Optimal Vitamin D Status for Colorectal Cancer Prevention. A Quantitative Meta Analysis
Previous studies, such as the Women's Health Initiative, have shown that a low dose of vitamin D did not protect against colorectal cancer, yet a meta-analysis indicates that a higher dose may reduce its incidence. Five studies of serum 25(OH)D in association with colorectal cancer risk were identified using PubMed. The results of all five serum studies were combined using standard methods for pooled analysis. The pooled results were divided into quintiles with median 25(OH)D values of 6, 16, 22, 27, and 37 ng/mL. Odds ratios were calculated by quintile of the pooled data using Peto's Assumption-Free Method, with the lowest quintile of 25(OH)D as the reference group. A dose-response curve was plotted based on the odds for each quintile of the pooled data. Data were abstracted and analyzed in 2006. Odds ratios for the combined serum 25(OH)D studies, from lowest to highest quintile, were 1.00, 0.82, 0.66, 0.59, and 0.46 (p(trend)<0.0001) for colorectal cancer. According to the DerSimonian-Laird test for homogeneity of pooled data, the studies were homogeneous (chi(2)=1.09, df=4, p=0.90. The pooled odds ratio for the highest quintile versus the lowest was 0.49 (p<0.0001, 95% confidence interval, 0.35-0.68). A 50% lower risk of colorectal cancer was associated with a serum 25(OH)D level > or =33 ng/mL, compared to < or =12 ng/mL. The evidence to date suggests that daily intake of 1000-2000 IU/day of vitamin D(3) could reduce the incidence of colorectal with minimal risk.
Optimal Vitamin D Status for Colorectal
A Quantitative Meta Analysis
Edward D. Gorham, MPH, PhD, Cedric F. Garland, DrPH, Frank C. Garland, PhD, William B. Grant, PhD,
Sharif B. Mohr, MPH, Martin Lipkin, MD, Harold L. Newmark, ScD, Edward Giovannucci, MD, ScD,
Melissa Wei, BS, Michael F. Holick, MD, PhD
Background: Previous studies, such as the Women’s Health Initiative, have shown that a low dose of
vitamin D did not protect against colorectal cancer, yet a meta-analysis indicates that a
higher dose may reduce its incidence.
Methods: Five studies of serum 25(OH)D in association with colorectal cancer risk were identiﬁed
using PubMed. The results of all ﬁve serum studies were combined using standard methods
for pooled analysis. The pooled results were divided into quintiles with median 25(OH)D
values of 6, 16, 22, 27, and 37 ng/mL. Odds ratios were calculated by quintile of the pooled
data using Peto’s Assumption-Free Method, with the lowest quintile of 25(OH)D as the
reference group. A dose–response curve was plotted based on the odds for each quintile of
the pooled data. Data were abstracted and analyzed in 2006.
Results: Odds ratios for the combined serum 25(OH)D studies, from lowest to highest quintile,
were 1.00, 0.82, 0.66, 0.59, and 0.46 (p
!0.0001) for colorectal cancer. According to the
DerSimonian-Laird test for homogeneity of pooled data, the studies were homogeneous
"1.09, df"4, p"0.90. The pooled odds ratio for the highest quintile versus the lowest
was 0.49 (p!0.0001, 95% conﬁdence interval, 0.35– 0.68). A 50% lower risk of colorectal
cancer was associated with a serum 25(OH)D level !33 ng/mL, compared to "12 ng/mL.
Conclusions: The evidence to date suggests that daily intake of 1000 –2000 IU/day of vitamin D
reduce the incidence of colorectal with minimal risk.
(Am J Prev Med 2007;32(3):210–216) © 2007 American Journal of Preventive Medicine
he Women’s Health Initiative
that a low dose of vitamin D did not protect
against colorectal cancer within 7 years of
follow-up; however, a meta-analysis indicates that a
higher dose may reduce its incidence.
There were approximately 145,300 new cases and
56,300 deaths from colorectal cancer in the United
States during 2005.
