What are the recommendations for preventing and managing Medication-Related Osteonecrosis of the Jaw (MRONJ) in patients taking bisphosphonates (e.g. zoledronic acid), denosumab, or anti-angiogenic medications, according to studies from the American Association of Oral and Maxillofacial Surgeons (AAOMS) and systematic reviews?

Preventing and Managing Medication-Related Osteonecrosis of the Jaw (MRONJ)

All patients scheduled to receive bisphosphonates, denosumab, or anti-angiogenic medications must undergo comprehensive dental evaluation with radiographs before starting therapy, complete all necessary dental procedures with full mucosal healing, and avoid elective invasive dental surgery during active treatment. 1, 2, 3

Definition and Diagnostic Criteria

MRONJ requires all three criteria to be present: 1, 3, 4

• Current or previous treatment with a bone-modifying agent (bisphosphonate, denosumab) or angiogenic inhibitor
• Exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region persisting for longer than 8 weeks
• No history of radiation therapy to the jaws or metastatic disease to the jaws

The 8-week timeframe is critical—shorter durations may represent normal healing and should not be diagnosed as MRONJ. 2, 4

Risk Stratification by Medication and Dose

The incidence of MRONJ varies dramatically based on medication regimen: 3

• Oncologic doses (monthly IV bisphosphonates or subcutaneous denosumab): 1-9% incidence, increasing substantially after 2 years of treatment 1, 3
• Osteoporosis doses (every 6 months): 0-1% incidence 3
• Oral bisphosphonates: 0-0.5% incidence 3

Switching from zoledronic acid to denosumab significantly increases MRONJ risk (hazard ratio 4.36) compared to continuing zoledronic acid alone, likely due to additive effects on jawbone with residual zoledronic acid activity. 5

Prevention Protocol: Before Initiating Therapy

Mandatory Pre-Treatment Dental Assessment

Before starting bone-modifying agents in non-urgent settings, patients must undergo: 1, 2, 3

• Comprehensive dental and periodontal examination
• Panoramic radiograph (orthopantomography) and/or full-mouth intraoral radiographs
• Complete all medically necessary dental procedures before starting therapy
• Ensure full mucosal coverage of bone before initiating bisphosphonates or denosumab

Address Modifiable Risk Factors

The multidisciplinary team must address these risk factors before therapy initiation: 1, 3

• Poor oral health and active dental disease
• Uncontrolled diabetes mellitus
• Tobacco use
• Ill-fitting dentures causing mucosal trauma

Baseline Laboratory Monitoring

Before starting therapy, measure: 1, 3

• Serum calcium (mandatory for all patients)
• Renal function assessment (mandatory for IV bisphosphonates like zoledronic acid)

Zoledronic acid is contraindicated in patients with creatinine clearance <30 ml/min. 1

Calcium and Vitamin D Supplementation

Oral calcium and vitamin D supplementation is strongly recommended when using denosumab or zoledronic acid unless contraindicated. 1 Oral bisphosphonates and calcium should not be taken concurrently—maintain at least a 2-hour interval to allow maximum absorption. 1

Prevention Protocol: During Active Therapy

Routine Dental Monitoring Schedule

Implement this monitoring schedule for all patients on bone-modifying agents or anti-angiogenic therapy: 1, 2, 3

• Dental follow-up visits every 6 months
• Complete dental examination with orthopantomography and intraoral radiographs
• Annual orthopantomography
• Evaluation of oral mucosa integrity
• Reinforcement of oral hygiene education

Management of Dental Procedures During Treatment

Elective dentoalveolar surgery (non-medically necessary extractions, alveoloplasties, dental implants) should NOT be performed during active therapy with bone-modifying agents at oncologic doses. 1, 2, 3

Exceptions may be considered only when a dental specialist with MRONJ expertise has reviewed benefits and risks with the patient and oncology team. 1

If Dentoalveolar Surgery Must Be Performed

When medically necessary dental surgery cannot be avoided: 1, 2, 3

• Evaluate the patient every 6-8 weeks until complete mucosal coverage occurs
• Maintain communication between dental specialist and oncologist regarding healing status
• Consider prophylactic antibiotics before invasive dental care 1
• Use wound closure techniques that avoid exposure and contamination of bone 2

Drug Holiday Controversy

There is insufficient evidence to support or refute the need for discontinuation of bone-modifying agents before dentoalveolar surgery. 1 Administration may be deferred at the discretion of the treating physician in conjunction with discussion with the patient and oral health provider. 1

