In a recently released article in Pediatrics(10.1542/peds.2020-0815), Dr. Francesca Crowe and colleagues describe an international clinical trial that examined the effect of vitamin D supplementation on rickets and growth among socioeconomically deprived inner-city children living in Kabul, Afghanistan. This double-blind placebo-controlled trial included 3,046 children ages 1-11 months who were randomized to receive either 100,000 IU (international units; 100,000 IU = 2.5 mg) of oral Vitamin D3 (cholecalciferol) or placebo every 3 months for an 18-month period. Household characteristics, growth parameters and dietary recall by caregivers for intake of energy, protein and calcium were collected for all children; serum 25 (OH) Vitamin D and parathyroid hormone levels, and radiographs, were obtained on a randomly selected subset of participants. The primary outcome for the original clinical trial was the effect of the described Vitamin D supplementation on the rate and severity of pneumonia; the planned secondary analysis described here included the main outcomes of linear growth and risk of rickets.
At enrollment, just over half of the children in the Vitamin D and placebo groups, respectively, were breastfed, and almost precisely half were receiving deficient intakes of calcium (<300 mg/day). The rates of infant malnutrition among these poverty-stricken families were notable: 12% were underweight (z score showing weight-for-age >2 standard deviations [SD] below the mean), 13% were stunted (z score for length-for-age >2 SD below the mean) and 7% were wasted (z score for weight-for-length >2 SD below the mean). Ultimately, this was a “negative” trial, in that rates of any or severe rickets, and rates of growth did not differ between the groups at trial end. But the big question here is why this strategy did not show a benefit for the treatment as compared to the placebo group. The authors walk us through the nuances of this fascinating question, which may relate to the high prevalence of stunting as well as rates of both vitamin D and calcium insufficiency in their study population.
In the United States, pediatricians are appropriately focused on making sure every partially and exclusively breastfed infant (and also infants receiving less than 1000 ml/day of vitamin D-fortified milk or formula) gets vitamin D supplementation from birth onward.  But in developing countries, including Afghanistan where this study was conducted, it is more common for rickets to be due to both vitamin D deficiency and calcium deficiency.  Globally, particularly in Africa and Asia, calcium deficiency has emerged as the leading cause of childhood rickets.  This study by Crowe and colleagues tackles yet-unsolved questions about childhood growth and rickets that are of great importance worldwide and gives readers a terrific new perspective on a familiar topic.
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