Rev. bras. ortop. vol.50 número3

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w w w . r b o . o r g . b r

Original

Article

Use

of

risedronate

for

consolidation

and

callus

formation

in

Colles

fractures

in

postmenopausal

women:

SOLID

study

Lindomar

Guimarães

Oliveira

a,∗

,

Sérgio

Ragi

Eis

b,†

,

Henrique

Mota

Neto

c

,

Frederico

Barra

de

Moraes

d

_,

_Luiz

_Antônio

_Silveira

_Simões

_Pires

e

_,

José

Wanderley

Vasconcelos

f

a_Clínica_de_Ortopedia_e_Fraturas,_Goiânia,_GO,_Brazil

b_Clínica_de_Diagnóstico_e_Pesquisa_da_Osteoporose_do_Espírito_Santo,_Vitória,_ES,_Brazil c_Universidade_Estadual_do_Ceará,_Fortaleza,_CE,_Brazil

d_School_of_Medicine,_Universidade_Federal_de_Goiás,_Goiânia,_GO,_Brazil

e_Orthopedics_and_Traumatology_Service,_Hospital_São_Lucas,_Pontifícia_Universidade_Católica,_Porto_Alegre,_RS,_Brazil f_Centro_de_Pesquisa_SOS_Trauma,_São_Luiz,_MA,_Brazil

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received3June2014 Accepted25June2014 Availableonline17April2015

Keywords:

Fractureconsolidation Collesfracture Bisphosphonates

a

b

s

t

r

a

c

t

Objective:Thisopen,randomizedandblindedparallel-groupmulticenterstudyevaluated theefficacyofActonel®₍₃₅_mg)_plus_{calcium/vitamin}_D_versus_{calcium/vitamin}_D_alone_for preservingbonemineraldensity(BMD)inpostmenopausalwomenwithCollesfractures.

Methods:PatientswithaCollesfractureforsevendayswererandomizedtoreceiveeither Actonel®₍₃₅_mg)_once_a_week_plus_{calcium/vitamin}_D_(ACD_group)_or_{calcium/vitamin}_D alone(CDgroup).Thepatientswereevaluatedafter90and180daysoftreatment.

Results:59ACDpatientsand56CDpatientscompletedalltheevaluations.Attheendofthe study,theBMDoftheradiusatthefracturelocationshowedanegativechangeintheCD group(32.8%).ThelossofBMDintheACDgroup(20.8%)wasslightlylessthanthatintheCD group.TherewasadifferenceintheproportionsofpatientswithBMDlossesattheendof thestudyperiodinthetwotreatmentgroups,infavoroftheACDgroup,althoughthiswas notstatisticallysignificant.Therewasnosignificantdifferenceinradiologicalidentification ofcallusformationbetweenthetreatmentgroups.Inthemajorityofthepatients,thecallus couldberadiologicallyidentifiedafter90days.

Conclusion:PostmenopausalwomenwithCollesfractureswhoreceivedrisedronatesodium pluscalcium/vitaminDdidnot showanysignificant differenceinBMDlossinforearm

∗ _{Corresponding}_author_.

E-mail:Lindomar@terra.com.br(L.G.Oliveira).

† _In_memoriam.

http://dx.doi.org/10.1016/j.rboe.2015.04.004

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fractures,incomparisonwiththosewhoreceivedcalcium/vitaminDalone.Risedronate aprotectiveeffectregardingBMDlossduetoimmobilization.Thetimetakenforfracture consolidationtobeachievedwasunaffected.

Uso

de

risedronato

na

consolidac¸ão

e

formac¸ão

do

calo

na

fratura

de

Colles

em

mulheres

na

pós-menopausa

–

Estudo

Solid

Palavras-chave:

Consolidac¸ãodafratura FraturadeColles Difosfonatos

r

e

s

u

m

o

Objetivo: Esteestudomulticêntrico,randomizado,aberto,grupoparaleloavalioua eficá-ciadeActonel® ₃₅_mg_mais_{cálcio/vitamina}_D_versus_{cálcio/vitamina}_D_isoladamente_na preservac¸ão da densidade mineral óssea(DMO) em mulheres pós-menopausadas com fraturadeColles.

