Abstract

Long-term extension trials to prove the efficacy and safety of bisphosphonates

Author(s): Paul D Miller

Bisphosphonates are nonmetabolizable analogs of pyrophosphates. They have a high selectivity to bone remodeling sites, become retained and recycled, providing a long duration of continual effect after discontinuation. Bisphosphonates have been registered for postmenopausal osteoporosis for 20 years. Four bisphosphonates are currently registered for postmenopausal osteoporosis – alendronate, risedronate, ibandronate and zoledronic acid. They were all registered on the evidence of fracture-risk reduction over 3 years compared with placebo. Beyond 3 years, there are very few bisphosphonate data where a placebo group has been maintained and none where the original randomized sample size for registration has been continued. Hence, long-term fracture efficacy data depends on observing the fracture-risk reduction in the group continued on long-term bisphosphonates to the risk reduction observed during the first 3 years of the clinical trial, where the placebo group was maintained. In this regard, long-term bisphosphonate administration seems to maintain a reduction in fracture risk. In addition, with the exception of a low risk of acute renal failure with rapid administration of intravenous zoledronic acid, long-term bisphosphonates are exceptionally safe. The reports of osteonecrosis of the jaw and atypical subtrochanteric femur fractures are associations with long-term bisphosphonates without established causality. Bisphosphonates are highly effective and safe to reduce incident fractures in postmenopausal osteoporosis when used in the right population for the right duration.