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Vitamin D and Prevention of Cancer — Is it ready for Prime Time – March 2011

Vitamin D and Prevention of Cancer — Ready for Prime Time?

JoAnn E. Manson, M.D., Dr.P.H., Susan T. Mayne, Ph.D., and Steven K. Clinton, M.D., Ph.D.
March 23, 2011 (10.1056/NEJMp1102022)

Given that the potential role of vitamin D in cancer prevention has been widely touted, many people were surprised that cancer-related considerations didn't figure prominently in the new Dietary Reference Intakes for vitamin D established by the Institute of Medicine (IOM).1 An IOM committee on which we served, charged with determining the population needs for vitamin D in North America, reviewed the evidence linking vitamin D with both skeletal and nonskeletal health outcomes. The committee concluded that vitamin D plays an important role in bone health and that the evidence provides a sound basis for determining the population's needs. For outcomes beyond bone health, however, including cancer, cardiovascular disease, diabetes, and autoimmune disorders, the evidence was found to be inconsistent and inconclusive as to causality.

Based on vitamin D's importance to bone health, the recommended dietary allowances (RDAs) are 600 IU per day for persons 1 to 70 years of age and 800 IU per day for persons over 70 — intakes corresponding to a serum 25-hydroxyvitamin D level of at least 20 ng per milliliter (50 nmol per liter). Because of wide variation in skin synthesis of vitamin D and the known risks of skin cancer, we derived the RDAs under the assumption that sun exposure would be minimal. The committee also concluded that the prevalence of vitamin D inadequacy in North America has been overestimated. Most North Americans have serum 25-hydroxyvitamin D concentrations above 20 ng per milliliter, which is adequate for bone health in at least 97.5% of the population.1

The committee's comprehensive review of the evidence regarding vitamin D's role in preventing cancer, however, revealed that the research is inconsistent and doesn't establish a cause–effect relationship. Other recent reviews have reached similar conclusions.2,3 No large-scale randomized clinical trial of vitamin D has been completed with cancer as the primary prespecified outcome. Most evidence is derived from laboratory studies, ecologic correlations, and observational investigations of serum 25-hydroxyvitamin D levels in association with cancer outcomes. Although this serum measure is a useful marker of current vitamin D exposure, associational studies have important limitations. Specifically, low serum 25-hydroxyvitamin D levels are also linked with confounding factors related to higher cancer risk, including obesity (vitamin D becomes sequestered in adipose tissue), lack of physical activity (correlated with less time outdoors and less solar exposure), dark skin pigmentation (less skin synthesis of vitamin D in response to sun), and diet or supplementation practices. Reverse-causation bias may also occur if poor health reduces participation in outdoor activities and sun exposure or adversely affects diet, resulting in lower vitamin D levels. Association therefore cannot prove causation. Many micronutrients that seemed promising in observational studies (e.g., beta carotene, vitamins C and E, folic acid, and selenium) were not found to reduce cancer risk in randomized clinical trials, and some were found to cause harm at high doses.4

The theory that vitamin D can help prevent cancer is biologically plausible. The vitamin D receptor is expressed in most tissues. Studies in cell culture and experimental models suggest that calcitriol promotes cell differentiation, inhibits cancer-cell proliferation, and exhibits antiinflammatory, proapoptotic, and antiangiogenic properties. Such findings suggest, but don't prove, that vitamin D has a role in preventing the development of cancer or slowing its progression.

Although several observational studies have linked low serum 25-hydroxyvitamin D levels with increased cancer incidence and mortality, randomized-trial evidence is sparse.1,2 Three vitamin D trials, including one trial comparing a combination of vitamin D with calcium to calcium alone, have assessed the occurrence of newly diagnosed cancers or cancer mortality as secondary outcomes, but the results were null (see tableVitamin D Supplementation and Total Cancer Incidence: Secondary Analyses from Randomized Clinical Trials.).1-3

Regarding breast-cancer risk specifically, three observational cohort studies of plasma 25-hydroxyvitamin D levels had inconsistent results: one small study found an inverse association, one large study found no association, and one large study found no overall trend but an inverse association in one subgroup.1,2 An inverse association observed in crude analyses in one study disappeared after adjustment for body-mass index and physical activity. Only one randomized trial (the Women's Health Initiative WHI trial) was large enough to assess breast cancer as a separate, although secondary, outcome; overall, it showed no significant effect of the intervention on breast-cancer incidence (hazard ratio, 0.96; 95% confidence interval CI, 0.86 to 1.07) or related mortality (hazard ratio, 0.99). After stratifying the study population according to baseline vitamin D intake (diet plus supplements), the investigators found that women with the lowest baseline intakes had a reduced risk of breast cancer with the intervention (hazard ratio, 0.79; 95% CI, 0.65 to 0.97), whereas women with the highest baseline intakes (?600 IU per day) actually had a significantly increased risk (hazard ratio, 1.34; 95% CI, 1.01 to 1.78; P for interaction=0.003).

