Surge of information on benefits of vitamin D, but no interventional trial data exist yet to ensure safety

There is a wealth of new information touting the benefits of vitamin D on bone, diabetes, cancer, cardiovascular disease and more, but it is yet to be determined if endocrinologists are armed with adequate information to make an informed judgment on vitamin D for their patients.

There are currently more than 1,000 ongoing studies examining the benefits of vitamin D, according to ClinicalTrials.gov. However, only one interventional trial, the newly launched Vitamin D and Omega-3 Trial (VITAL), will be large enough to assess the balance of benefits and risks of vitamin D for multiple chronic disease outcomes, but results will not be available for 5 years.

JoAnn E. Manson, MD, DrPH, principal investigator of VITAL and professor of medicine at Harvard Medical School, said the study has begun enrollment and will test 2,000 IU of vitamin D per day in 20,000 U.S. men and women during 5 years.

“Vitamin D is a promising but as yet unproven nutrient for prevention of cancer, CVD, diabetes, autoimmune diseases and other outcomes,” Manson told Endocrine Today. “We should be cautious not to jump on the bandwagon and recommend megadoses of this supplement before VITAL and other trials can rigorously test both efficacy and safety.”

Until those data are available, there are many unanswered questions about the benefits of vitamin D: Are supplements the answer to vitamin D deficiency? Are natural methods preferable? What are the optimal serum blood levels of vitamin D? Is overdosing possible?

To clarify some of these questions, Endocrine Today spoke with several leading vitamin D researchers, endocrinologists and a physician who conducted vitamin D research at his own family practice.

Explosion of new data

From 1995 to 1999, the average number of papers with the term “vitamin D” in the title or abstract was about 700 to 900 per year. In contrast, the publication rate has drastically increased to more than 2,400 papers on vitamin D published just in 2009, according to Anthony W. Norman, MD, distinguished professor of biochemistry and biomedical sciences at the University of California, Riverside.

“There has literally been an explosion of new data on vitamin D,” Norman told Endocrine Today.

In an Endocrine Today blog, Michael Kleerekoper, MD, estimated that major U.S. medical laboratories have been performing “upwards of 30,000 assays for 25-hydroxyvitamin D each month.”

As a result of the positive press surrounding vitamin D, physicians are slowly getting on board and learning the benefits, William B. Grant, PhD, a vitamin D researcher and founding director of the Sunlight, Nutrition and Health Research Center (SUNARC) in San Francisco, said in an interview.

“Americans do not get enough vitamin D — the benefits are tremendous and the adverse effects are minimal,” Grant said.

He referenced various studies that have shown benefits of vitamin D on reduced risk for metabolic diseases, cancer, infectious diseases, autoimmune diseases, CV diseases, fractures, congestive heart failure and periodontal disease, to name a few. Most studies, however, were observational, not randomized trials.

James Lundblad, MD, PhD, said endocrinologists seem to be aware of the positives associated with vitamin D.

James Lundblad

“However, they should be critical of excessive claims of benefit,” Lundblad, endocrinologist at Oregon Health & Science University, said in an interview. “There is a great deal of hype surrounding the potential benefits of vitamin D replacement, and perhaps these are overstated, particularly those within the range of moderate vitamin D deficiency as defined by the newer proposed lower limit of normal of 30 ng/mL.”

Results of a study published in the Journal of the American Medical Association in May showed an increased risk for falls and fractures tied to a single, annual high dose of vitamin D among older women. These data go against the plethora of other information that demonstrate benefits of vitamin D.

Could negative data such as these cause endocrinologists to consider whether the benefits of vitamin D are overstated?

Understanding potential negatives

The list of positives for vitamin D is well-documented, but potential negatives may not be understood. A possible danger in the absence of supporting data is the perception that achieving even higher levels of vitamin D may afford significant additional benefit, Lundblad said.

“In my experience, providers do not routinely monitor for the potential adverse effects of hypercalcemia, much less hypercalciuria. In my own practice, however, I rarely see elevated vitamin D levels, and recommended replacement regimens (up to 2,000 IU cholecalciferol per day) are well below accepted limits,” Lundblad said.

Bruce W. Hollis, PhD, director of pediatric nutritional sciences at the Medical University of South Carolina, Charleston, has conducted vitamin D research for more than 30 years. Fear of vitamin D overdose should not be an area of concern for physicians because in all his years of experience he has yet to see one, he said.

Hollis said the only known pathway to vitamin D toxicity is hypercalciuria followed by hypercalcemia; however, he noted that neither has been observed in larger studies on intakes up to 40,000 IU per day. Most studies, however, have been short-term.

“Our own NIH-sponsored, FDA-oversight trials have dosed pregnant and lactating women with up to 6,000 IU per day for months and have not had a single adverse event due to the vitamin D, Hollis said.

