Medication Related Osteonecrosis of the Jaw (MRONJ). Review and recent advances

Bone targeting agents, bisphosphonates and denosumab, are a significant part of supportive care in patients with advance cancer and bone metastasis. These medications have been related with the development of osteonecrosis of the jaw (MRONJ), which, if not diagnosed and treated early, can significantly compromise patients' quality of life (Ruggiero et al 2014, Owosho et al 2016, Schiodt et al 2018, Migliorati et al 2019). Osteonecrosis of the jaw was first reported in 2003, in patients with cancer who received bisphosphonates (Marx 2003, Migliolati 2003, Wang et al 2003).

Targeted therapies, without known antiresorptive properties, mainly inhibitors of angiogenesis, have also been related to MRONJ (Guarneri et al 2010, Fusco et al 2016, Pimolbutr et al 2018, Mahedi Mohamed et al 2018, Nicolatou-Galitis et al 2019a). Concurrent administration of targeted therapies and antiresorptives, or sequential administration of zoledronic acid and denosumab may increase the risk of osteonecrosis of the jaw (Christodoulou et al 2009, Beusenlinck et al 2012, Smidt-Hansen et al 2013, van Cann et al 2018, Yarom et al 2018, Srivastava et al 2021).

This manuscript aims to discuss the recent advances on our knowledge about MRONJ and important aspects that can affect our best practice and management of patients with advance cancer and metastatic bone disease.

The most widely accepted update for the definition for MRONJ was proposed by the American Association of Maxillofacial Surgeons in 2014, as follows: Medication-Related Osteonecrosis of the Jaw (MRONJ) is defined as a complication, which affects the jawbone of patients that meet all of the following criteria: (a) patients were in the past or are now on treatment with bone targeting agents (BTAs) and/or antiangiogenics, (b) clinically they have exposed bone or bone that can be probed through an intraoral or extraoral fistula for more than 8 weeks, and (c) they have no history of radiation therapy or obvious metastatic disease to the jaws (Ruggiero et al 2014).

As it can be seen, the definition is based on the medical history and clinical presentation (Figure 1 and 2). This definition is discussed by different International Societies asking for modifications supported by recent research findings. The European Task Force for MRONJ believes that the current definition does not identify all patients with MRONJ, while the 8-week period of bone exposure or probing of the necrotic bone may delay diagnosis and management. The authors suggested to hold the 8-week period only for cases of dental extraction (Schiodt et al 2019). Furthermore, the non-exposed type of MRONJ, described by several researchers, should be included in the definition (Fedele et al 2010, Patel et al 2012, Schiodt et al 2014, Fedele at al 2015). The non-exposed type of MRONJ is considered in patents with pain of non-dental etiology, tooth mobility, purulence, swelling and numbness. About 25% of MRONJ cases present without jawbone exposure. A biopsy is required to document the vitality of the bone in these cases (Schiodt et al 2014, Fedele et al 2015,).

Figure 1:

Figure 2:

The American Association of Oral and Maxillofacial Surgeons described four stages of MRONJ, stage 0, 1, 2 and 3 to assist treatment decision making, while the radiological findings were included to assist staging (Table 1) (Ruggiero et al 2014).

The European Task Force for MRONJ believes that Stage 0 is a diagnostic challenge, as there are overlaps with dental and non-dental diseases. Furthermore, it does not fulfill the definition of the disease for exposed bone and may be misleading and difficult to interpret (Schiodt et al 2019). Following those considerations, the MASCC/ISOO/ASCO Group suggested that patients with clinical symptoms, without exposed bone should be considered as patients at risk to develop MRONJ and agreed that MRONJ should be classified at the 3 stages, as they are described in Table 1 (Yarom et al 2019).

A prospective controlled study, in a total of 5723 cancer patients, showed that the risk of MRONJ was 1.3% in patients who received zoledronic acid and 1.8% in patients who received denosumab (Saad et al 2012).

Systematic factors that may increase the risk for MRONJ development are the dose and duration of administration, the underlying disease, cancer type and stage, the type of the antiresorptive medication, comorbidities and the co-administration of other chemotherapeutics and biological therapies (Rugani et al 2016, Fung et al 2017, Otto et al 2018, Hallmer et al 2020, Hata et al 2022, Ikesue et al 2022, Fusco et al 2022). For example, the overall MRONJ prevalence was 2.09% in the breast cancer group, 3.8% in the prostate cancer group, and 5.16% for multiple myeloma patients (Rugani et al 2016). Patients with cancer that had a short survival time (lung and other cancers with median survival time less than 10 months) did not develop MRONJ. This could be attributed to the shorter duration of zoledronic acid in those patients (Hata et al 2022). Denosumab, as it was shown in a recent study, poses a significant risk for developing MRONJ as opposed to zoledronic acid (9.6% versus 4.8%) in patients treated for bone metastasis, and thus, these patients require close monitoring (Ikessue et al 2022). In another study, the incidence of MRONJ, in patients with breast cancer treated with zoledronic acid was 4.1% and in patients treated with denosumab, it was 13.6%. In the same study, corticosteroid use was associated with a decreased risk for MRONJ, and diabetes was associated with an increased use of MRONJ (Hallmer et al 2020). Furthermore, sequential treatment with bisphosphonate and denosumab was found to increase the prevalence of MRONJ (Higuchi et al 2018, Yarom et al 2018, Srivastava et al 2021). In a study, the pooled weighted prevalence of MRONJ in sequential treatment with bisphosphonates and denosumab was 13%, while with bisphosphonates only was 5% and denosumab only was 4% (Srivastava et al 2021).

