Curr Nutr Rep (2012) 1:24–29
DOI 10.1007/s13668-011-0005-8
CANCER (MF LEITZMANN, SECTION EDITOR)
Vitamin D and Cancer Prevention
Hajo Zeeb
Published online: 17 January 2012
# Springer Science+Business Media, LLC 2012
Abstract Vitamin D and its potential role in the prevention of cancer have received widespread attention in
recent years. A broad range of potential vitamin D–
related mechanisms affecting carcinogenesis have been
identified. Epidemiology now provides evidence for a
cancer protective role of elevated levels of serum vitamin D, particularly for colorectal cancer, and less clearly for
breast cancer, while for many other cancers, including cancer
of the prostate, no associations have been demonstrated. There
continues to be a gap between results from observational trials
assessing vitamin D status and those from randomized trials of
vitamin D supplementation that cannot be resolved easily.
However, whether new randomized trials on vitamin D and
cancer development should be conducted in the future remains
debatable.
Keywords Vitamin D . Ultraviolet light . Supplementation .
Cancer . Prevention . Epidemiology . Case–control study .
Cohort study . Randomized controlled trial . Colorectal
cancer . Breast cancer . Prostate cancer
Introduction
Evidence linking vitamin D (25[OH] cholecalciferol) (25
[OH] vitamin D) to cancer risk has been accumulating
over many decades. Scientific approaches from a variety
of disciplines, including major contributions from cancer
H. Zeeb (*)
BIPS—Institute for Epidemiology and Prevention Research,
Achterstr. 30,
D-28359 Bremen, Germany
e-mail: zeeb@bips.uni-bremen.de
epidemiology, are used in this research field. Geographical
correlation, or ecological studies played a major role in
the initial scientific discussion on vitamin D. The early
ecological studies were conducted in the United States
and provided evidence indicative of a north–south gradient in the risk of specific cancers. This prompted the
hypothesis of a protective influence of vitamin D levels,
modulated by the amount of average solar irradiation,
on the risk of cancer at various sites, and also for other
chronic conditions, such as cardiovascular and neurological diseases. UV irradiation, on the other hand, is wellknown for its carcinogenic potential with regard to skin
cancer—an effect not associated with vitamin D.
Vitamin D is necessary for human survival and has wellestablished supportive influences on bone formation and the
neuromuscular system, mainly through its effect on calcium
metabolism. Other functional properties of 25(OH) vitamin
D and the physiologically active form, 1α,25(OH)2 vitamin
D, include anticarcinogenic and anti–cell proliferative
effects established in the laboratory. Vitamin D is synthesized through a chain of processes initiated by UV irradiation of the skin. In addition, there are food sources of
vitamin D, as well as nutritional supplements and pharmaceutical preparations containing vitamin D. Some controversy exists as to the optimal serum levels of vitamin D, and
these levels may well differ depending on the health outcome of interest [1].
This paper gives an overview of the physiology and
characteristics of vitamin D, describes current data on vitamin D levels in various populations, and then examines the
evidence from epidemiologic studies on vitamin D and
cancer, with a focus on recent observational studies in large
populations. The main theme of this paper is thus the question of whether high serum levels of vitamin D are associated with lower risks of cancer.
Curr Nutr Rep (2012) 1:24–29
Vitamin D
UVB skin exposure is the main source of vitamin D for most
people, with foods such as fish and dairy products or vitamin D supplements providing the remainder. Some
countries allow vitamin D food fortification. Skin exposure
to UVB light photoisomerizes 7-dehydrocholesterol, a precursor substance, which leads to production of vitamin D3
(Fig. 1). In turn, vitamin D3 is metabolized to 25(OH)
vitamin D in the liver and is stored or released into the
bloodstream. The concentration of 25(OH) vitamin D serves
as a biomarker for the vitamin D status of individuals. The
kidney produces the biologically active form, 1α,25(OH)2
vitamin D.
