Medication related osteonecrosis of the jaw

The purpose of this document is to provide information to health professionals regarding medication related osteonecrosis of the jaw (MRONJ). It should be noted that MRONJ is a novel term, used to broaden the definition of what was previously called bisphosphonate related osteonecrosis of the jaw (BRONJ).^r Several other medications, most notably denosumab, are associated with this uncommon complication of antiresorptive therapy in the treatment of skeletal related events in malignancy.

Definition

Medication related osteonecrosis of the jaw has been defined by consensus of the American Association of Oral and Maxillofacial Surgeons. Patients may be considered to have MRONJ if all of the three following characteristics are present:

1. ​current or previous treatment with antiresorptive or antiangiogenic agents
2. the persistence of exposed bone in the oral cavity for more than 8 weeks
3. no history of radiation therapy or obvious metastatic disease to the jaws.^r

Medication related osteonecrosis of the jaw (MRONJ) was first reported in 2002 and has become an increasingly recognised problem in patients receiving bisphosphonates and denosumab for bony malignancies.^r Bone destruction is associated with osteoporosis, lytic bone disease and skeletal fractures, frequently affecting the vertebrae, calvarium (vault of the skull), sternum, ribs, proximal humeri and femurs.

Bisphosphonates and denosumab (antiresorptive agents) are used in a number of settings including the treatment of osteoporosis, the management of tumour-induced hypercalcaemia and in the reduction of skeletal related events (SRE) in malignancy, particularly multiple myeloma, breast and prostate cancer.^r Osteonecrosis of the jaw secondary to bisphosphonate or denosumab treatment is an uncommon but potentially serious complication.

Pathophysiology

The pathogenesis of MRONJ is not well understood, but important contributing factors include:

• inhibition of osteoclast activity and reduced bone turnover and remodelling
• prevention of release of bone specific factors that promote bone formation
• antiangiogenic effects of some bisphosphonates (zoledronic acid) which may result in impaired blood supply to bone
• local trauma - up to 65 to 70% of cases had an invasive dental procedure to the affected site prior to developing MRONJ 
• periodontal or periapical infection/inflammation.^r

Bisphosphonates are a class of drug that act by inhibiting bone turnover and preventing bone resorption. Two classes of bisphosphonates are in clinical use:

• ​potent nitrogen-containing agents including zoledronic acid, pamidronate, alendronate, risedronate and ibandronate
• a less potent class of non-nitrogen-containing bisphosphonates including etidronate, tiludronate and clodronate.^r 

Denosumab is a fully humanized monoclonal antibody directed against RANKL (receptor activator of NFkB ligand). RANKL is secreted by activated osteoblasts and upon binding to its receptor, RANK, results in osteoclast maturation and proliferation, thus playing a critical role in regulating bone resorption. Denosumab binds with high affinity and specificity to RANKL thus exerting a potent antiresorptive effect.^r

Incidence/prevalence

In a combined analysis of three phase III trials (n = 5723) in patients with metastatic bone disease receiving antiresorptive agents, 89 patients were determined to have osteonecrosis of the jaw (ONJ): 37 (1.3%) received zoledronic acid and 52 (1.8%) received denosumab, and ONJ treatment was deemed to be conservative in 95% of the patients. The difference in these figures was not considered statistically significant.  Of the total number of patients who developed ONJ, 61.8% had had a tooth extraction^r.

The Saad et al^r paper also stated that ONJ is more common in patients receiving IV than PO bisphosphonates, and there appears to be a higher incidence in patients with metastatic breast cancer or myeloma.

A CALGB randomized clinical trial looking at the optimal treatment duration of zoledronic acid in breast cancer, prostate cancer and myeloma patients,^r stated the incidence of ONJ increases with cumulative drug exposure, from 1.5% of patients treated for 4 to 12 months, to 7.7% of patients treated for 37 months to 48 months.

The risk of ONJ in patients taking oral bisphosphonates for postmenopausal osteoporosis is estimated to be approximately 1 in 10,000 to 1 in 100,000 patient-years.^r

Risk factors

Symptoms and signs

Areas of exposed and/or necrotic bone are synonymous with MRONJ. It may occur spontaneously or following prior dental surgery, and may present as non-healing extraction sockets. It occurs more commonly (2:1) in the mandible than the maxilla.^r

Symptoms that may occur include:

• jaw pain
• loose tooth/teeth
• bone enlargement
• gingival swelling
• erythema
• ulceration.

Exposed bone may remain asymptomatic for months or years, becoming symptomatic when the surrounding areas become erythematous.^r​

Grading

Table adapted from AAOMS position paper on Medication Related Osteonecrosis of the Jaw 2014^r

Access a photographic example of MRONJ^r

Prevention of MRONJ

As there is no effective treatment for MRONJ, effective preventative strategies are essential. 

Several trials have demonstrated the superior efficacy of denosumab to zoledronic acid in reducing SREs in the setting of metastatic breast and castration-resistant prostate cancer, for which it is currently PBS approved.^r

In a randomized clinical trial involving 1,544 patients with bone metastases from breast cancer or prostate cancer, zoledronic acid administered every 12 weeks was non inferior to zoledronic acid administered every 4 weeks for reducing the occurrence of skeletal-related events.^rr

Recommendations prior to commencing antiresorptive and antiangiogenic therapy include:

• a detailed medical history to identify existing risk factors for MRONJ
• a comprehensive oral and dental assessment prior to commencing bone-modifying therapy where possible
• appropriate preventive dentistry
• treat active oral infections, and any sites that may be at risk of developing osteonecrosis
• educate the patient on the necessity of maintaining excellent oral hygiene (including additional regular brushing and flossing), and timely symptom reporting during and after treatment
• ensure dentures are properly fitted to prevent soft-tissue injury
• teeth with a poor prognosis or in need of extraction should be treated.^rr

Recommendations during and post antiresorptive and antiangiogenic therapy include educating the patient to:

• maintain excellent oral hygiene
• attend regular dental reviews
• avoid invasive dental procedures wherever possible.^rr​

The risk versus benefit of continuing bisphosphonate therapy should be assessed individually and there is minimal literature to guide this decision. Dickinson et al 2009 recommend suspending bisphosphonate treatment for at least 3 months and recommencing with bisphosphonate every 3 months or oral clodronate only in multiple myeloma patients at intermediate or high risk for SRE, preferably after resolution of BRONJ.^r

Treatment of established MRONJ

Treatment for established MRONJ is difficult. Patients may have incomplete healing, recurrent infections and chronic pain. Treatment is usually conservative as debridement and surgical intervention tends to worsen the problem. The following measures are recommended to improve pain and mucosal disease control and prevent extension of the problem:

• analgesia
• regular rinses with chlorhexidine 0.2% mouthwash
• intermittent or long term antibiotic therapy
• regular dental follow-up
• avoidance of debridement/surgical intervention (see AAOMS guidelines below).

AAOMS guidelines for treatment of MRONJ based on stage ^r

* Exposed or probable bone in the maxillofacial region without resolution for greater than 8 weeks in patients treated with an antiresorptive and/or an antiangiogenic agent who have not received radiation therapy to the jaws.
+ Regardless of the disease stage, mobile segments of bony sequestrum should be removed without exposing uninvolved bone. The extraction of symptomatic teeth within exposed necrotic bone should be considered since it is unlikely that the extraction will exacerbate the established necrotic process.

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