Dietary calcium supplementation for preventing colorectalcancer and adenomatous polyps (Review)Weingarten MAMA, Zalmanovici Trestioreanu A, Yaphe JThis is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2010, Issue 9http://www.thecochranelibrary.comDietary calcium supplementation for preventing colorectal cancer and adenomatous polyps (Review)Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.T A B L E O F C O N T E N T S1 HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2 PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2 BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3 OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3 METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4 RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5 DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7 AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7 ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9 CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15 DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Analysis 1.1. Comparison 1 Calcium versus placebo, Outcome 1 Number of subjects diagnosed with colorectal cancer. 15Analysis 1.2. Comparison 1 Calcium versus placebo, Outcome 2 Number of subjects with at least one new adenoma. 16Analysis 1.3.Comparison1 Calcium versus placebo,Outcome 3 Number ofsubjects withat least oneadverseeventrequiring discontinuation of treatment. . . . . . . . . . . . . . . . . . . . . . . . . . 16Analysis 1.4. Comparison 1 Calcium versus placebo, Outcome 4 Number of subjects that dropped - out. . . . . 1717 ADDITIONAL TABLES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18 WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18 HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18 CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18 DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18 NOTES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19 INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .i Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps (Review)Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.[Intervention Review]Dietary calcium supplementation for preventing colorectalcancer and adenomatous polypsMichael Asher MA Weingarten1, Anca Zalmanovici Trestioreanu2, John Yaphe31Department of Family Medicine, Rabin Medical Centre, Petah Tikva, Israel.2Department of Family Medicine, Beilinson Campus,Rabin Medical Center, Petah-Tiqva, Israel.3School of Health Science, University of Minho, Braga, PortugalContact address: Michael Asher MA Weingarten, Department of Family Medicine, Rabin Medical Centre, Beilinson Campus, PetahTikva, 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 calciumsupplementation for preventing col-orectal cancer andadenomatous polyps. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD003548. DOI:10.1002/14651858.CD003548.pub4.Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.A B S T R A C TBackgroundSeveral 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 difcult to perform owing to the large number of patients and the longfollow-up required; studies using the appearance of colorectal adenomatous polyps as a surrogate endpoint are therefore considered inreviewing the existing evidence.ObjectivesThis systematic review aims to assess the effect of supplementary dietary calciumon the incidence of colorectal cancer and the incidenceor recurrence of adenomatous polyps.Search methodsWe searched the Cochrane Controlled Trials Register, the Cochrane Colorectal Cancer Group specialised register, MEDLINE, Cancerlit, and Embase, to December 2009. The reference lists of identied studies were inspected for further studies, and the review literaturewas scrutinized.Selection criteriaRandomised controlled trials of the effects of dietary calciumon the development of colonic cancer and adenomatous polyps in humansare reviewed. Studies of healthy adults and studies of adults at higher risk of colon cancer due to family history, previous adenomatouspolyps, orinammatorybowel diseasewereconsidered; datafromsubjectswithfamilial polyposiscoli areexcluded. Theprimaryoutcomes were the occurrence of colon cancer, and occurrence or recurrence of any new adenomas of the colon. Secondary outcomeswere any adverse event that required discontinuation of calcium supplementation, and drop-outs before the end of the study.Data collection and analysisTwo reviewers independently extracted data, assessed trial quality and resolved discrepancies by consensus. The outcomes were reportedas odds ratios (OR) with 95% condence intervals (CI). The data were combined with the xed effects model.1 Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps (Review)Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.Main resultsTwostudieswith1346subjectsmettheinclusioncriteria.Bothtrialswerewelldesigned,double-blind,placebocontrolledtrials,included participantswith previousadenomas.The doses ofsupplementaryelemental calcium used were 1200mg daily fora meanduration of 4 years, and 2000 mg/day for three years.The rates of loss to follow -up were 14 % and 11%.Forthedevelopment ofrecurrentcolorectaladenoma,areductionwasfound(OR 0.74,CI0.58,0.95)whentheresults from bothtrials were combined.Authors conclusionsAlthough the evidence from two RCTs suggests that calcium supplementation might contribute to a moderate degree to the preventionof colorectal adenomatous polyps, this does not constitute sufcient evidence to recommend the general use of calcium supplementsto prevent colorectal cancer.P L A I N L A N G U A G E S U M M A R YDaily intake of 1 gr dietary calcium may have moderate protective effect on development of colorectal adenomatous polypsTherehavebeensuggestions, basedonobservational studiesandonlaboratorymarkers, thatdietarycalciummayprotectagainstcolorectal cancer. This systematic review ofthe literature identied two well conductedrandomisedplacebo-controlled interventionstudies involving 1346 subjects followed for 3-4 years. The results suggest that there may be a moderate protective effect (OR 0.74; CI0.58,0.95) for dietary supplementation of at least 1200mg elemental calcium per day on the development of colorectal adenomatouspolyps. However, no trial has directly demonstrated an effect of calciumsupplementation on the development of colorectal cancer itself.B A C K G R O U N DColon cancer is one of the leading cancers in men and women andit is associated with more industrialised societies; European Unionaverage incidence between 1988-1992 was 33.8/100000 for menand 23.7/100000 for women. The risk of colorectal cancer beginsto increase after the age of 40 and rises sharply fromthe age of 50-55 years.Early detection and treatment may have some effect on reducingthe