Differential Effects of Anti-Epileptic Drugs on Bone Health in Rats. Dose-Dependent Impairment of Biomechanical and Microstructural Properties of Rat Femur by Levetiracetam
Abstract number :
2.233
Submission category :
Antiepileptic Drugs-All Ages
Year :
2006
Submission ID :
6672
Source :
www.aesnet.org
Presentation date :
12/1/2006 12:00:00 AM
Published date :
Nov 30, 2006, 06:00 AM
Authors :
1Lise Sofie H. Nissen-Meyer, 2Sigrid Svalheim, 2Erik Taub[oslash]ll, 3Tove Lekva, 1Sjur Reppe, 4Lene B. Solberg, 4Gunhild Melhus, 4Finn P. Reinholt, 2Leif G
A serious complication of long-term treatment with anti-epileptic drugs (AEDs) is increased risk for fractures. Phenytoin (PHT) and valproate (VPA) are both known to influence bone health, whereas levetiracetam (LEV) belongs to a new class of drugs with no reported adverse effects on bone., Female Wistar rats were fed twice daily for 90 days through a gastric tube with either LEV 50 mg/kg (n=10), 150 mg/kg (n=12), VPA 300 mg/kg (n=12), PHT 75 mg/kg (n=9) or control solution (n=12). We studied the effect of LEV, VPA and PHT on bone densitometric indices, biomechanical strength and bone turnover serum markers., Mean serum drug concentration 4 hours after last dose was 122, 277, 431 and 74 [mu]mol/l in low-dose LEV, high-dose LEV, VPA and PHT treated animals, respectively. Whereas PHT and VPA reduced bone mineral density (BMD) and content (BMC) in one or more bone compartments, LEV did not. Only VPA increased bone turnover, whereas treatment with low-dose LEV caused significant reduction in levels of serum osteocalcin (a bone formation marker) relative to controls. Interestingly, low-dose LEV also caused reduced biomechanical strength of the femoral neck. Histomorphological analyses showed retention of cartilage remnants at the growth plate metaphysis in low-dose LEV-treated [italic]vs.[/italic] control rats (n=6, each group), suggesting reduced cartilage resorption secondary to impaired local bone mineralization. VPA and PHT promoted cellular differentiation and mineralization of primary rat calvarial osteoblasts [italic]in vitro[/italic], while LEV was without effect., Our data demonstrate differential effects of PHT, VPA and LEV on bone mass and strength, suggesting a different mechanism of action. Remarkably, the ability of low-dose LEV to cause decreased biomechanical strength of the femoral neck, without affecting BMD, suggests a primary effect of this drug on bone quality. This should warrant further studies in humans to rule out potential adverse effects of LEV on bone development and growth, especially in children and adolescents.,
Antiepileptic Drugs