Co-treatment with metformin and naringin attenuates bone alterations induced by a high-fructose diet in male Wistar rats.

Abstract

A high-fructose diet (HFD) is associated with skeletal alterations, including bone loss and increased fracture risk. Metformin (Met) is widely used to treat metabolic syndrome, although it does not fully reverse associated complications. Naringin (NAR), a natural flavonoid, has shown antioxidant and osteoprotective properties. This study aimed to evaluate whether the co-administration of Met and NAR attenuates bone alterations during the progression of HFD-induced metabolic dysfunction. Male Wistar rats were divided: 1) control; 2) HFD (10% w/v fructose); 3) HFD + Met (100 mg/kg/day, oral); 4) HFD + NAR (40 mg/kg/day, subcutaneous); 5) HFD + Met+NAR. Treatments began on day 21 of HFD administration and continued until day 60. Bone mineral density (BMD), μCT analysis, histomorphometry, histology, and oxidative stress parameters were assessed. HFD increased body weight, waist circumference, triglycerides, and reduced HDL-C. Treatments normalized waist circumference, while NAR and Met+NAR improved the lipid profile. HFD reduced BMD, bone volume, and trabecular thickness, and increased trabecular separation. These alterations were attenuated by all treatments, with Met+NAR showing the greatest improvement, including normalization of trabecular structure and increased trabecular thickness beyond control values. HFD also increased marrow adiposity and reduced osteocyte number, whereas NAR and Met+NAR restored these parameters. Oxidative stress was elevated in HFD rats and improved with treatments. Co-administration of Met and NAR ameliorates HFD-induced bone alterations, likely through modulation of oxidative stress. These findings provide preclinical evidence supporting the potential utility of this combination in mitigating diet-induced skeletal alterations.