Low concentrations of 25-hydroxyvitamin D (25[OH]D) are most likely an effect of health disorders and not a cause of illness, concludes a comprehensive review of observational studies and randomized clinical trials of vitamin-D status and health outcomes published online December 6 in Lancet Diabetes & Endocrinology. The new analysis, showed moderate to strong associations between lower concentrations of Vitamin D and higher risk for conditions ranging from cardiovascular disease to infectious disease, glucose-metabolism disorders, and mood disorders.
Researchers found no effect on disease occurrence as a result of supplementation, by evaluating 172 randomized clinical trials, including 34 intervention studies involving vitamin-D supplementation of patients with low 25(OH)D concentrations.
“The discrepancy between observational and interventional studies suggests that low Vitamin D is a marker of ill health,” write the researchers, led by Philippe Autier, MD, MPH, PhD, vice president of population studies at the International Prevention Research Institute, Lyon, France.
The authors speculate that a key mechanism that causes lower 25(OH)D concentrations in people with illness is disease-related inflammation. “Inflammatory processes involved in disease occurrence and clinical course would reduce 25(OH)D, which would explain why low vitamin-D status is reported in a wide range of disorders,” they state. In the interventional studies, which involved 2805 individuals, participants had a baseline mean 25(OH)D concentration less than 50 nmol/L. Supplementation with 50 µg/day of vitamin D resulted in no significant improvement in health status.
They add that ongoing trials will provide more information, but in the meantime they advise against vitamin-D supplementation.

No Effect of Vitamin-D Supplementation in Diabetes, Cancer
As part of their review, the authors also conducted a meta-analysis of 16 trials that focused on the effects of vitamin-D supplementation on HbA1c, the standard measure of long-term blood glucose control in diabetes. Although the observational studies showed an association between type 2 diabetes and low vitamin-D levels, supplementation with the vitamin had no effect on reducing HbA1c.
The data also showed that high 25(OH)D concentrations were associated with a protective effect on colorectal cancer, but not other cancers. However, 2 large intervention trials showed no reduced risk of any cancers, including colorectal, with vitamin-D supplementation.
One exception was seen in the elderly population (mainly women), who showed a slight reduction in all-cause mortality if they received vitamin-D supplementation of 20 µg/day. However, the authors speculate that the improvement could be related to vitamin-D deficits caused not directly by the illness itself but by lifestyle changes resulting from the illness, such as a lack of mobility, restrictions on exposure to sunlight, or dietary modifications related to treatment.
“In elderly people, restoration of vitamin-D deficits due to aging and lifestyle changes induced by ill health could explain why low-dose supplementation leads to slight gains in survival,” they suggest.
Further Insights Will Emerge From Ongoing Trials
The researchers note that important further insights should emerge from 5 trials that are currently under way. These trials involve between 2150 and 20,000 patients aged 50 years or older and are investigating the effects of 40 to 80 µg/day of vitamin-D supplementation on the risk of cancer, cardiovascular disease, diabetes, infections, declining cognitive function, and fractures.
“The first results are not expected before 2017, but these studies have the potential to test our hypotheses,” they observe.
The editors say the key factors that drive continued research into vitamin D for the prevention of nonskeletal disorders include “the relatively low toxicity of vitamin D, the glimmer of positivity from some trials, and the large body of evidence from prospective observational studies.”
Dr. Autier agreed, adding that commercial influences, such as the vitamin-D supplement industry and manufacturers of vitamin-D testing products, have also helped fuel the enthusiasm.
“Commercial influences were more than happy about the explosion of observational data on vitamin D and diseases,” he told Medscape Medical News. “A third main player is the artificial UV tanning industry, which encourages tanning booths because of the ‘vitamin-D sufficiency’ issue.”
Vitamin-D Supplementation “Ill-Advised”
For proponents of nonskeletal health benefits from vitamin D, there is no shortage of potential explanations for the lack of results in interventional studies, the editors add.
“For those who ‘believe,’ the lack of benefit found in most trials completed thus far can be attributed to issues including inadequate supplementation, testing of a population not sufficiently vitamin-D deficient at baseline, incorrect formulation, underpowering, or insufficient follow-up,” they observe.
Dr. Autier noted that trials conducted prior to about 2000, such as the large Women’s Health Initiative, did indeed use low doses or involved too few subjects to reach a sound conclusion, but he added, “More recently published randomized trials have taken care of these aspects, and these arguments are less relevant than, say, 5 years ago.”
Some supplementation if an individual’s vitamin-D concentration falls below a “sufficiency” threshold of 75 nmol/L continues to be recommended — an ill-advised practice, Dr. Autier asserted.
“The wealth of evidence from randomized trials shows that this medical behavior is not grounded and taking vitamin-D supplements will make no difference on health status,” he said. “It would be wiser to seek reasons underlying the low vitamin-D level, such as inflammatory processes or undiagnosed cardiovascular diseases, and fix them.”

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