correspondence
Osteonecrosis of the Jaw and Bisphosphonates
to the editor: Cases of osteonecrosis of the jaw
in connection with the use of bisphosphonates
were reported in 2003.1,2 In 2004, the International
25
Myeloma Foundation conducted a Web-based sur-
vey to assess the risk factors for osteonecrosis of
20
the jaw. Of 1203 respondents, 904 had myeloma
(%)
and 299 breast cancer. Both osteonecrosis and sus-
15
picious findings, including bone erosions and
spurs plus exposed bone, were assessed. Sixty-
Incidence
Zoledronic acid
10
two patients with myeloma had osteonecrosis of
the jaw and 54 had suspicious findings; 13 pa-
Estimated
5
tients with breast cancer had osteonecrosis and
Pamidronate
P=0.002
23 had suspicious findings -- a total of 152 pa-
tients with either osteonecrosis or suspicious
0
0
12
24
36
findings. Of the patients with myeloma, 71 per-
Months from Start of Therapy
cent had received zoledronic acid and 29 percent
had received only pamidronate.
Figure 1. Time to the Onset of Osteonecrosis of the Jaw in Patients
Figure 1 displays the cumulative incidence of
with Myeloma Receiving Zoledronic Acid or Pamidronate.
osteonecrosis of the jaw among patients receiving
Among patients receiving zoledronic acid, the occurrence of osteonecrosis of
either zoledronic acid alone or pamidronate alone
the jaw is particularly notable at months 4, 8, 9, 11, 13, 15, and 18. With data
who responded to the survey. With censoring at 36
censored at 36 months, the estimated incidence among patients receiving
months, osteonecrosis of the jaw developed in 10
zoledronic acid was 10 percent and that among those receiving pamidronate
was 4 percent. Without censoring, the mean time to the onset of osteonecro-
percent of 211 patients receiving zoledronic acid,
sis among patients receiving zoledronic acid was 18 months, as compared
as compared with 4 percent of 413 patients receiv-
with 6 years for patients receiving pamidronate (P=0.002).
ing pamidronate (P=0.002 by the log-rank test).
The earlier onset of osteonecrosis of the jaw among
patients receiving zoledronic acid during the first
36 months reflects remarkably well the reported in-
In September 2004, Novartis, the manufacturer
crease in the occurrence of osteonecrosis in the first of pamidronate (Aredia) and zoledronic acid
36 months after the Food and Drug Administration (Zometa), issued post-marketing guidelines3 for
approved the drug in 2001.
both drugs in relation to osteonecrosis of the jaw
The censored 36-month estimates of osteo- that emphasized a particular risk with surgical in-
necrosis, suspicious findings, or both did not dif- tervention. The International Myeloma Foundation
fer between patients with myeloma and those with is working collaboratively with Novartis to raise
breast cancer (P>0.50). No other therapies, includ- awareness and develop enhanced guidelines. The
ing corticosteroids and thalidomide, conferred an full results of the study were presented to the Food
added risk over time (P>0.50). However, a history and Drug Administration at an Oncology Drug Ad-
of underlying dental problems, such as infection or visory Committee meeting held on March 4, 2005.4
dental extraction, was present in 81 percent of pa- Brian G.M. Durie, M.D.
tients with myeloma and in 69 percent of patients CedarsSinai Outpatient Cancer Center
with breast cancer who had osteonecrosis of the Los Angeles, CA 90048-1804
jaw, as compared with 33 percent of those without bdurie@salick.com
osteonecrosis (P<0.001 and P=0.01, respectively, Michael Katz, M.B.A.
in a two-sided test). Maxillofacial surgery was a par- International Myeloma Foundation
ticular problem for patients with osteonecrosis of North Hollywood, CA 91607-3421
the jaw, since the surgery resulted in areas of non- John Crowley, Ph.D.
healing bone and soft tissue that were larger than Cancer Research and Biostatistics
those in patients who did not undergo surgery.
Seattle, WA 98101-1468
n engl j med 353;1
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july 7, 2005
99
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The new england journal of medicine
1.
Marx RE. Pamidronate (Aredia) and zoledronic acid (Zometa)
persons results from physiologic trauma to the
induced avascular necrosis of the jaws: a growing epidemic. J Oral
mucosa, leading to hypovascularity and focal bone
Maxillofac Surg 2003;61:1115-7.
2.
Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteone-
death.4 Interestingly, this site is frequently involved
crosis of the jaws associated with the use of bisphosphonates:
in osteonecrosis.
a review of 63 cases. J Oral Maxillofac Surg 2004;62:527-34.
Radical resection appears to be of limited use in
3.
