Inourprospectivecohortstudy,useofcalciumorcalcium+vitaminDsupplementation tended to increase the risk of CHD among postmenopausal women during 6.75 years of followup.
The Social Insurance Institution (SII) carries out reimbursement of the costs of medicines used for severe and chronic illnesses. The National Registry of Specially Refunded drugs and the National Cause of Death Register have made it possible to reliably determine CHD events better than would be possible by way of questionnaires.
However,wecouldnotdeterminethedoseresponseeffectofcalciumsupplementationon CHD morbidity because use of calcium supplements was based on selfreports, not on registry data. The supplements contain different doses of calcium. Therefore, it was difficult to determine the daily dose of calcium in this large populationbased cohort study. Nonetheless, our main results suggest a harmful effect of the use of calcium supplementationonCHDrisk.
It is well known that CHD is a leading cause of death in postmenopausal women around the world, and the incidence of CHD increases substantially after menopause.
Many postmenopausal women use calcium or calcium + vitamin D supplementation to preventosteoporosis,andforalongtimetherehasbeenspeculationaboutHTandCHD risk. However, in several recent clinical trials concerning HT, women have been given calciumorcalcium+vitaminD.Infact,theadverseeffectofHTonCHDeventsinthese trials may have been modified by calcium supplementation. The WHI investigators published the results of a randomized controlled trial on the effect of calcium carbonate andvitaminDsupplementation(Hsiaetal.2007).Themainresultwasthattherewasno overalleffectofcalcium/vitaminDsupplementsoncardiovascularevents.Amongwomen taking calcium/vitamin D supplements, the HR for myocardial infarction or CHD death was 1.04 (95% CI 0.92–1.18). For the combined endpoint of MI, CHD death, coronary arterybypassandpercutaneouscoronaryintervention,theHRwas1.08(95%CI0.99–1.91) (Hsiaetal.2007).ItisgoodtoknowthattheWHIinvestigatorsusedlowdosevitaminD supplements. Vitamin D deficiency has been associated with an increased risk of CVD (Wang et al. 2008) and vitamin D supplementation with decreased mortality (Autier &
Gandini2007).
InarandomizedplacebocontrolledtrialinNewZealand,1471postmenopausalwomen (meanageof74.3years)wererandomizedtoreceivecalciumsupplementation(n=732)or placebo (n=739) and they were followed for over 5 years. The effects of calcium supplementation on MI, stroke and sudden death were determined. There was a significant increase in the rates of vascular events in the women allocated to calcium supplementation(Bollandetal.2008).Theresultsweresimilartothefindingsinastudy byPrinceetal.(2006)whorandomized1460postmenopausalwomentocalciumcarbonate or placebo for 5 years. In the calcium supplementation group, the risk of ischemic heart diseaseincreasedby12%(NS)(Princeetal.2006).
The results of a metaanalysis carried out by Bolland et al. (Bolland et al. 2010) confirmedthese results. In this pooled analysis concerning around 12000 participants in 11 randomized controlled trials, calcium supplements were associated with an approximately30%increaseintheincidenceofMI,andsmaller,nonsignificant,increases intherisksofstrokeandmortality.Whenrecurrenteventsin10–17%oftheparticipants wereincludedintheanalysis,theresultsweresimilar,althoughtherelativeriskstended tobeslightlylarger.Thefindingswereconsistentacrossthetrials,withincreasedrelative risk of MI with calcium observed in six of the seven trials in which at least one event occurred,althoughnoindividualtrialrevealedastatisticallysignificantlyeffect.Therisk of MI with calcium tended to be greater in those with dietary calcium intake above the medianbutwasnotindependentofage,sex,andtypeofsupplement.Consistentwiththe results reported by Bolland et al. and Prince and coworkers, we found that calcium supplementationinCHDfreewomentendedtoincreasetheriskofCHD(by24%).
