Vitamin D deficiency in children with epilepsy: Do we need to detect and treat it?

Children and adolescents treated with antiepileptic drugs are known to have problems with bone metabolism, bone mineral density loss, and 2-3 times the fracture risk of healthy controls. We reviewed the literature regarding bone mineral density in children with epilepsy and vitamin D therapy in children treated with anti-epileptic drugs. Studies of bone mineral density markers in children with epilepsy have mostly found little significant difference in bone mineral density markers in children with epilepsy. They have been limited by small sample size and many of the studies have not corrected for confounding factors such as comorbidities, mobility, nutrition, and obesity. Studies of vitamin D therapy in children with epilepsy have shown little evidence of effect and have been similarly limited by lack of stratification with regard to confounding factors. There is a need for larger studies, using clinically significant outcomes such as fractures, including at risk populations such as symptomatic generalised epilepsy, impaired mobility, and polytherapy. At the present time in the absence of good evidence to the contrary, there remains concern that children with epilepsy are at risk of poor bone health and that vitamin D therapy may be beneficial. As low-dose vitamin D supplementation (400 IU per day) is now recommended for healthy children and it is biologically feasible that children with epilepsy may be at higher risk of clinically significant deficiency, it is important that neurologists ensure that low-dose vitamin D supplementation should be prescribed and compliance followed up in children with epilepsy.

Introduction

Vitamin D deficiency is common in children, with an estimated prevalence of 9% in American children aged 1-21 years (serum vitamin D less than 15 ng/mL).[1] The association between vitamin D, antiepileptic drugs, and poor bone health in individuals with epilepsy was first recognized in 1979[2] and is thought to be particularly relevant in childhood as this is the time of maximum bone mineralization. Children and adolescents treated with antiepileptic drugs are known to have problems with bone metabolism,[3] bone mineral density loss,[4] and 2–3 times the fracture risk of healthy controls.[5] It has been postulated that this might be because of the effects of antiepileptic drugs and the ketogenic diet, and confounding factors such as mobility, nutrition, and obesity. The mechanism of bone problems may be related to increased liver vitamin D breakdown secondary to induction of cytochrome p450 and stimulation of osteoclastic activity, direct effects on bone cells, resistance to parathyroid hormone, inhibition of calcitonin secretion, and impaired calcium absorption.[6]

Significant disparity exists among clinicians, with less than half performing any sort of screening for vitamin D status and bone health in patients with epilepsy.[7] The existing guidelines are inconsistent. The International Society for Clinical Densitometry has not specified epilepsy in its recent position development statement[8] as an indication for bone mineral density measurements in children. A Cochrane review[9] in 2009, which did not include a recent randomized controlled trial,[10] found no reliable evidence to support the routine use of vitamins in patients with epilepsy. The American Academy of Pediatrics has recommended that all children receive 400 IU of vitamin D supplements as infants and continue through adolescence, but does not recommend vitamin D doses specifically for children on antiseizure drugs.[11] However, a recent systematic review and meta-analysis of randomized controlled trials concluded that vitamin D supplementation is not effective in improving bone mineral density in healthy children and adolescents,[12] but suggested that supplementation of deficient children may be clinically useful.

Bone Mineral Density among Children with Epilepsy

Table 1 lists 26 articles which are studies of markers of bone health in children with epilepsy. There are 14 cohort studies comparing bone mineral density and/or bone biochemistry in children treated with antiepileptic drugs and healthy controls. Of these, seven studies found a significant difference, four found no significance, and three studies did not comment on the statistical significance of any difference between the groups. There are 12 cohort studies observing bone mineral density and/or bone biochemistry in children treated with antiepileptic drugs. These found a prevalence of 25-OH vitamin D levels less than 20 of between 25% and 75% in children treated with antiepileptic drugs (with varying degrees of ambulation, duration of epilepsy, and number of antiepileptic drugs). There is great variation between studies in terms of controlling for confounding factors (e.g. mobility and diet).

Table 1

Studies of bone mineral density markers in children with epilepsy

Treatment with Vitamin D Supplements: Clinical Trial

Table 2 shows six studies of vitamin D therapy in children treated with antiepileptic drugs (AEDs). The only randomized controlled trial[37] was limited in terms of duration of therapy, lack of controlling for diet/exercise, and lack of study of compliance despite not attaining target vitamin D levels. It demonstrated no significant difference between high- and low-dose vitamin D, and no change in bone mineral density compared to healthy controls after 1 year of treatment. This may be a better outcome than in unsupplemented children with epilepsy whose bone mineral density has been shown to decrease with time in previous studies. Two cohort studies showed a significant increase in bone mineral density (one large and one small), two cohort studies showed a significant improvement in bone biochemistry, and one cohort study showed a significant improvement in bone biochemistry and healing of rickets with vitamin D therapy. Three of the six studies used bone biochemistry as an indirect marker of bone health, rather than bone mineral density. It is difficult to compare the bone mineral density improvements as the studies use different units rather than a standardized z-score. As there is little description of comorbidities (the RCT is the only study to give a detailed description of comorbidities), there is potential for confounding with regard to comorbidities, such as mal-absorptive disorders, treatment with drugs other than AEDs which may affect bone health, nutrition, and immobility in those studies not pre-selecting an immobile group.

Table 2

Studies of vitamin D therapy in children with epilepsy

Discussion

Most of the studies of bone mineral density markers in children with epilepsy [Table 1] have found little significant difference in bone mineral density markers in children with epilepsy. However, these studies may be biased as most included a small sample, and did not include large enough numbers to enable comparison between specific antiepileptic drugs or therapies, or between different epileptic syndromes. Of those studies in which this comparison was attempted, a significant association between sodium valproate and markers of poor bone health was found; but as this was only in small numbers, it might represent a spurious association that has not been excluded. In addition, many of the studies did not correct for confounding factors such as mobility, nutrition, and obesity. One small study that considered the effect of ambulatory status[32] did however, find a significant difference in bone health between ambulant and non-ambulant children. Studies of vitamin D therapy in children with epilepsy have been similarly limited by lack of stratification with regard to factors that influence bone health such as comorbidities, nutrition, obesity, and mobility. Hence although there is little evidence for an effect, there is limited evidence for no effect. The only randomized controlled trial[14] was limited in terms of duration of therapy, lack of controlling for diet/exercise, and lack of study of compliance despite not attaining target vitamin D levels.

Conclusion

Studies to date are inconsistent and of limited quality. In particular, there is a need for larger studies, using clinically significant outcomes such as fractures, including at risk populations such as symptomatic generalised epilepsy, impaired mobility, and polytherapy. At the present time in the absence of good evidence to the contrary, there remains concern that children with epilepsy are at risk of poor bone health and that vitamin D therapy may be beneficial. As low-dose vitamin D supplementation (400 IU per day) is now recommended for healthy children and it is biologically feasible that children with epilepsy may be at higher risk of clinically significant deficiency, it is important that neurologists ensure that low-dose vitamin D supplementation should be prescribed and compliance followed up in children with epilepsy.[41]