BRONJ is a very rare condition, with a highly inhomogeneous distribution based on the chemical structure and the potency of BP, schedule of administration, duration of treatment, and the type of bone disorder (malignant vs. not malignant bone disease). Cases of spontaneous not BP-related ONJ are very rare in the general population [4]. Based on case series, case-controlled studies, and cohort studies, the cumulative incidence of BRONJ is estimated to be between 0.8 and 12 % in patients receiving i.v. BP [22–29]. The incidence is higher in oncological patients, mainly affected by multiple myeloma (3.8 cases per 100 patients), prostate cancer (2.9 per 100 patients), and breast cancer (2.5 per 100 patients) [27]. The incidence is also influenced by dental procedures. In an Australian population-based survey [30], the frequency of BRONJ in cancer patients treated with i.v. BP is as low as 0.88–1.15 %, but it reaches 6.7–9.1 % after dental extraction [31]. BRONJ is even more rare in patients affected by osteoporosis receiving oral BP (0.01–0.04 %) from an Australian survey, with incidence rising to 0.09–0.34 % after dental extraction [31].

The discrepancy of the frequency in cancer population compared with osteoporosis can be partly related to different biology of the bone disease and to the different types of BP administered, the schedule of administration, and the cumulative dose of BP. As far as duration of treatment, the risk in multiple myeloma patients seems to be increased after 2 years of monthly administration of i.v. N-BP [23, 29].

Despite the observation that invasive dental procedures increase the risk of BRONJ, likely as a consequence of bone exposure and the increased risk of infections, cases of spontaneous BRONJ have been described in toothless patients, possibly related to the mucosal trauma from dental prosthesis, but sometimes no preceding factor is observed [32].

In the study by Hsiao that analyzed patients undergoing root canal treatments, the probability of healing after conventional root canal procedures in patients treated with oral BP was not statistically different from patients not receiving BP [33]. In the endodontic literature, very few publications reported cases of BRONJ in patients treated with BP [34–37]. Gallego described one case of BRONJ possibly precipitated by the mucosal damage induced by rubber dam clamp [34]. Goodell reported two cases of BRONJ precipitated by endodontic procedures. One patient was a 72-year-old man affected by prostate cancer and treated with i.v. BP that developed an ulcerated area after endodontic treatment on tooth #18. Tooth #18 also had a porcelain-fuse-to-metal restoration. The second case was a 74-year-old man affected by prostate cancer that has been treated with oral BP followed by i.v. BP. The patient received a nonsurgical endodontic treatment on tooth #15. After the procedure, the patient complained of persistent pain and underwent an apicoectomy without benefit of the symptoms. The patient developed tooth mobility in correspondence of fixed partial denture and exposed bone. The conservative treatment did not obtain any benefit, and he complained of pain and foul odor. After debridement of the maxilla and extraction of tooth #15 followed by antibiotic treatment, the patient improved, and the follow-up at 6 months showed a subjective and clinical amelioration [35]. Two more cases of BRONJ secondary to nonsurgical and surgical root canal treatments have been described by Sarathy et al. [36]. Finally, one case has been described by Katz in a 60-year-old female affected by multiple myeloma and treated with i.v. BP that underwent a bone graft procedure in the area of teeth #2–3. Tooth #3 was also treated with nonsurgical root canal and periradicular surgery. The clinical examination showed an area of exposed bone adjacent to tooth #2–4. The patient received a conservative treatment on #2 with rapid improvement [37].

Despite the extensive research directed to determine the etiopathology of BRONJ, data that demonstrate the causality of BP in the development of BRONJ are still circumstantial, and hypothesis about the risk factors and the mechanisms involved are even less clear. Due to the low frequency of ONJ compared with the extensive use of BP, it is evident that cofactors should be implicated in the development of this complication.

Several attempts have been addressed to identify risk factors, related to both patient’s features and drug characteristics [16, 19, 25, 30, 38]. In the 2009 paper by the American Association of Oral and Maxillofacial Surgeons, the risk factors are categorized in drug-related factors, local, demographic, genetic, and preventive [16]. The drug-related factors evaluate the type of BP, the potency of BP, the schedule of administration, and the duration of the treatment and more recently even their pharmacokinetics and pharmacodynamics [39]. About the potency, pamidronate and zoledronic acid are the types of BP more frequently associated with ONJ. Concerning the exposition to the treatment, several studies observed an increased risk for patients affected by multiple myeloma treated over 2 years, and the updated guidelines for the treatment of patients affected by multiple myeloma suggest a 2-year treatment and to evaluate case by case for longer therapy [40]. For breast cancer patients, the American Society of Clinical Oncology guidelines do not indicate a limit for the use of bone-modifying agents like BP and denosumab but suggest that should be continued based on the patients’ performance status [41]. The 2013 American National Osteoporosis Foundation guidelines observe that no treatment should be administered for indefinite time, but due to the lack of evidence in this field, especially for treatments longer than 5 years, they conclude that the duration of treatment should be individualized based on the fracture risk of each patient [42]. About local risk factors, the mandible is interested two times more than the maxilla. In the mandible the region of lingual tori and mylohyoid ridge are more prone to develop the complication, and in the maxilla the palatal tori is more often interested by ONJ [17, 39]. Cancer type should be taken into account as well, since multiple myelomas seem to be more prone to develop this complication [4, 27]. Moreover, the concomitant use of other drugs such as steroids and thalidomide may affect the bone biology as observed in some papers, but not confirmed by others [25]. Despite that lesions can be spontaneous, invasive dental procedure is one of the major risk factors for the development of BRONJ [17].

