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. Radiological 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 """"""""anticonvulsant osteomalacia"""""""" (Sheth et.al., 1995). Sheth et al. (1995) also identified an 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. Study participation includes a physical exam, dietary, physical activity, injury history and reproductive history assessments, AED serum level monitoring, blood draws, urine samples, calcaneus ultrasound of the heal and dual energy x-ray absorptiometry (DXA) of the lumbar spine, proximal femur and whole body. Most subjects will have their blood work performed at the General Clinical Research Center. The remaining study procedures will occur at the VA Hospital in Menlo Park. An estimated total of 196 subjects will be involved in the study. All subjects must be between the ages of 18 and 40 and it is required that the subject have chronic epilepsy that is, that the subject is highly likely to continue on the same AED for 12 months subsequent to study initiation. Normative control data will be used. All controls will be women without a history of epilepsy. As of 1/99, 61 women have been enrolled in the study. Of these, 5 have dropped due to change in medication or change in eligibility requirements. Fifty-six women are currently active participants in the study. Fifty women have completed the baseline appointment. Of these, 35 have also completed the six-month appointment. Nineteen women have completed all three study appointments. The study goal is completed data from 177 women. At the current rate, the expected completion date for this study is 12/31/2000.
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