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eMedicine Specialties > Otolaryngology and Facial Plastic Surgery > Palatal & Maxillofacial Surgery

Remy H Blanchaert, Jr, DDS, MD, Consulting Staff, Wesley Medical Center
Christopher M Harris, DMD, MD, Residency Program Director, Department of Oral and Maxillofacial-Head and Neck Surgery, Naval Medical Center at
Portsmouth
Updated: May 5, 2009

Introduction
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a condition found in patients who have received intravenous and oral
forms of bisphosphonate therapy for various bone-related conditions. Bisphosphonate-related osteonecrosis of the jaw (BRONJ)
manifests as exposed, nonvital bone involving the maxillofacial structures. Bisphosphonate-related osteonecrosis of the jaw (BRONJ)
is thought to be caused by trauma to dentoalveolar structures that have a limited capacity for bone healing due to the effects of
bisphosphonate therapy.

Exposed, necrotic bone in the left anterior maxilla.

History of the Procedure

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is relatively new to the medical and dental literature. See Surgical therapy.

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Frequency
The true incidence of bisphosphonate-related osteonecrosis of the jaw (BRONJ) has yet to be determined. The estimated incidence,
according to a package insert in a special mailing by Merck Pharmaceuticals, is 0.7 per 100,000 persons per year.1,2 Most reports and
experts disagree with this figure. Several recent studies of patients with multiple myeloma and patients with breast cancer who received
intravenous aminobisphosphonate therapy for metastatic bone lesions demonstrated 6-11% of the patients developed
bisphosphonate-related osteonecrosis of the jaw (BRONJ). The incidence of bisphosphonate-related osteonecrosis of the jaw
(BRONJ) has been strongly correlated with the aminobisphosphonates pamidronate (Aredia) and zoledronic acid (Zometa) and is even
higher in patients who have had recent dental extractions.3,4

Kahn et al evaluated the association of osteonecrosis of the jaw with bisphosphonate use. Data that links the incidence of
osteonecrosis of the jaw and its etiologic factors are limited, and the incidence of osteonecrosis of the jaw in the general population (ie,
those not taking bisphosphonates) is unknown. Evidence is insufficient to confirm a causal link between low-dose bisphosphonate use
in osteoporosis with osteonecrosis of the jaw. Osteonecrosis of the jaw is primarily associated with high-dose bisphosphonate use in
cancer patients.5

Etiology
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a condition in which bones of the maxillofacial skeleton, in particular the
tooth-bearing areas, become necrotic and exposed to the oral cavity. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) can
be spontaneous, commonly appearing in the mylohyoid ridge area. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) may
also be caused by trauma, such as a tooth extraction or dental surgery. Exposed alveolar bone, which may be painful, is noted on
examination.

Pathophysiology
Bisphosphonates are believed to bind to osteoclasts and interfere with bone remodeling. They interfere with the cholesterol
biosynthesis pathway by inhibition of farnesyl diphosphate synthase. In time, the cytoskeleton of the osteoclast becomes dysfunctional
and the ruffled border needed for bone resorption is unable to form. Aminobisphosphonates have also been shown to have
antiangiogenic properties. The overall effect is a decrease in bone turnover and inhibition of the bone’s reparative ability.6,7 Injury to the
bone in these patients via tooth extraction, dental surgery, or mechanical trauma is thought to initiate bisphosphonate-related
osteonecrosis of the jaw (BRONJ).

Presentation
Symptoms may include the following:

Pain

Swelling

Cellulitis

Halitosis

Trismus

Physical findings may include the following:

Mandibular and or maxillary bone exposure

Pathologic fracture

Oral-cutaneous fistula

Clinical infection

Indications
Gross examination reveals a varied amount of exposed, nonvital bone of the maxilla, mandible, or both.

Relevant Anatomy
Please see the eMedicine article Facial Bone Anatomy.

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Workup

Laboratory Studies
Rule out a primary malignancy, benign bone lesion, osteomyelitis, or metastatic lesion by biopsy when indicated.

A recent study suggests an increase in serum C-terminal telopeptide (CTX) after a “drug holiday” from oral bisphosphonates may help
guide surgical treatment.8 These data have not been corroborated and have not been shown to be reliable. The value of this test is
uncertain.

