From Bone Health to Lifespan: Pleiotropic Effects of Antiresorptive Agents.

Abstract

Osteoporotic fractures are a major contributor to morbidity and excess mortality, particularly among older adults. Antiresorptive agents, including selective estrogen receptor modulators (SERMs), bisphosphonates (BPs), and denosumab, are widely used to prevent fractures, with robust support from clinical evidence. Beyond reducing fracture risk, emerging data indicate that these therapies may provide survival benefits through mechanisms that extend beyond skeletal protection. This review summarizes current evidence on the association between antiresorptive therapy and all-cause mortality, integrating findings from randomized controlled trials and large-scale observational cohorts. Intravenous and nitrogen-containing BPs, as well as denosumab, demonstrate the most consistent mortality reduction, especially in older or post-fracture populations. SERMs may provide modest benefits in selected women with increased cardiovascular or oncologic risk. The observed mortality reduction may be mediated not only by fracture prevention but also by pleiotropic effects, such as vascular protection, immune modulation, metabolic regulation, and anti-cancer actions. These findings underscore the importance of recognizing osteoporosis as a systemic disease and support early, sustained antiresorptive treatment to improve both skeletal and survival outcomes. Further studies are needed to clarify the underlying mechanisms and to guide individualized treatment strategies across diverse patient populations.