Professional Documents
Culture Documents
1 January 2012
Background. The increase in reported cases of osteonecrosis of the jaw has increased the clinical significance of
bisphosphonate therapeutic agents in the dentistry field.
Methods. We present a rare and severe case of bisphosphonate-related osteonecrosis of the jaw caused by medicamentous
treatment of complex regional pain syndrome. This article reviews the current international prevention and treatment
guidelines with regard to bisphosphonate treatment.
Results. Even rare indications for bisphosphonate treatment may lead to devastating effects on the patient.
Conclusions. Dentists and physicians who prescribe bisphosphonates should be familiar with the side effects of these drugs
and the management of these side effects. To prevent negative outcomes, it is important that there be a close collaboration
among the doctors involved and that a thorough medical history is obtained; this is especially true because the range of
indications for bisphosphonate treatment increases every year. (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;113:41-47)
CASE REPORT
We report the case of a 41-year-old woman who was
bitten by a dog on her right calf in November 2002; she
subsequently developed recurrent painful complaints
and pressure-sensitive scars in the wound area. In November 2003, a wound revision with scar excision was
performed. The patient reported exacerbation of the
symptoms after surgery. Assuming that the persistent
pain was caused by a systemic pain-processing disorder
related to a neuropathic syndrome, the patient was
admitted to the pain clinic at the Department of Anaesthesia and Critical Care. The patient subsequently experienced myofascial pain in the area of the right elbow
and shoulder as well as panic disorders; the panic
disorders were treated with behavior therapy and an
anticonvulsant drug, pregabalin.
The disease followed a complicated course. The patient was admitted to the day unit of the pain clinic for
a multimodal treatment approach. This approach included a complex pain-treatment regime and adjuvant
41
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January 2012
42
Drug
Dosage
1-0-1
0-0-8 drops
0-0-20 drops
0-1-0
1-0-0
2-1-0
1-0-1
1-0-0
1-0-0
1-0-1
0-0-1
0-0-1
1-0-0
psychotherapy. This therapy was followed by the following regimen: antineuropathic regimen with antidepressant and anticonvulsive agents (olanzapine, mirtazapine, and doxepin), bisphosphonate infusions (72
mg zolendronate from November 2004 to November
2005, 195 mg pamidronate from November 2005 to
January 2006 (total doses), and intravenous tropisetron), and a ganglionic local opioid application at the
cervical sympathetic ganglia. The analgesic effect of
the antiplatelet drug clopidogrel provided only temporary relief; therefore, this treatment regimen was discontinued. The patient developed severe depression for
which she was prescribed several drugs (Table II). In
addition, the patient developed a toothache in the left
mandible, and tooth 18 was extracted by a dentist in
January 2006 because of pain that was refractory to
treatment. Subsequently, the patient developed a
wound-healing disorder in the socket of tooth 18. In
April 2006, epiperiosteal surgical socket revision and
debridement were performed, and tooth 19, which had
loosened, was extracted. The alveolar crest bone was
necrotic and sequestering in the former socket of tooth
37. The wound was closed using a multilayer technique. The patient developed a wound-healing disorder
that was initially treated with local anti-infective agents
(chlorhexidine gel) and systemic antibiotic therapy
(clindamycin: 600 mg, 3 times a day) (Fig. 1). The
patient developed an intraoral fistula and cervical
lymphadenitis. Computed tomography was performed
in May 2006, which showed a large defect together
with destruction of the cortical bone of the left mandible (Fig. 2). The left submandibular lymph nodes were
enlarged, and the patient developed chronic pain in the
left mandible. We performed a continuity resection of
the mandible because medicamentous treatment was
not successful, and extensive cortical destruction was
observed. In May 2008, we performed resection involving the area from the left mandibular angle to region 33.
The inferior alveolar nerve was conserved and lateral-
Fig. 1. Persistent small wound healing disorder on the alveolar ridge of the lower left mandible (black arrow).
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ORIGINAL ARTICLE
Bittner et al. 43
Fig. 3. Cone-beam computed tomography with panorex reconstruction, after resection and reconstruction of the mandible by using a scapular transplant.
Fig. 5. Histopathological slide of an exudate containing neutrophils (black arrows) (hematoxylin and eosin, 100 magnification).
Following this radical surgical intervention, the patients pain declined and the integrity of the oral mucosa was maintained.
Prosthetic reconstruction of the left quadrant by using a removable partial denture has been planned for
this patient. The patient occasionally experiences pain
at alternating sites and visits the pain clinic 2 times a
week for treatment with intravenous infusions of procaine, paracetamol, metamizole, and ondansetron.
DISCUSSION
This report emphasizes the need for an interdisciplinary
treatment approach with regard to bisphosphonate therapy. Continuing medical education plays a crucial role
in state-of-the-art treatment for recently described or
rarely occurring adverse drug effects.
