Osteonecrosis of the Jaw (ONJ) International Consensus 2015

Aliya Khan MD, FRCPC, FACP, FACE Clinical Professor of Medicine

McMaster University for the International ONJ Task Force

ONJ Task Force : multidisciplinary international taskforce sponsored by : American Society of Bone and Mineral Research American Association of Oral and Maxillofacial SurgeonsCanadian Association of Oral and Maxillofacial Surgeons Canadian Academy of Oral and Maxillofacial Pathology and

Oral Medicine European Calcified Tissue Society International Bone and Mineral Society International Society of Clinical Densitometry International Osteoporosis Foundation International Association of Oral and Maxillofacial SurgeonsInternational Society of Oral Oncology Japanese Society for Bone and Mineral Research Osteoporosis CanadaPan Arab Osteoporosis Society The Endocrine Society

Key questions formalized addressing diagnosis and management of ONJ in osteoporosis and oncology patient populations Authors:: Khan AA1, Morrison A2, Hanley DA3,

Felsenberg D4, McCauley LK5, O’Ryan F6, Reid IR7, Ruggiero S8, Taguchi A9, Tetradis S10, Watts NB11, Brandi ML12, Peters E13, Guise T14, Eastell R15, Cheung AM16, Morin S17, Masri B18, Cooper C19, Morgan S20, Obermayer-Pietsch B21, Langdahl BL22, Al Dabagh R23, Davison KS24, Kendler D25, Sándor GK26, Josse, RG28, Bhandari, M29, El Rabbany, M30, Pierroz, DD31, Sulimani, R32, ,Saunders, DP33, Brown JP34, Compston 0 on behalf of the International Task Force on Osteonecrosis of the Jaw

Systematic review 2003-2014Pubmed and EMBASE searched = 886 citations

identifiedTitle and abstract review – 292 not relevant to

questions594 citations full papers acquiredRemove not english – 34 citations removed560 citationsRemove reviews and proceedings – 5 citations removed555 citationsExpert reviewers’ additions – 55 citations added

610 papers for full reviewPapers reviewed , graded based on level of evidence

ONJ- agreed upon definition and diagnosis accumulation of dead alveolar or palatal

bone that is exposed to the oral cavity persisted for at least 8 weeks absence of local malignancy or head & neck

irradiation ~ expected majority of lesions would have healed

Diagnosis –Hx and Exam- remain most sensitive diagnostic tools

exposed bone in the oral cavity >= 8 weeks consistent diagnostic hallmark of ONJ

Osteonecrosis of the jaw: possible pathophysiological mechanisms

Suppression of bone turnover

Infection/inflammation

Inhibition of angiogenesis

Immunomodulatory effects

Questions:1. How common is ONJ? Osteoporosis and Oncology 2 Who develops ONJ? risk factors and co- morbidity 3. Can ONJ be prevented ? Role of drug interruption

Incidence in osteoporosis : ONJ 1ST reported with BP use 2003 Marx 2003

Data available largely case series, retrospective observational, retrospective cohort, very limited prospective data evaluating true incidence in osteoporosis patients estimated incidence ~0.1% to <1/100,000 person

years exposure Ruggiero 2004, Marx 2005, Farrugia

2006,Felsenberg 2006, Pazianas 2007, Mavrokokki 2007,Lyles 2007,Cartsos 2008,Fellows 2009,Hong 2009, Grbic 2010 ,Lo 2010, Urade 2011 , Baillargeon 2011, Khan 2011,Vestergaard 2012,Cummings 2009, Yamazaki 2012,Malden 2012, Bone 2013, Lapi 2013, Taylor 2013 , Ulmer 2014

