Localization of the damage to the jaw can be explained by the constant stress of strong occlusal masticatory forces. The heightened daily bone remodeling requirements lead to higher concentrations of BPs being taken up in the jaws. That is, given that the bones of the jaw are sites of elevated bone turnover, BP levels within the maxilla and mandible would be selectively elevated [2]. Furthermore, the necrosis is more common in areas where a thin mucosa covers a bony exostosis or bony prominences such as lingual, mylohyoid, and palatal tori [14, 19]. Most (50–80%) cases of BIONJ are preceded by dentoalveolar surgery or dental trauma [11, 20–23]. Dental procedures, such as extractions or implants, are recognized as precipitating events since they increase the demand for osseous repair that exceeds the capacity of the hypodynamic bone, resulting in localized bone necrosis. Recent data indicated that the risk of developing ONJ was 53 times higher in patients with previous dental extraction than in patients who had not had a dental extraction during BPs treatment [24, 25]. Physiologically, no complications occur in the healing of a wound in the oral cavity, but when the mandible or maxilla is injured by a pathological process or high radiation doses, the reduced healing potential could increase the risk of necrosis and osteomyelitis at these sites [2].

Moreover, the mandible and maxilla are more frequently the site of infection than all other bones in the body. The jaw is separated from the oral cavity, an area vulnerable to trauma and microbiologically diverse, by a fragile barrier consisting of a thin mucosa and periosteum. Also, profound caries, endodontitis, and periodontitis further contribute to the onset of infections involving the bones of the jaw.

Recently, a novel etiopathogenetic mechanism linking BPs, local infections, and local pH was proposed. Both infections and dentoalveolar surgery have the potential to lower the pH (acidosis) of the oral cavity and associated structures. Physiologically, BPs bind to the bone at neutral pH and dissociate from hydroxyapatite in an acidic milieu. Thus, the consequences of a decrease in pH are not only direct cytotoxic effects on different cells, but also a local increase in active BPs. A recent study conducted by Otto et al. investigated the effects of the N-BPs zoledronate, ibandronate, and the non-N-BP clodronate at different concentrations and at different pH values (7.4, 7.0, 6.7, and 6.3) on mesenchymal stem cells in vitro. The results showed that high doses of N-BPs and a local acidic milieu, such as are frequently present in infections of the jaw, caused a significant decrease in cell survival and activity. Both zoledronate and ibandronate exhibited dose- and pH-dependent cellular toxicity, whereas the response of cells exposed to equimolar concentrations of clodronate was comparable to that in the BP-free controls [3]. These results may be explained by the protonated activation of N-BPs at low pH [26–28].

Advanced age, diabetes mellitus, renal insufficiency, immunosuppressant therapies such as corticosteroids, specific treatments other than BPs, alcohol consumption, cigarette smoking, among others, are considered co-morbid factors for ONJ, as the available data are conflicting and not strong enough to support these conditions as risk factors. Some studies have suggested that neither treatments for breast cancer, such as anthracyclines, tamoxifen, taxanes, trastuzumab, and aromatase inhibitors, nor multiple myeloma treatments, such as anthracyclines, melphalan, and thalidomide, nor patient age, renal insufficiency, alcohol use, and smoking were significantly associated with a greater risk for ONJ [24]. In contrast, others showed a correlation between cyclophosphamide or erythropoietin use in multiple myeloma patients, advanced age, and renal dialysis and the development of ONJ. Moreover, according to recent studies, patients under treatment with the anti-angiogenic drug bevacizumab for metastatic cancers have a greater risk of developing ONJ, while the anti-angiogenic drug sunitinib has been linked with ONJ progression [29–32]. The role of glucocorticoids in the development of necrosis of the jaw remains unclear, but it is well known that the long-term use of systemic steroids promotes aseptic necrosis of the bones, particularly of the femoral heads. However, based on published data, it is probable that high cumulative doses of glucocorticoids are a triggering factor for ONJ [24, 33–35]. Finally, because BP users develop bone necrosis only rarely, individual genetic variations in drug metabolism may influence susceptibility or resistance to BIONJ [2]. A study conducted among multiple myeloma patients treated with intravenous BPs demonstrated an association between a single-nucleotide polymorphism in the cytochrome P450-2C gene (CYP2C8) and an increased risk of BIONJ [36].

Thus, summarizing, BIONJ encompasses a wide range of etiologic factors and may result from one or more of them. It is now well established that intravenous BPs and dentoalveolar procedures are the main risk factors for BIONJ.