Complex regional pain syndrome (CRPS), also
known as Morbus Sudeck, Sudecks dystrophy, reflex
sympathetic dystrophy, or algodystrophy, belongs to
the group of neurotraumatic diseases. The disease is
usually triggered by external factors, such as trauma (ie,
dog bites or surgeries), and the patients develop dys-
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January 2012
Table III. Treatment recommendations for complex regional pain syndrome: recommended medication and dosage
for adults according to the guidelines of the German Society of Neurology (2008)9
Treatment
Bisphosphonates
Alendronate
Pamidronate
Clodronate
Steroids
Prednisolone
Methylprednisolone
Antineuropathics
Gabapentin
Evidence
Dose
Particularities
11
40 mg/d for 8 wk
60 mg IV once
300 mg/d IV for 10 d
100 mg/d
80 mg/d
11
Intrathecal baclofen
IV, intravenous; max., maximum; two arrows, highly proven evidence; 1 arrow, proven evidence; horizontal arrows, clinical evidence.
continuously risen, suggesting that BRONJ may become a serious problem in the case of patients undergoing bisphosphonate treatment.14,16,17
Patients who receive a high dose of intravenous
bisphosphonate medication over an extended period
have an especially high risk of developing BRONJ.18,19
Other possible risk factors and comorbidities that have
been reported in the literature are corticosteroid use,20,21
diabetes mellitus,22 clinically and radiographically apparent periodontitis,23 tooth extraction,23 and smoking.3 Furthermore, genetic alterations in the cytochrome P450-2C gene (CYP2C8) are reported to be
associated with an increased risk of BRONJ in patients
who have multiple myeloma and have been treated
using intravenous bisphosphonates.24 There are some
additional hypotheses regarding the pathogenesis of
BRONJ; bisphosphonates are localized in bone that is
undergoing inflammation and resorption, and they trigger apoptosis in the osteoclasts that internalize them.13
Antiangiogenic effects were reported in animal studies,
and these effects might contribute to the development
of osteonecrosis by limiting healing ability because of
reduced vascularization.25 Bisphosphonates may also
exert a toxic effect on soft tissue.26 Further studies are
required to determine the true pathogenesis of BRONJ
and possible genetic risk factors.4
We used the classification of the American Association of Oral and Maxillofacial Surgeons (AAOMS)27
to define BRONJ. Patients may be considered to have
BRONJ if the following characteristics are observed.
1. Current or previous treatment with a bisphosphonate
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ORIGINAL ARTICLE
Bittner et al. 45
Table IV. Staging of and treatment strategies for BRONJ according to AAOMS10
BRONJ Stage
At-risk category
Stage 0
Stage 1
Description
Treatment strategies
Stage 2
Stage 3
AAOMS, American Association of Oral and Maxillofacial Surgeons; BRONJ, bisphonate-related osteonecrosis of the jaw; IV,
intravenous.
In contrast to these general guidelines, AAOMS provides detailed classification and treatment guidelines
for BRONJ (Table IV).31
In severe cases, such as the case reported in this
study, jaw resection may be required,32 which emphasizes the seriousness of BRONJ. In the worst cases,
even a minor dental intervention may lead to the loss of
large parts of the jaw. This treatment is demanding for
the surgeon and the patient and tends to be expensive
for the health insurance providers and other benefactors. Therefore, an interdisciplinary treatment approach
is mandatory for patients who will receive or are receiving bisphosphonates. Rigid titanium plates or vascularized bone and soft tissue can be used for reconstruction, especially for that of the mandible.33 It has
not yet been determined whether reconstruction with
vascularized bone is superior to the use of a rigid
titanium plate. Bone healing at the resection site and the
risk of redeveloping BRONJ in a transplant has not yet
been adequately investigated.33 Therefore, an evidence-
CONCLUSIONS
General practitioners and specialized physicians should
closely monitor the dental status of their patients before
prescribing bisphosphonate medication. It is therefore
important that dentists, oral surgeons, and maxillofacial
surgeons obtain an accurate patient history. Currently,
however, improvements need to be made with respect
to these 2 issues, ie, the patients dental status should be
better monitored and more accurate patient history
should be obtained; in addition, it is important to be
aware of the latest developments with respect to
BRONJ. Sufficient interdisciplinary prevention and
treatment of BRONJ can be brought about only by
effecting these improvements. Although BRONJ is a
rare complication of bisphosphonate treatment, its sequelae can be frustrating and devastating for the patient.
Therefore, all patients should undergo the clinical
examination and radiological tests that have been recommended by professional societies (eg, DGZMK,
AAOMS), and chronically inflamed areas of the oral
mucosa or the jaw should be treated appropriately34
before initiating bisphosphonate therapy.
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Reprint requests:
Urs D.A. Mller-Richter, MD, DMD, PhD
Department of Oral and Maxillofacial Plastic Surgery
University Hospital Wrzburg
Pleicherwall 2
97070 Wrzburg, Germany
mueller_u2@klinik.uni-wuerzburg.de