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

[Guest guest]

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<http://www.nejm.org/doi/full/10.1056/NEJMp1102022?query=TOC & #ref1>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<http://www.nejm.org/doi/full/10.1056/NEJMp1102022?query=TOC & #ref1>

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<http://www.nejm.org/doi/full/10.1056/NEJMp1102022?query=TOC & #ref\

2>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<http://www.nejm.org/doi/full/10.1056/NEJMp1102022?query=TOC & #ref4>

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<http://www.nejm.org/doi/full/10.1056/NEJMp1102022?query=TOC & #ref1>Thr\

ee

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

table<http://www.nejm.org/action/showImage?doi=10.1056%2FNEJMp1102022 & iid=t01><h\

ttp://www.nejm.org/action/showImage?doi=10.1056%2FNEJMp1102022 & iid=t01>Vitamin

D Supplementation and Total Cancer Incidence: Secondary Analyses from

Randomized Clinical

Trials.).1-3<http://www.nejm.org/doi/full/10.1056/NEJMp1102022?query=TOC & #ref1>

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<http://www.nejm.org/doi/full/10.1056/NEJMp1102022?query=TOC & #ref1>A\

n

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<http://www.nejm.org/doi/full/10.1056/NEJMp1102022?query=TOC & #ref\

1>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 <http://www.nejm.org/doi/full/10.1056/NEJMp1102022?query=TOC & #ref1>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 α-Tocopherol, β-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<http://www.nejm.org/doi/full/10.1056/NEJMp1102022?query=TOC & #ref5>(whi\

ch

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<http://www.nejm.org/doi/full/10.1056/NEJMp1102022?query=TOC & #ref5>\

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<http://www.nejm.org/doi/suppl/10.1056/NEJMp1102022/suppl_file/nejmp1102022\

_disclosures.pdf>provided

by the authors are available with the full text of this article at

NEJM.org.

This article

<http://www.nejm.org/doi/full/10.1056/NEJMp1102022?query=TOC & >(10.1056/NEJMp1102\

022)

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.).

--

Ortiz, MS, RD

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