Métodos: PacientescomfraturadeCollesemsetediasforamaleatoriamentedesignadas parareceberActonel®₃₅_mg_semanalmente_mais_{cálcio/vitamina}_D_(Grupo_AO_[GAO])_ou cálcio/vitaminaD(grupoO[GO])isoladamente.Aspacientesforamavaliadasapós90e180 diasdetratamento.

Resultados: Completaramasavaliações59pacientesnoGAOe56noOG.Nofimdoestudo,a DMOdorádionolocaldafraturamostrouvariaçãonegativanoGO(32,8%)quefoi discreta-mentemenornoGAO(20,8%),assimcomoumaperdamenornaDMOnoGAOcomparado comoOG.HouvediferençanaproporçãodepacientecomperdadaDMOnofimdoestudo nosdoisgruposdetratamentoemfavordoGAO,apesardenãoestatisticamente signifi-cante.Nãohouvediferençasignificativanaidentificaçãoradiológicadaformaçãodocalo entreosgruposdetratamento.Namaioriadaspacientesaidentificaçãoradiológicadocalo ocorreudepoisde90dias.

Conclusão: Mulherespós-menopausadascomfraturadeCollesquereceberamrisedronato sódico, além docálcio/vitamina D, comparado comcálcio/vitamina Dnão mostraram diferençasignificativanaperdadaDMOnafraturadoantebraço,comtendênciadeefeito protetordorisedronatonaperdadaDMOdevidoàimobilização.Otempoatéaconsolidação dafraturanãofoiafetado.

Introduction

The potential for accelerating or improving the formation ofacallusandpreventingprogressionoffracturesto pseu-darthrosishasbeen correlatedwithmechanicalprocedures for stabilizing bone fragments. However, this reality has changesinthelightoftheprovenefficacyofphysicalmethods ormedications.1

Bisphosphonateshavebeen studiedregardingtheir pos-sible positive or negative influence on formation of bone calluses.Thisgivesrisetoquestionsthatrelatetohow bis-phosphonatesmightinterferewithboneconsolidation;what theirinfluenceonthehistology,morphologyand biomechan-icsofthecallusmightbe;whatthebesttimeafterthefracture forstartingmedicationwouldbe;whetherbisphosphonates mighthaveanyeffectonconsolidationamongpatientswho usedthem previously, beforethe fracture;and whether all typesofbisphosphonatesactinthesamemannerwithregard toformationofthebonecallus.2–4

At therapeutic doses for osteoporosis, different

bis-phosphonates have not shown negative effects on bone

consolidationbuthaveshownimprovementstothe biome-chanical aspects of bone.5–9 _Experimental _studies _using risedronate haveshown thatconsolidation occurs,without anychangetothetimetaken,butwithbonecallusofbetter histologicalquality.10,11

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Materials

and

methods

Studydesign

Thiswasacomparativeparallel-groupopenrandomized mul-ticenter phase IV study conducted in six study centers in Brazil:Goiânia(one),Fortaleza(one),Niterói(one),SãoLuísdo Maranhão(one)andSãoPaulo(two).Thestudywasapproved bytheappropriateethicscommitteesandthepatientsgave theirfreeand informedconsentinwriting,beforeany pro-ceduresrelatingtothestudywerestarted.Furthermore,the studywasconductedinaccordancewithgoodclinical prac-ticesandwiththeethicalprinciplesthatoriginatedfromthe DeclarationofHelsinki.

Eachpatientwasevaluatedovera180-dayperiod,through sevenevaluationvisits:VO(baseline):visitmadesevendays afterColles fracture occurred;VR,randomizationvisit (day 0),madesevendaysafterthebaseline;andsubsequent vis-itsmade15(V1),30(V2),45(V3),90(V4)and180(V5)daysafter therandomizationdate.Amongthevisits,anintervalofthree dayswasallowed.

Patients

Womenwhohadbeenpostmenopausalforatleasttwoyears wereeligibletoparticipateiftheypresentedaCollesfracture thatwasconfirmedwithinaperiodofsevendaysbeforeentry intothestudy.Thepatientswerestratifiedbyageina1:1ratio (<65and≥65years)andaccordingtoT-score≤−2.0standard deviationsinthelumbarspine(L1–L4 and/orL2–L4)and/or femoralneckand/ortotalfemurand/or33%radius.

