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Dietary calcium supplementation for preventing colorectal
cancer and adenomatous polyps (Review)

Weingarten MAMA, Zalmanovici Trestioreanu A, Yaphe J
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2010, Issue 9
http://www.thecochranelibrary.com
Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps (Review)
Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Calcium versus placebo, Outcome 1 Number of subjects diagnosed with colorectal cancer.
Analysis 1.2. Comparison 1 Calcium versus placebo, Outcome 2 Number of subjects with at least one new adenoma.
Analysis 1.3. Comparison 1 Calcium versus placebo, Outcome 3 Number of subjects with at least one adverse event
requiring discontinuation of treatment. . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.4. Comparison 1 Calcium versus placebo, Outcome 4 Number of subjects that dropped - out. . . . .
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
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1
1
2
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4
5
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[Intervention Review]
Dietary calcium supplementation for preventing colorectal

cancer and adenomatous polyps
Michael Asher MA Weingarten1 , Anca Zalmanovici Trestioreanu2 , John Yaphe3
1
Department of Family Medicine, Rabin Medical Centre, Petah Tikva, Israel. 2 Department of Family Medicine, Beilinson Campus,
Rabin Medical Center, Petah-Tiqva, Israel. 3 School of Health Science, University of Minho, Braga, Portugal
Contact address: Michael Asher MA Weingarten, Department of Family Medicine, Rabin Medical Centre, Beilinson Campus, Petah
Tikva, 49100, Israel. weingml@post.tau.ac.il.
Editorial group: Cochrane Colorectal Cancer Group.
Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 9, 2010.
Review content assessed as up-to-date: 20 January 2010.
Citation: Weingarten MAMA, Zalmanovici Trestioreanu A, Yaphe J. Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD003548. DOI:
10.1002/14651858.CD003548.pub4.
ABSTRACT
Background
Several dietary factors have been considered to be involved in the increasing incidence of colorectal cancer in industrialised countries.
Experimental and epidemiological evidence has been suggestive but not conclusive for a protective role for high dietary calcium intake.
Intervention studies with colorectal cancer as an endpoint are difficult to perform owing to the large number of patients and the long
follow-up required; studies using the appearance of colorectal adenomatous polyps as a surrogate endpoint are therefore considered in
reviewing the existing evidence.
Objectives
This systematic review aims to assess the effect of supplementary dietary calcium on the incidence of colorectal cancer and the incidence
or recurrence of adenomatous polyps.
Search methods
We searched the Cochrane Controlled Trials Register, the Cochrane Colorectal Cancer Group specialised register, MEDLINE, Cancerlit
, and Embase, to December 2009. The reference lists of identified studies were inspected for further studies, and the review literature
was scrutinized.
Selection criteria
Randomised controlled trials of the effects of dietary calcium on the development of colonic cancer and adenomatous polyps in humans
are reviewed. Studies of healthy adults and studies of adults at higher risk of colon cancer due to family history, previous adenomatous
polyps, or inflammatory bowel disease were considered; data from subjects with familial polyposis coli are excluded. The primary
outcomes were the occurrence of colon cancer, and occurrence or recurrence of any new adenomas of the colon. Secondary outcomes
were any adverse event that required discontinuation of calcium supplementation, and drop-outs before the end of the study.
Data collection and analysis
Two reviewers independently extracted data, assessed trial quality and resolved discrepancies by consensus. The outcomes were reported
as odds ratios (OR) with 95% confidence intervals (CI). The data were combined with the fixed effects model.
Main results
Two studies with 1346 subjects met the inclusion criteria. Both trials were well designed, double - blind, placebo controlled trials,
included participants with previous adenomas. The doses of supplementary elemental calcium used were 1200 mg daily for a mean
duration of 4 years, and 2000 mg/day for three years.The rates of loss to follow -up were 14 % and 11%.
For the development of recurrent colorectal adenoma, a reduction was found (OR 0.74, CI 0.58,0.95) when the results from both
trials were combined.
Authors conclusions
Although the evidence from two RCTs suggests that calcium supplementation might contribute to a moderate degree to the prevention
of colorectal adenomatous polyps, this does not constitute sufficient evidence to recommend the general use of calcium supplements
to prevent colorectal cancer.
PLAIN LANGUAGE SUMMARY

Daily intake of 1 gr dietary calcium may have moderate protective effect on development of colorectal adenomatous polyps
There have been suggestions, based on observational studies and on laboratory markers, that dietary calcium may protect against
colorectal cancer. This systematic review of the literature identified two well conducted randomised placebo-controlled intervention
studies involving 1346 subjects followed for 3-4 years. The results suggest that there may be a moderate protective effect (OR 0.74; CI
0.58,0.95) for dietary supplementation of at least 1200mg elemental calcium per day on the development of colorectal adenomatous
polyps. However, no trial has directly demonstrated an effect of calcium supplementation on the development of colorectal cancer itself.
BACKGROUND
Colon cancer is one of the leading cancers in men and women and
it is associated with more industrialised societies; European Union
average incidence between 1988-1992 was 33.8/100000 for men
and 23.7/100000 for women. The risk of colorectal cancer begins
to increase after the age of 40 and rises sharply from the age of 5055 years.
Early detection and treatment may have some effect on reducing
the mortality from colon cancer but effective primary prevention is
the more important public health goal. Several dietary factors have
been considered responsible for the changing incidence including
calcium, fiber, sugar, fat, vegetables, and meat among others. The
underlying mechanisms are not clear, but may in part be due to
alterations in bile acids which have been found to be carcinogenic
in animals (Nagengast 1995). Dietary calcium has been suggested
as a chemoprotective agent against colorectal cancer; it is thought
to bind fatty acids and bile acids in the colon thus inhibiting the
fat-induced hyperproliferation of colon epithelial cells (Newmark
1992). The mechanism may be mediated by the precipitation of
colonic cytotoxic surfactants thus inhibiting luminal cytotoxicity
(van der Meer 1997). Calcium has also been shown to reduce
pathological cytokinetic crypt activity primarily in patients with
a high familial risk of colorectal cancer (Rozen 1989). Although

