Medication Related Osteonecrosis of the Jaw[MRONJ]Brendan Da Silva Proserpine Hospital

Case:

70 year old Caucasian male. History of monthly Denosumab injections (Xgeva) for metastatic cancer taken since

2011. History of abiraterone, prednisone and MS contin for cancer treatment. History of radiation therapy to spine and ribs. Current medications include Fentanyl, Endep and dexamethasone for pain relief.

Social and Dental History

Previous smoker for 50 years but has since quit. Does not consume alcohol. Under continued care of a nurse at an aged care facility. Cleans teeth at least once a day. Last dental procedure was extractions of teeth 36 and 34 at Mareeba in 2012. Noticed two areas since extractions performed. No chief complaint.

Denosumab

RANKL monoclonal antibody indicated for individuals with osteoporosis, hypercalcemia of malignancy or bone metastases.

Typical dosage for osteoporosis (Prolia) is 50mg biannually whilst Xgeva has 120mg injections every 4 weeks.

Neutralises the RANK Ligand which is required for osteoblast production and activates RANK receptors on osteoclasts and their precursors.

Denosumab vs bisphosphonates

Denosumab vs bisphosphonates

Bone turnover marker suppression is greater in cancer patients undergoing denosumab compared to the bisphosphonate zoledronate.

However due to bone remodelling obstruction, clinical effects such as osteonecrosis of the jaw are at similar indices.

The RANKL-RANK pathway is not only limited to osteoclastogenesis, RANKL is a cytokine for T cell activation and growth. Consequently, interference with the T cell biochemistry has an influence on the adaptive immune system leading to potentially higher risk of infections and thus poorer wound healing.

Diagnosing MRONJ

Characteristics determined by the American Association of Oral and Maxillofacial Surgeons [AAOMS] include:1. Current or previous treatment with anti-resorptive or anti-angiogenic agents;2. Exposed bone or bone that can be probed through an intraoral or extraoral fistula in the

maxillofacial region that has persisted for more than eight weeks;3. No history of radiation therapy to the jaws or obvious metastatic disease to the jaws.

AAOMS Staging MRONJ

Pathophysiology of MRONJ

The exact pathophysiology has not been determined for MRONJ however several theories have sought to explain the mechanism:1. Inhibition of osteoclastic bone resorption and bone remodelling: Due to bisphosphonates and

denosumab inhibiting osteoclastic resorption it directly effects bone healing and skeletal site remodelling.

2. Inflammation or infection: Patients whose necrotic bone was biopsied found bacteria including Actinomyces species.

3. Inhibition of angiogenesis: Patients displaying MRONJ also demonstrated avascular necrosis. Bisphosphonates have shown to decrease angiogenesis through reducing vascular endothelial growth factor levels.

How MRONJ Presents:

How MRONJ Presents:

Saad and Otto et al both found greater indices of osteonecrosis in the mandible then the maxilla in both bisphosphonates and denosumab.

Radiographically there is evidence of: Focal or diffuse sclerosis, Congealing of the lamina dura, Mandibular canal prominence, Delayed healing, Persisting alveolar sockets, Bone osteolysis, “Moth eaten” appearance

AAOMS Treatment of MRONJ

Our patient:

70 year old Caucasian male. History of monthly Denosumab injections (Xgeva) for metastatic cancer taken since

2011. History of radiation therapy to spine and ribs. Last dental procedure was extractions of teeth 36 and 34 at Mareeba in 2012.

MRONJ Presentation

34 and 36/37 area demonstrate exposed bone. No evidence of healing. Bone sequelae visible. No pain or symptoms for the patient. No evidence of infection presented.

MRONJ Presentation

Orthopantomogram demonstrates: Focal osteosclerosis Focal osteolysis “Moth eaten” appearance of

osteonecrosis More prominent left mandibular canal. No evidence of healing

Diagnosis of MRONJ Subcutaneous injections of denosumab Left mandible demonstrates bone exposure for least two

years. Radiation therapy of spine and ribs but not in maxillofacial

area. CONFIRMS MRONJ DIAGNOSIS.

No evidence of infection or erythema. Patient is not symptomatic. STAGE 1 MRONJ

Treatment of Stage 1 MRONJ

0.12% Chlorhexidine gluconate antiseptic bisquanide mouthrinses. Any development of infection requires:

Penicillin V 500mg QDS Guided surgical debridement through oral and maxillofacial surgeon referral.

Preventing MRONJ in patients

For patients commencing or taking denosumab, practitioners should treat as if taking bisphosphonates. Therefore: Inform of benefits and risks of denosumab therapy. Perform necessary extractions prior to commencing denosumab therapy. Monitor oral health regularly along with implants for loss of osseointegration. If extractions required assess C-terminal telopeptide concentration (CTX) for bone turnover:

Fasted morning serum CTX concentration Risk of MRONJ/BRONJ<70 pg/mL High risk

70 -150 pg/mL Moderate risk

>150 pg/mL Negligible risk

Preventing MRONJ in patients

If extractions required assess C-terminal telopeptide concentration for bone turnover: Liaise with practitioner for temporary “drug holiday”. Increase of 25 pg/mL with every month drug is ceased. Prior to extraction take a review CTX assessment to confirm levels. Therapy can be restarted at least 10 days after extraction. Monitor extraction site and refer if after eight weeks bone still visible.

If extractions are unavoidable: Complete procedure with minimal trauma. Primary closure with sutures. Monitor extraction site and refer if after eight weeks bone still visible.

Questions?