Zoledronate RCT 5mg annualHORIZON PFT 7765 Zol-case DM with dental abcess; PBO-I case prednisoneBoth resolved with antibiotics and debridement4 additional clinical trials with 5 mg zoledronate

reviewed HORIZON RFT 2127 pts 1.9 yrs Zol vs pboGIO 833pts 1 yr Zol 5mg vs Ris 5 mg –no ONJMale 302 pts 2 yr Zol 5mg vs ALN 70mg/week – no ONJPrevention OPS 581 pts 2 yr Zol vs pbo –no ONJAdverse event database searched 60 MedRA terms- no

spontaneous casesIncidence adjudicated ONJ in 5,903 treated zol in 5 trials

<1 in 14,200 patient treatment yrs

Grbic 2010 et al JADA

HORIZON PFT 7756 pts-3889 zol

Zol at 6 months mean sCTX 0.04-0.18ng/ml- low end of premen range

sCTX <= 0.15 ng/ml in 78.5% at 6 months, 47% at 24 months, 39.1% at 36 months

considered moderate or high risk based on Marx et al criteria predicting ONJ risk

ONJ patient on zoledronate –did not have sCTXONJ patient on pbo – sCTX not suppressed 0.27-

0.37 ng/ml – would have been considered low risk based on Marx

BP Rx commonly lowers sCTX <0.15ng/mlRisk ONJ rare – CTX not predictor of ONJ risk

Dmab in FREEDOM -8 casesPatient #;Drug Exposure;Outcome1--11th dose (5.5 yrs);Healed2--11th dose (5.5 yrs);Healed3--12th dose (6 yrs);Healed4--12th dose (6 yrs);Healed5--3rd dose (1.5 yrs);Healed6--4th dose (2 yrs);HealedIn the long-term treatment group (patients 1-4), 2

of the 4 patients have continued on denosumab, while 2 discontinued.

In the cross-over group (patient 5 & 6), 1 patient has continued on denosumab, and 1 patient discontinued.

YEAR 7 :1 additional case long term , 1 in cross over

Dmab :post marketing safetyestimated exposure 1,960,405 patient-years

or 2,427,475 patients. 47 cases adjudicated –AAOMS criteria All patients at least >=1 other risk factors :concurrent GC use, concurrent

chemotherapy, prior BP use, invasive dental procedures, older age

1/3 resolution, 1/3 were ongoing , remainder unknown

Geller M et al ASBMR 2014FR0388

Estimated frequency of ONJ in OPS Felsenberg -2006 - -0.001%Lo 2010 Kaiser Permanente database-

0.05-0.21%Sedghizadeh 2009 institutional

retrospective-4%Mavrokokki 2007 Survey Australia – 0.01-

0.04%Khan 2011 Survey oral surgeons Canada

– 0.001%Ulmer 2014 Survey Sweden Oral Surg

+dental .067%Incidence very low in osteoporosis

patients Recognize exists and need to know how to

predict and minimize risk

Incidence in oncology patients

frequency - high dose BP/ Dmab for cancer related skeletal disease is ~1-15%-Quality- prospective ,retrospective studies , case

series Additional drugs – GC, chemotherapy, antiangiogenic

drugs, radiotherapy, poor oral hygieneMore intensive osteoclast inhibition Tosi 2005,Cafro 2005,Pozzi 2005Abu-Id 2008,Durie

2005, Wilkinson 2007, Jadu 2007,Cartsos 2008,Khan 2009, Christodoulou 2009, Dimoupoulos 2009, Vahtesevanos 2009,Stopeck 2010, Coleman 2011, Saad 2012, Smith 2012, Tennis 2012, Scagliotti 2012, Amadori 2013, Rathbone 2013 ,Barrett-Lee 2014

In cancer patients incidence- related to dose & duration of Rx

-1st large prospective evaluation of ONJ in oncology patients -Preplanned analysis Incidence of ONJ obtained prospectively in 5723

pts with metastatic bone disease Enrolled in 3 registration trials comparing Dmab

120mg vs Zol 4mg monthly efficacy, safety identical design with pooling of data – solid

tumour or myelomaoral exams q6 months 89 adjudicated cases of ONJ37 (1.3%) zol;52 (1.8%) Dmab p=0.13 nsMedian time of exposure 14 months both groups36 month studyLipton 2012

