New research, recent controversies call vitamin D benefits into question
The idea of “sunshine in a bottle” — vitamin D supplementation — has been promoted as a possible fix for everything from bone and immune system health to depression, dementia and diabetes, and the premise sells. According to recent CDC statistics, approximately 45% of middle-aged women and 38% of middle-aged men report taking a vitamin D supplement, and hundreds of thousands of Americans get tested for vitamin D deficiency each year.
Many clinicians, too, tout the promise and possible benefits of vitamin D, which, despite its name, is a hormone that promotes the absorption of calcium in the body. But for every positive claim attached to the over-the-counter supplement, new research suggests there is more to the story.
“It’s natural in medical thinking that if a person is deficient in something and you have a disease, maybe replacing that deficiency would either prevent it, improve it or, possibly, even cure it,” Bart L. Clarke, MD, a professor of medicine in the division of endocrinology, metabolism, diabetes and nutrition at the Mayo Clinic College of Medicine in Rochester, Minnesota, and president of the American Society for Bone and Mineral Research, told Endocrine Today. “Like most things in medicine, the pendulum swings from cynicism to enthusiasm, and over time, as more data become available, things settle back down to some middle level, where it probably should have been all along.”
What constitutes the “optimal” level of vitamin D — and what that even means — remain issues of intense debate. Recent negative media attention called into question the Endocrine Society’s recommendations for vitamin D supplementation, and a published report highlighted ethical conflicts for a famous vitamin D proponent. Most recently, the large-scale VITAL trial, conducted with 25,871 adults, including 5,106 black participants, suggested the supplement failed to prevent major cardiovascular events and the development of invasive cancers over 5 years. The harshest critics contend the supplement is worthless.
Still, a deeper dive into the VITAL results, as well as other research conducted in adults with specific cancers, reveals a signal for benefits with vitamin D for certain subsets of patients.
For many researchers, the real benefit of vitamin D remains an open question.
“The key message here is that the results of the VITAL trial are complex,” the study’s principal investigator, JoAnn E. Manson, MD, DrPH, FACE, chief of the division of preventive medicine at Brigham and Women’s Hospital and professor of medicine and the Michael and Lee Bell Professor of Women’s Health at Harvard Medical School, told Endocrine Today. “There is no simple summary and no one-size-fits-all recommendation based on the results of the VITAL trial.”
Manson said the study, which also looked at omega-3 supplementation, showed a signal for CV health benefits with fish oil, particularly relevant to those with low fish consumption at baseline, and a signal for a cancer death benefit with vitamin D supplementation.
“We need to see if these signals strengthen over time,” Manson said. “We will be following the cohort for at least 2 more years.”
Possible cancer benefit
In the vitamin D portion of VITAL, invasive cancer was diagnosed in 1,617 participants, including 793 in the vitamin D group and 824 in the placebo group, for an HR of 0.96 (95% CI, 0.88-1.06). In the analyses of secondary endpoints, HRs were 0.83 for overall cancer death (95% CI, 0.67-1.02), 1.02 for breast cancer (95% CI, 0.79-1.31), 0.88 for prostate cancer (95% CI, 0.72-1.07) and 1.09 for colorectal cancer (95% CI, 0.73-1.62).
“The findings are along the lines of what I expected to see,” Kimmie Ng, MD, MPH, director of clinical research at Dana-Farber Cancer Institute’s Gastrointestinal Cancer Center and assistant professor of medicine at Harvard Medical School, told Endocrine Today. “There hasn’t been a randomized controlled trial of chemoprevention using vitamin D that has shown a significant benefit in terms of reducing the risk for developing colorectal cancer. Many of the previous randomized controlled trials looked at cancer or cancer death as a secondary endpoint. This one actually was powered to detect an effect on whether it can protect against cancer. This was a very well-designed, adequately powered study.”
Laboratory, ecological and epidemiologic data have hinted at a possible cancer benefit with respect to vitamin D for years, according to Ng. The first evidence came from population studies suggesting people diagnosed with cancer living in the southern part of the U.S. had better cancer-related outcomes or mortality vs. those living in the northern U.S.
“At the same time, there was a lot of laboratory evidence that vitamin D can decrease cell proliferation, encourage cell differentiation and apoptosis and prevent angiogenesis. It has anti-inflammatory effects and can modulate the immune system,” Ng said. “All of those processes are quite dysregulated in cancer. This led to the hypothesis that vitamin D may have anticancer activity.”
The observed outcomes in VITAL, Ng said, may have to do with the 5-year duration of the trial.
“A lot of other chemoprevention studies, like with aspirin and other agents, seem to suggest that even durations of 10 years or 20 years may be necessary to really show a protective effect,” Ng said.
Subgroup analyses in VITAL revealed intriguing data. An analysis of cancer-related deaths highlighted a possible benefit in total cancer mortality when early follow-up data were excluded to account for cancer latency issues. Subgroup analysis based on BMI suggested that normal-weight patients who received vitamin D had a lower incidence of cancer compared with those who received placebo.
“The interaction with BMI is biologically consistent with what we know about absorption and metabolism of vitamin D,” Ng said. “Patients who are obese probably need much higher levels of supplementation to reach the same blood level.”
