Long‐Term Valproate and Lamotrigine Treatment May Be a Marker for Reduced Growth and Bone Mass in Children with Epilepsy

Abstract

Summary:Purpose: To determine whether long-term treatment with valproate (VPA) and/or lamotrigine (LTG) in children with epilepsy is associated with altered growth and/or bone metabolism.Methods: Twenty-seven boys and 26 girls, aged 3 to 17 years (9.2 ± 3.9, mean ± SD), with epilepsy treated with VPA and/or LTG for Ն2 years were evaluated for growth, nutrient intakes, physical activity, bone mineral density (BMD), and blood biochemical indices of mineral and bone metabolism.Results: Twenty-three (43.4%) of the children had a body height below the 10th percentile. Z-scores for BMD below -1.5 occurred in 24.4% of the children. When patients were divided into two groups according to daily activity score, a significantly lower Z-score for total body BMD (p ‫ס‬ 0.007), percentile for body height (p ‫ס‬ 0.05), and plasma parathyroid hormone (PTH; p ‫ס‬ 0.04), osteocalcin (p ‫ס‬ 0.04) and 25-hydroxyvitamin D (25OHD) (p ‫ס‬ 0.01) were found in the inactive compared with the active group. Z-score for total body BMD was correlated with daily activity score (r ‫ס‬ 0.43, p ‫ס‬ 0.008). Plasma intact osteocalcin and intact PTH values correlated significantly (r ‫ס‬ 0.36, p ‫ס‬ 0.02). Plasma 1,25-dihydroxyvitamin D was within normal range for all subjects. When patients were divided into LTG-alone, VPA-alone, and LTG-plus-VPA treatment groups, significantly lower (p < 0.05) plasma osteocalcin and percentile for body height were found in the VPA-plus-LTG treatment group.Conclusions: Long-term VPA and LTG therapy, particularly when combined, is associated with short stature, low BMD, and reduced bone formation. These alterations may be mediated primarily through reduced physical activity rather than through a direct link to the VPA and/or LTG therapy.

<b>Effects of the antiepileptic drugs topiramate and lamotrigine on bone metabolism in </b><b>rats </b>

“…Previous clinical studies demonstrated that lamotrigine did not adversely affect bone metabolism (16, 27, 36), except in combination with valproate (14). In support of this finding, lamotrigine treatment did not affect bone strength, BMD, or bone turnover in the present study.…”

Vitamin D levels in epileptic children on long-term anticonvulsant therapy

“…17,34,36,38,39 These latter studies found this to be the case for non-enzyme-inducing anticonvulsants (valproic acid) use 36,38 or new anticonvulsants (lamotrigine, topiramate, oxcarbazepine, sulthiamine). 17,39 In this study, none of the subjects had vitamin D deficiency, but we found higher prevalence of vitamin D insufficiency in epileptic children (39%) compared to control subjects (13%). Other studies showed a variety of results on the prevalence of vitamin D deficiency in epileptic children using long-term anticonvulsants.…”

“…13 The long-term use of anticonvulsants has been associated with increased incidence of rickets or osteomalacia, increased risk of fracture, and reduced bone mineral density. [13][14][15][16][17][18][19][20] All these conditions are associated with vitamin D deficiency. 13,15 The effects of anticonvulsants on vitamin D levels have been studied for 40 or more years.…”

“…Most enzyme-inducing anticonvulsants (phenytoin, phenobarbital, primidone, and carbamazepine) were associated with low levels of vitamin D. 16,[25][26][27][28][29][30][31][32] Other studies showed insignificant effects, 24,[33][34][35] especially with valproic acid and newer anticonvulsants. 17,19,32,36 The prevalence of vitamin D deficiency has varied between 23 to 76%, depending on the definition of vitamin D deficiency, anticonvulsant type, number and duration of use, as well as the location of the study. 25,[27][28][29][30] Studies to assess for an association between anticonvulsants and vitamin D deficiency have had inconsistent results, especially for non-enzymeinducing anticonvulsants such as valproic acid.…”

Adverse Metabolic Effects of Antiepileptic Drug Treatment

“…Although this is still considered an important mechanism, later studies have shown that AEDs may cause bone loss even in the absence of vitamin D deficiency (Farhat et al, 2002;Andress et al, 2002). Furthermore, valproate, a CYP450 inhibitor, has also been shown to have an adverse effect on bone health, probably via completely different mechanisms (Sheth et al, 1995;Sato et al, 2001;Guo et al, 2001;. Decreased intestinal absorption of calcium, resistance to parathyroid hormone, calcitonin deficiency, interference with vitamin K metabolism, and a direct drug-effect on bone cell functions have also been suggested as possible mechanisms (Feldkamp et al, 2000;Petty et al, 2007).…”