Review

Medication-related osteonecrosis of the jaw (MRONJ) stage III: Conservative and conservative surgical approaches versus an aggressive surgical intervention: A systematic review

Medication-related osteonecrosis of the jaw (MRONJ) is a relatively new pathology that involves the head and neck region. The first cases were described by Marx in 2003 (Marx, 2003) and Carter (Carter and Goss, 2003). They described MRONJ as a non-healing, avascular necrosis of the bones in the maxillofacial area that occurred after bisphosphonate (BP) treatment. Hence, this pathology was previously termed bisphosphonate-related osteonecrosis of the jaws (BRONJ), and it could be caused by either oral or intravenous BP treatment (Bagan et al., 2010).

BRONJ was defined as an exposure of necrotic bone in the oral cavity that lasted more than 8 weeks in patients with a previous history of BP treatment, but no previous radiotherapy (Ruggiero et al., 2004). However, over the past decade, it was shown that, in addition to BPs, MRONJ could be caused by denosumab and other anti-angiogenic drugs via a mechanism similar to the mechanism associated with BPs (Aghaloo et al., 2010, Sivolella et al., 2013, Santos-Silva et al., 2013; Ramírez et al., 2015). This finding eventually led to the introduction of the concept of MRONJ, defined in 2014 by the American Association of Oral and Maxillofacial Surgery (AAOMS) as “an exposure of necrotic bone in the oral cavity that lasts more than 8 weeks, in patients treated with anti-resorptive or anti-angiogenic drugs, without previous head and neck radiotherapy, and without bone metastases in the maxillofacial region” (Ruggiero et al., 2014).

MRONJ can significantly impair the patient's health and quality of life. Symptoms often include pain, swelling, bony sequestra, and in more severe cases, fistulae (intra- and extra-oral) and pathological fractures (Ruggiero et al., 2014, El-Rabbany et al., 2017). Importantly, the disease is more prevalent in the lower jaw than in the upper jaw. The most accepted hypothesis for the latter observation is that the disease arises due to a combination of trauma to the bone and a diminished ability to heal, and the lower jaw has little vascularization compared to the upper jaw (Khan et al., 2015). However, it is likely that the pathophysiology is more complex than previously thought. For example, because the mandible has less vascularization than the maxilla, a lower concentration of bisphosphonates would be delivered to the mandibular bone compared to the maxillary bone. Therefore, it is logical to assume that fewer MRONJ cases should occur in the lower jaw than in the upper jaw. However, the opposite was found in clinical observations (Ruggiero et al., 2014, Khan et al., 2015, Gryselyn et al., 2016). Consequently, unlike our clear understanding of the prevalence of mandibular osteoradionecrosis, it is not fully understood why MRONJ is more prevalent in the mandible than in the maxilla (Lyons and Ghazali, 2008).

According to the AAOMS, MRONJ was divided into four different stages (stages 0 to III) (Ruggiero et al., 2014). The AAOMS has suggested treatment strategies, including medical management for the earlier stages (stages 0, I), and preferably, surgical interventions for the later stages (stages II, III) (Table 1). This stage-specific approach permits a more standardized treatment protocol in the earlier stages. However, for the later stages, individual assessment of each patient is necessary (Ramaglia et al., 2018).

Although surgical treatment is typically recommended for the later stages, the extent of operative treatment remains controversial (Khan et al., 2015, Lopes et al., 2015, Sacco et al., 2018). The range of treatment modalities includes the simplest conservative treatment, and when necessary/possible, combined with a sequestrectomy (Favia et al., 2018, Coropciuc et al., 2017), to bony resection of all affected bone, with or without reconstruction with a microvascular free flap (Sacco et al., 2018, Favia et al., 2018, Blus et al., 2017, Vercruysse et al., 2014). To address this controversy, we performed a systematic review of the available literature on this topic. We aimed to determine which of these treatment options should be the standard treatment in patients with MRONJ grade III.