Medication-related osteonecrosis of the jaw (MRONJ)

The American Surgery of Bone Mineral Research (ASBMR) in 2007 defined MRONJ as “necrotic bone area exposed to the oral environment with more than eight weeks of permanence, in the presence of chronic treatment with Bisphosphonates (BP), in the absence of radiation therapy to the head and neck”.
Historically, the first drugs associated with the condition were BP, which led to coining of the term MRONJ. However, scientist need to include other drugs in the etiopathogenesis of osteonecrosis, such as other antiresorptive: Denosumab (DS) and antiangiogenic agents. MRONJ treatment is controversial nowadays and depend on Stages of the illness. Some authors recommend high toilettes and resection bone so other, prefer atraumatic therapies focused in antiseptic agents and interdisciplinary (dentist-physician) control.
The most common antiseptic agents used are Povidone Iodine, Rifamycin, Cetyl pyridinium chlorid and Chlorhexidine. Alcohol preparations have the fastest onset of action, followed by chlorhexidine and then povidone iodine. However, residual antimicrobial activity is greatest with chlorhexidine. Formulations that contain both chlorhexidine and alcohol combine the rapid onset of alcohol with the persisting effects of chlorhexidine.

M edication-related osteonecrosis of the jaw (MRONJ) is a condition where exposed bone or bone can be detected through an intraoral or extraoral fistula/e in the maxillofacial region, does not heal within eight weeks, and occurs in a patient who has received a bone-modifying agent (BMA) or an angiogenic inhibitor agent, with no history of head and neck radiation.
It was first reported in dental literature in 2003 and was initially used to describe the spectrum of dental problems seen in cancer patients treated with IV bisphosphonates for prevention of skeletal-related events. While varying terminology such as antiresorptive-related osteonecrosis of the jaw, bisphosphonate-related osteonecrosis of the jaw, avascular necrosis of jaw, osteonecrosis of the jaw, and phossy jaw have been used, MRONJ is currently the most accepted term.
In the last two decades, there has been a steady increase in its incidence. MRONJ occurs in approximately 1% to 9% of patients with advanced cancer who are receiving a BMA, in contrast to a much smaller percentage of patients who receive BMA pharmacotherapy for osteoporosis. As of 2010, 2408 cases were reported in literature: 88% associated with intravenous therapy (such as zoledronate and pamidronate), 11% received oral bisphosphonates, 89% had an underlying condition (multiple myeloma (43%), breast cancer (32%), prostate cancer (9%), other (5%) and 11% had osteoporosis (Filleul et al. 2010). Of interest, 67% of these cases were preceded by tooth extraction, 7% from other factors such as ill-fitting dentures, and in 26% of cases, there was no identified predisposing factor (Filleul et al. 2010). Other conditions in which higher rates of spontaneous necrosis may rarely occur include patients with hypercoagulable states and patients taking bisphosphonates who develop hypocalcaemia and secondary hyperparathyroidism.
The overall reported prevalence of MRONJ is 0.1% (10 cases per 10,000) in patients receiving oral bisphosphonate therapy for osteoporosis, marginally higher than the incidence in the general population. Duration of oral bisphosphonate therapy for osteoporosis appears a dose-dependent risk, with increased risk after four years of oral therapy (0.21%, 21 cases per 10,000), and is compounded if the patient is also being treated with longterm glucocorticoids or anti-angiogenic drugs. A prevalence of 1.7 cases per 10,000 has been reported for patients undergoing annual intravenous zoledronic therapy for three years, with no change after six years therapy. For denosumab, the risk of MRONJ is reported to be four cases per 10,000. Compared with patients receiving higher doses of anti-resorptives for cancer treatment, the risk of MRONJ for patients with osteoporosis exposed to anti-resorptive medications is approximately 100 times smaller. The risk of ONJ among cancer patients exposed to zolendronate ranges between 50-100 times higher than cancer patients treated with placebo, and the cumulative incidence of MRONJ ranges from 0.7% -6.7%).When limited to studies with Level 1 evidence, the risk of MRONJ in subjects exposed to zolendronate approximates 1% (100 cases per 10,000 patients). The risk for ONJ among cancer patients exposed to denosumab is comparable to the risk of ONJ in patients exposed to zolendronate.
The pathophysiology of MRONJ is unknown. Current theories centre on 5 main ideas: inhibition of bone remodelling, infection and inflammation, a lack of immune resilience, soft tissue toxicity and altered angiogenesis. The strongest evidence supports the former two.
The diagnosis of MRONJ is primarily clinical. It is worth remembering that the requirement to have exposed bone for a diagnosis has been debated. Other disease processes such as neoplastic infiltration of bone and osteomyelitis should be excluded. Further imaging may be required, and specialist interpretation is recommended. Radiographic features on plain film may not demonstrate early disease, however some non-specific features include increased prominence of the lamina dura around dentition, diffuse sclerosis, patchy lucencies and cortical erosions. More advanced features include sequestrum formation and periosteal reactions. A position paper of the American Association of Oral and Maxillofacial Surgeons describes a clinical staging process (Table 1).
While it is well-recognised that bisphosphonates and denosumab are implicated, several drugs carry the risk of this debilitating adverse effect. These include antiangiogenic agents, monoclonal antibodies, tyrosine kinase inhibitors and variant fusion proteins, with case reports for mammalian target of rapamycin inhibitors, radiopharmaceutical Radium 233, methotrexate, prednisolone and selective estrogen receptor modulator Raloxifene. The risk appears to be higher when utilized in conjunction with bone-modulating therapies ( Table 2). As a guide to identifying some novel drugs, their distinct and identifying nomenclature is shown in Figure 1.
MRONJ can be challenging to treat and can cause significant pain and reduced quality of life. Prevention is far preferable. Risk management when considering treating a patient who may potentially develop MRONJ necessitates informed consent with specific discussion of the patient's individual risk profile. Treatment of this condition aims to eliminate pain, control infection of soft and hard tissues and minimize progression of bony necrosis. It is largely dependent on the stage of disease and the patient's underlying medical history. With bisphosphonates, a drug holiday is often not useful due

