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| Journal of the New Zealand Medical Association,
01-December-2006, Vol 119 No 1246
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Osteonecrosis of the jaw and
bisphosphonates—putting the risk in perspective
Mark Bolland, David Hay, Andrew
Grey, Ian Reid, Tim Cundy
Osteonecrosis of the jaw (ONJ) is a recently recognised (but
poorly understood) dental condition that is associated with use of potent
bisphosphonate therapy, usually in the context of malignancy.
Recent publicity about ONJ in the lay media in New Zealand,
and cautious recommendations by North American dental
authorities,1 have created uncertainty, and in
some cases alarm, amongst patients, doctors, and dentists about the safety of
bisphosphonates. Specifically, some dentists are declining to perform dental
work in patients who are receiving bisphosphonate therapy for non-malignant
skeletal conditions, and some patients are discontinuing or declining effective
therapy for osteoporosis because of concern about ONJ.
The aim of this article is to examine the risks and benefits
of bisphosphonate treatment in light of the current evidence pertaining to
osteonecrosis of the jaw (ONJ).
What is ONJ?ONJ is characterised by exposed areas of jawbone, more
commonly affecting the mandible than the
maxilla.2–5 Most cases are precipitated
by tooth extraction or other dental surgery, but 25% occur without obvious
preceding oral trauma.3 The problem may
progress to bone necrosis and sinus or fistula formation, but its natural
history is not known. While pain is a typical presenting feature, approximately
33% of cases are asymptomatic. Plain X-rays may be normal in the early stages,
but later show poorly defined osteolysis with or without sequestrum formation.
Histology has been reported as showing necrotic bone, bacterial debris and
granulation tissue.3–5
The clinical syndrome of ONJ was first described in
association with bisphosphonate use by Marx in
2003.2 The pathophysiology of ONJ is unknown,
however it is important to emphasise that ONJ appears to be unrelated to
avascular osteonecrosis of long bones, or to radiation-induced osteonecrosis.
Previously, the bisphosphonate-associated disorder had only
been observed in the jaw, however one patient has been recently reported with
ONJ of the jaw and auditory canal.6 It is
hypothesised that high doses of bisphosphonates suppress bone remodelling in the
jaw to a degree that impairs the ability to repair microdamage induced by oral
trauma and/or infection.
The role of other potential risk factors such as
chemotherapeutic agents, corticosteroids, poor oral health, and other dental
comorbidities has not been established.4 The
optimal management of established disease is uncertain at present but pain and
infection control, conservative debridement of necrotic bone, and bisphosphonate
withdrawal are recommended.5
Who receives bisphosphonates?Before considering the incidence of ONJ in
bisphosphonate-treated patients, it is important to emphasise that these agents
are prescribed to two groups of patients: one with non-malignant skeletal
diseases, in particular osteoporosis and Paget’s disease of bone; the
other with cancer-related skeletal disease, most commonly metastatic breast
cancer and multiple myeloma.
Important differences exist between these patient groups in
the dose of bisphosphonate prescribed, in concomitant medical therapies, and in
the risk of developing ONJ (see below). Thus, patients with malignant skeletal
disease typically receive 12-fold higher doses of bisphosphonates (4 mg
intravenous zoledronate or 90 mg intravenous pamidronate monthly,
alendronate not used) than patients with non-malignant skeletal disease
(osteoporosis, alendronate 70 mg weekly, intravenous pamidronate 90 mg annually,
zoledronate 4–5 mg annually; Paget’s disease, intermittent courses
of treatment every 2–3 years with alendronate 40 mg daily for 6 months,
intravenous pamidronate 60–180mg, or intravenous zoledronate 4–5mg).
In addition, patients with cancer are typically receiving cytotoxic agents that
may influence general and oral health.
How common is bisphosphonate-associated ONJ?A recent review summarised published cases of
ONJ.5 95% of the reported cases of ONJ occurred
in patients with malignant skeletal disease. Of the three cases of ONJ that have
occurred in association with bisphosphonate treatment for Paget’s disease,
2 were prescribed inappropriately high doses of bisphosphonates (alendronate 40
mg/day for 5 years, pamidronate 90 mg monthly for 18 months). In this review, 15
cases of ONJ were reported in patients receiving bisphosphonate treatment for
osteoporosis.4
By March 2006, approximately 170 cases worldwide of ONJ in
association with alendronate had been reported to the manufacturer
(Merck).7 There are few clinical details
available for the majority of these cases. These cases have occurred on a
background of very extensive use of bisphosphonates for osteoporosis and
Paget’s disease in the past decade.
In 2004, it was estimated that there had been approximately
20 million patient-years of alendronate treatment for these
conditions.8 It is possible that
under-reporting of cases has occurred, but this would have to be very
substantial to significantly alter the very low incidence.
No cases of ONJ were reported in randomised controlled
trials of alendronate, risedronate or ibandronate that collectively included
more than 60,000 patients treated for at least 2 years. Therefore, while the
incidence of ONJ in patients treated with bisphosphonate for Paget’s
disease and osteoporosis is difficult to determine, it is very likely to be less
than 1/60,000 and is perhaps as low as 1/200,000.
The incidence of ONJ in patients receiving high-dose
bisphosphonate treatment for metastatic malignancy is much higher. Estimates
range up to 10%,5 but the best available data,
collected retrospectively on 4000 patients from a single institution, suggest
that about 0.85% of these patients are
affected.9
Patients with ONJ in this setting have all had metastatic
malignancies, most commonly multiple myeloma or breast cancer, and often have
been receiving chemotherapeutic agents, or corticosteroids, or had other dental
comorbidities.4
The roles of these possible predisposing factors have not yet been
determined.
