Osteonecrosis of the Jaw (ONJ - PowerPoint Presentation

Slide1

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

Slide2

ONJ Task Force : multidisciplinary international taskforce sponsored by : 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

Slide3

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

, McCauley 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

Slide4

Systematic review 2003-2014Pubmed

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

Slide5

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

Slide6

Osteonecrosis of the jaw: possible pathophysiological mechanisms

Suppression of bone turnover

Infection/inflammation

Inhibition of angiogenesis

Immunomodulatory

effects

Slide7

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

Slide8

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

Slide9

Zoledronate RCT 5mg annualHORIZON 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 pboGIO 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

Slide10

HORIZON PFT 7756 pts-3889 zolZol

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 riskONJ 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/ml

Risk ONJ rare – CTX not predictor of ONJ risk

Slide11

Dmab in FREEDOM -8 casesPatient

#

;

Drug

Exposure;Outcome

1--11

th

dose (5.5

yrs

)

;Healed2--11th dose (5.5 yrs);Healed3--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

Slide12

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

Slide13

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

Slide14

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

Slide15

Slide16

-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

Slide17

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 17Saad 2012

Slide18

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

Slide19

risk factors in oncology patients

IV BPS (

dose,duration

)

Dmab

dental

extraction

chemotherapy

periodontal

diseaseOral BPGCDMDentureSmokingHyperthyroidismDialysisAntiangiogenics Age

Slide20

Khan AA et al in submission

Slide21

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

Slide22

Osteoporosis : risk factors SuppurationDental extraction Oral BP usedenosumab

Slide23

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 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

Slide24

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 2012Sunitinib: Koch 2011, Fleissig 2012

Slide25

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

Slide26

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

Slide27

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

I

n 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

Slide28

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