Vitamin D supplements for fracture prevention in schoolchildren in Mongolia: analysis of secondary outcomes from a multicentre, double-blind, randomised, placebo-controlled trial.

BACKGROUND: Vitamin D supplementation has been shown to increase total hip areal bone mineral density in healthy children and adolescents. We aimed to investigate whether supplementing schoolchildren living in Mongolia with weekly vitamin D3 for 3 years affected fracture risk. METHODS: We did a multicentre, double-blind, randomised, placebo-controlled trial across 18 public schools in Ulaanbaatar, Mongolia. Schoolchildren were eligible if they were aged 6-13 years at screening, had a negative QuantiFERON-TB Gold In-tube assay (QFT) result, were not hypersensitive to vitamin D or immunocompromised, did not use vitamin D supplements, did not have clinical signs of rickets, and had no intention of leaving Ulaanbaatar within 3 years. Participants were randomly assigned (1:1) to receive either vitamin D (oral dose of 14 000 international units [IU] vitamin D3, once per week) or placebo for 3 years using permuted block randomisation stratified by school of attendance. Participants, care providers, and all trial staff were masked to group assignment during the intervention. Prespecified secondary outcomes were incidence of fractures and adverse events, ascertained using questionnaires. The fracture and safety analyses included participants who completed at least one follow-up fracture questionnaire. We estimated adjusted risk ratios (RRs) and 95% CIs using generalised linear models with binomial distribution and a log link function with adjustment for school of attendance. The trial is registered with ClinicalTrials.gov, NCT02276755, and the intervention ended in May, 2019. FINDINGS: Between Sept 2, 2015, and March 20, 2017, 11 475 children were invited to participate in the study and 8851 were recruited and randomly assigned to receive either vitamin D (n=4418) or placebo (n=4433). 8348 participants were included in the fracture and safety analyses (4176 [94·5%] in the vitamin D group and 4172 [94·1%] in the placebo group). Of these, 4125 (49·4%) were female, 4223 (50·6%) were male, and 7701 (92·2%) were of Khalkh ancestry. Median age was 9·2 years (IQR 8·0-10·7) and 7975 (95·5%) participants had baseline serum 25-hydroxyvitamin D concentrations less than 50 nmol/L. During a median follow-up of 3·0 years (IQR 2·9-3·1), 268 (6·4%) participants in the vitamin D group and 253 (6·1%) in the placebo group reported one or more fractures (adjusted RR 1·10, 95% CI 0·93-1·29; p=0·27). Incidence of adverse events did not differ between study groups. INTERPRETATION: Oral vitamin D supplementation at a dose of 14 000 IU/week for 3 years was safe, but did not influence fracture risk in schoolchildren living in Mongolia who had a high baseline prevalence of vitamin D deficiency. FUNDING: US National Institutes of Health.

Maternal vitamin D intakes during pregnancy and child health outcome.

We conducted a follow up of the children in Mongolia whose mothers received one of the three doses of vitamin D (600, 2000, or 4000 IU daily) during pregnancy as part of the randomized, double-blind, clinical trial of vitamin D supplementation to determine their impact on child health to two years. In the parental trial, 119 pregnant women were assigned to 600 IU/day, 121 were assigned 2000 IU/day, and 120 were assigned 4000 IU/day starting at 12-16 weeks' gestation and continuing throughout pregnancy. At baseline, maternal serum 25(OH)D concentrations were similar across arms; 91 % were 50 nmol/l. As expected, there was a dose-response association between the amount of vitamin D consumed (600, 2000, or 4000 IU daily) and maternal 25(OH)D levels at the end of the intervention. Total 311 children of 311 mothers were followed for 2 years to evaluate health outcomes. We determined the child's health outcomes (rickets, respiratory disease [pneumonia, asthma], and diarrhea/vomiting) using a questionnaire and physical examination (3, 6, and 24 months of age). Low levels of mothers' serum 25(OH)D during pregnancy increased the risk of developing rickets, respiratory illness, and other diseases in children during the early childhood period. Rickets was diagnosed in 15.6 % of children of women who received 600 IU of vitamin D during pregnancy, which was higher than in other vitamin D groups. Children in the group whose mothers received low doses of vitamin D (600 IU/day) had a greater probability of developing respiratory diseases compared to the other groups: pneumonia was diagnosed in n = 36 (35.0 %) which was significantly higher than the group receiving vitamin D 4000 IU/day (n = 34 (31.5 %) p = 0.048). In the group whose pregnant mother consumed 600 IU/day of vitamin D, the risk of child pneumonia was ∼ 2 times higher than in the group who consumed 4000 IU/day (OR=1.99, 95 % CI: 1.01-3.90). The incidence of diarrhea and vomiting in children was 12.1 % lower in the 2000 IU/day group and 13.1 % lower in the 4000 IU/day group compared with the 600 IU/day group (p = 0.051). The offspring of pregnant women who regularly used vitamin D at doses above 600 IU/day had lower respiratory disease, rickets, and diarrheal risks at 2 years.

Vitamin D, respiratory infections, and chronic disease: Review of meta-analyses and randomized clinical trials.

