If I had a clinically isolated syndrome with MRI diagnostic of MS, I would take vitamin D 10,000 IU daily: No
Mult Scler February 2013 vol. 19 no. 2 140-142
Caroline Papeix, Catherine Lubetzki
Université Pierre et Marie Curie AP-HP, France
Catherine Lubetzki, Department of Neurology, Pitié-Salpêtrière Hospital, 75013 Paris, France. Email: catherine.lubetzki at psl.aphp.fr
We see MS professionals, with a lot a stake to keep the status quo (note the conflict of interest section) valiently state why vitamin D has not yet been absolutely proven, and can never be absolutely proven to help MS (people in the placebo group can get vitamin D from food and sun).
There are several opinions in the same publication which state that 10,000 IU of vitamin D SHOULD be given, but the publisher keeps those opinions behind a $32 paywall. Interesting.
Vitamin D supplementation, which was initially restricted to the field of bone mineralisation, has recently emerged as a potentially promising treatment in a variety of domains, such as auto-immune diseases, cancer and diabetes.1 In multiple sclerosis (MS), a beneficial effect of vitamin D has been recently suggested by epidemiological2 and genetic3 studies, and related to its general impact on immune function.4 Are these interesting data sufficient to advise MS or clinically isolated syndrome (CIS) patients to take vitamin D? We believe that conclusive demonstration of the efficacy in MS is still missing, and that the links between 25OH vitamin D intake, vitamin D status, and neurologic outcome remain hypothetical.
In several recent association studies, a significant negative correlation was reported between vitamin D serum level and relapse rate in relapsing–remitting (RR) MS patients,5⇓⇓–8 leading to the assumption of a causal relationship between those two variables. In paediatric MS, a retrospective study of 110 patients 9 showed that every 10 ng/ml increase in serum vitamin D3 level was associated with a 34% decrease in the rate of subsequent relapses. Concerning disability level, two cross-sectional studies, including 136 and 267 MS patients, respectively,10,5 revealed an inverse association between vitamin D serum level and degree of disability.
These studies, however, failed to consider important confounders such as body mass index, season, vitamin D binding protein concentration and affinity.11 In addition, the influence of daily life activity on vitamin D level, i.e. that permanently disabled patients usually restrict their outdoor activities, and therefore their exposure to the sun, was not taken into account. Other concerns are the different vitamin D assays currently available, and standardisation is still an unmet need.
An early publication12 reported in 1986 that vitamin D supplementation for two years was associated with a 50% decrease in the number of relapses, but this uncontrolled study included only 10 patients. Since then, several randomised phase 2 studies have evaluated the influence of vitamin D supplementation on disease activity. These studies, in which most but not all patients were on immunomodulators, have all been negative concerning clinical endpoints. The study by Kampman et al.13 of 68 MS patients showed no difference in clinical outcome at 96 weeks. The study reported by Burton et al.14 of 49 patients treated during one year showed a decrease in the relapse rate in the vitamin D group (−41% vs −17% in the control group), but this trend was not significant. The one-year trial conducted by Shaygannejad et al. of 50 RRMS patients15 did not show any significant difference in Expanded Disability Status Scale (EDSS) and relapse rates. Although it is important to take into account that these studies differed in the dose of vitamin D used, the study by Stein et al.16 failed to detect any beneficial effect of high versus low doses of vitamin D supplementation on clinical relapses. These negative results can certainly be related to the small size of these phase 2 studies, not allowing for the detection of a clinical effect. Concerning studies with magnetic resonance imaging (MRI) endpoints, however, one single, double-blind, placebo-controlled, randomised study including 66 MS patients showed a positive impact of vitamin D supplementation, with fewer new T2 lesions and a significantly lower number of T1 enhancing lesions after one year.17 In contrast, two other controlled studies of 68 and 62 MS patients failed to demonstrate a significant effect on MRI endpoints.18,13
Controlled phase 3 studies of vitamin D supplementation in MS are needed. These studies, however, will face a general problem shared with studies of vitamin D in other health domains. Indeed, the vitamin D intake in the “placebo” group depends on the patients’ daily diet and metabolism. Given the major difficulty of measuring vitamin D content in food, assessment of dietary exposure is a challenge. Moreover, response to supplemental vitamin D is likely to be different depending on diverse population groups, such as women of reproductive age and dark-skinned individuals. These limitations are major pitfalls for creating homogenous trial groups. In this respect, it is striking to see that, even for bone mineral density, no good evidence exists for an effect of supplemental vitamin D, independent of calcium, phosphate and other nutrients.11 Concerning adverse events, although rare cases of hypercalcaemia have been reported with daily intake of vitamin D and calcium,19 the safety profile of vitamin D is very good. One has to keep in mind, however, that these safety data derive mostly from short-term studies, and that non-skeletal effects of long-term treatments, such as soft-tissue calcification and aortic calcifications, should be clarified.
Although genetic and epidemiological data are interesting, available evidence supporting vitamin D supplementation in MS is still lacking. We believe that vitamin D supplementation should be proposed, as for any drug-based therapy, only when sufficient evidence of efficacy has been gathered. If all MS patients receive vitamin D because “it might be useful, and it is not harmful”, then it will not be possible to demonstrate either efficacy or lack of efficacy. As stated above, however, such late-phase studies face particular methodological challenges. There is a need to improve dietary assessment methods and to take into account key confounders before initiating such late-phase studies.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest Caroline Papeix reports consulting fees from Roche, Novartis, Sanofi Aventis, Genzyme and Teva Pharma; lecture fees from Merck Serono, Biogen Idec, Sanofi Aventis and Teva, Novartis and Genzyme; and participation in clinical trials for Biogen Idec, Novartis, Merck Serono, Bayer-Schering, Sanofi Aventis, Teva Pharma, Genzyme and Roche.
Catherine Lubetzki reports consulting fees from Roche, Novartis, Sanofi Aventis and Teva Pharma; lecture fees from Merck Serono, Biogen Idec, Sanofi Aventis and Teva; and participation in clinical trials for Biogen Idec, Novartis, Merck Serono, Bayer-Schering, Sanofi Aventis, Teva Pharma, Genzyme and Roche.
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