- Zeitschriftendaten
- Format
- Zeitschrift
- eISSN
- 1792-362X
- Erstveröffentlichung
- 14 Aug 2014
- Erscheinungsweise
- 4 Hefte pro Jahr
- Sprachen
- Englisch
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
Osteonecrosis of the maxilla, presenting as exposed necrotic bone (compact arrow), after a dental extraction. Sockets without teeth (phantom sockets) (transparent arrow), are seen on the necrotic bone. Patient was asymptomatic at presentation.
Figure 2
Osteonecrosis on the maxilla was diagnosed after probing necrotic bone through a fistula (arrow). A plastic material (gutaperka) was inserted into the fistula to better disclose the fistula. Patient presented with pain and swelling.
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).
MRONJ Stages, American Association of Oral and Maxillofacial Surgeons 2014
|
Without clinical evidence of necrotic bone With nonspecific clinical findings With symptoms |
Exposed and necrotic bone or fistula probing the bone Asymptomatic patients No evidence of infection |
Exposed and necrotic bone or fistula probing the bone Infection evident by pain and erythema at the site of the exposed bone with or without purulent drainage |
Exposed and necrotic bone or fistula probing the bone Symptoms of pain and infection Extraoral fistula Oral antral or oral nasal communication |
|
Alveolar bone loss, resorption not attributed to periodontal disease Trabecular pattern changes Dense bone Lamina dura thickening Decreased periodontal ligament space |
Radiological findings localized to the alveolar bone |
Radiological findings localized to the alveolar bone |
Findings extending beyond the region of alveolar bone Pathologic fracture Osteolysis extending to the inferior border of the mandible or sinus floor |
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
Panoramic radiograph of a cancer patient, who received antiresorptives and presented with a non-healing socket (phantom socket) two months after the dental extraction of the mandibular molar tooth. Patient was diagnosed with MRONJ stage 2.
Figure 4
Cone Beam Computed Tomography of a cancer patient, who received antiresorptives. Osteolytic areas (arrows) and bone sequestrum (stars) are observed in the maxilla. Fullness of left sinus is also seen (asterisks). Patient was diagnosed with MRONJ stage 3.
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.
Conservative or surgical management continues to be an issue for discussion, while an increasing number of Centers are in favor of surgical management [Coropciuc et al 2017, Hayashida et al 2017, Ramaglia et al 2018, Yarom et al 2019, Yamada et al 2019, Schiodt et al 2019, Nonnenmuhlen et al 2019). Retrospective study with 75 patients at stage 1, who were managed conservatively, showed that only 8 patients were healed. The rest patients continued to show exposed necrotic bone, while 67 of all 92 osteonecrosis lesions worsened. Of those, 28 lesions progressed to extended areas of necrosis. The authors concluded that conservative management could lead to healing only in rare cases and can be useful only in patients who cannot undergo surgery (Ristow et al 2019).
The MASCC/ISOO/ASCO paper suggests being conservative at stages 1 and 2 and operate at stage 3 (Yarom et al 2019). On the other hand, the EU Task Force suggests treating surgically and early. Surgical treatment is superior to non-surgical management in promoting long-term mucosal healing as well as absence of symptoms or radiological signs indicative of bone necrosis. Early surgical intervention on localized disease may prevent progression and the need for subsequent extensive surgery. Non-surgical treatment may be a valid management particularly in frail elderly patients and in end-of-life oncology palliative setting (Schiodt et al 2019). The expertise of the surgeon, in the several Centers, seems to be an important factor for the selection of surgical management (Nicolatou-Galitis et al 2019b).
There is a limited information whether the interruption of antiresorptive medication can favor the healing of dental extraction or other dental surgical intervention. In one study, most cases of MRONJ developed within three years after the interruption of the antiresorptive medication. The higher prevalence was found within the first year of the interruption (Jung et al 2019). The interruption of denosumab seemed to favor the successful healing after dental extraction or after surgical intervention for the treatment of MRONJ, in a study with 13 patients (Owosho et al 2016). The study authors commented, however, that the role of interruption of the antiresorptive during the dental extraction or the management of MRONJ remains unclear.
