Denosumab May Boost Muscle Strength Beyond Its Bone Benefits

Osteoporosis and sarcopenia frequently co-occur in older adults, a condition called osteosarcopenia that dramatically increases fall and fracture risk. Currently, no approved pharmacological treatment exists for sarcopenia, making it clinically significant if existing osteoporosis drugs could simultaneously benefit muscle tissue. Denosumab—a monoclonal antibody that blocks RANKL, a key driver of bone resorption—has emerged as a candidate with potential dual-action effects on both bone and muscle.

This systematic review, conducted per PRISMA guidelines and registered in PROSPERO, searched PubMed, Embase, Scopus, and the Cochrane Library through May 2025. From 270 initial records, seven studies met inclusion criteria: three prospective longitudinal studies, two retrospective cohort studies, and one randomized controlled trial, conducted across Egypt, Switzerland, Italy, Germany, Australia, Thailand, the UK, and the USA. Studies assessed muscle strength (primarily handgrip), muscle mass (via DXA), physical performance (TUG, gait speed, chair rise test), and fall incidence in patients receiving denosumab 60 mg subcutaneously every six months, compared to bisphosphonates (alendronate or zoledronate) or placebo.

Most studies reported favorable outcomes for denosumab. El Miedany et al. (Egypt, n=407) found significant improvements in grip strength, gait speed, and fall risk scores over five years compared to zoledronate and alendronate, with notable worsening one year after discontinuation. Bonnet et al. (Switzerland, n=40) showed denosumab uniquely increased appendicular lean mass and handgrip strength, correlated with lumbar spine BMD changes. Chotiyarnwong et al. (multi-country RCT, n=7,762) demonstrated approximately 20% reduction in fallers with denosumab versus placebo, with greater benefit in adults under 75. Rupp et al. (Germany, n=150) found a significantly higher increase in chair rise test force in the denosumab group versus bisphosphonates. Casabella et al. (Italy, n=60, breast cancer patients on aromatase inhibitors) reported significant improvements in relative skeletal muscle index (RSMI) and whole-body composition with denosumab versus alendronate. Pizzonia et al. (Italy, n=40, post-hip fracture) noted a trend toward sarcopenia improvement with denosumab.

The biological plausibility is supported by preclinical evidence: RANK and RANKL are expressed in skeletal muscle, and RANKL promotes muscle inflammation, upregulates myostatin, and impairs insulin sensitivity. Denosumab-mediated RANKL inhibition could theoretically reverse these processes, preserving or improving muscle function independently of its bone effects.

Despite these promising signals, the evidence base has significant limitations. The one fully powered RCT in long-term care residents found no significant effect on muscle outcomes, and the overall body of evidence is characterized by small sample sizes, heterogeneous populations, variable comparators, and inconsistent outcome measurement tools. Meta-analysis was deemed inappropriate due to this heterogeneity. Until purpose-designed trials with standardized sarcopenia endpoints are completed, denosumab cannot be recommended specifically for muscle health.