Vitamin D: When Enough Is Enough

Vitamin D enthusiasts have long promoted high doses to obtain hoped-for benefits, but clinical trials are not finding them.

Clinical trials of high doses of vitamin D are not finding the benefits that some advocates had promoted and are even hinting at some adverse effects.

“The enthusiasm for high-dose vitamin D has certainly outpaced the evidence. And now that we’re getting the results of randomized clinical trials of higher doses, we’re seeing that more is not better, and in many cases is worse,” says JoAnn Manson, MD, DrPH, professor of medicine at Harvard Medical School and principal investigator of the VITAL trial, one of the largest trials of moderate-dose vitamin D.

The accumulating evidence is reinforcing the idea that adequate vitamin D is needed to maintain health, but once a person achieves an adequate level, further increases do not accrue further benefits.

The Bounds of Bone Benefits

The need for vitamin D for bone health is well-established, so researchers at the University of Calgary led by David A. Hanley, MD, and Stephen K. Boyd, PhD, decided to examine the effects of increased doses. In a study published in August in JAMA, some 300 healthy adults were randomized to receive daily doses of vitamin D₃ for three years at 400 IU, 4,000 IU, or 10,000 IU. The researchers included the 4,000 IU level because the U.S. National Academy of Medicine and Health Canada consider it to be the tolerable upper intake level.

“The enthusiasm for high-dose vitamin D has certainly outpaced the evidence. And now that we’re getting the results of randomized clinical trials of higher doses, we’re seeing that more is not better, and in many cases is worse.” – JoAnn Manson, MD, DrPH, professor of medicine, Harvard Medical School; principal investigator, VITAL trial

The researchers assessed participants’ tibia and distal radius using high-resolution peripheral quantitative computed tomography, a measure of bone density that is much more sensitive than the standard dual energy x-ray absorptiometry. They hypothesized that higher doses might increase bone density, so were surprised when the subjects who received 4,000 IU or 10,000 IU had statistically significantly lower radial bone mineral density than patients who received 400 IU. Those who received the 10,000 IU dose also had lower tibial bone mineral density.

“Our conclusion strengthens the position that once you achieve a certain level of vitamin D sufficiency, there is no further benefit of pushing the dose higher for bone. Our study actually raises the possibility that there is harm in pushing the dose higher, which is something that other studies have raised as well,” Hanley tells Endocrine News. “Two studies using huge doses of vitamin D as an intermittent, once-yearly bolus have actually shown an increase in fractures and falls.”

Hanley’s group found that participants receiving the 10,000 IU dose had increased levels of a marker of bone resorption known as CTx and suppression of parathyroid hormone, which hints at a mechanism by which high vitamin D levels could harm bone density.

Any Role in Diabetes Prevention?

The role of vitamin D beyond bone health is a hot topic in endocrinology, with perhaps the most interest relating to preventing type 2 diabetes — which was the focus of the Vitamin D and Type 2 Diabetes (D2d) study. This trial enrolled more than 2,400 participants with prediabetes and randomly assigned them to receive either a daily dose of 4,000 IU vitamin D or placebo over two-and-a-half years. The subjects were enrolled regardless of their vitamin D blood levels, and the serum 25-hydroxyvitamin D levels of the group that received vitamin D rose from a mean of about 28 ng/mL at baseline to 54 ng/mL at 24 months, whereas the placebo group’s levels remained at a mean of about 28 ng/mL.

The study was powered to detect a 25% lower risk of the participants’ prediabetes progressing to diabetes, but the investigators reported a reduction of 12% in the risk of diabetes, which was not statistically significant. The authors noted that similar trials from Norway and Japan reported nearly identical reductions in diabetes risk.

Anastassios G. Pittas, MD, professor of medicine at Tufts Medical Center and lead author of the D2d study, which was published in August in the New England Journal of Medicine, says that he is collaborating with the investigators from the other trials to perform an individual participant data meta-analysis.

