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Medica'onRelatedOsteonecrosisoftheJaw(MRONJ):preven'on
andmanagement
SalvatoreL.RuggieroDMD,MD,FACSNewNewYorkCenterforOrthognathicandMaxillofacialSurgery
ClinicalProfessorUniversityHospitalatStonyBrook
HofstraNorthShore/LIJSchoolofMedicine
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Faculty Disclosure
Consultant for Amgen Corporation
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Lectureoutline
• Frequencyofdisease• Pathophysiology• PrevenGonstrategies• Treatmentstrategiesandoutcomes• Newareasofresearch
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Population at risk
2004:>3millionpaGentsworldwideand1/3 ofallAmericanswithbreastcancerhad receivedIVBp’s2009:salesofzoledronicacidnearly$1.5billion2010-11:expandedroleforIVBp’s(Dbalso!)
ü survivalbenefitsü tumorsuppression
2011:newmedicaGons(Db,AA)a/wMRONJrisk
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MRONJ Frequency
• Durie(2005,NEJM):12.8%• Dimopoulos(2005,ASH):6.7%• Tossi(2005,ASH):2.7%• Pozzi(2005,ASH):1.8%• Cafro(2005,ASH):12%• Mavrokokki(2007,JOMS):1.1-9.1%
• Hoff(2008,JBMR):1.2-2.8%• Ibrahim(2008,Oncologist):1.5%• Boonyapakorn(2008,OralOncol):28%
• Morgan(2010ASCOmeeGng):3.5%
IVBisphosphonates
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“Among patients exposed to antiresorptive medications, what is the risk of developing ONJ following dentoalveolar procedures (tooth extraction, implant placement, etc.)”???
OralBPs:bestcurrentesGmate0.5%• Kunchar(JOMS,2009):prospecGvestudy(194pts)exposedto
oralBPthathadextracGons.1paGentdevelopedONJ
IVBPs(cancerpt):bestcurrentesGmate1.6%-14.8%• Yamazaki(IJOMS,2012):retrospecGvestudycohortstudy(1,347
pts)14.8%• MozzaG(OralOncol,2012):prospecGvecohortstudy(176pts)
2.8%• Scoleia(JOMS,2013):prospecGvecohortstudy(63pts)1.6%
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“Combination of Bisphosphonates and Antiangiogenic Factors Induces Osteonecrosis of the Jaw More Frequently than Bisphosphonates Alone”
• RetrospecGvereviewof116paGentsreceivingBps+/-anGangiogenictherapy
• BpduraGon/dosesimilarinbothgroups• FrequencyofONJ:
ü 16%Bp,+anGangiogenicagentü 1.1%Bpalone(p=0.008)
ChristodoulouC,PervenaA,etal.Oncolgy2009
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Pathogenesis of MRONJ (multifactorial)
Metabolic
Vascular/GeneGc
InfecGon
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MRONJ: Criteria for diagnosis
• HistoryofBP/DB/AAtherapy• NohistoryofXRTtothemaxillofacialregion• exposedboneorbonethatcanbeprobedinthemaxillofacialareathatoccurredspontaneouslyorfollowingdentoalveolarsurgery
• noevidenceofhealingformorethan8weeksfollowingappropriatecare
AAOMSMRONJ:2014update
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MRONJ prevention strategies
Pre-treatmentforcancertherapy(IVBp/Db/AA)
• MeasurableriskwithinashortperiodofGme(1.6%-15%)• AdelayinstarGngIVBPtherapyshouldbeconsideredin
ordertoopGmizethedentalcondiGon(ifpossible)• MayapplytoselectanGangiogenicmedicaGons• Strategiessimilartothoseforpre-irradiaGondental
treatment
AAOMS,2014
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MRONJ prevention strategies
• Pre-treatmentdentalexamtodetectpotenGal
dentalandperiodontalinfecGons
• Removeabscessedandnon-restorableteeth
