Bisphosphonate antifracture efficacy

Abstract

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.