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Vol. 113 No.

1 January 2012

Hemimandibulectomy after bisphosphonate treatment for complex


regional pain syndrome: A case report and review on the
prevention and treatment of bisphosphonate-related osteonecrosis
of the jaw
Thomas Bittner, MD, DMD, Natascha Lorbeer, DMD, Tobias Reuther, MD, DMD, PhD,
Hartmut Bhm, MD, DMD, Alexander C. Kbler, Prof MD, DMD, PhD, and
Urs D.A. Mller-Richter, MD, DMD, PhD, FEBOMFS, Wrzburg, Germany
RZBURG
UNIVERSITY HOSPITAL WU

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)

Bisphosphonates have become increasingly important


in dental medicine in recent years. The possible negative impact on the oral system and related dental practitioner knowledge of the action of bisphosphonates is
imbalanced because these drugs are mainly prescribed
by gynecologists, oncologists, urologists, and other
specialists. Therefore, educating dentists and physicians who treat maxillofacial diseases about bisphosphonate-associated side effects, especially bisphosphonate-related osteonecrosis of the jaw (BRONJ), is
important.
The correlation between the therapeutic use of bisphosphonates and osteonecrosis of the jaw, which was
first described in 2003,1 has now become a significant
issue. The probability of developing osteonecrosis after
intravenous administration of bisphosphonates is reported to be 5.48% within a 6-year period.2-4
Bisphosphonates were originally prescribed for the
treatment of bone metastases from malignant tumors
or to prevent severe osteoporosis. However, the indications for bisphosphonate treatment have recently

Department of Oral and Maxillofacial Plastic Surgery, University


Hospital Wrzburg, Wrzburg, Germany.
Received for publication Nov 22, 2010; returned for revision Dec 20,
2010; accepted for publication Jan 8, 2011.
2012 Elsevier Inc. All rights reserved.
2212-4403/$ - see front matter
doi:10.1016/j.tripleo.2011.01.017

been extended to include a wide spectrum of diseases


(Table I).5
The increasing use of bisphosphonates is of considerable importance in dental treatment, and the use of
these drugs requires a detailed medical history to identify patients at risk for BRONJ. We present a remarkable case that emphasizes both the relevance of this
topic and the need for awareness regarding the current
indications for bisphosphonate treatment.

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

ORAL AND MAXILLOFACIAL SURGERY


Bittner et al.

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42

Table I. Spectrum of indications for bisphosphonate


treatment

Table II. Drugs administered to the patient for chronic


pain and psychiatric disorder

Indications for Bisphosphonate Treatment

Drug

Dosage

Giant cell tumors of the jaw (previous therapy: intralesional steroid


injection, subcutaneous or nasal application of calcitonin)38,40
Osteogenesis imperfecta (increased survival of osteoblasts)37
Chronic osteomyelitis: chronic, recurrent, multifocal, and diffuse
sclerosing osteomyelitis39,42
Fibrous dysplasia35
Orthopedic implants (to reduce bone loss after uncemented total
hip and knee arthroplasty)36
Hypercalcemia caused by malignant diseases or bone metastases
Osteoporosis
Morbus Paget
Chronic pain41

Topiramate (150 mg)


Diazepam 10 mg/mL
Doxepin HCl 40 mg/mL (Saturday/Sunday)
Ondansetron (4 mg)
Clonidine (250 mg)
Opipramol (50 mg)
Olanzapine (5 mg)
Desloratadine (5 mg)
Bisoprolol (5 mg)
Thiamine nitrate/pyridoxine (25 mg each)
Desogestrel (75 g)
Mirtazapine (45 mg)
Pantoprazole (40 mg)

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).

Fig. 2. Computed tomography scan (axial reconstructions of


the lower mandible) shows distinct structural alterations of
the bone and disintegration of the lingual cortical bone. The
osseous defect appears to extend to the area of tooth 34.

ized. The resection was immediately reconstructed with


a free scapular transplant from the left shoulder (Fig. 3).
Histopathological examination of the resected mandibular specimen revealed chronic osteomyelitis together
with moderate bacterial colonization (Figs. 4 and 5).

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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).

Fig. 4. Histopathological slide shows inflammatory infiltrate


in the cortical bone (black arrows) (hematoxylin and eosin,
40 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-

trophy and atrophy of the extremities over time.


Patients with this disorder often develop circulatory disorders, edema, skin alterations, and eventually, persistent
pain. It is proposed that changes in impulse activity caused
by inflammation in small afferent and postganglionic axons contribute to CRPS.6 The pathogenesis of this disease
has not been completely elucidated but seems to involve a
disordered healing process.7 Similar cases where pain
syndrome developed after animal bites have been described in the literature.8 The treatment of CRPS can be
long and frustrating for the patient and physician.9 A
multimodal treatment regimen is recommended by several
societies (eg, Guidelines of the German Society of Neurology 2008; Table III).9
Bisphosphonates have been successfully used for
more than 20 years to treat rapidly progressive diseases
like multiple myeloma, bone metastasis from solid tumors, osteoporosis and other bone metabolic diseases,
and chronic pain syndrome.10,11 The molecular structure of bisphosphonates is similar to that of pyrophosphates, except that bisphosphonates have a phosphoruscarbon-phosphorus bond in the center of their structure;
this bond is resistant to enzymatic cleavage.12 Bisphosphonates work by inhibiting osteoclastic function and
osteoclastic stimulation or by decreasing the life of
osteoclasts13; they bind covalently to the hydroxylapatite of bones. Their half-life can vary from a few
months to several years depending on the specific drug
used, and they can be administered orally or intravenously.
Several studies published in 2003 reported jaw necrosis in patients who underwent bisphosphonate treatment for the first time.1,14,15 Most of these patients had
preexisting oncological diseases and usually developed
necrosis because of dental or surgical intervention.
Since 2003, the number of case reports on BRONJ has

