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Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies

BMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g1903 (Published 01 April 2014) Cite this as: BMJ 2014;348:g1903

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Re: Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies

Among other things, the paper by Chowdhury and colleagues reported the results of meta-analyses for cancer-specific incidence and mortality rates with respect to bottom versus top third of baseline 25-hydroxyvitamin D [25(OH)D] levels (Figure 1 and eFigure 2b) [1]. For healthy participants, the relative risk from 12 studies was 1.35 (95% confidence interval, 1.13 to 1.61), while for participants with preexisting cancer, the relative risk from five studies was 1.60 (1.32-1.94). A review of the studies included found that the follow-up time after blood draw ranged from 3.8 to 24 years for the healthy participants' studies and from six to 13 years for the participants with preexisting cancer studies. While there is concern that the longer the follow-up period, the weaker the observed effect of higher 25(OH)D level will be [2], follow-up period did not seem to be an important factor in the meta-analyses. Also, inspection of the studies used for the participants with pre-existing disease did not find an effect related to the tertile ranges.

Interestingly, in one of the studies included, the relative risk of non-vascular disease had two parallel regression lines, one for those with prior disease (range ~1.6 at 40 nmol/L to 1.06 at 80 nmol/L) and one for those with no prior disease (range ~0.99 at 40 nmol/L to 0.65 at 80 nmol/L) [3].

The implication of this finding is that vitamin D has a much stronger impact on survival after development of cancer than in reducing the risk of developing cancer. In fact, this point was made with respect to ecological study findings of cancer incidence and mortality rates in the United States with respect to calculated ultraviolet-B (UVD) doses:
"The relative risks for cancer incidence are similar to those for cancer mortality for most sites. For several sites (breast, colon, rectum, esophagus, other biliary, vulva), the relative risks of mortality are higher, possibly suggesting that the maintenance of adequate vitamin D levels is more critical for limiting tumor progression than for preventing tumor onset." [4].

A similar observation was made in an ecological study of cancer incidence and mortality rates in China with respect to calculated UVB doses:
"Mortality rates for all cancers and cancers of the esophagus, stomach, colon and rectum, liver, lung, breast, and bladder were inversely correlated with ambient UVB. This correlation was present in men and women and rural residents for all these cancers but not urban residents for cancers of the esophagus, colon and rectum and liver. ... Only incidence rates for cancers of the esophagus, stomach, colon and rectum and cervix were inversely correlated with ambient UVB." [5].

It is noted that findings of reduced risk of cancer from ecological studies are much stronger than those of observational studies, in part due to larger numbers of cases, and in part due to the stronger effect of vitamin D on cancer mortality rates than on cancer incidence rates [6, 7].

That vitamin D would exert a more important impact on cancer mortality than cancer incidence is reasonable since there are many risk factors for cancer incidence but only a few natural mechanisms in the body to reduce the progression and metastasis of cancer. Vitamin D can reduce both angiogenesis around tumors, which is important for tumor progression, as well as reduce metastasis [7].

The most important implication of this apparently general finding is that investigating whether higher 25(OH)D levels reduce the incidence of cancer is a much more difficult way to determine the importance of vitamin D in reducing risk of cancer death. Thus, more emphasis should be put on investigating the role of serum 25(OH)D level and vitamin D3 supplementation in increasing survival after diagnosis of cancer. For example, a one-year study of men with low-risk prostate cancer with vitamin D3 supplementation (4000 IU/d) found that "24 of 44 subjects (55%) showed a decrease in the number of positive cores or decrease in Gleason score; five subjects (11%) showed no change; 15 subjects (34%) showed an increase in the number of positive cores or Gleason score" [8].

More emphasis might also be placed on case-control studies of cancer incidence with respect to 25(OH)D levels. There is no evidence that having undiagnosed cancer such as breast or colorectal cancer affects 25(OH)D levels [2] and the 25(OH)D level-breast cancer incidence relation is quite robust based on comparison of findings from six studies from four countries [9].

The inverse association between 25(OH)D levels and poor cancer survival has been found for breast, colorectal, hematologic, lung, and prostate cancer [10]. It has also been suggested that the lower 25(OH)D levels of African Americans (~40 nmol/L) compared to white Americans (~65 nmol/L) explains the 0-50% (mean ~25%) lower survival rate of African Americans after consideration of socioeconomic status, stage at diagnosis, and treatment [11].

One additional thing that would help advance the research on vitamin D and cancer is for vitamin D randomized controlled trials to be designed properly and not on the model appropriate for pharmaceutical drugs. Those trials assume that the agent supplied in the trial is the only source and that there is a linear dose-response relation. Neither assumption is correct for vitamin D. See Heaney [12] for the appropriate guidelines.

After the emphasis changes to investigating the role of vitamin D in cancer survival for both observational studies and randomized controlled trials, hopefully this statement by Daniel Bikle will be retracted: "the clinical studies for most cancers have not yet delivered compelling evidence that the promise from preclinical studies has been fulfilled in the clinic." [13].

References
1. Chowdhury R, Kunutsor S, Vitezova A, Oliver-Williams C, Chowdhury S, Kiefte-de-Jong JC, et al. Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ. 2014;348:g1903.
2. Grant WB. Effect of follow-up time on the relation between prediagnostic serum 25-hydroxyitamin D and all-cause mortality rate. Dermatoendocrinol. 2012;4:198-202.
3. Tomson J, Emberson J, Hill M, Gordon A, Armitage J, Shipley M, et al. Eur Heart J. 2013;34:1365-74.
4. Boscoe FP, Schymura MJ. Solar ultraviolet-B exposure and cancer incidence and mortality in the United States, 1993-2000. BMC Cancer. 2006;6:264.
5. Chen W, Clements M, Rahman B, Zhang S, Qiao Y, Armstrong BK. Relationship between cancer mortality/incidence and ambient ultraviolet B irradiance in China. Cancer Causes Control. 2010;21:1701-9.
6. Grant WB. Ecological studies of the UVB–vitamin D–cancer hypothesis; review. Anticancer Res. 2012;32:223-36.
7. Moukayed M, Grant WB. Molecular link between vitamin D and cancer prevention. Nutrients. 2013;5:3993-4023.
8. Marshall DT, Savage SJ, Garrett-Mayer E, Keane TE, Hollis BW, Horst RL, et al. Vitamin D3 supplementation at 4000 international units per day for one year results in a decrease of positive cores at repeat biopsy in subjects with low-risk prostate cancer under active surveillance. J Clin Endocrinol Metab. 2012;97:2315-24.
9. Grant WB. A review of the evidence regarding the solar ultraviolet-B–vitamin D–cancer hypothesis. Standardy Medyczne/Pediatria. 2012;9:610-9.
10. Robsahm TE, Schwartz GG, Tretli S. The inverse relationship between 25-hydroxyvitamin D and cancer survival: Discussion of causation. Cancers 2013;5:1439-55.
11. Grant WB, Peiris AN. Differences in vitamin D status may account for unexplained disparities in cancer survival rates between African and White Americans. Dermatoendocrinol. 2012;4:85-94.
12. Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014;72:48-54.
13. Bikle DD. Vitamin D and cancer: the promise not yet fulfilled. Endocrine. 2014;46:29-38.

Competing interests: I receive funding from Bio-Tech Pharmacal (Fayetteville, AR), the Sunlight Research Forum (Veldhoven) and the UV Foundation (McLean, VA).

15 April 2014
William B. Grant
Researcher
Sunlight, Nutrition and Health Research Center
PO Box 641603, San Francisco, CA 94164-1603, USA