mortality fromcoloncancer but effective primary preventionisthe more important public health goal. Several dietary factors havebeen considered responsible for the changing incidence includingcalcium, ber, sugar, fat, vegetables, and meat among others. Theunderlying mechanismsare notclear, but mayin part beduetoalterations in bile acids which have been found to be carcinogenicin animals (Nagengast 1995). Dietary calcium has been suggestedas a chemoprotective agent against colorectal cancer; it is thoughtto bind fatty acids and bile acids in the colon thus inhibiting thefat-induced hyperproliferation of colon epithelial cells (Newmark1992). The mechanism may be mediated by the precipitation ofcolonic cytotoxic surfactants thus inhibiting luminal cytotoxicity(vanderMeer1997). Calciumhas alsobeenshowntoreducepathologicalcytokineticcrypt activityprimarily inpatientswitha high familialrisk of colorectalcancer(Rozen 1989). Althoughseveralanimalstudieshaveshownaprotectiveeffect ofcalciumin colon carcinogenesis (e.g. Pence 1993), the empirical evidencefromcohort studies (e.g. Giovannucci 1998) andcase control stud-ies (e.g. Slattery 1997) is inconsistent on the question whether in-creased dietary calcium levels do indeed prevent the developmentof coloncancerinhumans. Someepidemiological studieshavesuggested a protective effect for total calcium intake above1500to 1800mg daily (Newmark 1992), but for colorectal adenomas,which are potential precursors of most large bowel cancers, the ev-idence is conicting (Bergsma-Kadijk 1996, Martinez 1998, Hill1978). The evidence from 24 case-control and cohort studies andfromover 20 epidemiological studies has been reviewed, and failedto nd clear support for a signicant protective effect of calciumon colon cancer (Bergsma-Kadijk 1996; Martinez 1998). Calciumintake was associated with a decreased risk of colorectal cancer ina recent meta-analysis of observational studies (Huncharek 2009).Thereareonlyasmall numberof completedrandomisedcon-trolled trials, but the little evidence they provide is of better qualitythan that based on epidemiological studies, which could at best beused to strenghten the evidence from the randomised controlledtrials if similar results were obtained.2 Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps (Review)Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.Intervention studies with colorectal cancer as an endpoint are dif-cult toperform owingtothe largenumberofpatientsandthelong follow-uprequired. Since almost all colorectal cancers developfromadenomas, and since 5%of all adenomas develop into cancer(Midgeley 1999), studies regarding the development of colorectaladenomatouspolypsasasurrogateendpointmayreasonablybeconsidered in reviewing the existing evidence. Colorectal adenomacould also be a reasonable target for primary prevention .The aimofthisreviewistoassesscriticallytheevidencefrom completedrandomisedcontrolledtrialsthatcalciumsupplementationmaybesuccessful inreducingcoloncancerrisk. Thisreviewwill beupdated as results from new trials become available.O B J E C T I V E SThis systematic review and meta-analysis aims to assess the effectofsupplementarydietarycalciumontheincidenceofcolorectalcancer and the incidence or recurrence of adenomatous polyps inadults atdifferent levels ofrisk,and thedevelopment ofadverseeffects.The hypothesis to be tested is that higher levels of calcium intakehaveabenecial effectinthepreventionofcoloniccancerandadenomatous polyps.M E T H O D SCriteria for considering studies for this reviewTypes of studiesRandomised controlled trials of the effects of dietary calcium onthedevelopmentof coloniccancerandadenomatous polypsinhumansarereviewed. Therationaleforexcludingotherexperi-mental designs isthatrandomisedcontrolledtrialsprovidethebest current evidence upon which people can base their decisions;cohort studies are subject to recruitment bias, while case-controland epidemiological studies of cancer risk are subject to survivorbias and they are also particularly prone to errors in dietary recall.Trials reporting only physiological or laboratory parameters, suchasepithelialcellproliferationrates,arenotconsideredclinicallyrelevant and are not reviewed here.Types of participantsStudies of healthy adults, irrespective of gender or nationality andstudies of adults at higher risk of coloncancer due to family history,previous adenomatous polyps, or inammatory bowel disease areconsidered. Datafromsubjects withfamilial polyposis coli areexcluded.Types of interventionsStudiesareincludedwhichusedsupplementationwithcalciumsaltsindosesabove1200mgelementalcalciumperday,withaduration of intervention longer than six months.For the control group we accepted either placebo supplementationor no intervention.Trialsreportingcombinedinterventions inwhichtherewasnoarm testingforcalcium supplementationalonearenotincludedin this review.Types of outcome measuresPrimary-occurrence of colon cancer-occurrence of any new adenomas of the colonSecondary-any adverse event that required discontinuationof calcium sup-plementation-drop-outs (lost to follow up) before the end of the study.Search methods for identication of studiesRelevant randomised controlled trials were identied by the searchstrategy described by Dickersin et al (Dickersin 1994).The following search terms were used : calcium, prevention, can-cer, neoplasms,colonic, colorectal, polyps, adenomas,adenoma-touspolyps,human,randomizedcontrolledtrials,randomallo-cation, intervention studies. Searches for colo*, adenom*, polyp*were also performed. We searched the Cochrane Controlled TrialsRegister ( CochraneLibraryIssue4,2009),theCochraneColorectal CancerGroup(CCCG) specialised register, the MEDLINE ( from 1966 to De-cember 2009 ), Cancerlit ( from 1963 to December 2009 ), Em-base ( from1980toDecember 2009). TheEmbaseandtheCCCGspecialisedregistersearchesweredoneaccordingtothesearch strategy of the CCCG.The reference lists in reports of all identied studies were inspectedfor further studies. In addition the existing review literature (e. g.Bostick 1997) was scrutinized.Data collection and analysisTworeviewers (MAW, AZ) independently reviewedthe abstracts ofpotential studies to be included in the review. For possibly relevantarticles or in cases of disagreement between the two reviewers thefull article was obtained and inspected independently.Trials werecategorised by patient baseline status (healthy versus adenomatouspolypsorotherriskfactorsforcoloniccancer). Thedatafromthestudiesweredivided, asfaraspossiblefrompublishedandunpublished information, into groups according to age at entry.3 Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps (Review)Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.Tworeviewers(YY, AZ)independentlyextractedthedatafromthe included trials. Disagreements were documented and resolvedbydiscussionandtheauthors of thestudywerecontactedforclarication. Justicationforexcludingstudiesfromthereviewwere also documented.Data extracted included:-characteristics of trials - publication status, year, country of study,setting, design, inclusion criteria, confounding variables, mannerof recruitment, methods, analysis, results.