Short-term semaglutide exposure is associated with increased osteoblast-covered surface in male Swiss mice: a histomorphometric exploratory study

Abstract Background Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used for glycemic control and weight reduction. Because weight loss may be accompanied by bone loss, the skeletal consequences of GLP-1 RA therapy remain clinically relevant and biologically uncertain. This exploratory study investigated whether short-term exposure to semaglutide at two allometrically scaled doses was associated with changes in trabecular bone microarchitecture and static and dynamic histomorphometric indices of bone remodeling in male mice. Methods For this purpose, male Swiss mice received a vehicle, a low (0.021 mg/kg) or an intermediate (0.049 mg/kg) dose of semaglutide once weekly for 28 days. Calcein was administered 8 and 3 days before euthanasia for dynamic bone labeling. Femoral trabecular histomorphometry was performed according to ASBMR nomenclature. Osteoblast surface/bone surface (Ob.S/BS) was prespecified as the primary exploratory endpoint. Renal and hepatic oxidative stress analyses included reduced glutathione (GSH), lipid peroxidation (LPO), superoxide dismutase (SOD), and glutathione S-transferase (GST) as secondary outcomes. Results Compared with the vehicle group, osteoblast surface/bone surface (Ob.S/BS), the primary endpoint, was significantly higher in both semaglutide-treated groups (global p = 0.005), with large effect sizes (Hedges’ g = 1.65 and 1.85 for the low- and intermediate-dose groups, respectively). No significant differences were observed in trabecular structural parameters, dynamic indices of bone formation, or oxidative-stress biomarkers after multiplicity adjustment. Conclusions In this exploratory study, short-term semaglutide exposure was associated with higher osteoblast surface without detectable changes in trabecular microarchitecture or dynamic indices of bone formation after 28 days, suggesting an early, static histomorphometric signal compatible with increased osteoblast-covered bone surface but insufficient to establish a sustained osteoanabolic effect.