Bisphosphonate-Related Osteonecrosis of the Jaw

• Christine Eisenhower, Pharm.D.

 Basic Information

Definition

The American Society for Bone and Mineral Research (ASBMR) defines bisphosphonate-related osteonecrosis of the jaw (BRONJ) as an exposure of bone in the maxillofacial region that does not heal within 8 weeks. This applies to patients receiving therapeutic doses of bisphosphonates (BPs) who have not undergone radiation therapy to the craniofacial region. Osteoclast apoptosis may occur due to the antiresorptive effects of BPs, preventing the release of bone-regenerative proteins and thus preventing bone renewal and remodeling. This results in tissue loss and exposed bone. BRONJ primarily involves the jawbone due to its higher risk for complications from minor injury and infection when the healing potential or vascular supply is compromised.

Cases of osteonecrosis of the jaw (ONJ) have also been reported in patients with malignancy treated with high doses of denosumab as well as chemotherapeutic and immunosuppressive agents, such as bevacizumab, sirolimus, sorafenib, and sunitinib. The American Association of Oral and Maxillofacial Surgeons (AAOMS) therefore now uses the term “medication-related osteonecrosis of the jaw” (MRONJ). This term is controversial, as patients with MRONJ may have a history of initial treatment with BPs.

Synonym

1. Bisphosphonate-induced osteonecrosis of the jaw

2. BIONJ

3. Bisphosphonate-associated osteonecrosis of the jaw

4. BAONJ

5. Medication-related osteonecrosis of the jaw

6. MRONJ

7. Antiresorptive agent-related osteonecrosis of the jaw (ARONJ)

ICD-10CM CODE
M87.180	Osteonecrosis due to drugs, jaw

Epidemiology & Demographics

Incidence

1. •

   A 2015 systematic review and consensus of 14 national and international societies describe the incidence of BRONJ in patients receiving oral BPs for the treatment of osteoporosis as 1.04 to 69 per 100,000 patient-years. The incidence of BRONJ in patients receiving IV BPs ranged from 0 to 90 per 100,000 patient-years.

2. •

   Several studies compare the incidence of ONJ in patients with malignancy who are receiving denosumab to those receiving BPs; however, many studies include patients who were previously treated with BPs.

3. •

   BRONJ has been estimated at 3.9% with oral BPs and at 14.8% with IV BPs at 42 months after tooth extraction.

Peak Incidence

1. •

   ONJ has been identified as early as 7 months after the use of IV BPs in patients with cancer and as early as 13 months in patients with osteoporosis. Incidence may depend on when dentoalveolar surgery occurs during BP treatment.

2. •

   A 2017 retrospective secondary analysis of 349 patients made the following estimates of median time to onset for 50% of patients to develop ONJ: (1) 6 years for those treated with oral alendronate, (2) 2.2 years for those treated with IV zoledronate, (3) 5.3 years for patients with osteoporosis, and (4) 2.2 years for those with cancer.

3. •

   A 2016 case series of 13 patients with metastatic bone tumors receiving denosumab and with no history of BP treatment reported that ONJ occurred after 5 to 36 doses with denosumab 120 mg every 4 to 6 weeks.

Prevalence

1. •

   Prevalence in 2008 estimated at 13.3% of patients with cancer who received an IV BP.

2. •

   Most prevalent in patients with multiple myeloma or breast cancer versus other cancers or osteoporosis.

Predominant Sex and Age

1. •

   Sex not statistically associated with BRONJ.

2. •

   Age as a risk factor for adults is variably reported in the literature.

Genetics

1. •

   Single nucleotide polymorphisms (SNPs) have been identified in the CYP2C8 gene among patients with multiple myeloma and exposure to IV BPs.

2. •

   Polymorphisms in the RBMS3 gene in white patients have been associated with a nearly 6-fold increase in the risk of developing BRONJ.

3. •

   A 2014 study of patients in Taiwan who received alendronate estimated an incidence rate of 283 per 100,000 persons per year, suggesting a higher incidence in this ethnic group.

Risk Factors

1. •

   Patients with cancer who are exposed to IV BPs and undergo dentoalveolar surgery have an estimated 5- to 21-fold increased risk for BRONJ compared with similar patients who do not undergo this surgery.

2. •

   The 2014 AAOMS position paper estimates that the risk of ONJ is about 100 times greater for patients with cancer who receive antiresorptive agents versus patients with osteoporosis.

3. •

   With IV formulations such as zoledronic acid, the risk ratio for developing BRONJ is 14.6 with IV versus oral products.

4. •

   Longer duration of antiresorptive therapy.

5. •

   Malignancy.

6. •

   Concomitant chemotherapeutic agents and corticosteroids.