“Also, no one has had a blood level that exceeded 100 ng/mL. Thus, as long as a physician is not raising the level above 100 ng/mL, there will be no problem,” he added.

Several previous studies have also questioned whether excess vitamin D causes kidney stones. A Women’s Health Initiative (WHI) study in 2006 examined 36,282 women and found that those assigned to active calcium and vitamin D had 17% more kidney stones compared with women assigned placebo (34 cases per 10,000 women vs. 29 cases per 10,000 women).

However, many experts believe it was more likely that the stones were due to calcium rather than vitamin D in the combined supplement.

Vitamin D and pregnancy

In April, the public health research organization Grassroots Health hosted a seminar as part of its campaign to unveil the latest research on the positives of vitamin D.

At the seminar, Hollis was part of a research team that presented data showing that pregnant women taking vitamin D supplements during pregnancy prevented preterm labor and births and infections. These data support previous results that indicate vitamin D deficiency is an issue for pregnant women and contradict popular belief in the 1950s and 1960s that vitamin D could cause birth defects.

Hollis and colleagues randomly assigned 494 pregnant women at 12 to 16 weeks gestation to three treatment groups: 400 IU vitamin D per day until delivery; 2,000 IU per day; and 4,000 IU per day. The women were evaluated monthly for safety and potential complications such as preeclampsia, infections, preterm labor/birth and gestational diabetes.

Carol Wagner, MD, professor of pediatrics at Medical University of South Carolina, Charleston, and another researcher for the study, found no adverse events related to vitamin D in any of the three arms of the study. In fact, the greatest effects were found among women taking 4,000 IU of vitamin D per day.

“What was achieved in our high-dose group was sufficiency within the physiologic range that is demonstrated in people who live in a sun-rich environment with skin exposure,” Wagner told Endocrine Today.

At the 13th Vitamin D Workshop in 2007 and again at a workshop in 2009, Norman and more than 425 researchers from 32 countries concluded that although the problem of insufficient vitamin D is globally understood, merely eating vitamin D-rich foods is not adequate enough to solve the problem for most adults. Wagner agreed and said studies such as this will help feed the momentum to address a health issue of this magnitude.

“Because of modern-day lifestyles and the concern for deleterious effects of UVA, in particular, we have limited sunlight exposure that has led to this epidemic in substrate vitamin D deficiency. Correction of that deficiency state is sensible and can be approached with reason and careful thought,” Wagner said. “All of us involved in this effort adhere to the mantra of doing no harm.”

High-dose falls

Results of the double blind, placebo-controlled study published in the May 12 issue of JAMA showed that 2,256 elderly women given a single high dose of vitamin D once a year had 15% more falls and 26% more fractures than the placebo group. This contradicts several other studies, including the WHI study, which found that vitamin D prevented fractures.

Researchers at the University of Melbourne, Australia, assessed whether a single, annual dose of 500,000 IU cholecalciferol administered orally to women aged 70 years and older would improve adherence and reduce the risk for falls and fracture over 3 to 5 years.

Anthony W. Norman

Women in the vitamin D group had 171 fractures compared with 135 in the placebo group, and 837 women in the vitamin D group fell 2,892 times compared with 769 women in the placebo group who fell 2,512 times.

“This is a puzzling study,” Norman said. He noted that only 5% of the women included in the study had 25(OH)D levels determined. The levels fell sharply after 3 months in the first year to a lower value, and in the second year, the 25(OH)D levels fell to the approximate value the women had before start of the study.

“I am not sure that there can be a definitive outcome or conclusion for this study, beyond that a single dose of 500,000 IU per year does not maintain blood levels at a high enough level to support a major benefit in all physiological systems that vitamin D can effect,” Norman said.

Joseph Shaker, MD, an endocrinologist at Froedtert and Medical College of Wisconsin, said the results are interesting because other studies have shown a benefit of vitamin D in terms of muscle function and falls. In these studies that show decreased falls with vitamin D, it is usually given at lower, more frequent doses, such as 800 IU per day, Shaker said.

“It is possible that the large dose of vitamin D given once yearly could adversely affect the metabolism of vitamin D, Shaker said.

“It is also possible that the large dose of vitamin D improved physical performance resulting in more active patients with a greater chance to fall. Another theory is that the high-dose vitamin D may have decreased the rate of wintertime infections, resulting in more active patients during the winter with increased opportunity for falls and fractures,” he said.

Research into practice

Dave McCarthy, MD, said medical research on the high prevalence of vitamin D deficiency motivated him to introduce the findings into his family practice, and his patients have had a substantial reduction in influenza and infections.

“When combined with supplemental magnesium, vitamin D repletion has dramatically changed my practice,” said McCarthy, whose family practice is affiliated with The Memorial Hospital of Belleville, Ill.

