Beyond bone effects: the role of denosumab in muscle Health - A systematic review

Background: Denosumab, a monoclonal antibody targeting RANKL, is widely used for the treatment of osteoporosis. In addition to its skeletal benefits, emerging evidence suggests that denosumab may also exert positive effects on muscle health by modulating inflammation, myostatin expression, and insulin sensitivity through the RANK/RANKL/OPG pathway. Aims: To systematically review the available literature on the effects of denosumab on muscle-related outcomes, including muscle strength, muscle mass, physical performance, and fall risk. Methods: A systematic review was conducted in accordance with PRISMA guidelines. Databases including PubMed, Embase, and Cochrane Library were searched through May 2025 for studies evaluating the impact of denosumab on muscle health in human subjects. Outcomes of interest included grip strength, lean muscle mass, gait speed, fall incidence, and physical performance tests. Results: Seven studies met the inclusion criteria, including randomized trials and observational cohorts. Most reported favorable outcomes for denosumab compared to bisphosphonates or placebo, particularly in grip strength and physical performance. Preclinical studies further support the biological role of RANKL in muscle dysfunction. However, one recent randomized controlled trial in older adults residing in long-term care settings found no significant effect on muscle outcomes, highlighting inconsistencies in the evidence. Discussion: Denosumab shows potential for improving muscle-related outcomes in older adults, particularly those with osteosarcopenia. Conclusions: Current evidence is heterogeneous and inconclusive. Further high-quality randomized trials are needed to clarify the effects of denosumab on muscle health and its possible role in sarcopenia prevention and management.