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OfficialreprintfromUpToDate
www.uptodate.com2015UpToDate

Osteogenesisimperfecta:Managementandprognosis
Authors
JohnFBeary,III,MD
ArkadiAChines,MD

SectionEditor
HelenVFirth,DM,FRCP,DCH

DeputyEditor
ElizabethTePas,MD,MS

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Nov2015.|Thistopiclastupdated:Oct07,2015.
INTRODUCTIONOsteogenesisimperfecta(OI)isaninheritedconnectivetissuedisorderwithmany
phenotypicpresentations.Itisoftencalled"brittlebonedisease."Severelyaffectedpatientssuffermultiple
fractureswithminimalornotrauma,andinfantswiththeworstformofOIdieintheperinatalperiod.Mildformsof
OImaymanifestwithonlyprematureosteoporosisorseverepostmenopausalbonemineralloss.
ThegoalsoftherapyforpatientswithOIaretoreducefracturerates,preventlongbonedeformitiesandscoliosis,
minimizechronicpain,andmaximizemobilityandotherfunctionalcapabilities[13].PatientswithOIshouldbe
referredforevaluationbyspecialistsingeneticsand,ifclinicallyindicated,orthopedicswithexpertiseintreatingOI
atthetimeofdiagnosis[4].Treatmentrequiresacoordinatedmultidisciplinaryteamapproachandconsistsof
physicaltherapy,surgicalinterventions,medications,and,insomecases,experimentaltherapies[57].Patients
withOIneedadditionalhealthsupervisionfromtheirprimarycareprovidersandmonitoringforpotential
complications.
ThemanagementandprognosisofOIarepresentedhere.Thepathogenesis,clinicalfeatures,diagnosis,and
differentialdiagnosisarediscussedseparately.(See"Osteogenesisimperfecta:Clinicalfeaturesanddiagnosis".)
BISPHOSPHONATETHERAPYBisphosphonatesarethemainstayofpharmacologicfractureprevention
therapyformostformsofOI(exceptfortypeVI(table1)inwhichbonemineralizationisdefective),althoughnone
areapprovedspecificallyforuseineitherchildrenoradultswithOI.Wesuggesttreatmentwithintravenous
pamidronateforpatientswithallformsofOI,excepttypeVI,inwhomclinicalbenefitsarelikelytooutweigh
potentiallongtermrisks(ie,thosewithlongbonedeformities,vertebralcompressionfractures,and3fractures
peryear).(See"Osteogenesisimperfecta:Clinicalfeaturesanddiagnosis",sectionon'Pathology'.)
Bisphosphonatesarestableanalogsofpyrophosphateandarepotentinhibitorsofboneresorptionandbone
turnover.Theyareusedwidelyintreatmentofosteoporosisinadultsandhavereducedtheriskoffracturesin
womenwithpostmenopausalosteoporosis,menwithosteoporosis,andpatientswithglucocorticoidinduced
osteoporosisinmultipleclinicaltrials.
ReportsofbisphosphonatesforchildrenwithOIareencouraging,withareducedfracturefrequencyofupto100
percentinobservationalstudies[7,8].Thelongtermeffectsonstructuraloutcomessuchasscoliosisandbasilar
invaginationareunclear.Theoptimaldoserange,dosinginterval,durationoftreatment,andthelongtermefficacy
andsafetyprofileofthesedrugsinthetreatmentOIhaveyettobeestablished[9].Furtherstudy,particularlyin
theformofrandomizedtrials,isneeded.
IntravenouspamidronateThemajorityofinformationabouttheuseofbisphosphonatesinOIcomesfrom
uncontrolledstudiesofcyclicalinfusionsofpamidronateinvariousregimensinchildrenwithOI[10].Thesereports
havenotedincreasedbonemineraldensity(BMD),decreasedfracturerate,andimprovedfunctionalabilities,
mobility,ambulation,andpain,withoutnegativeeffectsonfracturehealingorgrowthrateinmoststudies,even
whenusedinyoungchildren[8,1119].Asingle,observationalstudyof14prepubertalchildrenwithmildformsof
OI(typesIandIV)treatedwithpamidronatefoundasignificantincreaseinheightandsittingheightstandard
deviationscoresduringthefirstyearoftreatment.
Intheonlycontrolledtrial,18children(agerange4to13years)withtypesIIIandIVOIwererandomlyassignedto
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treatmentwithintravenouspamidronate(10mg/m2perdayforthreedayseverythreemonths)ornotreatmentfor
oneyear.Fourchildrenineachgroupalsoreceivedrecombinantgrowthhormone(rGH)[20].Afteroneyear,
treatedpatientshadsignificantlyincreasedlumbarspineBMD,midvertebralheight,andtotalvertebralarea,
comparedwithcontrols.Upperextremityfractureratedecreasedsignificantlyinthefirst,butnotsecond,yearof
treatmentcomparedwiththebaselinerate(0.89atbaselineand0.22and0.29afteroneandtwoyearsof
treatment,respectively).Therewasatrendtowarddecreasedfracturerateinthelowerextremitiesinthefirstyear
oftreatmentcomparedwithbaseline(1.44versus0.67respectively).Growthrate,grossmotorfunction,muscle
strength,andpaindidnotchangesignificantlyintreatedpatientscomparedwithcontrols.Inthesevenpatients
whoextendedtreatmentforanadditional6to12months,bonedensity,midvertebralheight,andvertebralarea
weremaintainedbutdidnotincreasebeyondthe12monthvalues.
