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Plasma 25-hydroxyvitamin D concentration and subsequent risk of total and site specific cancers in Japanese population: large case-cohort study within Japan Public Health Center-based Prospective Study cohort

BMJ 2018; 360 doi: https://doi.org/10.1136/bmj.k671 (Published 07 March 2018) Cite this as: BMJ 2018;360:k671

The follow-up period between blood draw and cancer incidence was too long to expect significant findings for individual cancers

The prospective study on cancer incidence in Japan with respect to serum 25-hydroxyvitamin D [25(OH)D] concentration at baseline (1) has some interesting findings, but is hampered by two systemic problems: the long follow-up period (15.9-yr median) and the fact that Japan underwent a nutrition transition from the traditional Japanese diet to the Western diet between about 1965 and 1995 (2).

Serum 25(OH)D concentrations change in time due to seasonal variations in solar UVB doses, changes in time spent out of doors, diet, and age. Elderly adults are less efficient at producing vitamin D from UVB exposure due to reduced 7-dehydroxycholesterol in the skin (3). Thus, the longer the follow-up period, the lower the probability that baseline 25(OH)D concentration will be the concentration associated with cancer incidence. This effect has been demonstrated for breast and colorectal cancer (4) and all-cause mortality rate (5).

The effect of the nutrition transition in Japan has been to increase the prevalence of dementia (2) and colorectal cancer (6) with a lag time of about 20 years after the changes. For dementia, rates increased in an approximately linear manner from 1985 to 2008, overlapping significantly with the period of the study in Ref. 1. Thus, dietary changes could have overwhelmed effects of vitamin D for several of the cancers linked to Western diets such as colorectal and breast cancers.

Regarding the statement in the paper, "Despite the strong ecological and experimental animal evidence, however, evidence linking circulating concentration of vitamin D to the overall cancer risk in humans is sparse and inconsistent.", many of the studies referenced were flawed either by long follow-up periods or by poor clinical trial design (7). However, inspection of those with strong designs, there is strong support for the vitamin D-cancer hypothesis. For breast cancer, case-control studies in which 25(OH)D concentration was measured near the time of cancer diagnosis show a strong inverse correlation between 25(OH)D concentration and cancer incidence (4, 8). Breast cancer develops rapidly so that studies with follow-up periods longer than three years seldom find significant inverse correlations. See, also, the pooled analysis of cancer incidence with respect to serum 25(OH)D concentration by McDonnell et al. (9).

Three clinical trials also provide strong support for the vitamin D-cancer hypothesis (10-12). A reanalysis of the Women's Health Initiative found that "In 15,646 women (43%) who were not taking personal calcium or vitamin D supplements at randomization, CaD significantly decreased the risk of total, breast, and invasive breast cancers by 14-20% and nonsignificantly reduced the risk of colorectal cancer by 17%. In women taking personal calcium or vitamin D supplements, CaD did not alter cancer risk (HR: 1.06-1.26)." (8). Since those in the treatment arm were given only 400 IU/d vitamin D3 plus 1000 mg/d calcium, these findings are exactly what would be expected based on the 25(OH)D concentration-breast cancer incidence relationship from case-control studies (7). The recent trial by Lappe et al. (9) in which the treatment group received 2000 IU/d of vitamin D3 and 1500 mg/d of calcium, found, based on intention to treat "A new diagnosis of cancer was confirmed in 109 participants, 45 (3.89%) in the vitamin D3 + calcium group and 64 (5.58%) in the placebo group (difference, 1.69% [95% CI, -0.06% to 3.46%]; P = 0.06)." However, the results of the analysis based on achieved 25(OH)D concentration found that those who achieved concentrations of 130-210 nmol/l had significantly reduced incidence of all-cancer compared to those with <70 nmol/l, as discussed in the online supplement. The authors were not permitted by the journal to discuss this analysis in the printed text since it was not included in the original trial protocol.

References
1. Budhathoki S, Hidaka A, Yamaji T, et al. Plasma 25-hydroxyvitamin D concentration and subsequent risk of total and site specific cancers in Japanese population: large case-cohort study within Japan Public Health Center-based Prospective Study cohort. BMJ. 2018;360:k671.
4. Grant WB. 25-Hydroxyvitamin D and breast cancer, colorectal cancer, and colorectal adenomas: case–control versus nested case–control studies, Anticancer Res. 2015;35(2):1153-60.
2. Grant WB. Trends in diet and Alzheimer’s disease during the nutrition transition in Japan and developing countries. J Alz Dis, 2014;38(3):611-20.
3. MacLaughlin J, Holick MF. Aging decreases the capacity of human skin to produce vitamin D3. J Clin Invest. 1985;76(4):1536-8.
5. Grant WB. Effect of follow-up time on the relation between prediagnostic serum 25-hydroxyitamin D and all-cause mortality rate. Dermatoendocrinol. 2012;4(2):198-202.
6. Kuriki K, Tajima K. The increasing incidence of colorectal cancer and the preventive strategy in Japan. Asian Pac J Cancer Prev. 2006;7(3):495-501.
7. Grant WB, Boucher BJ, Bhattoa, Lahore HJ. Why vitamin D clinical trials should be based on 25-hydroxyvitamin D concentrations. J Steroid Biochem Mol Biol. 2018;177:266-9.
8. Grant WB, Boucher BJ. Randomized controlled trials of vitamin D and cancer incidence: A modeling study. PLos One. 2017;12(5):e0176448.
9. McDonnell SL, Baggerly C, French CB, et al. Serum 25-hydroxyvitamin D concentrations ≥40 ng/ml are associated with >65% lower cancer risk: Pooled analysis of randomized trial and prospective cohort study. PLoS One. 2016;11(4):e0152441.
10. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007;85(6):1586-91.
11. Bolland MJ, Grey A, Gamble GD, Reid IR. Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set. Am J Clin Nutr. 2011;94(4):1144-9.
12. Lappe J, Watson P, Travers-Gustafson D, et al. Effect of vitamin D and calcium supplementation on cancer incidence in older women: A randomized clinical trial. JAMA. 2017;317(12):1234-43.

Competing interests: I receive funding from Bio-Tech Phamacal, Inc. (Fayetteville, AR) and serve on the board of directors of the Vitamin D Council (San Luis Obispo, CA).

22 March 2018
William B. Grant
Researcher
Sunlight, Nutrition and Health Research Center
PO Box 641603, San Francisco, CA 94164-1603