An observation of higher age-
adjusted mortality rates of colorectal cancer in the
northern and northeastern United States compared to
the southwest, Hawaii, and Florida led to a theory that
vitamin D of mainly solar origin may reduce risk of
through a mechanism involving cal-
cium metabolism, intercellular adherence, and contact
inhibition. Since then, ﬁve observational studies have
explored the association of serum levels of the main
circulating form of vitamin D, 25-hydroxyvitamin D
(25[OH]D) with risk of colorectal cancer.
ever, an overall dose–response gradient for the effect of
serum levels of 25(OH)D on colorectal cancer risk has
not been determined. This meta-analysis provides an
estimated dose–response gradient that may be of help
in planning for a useful role of vitamin D in control of
The PubMed database was searched for the period from
January 1966 to December 2005 by using the terms (“vitamin
From the University of California San Diego, Department of Family
and Preventive Medicine, School of Medicine (Gorham, C.F. Gar-
land, F.C. Garland, Mohr) La Jolla, California; SUNARC-Sunlight,
Nutrition and Health Research Center (Grant), San Francisco,
California; Strang Cancer Prevention Center (Lipkin), New York,
New York; Susan Lehman Cullman Laboratory for Cancer Research,
Rutgers, The State University of New Jersey (Newmark), Piscataway,
New Jersey, and Cancer Institute of New Jersey, New Brunswick, New
Jersey; Harvard School of Public Health, Departments of Nutrition
and Epidemiology (Giovannucci, Wei); and Vitamin D Laboratory,
Section of Endocrinology, Nutrition and Diabetes, Department of
Medicine, Boston University School of Medicine (Holick), Boston,
Address correspondence and reprint requests to: Edward D.
Gorham, PhD, Research Epidemiologist, Naval Health Research
Center (Code 24, Bldg 346), P.O. Box 85122, San Diego CA 92186-
5122. E-mail: email@example.com.
UNDER EMBARGO UNTIL FEBRUARY 6, 2007, 12:01 AM LOCAL TIME
210 Am J Prev Med 2007;32(3) 0749-3797/07/$–see front matter
© 2007 American Journal of Preventive Medicine • Published by Elsevier Inc. doi:10.1016/j.amepre.2006.11.004
D,” or “25-hydroxyvitamin D”), and (“cohort” or “case–
control” or “case–cohort” or “incidence” or “occurrence” or
“epidemiology”) and “human” as medical subject heading
(MeSH) terms and words in the abstract. Articles were
included if they were published in medical journals and
included measures of association by quantile. A total of ﬁve
studies were identiﬁed and all ﬁve met the inclusion crite-
Information on study design, participant characteris-
tics, multivariate adjustment, and serum levels of 25(OH)D
was abstracted by two investigators. Data were abstracted and
analyzed in 2006.
Statistical Analysis for 25(OH)D
Summary odds ratio. A summary odds ratio of the highest
versus lowest quintile for all studies was obtained using Peto’s
Assumption-Free Method for combining odds ratios.
method provides a weighted average of the natural logarithms of
the odds ratios from each study. The weights were the inverse of
the variances of the logarithms of each odds ratio.
The p value for the summary odds ratio was calculated
using a z-test, where the numerator was the natural logarithm
of the pooled odds ratio and the denominator was the
standard error of the pooled odds ratio, which is the
standard method for calculating the p value when using
Peto’s Assumption-Free Method.
Odds ratios comparing
the highest with the lowest quantiles for each study were
displayed in a forest plot.
Conﬁdence intervals were
computed using the method of Woolf.
Laird statistic was calculated to assess homogeneity.
calculations were performed using Rev Man (Oxford, En-
gland: The Cochrane Collaboration).
Dose–response gradient. A data set was created consisting of
one record per participant in each study. The records in this
data set identiﬁed whether the participant was a case or
noncase, the median or midpoint of the participant’s quantile
of serum 25(OH)D at baseline, in ng/mL, a number identi-
fying the study, and a serial number for each individual. If the
median value was provided by the study,
it was used. If
midpoint values were calculated by computing the
arithmetic mean of the upper and lower bounds of the
Data presented in nmol/L were converted to ng/mL using
the conversion factor 1 ng/mL"2.5 nmol/L. The records
were put into order by serum 25(OH)D level, then divided
into ﬁve quintiles, with each quintile containing approxi-
mately one ﬁfth of the records.