Pamidronateisadministeredintravenouslyincyclesofthreeconsecutivedaysattwotofourmonthintervalswith
dosesrangingfrom0.5to1mg/kg/day,dependinguponage,withacorrespondingannualdoseof9mg/kg.The
smallesteffectivedoseshouldbeused,withcarefulmonitoringofvertebralgeometry,longbonefractures,and
BMDbeforeimitatinganewcycleoftreatment.
Theshorttermendocrineandmetaboliceffectsofintravenouspamidronatetherapyobservedin165children(age
twoweeksto17.9years)whoreceivedcyclicinfusionsincluded[21]:
Shortlivedloweringofserumcalciumconcentrationsfollowingthreesequentialdailyinfusions(nonerequiring
supplementalintravenouscalcium)
Increasedparathyroidhormone(PTH)levels
Increased1,25dihydroxyvitaminDlevels
DecreasedurinaryexcretionoftypeIcollagendegradationproducts(NtelopeptideoftypeIcollagen,also
calledaminoterminalcollagencrosslinksorNTX),amarkerofboneturnover
Overthelongerterm(atleastfouryearsoftherapyin40patients),therewasnosignificantoverallchangein
serumcalciumconcentrationsfrombaseline[21].MeanPTHlevelswereelevatedby30percentfrombaselineand
subsequentlyremainedstable.TheexcretionofNTXadjustedforurinarycreatininedecreasedrapidlyduringthe
firstyearandmoreslowlythereafter.Afterfouryearsofbisphosphonatetherapy,theadjustedurinaryNTXwas63
percentlowerthanthebaselinevalueandwaslowerthanthatinhealthychildren,indicatingasustainedreduction
intherateofboneturnoverthatisincreasedinOIchildren.
Asimilarassociationbetweenpamidronatetherapyanddecreasedboneturnoverwasfoundinastudyof29
childrenwithOItypesI,III,andIVwhoweretreatedwithpamidronateforthreeyears[14].Treatmentwasinitiated
beforetwoyearsofage.Treatmentwithpamidronatewasassociatedwithimprovedbonestrengthandgross
motorfunction.However,theaverageboneformationrateperbonesurfaceinthetreatedchildrenwas17percent
thatofchildrenwithsevereOIwhowereuntreatedand25percentthatofhealthycontrols.
Theredonotappeartobeanyadverseshorttermeffectsonbonequalityorfracturehealingdespitethesignificant
reductionintherateofboneturnoverwithbisphosphonatetreatment[22].Iliacbonebiopsyresultsin45patients
treatedwithpamidronateforameanof2.4yearsrevealedthatboneformationandbonemineralizationwerenot
impaired[23].ChronicsuppressionofboneturnoverinchildrenwithOIdoesnotappeartobeassociatedwithany
detrimentaleffectsonlineargrowthrate[15,24,25].However,itappearsthatmostofthebenefitofpamidronate
therapyoccursduringthefirsttwotofouryearsoftherapy[17,26].
Nonetheless,itisprudenttoreserveitsuseforpatientsinwhomclinicalbenefitsarelikelytooutweighthelong
termrisks(ie,thosewithlongbonedeformities,vertebralcompressionfractures,and3fracturesperyear)since
thelongtermeffectsofpamidronatetherapyareunknown[1,10,14,27].
IntravenouszoledronicacidTreatmentwithintravenouszoledronicacid(zoledronate)requiresinfusionevery
sixmonths,ratherthanmonthlyaswithpamidronate.Thesafetyandefficacyofzoledronictherapywasevaluated
inastudyof17patientswithmild(typeI)OIaged1.5to16.8yearswhoweretreatedforonetothreeyears.Bone
densityincreasedaftertwoyearsoftreatment.Twopatientsdevelopedsymptomatichypocalcemia.Althoughthe
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incidenceoffracturesinthetwoyearsprecedingtreatmentwashigherthanduringthefirstyearoftreatment(6.5
versus4fractures/year),itisdifficulttodeterminefromthereportedresultswhetherthefractureratedecreased,
becauseofashortdurationoffollowupandsmallnumberoffractures.
OralrisedronateThesafetyandefficacyoforalrisedronatehasbeenevaluatedintworandomizedtrials
[28,29].Inthefirst,53childrenwererandomlyassignedtoreceiveoneofthreedoses(0.2,1,or2mg/kgper
week)ofrisedronatefortwoyears[28].BMDincreasedandlongbonebowingdeformitiesdecreasedwith
increasingrisedronatedose.Thefractureratedecreasedsignificantlyinallthreegroupsduringthetreatmentperiod
comparedwiththeprevioustwoyears,buttherewasnodifferenceamongthegroups.
Inthesecondtrial,147childrenwithmostlymildphenotypewererandomlyassignedtoreceiveoralrisedronate
(2.5mgifweightwas10to30kgor5mgifweightwas>30kg)orplaceboforoneyear,followedbyopenlabel
treatmentinallsubjectsfortwoadditionalyears[29].Thereweresignificantdifferencesbetweentherisedronate
andplacebogroupsinmeanlumbarspinearealBMD(16.3versus7.6percentincrease,respectively)andclinical
nonvertebralfractures(occurredin31versus49percent,respectively).Notreatmenteffectwasobservedfor
morphometric(radiographic)vertebralfracturesafteroneyearoftreatment.Adverseeventsweresimilarinthetwo
groups.TherewerenosignificantdifferencesbetweenthetwogroupswithregardtoBMDorfracturesduringthe
openlabelphase.
OralalendronateTheeffectofdailyoralalendronate(5or10mgbasedonbodyweight:beloworabove40kg,