-characteristics of participants - study population, number of par-ticipants ineach group, age, gender, nationality, details onpatientsbasic bowel status, risk factors, average calcium intake in relationto the recommended daily allowance.-characteristics of interventions - calcium preparation used, dose,length of treatment and follow-up.-outcomemeasures- number of subjectsinwhomanewade-nomatous polyp occured in the intervention and control groups,number of subjects in whomcolon cancer occured in both groups,numberof subjects who developed adverse or medical events re-lated to the intervention,drop-outsbeforethe end ofstudyandreasons for dropping out.Data synthesisDichotomous data was analysed by calculating the odds ratio foreachtrial withthe uncertainityineach result beingexpressed as95% condence intervals.Results are shown using the approach recommended in theCochrane Handbook (Clarke 2000). All analyses were performedon the basis of intention to treat. We expected heterogeneity be-tween study results because of different age categories, baseline risklevels, doses and preparations used and duration of studies. Sub-group analysis was planned to assess the impact of these possiblesources of heterogeneity. In the absence of heterogeneity the xedeffects model is used appropriately. Associationsfor lower versushigher levels of calcium intake are reported.The characteristics of eligible trials including those that were ex-cluded and the reasons for exclusion are presented in the Tables.ThequalityofthereportsoftherandomisedtrialswasassessedusingthemethodofJadadetal (Jadad1996). Concealmentofrandomisationwas assessedaccording toCochrane Collabora-tionstandards. Subgroupanalyseswasplannedforeachqualityitem.Tworeviewers independentlyassessedthemethodologicalquality of each study. The studies were assessed for the quantica-tion of concomitant use of other nutrients that have been impli-cated in colon carcinogenesis.Additional information was obtained from the authors where thepublications presented insufcient detail.R E S U L T SDescription of studiesSee: Characteristics of includedstudies; Characteristics of excludedstudies.SeetableofCharacteristicsofincludedstudies. Twostudies,with1346subjectsassignedto calciumsupplements orplacebo,met the prestated criteria for inclusion in this review.Thetwostudiesweremulticentretrials; onewasconductedinten European countries- Belgium,Denmark,France,Germany,Ireland, Israel, Italy, Portugal, Spain, theUK(Bonithon-Kopp2000), and the other study involved six clinical centers in the USA(Baron 1999 a).ParticipantsThe entry criteria in the two trials were similar, including partic-ipantswithpreviousadenomasandtherefore consideredat highrisk for recurrence. Subjects included had a qualifying colonoscopyandpolypectomyperformed toensurethatthecolonorrectumwere free of polyps at baseline.InterventionBoth studies used placebo inthe control group. 1200 mg elementalcalcium daily for a mean duration of 4 years was administered inone study (Baron 1999 a), and 2000 mg/day for three years in thesecondstudy(Bonithon-Kopp2000). Themeandietaryintakewas similar for the groups as stated in the studies.OutcomesThe included studies reported the number of subjects with at leastonerecurrentadenoma, orcolorectal cancer, anddescribedthedrop-outsandthereasonsforleavingthestudybeforetheend.Detailed data for the adverse event that required discontinuationof treatment could not be obtained in one study (Bonithon-Kopp2000). Informationonadverseevents that occuredduringthetrials is presented in Table 1.Risk of bias in included studiesSeetableofCharacteristicsofincludedstudies. Bothstudieswere well designed, double - blind, placebo controlled trials.AllocationBoth studies were randomised controlled trials with an adequategenerationofallocationsequence.However, onlyonecontainedan adequate report of concealment of allocation (Bonithon-Kopp2000).Blinding to interventionBoth trials were double - blinded and the method of blinding wasdescribed and was adequate.Follow - upInonestudy25subjects wereexcludedinitiallyafter theran-domisation for lack of documentation of histologically conrmedadenoma, andtotal loss tofollow-upinthis 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.4 Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps (Review)Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.Amaximumscore of 5, according to the Jadad criteria of quality ofstudies for randomisation, blinding and follow -up, was obtainedbybothtrials.However,theassessmentforinclusionwasbasedprimarily on concealment of allocation.Effects of interventionsFor numerical details see Analyses453 references were identied , the abstracts inspected , and 448excluded for the following reasons: not randomised, observationalstudies, study subjects not responding to inclusion criteria, inter-ventionofinterestnotused,norelevant outcomesreported,re-ports of biochemical endpoints, repeated reports of the same study,reviewarticles. Five reports were considered potentially eligible forinclusionbut, afterinspectionofthefull papersthreewereex-cluded; one used a mixture for supplementation with no separatearm for calcium supplementation alone (Hofstad 1998), one wasnot randomised to the intervention (Hyman 1998), one includeddata from a similar report of the same study and we included onlythe 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 etaltrial,therewerethreearms-calcium,ber,andplacebo.Wehave analysedonlythe calcium andplacebo arms inthis review.Details of the results are presented in the summary analysis.Primary outcomes:a)number of subjects with a new diagnosis of colorectal cancerThere were too few events for any meaningful conclusionb)number of subjects with any new adenomaInformationfor the primaryoutcomeofthe numberof subjectswithat least onerecurrent adenomawas foundinbothtrials.When combined, a moderate, statistically signicant reduction ofrecurrenceofadenomasfavouringthe participantsreceivingcal-ciumwas obtained (OR0.74; CI 0.58,0.95). Individually, only thelarger trial(n=930)achieved a statisticallysignicanteffect (OR0.73;CI0.55,0.96)butnotthesmallertrial(n=416. OR0.78;CI0.45,1.33),butthecombinedresultsarestronglyinuencedby the larger trial (Baron 1999 a).Secondary outcomes:a)number of subjects experiencing any adverse event that requireddiscontinuation of