Imaging Studies
In patients with bisphosphonate-related osteonecrosis of the jaw (BRONJ), panoramic and plain radiography of the mandible reveal
areas of sclerosis, destruction, sequestration, or pathologic fractures. Delayed or persistent tooth sockets after extraction may also be
revealed in these patients.

A recent study evaluating the computed tomography (CT) and magnetic resonance imaging (MRI) features of bisphosphonate-related
osteonecrosis of the jaw (BRONJ) demonstrated characteristic findings with these studies. The CT scans revealed increased
medullary density, periosteal reaction, and bone sequestration. MRI revealed a low signal in T1 and T2 images with exposed
bone. This is likely due to a decrease in water content. Unexposed, diseased bone showed hypointensity in T1 images and
hyperintensity in T2 images. These findings suggest an increase in water content.9

Diagnostic Procedures
The following diagnostic procedures may be beneficial in the diagnosis of bisphosphonate-related osteonecrosis of the jaw (BRONJ):

Panoramic or plain-film imaging

CT scanning

MRI

Area biopsy (if indicated)

Histologic Findings
Histologically, nonvital bone that is devoid of osteoblasts and osteoclasts are noted. Fungal contamination of exposed bone has been
noted. In affected but unexposed bone, inflammatory infiltrates, fibrous tissue, and a combination of lamellar and woven bone is
noted. Viable osteocytes are seen within this bone.

Staging
The following staging system has been proposed by the American Association of Oral and Maxillofacial Surgeons (AAOMS):

Stage I
Exposed, necrotic bone
Asymptomatic patient
No infection

Stage II
Exposed, necrotic bone
Symptomatic patient (ie, patient experiencing pain)
Infection

Stage III
Exposed, necrotic bone
Symptomatic patient (ie, patient experiencing pain)
Infection
One of the following:
Pathologic fracture

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Oral cutaneous fistula

Osteolysis extending to the inferior border of the mandible

Treatment

Medical Therapy
Nonsurgical management of bisphosphonate-related osteonecrosis of the jaw (BRONJ) may consist of the following:

Antimicrobial rinses

Systemic antibiotics

Systemic or topical antifungals

Discontinuation of bisphosphonate therapy

No dental therapy or minimally invasive dental therapy (ie, root canal therapy instead of extraction)

Surgical Therapy
Surgical intervention for bisphosphonate-related osteonecrosis of the jaw (BRONJ) remains limited because of the impaired ability of
the bone to heal. Because no long-term or controlled studies on the management of bisphosphonate-related osteonecrosis of the jaw
(BRONJ) have been published, the article from AAOMS, which is based on the consensus of a panel discussion, is the best available
guide to therapy.2 The suggested treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is determined by the
patient’s classification according to the following stages:

Stage I
Antimicrobial rinses (ie, chlorhexidine 0.12%)
No surgical intervention

Stage II
Antimicrobial rinses (ie, chlorhexidine 0.12%)
Systemic antibiotics or antifungals (infections may exacerbate BRONJ)
Analgesics

Stage III
Antimicrobial rinses (ie, chlorhexidine 0.12%)
Systemic antibiotics or antifungals (infections may exacerbate BRONJ)
Analgesics
Surgical debridement or resection

Outcome and Prognosis

Long-term data are not available concerning the appropriate management of bisphosphonate-related osteonecrosis of the jaw
(BRONJ). Traditional reconstructive efforts are generally not recommended by most experts. The role of adjunctive procedures (ie,
hyperbaric oxygen [HBO]) and vascularized tissue transfers in the reconstructive management of bisphosphonate-related
osteonecrosis of the jaw (BRONJ) have yet to be elucidated.

Future and Controversies

The wide use of oral bisphosphonates and their role in bisphosphonate-related osteonecrosis of the jaw (BRONJ) have yet to be
completely determined. Long-term studies identifying the patients who are at risk for this disease process are still pending.

Multimedia

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Media file 1: Exposed, necrotic bone in the left anterior maxilla.

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Media file 2: Extensive stage III bisphosphonate-related osteonecrosis of the jaw (BRONJ) of the mandible in
a patient treated with intravenous bisphosphonate therapy.

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Media file 3: Stage I bisphosphate-related osteonecrosis of the jaw (BRONJ) of the right mylohyoid ridge area.

