Effect of Vitamin D Supplementation, Omega-3 Fatty Acid Supplementation, or a Strength-Training Exercise Program on Clinical Outcomes in Older Adults: The DO-HEALTH Randomized Clinical Trial

Question  Do vitamin D, omega-3, and a strength-training exercise program alone or in combination prevent 6 health outcomes among relatively healthy adults aged 70 years or older?

Findings  In this randomized trial that included 2157 adults aged 70 years or older, 3-year treatment with vitamin D₃ (2000 IU/d), with omega-3 fatty acids (1 g/d), or with a strength-training exercise program did not result in statistically significant differences in improvement in systolic or diastolic blood pressure, nonvertebral fractures, physical performance, infection rate, or cognition.

Meaning  These findings do not support the use of vitamin D, omega-3, or a strength-training exercise program for these clinical outcomes among relatively healthy older adults.

Reference: JAMA. 2020;324(18):1855-1868.

Effect of Vitamin D3 Supplementation on Severe Asthma Exacerbations in Children With Asthma and Low Vitamin D Levels. The VDKA Randomized Clinical Trial

Question  In high-risk children with persistent asthma and low vitamin D levels, does vitamin D₃ supplementation prolong the time to a severe asthma exacerbation?

Findings  In this randomized clinical trial that included 192 children, vitamin D₃ supplementation, compared with placebo, did not significantly improve the time to a severe asthma exacerbation (adjusted hazard ratio, 1.13).

Meaning  The findings from this trial do not support the use of vitamin D₃ supplementation to improve the time to a severe asthma exacerbation in children with asthma and low serum vitamin D levels.

Reference: JAMA. 2020;324(8):752-760.

Effect of Long-term Vitamin D3 Supplementation vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores. A Randomized Clinical Trial

Question  Can long-term supplementation with vitamin D₃ prevent depression in the general adult population?

Findings  In this randomized clinical trial that included 18 353 adults aged 50 years or older without depression or clinically relevant depressive symptoms at baseline, vitamin D₃ supplementation compared with placebo did not result in statistically significant differences in the incidence and recurrence of depression or clinically relevant depressive symptoms (hazard ratio, 0.97) or for change in mood scores over a 5-year treatment period.

Meaning  These findings do not support the use of vitamin D₃ in adults to prevent depression.

Reference: JAMA. 2020;324(5):471-480. doi:10.1001/jama.2020.10224

Six-Year Follow-up of a Trial of Antenatal Vitamin D for Asthma Reduction

BACKGROUND
We previously reported the results of a trial of prenatal vitamin D supplementation to prevent asthma and recurrent wheeze in young children, which suggested that supplementation provided a protective effect at the age of 3 years. We followed the children through the age of 6 years to determine the course of asthma and recurrent wheeze.

METHODS
In this follow-up study, investigators and participants remained unaware of the treatment assignments through the children’s sixth birthday. We aimed to determine whether, when maternal levels of 25-hydroxyvitamin D were taken into account, children born to mothers who had received 4400 IU of vitamin D3 per day during pregnancy (vitamin D group) would have a lower incidence of asthma and recurrent wheeze at the age of 6 years than would those born to mothers who had received 400 IU of vitamin D3 per day (control group). Time-to-event methods were used to compare the treatment groups with respect to time to the onset of asthma or recurrent wheeze. Multivariate methods were used to compare longitudinal measures of lung function between the treatment groups.

RESULTS
There was no effect of maternal vitamin D supplementation on asthma and recurrent wheeze in either an intention-to-treat analysis or an analysis with stratification according to the maternal 25-hydroxyvitamin D level during pregnancy. There was no effect of prenatal vitamin D supplementation on most of the prespecified secondary outcomes. We found no effects of prenatal supplementation on spirometric indexes. Although there was a very small effect on airway resistance as measured by impulse oscillometry, this finding was of uncertain significance.

CONCLUSIONS
Vitamin D supplementation during the prenatal period alone did not influence the 6-year incidence of asthma and recurrent wheeze among children who were at risk for asthma. (Funded by the National Heart, Lung, and Blood Institute; VDAART ClinicalTrials.gov number, NCT00920621. opens in new tab.)

Reference: N Engl J Med 2020; 382:525-533

Effect of Vitamin D and Omega-3 Fatty Acid Supplementation on Kidney Function in Patients With Type 2 Diabetes

Question  In adults with type 2 diabetes, do vitamin D or omega-3 fatty acid supplements help prevent development or progression of kidney disease?

