QuickReferenceGuideDecreasingtheRisksofDevelopingDrugInduced

OsteonecrosisoftheJaws(DIONJ)AdaptedfromtheDivisionofOral&MaxillofacialSurgeryPositionStatement

RobertMarx,DDS AndonisTerezides,DDS

DisclaimerThe Division of Oral and Maxillofacial Surgery at the University Of Miami Miller School Of Medicine and authors provides this position statement/reference guidelines based on the equally valid data from evidenced based and experienced based studies. It is not associated with any other position paper or meant to be in competition or critical of other position papers by any organization. It remains an independent resource for clinicians.

It is intended to be a resource for practitioners in all specialties of dentistry and medicine, as well as patients, industry, and other interested parties.

This reference guide is not intended to be a standard of care or an absolute/definitive algorithm for either prevention or treatment but rather only an informational document for the reader to devise individual management or treatment plans to optimize patient care on a case by case basis. As already stated these guidelines represents the best independent evidence and experience related to DIONJ at the time of its development. Most assuredly new data and new drugs will come about that may modify and add to these guidelines. The Division of Oral and Maxillofacial Surgery at the University Of Miami Miller School Of Medicine or its authors make no expressed or implied warranty regarding the content, accuracy, completeness, reliability, probability or legality of the information continued within this statement/reference guidelines. This includes without limitation, the warranties of merchantability, fitness for any particular purpose and non-infringements or proprietary rights. However, the authors attest that no conflict of interest exists and that no outside industrial, legal or academic interests influenced the clinical science contained in the this paper. In no event shall the University of Miami or the authors be liable to the reader or user of this position statement/ reference guidelines or anyone else for any decision made or action taken by him or her in reliance in such information.

Drug Induced Osteonecrosis of the JawsExposed non-healing bone in the mandible or maxilla that persists for more than eight weeks in a person who received a systemic drug known to cause

ONJ but who has not received local radiation to the jaws.

DIONJ StagingStage O:• Radiographic evidence of bisphosphonate toxicityStage I:• Exposed bone limited to one quadrantStage II:• Exposed bone involving two quadrantsStage III:• Exposed bone involving three or four quadrants• Osteolysis/Extension to Inferior Border of Mandible• Pathologic Fracture• Extension in to Maxillary Sinus or Nasal Cavity

ICD-10 CodeM87.180 Drug Induced Osteonecrosis

OsteoporosisDrugsDrug Classification Action Dose Route %ofReported

Cases*

Alendronate(FosamaxGeneric)

Bisphosphonate OsteoclastToxicity

70mg/wk Oral 82%

Residronate(ActonelAtelvia)

Bisphosphonate OsteoclastToxicity

35mg/wk Oral 1%

Ibandronate(Boniva)

Bisphosphonate OsteoclastToxicity

150mg/mos Oral 1%

Zoledronate(Reclast)

Bisphosphonate OsteoclastToxicity

5mg/yr IV 6%

Denosumab(Prolia)

MonoclonalAntibody

OsteoclastImpairment

60mg/6mos Subcutaneous 10%

DrugsinTreatmentofCancer,Complications,andMetastasis

Drug Classification Action Dose Route %ofReported*Cases**

Zoledronate(Zometa)

Bisphosphonate OsteoclastToxicity

4mg/mo IV 67%

Pamidronate(Aredia)

Bisphosphonate OsteoclastToxicity

90mg/mo IV 18%

Bevacizumab(Avastin)

MonoclonalAntibody

VEGFInhibitor

100-400mg/14days

IV <1%

Sunitinib (Sutent) TyrosineKinaseInhibitor

OsteoclastToxicity

5mg/yr IV <1%

Denosumab(Xgeva)

MonoclonalAntibody

OsteoclastInhibitor

120mg/mo Subcutaneous 15%

OFFENDINGDRUGSDecreasingRisksofDrugInducedOsteonecrosisoftheJaws(DIONJ)

AdaptedfromtheUniversityofMiamiDivisionofOral&MaxillofacialSurgeryPositionStatement

*Data from University of Miami Division of Oral and Maxillofacial Surgery as of July 1, 2016.

