ANALYSIS OF BONE HEALTH IN AED EXPOSED WOMEN WITH EPILEPSY

暴露于 AED 的癫痫女性的骨骼健康分析

• 批准号: 6115081
• 负责人: MARTHA J MORRELL
• 金额: $ 4.03万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6115081
• 关键词: anticonvulsants; blood chemistry; bone density; bone metabolism; bone metabolism disorder; calcium metabolism; chronic disease /disorder; clinical research; cytochrome P450; drug adverse effect; drug screening /evaluation; enzyme inhibitors; epilepsy; female; gastrointestinal absorption /transport; human subject; human therapy evaluation; hypocalcemia; liver function; longitudinal human study; parathyroid hormones; pharmacokinetics; photon absorptiometry; sodium; vitamin D

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.

背景：自20世纪60年代末以来， 抗癫痫药物与骨代谢紊乱有关， 包括成人和儿童。其中最严重的表现是 疾病是骨质减少、骨软化和骨折。放射学 或骨疾病的组织学证据（Valimake et.例如，1994年; Sheth 等，1995年; Chung和Changil，1994年; Mosekilde和Melsen，1980年）， 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（PTH）和活性维生素D水平降低 （Bogliun等，1986; Gough等，1986年;马库斯，1992年） 在服用抗癫痫药物的患者中检测到目前，临床意义 这些生化异常还没有被确定 表征了 骨和化学异常的严重程度被认为 与AED持续时间相关（Chung和Changil，1994）， 使用的抗癫痫药的数量（AED多药疗法）（Gough等， 1987; Bogliun等人，1986年）。在单药治疗中，最常见的AED 与骨代谢改变有关的是苯妥英、扑米酮和 苯巴比妥（Gough等，1986; Chung和Changil，1994; Valimaki 呃，1994; Sheth等人，1995年）。其他AED与 骨疾病也被注意到。尽管之前的一项研究发现 与卡马西平相关的矛盾结果（Tsunesen等，1983年）， 最近的一项研究发现卡马西平单药治疗 和“抗惊厥骨软化症”（Sheth等，1995年）。Sheth等人 （1995）也确定了丙戊酸盐单药治疗与 降低儿童的骨密度。需要进一步的研究来 阐明这些发现。 已经提出了几种理论来解释某些 抗癫痫药物和骨骼疾病诱导肝细胞色素P450的药物 酶可诱导维生素D代谢为无活性代谢物 （Gough等人，1986，Perucca，1987）。降低活性物质的可用性 维生素D会导致肠道钙吸收减少， 最终导致低钙血症 低钙血症会导致循环PTH代偿性升高 并最终增加骨钙储存的动员。 其次，AEDs可能直接干扰肠吸收， 钙导致低钙血症和反馈性PTH分泌过多。 第三，有证据表明抗癫痫药物可能直接影响骨骼 细胞功能，可能通过抑制细胞对 PTh（Marcus，1992; Valimake等人，一九九四年） 方法：这是一项关于骨转换和骨量的前瞻性研究 成人女性AED单药治疗。三种类型的AED将被 研究：1）AED不影响细胞色素P450肝- 混合功能系统;拉莫三嗪2）诱导细胞色素 P450肝-混合功能系统：卡马西平、苯妥英3）AED 抑制细胞色素P450肝脏混合功能系统： 双丙戊酸钠