several animal studies have shown a protective effect of calcium
in colon carcinogenesis (e.g. Pence 1993), the empirical evidence
from cohort studies (e.g. Giovannucci 1998) and case control studies (e.g. Slattery 1997) is inconsistent on the question whether increased dietary calcium levels do indeed prevent the development
of colon cancer in humans. Some epidemiological studies have
suggested a protective effect for total calcium intake above 1500
to 1800mg daily (Newmark 1992), but for colorectal adenomas,
which are potential precursors of most large bowel cancers, the evidence is conflicting (Bergsma-Kadijk 1996, Martinez 1998, Hill
1978). The evidence from 24 case-control and cohort studies and
from over 20 epidemiological studies has been reviewed, and failed
to find clear support for a significant protective effect of calcium
on colon cancer (Bergsma-Kadijk 1996; Martinez 1998). Calcium
intake was associated with a decreased risk of colorectal cancer in
a recent meta-analysis of observational studies (Huncharek 2009).
There are only a small number of completed randomised controlled trials, but the little evidence they provide is of better quality
than that based on epidemiological studies, which could at best be
used to strenghten the evidence from the randomised controlled
trials if similar results were obtained.
Intervention studies with colorectal cancer as an endpoint are difficult to perform owing to the large number of patients and the
long follow-up required. Since almost all colorectal cancers develop
from adenomas, and since 5% of all adenomas develop into cancer
(Midgeley 1999), studies regarding the development of colorectal
adenomatous polyps as a surrogate endpoint may reasonably be
considered in reviewing the existing evidence. Colorectal adenoma
could also be a reasonable target for primary prevention .The aim
of this review is to assess critically the evidence from completed
randomised controlled trials that calcium supplementation may
be successful in reducing colon cancer risk. This review will be
updated as results from new trials become available.
OBJECTIVES
This systematic review and meta-analysis aims to assess the effect
of supplementary dietary calcium on the incidence of colorectal
cancer and the incidence or recurrence of adenomatous polyps in
adults at different levels of risk, and the development of adverse
effects.
The hypothesis to be tested is that higher levels of calcium intake
have a beneficial effect in the prevention of colonic cancer and
adenomatous polyps.
METHODS
Criteria for considering studies for this review
Types of studies
Randomised controlled trials of the effects of dietary calcium on
the development of colonic cancer and adenomatous polyps in
humans are reviewed. The rationale for excluding other experimental designs is that randomised controlled trials provide the
best current evidence upon which people can base their decisions;
cohort studies are subject to recruitment bias, while case-control
and epidemiological studies of cancer risk are subject to survivor
bias and they are also particularly prone to errors in dietary recall.
Trials reporting only physiological or laboratory parameters, such
as epithelial cell proliferation rates, are not considered clinically
relevant and are not reviewed here.
Types of participants
Studies of healthy adults, irrespective of gender or nationality and
studies of adults at higher risk of colon cancer due to family history,
previous adenomatous polyps, or inflammatory bowel disease are
considered. Data from subjects with familial polyposis coli are
excluded.
Types of interventions
Studies are included which used supplementation with calcium
salts in doses above 1200 mg elemental calcium per day, with a
duration of intervention longer than six months.
For the control group we accepted either placebo supplementation
or no intervention.
Trials reporting combined interventions in which there was no
arm testing for calcium supplementation alone are not included
in this review.
Types of outcome measures

Primary
-occurrence of colon cancer
-occurrence of any new adenomas of the colon
Secondary
-any adverse event that required discontinuation of calcium supplementation
-drop-outs (lost to follow up) before the end of the study.
Search methods for identification of studies

Relevant randomised controlled trials were identified by the search
strategy described by Dickersin et al (Dickersin 1994).
The following search terms were used : calcium, prevention, cancer, neoplasms, colonic, colorectal, polyps, adenomas, adenomatous polyps, human, randomized controlled trials, random allocation, intervention studies. Searches for colo*, adenom*, polyp*
were also performed. We searched the Cochrane Controlled Trials
Register ( Cochrane
Library Issue 4,2009 ), the Cochrane Colorectal Cancer Group
(CCCG) specialised register, the MEDLINE ( from 1966 to December 2009 ), Cancerlit ( from 1963 to December 2009 ), Embase ( from 1980 to December 2009 ). The Embase and the
CCCG specialised register searches were done according to the
search strategy of the CCCG.
The reference lists in reports of all identified studies were inspected
for further studies. In addition the existing review literature (e. g.
Bostick 1997) was scrutinized.
Data collection and analysis

Two reviewers (MAW, AZ) independently reviewed the abstracts of
potential studies to be included in the review. For possibly relevant
articles or in cases of disagreement between the two reviewers the
full article was obtained and inspected independently.Trials were
categorised by patient baseline status (healthy versus adenomatous
polyps or other risk factors for colonic cancer). The data from
the studies were divided, as far as possible from published and
unpublished information, into groups according to age at entry.
Two reviewers (YY, AZ) independently extracted the data from

the included trials. Disagreements were documented and resolved
by discussion and the authors of the study were contacted for
clarification. Justification for excluding studies from the review
were also documented.
Data extracted included:
-characteristics of trials - publication status, year, country of study,
setting, design, inclusion criteria, confounding variables, manner
of recruitment, methods, analysis, results.
-characteristics of participants - study population, number of participants in each group, age, gender, nationality, details on patients
basic bowel status, risk factors, average calcium intake in relation
to the recommended daily allowance.
-characteristics of interventions - calcium preparation used, dose,
length of treatment and follow-up.
-outcome measures - number of subjects in whom a new adenomatous polyp occured in the intervention and control groups,
number of subjects in whom colon cancer occured in both groups,
number of subjects who developed adverse or medical events related to the intervention, drop-outs before the end of study and
reasons for dropping out.
Data synthesis
Dichotomous data was analysed by calculating the odds ratio for
each trial with the uncertainity in each result being expressed as
95% confidence intervals.
Results are shown using the approach recommended in the
Cochrane Handbook (Clarke 2000). All analyses were performed
on the basis of intention to treat. We expected heterogeneity between study results because of different age categories, baseline risk
levels, doses and preparations used and duration of studies. Subgroup analysis was planned to assess the impact of these possible
sources of heterogeneity. In the absence of heterogeneity the fixed
effects model is used appropriately. Associations for lower versus
higher levels of calcium intake are reported.
The characteristics of eligible trials including those that were excluded and the reasons for exclusion are presented in the Tables.
The quality of the reports of the randomised trials was assessed
using the method of Jadad et al (Jadad 1996). Concealment of
randomisation was assessed according to Cochrane Collaboration standards. Subgroup analyses was planned for each quality
item.Two reviewers independently assessed the methodological
quality of each study. The studies were assessed for the quantification of concomitant use of other nutrients that have been implicated in colon carcinogenesis.
Additional information was obtained from the authors where the
publications presented insufficient detail.
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies.
See table of Characteristics of included studies. Two studies,
with 1346 subjects assigned to calcium supplements or placebo,
met the prestated criteria for inclusion in this review.
The two studies were multicentre trials; one was conducted in
ten European countries - Belgium, Denmark, France, Germany,
Ireland, Israel, Italy, Portugal, Spain, the UK (Bonithon-Kopp
2000), and the other study involved six clinical centers in the USA
(Baron 1999 a).
Participants
The entry criteria in the two trials were similar, including participants with previous adenomas and therefore considered at high
risk for recurrence. Subjects included had a qualifying colonoscopy
and polypectomy performed to ensure that the colon or rectum
were free of polyps at baseline.
Intervention
Both studies used placebo in the control group. 1200 mg elemental
calcium daily for a mean duration of 4 years was administered in
one study (Baron 1999 a), and 2000 mg/day for three years in the
second study (Bonithon-Kopp 2000). The mean dietary intake
was similar for the groups as stated in the studies.
Outcomes
The included studies reported the number of subjects with at least
one recurrent adenoma, or colorectal cancer, and described the
drop-outs and the reasons for leaving the study before the end.
Detailed data for the adverse event that required discontinuation
of treatment could not be obtained in one study (Bonithon-Kopp
2000). Information on adverse events that occured during the
trials is presented in Table 1.
Risk of bias in included studies

