in Raloxifene users is highly relevant for clinicians. Unfortunately, Raloxifene and Bazedoxifene are, in the EU and in Switzerland, only labelled for the use in the prevention and treatment of postmenopausal osteoporosis. SERMs may induce or augment vasomotor symptoms. Therefore, SERMs are not a first line therapy in early postmenopause. Looking at other hormonal options, Hormone Replacement Therapy (HRT) remains the first line therapy for fracture reduction in the peri- and early postmenopause. SERMs are an appropriate choice for the continuation of fracture prevention after an initial HRT, particularly for the prevention of vertebral fractures. SERMs are safe if (as in oral HRT) the slightly increased risk for venous thrombo-embolism is respected. In conclusion, SERMs have today their well established place in the prevention and treatment of postmenopausal osteoporosis, particularly in women with a simultaneously increased breast cancer risk.

Odanacatib: Location and timing are everything

Odanacatib: Location and timing are everything

Effect of teriparatide on bone mineral density and fracture in postmenopausal osteoporosis: meta-analysis of randomised controlled trials

To determine the efficacy of teriparatide supplementation for improving bone mineral density (BMD) and fracture risk in postmenopausal osteoporosis and if effects vary with factors. We identified eight randomised controlled trials (n = 2388) using electronic databases, supplemented by a hand-search of the reference lists. All trials aimed to evaluate the efficacy of daily subcutaneous teriparatide injection in postmenopausal osteoporosis. The main outcomes were fracture risk and percentage change of BMD from baseline. Data were pooled by employing a random-effect model. In trials that reported BMD as an outcome, treatment was associated with an increase of bone mass of 8.14% [95% confidence interval (CI): 6.72-9.55%; eight trials, n = 2206] in spine and 2.48% (95% CI: 1.67-3.29%; seven trials, n = 1303) at the hip. In trials that reported fracture as an outcome, treatment was associated with a 70% risk reduction in vertebral fractures (risk ratio 0.30, 95% CI: 0.21-0.44; three trials, n = 1452) and 38% risk reduction in non-vertebral fractures (risk ratio 0.62, 95% CI: 0.44-0.87; three trials, n = 1842). The PTH treatment with total calcium intake more than 1500 mg was related to a significant increase in BMD gains at total hip (1.40% vs. 3.72%; p = 0.004). However, long-term duration did not appear to contribute to differences in responsiveness to teriparatide. Evidence supports the use of teriparatide in treatment of women with postmenopausal osteoporosis who are at risk for fracture. Further studies directly comparing concurrent therapy and calcium supplement with long-term duration are warranted.

Relationship between bone mineral density changes with denosumab treatment and risk reduction for vertebral and nonvertebral fractures.

Dual-energy X-ray absorptiometric bone mineral density (DXA BMD) is a strong predictor of fracture risk in untreated patients. However, previous patient-level studies suggest that BMD changes explain little of the fracture risk reduction observed with osteoporosis treatment. We investigated the relevance of DXA BMD changes as a predictor for fracture risk reduction using data from the FREEDOM trial, which randomly assigned placebo or denosumab 60 mg every 6 months to 7808 women aged 60 to 90 years with a spine or total hip BMD T-score < −2.5 and not < −4.0. We took a standard approach to estimate the percent of treatment effect explained using percent changes in BMD at a single visit (months 12, 24, or 36). We also applied a novel approach using estimated percent changes in BMD from baseline at the time of fracture occurrence (time-dependent models). Denosumab significantly increased total hip BMD by 3.2%, 4.4%, and 5.0% at 12, 24, and 36 months, respectively. Denosumab decreased the risk of new vertebral fractures by 68% (p < 0.0001) and nonvertebral fracture by 20% (p = 0.01) over 36 months. Regardless of the method used, the change in total hip BMD explained a considerable proportion of the effect of denosumab in reducing new or worsening vertebral fracture risk (35% [95% confidence interval (CI): 20%–61%] and 51% [95% CI: 39%–66%] accounted for by percent change at month 36 and change in time-dependent BMD, respectively) and explained a considerable amount of the reduction in nonvertebral fracture risk (87% [95% CI: 35% – >100%] and 72% [95% CI: 24% – >100%], respectively). Previous patient-level studies may have underestimated the strength of the relationship between BMD change and the effect of treatment on fracture risk or this relationship may be unique to denosumab. © 2012 American Society for Bone and Mineral Research

