1202-P: Glucose Lowering with an SGLT2I Improves Trabecular Bone but Does Not Correct Bone Brittleness in TallyHo Model of T2D

Higher fracture risk in T2D is attributed to disease specific deficits in micro-structural and material properties of bone. The TallyHO (TH) mouse is a polygenic model of early-onset T2D/obesity analogous to adolescent-onset T2D in humans. Male TH mice commence rapid weight gain at 4 weeks of age and by ∼10-14 weeks insulin resistance progressing to frank hyperglycemia is apparent in ∼75% of mice. Compared to SWR/J control strain, TH mice exhibit lower: 1) bone formation markers; 2) trabecular bone volume; and 3) fracture resistance. Utilizing this model, we examined the impact of glucose-lowering therapy by SGLT2I on diabetic bone. TH male mice (8-10 weeks) with confirmed hyperglycemia and age-matched, nondiabetic, male SWR/J mice were monitored ± canagliflozin (CANA: 125 ppm in chow) for 10 weeks of treatment. At study end, measurements of body weight, BG, HbA1c, serum insulin, and urine calcium/CR were obtained; femurs were harvested for analysis by µCT and three-point bending. At 20 weeks, these severely hyperglycemic TH mice (BG: 687±106 vs. 151±26 mg/dL; p<0.0001) were obese and had longer femurs with increased cortical bone (↑Ct.Ar, Ct.Th; p<0.001 for all) compared to SWR/J. However, trabecular bone was reduced (↓Tb.BV/TV, Conn.D, Tb.N, Tb.TMD; p<0.001 for all) and TH bones were more brittle (↓toughness; p<0.0001). CANA treatment of TH mice significantly lowered BG and HbA1c while increasing weight gain and insulin secretion (p<0.0001 for all). With glycemic improvement, trabecular bone improved (↑Tb.BV/TV, p=0.0002; Tb.Th, p<0.0001; Tb.TMD; p=0.002) compared to untreated TH mice, but toughness was not altered. Unexpectedly, CANA treatment of SWR/J mice lowered toughness of the femur diaphysis. Hypercalciuria was a consistent feature of both groups of TH mice; CANA also increased Ca excretion in SWR/J mice. CANA therapy may protect against elevated fracture risk in T2D with respect to trabecular rich sites but may not be beneficial if bone becomes brittle with duration.