Themaininclusionandexclusioncriteriawereasfollows:

Inclusion criteria: postmenopausalfor atleast two years; Collesfractureconfirmedwithoccurrencesevendaysbefore entryintothestudy;T-score≤−2.0standarddeviationsinthe lumbarspine(L1–L4and/orL2–L4)and/orfemoralneckand/or totalfemurand/or33%radius.

Exclusioncriteria:previousfractureinthesamewristor fore-arm;fracturethat,intheopinionoftheorthopedicsurgeon or person responsible for the case, shouldonly be treated surgically;distalfractureoftheradiusorfracturesin contralat-eralbonesthatoccurredpreviouslyorconcomitantly,which mightimpedecomparisonsoftheBMDevaluationsoverthe courseofthestudy;use ofmedicationsconcomitantlythat mightaffectthecalciummetabolism;previoustreatmentwith bisphosphonatesformorethan 12monthsoverthe last36 months;useofbisphosphonatesforanyperiodoftimeover thelastthreemonths;cumulativeuseofbisphosphonatesfor morethan 36monthson any occasion;rheumatoid arthri-tisoranyotherdiseasewithinvolvementofthewrist;hyper orhypothyroidismthatisknowntobestable,withor with-outtreatment;hypocalcemia,liverdisease,kidneydiseaseor rheumaticdiseases.

Studytreatments

At the randomization visit, the eligible patients were designated to receive one of the two study treatments: Actonel®₊_Oscal®_group_(GAO):₃₅_mg_of_sodium_risedronate

onceaweekplus1000mgofcalciumand400IUofvitaminD onsixdaysaweek(i.e.notonthedayonwhichrisedronate wouldbetaken);orOscal®_group_(GO):₁₀₀₀_mg_of_calcium_and 400IUofvitaminDdaily(i.e.sevendaysaweek).

Efficacyassessments

Efficacywas based onthe changes seeninthe T scoresin theproximalregionoftheforearm(33%oftheregionofthe radius),fromthebaselinetoV4(90days)andV5(180days) afterthetreatmentandwasexpressedaspercentagesforthe twoarmsfracturedandnon-fractured).

Thedifferencewascalculatedinthefollowingmanner:T

scoreatV4minusTscoreatbaseline,dividedbyTscoreat baseline.

ThesamecalculationwasusedforthechangeinTscore fromthebaselinetoV5(180days);themeanchangeinTscore intheproximalforearm(33%oftheregionoftheradius)from thebaselinetoV4andV5inthetwoarms(fracturedand non-fractured),withradiologicalidentificationofcallusformation bymeansofX-rays.

Bonemineraldensity(BMD):BMDwasmeasuredbymeans ofdual-energyX-rayabsorptiometry(DXA),usingaGE/Lunar densitometer(DPXIQ,DPXNT,MD+Prodigy)orHologic densit-ometer(QDR2000,QDR200+,QDR4500,DelphiorDiscovery) onthelumbarspineandproximalfemur(femoralneckand totalhip)andthedistalregionoftheforearm(fracturedand non-fractured),atthebaselineandthenat90and180days. TheBMDmeasurementswererepeatedusingDXAforthe dis-talregionoftheforearm(fracturedandcontralateral).

X-rays:Radiologicalimagesofthewristandarm(fractured andcontralateral)wereobtainedintwoviews(posteroanterior andlateral),atthebaselineand15,30,45and180daysafter thefracture.ThemainX-rayparametersformonitoringthe consolidationofthefracturewereformationandviewingof bonebridgesalongthefracturelines,identifiedinthecortexin eachview.Fractureconsolidationwasdefinedasthepresence ofbonebridgesinthreeofthefourcorticalimagesevaluated intheseviews.

Qualitycontrolprocedureswereestablishedbymeansof training andcertification ofthe teaminvolvedinusingthe densitometryandX-rayequipment,withcentralanalysisof the tests performed, performed by the coordinator of the OsteoporosisResearchand DiagnosisCenter(CEDOES).The examinerswereblindedwithregardtothestudytreatment administeredineachcase.

Safetyassessments

Safetywasassessedaccordingtothetypeandseverityofthe adverseeventsthatwerereportedbythepatientsorobserved insomeotherwaybytheinvestigator.