A well-established function of the physiologically active
form of vitamin D is the maintenance of calcium (and
phosphorus) homeostasis by influencing both the intestinal
uptake and the urinary excretion in the kidney. Both mechanisms aid in the mineralization of bones as well as in the
functioning of neuromuscular processes. Because the calcium level in the body may only vary within a narrow range
before problems, including muscular symptoms or, more
severely, cardiac arrhythmias may occur, there is a finely
tuned interplay with parathyroid hormone that ensures that
Fig. 1 Sources, sites, and
processing of vitamin D
metabolites. GI,
gastrointestinal. (From Zhang
and Naughton [5]; redrawn
with permission)
25
low calcium serum levels are increased through several
mechanisms, including increased transformation of inactive
into active 1α,25(OH)2 vitamin D [2].
With regard to cancer prevention, there is a growing body
of literature linking in particular the active form of vitamin
D to various aspects of cell proliferation and differentiation
[3]. Most of these mechanisms have thus far only been
established in vitro. The exact mechanisms concerning, for
example, the inhibition of cell proliferation are under investigation and may vary between different types of tumors.
However, current understanding includes direct regulation
of genes responsible for cell proliferation as well as actions
of vitamin D on growth-stimulating factors such as insulinlike growth factor (IGF), for example, through increased
synthesis of IGF-binding protein. Other putative actions of
vitamin D, including activation of immune responses and
anti-inflammatory effects, are under investigation.
Of particular interest with respect to potential antineoplastic properties of vitamin D is the finding that most cells,
including many cancer cells, carry vitamin D receptors
(VDR), thus making them targets for actions of vitamin D.
VDR is a hormone receptor that, once activated through
binding of the active form of vitamin D, exerts influence
on gene regulation such that the expression of target genes is
26
altered. VDR gene polymorphisms have been investigated
in connection with numerous cancer sites, and although
there is ample conflicting evidence, there are some indications of an association of VDR polymorphisms with, among
others, breast and prostate cancer risk [4].
Population Vitamin D Levels
To understand the comparisons done in epidemiologic and
clinical studies on vitamin D and cancer and the actual
serum vitamin D levels studied, some knowledge on vitamin
D serum levels in populations is required. Clinical vitamin
D deficiency with 25(OH) vitamin D levels on the order of
25 nmol/L (10 ng/mL) or less leads to diseases such as
osteomalacia and rickets. Serum levels below 50 nmol/L
are common and are particularly prevalent in older adult
populations and those at high latitude receiving limited
hours of sufficient sunlight [5]. For the United States, recent
representative data from the National Health and Nutrition
Examination Survey (NHANES) mortality study indicate
that 31.5% of participants had concentrations between 20
and 50 nmol/L, 42.5% had concentrations between 50 and
75 nmol/L, and 26% were found with levels of 75 nmol/L or
greater. There are major variations with regard to ethnicity,
gender, and other aspects, such as regular sun exposure and
vitamin D intake through normal diet or supplements [6]. A
recent US study estimated the vitamin D levels that children
obtain from their usual sun exposure. According to this
study, Caucasian children in northern US states could reach
the recommended level of 600 IU/d of vitamin D3 in spring
and summer only if they were not using sunscreen with the
recommended sun protection factor of 15 or more [7]; for
children with darker skin types, reaching recommended
levels is even more difficult. In Germany, a national survey
from 1998 showed that more than 50% of adult survey
participants of both genders had levels below 50 nmol/L
[8]; levels above 75 nmol/L were found in only 7% of
migrant children, compared with 13% in the non-migrant
population in a recent representative nationwide children
and adolescent health survey [9]. However, whether vitamin
D levels in the range above 30 nmol/L but below 50 or even
75 nmol/L are a matter of health concern is under some
dispute [10, 11].
Evidence on Vitamin D and Cancer
Historically, initial considerations on the possible link between UV radiation exposure and cancer were derived from
geographical correlation, or ecological studies. This type of
study is based on aggregated data. Cancer incidence or
mortality rates are compared between different regions,
Curr Nutr Rep (2012) 1:24–29
counties, or provinces. Differences and trends in rates are
investigated according to estimated solar radiation exposure
of the areas, which differs according to latitude. Thus, the
common feature of these studies is the absence of information on individual sun exposure and, more specifically,
vitamin D levels.
