Residency · Residency · Oral Maxillofacial Surgery
Medication-Related Osteonecrosis of the Jaw (MRONJ)
Introduction
Medication-related osteonecrosis of the jaw (MRONJ) is a potentially debilitating condition characterized by exposed necrotic bone in the maxillofacial region in patients treated with antiresorptive or antiangiogenic medications. The OMFS surgeon is frequently the primary specialist managing this condition and must be well versed in its prevention, staging, and treatment.
Etiology and Pathophysiology
Implicated Medications
The principal medications associated with MRONJ include bisphosphonates (nitrogen-containing), available in oral formulations (alendronate, risedronate, ibandronate) and intravenous formulations (zoledronic acid, pamidronate). Denosumab, a RANKL inhibitor, also carries significant risk. Antiangiogenic agents such as bevacizumab, sunitinib, and sorafenib, as well as mTOR inhibitors including everolimus and temsirolimus, are additionally implicated.
Pathophysiology
The pathophysiology is multifactorial, involving suppression of osteoclast-mediated bone remodeling, impaired angiogenesis, immune dysfunction, and microbial biofilm formation. Bisphosphonates have a long skeletal half-life, up to 10 years for zoledronic acid, meaning their effects persist well beyond discontinuation. Denosumab has a shorter duration of action, and risk may decrease after discontinuation. The jaw is uniquely susceptible due to its high bone turnover, thin mucosal coverage, and constant microbial exposure.
Risk Factors
Medication-related risk factors include the intravenous route, higher cumulative dose, and longer duration of therapy. Local factors include dentoalveolar surgery (particularly extractions), periodontal disease, poorly fitting dentures, and dental implant placement. Systemic factors include concurrent corticosteroid use, diabetes, smoking, chemotherapy, and anemia.
Diagnostic Criteria (AAOMS 2022)
All three criteria must be met for diagnosis: current or previous treatment with antiresorptive or antiangiogenic agents; exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region persisting for more than 8 weeks; and no history of radiation therapy to the jaws or metastatic disease to the jaws.
Staging and Clinical Features
| Stage | Bone Exposure | Symptoms / Signs | Extent |
|---|---|---|---|
| 0 | None clinically | Nonspecific (pain, osteosclerosis, widened PDL) | Radiographic changes only |
| 1 | Exposed/necrotic bone or fistula to bone | Asymptomatic, no infection | Alveolar bone |
| 2 | Exposed/necrotic bone or fistula to bone | Pain, erythema, purulent drainage (infection) | Alveolar bone |
| 3 | Exposed/necrotic bone with infection | Pathologic fracture, extraoral fistula, OAC/ONC | Beyond alveolar bone (inferior border, sinus floor) |
Stage 0 has no clinical evidence of necrotic bone but presents with nonspecific symptoms or radiographic findings such as osteosclerosis, thickened lamina dura, or widened PDL space. Stage 1 features exposed or necrotic bone or a fistula probing to bone in an asymptomatic patient without infection. Stage 2 involves exposed or necrotic bone or a fistula with evidence of infection, including pain, erythema, and purulent drainage. Stage 3 involves exposed or necrotic bone with infection extending beyond the alveolar bone, manifesting as pathologic fracture, extraoral fistula, oroantral or oronasal communication, or osteolysis extending to the inferior border or sinus floor.
Prevention
A pre-treatment dental evaluation with a complete dental assessment and completion of necessary invasive procedures should be performed before initiating antiresorptive or antiangiogenic therapy. Oral hygiene should be optimized and active infection eliminated. When extractions are necessary during therapy, atraumatic technique with primary closure is employed. Elective dentoalveolar surgery should be avoided in high-risk patients. Drug holidays may be considered in consultation with the prescribing physician for patients on long-term oral bisphosphonates requiring invasive procedures, though evidence supporting this practice is limited. Serum CTX (C-terminal telopeptide) levels have been proposed as a risk assessment tool but lack validated predictive value.
Management by Stage
Stage 0
Stage 0 is managed systemically with pain control and antibiotics if indicated, conservative management of symptomatic areas, patient education, and close monitoring.
Stage 1
Stage 1 is managed with antimicrobial mouth rinse (chlorhexidine 0.12%) and clinical follow-up without surgical intervention unless disease progresses. Sharp bony edges are smoothed to reduce soft-tissue trauma.
Stage 2
Stage 2 is managed with antimicrobial mouth rinse and systemic antibiotics (penicillin or amoxicillin first-line; clindamycin or fluoroquinolone for penicillin allergy), pain management, and superficial debridement of necrotic bone without exposing uninvolved bone. Surgical intervention is considered if medical management fails.
Stage 3
Stage 3 requires systemic antibiotics and antimicrobial rinse along with surgical resection of necrotic bone with tension-free primary closure. Segmental resection with reconstruction may be necessary. Adjunctive therapies include platelet-rich fibrin (PRF), hyperbaric oxygen (limited evidence), and pentoxifylline with tocopherol.
Surgical Principles When Surgery Is Indicated
The goal of surgery is to achieve a viable, bleeding bony margin with tension-free soft-tissue closure. All sequestra and necrotic bone are removed until punctate bleeding (the paprika sign) is achieved. Sharp bony edges are smoothed. The use of PRF membranes or BMP may enhance healing. Periosteal release for tension-free closure is critical to success.
Clinical Pearls
Prevention is paramount, and dental clearance before initiating antiresorptive therapy significantly reduces MRONJ risk. Intravenous bisphosphonate and denosumab in oncologic doses carry much higher risk than oral bisphosphonates prescribed for osteoporosis. Stage 2 disease often responds to antibiotics and local debridement, and aggressive surgery should be avoided in early stages. Drug holidays should be discussed with the prescribing physician and are most relevant for patients on oral bisphosphonates. Informed consent discussing MRONJ risk should always be documented before performing dentoalveolar procedures in at-risk patients.
References
- Ruggiero SL, Dodson TB, Aghaloo T, et al. American Association of Oral and Maxillofacial Surgeons' Position Paper on Medication-Related Osteonecrosis of the Jaws — 2022 Update. J Oral Maxillofac Surg. 2022;80(5):920-943.
- Khan AA, Morrison A, Hanley DA, et al. Diagnosis and management of osteonecrosis of the jaw: A systematic review and international consensus. J Bone Miner Res. 2015;30(1):3-23.
- Yarom N, Shapiro CL, Peterson DE, et al. Medication-related osteonecrosis of the jaw: MASCC/ISOO/ASCO clinical practice guideline. J Clin Oncol. 2019;37(25):2270-2290.
- Aghaloo T, Hazboun R, Engke N. Pathophysiology of osteonecrosis of the jaws. Oral Maxillofac Surg Clin North Am. 2015;27(4):489-496.