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.


K.M. Thrailkill: None. R. Bunn: None. S. Uppuganti: None. P.D. Ray: None. I. Popescu: None. E. Kalaitzoglou: None. J. Fowlkes: None. J.S. Nyman: Advisory Panel; Self; ActiveLife Scientific, Inc. Consultant; Self; Sanofi Genzyme. Research Support; Self; ActiveLife Scientific, Inc., Sanofi Genzyme.


National Institutes of Health (R21AR070620, R01DK084045); U.S. Department of Veterans Affairs (1l01BX001018)

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