In the United States, a marked north–south gradient, with
incidence and mortality rates for colon cancer declining
toward more southern states, was reported in 1980 by Garland and Garland [12]. Increasing levels of average UV
radiation, and thus presumed vitamin D levels in the population, have been interpreted as potential explanations for
these lower cancer rates. Similar studies have been conducted in other regions of the world, and suggestive evidence for associations between high solar irradiation and
multiple cancer sites was presented [13]. In Europe, associations opposite to those from the US studies have been
found for some cancers, with the highest cancer rates in
countries with the highest reported average vitamin D serum
levels. Incidentally, the situation with regard to the geographical distribution of vitamin D levels in Europe appears
to be quite different from that in the United States, as
populations in northern European countries have higher
vitamin D levels than people living in southern Europe.
Nutritional differences such as the more frequent consumption of fish are probably the reason for this observation, but
other differences, including sun-seeking behavior, use of
supplements, and other factors, may play a role. Thus, it
appears obvious that lower vitamin D levels and increasing
latitude do not generally equate, and other cancer risk factors also vary with latitude. Ecological studies are limited in
taking account of these potential confounding factors and
suffer from further difficulties, although methodologic
advances, including much more detailed exposure assessment from meteorological data and approaches to confounder
control, have been implemented [14]. These studies may be
useful for guidance in hypothesis development as well as for
cross-checking the plausibility of other studies, but they cannot provide a basis for causal inference.
Colorectal Cancer and Colon Adenoma
Colorectal cancer and colonic adenomas as precursors of
colon cancer have been studied extensively for a potential
association with low vitamin D levels, and evidence from
many high-quality studies continues to accumulate in favor
of a causal link.
In a 2008 summary report by the International Agency
for Research on Cancer [2], joint analyses of the risk estimates from published cohort and case–control studies documented an inverse relationship between 25(OH) vitamin D
levels and colon carcinoma, as well as adenoma of the
Curr Nutr Rep (2012) 1:24–29
colon. For colorectal cancer, there was a 15% risk reduction
(relative risk [RR], 0.85 [95% CI, 0.79–0.91]) for each 25nmol/L increase in measured serum vitamin D level. The
risk reduction was slightly less strong for adenoma (RR,
0.93 [95% CI, 0.88–0.99]).
Two more recent overviews yielded similar findings, with
an indication that the risk of rectal cancer is more strongly
affected than the risk of colon cancer [15, 16]. For rectal
cancer, a 59% risk reduction associated with an increase of
50 nmol/L of 25(OH) vitamin D was reported from this
meta-analysis of prospective studies, and a 22% reduction
for colon cancer was reported. A less marked effect of
vitamin D (6% reduction of colorectal cancer risk) was
reported from another large meta-analysis. Data from 60 observational studies were analyzed, and whereas vitamin D
associations with colorectal cancer risk were of small magnitude, a marked risk reduction (up to 45%) associated with
intake of calcium was reported [16]. All in all, results from
observational studies on colon adenoma and colorectal cancer
clearly suggest a protective role of high vitamin D levels.
These observational study results, however, are not supported by results from intervention trials on vitamin D
supplementation. One of the largest studies to date is the
Women’s Health Initiative, a randomized, double-blind,
placebo-controlled, multicenter study. More than 18,000
women receiving 10 μg (400 IU) of vitamin D3 and
1,000 mg of elemental calcium daily over an average of
7 years did not show reduced colorectal cancer risk as
compared with women receiving placebo [17]. Extensive
sensitivity analyses left the main results unchanged. Although
the study was reported to be adequately powered to detect a
22% risk reduction, the duration of 7 years was criticized as
too short to allow firm conclusions to be drawn about the
development of colorectal cancer. However, in a nested case–
control study, cases identified during the trials were found to
have significantly lower baseline vitamin D levels compared
with controls, with a 2.5-fold risk increase in the lowest
vitamin D level quartile (<31 nmol/L) as compared with the
highest quartile (>58 nmol/L).
