Skeletal Effect of Semaglutide and Tirzepatide in Patients with Increased Risk of Fractures.

CONTEXT: Glucagon-like peptide-1 receptor agonists (GLP1-RA) have potent glucose-lowering and weight loss benefits, but their effects on bone remain unclear. OBJECTIVE: To investigate changes in bone mineral density (BMD) in patients using semaglutide (SEM) and tirzepatide (TIR), a dual agonist of GLP-1/glucose dependent insulinotropic polypeptide. METHODS: Single-center retrospective study. Adult patients using SEM/TIR for ≥6 months with DXA scans before initiation and at least 6 months after were matched by age, sex, BMI, and diabetes mellitus (DM) to non-users with at least two DXA scans over the same period. The primary outcome was percentage change in total hip (TH) BMD. RESULTS: We included 255 patients using SEM or TIR in the GLP-1 RA group (92% female, mean age 64±9 years, BMI 31.0±5.6 kg/m²) and 255 controls. After a median follow-up of 17 months, the GLP-1 RA group achieved median 5% weight loss. Both groups had significant declines in BMD at TH and FN, with similar magnitude between groups. In the GLP-1RA group, weight loss was directly associated with bone loss at the TH and FN (r=0.32 for TH, r=0.17 for FN, both p<0.01). Among patients without DM, greater TH bone loss was noted in GLP-1 RA group compared to controls (-1% vs -0.6%, p=0.04), whereas TH bone loss was similar between groups among patients with DM. CONCLUSION: SEM/TIR use was associated with greater annualized TH bone loss in patients without DM, whereas TH bone loss was comparable between GLP-1 RA and controls in patients with DM. These findings suggest GLP-1 RA's effects on bone may differ by DM status, with weight loss driving bone loss in patients without DM.