Practice Essentials

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 maxilla.

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The 2014 update of a position paper from the American Association of Oral and Maxillofacial Surgeons (AAOMS) 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]

The AAOMS’s 2022 update to its position paper on medication-related osteonecrosis of the jaw (MRONJ) lists medication families that have been implicated as risk factors for the condition since the 2014 update. These include the following^[2]:

Tyrosine kinase inhibitors (TKIs) - For instance, sunitinib
Monoclonal antibodies - Bevacizumab
Fusion proteins - Aflibercept
mTOR (mammalian target of rapamycin) inhibitors - Everolimus
Radiopharmaceuticals - Radium 223
Selective estrogen receptor modulators - Raloxifene
Immunosuppressants - Methotrexate and corticosteroids

The paper also states, however, that while there are strong data supporting antiresorptive drugs as risk factors for MRONJ, there is less evidence for other medications, such as antiangiogenics, corticosteroids, and immune modulators.^[2]

Workup in bisphosphonate-related osteonecrosis of the jaw

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

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.

Computed tomography (CT) scanning and magnetic resonance imaging (MRI) may also be beneficial in the assessment of bisphosphonate-related osteonecrosis of the jaw (BRONJ).

Management of bisphosphonate-related osteonecrosis of the jaw

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 intervention for bisphosphonate-related osteonecrosis of the jaw (BRONJ) remains limited because of the impaired ability of the bone to heal. Surgical débridement or resection is used in patients with the stage III form of the condition, as defined by the American Association of Oral and Maxillofacial Surgeons (AAOMS).

History of the Procedure

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

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.^{[3, 4]}Most reports and experts disagree with this figure. Several 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.^{[5, 6]}

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.^[7]

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.^[8]

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.^[9]

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.^[10]

A case-control study by Van Poznak et al indicated that in patients with metastatic cancer who have been treated with bisphosphonates, a lower incidence of osteonecrosis of the jaw occurs in those who have received pamidronate than in patients who have been treated with zoledronic acid (odds ratio [OR] = 0.18). In addition, exposure to the cancer drug bevacizumab was found more often in study patients with jaw osteonecrosis (OR = 5.15). The investigators also reported that genetically, VEGFC rs2333496 may have a protective effect against osteonecrosis of the jaw, while VEGFC rs7664413 and PPARG rs1152003 may increase the risk.^[11]

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.^{[12, 13, 14]}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

[Guideline] AAOMS. Position Paper: Medication-Related Osteonecrosis of the Jaw—2014 Update. American Association of Oral and Maxillofacial Surgeons. Available at https://www.aaoms.org/docs/position_papers/mronj_position_paper.pdf?pdf=MRONJ-Position-Paper. Accessed: Feb 26 2015.
[Guideline] Ruggiero SL, Dodson TB, Aghaloo T, Carlson ER, Ward BB, Kademani D. American Association of Oral and Maxillofacial Surgeons' Position Paper on Medication-Related Osteonecrosis of the Jaws-2022 Update. J Oral Maxillofac Surg. 2022 May. 80 (5):920-43. [QxMD MEDLINE Link]. [Full Text].
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].
[Guideline] AAOMS. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg. 2007 Mar. 65(3):369-76. [QxMD MEDLINE Link].
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. 2005 Dec 1. 23(34):8580-7. [QxMD MEDLINE Link].
Mavrokokki T, Cheng A, Stein B, et al. Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg. 2007 Mar. 65(3):415-23. [QxMD MEDLINE Link].
Khan AA, Sandor GK, Dore E, Morrison AD, Alsahli M, Amin F, et al. Bisphosphonate associated osteonecrosis of the jaw. J Rheumatol. 2009 Mar. 36(3):478-90. [QxMD MEDLINE Link].
Choi WS, Lee JI, Yoon HJ, Min CK, Lee SH. Medication-related osteonecrosis of the jaw: a preliminary retrospective study of 130 patients with multiple myeloma. Maxillofac Plast Reconstr Surg. 2017 Jan 5. 39 (1):1. [QxMD MEDLINE Link]. [Full Text].
Wehrhan F, Gross C, Creutzburg K, et al. Osteoclastic expression of higher-level regulators NFATc1 and BCL6 in medication-related osteonecrosis of the jaw secondary to bisphosphonate therapy: a comparison with osteoradionecrosis and osteomyelitis. J Transl Med. 2019 Mar 4. 17 (1):69. [QxMD MEDLINE Link]. [Full Text].
Miniello TG, Araujo JP, Silva MLG, et al. Influence of Bisphosphonates on Clinical Features of Osteoradionecrosis of the Maxilla and Mandible. Oral Dis. 2019 Mar 1. [QxMD MEDLINE Link].
Van Poznak C, Reynolds EL, Estilo CL, et al. Osteonecrosis of the jaw risk factors in bisphosphonate-treated patients with metastatic cancer. Oral Dis. 2020 Dec 4. [QxMD MEDLINE Link].
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. 1999 Jan 5. 96(1):133-8. [QxMD MEDLINE Link].
Rodan GA, Reszka AA. Bisphosphonate mechanism of action. Curr Mol Med. 2002 Sep. 2(6):571-7. [QxMD MEDLINE Link].
Ohbayashi Y, Nakai F, Iwasaki A, et al. Symposium: Imaging modalities for drug-related osteonecrosis of the jaw (6), assessment of mandibular metabolism due to long-term administration of an anti-resorptive agent by bone scintigraphy (secondary publication). Jpn Dent Sci Rev. 2019 Nov. 55 (1):51-7. [QxMD MEDLINE Link]. [Full Text].
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. 2007 Dec. 65(12):2397-410. [QxMD MEDLINE Link].
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. 2008 Mar. 105(3):358-64. [QxMD MEDLINE Link].
Baba A, Ojiri H, Goto TK, et al. Symposium: Imaging modalities for drug-related osteonecrosis of the jaw (4), CT and MR imaging findings of antiresorptive agent-related osteonecrosis of the jaws/medication-related osteonecrosis of the jaw (secondary publication). Jpn Dent Sci Rev. 2019 Nov. 55 (1):58-64. [QxMD MEDLINE Link]. [Full Text].
Wasserzug O, Kaffe I, Lazarovici TS, et al. Involvement of the maxillary sinus in bisphosphonate-related osteonecrosis of the jaw: Radiologic aspects. Am J Rhinol Allergy. 2017 Jan 1. 31 (1):36-9. [QxMD MEDLINE Link].
Hinson AM, Siegel ER, Stack BC Jr. Temporal correlation between bisphosphonate termination and symptom resolution in osteonecrosis of the jaw: a pooled case report analysis. J Oral Maxillofac Surg. 2015 Jan. 73(1):53-62. [QxMD MEDLINE Link].

Media Gallery

Exposed, necrotic bone in the left anterior maxilla.
Extensive stage III bisphosphonate-related osteonecrosis of the jaw (BRONJ) of the mandible in a patient treated with intravenous bisphosphonate therapy.
Stage I bisphosphate-related osteonecrosis of the jaw (BRONJ) of the right mylohyoid ridge area.
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.