Kanda Junkichi, Izumo Nobuo, Kobayashi Yoshiko, Onodera Kenji, Shimakura Taketoshi, Yamamoto Noriaki, Takahashi Hideaki E, Wakabayashi Hiroyuki
Department of Clinical Pharmacotherapy, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences.
General Health Medical Center, Yokohama University of Pharmacy.
Biol Pharm Bull. 2017;40(11):1934-1940. doi: 10.1248/bpb.b17-00482.
Long-term treatment with antiepileptic drugs (AEDs) is accompanied by reduced bone mass that is associated with an increased risk of bone fractures. Although phenytoin has been reported to adversely influence bone metabolism, little is known pertaining to more recent AEDs. The aim of this study was to evaluate the effects of gabapentin or levetiracetam on bone strength, bone mass, and bone turnover in rats. Male Sprague-Dawley rats were orally administered phenytoin (20 mg/kg), gabapentin (30 or 150 mg/kg), or levetiracetam (50 or 200 mg/kg) daily for 12 weeks. Bone histomorphometric analysis of the tibia was performed and femoral bone strength was evaluated using a three-point bending method. Bone mineral density (BMD) of the femur and tibia was measured using quantitative computed tomography. Administration of phenytoin significantly decreased bone strength and BMD, which was associated with enhanced bone resorption. In contrast, treatment with gabapentin (150 mg/kg) significantly decreased bone volume and increased trabecular separation, as shown by bone histomorphometric analysis. Moreover, the bone formation parameters, osteoid volume and mineralizing surface, decreased after gabapentin treatment, whereas the bone resorption parameters, osteoclast surface and number, increased. Levetiracetam treatment did not affect bone strength, bone mass, and bone turnover. Our data suggested that gabapentin induced the rarefaction of cancellous bone, which was associated with decreased bone formation and enhanced bone resorption, and may affect bone strength and BMD after chronic exposure. To prevent the risk of bone fractures, patients prescribed a long-term administration of gabapentin should be regularly monitored for changes in bone mass.
抗癫痫药物（AEDs）的长期治疗会导致骨量减少，这与骨折风险增加相关。尽管据报道苯妥英会对骨代谢产生不利影响，但对于更新的AEDs却知之甚少。本研究的目的是评估加巴喷丁或左乙拉西坦对大鼠骨强度、骨量和骨转换的影响。雄性Sprague-Dawley大鼠每天口服苯妥英（20mg/kg）、加巴喷丁（30或150mg/kg）或左乙拉西坦（50或200mg/kg），持续12周。对胫骨进行骨组织形态计量学分析，并使用三点弯曲法评估股骨骨强度。使用定量计算机断层扫描测量股骨和胫骨的骨密度（BMD）。苯妥英的给药显著降低了骨强度和BMD，这与骨吸收增强有关。相比之下，骨组织形态计量学分析显示，加巴喷丁（150mg/kg）治疗显著降低了骨体积并增加了小梁间距。此外，加巴喷丁治疗后，骨形成参数类骨质体积和矿化表面减少，而骨吸收参数破骨细胞表面和数量增加。左乙拉西坦治疗对骨强度、骨量和骨转换没有影响。我们的数据表明，加巴喷丁会导致松质骨稀疏，这与骨形成减少和骨吸收增强有关，并且长期接触后可能会影响骨强度和BMD。为预防骨折风险，长期服用加巴喷丁的患者应定期监测骨量变化。
