Skeletal effect of semaglutide and tirzepatide in patients with increased risk of fractures

Abstract 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 nonusers with at least 2 DXA scans over the same period. The primary outcome was the 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 a median 5% weight loss. Both groups had significant declines in BMD at TH and FN, with a 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 < .01). Among patients without DM, greater TH bone loss was noted in the GLP-1 RA group compared to controls (−1% vs −0.6%, P = .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.