Comparative evaluation of Sodium-glucose co-transporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors influence on bone turnover markers in rats with experimental type 2 diabetes mellitus

Background: Type 2 diabetes mellitus (DM) is accompanied by increased risk of osteoporotic fractures. Data on type 2 sodium-glucose co-transporter inhibitors (SGLT-2i) in fracture risk are contradictory. A simultaneous comparison of high- and low-selective SGLT-2i effects on bone turnover parameters with the effects of other drug classes has not been performed previously.

Aim: To evaluate and to compare the influence of empagliflozin (EMPA), canagliflozin (CANA) and sitagliptin (SITA) on bone remodeling parameters in type 2 diabetic rats.

Materials and methods: Type 2 DM was modelled in male Wistar rats by high-fat diet and strepTozotocin+nicotinamide injection. Four weeks after the following groups were formed: “DM” without treatment, as well as 8-week treatment with SITA 50 mg/kg (“DM+SITA”), CANA 25 mg/kg (“DM+CANA”), EMPA 2 mg/kg (“DM+EMPA”). Animals in “Control” group were not subjected to any interventions. Calcium, phosphorus, fibroblast growth factor-23 (FGF23), osteocalcin (OC), osteoprotegerin (OPG), RANKL concentrations were measured in the blood sampled at the end of the treatment, as well as bone histoarchitectonics was evaluated.

Results: Calcium concentration was higher in “DM+EMPA” group (2.79 (2.69; 2.83 mmol/L) comparing with “Control” (2.65 (2.53; 3.15)), phosphorus level in “DM+EMPA” was higher than in all other groups. FGF23 was decreased in “DM” group (0.24 (0.11; 0.31) pmol/L), while EMPA treatment was associated with higher FGF23 level (1.1 (0.62; 1.1). OC was lower in “DM” (10.69 (9.97; 11.03) ng/mL) than in “Control” group (49.1 (47.98; 54.57), treatment with SITA and EMPA was associated with increase in OC level (19.57 (18.85; 24.44) и 16.00 (15.72; 17.00), respectively), with OC concentration being higher in “DM+SITA” group. There were no differences in OPG and RANKL levels between “DM” and “Control” groups, whereas OPG was lower in “DM+CANA” (1.85 (1.19; 1.90) pmol/L) and “DM+EMPA” (1.26 (0.76; 1.88) than in “DM+SITA” (6.28 (3.05; 3.99). RANKL/OPG ratio was the highest in “DM+EMPA” and “DM+CANA” groups, with no significant between-group difference. In «DM+EMPA» and «DM+CANA» groups there was a decrease in the area of bone trabeculae in the epiphyseal part (56.70 (53.80; 58.05)% и 52.30 (50.50; 54.85)%) in comparison with “Control” group (62.30 (61.30; 64.20)%). All study drugs administration led to similarly satisfactory glycemic control.

Conclusion: SITA influence on bone remodeling is neutral, while EMPA and CANA administration leads to increase of bone resorption. Drugs’ influence on bone metabolism is not due to their effect on glycemic profile

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