vitamin d:multiple sclerosis and dosing in infants

several articles have come out over the past few months on vitamin d. there are a slew of them sent out over the past couple of years in the dropbox, including review articles (eg vit d review nejm 2007, or N Engl J Med 2007;357:266-81) highlighting the vast array of possible important actions of vitamin D in immune function, cancer prevention, heart disease prevention, as well as the better documented effects in bone health and preventing falls in elderly. last year there was an article finding that obese adolescents with low vitamin D had improved insulin sensitivity on repleting vitamin D levels (see vit d and insulin sens adol am j clin nutr 2013 in dropbox, or doi: 10.3945/ajcn.112.050013). here are 3 more articles with more mixed results.

1. large meta-analysis of vitamin d supplementation and bone mineral density/BMD (see vit d and bmd review lancet 2014 in dropbox, or doi.org/10.1016/S0140-6736(13)61647-5). included 23 studies (mean duration 2 yrs, 4082 people, 92% women, average age 59). mean baseline 25-OH vit D was <50 nmol/L (<20 ng/ml) in 8 studies. in general they found not much benefit from vit d supplementation, the only really significant one being in femoral neck BMD, specifically in those with the lowest baseline 25-OH vit D levels and in those supplemented with <800 as opposed to >=800 IU/d.

a couple of issues. there seem to be large individual variations in the physiologic effect of vit D deficiency, with only approx 50% having secondary hyperparathyroidism (none of the studies geared therapy to the hyperPTH group). and, somewhat surprisingly, in this meta-analysis the improvement in BMD was not in the highly cortical bone of the forearm, where hyper PTH has the most osteopenic effect and is the purported mechanism for osteopenia. the authors argue that vitamin D is mostly important for the maintenance of circulating calcium in a specific range, and in fact in high doses can stimulate osteoclastogenesis. it is important to keep in mind that BMD is a surrogate marker, which does not necessarily predict risk of fracture (BMD is a quantitative assessment of bone density, not a qualitative evaluation of its microstructure/strength, and there can be discordance -- eg fluoride increases bone density but actually increases risk of fracture).

it is not easy to reconcile this meta-anal with others. i sent out an email/blog last year on a meta-anal in NEJM (see vit d and fracture prevent nejm 2012 or DOI: 10.1056/NEJMoa1109617) which included 31K people (mean age 76 and 91% women) which found a nonsignificant 10% reduction in risk of hip fracture and a significant 7% reduction in risk of any nonvertebral fracture, with those in the highest vitamin D intake (median 800 IU) having a significant 30% reduction in risk of hip fracture and 14% reduction in risk of any non-vertebral fracture. this result was consistent across age groups, community-dwelling vs in an institution, baseline 25-OH vitD levels, and additional calcium intake, concluding that higher dose vitamin D (>=800IU/d) was "somewhat favorable in prevention of hip fracture and any nonvertebral fracture in persons 65 years of age or older".

2. article in JAMA neurology looked at vitamin d status and progression of multiple sclerosis (see vit d and multiple sclerosis jama 2014, or doi:10.1001/jamaneurol.2013.5993). this study was an intervention study looking at the efficacy of early vs delayed use of b-interferon in pts with clinically isolated syndrome (CIS) to assess progression to clinically definite MS (CDMS) or MS defined by clinical and MRI criteria (MDMS).  in this 5 yr study, they measured 25-OH vit d in the beginning and several points in the study. 400 pts. finding:

            --average 25(OH)D following a CIS strongly associated with MS activity and progression (MRI and clinical) of MS over 4-5 years.

            --those with serum 25(OH)D >50nmol/L (20 ng/ml) had 4x lower change in T2 lesion volume on MRI, 2-fold lower rate of brain atrophy, and lower disability on the Expanded Disability Status Scale (EDSS)

            --and, the above findings were in a population on meds to decrease MS progression/relapse

there have been observational data that low vitamin D levels are associated with development of MS, thought to be related to the vitamin D effects on immune function (there are vit d receptors pretty much everywhere in the body, not just the bone and muscle).  i sent out an article 1-2 years ago which showed improved response to TB meds in a cohort also given vit d supplementation (see vit d and tb treatment pnas 2012 in dropbox, or doi:10.1073/pnas.1200072109/-/DCSupplemental).  but, the current study was an observational component of an intervention trial for b-interferon, and it is limited by inherent biases of observational studies (and those with higher vit D levels in the study tended to be younger, have lower BMI, lower number of T2 lesions on MRI, and higher brain volume when they presented with CIS, though the above results did control for age, sex, treatment time and T2 lesion score)). also almost all white. but at least they looked at patients with very early MS symptoms (independent of vitamin D levels) and looked at clinical/MRI progression. also, no ceiling effect was observed with vit D levels.

3. study done in montreal to assess different doses of vitamin d in breast-fed one-month olds and assess 25(OH)D levels at 3,6,9 and 12 months of age (see vit d infant supplementation jama 2103 in dropbox, or JAMA. 2013;309(17):1785-1792). vitamin D3 doses were 400, 800, 1200, or 1600 units.  current recommendations are 400IU/d supplement in US and Canada, though some countries have higher recs (france and finland recommend ?1000IU/d).  results, assessing 2 different 25(OH)D goals:

    --for the goal of 25(OH)D level >75mmol/L (30ng/ml): at 3 months, 55% in 400IU group, 81% with 800IU, 92% with 1200IU, 100% with 1600 IU.  But not sustained at 12 months in any group, with falloff proportional to dose: about 35% of those on 400IU/d up to 80% in those on 1600 IU/d

    --for the goal of 25(OH)D level >50mmol/L (20ng/ml): essentially all achieved this goal at 3 months and at 12 months.

    --bone mineral content and plasma PTH levels increased over time, while ionized calcium, and urinary calcium/creat ratios declined over time,  but no diff between groups in any of these measures

    --of note, the 1600IU dosage was discontinued during the study because of 25(OH)D levels that were felt to be dangerously high.

so, all in all, seems reasonable to continue with the 400IU recommendation at this point, since by all of the markers noted including bone mineral content, this was as good as higher doses. the real clinical outcome, both for bone and non-bone benefits of vitamin D, will require longer term followup into later childhood. other issues include the applicability of the results of this study to kids of different ethnicities/skin pigmentation, or living at different latitudes.

so, overall, the data on vitamin D remains mixed. my sense, pending large intervention studies, is that there may well be important benefits to correcting vitamin D deficiency (decreased falls in elderly have been documented, but also effects on bone, immunologic function, potentially preventing cancer) outweigh the pretty much insignificant toxicity (except for patients on very high doses)