respectively)wasstudiedin139children,aged4to18years,withsevereOIinarandomizedtrial[30].Aftertwo
yearsoftreatment,alendronateproducedasignificantincreaseinlumbarspineBMDcomparedwithplacebo(51
versus12percent).However,therewerenosignificantdifferencesbetweengroupswithregardtogrowthvelocity,
incidenceoflongbonefractures,bonepain,orpediatricdisabilityscore.Thesafetyandtolerabilityofalendronate
werefavorableandcomparablewiththatofplacebo.Longertermdata,includingbonebiopsies,fractureincidence,
andfracturehealing,willberequiredtofullyassessthebonesafetyandefficacyofalendronateinOIchildren.
IntravenousneridronateTheeffectsoftreatmentwithintravenousneridronatewereevaluatedinatrialin
which64prepubertalItalianchildren(6to11years)withOIwererandomlyassignedtotreatmentwithneridronate
(2mg/kginfusedintravenouslyeverythreemonths)ornotreatmentforoneyear[31],afterwhichallpatientswere
treatedwithneridronate.Attheendofthefirstyear,patientsinthetreatmentgrouphadgreaterincreaseinspine
andhipBMD(18to25percentversus3to6percent),andfewerfractures(relativerisk0.36,95%CI0.150.87)
comparedwiththecontrolgroup.Neridronatewaswelltoleratedinthisstudy.Neridronateisnotavailableinthe
UnitedStates.
Theefficacyofcyclicalneridronatetherapyininfantswasevaluatedinastudyinwhich10infantswithOItypeIII
startedcyclicalneridronatejustafterdiagnosis(atapproximatelyonemonthofage)oratsixmonthsofage[32].
Theseinfantswerecomparedwithhistoricalcontrolsmatchedforage,sex,andclinicalseverity.Duringthefirst
sixmonths,infantsreceivingneridronatehadbettergrowthinweightandheightandfewerfracturesthanthose
waitingtostarttherapyorhistoricalcontrols.Duringthesecondsixmonths,infantsinbothofthetreatmentgroups
hadfewerfracturesthanhistoricalcontrols.
OralolpadronateResultssimilartothosewithpamidronatewerereportedwithoralolpadronateinthreeboys
withsevereOI[33].Inatrialinwhich34childrenwithOIwererandomlyassignedtoolpadronate(10mg/m2)or
placebo,activetreatmentfortwoyearswasassociatedwithareducedriskoflongbonefractures(hazardratio
0.69,95%CI0.520.91)[34].Therewasnoeffectonvertebralheight,children'sfunction,ormarkersofbone
turnover.OlpadronateisnotavailableintheUnitedStates.
PretreatmentevaluationandmonitoringTherearenowrittenguidelinesorprotocolsforpretreatment
evaluationandmonitoringwhenusingbisphosphonatetherapyinchildrenwithOI.Wegivethefollowing
suggestions,keepinginmindthattheseareindividualizedbaseduponanumberoffactorsincludingageofthe
patient,diseaseseverity,previoustreatment,andresponsetotherapy.Inprinciple,pretreatmentevaluationand
monitoringofbisphosphonatetreatmentinchildrenwithOIissimilartothatinadultswithosteoporosis.
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CalciumandvitaminDintakearebasedupontherecommendeddailyallowances(RDAs)forachild'sage(700to
1300mg/dayforcalciumand400to600int.unitsforvitaminD).Thechildshouldbesupplementedbefore
bisphosphonatetreatmentisinitiatedifdietaryintakeisinadequate.Indicesofcalciumhomeostasis(eg,calcium,
phosphorous,PTH)andrenalfunctionshouldbeassessedbeforeinitiationoftreatmentandfollowedevery6to12
months.Calciumlevelsshouldalsobeassessedbeforeeachintravenousbisphosphonateinfusiontoassurethat
thechildisnothypocalcemic.(See"Dietaryhistoryandrecommendeddietaryintakeinchildren",sectionon
'Recommendeddietaryintakes'and"VitaminDinsufficiencyanddeficiencyinchildrenandadolescents",section
on'RecommendationsforvitaminDintake'.)
IntravenousversusoraltherapyTherearenodatadirectlycomparingintravenousandoralbisphosphonate
therapyinchildrenwithOI.Inonesmall,randomizedtrialcomparingoralalendronatewithintravenouspamidronate
forchildrenwithOI,BMDincreasedsimilarlyinbothgroups[35].Nonetheless,manycliniciansbelievethat
intravenouspamidronateismoreeffectiveintreatingbonepainandpossiblyhasagreatereffectonfracturerisk
reductionthanoraltherapy[10].
InadultsAdultswithOImayhaveahigherfractureriskthanhealthypeersbecausetheyareunlikelytoreach
anequivalentpeakBMD.Inaddition,thestructuraldefectsofcollagenmaycontributetodecreasedbonestrength,
independentlyofBMD,therebyincreasingtheriskoffractures.Postmenopausalbonelossbeginningfromalower
thannormalpeakmayincreasefractureriskinuntreatedwomenwithOIcomparedwithpostmenopausalwomen
ingeneral.Thus,treatmentwithselectiveestrogenreceptormodulators(SERMs)orbisphosphonatesshouldbe
consideredimmediatelyaftermenopausetopreventacceleratedbonelossandosteoporoticfracturesinwomen
withthesuperimposedproblemsofpostmenopausalosteoporosisandOI(selfhistoryorfamilyhistory).(See
"Overviewofthemanagementofosteoporosisinpostmenopausalwomen".)