Changes to the precautions and post-marketing experience sec-
tions of Aredia (pamidronate disodium) injection and Zometa
cases of osteonecrosis of the jaw and may be con-
(zoledronic acid) injection prescribing information related to osteo-
traindicated; the disease may progress despite sur-
necrosis of the jaw. September 24, 2004 (package inserts).
gery and cessation of bisphosphonate therapy.3 Fac-
(Accessed June 16, 2005, at http://www.novartis.com.)
4.
ODAC meeting transcripts. (Accessed June 16, 2005, at http://
tors such as underlying disease status, prognosis,
odac.myeloma.org.)
extent of the lesion, presence or absence of jaw
pain, and presence or absence of infection (not just
surface bacterial colonization) should be consid-
to the editor: Bisphosphonates are powerful os-
ered when planning further treatment. Once bone
teoclast inhibitors with antitumor and antiangio- resorption has been curtailed, there may be little
genic properties and a half-life of many years. The benefit in giving lower doses of bisphosphonates,
use of these drugs significantly reduces skeletal- especially in patients receiving long-term bisphos-
related events in patients with multiple myeloma phonate therapy.5
and other cancers.1 However, long-term use can
In our view, until studies in animals and pro-
result in suppression of bone turnover and com- spective clinical trials shed more light on this condi-
promised healing of even physiologic microinju- tion, patients should be informed of the risk of os-
ries within bone that occur as a result of day-to- teonecrosis. Dentists and oral surgeons should
day stresses.2
judiciously remove all dental infections before or
Osteonecrosis of the jaw has been reported re- within a few weeks of the initiation of bisphospho-
cently in patients with cancer who were receiving nate therapy in this high-risk population of patients
either pamidronate or zolendronate, or both, and with cancer. Moreover, among patients receiving
in those receiving alendronate for osteoporosis.3 bisphosphonates in whom dental infections devel-
Osteonecrosis of the jaw presents as an exposure of op, withdrawal of the drugs until the infection is
the mandible or maxilla that can be either painless controlled may be warranted.
or painful. Unlike osteoradionecrosis, osteonecro- Sook-Bin Woo, D.M.D.
sis involves the maxilla fairly frequently, and as Brigham and Women's Hospital
many as one fifth of cases occur spontaneously. We Boston, MA 02115
have seen more than 20 cases of osteonecrosis of Karen Hande, N.P.
the jaw in patients with myeloma at our institution Paul G. Richardson, M.D.
during the past six months, although we had seen DanaFarber Cancer Institute
very few in previous years; the reasons for this in- Boston, MA 02115
creased incidence are unclear.
1.
Berenson JR, Rosen LS, Howell A, et al. Zoledronic acid reduces
Osteonecrosis of the jaw probably results from skeletal-related events in patients with osteolytic metastases. Can-
the inability of hypodynamic and hypovascular bone cer 2001;91:1191-200.
2.
Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak
to meet an increased demand for repair and remod- CYC. Severely suppressed bone turnover: a potential complication
eling owing to physiologic stress (mastication), iat- of alendronate therapy. J Clin Endocrinol Metab 2005;90:1294-301.
rogenic trauma (tooth extraction or denture injury), 3. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteo-
necrosis of the jaws associated with the use of bisphosphonates:
or tooth infection in an environment that is trauma- a review of 63 cases. J Oral Maxillofac Surg 2004;62:527-34.
intense and bacteria-laden. Coexisting factors may 4. Peters E, Lovas GL, Wysocki GP. Lingual mandibular sequestra-
include the use of other medications with antian- tion and ulceration. Oral Surg Oral Med Oral Pathol 1993;75:739-43.
5.
Ott SM. Long-term safety of bisphosphonates. J Clin Endocrinol
giogenic properties (such as glucocorticoids, tha- Metab 2005;90:1897-9.
lidomide, and bortezomib in patients with myelo-
ma), diabetes mellitus, irradiation of the jawbone,
peripheral vascular disease, and hyperviscosity syn- to the editor: The main known risk factors for os-
dromes. It is hypothesized that benign sequestra- teonecrosis of the jaw are dental procedures, poor
tion of the lingual mandibular plate in healthy dental hygiene, corticosteroid therapy, and local
100
n engl j med 353;1
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correspondence
radiotherapy. More recently, treatment with bis- termine which patients are at increased risk for os-
phosphonates, such as pamidronate and zoledronic teonecrosis of the jaw, what is the optimal and safe
acid, was reported to be associated with osteonecro- duration of treatment, and what recommendations
sis of the jaw among cancer patients.1,2 However, should be made for the follow-up of patients being
other confounding risk factors for osteonecrosis treated with bisphosphonates.
were also noted in published reports, especially den- Marie Maerevoet, M.D.
tal procedures during therapy.3 As a consequence, Charlotte Martin, M.D.
the manufacturer of zoledronic acid recently modi- Lionel Duck, M.D.
fied its U.S. post-marketing and precautions infor- Clinique St.-Pierre
mation with the following statement regarding den- 1340 Ottignies, Belgium
tal care: "While on treatment, these patients should li.duck@clinique-saint-pierre.be
avoid invasive dental procedures, if possible" (www. 1. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteo-
pharma.us.novartis.com).
necrosis of the jaws associated with the use of bisphosphonates:
a review of 63 cases. J Oral Maxillofac Surg 2004;62:527-34.
