Osteonecrosis of the Jaw
Noopur Raje, MD
Center for Multiple Myeloma
MGH Cancer Center
Disclosures
Consultant: Amgen, Celgene, Novartis
Research Grants: Astrazeneca, Acetylon
1
Clinical Diagnosis of ONJ
Exposed bone in MF area that
Occurred spontaneously
Or
Was induced by dental surgery
With e/o delayed healing for > 6 weeks after
appropriate care.
May be associated with: pain, infection
No previous XRT
Clinical features: Pt #2
Patient #2: p/w roughness and irritation
h/o dex 4 mths, CTX, EDAP 3/3 mths, PBSCT and
Pamidronate 61 mths and Zometa 20 mths
h/o dental extraction
Raje et al. Clin Can Res 2008
2
Radiology: Pt #2
Loss of cortical bone and mixed radiolucency @ site of
exposed bone
Raje et al. Clin Can Res 2008
Staging
System
Migliorati CA et al . Nat Rev Endocrinology 2011
3
ONJ Incidence
Hoff AO et al Ann. N.Y. Acad.Sci 2118 (2010)
MRC Myeloma IX--
Analysis Schematic for ZOL vs CLO
R
Zoledronic acid (4 mga IV q 34 wk) +
A
intensive or nonintensive chemotherapy
N
(n = 981)
D
N = 1,960
O
Patients with newly
M
diagnosed MM
N
Treatment continued at least until disease progression
I
(stage I, II, III)
S
A
Clodronate (1,600 mg/d PO) +
T
intensive or nonintensive chemotherapy
I
(n = 979)
O
Endpoints (ZOL vs CLO)
Primary: PFS, OS, and ORR
Secondary: Time to first SRE, SRE incidence, and Safety
Abbreviations: CLO, clodronate; IV, intravenous; MM, multiple myeloma; ORR, overall response rate; OS, overall
survival, PFS,
8 progressionfree survival; PO, oral; SRE, skeletalrelated event; ZOL, zoledronic acid.
a Doseadjusted for patients with impaired renal function, per the prescribing information.
4
MRC Myeloma IX--
Adverse Events (Safety Population)
Patients, n (%)
Intensive pathway
Non-intensive pathway
ZOL
CLO
ZOL
CLO
(n = 555)
(n = 556)
Pa
(n = 428)
(n = 423)
Pa
Acute renal failure
29 (5.2)
33 (5.9)
.70
28 (6.5)
27 (6.4)
1.0
ONJb
21 (3.8)
2 (0.4)
< .0001
14 (3.3)
1 (0.2)
.0009
Thromboembolic
104 (18.7)
82 (14.7)
.08
53 (12.4)
35 (8.3)
.06
Infection SAE
52 (9.4)
62 (11.2)
.37
16 (3.7)
28 (6.6)
.06
Abbreviations: CLO, clodronate; ONJ, osteonecrosis of the jaw; SAE, serious adverse event; ZOL, zoledronic acid.
a Statistical significance determined by Fisher's exact test.
b
9
ONJ cases were confirmed by an independent adjudication committee.
Time to ONJ
Berenson JR et al. Am J Hematol 2011
5
Risk Factors
Poor dental hygiene
Trauma
Corticosteroid use
Anti-angiogenic Agents
Polymorphisms of p450 of CYP 2C8
Managing ONJ
· Make a diagnosis
· Assess its severity
It takes on a wide spectrum!
· Maintain excellent dental hygiene and regular exams
· Keep surgical intervention to a minimum
· There is no standard treatment
Antibacterial and antifungal rinses (chlorhexidine
gluconate and nystatin)
Systemic oral antibacterial, antiviral, and antifungal
treatment
6
Preventive Dental Measures Reduce
Incidence of ONJ
·A retrospective study in cancer pts receiving BPs
0.04
76%
0.03
ear)
0.03
0.02
(subjects/yIR 0.01
0.007
0
PRE Group
POST Group
IR = Incidence rate; PRE = Preimplementation of preventive measures; POST = Postimplementation of preventive measures.
