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). 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

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 Several trials have demonstrated the superior efficacy of denosumab to zolendronic acid in reducing SREs in the setting of metastatic breast and castration-resistant prostate cancer, for which it is currently PBS approved.^rrr Osteonecrosis of the jaw secondary to bisphosphonate or denosumab treatment is an uncommon but potentially serious complication.

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:^r

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.

Pathophysiology

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

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^r 
• periodontal or periapical infection/inflammation.^r

Incidence/prevalence

Bone destruction affects 70% of patients with multiple myeloma and is a significant cause of morbidity.^r It 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.

Medication related osteonecrosis of the jaw (MRONJ) was first reported in 2002 and has become an increasingly recognised problem in patients receiving bisphosphonates and more recently denosumab for bony malignancies.^rr With regards to bisphosphonates, less than 10% of reported cases have been in patients receiving oral bisphosphonates for osteoporosis. Approximately 92% of reported cases received either zoledronic acid or pamidronate, both potent nitrogen containing bisphosphonates. It should be noted however, that these agents form the mainstay of treatment for bone disease in malignancy.^r

The true incidence of bisphosphonate related osteonecrosis of the jaw is largely unknown. The majority of the data has been derived from case series and retrospective reviews each with statistical limitations. The current estimations put the overall incidence at between 1 and 11%. Multiple myeloma patients treated with bisphosphonates have a higher reported incidence at 2.3 to 11%, while bisphosphonate treated breast and prostate cancer patients have a reported incidence of 1.2 to 6.5%.^r

Available evidence estimating the prevalence of ONJ in different types

Study	nONJ cases/total population	Overall prevalence	Stratified by tumour type
			MM	BC	PC
Bamias et al. (80)	17/227	6.9%	9.9%	2.9%	6.5%
Zervas et al. (82)	28/254	11.0%	11.0%	-	-
Badros et al. (109)	11/340	3.2%	3.2%	-	-
Ortega et al.  (110)	5/178	2.8%	-	1.6%	1.9%
Dimopoulos et al. (81)	15/202	7.4%	7.4%	-	-
Wang et al. (111)	15/442	3.4%	3.8%	2.5%	2.9%
Jadu et al. (112)	21/655	3.2%	3.2%	-	-
Hoff et al. (83)	29/1,886	1.5%	2.4%	1.2%	-
Estilo et al. (9)	35/4,835	0.7%	-	-	-

Abbreviations: BC, breast cancer: MM, multiple myeloma; ONJ, osteonecrosis of the jaw; PC, prostate cancer
©The Oncologist 2009

There is limited evidence evaluating the incidence of ONJ associated with denosumab. In the large randomised control trials there appears to be a similar risk to bisphosphonates, with an incidence of approximately 1-2%.^rrr One meta-analysis suggests that the risk is higher with denosumab particularly in the setting of metastatic prostate cancer.^r It should be note that approximately two thirds of cases of ONJ occurred following tooth extraction.^r

Risk factors

Risk factors for developing MRONJ
Prolonged exposure to bisphosphonates	Increasing evidence that ONJ is related to duration of treatment and total cumulative bisphosphonate exposure. Current treatment guidelines from the Mayo clinic and ASCO recommend a limit of 2 years duration for bisphosphonate treatment.rr
Type of bisphosphonate	The potent nitrogen-containing bisphosphonates appear to be most associated with ONJ Intravenous administration results in greater drug exposure than oral administration Several studies have suggested a higher incidence of ONJ with zoledronic acid than with pamidronaterrr
Dental extraction/local trauma	Approximately 65 to 70% of reported cases have had dental or oral surgical procedures prior to the development of ONJr
Dental co-morbidities	Up to 30% of reported cases have had dental or oral surgical procedures prior to the development of ONJr
Concomitant drugs	Both steroids and chemotherapy have been implicated in the development of ONJ in some studies, however most patients with multiple myeloma or bony malignancies have received one or both of these and hence the relative contribution of either of these is difficult to accurately determine Thalidomide in combination with zoledronic acid or pamidronate has also been implicated with increased risk of ONJ,r other studies however have failed to show this associationrr Bevacizumab and sunitinib have been implicated in increased risk of ONJ through restrospective analysis of large phase III trials of these drugs as well as several case reports.r The strength of evidence is greater for bevacizumab and the mechanism is thought to be via inhibition of VEGF-mediated angiogenesis. Other tyrosine kinase inhibitors have not been associated with MRONJ.
Other concomitant risk factors	Poor oral hygiene Smoking Alcohol use Diabetes