See table of Characteristics of included studies. Both studies
were well designed, double - blind, placebo controlled trials.
Allocation
Both studies were randomised controlled trials with an adequate
generation of allocation sequence. However, only one contained
an adequate report of concealment of allocation (Bonithon-Kopp
2000).
Blinding to intervention
Both trials were double - blinded and the method of blinding was
described and was adequate.
Follow - up
In one study 25 subjects were excluded initially after the randomisation for lack of documentation of histologically confirmed
adenoma, and total loss to follow -up in this trial was 14%
(Bonithon-Kopp 2000). The other study had a 11% loss to follow
- up (Baron 1999 a). Both studies described the reasons for drop
- out.
A maximum score of 5, according to the Jadad criteria of quality of

studies for randomisation, blinding and follow -up, was obtained
by both trials. However, the assessment for inclusion was based
primarily on concealment of allocation.
Effects of interventions
For numerical details see Analyses
453 references were identified , the abstracts inspected , and 448
excluded for the following reasons: not randomised, observational
studies, study subjects not responding to inclusion criteria, intervention of interest not used, no relevant outcomes reported, reports of biochemical endpoints, repeated reports of the same study,
review articles. Five reports were considered potentially eligible for
inclusion but, after inspection of the full papers three were excluded; one used a mixture for supplementation with no separate
arm for calcium supplementation alone (Hofstad 1998), one was
not randomised to the intervention (Hyman 1998), one included
data from a similar report of the same study and we included only
the paper with the most information (Baron 1999 b).
Two studies that included 1595 subjects met the inclusion criteria
(Baron 1999 a; Bonithon-Kopp 2000). In the Bonithon-Kopp et
al trial, there were three arms - calcium, fiber, and placebo. We
have analysed only the calcium and placebo arms in this review.
Details of the results are presented in the summary analysis.
Primary outcomes:
a)number of subjects with a new diagnosis of colorectal cancer
There were too few events for any meaningful conclusion
b)number of subjects with any new adenoma
Information for the primary outcome of the number of subjects
with at least one recurrent adenoma was found in both trials.
When combined, a moderate, statistically significant reduction of
recurrence of adenomas favouring the participants receiving calcium was obtained (OR 0.74; CI 0.58,0.95). Individually, only the
larger trial (n=930) achieved a statistically significant effect (OR
0.73; CI 0.55,0.96) but not the smaller trial (n=416. OR 0.78;
CI 0.45,1.33), but the combined results are strongly influenced
by the larger trial (Baron 1999 a).
Secondary outcomes:
a)number of subjects experiencing any adverse event that required
discontinuation of treatment
One trial (Baron 1999 a) did not find a difference between the
treatment and control groups( OR 0.93; CI 0.42,2.05). The report
of the other trial did not supply separate data for the 50 subjects
who stopped the assigned treatment prematurely because of side
effects; the proportions for those who stopped prematurely did
not differ significantly between groups (p=0.27) (Bonithon-Kopp
2000).
b)number of subjects that dropped-out from the studies
No difference could be found for subjects that were lost to followup in the two groups( OR 1.11; CI 0.80,1.55)
There was no evidence of heterogeneity between studies as assessed

by inspection of the graphical presentations, therefore the fixed
effect model was used for combining the studies. Planned subgroup analyses were not performed; the studies included high risk
subjects only and reported that subgroup analyses conducted for
age or baseline dietary intake of calcium within the trials did not
change the conclusions derived from the overall result. Data for
these subgroups were not available for the treatment and control
groups separately.
DISCUSSION
The role of calcium in colon cancer prophylaxis has been suspected
on the basis of animal experiments, such as that which showed
fewer cancers following injection of carcinogens in rats that received calcium supplements in their feed (Adell-Carceller 1997).
In an attempt to examine the question in humans, dietary surveys have been used to identify a corelation between dietary calcium intake and recurrence of colorectal adenomas, and indeed it
seemed that calcium might be protective (the rate ratio for the fifth
quintile versus the first was 0.63 (95% confidence interval, 0.391.02)) (Hyman 1998). The next step was to see if patients who
took extra dietary supplements of their own accord fared better
than those who did not, and once again for calcium supplementation there seemed to be a protective effect (odds ratio, 0.51; 95
percent confidence interval, 0.27-0.96, Whelan 1999).
Adenomas rather than cancers were studied because they are so
much more common, despite the limited applicability of findings
from adnomas to cancer.
In order to relate calcium supplementation more closely with actual carcinogenesis, rather than extrapolating from the effect on the
development of adenomas, attempts have been made to examine
the effects of dietary calcium on human colonic or rectal epithelial
proliferation, and some early studies suggested that calcium does
indeed impede epithelial proliferation (OSullivan 1993). However, more recently, these results have not been confirmed, but it
has also become clear that the proliferative index does not predict
future colorectal neoplasia, although it may be weakly associated
with the presence of current adenomas. The authors conclude that
these results have important implications for the design of future
intervention studies: Although it may be attractive to include the
measurement of intermediate markers in large controlled trials,
until we have more confidence in their performance, we should
rely on better proven and more reliable intermediates, such as adenomas (Sandler 2000). Doubt on the importance of dietary calcium is cast by the results of a large case control study embedded in
a major fecal occult blood screening programme - no association
of colon cancer was found with reported calcium intake (Little
1993). As indicated in the Background section, many epidemiological geographical studies have been reported, but on system-
atic review they present an inconsistent and inconclusive picture

