Transcript BP associated ONJ

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 :
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American Society of Bone and Mineral Research
American Association of Oral and Maxillofacial Surgeons
Canadian 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 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 2003-2014
 Pubmed and EMBASE searched = 886 citations
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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 that is
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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
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Zoledronate RCT 5mg annual
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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 833pts 1 yr Zol 5mg vs Ris 5 mg –no ONJ
Male 302 pts 2 yr Zol 5mg vs ALN 70mg/week – no ONJ
Prevention OPS 581 pts 2 yr Zol vs pbo –no ONJ
Adverse event database searched 60 MedRA 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 sCTX 0.04-0.18ng/ml- low end
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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 sCTX
ONJ 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/ml
Risk ONJ rare – CTX not predictor of ONJ risk
Dmab in FREEDOM -8 cases
 Patient #;Drug Exposure;Outcome
 1--11th dose (5.5 yrs);Healed
 2--11th dose (5.5 yrs);Healed
 3--12th dose (6 yrs);Healed
 4--12th dose (6 yrs);Healed
 5--3rd dose (1.5 yrs);Healed
 6--4th 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
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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 hygiene
 More 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
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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 myeloma
oral exams q6 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%
 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 associated oral
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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 patients
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IV BPS (dose,duration)
Dmab
dental extraction
chemotherapy
periodontal disease
Oral BP
GC
DM
Denture
Smoking
Hyperthyroidism
Dialysis
Antiangiogenics
Age
Table XYZ. Risk factors associated with the development of osteonecrosis of the jaw - summary
table.
Risk Factor
Dental extraction
Estimated risk (OR, RR and/or HR)
OR = 5.3, 9.09*, 16.4*, 32.97*
HR = 9.78-53.2*,
Age (per additional decade)
OR = 1.09*
Zoledronic acid infusion
HR = 15.01*, 28.09*
RR = 9.5*
Each zoledronic acid infusion
OR = 2.02*
Pamidronate infusion
OR = 12.32*
Each pamidronate infusion
OR = 1.78*
Diabetes
HR = 3.40*
Glucocorticoid therapy
OR = 6.5
Smoking
OR = 2.5*
HR = 3.44*
Denture use
OR = 2.02*, 4.9*, 1.43*,
Periodontitis
OR = 2.95*, 13*,
Routine dental care
OR = 0.27*
*: multivariate estimate (ie. controlled for selective confounders)
References
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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 65,220
 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
ONJ incidence with/ without invasive oral
procedures and events – Watts et al FR0387
 Invasive oral procedures /events- implants, extraction,
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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 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
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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 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 (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
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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
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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 C
 Avoid invasive dental procedures if possible
 Need further studies to establish guidelines for
prevention and effective treatment of ONJ