Definitionofthestudypopulation

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(PP)consistedofpatientswhoweretreatedwithoutsignificant violationsoftheprotocolwhohadatleastoneBMDevaluation intheproximalregionoftheforearm(33%oftheregionofthe radius)onthesideofthefracture,atthebaselineandatV4 (90days).

Statisticalplan

AllthetestsappliedwereperformedusingSASv9.1andthe statisticalsignificancelevelwastakentobe5%.

Calculations were based on comparison of the groups

regardingthe mean change inBMD after90 days of treat-ment,expressedasapercentage.Powerof80%,significance levelof5%and discontinuationrateof10%were used.The standarddeviationwasassumedtobe0.08,withadifference ofinterestof4%betweenthegroups(meanpercentagechange inBMDafter90daysoftreatment).Therefore,theestimated totalnumbertoberecruitedwas140patients(70pergroup).

Thepercentagechange(%)inBMDafter90days(V4)and 180daysoftreatmentwascalculatedinthefollowingmanner:

– %changeatV4=[(T-scoreV4−T-scoreV0)/|T-scoreV0|]*100 – %changeatV5=[(T-scoreV5−T-scoreV0)/|T-scoreV0|]*100

The demographic variables of continuous nature were

described separately for the two treatment groups using

means, standard deviations and ranges. Comparisons

betweenthetreatmentgroupswereindicatedusingStudent’s

ttestvalues.Thediscretedemographicvariableswere sum-marizedin frequencytablesand comparisonsbetweenthe treatmentgroupswerebasedonpvaluesfromthechi-square testorFishertest,dependingonthefrequencyoftheevents.

The Mann–Whitney U test (independent observations)

was appliedforcomparisonbetweenthe treatmentgroups regardingchangesinT-scores(%)fromthevisitV0tothevisit V4andfromthevisitV0tothevisitV5.

TheWilcoxonsignedranktest(dependentobservations) was applied to compare the visits (V4 and V5) regarding changesinT-score(%),ineachtreatmentgroup.Tocompare thetreatmentgroupsbetweenthevisitsregardingmean T -scores,amodelofanalysisofvariance(ANOVA)wasapplied, withthefactorsfromthetreatmentgroups(Actonel+Oscal andOscal),visits(V0,V4andV5)andtherespective interac-tionsbetweenthem.Tocomparethetreatmentgroupswith regard to radiological identification of the callus, the chi-square test or Fisher F test was applied, according to the frequencyoftheevents.

Results

Patients

Thepatients’distributionispresentedinFig.1.Attheendof the study,59 patientsinGAOand56 inGOhad completed all the evaluations as planned.A total of 137 patients (70 in GAO and 67 in GO) received at leastone dose ofstudy medicationandwereevaluatedregardingefficacyandsafety. Thegroupswere showntobehomogenous atthebaseline regardingdemographicandclinicalcharacteristics(Table1).

Therewerenostatisticallysignificantdifferencesbetween the groups in relation to the side on which the fracture occurred:36/71patients(50.7%)hadaCollesfractureinthe left forearm inGAOand 38/70(54.3%)inGO (p=0.670).For the majority ofthe patients, the universal classificationof

Randomized N=141

Withdrawn: n=39 Reason for withdrawal: Did not attend the

inclusion/exclusion criteria: 35 Away from home: 2

Patient withdrew:1 Loss of follow-up:1

Group GAO N=71

Group GO N=70

Visit 4 (90 days) N=63

Visit 4 (90 days) N=60

Withdrawn = 10 Reason for withdrawal: Loss of follow-up: 3 Adverse event: 2

New reduction of fracture: 1 Death: 1

Patient withdrew consent: 1 Medical decision: 1 Lack of adherence*: 1 Withdrawn: n=8

Reason for withdrawal: Loss of follow-up: 6 Patient withdrew consent: 1 Lack of adherence*: 1

Withdrawn: n=4 Reason for withdrawal: Loss of follow-up: 2 Adverse event: 1 Lack of adherence*: 1

Withdrawn: n=4 Reason for withdrawal: Loss of follow-up: 3 Violation of protocol: 1

*Use of less than 80% of the study medication

Included N=180

Visit 5 (completion of study)

N=59

Visit 5 (completion

of study) N=56

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Table1–Demographiccharacteristicsandbaselineclinicalcharacteristics.

