Primary Care Corner with Geoffrey Modest MD: New Vitamin D Articles

vitamin D deficiency has been associated with many different medical conditions noted over the past decade, presumably related to there being vitamin d receptors on almost cell types in the body. in general, vitamin D supplementation has been shown to benefit rickets, fractures and falls (though recent meta-anal did not find consistent positive effect on bone density). there are also strong associations with multiple sclerosis, an array of autoimmune disorders, infections, cardiac disease, and cancer. there has been a slew of posts about vit d, some showing increased insulin sensitivity or improved lipids with vitamin d supplementation, one showing improved response to TB infection by antiTB drugs when simultaneously given vitamin D. the data on vitamin D and risk of non-skeletal diseases, however, is still unclear, and the 2011 endocrine society guidelines clearly recommend vitamin D only for the proven skeletal issues (see doi: 10.1210/jc.2011-0385)

one BMJ article was an umbrella review (systematic collection and eval of info from multiple systematic reviews and meta-analyses on all clinical outcomes assessed) was done of observational studies of associations between circulating vit D levels and clinical outcomes, along with meta-anal of RCTs on supplementation (see here). they assessed 107 reviews and 74 meta-anals, looking at 137 outcomes (!!). results:

–probable associations between high vit D concentrations or supplementation: decrease dental caries in kids, increased newborn birth weight at term, decreased PTH levels in patients with ESRD on dialysis (in contrast to previous reports, they did not find evidence that vitamin d by itself improves bone mineral density or reduces the risk of fracture of falls in older people).
–suggestive health benefits: decreased risk of colorectal ca, non-vertebral fx, cardiovasc dz, htn, ischemic stroke, cognition, depression (from cohort studies), BMI, metabolic syndrome, type 2 diabetes, SGA newborns, gestational diabetes
–no conclusion: a huge list, mostly everything except the above 2 categories (see their Table 6) also impressive associations in their Forest plot as figure 3 (though, these are all from observational studies!!); figure 4 (less impressive) is the RCT review, though most of which had very few participants, which pretty much reflects the “probable associations” point above.

another BMJ article looked at either 25OHD levels or vit D supplementation and cause-specific mortality (see here). results:

–primary prevention observational studies: bottom vs top 1/3 of 25OHD levels (median 25OHD level in was 20.7 ng/ml):

–death from cardiovasc disease: RR 1.35 (1.13-1.61)
–death from cancer: RR 1.14 (1.01-1.29)
–death for non-vascular, non cancer:  RR 1.30 (1.07-1.59)
–all-cause mortality: RR 1.35 (1.22-1.49). there was a dose-response: as compared to people with 25OHD of 30, 21-29 with RR 1.07, 10-20 with RR 1.20, <10 with RR 1.50
–on subgroup analyses in observational studies, mortality higher in studies with lower baseline use of vitamin D supplements

–in RCTs, there were different RRs depending on type of vitamin D supplementation — all-cause mortality with vit D3 (cholecalciferol, from UVB radiation, supplement animal-derived) had RR 0.89 (0.80-0.99) and with vit D2 (ergocalciferol, plant-derived) RR=1.04 (0.97-1.11).
–with vit D2 supplementation, increased RR of mortality in studies with lower intervention doses and shorter average intervention periods. (this could be reverse causation: sicker patients, more likely to die sooner, may get less sun or take fewer supplements and therefore have lower 25OHD levels. also there is a report of patients finding decreased vit d with acute changes in systemic inflammatory response — eg see Am J Clin Nutr 2011;93:1006–11.

so, these studies confirm the many observational studies finding impressive associations between vitamin d levels and several clinical outcomes, including mortality.  but we really need good intervention studies to see if this pans out, or if potential confounders could explain the association (eg shared determinants, such as obesity, medical comorbidities or social status). Their figure 7, which looked at various subgroup analyses, showed a very consistent difference. but the studies do highlight risks, the most consistent being hypercalcemia, esp in the setting of chronic kidney disease.  there are ongoing RCT trials (eg VITAL trial of 26K men and women randomized to 2000 IU vit D3 assessing outcome of cancer, CAD, and stroke — due out in 2017). so, as with pretty much all nutritional studies, observational studies show positive effects of supplements, but the real proof needs big RCTs (though for vitamin d, i do think the observational data are pretty impressive, the basic physiology of having vitamin D receptors being everywhere, the limited data showing positive effects of vitamin D on immunologic function, and the low toxicity/cost of supplementation does make me check/treat low 25OHD levels, though will switch preferentially to D3 supplements given this last study).


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