Osteonecrosis of the Jaw ONJ International Consensus 2015

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Osteonecrosis of the Jaw (ONJ) International Consensus 2015 Aliya Khan MD, FRCPC, FACP, FACE

Osteonecrosis of the Jaw (ONJ) International Consensus 2015 Aliya Khan MD, FRCPC, FACP, FACE Clinical Professor of Medicine Mc. Master University for the International ONJ Task Force

ONJ Task Force : multidisciplinary international taskforce sponsored by : �American Society of Bone

ONJ Task Force : multidisciplinary international taskforce sponsored by : �American Society of Bone and Mineral Research �American 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 Surgeons �International Society of Oral Oncology �Japanese Society for Bone and Mineral Research �Osteoporosis Canada �Pan Arab Osteoporosis Society �The Endocrine Society

Key questions formalized addressing diagnosis and management of ONJ in osteoporosis and oncology patient

Key questions formalized addressing diagnosis and management of ONJ in osteoporosis and oncology patient populations �Authors: : Khan AA 1, Morrison A 2, Hanley DA 3, Felsenberg D 4, Mc. Cauley LK 5, O’Ryan F 6, Reid IR 7, Ruggiero S 8, Taguchi A 9, Tetradis S 10, Watts NB 11, Brandi ML 12, Peters E 13, Guise T 14, Eastell R 15, Cheung AM 16, Morin S 17, Masri B 18, Cooper C 19, Morgan S 20, Obermayer-Pietsch B 21, Langdahl BL 22, Al Dabagh R 23, Davison KS 24, Kendler D 25, Sándor GK 26, Josse, RG 28, Bhandari, M 29, El Rabbany, M 30, Pierroz, DD 31, Sulimani, R 32, , Saunders, DP 33, Brown JP 34, Compston 0 on behalf of the International Task Force on Osteonecrosis of the Jaw

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

Systematic review 2003 -2014 �Pubmed and EMBASE searched = 886 citations identified �Title and abstract review – 292 not relevant to questions � 594 citations full papers acquired �Remove not english – 34 citations removed � 560 citations �Remove reviews and proceedings – 5 citations removed � 555 citations �Expert reviewers’ additions – 55 citations added � 610 papers for full review �Papers reviewed , graded based on level of evidence

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

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

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

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 1 ST reported with BP use 2003 Marx 2003

Incidence in osteoporosis : �ONJ 1 ST 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 5 mg annual �HORIZON PFT 7765 �Zol-case DM with dental abcess; PBO-I

Zoledronate RCT 5 mg annual �HORIZON PFT 7765 �Zol-case DM with dental abcess; PBO-I case prednisone �Both resolved with antibiotics and debridement � 4 additional clinical trials with 5 mg zoledronate reviewed �HORIZON RFT 2127 pts 1. 9 yrs Zol vs pbo �GIO 833 pts 1 yr Zol 5 mg vs Ris 5 mg –no ONJ �Male 302 pts 2 yr Zol 5 mg vs ALN 70 mg/week – no ONJ �Prevention OPS 581 pts 2 yr Zol vs pbo –no ONJ �Adverse event database searched 60 Med. RA terms- no spontaneous cases �Incidence 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 s. CTX 0. 04

HORIZON PFT 7756 pts-3889 zol �Zol at 6 months mean s. CTX 0. 04 -0. 18 ng/ml- low end of premen range �s. CTX <= 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 s. CTX �ONJ patient on pbo – s. CTX not suppressed 0. 27 -0. 37 ng/ml – would have been considered low risk based on Marx �BP Rx commonly lowers s. CTX <0. 15 ng/ml �Risk ONJ rare – CTX not predictor of ONJ risk