(Martinez 1998).The findings of several large cohort studies and
one case-control study performed worldwide, in Europe, USA,
Hawai, China suggest that an increased intake of calcium may prevent the development of colorectal adenomas and cancer (Flood
2005; Kesse 2005; Larsson 2006; Park 2007; Shin 2006). Among
the major potential sources of bias in epidemiological studies of
diet and cancer are survivor bias, problems with dietary recall, and
difficulties in identifying and controlling for countless confounding variables. We must therefore seek evidence from prospective
controlled trials of calcium supplementation. The association between calcium and vitamin D intake and adenomatous polyps recurrence was evaluated and did not find significant results in a randomized controlled trial, where participants were randomized to
either intensive counseling to adopt a low-fat, high fiber, fruit and
vegetable enriched eating plan, or to be given a standard brochure
on healthy eating (Hartman 2005).
suggest a clinically relevant protective effect of dietary calcium

supplementation on the development of colorectal adenomatous
polyps. Only in the larger, American, trial did the effect reach
statistical significance. It is difficult to assess which factors contributed to the small difference in the results of the studies. Baron
et al (Baron 1999 a; Baron 1999 b) used a lower dose of calcium (1200mg/day versus 2000mg/day in the smaller European
trial), but for a longer period (4 years versus 3 years). It was larger,
achieving an adequate sample size, unlike Bonithon-Kopp et al.
(Bonithon-Kopp 2000) whose smaller sample size reduced the
power of the study with a lack of statistical significance. There
were more events in the control group in Baron et al, which could
be attributed to the longer follow-up. The adequacy of concealment was only documented in Bonithon-Kopp et al. Otherwise,
the methodological differences between the two trials were also so
slight that no meaningful sub-analysis was possible in order to try
and explain the differences in the results.
A recent large randomized controlled trial, the Womens Health

Initiative (WHI) Study (Wactawski-Wende 2006), including
36282 post-menopausal women receiving calcium and vitamin D
or placebo for an average of seven years, did not demonstrate any
effect of the supplements on the incidence of colon cancer. However, we did not include this study in our review for a number
of reasons. First, the WHI study used combined calcium and vitamin D supplements and the independent effect of vitamin D
on prevention of colon cancer is not known. Second, the colon
was not evaluated for adenomas or cancer at baseline ; the study
did not use clear methods of diagnosing colon cancer, unlike the
studies included in our review which used colonoscopy for evaluation. The studies included in our review also used higher doses
of calcium. In future, a larger trial using the doses of calcium used
in the studies we included, without vitamin D and for a longer
follow-up period may yield different results.
Within-trial subgroup analyses for age, sex, and compliance

showed no significant differences in the results for both trials. Despite the relatively large numbers of subjects who successfuly completed the trials, there was not enough data to perform sub-group
analyses for other risk factors. Recent studies based on subsets
of subjects from the original trials included in the review found
associations between colorectal adenoma characteristics and the
risk of recurrence. The number of adenomas and their proximal
location at baseline were the main predictors of recurrence; patients with three or more adenomas with at least one of them located on the proximal colon had a much higher risk of overall recurrence, proximal recurrence and advanced adenoma recurrence
( Bonithon-Kopp 2004). Calcium supplementation may have a
more pronounced antineoplastic effect on advanced colorectal lesions than on other types of polyps (Wallace 2004). Multiple adenomas and the presence of large or advanced adenomas have been
identified as risk factors for adenoma recurrence( Martinez 2001).
Results also suggest that the protective effect of calcium could be
greater when serum levels of 25- hydroxyvitamin D are in the
higher range( Grau 2003).
Colorectal cancer itself is sufficiently rare that it is extremely difficult to conduct a randomised controlled trial large enough and
long enough to isolate the protective effect of any given single nutrient or nutritional supplement. That is why we have to rely on
the indirect evidence supplied by studying the development of the
far more common colorectal adenomatous polyps, some of which
may be pre-cancerous. There are major difficulties in the conduct
of such trials, such as concommitent use of other supplements that
might also affect carcinogenesis, fibre, anti-oxidants and others.
The effects of other nutrients have been reviewed elsewhere - e.g.
fiber (Asano 2002). The trials must also take into account regular
dietary calcium intake as well as the supplement, and the different
baseline risk of colorectal cancer in different people - those with
inflammatory bowel disease, family history and familial polyposis
and previous history of colon neoplasia. To date only two groups
have succeeded in completing such trials, one in North America
and one in Europe.
These two trials were conducted well and produced results that
Only subjects at high risk due to previous adenomas were included

in the trials, so that we may conclude that the intervention could
be applied to this category of population, if confirmed as effective
by further studies. Perhaps a higher dose of calcium for a longer
period is needed, but these doses may be less tolerable and the
risk-benefit ratio must be weighed. Studies on healthy adults not
considered at high risk would be difficult to conduct considering
the problems of recruitment of sufficient subjects, the necessity
of a qualifying and subsequent follow-up colonoscopies, as well
as the long-term adherence to treatment requested from a healthy
adult.
In general, where we find weak clinical effects it is interesting to
look for reasons to explain why only some individuals respond to
the therapeutic intervention and not others. The genetic propen-
sity to colon cancer has been studied in relation to calcium intake

and it seems that people with the BB BsmI genotype for the vitamin D receptor may be at reduced risk of colorectal adenoma.
However, they seem to be less at risk when exposed to lower rather
than higher levels of calcium and vitamin D intake. So the direction of the effect is opposite to that we expect from previous
observations, and more work is needed to identify and explain any
heterogeneity of response (Kim 2001).
Calcium supplementation is attractive as a potential intervention
to reduce the risk of colorectal adenomas and colorectal cancer; it
is relatively cheap and readily
available. Although it is likely to be safe, this, and its efficacy
would need to be more clearly demonstrated in further controlled
studies before any attempt at widespread introduction into clinical
practice. Given the small number of studies eligible for inclusion
in this review, and the conflicting evidence derived from them, no
better conclusions can be drawn at this stage than those resulting
from the vast amount of epidemiological data.
history of adenomatous polyps. There is however no evidence that

such supplements would be detrimental in doses of up to 2 grams
elemental calcium per day.
Implications for research

Large multicentre trials could have the power to answer the outstanding questions - whether calcium supplementation has a protective effect in patients at particularly high risk, or in totally
healthy subjects. Further work is needed on the factors involved
in individual susceptibility to colorectal cancer in order to identify
any subgroups that might benefit from calcium supplementation.
Further trials with an adequate sample size and duration need to
be conducted to confirm the effects of this intervention, including
assessments of dose-response relationships and the risk- benefit
balance.
ACKNOWLEDGEMENTS
AUTHORS CONCLUSIONS
Implications for practice
Although the evidence from two RCTs suggests that calcium supplementation might contribute to the prevention of colorectal adenomatous polyps, this does not constitute sufficient evidence to
recommend the general use of calcium supplements to prevent
colorectal cancer in healthy adults or in adults with a previous
We thank Professor Elliot Berry for the original suggestion to study

this subject, and the principal investigators, Dr Baron and Dr
Bonithon-Kopp, for their cooperation and prompt replies to our
queries. Dr Karla Soares gave us valuable methodological advice.
The Cochrane Colorectal Cancer Group (CCCG) was very helpful with the literature search and in particular Dr Henning Keinke
Andersen was extremely supportive throughout. Clalit Health Services of Israel gave AZ study leave to attend a workshop at the
CCCG.
REFERENCES
References to studies included in this review

