Bisphosphonate-Related Osteonecrosis of the Jaw 

Updated: Mar 11, 2019
Author: Remy H Blanchaert, Jr, DDS, MD; Chief Editor: Arlen D Meyers, MD, MBA 

Overview

Background

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. See the image below.

Exposed, necrotic bone in the left anterior maxill Exposed, necrotic bone in the left anterior maxilla.

The 2014 update of a position paper from the American Association of Oral and Maxillofacial Surgeons recommended changing the name of bisphosphonate-related osteonecrosis of the jaw (BRONJ) to medication-related osteonecrosis of the jaw (MRONJ), owing to the increased number of maxillary and mandibular osteonecrosis cases that have been linked to other antiresorptive (denosumab) or antiangiogenic treatments.[1]

See Cancer Chemotherapy: Keys to Diagnosing Common Toxicities, a Critical Images slideshow, to help recognize some of the more common complications of chemotherapy.

History of the Procedure

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

Epidemiology

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.[2, 3] 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.[4, 5]

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.[6]

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.

A retrospective study by Choi et al indicated that previous dental extraction is the greatest risk factor for bisphosphonate-related osteonecrosis of the jaw. The study involved 133 patients with multiple myeloma who had undergone bisphosphonate therapy, with bisphosphonate-related osteonecrosis of the jaw found in nine of them. Among these patients, 6 had a history of extraction, with the investigators suggesting that extraction-related jaw damage is the “most potent trigger” for bisphosphonate-related osteonecrosis of the jaw.[7]

A study by Wehrhan et al indicated that there is significantly greater osteoclastic expression of NFATC1 and BCL6—a master upstream osteoclastic activator and an osteoclastic suppressor, respectively—in cases of bisphosphonate-related osteonecrosis of the jaw (BRONJ) than there is in controls or in patients with osteomyelitis of the jaw bone.[8]

A retrospective study by Miniello et al indicated that in patients suffering from osteonecrosis of the jaw due to radiotherapy of the head and neck, those who are undergoing bisphosphonate therapy tend to develop osteonecrosis earlier and to acquire it more often in the maxilla than do patients not being treated with bisphosphonates.[9]

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.[10, 11, 12] 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 Medscape Reference article Facial Bone Anatomy.

 

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.[13] 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.[14, 15]

A retrospective study by Wasserzug et al indicated that bisphosphonate-related osteonecrosis of the jaw affects the maxillary sinus. The investigators found that among 50 patients in whom bisphosphonate-related osteonecrosis involved the maxilla, CT scan studies in 36 of them (72%) revealed evidence of maxillary sinus opacification (with such opacification reportedly being found incidentally in just 19% of the general population).[16]

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

A staging system has been proposed by the American Association of Oral and Maxillofacial Surgeons (AAOMS).

Stage I is as follows:

  • Exposed, necrotic bone

  • Asymptomatic patient

  • No infection

Stage II is as follows:

  • Exposed, necrotic bone

  • Symptomatic patient (ie, patient experiencing pain)

  • Infection

Stage III is as follows:

  • Exposed, necrotic bone

  • Symptomatic patient (ie, patient experiencing pain)

  • Infection

  • One of the following: Pathologic fracture, 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.[3] The suggested treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is determined by the patient’s classification according to the stages described below.

Stage I is as follows:

  • Antimicrobial rinses (ie, chlorhexidine 0.12%)

  • No surgical intervention

Stage II is as follows:

  • Antimicrobial rinses (ie, chlorhexidine 0.12%)

  • Systemic antibiotics or antifungals (infections may exacerbate BRONJ)

  • Analgesics

Stage III is as follows:

  • 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.

A study by Hinson et al indicated that stopping bisphosphonate therapy before or at the start of treatment for bisphosphonate-related osteonecrosis of the jaw (BRONJ) permits faster resolution of maxillofacial symptoms than does discontinuing bisphosphonate use during or continuing it throughout osteonecrosis management. The study, of 84 patients, found that the median time to resolution of osteonecrosis symptoms in patients who halted bisphosphonate therapy before or at the initiation of treatment was 3 and 6 months, respectively, compared with 12 months for patients who remained on bisphosphonate during jaw treatment.[17]

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.