Observational studies of serum vitamin D levels and colorectal cancer generally support an inverse association.1-3 According to a meta-analysis of prospective data from five studies, subjects with a serum 25-hydroxyvitamin D level of 33 ng per milliliter or higher had about half the risk of colorectal cancer of those with levels of 12 ng per milliliter or lower. The European Prospective Investigation into Cancer and Nutrition study recently reported a similarly strong inverse association. A prospective study from the Japan Public Health Center did not find an inverse relation between plasma 25-hydroxyvitamin D levels and the occurrence of colon cancer, although an inverse association with rectal cancer was apparent. Randomized trial evidence is limited. In a British trial comparing vitamin D3 with placebo, the intervention was not associated with a change in colorectal-cancer incidence (relative risk, 1.02; 95% CI, 0.60 to 1.74). Similarly, in the WHI trial, calcium plus vitamin D3 did not reduce the incidence of colorectal cancer (relative risk, 1.08; 95% CI, 0.86 to 1.34) or related mortality (relative risk, 0.82; 95% CI, 0.52 to 1.29).

Although ecologic studies suggest that mortality due to prostate cancer is inversely related to sun exposure, observational analytic studies of serum 25-hydroxyvitamin D and prostate cancer haven't supported this conclusion.1-3 Eight of 12 nested case–control studies showed no association between baseline serum 25-hydroxyvitamin D levels and prostate-cancer risk, and just 1 showed a significant inverse association; a more recent nested case–control analysis of data from the ?-Tocopherol, ?-Carotene Cancer Prevention Study showed no association. Moreover, a meta-analysis of 45 observational studies of dairy-product intake and prostate-cancer risk showed no significant association with dietary intake of vitamin D. No relevant randomized clinical trials were identified.

The large-scale Cohort Consortium Vitamin D Pooling Project of Rarer Cancers showed no evidence linking higher serum 25-hydroxyvitamin D concentrations to reduced risk of less common cancers, including endometrial, esophageal, gastric, kidney, pancreatic, and ovarian cancers and non-Hodgkin's lymphoma5 (which together account for approximately half of all cancers worldwide). Moreover, the report provided evidence suggestive of a significantly increased risk of pancreatic cancer at high 25-hydroxyvitamin D levels (?40 ng per milliliter).5 An increased risk of esophageal cancer at higher 25-hydroxyvitamin D levels has also been reported.

Despite biologic plausibility and widespread enthusiasm, the IOM committee found that the evidence that vitamin D reduces cancer incidence and related mortality was inconsistent and inconclusive as to causality. New trials assessing moderate-to-high-dose vitamin D supplementation for cancer prevention are in progress and should provide additional information within 5 to 6 years. Although future research may demonstrate clear benefits of vitamin D related to cancer and other nonskeletal health outcomes, and possibly support higher intake requirements, the existing evidence falls short.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article (10.1056/NEJMp1102022) was published on March 23, 2011, at NEJM.org.
Source Information

From the Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston (J.E.M.); the Department of Epidemiology and Public Health, Yale Schools of Public Health and Medicine, New Haven, CT (S.T.M.); the Division of Medical Oncology, Ohio State University, Columbus (S.K.C.); and the Institute of Medicine Committee on Dietary Reference Intakes for Vitamin D and Calcium (J.E.M., S.T.M., S.K.C.).