ONJ :Dmab vs ZolONJ resolution Dmab 40.4% Zol 29.7%32 patients resolution – 25 D/C blind Rx, 7

continued RxSRE 35.2% vs ONJ 1.6%Benefit of Rx outweighed risk of ONJ by

factor 17

Saad 2012

Other risk factors in oncology patients: prospective evaluationMajority of patients with ONJ had associated

oral event – tooth extraction (~2/3 of pts) , coinciding oral infection(~1/2) or risk factors for ONJ –

Corticosteroid use (73% with ONJ vs 62.3% without)

Antiangiogenic use (15.7% with ONJ vs 8% without)

Anemia(Hb<10g/dL)44.9% with ONJ v 40.9% without

Diabetes (22.5% with ONJ vs 15.5% without) Saad 2012

risk factors in oncology patientsIV BPS (dose,duration)Dmab dental extraction chemotherapy periodontal diseaseOral BPGCDMDentureSmokingHyperthyroidismDialysisAntiangiogenics Age

Khan AA et al in submission

Risk factors in OPS –oral BP 2nd prevention of fracture

Italian Claims database –Nested case control 55yrs+ with an osteoporotic fracture Total cohort > age 55 was 65,220during followup 61 cases ONJ identified

(median 2.7 yrs)each case matched for age, sex randomly

to 20 controls from cohort- - 1120 controlsBP users 46 (24.8-85.5)/100,000 person yrsBP use OR 2.8 (CI 1.3-5.9) vs nonusers longer exposure oral BP associated with

inc. ONJ risk Lapi 2013

Osteoporosis : risk factors SuppurationDental extraction Oral BP usedenosumab

ONJ incidence with/ without invasive oral procedures and events – Watts et al FR0387Invasive oral procedures /events- implants,

extraction, tooth loss, scaling, root planing during extension of FREEDOM

At year 3 of extension- recorded OPE recorded and q6months

78% women particpated 8 cases ONJ-7/1500 with OPE,1/2036 no OPEONJ incidence 0.4% in women reporting OPEONJ incidence 0.05% in women not reporting OPEExposure adjusted incidence ONJ 4.2/10,000

pt/yrs

Antiangiogenics Case reports suggest combination of AA +BP or

Dmab more likely to be associated with ONJ Several Studies and case reports of ONJ without

concomitant BP Currently insufficient evidence to confirm a causal

association with ONJData suggests concurrent Rx with BP may

increase risk of ONJ Further data is needed Bevacizumab :Estilo 2008, Greuter 2008, Serra 2009, Guarneri 2010.

Hopp 2011, Katsenos 2012 Sunitinib: Koch 2011, Fleissig 2012

Interruption of drug therapy-considerations Long term skeletal retention of BP No data confirming decreased ONJ risk

by with holding BPBone injury associated with increased

uptake of BP locally-scanning Post invasive oral surgery may be

increased deposition BP locallyosteoporosis patient at low risk of ONJ

not necessary to interrupt Rx if required for skeletal health

Prevention :

Data obtained in oncology and osteoporosis pop’n

Case series, case control, cohort (level 3-5)

Dental exam, good oral hygiene, treatment periodontal disease, antibiotic prophylaxis perioperatively for dental surgery in oncology pts

Fewer cases of ONJ in preventive oral care

Kunchar 2008, Montefusco 2008, Regev 2008, Lodi 2010, Ripamonti 2009, Bonacina 2011, Ferlito 2011, Bantis 2011,Francini 2011, Schubert 2012, Mozzati 2012,Vandone 2012, Scoletta 2013

Prevention Strategies :Identify and Rx dental disease prior to initiation

of high dose anti-resorptive therapy if possible Grade C ( level 3 evidence + consensus)

Optimize and emphasize oral hygiene: Grade C Weigh risks for ONJ, risk fragility fracture, SRE In high risk for ONJ including cancer patients

receiving oncology doses BP or Dmab consideration should be given to withholding anti-resorptive therapy following extensive oral surgery until surgical site heals with mature mucosal coverge–Grade D

In low risk for ONJ – no need to interrupt therapy

All cancer patients need dental exam and appropriate preventive dental care prior to starting Dmab or BP

Maintain good oral hygiene Grade CAvoid invasive dental procedures if possible Need further studies to establish guidelines

for prevention and effective treatment of ONJ