Editor’s note: This is a response by Dr William Grant to a paper recently published in the journal Nature Reviews Endocrinology, titled “Common misconceptions about vitamin D-implications for clinicians.”
The perspective on vitamin D by Rosen and Taylor1 defends the Institute of Medicine’s recommendations on vitamin D. According to http://www.ncbi.nlm.nih.gov/pubmed/, there have been 7891 publications with vitamin D in the title or abstract published since its posting date, but not acknowledged by Rosen and Taylor. This correspondence responds to some of the claims by these authors.
Claim #1: The potential for reverse causality exists. That may be the case for cross-sectional studies but not for case-control or cohort studies. For example, the observed reduction of breast and colorectal cancer decreases linearly with increasing follow-up time after blood draw,2 implying that serum 25-hydroxyvitamin D [25(OH)D] levels are unaffected by the existence of cancer at the time of diagnosis.
Claim #2: There is no clear dose-response relation between vitamin D and non-skeletal health conditions. There are serum 25(OH)D level-disease incidence rate relations for breast and colorectal cancer3 and cardiovascular disease4 based on observational studies.
Claim #3: A causal link between vitamin D and cancer has not been established. Hill’s criteria for causality can be used here. A review in 2009 concluded that the evidence that vitamin D reduced the risk of several types of cancer including breast and colorectal cancer largely satisfied Hill’s criteria.5 A recent review found that evidence regarding breast cancer has strengthened.6 Also, there is mounting evidence that higher serum 25(OH)D levels are associated with improved survival rates after diagnosis of cancer.7
Claim #4: Some cancers have an increase in prevalence with increasing serum 25(OH)D levels. That claim is based on limited studies from China, Sweden, and the U.S. (Ref. 13 in Ref. 1). One such cancer is pancreatic cancer. A recent study in the U.S. found a significant inverse correlation between serum 25(OH)D level and risk of pancreatic cancer,8 and pancreatic cancer is one of approximately 20 types of cancer for which solar ultraviolet-B doses are associated with reduced risk.9
Claim #5: Vitamin D supplementation has not been shown to prevent infections. A recent meta-analysis of nine low-bias-risk randomized controlled trials and respiratory tract infections found a summary odds ratio of 0.64 (95% confidence interval, 0.49-0.84).10
Claim #6: Preliminary reports indicate the possibility of a U-shaped risk curve with increased risk starting around 75-125 nmol/l. Two recent studies of frailty status among the elderly in the U.S. suggest that vitamin D supplementation after diagnosis of osteoporosis may explain such findings: for men there was a linear inverse relation between serum 25(OH)D level and frailty status,11 while for women, there was a U-shaped relation.12
Claim #7: Vitamin D does not affect risk of pre-eclampsia. See Ref. 13, a recent systematic review and meta-analysis on vitamin D and pre-eclampsia.
Claim #8: Vitamin D requirements for pregnant women are not higher than nonpregnant women. This statement has been countered by the randomized controlled trials of vitamin D during pregnancy in South Carolina, which found that 4000 IU/d vitamin D3 was required in order to raise serum 1,25-dihydroxyvitamin D levels to optimal.14 1,25-dihydroxyvitamin D affects expression of hundreds of genes, which is very important during fetal development.
- Rosen CJ, Taylor CL. Common misconceptions about vitamin D-implications for clinicians. Nat. Rev. Endocrinol. 9, 434–843 (2013)
- Grant WB. Effect of interval between serum draw and follow-up period on relative risk of cancer incidence with respect to 25-hydroxyvitamin D level; implications for meta-analyses and setting vitamin D guidelines. Dermatoendocrinol. 3, 199–204 (2011)
- Grant WB. Relation between prediagnostic serum 25-hydroxyvitamin D level and incidence of breast, colorectal, and other cancers. J. Photochem. Photobiol. B. 101, 130–136 (2010)
- Grant WB. An estimate of the global reduction in mortality rates through doubling vitamin D levels. Eur. J. Clin. Nutr. 65, 1016–1026 (2011).
- Grant WB. How strong is the evidence that solar ultraviolet B and vitamin D reduce the risk of cancer? An examination using Hill’s criteria for causality. Dermatoendocrinol. 1, 17–24 (2009).
- Mohr SB, et al. Does the evidence for an inverse relationship between serum vitamin D status and breast cancer risk satisfy the Hill criteria? Dermatoendocrin. 4, 152–157 (2012)
- Grant WB, Peiris AN. Differences in vitamin D status may account for unexplained disparities in cancer survival rates between African and White Americans. Dermatoendocrinol. 4, 85–94 (2012).
- Wolpin BM, et al. Plasma 25-hydroxyvitamin D and risk of pancreatic cancer. Cancer Epidemiol. Biomarkers Prev. 21, 82–91 (2012).
- Grant WB. A review of evidence that ultraviolet-B irradiance and vitamin D reduce risk for cancer. US Endocrinology. 9, 50–54 (2013).
- Bergman P, Lindh AU, Bjorkhem-Bergman L, Lindh JD. Vitamin D and respiratory tract infections: A systematic review and meta-analysis of randomized controlled trials. PLoS One. 8, e65835 (2013).
- Ensrud KE, et al. Circulating 25-hydroxyvitamin D levels and frailty in older men: the osteoporotic fractures in men study. J. Am. Geriatr. Soc. 59, 101–106 (2011).
- Ensrud KE, et al. Circulating 25-hydroxyvitamin D levels and frailty status in older women. J. Clin. Endocrinol. Metab. 95, 5266–5273 (2010).
- Tabesh M, Salehi-Abargouei A, Tabesh M, Esmaillzadeh A. Maternal vitamin D status and risk of pre-eclampsia: A systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 2013 Jun 19. [Epub ahead of print]
- Wagner CL, et al. Health characteristics and outcomes of two randomized vitamin D supplementation trials during pregnancy: A combined analysis. J. Steroid. Biochem. Mol. Biol. 136, 313–320 (2013).