In our study, it is impossible to verify whether the increased risk of CHD is purely relatedtocalciumorvitaminD.Inarandomized5yeartrialcarriedoutbyTuppurainen etal.(Tuppurainenetal.1995)vitaminDsupplementationincreasedcholesterollevelsin 464 healthy postmenopausal women (a subgroup of the OSPTRE study population). In addition,Heikkinenetal.(Heikkinenetal.1997)reportedthatcholecalciferol(300IU/day) increased serum LDLcholesterol levels by 4.1% (p = 0.035) in healthy early postmenopausalwomen.Theresultsofthesestudies(Tuppurainenetal.1995,Heikkinen et al. 1997) confirmed the positive effect of HT with sequential estradiol valerate and cyproterone acetate on serum lipid concentrations. However, the beneficial effects ofHT on serum LDLcholesterol were reduced when estradiol valerate was combined with vitaminD3(Heikkinenetal.1997).
The relationships between dietary calciumintake and cardiovascular events have also been examined. A strong inverse association between calcium intake and standardized ratesofischemicheartdiseasemortalityintheUnitedKingdomhasbeenreported(Knox 1973).Accordingtotheresultsofsomestudies(Knox1973,Dawsonetal.1978,Hopkins&
Williams1981),populationslivinginhardwaterareas(highcalciumcontent)havelower CVDmortalitythanpeoplelivinginsoftwaterareas.IntwoUSprospectiveobservational studies,womenintheIowaHealthStudyinthehighestfourthofcalciumintakehada30–
40%lowerrateofcardiovascularmortalitythanthoseinthelowestfourth(Bosticket al.
1999),andthoseinthehighestfifthofcalciumintakehada30–40%lowerriskofischemic stroke than those in the lowest fifth in the Nurses’ Health Study (Iso et al. 1999). No relationshipbetweendietaryorsupplementalcalciumintakeandischemicheartdiseaseor strokewasobservedinprospectivestudiesofUSmen(Ascherioetal.1998,AlDelaimyet al.2003),orofDutchcivilservants(VanderVijveretal.1992).Incontrasttotheresultsof observational and interventional studies of calcium supplements, these observational studies do not show increased cardiovascular risks with higher dietary calcium intake.
Therefore, these differences suggest that cardiovascular risks from high calcium intake mightberestrictedtouseofcalciumsupplements.
Current findings are consistent with the results of trials among patients with renal failure, in which calcium supplements have been associated with an increase risk of
mortality(Blocketal.2007).Thereareveryfewdataontherelationshipbetweencalcium andCHDinhumans.NonfatalMIinUSmenusingcalciumsupplements,comparedwith nonusers, was not increased significantly, although the relative risks for each fifth of supplementintakerangedbetween1.02and1.07(AlDelaimyetal.2003).
AlthoughtheconclusionsinametaanalysisbyBollandetal.(Bollandetal.2010)andin a review by Wang et al. (Wang et al. 2010) are not convergent, their results concerning calciumsupplementationaresimilar.Wangetal.publishedasystematicreviewinwhich they reported that five prospective studies of patients receiving dialysis and one study involving a general population showed consistent reductions in CVD mortality among adultswhoreceivedvitaminDsupplements.Afurtherfourprospectivestudiesofinitially healthy persons showed no differences in the incidence of CVD between calcium supplement recipients and nonrecipients. The results of secondary analysis of 8 randomized trials showed a slight but statistically nonsignificant reduction in CVD risk (pooledRR0.90,95%CI0.77–1.05)withvitaminDsupplementationatmoderatetohigh doses(approximately1000IU/d)butnotwithcalciumsupplementation(pooledRR1.14, 95% CI 0.92–1.41), or a combination of vitamin D and calcium supplementation (pooled RR 1.04, 95% CI 0.92–1.18) compared with placebo. Wang et al. concluded that the evidence from limited data suggests that vitamin D supplements at moderate to high doses may reduce CVD risk, whereas calcium supplements seem to have minimal cardiovascular effects. In fact, there was a slight but nonsignificantly increased risk of CVDwithcalciumorcalcium+vitaminDsupplementationcomparedwithplacebo.The metaanalysisoftrialleveldatacarriedoutbyBollandetal.(Bollandetal.2010)showed anincreasedincidenceofMIinthoseallocatedtocalcium;pooledRR1.27(95%CI1.01–
1.59).Therefore,theirconclusionwasthatcalciumsupplements(withoutcoadministered vitamin D) are associated with an increased risk of MI. The results of our study are convergent with those published by Bolland et al. (Bolland et al. 2008), although the womeninourstudywereyounger(median57.2years)thantheirs(meanage74years).
