Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ)

Fig. 14.1

(a) Patient affected by metastatic breast cancer treated with i.v. zoledronic acid for 16 months. The arrow shows the presence of exposed bone in the posterior right maxilla after a tooth extraction. (b) Multislice CT scan with bone algorithm. Cortical osteosclerosis with maxilla sinus inflammation is detectable
BP belong to the category of bone antiresorptive agents, prescribed to patients with altered bone turnover, mainly osteoporosis, Paget’s disease, bone metastasis, and multiple myeloma [13]. BP inhibit the mevalonate pathway and consequently osteoclastogenesis and bone resorption [14]. However, in the past few years, a growing amount of data supports the theory that there might be new target cells and BP might have a more pleiotropic effect [15]. Based on the chemical structures, BP are divided into two main categories: nitrogen- and not-nitrogen-containing BP (Table. 14.1). The nitrogen-containing BP are more potent, and comprehend pamidronate and zoledronic acid, the two main drugs prescribed in oncological patients. Pamidronate was approved by FDA in 2001 and zoledronic acid in 2002 [16] and they are the BP more often related to ONJ, compared with not-nitrogen-containing BP. Not-nitrogen-containing BP are prescribed in patients with osteoporosis; they are usually orally available and are less potent BP.

Table 14.1

Major bisphosphonates, potency, primary indication, and route of administration
Drug name
Potency
Primary indication
Route of administration
Non-N-BP
Etidronate disodium
Osteoporosis, Paget’s disease
Oral and i.v.
Tiludronic acid
10×
Paget’s disease, hypercalcemia in malignancy
Oral
Sodium clodronate
10×
Bone pain, bone metastasis, hypercalcemia
Oral
N-BP
Pamidronate disodium
100×
Paget’s disease, bone pain, bone metastasis, hypercalcemia
i.v.
Alendronate
>100–<1,000×
Osteoporosis
Oral and i.v.
Risedronate sodium
>1000–<10,000×
Osteoporosis, Paget’s disease
Oral
Ibandronic acid
>1,000–<10,000×
Osteoporosis, bone metastasis, hypercalcemia
Oral and i.v.
Zoledronic acid
>1,000–<10,000×
Bone metastasis, Paget’s disease, hypercalcemia
i.v.
Non-N-BP not-nitrogen-containing bisphosphonates, N-BP nitrogen-containing bisphosphonates
Criteria for the definition of BRONJ have been established by the American Association of Oral and Maxillofacial Surgeons (AAOMS) in 2007 [17] and take into account three characteristics: current or previous treatment with a BP, identification of exposed bone in the maxillofacial region that has persisted for more than 8 weeks, and no history of radiation therapy to the jaws. Since not all the cases manifest with exposed bone, a revision of the definition has been proposed [18, 19] with the introduction of stage “0” (Table 14.2a).

Table 14.2a

ONJ staging system
Stage
Clinical presentation
At risk
No evidence of necrotic bone in patients treated with oral or i.v. BP
Stage 0
No clinical evidence of necrosis, but nonspecific clinical findings and symptoms
Stage 1
Asymptomatic patient with exposed necrotic bone, no evident infection
Stage 2
Symptomatic patient with exposed necrotic bone + infection (pain, erythema ± purulent discharge)
Stage 3
Exposed necrotic bone in symptomatic patient with pain, infection, and one or more of the following:
 Exposed and necrotic bone extending beyond the region of alveolar bone resulting in pathologic fracture
 Extraoral fistula
 Oral-antral or oral-nasal communication
 Osteolysis extending to the inferior border of the mandible or sinus floor
Modified from Ruggiero et al. [16]
Despite the extensive ongoing research, the mechanism that induces ONJ is still unclear. Recently several cases of ONJ related to other antiresorptive agents such as denosumab, an anti-RANKL monoclonal antibody, have been described, hypothesizing that ONJ is not related to BP, but to a class of drugs with antiresorptive activity, and a new terminology has been proposed: antiresorptive agent-induced osteonecrosis of the jaw (ARONJ) [20, 21]. Moreover, few cases of ONJ have been described in cancer patients treated with anticancer drugs [21] and the terminology might change again in the future. All these observations highlight the complexity of the pathogenesis of ONJ.
In the following chapter, we will try to better define the characteristics, the diagnostic, and the therapeutic approach to ONJ in the context of endodontic surgery. Currently very few cases of ONJ after endodontic surgery have been described in literature and guidelines on this topic are scarce.
In the course of this chapter, we will use the term ONJ as a generic term of necrosis of the jaw and BRONJ when specifically related to bisphosphonates, and we will use the more wide term of ARONJ when the ONJ can be related to both bisphosphonates and other antiresorptive agents.

Epidemiology

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 [2229]. 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 [3437]. 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].

Risk Factors

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].

Etiopathology: Osteonecrosis and/or Osteomyelitis

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.

Clinical Presentation and Staging

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).

Table 14.2b

Staging system proposed by Bedogni based on clinical and radiological findings
 
Clinical signs and symptoms
CT findings
Stage 1
Focal BRONJ
Bone exposure
Increased bone density limited to the alveolar bone region (trabecular thickening and/or focal osteosclerosis), with or without the following signs:
Sudden dental mobility
Markedly thickened and sclerotic lamina dura
Nonhealing postextraction socket
Persisting alveolar socket
Mucosal fistula
Cortical disruption
Swelling of the gum
 1a. Asymptomatic
Abscess formation
 1b. Symptomatic (pain and purulent discharge)
Trismus
Gross mandibular deformity and/or hypoesthesia of the lips
Stage 2
Diffuse BRONJ
Same signs and symptoms as stage 1
Increased bone density extended to the basal bone (diffuse osteosclerosis), with or without the following signs:
Prominence of the inferior alveolar nerve canal
Periosteal reaction
Sinusitis
Sequestrum formation
Oral-antral fistula
 2a. Asymptomatic
 2b. Symptomatic (pain and purulent discharge)
Stage 3
Complicated BRONJ
Same signs and symptoms as stages 1 and 2, with one or more of the following clinical signs and symptoms:
Osteosclerosis of adjacent bones (zygoma, hard palate), pathologic mandibular fracture, and/or osteolysis extending to the sinus floor
Extraoral fistula
Displaced mandibular stumps
Nasal leakage of fluids
Modified from Bedogni et al. [19]
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).

Prevention of BRONJ

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].

Management of Patients Receiving Bisphosphonate in Endodontic Therapy and Endodontic Surgery

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, 5153].
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].

Diagnostic Criteria for BRONJ/ARONJ

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Oct 11, 2015 | Posted by in Endodontics | Comments Off on Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ)
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