Type 2 diabetes mellitus (T2DM) is associated with an increased risk of skeletal fragility that cannot be fully explained by changes in bone mineral density (BMD). Altered bone remodeling has been implicated in impaired bone quality in diabetes; however, the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on bone metabolism remain unclear. In this study, the effects of ipragliflozin (IPRA) on bone metabolism were investigated in T2DM mice using bone histomorphometric analysis. Male db/db mice were treated with IPRA (1.0 or 10.0 mg/kg) for 9 weeks. BMD of the femur and tibia was measured, and trabecular bone microarchitecture and remodeling parameters were evaluated in the proximal tibial metaphysis. Compared with non-diabetic control mice, db/db mice exhibited significantly reduced BMD of the femur and tibia. IPRA administration did not result in significant changes in BMD at either dose. In contrast, bone histomorphometric analysis revealed marked deterioration of trabecular bone microarchitecture in db/db mice, accompanied by increased bone resorption and decreased bone formation. IPRA administration was associated with favorable changes in trabecular bone microarchitecture-related parameters, including increases in bone volume per tissue volume and trabecular thickness and a decrease in trabecular separation, particularly at the higher dose. In addition, osteoclast-related parameters were reduced and bone formation-related parameters were increased in db/db mice treated with IPRA at the higher dose, indicating partial attenuation of diabetes-associated alterations in bone remodeling. These findings suggest that IPRA modulates dysregulated bone remodeling and affects trabecular bone microarchitecture at the tissue level in T2DM, without inducing detectable changes in BMD.
