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These multifactorial disorders are characterized by progressive decline in bone density and muscle mass, increasing the chances of immobility and eventually disability. Such manifestations are driven by a complex molecular crosstalk between bones and muscles. This review highlights the key role of the irisin\u2010sclerostin\u2010inflammation triad in the pathophysiology of musculoskeletal degeneration. Irisin is a myokine induced by exercise. It is associated with osteogenesis and muscle regeneration. Sclerostin is an osteocyte\u2010derived Wnt antagonist, inhibits bone formation and is linked to impaired muscle regeneration. Inflammatory mediators such as TNF\u2010\u03b1 and IL\u20106 drive muscle catabolism and bone resorption through the NF\u2010\u03baB and STAT3 signaling pathways. Dysregulation of this triad accelerates musculoskeletal degeneration, particularly in chronic diseases and aging. We described the correlation between these diseases and mediators with age and gender. Additionally, we discussed current and emerging therapeutic strategies targeting these mediators, including anti\u2010sclerostin antibodies for high\u2010risk osteoporosis, cytokine\/JAK\u2010pathway inhibitors for inflammatory disease, and structured resistance\/weight\u2010bearing exercise as a cornerstone intervention. We highlighted assay standardization needs, proposed human\u2010focused models, and outlined priorities for precision, combination strategies targeting the triad in bone\n                      <jats:bold>\u2010<\/jats:bold>\n                      muscle wasting disorders.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cbf.70187","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T10:48:56Z","timestamp":1772966936000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Irisin, Sclerostin, and Inflammatory Axis: Implication in Bone\u2010Muscle Wasting Diseases"],"prefix":"10.1002","volume":"44","author":[{"given":"Mohamad","family":"Maged","sequence":"first","affiliation":[{"name":"Applied Biotechnology Program, School of Biotechnology Nile University Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sameh","family":"Heikal","sequence":"additional","affiliation":[{"name":"Applied Biotechnology Program, School of Biotechnology Nile University Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salma","family":"Ibrahim","sequence":"additional","affiliation":[{"name":"Faculty of Nutrition and Food Technology October University for Modern Sciences and Arts (MSA) Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sameh E.","family":"Hassanein","sequence":"additional","affiliation":[{"name":"Bioinformatics Program, School of Biotechnology Nile University Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,23]]},"reference":[{"key":"e_1_2_16_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)32340-0"},{"key":"e_1_2_16_3_1","unstructured":"Musculoskeletal health. 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