The evidence for antiresorptive osteoporosis treatment in the elderly and old

Purpose The mean age at diagnosis of osteoporosis is in the late 1960s, and fracture risk and need for fracture prevention rises sharply with increasing age. However, what is the evidence that supports the use of antiresorptive osteoporosis treatments in elderly people? Methods This study was a meta-analysis and meta-regression of the published literature on the clinical efficacy of antiresorptive therapy in the reduction of fracture risk in elderly (age > 70 years) and old (age > 80 years). A systematic literature search was performed. Studies included were randomised placebo controlled trials of post-menopausal women or men where the primary endpoint was vertebral, non-vertebral or hip fracture risk reduction. No papers on fractures in males were published, so BMD as primary endpoint was accepted. Results Thirteen studies in women were included. We found increasing vertebral fracture risk reduction with increasing age, increasing BMI, and longer duration of treatment. A high baseline BMD was associated with a lesser effect. For non-vertebral fracture risk reduction, we found no effect of follow-up, age or BMD. For hip fracture risk reduction, we found no effect of treatment with increasing age or BMD, and no certain effect of duration of treatment. For men, three BMD studies were included, in these, we found a non-significant trend toward fracture reduction. Conclusions For women, pooled analyses showed increasing effect of antiresorptive drugs with increasing age, increasing BMI, and longer duration of treatment on vertebral fractures. The data on non-vertebral or hip fractures showed no effect on follow-up, age, or BMD. The data in men are scant at all sites and inconclusive.

Effect of Osteoporosis Treatment on Mortality: A Meta-Analysis

Substantial morbidity and mortality is associated with fragility fractures. Between 10% and 20% of individuals who suffer hip fractures die within 1 year, and there is also significant mortality following vertebral and other nonvertebral fractures. Systematic reviews and meta-analyses have provided clear evidence that effective osteoporosis treatment can reduce the incidence of both vertebral and nonvertebral fractures, but it is unclear whether it can reduce mortality. Only one large randomized controlled trial of osteoporosis treatment investigating the effectiveness of zoledronic acid reported a statistically significant survival benefit in patients with vertebral and other nonvertebral fractures. This retrospective literature review examined placebo-controlled randomized trials of osteoporosis treatment to determine whether effective osteoporosis treatment reduced mortality. Data from randomized placebo-controlled trials of osteoporosis treatments were obtained from MEDLINE, the Cochrane Central Register of Trials and the annual conference abstracts (2000–2008) of the American Society for Bone and Mineral Research. Other sources of data were company web sites, published meta-analyses, and the Food and Drug Administration web site. All included trials used approved doses of medications with proven efficacy in preventing both vertebral and nonvertebral fractures, had trial durations longer than 1 year, and a number of study deaths greater than 10. Specific exclusion criteria included trials of estrogen and/or selective estrogen receptor modulators. The 8 studies meeting inclusion and exclusion criteria and included in the primary analysis investigated 4 agents (risedronate, strontium ranelate, zoledronic acid, and denosumab). In 2 other trials meeting eligibility criteria (both using alendronate), the treatment dose was changed during the study; therefore, data from these studies were only included in secondary analyses. Osteoporosis treatment in the primary analysis was associated with an 11% reduction in mortality; the relative risk (RR) was 0.89, with a 95% confidence interval (CI) of 0.80 to 0.99 (P = 0.036). Similar results were found in the secondary analysis including the 2 alendronate studies (RR, 0.90; 95% CI, 0.81–1.0; P = 0.044). Meta-regression analyses showed that reduced mortality was not associated with mean age, incidence of hip or nonvertebral fracture in the placebo group, or vertebral or nonvertebral fracture risk reduction, but was related to the mortality rate in the placebo group (P = 0.030). The mortality benefit appeared to be similar among the different drug classes in the analysis. These findings show that the use of agents with proven efficacy for vertebral and nonvertebral fracture to treat older, frailer individuals with osteoporosis who are at high risk of fractures reduces mortality by approximately 10%.