References

1 Institute of Medicine. Dietary reference intakes for calcium and vitamin D. Washington, DC: National Academies Press, 2011. CLICK HERE
2 Chung M, Balk EM, Brendel M, et al. Vitamin D and calcium: a systematic review of health outcomes. Evidence report no. 183. Rockville, MD: Agency for Healthcare Research and Quality, 2009. (AHRQ publication no. 09-E015.) CLICK HERE
3 International Agency for Research on Cancer. Vitamin D and cancer — a report of the IARC working group on vitamin D. Lyon, France: World Health Organization Press, 2008.
4 Byers T. Anticancer vitamins du jour — the ABCED's so far. Am J Epidemiol 2010;172:1-3 CLICK HERE
5 Helzlsouer KJ. Overview of the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol 2010;172:4-9
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VitaminWiki expects many rebuttal comments on this paper

See also VitaminDWiki


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Following bibliography is from Dr. Grant, March 23, 2011

See his comments and many others by CLICKING HERE

Responses to the Institute of Medicine’s report on vitamin D and calcium along with selected papers that seemed to help steer the IOM’s decision


IOM (Institute of Medicine). 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx

A summary of the IOM report

Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, Kovacs CS, Mayne ST, Rosen CJ, Shapses SA. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011 Jan;96(1):53-8.

Supporting document

Chung, M., Balk, E. M., Brendel, M., Ip, S., Lau, J., Lee, J., et al. (2009). Vitamin D and calcium: a systematic review of health outcomes. Evid Rep Technol Assess (Full Rep)(183), 1-420. (Prepared by Tufts Evidence-based Practice Center under Contract No. 290-2007-10055-I). AHRQ Publication No. 09-E015, Rockville, MD: Agency for Healthcare Research and Quality. August 2009. http://www.ahrq.gov/downloads/pub/evidence/pdf/vitadcal/vitadcal.pdf

Critical responses to the IOM report and those reporting higher vitamin D requirements than in the report

Bischoff-Ferrari, H, Willett W. Comment on the IOM Vitamin D and Calcium Recommendations. For Adult Bone Health, Too Low on Vitamin D—and Too Generous on Calcium. The Nutrition Source. Harvard University, 2011. http://www.hsph.harvard.edu/nutritionsource/what-should-you-eat/vitamin-d-fracture-prevention/
Bosomworth NJ. Mitigating epidemic vitamin D deficiency: The agony of evidence. Can Fam Physician. 2011 Jan;57(1):16-20.
Boucher BJ. The 2010 recommendations of the American Institute of Medicine for daily intakes of vitamin. Public Health Nutrition. 2010 Apr;14(4):740. (see below)
Cannell J. Era or error?, Public Health Nutrition. 2010 Apr;14(4):743. (see below)
Cannell J. The FNB has failed millions. Guest Editorial. Townsend Letter. 2011 Feb/Mar 2011;(331,332):103. http://www.townsendletter.com/FebMarch2011/FebMarch2011.html
Garland CF, French CB, Baggerly LL, Heaney RP. Vitamin D Supplement Doses and Serum 25-hydroxyvitamin D in the Range Associated with Cancer Prevention. Anticancer Res 2011;31: 617-22.
Gillie O. Editorial: Blinded by science, pragmatism forgotten. Public Health Nutrition, 2011 Apr;14(4):566-7. (see below)
Giovannucci E. Vitamin D, how much is enough and how much is too much? Public Health Nutrition. 2011 Apr;14(4):740-1.(see below)
Gorham ED, Garland CF. Vitamin D and the limits of randomized controlled trials. Public Health Nutrition. 2011 Apr;14(4):741-3. (see below)
Grant WB. Additional strong evidence that optimal serum 25(OH)D levels are at least 75 nmol/l. Int J Epi (accepted Mar. 21)
Grant WB. Differences in sunshine duration and vitamin D production may explain much of the English north-south divide in mortality rates. BMJ. Rapid Responses. 21 Feb. 2011. http://www.bmj.com/content/342/bmj.d508/reply#bmj_el_250339
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. Dermato-Endocrinology. In press
Grant WB. Is the Institute of Medicine Report on calcium and vitamin D good science? Biol Res Nurs. 2011 Apr;13(2):117-9. http://brn.sagepub.com/content/early/2011/01/10/1099800410396947.long
Grant WB. Additional strong evidence that optimal serum 25(OH)D levels are at least 75 nmol/l. Int J Epi (accepted Mar. 21)
Heaney RP, Holick MF. Why the IOM recommendations for vitamin D are deficient. J Bone Miner Res. 2011;26(3):455-7.
Heaney RP, Grant WB, Holick MF, Amling M. The IOM Report on Vitamin D Misleads. J Clin Endocrinol Metab. eLetter. (4 March 2011) http://jcem.endojournals.org/cgi/eletters/96/1/53
Heaney RP. Finding the appropriate referent for vitamin D. Public Health Nutrition. 2010 Apr;14(4):749-50.
Holick MF. The D-batable institute of medicine report: a D-lightful perspective. Endocr Pract. 2011 Jan-Feb;17(1):143-9.
Hollis BW, Wagner CL. The vitamin D requirement during human lactation: the facts and IOM's ‘utter’ failure. Public Health Nutrition. 2011 Apr;14(4):748-9. (see below)
Hypponen E, Boucher B. Dietary reference intakes for vitamin D. BMJ Rapid Response. 13 Jan. 2011 http://www.bmj.com/content/341/bmj.c6998/reply#bmj_el_247954?sid=8fe2e3bf-cf21-466e-a3ea-904ffac19269
Katz DL. The Public Health Implications of the 2010 Dietary Guidelines; An Expert Interview With David L. Katz, MD, MPH by Janet Kim, MPH. Feb. 15, 2011. http://www.medscape.com/viewarticle/737342_6
Mark S, Lambert M, Delvin EE, O'Loughlin J, Tremblay A, Gray-Donald K. Higher vitamin D intake is needed to achieve serum 25(OH)D levels greater than 50?nmol/l in Québec youth at high risk of obesity. Eur J Clin Nutr. 2011 Mar 2.
Norman AW, Henry HL. Vitamin D nutritional policy is at a crossroads. Poster presented at American Society of Nutrition conference “Controversies in Clinical Nutrition” San Francisco. February 2011. anthony.norman at ucr.edu
Norman AW. Vitamin D nutritional policy is at a crossroads. Public Health Nutrition,. 2010 Apr;14(4):744-5. (see below)
Roth DE. Vitamin D supplementation during pregnancy: safety considerations in the design and interpretation of clinical trials. J Perinatol. 2011 Jan 20.
Schwalfenberg GK, Whiting SJ. A Canadian response to the 2010 Institute of Medicine vitamin D and calcium guidelines. Public Health Nutrition. 2011 Apr;14(4):746-8. (see below)
Vieth R. Vitamin D nutrient to treat TB begs the prevention question. Lancet. 2011 Jan 15;377(9761):189-90.
Yngve A, Tseng M, Haapala I, McNeill C, Hodge A. Vitamin D. The big D-bate. Public Health Nutrition. 2011 Apr;14(4):565.

