Genetic ablation of SGLT2 function in mice impairs tissue mineral density but does not affect fracture resistance of bone.

Abstract

Selective sodium-dependent glucose co-transporter 2 inhibitors (SGLT2Is) are oral hypoglycemic medications utilized increasingly in the medical management of hyperglycemia among persons with type 2 diabetes (T2D). Despite favorable effects on cardiovascular events, specific SGLT2Is have been associated with an increased risk for atypical fracture and amputation in subgroups of the T2D population, a population that already has a higher risk for typical fragility fractures than the general population. To better understand the effect of SGLT2 blockade on skeletal integrity, independent of diabetes and its co-morbidities, we utilized the "Jimbee" mouse model of slc5a2 gene mutation to investigate the impact of lifelong SGLT2 loss-of-function on metabolic and skeletal phenotype. Jimbee mice maintained normal glucose homeostasis, but exhibited chronic polyuria, glucosuria and hypercalciuria. The Jimbee mutation negatively impacted appendicular growth of the femur and resulted in lower tissue mineral density of both cortical and trabecular bone of the femur mid-shaft and distal femur metaphysis, respectively. Several components of the Jimbee phenotype were characteristic only of male mice compared with female mice, including reductions: in body weight; in cortical area of the mid-shaft; and in trabecular thickness within the metaphysis. Despite these decrements, the strength of femur diaphysis in bending (cortical bone), which increased with age, and the strength of L6 vertebra in compression (primarily trabecular bone), which decreased with age, were not affected by the mutation. Moreover, the age-related decline in bone toughness was less for Jimbee mice, compared with control mice, such that by 49-50weeks of age, Jimbee mice had significantly tougher femurs in bending than C57BL/6J mice. These results suggest that chronic blockade of SGLT2 in this model reduces the mineralization of bone but does not reduce its fracture resistance.