Odds ratios were then calculated for the association be-
tween quintile of serum 25(OH)D and risk of colorectal
cancer in the pooled data, using the lowest quintile as the
reference group. Conﬁdence intervals were computed using
the method of Woolf.
A dose–response curve was then
plotted using the odds ratios for each quintile of the pooled
A least-squares trend line was constructed to examine
the dose–response relationship
; p values for trend were
calculated using the Mantel-Haenszel chi
25(OH)D concentrations associated with a 50% reduction in
colorectal cancer risk, compared to the lowest quintile of
25(OH)D, were obtained by drawing a vertical line from the
point on the dose–response curve corresponding to an odds
ratio 0.50 to the point of intersection with the horizontal axis.
Computations were performed using SAS, Version 9.1 (SAS
Institute, Cary NC, 2004).
When the upper limit of the top quantile was not provided,
the median of that quantile was estimated based on an assump-
tion that the median of the values above the lower limit were so
close to that limit that the value of the lower limit that was
provided was the best available estimate of the median of the
quantile. This is an adaptation of a general procedure for
handling open intervals.
Further corrections might have raised
the assumed value of this limit by 1%–2%, which would have had
virtually no detectable effect on the slope of the dose–response
Five studies of the association of serum 25(OH)D with
risk of colorectal cancer were identiﬁed.
nested case– control studies of prediagnostic serum
collected from healthy volunteer donors who were then
followed from 2–25 years for incidence (Table 1).
Three studies reported statistically signiﬁcant trends
toward lower odds ratios in individuals with higher
levels of 25(OH)D,
while two reported trends in the
same direction that were of borderline signiﬁcance or
All studies were included in the
The anatomic site of interest was the colon for the
studies by Garland et al.
and Braun et al.,
and rectum combined for the studies by Feskanich et al.
and Wactawski-Wende et al.
The association reported by
Tangrea et al.
was limited to the distal colon.
There was a downward linear gradient in risk of
colorectal cancer with increasing serum 25(OH)D in
the meta-analysis (R
"0.98, p for trend !0.0001) (Fig
ure 1). The odds ratios for the pooled data were, from
lowest to highest quintile: 1.00, 0.82, 0.66, 0.59, and
0.46 (p trend !0.0001 (Table 1).
A serum 25(OH)D !33 ng/mL (83 nmol/L) was
associated with a 50% lower risk of colorectal cancer
incidence, compared with !12 ng/mL (Figure 1). The
ﬁve studies were homogeneous (DerSimonian-Laird
"1.09, df"4, p"0.90). The overall Peto odds ratio
summarizing the estimated risk in the highest com-
pared to the lowest quantile across all studies was 0.49
(p!0.0001) (Figure 2).
A meta-analysis increases power by combining the
results of many studies. All known published studies of
serum 25(OH)D and risk of colorectal cancer were
included, and the results were homogenous. Pooling of
such independent studies increases precision, because
random ﬂuctuation in any one study tends to be
counterbalanced by results of other studies.
The data from two different studies of serum
25(OH)D in the Johns Hopkins cohort in Washington
County MD had trends that were uneven but consistent
March 2007 Am J Prev Med 2007;32(3) 211
with lower risk of colon cancer in association with
higher serum 25(OH)D. One of these reported on the
ﬁrst 8 years of follow-up
and another reported on later
The slightly stronger association that was
present in the ﬁrst study suggests that 25(OH)D may
exert an effect on cancer risk rather quickly, in the
Because data on serum 25(OH)D in individuals were
not available from each study, midpoints of the quan-
tiles were used for pooling. As a result, estimates of risk
for each quantile may have been less accurate than if
data points on each individual had been used. This is
unlikely to have affected the overall dose–response
relationship, but it may have obscured some of the
detail in the highest and lowest quantiles of the distri-
bution, such as changes in the shape of the dose–
response curve at the high and low extremes.
