JNCI | Editorials 1563
Affiliations of authors: Nutritional Sciences Research Group, National
Cancer Institute, National Institutes of Health, Bethesda, MD (CDD); Office of
Dietary Supplements, National Institutes of Health, Bethesda, MD (JTD);
School of Medicine and Friedman School of Nutrition Science and Policy,
Tufts University, Boston, MA (JTD) .
Correspondence to: Johanna T. Dwyer, DSc, RD, NIH, Office of Dietary
Supplements, 6100 Exec Blvd, MSC7517 Room 3B01, Bethesda, MD 20892
( e-mail: Dwyerj1@od.nih.gov .)
Published by Oxford University Press 2007.
Although vitamin D is best known for its role in strengthening
bone and preventing rickets, it is increasingly apparent that it may
have beneficial health effects beyond the skeletal system, among
them perhaps the prevention of a number of diseases, including
cancer ( 1 ). These health effects have been the focus of two recent
National Institutes of Health – sponsored conferences ( 2 , 3 ) and a
number of reviews ( 4 – 6 ).
Could vitamin D also have a role in decreasing total mortal-
ity? A meta-analysis by Autier and Gandini ( 7 ) of 18 randomized
clinical trials of supplemental intakes of vitamin D found a 7%
reduction in total mortality from any cause (RR = 0.93, 95%
confi dence interval [CI] = 0.87 to 0.99). Supplement intakes in
those studies generally ranged from 400 to 800 IU/day, which is
within the range recommended by the Institute of Medicine ’ s
Food and Nutrition Board – – up to 2000 IU/day. In this issue of
the Journal, Freedman et al. ( 8 ), using data from the National
Health and Nutrition Examination Study (NHANES III) of
1988 – 1992 with a 6- to 12-year follow up, found no differences
in total cancer mortality by serum 25-hydroxy vitamin D
[25(OH)D] levels but an intriguing difference in colon and pos-
sibly breast cancer mortality by baseline vitamin D status.
Individuals with 25(OH)D levels of 80 nmol/L or more had a
72% lower risk of colon cancer mortality (95% CI = 0.11 to 0.68)
compared with individuals whose 25(OH)D levels were less than
50 nmol/L ( P trend <.02).
Evidence from diverse sources, including in vitro, animal, eco-
logic, and epidemiologic studies, suggests a role for vitamin D in
decreasing colorectal cancer incidence ( 9 – 13 ). In a recent meta-
analysis of studies that prospectively examined serum 25(OH)D
levels in relation to colorectal cancer, individuals with 25(OH)D
concentrations of 82 nmol/L or more had a 50% lower incidence
of colorectal cancer than those with 25(OH)D of 30 nmol/L or less
( 13 ). However, in the Women’s Health Initiative (WHI) study
vitamin D and calcium supplementation trial, daily supplementa-
tion of 18 176 women with 1000 mg calcium and 400 IU vitamin D
for an average of 7 years was not associated with an altered risk of
colorectal cancer ( 14 ). Possible explanations for the overall null
effects could be that participants were allowed to take additional
vitamin D supplements on their own, participants already had
higher mean intake of vitamin D than the reported national aver-
age, and adherence was only approximately 65%. In contrast, a
nested case – control study within the WHI found that lower base-
line serum 25(OH)D levels were associated with an increased risk
of colorectal cancer ( 14 ). Similarly, a recent pooled analysis from
the Health Professional Follow-Up Study and the Nurses’ Health
Study found that higher plasma 25(OH)D levels were statistically
signifi cantly associated with a decreased risk of colorectal cancer
( 15 ). The study by Freedman et al. ( 8 ) expands these observations
and suggests that vitamin D status is associated with decreased
colorectal cancer mortality.
There are many plausible biological mechanisms that might
mediate the association of vitamin D with reduced mortality from
colorectal cancer. 1,25(OH)D plays an important role in the regu-
lation of many cellular processes associated with carcinogenesis,
including differentiation, proliferation, and apoptosis. Moreover,
normal colonic cells, as well as malignant human cancer cell
samples, contain 25(OH)D-hydroxylase (CYP27B1), the enzyme
that converts 25(OH)D to the active metabolite 1,25(OH) 2 D ( 16 ).
These cells also possess the vitamin D receptor gene. Therefore,
serum concentrations of 25(OH)D may be indicative of colonic
exposure to 1,25(OH)D.
If vitamin D has effects on colorectal cancer, they are not likely
to occur in isolation; rather, they may be modifi ed by other dietary
factors and energy balance. For example, vitamin D status is
related to body mass index, body fatness, and physical activity ( Fig.
1 ). In several studies, including NHANES III, both obesity and
low physical activity have been associated with lower levels of
serum 25(OH)D ( 17 ). Body fat is a storage site for vitamin D in
humans, although the exact mechanism whereby higher body fat
results in lower 25(OH)D is not known defi nitively ( 17 ). Moreover,
both obesity and low physical activity have been linked to increased
colorectal cancer risk ( 18 – 20 ). It is unknown whether the increased
risk of colon cancer with obesity and low physical activity is medi-
ated through decreased 25(OH)D levels. Thus, while serum
25(OH)D is a marker of vitamin D exposure, it may also be a
marker of other risk factors for colorectal cancer, such as high
body mass index levels, low physical activity levels, or perhaps a
preexisting cancer that independently caused low 25(OH)D levels.
Vitamin D should not be investigated in isolation because many
other nutritional factors (e.g., high intakes of alcohol and fat,
especially animal fat and processed meats, and low intakes of vege-
tables, calcium, fi ber, folic acid, and selenium) are also associated
with colorectal cancer risk.