“There are now very few patients with infections, and asthmatics who are coming off medications are staying off of them. Elevations in blood pressure now require many fewer medications,” he said.

McCarthy has been employing these methods since February 2007, and patient acceptance has been high. He said he checks each patient’s 25(OH)D level and supplements to reach a target of 80 ng/mL in adults and children. Of the first 1,500 patients McCarthy tested, 40% began with vitamin D levels less than 20 ng/mL and 70% less than 35 ng/mL. Only 1% initially had values within his target range.

According to McCarthy, his target range is based upon several factors:

• A lifeguard study that found vitamin D levels in the 70 ng/mL range up to 100 ng/mL (nature’s level) were associated with no adverse effects;
• Data in patients with breast cancer showing a reduction in the incidence of new cancer with postulated 0 point at 80 ng/mL;
• Colon cancer data showing a reduction in the incidence of new cancer (linear) with postulated 0 point at 75 ng/mL;
• More than 200 polymorphisms of the vitamin D receptor requiring higher D levels to attain same desired outcomes;
• When a patient misses dosing, an attained level of 80 ng/mL gives the patient an additional month of good levels off of vitamin D.

McCarthy said the optimal level of 25(OH)D still remains to be determined with precision, as the peak effects have yet to be found.

Data on the horizon

The VITAL study is expected to shed light on the role of vitamin D in chronic diseases prevention.

The randomized trial will test a dose of 2,000 IU per day among 20,000 eligible men aged 60 years and older and women aged 65 years and older without a history of cancer, CVD or stroke.

In addition, “the trial will assess the risk of hypercalcemia and other biomarker changes in follow-up bloods, as well as study outcomes from cancer to cognitive function to depression to autoimmune disorders,” lead investigator Manson said.

She and colleagues will explore whether vitamin D supplementation may be able to reduce some of the health disparities seen by race and ethnicity. For example, black Americans have a higher risk for vitamin D deficiency and a greater frequency of diabetes, hypertension and certain types of cancer, she said.

“We are excited about the potential of vitamin D to reduce this health gap, but it is important to get answers from clinical trials before recommending mega-doses of this supplement,” she said.

On a larger scale, “These low-cost supplements, if found to be effective, have the potential of reducing the burden of chronic disease in this country and throughout the world,” Manson said.

More information about VITAL is available here.

More research needed

Norman said it is now widely appreciated by vitamin D scientists that 50% of people in North America and Western Europe are vitamin D-insufficient, and that in the rest of the world, two-thirds of the people are vitamin D-insufficient or deficient.

Still, the need for further research is evident.

“There is the emerging view that the relative daily intake of vitamin D should be increased from the currently recommended 200 IU, 400 IU, 600 IU per day to a significantly higher level of 2,000 IU to 4,000 IU per day, Norman said.

“There is a conundrum. How can a physician of a government recommend major increases in vitamin D intake, without appropriate evidence-based research studies on very large groups, for example, 2,000 IU for 3 to 5 years, to ensure safety?” Norman said.

Shaker said the higher doses that are now often recommended could have unpredicted adverse effects over the long run. Unselected use of these much higher doses may be based on over-interpretation of the literature, as well as some of the recent information in the lay press about vitamin D.

“Clearly, long-term, controlled clinical trials with vitamin D would be useful in determining the benefits of vitamin D on multiple outcomes, as well as determining any possible adverse effects,” Shaker said. “Such studies may require a large number of patients followed for a long period of time.”

VITAL and future trials are expected to provide this information, according to Manson.

As for the results of the high-dose falls study, Lundblad said the main concern is that it may lead to reluctance on the part of some clinicians to aggressively treat low vitamin D levels.

“The study does, however, highlight the need for prospective, randomized studies to reveal unanticipated consequences. The biological and biochemical consequences of high-dose therapy are unclear but, possibly, are related to high levels of vitamin D achieved transiently in this experiment,” Lundblad said.

“If reproducible, we might rethink our strategy of relatively high-dose episodic administration in favor of lower daily dosing,” Lundblad concluded.

The bottom line, according to Kleerekoper, is to be careful of the currently available epidemiological evidence.

As he said in a slide presentation provided to Endocrine Today, “Our patients find all the new hot stuff in their morning newspapers, the TV or their BlackBerry before you do. Neither they nor we can put these ‘new’ data into perspective; almost always you can find conflicting conclusions. Nonetheless, we need to be aware of all of this and, even though our time is our most precious commodity, we need to take the time to keep up to date on these late-breaking health care statistics.” – by Angelo Milone

For more information:

• Sanders KM. JAMA. 2010;303:1815-1822.

A recent study showed negative effects of vitamin D supplementation, contradicting previous studies. Could the benefits of vitamin D be overstated?