At the American Society of Clinical Oncology annual meeting in 2017, Ng and colleagues presented data from a randomized controlled trial of 139 patients with metastatic colorectal cancer that suggested 4,000 IU of daily vitamin D, when added to chemotherapy, significantly improved progression-free survival in patients when compared with daily supplementation of 400 IU.
“It supports the findings in VITAL that there may be a protective effect on cancer mortality,” Ng said.
Meta-analyses of trials mostly done for bone health have not shown any benefit for vitamin D with respect to CV outcomes, according to Erin D. Michos, MD, MHS, associate professor of medicine at Johns Hopkins University School of Medicine.
“But the question is: Is the dose too low, or were the studies not powered or designed to look for CV outcomes?” Michos told Endocrine Today. “This wasn’t definitive.”
In the VITAL cohort, a major CV event occurred in 396 vitamin D participants and 409 placebo participants, for an HR of 0.97 (95% CI, 0.85-1.12). Researchers observed similar findings for the expanded composite endpoint of major CV events plus coronary revascularization (HR = 0.96; 95% CI, 0.86-1.08), myocardial infarction (HR = 0.96; 95% CI, 0.78-1.19), stroke (HR = 0.95; 95% CI, 0.76-1.2) and CV death (HR = 1.11; 95% CI, 0.88-1.4).
The findings, researchers wrote, were consistent with results from previous vitamin D trials, at both moderate and high doses. Most recently, in the ViDA trial, the rate of CVD was not lower among participants who received monthly administration of high-dose vitamin D when compared with placebo.
“Overall, the thing I take away is that low vitamin D may not be a causal factor of heart disease,” Michos said. “It is a risk factor for heart disease; but it may just be that someone with lower levels is just not in as good health, and it might just be a marker of a poor health state, as opposed to something causal where you can treat it and improve outcomes.”
In VITAL, the baseline population had largely normal vitamin D levels, and 40% were taking statins at baseline, according to Carlos Bernal-Mizrachi, MD, the Philip E. and Carolyn E. Cryer Professor of Medicine in the division of endocrinology, metabolism and lipid research at Washington University and chief of endocrinology at St. Louis VA Medical System.
“It was not surprising that adding vitamin D supplementation did not decrease CVD,” Bernal-Mizrachi told Endocrine Today. “Perhaps future results from high-risk populations, such as people with diabetes with vitamin D deficiency, could help us to prove whether vitamin D is effective against CVD in these more specific groups and ultimately identify evidence-based cutoff points.”
Manson noted, however, that CV risks were not reduced by vitamin D supplementation even in those who had low levels — less than 20 ng/mL — at baseline and that a 5-year trial in patients with vitamin D deficiency with half assigned to placebo would be unethical.
In a meta-analysis published in October in The Lancet Diabetes & Endocrinology,Mark J. Bolland, MBChB, PhD, associate professor in the department of medicine at the University of Auckland, New Zealand, and colleagues analyzed 81 randomized controlled trials that compared vitamin D with no treatment, placebo or lower-dose vitamin D supplements, reporting on fracture, falls or bone mineral density. In pooled analyses, vitamin D had no effect on total fracture, hip fracture, falls or BMD at any site, with results persisting in subgroup analyses using doses greater than 800 IU per day.
However, research suggests that vitamin D works synergistically with calcium, Clarke noted, and studies that try to separate the two will often not show any benefit.
“This is the latest in a series of different meta-analyses performed by the same group in New Zealand, showing that these things by themselves don’t seem to have any effect,” Clarke said. “The studies that have been done with combination therapy — calcium and vitamin D — do show hip fracture prevention, etc. Most of us think that if we’re going to treat with vitamin D for bone purposes, we’re automatically assuming that either the patient is getting enough calcium through diet or we’re going to recommend a calcium supplement to bring them up to [Institute of Medicine] standards.”
Potential adverse effects
In a double-blind, randomized controlled trial published in September in Clinical Endocrinology,John Aloia, MD, chief academic officer at NYU Winthrop Hospital and dean of the Winthrop Campus at Stony Brook University School of Medicine in Mineola, New York, and colleagues analyzed data from 132 healthy, white postmenopausal women aged 50 years and older with a 25-hydroxyvitamin D level less than 32 ng/mL (baseline mean, 28 ng/mL) and no history of osteoporotic fracture. Researchers randomly assigned the women to 10,000 IU daily vitamin D — the upper-limit intake recommended by the Endocrine Society — or 600 IU vitamin D, the recommendation from the Institute of Medicine, along with 2,000 mg daily calcium for both groups for 1 year.
Researchers found that hypercalciuria, assessed via 24-hour urinary calcium excretion, occurred in both the high-dose and low-dose groups; however, women assigned to the high-dose vitamin D group were 3.6 times more likely to develop hypercalciuria vs. those in the lower-dose group (OR = 3.6; 95% CI, 1.39-9.3).
“Many patients don’t think of this as medication,” Michos said. “There can actually be some harm with supplements. We know antioxidants, like high doses of vitamin A and E, are associated with increased harm. It’s hard to overdose on vitamin D, but you can if you have really massive doses.”