** Percentages are anticipated to change as the newer drugs are more frequently used.

Bisphosphonatesn Cause osteoclast death at resorption sitesn Cause osteoclast precursor inhibition and death in bone

marrown Half-Life= 11+ years in boneDenosumab (Xgeva or Prolia)n Osteoclast inhibition at resorption sitesn Osteoclast inhibition in blood and tissue spacesn Osteoclast precursor inhibition in bone marrown Half-Life= 26 days in boneBevacizumab (Avastin)n Blocks Action of VEGF in normal cells and cancer cellsn Half-Life= 50 days in boneSunitib (Sutent)n Blocks action of multiple Growth Factors (VEGF, PDGF,

TGF-b, etc)n Half-Life= 4.6 days in bone

Risk FactorsnIncreased Dose (Fosamax vs. Boniva)nIncreased Potency (Oral vs. IV)nIncreased Frequency (Weekly vs Monthly vs Yearly)nHalf-Life (in bone)nDuration of Use/Exposure

Initiating FactorsnExtractionsnSpontaneousnTraumatic OcclusionnAlveolar Surgery (Implants, Periodontal, Apicoectomy)

Vulnerable SitesnAlveolar BonenTori nMandible >Maxilla 2:1nLingual Cortex

Co-MorbiditiesComorbidities Do Not Cause ONJ-

But they do make the ONJ Occur Sooner, More Severe, and More Extensiven***Other Drugs (Chemotherapy, Methotrexate, Steroids)***nDiabetesnSmokingnCancernPeriodontitis,

CTXLimitations• ActiveCancerPatients- (PatientswithMetastaticCancer,MultipleMyeloma- beingtreatedwithIVBisphosphonates)showFalseHighCTXresults.

• MethotrexatePatients- CTXresultsremaintoolow• SystemicSteroidPatients- CTXresultsremaintoolow• 8+yearsofBisphosphonates- CTXresultswillfirstriseandthendecreaseagain.

A9-12MonthDrugHolidayisusedinsteadtoguidetreatmentdecisionandtimingofsurgery.

IndicationsfortheSerumCTXTest• PatientsonOralorIVBisphosphonatesforOsteoporosis.

o Thosewith2+yearsofBisphosphonateTreatment(withadditionalcomorbidities)

o Thosewith3+yearsofBisphosphonateTreatment(withoutadditionalcomorbidities)

• GuideTreatmentDecisionso DeterminationofNeedforDrugHolidayPriortoSurgeryo MonitoringBoneTurn-OverImprovementDrugHoliday

• Results> 151pg/ml=generallysafetoproceedwithsurgery

Guiding Treatment Decisions with CTX

OSTEOPOROSIS PATIENTS (Oral Bisphosphonates / IV Reclast / S.C. Denosumab)Recommendations BEFORE Initiating Drug Therapy

Dental/OMFSExaminationProphylaxis/DentalHygiene/PeriodontalTreatment

CariesControlEndodonticTherapy/Crown&Bridge

FluorideCarriers/RxFluorideToothpasteLightenExcessive/HeavyOcclusalContacts(BalancedOcclusion)

ExtractionofNon-Salvageable/HopelessTeethSelectiveRemovalofExcessivelyLarge/Multi-LobulatedTori

***NonSurgicalRestorative/GeneralDentalCareIsSafeAtAllTimes****

IVBisphosphonate(Reclast/Zolendronate)

DIONJRiskIncreasesBy4th Dose**KeepInMindManyPatientsMayHaveBeenOn

OralBisphosphonateBefore**

S.C.RANK-LInhibitor(Prolia/Denosumab)

DIONJRiskIncreasesAfter2Doses**KeepInMindManyPatientsMayHaveBeenOn

OralBisphosphonateBefore**

OralBisphosphonate(Fosamax,Actonel,Boniva,etc)DIONJRiskIncreasesBetween

2-3YearsofUse

IfElectiveDentalTreatments(IncludingExtractions,PeriodontalSurgery,DentalImplants)AreCompleted3-6MonthsBeforeReachingTheseRiskThresholds,RoutineWoundHealing&OsseointegrationIsToBeExpected

OSTEOPOROSIS PATIENTS (Oral Bisphosphonates / IV Reclast / S.C. Denosumab)Recommendations DURING Drug Therapy

OSTEOPOROSIS PATIENTS (Oral Bisphosphonates /IV Reclast/ S.C. Denosumab)Management of Exposed Bone / DIONJ

InitialConservativeManagement• AvoidDebridements /InvasiveSurgicalProcedures• OKtoSmoothSharpEdgesForPatientComfort• PainisRelatedtoSecondaryInfection- TreatWithAntibiotics&

Antimicrobials:o Chlorhexidine(0.12%)Rinseo PenicillinVK500mg- 1tabpoq6hx14dayso Doxycycline100mg- 1tabpoqdayx14days

