Clinical profile of individuals with bisphosphonate-related osteonecrosis of the jaw: an integrative review

ABSTRACT BACKGROUND: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is still the most prevalent type of osteonecrosis with clinical relevance. In Brazil, bisphosphonate use is high but there is a lack of epidemiological studies on BRONJ. OBJECTIVE: To determine the clinical profile of BRONJ in a Brazilian population through an integrative review. DESIGN AND SETTING: Integrative review of BRONJ in a Brazilian population. METHODS: Cases and clinical research on Brazilians with BRONJ between 2010 and 2019, indexed in PubMed/MEDLINE, Scopus, Web of Science and LILACS were reviewed. Age, sex, type and time of bisphosphonate intake, administration route, related diseases, region of the BRONJ, diagnostic criteria, staging, triggering factor and type of treatment were analyzed. RESULTS: Fifteen articles on 128 subjects were included. Most patients were women (82.03%); the mean age was 63 years. Intravenous zoledronic acid was mostly used (62.50%), for breast cancer treatment (46.87%). The main localization of BRONJ was the mandible (54.68%), associated mainly with tooth extractions (45.98%). The diagnostic criteria were clinical (100%) and radiographic (89.06%), mostly in stage II (68.08%). The surgical treatments were sequestrectomy (37.50%) and platelet-rich plasma (PRP) (36.71%). Microbial control was done using chlorhexidine (93.75%) and infection control using clindamycin (53.90%). CONCLUSIONS: BRONJ had higher prevalence in Brazilian women receiving treatment for breast cancer and osteoporosis. The mandible was the region most affected with a moderate stage of BRONJ, particularly when there were histories of tooth extraction and peri-implant surgery. Sequestrectomy with additional drugs and surgical therapy was the treatment most accomplished.


INTRODUCTION
Bisphosphonates (BPs) are drugs with oncological indication that have been used since 1960. 1 They are currently indicated as therapy for multiple myeloma, malignant hypercalcemia, prevention of bone metastases and pathological fractures. 2 BPs may also be prescribed for other diseases such as rheumatoid arthritis, osteoporosis and osteopenia. [3][4][5] The mechanism of action of BPs consists of decreasing local vascular support and regulating bone metabolism, thereby reducing the action of osteoclasts and decreasing angiogenesis.
Therefore, bone remodeling and deposition of physiological bone matrix are also affected. 6,7 These effects on bone metabolism associated with local triggering factors, such as infection and tissue inflammation in the mouth, are named bisphosphonate-related osteonecrosis of the jaw (BRONJ). 8 Among the main triggering factors of BRONJ are the following: exodontia, peri-implant surgery and traumas in the buccal mucosa. 1,[9][10][11] The clinical characteristics of BRONJ can include asymptomatic manifestations, severe pain, presence of infections and bone exposure. 6 In 2014, there was a change in the nomenclature for this disease, to take into account its relationship with other drugs. The names currently used follow the pattern [medication]-related osteonecrosis of the jaw. This relates to the use of anti-resorptive and antiangiogenic medications, 8,[12][13][14] and more recent studies also mention the use of tyrosine kinase-inhibitor drugs and mammalian-target inhibitors of rapamycin. [8][9][10][11][12][13][14] Although, as mentioned before, other medications relating to maxillary osteonecrosis do exist, BPs are still the most relevant drugs in relation to osteonecrosis of the jaws. 8 The Brazilian population has high rates of breast and prostate cancer, 15 and for this reason, BPs are highly indicated, which exposes these individuals to the risk of BRONJ.
The clinical profile of BRONJ and treatment protocols can vary according to specific demographic factors. Therefore, there is a need for population-specific studies. However, there are no studies in the literature reporting on the features of BRONJ and its treatment in Brazil.

OBJECTIVE
This integrative review aimed to determine the clinical profile of osteonecrosis of the jaw exclusively associated with bisphosphonate therapy in the Brazilian population.

METHODS
The guiding question of this review was: and for PubMed we add the descriptor "Brazil". The descriptors entered in the databases are described below.
The selection of the articles that were assessed in full for the analysis on each of the variables of this review is described in Figure 1.
The systemic medication used consisted of antibiotic therapy with clindamycin in 69 cases (53.90%) and amoxicillin in four cases (3.12%). 12,17,26 Other antibiotics were also reported to have been used as part of BRONJ treatments but without any detailed description. Thus, for this reason, they were not included in this review. BPs, ALE is the BP that is most associated with BRONJ. 4,5,9, In Europe, individuals with rheumatoid arthritis have higher incidence of BRONJ than individuals with osteoporosis, since ALE is the treatment of choice and its use is prolonged. [29][30][31] In addition to the type of diagnosis of the disease and type of BP, surgical manipulation of the jaws 19,32 accounts for 60% of the local trigger factors for developing BRONJ. [32][33][34] Thus, in these Brazilian cases, the triggering factor most reported was tooth dental extraction (45.98%), Bisphosphonate-related osteonecrosis of the jaws--an initial case series report of treatment combining partial bone resection and autologous platelet-rich plasma.