Baron 1999 a {published data only}
Baron JA, Beach M, Mandel JS, van Stolk RU, Haile

RW, Sandler RS, Rothstein R, Summers RW, Snover DC,
Beck GJ, Bond JH, Greenberg ER. Calcium supplements
for the prevention of colorectal adenomas. Calcium Polyp
Prevention Study Group. N Engl J Med 1999;340(2):
1017.
Bonithon-Kopp 2000 {published data only}
Bonithon - Kopp C, Kronborg O, Giacosa A, Rath U,

Faivre J. Calcium and fibre supplementation in prevention of
colorectal adenoma recurrence : a randomised intervention
trial. European Cancer Prevention Organisation Study
Group. Lancet 2000;356(9238):13006.
Faivre J, Boutron MC, Doyon F, Pignatelli M, Kronborg O,
Giacosa A, de Oliviera H, Benito E, OMorain C. The ECP
calcium fibre polyp prevention study preliminary report.
ECP Colon Group. Eur J Cancer Prev 1993;2 Suppl 2:
99106.
Faivre J, Couillault C, Kronborg O, Rath U, Giacosa A, de
Oliviera H, Obrador T, OMorain O. Chemoprevention of

metachronous adenomas of the large bowel: design and
interim results of a randomised trial of calcium and fibre.
ECP Colon Group. Eur J Cancer Prev 1997;6:1328.
Faivre J, Doyon F, Boutron MC. The ECP calcium fibre
polyp prevention study. The ECP Colon Group.. Eur J
Cancer Prev 1991;1 Suppl 2:839.
References to studies excluded from this review

Baron 1999 b {published data only}
Baron JA, Beach M, Mandel JS, van Stolk RU, Haile RW,
Sandler RS, Rothstein R, Summers RW, Snover DC, Beck
GJ, Frankl H, Pearson L, Bond JH, Greenberg ER. Calcium
supplements and colorectal adenomas.Polyp Prevention
Study Group. Ann NY Acad Sci 1999;889:13845.
Hofstad 1998 {published data only}
Hofstad B, Almendingen K, Vatn M, Andresen SN,
Owen RW, Larsen S, Osnes M. Growth and recurrence of
colorectal polyps: a double-blind 3-year intervention with
calcium and antioxidants.. Digestion 1998;59:14856.
Hyman 1998 {published data only}

