{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:53:35Z","timestamp":1791204815144,"version":"4.1.0"},"reference-count":110,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>Incretin hormones, primarily glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are key regulators of postprandial glucose homeostasis and exert pleiotropic actions beyond pancreatic \u03b2-cell function. Increasing evidence identifies the incretin axis as a critical mediator linking nutrient intake to skeletal remodeling. Preclinical studies demonstrate that incretin signaling influences bone turnover through coordinated effects on osteoblasts, osteoclasts, osteocytes, and mesenchymal stromal cells. These actions involve modulation of major pathways, including cAMP\/PKA, MAPK, Wnt\/\u03b2-catenin signaling, and the RANK-L\/OPG axis, ultimately promoting osteogenesis while suppressing bone resorption. Genetic and pharmacological models highlight the importance of intact incretin receptor signaling for maintaining bone mass, microarchitecture, and matrix quality. In particular, GIP appears to exert direct anabolic and antiresorptive effects on bone cells, whereas GLP-1 influences skeletal homeostasis through both direct mechanisms and indirect endocrine pathways. Despite robust mechanistic insights, translation to clinical settings remains challenging. Studies on incretin-based therapies, including GLP-1 receptor agonists and dual GIP\/GLP-1 agonists, report heterogeneous effects on bone turnover markers and inconclusive outcomes on fracture risk. A major confounding factor is therapy-induced weight loss, which may negatively impact skeletal integrity and obscure direct drug effects. This review integrates current knowledge on the molecular and cellular mechanisms of incretin action in bone, critically examines available clinical data, and highlights key gaps in the field. A deeper understanding of incretin-bone interactions is essential to clarify whether targeting this axis may represent a viable strategy for preserving skeletal health in metabolic disease.<\/jats:p>","DOI":"10.3389\/fendo.2026.1907875","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:17:55Z","timestamp":1791202675000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The incretin-bone axis: molecular mechanisms and clinical implications"],"prefix":"10.3389","volume":"17","author":[{"given":"Andrea","family":"Muscar\u00e0","sequence":"first","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Messina","place":["Messina, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Bellone","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of 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