Department of Medicine, Bone Mineral Service and Neurology, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, Victoria, Australia.
Epilepsia. 2010 Jun;51(6):984-93. doi: 10.1111/j.1528-1167.2009.02516.x. Epub 2010 Feb 12.
Bone disease and fractures are common with chronic antiepileptic drug (AED) therapy, but the underlying mechanisms are poorly understood. This study aimed to characterize adverse bone effects of valproate and to identify mouse strains either resistant or sensitive to these effects.
Seven mouse strains (n = 40/strain; 10/diet) were screened for the effect of chronic (8 weeks) valproate treatment (0, 2, 4, and 6 g/kg food) on total bone mineral content (BMC, by dual energy x-ray absorptiometry). In a confirmatory study the effect of valproate (0 or 4 g/kg food) over 16 weeks was assessed in five of the mouse strains (n = 60/strain; 30/diet) identified in the screening phase as either sensitive or resistant. Ex vivo volumetric bone measures and structural changes were assessed using peripheral quantitative computed tomography (pQCT) and histomorphometry.
Chronic valproate treatment reproducibly affected bone in C3H/HeJ mice, with a 9.1% (p < 0.01) reduction in total BMC and a 10.7% (p < 0.01) reduction in trabecular volumetric density, indicating a sensitive strain to AED-induced bone loss. Histomorphometry was consistent, revealing reductions in trabecular volume (19.6%, p < 0.05) and number (14.3%, p < 0.04), and a 19.9% (p < 0.05) increase in trabecular separation. In contrast the A/J mice were reproducibly resistant to the bone effects.
Mouse strains sensitive and resistant to the adverse bone effects of chronic valproate treatment were identified. The strain-specific effects suggest a role of genetic factors in the pathogenesis of AED-induced bone disease. This novel model provides a new, powerful tool to investigate the pathophysiology and therapy of AED-associated bone disease.
慢性抗癫痫药物（AED）治疗会导致常见的骨骼疾病和骨折，但潜在机制尚不清楚。本研究旨在描述丙戊酸的不良骨骼作用，并确定对这些作用具有抗性或敏感性的小鼠品系。
筛选 7 种小鼠品系（n=40/品系；10/饮食），以评估慢性（8 周）丙戊酸治疗（0、2、4 和 6 g/kg 食物）对总骨矿物质含量（BMC，通过双能 X 射线吸收法）的影响。在一项确认性研究中，在筛选阶段确定为敏感或抗性的 5 种小鼠品系（n=60/品系；30/饮食）中，评估了丙戊酸（0 或 4 g/kg 食物）16 周的作用。使用外周定量计算机断层扫描（pQCT）和组织形态计量学评估体外体积骨测量和结构变化。
慢性丙戊酸治疗可重现性地影响 C3H/HeJ 小鼠的骨骼，总 BMC 减少 9.1%（p<0.01），小梁体积密度减少 10.7%（p<0.01），表明该品系对 AED 诱导的骨丢失敏感。组织形态计量学结果一致，显示小梁体积减少 19.6%（p<0.05），数量减少 14.3%（p<0.04），小梁分离增加 19.9%（p<0.05）。相比之下，A/J 小鼠对骨骼作用具有重现性抗性。
确定了对慢性丙戊酸治疗不良骨骼作用敏感和抗性的小鼠品系。该品系特异性作用提示遗传因素在 AED 诱导的骨骼疾病发病机制中的作用。这种新型模型为研究 AED 相关骨骼疾病的病理生理学和治疗提供了新的、强大的工具。