Breast Cancer
Laboratory studies underline the ability of high levels of
vitamin D to suppress carcinogenesis directly in mammary
tissue, and the mechanistic pathways were recently
reviewed [18•]. In terms of epidemiology, breast cancer
and its relationship to vitamin D have been studied in
observational as well as randomized trials; however, the
results were less consistent when compared with those for
colorectal cancer. In a 4-year randomized clinical trial involving 1,179 women in Nebraska, the secondary outcome
was all cancers, about one third of which were breast
27
cancers. Women in the intervention arm received a relatively
high dose of 27.5 μg (1,100 IU) of vitamin D in combination with calcium. An inverse association between vitamin
D and cancer, with 33% risk reduction for every 25-nmol/L
increase in serum vitamin D level, was reported. Due to
small numbers, no separate results for breast cancer were
reported [19]. Uncertain compliance as well as issues regarding the statistical approach were discussed as problems
involved with this trial [2], and the baseline vitamin D levels
in control and intervention groups—above 70 nmol/L—
were noted to be rather high. Specific results for breast
cancer from the Women’s Health Initiative trial (see above)
after 7 years were negative, and the nested case–control
study showed no differences between baseline vitamin D
serum levels in case–control comparisons [20]. Several new
randomized supplementation trials are currently under way.
Comprehensive meta-analyses of observational and clinical studies point to a modest reduction in breast cancer risk
associated with higher levels of serum vitamin D. A recent
report found a 27% risk reduction in the joint analysis of
case–control studies [21]. However, the risk reduction was
largely confined to case–control studies that measured serum vitamin D levels after diagnosis, whereas for case–
control studies nested in cohorts with vitamin D measurements many years before diagnosis, the reduction was weak
and nonsignificant. Chen et al. [22] also reported significant
inverse relationships between both vitamin D intake and
serum levels of vitamin D and breast cancer risk from a
pooled analysis of 11 studies, but no associations for the
studies relating circulating levels of the biologically active
1,25(OH)2 vitamin D levels to breast cancer risk. In separate
analyses, cohort and case–control studies yielded slightly
different results. A significant risk reduction in the highest
quartile of vitamin D intake was only found in the cohorts.
A current comprehensive review of vitamin D and breast
cancer additionally points out that several new cohorts from
Scandinavian and other European countries have failed to
show an association between vitamin D and breast cancer
risk [23••]. Thus, the question of a vitamin D–breast cancer
link appears still partly unresolved, and efforts to obtain
more evidence from high-quality observational and perhaps
intervention trials are warranted.
Prostate Cancer
Prostate cancer is one of the most common cancers in men,
and its etiology remains largely unclear. Ecological studies
have repeatedly pointed out inverse associations between
solar UV levels and prostate cancer risk. Conversely, observational studies generally have not shown protective effects
of vitamin D. A new pooled analysis of 11 studies found no
associations between vitamin D and prostate cancer risk (RR
28
per 25-nmol/L increase, 0.99 [95% CI, 0.95–1.03]) [24].
Similar null results were obtained in an even more extensive
systematic review and meta-analysis [25•], which also included a recent study nested in the randomized, placebocontrolled Prostate Cancer Prevention Trial. This study also
showed no association between risk of prostate cancer and
intake of vitamin D or any other nutrient [26]. Current
epidemiologic evidence thus does not support a link between vitamin D and prostate cancer. There is at least one
reason for caution, however: all available studies focus on
vitamin D serum levels or vitamin D intake in adulthood.
Whether vitamin D levels in childhood or adolescence are
important for prostate cancer risk late in life cannot be
assessed from current studies.
