Decreased bone strength in skeletally mature female mice with T2D is associated with changes in OLCN and spatially...

Women with Type-2 diabetes (T2D) have a higher incidence of fractures and associated mortality compared to men. However, most animal models for studying diabetes-induced bone effects use males and the impact of T2D on bone quality in skeletally mature females remains unknown. We developed a mouse model to determine the effect of T2D on female bone quality. T2D was induced in 16-week-old female C57BL/6J mice using a High-Fat Diet and Streptozotocin (HFD + STZ), controls received a Low-Fat Diet and sham injections (LFD + VEH). The diabetic group displayed hyperglycemia, hypoinsulinemia, and increased body fat. T2D altered bone architecture spatially, the T2D group displayed decreased cortical and trabecular bone volume (BV) and total volume (TV) with varying magnitude at specific locations compared to the control. T2D also reduced bone yield and ultimate loads under four-point bending, without affecting tissue-level properties. Moreover, changes in TV with T2D explained up to 70 % of the variance in bone strength, suggesting that the weakening effect of T2D on female bone strength is architecture-driven. Compromised architecture with T2D was associated with changes in the Osteocyte Lacuno-Canalicular Network (OLCN). T2D decreased canalicular density, the total number of nodes and increased lacunae surface area. These changes in the OLCN with T2D explained up to 37 % of bone architecture variance. In summary, our novel T2D female mouse model displayed a bone phenotype with compromised OLCN associated to impaired architecture, which led to decreased bone strength. These outcomes suggest that the effect of T2D on female bone strength is architecture-driven rather than material-driven.