DISCUSSION
Mandible (    Among the triggering factors for BRONJ, implant surgery still remains a matter of controversy in the literature. 8 A systematic review found that there was no evidence to demonstrate safety in performing dentoalveolar surgical procedures such as placement of dental implants in individuals exposed to BPs. Therefore, such procedures should be considered to be local risk factors. 44 In one Brazilian population, implant placement was considered to be the second most prevalent trigger factor (13.86%), with epidemiological values similar to those of a European population (13.50%). 35 Placement of dental implants in individuals who are using BPs presents local and systemic risk factors for development of BRONJ, regardless of the route of BP administration. Hence, these patients should not be treated in a conventional manner. The imminent risk of BRONJ and the risk of failure of peri-implant treatment should be always considered in drawing up the treatment plan. Patients should always be made aware of their systemic and dental condition.
Among the jaw bones, the chance of developing BRONJ is twice as high in the mandible as in the maxilla. 8,32,42,45 In the present review, we observed greater involvement of the mandible, i.e. similar to the findings in North American, 27,30,46 European 31,34,35,[37][38][39]47,48 and Asian [40][41][42][43] populations. Despite the lack of detailed information regarding the location of BRONJ that was seen in the present review, we found that the posterior region of the mandible was the most involved, which coincided with findings from the rest of the world's population. 31,34,35,[37][38][39][40][41][42][43]47,48 Therefore, in all cases, bone manipulation must be done in a precise, fast and atraumatic manner.
The fact that women have been found to be more affected by BRONJ, both in Brazil and in the rest of the world, [27][28][29][30][31][34][35][36][37][38][39][40][41][42][43][47][48][49][50] may be related to administration of BPs after the menopause and to high incidence of breast cancer and osteoporosis. In Brazil, under these two conditions, there is an indication for using BPs. In the present study, breast cancer and osteoporosis were the underlying diseases that led to the highest prevalence of BRONJ, and similar results were found in European populations. 36,38 Although the prevalence of BRONJ has mainly been associated with occurrences of breast cancer in the United States, multiple myeloma is the second most prevalent disease related to this oral complication. 27,34,38,46 The South Korean population is the only population in which BRONJ is more related to osteoporosis than to other underlying diseases. 42,43 Therefore, it is important for medical specialists such as mastologists and/or gynecologists to be aware that patients who use BPs are at greater risk of developing BRONJ. One preventive measure could be to refer patients for dental assessment, before or during the first months of prescription of BPs, in order to eliminate some foci of infection that can expose these patients to the risk of developing BRONJ.
This integrative review identified that the majority of the Brazilian cases were diagnosed during stage 2 of BRONJ, and this is similar to findings from other countries. 30,31,[36][37][38][41][42][43]46,48 High prevalences of other stages are unusual, but when this occurs, it is usually stage 3, in which there is involvement of adjacent structures such as the maxillary sinus or occurrence of pathological fracture of the mandible. 35,[47][48][49] In the present review, stage 3 had the second highest prevalence, affecting 18.43% of this Brazilian population.
The diagnosis of BRONJ in these Brazilian cases was clinical in all of them. Since 2014, AAOMS has recommended the use of complementary imaging tests to finalize the staging and evaluate possible bone alterations that can precede BRONJ. Despite this recommendation for concomitant use of computed tomography (CT) as the most appropriate examination, the present review identified that only 40.62% of the cases were diagnosed by means of cone beam computed tomography (CBCT). This suggests not only that there is probably a lack of knowledge of indication of 3D imaging such as CBCT to perform better examinations, but also that there is a lack of local resources or else that these examinations have a high cost. The radiographic evaluation criterion was not included in this integrative review because of the lack of detailed information in the studies selected.
In addition, it is important to mention that, although AAOMS recommends that BRONJ should be diagnosed using clinical and imaging methods, we would emphasize that there is a need to make differential diagnoses in relation to other lesions with clinical signs of bone exposure, such as bone metastases and clinical manifestations of multiple myeloma in the jaw through histopathological analysis. [50][51][52] Nonetheless, such lesions have been found to be very scarce, accounting for only 2.34%.
The etiology and progression of BRONJ are related to infection and inflammation. 8 In these Brazilian cases, sequestrectomy, resection and curettage were used, almost always in association with chlorhexidine mouthwashes and antibiotic therapy when necessary. In this last case, clindamycin was the main antibiotic selected, while other antibiotics like amoxicillin, tetracycline and metronidazole were also used but less frequently. Some studies have reported that the penicillin group was the first choice among antibiotics in Europe, 34,35,47 and clarithromycin in Asia. 40 Among the types of treatment mentioned earlier, surgical treatment is widely used in different populations around the world. 29,34,41,46,47,53 Regardless of the type of surgical approach used, debridement or sequestrectomy until accessing the bleeding bone is recommended for improving the chances of success in the treatment. 38 The limitation of the present study was its inability to provide detailed information about the location of BRONJ, type and dose of medications, radiographic features, biopsy and follow-up because of the lack of detailed information in the studies selected.
In addition, there were no randomized studies or investigations on BRONJ in Brazilian populations. For this reason, we suggest that such studies need to be conducted and need to provide detailed information, as mentioned earlier.

CONCLUSION
The manifestation of BRONJ in this Brazilian population was greatest in the mandibles of younger females, with greater associations with breast cancer and osteoporosis. The major risk factor was previous exodontia, and BRONJ was diagnosed mainly in the intermediate staging (II). Surgical intervention was the treatment most commonly used among these Brazilian patients.
This review identified greater use of chlorhexidine solution and prescription of clindamycin as the first-choice antibiotic therapy.
PRP was the complementary therapy most used.