Osteonecrosis of the
Jaw (ONJ), a Possible Side Effect of Bisphosphonate Therapy
Acronyms
and Definitions (from ref (3)).
BRONJ -
bisphosphonate-related osteonecrosis of the jaw
Dentoalveolar surgery - surgical procedures that involve trauma to the
supporting osseous structures of the jaw (e.g., tooth extraction, dental
implant placement)
Introduction
Before starting on Zometa or any IV bisphosphonate
(such as Aredia) the general recommendations to avoid developing ONJ
are(per white paper, FDA label, dear Doctor letters and position papers)
-
-
Have a comprehensive dental
examination done and appropriate preventive dentistry performed at
that time.
-
Active oral infections should be
treated.
-
Sites at high risk for infection
should be eliminated.
-
While on therapy, patients should
maintain excellent oral hygiene and avoid invasive dental procedures,
if possible.
Additionally, continuing to see
your dentist/dental hygienist while on chemotherapy is very important --
have your teeth cleaned, etc. at least every 6 months. There are also
fluoride mouth rinses (you shouldn't use a mouth rinse with alcohol) for
you to rinse the mouth out with.
Many papers and websites discuss ONJ in detail.
Here are some of the best.
The American Society for Bone and Mineral
Research has now become involved in ONJ and recently published a paper
covering all aspects of ONJ per their task force. The paper is available
free on-line.(1). Among the areas covered are:
-
ONJ definition: the presence of exposed
bone in the maxillofacial region that did not heal within 8 wk after
identification by a health care provider.
-
Risk of ONJ from published and
unpublished data: the risk of ONJ associated with oral bisphosphonate
therapy for osteoporosis seems to be low, estimated between 1 in
10,000 and <1 in 100,000 patient-treatment years. They noted
that it might be higher as information is rapidly evolving.
-
Risk of ONJ in patients with cancer
treated with high doses of intravenous bisphosphonates: range of
1–10 per 100 patients (depending on duration of therapy).
-
Future diagnostic imaging methods to
help identify patients at earlier stages of ONJ: optical coherence
tomography; MRI combined with contrast agents and the manipulation of
image planes.
-
Management is largely supportive.
See the task force report for more information (1, 6).
A review article is by
Ruggiero et al
published in the J. of Oncology Practice (January 2006). They state
"For patients currently receiving bisphosphonates who require dental
procedures, there is no evidence to suggest that interrupting bisphosphonate
therapy will prevent or lower the risk of ONJ. Frequent clinical assessments
and conservative dental management are suggested for these patients. For
treatment of patients who develop ONJ, a conservative, nonsurgical approach
is strongly recommended."
Another review article published in May 2006
is by Sook-Bin Woo et al, Systematic Review: Bisphosphonates and
Osteonecrosis of the Jaws,
Ann Intern Med
2006;144:753-761. This paper has a nice table on managment
recommendations for ONJ which stratifys patients into 3 different
categories: those starting bisphosphonates, those on bisphosphonates without
ONJ and those with ONJ. See also references 1-6.
A 2008 review paper from France by Michele
Tubiana-Hulin et al (8) makes the following key points:
-
Identified risk factors were
long-lasting exposure to BPs, intravenous nitrogen-containing BPs,
and poor dental status.
-
Three major hypotheses could explain
the genesis of ONJ: excess of bone turnover inhibition,
antiangiogenic effect, and local infection.
-
Before starting ONJ treatment, the
dental status must be controlled and followed during treatment as
dental procedures could worsen the risk of ONJ. When ONJ does occur,
its management needs to be adapted according to its extent.
An excellent website with information on ONJ
is
http://courses.washington.edu/bonephys/opjawON.html and the links and
references found therein.
Also, in 2006, a
Minisymposium on Bisphosphonates and Osteonecrosis of the Jaw was held.
The titles included are: Bisphosphonates: Sacrificing the Jaw to Save the
Skeleton? by Martha J. Somerman and Laurie K. McCauley; Jaw Bone Necrosis
and Bisphosphonates: Microanatomical Questions by Alan Boyde;
Bisphosphonates for Metastatic Bone Disease - Too Much of a Good Thing? by
Matthew R. Smith
A patient written document who is also a
retired dentist can be found at
http://cancer.prostate-help.org/download/onj.pdf
The American Dental Association has
the results of a panel of experts at
http://www.ada.org/prof/resources/topics/osteonecrosis.asp,
This provides a useful guide to patients who
are on bisphosphonates.