BACKGROUND: Observational studies have suggested associations of vitamin D deficiency (VDD) with respiratory tract infections, impaired bone health, and myriad chronic diseases. OBJECTIVE: To assess potential causal relationships between vitamin D supplementation and a reduced risk of these conditions, a review of the evidence across available meta-analyses of randomized control trials (RCTs) and RCTs was performed. METHOD: PubMed, Embase, Cochrane Library, and Web of Science were searched from their inception to March 2021. We included only RCTs and meta-analyses of RCTs focusing on the association between vitamin D and respiratory disease, bone health, cardiovascular disease (CVD), diabetes mellitus, and cancer. RESULTS: A total of 107 RCTs and 62 meta-analysis of RCTs were included. Although most RCTs did not support benefits of vitamin D supplementation, suggestive evidence for benefit was found in populations at greater risk of VDD and for acute respiratory infections, fractures in institutionalized older adults, type 2 diabetes among patients with prediabetes, and cancer mortality. In contrast, no compelling evidence for benefit was found for other respiratory conditions, fractures in community-dwelling adults, falls, cancer incidence, or CVD. CONCLUSIONS: Current evidence from RCTs and meta-analyses of RCTs is inconsistent regarding the effects of vitamin D supplementation on respiratory infections and chronic diseases. Individuals most likely to benefit are those with baseline VDD or with selected high-risk conditions. Public health initiatives are needed to eliminate VDD globally, and future research will be enhanced by a 'precision prevention' approach to identify those most likely to benefit from vitamin D supplementation.

Vitamin D Supplements for Prevention of Tuberculosis Infection and Disease.

BACKGROUND: Vitamin D metabolites support innate immune responses to Mycobacterium tuberculosis. Data from phase 3, randomized, controlled trials of vitamin D supplementation to prevent tuberculosis infection are lacking. METHODS: We randomly assigned children who had negative results for M. tuberculosis infection according to the QuantiFERON-TB Gold In-Tube assay (QFT) to receive a weekly oral dose of either 14,000 IU of vitamin D3 or placebo for 3 years. The primary outcome was a positive QFT result at the 3-year follow-up, expressed as a proportion of children. Secondary outcomes included the serum 25-hydroxyvitamin D (25[OH]D) level at the end of the trial and the incidence of tuberculosis disease, acute respiratory infection, and adverse events. RESULTS: A total of 8851 children underwent randomization: 4418 were assigned to the vitamin D group, and 4433 to the placebo group; 95.6% of children had a baseline serum 25(OH)D level of less than 20 ng per milliliter. Among children with a valid QFT result at the end of the trial, the percentage with a positive result was 3.6% (147 of 4074 children) in the vitamin D group and 3.3% (134 of 4043) in the placebo group (adjusted risk ratio, 1.10; 95% confidence interval [CI], 0.87 to 1.38; P = 0.42). The mean 25(OH)D level at the end of the trial was 31.0 ng per milliliter in the vitamin D group and 10.7 ng per milliliter in the placebo group (mean between-group difference, 20.3 ng per milliliter; 95% CI, 19.9 to 20.6). Tuberculosis disease was diagnosed in 21 children in the vitamin D group and in 25 children in the placebo group (adjusted risk ratio, 0.87; 95% CI, 0.49 to 1.55). A total of 29 children in the vitamin D group and 34 in the placebo group were hospitalized for treatment of acute respiratory infection (adjusted risk ratio, 0.86; 95% CI, 0.52 to 1.40). The incidence of adverse events did not differ significantly between the two groups. CONCLUSIONS: Vitamin D supplementation did not result in a lower risk of tuberculosis infection, tuberculosis disease, or acute respiratory infection than placebo among vitamin D-deficient schoolchildren in Mongolia. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT02276755.).

Comparison of seasonal serum 25-hydroxyvitamin D concentrations among pregnant women in Mongolia and Boston.

Adequate vitamin D status during pregnancy is important for developing fetal bone strength and density and may play a role in preventing a range of skeletal and non-skeletal diseases in both mothers and children. We previously identified Mongolian women of reproductive age to have the lowest vitamin D levels yet observed in any population globally, which renders this population uniquely important in vitamin D research. In this study, we measured the seasonal distribution of 25-hydroxyvitamin D (25(OH)D) concentration in 390 healthy third trimester pregnant women living in urban and rural Mongolia using DiaSorin LIAISON and compared this distribution to that of 206 third trimester women living in Boston, USA. Also, we analyzed seasonally-independent associations between (25(OH)D) levels and selected predictors in both groups using quantile regression. Mean 25(OH)D levels were significantly higher and less seasonal in Boston (seasonal range: 27.1 ±â€¯7.0-31.5 ±â€¯7.7 ng/ml) than in Mongolia (seasonal range: 11.2 ±â€¯3.9-19.2 ±â€¯6.7 ng/ml). Adjusting for month of blood draw, higher 25(OH)D levels were significantly associated with older age, lower gravidity, lower BMI, and lack of a college or university degree among Boston participants, however, only gravidity was robust to multivariable adjustment. No assessed characteristics were independently predictive in Mongolia, likely due to universally low 25(OH)D levels and a resulting lack of between-person variation. In conclusion, vitamin D status among pregnant Mongolians is severely depressed throughout the year and should be addressed through fortification and supplementation, while in the U.S., deficiency is associated with specific characteristics targetable through supplementation.