The pathophysiology of MRONJ continues to be partly understood and it is certainly multifactorial. It is the basic science and knowledge for the prevention, diagnosis, and treatment of MRONJ. However, reduced turnover and infection, an almost universal finding, are thought to be central to the pathogenesis of MRONJ and potentially reduce the efficacy of the host defense against infection. Recent evidence questions the simplified etiology of low bone turnover causing MRONJ (Katsarelis et al 2015 (Fassio et al 2017). Antiresorptive medications, bisphosphonates promote osteoclast apoptosis and deposit in the bone, where they persist for a long time. On the contrary, denosumab does not accumulate inside the bone and inhibits osteoclastic bone resorption causing apoptosis. Other possible mechanisms include bone and mucosal injury, antiangiogenic effects, altered immunity, while genetics are under investigation. To date, the proposed mechanisms highlight the unique localization of MRONJ in the jaw bones (Chang et al 2018). The role of dental infections and the oral microbiome is central to osteonecrosis, and systemic conditions such as rheumatoid arthritis and diabetes mellitus contribute through impact of immunity resiliency. A better understanding of osteoimmunology and the relationship of angiogenesis to the development of MRONJ is needed along with detailed studies of the impact of drug holidays on the clinical condition of MRONJ (Chang et al 2018).
In conclusion, the recent advances in our knowledge for MRONJ may be summarized as follow:
Definition: The present definition needs to be updated to include the non-exposed type of MRONJ. The 8-week period prior to the diagnosis of osteonecrosis is suggested to hold only for cases of dental extractions. MRONJ is classified in 3 stages, while stage 0 represents patients who are at risk to develop osteonecrosis. The risk of MRONJ depends on different factors and should be interpreted in each patient individually. Patients with combination or sequential therapies may be at higher risk. Periodontal/dental infection is the most common local risk factor. The EU Task Force for MRONJ suggests that the dental extraction should not be declined for the treatment of recurrent dental/periodontal infections that cannot be resolved with restorative treatment, as the persistence of infection per se represents a significant risk factor for MRONJ development. At first visit, both panoramic radiograph and CBCT are necessary to disclose the status of the maxilla and mandible. CBCT is superior to disclose the radiographic findings early and defines the stage of MRONJ with increased accuracy. Surgical management is advantageous to non-surgical. Antiresorptive medication may be re-administered after healing of a post extraction socket and after two to four months, in the maxilla and mandible respectively. Healing is assessed with complete mucosal coverage of the post extraction area, while bone formation has to be documented radiographically in the socket. Antiresorptive medication may be re-administered after healing of osteonecrosis if the patient has progressive bone disease. If osteonecrosis recurs, we consider to permanently quit the antiresorptive. Patients' quality of life is the critical factor for the decision. Good oral health is important. Patients should be referred to dentists prior to the initiation of cancer therapy and be followed during and after therapy.
Figure 1
Figure 2
Figure 3
Figure 4
MRONJ Stages, American Association of Oral and Maxillofacial Surgeons 2014
|
Without clinical evidence of necrotic bone With nonspecific clinical findings With symptoms |
Exposed and necrotic bone or fistula probing the bone Asymptomatic patients No evidence of infection |
Exposed and necrotic bone or fistula probing the bone Infection evident by pain and erythema at the site of the exposed bone with or without purulent drainage |
Exposed and necrotic bone or fistula probing the bone Symptoms of pain and infection Extraoral fistula Oral antral or oral nasal communication |
|
Alveolar bone loss, resorption not attributed to periodontal disease Trabecular pattern changes Dense bone Lamina dura thickening Decreased periodontal ligament space |
Radiological findings localized to the alveolar bone |
Radiological findings localized to the alveolar bone |
Findings extending beyond the region of alveolar bone Pathologic fracture Osteolysis extending to the inferior border of the mandible or sinus floor |
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