ANALYSIS OF BONE HEALTH IN AED EXPOSED WOMEN WITH EPILEPSY

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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.