MRONJ –

ein häufiges Problem in

der osteologischen Therapie?

Christian Muschitz

II. Med. Abteilung – KH Barmherzige Schwestern Wien

Medizinische Universität Wien

Österreichische Osteoporose LL 2017

Bei der Mehrzahl der Patientinnen ist die

Osteoporose eine chronische Erkrankung

mit einem dauerhaft erhöhten Frakturrisiko.

Empfehlung der Österreichischen Expertenkommission

www.arzneiundvernunft.at

AUVA – Frakturstudie 2000 - 2012

Muschitz C et al. Osteoporos Int. 2017

N = 433.499 patients; N = 575.722 de novo fractures

Osteoporose - Frakturen

n (%)b Total (N = 115,776)

Sex

Female 83,690 (72.3)

Male 32,086 (27.7)

Age (years)

Median (IQR) 81 (74–87)

Mean (SD) 80.4 (8.3)

66–70 17,998 (15.5)

71–75 17,847 (15.4)

76–80 20,596 (17.8)

81–85 24,119 (20.8)

≥ 86 35,216 (30.4)

OP treatmentd

Any OP treatment 32,757 (28.3)

Denosumab 1,578 (1.4)

Bisphosphonate 29,030 (25.1)

Teriparatide 0

Raloxifene 656 (0.6)

HRT 3,597 (3.1)

Adachi J et al. ASBMR 2019

Annual incidence of index fractures (any site) per 1,000 persons (95% confidence interval)

from 2011 to 2015 ranged from 15.23 (15.04–15.42) to 16.08 (15.90–16.27)

Osteoporose - Frakturen

Adachi J et al. ASBMR 2019

0

5

10

15

20

25

30

Pati

en

ts w

ith

an

In

dex F

ractu

re,

%

Index fracture type

27.3

n = 31,613

15.4

n = 17,85912.6

n = 14,559 11.4

n = 13,237 9.4

n = 10,894 7.2

n = 8,3286.7

n = 7,721 4.2

n = 4,828 3.2

n = 3,7352.6

n = 3,002

Hipa Wrista Clavicle,

ribs, or

sternum

HumerusaTibia, fibula,

or knee

Pelvis Radius or

ulnaa

Vertebrala Multisite Femura

14,7%

Osteoporose - Frakturen

Adachi J et al. ASBMR 2019

2nd fracture type n

Hip 5,745

Clavicle, ribs, or sternum 2,460

Wrist 2,249

Humerus 2,088

Pelvis 1,977

Vertebral 1,819

Multisite 1,518

Tibia, fibula or

knee1,317

Radius or ulna 741

Femur 715

All Index

Fractures:

N = 115,776

2nd

Fracture of

Any Type

n =

20,629

17.8%

No 2nd

fracture:

n = 95,147;

82.2%3,5%

3,6%

6,4%

7,4%

8,8%

9,6%

10,1%

10,9%

11,9%

27,8%

0% 10% 20% 30%

2nd Fracture

Typesa

Median time (IQR) between index and 2nd fracture, days: 555

Störungen der MikroarchitekturTransiliakale Biopsie – Nano-CT: Auflösung 9.3 µm

Feichtinger X, Muschitz C, al. Sci Rep. (Nature) 2018

Treatment options for osteoporosis

Imbalance in

bone remodeling

Anticatabolic drugs Anabolic drugs

Bisphosphonates

RANKL-AK

SERMs

Teriparatide

Romosozumab1

1

2

Vitamin D ±calcium supplementation

MHT

1 FDA approval 10/Apr/2019

Kontrolle

Kuo T et al. Biomarker Res. 2017

Seeding of Osteoblasts/Osteoclasts

Osteoblasts

Osteoclasts

Osteoblasts at high-strain locations and osteoclasts at low-strain locations

Tourolle DC et al. ASBMR 2019

Osteoporose ± Behandlung

Baseline 2.5 Years 5 Years 10 Years

Tre

atm

en

t

(Virtu

al D

en

os

um

ab

)

Co

ntro

l

(No

Tre

atm

en

t)

20

18

16

14

12

10

8

6

4

2

0

0 5 10

Years From Start of

Treatment

Tra

be

cu

lar

BV

/TV

(%

)

Treatment Control

Tourolle DC et al. ASBMR 2019

In Silico Trial

Se

rum

De

no

su

ma

b

Co

nc

en

tra

tio

n

(ng

/mL

6

4

3

1

0

5

6

Months42 8 1210

Denosumab Osteoclastic CellsBMD

(%) C

ha

ng

e in

B

iop

sy B

MD

(IS%

)

4000

0

35

25

15

5

0

0

Den

os

um

ab

C

on

ce

ntr

ati

on

(a

tto

mo

l)

30

20

102

Os

teo

cla

stic

C

ells

(%) C

ha

ng

e in

B

iop

sy B

MD

(IS%

)

4000

0

Os

teo

cla

stic

C

ells

35

25

15

5

0

Den

os

um

ab

C

on

ce

ntr

ati

on

(a

tto

mo

l)

30

20

10

25

15

5

20

10

0

Denosumab Osteoclastic CellsBMD

1

2

1200 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114

Denosumab

Tourolle DC et al. ASBMR 2019

Densoumab - FREEDOM Studie

Control (No Treatment)

Osteoblasts Osteoclasts

Treatment (Virtual

Denosumab)

Bone

Structure

Cells+ Bone

Structure

Cells+

Still images represent modeling at year 9.