Dmab in FREEDOM -8 cases �Patient #; Drug Exposure; Outcome � 1 --11 th

Dmab in FREEDOM -8 cases �Patient #; Drug Exposure; Outcome � 1 --11 th dose (5. 5 yrs); Healed � 2 --11 th dose (5. 5 yrs); Healed � 3 --12 th dose (6 yrs); Healed � 4 --12 th dose (6 yrs); Healed � 5 --3 rd dose (1. 5 yrs); Healed � 6 --4 th dose (2 yrs); Healed �In 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 safety �estimated exposure 1, 960, 405 patient-years or 2, 427,

Dmab : post marketing safety �estimated 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 2014 FR 0388

Estimated frequency of ONJ in OPS �Felsenberg -2006 - -0. 001% �Lo 2010 Kaiser

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

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 hygiene �More intensive osteoclast inhibition �Tosi 2005, Cafro 2005, Pozzi 2005 Abu-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

-1 st large prospective evaluation of ONJ in oncology patients Preplanned analysis �Incidence of

-1 st 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 120 mg vs Zol 4 mg monthly efficacy, safety � identical design with pooling of data – solid tumour or myeloma �oral exams q 6 months � 89 adjudicated cases of ONJ � 37 (1. 3%) zol; 52 (1. 8%) Dmab p=0. 13 ns �Median time of exposure 14 months both groups � 36 month study �Lipton 2012

ONJ : Dmab vs Zol �ONJ resolution Dmab 40. 4% Zol 29. 7% �

ONJ : Dmab vs Zol �ONJ resolution Dmab 40. 4% Zol 29. 7% � 32 patients resolution – 25 D/C blind Rx, 7 continued Rx �SRE 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 evaluation �Majority of patients with ONJ had

Other risk factors in oncology patients: prospective evaluation �Majority 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<10 g/d. L)44. 9% with ONJ v 40. 9% without �Diabetes (22. 5% with ONJ vs 15. 5% without) �Saad 2012

risk factors in oncology patients � IV BPS (dose, duration) � Dmab � dental

risk factors in oncology patients � IV BPS (dose, duration) � Dmab � dental extraction � chemotherapy � periodontal disease � Oral BP � GC � DM � Denture � Smoking � Hyperthyroidism � Dialysis � Antiangiogenics � Age

Khan AA et al in submission

Khan AA et al in submission

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

Risk factors in OPS –oral BP 2 nd prevention of fracture Italian Claims database –Nested case control 55 yrs+ with an osteoporotic fracture �Total cohort > age 55 was 65, 220 �during followup 61 cases ONJ identified (median 2. 7 yrs) �each case matched for age, sex randomly to 20 controls from cohort- - 1120 controls �BP users 46 (24. 8 -85. 5)/100, 000 person yrs �BP 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 �Suppuration �Dental extraction �Oral BP use �denosumab

Osteoporosis : risk factors �Suppuration �Dental extraction �Oral BP use �denosumab

ONJ incidence with/ without invasive oral procedures and events – Watts et al FR

ONJ incidence with/ without invasive oral procedures and events – Watts et al FR 0387 �Invasive oral procedures /events- implants, extraction, tooth loss, scaling, root planing during extension of FREEDOM �At year 3 of extension- recorded OPE recorded and q 6 months � 78% women particpated � 8 cases ONJ-7/1500 with OPE, 1/2036 no OPE �ONJ incidence 0. 4% in women reporting OPE �ONJ incidence 0. 05% in women not reporting OPE �Exposure adjusted incidence ONJ 4. 2/10, 000 pt/yrs

Antiangiogenics �Case reports suggest combination of AA +BP or Dmab more likely to be

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 ONJ �Data 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

Interruption of drug therapy-considerations �Long term skeletal retention of BP �No data confirming decreased ONJ risk by with holding BP �Bone injury associated with increased uptake of BP locally-scanning �Post invasive oral surgery may be increased deposition BP locally �osteoporosis 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

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

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

�All cancer patients need dental exam and appropriate preventive dental care prior to starting Dmab or BP �Maintain good oral hygiene Grade C �Avoid invasive dental procedures if possible � Need further studies to establish guidelines for prevention and effective treatment of ONJ