Demographiccharacteristics GAO

N=71

GO

N=70

pvalue (GAOvs.GOa₎

Age,years

Mean±SD 67.1±10.9 64.9±10.4 0.224a

Limits 44–90 44–92

Agestratum,N(%)

<65years 33(46.5) 34(48.6)

≥65years 38(53.5) 36(51.4)

Ethnicity

White 50(70.4) 57(81.4) 0.389b

Black 6(8.5) 4(5.7)

Mixed 15(21.1) 9(12.9)

Weight(kg)

Mean±SD 58.5±11.5 61.3±12.0 0.1502a

Limits 36–88 34–89

Height(cm)

Mean±SD 150±6 152±6 0.0482a

Limits 137–165 140–174

Lengthoftimesincemenopause(years)

Mean±SD 19.8±12.1 18.3±9.8 0.4392a

Limits 3–55 2–43

LengthoftimefromCollesfractureoccurrencetobaseline,days

Mean±SD 3.5±1.7 3.4±1.8 0.580a

a _t_test_for_independent_variables.

b _Chi-square_test.

Table2–ChangeinTscoreinproximalforearm(33%)onfracturedside,expressedaspercentage,inmodifiedITT population.

V4 V5 pvaluea

GAO

No.ofpatients N=59 N=59

Mean±SD −25.7±40.7 −20.8±39.5

Min/Median/Max −200/−15.2/27.8 −200/−9.1/15.4 0.727

GO

Mean±SD −31.9±62.5 −32.8±68.0

Min/Median/Max −400/–21.4/75 −366.7/−18.9/90 0.769

pvalueb_(groups) _0.352 _0.069

a _Wilcoxon_signed_rank_test.

b _{Mann–Whitney}_U_test.

theCollesfracturewasI _orII_/IIa:_15/71_patients_(21.1%)_and 46/71(64.8%),respectively,inGAO;and16/70(22.9%)and43/70 (61.4%),respectively,inGO(p=0.917).

TheBMDmeasurement(evaluatedbymeansoftheTscore) didnotshowanystatisticallysignificantdifferencebetween thetreatmentgroupsatthebaseline,inforearmsdiagnosed withfractures,inforearmswithoutfracturesandinthe lum-barspine,femoralneckandtotalfemur.Themajorityofthe patientsinthetwotreatmentgroupsusedatleast80%ofthe totalnumberofpillsplannedpervisit.

Findingsonthesideofthefracturedforearm

Onthesideofthefracturedforearm,adecreaseinBMDwas observed(evaluatedusingthe%oftheTscore)fromV0 to

V4(90days)andV5(180days)inthetwotreatmentgroups, rangingfrom20.8%to32.8%(Table2).

There was atendency towardgreater reductioninBMD (evaluatedusingthe Tscore)amongthepatientsinGO.At V4,thisreductionwasapproximately15%inGAOand21%in GO.AtV5,thislossofBMDwasapproximately9%inGAOand 19%inGO.Nostatisticallysignificantdifferencebetweenthe groupswasreachedateithervisit:p=0.352and0.069forV4 andV5,respectively(Table2).Likewise,nostatistically signif-icantdifferenceinTscorevariationwasfoundincomparing V4andV5inthetwogroups(p=0.727and0.769forGAOand GO,respectively).

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Table3–ChangeinTscoreinproximalforearm(33%)on fracturedside,expressedaspercentage,inPP

population.

Groups V4 pvalue(groups)a

GAO

No.ofpatients N=45 Mean±SD −24.6±41.9 Min/Median/Max −200/−15.2/27.8

GO

No.ofpatients N=46 Mean±SD −27.4±30.8

Min/Median/Max −166.7/−23.0/20% 0.110

a _{Mann–Whitney}_U_test.

FromV0 toV4 (day90),mostofthepatientsinthetwo treatmentgroupspresentedlossofBMD:46/63(73.0%)inGAO and46/60(76.7%)inGO.Themean±SDforthelossofBMD was−0.5(0.4)inGAOand−0.7(0.4)inGO.ComparingV0with V5(day180),alossofBMDcouldbeseenin39/59patients (66.1%)inGAOandin43/56(76.8%)patientsinGO.Themean ±DPofthedifferenceinBMDbetweenV0andV5was−0.5 (0.4)forGAOand−0.7(0.4)forGO.