andteethwithsevereperiodontaldisease
• Removeteethwithpoorlong-termprognosis
• Educatepa*entsonoralhygieneandsignsofdisease
ProphylacGctreatmentpriortoiniGaGngmonthlyIVBP/Db/AAtherapy(ORNmodel)
AAOMS2014
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MRONJ prevention strategies
• Avoidinvasivedentalprocedureswhenpossible• MaintainrouGnedentalcare,avoidson-Gssueinjury(especiallyatlingualplateandtori)• AggressivelymanagedentalinfecGonsnon-surgically(rootcanaltxifpossible,AAEposiGonpaper)• RegulardentalassessmentsaneriniGaGngBPtherapy(frequencydependentuponrisk)• ConsideranGangiogenicmedicaGonsaswell
AsymptomaGcpaGentsreceivingmonthlyIVBP/Db/AAtherapy
AAOMS,2014
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Drug holiday
Considerthefollowing:• 50%ofserumBPeliminatedinfirstpass• OsteocyteshavealowaffinityforBP• OsteoblastsincorporateBPintobone• OsteoclastistheonlycellularreservoirforBP• Osteoclastlifespanis2weeks….• Therefore:amountoffreeBPanera2monthholiday
(4xlifespanofosteoclast)shouldbeextremelylow.
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“Bp uptake in areas of tooth extraction or periapical disease”
• LabeledZaadministeredtomicefollowingexoorinducedPAdisease
• SignificantlyincreaseduptakeinallexositesandatalveolarridgeadjacenttoPAdefect
• Uptakemaximizedby3days
• Non-woundedsitewithminimaluptake
• HighBpcontent@siteswithincreasedboneturnover(exo)
CheongS,etal:JOMS,2014KangB,etal:JBoneMinRes2013
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ONJlesionscreatedinmiceexposedtoOPG-FcandZAandthendrugsstopped• OPG-FcbutnotZA
disconGnuaGonreversedradiographicfeaturesofONJ*
• SerumTRACP-5blevelsincreasedanerOPG-FcbutnotZAdisconGnuaGon*
• OPG-FcnotZAdisconGnuaGonreverseshistologicfeaturesofONJ*
*staGsGcallysignificant
deMolonR,etal.JBoneMinRes,2017
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ONJlesionscreatedinmiceexposedtoOPG-FcandZAandthendrugsstopped• OPG-FcbutnotZA
disconGnuaGonreversedradiographicfeaturesofONJ*
• SerumTRACP-5blevelsincreasedanerOPG-FcbutnotZAdisconGnuaGon*
• OPG-FcnotZAdisconGnuaGonreverseshistologicfeaturesofONJ*
*staGsGcallysignificant
deMolonR,etal.JBoneMinRes,2017
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ONJlesionscreatedinmiceexposedtoOPG-FcandZAandthendrugsstopped• OPG-FcbutnotZA
disconGnuaGonreversedradiographicfeaturesofONJ*
• SerumTRACP-5blevelsincreasedanerOPG-FcbutnotZAdisconGnuaGon*
• OPG-FcnotZAdisconGnuaGonreverseshistologicfeaturesofONJ*
*staGsGcallysignificant
deMolonR,etal.JBoneMinRes,2017
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Drug holiday of at-risk medication therapy for prevention or management of ONJ
• Nostudiesthatdefine“who”,“when”andfor“howlong”forptswithOP• NodatatosupportorrefutethatdrugholidaysalterONJrisk• ASBMRrecommendsaholidayforhighriskptsandexposureh/o>4yrs(2014)
• AAOMSrecommendsholidayforexposureh/o>4yrsbasedonpharmacokineGcsoforalBPtherapy
• NoclinicalstudiestosupportorrefutethestrategyofstoppingmonthlyanGresorpGvetherapy(BP,denosumab)inptswithcancer
• NodataforanG-angiogenictherapy
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Treatment objectives in the management of MRONJ
• Eliminatepain
• ManageoreliminateinfecGon
• PreventaddiGonalexposure/necrosis
• TreatmentwithcuraGveintent?
