ANALYSIS OF BONE HEALTH IN AED EXPOSED WOMEN WITH EPILEPSY

背景：自20世纪60年代末以来，人们就知道 抗癫痫药物与老年人骨代谢紊乱有关 无论是成人还是儿童。这些最严重的表现 疾病包括骨量减少、骨软化和骨折。放射科 或骨病的组织学证据(Valimake et.Al.，1994；Sheth 等，1995；Chung和Changil，1994；Mosekide和Melsen，1980)as 以及生化异常，包括低钙血症， 低磷血症，血清碱性磷酸酶升高，升高 甲状旁腺激素与活性维生素D水平降低 (Bogliun等人)1986年；高夫等人，1986年；马库斯，1992年)一直是 在服用AEDs的患者中检测到。目前，其临床意义 在这些生化异常中还没有定论 特色化的。 骨骼和化学异常的严重性被认为是 与AED暴露的持续时间相关(Chung和Changil，1994) 使用的抗癫痫药物的数量(AED综合疗法)(Gough等人， 1987年；Bogliun等人，1986年)。在单一疗法中，AEDs最常见的是 与骨代谢改变相关的有苯妥英、扑米酮和 苯巴比妥(Gough et al.，1986；Chung and Changil，1994；Valimaki Er.al，1994；Sheth et.，1995)。其他抗癫痫药物与其他药物之间的联系 骨病也被注意到了。尽管之前的一项研究发现 与卡马西平相关的相互矛盾的结果(Tjellesen等人，1983)， 最近的一项研究发现，卡马西平单一疗法与 和“抗痉挛于骨软化症”(Sheth等人，1995)。Sheth et al. (1995)还确定了丙戊酸盐单一疗法和 儿童的骨密度降低。还需要更多的研究来 解释这些发现。 已经提出了几种理论来解释某些因素之间的联系 抗癫痫药物和骨病。肝细胞色素P450诱导剂 酶可诱导维生素D代谢为不活跃的代谢物 (Gough等人，1986，Perucca，1987)。降低Active的可用性 维生素D会导致肠道钙吸收减少和 最终导致低钙血症。 低钙血症会导致循环甲状旁腺素的代偿性增加。 并最终增加骨钙库的动员。 其次，抗癫痫药物可能直接干扰肠道吸收。 钙导致低钙血症和反馈性甲状旁腺素高分泌。 第三，有一些迹象表明，AEDs可能直接影响骨骼。 细胞功能，可能是通过抑制细胞对 Pth(Marcus，1992；Valimake等人，1994) 方法：这是一项关于骨转换和骨量的前瞻性研究。 接受AED单一疗法的成年女性。将有三类AEDs 研究：1)不影响肝细胞色素P450的AED- 混合功能系统；2)诱导细胞色素的拉莫三嗪 P450肝功能混合系统：卡马西平、苯妥英钠 抑制细胞色素P450肝脏混合功能系统： 双丙戊酸钠。

Background: It has been known since the late 1960s that certain antiepileptic drugs are associated with disorders of bone metabolism in both adults and children. The most severe manifestations of these disorders are osteopenia, osteomalacia, and fractures. Radiologicla or histologic evidence of bone disease (Valimake et. al., 1994; Sheth et.al., 1995; Chung and Changil, 1994; Mosekilde and Melsen, 1980) as well as biochemical abnormalities, including hypocalcemia, hypophosphatemia, elevated serum alkaline phosphatase, elevated parathyroid hormone (PTH) and reduced levels of active vitamin D (Bogliun et.al. 1986; Gough et.al., 1986; Marcus, 1992) have been detected in patients taking AEDs. At present, the clinical significance of these biochemical abnormalities has not been conclusively characterized. The severity of bone and chemical abnormalities has been thought to correlate with the duration of AED exposue (Chung and Changil, 1994) and the number of antiepileptic agents used (AED polytherapy) (Gough et.al., 1987; Bogliun et.al., 1986). In monotherapy, the AEDs most commonly associated with altered bone metabolism are phenytoin, primidone, and phenobarbital (Gough et.al., 1986; Chung and Changil, 1994; Valimaki er.al.,1994; Sheth et.al., 1995). Associations between other AEDs and bone disease have also been noted. Although a previous study found conflicting results relative to carbamazepine (Tjellesen et.al., 1983), a recent study found an association between carbamazepine monotherapy and "anticonvulsnat osteomalacia" (Sheth et.al., 1995). Sheth et al. (1995) also identified and association between valproate monotherapy and reduced bone density in children. Additional studies are needed to elucidate these findings. Several theories have been proposed to explain the link between certain AEDs and bone disease. Agents which induce hepatic cytochrome P450 enzymes may induce the metabolism of vitamin D to inactive metabolites (Gough et.al., 1986, Perucca, 1987). Decrease availability of active vitamin D would result in decreased intestinal calcium absorption and eventually hypocalcemia. Hypocalcemia would lead to a compensatory increase in circulating PTH and ultimately increase the mobilization of bone calcium stores. Secondly, AEDs may interfere directly with intestinal absorption of calcium leading to hypocalcemia and feedback hypersecretion of PTH. Thirdly, there is some suggestion that AEDs may directly affect bone cell function, possibly through inhibition of the cellular response to PTh (Marcus, 1992; Valimake et.al., 1994) Methodology: This is a prospective study of bone turnover and bone mass in adult women on AED monotherapy. Three classes of AEDs will be investigated: 1) AED which does not affect the cytochrome P450 hepatic- mixed function system; lamotrigine 2) AEDs which induce the cytochrome P450 hepatic-mixed function system: carbamazepine, phenytoin 3) AED which inhibits the cytochrome P450 hepatic-mixed function system: divalproex sodium.