Findingsonthenon-fracturedside

Inthenon-fracturedforearm,theBMDevaluatedaccordingto thechangeinTscore(%)fromV0untilthevisitsV4andV5 rangedfrom4.2%upwards(anincreasefromV0toV4,i.e.day 90)to−6.0%downwards(areductionfromV0toV5,i.e.day 180)(Table4).

AtV4,theincreaseinBMD(evaluatedaccordingtotheT

score)wasseentobegreaterinGO(4.2%)thaninGAO(1.9%); andatV5,therewasareductioninBMD(evaluatedaccording totheTscore)inthetwogroups.ItwasgreaterinGO(−5.7%) thaninGAO(−2.2%).Nostatisticallysignificantdifferences wereobservedbetweenthetreatmentgroupsatthetwovisits orbetweenthevisitsforthetwotreatmentgroups(Table4).

Furthermore,approximately30%and42%ofthepatients inthetwotreatmentgroupsshowedlossesofBMDfromthe baselinetoV4(day90)andtoV5(day180),respectively.

In relation to the proportion of patients with losses of BMD at V4, there was a statistically significant difference

Table5–LossofBMDintheproximalforearm(33%of radius)betweenvisitsV0andV5(day180),inmodified ITTpopulation.

GAO GO

Fractured

N 59 56

LossofBMD 39(66.1%) 43(76.8%)

Mean±SD −0.5(0.4) −0.7(0.4)

Non-fractured

N 59 56

LossofBMD 25(42.4%) 24(42.9%)

Mean±SD −0.3(0.3) −0.3(0.2)

pvaluea _0.010 _0.0003

a _Chi-square_test.

between the fractured and non-fractured sides in the two treatmentgroups(GAOandGO;p<0.0001forboth).This dif-ferenceinpatternobservedintheforearmsbetweenthesides wasprobablyrelatedtotheimmobilizationofthefractured side(Table5).

TheANOVA modelcompared the mean T scoresin the

twotreatmentgroupsbetweenthevisits,usingthetreatment group(GAOorGO)andthevisits(V0,V4andV5)asfactors, along withtheir respectiveinteractions.There was no evi-denceofsignificantinteractionbetweenthefactors,eitherfor thesidewiththefracture(p=0.134)orforthenon-fractured side(p=0.982).Thissuggeststhatthetwotreatmentgroups hadsimilarpatternsoverthecourseoftime(Figs.2and3).

Onthesidewiththefracture,therewasastatistically sig-nificantdifferencebetweenthevisits,suchthatthemeanT

scoreswere significantlylower atV4 and V5,inrelationto V0 (p<0.001),althoughno differences were foundbetween thetreatmentgroups(p=0.825)(Fig.2).Onthesidewiththe fracture, therewas no evidence of any statistically signifi-cantvariationbetweenthegroups(p=0.554)orvisits(p=0.081) (Fig.3).

Radiologicalevaluation

Theresultsfromradiologicalidentificationofthecallusover thecourseofthevisitsdidnotshowanyevidenceofany sig-nificantdifferencebetweenthetreatmentgroupsatthevisits

Table4–ChangeinTscoreinproximalforearm(33%)onnon-fracturedside,expressedaspercentage,inmodifiedITT population.

V4 V5 pvaluea_(visits)

GAO

Mean±SD 1.9±17.4 −2.2±28.2

Min/Median/Max −36.4/0/79.2 −133.3/0/75.5 0.223

GO

Mean±SD 4.2±37.4 −5.7±29.8

Min/Median/Max −142.9/3.8/150 −142.9/0/34.6 0.128

pvalueb_(groups) _0.438 _0.861

a _Wilcoxon_signed_rank_test.

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–3.2 –3 –2.8 –2.6 –2.4

V0 V4 (D90) V5 (D180)

GAO GO

ANOVA P=0.825 (group) P<0.001 (visit) P=0.134 (grupo *visit)

*

T Score

Fig.2–ResultsfromtheANOVAmodelforthefracturedside.

–3.2 –3 –2.8 –2.6 –2.4

V0 V4 (D90) V5 (D180)

GAO GO

ANOVA P=0.554 (group) P=0.081 (visit) P=0.982 (grupo *visit)

*

T Score

Fig.3–ResultsfromtheANOVAmodelforthenon-fracturedside.