• PaGenteducaGon
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Treatment recommendations
• ConsultaGonbetweenoralsurgeons,generaldenGstsandthetreaGngoncologistisstronglyrecommended
• SuperficialbonydebridementtoreducesharpsurfacespreventtraumatoadjacentsonGssues
• Removalofmobilesequestrum
• AremovableapplianceorprotecGvestent
• Avoidinvasivedentalprocedureswhenpossible
Allpa&ents(allstages)withestablishedMRONJ
AAOMS,2014
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Treatment recommendations
Pa&entswithestablishedMRONJ
• ElecGvedentoalveolarsurgeryshouldbeavoided• Biopsyisnotrecommendedunlessmetastasistothejawisstronglysuspected• DecisionsregardingstoppinganG-resorpGveorAAtherapyshouldbemadeinconsultaGonwiththetreaGngoncologistandoralsurgeon,takingintoaccountthepotenGalriskoffurtherosteonecrosisversustheriskofskeletalcomplicaGons.Benefitofan*-resorp*ves>Riskformostpa*ents.• NospecificdataforAAs
AAOMS,2014
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Treatment recommendations
Stage1
• Anon-surgicalapproachisrecommendedtopreventfurtherosseousinjury
• DailyirrigaGon/mechanicaldebridementandoralanGmicrobialrinses(0.12%chlorhexidine)
• Clinicalfollowupevery3monthsAAOMSMRONJ:2014
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Treatment recommendations
Stage2
• Culture-directedanGbioGctherapy(longtermandmaintenance)
• Paincontrol• DailyirrigaGonsandoralanGmicrobialrinses(0.12%chlorhexidine)
• Clinicalfollowupevery3months
AAOMSMRONJ:2014
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Treatment recommendations
Stage3
• Culture-directedanGbioGctherapy(PO/IV,longtermandmaintenance)• Paincontrol• DailyoralanGmicrobialrinses(0.12%chlorhexadine)• Surgicaldebridement/resecGontoreducethevolumeofnecroGcbone
AAOMSMRONJ:2014
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Treatment strategies for mandibular MRONJ
Non-operaGvetherapies Sequestrectomy ResecGon
NoreconstrucGon
reconstrucGonwithplateandvascularized
bone/sonGssue
reconstrucGonwithplate(+/-sonGssue)
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4/2016
64yofemalewithmulGplemyelomaanda2yearhistoryofmonthlyZometatreatmentStage3MRONJ
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5/2016
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5/20176monthspost-op
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Treatment strategies for maxillary MRONJ
Non-operaGvetherapies Sequestrectomy
PosteriorMaxilla
ExtensiveSinusopacificaGon
DebridementwithFESS
(+/-sonGssueclosure,
obturator)
Nosinusdisease
Debridement(+/-sonGssue
closure,obturator)
AnteriorMaxilla
Simpledebridementwithprimaryclosureor
delayedhealing
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68yofemalewithstageIVbreastcancerwhoreceivedmonthlydenosumabtreatmentforbonemetastasis.Implantsplacedyearspriortotreatment.Stage3MRONJ
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1monthfollowingrightinfra-structuremaxillectomy
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Treatment Outcomes
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Can modifying risk factors affect
outcome or occurrence of disease?
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Dental treatment intervention
Dimopoulos,etal.2007ASHmeeGng:• 5foldreducGonofMRONJinthegroupwithincreaseddentalsurveillance
andavoidanceofdentalsurgery
RipamonG,et.al.AnnOncol.2009• RS/PSstudy966pt:50%reducGoninONJrate
Bonacina,et.al.JCDA.2011• PS282pts:5-10%ONJwithnodentaltx.0%withcare
Vandone,et.al.AnnOncol.2012• PSstudy211pts:50%reducGoninONJratesingroupwithscreeningand
prevenGvecare
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Can modifying risk factors affect
outcome or occurrence of disease?
