GLP-1 receptor agonists: the evolution of evidence for fracture risk, body composition, and clinical implications

Older adults, particularly those with diabetes mellitus, are at increased risk of significant functional decline, morbidity, and mortality after fragility fractures. Glucagon-like peptide-1 receptor agonist (GLP-1RA) medications have become increasingly important therapies for diabetes, obesity, and cardiometabolic risk reduction. However, GLP-1RAs appear to exert effects on skeletal health, and this may be clinically relevant in older adults. Recent observational data suggests a modest increase in fracture risk among older adults initiating GLP-1RA therapy, raising concerns about unintended musculoskeletal consequences. Notably, this study specifically looked at fragility fractures as a primary endpoint and was not an incidental safety finding. Potential mechanisms include reduced mechanical loading from weight loss, loss of skeletal muscle mass and bone density, altered bone cellular signaling, decreased nutritional intake, and increased fall risk. Emerging strategies, including clinical trials focusing on pharmacotherapy to address the composition of weight loss and lifestyle interventions, are investigating methods to mitigate unintentional effects of these GLP-1RAs. This mini-review synthesizes the evolving evidence on GLP1-RA medications and skeletal health, explores underlying mechanisms, and outlines clinical strategies to balance the benefits and risks of these therapies.