Vitamin D and the landscape for the ideal study design to measure cancer preventive effects

pill-316601_960_720With growing global prosperity, it seems paradoxical that many people worldwide should have a vitamin deficiency. And yet, vitamin D deficiency is a growing public health problem in many countries. Suboptimal vitamin D levels, defined as below 50nmol/L, have been found in as many as 60% of people in European countries [1] and 42% in the US [2]. Vitamin D deficiency has also been a growing concern in some Middle Eastern and Asian countries due to cultural or religious beliefs [3]. Across ages, races, and locations, there is evidence that the prevalence of low vitamin D is increasing globally [4, 5].

Vitamin D can be obtained from fatty fish as well as fortified cereals and dairy products.  However, the majority of bioavailable vitamin D comes from sun exposure. Since industrialization, office work has taken precedence over farming and agriculture; indoor gyms and shopping malls have replaced leisure time spent outdoors. The observations of local physicians Mellanby and McCollum among children with rickets in the mid-1800s during the European industrial revolution have reinforced this theory [3]. As the modern lifespan extends to cancer and chronic-disease-reaching ages, epidemiologists have observed numerous potential health consequences due to vitamin D deficiency later in life as well.

The link between inadequate vitamin D levels and cancer is not new. Ecological studies found associations between residential latitude and several cancers, such as colorectal, breast, and prostate cancers [6, 7]. Theoretically, the less vitamin D a person gets from shorter sunlight hours, the higher the cancer risk. This idea is also consistent with biological knowledge. Vitamin D could inhibit uncontrolled cell growth, particularly because the active form of vitamin D–25-hydroxyvitamin D (or calcidiol) – has antioxidant properties and is produced locally by several tissues [8].

These ecological studies only examine populations as a whole and are not able to adjust for confounding factors that might be associated with both vitamin D and cancer risk, such as race, general state of health, or individual variation in serum

25-hydroxyviatmin D. Although randomized control trials have lent some support to the associations, the trials consisted of many patients with low baseline vitamin D levels and, further, involved supplementation of vitamin D [9].  Some did not measure baseline vitamin D at all [10, 11]. By design, randomized control trials cannot measure the preventive effects of consistent and adequate vitamin D levels acquired naturally and maintained long-term. Conversely, prospective observational studies are able to observe long-term 25-hydroxyvitamin levels. However, these studies suffer from causation issues similar to other observational studies. In addition, these associations have been studied for mostly common cancers—breast, prostate, and colorectal cancers—and have inconsistent findings [9, 12, 13].  To complicate matters further, 25-hydroxyvitamin levels may be influenced by a host of factors also related to cancer, including physical activity and obesity, and variations in measurement techniques.

In a recent study, J-S Ong and colleagues [14] measured genetic variants associated with low serum 25-hydroxyvitamin D, and their effect on ovarian cancer, a relatively uncommon although lethal cancer with 46% five-year survival in the US [15]. For each genetically predicted 20nmol/L decrease in 25-hydroxyvitamin D, overall ovarian cancer risk was estimated to increase by 27%. These results, if true, have important implications for ovarian cancer prevention.

In addition to providing new evidence for a potential protective effect of vitamin D and ovarian cancer, this study mirrors a recent Mendelian randomization study in which a similar effect was observed for multiple sclerosis [16]. However, a lot of questions remain. These include: 1) are there other non-causal explanations for these genetic findings for a protective effect of vitamin D on ovarian cancer? 2) if causal, is there evidence of a threshold effect on vitamin D levels?  3) can we observe similar effects for other cancers, and other chronic diseases? and 4) what would be an adequate size of a randomized trial needed in order to identify similar effects for a relatively rare cancer?

Optimal serum 25-hydroxyvitamin D (25[OH]D or calcidiol) concentrations needed to prevent cancer and maintain general health have yet to reach scientific consensus. The Institute of Medicine, a component of the US National Academy of Sciences, recommends maintaining serum 25-hydroxyvitaminD levels between 50 to 100 nmol/L to avoid overall health risks [17]. However, many countries provide recommendations specific to their own populations or subpopulations, with wide heterogeneity. Part of the hesitation to establish official vitamin D recommendations lies in the fact that the effects of long-term supplemental vitamin D remain unknown.  Although rare, it is possible to achieve vitamin D toxicity through excessive supplemental intake. Until consistent data on the effects of vitamin D and cancer are available, the safest way to stay within a healthy range of vitamin D levels is to use judicious sun exposure, and maintain a balanced diet.

