Denosumab Versus Zoledronic Acid for Muscle Strength and Physical Performance in Postmenopausal Osteoporosis: A...

Osteoporosis and sarcopenia frequently coexist in older adults, yet whether denosumab provides muscle-related benefits beyond bone remains uncertain. We compared denosumab and zoledronic acid across functional, imaging, biologic and study-defined sarcopenia outcomes based on an Asian Working Group for Sarcopenia (AWGS) 2025-informed framework and examined whether early osteoprotegerin (OPG)/soluble receptor activator of nuclear factor-kappa B ligand (sRANKL) responses tracked with later benefit.

This prospective observational cohort study included 186 postmenopausal women with osteoporosis and prescreened sarcopenia risk (82 denosumab, 104 zoledronic acid). Assessments at baseline and 12, 24 and 36 months included grip strength, gait speed, 5-times chair stand, lumbar spine and femoral neck bone mineral density (BMD), dual-energy X-ray absorptiometry (DXA)-derived appendicular skeletal muscle mass index (ASMI), computed tomography (CT)-derived T12-L4 skeletal muscle volume index (SMVI), skeletal muscle density (SMD), intermuscular fat volume index (IMFI), visceral fat volume index (VFI) and OPG/sRANKL-centred biologic markers. Continuous outcomes were analysed using linear mixed-effects models, categorical outcomes with Fisher exact tests and responder and mediation analyses.

Denosumab showed greater functional improvement than zoledronic acid. At 12 months, grip strength increased by 1.45 ± 0.51 versus 0.66 ± 0.34 kg, gait speed by 0.041 ± 0.013 versus 0.017 ± 0.011 m/s and 5-times chair stand time by -0.82 ± 0.27 versus -0.32 ± 0.18 s (all p < 0.001). At 36 months, changes were 2.52 ± 0.63 versus 0.99 ± 0.45 kg, 0.070 ± 0.017 versus 0.027 ± 0.012 m/s and -1.47 s (-1.63, -1.34) versus -0.63 s (-0.82, -0.50) (all p < 0.001). ASMI did not differ at 12 months (p = 0.119) but favoured denosumab at 24 and 36 months (both p < 0.001; 36-month change, 0.192 ± 0.059 vs. 0.089 ± 0.050 kg/m²). Sarcopenia prevalence was lower with denosumab at 12, 24 and 36 months (52.1% vs. 69.8%, 30.2% vs. 50.7% and 20.0% vs. 46.0%), and remission was higher (36.7% vs. 15.5%, 63.5% vs. 37.3% and 75.0% vs. 37.0%). Denosumab also produced greater increases in SMVI and SMD and greater reductions in IMFI and VFI. The OPG/sRANKL ratio increased more strongly at 12 months (2.503 [2.053, 3.429] vs. 0.807 [0.549, 0.994], p < 0.001). High responders had larger 36-month gains in grip strength (2.80 ± 0.65 vs. 2.21 ± 0.44 kg, p < 0.001) and CT-defined SMVI (2.816 ± 0.861 vs. 2.199 ± 0.524, p = 0.002). Twelve-month OPG/sRANKL change showed a pattern statistically consistent with partial mediation of the association between treatment group and 36-month grip strength (37.0%) and CT-defined SMVI (39.9%).

Compared with zoledronic acid, denosumab was associated with stronger early OPG/sRANKL activation, earlier functional improvement, more favourable CT-defined remodelling, later DXA-derived muscle-mass gain and lower study-defined sarcopenia burden based on an AWGS 2025-informed framework over 3 years. These findings support validation of RANKL inhibition in osteosarcopenic phenotypes.