For many years, various organizations and studies have said you can get too much vitamin D while others say the opposite. Fortunately, clinical trials could provide answers to this controversial question soon.
There is little debate over the role of vitamin D and calcium in bone health, but the question of whether much higher intakes of vitamin D could have a host of nonskeletal benefits remains hotly debated. New studies linking vitamin D deficiency to nonskeletal problems are popping up with great frequency, but correlation is not causation, and most meta-analyses have not found evidence to bolster claims of wide-ranging benefits.
“We are at a crossroads in terms of vitamin D research,” says JoAnn Manson, MD, DrPH, a professor at Harvard Medical School who served on a recent Institute of Medicine (IOM)task force on reference intakes for vitamin D. “We have numerous observational studies suggesting associations between low vitamin D levels and increased risk of myriad diseases, but we don’t yet know whether there is a cause and effect relationship. We do know that vitamin D deficiency is a health problem … associated with bone disorders. Th e real issue is whether you have greater health benefits from exceeding, rather than meeting, the recommended dietary allowance for vitamin D. We don’t yet know that giving vitamin D supplementation will lower the risk of cardiovascular disease, cancer, diabetes, cognitive decline, depression, and a host of other diseases.
The message that is going out to the public is that the higher the intake of vitamin D the better, and I think even many clinicians are confused and question this assumption,” Manson says.
Will vitamin D fulfill the promise that many predict or turn out to be the next vitamin E? Large randomized trials testing the effects of moderate to high doses are under way that could provide answers soon.
Associations Piling Up
Journals seem to be filled with studies like the recent one in Neurology that linked low vitamin D levels with an increased risk of dementia and Alzheimer’s disease, an article that received a good deal of attention in the lay press.
Recent articles in the Journal of Clinical Endocrinology & Metabolism include: A study in Ireland linked low vitamin D with poor physical function in severely obese patients.Another Irish study found that markers of inflammation were higher in vitamin D-deficient older patients. A meta-analysis tied a 10 nmol/L (4 ng/ml) increase in vitamin D levels to a 4% increase in survival among cancer patients. A meta-analysis of observational studies linked low vitamin D with schizophrenia.
Of course, these studies cannot differentiate whether low vitamin D levels cause the disorders or the disorders themselves contribute to the low vitamin D levels, or some combination of the two. In addition, people with low vitamin D levels because of poor general nutrition are more likely to be ill, and conditions such as obesity and a lack of outdoor physical activity can also contribute to low levels, Manson says.
Another element complicating the interpretation of these studies is that they use different definitions of deficiency and sufficiency. “There is no consensus definition of vitamin D deficiency,” the U.S. Preventive Services Task Force noted in a recent draft statement on vitamin D screening.
Two recent influential guidelines illustrate this point. In 2011, IOM guidelines on reference intakes for vitamin D used a blood level of 20 ng/ml of 25-hydroxyvitamin D as the benchmark for deficiency because that level meets the needs for good bone health for at least 97.5% of the population. That guideline addressed needs on a population and public health level but not treatment of specific medical conditions. That same year, the Endocrine Society guideline on the treatment and prevention of vitamin D deficiency agreed with this 20 ng/ml level. But the guideline classified levels from 21 to 29 ng/ml as “insufficient” and recommended that people aim for a level of 30 ng/mL or higher.
The 2011 IOM guideline greatly increased the recommended dietary allowances (RDA) for all age groups: For people from 1 to 50 years old, the RDA increased from 200 to 600 international units (IU) a day; for people 50 to 70 years old, from 400 to 600 IU; and for those over 70, from 600 to 800 IU. The Endocrine Society guideline agreed that people need “at least” these intakes to maximize bone health and muscle function, but that raising the blood level above 30 ng/mL could require substantially more, on the order of 1,500–2,000 IU per day. Th e carefully worded guideline says, “It is unknown whether 1,000 IU/day is enough to provide all the potential nonskeletal health benefi ts associated with vitamin D.”