Hyman J, Baron JA, Sandler RS, Haile RW, Mandel
JS, Mott LA, Greenberg ER. Dietary and supplemental
calcium and the recurrence of colorectal adenomas.. Cancer
Epidemiol Biomarkers Prev 1998;7(4):2915.
Hartman 2005
Hartman TJ, Albert PS, Snyder K, Slattery ML, Caan B,
Paskett E, et al.The association of calcium and vitamin D
with risk of colorectal adenomas. The Journal of nutrition
2005;135(2):2529.
Additional references
Hill 1978
Hill MJ, Morson BC, Bussey HJ. Aetiology of adenomacarcinoma sequence in large bowel. Lancet 1978;1:2457.
Adell-Carceller 1997
Adell-Carceller R, Segarra-Soria M, Gibert-Jerez J, Salvador
Sanchis JL, Lazaro-Santander R, Escrig-Sos J, Ruiz-Castillo
J. Inhibitory effect of calcium on carcinogenesis at the site
of colonic anastomosis: an experimental study.. Dis Colon
Rectum 1997;40(11):13761381.
Asano 2002
Asano T, McLeod RS. Dietary fibre for the prevention of
colorectal adenomas and carcinomas. Cochrane Database
of Systematic Reviews 2002, Issue 4. [DOI: 10.1002/
14651858.CD003430]
Bergsma-Kadijk 1996
Bergsma-Kadijk JA, van t Veer P, Kampman E, Burema
J. Calcium does not protect against colorectal neoplasia.
Epidemiology 1996;7(6):5907.
Bonithon-Kopp 2004
Bonithon-Kopp C, Piard F, Fenger C, Cabeza E, O Morain
C, Kronborg O, Faivre J. Colorectal adenoma characteristics
as predictors of recurrence. Dis Colon Rectum 2004;47(3):
32333.
Bostick 1997
Bostick RM. Human studies of calcium supplementation
and colorectal epithelial cell proliferation. Cancer
Epidemiology Biomarkers Prev 1997;6:97180.
Clarke 2000
Clarke M, Oxman A, editors. Cochrane Handbook
[Cochrane Reviewers Handbook 4.1 [updated June 2000]].
Cochrane Reviewers Handbook 4.1. Version 4.1. Oxford,
England: The Cochrane Collaboration, 2000.
Dickersin 1994
Dickersin K, Schrerer R, Lefebvre C. Identifying relevant
studies for systematic reviews.. BMJ 1994;309:128691.
Flood 2005
Flood A, Peters U, Chatterjee N, Lacey Jr JV, Schairer
C, Schatzkin A. Calcium from diet and supplements
is associated with reduced risk of colorectal cancer in
a prospective cohort of women. Cancer Epidemiology
Biomarkers and Prevention 2005;14(1):12632.
Giovannucci 1998
Giovannucci E, Stampfer MJ, Colditz GA, Hunter DJ,
Fuchs C, Rosner BA, Speizer FE, Willett WC. Multivitamin
use, folate, and cancer in women in the Nurses Health
Study. Annals of Internal Medicine 1998;129:51724.
Grau 2003
Grau MV, Baron JA, Sandler RS, Haile RW, Beach
ML, Church TR, Heber D. Vitamin D, calcium
supplementation, and colorectal adenomas: results of a
randomized trial. J Natl Cancer Inst 2003;95(23):176571.
Huncharek 2009
Huncharek M, Muscat J, Kupelnick B. Colorectal cancer
risk and dietary intake of calcium, vitamin D and
diary products: a meta-analysis of 26335 cases from 60
observational studies. Nutrition of cancer 2009;61(1):
4769.
Jadad 1996
Jadad AR, Moore A, Caroll D, Jenkinson C, Reynolds
JM, Gavaghan DJ, et al.Assessing the quality of reports
of randomized clinical trials : is blinding necessary?.
Controlled Clinical Trials 1996; Vol. 17:112.
Kesse 2005
Kesse E, Boutron Ruault MC, Norat T, Riboli E, Clavel
Chapelon F. Dietary calcium, phosphorus, vitamin D, dairy
products and the risk of colorectal adenoma and cancer
among French women of the E3N-EPIC prospective study.
International Journal of Cancer 2005;117(1):13744.
Kim 2001
Kim HS, Newcomb PA, Ulrich CM, Keener CL, Bigler
J, Farin FM, Bostick RM, Potter JD. Vitamin D receptor
polymorphism and the risk of colorectal adenomas:
Evidence of interaction with dietary vitamin D and calcium.
Cancer-Epidemiology-Biomarkers-and-Prevention. 2001;10
(8):869874.
Larsson 2006
Larsson SC, Bergkvist L, Rutegard J, Giovannucci E, Wolk
A. Calcium and dairy food intakes are inversely associated
with colorectal cancer risk in the Cohort of Swedish Men.
American Journal of Clinical Nutrition 2006;83(3):66773.
Little 1993
Little J, Logan RFA, Hawtin PG, Hardcastle JD, Turner
ID. Colorectal adenomas and diet: A case-control study of
subjects participating in the Nottingham faecal occult blood
screening programme. British-Journal-of-Cancer 1993;67
(1):177184.
Martinez 1998
Martinez ME, Willett WC. Calcium, vitamin D, and
colorectal cancer: a review of the epidemiologic evidence.
Cancer Epidemiol Biomarkers Prev 1998;7:1638.
Martinez 2001
Martinez ME, Sampliner R, Marshall JR, Bhattacharyya
AK, Reid ME, Alberts DS. Adenoma characteristics
as risk factors for recurrence of advanced adenomas.
Gastroenterology 2001;120:107783.
Midgeley 1999
Midgeley R, Kerr D. Colorectal Cancer. Lancet 1999;353
(9150):391399.
Nagengast 1995
Nagengast FM, Grubben MJAL, van Munster IP. Role of
bile acids in colorectal carcinogenesis. Eur J Cancer 1995;
31 A:106770.
Newmark 1992
Newmark HL, Lipkin M. Calcium vitamin D and colon
cancer. Cancer Research 1992;52:2067s207s.
OSullivan 1993
OSullivan KR, Mathias PM, Beattie S, OMorain C.
Effect of oral calcium supplementation on colonic crypt
cell proliferation in patients with adenomatous polyps of
the large bowel. European-Journal-of-Gastroenterology-andHepatology 1993;5(2):8589.
Park 2007
Park SY, Murphy SP, Wilkens LR, Nomura AMY,
Henderson BE, Kolonel LN. Calcium and vitamin D intake
and risk of colorectal cancer: The Multiethnic Cohort
Study. American Journal of Epidemiology 2007;165(7):
78493.
Pence 1993
Pence BC. Role of calcium in colon cancer prevention:
experimental and clinical studies. Mutat Res 1993;290:
8795.
Rozen 1989
Rozen P, Fireman Z, Fine N, Wax Y, Ron E. Oral calcium
supresses increased rectal epithelial proliferation of persons
at risk of colorectal cancer. Gut 1989;30:650655.
Sandler 2000
Sandler RS, Baron JA, Tosteson TD, Mandel JS, Haile
RW. Rectal mucosal proliferation and risk of colorectal
adenomas: Results from a randomized controlled trial.
Cancer-Epidemiology-Biomarkers-and-Prevention. 2000;9
(7):653656.
Shin 2006
Shin A, Li H, Shu XO, Yang G, Gao YT, Zheng W.
Dietary intake of calcium, fiber and other micronutrients in
relation to colorectal cancer risk: Results from the Shanghai
Womens Health Study. International Journal of Cancer
2006;119(12):293842.
Slattery 1997
Slattery Ml, Caan BJ, Potter JD, Berry TD, Coates A,
Duncan D, Edwards SL. Dietary energy sources and colon
cancer risk. American Journal of Epidemiology 1997;145:
199210.
van der Meer 1997
Van der Meer, Lapre JA, Govers MJ, Kleibeuker JH.
Mechanisms of the intestinal effects of dietary fats and milk
products on colon carcinogesis. Cancer Letter 1997; Vol.
114:7583.
Wactawski-Wende 2006
Wactawski-Wende J, Kotchen JM, Anderson GL, Assaf AR,
Brunner RL, OSullivan MJ, et al.Calcium plus Vitamin D
Supplementation and the Risk of Colorectal Cancer. N Engl
J Med 2006;354(7):684696.
Wallace 2004
Wallace K, Baron JA, Cole BF, Sandler RS, Karagas MR,
Beach MA, Haile RW, Burke CA, Pearson LH, Mandel JS,
Rothstein R, Snover DC. Effect of calcium supplementation
on the risk of large bowel polyps. J Natl Cancer Inst 2004;
96(12):921925.
Whelan 1999
Whelan RL, Horvath KD, Gleason NR, Forde KA, Treat
MD, Teitelbaum SL, Bertram A, Neugut AI. Vitamin
and calcium supplement use is associated with decreased
adenoma recurrence in patients with a previous history of
neoplasia. Diseases-of-the-Colon-and-Rectum. 1999;42(2):
212217.
Indicates the major publication for the study
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Baron 1999 a
Methods
multicentre
Randomisation :
computerised generation of allocation sequence,
blocked according to study center ( 2 )*
Allocation concealment : not mentioned
Double- blind : yes ( 2 )
Intention to treat :
not mentioned
89% included in the main analysis from the main study period.
Every six months
questionnaires on adherence to
intervention, medication,nutritional supplements
Two periods included in the study : from qualifying and including the first f / u colonoscopy (at 1 year)
and the main study period after the first and including the second f / u colonoscopy ( at 4 years)
f / u described ( 1 ) 89% completed study
Design : parallel
Jadad score = 5
Participants
N =930
670 - men
260 -women
Mean age (SD) :
61 (9) yrs with recent history of colorectal adenomas confirmed histologically removed within 3 months
before recruitment , free of polyps on complete colonoscopy
Inclusion criteria
- < 80 yrs
-in good health
Exclusion criteria
-FAP, CRC
-malabsorbtion
-conditions worsened by calcium
Baseline characteristics and dietary pattern similar in both groups, no significant differences. Less
than 3% taking calcium supplements at the start of the trial discontinued
it
Interventions
Treatment group:
calcium carbonate 3g
(1200 mg elemental calcium ) daily
N = 464
Control group:
identical placebo
N = 466
Mean duration :
4 yrs
10
Baron 1999 a
(Continued)
Diet assessed at enrollment and at the end of the study by a validated food questionnaire
Mean daily dietary calcium intake 865+/- 423
mg in Tx group
889+/- 451 in C group
Compliance assessed as percentage of tablets taken,
similar in both groups. > 80% of subjects
taking study agents > 90% of the time at 4 yrs
Outcomes
-the proportion of subjects in whom at least one adenoma was detected after the first f / u
and including the
second f / u colonoscopy
-the average number of adenomas in both groups
All polyps removed were histologically diagnosed
Notes
Recruitment
1988 - 1992
Six clinical centers in USA
913 subjects underwent at least one f / u colonoscopy. 832 ( 89%) included in the main analysis
409- Tx group
423- C group and had two f / u
colonoscopies with polyps removed. Interim
colonoscopies only when necessary
Drop-outs:
55 (11, 8%)- Tx group: 22 died ,11lost interest, 8 ill or moved, 2 unknown /other
43 (9,2%)- C group: 25 died,
14 lost interest,
10 ill /moved, 6
other/unknown
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Unclear
B - Unclear
11
Bonithon-Kopp 2000
Methods
multicentre
Randomisation :
stratified by center balanced every six patients
2calcium, 2fibre,
1placebo calcium, 1placebo fibre
(2)
Allocation concealment :
independent randomisation center
Double-blind: yes ( 2 )
Intention to treat:
yes
f / u described (1)
f / u complete colonoscopy at 3
yrs 86%
Design: parallel
Jadad score= 5
Participants
N =640
Mean age (SD) :
58.8 ( 8.8 ) yrs
Tx group,
59.3 ( 8.4 ) yrs
C group, with history of colorectal adenomas.
Polyps removed
at qualifying colonoscopy.
Inclusion criteria
-at least two adenomas or one > 5mm on complete colonoscopy confirmed by pathologist
- age 35-75
- no debilitating
disease
Exclusion criteria
- FAP, IBD, CRC, colonic resection
-contraindication
to calcium / fibre
-current calcium treatment that could not be stopped
Baseline characteristics and mean dietary intake similar in both groups, no significant differences
Interventions
Treatment group:
- calcium gluconolactate and carbonate PO twice daily (2000 mg elemental calcium daily)
N =204
- fibre -isphagula
3.5g per day
N =224
Control group:
placebo sucrose with taste, appearance and excipient as the intervention
N =212
Diet assessed by a standard validated questionnaire at baseline and at 3 yrs
Mean calcium intake: 944 (364) mg - calcium group
1023 (404) mg
12
Bonithon-Kopp 2000
(Continued)
C group, p =0.28
Duration- 3 yrs
Compliance assessed by unused sachets
returned, standard interview, fecal
calcium. 69% in
Tx and 82% in C
groups, p =0.044 took > 80% of the
sachets prescribed
Outcomes
- at least one new