Medication-related osteonecrosis of the jaw (MRONJ)
to the incorporation of the drug into bone tissue. In contrast, many newer medications have a shorter half-life, and therefore a drug holiday may be considered by the treating physician.
Management is often multidisciplinary and the patient should be referred to appropriate specialists. Treatment, according to the stage of the disease, may include conservative measures such as antimicrobial mouth rinses, antibiotics if clinically indicated, effective oral hygiene, and conservative surgical interventions, such as small sequestrum removal. More aggressive surgical intervention may be indicated for more severe cases. Possible adjunctive therapies include hyperbaric oxygen therapy, platelet rich plasma, bone morphogenic protein, and parathyroid hormone.
Preventive oral care methods combined with effective oral health practices are associated with a lower rate of MRONJ. It is strongly recommended that patients see a dentist prior to therapy to ensure that any teeth of questionable prognosis are assessed and extracted if necessary, with adequate healing time. Any dental prosthesis should be well fitting in order to reduce trauma. Dental screening, prophylaxis, oral hygiene instruction, tobacco and alcohol cessation counselling, and timely treatment is recommended to reduce risk. Consensus recommendations from the American Association of Oral and Maxillofacial Surgeons (AAOMS) and the International Task Force on Osteonecrosis of the Jaw agree that elective dentoalveolar oral surgery does not appear to be contraindicated in patients undergoing antiresorptive therapy for osteoporosis, however, identification and treatment of dental disease prior to the initiation of antiresorptive therapy, if possible, is recommended. Patients should be adequately informed of the small risk of MRONJ.

At risk
No apparent necrotic bone in patients who have been treated with oral or intravenous bisphosphonates Stage 0 No clinical evidence of necrotic bone but nonspecific clinical findings, radiographic changes, and symptoms

Stage 1
Exposed and necrotic bone or fistulas that probes to bone in patients who are asymptomatic and have no evidence of infection

Stage 2
Exposed and necrotic bone or fistulas that probes to bone associated with infection as evidenced by pain and erythema in the region of exposed bone with or without purulent drainage

Stage 3
Exposed and necrotic bone or a fistula that probes to bone in patients with pain, infection, and 1 of the following: exposed and necrotic bone extending beyond the region of alveolar bone (i.e, inferior border and ramus in mandible, maxillary sinus, and zygoma in maxilla) resulting in pathologic fracture, extraoral fistula, oral antral or oral nasal communication, or osteolysis extending to inferior border of the mandible or sinus floor  The first segment is the decision of the drug developer. The next segment is the target or disease class, to which a vowel may be added to allow pronunciation, Before 2009, tumour specific segments were used, but this practice has been discontinued because most monoclonal antibodies with oncology indications are investigated for more than one type of tumour. The third segment of the name indicates the source (eg, human, mouse) and is useful for predicting immunogenicity. The last syllable indicates the drug category. CT scan and OPG demonstrating stage 3 MRONJ of the right mandible in a 79 year old. The patient was being treated with Denosumab for multiple myeloma and had a routine dental extraction three months prior to presentation. Image 3 OPG and clinical photograph of the same patient after resection of the mandible and reconstruction with a fibula free flap.
MRONJ in the right Maxilla in a 78-yearold female undergoing treatment for disseminated ovarian cancer with dexamethasone and doxorubicin.

* Most reports have patients with previous bisphosphonate exposure.
Radium 223 (Xofrigo) Used to localize and manage bone metastases, sometimes in combination with chemotherapy.  In the last two decades, there has been a steady increase in the incidence of medication related osteonecrosis of the jaw (MRONJ). Besides bisphosphonates, several other medication classes have also been implicated in the development of MRONJ. MRONJ can be challenging to treat and can cause significant pain and reduced quality of life. Prevention is far preferable. This guide summarizes pertinent information on this condition, with a focus on prevention and risk management.

BDSc (UniMelb), MRACDS (GDP), DClinDent (OralMed) (UWA), MRACDS (OralMed), Cert ADL, FOMAA, FPFA
Amanda is an Oral Medicine Specialist. Her clinical and research interests include orofacial pain, temporomandibular joint disorders, oral mucosal disease, dental sleep medicine and paediatric oral medicine. She is Treasurer of the Australian Dental Association (WA), Editor, Examiner and WA region secretary for the Royal Australasian College of Dental Surgeons (RACDS) and has been on the WA Dental CPD committee for many years. She is heavily involved with various professional committees, and also dedicates her energy to supporting various community and volunteer causes. She is also passionate about her speciality, regularly lecturing, running oral medicine interest pages and dental forums, and teaching at the University of Western Australia. She is in private practice in Perth and Bunbury and has a public appointment at the Oral Health Centre of Western Australia.

MBBS, BDSc, Grad Dip (OMS), FRACDS (OMS)
Mr Leon Smith is a dual qualified specialist oral and maxillofacial surgeon. He is a Fellow of the Royal Australasian College of Dental Surgeons and has completed post-fellowship training in orthognathic surgery, facial trauma surgery and head and neck surgery at Royal Melbourne Hospital and Royal Darwin Hospital. He has a special interest in oral surgery, orthognathic surgery, oral and facial implant surgery and facial trauma surgery. Leon is actively involved in training advanced surgical trainees in oral and maxillofacial surgery. He is also a Specialist Consultant at Royal Perth Hospital, and is in private practice at Specialist Oral and Maxillofacial Surgery in Mt Lawley, Perth.