treatmentOnetrial(Baron1999a)didnotndadifferencebetweenthetreatment and control groups( OR0.93; CI 0.42,2.05). The reportof the other trial did not supply separate data for the 50 subjectswho stopped the assigned treatment prematurely becauseof sideeffects;theproportionsforthosewhostoppedprematurelydidnot differ signicantly between groups (p=0.27) (Bonithon-Kopp2000).b)number of subjects that dropped-out from the studiesNo difference could be found for subjects that were lost to follow-up in the two groups( OR 1.11; CI 0.80,1.55)There was no evidence of heterogeneity betweenstudies as assessedbyinspectionofthegraphical presentations, thereforethexedeffectmodel wasusedforcombiningthestudies. Plannedsub-group analyses were not performed; the studies included high risksubjects only and reported that subgroup analyses conducted forage or baseline dietary intake of calcium within the trials did notchangetheconclusionsderived from theoverallresult.Dataforthese subgroups were not available for the treatment and controlgroups separately.D I S C U S S I O NThe role of calciumincoloncancer prophylaxis has beensuspectedonthebasisofanimal experiments, suchasthatwhichshowedfewercancersfollowinginjectionofcarcinogensinratsthatre-ceived calcium supplements in their feed (Adell-Carceller 1997).Inanattempttoexaminethequestioninhumans, dietarysur-veys have been used to identify a corelation between dietary cal-cium intake and recurrence of colorectal adenomas, and indeed itseemed that calciummight be protective (the rate ratio for the fthquintile versus the rst was 0.63 (95% condence interval, 0.39-1.02))(Hyman1998). Thenextstep wastoseeifpatientswhotookextradietarysupplementsoftheirownaccordfaredbetterthan those who did not, and once again for calcium supplemen-tation there seemed to be a protective effect (odds ratio, 0.51; 95percent condence interval, 0.27-0.96, Whelan 1999).Adenomasratherthancancerswerestudiedbecausetheyaresomuch more common, despite the limited applicability of ndingsfrom adnomas to cancer.In order to relate calcium supplementation more closely with ac-tual carcinogenesis, rather thanextrapolating fromthe effect onthedevelopment of adenomas, attempts have been made to examinethe effects of dietary calciumon human colonic or rectal epithelialproliferation, and some early studies suggested that calcium doesindeedimpedeepithelialproliferation(OSullivan1993).How-ever, more recently, these results have not been conrmed, but ithas also become clear that the proliferative index does not predictfuture colorectal neoplasia, although it may be weakly associatedwith the presence of current adenomas. The authors conclude thatthese results have important implications for the design of futureintervention studies: Although it may be attractive to include themeasurementofintermediatemarkersinlargecontrolledtrials,untilwehavemorecondenceintheirperformance,weshouldrely on better proven and more reliable intermediates, such as ade-nomas (Sandler 2000). Doubt on the importance of dietary cal-ciumis cast by the results of a large case control study embedded ina major fecal occult blood screening programme - no associationofcoloncancerwasfoundwithreportedcalciumintake(Little1993).AsindicatedintheBackgroundsection, manyepidemi-ological geographical studies have been reported, but on system-5 Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps (Review)Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.atic review they present an inconsistent and inconclusive picture(Martinez 1998).The ndings of several large cohort studies andonecase-control studyperformedworldwide, inEurope, USA,Hawai, China suggest that an increased intake of calciummay pre-vent the development of colorectaladenomasand cancer (Flood2005; Kesse 2005; Larsson 2006; Park 2007; Shin 2006). Amongthemajorpotentialsourcesofbiasinepidemiologicalstudiesofdiet and cancer are survivor bias, problems with dietary recall, anddifculties in identifying and controlling for countless confound-ingvariables.Wemusttherefore seek evidencefrom prospectivecontrolled trials of calcium supplementation. The association be-tween calcium and vitamin D intake and adenomatous polyps re-currence was evaluated and did not nd signicant results in a ran-domized controlled trial, where participants were randomized toeither intensive counseling to adopt a low-fat, high ber, fruit andvegetable enriched eating plan, or to be given a standard brochureon healthy eating (Hartman 2005).Arecent largerandomizedcontrolledtrial,theWomensHealthInitiative (WHI) Study (Wactawski-Wende 2006), including36282 post-menopausal women receiving calcium and vitamin Dor placebo for an average of seven years, did not demonstrate anyeffect of the supplements on the incidence of colon cancer. How-ever,wedidnotincludethisstudyinourreviewforanumberof reasons. First, the WHI study used combined calcium and vi-taminDsupplementsandtheindependenteffectofvitaminDonpreventionofcoloncancerisnotknown. Second,thecolonwas not evaluated for adenomas or cancer at baseline ; the studydid not use clear methods of diagnosing colon cancer, unlike thestudies included in our review which used colonoscopy for evalu-ation.The studies included in our reviewalso used higher dosesof calcium. In future, a larger trial using the doses of calcium usedinthestudiesweincluded,withoutvitaminDandforalongerfollow-up period may yield different results.Colorectal cancer itself is sufciently rare that it is extremely dif-cult to conduct a randomised controlled trial large enough andlong enough to isolate the protective effect of any given single nu-trient or nutritionalsupplement. That is why we have to rely onthe indirect evidence supplied by studying the development of thefar more common colorectal adenomatous polyps, some of whichmay be pre-cancerous. There are major difculties in the conductof such trials, such as concommitent use of other supplements thatmightalsoaffectcarcinogenesis, bre, anti-oxidantsandothers.The effects of other nutrients have been reviewed elsewhere - e.g.ber (Asano 2002). The trials must also take into account regulardietary calcium intake as well as the supplement, and the differentbaselinerisk of colorectal cancerin different people - those withinammatory bowel disease, family history and familial polyposisand previous history of colon neoplasia. To date only two groupshave succeeded in completing suchtrials, onein North Americaand one in Europe.Thesetwotrialswereconductedwellandproducedresultsthatsuggest aclinicallyrelevantprotectiveeffectof dietarycalciumsupplementation on the development of colorectal adenomatouspolyps. Onlyinthelarger, American, trial didtheeffectreachstatistical signicance. Itisdifculttoassesswhichfactorscon-tributed to the small difference in the results of the studies. Baronet al (Baron1999a; Baron1999b) usedalowerdoseof cal-cium(1200mg/dayversus 2000mg/dayinthe smaller Europeantrial), but for a longer period (4 years versus 3 years). It was larger,achievinganadequatesamplesize,unlikeBonithon-Koppet al.