V1(p=0.674),V2(p=0.755)andV3(p=0.749),withregardtothe proportionofthepatientsinwhomthecalluswasidentified onX-rays.Attheothervisits(V4andV5),thecalluswasseen bymeansofX-raysinalmostallthepatients,inbothgroups, andnostatisticalcomparisonwasmade.

Safety

InGAO,23/71randomizedpatients(32.4%)reported thatat least one adverse event occurred during the study period, totaling 34 suchevents. In GO, 23/70 randomizedpatients (32.9%)reportedthatadverseeventsoccurredduringthestudy period,totaling 41 suchevents.Three adverseevents were consideredbytheinvestigatortobeserious.InGAO,onecase ofrenewedfracturingofthewristwasreported.Thiswas con-sideredtobeofmoderateintensityandneededhospitalization andsurgeryforexternalfixationtobeimplemented.Itwas reportedthatthepatienthadrecovered.InGO,twocasesof adverseeventsoccurred.Oneoftheseconsistedofa hypoe-choicaccumulationintherightcalf,whichwasconsideredto beofmoderateintensity.Thiscaserequiredhospitalization

andthepatientwasstillrecoveringatthetimeofthisreport. Theotheradverseeventcomprisedcardiorespiratoryarrest, whichoccurredatthepatient’shome,wasofsevereintensity andresultedindeath.

Noneofthesethreeadverseeventswasconsideredbythe investigatortoberelatedtothestudymedication.InGO,both oftheadverseeventsledtointerruptionofthetreatment.For the patientinGAO,administrationofthestudy medication wasnotimmediatelystoppedbecauseoftheadverseevent, buttheeventledtowithdrawalfromthestudy.

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Discussion

Inthepresentstudy,after90daysofrisedronateuse,no signifi-cantvariationinthelossofBMDwasseeninthefracturedarm, orinthenon-fracturedarm.Thesamepatternwasobserved after180daysoftreatment,whichsuggeststhatrisedronate hasaprotectiveeffectduetotheimmobilization.

Several medications have been used to improve bone

consolidation, both for accelerating the process and also for improving the quality of the bone callus, i.e. through improvingthemicroarchitecture,volumeandbiomechanical strengthofthecallus.Thesemedicationsincludestrontium ranelateanddrugsthatactontheWntsignalingsystem,such teriparatideandtheantibodiesanti-sclerostinandDKK-1.12–15 Somemedications havebeenrecognizedasharmfulto cal-lusformationandtheseincludecorticoids,chemotherapeutic agents,antibiotics,anti-inflammatoryagents,anticoagulants andanticonvulsants.16

However,bisphosphonates arethe drugsthathavebeen studiedmost.Thesefavorformationofamorevoluminous callus with mineralization and make the callus mechani-callymorecompetent,butwithaslowerremodelingrate.17–22 Anotherfactordiscussedintheliteraturehasbeenthetime atwhichbisphosphonateuseshouldstart,afterafracturehas occurred.Someevidencefavorsstartingtouse bisphospho-nates15daysaftertheevent,whileotherevidencesuggests that, independent of the time at which they are admin-istered, they do not interfere with bone consolidation or withpostoperative healing followingoccurrences of osteo-poroticfractures.23,24 _The_time_taken_to_reach_{consolidation} isunrelatedtothe severityoftheosteoporosis orthe type offracture.25_Therapy_using_{bisphosphonates}_can_be contin-uedafteroccurrencesoffracturesofthedistalradius,without deleteriousclinicaleffectsonconsolidation.26

When used for long periods, bisphosphonates may

increasetheoccurrencesofmicroandmacrofracturesin ani-malsandhumans.Theyalsogiverisetopreferentialfracture sites.However,biomechanicalgainsregardingthebone cal-lusareobserved(sizeandexternaldiameter).Itseemsthat theorganismcompensatesforthenegativeeffectofthe med-icationandmodulatesthemorphologyofthecallussoasto obtainbetterbiomechanicalfunction(mechanostat).27

