Elsevier

Clinical Nutrition ESPEN

Volume 29, February 2019, Pages 36-40
Clinical Nutrition ESPEN

Randomized Controlled Trial
Effect of high dose vitamin d supplementation on vitamin d nutrition status of pre-pubertal children on anti-epileptic drugs – A randomized controlled trial

https://doi.org/10.1016/j.clnesp.2018.11.007Get rights and content

Summary

Background and aims

Patients on long term anti-epileptic drug therapy are prone for Vitamin D deficiency for a myriad of reasons. The aim of this research was to study the effect of high dose vitamin D supplementation on vitamin D nutrition status of children newly started on anti-epileptic drug therapy.

Materials

This randomized controlled trial was conducted in a tertiary care Children's Hospital at New Delhi from November 2011 to March 2013. Eighty three children in the age group 5–10 years newly started on anti-epileptic drugs (AED) were randomized into two groups; group A – the intervention group, to whom 60,000 IU vitamin D3 was given orally/month under direct supervision along with AED for a period of 6 months, and group B- the control group, to whom AED without vitamin D3 was given. Serum 25(OH)D, ionized calcium (iCa), total calcium (tCa), inorganic phosphate (iP), alkaline phosphatase (ALP) and parathyroid hormone (PTH) levels were assayed at baseline and at the end of 6 months and were compared within and between the two groups.

Results

The mean 25(OH)D in Group A was maintained at 6 months follow up [ 26 ng/ml, 95% CI 20–34 ng/ml] compared to baseline [25 ng/ml, 95% CI −19 to 33 ng/ml] [ p = 0.83]. In group B, there was a significant decrease in 25(OH)D levels at 6 months [13 ng/ml (95% CI 9 ng/ml–17 ng/ml)] compared to baseline [18 ng/ml (95% CI 13–24 ng/ml)] [p = 0.01]. At 6 months, mean serum 25(OH)D was significantly higher in group A as compared to group B (p = 0.005).

Conclusion

To conclude, oral administration of 60,000 IU vitamin D3/month is sufficient to maintain serum 25(OH)D level and prevent development of vitamin D deficiency in children newly started on AED over a period of 6 months. Non supplementation leads to the lowering of serum 25(OH)D in these children.

Trial Registration Number

CTRI/2017/08/009234.

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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