CRN REACTS TO INSTITUTE OF MEDICINE; DRI RECOMMENDATIONS FOR VITAMIN D; —Increased DRI, Step In Right Direction Still Falls Short, CRN Says http://www.crnusa.org/CRNPR10_CRNVitDDRIresp113010.html

Society of Integrative Oncology, quoting Kathy Crew, Gregory A. Plotnikoff and Michael Holick http://www.integrativeonc.org/index.php/institute-of-medicine-report-on-vitamin-d

Spreen A. Vitamin D conspiracy leads straight to Big Pharma. 02/19/2011 http://www.healthiertalk.com/vitamin-d-conspiracy-leads-straight-big-pharma-3396

A series of critical letters were published in Public Health Nutrition. Vol 14, issue 4 -the following letters at the bottom are at the end of the issue

You must be registered in the VitaminDWiki to see the letters CLICK HERE

  • The 2010 recommendations of the American Institute of Medicine for daily intakes of vitamin
    • Barbara J. Boucher
  • Vitamin D, how much is enough and how much is too much?
    • Edward Giovannucci
  • Vitamin D and the limits of randomized controlled trials,
    • Edward D. Gorham and Cedric F. Garland
  • Era or error?,
    • John Cannell
  • Vitamin D nutrition is at a crossroads,
    • Anthony W. Norman
  • The Institute of Medicine did not find the vitamin D–cancer link because it ignored UV-B dose studies
    • William B. Grant
  • A Canadian response to the 2010 Institute of Medicine vitamin D and calcium guidelines
    • Gerry K. Schwalfenberg and Susan J. Whiting
  • The vitamin D requirement during human lactation: the facts and IOM's ‘utter’ failure;
    • Bruce W. Hollis and Carol L. Wagner CLICK HERE to see it
  • Finding the appropriate referent for vitamin D,
    • Robert P. Heaney

Example of letter - costs money to get a clean image, but this is what you can see for free

Image

Neutral

D Is for Debate. UC Berkeley Wellness Letter, March, 2011 http://www.wellnessletter.com/html/wl/2011/wlFeatured0311.html