Modifica'onofBPtherapy
• Badros,etal.2007ASHmee'ng:ü MRONJrecurrenceand#ofnon-healedpaGentslinkedtoBPre-challenge
• Corso,etal.2007Leukemia:ü ONJrisk8xlowerwithreducedscheduleZAü HigherONJriskwithZAcomparedtopamidronate
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• Open-labelclinicaltrialin269academicandcommunitysitesacrossUSA• PtwithBC,MM,PC(n=1822)• Randomizedtoreceivezoledronicacidata4or12weekintervalover2years• NodifferenceinSRE• 18cases(2%)ONJin4wkgroup,9cases(1%)in12wkgroup(p=.08)
HimelsteinAL,FosterJC,etal.JAMA,Jan2017
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New strategies for the treatment and management of
MRONJ
Earlysurgicalinterven'on• Graziani,2012(JOMS):68%• Mucke,2010(JCancerRes):70%• Carlson,2009(JOMS):90%• Stockman,2009(CancerCare):90%• Stanton,2007(JOMS)80%
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JOralMaxillofacSurg73:S94-S100,2015
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0
20
40
60
80
100
120
140
160
180
Non-opera'vetreatment Opera'vetreatment
Num
bero
fpa'
ents
Healed/Improved
Stable/Worse
**Surgicaltreatment28xmorelikelytoresultinHealed/Improvedoutcome(p-value<0.0001)
Outcomebasedonmodeoftherapy
N=337
RuggieroSL,KohnN:JOMS,2015
N=337
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DemonstratedefficacyintxofRIFandORN(Europe)ü DelanianS,etal:HeadandNeck,2005(ORN)
Pentoxifylline:improvesperipheralbloodflow,inhibitsdermalfibroblasts,increasescollagenaseacGvity
α-tocopherol:impairsGssuefibrosis,potentscavengerofoxygenradicalsü 6casesprospecGvelyreviewedü Nocontrolsü Decreasedpainandsmallersizeofexposedbone
Epstein,etal.OOO,2010
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“Pentoxifylline and tocopherol in the treatment of medication-related osteonecrosis of the jaw (MRONJ): a blinded, prospective, randomized controlled trial to evaluate a novel non-operative treatment study”
• Aim:TodetermineifPTX-VitEregimeninaddiGontothestandardofcaretreatmentsignificantlyreducesthemeanarea(mm2)ofexposedbonecomparedtostandardofcarealone
• Standardofcareisdefinedastheclinicalguidelinesofthe2014AAOMSPosiGonPaperonMedicaGon-RelatedOsteonecrosisoftheJaw(MRONJ)
• MulG-centerstudy(UW,NYCOMS,UAB,UM)
SupportedbyagrantfromOMFSFoundaGon&Osteoscience
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Management of MRONJ: points to consider in 2018
• EmphasisonprevenGonü Dental,Medical
• ConGnuedEducaGonü PaGentsü PracGoners(Dental,Medical)
• EarlysurgicalintervenGon?ü Successrates70-90%
• RaGonalefordrugholidays?
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Future research initiatives
• ConGnueddevelopmentandimplementaGonofnew,evidence-basedstrategiesforthesurgicalandnon-surgicalmanagementofONJ
• ModificaGonofanGresorpGvetherapy(dosingschedulechanges)ü ResultsfrommulGcenterstudy
• AnimalmodelsystemsdirectedatvalidaGngtreatmentstrategies• PTHandotheranabolicagentsinONJtreatmentü SystemictherapyforoncologypaGents?
ü RoleforanG-sclerosGninhibitors(Romosozumab)?• RiskassessmentbasedongeneGcprofileü suscepGbility,resistance
• Establish/evaluatetheriskofONJrelatedtonewanG-angiogenictherapiesü animalmodel?
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Thank You!!