Medication Related Osteonecrosis of the Jaw

Medication related osteonecrosis of the jaw (MRONJ) is exposed or probe accessible necrotic bone in the maxillofacial region. It persists for more than 8 weeks in a patient who has received antiresorptive agents (bisphosphonates, denosumab) or antiangiogenic drugs (bevacizumab, sunitinib, cabozantinib) and has had no head and neck radiotherapy.

Incidence is 1 to 15 percent in cancer patients on high dose intravenous zoledronic acid (4 mg every 3 to 4 weeks) or denosumab (120 mg monthly). In osteoporosis patients on oral alendronate (70 mg weekly), zoledronic acid 5 mg yearly or denosumab 60 mg every 6 months, it is 0.01 to 0.1 percent.

Mechanism involves suppressed bone remodelling, reduced angiogenesis, infection, inflammation, and toxicity to oral epithelium. Triggers are dentoalveolar surgery (extraction accounts for about 50 to 60 percent), periodontal and periapical infection, ill fitting dentures, and spontaneous cases in thin mucosa.

Risk factors: cumulative dose and duration (over 2 years), mandible (65 to 75 percent), diabetes, corticosteroids, smoking, poor oral hygiene, chemotherapy.

Staging:

• Stage 0: no exposed bone, nonspecific symptoms and radiographic change.
• Stage 1: exposed bone, asymptomatic.
• Stage 2: exposed bone with pain and infection.
• Stage 3: extensive disease with pathological fracture, extraoral fistula, or oro antral communication.

• Exposed yellowish white necrotic bone, in the mandible lingual or mylohyoid ridge, or palatal torus, persisting beyond 8 weeks.
• Pain, swelling, halitosis, purulent drainage, tooth mobility, sinus tract.
• Numbness (Vincent sign) when the inferior alveolar nerve is involved.
• Non-exposed variant: unexplained jaw pain, tooth loosening, sinus tract, swelling.
• Complications: pathological jaw fracture, oroantral or oronasal fistula, extraoral sinus, maxillary sinusitis, sepsis.
• Red flags: facial swelling, trismus, spreading cellulitis, mandibular fracture, systemic fever, and evidence of metastatic cancer (exclude jaw metastasis).

• Diagnostic criteria: current or previous antiresorptive or antiangiogenic therapy, exposed bone or bone probed through a fistula for over 8 weeks, no history of jaw radiotherapy or metastatic jaw disease.
• Panoramic radiograph: poorly healed extraction socket, osteolysis, osteosclerosis, sequestrum, thickened lamina dura.
• CT or cone beam CT: cortical erosion, sequestrum, periosteal reaction, bone sclerosis; MRI or bone scintigraphy to detect early disease.
• Biopsy only when malignancy is suspected: avoid unless necessary.
• Swab culture of drainage (Actinomyces is present in most specimens, which is often reported as sulphur granules).
• Bone turnover marker (serum C-terminal telopeptide) is not reliable for predicting risk.
• Exclude osteomyelitis, metastasis, osteoradionecrosis, alveolar osteitis, periodontal disease, sinusitis, osteosarcoma, and fibrous dysplasia.

• Prevention before therapy: dental assessment and treatment of infection or poor teeth before starting intravenous antiresorptives. Do extractions at least 14 to 21 days (ideally 4 to 6 weeks) before the first dose. Instruct on hygiene.
• Stage 0: conservative; analgesia, treat local dental cause, and continue antiresorptive therapy.
• Stage 1: chlorhexidine gluconate 0.12 to 0.2 percent mouthwash 10 to 15 mL for 1 minute twice daily; review every 3 months; education; no surgery.
• Stage 2: antimicrobial rinse plus amoxicillin 500 mg orally every 8 hours for 14 to 28 days (or amoxicillin clavulanate 625 mg every 8 hours).
• Penicillin allergy: clindamycin 300 mg orally every 6 hours or doxycycline 100 mg every 12 hours for 14 to 28 days.
• Add metronidazole 400 mg every 8 hours if anaerobic infection. Analgesia is paracetamol 1 g every 6 hours and ibuprofen 400 mg every 8 hours.
• Offer surgical debridement of necrotic bone with a conservative approach (minimal sequestrectomy) when symptoms persist.
• Stage 3: surgical resection of necrotic bone to bleeding margins, with closure using tension free flaps. Give intravenous antibiotics (ampicillin sulbactam 3 g every 6 hours or piperacillin tazobactam 4.5 g every 6 hours until sepsis controlled).
• With pathological fracture: reconstruction (fibula free flap, reconstruction plates).
• Adjuncts: teriparatide 20 micrograms subcutaneously once daily for 6 to 8 weeks to 6 months for osteoporosis related disease. Pentoxifylline 400 mg twice daily with tocopherol 1000 IU daily for 6 to 12 months. Platelet rich fibrin and laser therapy have been used in specialist units.
• Drug holiday: in patients taking oral bisphosphonate for osteoporosis with MRONJ risk (over 4 years of therapy), discuss suspending the drug 2 months before invasive dental surgery and restarting after healing.
• In cancer patients, discuss the drug holiday with the oncologist. Do not stop denosumab without a replacement because of rebound vertebral fractures.
• Follow up: 3-monthly review for stable disease. Healing rates are 40 to 60 percent with conservative therapy and about 85 percent with resection.
• Counselling: meticulous oral hygiene, avoid ill fitting dentures, report mouth pain, and tell every dentist about the medicine.