Bisphosphonate-related osteonecrosis of the jaw (BRONJ)

Bisphosphonate Related OsteoNecrosis of the Jaw (BRONJ)

• pathogenesis of BRONJ has not been well determined
  • various risk factors such as dentoalveolar surgery, therapy duration, and concomitant steroid usage have been linked to BRONJ

The American Society for Bone and Mineral Research define BRONJ as follows

• patients may be considered to have BRONJ if they have all of the following criteria.
  • current or previous treatment with a bisphosphonate; AND
  • exposed bone in the maxillofacial region that has persisted for more than eight weeks; AND
  • no history of radiation therapy to the jaws

However, stage 0 BRONJ where there is no exposed bone is not compatible with this definition. Therefore an update of the definition was performed as "exposed or otherwise necrotic bone" (1).

Epidemiology:

• 0.7/100,000 person/years of exposure
• prevalence of BRONJ was reported as 0.06% in long-term oral bisphosphonate receivers (2)

Risk factors:

• bisphosphonate potency
  • since intravenous administration leads to a higher drug exposure than the oral route, osteonecrosis related to oral bisphosphonate therapy is less common than that related to intravenous forms such as zolendronate which is also more potent than oral bisphosphonates
    
    
• duration of bisphosphonate therapy
  • longer duration (for more than two years) - been associated with an increased risk of oral BRONJ
    
    
• local factors
  • dentoalveolar surgical procedures such as teeth extractions, dental implant placement, periapical surgery, and periodontal surgery involving osseous injury; as well as concomitant oral disease and poor oral hygiene
    
    
• some systemic factors are associated with increased risk of BRONJ such as renal dialysis, anaemia, immunosuppression, rheumatoid arthritis, smoking, obesity and diabetes
  
  
• prednisolone and methotrexate used in autoimmune diseases are associated with an additional inhibition of remodeling in oral bisphosphonate use - hence increasing risk of BRONJ

Presentation:

• may be symptomatic or asymptomatic
  • if asymptomatic
    • may present with exposed alveolar bone during routine dental evaluations
  • symptomatic
    • symptoms such as pain and evidence of local or widespread infections
    • may state a trauma due to dental prosthesis or a former dental procedure whereas some cases do not have an obvious preceding factor

Investigation:

• Xrays, dental cone beam or spiral computed tomographies can be used to detect BRONJ
  • however, panoramic and periapical radiographs may not be as helpful in identifying the changes in the initial phase of osteonecrosis
  • CT has also not been proven to be useful in early detection of asymptomatic BRONJ patients
• if there is no clinically exposed bone, scintigraphy, PET scan, or MRI may identify early areas of bony involvement

Staging:

• Stage 0 - non-specific symptoms or clinical and radiographic findings and without clinical evidence of necrotic bone
• Stage 1 - asymptomatic patients having an exposed and necrotic bone, but no evidence of infection are regarded as stage 1
• Stage 2 - corresponds to a situation including exposed and necrotic bone associated with infection
• Stage 3 - exposed and necrotic bone in patients with pain, infection, and one or more of the following:
  • exposed and necrotic bone extending beyond the region of alveolar bone, resulting in pathologic fracture,
  • extra-oral fistula, oral antral/oral nasal communication,
  • or osteolysis extending to the inferior border of the mandible of sinus floor

Management:

• seek specialist advice
• cessation of bisphosphonate therapy - may be reviewed after treatment of BRONJ
• primary aim of BRONJ management is prevention of infection of the necrotic bone and reduction of symptoms
• analgesia as required
• stage 1 - antimicrobial mouth rinses are recommended
• stage 2 or 3 - if there is any evidence of infection (i.e., stage 2 and 3), in addition to mouth rinses, treatment with oral antibiotics
• in order to remove necrotic bone and create soft tissue coverage of remaining healthy bone, surgical procedures are performed in stages 2 and 3
  • spontaneous sequestration or resolution following debridement surgery may occur following discontinuation of bisphosphonates

Prevention:

• the risk of oral BRONJ appears to rise in treatment periods longer than 3 years - reduction of this period may be helpful in patients with comorbidities such as chronic steroid use
• dental consultation/examination
  • prior to bisphposphonate treatment
    • if the patient has poor dental health before starting on oral bisphosphonates, he or she should be examined by a dentist in order to optimise oral hygiene
  • if any oral surgical treatment is planned, strategy should be based on the duration of bisphosphonate therapy, as well as concomitant drug use
  • patients who underwent dental implant placement procedures should be followed up regularly

Notes:

• denosumab and jaw osteonecrosis
  • a study found incidence of medication-related osteonecrosis of the jaw (MRONJ) in breast cancer patients with bone metastases to be considerably higher, especially on denosumab vs available data in literature (11.6% denosumab only, 2.8% bisphosphonates only, and 16.3% in those receiving bisphosphonates followed by denosumab) (3)

Reference:

1. McLeod NM, Brennan PA, Ruggiero SL. Bisphosphonate osteonecrosis of the jaw: a historical and contemporary review. Surgeon. 2012;10(1):36-42.
2. Ault A. Jaw necrosis affects 1 in 1, 700 on oral bisphosphonates. Internal Medicine News. 2008;41, article 23
3. Brunner C et al. Incidence of Medication-Related Osteonecrosis of the Jaw in Patients With Breast Cancer During a 20-Year Follow-Up: A Population-Based Multicenter Retrospective Study. JCO 0, JCO.24.00171