• RefractoryCasesadd:o Flagyl500mg- 1tabpoTIDx10days

• ConsiderAntifungalTreatmento MycelexTrocheso NystatinRinse

Drug HolidayOral & IV Bisphosphonates- 9 Months

SC Denosumab- 3 Months

50%ofPatients

SpontaneousResolutionof

DIONJ

J

40%ofPatients

RequireAlveolarDebridementorLocalAlveolarResectionto

AchieveResolutionofDIONJ

J

10%ofPatients

RequireAggressiveSurgicalManagementtoAchieveResolutionofDIONJ

MandibleContinuityResection

TitaniumReconstructionPlate

MaxillaSubmucosalResection/

Antrostomy/RadicalSinusotomy2LayerClosure-

BuccalFatPadReconstructionwithMucosalAdvancementFlap

AdjunctiveGrowth/HealingFactorsPRP- PlateletRichPlasmaPRF- PlateletRichFibrin

**Futurebone-graftreconstructionmaybeconsidered**

CANCER PATIENTS (IV Bisphosphonates / S.C. Denosumab)Recommendations BEFORE Initiating Drug Therapy

Dental/OMFSExaminationProphylaxis/DentalHygiene/PeriodontalTreatment

CariesControlEndodonticTherapy/Crown&Bridge

FluorideCarriers/RxFluorideToothpasteLightenExcessive/HeavyOcclusalContacts(BalancedOcclusion)

***NonSurgicalRestorative/GeneralDentalCareMayContinueUpTo&AfterInitiationofDrugTherapy****

ExtractionsofNon-RestorableTeeth,TeethWithPoorPrognosisAlveoloplasty&SmoothOfSharpBoneEdges

PrimaryClosure

SelectiveRemovalofTori&Exostoses(ExcessivelyLarge/Multi-Lobulated)

***2MonthsHealingBeforeCommencingIVBisphosphonates/SCDenosumabIsPreferredIfPossible/AgreedUponByMedicalOncologist.However,TimelyCancerTreatmentRemainsGreaterPriority***

RiskFactorsIncreaseBy4th DoseofIVBisphosphonateor2nd DoseofSCDenosumab-SoTreatmentMayStillBeInitiated&CompletedWithinThis2-4MonthWindow

CANCER PATIENTS (IV Bisphosphonates / S.C. Denosumab)Recommendations DURING Drug Therapy

Dental/OMFSExaminationProphylaxis/DentalHygiene/SupragingivalScaling

CariesControlEndodonticTherapy/Crown&Bridge

FluorideCarriers/RxFluorideToothpasteSplintMobileTeeth

ExerciseCautionWhenTakingIntraoralRadiographs&UsingRubber-DamClampsToAvoidTraumatizingMucosalTissues

***NonSurgicalRestorative/GeneralDentalCareIsSafe****

DrugHoliday&ConservativeNon-SurgicalManagementIsPreferredAntibiotics&ChlorhexidineRinseToManagePainandInfection

Non-RestorableTooth- ConsiderRootCanalTherapywithAmputationofCrown(LeavingRootsinPlace)Incision&Drainage

ElectiveExtractions&PeriodontalSurgeryContraindicated

• After4thDoseofIVBisphosphonate

• After2nd DoseS.C.Denosumab

MedicallyNecessary/EmergentConditionsNotAmenabletoDrugHolidayand/orConservativeMeasuresInformedConsent/ProceedtoSurgery(Atraumatic/Minimally-Invasive)

ConsiderUseofAdjunctiveGrowth/HealingFactors(PRPorPRF)MonitorHealingClosely

ElectiveDentalImplantSurgeryContraindicated• After4thDoseofIV

Bisphosphonate• After2nd Dose

S.C.Denosumab

CANCER PATIENTS IV Bisphosphonates / S.C. DenosumabManagement of Exposed Bone / DIONJ

60%ofPatientsCanBeManagedtoAchieve

Pain-Free/Infection-FreeStateWithContinuedExposedBone

(NoSurgeryRequired)

Initial/Long-TermConservativeManagement

• AvoidDebridements /InvasiveSurgicalProcedures

• OKtoSmoothSharpEdges• PainisRelatedtoSecondary

Infection- TreatWithAntibiotics&Antimicrobials:o Chlorhexidine(0.12%)Rinseo PenicillinVK500mg- 1tabpo

q6hx14dayso Doxycycline100mg- 1tabpo

qdayx14days• RefractoryCasesadd:

o Flagyl500mg- 1tabpoTIDx10days

• ConsiderAntifungalTreatmento MycelexTrocheso NystatinRinse

40%ofPatientsRequireSurgicalIntervention

IFSURGERYISUNAVOIDABLE(SevereChronic/Refractory

Infections,Oral-CutaneousFistula,PathologicFracture,StageIIIDIONJ)