7. •

   History of periodontal and dental abscesses.

8. •

   Bacterial infection.

9. •

   Chronic inflammation.

10. •

    Poor oral hygiene.

11. •

    Concomitant diabetes type 2.

12. •

    Ill-fitting dentures, resulting in mechanical injury.

13. •

    Renal impairment and advanced age may be associated with increased ONJ severity.

Physical Findings & Clinical Presentation

1. •

   Exposed areas of necrotic bone in the maxilla or mandible, with 65% of cases involving the mandible. Multifocal or bilateral involvement may be present. Pathologic fracture of the jaw may occur.

2. •

   Pain in the maxillofacial region, although one third of lesions may be painless.

3. •

   Paresthesia of the chin is an early sign.

4. •

   Tooth mobility or spontaneous tooth loss.

5. •

   Mucosal swelling, erythema, ulceration, altered sensation.

6. •

   Infection.

Etiology

1. •

   Exposure to BPs as well as other antiresorptive and chemotherapeutic agents.

Diagnosis

The AAOMS considers a diagnosis of BRONJ if the following three characteristics are present:

1. 1.

   Current or previous treatment with a BP.

2. 2.

   Exposed bone or bone that can be probed through intraoral or extraoral fistulae in the maxillofacial region persisting for more than 8 weeks.

3. 3.

   No history of radiation therapy to the maxillofacial region or evident metastatic disease to the jaw.

Differential Diagnosis

1. •

   Suppurative osteomyelitis of the jaw (SOJ).

2. •

   Osteoradionecrosis of the jaw (ORNJ).

3. •

   Alveolar osteitis, gingivitis, sinusitis, fibro-osseous lesion, sarcoma, sclerosing osteomyelitis, periodontitis, dental caries, and temporomandibular joint disorders.

Workup

1. •

   Treatment history, including medications and radiation therapy.

2. •

   Past medical history, including malignancy.

Laboratory Tests

A validated diagnostic test is not available to identify patients at an increased risk of BRONJ. Tissue biopsy should only be performed if metastatic disease is strongly suspected and its detection would change the management of BRONJ. Histopathology of BRONJ shows empty osteocytic lacunae, empty Haversian and Volkmann canals, an absence of inflammatory cells or blood vessels in the marrow space, and absence of extracellular collagenase.

Imaging Studies

Panoramic and periapical radiographs

Treatment

Goals of treatment for BRONJ include:

1. •

   Control or reduce pain.

2. •

   Control secondary infection.

3. •

   Minimize progression or occurrence of bone necrosis, as well as extension of lesion(s).

Nonpharmacologic Therapy

Literature suggests that success rates with surgical management are higher and less variable than with conservative management. The AAOMS recommends surgery for patients with stage III BRONJ. However, a surgical margin with viable bone can be difficult to obtain. The entire jawbone likely has been exposed to accumulation of BPs, and therefore successful eradication of necrotic bone is often not possible. Those areas of necrosis that consistently irritate soft tissues should undergo debridement as necessary because dead tissue will interfere with wound healing and will be prone to infection. Another consideration is that some patients may not be surgical candidates if their overall health is poor and/or if chemotherapy is incomplete.

A small study of 54 patients by Kim et al. (2014) suggests that a drug holiday of at least 4 months after surgery may improve prognosis. Limited evidence supports the use of hyperbaric oxygen as adjunct to surgery and antibiotics to slow progression and improve pain. Small case reports have documented the use of platelet-rich plasma, low-level laser irradiation, parathyroid hormone, and bone morphogenic protein; however, the efficacy of these methods has not been established through controlled studies.

The AAOMS recommends the following surgical strategies based on BRONJ staging:

1. •

   Stage 0 (no clinical evidence of necrotic bone, nonexposed bone variant): no surgery.

2. •

   Stage I (exposed and necrotic bone, or fistulae that probe to bone, asymptomatic): no surgery.

3. •

   Stage II (exposed and necrotic bone, or fistulae that probe to bone, with pain or infection): superficial debridement.

4. •

   Stage III (exposed and necrotic bone with pain, infection, and one of the following features: necrosis extending beyond alveolar bone, pathologic fracture, extraoral fistula, oral antral or nasal communication, osteolysis extending to mandible of sinus floor): surgical debridement or resection for palliation of infection and pain.

Acute General Rx

Both chlorhexidine mouth rinse and antibiotics for 1 to 3 weeks have been found useful for stage reduction. Most microbes are sensitive to penicillin antibiotics.

1. •

   Chlorhexidine 0.12% antibacterial mouth rinse daily for stages I to III.