(Bonithon-Kopp2000) whosesmallersamplesizereducedthepowerofthestudywithalackofstatistical signicance. Therewere more events in the control group in Baron et al, which couldbeattributedto thelongerfollow-up.Theadequacyofconceal-ment was only documented in Bonithon-Kopp et al. Otherwise,the methodological differences between the two trials were also soslight that no meaningful sub-analysis was possible in order to tryand explain the differences in the results.Within-trial subgroup analyses for age, sex, and complianceshowed no signicant differences in the results for both trials. De-spite the relatively large numbers of subjects who successfuly com-pleted the trials, there was not enough data to perform sub-groupanalyses forotherriskfactors. Recent studies basedonsubsetsofsubjectsfrom theoriginaltrialsincludedinthereviewfoundassociationsbetweencolorectal adenomacharacteristicsandtherisk of recurrence. The numberofadenomas and their proximallocationatbaselinewerethemainpredictorsofrecurrence; pa-tients with three or more adenomas with at least one of them lo-cated on the proximal colon had a much higher risk of overall re-currence, proximal recurrence and advanced adenoma recurrence(Bonithon-Kopp2004).Calciumsupplementationmayhaveamore pronounced antineoplastic effect on advanced colorectal le-sions than on other types of polyps (Wallace 2004). Multiple ade-nomas and the presence of large or advanced adenomas have beenidentied as risk factors for adenoma recurrence( Martinez 2001).Results also suggest that the protective effect of calcium could begreaterwhenserumlevelsof 25- hydroxyvitaminDareinthehigher range( Grau 2003).Only subjects at high risk due to previous adenomas were includedin the trials, so that we may conclude that the intervention couldbe applied to this category of population, if conrmed as effectiveby further studies. Perhaps a higher doseof calcium for a longerperiodisneeded, butthesedosesmaybelesstolerableandtherisk-benet ratio must be weighed. Studies on healthy adults notconsidered at high risk would be difcult to conduct consideringtheproblemsofrecruitmentofsufcientsubjects, thenecessityofaqualifyingandsubsequentfollow-upcolonoscopies, aswellas the long-term adherence to treatment requested from a healthyadult.In general, where we nd weak clinical effects it is interesting tolook for reasons to explain why only some individuals respond tothe therapeutic intervention and not others. The genetic propen-6 Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps (Review)Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.sity to colon cancer has been studied in relation to calcium intakeandit seems that people withthe BB BsmIgenotypeforthe vi-tamin D receptor may be at reduced risk of colorectal adenoma.However, they seemto be less at risk when exposed to lower ratherthanhigherlevelsofcalciumandvitaminDintake. Sothedi-rectionoftheeffect isoppositetothatweexpect from previousobservations, and more work is needed to identify and explain anyheterogeneity of response (Kim 2001).Calcium supplementation is attractive as a potential interventionto reduce the risk of colorectal adenomas and colorectal cancer; itis relatively cheap and readilyavailable. Althoughit is likelytobesafe, this, andits efcacywould need to be more clearly demonstrated in further controlledstudies before any attempt at widespread introduction into clinicalpractice. Given the small number of studies eligible for inclusionin this review, and the conicting evidence derived fromthem, nobetter conclusions can be drawn at this stage than those resultingfrom the vast amount of epidemiological data.A U T H O R S C O N C L U S I O N SImplications for practiceAlthough the evidence from two RCTs suggests that calcium sup-plementationmight contribute to the preventionof colorectal ade-nomatouspolyps,thisdoesnotconstitutesufcientevidencetorecommendthegeneral useof calciumsupplementstopreventcolorectal cancerinhealthyadultsorinadultswithaprevioushistory of adenomatous polyps. There is however no evidence thatsuch supplements would be detrimental in doses of up to 2 gramselemental calcium per day.Implications for researchLarge multicentre trials could have the power to answer the out-standing questions - whether calcium supplementation has a pro-tectiveeffect inpatients at particularlyhighrisk, or intotallyhealthy subjects.Further work is needed onthe factorsinvolvedin individual susceptibility to colorectal cancer in order to identifyany subgroups that might benet fromcalciumsupplementation.Further trials with an adequate sample size and duration need tobe conducted to conrm the effects of this intervention, includingassessmentsof dose-responserelationshipsandtherisk- benetbalance.A C K N O W L E D G E M E N T SWe thank Professor Elliot Berry for the original suggestionto studythis subject, andtheprincipal investigators, Dr BaronandDrBonithon-Kopp, for their cooperation and prompt replies to ourqueries. Dr Karla Soares gave us valuable methodological advice.The Cochrane Colorectal Cancer Group (CCCG) was very help-ful with the literature search and in particular Dr Henning KeinkeAndersen was extremely supportive throughout. Clalit Health Ser-vicesofIsraelgaveAZstudyleavetoattendaworkshopattheCCCG.R E F E R E N C E SReferences to studies included in this reviewBaron 1999 a {published data only}Baron JA, Beach M, MandelJS, van StolkRU, HaileRW, Sandler RS, Rothstein R, Summers RW, Snover DC,Beck GJ, Bond JH, Greenberg ER. Calcium supplementsfor the prevention of colorectal adenomas. Calcium PolypPreventionStudyGroup. N EnglJ Med 1999;340(2):1017.Bonithon-Kopp 2000 {published data only}Bonithon- Kopp C, Kronborg O, Giacosa A, Rath U,Faivre J. Calcium and bre supplementation in prevention ofcolorectal adenoma recurrence : a randomised interventiontrial. European Cancer PreventionOrganisation StudyGroup. 