The incretin-bone axis: molecular mechanisms and clinical implications.
- 1Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
- 2Bone Physiopathology Research Unit, Translational Pediatrics and Clinical Genetics Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Abstract
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 β-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/β-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.
Related
- Protein lactylation in health and diseases: molecular mechanisms, biological significance, and clinical implications
- Circular RNAs in tumor biology and immunology: molecular mechanisms and therapeutic implications
- Microbiological mechanisms of immune response modulation: clinical implications
- Ginsenosides in hepatocellular carcinoma: preclinical evidence, mechanisms, and clinical implications
- Gut microbiota in esophageal cancer: mechanisms, clinical implications, and therapeutic potential
BibTeX
@article{muscara2026incretinbone,
title = {{The incretin-bone axis: molecular mechanisms and clinical implications.}},
author = {Andrea Muscarà and Federica Bellone and Michela Rossi},
journal = {Frontiers in endocrinology},
year = {2026},
month = oct,
doi = {10.3389/fendo.2026.1907875},
url = {https://europepmc.org/article/MED/42899073},
note = {CC BY},
}
RIS
TY - JOUR
TI - The incretin-bone axis: molecular mechanisms and clinical implications.
AU - Andrea Muscarà
AU - Federica Bellone
AU - Michela Rossi
PY - 2026
DA - 2026/10/05
JO - Frontiers in endocrinology
DO - 10.3389/fendo.2026.1907875
UR - https://europepmc.org/article/MED/42899073
AB - 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 β-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/β-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.
SN - 1664-2392
ER -