Abstracts

RATIONALE: Antiepileptic drugs (AEDs) are associated with bone disease. We have reported that women with epilepsy (WWE) have a greater than expected prevalence of hip osteopenia with significant deficits in WWE treated with carbamazepine (CBZ) and a high percentage of osteopenia in WWE on phenytoin (PHT)(enzyme inducers). However, no mechanism of AED associated bone disease is clearly elucidated.
METHODS: Indices of bone mineral metabolism and markers of bone formation and resorption were assessed in WWE aged 18-40 on AED monotherapy. AEDs were grouped by their effect on the cytochrome P450 enzyme system: inducers (PHT and CBZ), inhibitors (valproate/VPA), and those with no effect (lamotrigine/LTG). Serum and fasting urine were obtained for vitamin D, parathyroid hormone (PTH), insulin growth factor-1 (IGF-1), insulin growth factor binding protein-3 (IGFB-3), N-telopeptide (NTx)(marker of resorption), and osteocalcin (marker of formation).
RESULTS: We evaluated 80 WWE. There were 45 on enzyme inducing AEDs, 15 on enzyme inhibitors, and 20 on drugs with no effect. No significant differences among these groups were found for osteocalcin, NTx, or PTH. Although vitamin D levels for each group were within normal range, there was signficant reduction in vitamin D levels in patients on enzyme inducers as compared to those on drugs with no effect (p=0.038). IGF-I and IGFBP-3 levels were also within normal range. Significant reductions in IGF-I were found in patients on inducers (p=0.012) and inhibitors (p=0.029) when compared to WWE on drugs with no effect. There was a significant difference in IGFBP-3 between those on inducers and those on drugs with no effect (p=0.042), with a reduction seen in patients on inducers.
CONCLUSIONS: WWE on AED monotherapy had no significant differences in markers of bone resorption, bone formation, or PTH according to AED group. Significant reductions were found in vitamin D levels among those on inducers compared to those on drugs with no effect. Increased metabolism of vitamin D to inactive metabolites by enzyme inducing AEDs has been postulated as a possible mechanism for AED associated bone disease. Significant reductions in IGF-I were found among WWE on enzyme inducers and inhibitors versus those on drugs with no effect, and IGFBP-3 was found to be significantly reduced in WWE receiving enzyme inducing agents versus those with no effect. IGF-I is secreted by skeletal cells, enhances osteoblastic differentiation, and increases bone formation. IGFBP-3 is produced by bone cells, and has been shown to modulate IGF-mediated osteoblast proliferation and differentiation. The reductions seen in IGF-I and IGFB-3 suggest that abnormalities in IGF may be a mechanism of bone disease in patients receiving AEDs that alter activity of the cytochrome P450 enzyme system.
Support: Glaxo Wellcome, Inc.