Those nonskeletal benefi ts are the subject of lively debate, but there is a logical underpinning for the belief that vitamin D could have far-reaching effects, according to Michael F. Holick, MD, PhD, director of the General Clinical Research Unit and Bone Health Care Clinic at Boston University Medical Center. Holick chaired the expert panel that wrote the Endocrine Society guideline. “We know that basically every cell in your body has a vitamin D receptor. Th e vitamin D receptor has been found in the brain, skeletal muscle, colon, breast, prostate, and the list goes on. Cells that have a vitamin D receptor respond to 1,25-dihydroxyvitamin D. It regulates their growth and hormone production. It has a lot of different functions,” Holick tells Endocrine News.
Although many meta-analyses have failed to find significant nonskeletal effects, Holick believes these analyses have weaknesses because they are dominated by older studies in which vitamin D intakes were too low.
“Most studies have never used 1,000 and 2,000 IUs per day of vitamin D, and we think that that is the dose that most children and adults need, respectively, to satisfy their vitamin D requirements. A study in Finland showed that when children received 2,000 IUs of vitamin D a day during their first year of life, it reduced the risk for developing type 1 diabetes by 88% later in life. There is a lot of information out there to suggest that improvement in your vitamin D status will improve your overall health and welfare,” Holick says.
Stephen Fortmann, MD, a senior researcher at the Kaiser Permanente Center for Health Research, says that a strong rationale for purported benefits may not translate into actual benefits. For example, postmenopausal estrogen offered promise because it improved lipid levels as well as vascular function, but those effects “did not add up to preventing heart disease.” Fortmann was lead author of a study done at the behest of the U.S. Preventive Services Task Force and published in the Annals of Internal Medicine that surveyed a host of studies on vitamin and mineral supplements. Th e study concluded that there is “insufficient data to draw conclusions” about supplements having any effect in “preventing heart disease, cancer, or death.”
Clinical Trials to the Rescue
Th is dearth of evidence is likely to change soon for vitamin D because large, randomized clinical trials are already in the pipeline. Manson is a principal investigator of the largest one. The VITamin D and OmegA-3 TriaL (VITAL) is testing the effects of taking 2,000 IU in supplements per day versus placebo in almost 26,000 adults over age 50.The primary focus is on prevention of cancer and cardiovascular disease, but data will be collected on a host of other disorders, including diabetes, hypertension, cognitive decline, depression, respiratory disorders, and autoimmune diseases. It’s an ongoing five-year trial, with preliminary results expected in about three years.
Another multi-year trial based at Tufts University will test whether daily supplements of 4,000 IUs will prevent or delay the onset of type 2 diabetes in people with prediabetes. Both trials are sponsored by the National Institutes of Health.
For Patients who Can’t Wait
While awaiting that data, clinicians still need an answer for patients tempted to take large doses of vitamin D. Th ree endocrinologists interviewed for an Endocrine News article on osteoporosis in the April issue all aimed for levels of at least 30 ng/ml — with an eye toward maximizing bone health in at-risk patients.
Holick believes that maintaining a level of 40 to 60 ng/ml is desirable in the general population and a level up to 100 ng/ml is “perfectly safe.”
Others urge caution about going above 50 ng/ ml. “Th e data are not clear cut, but some evidence of toxicity has been associated with levels above 50 ng/ ml, including hypercalcemia and kidney stones,” says Cliff ord Rosen, MD, director of clinical and translational research at the Maine Medical Center Research Institute, who worked on the IOM guideline.
But even a level of 50 ng/ml leaves a lot of leeway above the IOM’s deficiency level of 20 ng/ml and the Endocrine Society’s sufficiency level of 30 ng/ml. And it leaves a lot of leeway for taking supplements — the IOM guideline found that intakes as high as 4,000 IU/day should be safe for adults, although longterm risks of such high intakes are unknown.
— Seaborg is a freelance writer based in Charlottesville, Va.
He wrote about male reproduction and
EDCs in the September issue.