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Media file 4: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) of the right mandible. Note the
moth-eaten appearance of the right mandibular angle area and unhealed extraction socket.

References

1. American Dental Association. Report of the Council of Scientific Affairs. Expert panel recommendations: Dental management
of patients on oral bisphosphonate therapy. American Dental Association. June 2006;[Full Text].

2. AAOMS. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of
the jaws. J Oral Maxillofac Surg. Mar 2007;65(3):369-76. [Medline].

3. Bamias A, Kastritis E, Bamia C, et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and
risk factors. J Clin Oncol. Dec 1 2005;23(34):8580-7. [Medline].

4. Mavrokokki T, Cheng A, Stein B, et al. Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in
Australia. J Oral Maxillofac Surg. Mar 2007;65(3):415-23. [Medline].

5. [Best Evidence] Khan AA, Sandor GK, Dore E, Morrison AD, Alsahli M, Amin F, et al. Bisphosphonate associated
osteonecrosis of the jaw. J Rheumatol. Mar 2009;36(3):478-90. [Medline].

6. Fisher JE, Rogers MJ, Halasy JM, et al. Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate
pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci U S
A. Jan 5 1999;96(1):133-8. [Medline].

7. Rodan GA, Reszka AA. Bisphosphonate mechanism of action. Curr Mol Med. Sep 2002;2(6):571-7. [Medline].

8. Marx RE, Cillo JE Jr, Ulloa JJ. Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX
testing, prevention, and treatment. J Oral Maxillofac Surg. Dec 2007;65(12):2397-410. [Medline].

9. Bedogni A, Blandamura S, Lokmic Z, et al. Bisphosphonate-associated jawbone osteonecrosis: a correlation between imaging
techniques and histopathology. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. Mar 2008;105(3):358-64. [Medline].

Keywords

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Bisphosphonate-Related Osteonecrosis of the Jaw: [Print] - eMedicine ... http://emedicine.medscape.com/article/1447355-print

bisphosphonate, osteonecrosis, jaw, osteonecrosis of the jaw, bisphosphonate-related osteonecrosis of the jaw, BRONJ, jaw
osteonecrosis, osteonecrotic jaw, amino-bisphosphonate therapy, osteonecrosis, bisphosphonate therapy, bone conditions,
bone-related conditions, aminobisphosphonate therapy, bone necrosis, mandibular necrosis, dental surgery, exposed maxilla bone,
zoledronic, bisphosphonates, zoledronic acid, Aredia, pamidronate, bone density, aminobisphosphonates, Zometa

Contributor Information and Disclosures

Author

Remy H Blanchaert, Jr, DDS, MD, Consulting Staff, Wesley Medical Center
Remy H Blanchaert, Jr, DDS, MD is a member of the following medical societies: American Association of Oral and Maxillofacial
Surgeons, American Dental Association, and American Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Christopher M Harris, DMD, MD, Residency Program Director, Department of Oral and Maxillofacial-Head and Neck Surgery, Naval
Medical Center at Portsmouth
Christopher M Harris, DMD, MD is a member of the following medical societies: American Association of Oral and Maxillofacial
Surgeons and American Dental Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine

Disclosure: Nothing to disclose.

Managing Editor

Robert M Kellman, MD, Professor and Chair, Department of Otolaryngology and Communication Sciences, State University of New
York, Upstate Medical University
Robert M Kellman, MD is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive
Surgery, American Academy of Otolaryngology-Head and Neck Surgery, American College of Surgeons, American Medical
Association, American Neurotology Society, American Rhinologic Society, American Society for Head and Neck Surgery, Medical
Society of the State of New York, and Triological Society
Disclosure: GE Healthcare Honoraria Review panel membership

CME Editor

Christopher L Slack, MD, Otolaryngology-Facial Plastic Surgery, Private Practice, Associated Coastal ENT; Medical Director,
Treasure Coast Sleep Disorders
Christopher L Slack, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Facial Plastic and
Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Arlen D Meyers, MD, MBA, Professor, Department of Otolaryngology-Head and Neck Surgery, University of Colorado School of
Medicine
Arlen D Meyers, MD, MBA is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive
Surgery, American Academy of Otolaryngology-Head and Neck Surgery, and American Head and Neck Society
Disclosure: Covidien Corp Consulting fee Consulting; US Tobacco Corporation unstricted gift unknown

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