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Recent studies demonstrate that disruption of muscle\u2013bone biochemical crosstalk emerges as a key driver of OS pathogenesis, and that targeting pivotal mediators and pathways can concurrently restore musculoskeletal homeostasis. However, the precise molecular mechanisms and targeted therapeutic strategies remain inadequately explored. This review systematically summarizes the epidemiological risk factors and pathophysiological mechanisms underpinning OS, with emphasis on the interplay within musculoskeletal metabolism among myokines (e.g., fibroblast growth factors 21, FGF21, and irisin), osteokines (e.g., osteocalcin, OCN, receptor activator of nuclear factor-\u03baB ligand, RANKL, and sclerostin, SOST), adipokines, and shared signaling pathways such as mitochondria-associated axes, Wnt\/\u03b2-catenin, and nuclear factor-\u03baB (NF-\u03baB), as well as discusses the potential efficacy of direct and indirect interventions targeting these factors and biochemical signals, which provides innovative strategies and prospective research directions for developing precision-targeted therapies against OS and other degenerative musculoskeletal disorders. In addition, we propose that precise modulation of muscle\u2013bone signaling constitutes a promising approach to treat OS. Future efforts should prioritize standardizing diagnostic criteria and advancing the development of therapies targeting critical muscle\u2013bone biochemical interaction nodes to optimize the management of musculoskeletal comorbidities in the aging population.<\/jats:p>","DOI":"10.1530\/joe-25-0234","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T11:57:44Z","timestamp":1756900664000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-5","source":"Crossref","is-referenced-by-count":24,"title":["Muscle\u2013bone biochemical crosstalk in osteosarcopenia: focusing on mechanisms and potential therapeutic strategies"],"prefix":"10.1530","volume":"266","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8500-1771","authenticated-orcid":true,"given":"Qinzuo","family":"Dong","sequence":"first","affiliation":[{"name":"First Clinical Medical College, Yunnan University of Chinese Medicine 1 , ,","place":["Kunming, 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