Non-vertebral fracture risk reduction by bazedoxifene

Non-vertebral fracture risk reduction by bazedoxifene

Osteoporosis-Related Nonvertebral Fracture Risk Reduction vs. Hitoric Control at Two Years with Risedronate 150mg Once-A-Month

Osteoporosis-Related Nonvertebral Fracture Risk Reduction vs. Hitoric Control at Two Years with Risedronate 150mg Once-A-Month

Comparing non-vertebral fracture risk reduction with osteoporosis therapies: looking beneath the surface

Data from pivotal trials of pharmacologic agents used to treat osteoporosis differ, suggesting that these agents vary in ability to reduce the risk of non-vertebral fractures (NVFs). However, variability among clinical trials in inclusion criteria, baseline characteristics, and definition of NVFs may account for many of these apparent differences. Data from pivotal trials of individual pharmacologic agents for osteoporosis differ, and suggest that differences may exist between anti-resorptive agents in their ability to reduce the risk of NVFs. Careful examination of these trials' inclusion criteria and patient characteristics indicates substantial differences between patient populations with respect to the baseline risk of NVFs. When baseline fracture risk is lower, the ability to produce a statistically significant reduction in fracture risk over the course of a clinical trial is reduced. Analysis of clinical trials reveals that the number and type of baseline vertebral fractures and also baseline bone mineral density, all associated with the risk of vertebral fracture, vary. The propensity to fall and patient frailty are additional factors associated with fracture risk that may influence study outcomes. One of the most significant variables, which also often differs considerably between trials, is the definition of an NVF. Variability between clinical trials in inclusion criteria, patients' baseline characteristics, and how NVFs are defined may account for much of the apparent difference between agents in their ability to reduce NVF risk.

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.

Nonvertebral fracture risk reduction with nitrogen-containing bisphosphonates

Osteoporosis is a systemic skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue resulting in compromised bone strength and an increased risk of fracture. There are two major fracture types: vertebral and nonvertebral. The latter include fractures involving the upper extremities, lower extremities (including hip), pelvis, and ribs. A recent review comparing the efficacy and safety of drugs approved by the US Food and Drug Administration for treatment of osteoporosis demonstrated that although all of the agents have been shown to reduce the incidence of radiographic vertebral fractures, they do not all reduce the incidence of nonvertebral fractures. This article summarizes the most currently available data relative to nonvertebral and hip fracture risk reduction for the N-containing bisphosphonates alendronate, ibandronate, risedronate, and zoledronic acid, and presents results of an analysis of comparative efficacy of these compounds using the technique of adjusted indirect comparisons.

Ibandronate: is there an effect on nonvertebral fractures?

Although ibandronate improves suboptimal compliance in patients receiving weekly bisphosphonates, there is a concern about its effect on the reduction of nonvertebral fractures. In the era of evidence-based medicine, randomized clinical trials are considered the highest quality evidence which guide us to the best clinical decision. Nevertheless, if level 1 evidence is not available, as is the case with ibandronate, evidences of lower levels could be used to draw relevant clinical decision. In this article, we discussed data from clinical trials (subgroup analyses of high-risk patients, meta-analysis of clinical trials) which suggested significant effect of ibandronate on the risk reduction of nonvertebral fractures.

Non-vertebral fracture risk reduction with oral bisphosphonates: challenges with interpreting clinical trial data

Non-vertebral fracture risk reduction with oral bisphosphonates: challenges with interpreting clinical trial data

Bisphosphonate antifracture efficacy

All bisphosphonates available for the treatment of postmenopausal osteoporosis reduce bone turnover, increase bone mineral density (BMD) and thereby reduce fracture incidence. Incident vertebral fractures are a key efficacy endpoint in bisphosphonate trials. They are less influenced by extrinsic factors (e.g., falls) than non-vertebral fractures and are highly predictive for future vertebral and non-vertebral fractures. The registration studies for daily oral alendronate, risedronate and ibandronate all demonstrated substantial reductions in vertebral fracture risk vs. placebo in postmenopausal women with established osteoporosis: 44% and 47% for daily alendronate, 41% and 49% for daily risedronate and 62% and 50% for daily and intermittent ibandronate, respectively. The effect of bisphosphonate treatment on non-vertebral fractures in these trials was variable, and highlights the difference in nature and incidence of non-vertebral fractures compared with vertebral fractures. Daily risedronate demonstrated a 39% reduction in non-vertebral fracture risk in the overall study population ( P = 0.02 vs. placebo), but failed to achieve a significant effect in a second study. Alendronate and ibandronate did not show a significant effect in the overall populations of their respective trials, however, in high-risk patients (femoral neck BMD < − 2.5), daily alendronate achieved a risk reduction of 36% on all clinical fractures. Also in high-risk subgroups, daily ibandronate showed 69% ( P = 0.012 vs. placebo) and 60% ( P = 0.037 vs. placebo) reductions in non-vertebral fracture risk (femoral neck BMD < − 3.0 or lumbar spine BMD < − 2.5 plus a history of clinical fracture in the past 5 years, respectively). Less frequent dosing regimens, which may improve patient compliance with treatment, have become standard in the management of postmenopausal osteoporosis. To establish the efficacy of a new regimen of a daily drug with proven antifracture efficacy, a bridging study is commonly used with surrogate endpoints of antifracture efficacy such as BMD and bone turnover markers. MOBILE (Monthly Oral iBandronate In LadiEs; a bridging study) confirmed that monthly oral ibandronate is non-inferior and even superior to daily oral ibandronate for gains in lumbar spine BMD (primary endpoint) and total hip BMD. These gains in BMD suggest that at least equivalent antifracture efficacy may be expected from this regimen in women with postmenopausal osteoporosis.