Previous studies have reported lower risk of colorectal
cancer in association with intense physical activity.
has been suggested that the association of physical activity
with risk of colon cancer could be indirect,
a result of higher serum 25(OH)D levels in people who
have high levels of physical activity, if the exercise is
performed outdoors and is associated with greater UVB
exposure. Alternatively, intensive physical activity may
have a beneﬁcial role on risk of colorectal cancer that is
independent of serum 25(OH)D, through an as yet
The study by Feskanich et al.
controlled for physical activity, and reported that there
was no inﬂuence of physical activity on the association
between serum 25(OH)D and risk of colorectal cancer,
although physical activity was independently predictive of
risk in this cohort.
Calcium intake also is associated with lower risk of
There is some correlation
(r "#0.33) between total oral intake of vitamin D and
because certain foods in the United States
that contain substantial amounts of calcium, such as
milk, are fortiﬁed with vitamin D. However, because
90%–95% of circulating vitamin D and its metabolites
in general result from exposure to solar UVB,
there is little correlation between intake of calcium and
serum 25(OH)D levels. Feskanich et al.
calcium intake and this did not inﬂuence the results for
25(OH)D. Tangrea et al.
found that calcium intake
was identical (1300 mg/day) in cases and controls, and
therefore could not account for the inverse association
of serum 25(OH)D with risk. Results of the other
studies were not adjusted for calcium intake.
Women are four times more likely than men to take
yet the associations of 25(OH)D
with colorectal cancer were about the same in men
Table 1. Serum 25-hydroxyvitamin D [25(OH)D] concentration associated with colorectal cancer, according to
Authors (year) ref Cancer site Gender
(25(OH)D, ng/mL) Total
Odds ratio by
Garland et al. (1989)
Colon Both 4–19, 20–26, 27–32, 33–41,
1.00, 0.48, 0.25,
No. of cases per quintile 9, 7, 5, 4, 9 34
No. of noncases per quintile 8, 13, 18, 17, 11 67
Braun et al. (1995)
Both !17, 18–20, 21–24, 25–29,
1.00, 0.33, 0.54,
No. of cases per quintile 16, 8, 11, 13, 9 57
No. of noncases per quintile 18, 26, 23, 21, 25 113
Tangrea et al. (1997)
Men !10, 10–13, 14–18, 19# 1.00, 0.83, 0.61,
No. of cases per quartile 33, 29, 23, 18 103
No. of noncases per quartile 47, 50, 54, 53 204
Feskanich et al. (2004)
Colorectal Women 16, 22, 27, 31, 40
1.00, 0.86, 0.68,
No. of cases per quintile 53, 47, 35, 29, 29 193
No. of noncases per quintile 77, 79, 75, 77, 75 383
Wactawski et al. (2005)
Colorectal Women 12, 14.7, 20.2, 23.4
1.00, 0.73, 0.71,
No. of cases per quintile 42, 45, 34, 27 148
No. of noncases per quintile 28, 41, 32, 45 146
Pooled data 6, 16.2, 21.8, 26.8, 37 1.00, 0.82, 0.66,
95% conﬁdence intervals
for odds ratios
No. of cases per quintile 129, 121, 107, 98, 80 535
No. of noncases per quintile 151, 172, 190, 195, 205 913
All were nested case– control studies.
Medians of quantiles are shown; cut points were not provided.
Dash (—) denotes no statistically signiﬁcant association (p$0.05).
212 American Journal of Preventive Medicine, Volume 32, Number 3 www.ajpm-online.net
Therefore, the inverse association of 25(OH)D
with risk of colorectal cancer could not have been ac-
counted for solely by an effect of the calcium content of
supplements that contain both calcium and vitamin D.
Evidence from oral intake studies of vitamin D is
supportive of the serum results. A majority of observa-
tional studies have demonstrated an inverse association
between intake of vitamin D and risk of colorectal
Many studies that found an association of oral
intake of vitamin D with risk of colorectal cancer were
conducted in populations that may have had a high
prevalence of vitamin D inadequacy, such as popula-
tions living mainly at latitudes $40 degrees.
ies of oral vitamin D intake that had equivocal ﬁndings
had either adjusted for calcium
or had vitamin D
intake mainly from ﬁsh products that may have con-
tained nitrosoamines, which would tend to increase the
risk of colorectal cancer.