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 ECPcalcium bre polyp prevention study preliminaryreport.ECP ColonGroup. Eur J Cancer Prev 1993;2Suppl 2:99106.Faivre J, Couillault C, Kronborg O, Rath U, Giacosa A, deOliviera H, Obrador T, OMorain O. Chemopreventionofmetachronousadenomas of the large bowel: design andinterim results of a randomised trial of calcium and bre.ECP Colon Group. Eur J Cancer Prev 1997;6:1328.Faivre J, Doyon F, Boutron MC. The ECP calcium brepolyp prevention study. The ECP Colon Group.. Eur JCancer Prev 1991;1 Suppl 2:839.References to studies excluded from this reviewBaron 1999 b {published data only}Baron JA, Beach M, Mandel JS, van Stolk RU, Haile RW,Sandler RS, Rothstein R, Summers RW, Snover DC, BeckGJ, Frankl H, Pearson L, Bond JH, Greenberg ER. Calciumsupplementsand colorectaladenomas.Polyp PreventionStudy Group. Ann NY Acad Sci 1999;889:13845.Hofstad 1998{published data only}HofstadB,AlmendingenK,VatnM,AndresenSN,Owen RW, Larsen S, Osnes M. Growth and recurrence ofcolorectalpolyps: a double-blind3-year intervention withcalcium and antioxidants.. Digestion 1998;59:14856.7 Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps (Review)Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.Hyman 1998{published data only}HymanJ,BaronJA, SandlerRS,HaileRW,MandelJS, MottLA, GreenbergER. Dietaryand supplementalcalcium and the recurrence of colorectal adenomas.. CancerEpidemiol Biomarkers Prev 1998;7(4):2915.Additional referencesAdell-Carceller 1997Adell-Carceller R, Segarra-Soria M, Gibert-Jerez J, SalvadorSanchis JL, Lazaro-Santander R, Escrig-Sos J, Ruiz-CastilloJ. Inhibitory effect of calcium on carcinogenesis at the siteof colonic anastomosis: an experimental study.. Dis ColonRectum 1997;40(11):13761381.Asano 2002Asano T, McLeod RS. Dietary bre for the prevention ofcolorectaladenomas and carcinomas. Cochrane DatabaseofSystematic Reviews2002, Issue 4. [DOI:10.1002/14651858.CD003430]Bergsma-Kadijk 1996Bergsma-Kadijk JA, van t Veer P, Kampman E, BuremaJ. Calcium does not protect against colorectalneoplasia.Epidemiology 1996;7(6):5907.Bonithon-Kopp 2004Bonithon-Kopp C, Piard F, Fenger C, Cabeza E, O MorainC, Kronborg O, Faivre J. Colorectal adenoma characteristicsas predictors of recurrence. Dis Colon Rectum 2004;47(3):32333.Bostick 1997Bostick RM. Human studies of calcium supplementationandcolorectal epithelial cell proliferation. CancerEpidemiology Biomarkers Prev 1997;6:97180.Clarke 2000ClarkeM, OxmanA, editors. CochraneHandbook[Cochrane Reviewers Handbook 4.1 [updated June 2000]].Cochrane Reviewers Handbook 4.1. Version 4.1. Oxford,England: The Cochrane Collaboration, 2000.Dickersin 1994Dickersin K, Schrerer R, Lefebvre C. Identifying relevantstudies for systematic reviews.. BMJ 1994;309:128691.Flood 2005FloodA, PetersU, ChatterjeeN, Lacey Jr JV, SchairerC,SchatzkinA. Calciumfromdietandsupplementsisassociatedwithreducedriskofcolorectalcancerinaprospectivecohortofwomen. Cancer EpidemiologyBiomarkers and Prevention 2005;14(1):12632.Giovannucci 1998Giovannucci E, StampferMJ, ColditzGA, Hunter DJ,Fuchs C, Rosner BA, Speizer FE, Willett WC. Multivitaminuse, folate,and cancer in womenin theNurses HealthStudy. Annals of Internal Medicine 1998;129:51724.Grau 2003GrauMV,BaronJA,SandlerRS,HaileRW,BeachML, ChurchTR, HeberD. VitaminD, calciumsupplementation, and colorectaladenomas: results of arandomized trial. J Natl Cancer Inst 2003;95(23):176571.Hartman 2005Hartman TJ, Albert PS, Snyder K, Slattery ML, Caan B,Paskett E, et al.The association of calcium and vitamin Dwith risk of colorectaladenomas. The Journal of nutrition2005;135(2):2529.Hill 1978Hill MJ, Morson BC, Bussey HJ. Aetiology of adenoma-carcinoma sequence in large bowel. Lancet 1978;1:2457.Huncharek 2009Huncharek M, Muscat J, Kupelnick B. Colorectalcancerriskanddietaryintakeofcalcium, vitaminDanddiary products: a meta-analysisof 26335cases from 60observationalstudies. Nutrition ofcancer 2009;61(1):4769.Jadad 1996Jadad AR, MooreA, CarollD, Jenkinson C, ReynoldsJM, Gavaghan DJ, etal.Assessing the qualityof reportsofrandomizedclinicaltrials: isblindingnecessary?.Controlled Clinical Trials 1996; Vol. 17:112.Kesse 2005Kesse E, Boutron Ruault MC, Norat T, Riboli E, ClavelChapelon F. Dietary calcium, phosphorus, vitamin D, dairyproducts and the risk of colorectaladenoma and canceramong French women of the E3N-EPIC prospective study.International Journal of Cancer 2005;117(1):13744.Kim 2001Kim HS, NewcombPA, Ulrich CM, Keener CL, BiglerJ, Farin FM, Bostick RM, Potter JD. Vitamin D receptorpolymorphismandtheriskofcolorectal adenomas:Evidence of interaction with dietary vitamin D and calcium.Cancer-Epidemiology-Biomarkers-and-Prevention. 2001;10(8):869874.Larsson 2006Larsson SC, Bergkvist L, Rutegard J, Giovannucci E, WolkA. Calcium and dairy food intakes are inversely associatedwith colorectal cancer risk in the Cohort of Swedish Men.American Journal of Clinical Nutrition 2006;83(3):66773.Little 1993LittleJ, Logan RFA, Hawtin PG, Hardcastle JD, TurnerID. Colorectal adenomas and diet: A case-control study ofsubjects participating in the Nottingham faecal occult bloodscreening programme. British-Journal-of-Cancer 1993;67(1):177184.Martinez 1998MartinezME, WillettWC. Calcium,vitaminD, andcolorectalcancer: a review of the epidemiologic evidence.Cancer Epidemiol Biomarkers Prev 1998;7:1638.Martinez 2001Martinez ME, Sampliner R, Marshall JR, BhattacharyyaAK,ReidME,AlbertsDS.Adenomacharacteristicsasriskfactorsforrecurrenceofadvanced adenomas.Gastroenterology 2001;120:107783.Midgeley 1999Midgeley R, Kerr D. ColorectalCancer. Lancet 1999;353(9150):391399.8 Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps (Review)Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.Nagengast 1995Nagengast FM, Grubben MJAL, van Munster IP. Role ofbile acids in colorectal carcinogenesis. Eur J Cancer 1995;31 A:106770.Newmark 1992Newmark HL, Lipkin M. Calcium vitamin D and coloncancer. Cancer Research 1992;52:2067s207s.OSullivan 1993OSullivanKR, MathiasPM, BeattieS, OMorain C.Effectof oral calcium supplementationon colonic cryptcell proliferationin patients with adenomatous polyps ofthe large bowel. European-Journal-of-Gastroenterology-and-Hepatology 1993;5(2):8589.Park 2007ParkSY,MurphySP,WilkensLR,NomuraAMY,Henderson BE, Kolonel LN. Calcium and vitamin D intakeand risk ofcolorectalcancer: The MultiethnicCohortStudy. American Journal of Epidemiology 2007;165(7):78493.Pence 1993PenceBC. Roleof calcium in colon cancer prevention:experimentaland clinical studies. Mutat Res1993;290:8795.Rozen 1989Rozen P, Fireman Z, Fine N, Wax Y, Ron E. Oral calciumsupresses increased rectal epithelial proliferation of personsat risk of colorectal cancer. Gut 1989;30:650655.Sandler 2000SandlerRS, Baron JA, Tosteson TD, Mandel JS, HaileRW. Rectalmucosal proliferationand risk of colorectaladenomas: Results froma randomized controlledtrial.Cancer-Epidemiology-Biomarkers-and-Prevention. 