The American Association of Endodontists has
also gotten into the ONJ arena, with their Winter 2007 Newsletter entitled,
"Bisphosphonate-Associated
Osteonecrosis of the Jaw." There is a long list of references for
further reading.
The reference (9) for the most recent position
paper.
So just what is the incidence rate of ONJ?
Existing data suggests that 6-10% of patients on IV bisphosphonates for
cancer therapy will have ONJ (see above paper by SB Woo et al.) This
is high enough to be a real concern, but so are skeletal related events
which Zometa, for example, has been shown to delay in onset.
Some thoughts from Dr.
Stephen Strum on his experience with ONJ.
Basically, he has none even
though he has used the amino-bisphosphonates for years, involving
hundreds of patients. He attributes this possibly, to instructing
his patients to use a comprehensive bone supplement which is needed to
prevent hypocalcemia (low serum calcium). Examples of these
comprehensive calcium supplements are Jarrow's BoneUp and Life
Extension's Bone Assure at doses not to exceed 1000mg/day (of a
calcium containing supplement.) (Note this is not an
endorsement of these products by HRPCa.org). He also emphasizes
the importance of adequate Vitamin D3 and calcitriol levels.
Vitamin D enhances absorption of calcium from the gastrointestinal
tract. Furthermore, he indicates that monitoring iPTH levels and
serum calcium should be done regularly(1). An easy way to
ascertain adequate calcium intake that he uses is the random spot urine
calcium to creatinine ratio.
Ardine et al(2), in a letter to the editor,
conclude that tailoring calcium and vitamin D consumption to each
patient, on the basis of measured serum calcium and serum PTH levels,
"could potentially limit the onset of ONJ." Too much calcium might lead
to kidney stones, too little might increase PTH levels.
An abstract from the ASCO annual meeting on ONJ raises some
additional concerns when using anti-angiogenic drugs in addition to
Zometa (3). Their key points are:
-
ONJ
associated with IV bisphosphonate use in cancer patients.
Chemotherapy may be an additional risk factor.
-
Thought to
be result of localized vascular insufficiency due to faulty bone
remodeling.
-
Incidence in
patients not receiving chemotherapy 0.8%
-
Prostate
cancer patients incidence 6.5%.
No. of
patients with ONJ who were treated with Avastin, Thalidomide,
Taxotere and prednisone: 6 of 36 or 17%.
All patients
received monthly Zometa with mean duration of Zometa use before
diagnosis of ONJ was 20 months, but one patient had oral alendronate
for 3 years and then developed ONJ after 5 months on Zometa.
Four of 6
had pain at the site of ONJ; 5 had mandibular ONJ.
Treatment:
sequestrectomy or oral rinse with chlorhexidine.
ONJ was diagnosed in 4 of 5
patients with a prior dental infection or invasive dental procedure.
It took an average of 11 cycles of the Avastin, Thalidomide,
Taxotere, prednisone combination before ONJ was diagnosed and all
patients with ONJ had received full doses of Avastin.
They conclude that the highest risk is for prior dental infections
or dental procedures.
The next adder to risk might be chemotherapy regimens that include
steriods and/or anti-angiogenic agents.
Randomized phase III trials are needed.
Controversies Regarding ONJ
A news item, "Bisphosphonates as Cause of ONJ Is Not Proven, Pathologist
Says Elsevier Global Medical News. 2008 Nov 5, F Lowry," illustrates one
aspect of ONJ. Ellen Eisenberg, D.M.D, pointed out that she is
"unable to tell the difference between ONJ that has occurred in patients
treated with radiation for head and neck cancer, in patients treated
with intravenous or long-term oral bisphosphonates, or in patients who
have not received either treatment." However, "Until results from
definitive studies show that bisphosphonates, whether oral or
intravenous, are indeed the cause of ONJ, it is imperative that any
patient about to embark on bisphosphonate therapy get a thorough dental
examination, so that any potential sites of infection or inflammatory
disease can be eliminated, Dr. Eisenberg said." She went on to say that
"bisphosphonates are extremely useful medications, and that harm would
be done to patients if the drugs were to be discontinued out of
premature fears of ONJ. An asbstract of hers from the Chicago Supportive
Care Conference is
Skeletal Complications: Bisphosphonate- vs
Radiation-Induced Osteonecrosis of the Jaw.