2. •

   Oral antibiotics for symptomatic stage II and oral or intravenous antibiotics for stage III.

3. •

   Analgesics for stages II or III.

Chronic Rx

1. •

   Determine whether discontinuation of BPs (or other agents associated with MRONJ) is appropriate.

   1. 1.

      Evaluate potential benefit of continuing BP, such as relief of bone pain in malignancy or prevention of fractures with high morbidity and mortality.

   2. 2.

      BPs have a prolonged half-life, so return to normal osteoclast function and bone turnover may be too gradual.

   3. 3.

      Consider other risks of BPs, such as spontaneous atypical fractures.

2. •

   If discontinuing BP therapy, consider alternative treatments for osteoporosis or bone pain.

3. •

   Anecdotal case reports exist for using teriparatide (unless the patient has bone metastases or is at risk for osteosarcoma) or pentoxifylline plus tocopherol to heal BRONJ.

Disposition

1. •

   Patients with involvement of the maxilla appear to have a greater likelihood of repeat surgery.

2. •

   Patients taking oral BPs may have less severe complications and may have a better response.

3. •

   Treatment with antibiotics and chlorhexidine mouth rinse, withdrawal of BPs, and surgical removal of loose sequestra may possibly reduce pain and lesions of osteonecrosis.

Referral

Oral and maxillofacial surgeon

Pearls & Considerations

Comments

1. •

   Patients may be asymptomatic for weeks to years before BRONJ is apparent.

2. •

   Radiographic changes may not be observed until significant disease has developed.

3. •

   Tooth extraction may be difficult to avoid in patients at high risk of BRONJ if an underlying bacterial infection is present.

4. •

   Patients with cancer are at highest risk because the dosages of BPs are much higher than for osteoporosis.

5. •

   Product labeling for BPs states that there is no evidence that discontinuation of therapy reduces the risk of ONJ; therefore, the optimal duration of therapy is unknown.

   1. 1.

      Results from the FLEX trial suggest that women with postmenopausal osteoporosis who have taken alendronate for 5 years and are at low risk of vertebral fractures may discontinue the drug for up to 5 years.

   2. 2.

      Results from the HORIZON-PFT extension trial suggest that women with postmenopausal osteoporosis who have taken IV zoledronic acid for 3 years and are at low risk of vertebral fractures may discontinue for up to 3 years.

6. •

   Use of BPs in pediatric patients has increased without identified cases of BRONJ to date. Further evaluation of long-term use of BPs in these patients is warranted.

Prevention

1. •

   Regular dental hygiene and routine (every 3 months for patients with cancer) dental examinations.

2. •

   Appropriate fitting of dentures with periodic mucosal examination.

3. •

   Assessment of patients for other risk factors of BRONJ.

4. •

   Completion of any anticipated dental procedures before beginning BP therapy.

5. •

   Careful monitoring of patients after dentoalveolar surgery.

6. •

   Asymptomatic patients receiving IV BPs: limit dental surgery to removal of nonrestorable teeth and avoid dental implants in patients who also have cancer.

7. •

   The 2014 AAOMS position paper supports a 2-month drug holiday before oral surgery for patients who have received BPs for greater than 4 years or for patients exposed to less than 4 years of BPs and taking concomitant corticosteroids or antiangiogenics. Allow osseous healing to complete before restarting BPs. A 2017 retrospective study did not find a difference in ONJ incidence due to preextraction drug holidays of 2 or 3 months.

8. •

   After dentoalveolar surgery, delay initiation of BPs by at least 2 to 3 weeks to allow for osseous healing.

9. •

   Discontinuation of denosumab prior to dental procedures may be beneficial, as the medication has a shorter half-life (26 days) than BPs.

Evidence suggests a 3-fold reduction in the incidence of ONJ when preventive measures are practiced.

Patient/Family Education

1. •

   All health care providers should be aware of past and current BP use.

2. •

   Contact a health care provider if any of the following are observed:

   1. 1.

      Presence of exposed bone in the maxillofacial area.

   2. 2.

      Persisting pain in the maxillofacial area.

   3. 3.

      Signs of infection such as fever, pus, and swelling.

3. •

   Practice good dental hygiene and keep regular dental appointments.

Suggested Readings

• American Association of Oral and Maxillofacial Surgeons: Medication-Related Osteonecrosis of the Jaw. Retrieved from http://www.aaoms.org/docs/govt_affairs/advocacy_white_papers/mronj_position_paper.pdf.

• A.A. Khan, et al.: Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res. 30:3–23 2015 25414052

• O. Ristow, et al.: Treatment perspectives for medication-related osteonecrosis of the jaw (MRONJ). J Craniomaxillofac Surg. 43:290–293 2015 25541255