The three main hypotheses about the etiopathology of BRONJ evaluate the importance of local infections, the damage of the microcirculation (antiangiogenetic effect of BP), and the inhibition of the bone remodeling. It is still unclear if the osteonecrosis is the consequence of an osteomyelitis or if the osteomyelitis is secondary to the necrosis. Antiangiogenetic mechanism has been proposed by Ruggiero based on several research data of BP in vitro and in vivo [4], while other hypothesis are in support of altered bone remodeling and local infection [4]. It is important to note that since the frequency of BRONJ is extremely low (between 0.8 and 12 % in i.v. BP), BP probably act in a multifactorial context leading to avascular necrosis by a multistep pathogenesis.

The most widely used definition of BRONJ refers to the one given by the American Association of Oral and Maxillofacial Surgeons (AAOMS) in 2007 that refers to “patients with exposed bone of the maxillofacial region for at least 8 weeks (that) are currently on or have taken bisphosphonates and have no history of radiotherapy to the jaw” [17]. Differential diagnosis with similar conditions and delayed healing is necessary [16] as alveolar osteitis, sinusitis, gingivitis, and periodontal disease.

Based on the clinical presentation, BRONJ is classified into four stages (0–III) [16] (Table 14.2a).

Patients can present with asymptomatic exposed bone or can be symptomatic complaining pain, periapical/periodontal fistula, halitosis, tingling, and swollen gum.

An alternative definition and staging has been proposed by Bedogni that redefined BRONJ as follows: “bisphosphonate-related osteonecrosis of the jaw (BRONJ) is an adverse drug reaction described as the progressive destruction and death of bone that affects the mandible or maxilla of patients exposed to the treatment with nitrogen-containing bisphosphonates, in the absence of a previous radiation treatment” [19]. Bedogni proposes a staging on both clinical and radiological findings (Table 14.2b).

The majority of available guidelines [16, 38] suggests oral examination and removal of unsalvageable teeth: complete all-invasive procedures and complete recovery before the start of BP treatment. It has been demonstrated that the prevention reduces the risk of BRONJ, without completely eliminating the risk. For patients that are already receiving treatment, the approach is not quite clear. Avoiding invasive procedures and adequate prophylaxis should be guaranteed. Still controversial is the utility of suspension of BP for a maximum of 3 months before dental procedures.

Patients receiving BP should be aware of the risk of ONJ and should be educated as to the importance of dental hygiene and to report any pain, swelling, or exposed bone [16].

Dental extractions or invasive surgical procedure is considered one of the precipitating factors for the development of BRONJ [31, 43].

Nonsurgical endodontic treatment is preferred over extraction if pulpal disease is identified or for severely decayed teeth in patients with a history of receiving intravenous bisphosphonates or prolonged use of oral bisphosphonates [4, 33, 36]. In agreement with the position statement of the American Association of Endodontists of 2012, teeth to be extracted may be treated by crown resection, endodontic treatment of the roots, and restoration similar to preparing an overdenture abutment [44]. Moreover, nonsurgical root canal treatment is less traumatic to the oral tissue when compared to the extraction and is associated with ONJ only in 0.8 % of all cases [43].

When nonsurgical root canal treatment has failed, nonsurgical retreatment is considered as the first-choice treatment [45, 46].

Nonsurgical root canal treatment or retreatment has a success rate of up to 74 % for necrotic teeth with apical periodontitis [47]. Currently there are no data in the literature regarding the healing of periradicular lesions in patients taking intravenous bisphosphonates. We find only a short-term retrospective clinical and radiographic study that evaluated the healing of periradicular lesions in patients taking long-term oral bisphosphonates after nonsurgical root canal treatment. The authors conclude that these patients can expect a satisfactory outcome with evidence of periradicular healing [33].

When also nonsurgical root canal retreatment is impractical, surgical canal treatment is considered [45, 48]. The modern endodontic microsurgery is performed by using operating microscope, micro-instruments, ultrasonic tips, and biocompatible root-end filling materials and has a successful outcome in a follow-up of more than 1 year postoperatively in 89.0 % of cases [49, 50].

Currently there are few data about the outcome of surgical endodontic treatment in patients taking bisphosphonates. Sarathy et al. describe a case report where surgical endodontic treatment was a precipitating factor [36].

Surgical endodontic treatment is considered less invasive than tooth extraction, but several authors state that it is not recommended in patients taking bisphosphonates [36, 37, 51–53].

Surgical endodontic treatment should follow the same recommendation of any oral surgical procedures [54] and should be suggested to an assessment of the risk and potential benefits of the treatment for each individual patient [55].