Recent Abstracts (2007)
The paper by M. Fornier et al (6) examines the major hypothesis that the
etiology of ONJ is over-suppression of bone turn-over (Woo et al, Ann
Internal Med 2006). They say ONJ incidence is as high as 7.7% in
patients on chronic IV bisphosphonate therapy (Bamias et al, J. Clin
Oncol 2005). However, given that there is a decreased
incidence of skeletal complication with the use of IV bisphosphonates (Hortobagyi
et al, N Engl J Med 1966) investigating side effects such as ONJ becomes
important to see if they can be reduced or eliminated. Serum NTX
and BAP are biochemical markers of bone turn-over and they can be
suppressed with IV bisphosphonates.
This study used a database of 75 oncology patients who developed ONJ
between 2003-2006. Specific bisphosphonates were not mentioned in the
abstract.
Results
| |
sNTX (Serum cross-linked N-telopeptides of type I
collagen) |
BAP (Bone specific Alkaline Phosphatase) |
| Lab Normal Ranges |
5.5-19.5 nM BCE |
14.2-42.7 Units/L |
| Proximate to the time of ONJ diagnosis |
11.4 nM BCE (range 7.6–23.2)
|
21 Units/L (range 8–160) |
| % of patients with normal values at time of ONJ diagnosis |
96% |
86% |
| Evidence of a downward trend approaching diagnosis (1 yr and
6 mos.) |
No evidence |
No evidence |
Conclusion: Basically negative --
no systemic over-suppression of bone turn-over as revealed by sNTX
and BAP. Cautions: small sample size and lack of control for diurnal
variations of sNTX and retrospective nature of the patients. Also not
knowing what bisphosphonates were used limits what we know about sNTX
and BAP.
Nicla La Verde et al, focused on the possibility of
prevention/monitoring to reduce ONJ injuries. Note that ONJ occurs in
9.7% of patients (especially those on Zometa) in their study.
-
Study type: Retrospective.
-
Patients: 154 from October 2003 to October 2006. 95 female, 59 male;
primary tumors: 66 breast, 28 prostate, 26 lung, 9 myeloma, 4 NHL
and 21 other. All partients monitored starting in June 2005.
-
Interventions: Clinical oral cavity examination and dentists and
patients education.
-
Bisphosphonates studied: pamidronate 90mg monthly or Zoledronate (Zometa)
4mg monthly.
-
ONJ was diagnosed in 15/154 patients (9.7%); 8 before and 7 after
June 2005. These 15 patients consisted of 7 breast, 1 kidney, 2
lung, 1 head-neck, 1 thyroid, 1 NHL, 1 prostate and 1 sarcoma.
All received Zometa with a median number of courses per patient of
19.4. 4 patients were pre-treated with Pamidronate with a median
number of courses per patient of 31.
-
Therapies: 14 chemotherapy, 2 head-neck RT, 5 steroids, 7 estrogen
therapy.
-
There were 9 dentoalveolar procedures, 4 patients had diabetes.
-
First symptoms: multiple recurrent alveolar abscesses 9, pain 3,
dental mobility 1, paresthesia of the
lower lip 1, exposed bone 1. Main treatments were: antibiotics and
antifungals 11, curettages 3, surgical resections 4 (1 partial
maxillectomy, complicated by septic shock and oronasal communication, 2
partial mandibulectomies, 1 segmental mandibular resection).
-
There were 7 new ONJ cases diagnosed after June 2005 and these were
treated successfully without aggressive dentist interventions and
achieving good control of symptoms.
-
They conclude: ONJ frequent adverse event, especially with Zometa.
The monitoring program aims at avoiding an aggressive treatment and
employing a conservative approach and medical therapy
References
(1) Sundeep Khosla, (Chair), David Burr,
Jane Cauley, David W Dempster, Peter R Ebeling, Dieter Felsenberg,
Robert F Gagel, Vincente Gilsanz, Theresa Guise, Sreenivas Koka, Laurie
K McCauley, Joan McGowan, Marc D McKee, Suresh Mohla, David G Pendrys,
Lawrence G Raisz, Salvatore L Ruggiero, David M Shafer, Lillian Shum,
Stuart L Silverman, Catherine H Van Poznak, Nelson Watts, Sook-Bin Woo,
Elizabeth Shane, ASBMR Task Force on Bisphosphonate-Associated ONJ,
Bisphosphonate-Associated Osteonecrosis of the Jaw: Report of a Task
Force of the American Society for Bone and Mineral Research, Journal of
Bone and Mineral Research, October 2007:22:1479-1491 (doi:
10.1359/jbmr.0707onj)
http://www.jbmronline.org/doi/abs/10.1359/jbmr.0707onj
(2) Ardine M, Generali D,
Donadio M, Bonardi S, Scoletta M, Vandone AM, Mozzati M, Bertetto O,
Bottini A, Dogliotti L, Berruti A.,
Could the long-term persistence of low serum calcium levels and high
serum parathyroid hormone levels during bisphosphonate treatment
predispose metastatic breast cancer patients to undergo osteonecrosis of
the jaw? Ann Oncol. 2006 Aug;17(8):1336-7. Epub 2006 Mar 8. No
abstract available. PMID: 16524968
(3) J. B. Aragon-Ching, Y.