 

References

[1] Cashman KD, Dowling Kg, Skrabakova Z, Gonzalez-Gross M, Valtuena J, De Henauw S, et al. Vitamin D deficiency in Europe: pandemic? Am J Clin Nutr. 2016 Apr;103(4):1033-44. doi: 10.3945/ajcn.115.120873.

[2] Forrest KY, Stuhldreher WL. Prevalence and correlates of vitamin D deficiency in US adults. Nutr Res. 2011 Jan;31(1):48-54.

[3] Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences.  Am J Clin Nutr.  2008. vol. 87 no. 4 1080S-1086S.

[4] Hyppönen E, Power C.  Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors. Am J Clin Nutr. 2007;85(3):860.

[5] Mithal A, Wahl DA, Bonjour JP, Burckhardt P, Dawson-Hughes B, Eisman JA, et al. Global vitamin D status and determinants of hypovitaminosis D. Osteoporos Int. 2009;20(11):1807.

[6] Grant WB. An ecologic study of cancer mortality rates in Spain with respect to indices of solar UVB irradiance and smoking. Int J Cancer 2007; 120(5): 1123-1128

[7] Boscoe FP, Schymura MJ. Solar ultraviolet-B exposure and cancer incidence and mortality in the United States, 1993-2002. BMC Cancer 2006; 6:264. 264

[8] IARC. Vitamin D and Cancer. IARC Working Group Reports Vol.5, International Agency for research on Cancer, Lyon, 25 November 2008. https://www.iarc.fr/en/publications/pdfs-online/wrk/wrk5/Report_VitD.pdf [Accessed: Oct 23, 2016].

[9] Wactawski-Wende J, Kotchen JM, Anderson GL, Assaf AR, Brunner RL, O’Sullivan MJ, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006; 354(7): 684-696.

[10] Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ 2003; 326(7387): 469.

[11] Autier P, Gandini S. Vitamin D Supplementation and Total Mortality: A Meta-analysis of Randomized Controlled Trials. Arch Intern Med 2007;167(16): 1730-7.

[12] Li H, Stampfer MJ, Hollis JB, Mucci LA, Gaziano JM, Hunter D, Giovannucci EL, Ma J. A Prospective Study of Plasma Vitamin D Metabolites, Vitamin D Receptor Polymorphisms, and Prostate Cancer. PLoS Med JID – 101231360 EDAT- 2007/03/29 09:00 MHDA- 2007/03/29 09:00 PHST- 2006/09/12 [received] PHST- 2007/01/24 [accepted] AID – 06-PLME-RA-0688R2 [pii] AID – 10 1371/journal pmed 0040103 [doi] PST – aheadofprint 2007; 4(3): e103.

[13] Bertone-Johnson ER, Chen WY, Holick MF, Hollis BW, Colditz GA, Willett WC, Hankinson SE. Plasma 25- hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 2005; 14(8): 1991-1997.

[14] Ong S-J, Cuellar-Partida G, Lu Y, Australian Ovarian Cancer Study, Fasching PA, Hein A, et al.  Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study.  Int J Epidemiol. 2016 Sep 4. pii: dyw207.

[15] SEER Cancer Statistics Factsheets: Ovarian Cancer. National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/statfacts/html/ovary.html [Accessed Oct 25, 2016].

[16] Rhead B, Bäärnhielm M, Gianfrancesco M, Mok A, Shao X, Quach H, et al. Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk. Neurol Genet. 2016 Sep 13;2(5):e97. doi: 10.1212/NXG.0000000000000097.

[17] Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy Press, 2010.

 

 

 

Dana Hashim

Dana Hashim

Dana Hashim is a visiting scientist of the Genetics Section at IARC, and is collaborating in EPIC studies.  Her research focuses on identifying modifiable risk factors involved in cancers and preventing or reducing carcinogenic exposure circumstances.

Research Interests: Cancer etiology and prevention
Dana Hashim

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