TherecentstudybyBollandetal.(Bollandetal.2011)concernedtheeffectsofpersonal useofcalciumsupplementsoncardiovascularriskinconnectionwiththeWomen’sHealth InitiativeCalcium/VitaminD(WHICaD)studyandtheyupdatedtheirmetaanalysesof calcium supplements and cardiovascular risk. In the study Bolland and colleagues explored the possibility that findings in the WHI study may have been masked by the widespreaduseofpersonalcalciumsupplements(Bollandetal.2011).Originally,theWHI investigatorsreportednoeffectofcalciumandvitaminDsupplementsoncardiovascular events, but most of the participants were taking personal, nonprotocol calcium supplements at study entry. Among 16 718 women, 46% of whom were not taking personal calcium supplements at randomization, the hazard ratios for cardiovascular eventsinconnectionwithcalciumandvitaminDsupplementsrangedfrom1.13to1.22(p
=0.05 for clinical myocardial infarction or stroke, p=0.04 for clinical MI or revascularization),whereasinwomentakingpersonalcalciumsupplements,calciumand vitaminDsupplementsdidnotaltercardiovascularrisk.Inthemetaanalysesofplacebo controlledtrialsofcalciumsupplementsorcalciumplusvitaminDsupplements,complete triallevel data were available for 28072 participants from eight trials of calcium
supplements and WHI CaD participants not taking personal calcium supplements.
Calcium supplements and calcium plus vitamin D supplements increased the risk of MI (RR 1.24, 95% CI 1.07 to 1.45,p=0.004) and the composite of MI or stroke (1.15, 95% CI 1.03to1.27,p=0.009)(Bollandetal.2011).
As Bolland and colleagues state, this analysis of the WHI CaD study data does not provide definitive evidence of an adverse effect of calcium and vitamin D on cardiovascularevents.However,whenthesedataarepooledwithpreviouslyunpublished data from two other placebocontrolled trials of calcium and vitamin D, there are consistent increases in the risk of myocardial infarction and stroke that are statistically significant and are of similar size to the risks observed with calcium supplements used withoutvitaminD.Further,whentheresultsregardingcalciumandvitaminDaretaken togetherwiththosefromtrialsofcalciumusedasmonotherapy,theyprovideconsistent evidence from 13 randomized, placebocontrolled trials involving about 29 000 participants with about 1400 cases of myocardial infarction and stroke that calcium supplementswithorwithoutvitaminDincreasetheriskofcardiovascularevents(Bolland etal.2011).
According to the results of animal experimental and human observational studies, higher calcium consumption may reduce the risk of ischemic heart disease by lowering cholesterolorbyothermechanisms.Inanimalstudies,higherdietarycalciumlevelshave reducedbothaorticandcardiaccholesterolcontentandaorticatherosclerosis(Yacowitzet al.1971,Renaudetal.1983,Hinesetal.1985).
Inthelightoftheseformerandrecentstudiestherehasbeenspeculationaboutpossible mechanisms by which calcium supplements could have possible negative effects on vascular events. There is evidence that calcium supplements can acutely elevate serum calciumlevels(Reidetal.1986),therebypossiblyacceleratingcalcificationonthevascular wall.SerumcalciumlevelshavebeenpositivelyassociatedwithanincreasedriskofMIin large observational studies (Lind et al. 1997, Jorde etal. 1999, Foley et al. 2008). Primary hyperparathyroidism,aconditioninwhichserumcalciumlevelsareraised,hasalsobeen associated with increased risks of cardiovascular events and death (Nilsson et al. 2002, Vestergaardetal.2003).Ingestionofcalciumsupplementsmightaccountfortheabsence of detrimental vascular effects of dietary calcium intake in the observational studies reviewed (Green et al. 2003). Vascular calcification is predictive of vascular event rates (Pletcher et al. 2004), and the process of vascular calcification is similar to osteogenesis (Demer1995).Becausecalciumsupplementsincreasebonedensityitispossiblethatthey mayalsoincreasevascularcalcificationandtherebyvascularevents.
