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Vitamin D: Will ongoing studies provide enough high-quality evidence to assess efficacy in MS?

BY KERRY DOOLEY YOUNG

The conclusions from a recently published meta-analysis of the effects of vitamin D supplementation in people with multiple sclerosis are somewhat disappointing, but not unexpected.

The authors of the Cochrane review concluded that vitamin D is safe at the various doses, formulations, and treatment durations used in the 12 randomized controlled trials that qualified for the review. It remains unclear what effects vitamin D may have on health-related quality of life and fatigue, however.

“Vitamin D has been evaluated in a few small trials providing low- to very low-quality evidence,” Vanitha A. Jagannath, MD, of the American Mission Hospital in Bahrain and her co-authors wrote. “Seven new trials are currently ongoing, and we are hopeful that their findings will contribute better evidence towards informing practice.”

There have been high expectations for determining a clear role for vitamin D, as it’s an inexpensive treatment that poses little risk for MS patients, said Keith Van Haren, MD, a neurologist at Stanford (Calif.) University Medical Center.

Still, this state-of-play update from the Cochrane Review is unlikely to alter clinical practice, said Anthony T. Reder, MD, a neurologist at the University of Chicago. Physicians will continue to advise supplements to patients who have low levels of vitamin D, he said. “Almost all MS patients now are taking vitamin D worldwide. That’s not going to change.”

Previous epidemiological, immunological, and genetic studies have indicated a link between low vitamin D, measured as low blood 25-hydroxyvitamin D levels, and MS. Even without conclusive evidence of direct MS benefit, adequate vitamin D is seen as offering other kinds of protection to people with the disease, specialists said. Maintaining adequate blood levels of this vitamin can aid, for example, in protecting against the bone-thinning disease osteoporosis.

“The aggregate evidence is that it’s quite safe and therefore what have you got to lose?” Dr. Reder said. “There is epidemiologic evidence that if you have a low vitamin D level, you’re more likely to get MS, and you are more likely to have attacks if you do have MS and a low vitamin D level.”

Dr. Reder and other MS specialists applauded the intention of the Cochrane Review, noting research on vitamin D and MS poses particular challenges, as it involves a low-cost treatment sold by many firms and a highly complex disease.

Only big pharmaceutical companies are able to fund trials large enough to prove benefits of treatments when the expected effects are small. With MS and vitamin D, much of the work has been done by individual physicians relying on grant money, said Rebecca Spain, MD, a specialist in multiple sclerosis at Oregon Health & Science University and the Portland VA Medical Center.

“To do a really well-designed trial, that’s very expensive,” Dr. Spain said. “You’re not likely to find a funder who is going to do a really high quality randomized controlled trial that keeps all of the other factors consistent.”

The trials highlighted in the Cochrane Review, were not large enough to generate definitive conclusions. The size of the patient population in the key studies ranged from 23 participants to 232 participants per study.

“These are all pretty small trials when it comes to the questions that they are asking, which are big questions,” Dr. Spain said.

Dr. Rebecca Spain on challenges of vitamin D research

Researchers stress that low vitamin D levels would only be one of many factors affecting whether people develop MS and how the disease progresses in different people. Vitamin D has been linked to MS in part due to the prevalence of the disease seen in areas of the world with relatively shorter hours of sunlight, such as the northern United States, Canada, and the northern parts of Western Europe. Stanford’s Van Horn said it may prove difficult to overcome a potential vitamin D role in MS, as it could take effect years before symptoms of the disease appear.

“The genome may be programmed early in life, and the gears may be more stuck in place later in life,” Dr. Van Haren said. “That’s not an answer that anybody wants, because it would be a lot harder to achieve the therapeutic effects that vitamin D status appears to predict.”

It is also possible that genetic variations may allow some people with MS to benefit more from vitamin D supplementation that do others, Dr. Van Haren said. At this point, vitamin D doesn’t appear to be a game changer for MS, but is worth keeping as an add-on.

Dr. Rebecca Spain on genetics and geography in MS risk

“If you have a therapy that provides even a marginal advantage to some or all patients, then you want to weigh that advantage against the risk and the cost of the therapy,” Van Horn said. “In the case of vitamin D, that’s pretty low.”

The dozen trials examined in the Cochrane Review used different doses and formulations of vitamin D. And the results drawn from these studies were mixed as well. Several studies found that vitamin D did not reduce the number of relapses, the authors of the Cochrane paper said. Yet, a 2015 paper said the proportion of study participants judged free of relapse was significantly higher in an arm treated with vitamin D as alfacalcidol than in the comparison arm (89.5% vs 67.1%, respectively; P = 0.007), the review said.

“What they found, in a way, was that there was some evidence,” said Lilyana Amezcua, MD, of the University of Southern California’s Keck School of Medicine. “Not everything was negative, and one of the things that we can say that it was at least not harmful to supplement with vitamin D.”

The National MS Society is funding the Vitamin D to Ameliorate Multiple Sclerosis (VIDAMS) trial that’s being led by Dr. Ellen Mowry at the Johns Hopkins Multiple Sclerosis Center in Baltimore. VIDAMS is a multicenter effort to understand how vitamin D supplementation, along with a standard MS drug, might affect MS progression.

Dr. Rebecca Spain on the right dose of vitamin D in multiple sclerosis

“That one will give us a better answer in terms about vitamin D supplementation as an add-on, and it will also probably give us some information as to how much to supplement,” Dr. Amezcua said. “I’m really looking forward” to the results of that study.

The trial includes about 172 participants, who are taking glatiramer acetate (Copaxone). They have been randomly assigned to take either 600 IU of vitamin D (the current recommended daily allowance) or 5000 IU of vitamin D. The expected end date of this trial, which began in 2012, is 2019, according to the clinicaltrials.gov database. 

People with MS should work with their healthcare professionals to determine whether they need vitamin D supplement and how much they should take, advised Kathleen Costello, MS, ANP-BC, who is the associate vice president for clinical care for the National MS Society.

Ms. Costello said she expects clinicians to continue to urge patients to take vitamin D and that patients should work with them to determine what kind of vitamin D supplementation is useful, and how much vitamin D is appropriate. Patients can err in their own attempts to bolster vitamin D levels, such as taking too low or too high a dose, she cautioned.

“The best intentions may not get them where they need to be,” Ms. Costello said. Healthcare professionals need to measure vitamin D levels and then make a determination as to how much supplementation is needed.

None of the physicians quoted in this story had financial disclosures related to vitamin D.

Source: Jagannath VA, Filippini G, Di Pietrantonj C, Asokan GV, Robak EW, Whamond L, Robinson SA. Vitamin D for the management of multiple sclerosis. Cochrane Database of Systematic Reviews 2018, Issue 9. Art. No.: CD008422. DOI: 10.1002/14651858.CD008422.pub3.