Medica'onRelatedOsteonecrosisoftheJaw(MRONJ):preven'on

andmanagement

SalvatoreL.RuggieroDMD,MD,FACSNewNewYorkCenterforOrthognathicandMaxillofacialSurgery

ClinicalProfessorUniversityHospitalatStonyBrook

HofstraNorthShore/LIJSchoolofMedicine

Faculty Disclosure

Consultant for Amgen Corporation

Lectureoutline

•  Frequencyofdisease•  Pathophysiology•  PrevenGonstrategies•  Treatmentstrategiesandoutcomes•  Newareasofresearch

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

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

“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%

“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

Pathogenesis of MRONJ (multifactorial)

Metabolic

Vascular/GeneGc

InfecGon

MRONJ: Criteria for diagnosis

•  HistoryofBP/DB/AAtherapy•  NohistoryofXRTtothemaxillofacialregion•  exposedboneorbonethatcanbeprobedinthemaxillofacialareathatoccurredspontaneouslyorfollowingdentoalveolarsurgery

•  noevidenceofhealingformorethan8weeksfollowingappropriatecare

AAOMSMRONJ:2014update

MRONJ prevention strategies

Pre-treatmentforcancertherapy(IVBp/Db/AA)

•  MeasurableriskwithinashortperiodofGme(1.6%-15%)•  AdelayinstarGngIVBPtherapyshouldbeconsideredin

ordertoopGmizethedentalcondiGon(ifpossible)•  MayapplytoselectanGangiogenicmedicaGons•  Strategiessimilartothoseforpre-irradiaGondental

treatment

AAOMS,2014

MRONJ prevention strategies

• Pre-treatmentdentalexamtodetectpotenGal

dentalandperiodontalinfecGons

• Removeabscessedandnon-restorableteeth

andteethwithsevereperiodontaldisease

• Removeteethwithpoorlong-termprognosis

• Educatepa*entsonoralhygieneandsignsofdisease

ProphylacGctreatmentpriortoiniGaGngmonthlyIVBP/Db/AAtherapy(ORNmodel)

AAOMS2014

MRONJ prevention strategies

• Avoidinvasivedentalprocedureswhenpossible• MaintainrouGnedentalcare,avoidson-Gssueinjury(especiallyatlingualplateandtori)• AggressivelymanagedentalinfecGonsnon-surgically(rootcanaltxifpossible,AAEposiGonpaper)• RegulardentalassessmentsaneriniGaGngBPtherapy(frequencydependentuponrisk)• ConsideranGangiogenicmedicaGonsaswell

AsymptomaGcpaGentsreceivingmonthlyIVBP/Db/AAtherapy

AAOMS,2014

Drug holiday

Considerthefollowing:•  50%ofserumBPeliminatedinfirstpass•  OsteocyteshavealowaffinityforBP•  OsteoblastsincorporateBPintobone•  OsteoclastistheonlycellularreservoirforBP•  Osteoclastlifespanis2weeks….•  Therefore:amountoffreeBPanera2monthholiday

(4xlifespanofosteoclast)shouldbeextremelylow.

“Bp uptake in areas of tooth extraction or periapical disease”

• LabeledZaadministeredtomicefollowingexoorinducedPAdisease

• SignificantlyincreaseduptakeinallexositesandatalveolarridgeadjacenttoPAdefect

• Uptakemaximizedby3days

• Non-woundedsitewithminimaluptake

• HighBpcontent@siteswithincreasedboneturnover(exo)

CheongS,etal:JOMS,2014KangB,etal:JBoneMinRes2013

ONJlesionscreatedinmiceexposedtoOPG-FcandZAandthendrugsstopped•  OPG-FcbutnotZA

disconGnuaGonreversedradiographicfeaturesofONJ*

•  SerumTRACP-5blevelsincreasedanerOPG-FcbutnotZAdisconGnuaGon*

•  OPG-FcnotZAdisconGnuaGonreverseshistologicfeaturesofONJ*

*staGsGcallysignificant

deMolonR,etal.JBoneMinRes,2017

ONJlesionscreatedinmiceexposedtoOPG-FcandZAandthendrugsstopped•  OPG-FcbutnotZA

disconGnuaGonreversedradiographicfeaturesofONJ*

•  SerumTRACP-5blevelsincreasedanerOPG-FcbutnotZAdisconGnuaGon*

•  OPG-FcnotZAdisconGnuaGonreverseshistologicfeaturesofONJ*

*staGsGcallysignificant

deMolonR,etal.JBoneMinRes,2017

ONJlesionscreatedinmiceexposedtoOPG-FcandZAandthendrugsstopped•  OPG-FcbutnotZA

disconGnuaGonreversedradiographicfeaturesofONJ*

•  SerumTRACP-5blevelsincreasedanerOPG-FcbutnotZAdisconGnuaGon*

•  OPG-FcnotZAdisconGnuaGonreverseshistologicfeaturesofONJ*

*staGsGcallysignificant

deMolonR,etal.JBoneMinRes,2017

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

Treatment objectives in the management of MRONJ

• Eliminatepain

• ManageoreliminateinfecGon

• PreventaddiGonalexposure/necrosis

• TreatmentwithcuraGveintent?