Symptoms and signs

Adverse effects from bisphosphonates are generally infrequent and include:

• bisphosphonate related osteonecrosis of the jaw (BRONJ)
• fever and flu-like symptoms
• myalgias
• hypocalcaemia
• renal dysfunction
• nausea and diarrhoea.

MRONJ may remain asymptomatic for many weeks or months. When symptoms do develop patients may complain of:

• localised pain
• numbness
• soft-tissue swelling and inflammation
• loosening of previously stable teeth
• drainage/discharge
• exposed bone
• non-healing extraction sockets^r

Grading

Staging of MRONJ
At risk	No apparent necrotic bone in patients who have received treatment with either oral or IV antiresorptive or antiangiogenic therapy
Stage 0	No clinical evidence of necrotic bone. Non specific clinical findings and symptoms such as a dull aching pain in the body of the mandible and unexplained loosening of teeth
Stage 1	Exposed and necrotic bone in patients who are asymptomatic with no evidence of clinical infection
Stage 2	Exposed and necrotic bone associated with infection and pain
Stage 3	Exposed and necrotic bone in patients with pain, infection and one or more of the following: exposed and necrotic bone extending beyond the region of alveolar bone pathologic fracture extra oral fistula oral antral/oral nasal communication osteolysis extending to the inferior border of the mandible of sinus floor

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

Access a photographic example of MRONJ^r

Prevention (MRONJ)

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

Recommendations prior to commencing antiresorptive and antiangiogenic therapy include:

• a detailed medical history to identify existing risk factors for MRONJ
• a thorough oral and dental assessment
• 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:

Patients should:

• 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

MRONJ* staging	Treatment strategies+
At risk category No apparent necroytic bone in patients who have been treated with either oral or IV bisphosphonates	no treatment indicated patient education
Stage 0 No clinical evidence of necrotic bone, but non-specific clinical findings, radiographic changes and symptoms	systemic management, including the use of pain medication and antibiotics
Stage 1 Exposed and necrotic bone, or fistulae that probes to bone, in patients who are asymptomatic and have no evidence of infection	antibacterial mouth rinse clinical follow-up on a quarterly basis patient education and review of indications for continued bisphosphonate therapy
Stage 2 Exposed and necrotic bone, or fistulae that probes to bone, associated with infection as evidenced by pain and erythema in the region of the exposed bone with or without prurulent drainage	symptomatic treatment with oral antibiotics oral antibacterial mouthwash pain control debridement to relieve soft tissue irritation and infection control
Stage 3 Exposed and necrotic bone or a fistula that probes to bone in patients with pain, infection, and one or more of the following: exposed and necrotic bone extending beyond the region of the alveolar bone, (i.e., inferior border and ramus in the mandible, maxillary sinus and zygoma in the maxilla) resulting in pathologic fracture, extra-oral fistula, oral antral/oral nasal communication, or osteolysis extending to the inferior border of the mandible of sinus floor	antibacterial mouth rinse antibiotic therapy and pain control surgical debridement/resection for longer term palliation of infection and pain

* 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 boney 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.

Educate patient:

• about risk of developing osteonecrosis of the jaw
• about symptoms of osteonecrosis of the jaw and to report any jaw pain or dental symptoms promptly
• the importance of maintaining excellent oral hygiene
• to have regular 6 monthly dental reviews
• to remind their dentist that they are on a bisphosphonate
• to avoid invasive dental procedures while having treatment with antiresorptive and antiangiogenic medications.