Hemodialysis patients are at an increased risk of progressive coronary artery calcification(Blocketal.2007).Inpatientswithrenalfailure(bothdialysisandpredialysis populations)calciumsupplementsacceleratevascularcalcificationandincreasemortality (Goodmanetal.2000,Blocketal.2007,Russoetal.2007).Highcalciumintakeshavebeen associated with brain lesions observed in magnetic imaging scans (Payne et al. 2007), vascularcalcification(Goodmanetal.2000,Chertowetal.2002,Asmusetal.2005,Blocket al.2005),andmortality(Stevensetal.2004,Blocketal.2007).
Rasouli and Kiasari (Rasouli & Kiasari 2006) demonstrated in their study that serum calciumandphosphoruswithintheirnormalconcentrationrangesareassociatedwiththe prevalence and severity of CHD, which may be mediated via atherogenic lipids and (apo)lipoproteins.Theirstudyshowedthatserumcalciumandphosphorusandtheirion productswerealsoindependentriskfactorsofCHD(Rasouli&Kiasari2006).Information inthisareaisstilllimitedandrequiresmoreresearch.
The results of our 7year populationbased followup study suggest that calcium supplements are associated with an increased risk of CHD in postmenopausal women.
Our findings agree with those of Bolland et al. (Bolland et al. 2008, Bolland et al. 2010, Bollandetal.2011)suggestingthatthispotentiallydetrimentaleffectshouldbebalanced against the benefits of calcium on bone, particularly in older women. The results need further confirmation in clinical trials. More information is needed on the possible mechanism,andwhethertheincreasedriskofCHDisduetocalcium,vitaminD,ortheir combination.
7Summaryandconclusions
In this populationbased cohort study among 52 to 62yearold women at baseline, we evaluatedtheeffectsofHTonmortalityandtheriskofDM.Theagreementbetweenself reportedHTuseandnationwideprescriptiondatafromtheSocialInsuranceInstitutionof Finlandwasexaminedtoevaluatetheaccuracyofselfreports.Theeffectsofcalciumand calcium+vitaminDsupplementsontheincidenceofCHDinwomenwasalsoexamined.
Theresultsshowedthatprescriptioninformationisvaluableasregardsexaminationof the accuracy of selfreports of HT use. Selfreporting via a postal inquiry is a reliable method of recording longterm HT use in women before old age. Specification of brand names improves accuracy. Selfreporting is not reliable for detecting shortterm HT use, and it may overestimate the overall duration of HT use. Higher educational status is associatedwithahigherprevalenceofHTuseandmoreaccurateselfreportingofHTuse.
The results suggest that a history of HT does not affect overall or CHD mortality in women.Morethan5yearsofHTmayincreasetheriskoffatalbreastcancer.Theresults alsoshowthatuseofHTisprotectiveagainsttype2DM,and,inaddition,theysuggest that use of calcium or calcium + vitamin D supplements appears to increase the risk of CHDamongwomenbeforeoldage.
The present findings may help clinicians to explain the possible effects of HT on menopausal women. If HT is needed in connection with menopausal symptoms and/or prevention of osteoporotic fractures, the prevention of DM may also be a secondary benefit.Thepresentfindingssuggestthatthecliniciansshouldreassesstheuseofcalcium supplements in the prevention and treatment of osteoporosis when the possible harmful effectsofcalciumsupplementsonCVDeventsaretakentogether.
Basedonthefindingsofthepresentstudy,thefollowingconclusionsweredrawn:
x A postal inquiry is a reliable method of recording longterm use of HT. Higher educational status is related to more frequent selfreporting and to a higher prevalenceofHTuse.
x A history of HT use is not associated with overall or CHD mortality in postmenopausal women. More than 5 years of HT use may increase the risk of breastcancermortality.
x HTisassociatedwithadecreasedincidenceofT2DMinpostmenopausalwomen.
x Calcium or calcium + vitamin D supplementation appears to be related to an increasedriskofCHDamongwomenbeforeoldage.
8 References
AbramsSA,WenJ&StuffJE.Absorptionofcalcium,zinc,andironfrombreastmilkby fivetosevenmontholdinfants.Pediatricresearch1997;41:384390.
Africander D, Verhoog N & Hapgood JP. Molecular mechanisms of steroid receptor mediated actions by synthetic progestins used in HRT and contraception. Steroids 2011;76:636652.
AhmedSorour H & Bailey CJ. Role of ovarian hormones in the longterm control of glucose homeostasis. Interaction with insulin, glucagon and epinephrine. Hormone research1980;13:396403.