Balancing the risksOsteoporosis—Bisphosphonates are the
only available agents of proven effectiveness for the treatment or prevention of
osteoporosis in New Zealand (oestrogen replacement therapy is also
effective10 but not widely used).
Alendronate treatment reduces the risk of vertebral and
non-vertebral fractures by about 50%.11 The
absolute benefit in fracture prevention from treatment with alendronate depends
on the baseline risk of sustaining a fracture. For a 65-year-old woman with a
bone density T score of -2.5 and no other clinical risk factors for osteoporotic
fracture, the estimated probability of sustaining a hip fracture in the next 10
years is 5.9%.12 In this situation the number
of women that need to be treated (NNT) with a course of alendronate to prevent
one hip fracture is 35.
For an 80 year old woman with a previous osteoporotic
fracture and a bone density T score of < -2.5, the estimated probability
of sustaining a hip fracture in the next 10 years is
45%.12 In this situation, the NNT is 4.5. In
comparison, the number of women that need to be treated with a course of
alendronate to cause one case of ONJ—the number needed to harm
(NNH)—is very likely to be at least 60,000.
Osteoporotic fractures are not trivial events. Hip fracture
is associated with a 25% risk of death within 12 months of the event, and a high
risk of decreased independence in those who
survive.13,14 Clearly, the balance of risk and
benefit favours alendronate treatment for osteoporotic patients. In addition,
the NNH is sufficiently high that any form of screening or preventative dental
treatment is highly unlikely to be cost-effective or produce a meaningful
reduction in ONJ incidence.
Paget’s disease—Bisphosphonates
are a highly effective treatment for
Paget’s disease.15,16 Patients with
Paget’s disease typically receive infrequent (every 2–5 years)
courses of bisphosphonates, such that the overall drug exposure is less than
occurs in patients with osteoporosis. It is therefore very likely that the risk
of ONJ in patients with Paget’s disease treated with conventional doses of
bisphosphonates is even lower than that in patients with osteoporosis.
Metastatic malignancy—Bisphosphonates
reduce pain from skeletal metastases (NNT at 4 weeks is 11, NNT at 12 weeks is
4).17 In multiple myeloma, bisphosphonates
reduce pathological vertebral fractures by 41% with a corresponding NNT of
10.18
In patients with breast cancer metastatic to bone,
bisphosphonates reduce the number of skeletal events by 17%, the rate of
skeletal events by 29%, reduce pain, and may increase quality of life. The NNT
to prevent one skeletal event is 9.19 In
prostate cancer with bone metastases, zoledronate reduced skeletal events by 25%
over 18 months in one trial of men with androgen-insensitive prostate cancer
(NNT = 9).20 No other bisphosphonate has been
shown to be effective in metastatic prostate
cancer.20
Treatment with bisphosphonates has not been demonstrated to
prolong survival in any of these
malignancies.18-20 Thus, in the treatment of
metastatic malignancy, the absolute benefit from treatment (NNT 4–10
depending on endpoint) is much closer to the absolute harm from treatment (NNH
10–120). In this situation, screening or preventative dental treatment
prior to initiation of bisphosphonate treatment may be appropriate and
guidelines for dentists seeing such patients have been
published.5 The efficacy of the recommended
prevention strategies has not been evaluated.
Currently, it is not known whether lower doses of
bisphosphonates than are currently prescribed are effective in reducing
cancer-related skeletal morbidity. If, as seems likely, there is a dose-response
relationship between bisphosphonate treatment and risk of ONJ, the use of lower
doses of bisphosphonates for treatment of skeletal metastases may be associated
with a lower risk of ONJ.
How should we approach the problem of ONJ?Current evidence suggests that the risk of ONJ in patients
with cancer in whom high dose bisphosphonate therapy is being commenced is high
enough to justify the screening and intervention strategies recommended by
various dental authorities.1,5 It should be
acknowledged, however, that at present such strategies have not been
demonstrated to influence the incidence of ONJ.
Current evidence suggests that the risk of ONJ in patients
with non-malignant skeletal conditions who are receiving conventional doses of
bisphosphonates is so low that (a) systematic screening or prevention programmes
and (b) withholding dental procedures are not justified in this setting.
Adopting an ultra-conservative approach in these patients
runs the risk of denying necessary dental care to patients receiving
bisphosphonates, and denying patients with dental disease an effective therapy
for osteoporosis or Paget’s disease.
Recommendations for dental care in patients receiving
bisphosphonates for non-malignant skeletal disease have recently been
developed.21 Routine dental care, in the form
of an annual examination, should be encouraged in all patients.
Conflict of interest statement: None
of the authors have a conflict of interest.
Author information: Mark Bolland, Research
Fellow, Department of Medicine, University of Auckland; David
Hay, Oral Medicine Specialist, Oral Health Regional Service, Auckland District
Health Board; Andrew Grey, Associate Professor of Medicine , Department of
Medicine, University of Auckland; Ian R Reid, Professor of
Medicine, Department of Medicine, University of Auckland; Tim
Cundy, Professor of Medicine, Department of Medicine,
University of Auckland; Auckland
Correspondence: Mark Bolland, Osteoporosis
Research Group, Department of Medicine, University of Auckland, Private Bag 92
019, Auckland 1020. Fax: (09) 373 7677; email: m.bolland@auckland.ac.nz
References:
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