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Findings from a phase 3 randomized and placebo-controlled trial (funded by the U.S. NIH), which evaluated the use of supplemental vitamin D to prevent fractures among schoolchildren living in Mongolia, were recently published in The Lancet, Diabetes & Endocrinology. Children between the ages of 6 to 13 were given a weekly oral dose of 14,000 IU vitamin D3, or placebo, over a span of 3 years. This population was chosen in part because of a high incidence of vitamin D deficiency; 95.5% of children had a 25-OH vitamin D concentration of <50 nmol/L (<20 ng/mL), though children with overt signs of rickets were excluded from the study. This study is the only phase 3 trial examining vitamin D and fracture risk among such a highly deficient population of children.
Although supplementation both increased serum 25-OH vitamin D levels and reduced parathyroid hormone (in a subset of 100 children with available labs), unfortunately, no difference in the risk of fracture was observed with vitamin D supplementation. Mean serum levels of 25-OH vitamin D were 72.1 nmol/L and 26.1 nmol/L in the vitamin D and placebo groups, respectively, at the end of the trial. 6.4% and 6.1% of children receiving vitamin D and placebo, respectively, had at least one fracture during the 3-year trial, a non-significant difference.
Additionally, a subset of over 1400 children had bone ultrasonic speed of sound (SOS) measurements recorded by a Sunlight MiniOmni portable bone sonometer. This technique claims to measure bone strength versus bone mineral density, yet previous data suggests SOS is not well standardized, only weekly correlates with DXA (a validated technique associated with fracture risk), and may misclassify the bone status of children. In this study, radial SOS Z scores were not influenced by vitamin D supplementation.
This population of children also had a low calcium intake, assessed at baseline via dietary and lifestyle questionnaires. The mean calcium intake was 382 mg/day, with 64.2% of children consuming less than 500 mg/day. It’s worth noting that the U.S. DRI for calcium is 1000 mg per day for children aged 4-8, and 1300 mg for children 9-13 (the mean age of children in this study was 9.2 years). Nonetheless, no significant effect of estimated calcium intake on fracture risk was observed, i.e., even among children with a higher intake of calcium (>500 mg/day), vitamin D supplementation did not have a protective effect on fracture risk. SOS Z scores were also not modified by calcium intake.
There are some clear takeaways from this study, yet some questions remain unaddressed. Vitamin D supplementation alone, at least at the doses used in this study, is unlikely to prevent fractures among children with poor 25-OH vitamin D status, at least within a 3-year study period. The study was sufficiently powered to provide a 97.5% certainty that if there were any reduction in fracture risk, it is less than 7%. It’s also worth noting that the rate of fracture in this population is more than double that previously reported in a Norwegian population of children at a similar age, suggesting that there is substantial room for improvement in fracture risk.
However, perhaps the most obvious limitation of this study is the lack of calcium supplementation in a population with such a low intake, which severely restricts the ability to recognize any potential benefit of vitamin D that might have been observed if given along with calcium. Although the authors suggest that because no protective effects were observed among the children consuming higher amounts of calcium, even the group with a “high intake” still consumed an amount of calcium well below the DRI. Calcium intake was also assessed by parental recall, well known to be inaccurate. It’s unfortunate that the study design did not include even a subset of children who were provided calcium supplements. Furthermore, it’s possible that other nutrient deficiencies associated with healthy bone development were also lacking in the diets of these children.
The poor correlation between DXA and SOS measurements makes it difficult to know how to interpret the lack of improvement. Additionally, the SOS measurements were not prespecified outcomes, again limiting the importance of this finding (the study was originally designed to determine the effect of vitamin D supplementation on tuberculosis incidence).
A systematic review and meta-analysis published in Osteoporosis International (2021) found that lower 25-OH vitamin D levels do correlate with fracture risk in children, with levels ≤ 50 nmol/L associated with a 29% greater risk compared to levels greater than 50 nmol/L. It’s also plausible that although a reduction in fracture risk was not observed in the 3-year window of this study, children who received vitamin D would achieve a higher peak bone mineral density and may have a lower risk for fracture later in life. For example, physical activity as an intervention among children has been shown to increase their bone mineral content and density, reducing their later risk of fracture, and peak bone mass formation is associated with osteoporosis later in life.
While having a randomized and controlled trial helps to establish causality and the efficacy of vitamin D supplementation, it’s unfortunate that this one did not utilize better assessments of bone mineral density and fracture risk, or consider the potential benefit of calcium supplementation in a deficient population.
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