AlDelaimy WK, Rimm E, Willett WC, Stampfer MJ & Hu FB. A prospective study of calcium intake from diet and supplements and risk of ischemic heart disease among men.TheAmericanJournalofClinicalNutrition2003;77:814818.
AllenderPS,CutlerJA,FollmannD,CappuccioFP,PryerJ&ElliottP.Dietarycalciumand blood pressure: a metaanalysis of randomized clinical trials. Annals of Internal Medicine1996;124:825831.
Aloia JF, Vaswani A, Russo L, Sheehan M & Flaster E. The influence of menopause and hormonal replacement therapy on body cell mass and body fat mass. American JournalofObstetricsandGynecology1995;172:896900.
Aloia JF, Vaswani A, Yeh JK, Ross PL, Flaster E & Dilmanian FA. Calcium supplementation with and without hormone replacement therapy to prevent postmenopausalboneloss.AnnalsofInternalMedicine1994;120:97103.
AlonsoMagdalenaP,RoperoAB,CarreraMP,CederrothCR,BaquieM,GauthierBR,Nef S,StefaniE&NadalA.Pancreaticinsulincontentregulationbytheestrogenreceptor ERalpha.PloSone2008;3:e2069.
American College of Obstetricians and Gynecologists Womens Health Care Physicians.
Osteoporosis.Obstetricsandgynecology2004;104:66S76S.
AmericanCollegeofPhysicians.Guidelinesforcounselingpostmenopausalwomenabout preventive hormone therapy. American College of Physicians. Annals of Internal Medicine1992;117:10381041.
AmericanDiabetesAssociation.Screeningfortype2diabetes.Diabetescare2004;27Suppl 1:S114.
Anderson GL, Chlebowski RT, Rossouw JE, Rodabough RJ, McTiernan A, Margolis KL, Aggerwal A, David Curb J, Hendrix SL, Allan Hubbell F, Khandekar J, Lane DS, Lasser N, Lopez AM, Potter J & Ritenbaugh C. Prior hormone therapy and breast cancer risk in the Womens Health Initiative randomized trial of estrogen plus progestin.Maturitas2006;55:103115.
Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R, Curb D, Gass M, Hays J, Heiss G, HendrixS,HowardBV,HsiaJ,HubbellA,JacksonR,JohnsonKC,JuddH,Kotchen JM, Kuller L, LaCroix AZ, Lane D, Langer RD, Lasser N, Lewis CE, Manson J, MargolisK,OckeneJ,OSullivanMJ,PhillipsL,PrenticeRL,RitenbaughC,RobbinsJ, Rossouw JE, Sarto G, Stefanick ML, Van Horn L, WactawskiWende J, Wallace R, WassertheilSmoller S & Womens Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Womens Health Initiative randomized controlled trial. JAMA: the journal of the AmericanMedicalAssociation2004;291:17011712.
Appel LJ, Moore TJ, Obarzanek E, Vollmer WM, Svetkey LP, Sacks FM, Bray GA, Vogt TM,CutlerJA,WindhauserMM,LinPH&KaranjaN.Aclinicaltrialoftheeffectsof dietary patterns on blood pressure. DASH Collaborative Research Group. The New Englandjournalofmedicine1997;336:11171124.
Archer DF. Efficacy and tolerability of local estrogen therapy for urogenital atrophy.
Menopause(NewYork,N.Y.)2010;17:194203.
Ascherio A, Rimm EB, Hernan MA, Giovannucci EL, Kawachi I, Stampfer MJ & Willett WC.Intakeofpotassium,magnesium,calcium,andfiberandriskofstrokeamongUS men.Circulation1998;98:11981204.
AsmusHG,BraunJ,KrauseR,BrunkhorstR,HolzerH,SchulzW,NeumayerHH,RaggiP
& Bommer J. Two year comparison of sevelamer and calcium carbonate effects on cardiovascular calcification and bone density. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association European RenalAssociation2005;20:16531661.
AsthanaS,BakerLD,CraftS,StanczykFZ,VeithRC,RaskindMA&PlymateSR.High doseestradiolimprovescognitionforwomenwithAD:resultsofarandomizedstudy.
Neurology2001;57:605612.
