quick reference guide decreasing the risks of developing drug induced osteonecrosis of ... ·...
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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)