Other Cancer Sites
Many other cancers have been investigated with regard to
vitamin D. A major initiative to collect and jointly analyze
the evidence on rarer cancers is the Vitamin D Pooling
Project of Rarer Cancers (VDPP) [27, 28]. Ten cohorts from
heterogeneous populations were pooled to conduct studies
on seven cancer types, including gastric, pancreatic, and
kidney cancer, as well as non-Hodgkin’s lymphoma. Overall, there was no association between serum vitamin D
levels and any of the cancers. For pancreatic cancer, very
high levels of vitamin D (> 100 mmol/L) seemed to increase
risk by a factor of two [29].
Vitamin D for Cancer Patients
Beyond the question of a primary preventive role of vitamin
D, the question of whether vitamin D is useful for cancer
patients with regard to reducing recurrence and mortality
has also received attention recently [30, 31]. A small body
of evidence suggests that low serum vitamin D levels may
be predictive of a worse outcome in some cancers; however,
much more research will be needed to inform clinical practice. For prostate cancer, several interventions trials have not
shown any benefit of vitamin D supplementation. A joint
analysis of data from three studies found no improved
survival for supplement users; major heterogeneity between
the trials was noted [30].
Conclusions
The interest in vitamin D as a potential chemopreventive
agent in cancer prevention has virtually exploded during the
past decade. This can be interpreted as a late response by the
scientific community to early reports by Garland and
Curr Nutr Rep (2012) 1:24–29
Garland [12], who were the first to point out a potential role
for vitamin D in colorectal cancer prevention. Prevention
studies have moved from ecological approaches to analytical observational trials and in some cases to randomized
intervention studies, and from studies attempting to quantify
vitamin D intake to investigations relying on serum measurements. On the other hand, there is a continuous flow of
new findings from experimental studies showing a myriad of
potential mechanisms through which vitamin D and its metabolites could play a role in cancer development. As can be
expected in such a rapidly developing research arena, there is
conflicting evidence with regard to many of the issues under
investigation, but some consistency begins to emerge.
First, based on the accumulating evidence from many
different observational studies, colorectal cancer and adenoma of the colon are strong candidates for a preventive role of
high levels of vitamin D. The one missing piece of support
relates to intervention trials, which have not shown the same
effects as the observational trials. Although this may be
related to the individual characteristics of the available
trials, Gandini et al. [24] proposed an alternative line of
thought—that the vitamin D level may be indicative of the
propensity of an individual to develop colorectal cancer
rather than being a cause in itself. Lifestyle factors, including smoking, physical activity, and nutrition, would be
associated with this propensity. An improved scientific understanding of the conflicting observations is likely to be
achieved only through new studies or data obtained from
extending the existing longitudinal studies.
Second, for other cancers, the evidence on the preventive
potential of vitamin D is less convincing. The second-best
candidate is breast cancer, but if a risk reduction exists, it
may be of lower magnitude than that for colorectal cancer.
Prostate cancer studies, on the other hand, have resulted in
null findings in the majority of cases. This includes the use
of vitamin D supplementation for prostate cancer patients.
Similarly, the search for a causal role of vitamin D levels in
other, rarer cancers has not yielded results that strongly
indicate preventive potential. For some authors, however,
the reliance on randomized trials or analytical observational
studies seems unwarranted, as they consider evidence from
geographical correlation studies sufficient to recommend a
general increase in vitamin D levels for cancer prevention
and reduction of overall mortality [32]. Thus far, however,
many scientists remain cautious regarding changed recommendations on vitamin D levels. The well-known harms of
increased exposure to UVB as one way of increasing vitamin
D levels further complicate matters [33].
In summary, vitamin D, the “sunshine vitamin,” continues to be an interesting topic for cancer prevention studies,
and no doubt new molecular pathways and mechanisms will
be identified that contribute to an improved understanding
of vitamin D action. Are large-scale randomized trials the
Curr Nutr Rep (2012) 1:24–29
only way to provide more conclusive answers on vitamin D
in cancer prevention? Although the idea is scientifically
intriguing, caution is warranted given the costs and the
restricted scope of randomized clinical trials [28]. Finally,
in considering the importance of vitamin D for health, its
effects on other health end points and on overall mortality
also should be included in a comprehensive assessment.
Disclosure No potential conflicts of interest relevant to this article
were reported.
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