In contrast to the results on colorectal cancer mortality,
Freedman et al. ( 8 ) did not observe an association between
25(OH)D levels and total cancer mortality. It is unknown if or
when during the carcinogenic process vitamin D might be most
The “Sunshine Vitamin”: Benefits Beyond Bone?
Cindy D . Davis , Johanna T . Dwyer
JNCI Journal of the National Cancer Institute Advance Access published October 30, 2007
1564 Editorials | JNCI Vol. 99, Issue 21 | November 7, 2007
benefi cial and if the potential benefi cial effects may vary by the
specifi c type of cancer. If the benefi t of vitamin D is to prevent
or slow the progression of cancer in its early stages and if some
cancers have a latency of many decades for incidence, or even
longer for mortality endpoints, the determination of cancer
mortality in the 6- to 12-year period after assessment of vitamin D
status may have been insuffi cient to demonstrate an effect.
However, it is also possible that the potential benefi cial effect of
improved vitamin D status on colon cancer is stronger than for
other cancers or that the study was limited by the small number
of other cancer deaths. For example, even for lung cancer, the
most common cause of cancer mortality in this cohort, only 153
deaths occurred. However, in a larger study of 447 patients with
early stage non – small-cell lung cancer, higher circulating
25(OH)D was associated with increased survival (adjusted haz-
ard ratio for mortality = 0.45; 95% CI = 0.24 to 0.82) for the
highest versus lowest quartile of 25(OH)D ( 21 ). Similarly, in
15 166 patients with lung cancer, mortality was 15% lower
in patients diagnosed during autumn than in those diagnosed in
winter, suggesting that a high level of sun-induced 25(OH)D
offers a survival advantage for lung cancer patients ( 22 ).
Although these studies suggest that higher vitamin D status may
decrease lung cancer mortality, it is important to note that both
of these studies examined survival in patients with diagnosed
lung cancer. In contrast, the study by Freedman et al. ( 8 ) exam-
ined the role of vitamin D status on cancer mortality in presum-
ably healthy individuals.
The study by Freedman et al. ( 8 ) has several strengths. It used
NHANES III, which is a population-based survey, to assess the
health and nutritional status of noninstitutionalized individuals.
This cohort is somewhat more representative of race/ethnicity,
sex and income of US adult noninstitutionalized populations than
many of the other large cohorts, making it useful for examining
these differences and for hypothesis testing. NHANES III overs-
ampled non-Hispanic blacks and Mexican Americans, groups
thought to be at increased risk for many cancers. In addition,
vitamin D nutriture was assessed by using both a single 24-hour
dietary recall (which is problematic, since a single day’s intake
does not capture usual intakes) ( 23 ) and serum 25(OH)D, a marker
of vitamin D nutritional status that also accounts for vitamin D
synthesis from the pro-vitamin in the skin under the infl uence of
sunlight ( 24 ).
There are also some limitations with the use of the NHANES
III cohort. NHANES III was a cross-sectional study that identi-
fi ed associations but not causation. Residual confounding is a
particular problem in this study owing to peculiarities in
NHANES sampling that may have affected both measures of
vitamin D exposure and outcomes. Season and latitude, both
related to 25(OH)D levels, were linked in the dataset. That is,
data were collected in southern latitudes in the cooler months of
November through March (winter/lower latitude) and in the
more northerly latitudes in warmer months (April – October)
(summer/higher latitude). The 25(OH)D levels were determined
on blood samples obtained only at one time point, and thus they
may not have been representative of long-term chronic levels of
25(OH)D concentrations, nor would they refl ect the nadir of
25(OH)D reached during the year. There also might be fewer
lower 25(OH)D levels in the summer/higher latitude sample than
would be the case if all subjects had been examined in the winter.
This is a cause of concern because in Norway the maximal level
of 25(OH)D is reached between the months of July and September
and it is 20% – 120% higher than the corresponding winter value,
suggesting that season of diagnosis is a predictor of colon cancer
survival ( 25 , 26 ).
From the research perspective, continued exploration of the
effects of vitamin D beyond those on bone itself is warranted.
The behavior of serum 25(OH)D levels as a biomarker of
exposure, including what dietary vitamin D intakes are associ-
ated with various 25(OH)D levels and how these change from
season to season, needs further attention. For example, are
those who have low 25(OH)D levels in the summer also the
individuals with low levels in the winter? A better understanding
is also needed of the relationship between skin pigmentation
and the response to UVB radiation in increasing 25(OH)D
The relationship between nutritional factors and colorectal as
well as other cancers is complicated. Therefore, these fi ndings
must be put into the context of total diet and lifestyle. There are
many risk factors other than diet for colorectal cancer, and there
are many possible dietary risk factors other than vitamin D that
have been linked to cancer risk. From the clinical perspective,
based on bone health markers, the Adequate Intake for vitamin D
is 200 IU for adults younger than 50 years, 400 IU for those
between the ages of 50 and 70, and 600 IU for those 71 years and
older. It is recommended that intakes not exceed 2000 IU, the
current safe Upper Level. Whether vitamin D reduces cancer
risks and, if it does, whether these amounts suffi ce are actively
being debated. Randomized clinical trials of the effects of
vitamin D on the incidence of colonic polyps and invasive cancer
are needed. While vitamin D may well have multiple benefi ts
beyond bone, health professionals and the public should not in a
rush to judgment assume that vitamin D is a magic bullet and
consume high amounts of vitamin D. More defi nitive data on
both benefi ts and potential adverse effects of high doses are
Fig. 1. Interrelationship among risk factors for colon cancer.
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JNCI | Editorials 1565
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