Q6M = every 6 months.

MRONJ

ASBMR – ONJ is an area of exposed bone in the maxillofacial region that does not heal within 8 weeks after identification by a HCP, in a patient who was receiving or had been exposed to a BP and has not received radiation therapy to the craniofacial region1

The ASBMR now recognizes that ONJ is also associated with exposure to denosumab and to antiangiogenic agents2

AAOMS – “medication-related ONJ” (MRONJ) requires all 3 of the following:3

1. Current or previous treatment with antiresorptive or antiangiogenic agents

2. Exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region that has persisted for > 8 weeks

3. No history of radiation therapy to the jaws or obvious metastatic disease to the jaws

ONJ in a patient with prior BP exposure receiving denosumab4

Aghaloo 20104

Risk in patients receiving antiresorptive agents for osteoporosis

Risk in patients receiving higher-doseantiresorptive agents for cancer*<<

Perspectives of ONJ risk with antiresorptive agents1-3

Definitions and diagnostic criteria for osteonecrosis of the jaw (ONJ)

1. Khosla S, et al. J Bone Miner Res. 2007

2. 2. Khan AA, et al. J Bone Miner Res. 2015

3. 3. Ruggiero SL, et al. J Oral Maxillofac Surg. 2014

4. 4. Aghaloo TL, et al. J Oral Maxillofac Surg. 2010

ONJ – osteonecrosis of the jaw

ONJ is associated with invasive oral procedures and events, but the vast majority of denosumab-treated patients for osteoporosis undergoing these procedures do not develop ONJ.1-3

1. Ruggiero SL, et al. J Oral Maxillofac Surg. 2014

2. Khosla S, et al. J Bone Miner Res. 2007

3. Watts NB, et al. Presented at: ASBMR 2017

Most ONJ cases are associated with potentially inciting events1-3

Additional risk factors for ONJ1,2,4,5

• Tooth extractions

• Dentoalveolar surgery

• Periodontal disease treatment (scaling and root planing)

• Dental implants

• Natural (atraumatic) tooth loss

• Periodontal or peri-apical disease

• Intraoral trauma

• Inflammation

• Infection, osteomyelitis

• Denture use, ill-fitting dental appliances

• Diabetes or anemia

• Glucocorticoid therapy

• Immune deficiencies

• Smoking and alcohol

• Cancer

• Cancer therapy (immunosuppressive chemotherapy, anti-angiogenesis therapy)

• Coagulopathy

InvasiveOral Procedures

Dental-relatedConditions

OtherFactors

ONJ – osteonecrosis of the jaw

1. Ruggiero SL, et al. J Oral Maxillofac Surg. 2014

2. Khosla S, et al. J Bone Miner Res. 2007

3. Watts NB, et al. Presented at: ASBMR 2017

4. Khan AA, et al. J Bone Miner Res. 2015

5. Glueck CJ, et al. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996

ONJ – EBM Daten

Study – years of

treatment

Verum

N patients

Placebo

N patients

Zoledronic Acid

5mg iv q 12 mo

Horizon 1-31 1/3862 1/3852

Horizon 1-62

(Extension)

1/613 0/616

Denosumab

60mg sc q 6 mo

Freedom 1-33 0/3879 0/3883

Freedom 4-64 5/2343

3/2207‡

no placebo

Sr-Ranelate

2gr oral daily

Tropos 1-55 0/2554 0/2537

Alendronate

5mg oral daily

FIT 1-36 0/1022 0/1005

Teriparatide

20/40 µg sc daily

TPTD III7

20 months

0/541 (20µg)

0/552 (40µg)

0/544

PTH 1-84

100µg sc daily

rhPTH 1-84 III8

18 months

0/1286 0/1246

1 Black DM NEJM 2003, 2 Black DM JBMR 2012, 3 Cummings SR NEJM 2009, 4 Papapoulos S JBMR 2012, 5 Reginster JY JCEM 2005, 6Black DM Lancet 1996, 7 Neer R NEJM 2001, 8Greenspan SL Ann Intern Med 2007