AutierP&GandiniS.VitaminDsupplementationandtotalmortality:ametaanalysisof randomizedcontrolledtrials.ArchivesofInternalMedicine2007;167:17301737.
AvisNE,CrawfordS,StellatoR&LongcopeC.Longitudinalstudyofhormonelevelsand depressionamongwomentransitioningthroughmenopause.Climacteric:thejournal oftheInternationalMenopauseSociety2001;4:243249.
BachmannG,LoboRA,GutR,NachtigallL&NotelovitzM.Efficacyoflowdoseestradiol vaginal tablets in the treatment of atrophic vaginitis: a randomized controlled trial.
Obstetricsandgynecology2008;111:6776.
BachmannGA,SchaefersM,UddinA&UtianWH.Lowesteffectivetransdermal17beta estradiol dose for relief of hot flushes in postmenopausal women: a randomized controlledtrial.Obstetricsandgynecology2007;110:771779.
Baldereschi M, Di Carlo A, Lepore V, Bracco L, Maggi S, Grigoletto F, Scarlato G &
Amaducci L. Estrogenreplacement therapy and Alzheimers disease in the Italian LongitudinalStudyonAging.Neurology1998;50:9961002.
BanksE,BeralV,CameronR,HoggA,LangleyN,BarnesI,BullD,EllimanJ&HarrisCL.
Agreement between general practice prescription data and selfreported use of hormone replacement therapy and treatment for various illnesses. Journal of epidemiologyandbiostatistics2001;6:357363.
BargerLux MJ & Heaney RP. The role of calcium intake in preventing bone fragility, hypertension,andcertaincancers.TheJournalofnutrition1994;124:1406S1411S.
Barreto DV, Barreto FC, Liabeuf S, Temmar M, Boitte F, Choukroun G, Fournier A &
Massy ZA. Vitamin D affects survival independently of vascular calcification in chronic kidney disease. Clinical journal of the American Society of Nephrology : CJASN2009;4:11281135.
BarrettConnorE.Hormonereplacementtherapy.BMJ(Clinicalresearched.)1998;317:457 461.
BarrettConnorE&BushTL.Estrogenandcoronaryheartdiseaseinwomen.JAMA:the journaloftheAmericanMedicalAssociation1991;265:18611867.
BarrettConnor E & Grady D. Hormone replacement therapy, heart disease, and other considerations.AnnualReviewofPublicHealth1998;19:5572.
Barros RP, Machado UF & Gustafsson JA. Estrogen receptors: new players in diabetes mellitus.Trendsinmolecularmedicine2006;12:425431.
Bath PM & Gray LJ.Association betweenhormone replacement therapy and subsequent stroke:ametaanalysis.BMJ(Clinicalresearched.)2005;330:342.
BeanJA,LeeperJD,WallaceRB,ShermanBM&JaggerH.Variationsinthereportingof menstrualhistories.AmericanJournalofEpidemiology1979;109:181185.
Beilin LJ, Armstrong BK, Margetts BM, Rouse IL & Vandongen R. Vegetarian diet and bloodpressure.Nephron1987;47Suppl1:3741.
BellL,HalstensonCE,HalstensonCJ,MacresM&KeaneWF.Cholesterolloweringeffects of calcium carbonate in patients with mild to moderate hypercholesterolemia.
ArchivesofInternalMedicine1992;152:24412444.
BentleyLewis R, Koruda K & Seely EW. The metabolic syndrome in women. Nature clinicalpractice.Endocrinology&metabolism2007;3:696704.
Beral V & Million Women Study Collaborators. Breast cancer and hormonereplacement therapyintheMillionWomenStudy.Lancet2003;362:419427.
Beral V, Reeves G, Bull D, Green J & Million Women Study Collaborators. Breast cancer risk in relation to the interval between menopause and starting hormone therapy.
JournaloftheNationalCancerInstitute2011;103:296305.
Berkow SE & Barnard ND. Blood pressure regulation and vegetarian diets. Nutrition reviews2005;63:18.
Bierenbaum ML, Fleischman AI & Raichelson RI. Long term human studies on the lipid effectsoforalcalcium.Lipids1972;7:202206.
