Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse event where exposed bone in the jaw does not heal for several weeks in patients taking specific medications. Initially linked to bisphosphonates, the term MRONJ was adopted by the AAOMS to include other drugs like denosumab and anti-angiogenic agents. Identifying these medications and understanding risk factors is crucial for prevention and management.
Primary Culprits: Antiresorptive Agents
Antiresorptive agents are the most significant contributors to MRONJ risk. These drugs inhibit bone resorption, beneficial for conditions like osteoporosis and cancer metastases, but can complicate healing in high-turnover areas like the jaw.
Bisphosphonates
Bisphosphonates inhibit osteoclast activity, increasing bone density and reducing fracture risk. They persist in bone for years, especially with long-term use.
- Intravenous (IV) Bisphosphonates: Used for cancer patients with bone metastases or multiple myeloma. High-dose IV forms like zoledronic acid and pamidronate carry a significantly higher MRONJ risk, particularly with concurrent treatments like chemotherapy. Incidence is reported between 1–10% or more.
- Oral Bisphosphonates: Prescribed for osteoporosis and Paget's disease. Examples include alendronate and risedronate. The MRONJ risk is much lower with oral forms, less than 0.1%, but increases with prolonged use over several years.
Denosumab
Denosumab inhibits RANKL, a protein essential for osteoclasts, effectively reducing bone resorption. Like bisphosphonates, MRONJ risk is dose-dependent and higher in cancer patients on high-dose denosumab (Xgeva) compared to those on lower doses for osteoporosis (Prolia). Its effects diminish within months of discontinuation, offering more flexibility for drug holidays, though stopping can have other risks.
Other Implicated Medications
Anti-angiogenic Agents
Anti-angiogenic drugs, used in cancer therapy to target blood vessel growth, can impair jaw healing and increase MRONJ risk, especially with antiresorptive agents. Examples include monoclonal antibodies like bevacizumab and tyrosine kinase inhibitors like sunitinib.
Corticosteroids and Other Drugs
Long-term systemic corticosteroid use is a risk factor for MRONJ and can exacerbate risk in patients on antiresorptive medications. Certain chemotherapy agents and immunomodulators have also been implicated.
Key Risk Factors for MRONJ
MRONJ development is influenced by several factors beyond medication use:
- Invasive Dental Procedures: Procedures like extractions are common triggers due to exposed bone and impaired healing.
- Dosage and Duration: Higher doses and longer use of antiresorptive agents increase risk.
- Concurrent Medication Use: Combining antiresorptive drugs with corticosteroids or chemotherapy further elevates risk.
- Comorbidities: Conditions like diabetes and cancer can impair healing.
- Poor Oral Hygiene: Infections from conditions like periodontal disease can precipitate MRONJ.
- Age and Gender: Older age and female gender are often associated with higher incidence.
- Smoking: Tobacco use hinders wound healing.
Risk Factors Comparison Table
| Feature | Osteoporosis Patients | Cancer Patients |
|---|---|---|
| Drug Type | Primarily low-dose oral bisphosphonates (e.g., alendronate, risedronate) | Primarily high-dose intravenous bisphosphonates (e.g., zoledronic acid, pamidronate) or high-dose denosumab |
| Drug Dose | Low | High |
| Administration Route | Oral (low risk) | Intravenous or subcutaneous (higher risk) |
| Duration | Generally long-term (years) before significant risk emerges | Typically shorter duration but with much higher cumulative exposure due to dosing regimen |
| Risk of MRONJ | Very low (est. <0.1%) | Significantly higher (est. 1-10% or more) |
| Concomitant Medications | Potentially corticosteroids, but fewer concurrent therapies compared to oncology patients | Often on concurrent chemotherapy, corticosteroids, and anti-angiogenic agents, which multiply the risk |
Preventive Measures and Management Strategies
Prevention involves optimizing oral health before and during high-risk medication therapy and managing risk factors. Communication between doctors and dentists is crucial.
Prevention
- Pre-Therapy Dental Evaluation: A thorough dental exam and completion of necessary procedures before starting high-risk medications are essential.
- Optimize Oral Hygiene: Maintaining good oral hygiene and regular dental check-ups minimize infection sources.
- Managing Dental Procedures: Avoid invasive procedures during high-risk therapy if possible. If unavoidable, discuss a potential drug holiday, noting that effectiveness varies. For denosumab, timing procedures before a new dose is an option.
Management
MRONJ treatment follows guidelines like those from the AAOMS.
- Conservative Management: Early stages focus on symptom and infection control with oral rinses and antibiotics.
- Surgical Management: Advanced or unresponsive cases may require surgical removal of necrotic bone. Research suggests surgery can offer better long-term outcomes in some cases.
Conclusion
Antiresorptive agents, especially high-dose bisphosphonates and denosumab used for cancer, are the primary medications increasing MRONJ risk. This risk is compounded by factors like invasive dental procedures, poor oral health, and comorbidities. Informed, collaborative care involving patients, doctors, and dentists, focusing on proactive dental screening and preventative measures, is vital for mitigating and managing MRONJ while ensuring patients benefit from these essential medications. For detailed guidelines, refer to the American Association of Oral and Maxillofacial Surgeons (AAOMS) position papers.