ORAL AND MAXILLOFACIAL SURGERY


44 Bittner et al.

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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

Should be taken in the morning


Should be taken while standing upright
Should be taken on an empty stomach

100 mg/d
80 mg/d

Treatment should be tapered off within 2-3 wk


No long-term therapy

1200-2400 (3600 max.) mg/d

See guidelines for neuropathic pain in the


same publication
Skin alterations observed garlic odor
Do not exercise beyond acceptance limit, selfcontained therapy obligatory
Used if comorbidity is indicated Used if
condition is refractory to treatment
Only after positive tests
Used only if pain is refractory to treatment
and there is no psychological comorbidity
Used (1) if there is dystonia; (2) implantation
of a pump (after test injection); or (3) if
there is no relevant psychologic comorbidity

11

Topical dimethyl sulfoxide (DMSO)


Physical therapy, occupational therapy,
behavior therapy, motor learning
Psychotherapy and Relaxation techniques

Block of sympathetic trunks


Spinal cord stimulation

Intrathecal baclofen

50% ointment, 5 times per day


Preferably daily

2-3/ wk maximum number: 10-15

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

2. Exposure of bone in the maxillofacial region for


more than 8 weeks
3. No history of radiation therapy to the jaw
The combination of soft and hard tissue injuries that
may occur during oral surgery and bisphosphonate use
should be considered a significant risk factor for developing BRONJ. BRONJ is clinically and radiologically
similar to osteoradionecrosis; in both cases, the main
symptom is long-term exposure of bones, often without
pain, without any tendency for secondary soft tissue
closure.28 Radiological evidence of a persistent socket
after tooth extraction is suggestive in bisphosphonatetreated patients, although the radiograph might not
show any noticeable pathologic findings. The exposed
bone is often colonized by bacteria and fungi (ie, Actinomyces species, primarily Actinomyces israelii, and
Candida albicans).4,29
Current recommendations for prevention, especially for
high-risk patients (ie, patients with preexisting malignant
disease or those for whom long-term intravenous highdose bisphosphonate therapy has been planned), include
eliminating potential sources of dental infections before
starting bisphosphonate therapy, and periodic checkups
during the course of bisphosphonate treatment.
The current guidelines of the German Society of
Dental and Oral Medicine (Deutsche Gesellschaft fr
Zahn-, Mund-und Kieferheilkunde [DGZMK])30 are
summarized as follows:

Patients undergoing bisphosphonate treatment should


consult their dentist every 6 months.

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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

No apparent necrotic bone in patients who have been


treated with oral IV bisphosphonates
No clinical evidence of necrotic bone but nonspecific
clinical findings and symptoms obtained
Exposed and necrotic bone in asymptomatic patients,
without evidence of infection

No treatment indicated patient education (oral hygiene)

Stage 2

Exposed necrotic bone associated with infectionas


evidenced by pain and erythema in the region of
the exposed bone, with or without purulent drainage

Stage 3

Exposed necrotic bone in patients with pain, infection,


and one or more of the following: exposed necrotic
bone extending beyond the region of the alveolar
bone (ie, inferior border and ramus in the mandible;
maxillary sinus and zygoma in the maxilla),
resulting in pathologic fracture
Extraoral fistula and oral/antral nasal communication
observed
Osteolysis extending to the inferior border of the
mandible or the sinus floor

Systemic management, including the use of pain


medication and antibiotics
Antibacterial mouth rinse
Clinical follow-up every 3 mo
Patient education and review of indications for
continued bisphosphonate therapy
Symptomatic treatment with oral antibiotics
Oral antibacterial mouth rinse
Pain control Superficial debridement to relieve soft
tissue irritation
Antibacterial mouth rinse
Antibiotic therapy and pain control
Surgical debridement/resection for longer-term
palliation of infection and pain

AAOMS, American Association of Oral and Maxillofacial Surgeons; BRONJ, bisphonate-related osteonecrosis of the jaw; IV,
intravenous.

Patients should be instructed to consult their dentist


earlier than 6 months in case of problems, particularly pressure sores caused by dentures or progressive loosening of teeth.
Conservative treatment should be preferred to surgical
interventions, especially when treating periodontitis.
Inevitable surgical treatment should not be delayed
and should be performed under the same conditions
used for high-risk patients who received radiation to
the head and neck area.
Long-term recall of at least 3 months is recommended, especially before retreatment with bisphosphonates. In addition, the patients should receive
detailed instructions and symptom sensitization, so
that corresponding symptoms of BRONJ can be recognized and treated promptly.

The conservative clinical approach for infection


treatment includes intensive oral hygiene, which is
individually adapted to the patients needs, dental
cleaning, and timely endodontic therapy for nonvital
teeth.
If surgical intervention is required, it should be performed by a skilled oral or maxillofacial surgeon, or a
dentist who is familiar with the disease, with the following precautions30:

An atraumatic surgical technique should be used.


Systemic application of antibiotics should be initiated the day before surgical intervention. Antibiotic
therapy should be continued until completion of pri-

mary wound healing, at least until removal of stitches


on the 10th postoperative day.
No intended secondary wound healing in dentoalveolar surgery (eg, tooth extractions), but closure of the
wounds with periosteum and oral mucosa (multilayer).
Where required, epiperiosteal flaps should be used
for plastic closure of the wound to avoid the further
constraint of periosteal nutrition.

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-

ORAL AND MAXILLOFACIAL SURGERY


46 Bittner et al.

based recommendation cannot be made on the basis of


the currently available knowledge on the etiopathogenesis of BRONJ.

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