A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis

Abstract

Objective: Low vitamin D status has been associated with multiple sclerosis (MS) prevalence and risk, but the therapeutic potential of vitamin D in established MS has not been explored. Our aim was to assess the tolerability of high-dose oral vitamin D and its impact on biochemical, immunologic, and clinical outcomes in patients with MS prospectively.Methods: An open-label randomized prospective controlled 52-week trial matched patients with MS for demographic and disease characteristics, with randomization to treatment or control groups. Treatment patients received escalating vitamin D doses up to 40,000 IU/day over 28 weeks to raise serum 25-hydroxyvitamin D [25(OH)D] rapidly and assess tolerability, followed by 10,000 IU/day (12 weeks), and further downtitrated to 0 IU/day. Calcium (1,200 mg/day) was given throughout the trial. Primary endpoints were mean change in serum calcium at each vitamin D dose and a comparison of serum calcium between groups. Secondary endpoints included 25(OH)D and other biochemical measures, immunologic biomarkers, relapse events, and Expanded Disability Status Scale (EDSS) score. Results: Classification of evidence:This trial provides Class II evidence that high-dose vitamin D use for 52 weeks in patients with multiple sclerosis does not significantly increase serum calcium levels when compared to patients not on high-dose supplementation. The trial, however, lacked statistical precision and the design requirements to adequately assess changes in clinical disease measures (relapses and Expanded Disability Status Scale scores), providing only Class level IV evidence for these outcomes. Neurology ® 2010;74:1852-1859 GLOSSARY ALP ϭ alkaline phosphatase; ALT ϭ alanine aminotransferase; AST ϭ aspartate aminotransferase; EAE ϭ experimental autoimmune encephalitis; EDSS ϭ Expanded Disability Status Scale; IL ϭ interleukin; LS ϭ least squares; MMP-9 ϭ matrix metalloproteinase-9; MS ϭ multiple sclerosis; PTH ϭ parathyroid hormone; TCS ϭ T-cell score; TIMP-1 ϭ tissue inhibitory of metalloproteinase-1; TNF␣ ϭ tumor necrosis factor-␣.Multiple sclerosis (MS) has a well-documented geographic distribution, with increasing prevalence and risk with increasing distance from the equator.1-4 Limited sunlight and UVB exposure, MS risk factors based on observational studies, are intermediaries between latitude and MS.2-5 Low serum 25(OH)D also appears to be a risk factor, and is a direct product of skin exposure to UVB. [4][5][6][7] e-Pub ahead of print on April 28, 2010, at www.neurology.org.

Contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis

“…Furthermore, it should be noted that the 'physiological' zone between the 75 and 200 nmol/liter 25-OH-D serum levels grossly corresponds to the serum levels observed in outdoor workers [Haddad and Chyu, 1971;Haddock et al, 1982;Barger-Lux and Heaney, 2002;Azizi et al 2012], as well as in traditionally living populations in East Africa [Luxwolda et al 2012]. This zone is far below the toxic zone, which appears to be located above the 400 nmol/liter serum level [Hathcock et al 2007;Burton et al 2010].…”

Oral supplementation with 25(OH)D3 versus vitamin D3: Effects on 25(OH)D levels, lower extremity function, blood pressure, and markers of innate immunity

“…Estimated linear trends were statistically significant for all markers with the exception of IP-10 for the time interval after day 8 up to day 106. Notably, two previous trials that tested vitamin D with treatment doses of up to 40,000 IU vitamin D 3 per day among patients with multiple sclerosis (MS) (57) and obese patients (58) were not able to demonstrate any significant change in a number of markers of immunity. The difference in results between these trials and our study may be explained by the follow-up time points documented, which included early response only in our trial.…”

Increased incidence of chronic GvHD and CMV disease in patients with vitamin D deficiency before allogeneic stem cell transplantation

“…Several observational studies indicate associations between vitamin D deficiency and disorders of the immune system, such as multiple sclerosis, 33 type 1 diabetes, 34 rheumatoid arthritis 35 and rejection of solid organ allografts. 36 Some studies have also shown beneficial effects of vitamin D supplementation, most notably in the prevention of type 1 diabetes, 37 and amelioration of symptoms of multiple sclerosis by treatment with high dose vitamin D. 38 However, the relevance of these findings is questioned due to the lack of prospective, randomized trials. Such trials are difficult to carry out in diseases with low incidence and slow onset, such as diabetes type 1.…”