The effectiveness of drug holidays is likely limited due to the persistent, long-term pharmacologic activity of bisphosphonates on bone. 6 One trial showed that switching from bisphosphonates to denosumab in patients with elevated bone resorption markers resulted in better outcomes (71% vs 29% SRE-free; p<0.001), but this does not address the drug holiday question directly. 1

Ongoing Laboratory Monitoring

During treatment, monitor: 1, 3

• Serum calcium levels (before each denosumab injection and periodically with zoledronic acid)
• Renal function and serum creatinine throughout treatment (for IV bisphosphonates)
• Signs and symptoms of MRONJ at routine dental visits

Treatment of Established MRONJ

Referral and Staging

All suspected MRONJ cases must be referred to a dental specialist experienced in MRONJ management for staging and treatment. 1, 2, 3, 4

ASCO/MASCC staging system: 4

• At risk: No apparent necrotic bone in patients treated with bone-modifying agents
• Increased risk: No clinical evidence of necrotic bone but nonspecific clinical findings, radiographic changes, and symptoms
• Stage 1: Exposed/necrotic bone or fistulas probing to bone in asymptomatic patients without evidence of infection
• Stage 2: Exposed/necrotic bone or fistulas probing to bone with infection (pain, erythema, with/without purulent drainage)
• Stage 3: Exposed/necrotic bone or fistulas probing to bone with pain, infection, and one or more of: exposed bone extending beyond alveolar bone, pathologic fracture, extraoral fistula, oral-antral/oral-nasal communication, or osteolysis extending to inferior border of mandible or sinus floor

First-Line Treatment: Conservative Measures

Conservative measures comprise the initial approach to MRONJ treatment for all stages. 1, 3 This includes:

• Antimicrobial mouth rinses
• Systemic antibiotics when clinically indicated (infection present)
• Effective oral hygiene maintenance
• Conservative surgical interventions only (removal of superficial bone spicules)

Advanced Treatment Options

Aggressive surgical interventions (mucosal flap elevation, block resection of necrotic bone, soft tissue closure) may be used if MRONJ: 3

• Causes persistent symptoms despite conservative treatment
• Affects function
• Involves significant bone exposure (typically Stage 3)

One RCT found no evidence that hyperbaric oxygen therapy added to standard care improves healing compared to standard care alone (RR 1.56; 95% CI 0.77-3.18). 7 The evidence quality is very low, but this suggests hyperbaric oxygen should not be routinely recommended. 7

Medication Management During Active MRONJ

The decision to continue versus discontinue bone-modifying agent therapy must balance cancer treatment needs against MRONJ progression. 2 Neither denosumab nor zoledronic acid has been shown to prolong survival in patients with bone metastases from castration-resistant prostate cancer, though both delay skeletal-related events. 1 This information should inform the risk-benefit discussion when MRONJ develops.

Multidisciplinary Coordination Requirements

Essential communication pathways include: 2, 3

• Oncologist provides dentist with patient's medical diagnosis and complete antiresorptive/angiogenic inhibitor profile
• Dentist sends diagnosis and treatment plan to oncologist
• Coordinate timing if oral surgery becomes necessary
• Maintain ongoing dialogue throughout treatment course

Special Populations and Additional Considerations

Multiple Myeloma Patients

Bisphosphonates are recommended for all patients receiving myeloma therapy for symptomatic disease regardless of documented bone disease (category 1 recommendation). 1 Patients should have dental examination prior to starting bisphosphonate therapy and be monitored for osteonecrosis of the jaw. 1

Breast Cancer Patients on Adjuvant Bisphosphonates

The same prevention strategies apply, though MRONJ risk is substantially lower (0-1.8%) compared to oncologic dosing for metastatic disease. 3 Baseline dental examination and ONJ monitoring remain mandatory. 1

Concomitant Anti-Angiogenic Agents

Concomitant use of anti-angiogenic agents significantly increases MRONJ risk (hazard ratio 1.78). 5 These patients require heightened surveillance and stricter adherence to prevention protocols. 1

Critical Practice Pitfalls to Avoid

• Do not rely solely on radiographic signs for MRONJ diagnosis—this leads to overestimation of disease frequency. 4
• Do not perform biopsy of suspicious lesions—this may exacerbate the condition. 4
• Do not discourage patients from taking bisphosphonates for existing medical conditions due to MRONJ concerns—the benefits typically outweigh risks, especially at osteoporosis doses. 6
• Do not assume drug holidays are effective—evidence does not support this practice, and bisphosphonates have persistent long-term effects on bone. 1, 6
• Do not ignore the increased risk when switching from zoledronic acid to denosumab—this carries a 4-fold increased MRONJ risk. 5