“Our conclusion strengthens the position that once you achieve a certain level of vitamin D sufficiency, there is no further benefit of pushing the dose higher for bone. Our study actually raises the possibility that there is harm in pushing the dose higher, which is something that other studies have raised as well.” – David A. Hanley, MD, professor, Departments of Medicine, Oncology, and Community Health Sciences, University of Calgary, Alberta, Canada

“Once we combine all the data, we will have a total cohort of over 4,000 participants and that will allow us to better estimate the benefit, if any,” Pittas explains. “We are excited about this collaboration because the data suggest that vitamin D supplementation may decrease diabetes risk among persons at risk for diabetes not selected for vitamin D insufficiency by a smaller effect size — 10% to 15% — that none of these trials were individually powered to detect.”

VITAL Signs

The diabetes question may receive a more definitive answer in a few months when more results from the VITAL trial (VITamin D and OmegA-3 TriaL) will be published. VITAL is a randomized, placebo-controlled trial of 26,000 participants who received 2,000 IU/day of vitamin D, some with and some without an additional supplement of omega-3 fish oil, over five years. Participants were enrolled regardless of vitamin D status at baseline.

Principal investigator Manson noted that the primary outcomes results, published in fall 2018 in the New England Journal of Medicine, found that vitamin D did not significantly affect heart attack, stroke, or cancer incidence. However, it was associated with a decrease in cancer deaths that started one to two years after participants began treatment. Manson was also on a team that published a meta-analysis in the Annals of Oncology of randomized clinical trials of vitamin D supplementation that found that it did not reduce cancer incidence but significantly reduced cancer mortality.

Correcting Low Vitamin D Levels

In the D2d study, when investigators looked only at participants who had very low vitamin D levels (less than 12 ng/mL) at baseline, vitamin D supplementation significantly reduced the risk of diabetes — by 62%. “If vitamin D can help prevent diabetes, people with lower vitamin D levels might benefit more than those who already have higher vitamin D levels, so this result is not surprising,”  Pittas says. “However, because the D2d study was not designed to examine this question, further research is needed to confirm this observation.”

Manson says that evidence continues to mount supporting the 2011 vitamin D dietary intake recommendations from the Institute of Medicine (now the National Academy of Medicine) that 600 to 800 IU a day would meet the needs of the vast majority of the population. “If you start out with a low vitamin D level, then with even 400 IU a day, and certainly with 1,000 IUs, you’re going to have a very substantial increase in the blood level. After that, higher doses lead to proportionately smaller increments in the blood level,” she says.

Hanley says: “Studies in Canada indicate that 20% of the population may not have the 20 ng/mL blood level that the National Academy of Medicine concluded would indicate adequate vitamin D for bone health in 97.5% of healthy Americans and Canadians, but the low-dose supplement of 400 IU used in our study would probably protect that 20%.”

The Role of Obesity

Manson is intrigued by the idea that a person’s body mass index (BMI) may influence the efficacy of vitamin D supplementation. When the D2d results are stratified by BMI, participants with a BMI of less than 30 kg/m² experienced a 30% reduction in risk for developing type 2 diabetes, whereas those with a BMI above 30 experienced no risk reduction.

The VITAL trial found a 24% reduction in cancer incidence in normal-weight participants, but no reduction among those with a BMI of 27 or above. These findings raise the possibility of reduced bioactivity, or of vitamin D resistance akin to insulin resistance, among people with a high BMI. Manson believes these interactions warrant further study.

As studies of vitamin D supplementation knock down the belief of some patients that ‘if some is good, then more is better,’ Pittas notes that endocrinologists are accustomed to the effect of dosages: “Much more of something may not even be neutral, but may be detrimental. In endocrinology, we are all about balance.”

Seaborg is a freelancer writer based in Charlottesville, Va. He wrote about post-prandial glucose levels in the December issue.