1. Ripamonti C, et al. Presented at: 30th Annual SABCS; December 1316, 2007 San Antonio, Texas; Abstract 2056. In press
Annals of Oncology, 2008
ASCO Clinical Practice Guidelines:
Update
· Bisphosphonates
Indicated for MM pts w/ lytic bone disease
osteopenia
· Useful as an adjunct for pts w/ bone pain
· The bisphosphonates recommended are either
Zoledronic acid: 4 mg over 15 mins, IV q 3-4
wks
Palmidronate: 90 mg over > 2 hrs, IV q 3-4
wks
· Monitoring w/ serum creatinine (both BPs)
and/or urine albumin (for palmidronate only)
· PAM preferred in setting of renal dysfunction
· Re-evaluate after 2 years and consider stopping
if stable disease
Kyle R, et al. JCO. 200725: 2464-2472
7
Patient 2
CT
MRI
F18
FDG
Raje et al. Clin Can Res 2008
Biochemical Markers
Pt #
Urinary NTX
Calcium
Vitamin D
I-PTH
M:11-
8.4-10.2
(25-OH)
16-62
103nmol
mg/dL
20-100
pg/ml
F:4-64nmol
Ung/ml
1
17
8.5
25
111
2
29
9.4
29
56.25
3
67
10.7
25
138.56
4
21
11.2
28
73.51
5
18
8.3
22
42.67
6
15
9.2
18
64.73
7
16
9.0
10
116.85
8
39
8.3
nd
121.87
9
12
10
31
11.83
10
21
9.4
24
56.96
11
11
9.3
38
85.76
Average
24.18
9.39
25
79.99
Median
18
9.3
25
73.51
Std Dev
16.3
0.9
7.6
38.7
Raje et al. Clin Can Res 2008
8
NFAT TRANSCRIPTION FACTORS
ONJ
MM
Normals
PROTEIN KINASE C FAMILY
Raje et al. Clin Can Res 2008
? Bone Remodeling with
Bisphosphonates
DKK1
osteoblast
MCSF
OPG
MIP-1
RANKL
osteoclast
MCSF
?
MIP-1
DKK1
OPG
RANKL
osteoclast
osteoblast
9
High Dose Zoledronic Acid
increases Trabecular Bone
Pozzi et al, Clin Can Res 2009
High Dose Zoledronic Acid Decreases
Bone Formation
Zoledronic Acid
decreased osteoblast
numbers associated
with increased
tendency to fracture
Pozzi et al, Clin Can Res 2009
10
? Stress Fractures
Grasko, J Oral Maxillofacial Surg 2009
Urine NTx to tailor
Therapy
30 MM patients
in CR and or
6 m end of study
PR with h/o 8-
with BM aspirate
12 months of IV
and biopsy and
bisphosphonate
Skeletal Survey
therapy
Baseline NTX followed by monthly x 6
Serum Markers followed by monthly x 6
BM aspirate and core
Skeletal Survey
Zoledronic acid single dose
Raje et al. J Clin Oncol 2010 ASCO Ab
11
Results
NTx levels (n=28patients)
001
07144 NTx Values
002
003
100
004
90
005
80
006
70
007
l
60
008
eve
50
009
xLT
010
40
N
011
30
012
20
013
10
014
0
015
0123
4567
016
Months
017
018
Raje et al. J Clin Oncol 2010 ASCO Ab
Z-MARK Study Design
Prospective, single-arm, open-label, multicenter study
MM patients who
received IV
uNTx 50b
ZOL 4 mg Q4Wc,d,e
bisphosphonate
therapy 52 to 104
N=121
wk before first
ZOL dose on
ZOL 4 mg
SRE, PD, or
ZOL 4 mg
uNTx < 50b
Q12Wd,e
uNTX 50b
studya
Q4Wc,d,e
Bone marker-directed ZOL dosing x 96 wk
Abbreviations: MM, multiple myeloma; Q4W, every 4 weeks; Q12W, every 12 weeks; PD, progressive disease; uNTX, urinary N-
telopeptide; SRE, skeletal-related event; ZOL, zoledronic acid.
aPatient had to receive 4 doses of IV bisphosphonate; last prior IV bisphosphonate dose must have been administered 3
weeks before initial zoledronic acid dose on study.
bnmol/mmol creatinine.
cPatients will remain on zoledronic acid q 4 weeks for remainder of the study.
dAll patients were reminded to take supplemental oral calcium ( 500 mg) and vitamin D ( 400 IU) daily.
Raje et al, ASH 2010
eDose adjusted for patients with mildmoderate renal impairment at study entry.
12
Results
SREs by end of year 1
2 Patients receiving ZOL every 12 wk (Q12W)
· Spinal cord compression (1 patient)
· Radiation therapy to bone x 4 (1 patient)
0 Patients receiving ZOL every 4 wk (Q4W)
uNTX
Baseline uNTX
Median: 17 nmol/mmol Cr
Range: 771 nmol/mmol Cr
Median % change from baseline in uNTX
Wk 1236: range, 0%11.7%
Wk 48: 0%, range, -67.5%188.9%
Raje et al, ASH 2010
Nordic
Myeloma
Study Group
PAM 90 vs 30
ONJ 8 vs 2
cases
Gimsing P et al, Lancet Oncol 2010
13
Novel Drug Approaches
Teriparatide
Cheung A et al. N Engl J Med 2010
14