Post on 10-Jun-2020
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+