LittleinformationontreatmentinadultswithOIisavailable.Inonestudy,23menand23premenopausalwomen
withOI(typesI,III,andIV)wererandomizedtointravenousneridronate100mgeverythreemonthsorno
treatment(ratio2to1)foraperiodofoneyear,withbothgroupsreceivingtreatmentthesecondyear[36].The
averageageofthepopulationwas35years,andmeanlumbarspineBMDTscorewas3.4.BMDincreased
significantlyfrombaselineinthetreatmentgroupandcomparedwiththecontrolgroup.Aftertwoyears,BMD
increased6.4and7.5percentinmalesandfemales,respectively,inthetreatmentgroup.Theriskofclinical
fracturestendedtodecreaseduringtreatmentwithneridronate,althoughthestudywasnotpoweredforsuchan
endpoint.NeridronateisnotavailableintheUnitedStates.
Inanobservationalstudy,90adultswithOI(typesI,III,andIV)weretreatedwithintravenouspamidronate(n=
28),oralalendronate(n=10),oralrisedronate(n=17),ornottreated(n=35)foranaverageof52months[37].A
significantlyincreasingrateofBMDperyearoftreatmentwasseeninalltypesofOItreatedwithpamidronate,but
onlyinpatientswithtypeIOItreatedwithoralbisphosphonates.Fractureratedecreasedsignificantlyonlyinthe
typeIII/IVpatientstreatedwithpamidronate.
OfflabelbisphosphonatetreatmentofadultswithOImustbeconsideredonacasebycasebasisandingeneral
shouldbebasedupontheassessmentoffractureriskusingBMDandclinicalriskfactors,suchashistoryof
nontraumaticfracture,familyhistoryofosteoporosis,weight,smoking,andalcoholconsumptioninadditiontothe
riskassociatedwithOI.TherelativecontributionofOI,besideslowBMD,tothefractureriskinadultsasaresult
ofdefectivebonequalityisunknown.Nevertheless,wesuggestthatthetherapeuticthresholdshouldbelowerfor
adultswithOIwiththesameleveloffractureriskascomparedwiththosewithoutOI.(See"Osteoporoticfracture
riskassessment"and"Treatmentofosteoporosisinmen"and"Overviewofthemanagementofosteoporosisin
postmenopausalwomen".)
AdverseeffectsAdverseeffectsofpamidronatetherapyinclude[1]:
Aninfluenzalikesyndrome(fever,myalgias,malaise,rash,vomiting)followingthefirstinfusion[11,15,25].
Thislikelyreflectsacutecytokinereleaseinasubsetofpatientswithageneticprofilethathasyettobe
identified.Itisseenafterthefirstdoseandisunlikelytooccurwithsubsequentdoses.Thisinfluenzalike
syndromewasalsoseenafterthefirstdoseoforalibandronateinthemonthlydosingclinicaltrialandis
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recordedintheproductlabel.
Unexplainedrapidweightgainthatmayinterferewithrehabilitation[24].
Uveitis[1].Thisadverseeffectresolveswithdiscontinuationofthedrug.
Respiratorydistressininfantsyoungerthantwoyears[38].
Anumberofadversemusculoskeletaleventsareassociatedwithbisphosphonateuseinadults.Themostserious
amongthemisosteonecrosisofthejaw(ONJ),whichisprimarilyassociatedwithintravenousbisphosphonateuse
incancerpatientswhomayhavejawbonevulnerabilityresultingfromradiationtherapytotheheadandneckor
fromcancerchemotherapy[39,40].However,ONJhasalsobeenreportedinsomepatientsonoral
bisphosphonatesforosteoporosis.Therefore,itisimportanttodocumentgooddentalhealthbeforecommencing
bisphosphonatetherapy[41,42].Achartreviewstudyin15children(agerange2to16years)withOIwhohad
receivedbisphosphonateseitherpriortoorduringdentalextractions(atotalof60extractions,mostlyprimary
teeth)didnotidentifyanyevidenceofONJ[43].Thehealingtimewasnormal,andnocomplicationswere
recorded.FurtherstudiesareneededtoassesstheriskofthisrareeventinchildrenwithOI.(See"Risksof
therapywithboneantiresorptiveagentsinpatientswithadvancedmalignancy",sectionon'Osteonecrosisofthe
jaw'.)
Therearereportsofatypicallongbonefractures,particularlyinthesubtrochantericareaofthefemur,afterlong
termuseofbisphosphonates[44,45].BothONJandtheatypicallongbonefracturesmayberelated,atleastin
part,tosignificantsuppressionofboneturnoverthatinterfereswithnormalbonerepairandrenewalprocesses.
Finally,bone,joint,andmusclepains(referredtoasthemusculoskeletalsyndrome)havebeenreportedwith
bisphosphonatetherapy[46,47].Insomepatients,themusculoskeletalsyndromeisseenearlyintherapy,is
tolerated,andgoesawaywithtime.Inotherpatients,themusculoskeletalsyndromemayleadtodiscontinuation
ofbisphosphonatetherapy.
NeitherONJnoratypicalfractureshavebeenreportedinchildrenwithOItreatedwithbisphosphonates,andthe
pathogenesisoftheseconditionshasnotbeenclearlyestablished.Nevertheless,thesemusculoskeletaladverse
eventsshouldbekeptinmindwhenprescribingbisphosphonatestochildrenoradultswithOI.
Thesafetyofbisphosphonatesinpostmenopausalwomenisdiscussedseparately.(See"Theuseof
bisphosphonatesinpostmenopausalwomenwithosteoporosis".)
ORTHOPEDICANDOTHERSURGERYExperiencedorthopedicsurgeonswithaninterestinOIareidealto
