The Latest Advice on Vitamin D for MS

September 12, 2019

STOCKHOLM ― The recurring question of whether to give MS patients vitamin D supplementation was the subject of one of the first "hot topics" to be debated here at the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2019.

Although the session was structured as a debate with appointed speakers taking "for" and "against" positions, there was a high degree of consensus favoring daily supplementation of low doses of the vitamin.

Summarizing the evidence in favor of the general use of vitamin D supplementation for patients with MS, long-time vitamin D enthusiast Alberto Ascherio, MD, Harvard School of Public Health, Boston, Massachusetts, noted that in the Nurses' Health Study and his own study of 8 million military personnel, there was a strong inverse association of vitamin D levels and risk of developing MS.

Moreover, in the BENEFIT trial, long-term follow-up of patients with clinically isolated syndrome (CIS) showed that high vitamin D levels at the time of diagnosis were associated with reduced risk for new active lesions, reduced disability progression, and less brain volume loss after more than 11 years.

"This is the study that has convinced me that vitamin D is important," he commented.

A small Finnish randomized controlled trial yielded a "strong suggestion" of benefit in supplementing with 20,000 IU of vitamin D per week, or about 3000 IU/day. "That is what I now recommend," Ascherio said. "Unfortunately, that study has not been replicated," he added.

Latest Clinical Trials Disappointing

Taking the "against" position, Joost Smolders, MD, Canisius-Wilhelmina Hospital, Nijmegen, the Netherlands, reported that two recent randomized clinical trials of the use of high-dose vitamin D supplementation in MS patients both failed to reach their primary endpoints.

The SOLAR trial of 14,000 IU daily vs placebo did not show a significant benefit with respect to the number of patients who had no evidence of disease activity at 1 year, but there was a reduction in inflammatory lesions.

The CHOLINE trial, which studied very high doses of vitamin D (100,000 IU every 2 weeks) showed onlya nonsignificant trend toward a lower annualized relapse rate.

"Both these trials did not hit their primary endpoints, although in both, there were some improvements in secondary endpoints," Smolders said. "But it appears that the benefit is more modest than we would have hoped for."

He noted that very high doses of vitamin D have been shown to produce toxicity in mouse models of MS, with all the animals developing hypercalcemia.

"But in the high-dose vitamin D clinical studies, we very carefully monitored all calcium levels, and we did not see any evidence of hypercalcemia," Smolders pointed out. "So there is something different in patients with MS being given vitamin D supplements in the context of a clinical trial and these mice which have been induced with a condition resembling MS," he said.

"In both SOLAR and CHOLINE, we only saw modest benefits ― not substantially different from what has been seen with much lower doses ― so I think we can only recommend low doses," he said.

Ascherio agreed. "I think while there isn't a definite consensus, there is wide support for taking vitamin D supplements in people with MS, but in moderate doses ― about 3000 IU/day. I don't think many people would question that. There is no agreement on the use higher doses, which may be contraindicated in some patients."

Sunlight May Be More Relevant

Smolders cited an Australian study that suggests that exposure to ultraviolet (UV) light appears to be more relevant for MS risk. The association of lower MS risk with higher cumulative doses of UV light was stronger than with vitamin D levels themselves, and UV light has been shown to have independent anti-inflammatory effects, he noted.

Summing up, Ellen Mowry, MD, Johns Hopkins Hospital, Baltimore, Maryland, concluded: "I think we can say fairly conclusively that vitamin levels are inversely associated with MS risk and, in early MS, with both inflammatory activity and brain atrophy. But this may not apply to later stages of MS, and it does not appear to be uniform across all racial groups."

She cited a Kaiser Permanente study from Southern California that showed that low vitamin D levels were linked to MS risk in whites, but no such associations were seen in Hispanics or blacks, although sun exposure was linked to MS risk in all three populations.

Brain Volume Changes

Mowry reported that she and colleagues found that higher levels of vitamin D were associated with a meaningful preservation of normalized gray matter volume in CIS patients. And a new study that was reported this year showed that vitamin D supplementation during demyelinating episodes was associated with less axonal loss.

"But in the EPIC study in patients with later MS, we didn't see an association of vitamin D and with brain volume changes over a 5-year period, so perhaps what we saw in the very early CIS study has different implications to more established MS," she said.

Although the evidence is uncertain, vitamin D supplementation for MS patients has become very popular, Mowry stated. "Clinicians and patients have taken the risk studies and interpreted them for their own benefit.

"There are more randomized studies ongoing, but for now, we are left with the unanswered question. But we are still forced to make a decision when talking to newly diagnosed patients as to whether or not we advocate vitamin D supplementation and at what dose," she commented.

"I talk pretty frankly with my patients about the holes in the data, and while we are waiting for additional evidence, I tend to recommend some modest dose supplementation in people with low levels," she said.

Treat to a Target Window?

Mowry usually treats to a target window typically from 40 – 60 ng/mL. "I think those are the levels most supported by observational data. And that means we are not getting into the serum levels that have been associated with toxicity in animal studies," she said.

Mowry typically recommends doses from 2000 – 5000 IU/day.

She cautioned that MS patients may not metabolize vitamin D as efficiently as healthy individuals, so it is worth checking levels.

"This is a very individualized recommendation. I say to my patients, if you're going to choose between vitamin D supplementation and getting a good night's sleep and eating healthy food and exercising, then I would focus on the broader lifestyle applications, but for now, I continue to recommend modest dose vitamin D supplementation," she said.

Smolders said he agreed with Mowry's recommendations.

"I measure vitamin D levels in all patients at first diagnosis, primarily because it is a prognostic marker. When it is very low ― in ranges that we know compromise bone heath ― then we recommend patients take a supplement. I recommend up to 2000 – 4000 IU a day," he stated.

35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2019: Presented September 11, 2019.

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