ARTICLE IN BRIEF
- ✓ MS incidence was 62 percent lower in white service members with the highest levels of vitamin D, according to a prospective study based on blood samples from seven million military personnel.
An analysis of serum samples from more than seven million US military personnel found young adults with higher levels of circulating 25-hydroxyvitamin D have a significantly lower risk of developing multiple sclerosis.
MS incidence was 62 percent lower in white service members with the highest levels of vitamin D, according to Alberto Ascherio, MD, DrPH, associate professor of medicine at Harvard School of Public Health in Boston. The effect was not observed in blacks or Hispanics, but the authors noted that there were far fewer of them in the sample and darker skin pigmentation acts as a sunscreen, reducing levels of the vitamin arising from the action of sunlight.
The results were reported in the Dec. 20 Journal of the American Medical Association (2006:296:2832–2838). The authors pointed out that other studies have found a multifold increase in the incidence of MS with increasing latitude, both north and south of the equator. Although genetic predisposition contributed to this variation, they wrote, the change in MS risk with migration among people of common ancestry strongly supports a role for environmental factors, including vitamin D.
“This is the first large-scale prospective case-control study where samples in young adults have been measured and later compared with incidence of MS,” Dr. Ascherio told Neurology Today in a telephone interview. “If the findings can be confirmed, it suggests that many cases of MS might be prevented by increasing levels of vitamin D with supplements.”
The Department of Defense Serum Depository is “a unique resource” for researchers, he said, because it contains such a large number of samples. Dr. Ascherio noted, however, that it will be difficult to replicate the findings on such a large scale.
The researchers identified 257 confirmed MS cases in samples collected from active-duty personnel in the US Army, Navy, and Marines between 1992 and 2004, and each case was matched with a control subject by race or ethnicity, gender, and the date and location of samples. Vitamin D levels were established by averaging two blood samples collected before the onset of MS symptoms. The subjects were divided into five categories based on vitamin D levels, and odds ratios were compared. MS incidence was significantly lower in samples from 148 white subjects with the highest circulating levels of vitamin D and more than 99.1 nmol/L vitamin D. With the lowest category as a reference point (less than 63 nmol/L), the odds ratio for each subsequent group was 0.57, 0.57, 0.74, and 0.38, with a 59.5 percent confidence interval (0.36–0.97).
The inverse relationship was especially strong in samples collected from people 20 years old and younger, suggesting that vitamin D exposure before age 20 could be particularly important, Dr. Ascherio said. Because it is difficult to attain the higher serum levels observed in the study with sunlight or diet alone, vitamin D supplements are likely to be the only way to achieve the suggested protective benefit for most persons, he added.
“The study's findings are not meant to be conclusive; they're intended to point researchers in a specific direction,” Dr. Ascherio said. “We need to consider a large randomized trial to further explore the possible protective role of vitamin D against MS.”
“We are talking to other researchers about this,” he continued, “but such a trial will take a network of participants across the country, if not the world. It will be expensive, but if the results hold up, this could have a major impact on public health with regard to the disease.”
While the results seem to indicate a direct role for vitamin D in MS prevention, other possible explanations should be considered, Dr. Ascherio said. Exposure to ultraviolet light might contribute some other protection other than vitamin D production. Prior data on lower MS rates in women taking vitamin D supplements, however, appear to support a specific role (Neurology 2004;62:60–65), he said.
SUPPLEMENTS POSE QUESTIONS
The Institute of Medicine's current “adequate intake” of the vitamin is 200 IU daily for adults under 50 years, and the highest safe dose is set at 2,000 IU.
Currently the FDA's recommended daily allowance of vitamin D is 400 IU, far too low to provide the benefits suggested in the highest group of subjects with the lowest rates of MS, noted Dr. Ascherio.
“There was little difference in incidence below 60 nmol/L,” Dr. Ascherio added. “All subjects had levels above 100. But you can increase serum levels by about 40 nmol/L by taking 2,000 IUs daily, the upper limit of what is considered safe. I would say 10,000 IUs daily for five years would be needed to get the benefits we observed in the cohort, but we won't know until more studies are done.”
High-dose vitamin D supplementation is controversial because of concerns about toxicity, hypercalciuria, and kidney stones. However, data about these risks are scarce.
“A broad recommendation for a several-fold increase … among adolescents and young adults requires stronger evidence that that provided by observational studies alone,” he noted. He added that until randomized trials of higher supplementation levels have been performed, use of supplements should not be considered for prevention of MS.
“This is a unique study because the availability of serum samples before [disease onset] is without parallel,” commented George C. Ebers, MD, professor and former chair of clinical neurology at the University of Oxford in the UK, in an e-mail.
Dr. Ebers, director of the Wellcome Trust Centre for Human Genetics, has collaborated with Dr. Ascherio in the past, but was not involved in the new study.
“There are no data on place of residence early in life when MS risk seems to be established, so this suggests that MS might be prevented with higher levels of vitamin D later in life,” he noted.
“I suspect they were expecting that those who went on to get MS would have had low levels [of vitamin D]; but what they found was that the levels in those who did not develop MS were higher, those getting it were still largely in the normal range.”
He pointed out that the largest determinant of vitamin D levels – the time of year – may not have been adequately controlled for in the study. Nonetheless, he said, the data are interesting and valuable owing to their rarity.
HIGHER DOSES CONSIDERED
Sylvia Christakos, PhD, professor of biochemistry and molecular biology at the University of Medicine and Dentistry of New Jersey in Newark, has studied the molecular action of vitamin D, its metabolism, and role in different diseases for nearly 30 years.
“This is an important study,” she told Neurology Today in a telephone interview. “I suspect it will have a major impact on future prevention research efforts. I'm am especially glad that it was done in such a large sample.”
“Prior to this there was never sufficient power in studies to begin to make recommendations about vitamin D in MS,” she continued, “and almost all of them were done in animal models of encephalomyelitis, which is similar to human MS, but not the same.”
The studies had shown that vitamin D decreases severity and progression of encephalomyelitis in mice, she said, but until now, patient data “have been sparse.”
Dr. Christakos said that the FDA is considering raising the required daily allowance of vitamin D from 400 IU to 800 IU. “I was just at a meeting there and this seems to be coming soon, which I believe is the first step in the right direction. Many people are vitamin D-deficient, and it is becoming increasingly obvious that 400 IU is just not enough.”
Dr. Christakos added that bone and mineral researchers have also concluded that “much higher” vitamin D supplements can be taken for years without adverse consequences.” She said there is a dearth of evidence of adverse events, including hypercalciuria, in adults taking as much as 10,000 units daily (Am J Clin Nutr 2001;73:288–294).
“I think the most important population for treatment will be adolescents, as the paper suggests,” Dr. Christakos said. “It is important for people to become more conscientious about vitamin D supplements, especially in this younger group where the protective benefit appears most pronounced. I doubt that 1,000 units a day would hurt.”