Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations:a nested case-control studyBMJ 2010; 340 doi: https://doi.org/10.1136/bmj.b5500 (Published 22 January 2010) Cite this as: BMJ 2010;340:b5500
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The recent paper by Jenab et al., in which a strong inverse
association between (25-(OH)D) concentrations and risk of colorectal
cancer is established, is a very important contribution.
As one of the outcomes of the study, it is concluded that "Dietary
vitamin D intake did not show an association with colorectal cancer risk."
This is not surprising, and indeed, could have been predicted. The
reported range of intake was 1.5 to 8.2 µg/day (Table 3 of paper). Serum
25(OH)D level rises by ~0.7 nmol/L with 1 µg/day intake (Heaney, et al 1).
Therefore the whole range of expected average serum level changes due to
vitamin D intake is covered by 1.0 to 5.7 nmol/L. In 5 steps. This is
within the standard deviation of the serum levels of the quintiles (Table
This serves to highlight that it is the serum level of 25(OH)D, not
the dietary intake of vitamin D, that is the biologically relevant
measure. The very wide individual variation of serum level among persons
taking identical dietary intakes is a reality. This is also true of solar
synthesis of vitamin D by the skin. Many intervention studies are
undertaken that are based on controlling the intake, not even measuring
the serum level.
Regardless, bowing to the expected necessity of randomized clinical
trials before recommending public health steps, one wonders at the ethical
conundrum of designing a trial that withholds vitamin D or offers very low
intakes as a placebo. Not providing adequate means for increasing 25(OH)D
serum levels would very likely cause needless harm to the participants.
1 Heaney, et al Am. J. Chem. Nutrition 2003; 77: 204-210
Competing interests: No competing interests
Sorry not true, there tends to be inadequate methods in Research by
placing supplimentary nutrition in isolation to human needs to enable
While the need for supplimentary nutrition is clinically without question,
the limiting factor remains. Are thier addequate supporting nutrients?
In this case in question, by adding the twelve biochemic salts to high
dose Cod Liver Oil, D-3, Beta Carotine balanced absorbtion needed takes
Competing interests: No competing interests
Sir, the recent paper by Jenab et al. is an important epidemiological
contribution in which a strong inverse association between pre-diagnostic
25-hydroxy-vitamin-D (25-(OH)D) concentrations and risk of colorectal
carcinoma is established. Its strength is based on the fact that it is the
large-scale European study in this field. It has a well controlled case -
design. Furthermore, determining circulating 25-(OH)D concentrations
provides the best estimate of total vitamin D, i.e., the net result of
metabolism of vitamin D formed in the skin via the action of ultraviolet
the oral intake of vitamin D from the diet.
However, there is no in-depth comment on factors that can influence
circulating 25-(OH)D levels. The lack of data on sun exposure, tanning
and vitamin D supplementation intake may be considered as a limitation of
the study. I disagree with the authors, who state that this lack of data
compensated by the use of 25-(OH)D as a biomarker. They claim this to be
an advantage instead of a limitation, because this biomarker is used as an
estimate of the sum of endogenous and dietary vitamin D. Without denying
value as a biomarker for total vitamin D, it should be underlined that 25-
(OH)D levels are only an intermediate independent variable for the risk of
cancer, that in its turn depends on the variables UV exposure and vitamin
consumption. What really matters is the important issue of the
of these two sources of vitamin D in practice.
It is mandatory for public health authorities to be able to draw
about the life style that contribute to higher 25-(OH)D levels. The study
offers only limited and indirect information on sun exposure. In web
it is shown that the blood 25-(OH)D levels collected in August are about
twice as high as those collected in February / March. This illustrates the
importance of sun exposure. Regrettably, there is no information on
sun and tanning behaviour.
A similar omission is the fact that there is no discussion on
that may explain the observed differences between the European countries
with respect to observed colorectal cancer incidence. Candidates may be
above mentioned vitamin D sources and genetic factors.
From a dermatological point of view, there is currently a debate as
or not we should advice certain patient groups on adequate UV protection.1
Strict protection has been shown to decrease serum 25-(OH)D levels
dramatically. On the contrary, regular moderate UV exposure has been
advocated in order to uarantee adequate 25-(OH)D concentrations.2
The authors found that dietary vitamin D intake did not show an
with colorectal cancer risk. They conclude that new trials are needed to
the hypothesis that increasing circulating 25-(OH)D concentrations by
vitamin D supplementation is effective. This lack of association may be
caused by the fact that the range of quintiles is set in a dietary intake
which is too low (<2.1 ìg - > 5.8 ìg, corresponding to 84
IU - 232 IU)
according to current standards.2 Nowadays, there is a solid body of
in favour of a significantly higher intake (>1000 IU) being protective
the development of cancer. Indeed, recent observational studies on the
of vitamin D supplementation and colorectal cancer risk point to optimal
doses of 1000 - 2000 IU vitamin D.3
Unfortunately, the paper does not provide data on the association
the dietary vitamin D intake and circulating 25-(OH)D levels.
