Nissen-Meyer Lise Sofie H, Svalheim Sigrid, Taubøll Erik, Reppe Sjur, Lekva Tove, Solberg Lene B, Melhus Gunhild, Reinholt Finn P, Gjerstad Leif, Jemtland Rune
Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, Norway.
Epilepsia. 2007 Oct;48(10):1850-60. doi: 10.1111/j.1528-1167.2007.01176.x. Epub 2007 Jul 18.
Long-term treatment with antiepileptic drugs (AEDs) is associated with increased risk of fractures. Phenytoin (PHT) and valproate (VPA) have both been suggested to influence bone health, whereas levetiracetam (LEV) is scarcely studied. The present study compares the effect of these AEDs on bone mass, biomechanical strength, and bone turnover in rats.
Female rats received PHT (50 mg/kg), VPA (300 mg/kg), or LEV (50 and 150 mg/kg) for 90 days. Dissected femurs were analyzed using dual energy x-ray absorptiometry (DXA), three-point cantilever bending, and histomorphological evaluation. Serum levels of biochemical bone turnover markers were monitored using immunoassay quantification.
PHT and VPA reduced bone mineral density (BMD) and content (BMC) in one or more bone compartments, whereas LEV did not. VPA induced increased bone turnover, whereas modest changes were observed for PHT. Interestingly, low-dose LEV was associated with reduced biomechanical strength of the femoral neck (mainly trabecular bone). In addition, low-dose LEV treatment resulted in significantly reduced levels of serum osteocalcin, a marker of bone formation. Histomorphological analyses indicated increased retention of cartilage remnants at the growth plate metaphysis of rats treated with low-dose LEV vs. controls.
PHT, VPA, and LEV exert differential effects on bone mass and strength, suggesting different mechanisms of action. The weakening effect of low-dose LEV on the femoral neck, despite a constant BMD, suggests a primary effect on bone quality. These findings warrant further human studies of possible adverse effects of LEV on bone development and growth, particularly in children and adolescents.
长期使用抗癫痫药物（AEDs）会增加骨折风险。苯妥英（PHT）和丙戊酸盐（VPA）均被认为会影响骨骼健康，而左乙拉西坦（LEV）的相关研究较少。本研究比较了这些AEDs对大鼠骨量、生物力学强度和骨转换的影响。
雌性大鼠接受PHT（50mg/kg）、VPA（300mg/kg）或LEV（50和150mg/kg）治疗90天。使用双能X线吸收法（DXA）、三点悬臂弯曲法和组织形态学评估对解剖后的股骨进行分析。使用免疫分析定量法监测血清中生化骨转换标志物的水平。
PHT和VPA降低了一个或多个骨区室的骨矿物质密度（BMD）和骨矿物质含量（BMC），而LEV没有。VPA导致骨转换增加，而PHT观察到的变化较小。有趣的是，低剂量LEV与股骨颈（主要是小梁骨）生物力学强度降低有关。此外，低剂量LEV治疗导致血清骨钙素水平显著降低，骨钙素是骨形成的标志物。组织形态学分析表明，与对照组相比，低剂量LEV治疗的大鼠生长板干骺端软骨残余物的保留增加。
PHT、VPA和LEV对骨量和强度有不同的影响，提示作用机制不同。尽管BMD恒定，但低剂量LEV对股骨颈的削弱作用表明对骨质量有主要影响。这些发现值得进一步对LEV对骨骼发育和生长可能的不良影响进行人体研究，特别是在儿童和青少年中。