Strontium ranelate: vertebral and non-vertebral fracture risk reduction

Fractures are common at the spine and hip, but at least half the morbidity and mortality of fractures in the community come from fractures that involve other sites. Over half of all fractures arise in individuals without osteoporosis, whereas the highest risk group for fractures are individuals over 80 years of age. Reducing the burden of fractures should thus include an assessment of drug efficacy against all fractures in a wide range of individuals. For vertebral fractures, in the phase III Spinal Osteoporosis Therapeutic Intervention study of 1649 postmenopausal women with osteoporosis, 2 g strontium ranelate a day produced a risk reduction of 49% in the first year and 41% during 3 years. In the TReatment Of Peripheral OSteoporosis study, which was designed to examine the effect of strontium ranelate on non-vertebral fractures, of the 5091 patients, 3640 had spine X-rays. The vertebral fracture risk reduction was 45% at one year and 39% over 3 years. In a preplanned pooling of the above two studies, 1170 patients had vertebral osteopenia. Strontium ranelate reduced the risk of vertebral fracture in 3 years by 40% in these patients. In 409 patients with lumbar or femoral neck osteopenia, strontium ranelate reduced the risk of vertebral fractures by 62% over 3 years. In the pre-planned pooling of data from the two studies, in 1488 women aged between 80 and 100 years (mean age 84 +/- 3 years), the risk of vertebral fractures was reduced in one year by 59% and by 32% over 3 years. For non-vertebral fractures, in the TReatment Of Peripheral OSteoporosis study, treatment for 3 years reduced the fracture risk by 16%, and by 19% for major fragility fractures. In a post-hoc analysis of 1977 women at high risk of hip fracture (aged > or = 74 years and with a femoral neck bone mineral density T-score < or = -2.4) the hip fracture risk was reduced by 36%. In patients aged 80 and over in the pre-planned pooling of data from the two studies, the risk of an incident non-vertebral fracture was reduced by 41% in the first year and by 31% over 3 years. Strontium ranelate, a new anti-osteoporosis agent, has a broad range of antifracture efficacy.

Changes in bone mineral density explain little of the reduction in vertebral or nonvertebral fracture risk with anti-resorptive therapy

The structural basis for the reduction in vertebral and nonvertebral fracture risk in patients using anti-resorptive therapy is not well understood. As reduced bone mineral density (BMD) increases the risk for fracture and anti-resorptive agents increase BMD, it was commonly held that the increase in BMD explained the fracture risk reduction until several meta-analyses either failed to detect a significant association between vertebral fracture risk reduction and the incremental increase in BMD or reported that only a small proportion of the vertebral fracture risk reduction was explained by changes in BMD. Recently, it was reported that the risk of nonvertebral fractures decreased when an increase in BMD accompanied anti-resorptive treatment [J. Clin. Endrocrinol. Metab. 87 (2002) 1586]. However, a reanalysis of the data, using the same statistical methods after correcting for discrepancies in the reported BMD and person–year data, suggested that the magnitude of reductions in nonvertebral fracture risk was not associated with the magnitude of increases in BMD at the end of the first year or at completion of the studies. We infer that only a small proportion of risk reduction in vertebral and nonvertebral fractures observed with anti-resorptive drug therapy is explained by the increase in BMD. Further studies are needed to define the structural basis of the fracture risk reduction.