adenoma at 3 yr
examination
All removed polyps were pathologically diagnosed
Notes
21 centres from
ten countries
Recruitment
1991- 1994
25 subjects excluded initially
after the randomisation because not histologically confirmed adenomas (665 subjects initially)
Randomisation
after complete qualifiyng colonoscopy
Interim colonoscopies only if necessary, with polyps removed counted
as endpoints, only if removed
>12 months after the
qualifying colonoscopy ( 1 subject not counted only and
this had a hyperplastic polyp).
The proportions of final colonoscopies similar between groups p =0.41
Calcium group:
176 subjects completed study, 8 died, 2 severe illness, 5 lost to
f/u 13 refused to continue
Control group:
178 completed study, 9 died, 1
severe illness, 5 lost to f/u, 19 refused to continue
Risk of bias
Item
Authors judgement
Description
Allocation concealment?
Yes
A - Adequate
*( ) number of points obtained in the Jadad scale; FAP familial adenomatous polyposis; IBD inflammatory bowel disease
CRC colorectal cancer; SD standard deviation; yr year; Tx treatment; C control; f /u follow -up
13
Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Baron 1999 b
Included participants and data from a similar report of the same study
Hofstad 1998
Randomised, parallel
Participants: N= 116 polyp bearing subjects
Intervention: mixture of calcium and antioxidants vs. placebo
Not separate arm for calcium supplementation
Hyman 1998
Not randomised for calcium supplementation; assessment

based on a questionnaire .
14
DATA AND ANALYSES
Comparison 1. Calcium versus placebo
Outcome or subgroup title

1 Number of subjects diagnosed
with colorectal cancer
2 Number of subjects with at least
one new adenoma
3 Number of subjects with at least
one adverse event requiring
discontinuation of treatment
4 Number of subjects that dropped
- out
No. of
studies
No. of
participants
1346
Odds Ratio (M-H, Fixed, 95% CI)
0.34 [0.05, 2.15]
1346
0.74 [0.58, 0.95]
930
0.93 [0.42, 2.05]
1346
1.11 [0.80, 1.55]
Statistical method
Effect size
Analysis 1.1. Comparison 1 Calcium versus placebo, Outcome 1 Number of subjects diagnosed with
colorectal cancer.
Review:
Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps
Comparison: 1 Calcium versus placebo

Outcome: 1 Number of subjects diagnosed with colorectal cancer
Study or subgroup
Calcium
Placebo
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Baron 1999 a
1/464
3/466
67.1 %
0.33 [ 0.03, 3.22 ]
Bonithon-Kopp 2000
0/204
1/212
32.9 %
0.34 [ 0.01, 8.51 ]
668
678
100.0 %
0.34 [ 0.05, 2.15 ]
Total (95% CI)
Weight
Odds Ratio
M-H,Fixed,95% CI
Total events: 1 (Calcium), 4 (Placebo)

Heterogeneity: Chi2 = 0.00, df = 1 (P = 0.99); I2 =0.0%
Test for overall effect: Z = 1.15 (P = 0.25)
0.1 0.2
0.5
Favours calcium
10
Favours placebo
15
Analysis 1.2. Comparison 1 Calcium versus placebo, Outcome 2 Number of subjects with at least one new
adenoma.
Review:

Outcome: 2 Number of subjects with at least one new adenoma
Study or subgroup
Baron 1999 a
Bonithon-Kopp 2000
Total (95% CI)
Calcium
Placebo
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
127/464
159/466
79.1 %
0.73 [ 0.55, 0.96 ]
28/204
36/212
20.9 %
0.78 [ 0.45, 1.33 ]
668
678
100.0 %
0.74 [ 0.58, 0.95 ]
M-H,Fixed,95% CI

