Abstracts

Several studies have suggested anti-epileptic drugs to be risk factors for low bone mineral density. We have previously reported that phenytoin (PHT) and valproate (VPA) reduce bone mineral density and mechanical strength in female rat femurs compared to control. Levetiracetam (LEV) is a relatively new AED with unknown effects on bone. In the present study, we compared the effect of these drugs on bone densitometric indices, mechanical strength and bone turnover in rats. Female rats were fed perorally with a gastric tube twice daily with LEV 50 or 150 mg/kg, VPA 300 mg/kg, PHT 50 mg/kg or control solution for [sim]90 days (n=10-15 in each group). After sacrifice, blood was collected and whole femurs and lumbal columnae were dissected. BMD and bone mineral content (BMC) were measured by DXA in various regions of interest (ROI), and biomechanical parameters were assessed by 3-point cantilever bending (femoral diaphysis and collum). Biochemical markers of bone formation (osteocalcin) and resorption (Ratlaps) were analyzed in serum by ELISA. Whereas VPA and PHT tended to decrease BMD, both high- and low-dose LEV caused insignificant changes in BMD and BMC in all ROIs (whole femur, collum, trochanter, diaphysis and lumbal vertebrae) compared to controls. However, the various AEDs affected rat bone biomechanical properties differently depending on the skeletal compartment: In the femoral shaft (predominantly cortical bone), high dose LEV tended to reduce strength (momentum and energy absorption), comparable to VPA and PHT, whereas low dose LEV increased these parameters. Interestingly, in the femoral neck (mostly trabecular bone), low-dose LEV significantly decreased momentum, energy absorption and elasticity (with 15 and 17 %, respectively), while high-dose LEV had no effect. Serum osteocalcin levels were reduced in low-dose LEV and unchanged in high-dose LEV-treated rats vs. controls, whereas serum Ratlaps levels were not influenced by LEV at either dose. In VPA-treated animals, bone turnover appeared to be increased. In conclusion, our data demonstrating differential effects of AEDs on bone mass indices, bone strength parameters and bone turnover, suggest different mechanisms of action of these drugs in bone cells. The reduced mechanical strength of the femoral neck in response to low-dose levetiracetam, which was paralleled by lowered osteocalcin levels, suggests a dose-dependent effect of this drug on metabolically active trabecular bone.