Effect of the antidiabetic agent pioglitazone on bone metabolism in rats

Thiazolidinediones (TZDs) are synthetic peroxisome proliferator-activated receptor gamma (PPARγ) agonists used as therapy for type 2 diabetes. However, clinical studies reported that the therapeutic modulation of PPARγ activity using TZDs may induce negative effects on bone metabolism. This study aimed to evaluate the effect of the TZD pioglitazone on bone metabolism in rats. Male Wistar rats were treated orally with pioglitazone 5 or 20 mg/kg daily for 24 weeks. Bone strength was evaluated using a 3-point bending method, and bone histomorphometry was analyzed. Bone mineral density (BMD) was measured using quantitative computed tomography, and serum biochemical markers were examined. Pioglitazone caused a decrease in cortical and trabecular BMD of whole femur. A reduction in bone strength properties of the femoral mid-diaphysis was observed in the 20 mg/kg pioglitazone treated group. Bone histomorphometric analysis revealed that osteoblast surface and mineralizing surface were decreased, whereas osteoclast surface and number were increased after treatment with 20 mg/kg pioglitazone. Altogether, this study demonstrated that pioglitazone may repress bone formation and facilitate bone resorption. The resulting imbalance of bone metabolism leads to a reduction in BMD with a subsequent increase in bone fragility.