Optimizing Vitamin D Supplementation in MS Care

Vitamin D has become biologically compelling and epidemiologically suggestive yet clinically inconsistent in multiple sclerosis (MS) research. In this context, Zhang and colleagues present a meta-analysis that reframes the conversation away from whether vitamin D matters and toward how dosing may shape its clinical relevance, particularly for relapse risk in MS.

Drawing on nine randomized controlled trials (RCTs) encompassing 1,078 patients, this analysis evaluates the relationship between serum vitamin D levels and annualized relapse rate (ARR) while examining disability outcomes and biochemical response to supplementation.

Rather than revisiting well-established MS pathophysiology, the study focuses on mechanisms directly relevant to vitamin D’s proposed role. The active form of vitamin D, 1,25-dihydroxyvitamin D₃, binds the vitamin D receptor (VDR) to influence immune balance by suppressing pro-inflammatory Th17 cell differentiation and the release of pro-inflammatory cytokines, promoting regulatory T cells, and reinforcing blood–brain barrier integrity. These effects offer a biologically plausible link between vitamin D status and inflammatory disease activity, particularly relapse frequency.

Study Design

This study included nine randomized controlled trials published through April 2025, comprising of 1,078 adults with multiple sclerosis, primarily individuals with relapsing-remitting disease or clinically isolated syndrome. Investigators followed participants for a minimum of six months. Vitamin D interventions varied substantially across studies, ranging from low- or medium-dose daily supplementation to high-dose regimens exceeding 10,000 IU per day.

In most trials, participants continued background disease-modifying therapies, enhancing the clinical relevance of the findings. Across these studies, vitamin D supplementation was compared with placebo or lower-dose control interventions, with annualized relapse rate serving as the primary outcome measure. Secondary outcomes included changes in disability, assessed using the Expanded Disability Status Scale, and biochemical response as measured by serum 25-hydroxyvitamin D (25(OH)D) levels. Methodological quality and risk of bias were systematically evaluated using the Cochrane Risk of Bias 2 tool.

Key Findings

Vitamin D supplementation robustly increased serum 25(OH)D levels, regardless of dose. Across four studies, supplementation significantly raised 25(OH)D by a pooled mean difference of 44.97 nmol/L. This confirms that both high- and low/medium-dose regimens are effective at correcting vitamin D deficiency.

Clinical outcomes were more nuanced. When all vitamin D doses were pooled, supplementation did not significantly reduce ARR (mean difference −0.07; p = 0.17), nor did it improve disability as measured by EDSS (mean difference −0.11; p = 0.47). However, dose-stratified analysis told a more interesting story. Low- to medium-dose vitamin D supplementation was associated with a statistically significant reduction in ARR (mean difference −0.14; p = 0.01), whereas high-dose supplementation showed no effect on ARR (mean difference 0.05; p = 0.42).

Interpreting the Outcomes

These results suggest that more is not necessarily better. One plausible explanation is biological saturation; low to moderate vitamin D levels may be sufficient to achieve immunomodulatory effects, while higher doses fail to provide additional benefit, or potentially counterbalance benefit through unmeasured effects. The absence of EDSS improvement is not entirely surprising, given that disability progression reflects long-term neurodegeneration rather than short-term inflammatory activity, and follow-up durations in the included trials ranged from six months to three years.

Why This Matters

For clinicians, this analysis supports a practical, measured approach to vitamin D in MS. Supplementation reliably improves vitamin D status and, at appropriate doses, may modestly reduce relapse risk without influencing short-term disability outcomes. The findings reinforce vitamin D’s role as an adjunct to disease-modifying therapy and highlight the importance of dose optimization over escalation.

Reference
Zhang Y, Yu S, Zu Y, Lv J, Chen J, Feng X. Vitamin D deficiency and multiple sclerosis relapse: a meta-analysis. Front Neurol. 2026;16:1727615. doi:10.3389/fneur.2025.1727615