We report nine cases of well-documented osteo- 2. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa)
necrosis of the jaw that occurred in patients who induced avascular necrosis of the jaws: a growing epidemic. J Oral
were receiving therapy with zoledronic acid but Maxillofac Surg 2003;61:1115-7.
3.
Tarassoff P, Csermak K. Avascular necrosis of the jaws: risk fac-
had not undergone dental procedures. In Septem- tors in metastatic cancer patients. J Oral Maxillofac Surg 2003;61:
ber 2002, we started using zoledronic acid almost 1238-9.
exclusively for skeletal protection in patients with
cancer. Zoledronic acid was given every three or
four weeks at a dose of 4 mg intravenously during a the above letters were referred to novartis
period of 15 minutes. Between December 2003 and pharmaceuticals, the manufacturer of pamidro-
July 2004, nine cases of osteonecrosis of the jaw nate and zoledronic acid, which offers the fol-
were diagnosed at our institution (four in patients lowing reply: The letters published in this issue
with multiple myeloma and five in patients with of the Journal, as well as case reports published
metastatic breast cancer) among 194 patients since 2003,1-3 underscore the fact that osteonecro-
treated with zoledronic acid. Before receiving zole- sis of the jaw is a concern for cancer patients and
dronic acid, six patients had been treated first with their physicians. As the developer of Aredia (pam-
pamidronate (90 mg every three or four weeks). idronate) and Zometa (zoledronic acid), we have
Eight of the nine patients had biopsy-proven osteo- obtained expert advice on how to revise the labels
necrosis of the jaw. All the cases were diagnosed for these two drugs. Our labeling recommends a
while the patients were receiving zoledronic acid. dental examination to identify and correct predis-
The median duration of treatment with pamidro- posing conditions before bisphosphonate treat-
nate was 39 months (range, 4 to 58), with a median ment is started in patients with potential risk fac-
cumulative dose of 3060 mg (range, 360 to 5520). tors, including cancer.4 This approach may help
For zoledronic acid, the median duration of thera- identify and rectify dental problems before or
py before the appearance of osteonecrosis was 18 during treatment so that osteonecrosis of the jaw
months (range, 4 to 22), and the median cumula- may be prevented or its progression limited. Pa-
tive dose was 72 mg (range, 36 to 88).
tients taking bisphosphonates should avoid inva-
The percentage of cases of osteonecrosis of the sive dental procedures, if possible. Further, more
jaw that are associated with zoledronic acid is high conservative treatments for osteonecrosis of the
in our institution (4.6 percent). Nevertheless, our jaw may also include systemic antibiotics to con-
data confirm other previous reports concerning trol or prevent infection, as well as antimicrobial
the possible association between bisphosphonates oral rinses.
and osteonecrosis of the jaw. From our observa-
Dental surgery may exacerbate osteonecrosis of
tions, it is unclear which bisphosphonate, zole- the jaw in patients in whom the condition has de-
dronic acid or pamidronate, is the causal agent. veloped during bisphosphonate therapy. No data
However, our analysis provides more evidence that are available to suggest whether discontinuation of
further investigations should be performed to de- bisphosphonate treatment in patients requiring
n engl j med 353;1
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july 7, 2005
101
Downloaded from www.nejm.org by BRIAN G. DURIE on July 6, 2005 .
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
correspondence
dental procedures reduces the risk of osteonecro- 1. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa)
sis. Collaboration between the oncology and den- induced avascular necrosis of the jaws: a growing epidemic. J Oral
Maxillofac Surg 2003;61:1115-7.
tal communities will be important for gaining bet- 2. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteo-
ter insights into the optimal treatment of patients necrosis of the jaws associated with the use of bisphosphonates:
with osteonecrosis of the jaw.
a review of 63 cases. J Oral Maxillofac Surg 2004;62:527-34.
3.
Bagan JV, Murillo J, Jimenez Y, et al. Avascular jaw osteonecrosis
Peter Tarassoff, M.D., Ph.D.
in association with cancer chemotherapy: series of 10 cases. J Oral
Pathol Med 2005;34:120-3.
Yong-jiang Hei, M.D., Ph.D.
4.
Complete Zometa prescribing information. East Hanover, N.J.:
Novartis Pharmaceuticals
Novartis Pharmaceuticals, November 2004.
East Hanover, NJ 07936
Correspondence Copyright © 2005 Massachusetts Medical Society.
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