2000;9(7):653656.Shin 2006ShinA, LiH, ShuXO,YangG, GaoYT,ZhengW.Dietary intake of calcium, ber and other micronutrients inrelation to colorectal cancer risk: Results from the ShanghaiWomens HealthStudy. International Journal ofCancer2006;119(12):293842.Slattery 1997SlatteryMl,Caan BJ, PotterJD, BerryTD, CoatesA,Duncan D, Edwards SL. Dietary energy sources and coloncancer risk. American Journal of Epidemiology 1997;145:199210.van der Meer 1997VanderMeer, LapreJA, Govers MJ,KleibeukerJH.Mechanisms of the intestinal effects of dietary fats and milkproducts on colon carcinogesis. Cancer Letter 1997; Vol.114:7583.Wactawski-Wende 2006Wactawski-Wende J, Kotchen JM, Anderson GL, Assaf AR,Brunner RL, OSullivan MJ, et al.Calcium plus Vitamin DSupplementation and the Risk of Colorectal Cancer. N EnglJ Med 2006;354(7):684696.Wallace 2004Wallace 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 supplementationon the risk of large bowel polyps. J Natl Cancer Inst 2004;96(12):921925.Whelan 1999Whelan RL, Horvath KD, Gleason NR, Forde KA, TreatMD, TeitelbaumSL, BertramA, NeugutAI. Vitaminand calcium supplement use is associated with decreasedadenoma recurrence in patients with a previous history ofneoplasia. Diseases-of-the-Colon-and-Rectum. 1999;42(2):212217.Indicates the major publication for the study9 Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps (Review)Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.C H A R A C T E R I S T I C S O F S T U D I E SCharacteristics of included studies [ordered by study ID]Baron 1999 aMethods multicentreRandomisation :computerised generation of allocation sequence,blocked according to study center ( 2 )*Allocation concealment : not mentionedDouble- blind : yes ( 2 )Intention to treat :not mentioned89% included in the main analysis from the main study period.Every six monthsquestionnaires on adherence tointervention, medication,nutritional supplementsTwo periods included in the study : from qualifying and including the rst f / u colonoscopy (at 1 year)and the main study period after the rst and including the second f / u colonoscopy ( at 4 years)f / u described ( 1 ) 89% completed studyDesign : parallelJadad score = 5Participants N =930670 - men260 -womenMean age (SD) :61 (9) yrs with recent history of colorectal adenomas conrmed histologically removed within 3 monthsbefore recruitment , free of polyps on complete colonoscopyInclusion criteria- < 80 yrs-in good healthExclusion criteria-FAP, CRC-malabsorbtion-conditions worsened by calciumBaseline characteristics and dietary pattern similar in both groups, no signicant differences. Lessthan 3% taking calcium supplements at the start of the trial discontinueditInterventions Treatment group:calcium carbonate 3g(1200 mg elemental calcium ) dailyN = 464Control group:identical placeboN = 466Mean duration :4 yrs10 Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps (Review)Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.Baron 1999 a (Continued)Diet assessed at enrollment and at the end of the study by a validated food questionnaireMean daily dietary calcium intake 865+/- 423mg in Tx group889+/- 451 in C groupCompliance assessed as percentage of tablets taken,similar in both groups. > 80% of subjectstaking study agents > 90% of the time at 4 yrsOutcomes -the proportion of subjects in whom at least one adenoma was detected after the rst f / uand including thesecond f / u colonoscopy-the average number of adenomas in both groupsAll polyps removed were histologically diagnosedNotes Recruitment1988 - 1992Six clinical centers in USA913 subjects underwent at least one f / u colonoscopy. 832 ( 89%) included in the main analysis409- Tx group423- C group and had two f / ucolonoscopies with polyps removed. Interimcolonoscopies only when necessaryDrop-outs:55 (11, 8%)- Tx group: 22 died ,11lost interest, 8 ill or moved, 2 unknown /other43 (9,2%)- C group: 25 died,14 lost interest,10 ill /moved, 6other/unknownRisk of biasItem Authors judgement DescriptionAllocation concealment? Unclear B - Unclear11 Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps (Review)Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.Bonithon-Kopp 2000Methods multicentreRandomisation :stratied by center balanced every six patients2calcium, 2bre,1placebo calcium, 1placebo bre( 2 )Allocation concealment :independent randomisation centerDouble-blind: yes ( 2 )Intention to treat:yesf / u described (1)f / u complete colonoscopy at 3yrs 86%Design: parallelJadad score= 5Participants N =640Mean age (SD) :58.8 ( 8.8 ) yrsTx group,59.3 ( 8.4 ) yrsC group, with history of colorectal adenomas.Polyps removedat qualifying colonoscopy.Inclusion criteria-at least two adenomas or one > 5mm on complete colonoscopy conrmed by pathologist- age 35-75- no debilitatingdiseaseExclusion criteria- FAP, IBD, CRC, colonic resection-contraindicationto calcium / bre-current calcium treatment that could not be stoppedBaseline characteristics and mean dietary intake similar in both groups, no signicant differencesInterventions Treatment group:- calcium gluconolactate and carbonate PO twice daily (2000 mg elemental calcium daily)N =204- bre -isphagula3.5g per dayN =224Control group:placebo sucrose with taste, appearance and excipient as the interventionN =212Diet assessed by a standard validated questionnaire at baseline and at 3 yrsMean calcium intake: 944 (364) mg - calcium group1023 (404) mg12 Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps (Review)Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.Bonithon-Kopp 2000 (Continued)C group, p =0.28Duration- 3 yrsCompliance assessed by unused sachetsreturned, standard interview, fecalcalcium. 69% inTx and 82% in Cgroups, p =0.044 took > 80% of thesachets prescribedOutcomes - at least one newadenoma at 3 yrexaminationAll removed polyps were pathologically diagnosedNotes 21 centres fromten countriesRecruitment1991- 199425 subjects excluded initiallyafter the randomisation because not histologically conrmed adenomas (665 subjects initially)Randomisationafter complete qualiyng colonoscopyInterim colonoscopies only if necessary, with polyps removed countedas endpoints, only if removed>12 months after thequalifying colonoscopy ( 1 subject not counted only andthis had a hyperplastic polyp).The proportions of nal colonoscopies similar between groups p =0.41Calcium group:176 subjects completed study, 8 died, 2 severe illness, 5 lost tof/u 13 refused to continueControl group:178 completed study, 9 died, 1severe illness, 5 lost to f/u, 19 refused to continueRisk of biasItem Authors judgement DescriptionAllocation concealment? Yes A - Adequate*( ) number of points obtained in the Jadad scale; FAP familial adenomatous polyposis; IBD inammatory bowel diseaseCRC colorectal cancer; SD standard deviation; yr year; Tx treatment; C control; f /u follow -up13 Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps (Review)Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.Characteristics of excluded studies [ordered by study ID]Study Reason for exclusionBaron 1999 b Included participants and data from a similar report of the same studyHofstad 1998 Randomised, parallelParticipants: N= 116 polyp bearing subjectsIntervention: mixture of calcium and antioxidants vs. placeboNot separate arm for calcium supplementationHyman 1998 Not randomised for calcium supplementation; assessmentbased on a questionnaire .14 Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps (Review)Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.D A T A A N D A N A L Y S E SComparison 1. Calcium versus placeboOutcome or subgroup titleNo. ofstudiesNo. ofparticipantsStatistical method Effect size1 Number of subjects diagnosedwith colorectal cancer2 1346 Odds Ratio (M-H, Fixed, 95% CI) 0.34 [0.05, 2.15]2 Number of subjects with at leastone new adenoma2 1346 Odds Ratio (M-H, Fixed, 95% CI) 0.74 [0.58, 0.95]3 Number of subjects with at leastone adverse event requiringdiscontinuation of treatment1 930 Odds Ratio (M-H, Fixed, 95% CI) 0.93 [0.42, 2.05]4 Number of subjects that dropped- out2 1346 Odds Ratio (M-H, Fixed, 95% CI) 1.11 [0.80, 1.55]Analysis 1.1. Comparison 1 Calcium versus placebo, Outcome 1 Number of subjects diagnosed withcolorectal cancer.Review: Dietary calcium supplementation for preventing colorectal cancer and adenomatous polypsComparison: 1Calcium versus placeboOutcome: 1 Number of subjects diagnosed with colorectal cancerStudy or subgroup Calcium Placebo Odds Ratio Weight Odds Ration/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CIBaron 1999a 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]Total (95% CI) 668 678 100.0 % 0.34 [ 0.05, 2.15 ]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 1 2 5 10Favours calcium Favoursplacebo15 Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps (Review)Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.Analysis 1.2. Comparison 1 Calcium versus placebo, Outcome 2 Number of subjects with at least one newadenoma.Review: Dietary calcium supplementation for preventing colorectal cancer and adenomatous polypsComparison: 1Calcium versus placeboOutcome: 2 Number of subjects with at least one new adenomaStudy or subgroup Calcium Placebo Odds Ratio Weight Odds Ration/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CIBaron 1999a 127/464 159/466 79.1% 0.73[ 0.55, 0.96]Bonithon-Kopp 2000 28/204 36/212 20.9% 0.78[ 0.45, 1.33]Total (95% CI) 668 678 100.0 % 0.74 [ 0.58, 0.95 ]Total events: 155 (Calcium), 195(Placebo)Heterogeneity: Chi2= 0.05, df = 1 (P= 0.83); I2=0.0%Test for overall effect: Z= 2.40(P= 0.016)0.1 0.2 0.5 1 2 5 10Favours calcium FavoursplaceboAnalysis 1.3. Comparison 1 Calcium versus placebo, Outcome 3 Number of subjects with at least oneadverse event requiring discontinuation of treatment.Review: Dietary calcium supplementation for preventing colorectal cancer and adenomatous polypsComparison: 1Calcium versus placeboOutcome: 3 Number of subjects with at least one adverse event requiringdiscontinuation of treatmentStudy or subgroup Calcium Placebo Odds Ratio Weight Odds Ration/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CIBaron 1999a 12/464 13/466 100.0% 0.93[ 0.42, 2.05]Total (95% CI) 464 466 100.0 % 0.93 [ 0.42, 2.05 ]Total events: 12 (Calcium), 13 (Placebo)Heterogeneity: not applicableTest for overall effect: Z= 0.19(P= 0.85)0.1 0.2 0.5 1 2 5 10Favours calcium Favours placebo16 Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps (Review)Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.Analysis 1.4. Comparison 1 Calcium versus placebo, Outcome 4 Number of subjects that dropped - out.Review: Dietary calcium supplementation for preventing colorectal cancer and adenomatous polypsComparison: 1Calcium versus placeboOutcome: 4 Number of subjects that dropped - outStudy or subgroup Calcium Placebo Odds Ratio Weight Odds Ration/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CIBaron 1999a 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]Total (95% CI) 668 678 100.0 % 1.11 [ 0.80, 1.55 ]Total events: 83 (Calcium), 77 (Placebo)Heterogeneity: Chi2= 1.74, df = 1 (P= 0.19); I2=43%Test for overall effect: Z= 0.62(P= 0.53)0.1 0.2 0.5 1 2 5 10Favours calcium FavoursplaceboA D D I T I O N A L T A B L E STable 1. Adverse eventsStudy Intervention Side effects CommentsBaron 1999a calcium carbonate as 1200 mgelemental calcium daily- digestive symptoms: only consti-pation reported-urinary stones in two subjects inthe calciumgroup and one subjectin the placebo groupSimilar proportions in bothgroups haddigestive symptoms or stoppedtreatment because of toxicityBonithon -Kopp 2000calciumgluconolactate andcar-bonate as 2000 mg elemental cal-cium daily-diarrhea severe and abdominalpain reported as major side effectsMajor side effects more frecvent inthe calciumgroup than in placebogroup, were reported in six versusthree subjects respectively. Poorcompliancedenedas takinglessthan80%of the intervention was more fre-quent in thecalcium groupAny adverseevent -14.8%in thecalciumgroup vs. 6.7% placebo group , p= 0.04317 Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps (Review)Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.W H A T S N E WLast assessed as up-to-date: 20 January 2010.Date Event Description5 January 2010 New search has been performed Numberofstudiesfoundonlastsearcheswasadded. Nonewstudieswerefound for inclusionH I S T O R YProtocol rst published: Issue 3, 2002Review rst published: Issue 1, 2004Date Event Description23 July 2008 Amended Converted to new review format.7 September 2007 New citation required and conclusions have changed Substantive amendmentC O N T R I B U T I O N S O F A U T H O R SThe original idea for this review was Professor Berrys, of The Hebrew University, Jerusalem, but he withdrew as a co-author for lackof time.Dr Zalmanovici did most of the work, selecting the studies to be included, and assessing their quality. She also entered all the data intoRevman 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 wasalso responsible for the literature search, and was an independent assessorin selecting the trials to be included. He edited the reviewand wrote the Discussion.Dr John Yaphe assessed the selected reviews and criticized and improved the reviewD E C L A R A T I O N S O F I N T E R E S TNone known18 Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps (Review)Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.N O T E SThis is the third update of the review. The searches for new trials were performed December 2009,but didnt identify any new trialsto be included.I N D E X T E R M SMedical Subject Headings (MeSH)Dietary Supplements; Adenoma [complications]; Adenomatous Polyps [prevention & control]; Calcium, Dietary [therapeutic use];Colorectal Neoplasms [prevention & control]; Randomized Controlled Trials as TopicMeSH check wordsHumans19 Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps (Review)Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.