Medical therapies for weight loss have revolutionised management of metabolic disorders. Incretin therapies, including semaglutide, a glucagon-like peptide-1 receptor agonist (GLP1RA), and tirzepatide, a dual GLP1 and glucose-dependent insulinotropic polypeptide (GIP) agonist, have wide-ranging benefits, beyond glucose lowering and weight loss, thereby expanding their use across diverse populations and indications, and positioning them as potentially life-long therapies. Thus, there is a critical need to understand and manage the full spectrum of effects of these medications.

While weight loss with incretin therapies predominantly reflects loss of fat mass, at least 25% of the total weight loss is due to loss of fat-free mass, which includes bone mass. Bone loss is well documented following other forms of weight loss. Following bariatric surgery, 15-35% of weight loss is associated with 9-15% reductions in bone mineral density (BMD). Uniquely, incretin therapies may mitigate bone loss, in the face of weight loss. Preclinical data suggests that semaglutide protects against bone loss through upregulation of bone formation pathways. However, the evidence in human studies is mixed. Tirzepatide is associated with even greater metabolic benefits and weight loss compared to selective GLP1RA. However, the individual contributions of weight loss versus GLP1 versus GIP versus nutrition on bone loss are unknown.

Rapid bone loss is associated with increased fractures and as obesity and diabetes are already associated with increased fracture risk, understanding the bone-related effects of metabolic therapies and their predictive factors requires clarification. Establishing if these agents affect BMD is urgently needed to support more personalised risk-benefit prediction, optimise monitoring practices and inform long-term bone health strategies for the many people that are treated with incretin therapies.