‡ cross over

FREEDOM Extension: MRONJ

Case Status

DMAbExposure atONJ Onset

DMAb After ONJ Onset (# of doses) Key Case Details TEs

Severity per Amgen Criteria†

(AAOMS Stage) Treatment Modality

Time to ONJ

Healing

1 Resolved 1.1 y Yes (6) Endodontic thx post dental fracture 2 Moderate (2) Abx 4.5 mo

2 Resolved 5.3 y Yes (3) Improperly fitting dentures 0 Moderate (3) Abx, surgery 3.1 mo

3 Resolved 5.4 y Yes (1) Periodontal disease 1 Moderate (2) Abx, surgery 9.9 mo

4 Resolved 5.0 y Yes (8) Implants, sinus lift after TEs, dentures 2 Moderate (2) Surgery 20.0 mo

5 Resolved 5.1 y Yes (1) Trauma related to an exostosis 0 Moderate (1) Oral rinse, Abx 13.3 mo

6‡ Resolved 8.9 y Yes (2) Periodontal disease 2 Moderate (2) Abx, surgery 19.7 mo

7§ Resolved 6.4 y Yes (1)Dentures, root canal, scalings/root planings, natural tooth loss

2 Moderate (2)KCl, analgesic gel, oral rinse, surgery

11.6 mo

8** Resolved 1.6 y No New dentures 2 Severe (1) Oral rinse, Abx, surgery 7.5 mo

9 Resolved 6.9 y No “Mouth sore” 0 Severe (1) Surgery 5.2 mo

10 Resolved 9.6 y No Excised pyogenic granuloma 1 Moderate (2) Oral rinse 3.8 mo

11 Resolved 5.7 y No Upper denture fitting 3 Mild (2) Oral rinse, Abx 12.3 mo

12 Ongoing 5.8 y Yes (3) Periodontal disease, dentures 2 Mild (2) Oral rinse, Abx, surgery N/A

13§ Unknown 3.5 y NoNatural tooth loss; improperly fitting dentures

0 Moderate (2) No treatment Unknown

Watts N et al. J Clin Endocrinol Metab. 2019

Watts NB et al. J Clin Endocinol Metab. 2019

FREEDOM Extension: MRONJ

Of respondents, 45.1% reported at least one invasive OPE.

The exposure-adjusted ONJ rate in FREEDOM Extension was 5.2 per 10,000

person-years.

ONJ incidence was higher in those reporting an OPE (0.68%) than not

(0.05%).

ASBMR Task Force on Osteonecrosis of the Jaw – Summary of Findings

In 2007, the ASBMR task force on osteonecrosis of the jaw examined the link

between bisphosphonates and ONJ.1

It found the risk of ONJ to be low for people taking low dose oral

bisphosphonates (between 1 in 10,000 and <1 and 100,000 patient-treatment

years).

Although a recent report, based on a mail survey of bisphosphonate users, found the

incidence to be higher, the study design may be affected by selection bias.2

In contrast, the risk of ONJ is greater for people receiving high-dose

intravenous bisphosphonates for cancer (affecting 1% to 10% of patients).

In both settings, the risk increases with duration of treatment.

1 Khosla S. et al., J Bone Miner Res. 2007 2 Lo et al., J Oral Maxillofac Surg 2010

ONJ – ASBMR Position Statement

ONJ – DVO Leitlinie 2017

Kiefernekrosen unter einer Gabe von Bisphosphonaten und

Denosumab scheinen nach Ansicht der Leitliniengruppe bei einer

Osteoporose milder zu verlaufen als Kiefernekrosen im Rahmen einer

Antiresorptivagabe bei einer Malignomtherapie.

Es handelt sich bei einer für eine Osteoporose zugelassenen Therapie

um eine mutmaßlich seltene Nebenwirkung von etwa 1 : 100.000

ÖGKM Positionspapier 2016

Svejda B, Muschitz C et al. Wien Med Wochenschr. 2016

Bei einer Osteoporosetherapie tritt eine MRONJ des Kiefers als

assoziierte Therapiefolge sehr selten auf (0,001–0,01 %) und ist bei

einer Therapiedauer unter 4 Jahren kaum höher als die Inzidenz in der

Normalbevölkerung (< 0,001 %).

Nach 4 Jahren nimmt die Inzidenz um den Faktor 10 zu (0,01 – 0,1%).

Practical Considerations for Dental Procedures

Maintain good oral hygiene

Dental appliances should fit well and not create “sores”

Multiple extractions should be staged if possible

Use primary closure of extraction sockets

Prescribe a chlorhexidine mouth rinse until procedure area is healed

Prescribe antibiotics in patient with poor wound healing potential.

Khan AA et al. J Clin Densitom. 2017

Österreichische Osteoporose LL 2017

Bei der Mehrzahl der Patientinnen ist die

Osteoporose eine chronische Erkrankung

mit einem dauerhaft erhöhten Frakturrisiko.

Empfehlung der Österreichischen Expertenkommission

www.arzneiundvernunft.at

Bone

Structure

Cells+ Bone

Structure

Cells+