Preventing Nonvertebral Osteoporotic Fractures With Extended-Interval Bisphosphonates: Regimen Selection and Clinical Application

Raymond E. Cole, DO, CCD; Steven T. Harris, MD, FACP
Context: Nonvertebral fractures (NVFs) are the most costly and disabling type of osteoporotic fractures. Bisphosphonate therapy effectively reduces the risk for NVFs; however, fracture protection depends critically on adherence and persistence. Approved bisphosphonate regimens with extended dosing intervals increase patient convenience, help patients remain on therapy, and improve fracture protection in clinical practice.

Evidence Acquisition: To assess evidence for NVF reduction with extended-interval bisphosphonates, we searched PubMed for phase 3 clinical trials, meta-analyses, and reviews of approved nitrogen-containing bisphosphonate regimens with monthly or less frequent dosing (monthly oral ibandronate, monthly or intermittent oral risedronate, quarterly intravenous [IV] ibandronate, and yearly IV zoledronic acid). These references were augmented by ISI Web of Science cited reference searches, ISI Proceedings searches, and hand searches of relevant conference proceedings and review bibliographies.

Evidence Synthesis: Monthly oral and quarterly IV ibandronate reduce NVF risk significantly more than daily oral ibandronate and placebo, as shown by meta-analyses stratified by ibandronate dose (annual cumulative

exposure). Intermittent and monthly oral risedronate have shown bone density gains similar to those seen with daily oral risedronate. Incidence rates of NVF, reported as adverse events, were also similar. Yearly IV zoledronic acid reduced NVF risk by 25% and hip fracture risk by 41% compared with placebo in its pivotal trial for postmenopausal osteoporosis.

Conclusions: Extended-interval bisphosphonates offer similar or superior NVF protection with less lifestyle disruption compared with daily or weekly treatment. By removing obstacles to adherence and persistence, extended-interval oral and IV bisphosphonate regimens provide valuable therapeutic options to enhance real-world effectiveness and reduce NVF incidence.