Accepting

Abrams SA. Dietary Guidelines for Calcium and Vitamin D: A New Era. Pediatrics. 2011 Feb 21.
British Association of Dermatologists, Cancer Research UK, Diabetes UK, the Multiple Sclerosis Society, the National Heart Forum, the National Osteoporosis Society and the Primary Care Dermatology Society. Cancer Research UK, December 17 2010 http://info.cancerresearchuk.org/prod_consump/groups/cr_common/@nre/@sun/docume.nts/generalcontent/cr_052628.pdf
Davis CD, Milner JA. Nutrigenomics, Vitamin D and cancer prevention. J Nutrigenet Nutrigenomics. 2011 Mar 23;4(1):1-11.
Editors, J. American Assoc. of Physician’s Assistants. Limited evidence of benefits of vitamin D supplementation. www.jaapa.com • february 2011 • 24(2) • JAAPA E3
Elmets CA. New Institute of Medicine Recommendations on Vitamin D. Journal Watch Dermatology December 17, 2010 http://dermatology.jwatch.org/cgi/content/full/2010/1217/1
Hahne D. Vitamin D: Wenig harte Fakten zur Prävention chronischer Krankheiten. Dtsch Arztebl 2011; 108(9): A-452 / B-364 / C-364 MEDIZINREPORT
Hansen KE. High-Dose Vitamin D: Helpful or Harmful? Curr Rheumatol Rep. 2011 Mar 3.
Khosla S. What do we tell our patients about calcium and vitamin D supplementation? J Clin Endocrinol Metab. 2011 Jan;96(1):69-71. No abstract available.
Linus Pauling Institute http://lpi.oregonstate.edu/infocenter/vitamins/vitaminD/
Manson JE, Mayne ST, Clinton SK. Vitamin D and prevention of cancer—ready for prime time? N Engl J Med. 2011 March 23 epub, 10.1056/nejmp1102022
National Health Service, UK http://www.nhs.uk/news/2010/12December/Pages/sunlight-exposure-and-vitamin-d-advice.aspx
Reid IR, Avenell A. Evidence-based policy on dietary calcium and vitamin D. J Bone Miner Res. 2011;26(3):452-4.
Rosen CJ. Vitamin D insufficiency. N Engl J Med. 2011;364:248-54.
Slomski A. IOM endorses vitamin D, calcium only for bone health, dispels deficiency claims. JAMA. 2011 Feb 2;305(5):453-4, 456.
Stolzenberg-Solomon R, Weinsterein SJ, Helzlsouer K. Three Authors Reply. Am J Epidemiol (2011) 173(4): 476-477.
Tanne JH. Most Americans and Canadians get enough calcium and vitamin D, report says. BMJ 341:doi:10.1136/bmj.c6998 (Published 3 December 2010)

Published prior or independent to the IOM report and responses thereto but bearing on the issues

Abrams SA. What Are the Risks and Benefits to Increasing Dietary Bone Minerals and Vitamin D Intake in Infants and Small Children? Annu Rev Nutr. 2010 Aug 18.
Aloia J, Bojadzievski T, Yusupov E, Shahzad G, Pollack S, Mikhail M, Yeh J. The relative influence of calcium intake and vitamin D status on serum parathyroid hormone and bone turnover biomarkers in a double-blind, placebo-controlled parallel group, longitudinal factorial design. J Clin Endocrinol Metab. 2010 Jul;95(7):3216-24.
Cannell JJ, Hollis BW, Zasloff M, Heaney RP. Diagnosis and treatment of vitamin D deficiency. Expert Opin Pharmacother. 2008 Jan;9(1):107-18.
Grant WB. The UVB-vitamin D-cancer hypothesis is very strong. J Am Dietetic Assoc. 2011 Mar;111(3):365-6. Toner CD, Davis CD, Milner JA. Authors' response. J Am Diet Assoc. 2011 Mar;111(3):366.
Helzlsouer KJ. For the VDPP Steering Committee. Overview of the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epi, 2010 172: 4-9.
Souberbielle JC, Body JJ, Lappe JM, Plebani M, Shoenfeld Y, Wang TJ, et al. Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: Recommendations for clinical practice. Autoimmun Rev. 2010 Sep;9(11):709-15.
Toner CD, Davis CD, Milner JA. The vitamin D and cancer conundrum: Aiming at a moving target. J Am Diet Assoc. 2010 Oct;110(10):1492-1500.


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