Findings  In this 2 × 2 factorial randomized clinical trial that included 1312 participants with type 2 diabetes, there was no significant difference in the change in estimated glomerular filtration rate at 5 years with vitamin D₃ supplementation vs placebo (−12.3 vs −13.1 mL/min/1.73 m²) or with omega-3 fatty acid supplementation vs placebo (−12.2 vs −13.1 mL/min/1.73 m²).

Meaning  These findings do not support the use of vitamin D or omega-3 fatty acid supplementation for preserving kidney function in adults with type 2 diabetes.

Reference: JAMA. 2019;322(19):1899-1909.

Vitamin D Supplementation and Prevention of Type 2 Diabetes

BACKGROUND

Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown.

METHODS

We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D₃ or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508.

RESULTS

A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P=0.12). The incidence of adverse events did not differ significantly between the two groups.

CONCLUSIONS

Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D₃ supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694. opens in new tab.)

Reference: N Engl J Med 2019; 381:520-530

Effect of High-Dose Vitamin D Supplementation on Volumetric Bone Density and Bone Strength

Question  Does higher-dose vitamin D supplementation improve bone mineral density (BMD, measured using high-resolution peripheral quantitative computed tomography) and bone strength (measured as failure load)?

Findings  In this randomized clinical trial that included 311 healthy adults, treatment with vitamin D for 3 years at a dose of 4000 IU per day or 10 000 IU per day, compared with 400 IU per day, resulted in statistically significant lower radial BMD (calcium hydroxyapatite; −3.9 mg HA/cm³ and −7.5 mg HA/cm³, respectively); tibial BMD was significantly lower only with the daily dose of 10 000 IU. There were no significant differences in bone strength at either the radius or tibia.

Meaning  Among healthy adults, supplementation with higher doses of vitamin D did not result in improved bone health; further research would be needed to determine whether it is harmful.

Reference: JAMA. 2019;322(8):736-745.

Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease

BACKGROUND

It is unclear whether supplementation with vitamin D reduces the risk of cancer or cardiovascular disease, and data from randomized trials are limited.

METHODS

We conducted a nationwide, randomized, placebo-controlled trial, with a two-by-two factorial design, of vitamin D₃ (cholecalciferol) at a dose of 2000 IU per day and marine n−3 (also called omega-3) fatty acids at a dose of 1 g per day for the prevention of cancer and cardiovascular disease among men 50 years of age or older and women 55 years of age or older in the United States. Primary end points were invasive cancer of any type and major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes). Secondary end points included site-specific cancers, death from cancer, and additional cardiovascular events. This article reports the results of the comparison of vitamin D with placebo.

RESULTS

A total of 25,871 participants, including 5106 black participants, underwent randomization. Supplementation with vitamin D was not associated with a lower risk of either of the primary end points. During a median follow-up of 5.3 years, cancer was diagnosed in 1617 participants (793 in the vitamin D group and 824 in the placebo group; hazard ratio, 0.96; 95% confidence interval [CI], 0.88 to 1.06; P=0.47). A major cardiovascular event occurred in 805 participants (396 in the vitamin D group and 409 in the placebo group; hazard ratio, 0.97; 95% CI, 0.85 to 1.12; P=0.69). In the analyses of secondary end points, the hazard ratios were as follows: for death from cancer (341 deaths), 0.83 (95% CI, 0.67 to 1.02); for breast cancer, 1.02 (95% CI, 0.79 to 1.31); for prostate cancer, 0.88 (95% CI, 0.72 to 1.07); for colorectal cancer, 1.09 (95% CI, 0.73 to 1.62); for the expanded composite end point of major cardiovascular events plus coronary revascularization, 0.96 (95% CI, 0.86 to 1.08); for myocardial infarction, 0.96 (95% CI, 0.78 to 1.19); for stroke, 0.95 (95% CI, 0.76 to 1.20); and for death from cardiovascular causes, 1.11 (95% CI, 0.88 to 1.40). In the analysis of death from any cause (978 deaths), the hazard ratio was 0.99 (95% CI, 0.87 to 1.12). No excess risks of hypercalcemia or other adverse events were identified.