Because vitamin D forti-
ﬁcation is uncommon in Europe, these studies also had
very low oral vitamin D intakes. One observational
and a clinical trial using a low dose of vitamin
found no association with colorectal cancer, proba-
bly because of the low dose.
Classical dose–response curves for micronutrients
are either linear
or have a predominantly linear
This appears to be true for most
functions of vitamin D.
More studies of effects at
higher vitamin D intakes are needed. In the meantime,
our results suggest that a serum 25(OH)D level of !33
ng/mL could be associated with 50% lower incidence
of colorectal cancer, compared to serum 25(OH)D
Absence of Toxicity
According to an analysis of 30 studies reporting any
adverse effect of high serum 25(OH)D in adults, no
reproducible toxicity was reported below 100 ng/mL.
The median minimum threshold for toxicity in all
studies was 197 ng/mL. Therefore, the projected serum
25(OH)D level of approximately 33 ng/mL would be
below the threshold for minimal toxicity by a safety
factor of 6.
A “No Adverse Effect Level” (NoAEL) level of 2000
IU/day of vitamin D has been established by the
National Academy of Sciences (NAS).
The NAS re-
ported that no illness from vitamin D intoxication has
been described for intakes !3800 IU/day. One study
reported that no cases of toxicity have ever been
documented at doses !40,000 IU per day.
A vitamin D3 intake of 1000–2000 IU/day, and a target
of 33 ng/mL of serum 25(OH)D, are the most practical
estimates now available for decision makers who wish to
weigh the potential beneﬁts compared to risks of actions
that could reduce incidence of colon cancer. This trans-
lation of oral intake of vitamin D to serum 25(OH)D was
computed from data on conversion of radiolabeled vita-
to 25(OH)D following its administration to vol
Although the volunteers were White, it is likely
that the ﬁndings would apply to those of other ethnicities,
because the rate of conversion of vitamin D
is approximately the same in people of different ethnic
Raising the current estimated median intake of
of vitamin D to the current recom-
mended daily intake of the National Academy of Sciences
of 400 IU/day for mature adults
would increase median
Figure 1. Dose–response gradient for colorectal cancer ac-
cording to serum 25(OH)D concentration, all ﬁve studies
The ﬁve points are the odds ratios for each
quintile of 25(OH)D based on combined data from the ﬁve
studies. (The anatomic site was the colon for studies by
Garland et al.
and Braun et al.,
the distal colon and rectum
for Tangrea et al.,
and the colon and rectum for Feskanich
and Wactawski-Wende et al.
Figure 2. Forest plot of all studies of serum 25(OH)D and
risk of colorectal cancer.
The upper and lower 95%
conﬁdence limits on the odds ratio are denoted by horizontal
lines for each study, and the 95% conﬁdence limits for the
combined estimate for all studies are denoted by the points of
the diamond. The odds ratios compare the highest quintile to
March 2007 Am J Prev Med 2007;32(3) 213
serum 25(OH)D by only 5 ng/mL.
By contrast, an
increase of the intake to 1000 IU/day of vitamin D3 would
boost serum 25(OH)D by approximately 13 ng/mL,
raising the estimated median level in the population to 33
ng/mL, which would keep virtually all of the population
at levels below those associated with hypercalcemia or
adverse health effects.
Although a daily intake of 1000 IU would raise the
median population serum levels to 33 ng/mL, this
could be less than optimal because 50% of the popula-
tion would still be below this median level. By contrast,
an intake of 2000 IU/day, would raise the population
median to 46 ng/mL. This is well below an intake level
that would induce even mild hypervitaminosis.
vitaminosis would be a concern, with intakes of 5000–
10,000 IU per day and possibly higher, but not with
2000 IU per day.
Although every effort should be
made to reduce the occurrence of mild hypervitamin-
osis, the consequences of vitamin D inadequacy are
important enough that toleration of a small increase in
the risk of mild hypervitaminosis may be needed.
The studies cited in this analysis are based on Whites.