MedicalOncologistConsultforPossibleDrugHolidayWithClose

CancerMonitoring

SURGICALINTERVENTION

MandibleAlveolectomy

ContinuityResectionTitaniumReconstructionPlate

PosteriorMaxillaAlveolectomy/SubmucosalResection/

Antrostomy/RadicalSinusotomy2LayerClosure- BuccalFatPadReconstructionwithMucosal

AdvancementFlap

AnteriorMaxillaAlveolectomy/SubmucosalResectionNasalFloorInvolvementRequiringResection(GenerallyNotNecessary)

Bone-GraftReconstructionGenerallyNotFeasible

Soft-TissueReconstructionPedicledMyocutaneousorMicrovascular

Free-Flapmaybeusedifnecessary

AdjunctiveGrowth/HealingFactorsPRP- PlateletRichPlasmaPRF- PlateletRichFibrin

Post-OpDrug Holiday

3 Months

Pre-Op Drug HolidayIV Bisphosphonates- 9 Months

SC Denosumab- 3 Months

RESOLUTIONof

DIONJ

J

DIONJ Pharmacological Treatment Options

ANTIMICROBIAL RINSEn Chlorhexidine 0.12%- Swish/Spit 15ml TID

PRIMARY ANTIBIOTIC CHOICESn Penicillin VK 500mg PO q6h x 14 days n Doxycylcine 100mg po qday x 14 days (Antibiotic of choice

in Penicillin Allergic Patients)n Add Flagyl 500mg PO q8h x 10 days for refractory cases

SECONDARY ANTIBIOTIC CHOICESn Levaquin 500mg po q day x 7 days & Flagyl 500mg PO q8h x

10 days, (Extended Courses of Levaquin- Risk of Tendon Rupture)

n Erythromycin 400mg PO q8h x 7 days & Flagyl 500mg PO q8h x 10 days

n Ciproflaxacin 500mg PO q12h x 7 days, & Flagyl 500mg PO q8h x 10 days

n Unasyn 1.5g IV q6h & Flagyl 500mg IV q8h for hospitalization

MOST COMMON MICROBIAL ORGANISMSn Actinomycesn Veillonellan Eikenellan Moraxella

INEFFECTIVE ANTIOBIOTICSn Clindamycin

LONG TERM ANTIBIOITICSn Penicillin VK and Doxycycline are

acceptable long-term options with low side effects

INEFFECTIVE THERAPIES FOR DIONJn Ozone Treatmentn Hyperbaric Oxygenn Laser Treatmentn Pentoxyfiline

OralBisphosphonatesforOsteoporosis:§ RiskofDIONJSignificantlyIncreasesafter2-3yearsoftreatment§ Surgicalproceduresmaybesafelyperformedif:

§ CTX> 151pg/ml§ 9MonthDrugHolidaypre-op§ 3MonthDrugHolidaypost-op

§ Dentalimplantsarepossibleifplacedandandpermittedtoosseointegrate inaccordancewithDrugHolidayand/orCTXGuidelines

§ Bewarethatpatientswith8+yearsofbisphosphonatehistory(asCTXresultsfirstriseandthendropagain,meaningalongerdrugholidaymaybenecessary).

§ Consideruseofgrowth/healingfactors(PRPorPRF)

IVBisphosphonate(Reclast/Zolendronate)forOsteoporosis:§ RiskofDIONJSignificantlyIncreasesby4th dose§ Invasivesurgicalproceduresarepreferablyavoided,withstrongconsiderationforalternative

proceduressuchasrootcanaltherapy,orotherconservativenon-surgicalmanagement.§ Ifsurgicalinterventionisnecessary-

§ CTX> 151pg/ml§ 9MonthDrugHolidaypre-op§ 3MonthDrugHolidaypost-op

§ DentalImplantsmaybeconsideredifplacedandosseointegrated inaccordancewithDrugHolidayand/orCTXGuidelinespriortoreceiving4th dose.

§ Keepinmindthatmanypatientshavepreviouslybeenonanoralbisphosphonate,andthereforeDIONJRISKISSIGNIFICANTLYHIGHER.Alongerdrugholidayisindicated.ConsiderCTXguidanceindecisionmaking/timing.

