Osteonecrosis of the Jaws in Myeloma
Time Dependent Correlation with
AREDIA and ZOMETA Use
BRIAN G.M. DURIE, M.D., Michael Katz, Jason McCoy, MS and
John Crowley, PhD
Hematology/Oncology, Cedars-Sinai Outpatient Cancer Center, Los Angeles, CA, USA;
Web Support/Data Analysis, International Myeloma Foundation, Los Angeles, CA, USA; and
Statistics, Cancer Research and Biostatistics, Seattle, WA, USA.
Osteonecrosis of the Jaws What Is It?
Exposed bone in the
maxilla or mandible
Due to disruption of the
resorption-remodeling
cycle of bone and
inhibition of endothelial
cell proliferation
Poor healing and
secondary infection can
lead to loss of teeth and
segments of jaw bones.
Pictures courtesy Dr. Sal Ruggiero
How Frequent Is Osteonecrosis?
Rare prior to 2001
2003 Marx* reported 36 patients
2004 Ruggiero** et al reported 63 patients
diagnosed 2001-2003
Myeloma specialty groups report an
increased frequency
* JOMF SURG 61:115 2003
** JOMF SURG 62:527 2004
Questions About Osteonecrosis
Was the diagnosis missed prior to 2001?
Probably Not
It is an obvious dental problem
What caused the increased frequency of
ONJ?
Not Clear
Marx and Ruggerio et al proposed an
association with bisphosphonate use
Important Current Questions/ Issues
Is the likelihood of ONJ linked to use of Aredia
and/or Zometa?
To what extent do other therapies or disease
processes have an impact?
Are there identifiable risk factors?
What is the magnitude/severity of the
problem?
Are myeloma patients particularly at risk for
osteonecrosis (ONJ) e.g. versus breast cancer?
OUR STUDY
Anonymous WEB Based Survey: Summer 2004
Included 1203 Myeloma(904) and Breast
Cancer (299) patients
Recruited using IMF email lists/web site plus
"ACOR" myeloma and breast Listservs (email),
Nexcura (email) and Y-Me National Breast
Cancer Organization (web site)
Evaluates dates for diagnosis, treatments and
complications including dental findings
Increase in Treatment Options Over Time
Myeloma Rx
VELCADE
ZOMETA
THAL
THAL
Bortezomib (Velcade)
AREDIA
AREDIA
Thalidomide
Bisphosphonates
CLOD.
CLOD.
ALLO
ALLO
ALLO
SCT
SCT
SCT
Stem cell transplantation
High-dose chemotherapy
HDC
HDC
HDC
VAD
VAD
VAD
Vincristine, doxorubicin, dex
STEROIDS
STEROIDS
STEROIDS
STEROIDS
Radiation
RAD
RAD
RAD
RAD
Melphalan + Prednisone
MP
MP
MP
MP
1950-1960s 1970-1980s 1990s
2000s
Numbers of Patients Responding to Survey
Total Patients
1203
Myeloma
Breast
904
299
Osteonecrosis
Suspicious
ONJ
SONJ
(ONJ)
findings* (SONJ)
13
23
62
54
36
116
* SONJ: Suspicious findings: bone erosions; bone spurs; exposed bone
New Cases of ONJ Each
Year Among Respondents
57 patients
12 patients
Frequency of Therapeutic Interventions in
Myeloma Respondents
Overall
ONJ
Bisphosphonates
804/904 (89%)
57/62 (92%)
· AREDIA (ONLY)
267/904 (30%)
17/62 (27%)
· ZOMETA (EVER)
515/904 (57%)
40/62 (65%)
Steroids
738/904 (81%)
55/62 (89%)
· PREDNISONE
210/904 (23%)
24/62 (39%)
· DEXAMETHASONE 525/904 (58%)
64/62 (55%)
Thalidomide
496/904 (55%)
37/62 (59%)
Radiation to head/ neck
61/904 (7%)
3/62 (5%)
Stem Cell Transplant
426/904 (47%)
26/62 (42%)
Increasing Incidence of ONJ Among
Respondents from Date of Diagnosis
Months from Diagnosis
ONJ Among Respondents vs. Duration of
Aredia or Zometa Treatment
100%
Events / N
80%
Z only
10 / 211
Log-rank P=.01
A only
14 / 231
60%
A and Z
14 / 182
40%
20%
0% 0
24
48
72
96
120
144
Months from start of Aredia or Zometa
Duration of Aredia and/or Zometa use
censored at 3 years
25%
36-Month
Events / N Estimate
Z only
10 / 211
10%
P = .002
20%
A +/- Z
10 / 413
4%
15%
10%
5%
0% 0
12
24
36
Months from start of Aredia or Zometa
Prednisone Does Not Increase
the Likelihood of ONJ
Months from Diagnosis
Thalidomide and Dexamethasone Do Not
Increase the Likelihood of ONJ
Log-rank P > 0. 5
Thalidomide
60-Month
Dexamethasone
60-Month
Events / N Estimate
Events / N Estimate
Myeloma, Thalidomide use 33 / 485
8%
Myeloma, Dex use 29 / 515
6%
Myeloma, No Thalidomide
21 / 397
5%
Myeloma, No Dex
25 / 367
7%
50%
50%
40%
40%
30%
30%
20%
20%
10%
10%
0%
0%
0
24
48
72
96 120 144 168
0
24
48
72
96 120 144 168
Months from diagnosis
Months from diagnosis
Frequency of Prior Dental Problems*
ONJ
Overall
Patients
Total Population 396/1203(33%)
59/75 (79%)
Myeloma
294/904 (32%) 50/62 (81%)
Breast Cancer
102/299 (34%)
9/13 (69%)
Two sided P-value for dental problems and osteonecrosis:
in Breast:
0.0129
in Myeloma:
<0.0001
* Other than Suspicious ONJ findings
Conclusions
Amongst the respondents to this survey
Duration of bisphosphonate use in myeloma and
breast cancer is associated with increased risk of
Osteonecrosis (ONJ)
36 month estimates of ONJ are higher for Zometa
versus Aredia
None of the other therapies analyzed were
associated with increase risk of ONJ
Patients with prior dental problems have a higher
risk of ONJ
It is likely that precautions related to dental
care and bisphosphonates use may reduce
the likelihood of ONJ
Other Implications and Future Research
Further retrospective analysis will be important
to better understand ONJ in the near-term
Prospective evaluation for ONJ and
investigation of causal factors in clinical trials
should yield definitive answers in the long-term
Evaluation of improved dental precautions will
be important and could help determine to what
extent ONJ is a preventable problem
The oral surgery community has developed
specific recommendations for physicians and
patients relative to pre-ONJ elective surgery
and the risks of further surgery in an ONJ
setting
Acknowledgements
Special thanks to Judith Peterson
Special thanks to Vanessa Bolejack