Randomized Controlled TrialEffect of high dose vitamin d supplementation on vitamin d nutrition status of pre-pubertal children on anti-epileptic drugs – A randomized controlled trial
Introduction
Vitamin D deficiency is recognized as a worldwide problem across all age groups [1], [2], [3], [4], [5], [6]. The prevalence of vitamin D deficiency in children from India is reported to be in the range of 43–97% [7], [8], [9], [10], [11]. Patients on long term anti-epileptic drugs (AED) are more prone to Vitamin D deficiency [12], [13].The exact mechanism for adverse bone effect of anti-epileptic drugs (AED) has not been determined, although many factors are known to influence and modify these effects. Vitamin D deficiency associated with phenytoin, carbamazepine, phenobarbitone and primidone use is likely mediated by PXR (pregnane X receptor). It is shown that AEDs lead to the upregulation of 25-hydroxyvitamin D 3 [25(OH)D]-24-hydroxylase (CYP24) gene expression through the activation of PXR [14]. CYP24 is a mitochondrial enzyme responsible for inactivating vitamin D metabolites. Vitamin D deficiency leads to impaired calcium absorption from the intestine. Ensuing hypocalcemia triggers release of parathyroid hormone which acts on the bone to release the calcium stores, thus leading to bone loss. Valproic acid, an enzyme inhibitor, accelerates bone loss by activating the osteoclasts directly [15] while phenytoin decreases the intestinal absorption of calcium [16].
Various Authorities have recommended different dosages of Vitamin D supplementation for different age groups. Most of them have recommended 400 IU – 600/day for infants and children for general health [17]. The Endocrine Society, USA recommends an intake of 3000–6000 IU/day vitamin D for individuals on drugs affecting vitamin D metabolism such as AED [18]. The Indian Council of Medical Research (ICMR), recommends a RDA of 400 IU/day in populations with minimal sun exposure while there are no recommendations for individuals at higher risk of vitamin D deficiency [19]. There are very few studies on vitamin D supplementation in children on AED. The present study assesses the efficacy of high dose oral vitamin D3 supplementation (60,000 IU/month) in children receiving AED in preventing vitamin D deficiency.
Section snippets
Materials and methods
This was a randomized controlled trial. Children in age group 5–10 years, with normal nutritional status (BMI within ±2 Z scores of WHO reference standards) [20], newly started on AED in our hospital, or presenting within 2 weeks of AED initiation were enrolled. Children who were non ambulatory, receiving calcium/vitamin D supplements, those with clinical or biochemical evidence of rickets or any chronic disease influencing vitamin D metabolism (chronic kidney disease, chronic liver disease,
Primary outcomes
Mean serum 25(OH)D levels in supplemented and not supplemented groups at baseline and at 6 months.
Secondary outcome variables
Mean serum tCa, iCa, iP, ALP and PTH levels in both the groups at baseline and at 6 months.
Sample size and statistical analysis
The expected prevalence of severe vitamin D deficiency in children on AED therapy was determined to be 56% [21]. High dose vitamin D supplementation was expected to reduce the prevalence to half (28%) [21].The expected sample size to detect this difference with a confidence of 95% with a power of 80% was 50
Results
Of the 83 subjects enrolled, the data of 64 children (35 in group A and 29 in group B) followed up for 6 months were analyzed (Fig. 1). The baseline clinical and biochemical characteristics were similar in both the groups (Table 1).
Serum calcium: total and ionic
The mean serum total calcium (tCa) in group A and group B at baseline were similar. At 6 months follow up tCa level in group A showed a significant increase (p = 0.001), while in group B it showed a significant fall (p < 0.001) from baseline. At 6 months, mean tCa in Group A was significantly higher compared to group B (p = 0.009). Similar trend was observed in mean serum iCa levels (Table 2).
Serum inorganic phosphate
Mean serum iP of group A and group B patients at baseline was similar (p = 0.29). There was no change
Discussion
In this randomized controlled trial we have studied the serum levels of 25(OH)D and other biochemical markers of bone turn over in children newly started on AED, supplemented them with 60,000 IU vitamin D3 orally per month for 6 months and compared biochemical parameters in supplemented and unsupplemented children at baseline and follow up.
We found that serum 25(OH)D in the supplemented group was maintained at 6 month follow up while that the control group showed a significant fall. The
Conclusions
Oral administration of 60,000 IU vitamin D3/month of is safe and is sufficient to maintain serum 25(OH)D level and prevents development of vitamin D deficiency in children newly started on AED over a period of 6 months. It also improves serum calcium and maintains serum ALP and PTH levels. However, it does not decrease prevalence of vitamin D deficiency as compared to baseline. Hence, a higher dose might be required to normalize the 25(OH)D levels in these vulnerable children. Non
Financial disclosure
None.
Conflict of interest
None.
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