In conclusion, in this large-scale epidemiological investigation
variables that may determine the circulating 25-(OH)D concentrations in
practice are insufficiently addressed in light of the current knowledge on
1. Reichrath J.Skin cancer prevention and UV-protecion: how to avoid
D-deficiency? Br. J. Dermatol 2009;161(suppl. 3): 54-60
2. Holick MF. Vitamin D deficiency. N Eng J Med 2007;357:266-81.
3. Gorham ED, Garland CF, Garland FC, et. al. Optimal vitamin D status for
colorectal cancer prevention. A quantitative meta analysis. Am J Prev Med
Competing interests: No competing interests
A recent paper in the BMJ reported significant reduced risk of colon
cancer associated with higher serum 25-hydroxyvitamin D concentrations.1
While these results were useful, there was a statement in the paper with
which I take issue:
“Our findings suggest that the potential cancer risk benefits of
higher vitamin D levels should be balanced with caution for the toxic
potential. In fact, any public health advocacy of higher circulating 25-
(OH)D concentrations should be based on clear and conclusive evidence from
double blind randomized trials, as for any drug.”
There are a number of problems with this statement. First, for the
99% of the population without undiagnosed primary hyperparathyroidism,
sarcoidosis or other granulomatous diseases or a limited number of other
diseases where the body’s innate immune system puts too much 1,25-
dihydroxyvitamin D into the serum, thereby increasing the risk of
hypercalcemia, vitamin D intake or production of more than 10,000 IU/day
has no adverse effects.2 In addition, a recent paper concluded:
“Our analysis suggests that mean serum 25(OH) D levels of about 75 to
110 nmol/l provide optimal benefits for all investigated endpoints without
increasing health risks. These levels can be best obtained with oral doses
in the range of 1,800 to 4,000 IU vitamin D per day; further work is
needed, including subject and environment factors, to better define the
doses that will achieve optimal blood levels in the large majority of the
Second, oral vitamin D3 (cholecalciferol) is not a ‘drug’ but a
substance bioidentical to one naturally occurring in the body, being
manufactured in response to ultraviolet-B irradiance by an interaction
with 7-dehydrocholesterol in the epidermis. All mammals, including
humans, require vitamin D for optimal function and health.
Third, the requirement for conclusive evidence from double blind
randomized trials (RCTs) can be considered as likely to delay for five or
more years the revision of public health guidelines that would avoid
vitamin D deficiency, as currently defined, and that is thought likely to
save large numbers of thousands of lives per year. For example, the
International Agency for Research on Cancer (IARC) reviewed the evidence
that vitamin D reduces the risk of cancer and concluded that good evidence
existed specifically for colorectal cancer, though not other cancers, but
then called for RCTs to provide definitive evidence.4 As suggested in a
critique of this study, there were many errors and omissions in the
report, suggesting that the panel was more concerned with keeping people
out of the sun to reduce the risk of skin cancer than with protecting
people from other cancers where there is strong ecological and
observational evidence that vitamin D reduces risk.5 This comment is made
because the evidence that vitamin D reduces risk satisfies Hill’s criteria
for causality in a biological system for a number of cancers, though for
some better than others.6 RCT data would satisfy the last of Hill’s
criteria, but are not required since well-conducted meta-analyses of
observational studies that consider the important confounding factors are
currently considered almost as good as RCTs for determining health
Fourth, many RCTs performed to date on vitamin D and cancer used too
little vitamin D to be effective;8,9 the one that used doses large enough
to reduce fracture risks however, did find a 35% reduction in all-cancer
incidence from the end of the first to the end of the fourth year of
supplementation.10 Equally important as well-conducted RCTs, therefore,
is a careful review of all of the evidence within the framework of Hill’s
criteria, provided this includes checking for bias and the inclusion of
It was originally thought that the reason the IARC report on vitamin D and
cancer called for an RCT to determine whether vitamin D reduces the risk
of cancer was due to a strong interest in keeping people away from UV
irradiance primarily in order to stem the global increasing trends in
melanoma as reflected by their meta-analysis of the association of
melanoma with use of sunbeds.12 However, it may reflect the fact that its
primary mission is to identify risks for cancer rather than to identify
means for cancer risk reduction since a simple search at www.pubmed.gov
using the search words “IARC, cancer, risk” on January 28, 2010 found 670
entries while using the words “IARC, cancer, prevention” found only 225
Fifth, there is good observational and cross-sectional study evidence
for beneficial roles of vitamin D in reducing cardiovascular disease and
diabetes,13 infectious diseases,14,15 and other diseases.16
Sixth, studies of the potential effects of increasing mean serum
25(OH)D concentrations at the population level from 20-25 ng/mL to 40-45
ng/mL (50-62 nmol/l to 100-112 nmol/l) estimate that all-cause mortality
rates could be reduced by about 15% in Western Europe,17 the United
States,18 and Canada.19
Seventh, considering vitamin D to be a drug is unusual. If it were a
drug, then in the United States, the Food and Drug Administration would
regulate its use. However, the Institute of Medicine of the National
Academies has recently constituted a committee of 18 nutritionists to
revise dietary guidelines on vitamin D and calcium, with recommendations
due out in May 2010.20
1. Jenab M, Bueno-de-Mesquita HB, Ferrari P, van Duijnhoven FJ, Norat
T, Pischon T, et al. Association between pre-diagnostic circulating
vitamin D concentration and risk of colorectal cancer in European
populations:a nested case-control study. BMJ. 2010;340:b5500.
2. Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for
vitamin D. Am J Clin Nutr. 2007;85:6-18.
3. Bischoff-Ferrari HA, Shao A, Dawson-Hughes B, Hathcock J,
Giovannucci E, Willett WC. Benefit-risk assessment of vitamin D
supplementation. Osteoporos Int. 2009 Dec 3. [Epub ahead of print]
4. IARC Working Group Report 5: Vitamin D and Cancer. IARC, Lyon,
France (Nov. 25, 2008)
5. Grant WB. A critical review of Vitamin D and cancer: A report of
the IARC Working Group on vitamin D. Dermato-Endocrinology. 2009;1:25-33.
6. Grant WB. How strong is the evidence that solar ultraviolet B and
vitamin D reduce the risk of cancer? An examination using Hill’s criteria
for causality. Dermato-Endocrinology. 2009;1:17-24.
7. Weed DL. Interpreting epidemiological evidence: how meta-analysis
and causal inference methods are related. Int J Epidemiol. 2000:387-90.
8. Grant WB, Garland CF. A critical review of studies on vitamin D in
relation to colorectal cancer. Nutr Cancer. 2004;48:115-23.
9. Wactawski-Wende J, Kotchen JM, Anderson GL, Assaf AR, Brunner RL,
O’Sullivan MJ, et al. Calcium plus vitamin D supplementation and the risk
of colorectal cancer. N Engl J Med 2006;354:684–96.
10. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP.
Vitamin D and calcium supplementation reduces cancer risk: results of a
randomized trial. Am J Clin Nutr. 2007;85:1586-91.
11. Weed DL, Gorelic LS. The practice of causal inference in cancer
epidemiology. Cancer Epidemiol Biomarkers Prev. 1996;5:303-11.
12. International Agency for Research on Cancer Working Group on
artificial ultraviolet (UV) light and skin cancer. The association of use
of sunbeds with cutaneous malignant melanoma and other skin cancers: a
systematic review. Int J Cancer. 2007;120:1116–22.
13. Parker J, Hashmi O, Dutton D, Mavrodaris A, Stranges S, Kandala
NB, et al. Levels of vitamin D and cardiometabolic disorders: Systematic
review and meta-analysis. Maturitas. 2009 Dec 21. [Epub ahead of print]
14. Cannell JJ, Zasloff M, Garland CF, Scragg R, Giovannucci E. On
the epidemiology of influenza. Virol J. 2008;5:29.
15. Bikle DD. Vitamin D and the immune system: role in protection
against bacterial infection. Curr Opin Nephrol Hypertens. 2008;17:348-52.
16. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266-81.
17. Grant WB, Cross HS, Garland CF, Gorham ED, Moan J,
Peterlik M, et al. Estimated benefit of increased vitamin D status in
reducing the economic burden of disease in Western Europe. Prog Biophys
Mol Biol. 2009;99:104-13.
18. Grant WB. In defense of the sun: An estimate of changes in
mortality rates in the United States if mean serum 25-hydroxyvitamin D
levels were raised to 45 ng/mL by solar ultraviolet-B irradiance. Dermato-
19. Grant WB, Schwalfenberg GK, Genuis SJ, Whiting SJ. An estimate of
the economic burden and premature deaths due to vitamin D deficiency in
Canada, Molec Nutr Food Res. In press.
20. Institute of Medicine of the National Committees. Dietary
Reference Intakes for Vitamin D and Calcium.
January 26, 2010).
I receive funding from the UV Foundation (McLean, VA), the Sunlight Research Forum (Veldhoven), and Bio-Tech-Pharmacal (Fayetteville, AR) and have previously received funding from the Vitamin D Society (Canada).
Competing interests: No competing interests