Theeffectsofrisedronatehavebeenstudiedbothin rela-tion toimprovement ofbonemineral density and fracture preventioninpatientswithosteoporosis andin relationto use during bone consolidation. It has been observed that risedronate does not interfere negatively with bone callus formationandcanbeusedwithoutdeleteriouseffectson con-solidation.On the contrary,it increasesthe volume ofthe callusanditsbiomechanicalresistance.28,29

TheBMD of33% of the radiuson the fractured side at theendofsixmonths(V5)presentedanegativechange of 32.8%intheOscalgroupandonly20.8%intheActonel+Oscal group,whichshowedthatrisedronatehadatendencytoward havingaprotectiveeffectagainstlossofBMDcausedby post-fractureimmobilization(p=0.069).Eventhoughtherewasno statisticallysignificantdifferencebetweenthetwogroups,it wasseenthattherewaslowerlossofBMD(evaluatedusing

T scores) in the group treated with Actonel+Oscal (mean

decreaseof−0.5),inrelationtothegroupthatusedOscalalone (meandecreaseof−0.7),asshowninTable5.Thiswaspossibly duetothegreatvariabilityofthedata.

TheBMDof33%oftheradiusonthenon-fracturedsideat theendofsixmonths(V5)presentedanegativechangeof5.7% inGOandonly2.2%inGAO,withadifferenceof3%infavor ofrisedronate.However,therewasnostatisticallysignificant difference(p=0.861)(Table4).

AsshowninFig.2, theinitialBMDof33%oftheradius onthefracturedside(measuredusingtheTscore)decreased significantly(p<0.001)duringthetreatment(fromV0toV5), whilethisdifferencewasnotobservedonthenon-fractured side. This shows the significant influence of immobiliza-tion ofafractureonboneloss.Regarding theproportionof patientswithlossofBMDatV5,therewasastatistically sig-nificantdifferencebetweenthefracturedandnon-fractured sides,forbothtreatmentgroups(GAO,p=0.010;GO,p=0.0003) (Table 5). This pattern of difference observed between the groupswasprobablyrelatedtoimmobilizationofthefractured side(Table5).Thesedatashowthatrisedronateprovided pro-tectioninrelationtolossofBMDduringtheimmobilization ofalimb(osteoporosisofdisuse),whichisdiscussedinother studies.30

Therewasnosignificantdifferenceinradiological identifi-cationofthebonecallusatthetimesofthevisits(V1toV5), orbetweenthetreatmentgroups.Thus,useofrisedronatein ourstudydidnotpresentanynegativeclinicaleffectonbone consolidation.Inmostofthepatients,radiological identifica-tionofthecallusoccurredatV3,withasimilarpatterninthe twogroups.Furthermore,thesafetyprofileofrisedronatewas showntobesimilartothatofthecontrolgroup.

Limitationsofthestudy:Giventhatthisstudywasdesigned withoutcomparisonwithplacebo,webelievethattheremay havebeenanimportanteffectonBMD,sincethetestswere evaluated centrally,asdescribedinthe methodology. How-ever,basedonthewell-establishedsideeffectsthathavebeen describedpreviouslyforthisclassofmedications,aneffectin interpretingthesafetydatacannotbetotallyruledout.

Conclusions

PostmenopausalwomenwithCollesfractures whoreceived sodiumrisedronatepluscalciumandvitaminD,in compar-ison with calcium and vitamin D only, did not show any significantdifferenceregardinglossofBMDinthefractured andnon-fracturedforearmafter90days(primaryobjective) and 180days(secondaryobjective).Risedronatewasshown tohaveatendencytowardaprotectiveeffectregardingloss ofBMDduetoimmobilization.Thetimetakentoreach frac-tureconsolidationwasunaffectedandthetwogroupsshowed similarsafetypatterns.

Conflicts

of

interest

(9)

sponsoredbyServierLaboratories,Sanofi-Aventis,Lillyand BlauFarmacêutica.

Thisstudy receivedfinancial support and backing from Sanofi forits design, conduction, data-gathering, manage-ment, data analysis and data interpretation, along with editorialassistanceforthemanuscript.

Acknowledgments

OurspecialthankstoDrs.BenHurAlbergaria,MárcioPassini deSouza,Jorge dosSantosSilvaand Edson Cerqueira Gar-cia de Freitas for their valuable contributions toward the designofthis researchprojectand collaborationin discus-sionsregardingtheproject,andindraftingthefinaltextof thismanuscript.

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