CONCLUSIONS

Supplementation with vitamin D did not result in a lower incidence of invasive cancer or cardiovascular events than placebo. (Funded by the National Institutes of Health and others; VITAL ClinicalTrials.gov number, NCT01169259.)

Reference:
N Engl J Med 2019; 380:33-44

Vitamin D Supplementation in Pregnancy and Lactation and Infant Growth

BACKGROUND

It is unclear whether maternal vitamin D supplementation during pregnancy and lactation improves fetal and infant growth in regions where vitamin D deficiency is common.

METHODS

We conducted a randomized, double-blind, placebo-controlled trial in Bangladesh to assess the effects of weekly prenatal vitamin D supplementation (from 17 to 24 weeks of gestation until birth) and postpartum vitamin D supplementation on the primary outcome of infants’ length-for-age z scores at 1 year according to World Health Organization (WHO) child growth standards. One group received neither prenatal nor postpartum vitamin D (placebo group). Three groups received prenatal supplementation only, in doses of 4200 IU (prenatal 4200 group), 16,800 IU (prenatal 16,800 group), and 28,000 IU (prenatal 28,000 group). The fifth group received prenatal supplementation as well as 26 weeks of postpartum supplementation in the amount of 28,000 IU (prenatal and postpartum 28,000 group).

RESULTS

Among 1164 infants assessed at 1 year of age (89.5% of 1300 pregnancies), there were no significant differences across groups in the mean (±SD) length-for-age z scores. Scores were as follows: placebo, −0.93±1.05; prenatal 4200, −1.11±1.12; prenatal 16,800, −0.97±0.97; prenatal 28,000, −1.06±1.07; and prenatal and postpartum 28,000, −0.94±1.00 (P=0.23 for a global test of differences across groups). Other anthropometric measures, birth outcomes, and morbidity did not differ significantly across groups. Vitamin D supplementation had expected effects on maternal and infant serum 25-hydroxyvitamin D and calcium concentrations, maternal urinary calcium excretion, and maternal parathyroid hormone concentrations. There were no significant differences in the frequencies of adverse events across groups, with the exception of a higher rate of possible hypercalciuria among the women receiving the highest dose.

CONCLUSIONS

In a population with widespread prenatal vitamin D deficiency and fetal and infant growth restriction, maternal vitamin D supplementation from midpregnancy until birth or until 6 months post partum did not improve fetal or infant growth. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT01924013.)

Infants who are small for gestational age or have impaired postnatal linear growth continue to be of major concern with regard to public health in low- and middle-income countries.^1,2 However, environmental and dietary regulation of fetal and infant growth remain inadequately understood. Observational studies have shown numerous early-life risk factors for later anthropometric outcomes,^3,4 but there is limited evidence of benefit of prenatal micronutrient interventions on childhood linear growth.⁵

Vitamin D may influence fetal and postnatal growth through effects on calcium absorption,⁶parathyroid hormone expression,⁷ phosphate metabolism,⁸ growth-plate function,^9,10 and regulation of the insulin-like growth factor axis.¹¹ Meta-analyses of observational studies¹² and clinical trials¹³ have suggested that vitamin D may have a beneficial effect on fetal growth, but most previous trials have had methodologic limitations.¹³ In a previous small trial in Bangladesh, we found that early postnatal linear growth was higher in infants born to women who had received vitamin D supplementation as compared with those who had not received supplementation.¹⁴

In Bangladesh, approximately 30% of newborns are small for gestational age,¹ and the growth of 36% of children younger than 5 years of age is stunted (height-for-age z score, <−2).¹⁵ Vitamin D deficiency is common in Bangladeshi women of reproductive age.¹⁶ In the Maternal Vitamin D for Infant Growth (MDIG) trial conducted in Dhaka, Bangladesh, we evaluated the dose-dependent effects of prenatal vitamin D supplementation, with and without postpartum supplementation, on infant growth and other maternal, newborn, and infant outcomes.

Reference: N Engl J Med 2018; 379:535-546

Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults

Question  Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?

Findings  In this meta-analysis of 33 randomized clinical trials that included 51 145 participants, the use of supplements that included calcium, vitamin D, or both was not associated with a significant difference in the risk of hip fractures compared with placebo or no treatment (risk ratio, 1.53, 1.21, and 1.09, respectively).

Meaning  These findings do not support the routine use of these supplements in community-dwelling older adults.

Reference: JAMA. 2017;318(24):2466-2482.