Incretin-Based Therapies and the Associated Impact on Bone Health

Incretin-based therapies are being increasingly used in the treatment of type 2 diabetes mellitus and obesity, both of which are associated with impaired bone quality, altered skeletal remodeling, and increased fracture risk. Experimental studies suggest that incretin signaling may affect bone through osteoblast and osteoclast activity, Wnt/β-catenin signaling, adipose tissue inflammation, metabolic regulation, and the gut–bone axis. However, clinical evidence remains heterogeneous, with most studies indicating neutral or context-dependent effects on bone mineral density and fracture risk rather than consistent skeletal benefit. Interpretation is further complicated by treatment-induced weight loss, changes in lean mass and mechanical loading, diabetes-related skeletal fragility, and the limited number of trials specifically designed to assess bone endpoints. Evidence for newer dual and triple agonists is especially limited, despite their growing use and substantial weight-loss effects. Incretin-based therapies appear reassuring from a skeletal safety perspective; however, long-term studies with dedicated skeletal endpoints are needed to determine their effects on bone quality, falls, and fracture risk in high-risk populations. This review summarizes current mechanistic, preclinical, and clinical evidence on the effects of glucagon-like peptide-1 receptor agonists, dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors on bone turnover, bone mineral density, bone quality, and fracture outcomes.