Chronic antiepileptic monotherapy, bone metabolism, and body composition in non‐institutionalized children

Abstract

AIM The aim of this study was to determine the influence of chronic monotherapy with antiepileptic drugs (AEDs) on vitamin D levels, bone metabolism, and body composition.METHOD Eighty-five children (38 males, 47 females; mean age 12y 5mo, SD 3y 4mo) were treated with valproate and 40 children (28 males, 12 females; mean age 11y 10mo, SD 3y) were treated with other AEDs (lamotrigine, sulthiame, or oxcarbazepine), comprising the non-valproate group. Forty-one healthy children (29 males 12 females; mean age 12y 1mo, SD 3y 5mo) served as a comparison group. Height, weight, body impedance analysis, 25-hydroxyvitamin D, calcium, phosphate, two bone resorption markers (receptor activator of nuclear factor jB ligand [RANKL] and tartrate-resistant acid phosphatase 5b [TRAP5b]), osteoprotegerin, and leptin were measured. RESULTS No child was vitamin D deficient as defined by a 25-hydroxyvitamin D (25OHD) level ofless than 25nmol ⁄ l (<10ng ⁄ ml). Leptin, body fat, weight standard deviation score (SDS), and body mass index (BMI) SDS were all significantly higher (each p<0.001) in valproate-treated children than in the non-valproate group, as were calcium (p=0.027) and RANKL (p=0.007) concentrations. Similarly, leptin was significantly higher in the valproate group than in control participants (p<0.001), as were body fat (p=0.023), weight SDS (p=0.046), BMI SDS (p=0.047), calcium (p<0.001), and RANKL (p<0.001), whereas TRAP5b concentrations were significantly lower in the valproate-treated group (p=0.002). Furthermore, calcium and RANKL levels were significantly higher in the non-valproate group than in comparison participants (p<0.001 and p=0.016 respectively).INTERPRETATION Non-enzyme-inducing or minimal enzyme-inducing AED monotherapy does not cause vitamin D deficiency in otherwise healthy children with epilepsy. Valproate therapy is associated with increases in weight, body fat, and leptin concentration, as well as with a bone metabolic profile that resembles slightly increased parathyroid hormone action.Chronic antiepileptic drug (AED) therapy has been associated with vitamin D deficiency, low bone mass, increased fracture risk, and altered bone turnover.1 The underlying pathophysiological mechanisms are poorly understood but are probably multifactorial. Most older AEDs (e.g. phenobarbital, phenytoin, and carbamazepine) are strong cytochrome P450 (CYP450) enzyme inducers, thereby causing altered steroid and vitamin D metabolism, whereas valproic acid (valproate) and the newer AEDs such as lamotrigine and oxcarbazepine are non-enzyme inducers or minimal enzyme inducers. Some, but not all, studies in adults treated with new AEDs have observed vitamin D deficiency (as defined by a 25-hydroxyvitamin D [25OHD] level <25nmol ⁄ l [<10ng ⁄ ml]) and low bone mineral density (BMD).2-4 Studies on the effect of chronic AED therapy on bone metabolism in children have produced conflicting results. Valproate monotherapy was first reported to reduce BMD in children. 5 Since then, most studies have failed to demonstrate low bone ma...

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

“…25,32,38 Several studies have shown that valproic acid was not associated with vitamin D deficiency. 36,38 Mean daily intake of vitamin D in our study was lower than that recommended by the Institute of Medicine (IOM). This might be due to subjects consuming only small amounts of milk and fish (sources of vitamin D), or sub-optimal vitamin D supplementation.…”

“…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%).…”

“…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.…”

ENDOCRINOLOGY AND ADOLESCENCE: Osteoporosis in children: diagnosis and management

“…Older cytochrome P450-inducing AEDs such as phenytoin, phenobarbital and carbamazepine are associated with low bone mass and vitamin D deficiency resulting in increased fracture risk. However, the newer AEDs with minimum or no enzyme-inducing effects have demonstrated a better safety profile on bone metabolism (85). Immobility and neurological conditions that increase the risk of fall as well as co-morbidities limit the interpretation of human studies assessing the effect of AEDs on bone.…”

Effects of antiepileptic drugs on bone mineral density and bone metabolism in children: A meta-analysis

“…The initial search yielded 1603 research reports, of which 228 were excluded due to identical title or authors; 1056 were excluded due to ineligible study design (including non-human studies, review articles, case reports, comment, letter, experimental study, and/or fractureonly outcome). After full-text screening, 22 studies were included (Chung and Ahn, 1994;Baer et al, 1997;Akin et al, 1998;Kafali et al, 1999;Erbayat Altay et al, 2000;Verrotti et al, 2002;Voudris et al, 2002;Ecevit et al, 2004;Oner et al, 2004;Babayigit et al, 2006;Kumandas et al, 2006;Nicolaidou et al, 2006;El-Hajj Fuleihan et al, 2008;Nettekoven et al, 2008;Gniatkowska-Nowakowska, 2010;Rauchenzauner et al, 2010;Babacan et al, 2012;Dimić et al, 2013;Razazizan et al, 2013;Turan et al, 2014). Table 1 summarizes the characteristics of the included studies published between 1994 and 2014.…”