helpingOIpatientsreachthehighestfunctionallevelpossible.AlistofclinicsspecializinginOIisavailableonthe
OsteogenesisImperfectaFoundationwebsite.
Typicalorthopedicservicesthatareprovidedinintegrated,coordinatedclinicalcarecentersforOIinclude
managementoffractures(withquickmobilizationtopreventbonelossduetoinactivity)andplacementof
intramedullaryrodstopreventorcorrectlongbonedeformities.Telescopingrodsmaybeappropriateforpatients
olderthantwoyearswhoareactivelygrowing.Patientswithseverescoliosisalsomaybenefitfromsurgeryin
carefullyselectedcases.
Basilarskulldeformitythatcausesnervecompressionorotherneurologicsymptomsmayrequireneurosurgical
correction.Similarly,forthosewithhearingloss,theserviceofanotolaryngologistmaybeneeded.Stapedotomy
maybeappropriateforsomepatientswithpredominantlyconductivehearingloss[48].
FracturemanagementThemanagementoffracturesinpatientswithOIissimilartothemanagementof
fracturesinpatientswithoutOI.Earlymobilizationisparticularlyimportanttopreventbonelosssecondaryto
inactivity.
Theclinicalfeaturesandmanagementofspecificfracturesarediscussedseparately.(Seeappropriatetopic
reviews.)
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AnesthesiaSomeanesthesiarisksareassociatedwithpatientswithOIthatdistinguishthemfromthegeneral
population,although,ingeneral,anesthesiaissafeandwelltolerated[6].Chestdeformitiesandscoliosismay
compromisebreathing.Smallstaturewilldeterminethechoiceofequipment.SomepatientswithOImayshow
increasesinbodytemperatureduringandaftersurgery.Thereasonforthisisunclear.Precautionssuchas
avoidingwarmingblanketsorheavydrapesareofteneffectiveinthesecases.Someanestheticssuchasatropine
shouldbeavoided,ifpossible,sincetheycouldexacerbateincreasedbodytemperature.
PHYSICALANDOCCUPATIONALTHERAPYTheservicesoftrainedrehabilitationexpertsareessentialto
successfullytreatthemanydomainsaffectedinOIpatients.Theresultsofphysicalandoccupationaltherapy(PT
andOT)interventionsarenotalwaysdramatic,butthechildrenandtheirparentsappreciateevensmalladvances
thatcanbequitemeaningfultotheminthelongterm.
Physicaltherapistscanbeinstrumentalindesigningaphysicalactivityprogramthatminimizesfractureriskwhile
ensuringmobilizationtopreventcontracturesandbonelossfromimmobility[1,5].Occupationaltherapistscan
addresstheimpairmentsinactivitiesofdailylivingsecondarytoupperorlowerlimbdeformity.
PSYCHOSOCIALASPECTSConsiderationofthepsychosocialaspectsofOIisanotherimportantcomponent
oflongtermcare[49].TheextenttowhichindividualswithOIfeelstigmatizedbybeingphysicallydifferentfrom
theirpeersdependsupontheirdiseaseseverity,naturalhistory,anddegreetowhichitaffectsphysical
appearanceandsocializationandwhetherornototherfamilymembersareaffected[49].Parentsmayhavebeen
suspectedofchildabuseincaseswherethediagnosisisdelayed,leadingtofeelingsofguilt,frustration,and
anxiety.
Tryingtobalancetheriskoffracturewiththeperformanceofroutineactivities,suchasschoolattendance,canbe
difficult.Contactsportsshouldbeavoided,andotheractivitiesarerestrictedbasedupontheseverityofthe
condition.Adolescencecanbeparticularlytroublesome,whenconcernsaboutappearance,sexualdevelopment,
andpeeracceptanceareparamount[49].Duringyoungadulthood,problemsrelatedtoimmobilityandsocialand
financialdependencebecomemorepressing[49,50].
SupportforpatientswithOIandtheirfamiliesmayincludetheprovisionofinformation,contactwithotherpatients
andtheirfamilies,andreferralsforformalorinformalcounselingorrespitecare[4,49].
ResourcesThefollowinginformationonresourcesandsupportgroupsisavailableforpatientsandparentsof
patientswithOI:
OsteogenesisImperfectaFoundation
NationalOrganizationforRareDisorders
PRIMARYCARECONSIDERATIONSPrimarycareofchildrenwithOIrequiressomespecialconsiderations.
Inadditiontoroutinecareandimmunizations,specialattentionshouldbepaidtothefollowingaspectsofthe
examinationandhealthsupervision[4]:
Growthandheadcircumference.
Hearing(formalaudiologyinitiallyatninemonthsofageandthenatregularintervalsasdescribedbelow).
Visionscreeningeverytwotothreeyears,withreferraltoanophthalmologistasindicatedbyclinicalfindings.
Developmentalmonitoring,withreferraltoearlyinterventionservicesforthoseyoungerthanthreeyears,and
referraltophysicaltherapyandoccupationaltherapyasneededforthoseolderthanthreeyears.(See
'Physicalandoccupationaltherapy'above.)
Pneumococcalandinfluenzavaccinationshouldbeconsiderediftherearenocontraindications.(See
"Pneumococcal(Streptococcuspneumoniae)conjugatevaccinesinchildren"and"Pneumococcal
(Streptococcuspneumoniae)polysaccharidevaccinesinchildren"and"Pneumococcalvaccinationinadults"