§ Consideruseofgrowth/healingfactors(PRPorPRF)

SubCutaneousInjectionofRANK-LInhibitorProlia (Denosumab)forOsteoporosis:§ Riskincreasesafter2Doses

§ CTXguidelinesnotwell/fullyestablishedatpresenttime.§ 3MonthDrugHolidaypre-op§ 3MonthDrugHolidaypost-op

§ Keepinmindthatmanypatientshavepreviouslybeenonanoralbisphosphonate,andthereforeDIONJRISKISSIGNIFICANTLYHIGHER.Alongerdrugholidayisindicated.

§ MayconsiderpossibleCTXguidanceindecisionmaking/timing.§ Consideruseofgrowth/healingfactors(PRPorPRF)

IVBisphosphonate(Zometa/Zolendronic Acid,Aredia/Pamidronate)forMetastaticCancer:•RiskofDIONJSignificantlyIncreasesby4th dose•Invasivesurgicalproceduresarepreferablyavoided,withstrongconsiderationforalternativeproceduressuchasrootcanaltherapy,orotherconservativenon-surgicalmanagement.•Ifsurgicalinterventionisnecessary:

•9MonthDrugHolidaypre-op•3MonthDrugHolidaypostop•DuringDrugHoliday- closemonitoringofcancerbyMedicalOncologist

•CTXNOTUsefulorIndicatedinCancerPatients•Consideruseofgrowth/healingfactors(PRPorPRF)

SubCutaneousInjectionofRANK-LInhibitorXgeva (Denosumab)forMetastaticCancer:•RiskofDIONJincreasesafter2Doses•Invasivesurgicalproceduresarepreferablyavoided,withstrongconsiderationforalternativeproceduressuchasrootcanaltherapy,orotherconservativenon-surgicalmanagement.•Ifsurgicalinterventionisnecessary:

•3MonthDrugHolidaypre-op•3MonthDrugHolidaypost-op•DuringDrugHoliday- closemonitoringofcancerbyMedicalOncologist

•KeepinmindthatmanypatientspreviouslybeenonanIVBisphosphonateandthereforeDIONJRISKISSIGNIFICANTLYHIGHER.Alongerdrugholiday(9-12+months)isindicated•CTXNOTUsefulorIndicatedinCancerPatients•Consideruseofgrowth/healingfactors(PRPorPRF)

IVVEGFInhibitor(Bevacisumab /Avastin)§ Toofewcasesexistforguidelinesatpresenttime§ Informedconsentandproceedwithcaution§ Consideruseofgrowth/healingfactors(PRPorPRF)

IVTyrosineKinaseInhibitor(Sutinib /Sutent)§ Toofewcasesexistforguidelinesatpresenttime§ Informedconsentandproceedwithcaution§ Consideruseofgrowth/healingfactors(PRPorPRF)

Decreasing Risks of Drug Induced Osteonecrosis of the Jaws (DIONJ)Adapted from the University of Miami Division of Oral & Maxillofacial Surgery Position Statement

Decreasing Risks of Drug Induced Osteonecrosis of the Jaws (DIONJ)Adapted from the University of Miami Division of Oral & Maxillofacial Surgery Position Statement

Effects Of Continuing Or Stopping Alendronate After 5 Years Of TxBlack DM, Schwartz AV, Ensrud KE, et. al. JAMA December 27, 2006 Vol. 296 No 24

Conclusions: Women who discontinued alendronate after 5 years showed a moderate decline in BMD and a gradual rise in biochemical markers but no higher fracture risk other than for clinical vertebral fractures compared with those who continued alendronate. These results suggest that for many women, discontinuation of alendronate for up to 5 years does not appear to significantly increase fracture risk. However, women at very high risk of clinical vertebral fractures may benefit by continuing beyond 5 years.

DrugHoliday§ SafeandEffective§ Shouldbeinitiatedbytheprescribingphysician§ Allowsforsufficientrepopulationoffunctionalosteoclaststoaidinhealing

§ Shouldextendfor3monthspostoperativelytopermitsufficienthealing

JAMA Editorial- Alendronate: “Five Years of a good thing is enoughColon-Emeric CS. JAMA. 2006 Dec 27;296(24):2968-9

FDA Statement, September 2011September 9, 2011: Joint Meeting of the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting Announcement

n Every woman on bisphosphonates for osteoporsis must be re-examined after 3 years

n Nobody needs to take bisphosphonates for osteoprososis for more than 5 years

AlternativestoAnti-ResorptiveMedicationsforOsteoporosis(NoMechanismorRiskofDIONJ)

• Calcium&VitaminD3• Raloxifene (Evista)• rhPTH1-34(Forteo)

OralBisphosphonateWith“LowestRisk”ofDIONJ• Boniva(Ibandronate)