Denosumab for Primary Osteoporosis and Its Impact on Sarcopenia in the Chinese Population: Insights from Clinical Evidence and RANKL Pathway Mendelian Randomization.

Background: With the rapid aging of China's population, osteoporosis and sarcopenia have become major public health challenges. Denosumab, a first-line therapy for osteoporosis, may also improve muscle health, a possibility warranting further investigation. Objective: This study evaluated the efficacy of denosumab in treating primary osteoporosis in the Chinese population and explored its potential effects on sarcopenia. A Mendelian randomization (MR) analysis was additionally performed to investigate the causal role of the RANKL pathway in sarcopenia. Methods: This study included two components. In the clinical study, 45 patients with primary osteoporosis received denosumab, of whom 40 completed a 6-month follow-up and 15 completed a 1-year follow-up. Outcomes included bone turnover markers, bone mineral density, muscle strength, and physical performance measures. In the genetic study, two-sample MR was conducted using genome-wide association study (GWAS) summary statistics to assess the causal association between RANKL gene variants and sarcopenia-related traits, including appendicular lean mass and grip strength. Results: Denosumab significantly reduced bone turnover markers and improved muscle function after 6 months, with further gains in bone mineral density and muscle strength observed at 1 year (all P < 0.05). Muscle mass showed upward but non-significant trends. MR analysis revealed a significant negative association between RANKL expression and both appendicular lean mass and grip strength, with no evidence of heterogeneity or pleiotropy. Conclusion: Denosumab effectively treats osteoporosis and improves muscle function in Chinese patients. Genetic evidence supports a causal role of the RANKL pathway in sarcopenia, indicating that RANKL overexpression may contribute to its development. By integrating clinical and genetic evidence, our findings suggest that denosumab may represent a promising therapeutic option for patients with concurrent osteoporosis and sarcopenia.