and"Seasonalinfluenzainchildren:Preventionwithvaccines",sectionon'Indications'and"Seasonal
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influenzavaccinationinadults".)
Provisionofdentalreferralasindicatedfordentinogenesisimperfecta.
Helpwithtransitionstopreschoolandschool.Chronicillnessandphysicaldisabilitymayaffectschool
performance.ChildrenwithOIshouldreceiveaneducationalprogramtoaddresstheseissues[49].
Thecareandsupportservicesforchildrenwithchronicillnessand/orspecialhealthcareneedsarediscussedin
detailseparately.(See"Supportservicesforthecareofchronicallyillchildren"and"Childrenwithspecialhealth
careneeds",sectionon'Implicationsofchronicconditionsinchildhood'.)
MONITORINGFORCOMPLICATIONSPatientswithOIshouldundergoregularsurveillanceforpotential
complications(eg,hearingloss,worseningofosteoporosis)sothatappropriateinterventionisinitiatedassoonas
possible.
Wesuggestahearingtesttoevaluateforconductiveandsensorineuralhearingloss,dualenergy
absorptiometry(DXA)toassessbonemineraldensity(BMD),andspirometrytomonitorforrestrictive
defectssecondarytoribandvertebralfractureseverytwoyears(orsoonerifclinicallyindicated),particularly
inpatientswithmoderatetosevereOI.BMDwasrelatedtodiseaseseverity(functionaloutcome,rateof
fracture,andrateofsurgery)inonereviewofpatientswithOIwhocompletedaquestionnaire[51].
Appropriatereferralsshouldbemadeand/orpharmacologictherapiesinitiatedwhenabnormalitiesare
detected.(See"Hearingimpairmentinchildren:Treatment"and"Hearingamplificationinadults"and
"Overviewofthemanagementofosteoporosisinpostmenopausalwomen".)
PatientswithtypeIII(table1)deformingOIorothermoderatetoseveretypesofOIshouldhaveyearly
spirometryandanelectrocardiogramandanechocardiogrameverytwoyears(todetectaorticrootdilation
andvalvulardysfunction[52,53]).
Basilarskulldeformitycouldleadtobasilarinvagination.Thus,neurologicexaminationandcranial
assessmentshouldbeperformedasindicatedbysymptomsorbehavioralchanges,particularlyinpatients
withtypeIIIOIandotherformswithasimilarphenotype(typesVIItoIX).
Skeletalradiographsshouldbeperformedatthetimeofdiagnosisandtheneveryonetotwoyears(orsooner
ifclinicallyindicated)andcoordinatedwithorthopedicadvice.(See'Orthopedicandothersurgery'above.)
Childrenreceivingbisphosphonatetreatmentshouldhaveyearly(ormorefrequentlyasclinicallyindicated)
assessmentofBMDandradiologicassessmentoflongbonesandspinetodeterminetheeffectoftreatment
onvertebralgeometry,longbonefractures,andchangesinbonemass.
EXPERIMENTALTHERAPIES
GrowthhormoneTheuseofgrowthhormone(GH)inOIhasbeenstudiedinsmallgroupsofpatientssince
1975,althoughitisstillviewedasanexperimentaltherapy.ThetheoreticalbasisforusingGHistostimulatebone
formationandalsotoincreasestature.Nostudieshaveextendedbeyondtwoyears.
Inasinglerandomizedtrial,30prepubertalchildrenwithOI(typesI,III,andIV)wereobservedfor12months
duringongoingneridronatetherapyandthenrandomizedtorecombinantGH(rGH)plusneridronateorneridronate
alone[54].Bonemineraldensity(BMD)andgrowthvelocityweresignificantlyhigherinthegroupthatreceivedGH
comparedwiththecontrolgroup,althoughnodifferencewasseeninthefractureriskrate.Theincreaseinbone
agewassimilarinbothgroups.
AsummaryofexperiencewithGHtherapyforOIincludedoneinvestigator'sexperiencewith22OIpatients[55].
Inthisseries,treatmentwithGHhadbeneficialeffectsonboneturnover,BMD,andheightvelocityrate.Another
seriesof26childrenwithtypeIIIortypeIVOI(table1)ofmoderateseverityreceivedGH(0.1to0.2int.units/kg
perdayforsixofsevendaysperweek)foroneyear[56].Roughlyonehalfofthechildrenrespondedwithan
increaseinlineargrowthrateof50percentormorefromtheirpretreatmentrate.Thosewhohadsuchanincrease
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ingrowthalsohadincreasedvertebralBMDanddecreasedfracturerates.Higherlevelsofprocollagencarboxy
terminalpropeptides(PICPs)werecorrelatedwithagrowthresponsetoGH.AcutofflevelofPICPof86
microgram/mLwas73percentpredictiveofaresponsetoGHadministration.
CellreplacementtherapiesApilotstudyofallogeneichematopoieticcelltransplantation(HCT)wasperformed
infivechildrenwithOI[57].Threechildrenhadsuccessfulengraftment,and,inthesethree,improvementsin
growthvelocityandreductioninfractureratewerenotedfollowingtransplantation.Engraftingallogeneic
mesenchymalcells,eitherinuteroorpostnatally,mayprovideanotheravenuetotreatment[58,59].
InoneseriesofsixpatientswithsevereOIwhoreceivedallogeneicbonemarrowtransplantation,donorderived
mesenchymalcellsthatincorporatedareportergeneweresubsequentlyrecoveredfromskin,bone,andbone