BischoffFerrari HA, DawsonHughes B, Baron JA, Burckhardt P, Li R, Spiegelman D, SpeckerB,OravJE,WongJB,StaehelinHB,OReillyE,KielDP&WillettWC.Calcium intakeandhipfractureriskinmenandwomen:ametaanalysisofprospectivecohort studiesandrandomizedcontrolledtrials.TheAmericanJournalofClinicalNutrition 2007;86:17801790.
Block GA, Raggi P, Bellasi A, Kooienga L & Spiegel DM. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney international2007;71:438441.
BlockGA,SpiegelDM,EhrlichJ,MehtaR,LindberghJ,DreisbachA&RaggiP.Effectsof sevelamer and calcium on coronary artery calcification in patients new to hemodialysis.Kidneyinternational2005;68:18151824.
BollandMJ,AvenellA,BaronJA,GreyA,MacLennanGS,GambleGD&ReidIR.Effectof calcium supplements on risk of myocardial infarction and cardiovascular events:
metaanalysis.BMJ(Clinicalresearched.)2010;341:c3691.
BollandMJ,BarberPA,DoughtyRN,MasonB,HorneA,AmesR,GambleGD,GreyA&
ReidIR.Vasculareventsinhealthyolderwomenreceivingcalciumsupplementation:
randomisedcontrolledtrial.BMJ(Clinicalresearched.)2008;336:262266.
Bolland MJ, Grey A, Avenell A, Gamble GD & Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Womens HealthInitiativelimitedaccessdatasetandmetaanalysis.BMJ(Clinicalresearched.) 2011;342:d2040.
Bonds DE, Lasser N, Qi L, Brzyski R, Caan B, Heiss G, Limacher MC, Liu JH, Mason E, ObermanA,OSullivanMJ,PhillipsLS,PrineasRJ&TinkerL.Theeffectofconjugated equine oestrogen on diabetes incidence: the Womens Health Initiative randomised trial.Diabetologia2006;49:459468.
Bostick RM, Kushi LH, Wu Y, Meyer KA, Sellers TA & Folsom AR. Relation of calcium, vitamin D, and dairy food intake to ischemic heart disease mortality among postmenopausalwomen.AmericanJournalofEpidemiology1999;149:151161.
BraunsteinJB,KershnerDW,BrayP,GerstenblithG,SchulmanSP,PostWS&Blumenthal RS.Interactionofhemostaticgeneticswithhormonetherapy:newinsightstoexplain arterialthrombosisinpostmenopausalwomen.Chest2002;121:906920.
Bray F, McCarron P & Parkin DM. The changing global patterns of female breast cancer incidenceandmortality.Breastcancerresearch:BCR2004;6:229239.
BreslowNE&DayNE.Statisticalmethodsincancerresearch.VolumeIIThedesignand analysisofcohortstudies.IARCscientificpublications1987;82:1406.
BrettKM&MadansJH.Useofpostmenopausalhormonereplacementtherapy:estimates from a nationally representative cohort study. American Journal of Epidemiology 1997;145:536545.
BrintonLA,RichessonD,LeitzmannMF,GierachGL,SchatzkinA,MouwT,Hollenbeck AR & Lacey JV,Jr. Menopausal hormone therapy and breast cancer risk in the NIH AARPDietandHealthStudyCohort.Cancerepidemiology,biomarkers&prevention:
a publication of the American Association for Cancer Research, cosponsored by the AmericanSocietyofPreventiveOncology2008;17:31503160.
Bucher HC, Cook RJ, Guyatt GH, Lang JD, Cook DJ, Hatala R & Hunt DL. Effects of dietary calcium supplementation on blood pressure. A metaanalysis of randomized controlled trials. JAMA: the journal of the American Medical Association 1996;275:10161022.
Burger HG, Dudley E, Mamers P, Groome N & Robertson DM. Early follicular phase serum FSH as a function of age: the roles of inhibin B, inhibin A and estradiol.
Climacteric:thejournaloftheInternationalMenopauseSociety2000;3:1724.
BushTL,BarrettConnorE,CowanLD,CriquiMH,WallaceRB,SuchindranCM,Tyroler HA&RifkindBM.Cardiovascularmortalityandnoncontraceptiveuseofestrogenin women:resultsfromtheLipidResearchClinicsProgramFollowupStudy.Circulation 1987;75:11021109.