• PaGenteducaGon

Treatment recommendations

• ConsultaGonbetweenoralsurgeons,generaldenGstsandthetreaGngoncologistisstronglyrecommended

• SuperficialbonydebridementtoreducesharpsurfacespreventtraumatoadjacentsonGssues

• Removalofmobilesequestrum

• AremovableapplianceorprotecGvestent

• Avoidinvasivedentalprocedureswhenpossible

Allpa&ents(allstages)withestablishedMRONJ

AAOMS,2014

Treatment recommendations

Pa&entswithestablishedMRONJ

• ElecGvedentoalveolarsurgeryshouldbeavoided• Biopsyisnotrecommendedunlessmetastasistothejawisstronglysuspected• DecisionsregardingstoppinganG-resorpGveorAAtherapyshouldbemadeinconsultaGonwiththetreaGngoncologistandoralsurgeon,takingintoaccountthepotenGalriskoffurtherosteonecrosisversustheriskofskeletalcomplicaGons.Benefitofan*-resorp*ves>Riskformostpa*ents.• NospecificdataforAAs

AAOMS,2014

Treatment recommendations

Stage1

• Anon-surgicalapproachisrecommendedtopreventfurtherosseousinjury

• DailyirrigaGon/mechanicaldebridementandoralanGmicrobialrinses(0.12%chlorhexidine)

• Clinicalfollowupevery3monthsAAOMSMRONJ:2014

Treatment recommendations

Stage2

• Culture-directedanGbioGctherapy(longtermandmaintenance)

• Paincontrol• DailyirrigaGonsandoralanGmicrobialrinses(0.12%chlorhexidine)

• Clinicalfollowupevery3months

AAOMSMRONJ:2014

Treatment recommendations

Stage3

• Culture-directedanGbioGctherapy(PO/IV,longtermandmaintenance)• Paincontrol• DailyoralanGmicrobialrinses(0.12%chlorhexadine)• Surgicaldebridement/resecGontoreducethevolumeofnecroGcbone

AAOMSMRONJ:2014

Treatment strategies for mandibular MRONJ

Non-operaGvetherapies Sequestrectomy ResecGon

NoreconstrucGon

reconstrucGonwithplateandvascularized

bone/sonGssue

reconstrucGonwithplate(+/-sonGssue)

4/2016

64yofemalewithmulGplemyelomaanda2yearhistoryofmonthlyZometatreatmentStage3MRONJ

5/2016

5/20176monthspost-op

Treatment strategies for maxillary MRONJ

Non-operaGvetherapies Sequestrectomy

PosteriorMaxilla

ExtensiveSinusopacificaGon

DebridementwithFESS

(+/-sonGssueclosure,

obturator)

Nosinusdisease

Debridement(+/-sonGssue

closure,obturator)

AnteriorMaxilla

Simpledebridementwithprimaryclosureor

delayedhealing

68yofemalewithstageIVbreastcancerwhoreceivedmonthlydenosumabtreatmentforbonemetastasis.Implantsplacedyearspriortotreatment.Stage3MRONJ

1monthfollowingrightinfra-structuremaxillectomy

Treatment Outcomes

Can modifying risk factors affect

outcome or occurrence of disease?

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

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

• Open-labelclinicaltrialin269academicandcommunitysitesacrossUSA• PtwithBC,MM,PC(n=1822)• Randomizedtoreceivezoledronicacidata4or12weekintervalover2years• NodifferenceinSRE• 18cases(2%)ONJin4wkgroup,9cases(1%)in12wkgroup(p=.08)

HimelsteinAL,FosterJC,etal.JAMA,Jan2017

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%

JOralMaxillofacSurg73:S94-S100,2015

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

 DemonstratedefficacyintxofRIFandORN(Europe)ü  DelanianS,etal:HeadandNeck,2005(ORN)

 Pentoxifylline:improvesperipheralbloodflow,inhibitsdermalfibroblasts,increasescollagenaseacGvity

 α-tocopherol:impairsGssuefibrosis,potentscavengerofoxygenradicalsü  6casesprospecGvelyreviewedü  Nocontrolsü  Decreasedpainandsmallersizeofexposedbone

Epstein,etal.OOO,2010

“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

Management of MRONJ: points to consider in 2018

•  EmphasisonprevenGonü  Dental,Medical

•  ConGnuedEducaGonü  PaGentsü  PracGoners(Dental,Medical)

•  EarlysurgicalintervenGon?ü  Successrates70-90%

•  RaGonalefordrugholidays?

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?

Thank You!!