marrow[60].Lineargrowthwasmorerapidfollowingthemesenchymalcellinfusionsthaninthesixmonthperiod
betweenthemarrowtransplantationsandthefirstoftwoinfusionsofmesenchymalcells.
Althoughtransplantationofmesenchymalstemcellsorbonemarrowstromalcellshaveagoodtheoreticalbasis
forcorrectinggeneticdefectsofboneandcartilage[61,62],moreclinicalresearchisneededbeforethesetherapies
canberecommendedforpatientswithOI.
GenetherapyAntisensetherapyandgenetargetinghavebeenevaluatedinanimalmodelsofOI.Thegoalof
antisensetherapyinOIistosuppressorsilenceaparticularmutantalleleofthetypeIcollagengeneandnot
interferewiththeexpressionofthenormalallele[63].Thus,asevereformofOIcouldpotentiallybeturnedintoa
mildformofthedisease.Smallmoleculeswithcomplementarysequencesareusedtobindandsequesterthe
targetmessengerRNA,thuspreventingtranslationofthedefectivecollagenprecursor.
Anotherapproachunderexplorationisgenetargetingofthepatient'smesenchymalstemcells.Inapreliminary
study,adenoassociatedvirusvectorssuccessfullydisruptedthemutatedalleleexvivoinmesenchymalstem
cells[64].Infusionofthesecellsintoamousemodelresultedinboneformation.Thereareseveralpotential
problemsassociatedwithsuchagenetargetingapproachthatneedtobeaddressedbeforethistechniquecanbe
appliedtopatientswithOI[65].
PROGNOSISTheprognosisdependsuponthetypeofOI[66].PatientswithmildOI(typeI,(table1))typically
haveafewchildhoodfractures,nolongbonedeformity,andanormallifeexpectancy.Patientswithmoderateto
severe(typesIIItoIX,(table1))haveanincreasedriskofprematuredeathinbothchildhoodandadultlife
comparedwiththegeneralpopulation.
Shortenedlifespanmayberelatedtoimmobilityandthoracicdeformitiesinasubsetofpatientswithmoderately
severedisease.Theseproblemscreateanincreasedriskofseverepulmonaryinfectionsandsubsequentlossof
lungfunction.
SUMMARYANDRECOMMENDATIONS
Thegoalsoftherapyforpatientswithosteogenesisimperfecta(OI)aretoreducefracturerates,preventlong
bonedeformitiesandscoliosis,minimizepain,andmaximizemobilityandotherfunctionalcapabilities.(See
'Introduction'above.)
BisphosphonatesarethemainstayofpharmacologicfracturepreventiontherapyformostformsofOI(except
fortypeVI(table1)inwhichbonemineralizationisdefective),althoughnoneareapprovedspecificallyfor
useineitherchildrenoradultswithOI.LittleinformationontreatmentinadultswithOIisavailable.The
optimaldoserange,dosinginterval,durationoftreatment,andthelongtermefficacyandsafetyprofilehave
yettobeestablished.WesuggesttreatmentwithintravenouspamidronateforpatientswithallformsofOI,
excepttypeVI,inwhomclinicalbenefitsarelikelytooutweighpotentiallongtermrisks(ie,thosewithlong
bonedeformities,vertebralcompressionfractures,and3fracturesperyear)(Grade2C).Thesuggested
durationoftreatmentistwotofouryears.Thedecisiontousethesedrugsisbestmadebyspecialistsat
medicalcenterswithsignificantexperienceintreatingOI.
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Treatmentrequiresacoordinated,multidisciplinaryteamapproachandconsistsofphysicaltherapy,surgical
interventions,medications,and,insomecases,experimentaltherapies.PatientswithOIandparentsof
patientswithOIshouldbeadvisedtoseekcareinspecialtymedicalcenterswithsignificantexperiencein
treatingOI.AlistofclinicsspecializinginOIisavailableontheOsteogenesisImperfectaFoundation
website.(See'Orthopedicandothersurgery'aboveand'Physicalandoccupationaltherapy'aboveand
'Psychosocialaspects'aboveand'Primarycareconsiderations'aboveand'Experimentaltherapies'above.)
PatientswithOIshouldundergoregularsurveillanceforpotentialcomplicationssothatappropriate
interventioncanbeinitiatedassoonaspossible(see'Monitoringforcomplications'aboveand'Primarycare
considerations'above).Thisincludes:
Regularmonitoringofgrowthandheadcircumference.
Hearingtest,assessmentofbonemineraldensity(BMD),andspirometryeverytwoyears,particularly
inpatientswithmoderatetosevereOI.
Electrocardiogramandechocardiogrameverytwoyearsandyearlyspirometryinallpatientswithtype
IIIOIandothermoderatetoseveretypes(VIItoIX)(table1).
Neurologicexaminationandcranialassessmentasindicatedbysymptomsorbehavioralchanges.
Skeletalradiographsatthetimeofdiagnosisandtheneveryonetotwoyears(orsoonerifclinically
indicated)andcoordinatedwithorthopedicadvice.
TheprognosisdependsuponthetypeofOI,rangingfromanormallifeexpectancyinpatientswithtypeIOI
toperinatalmortalityinpatientswithtypeIIOI(table1).(See'Prognosis'aboveand"Osteogenesis
imperfecta:Clinicalfeaturesanddiagnosis",sectionon'Clinicalmanifestations'.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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Topic2915Version11.0