Manson noted that the VITAL study demonstrated safety in a large population assigned to a 2,000 IU daily dose over 5 years of follow-up.
“However, we do think patients should be cautioned against ‘mega-dosing’ on these supplements,” Manson said. “Very high doses may be associated with risks like hypercalcemia and hypercalciuria, and also CV outcomes may be adversely affected. Avoiding an excessive dose is important to keep in mind.”
Whom to screen
A clinical practice guideline issued by the Endocrine Society in 2011 states that there is currently not sufficient evidence to recommend screening individuals who are not at risk for vitamin D deficiency or to prescribe vitamin D to attain a noncalcemic benefit for CV protection. At the time, the task force also advised measuring serum 25-(OH)D level by a reliable assay as the initial diagnostic test in patients at risk for deficiency, with treatment with either vitamin D2 or vitamin D3 recommended for deficient patients.
Many high-risk populations should be screened for deficiency, Bernal-Mizrachi said, including nursing home residents, patients with osteoporosis or fractures, patients with limited sun exposure, black women of childbearing age, malnourished populations with low intake or people with severe liver disease or chronic renal failure.
‘No magic bullet’
There will be 23 ancillary studies coming from VITAL, Manson said, including analyses assessing the association between vitamin D and diabetes, cognitive function, depression, autoimmune disease and other health outcomes that could inform clinical decision-making.
Most experts agree that, for people already taking vitamin D supplements, there is no clear need to stop taking them. Any supplements, however, should be part of an overall healthy diet and lifestyle.
“There is no magic bullet,” Michos said. “I encourage people to eat a balanced diet, include some fish in their diet if they eat that, maintain a healthy weight, because obesity is associated with low vitamin D levels, and get a little sun. Most people don’t need to be taking a vitamin D supplement.”
Supplementation could confer a benefit for people with severe vitamin D deficiency — a level defined by the Institute of Medicine as less than 12 nmol/L, Michos said.
“I still treat those people in my clinical practice for bone health,” she said.
Ng agreed, adding that the recommended vitamin D target remains an issue of debate.
“I do think it’s still good to talk with your doctor about it,” Ng said. “It’s still good to check levels of vitamin D and make sure you have adequate levels for bone health. I would not recommend vitamin D to prevent cancer at this point. The data is still preliminary on whether it can be used to treat cancer.”
Clarke said the large-scale VITAL findings hardly close the door on the vitamin D debate. Still, he remains skeptical of any benefit.
“There have been a number of investigators who have hyped vitamin D findings,” Clarke said. “I think vitamin D is important, and the fact so many people around the world are deficient probably does lead to a variety of different things, maybe in the onset of disease; but once the disease gets started, it’s an open question as to whether replacing vitamin D would have therapeutic benefit. The hope is that this would be cheap and easy if it worked, and it would be great if it solved many different conditions, but that enthusiasm is always tempered by experience.” – by Regina Schaffer
- Aloia JF, et al. Clin Endocrinol. 2018;doi:10.1111/cen.13848.
- Bolland MJ, et al. Lancet Diabetes Endocrinol. 2018;doi:10.1016/S2213-8587(18)30265-1.
- Hurley DL, et al. Endocr Pract. 2018;doi:10.4158/PS-2018-0050.
- Keaney JF Jr, et al. N Engl J Med. 2018;doi:10.1056/NEJMe1814933.
- Khaw K, et al. Lancet Diabetes Endocrinol. 2017;doi:10.1016/s2213-8587(17)30103-1.
- Manson JE, et al. LBS.01 — Late Breaking Clinical Trials: Answers to Critical Questions in Cardiovascular Medicine. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.
- Manson JE, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1809944.
- Ng K, et al. J Clin Oncol 2017; 35(15s): abstract 3506.
- Ross AC, et al. Dietary Reference Intakes for Calcium and Vitamin D. Washington, D.C.: National Academies Press; 2011.
- For more information:
- Carlos Bernal-Mizrachi, MD, can be reached at Washington University, Division of Endocrinology, Metabolism and Lipid Research, 1 Brookings Drive, St. Louis, MO 63130; email: firstname.lastname@example.org.
- Bart Clarke, MD, can be reached at Mayo Clinic, E18-A, 200 1st St. SW, Rochester MN 55905; email: email@example.com.
- JoAnn Manson, MD, DrPH, FACE, can be reached at Harvard Medical School, 900 Commonwealth Ave., Third Floor, Boston, MA 02215; email: firstname.lastname@example.org.
- Erin D. Michos, MD, MHS, can be reached at 600 N. Wolfe St., Baltimore, MD 21287; email: email@example.com.
- Kimmie Ng, MD, MPH, can be reached at the Center for Gastrointestinal Oncology at Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215; email: firstname.lastname@example.org.
Disclosures: VITAL was supported by the NIH. Manson reports she received grants from the NIH, nonfinancial support from BASF, Pharmavite, Pronova BioPharma and Quest Diagnostics during the conduct of the VITAL study. Ng has received research funding from Pharmavite. Bernal-Mizrachi, Clarke and Michos report no relevant financial disclosures.
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