The effect of SGLT2 inhibitors, a new group of antidiabetic drugs, on the skeletal system is a matter of debate. There are concerns that they may unfavorably affect bones. The aim of the study was to investigate the effects of dapagliflozin and canagliflozin on musculoskeletal system in an experimental rat model of type 2 diabetes induced by a high-fat diet (HFD) and streptozotocin (STZ). The experiments were carried out on mature female rats. To induce diabetes, STZ was administered 2 weeks after the introduction of HFD. Administration of dapagliflozin (1.4 mg/kg p.o.) or canagliflozin (4.2 mg/kg p.o.) started 1 week after the STZ injection, and lasted 4 weeks. Skeletal muscle mass and strength, serum bone turnover marker concentration and other biochemical parameters, and bone mass, density, histomorphometric parameters and mechanical properties were determined. Diabetes induced decreases in skeletal muscle mass and osteoporotic changes, including decreases in bone density, and worsening of the histomorphometric parameters and cancellous bone mechanical properties. The SGLT2 inhibitors decreased glycemia and other diabetes-induced metabolic changes, and counteracted only some unfavorable effects of diabetes on bones. The effects of dapagliflozin and canagliflozin on metabolic parameters were similar, whereas there were some differences in their effects on the skeletal system. The study demonstrated possibility of differential skeletal effects of different SGLT2 inhibitors in diabetic conditions, indicating the need for caution concerning their use in patients at risk of bone fractures.