M. Ning, L. Latham, J. Guadagnini, P. M. Arlen, J. L. Gulley, J. Wright,
H. Parnes, W. D. Figg, W. L. Dahut,
Osteonecrosis of the jaw (ONJ) in androgen-independent prostate cancer
(AIPC) patients receiving ATTP (bevacizumab, docetaxel, thalidomide, and
prednisone, Journal of Clinical Oncology, 2007 ASCO Annual Meeting
Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 19594.
(4) Salvatore L. Ruggiero
and Bhoomi Mehrotra, Bisphosphonate-Related Osteonecrosis of the Jaw:
Diagnosis, Prevention, and Management, Annual Review of Medicine, Vol.
60: 85-96 (Volume publication date February 2009),
(doi:10.1146/annurev.med.60.063007.134350). This paper reviews the risk
factors, incidence, pathogenesis, prevention strategies and management
of ONJ.
(5)
http://www.aaoms.org/docs/position_papers/bronj_update.pdf
American Association of Oral and
Maxillofacial Surgeons Position Paper on Bisphosphonate-Related
Osteonecrosis of the Jaw—2009 Update; Approved by the Board of Trustees
January 2009
Task Force on Bisphosphonate-Related Osteonecrosis of the Jaws:
Salvatore L. Ruggiero, DMD, Thomas B. Dodson. DMD, MPH, Leon A. Assael,
DMD, Regina Landesberg, DMD, PhD, Robert E. Marx, DDS, Bhoomi Mehrotra.
(6)
M. Fornier, A. Farooki, C. Estilo, A. Conlin, S. Patil, M. Fleisher, J.
Huryn, C. Hudis, Serum Levels of Ntelopeptide (sNTX) and bone-specific
alkaline phosphatase (BAP) in oncology patients (pts) who developed
osteonecrosis of the jaw (ONJ) during therapy with intravenous
bisphosphonates (IB), European Journal of Cancer Supplements, Vol 5 No
4, Page 214, abstract P#2104.
(7)
Nicla La Verde, Karen Borgonovo, Paola Sburlati, Marina Chiara Garassino,
Celso Bianchi, Cristina Mantica, Silvia Perrone, Donata Pedretti,
Mariastella Dimaiuta, Gabriella Farina, AN EFFECTIVE PROGRAM OF
PREVENTION OF OSTEONECROSIS OF THE JAW (ONJ) IN CANCER PATIENTS (PTS)
TREATED WITH BISPHOSPHONATES (B), Annals of Oncology 18 (Supplement 9):
ix194, 2007, doi:10.1093/annonc/mdm329, abstract # 119PD.
(8) Tubiana-Hulin M, Spielmann M, Roux C,
Campone M, Zelek L, Gligorov J, Samson J, Lesclous P, Laredo JD, Namer
M., Physiopathology and management of osteonecrosis of the jaws related
to bisphosphonate therapy for malignant bone lesions. A French expert
panel analysis, Crit Rev Oncol Hematol. 2009 Jul;71(1):12-21. Epub 2008
Dec 12.
(9) Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra
B; American Association of Oral and Maxillofacial Surgeons, American
Association of Oral and Maxillofacial Surgeons position paper on
bisphosphonate-related osteonecrosis of the jaws--2009 update, J Oral
Maxillofac Surg. 2009 May;67(5 Suppl):2-12. A copy of this paper is
located at
http://www.aaoms.org/docs/position_papers/bronj_update.pdf
Author: Howard Hansen, November 21,
2007
Latest update: 1 April 2009 and 14/06/2009 and 18 July
2009.
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