Several studies have reported dental extractions and infection as the main local risk factors for the development of MRONJ. Dental extraction is a common predisposing event, before the appearance of MRONJ, ranging from 52% to 61% (Ruggiero et al 2014, Yazdi et al 2015). Following those literature data, the avoidance of dental extractions to resolve dental infections in patients, who received antiresorptives or antiangiogenics, were included in most recommendations (Matsuo et al 2014, Ruggiero et al 2014). Growing evidence, however, has suggested that dental and periodontal infection is the main local risk factor, which is related with increased risk for MRONJ development (Otto et al 2015, Kamimura et al 2018, Soutome et al 2018). The EU Task Force for MRONJ believes that a high proportion of MRONJ cases, which developed after a dental extraction, in fact they represent cases of non-exposed MRONJ, that had already developed before the actual dental extraction took place (Schiodt et al 2019).

Recent studies have shown the presence of histologically proven alveolar necrotic bone associated with dental/periodontal infection at the time of dental extraction (Nicolatou-Galitis et al 2020, Ristow et al 2021a). Both those studies showed that the alveolar bone, at the time of dental extraction, was already necrotic in about 70% of dental extractions of teeth with infection and symptoms, such as pain, swelling, purulence fistula, tooth mobility. Both groups of authors concluded that the dental extraction is the result of the infection and necrosis of the alveolar bone. Hence, the EU Task Force recommended that patients on antiresorptive therapy should not be declined dental extractions for the treatment of recurrent dental/periodontal infections that cannot be resolved with restorative treatment, as the persistence of the infection per se represents an important risk factor for MRONJ development (Schiodt et al 2019). The antiresorptive treatment may be re-started after two to four months, for maxilla and mandible respectively. Healing should be documented as the coverage of the post-extraction socket with normal mucosa and the radiographical presence of bone formation in the socket (Nicolatou-Galitis et al 2019b).

The radiological findings are assessed to define the stage of MRONJ and assist to treatment decisions (Ruggiero et al 2014, Yoneda et al 2017, Dutra et al 2019, Moreno-Rabie et al 2020, Wongratwanich et al 2021).

The most common radiological findings are osteolysis, mixed areas of osteolysis and bone sclerosis, osteosclerosis, bone erosion, bone sequestrum, post extraction phantom socket (Figure 3), subperiosteal reaction, increased thickness of lamina dura, narrowing of mandibular canal, maxillary antrum density and pathological fractures (Tsiklakis and Karayanni 2018). Panoramic radiograph (Figure 3) and Cone Beam Computed Tomography (CBCT, Figure 4) are useful to disclose the radiological findings of MRONJ. CBCT offers more accurate information, as it is a three-dimensional radiography and is superior to the panoramic radiograph to show the radiological findings of MRONJ (Bedogni et al 2014, Tsiklakis and Karayanni 2018, Ristow et al 2021b). The severity of radiological findings increases with the clinical staging (Cardoso et al 2017, Lentzen et al 2021).

Figure 3:

Figure 4:

Early radiological findings, prior to the development of MRONJ, have also been described. Bone sequestrum was observed, with the use of CBCT, in the 90% of patients, who later developed MRONJ (Soundia et al 2018). Osteosclerosis, osteolysis, increased density of the lamina Dura, non-healing socket, increased thickness of the cortical bone of the mandible and periodontal bone loss were considered as early radiological findings related to MRONJ by other authors (Moreno-Rabie et al 2020).

Periodontal and dental health are of critical importance for the prevention of MRONJ. Zoledronic acid and poor dental health were associated with increased incidence of BRONJ (Kizub et al 2021). On the other hand, good oral health reduced the risk for MRONJ (Dimopoulos et al 2009, Ripamonti et al 2009). The American Society of Clinical Oncology recommends that all patients should receive a dental examination and appropriate preventive dentistry before bone-modifying agent therapy and maintain optimal oral health during treatment (van Poznak et al 2011). A recent study showed that non-surgical periodontal therapy before the start of chemotherapy helps to reduce the inflammatory markers associated with the activity of periodontal disease, favoring a less inflammatory pattern, to avoid the exacerbation of periodontitis during cancer therapy. Less inflammatory pattern of periodontal tissues is expected to minimize the risk of MRONJ in addition to the maintenance of the oral health-related quality of life of the patient (Villafuerte et al 2021). The appropriately educated dentists to maintain the good oral health of patients, before, during and after cancer therapy, can significantly help, in collaboration with medical oncologists.