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GRAPHICS
Clinicalfeaturesofosteogenesisimperfecta(OI)bytype
Type
(MIM#)

Inheritance
(gene)

I
(#166200)

AD(COL1A1or
COL1A2)

Severity
Mild

Fractures

Bone
deformity

Fewto100

Uncommon

Stature

DI

Sclerae

Normalor
slightly

Rare

Blue

IIADark
blue

shortfor
family
II
(IIA

AD(IIACO1A1
orCOL1A2)

Perinatal
lethal

Multiple

Severe

#166210,
IIB
#610854)

AR(IIB
CRTAP)

III

AD(COL1A1or

(#259420)

COL1A2)

IV
(#166220)

AD(COL1A1or
COL1A2)

Moderateto
mild

Multiple

Mildto
moderate

Variably
short
stature

+/

Normalto
gray

AD(IFITM5)

Moderate

Multiplewith

Moderate

Variable

No

Normal

Rhizomelic

Mildshort

No

Normalto

shortening

stature

Yes

Mildshort

stature

Severe

Multiple

Moderateto

AR(SERPINF1)

(#610968)

rarelyADwith
parental
mosaicism

VII

AR(CRTAP)

Moderate

Moderate

Multiple

Multiple

(#610682)

Blueat
birth,
becoming
normal
withage

faintly
blue
No

stature
AR(LEPRE1)

AR(PPIB)

Lethal/severe

Lethal/severe

Multiple

Multiple

(#259440)
X
(#613848)

hypertrophic
callus

VI

IX

Veryshort

IIBLight
blue

severe

(#610967)

VIII
(#610915)

Severely
short

AR(SERPINH1)

Lethal/severe

Multiple

Moderateto
severe

Short
limbed

bulbous
"popcorn"
sepiphyses

dwarfism

Moderateto

Short

severe

limbed
dwarfism

Severe

Severe
short

Normalto
faintly
blue

No

Normal

Blue

Blue

No

Normal

stature
XI
(#607063)

AR(FKBP10)

Severe

Multiple

Severe

Severe
short

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stature
DI:dentinogenesisimperfectaAD:autosomaldominantAR:autosomalrecessiveCOL1A1:collagen,
typeI,alpha1COL1A2:collagen,typeI,alpha2CRTAP:cartilageassociatedproteinIFITM5:
interferoninducedtransmembraneprotein5SERPINF1:serpinpeptidaseinhibitor,cladeF,member
1LEPRE1:leucineandprolineenrichedproteoglycan1PPIB:peptidylprolylisomeraseBSERPINH1:
serpinpeptidaseinhibitor,cladeH,member1FKBP10:FK506bindingprotein10.
Modifiedandupdatedfrom:SteinerRD,PepinMG,ByersPH.OsteogenesisImperfecta.GeneReviewsat
GeneTests:MedicalGeneticsInformationResource,January2005.
Graphic78737Version13.0

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Disclosures
Disclosures:JohnFBeary,III,MDNothingtodisclose.ArkadiAChines,MDNothingtodisclose.HelenVFirth,DM,FRCP,DCH
Nothingtodisclose.ElizabethTePas,MD,MSNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthrougha
multilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.Appropriatelyreferenced
contentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy

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