Intake of vitamin D should be greater for Black people
and other individuals with more skin pigmentation
than is typical in Whites, because such individuals have
lower rates of photosynthesis of vitamin D3 in the
However, the NAS has not provided separate
guidelines for intake of vitamin D according to skin
pigmentation, and therefore a recommendation for
intake of $2000 IU per day cannot be made at this
Any effect of vitamin D on risk of colorectal cancer is
not likely to occur in isolation. Other research has
suggested that calcium and vitamin D tend to be
somewhat synergistic in reducing incidence of colorec-
Low vitamin D status and low intake
of calcium may contribute jointly to the high incidence
of cancer of the colon and rectum in individuals who
consume the typical Western diet in the United States
In addition, the time period required
to observe an effect on colorectal cancer risk following
an increase in vitamin D intake is not known, but some
evidence suggests that this could require !10 years.
The ﬁndings of the study by Tangrea et al.
strongest association was for the distal colon and rec-
tum suggest that the mechanism of vitamin D anticar-
cinogenesis may differ somewhat according to ana-
tomic site in the large bowel. Cancers of the distal colon
and rectum account for approximately two thirds of
and the high cancer incidence in
these anatomic sites in individuals with low serum
25(OH)D may account for much of the overall associ-
ation of vitamin D inadequacy with risk of colorectal
Overall, this meta-analysis supported the theory that
there is an inverse association between serum 25(OH)D
and risk of colorectal cancer. Although confounding is
possible, there are three lines of epidemiologic evi-
dence that support a causal basis for the association: the
geographic gradient with latitude and solar UVB irra-
observational studies linking deﬁcient
serum 25(OH)D levels with increased risk,
studies linking low oral intake of vitamin D with in-
Also, vitamin D receptor poly-
morphisms that interfere with vitamin D utilization may
increase risk of colorectal cancer, particularly in com-
bination with low levels of serum 25(OH)D.
incidence of colorectal cancer is higher in African
who synthesize less vitamin D per minute
spent in the sun.
It seems unlikely that a single
confounder could account for all of these associations.
The epidemiologic ﬁndings regarding vitamin D and
colon cancer are supported by numerous studies of the
mechanisms in vivo and vitro.
For example, an exper-
iment using human colon cancer cells (MC-26) grafted
into Balb/C mice found that dietary vitamin D reple-
tion reduced the volume of colon cancer-derived tu-
mors by 40%.
Another experiment found that dietary
vitamin D repletion reduced the volume of colon
cancer xenografts in Balb/C mice by 60%.
Vitamin D metabolites such as 1,25(OH)
D are pleio
tropic agents that induce cell cycle arrest and apoptosis
in cancer cell lines vitro and to show antitumor activity
against a variety of tumors in animal models.
experiments have revealed that increasing levels of
D are associated with reduced epithe
lial cell proliferation and increased apoptosis in hu-
D is also effective in reducing the
incidence of aberrant crypt foci induced by azoxymeth-
ane in rats.
Based on overall consideration of results from obser-
vational and laboratory studies, the existing evidence is
consistent with the hypothesis that increasing vitamin
intake to 1000 –2000 IU per day or raising the serum
level of 25(OH)D to 33 ng/mL or higher would be
associated with substantially lower incidence rates of
colorectal cancer, with only minimal risks.
This research was supported by a Congressional allocation to
the Hollings Cancer Center of the Medical University of
South Carolina, Charleston SC, through the Department of
the Navy, Bureau of Medicine and Surgery, under Work Unit
No. 60126. The views expressed in this report are those of the
authors and do not represent an ofﬁcial position of the
Department of the Navy, Department of Defense, or the U.S.
Government. The sponsor did not participate in study design,
data collection, analysis, interpretation of data, writing of the
report, or the decision to submit the paper for publication.
W.B.G., on behalf of SUNARC, has received consulting
fees, honoraria, speaking fees, and has given legal advice on
the primary risk factors for chronic diseases.
No other ﬁnancial conﬂict of interest was reported by the
authors of this paper.
214 American Journal of Preventive Medicine, Volume 32, Number 3 www.ajpm-online.net
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