Abstracts

Previous studies have suggested anti-epileptic drugs to be risk factors for low bone mineral density and fractures in humans. In this study we have investigated the effect of the antiepileptic drugs phenytoin (PHT) and valproate (VPA)on bone mineral density at specific sites of rat femurs representing cortical and trabecular bone. Because fractures are biological endpoints of reduced bone density, we also studied the mechanical strength in these bones. Female Wistar rats (80 days old) were fed perorally through a gastric tube with VPA (300 mg/kg), PHT (50 mg/kg), or control solution (CTR) twice daily for 90 days. After sacrification, blood was collected and whole femurs were dissected. The left femur was used for measurements of bone mineral density and content (BMD and BMC) by Dual energy X-ray absorptiometry (DXA). Regions of interest (ROI) included whole femur, collum and trochanter (mainly trabecular bone) and diaphysis (mainly cortical bone). Mechanical strength was investigated using the 3-point bending test (femoral diaphysis and collum). Mean animal weight was the same in all treatment groups (249 g, 246 g and 254 g in the VPA, PHT and CTR groups, respectively). Mean serum VPA concentration was 431 [micro]mol/l and PHT 37 [micro]mol/l 4 hours after last dose. VPA decreased BMD compared to CTR in all ROIs significantly in whole femur and collum, while the PHT group showed BMD lower than CTR in all ROIs except in the whole femur (significant in collum only). In both groups, BMC of collum and whole femur was significantly lower than CTR. Testing of the mechanical properties of the bones indicated that VPA reduced maximal strength and fracture energy in the femoral diaphysis. However, the fracture parameters did not show significant differences between the groups in this study. Our data indicate a catabolic effect of PHT and VPA at therapeutic drug concentrations in the rat femur. Valproate also appears to reduce the mechanical strength in the femoral diaphysis. Further studies are under way to clarify the effects of these agents on bone strength, as well as the responsible mechanisms involved.