Heterogeneity: Chi2 = 0.05, df = 1 (P = 0.83); I2 =0.0%
0.1 0.2
0.5
Favours calcium
10
Favours placebo
Analysis 1.3. Comparison 1 Calcium versus placebo, Outcome 3 Number of subjects with at least one
adverse event requiring discontinuation of treatment.
Review:

Outcome: 3 Number of subjects with at least one adverse event requiring discontinuation of treatment
Study or subgroup
Baron 1999 a
Total (95% CI)
Calcium
Placebo
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Weight
Odds Ratio
12/464
13/466
100.0 %
0.93 [ 0.42, 2.05 ]
464
466
100.0 %
0.93 [ 0.42, 2.05 ]
M-H,Fixed,95% CI

Heterogeneity: not applicable
0.1 0.2
0.5
Favours calcium
10
Favours placebo
16
Analysis 1.4. Comparison 1 Calcium versus placebo, Outcome 4 Number of subjects that dropped - out.
Review:

Outcome: 4 Number of subjects that dropped - out
Study or subgroup
Calcium
Placebo
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
Baron 1999 a
55/464
43/466
56.8 %
1.32 [ 0.87, 2.02 ]
Bonithon-Kopp 2000
28/204
34/212
43.2 %
0.83 [ 0.48, 1.43 ]
668
678
100.0 %
1.11 [ 0.80, 1.55 ]
Total (95% CI)
Weight
Odds Ratio
M-H,Fixed,95% CI

Heterogeneity: Chi2 = 1.74, df = 1 (P = 0.19); I2 =43%
0.1 0.2
0.5
Favours calcium
10
Favours placebo
ADDITIONAL TABLES
Table 1. Adverse events
Study
Intervention
Side effects
Baron 1999a
calcium carbonate as 1200 mg

elemental calcium daily
- digestive symptoms: only consti- Similar proportions in both

pation reported
groups had
digestive symptoms or stopped
-urinary stones in two subjects in treatment because of toxicity
the calcium group and one subject
in the placebo group
Bonithon Kopp 2000
calcium gluconolactate and car- -diarrhea severe and abdominal Major side effects more frecvent in
bonate as 2000 mg elemental cal- pain reported as major side effects the calcium group than in placebo
cium daily
group, were reported in six versus
three subjects respectively. Poor
compliance
defined as taking less than 80%
of the intervention was more frequent in the
calcium group
Any adverse event -14.8% in the
calcium
group vs. 6.7% placebo group , p
= 0.043
Comments
17
WHATS NEW
Last assessed as up-to-date: 20 January 2010.
Date
Event
Description
5 January 2010
New search has been performed
Number of studies found on last searches was added . No new studies were
found for inclusion
HISTORY
Protocol first published: Issue 3, 2002
Review first published: Issue 1, 2004
Date
Event
Description
23 July 2008
Amended
Converted to new review format.
7 September 2007
New citation required and conclusions have changed
Substantive amendment
CONTRIBUTIONS OF AUTHORS
The original idea for this review was Professor Berrys, of The Hebrew University, Jerusalem, but he withdrew as a co-author for lack
of time.
Dr Zalmanovici did most of the work, selecting the studies to be included, and assessing their quality. She also entered all the data into
Revman and wrote the Background, Methods and Results sections.
Professor Weingarten supervised the project, was the contact for CCCG and for the authors of the trials included in the review. He was
also responsible for the literature search, and was an independent assessor in selecting the trials to be included. He edited the review
and wrote the Discussion.
Dr John Yaphe assessed the selected reviews and criticized and improved the review
DECLARATIONS OF INTEREST
None known
18
NOTES
This is the third update of the review. The searches for new trials were performed December 2009, but didnt identify any new trials
to be included.
INDEX TERMS
Medical Subject Headings (MeSH)
Dietary
Supplements; Adenoma [complications]; Adenomatous Polyps [ prevention & control]; Calcium, Dietary [ therapeutic use];
Colorectal Neoplasms [ prevention & control]; Randomized Controlled Trials as Topic
MeSH check words

Humans
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Dietary calcium supplementation for preventing colorectal

cancer and adenomatous polyps (Review)

Dietary calcium supplementation for preventing colorectal

PLAIN LANGUAGE SUMMARY

a high familial risk of colorectal cancer (Rozen 1989). Although

Criteria for considering studies for this review

Types of outcome measures

Search methods for identification of studies

Data collection and analysis

Two reviewers (YY, AZ) independently extracted the data from

Risk of bias in included studies

A maximum score of 5, according to the Jadad criteria of quality of

There was no evidence of heterogeneity between studies as assessed

atic review they present an inconsistent and inconclusive picture

suggest a clinically relevant protective effect of dietary calcium

A recent large randomized controlled trial, the Womens Health

Within-trial subgroup analyses for age, sex, and compliance

Only subjects at high risk due to previous adenomas were included

sity to colon cancer has been studied in relation to calcium intake

history of adenomatous polyps. There is however no evidence that

Implications for research

We thank Professor Elliot Berry for the original suggestion to study

References to studies included in this review

Baron JA, Beach M, Mandel JS, van Stolk RU, Haile

Bonithon - Kopp C, Kronborg O, Giacosa A, Rath U,

Oliviera H, Obrador T, OMorain O. Chemoprevention of

References to studies excluded from this review

Hyman 1998 {published data only}

Indicates the major publication for the study

Characteristics of included studies [ordered by study ID]

- at least one new

Characteristics of excluded studies [ordered by study ID]

Reason for exclusion

Not randomised for calcium supplementation; assessment

DATA AND ANALYSES

Comparison 1. Calcium versus placebo

Outcome or subgroup title

Odds Ratio (M-H, Fixed, 95% CI)

0.34 [0.05, 2.15]

Odds Ratio (M-H, Fixed, 95% CI)

0.74 [0.58, 0.95]

Odds Ratio (M-H, Fixed, 95% CI)

0.93 [0.42, 2.05]

Odds Ratio (M-H, Fixed, 95% CI)

1.11 [0.80, 1.55]

Comparison: 1 Calcium versus placebo

0.33 [ 0.03, 3.22 ]

0.34 [ 0.01, 8.51 ]

0.34 [ 0.05, 2.15 ]

Total (95% CI)

Total events: 1 (Calcium), 4 (Placebo)

Comparison: 1 Calcium versus placebo

Total (95% CI)

0.73 [ 0.55, 0.96 ]

0.78 [ 0.45, 1.33 ]

0.74 [ 0.58, 0.95 ]

Total events: 155 (Calcium), 195 (Placebo)

Comparison: 1 Calcium versus placebo

Total (95% CI)

0.93 [ 0.42, 2.05 ]

0.93 [ 0.42, 2.05 ]

Total events: 12 (Calcium), 13 (Placebo)

Comparison: 1 Calcium versus placebo