BushTL,CowanLD,BarrettConnorE,CriquiMH,KaronJM,WallaceRB,TyrolerHA&
RifkindBM.Estrogenuseandallcausemortality.PreliminaryresultsfromtheLipid Research Clinics Program FollowUp Study. JAMA: the journal of the American MedicalAssociation1983;249:903906.
Bush TL, Whiteman M & Flaws JA. Hormone replacement therapy and breast cancer: a qualitativereview.Obstetricsandgynecology2001;98:498508.
C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC), Wensley F, GaoP,BurgessS,KaptogeS,DiAngelantonioE,ShahT,EngertJC,ClarkeR,Davey SmithG,NordestgaardBG,SaleheenD,SamaniNJ,SandhuM,AnandS,PepysMB, Smeeth L, Whittaker J, Casas JP, Thompson SG, Hingorani AD & Danesh J.
Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data. BMJ (Clinical research ed.)2011;342:d548.
Cagnacci A, Soldani R, Carriero PL, Paoletti AM, Fioretti P & Melis GB. Effects of low doses of transdermal 17 betaestradiol on carbohydrate metabolism in postmenopausal women. The Journal of clinical endocrinology and metabolism 1992;74:13961400.
Calle EE, Feigelson HS, Hildebrand JS, Teras LR, Thun MJ & Rodriguez C.
Postmenopausal hormone use and breast cancer associations differ by hormone regimenandhistologicsubtype.Cancer2009;115:936945.
CalleEE,MiracleMcMahillHL,ThunMJ&HeathCW,Jr.Estrogenreplacementtherapy and risk of fatal colon cancer in a prospective cohort of postmenopausal women.
JournaloftheNationalCancerInstitute1995;87:517523.
CanonicoM,PluBureauG,LoweGD&ScarabinPY.Hormonereplacementtherapyand risk of venous thromboembolism in postmenopausal women: systematic review and metaanalysis.BMJ(Clinicalresearched.)2008;336:12271231.
Cardozo L, Bachmann G, McClish D, Fonda D & Birgerson L. Metaanalysis of estrogen therapyinthemanagementofurogenitalatrophyinpostmenopausalwomen:second report of the Hormones and Urogenital Therapy Committee. Obstetrics and gynecology1998;92:722727.
CardozoL,LoseG,McClishD&VersiE.Asystematicreviewoftheeffectsofestrogens for symptoms suggestive of overactive bladder. Acta Obstetricia et Gynecologica Scandinavica2004;83:892897.
Cardozo L, Lose G, McClish D, Versi E & de Koning Gans H. A systematic review of estrogens for recurrent urinary tract infections: third report of the hormones and urogenitaltherapy(HUT)committee.Internationalurogynecologyjournalandpelvic floordysfunction2001;12:1520.
Carr MC. The emergence of the metabolic syndrome with menopause. The Journal of clinicalendocrinologyandmetabolism2003;88:24042411.
CashmanKD.Calciumintake,calciumbioavailabilityandbonehealth.TheBritishjournal ofnutrition2002;87Suppl2:S16977.
Cauley JA, Seeley DG, Ensrud K, Ettinger B, Black D & Cummings SR. Estrogen replacement therapy and fractures in older women. Study of Osteoporotic Fractures ResearchGroup.AnnalsofInternalMedicine1995;122:916.
ChenWY,HankinsonSE,SchnittSJ,RosnerBA,HolmesMD&ColditzGA.Associationof hormone replacement therapy to estrogen and progesterone receptor status in invasivebreastcarcinoma.Cancer2004;101:14901500.
ChenWY, MansonJE,HankinsonSE,RosnerB,HolmesMD,WillettWC&ColditzGA.
Unopposed estrogen therapy and the risk of invasive breast cancer. Archives of InternalMedicine2006;166:10271032.
Chen Z, Bassford T, Green SB, Cauley JA, Jackson RD, LaCroix AZ, Leboff M, Stefanick ML & Margolis KL. Postmenopausal hormone therapy and body compositiona substudy of the estrogen plus progestin trial of the Womens Health Initiative. The AmericanJournalofClinicalNutrition2005;82:651656.
Cherry N, Gilmour K, Hannaford P, Heagerty A, Khan MA, Kitchener H, McNamee R, ElsteinM,KayC,SeifM,BuckleyH&ESPRITteam.Oestrogentherapyforprevention