JOURNAL OF DENTISTRY AND DENTAL MEDICINE (ISSN:2517-7389)

Osteonecrosis of the Jaw; Treatment; Bisphosphonates

Patients who have metastatic bone dissemination not only suffer substantial pain, but may also develop fractures with devastating consequences. As it is known that the mechanisms of osteolysis associated with metastatic bone destruction are essentially mediated by osteoclasts, the inhibition of osteoclastic activity by bisphosphonates has become an important target in the drug for the treatment of such patients [1]. They inhibit both the osteoclastic activity and the recruited osteoclasts, and in addition, they decrease the life span of these cells. The efficacy of bisphosphonates has been established in numerous studies. Based on guidelines by the American Society of Clinical Oncology, bisphosphonates are standard treatments in patients with hypercalcemia associated with malignancy and metastases [2]. But since 2003, the use of bisphosphonates associated with maxillary osteonecrosis (BRONJ) has emerged as an important comorbidity, especially in patients treated with high doses of bisphosphonates over a long period of time [3]. Clinical symptoms and lesions are quite similar to those seen in patients with osteoradionecrosis. The necrotic bone is exposed to the oral cavity. The lesions are often painless; however, patients may experience pain because of the soft tissue inflammation surrounding the reactions and show symptoms and radiological signs of bone sequestration and/or osteomyelitis [4,5]. Risk factors for BRONJ include high doses of intravenous aminobiphosphonate, intravenous treatment for cancer (as compared to those treated orally), smoking, concomitant treatment with immunosuppressants and/or chemotherapy drugs, invasive dental procedures, oral infections, mechanical trauma to the jawbone and long-term treatment for bisphosphonates [3]. The American Association of Oral and Maxillofacial Surgeons [6] recommends suspected BRONJ if all of the following three characteristics are present: current or previous treatment with a bisphosphonate, bone exposed in the maxillofacial region persisting for more than 8 weeks, and no history of radiotherapy in the jaws. Four clinical stages of BRONJ were established:

Surgical treatment is needed in severe cases. Surgery may range from sequestrectomy to resection of the affected bone or the floor of the sinus in the mandible or maxilla. The gold standard treatments for stage 3 and advanced stage 2 of the disease are the surgical removal of necrotic bone tissue, sufficient free tension closure with mucoperiosteal flap and intravenous antibiotic therapy [8]. Although many studies on the types of treatment have been reported, BRONJ is still quite challenging and enlightened standards have yet to be established. Many patients have deteriorated after long-term therapy, conventional antibiotic treatment, and analgesics, and surgical intervention is necessary [9]. Therefore, this study sought to map and quantify through scientific and reliable database the work on the subject in question.

In this paper a bibliometric research was carried out, whose importance has been emphasized enough [10,11]. It is a “quantitative and statistical technique for measuring production indices and disseminating scientific knowledge” [12]. In this work it was used for the analysis of the academic production on the treatments for osteonecrosis of the jaws induced by bisphosphonates from publications indexed in the main collection of the Web database of Sciencetm. This type of study prioritizes indicators and bibliographic data in order to identify the trajectory of the scientific development of a certain subject or subject area [12]. Thus, the ISI Web of Knowledge/ Web of Science (SSCI Social Sciences Citation Index) was chosen as the database for its “academic recognition of being considered one of the most comprehensive journal bases covering several areas of scientific knowledge” [13]. The procedures for bibliometric analysis follow three steps similar to those proposed by Santos et al. (2014): the choice of the database and the criteria to be used for the collection; the data collection itself; the representation and analysis of the data. After data collection, the material was analyzed by exporting this data to the bibliometric HistCite analysis software package in order to organize information and facilitate analysis. The data were analyzed considering the evolution of the publications; the journals with the largest number of records; authors with more publications; the articles with the greatest impact and the institutions with the largest number of publications. In addition to these data, the relationships between the 20 articles with the greatest impact were analyzed. For this analysis, the work was divided into two groups: 1- Articles that received more quotes from other works throughout the ISI of Science (GCS) Web, defined here as citations for all indexed production in the database and 2 - group of articles that received further citations from the work of the selection group of this bibliometric study (LCS), defined as local citations, involved only the 875 articles selected for bibliometric analysis.

After conducting a bibliometric survey in the main collection of the Web of Sciencetm, 875 articles on bisphosphonate induced treatments for osteonecrosis of the jaws were identified. These articles are published in 299 different journals indexed to the database in question and written by 3846 authors who have links to 1237 institutions located in 59 countries. To achieve these articles, 13553 references were used with an average of approximately 15 references per article. In Table 1, these results are presented. In 2004, publications were launched and one article was published. In 2015, the year of greatest publication quality, 109 records were identified. And in 2017, 84 articles were published, reaching 875 records in the temporal cut (2004 - 2017). These publications are distributed in Figure 1 & 2 regarding the year of publication and number of records. The total number of publications was organized by the corresponding journals evidenced in Table 2. The journals with the highest number of publications records are “Journal of Oral and Maxillofacial Surgery” and “Journal of Cranio-Maxillofacial Surgery”, with 61 and 38 articles, respectively. The impact of each journal was verified by an index of division of the citations value, by the number of articles published, showing the Journal of Oral and Maxillofacial Surgery as the one with the highest index. The authors with the highest number of publications are distributed in Table 3 & 4. It presents 10 authors with the highest number of publications. The author who most published was Otto S followed by Walter C with 21 and 17 publications respectively.

From this research, it was possible to search for documents of high scientific quality indexed in the Web of Science and to have an overview of the scientific production of the developed world in relation to the subject. Regarding the annual evolution of the publication, it was observed that in the period between 2004 and 2006, the publications remained between 1 and 19 records, therefore, with small growth. The numbers only increased in 2007 with 44 records and in 2015 with 109 records, this last year being the peak of published productions. The first observations on this pathology, as well as the first attempts of treatment conduits were reported [2], which treated 63 cases of osteonecrosis of the jaws induced by bisphosphonates with surgical procedures, among them, sequestromias and bone resections. As already mentioned, BRONJ is a pathology that is difficult to treat because it presents causal and modifying mechanisms that are still poorly defined, resulting in constant research that looks for efficient forms of treatment. The publication of these methods in periodicals, mainly foreign ones, has the United States as the country with the highest scientific production, 222 published articles, followed by two European countries with 246 records and an Asian one with the number of 72. In a less favorable position with 44 in this study, we observe the relevance of Brazil in this study, which, even though it is a third-world country, occupies a prominent place in the production of knowledge, generating 146 global citations. Among the most relevant journals, that is, those with more articles, leads the ranking of the American “Journal of Oral and Maxillofacial Surgery” corroborating previous data on the origin of the most published articles. The journal is one of the leading journals in oral and maxillofacial surgery in the world and has 61 articles published, with a rate of 64.46 citations in other journals, which also has a higher impact factor. With 38 citations, is the second “Journal of Cranio-Maxillofacial Surgery”, the official journal of the European Association of Cranio-Maxillofacial Surgery? This information is important in the process of building scientific knowledge since it provides data that can support groups and research centers in the location of academic journals specialized in the topic with greater representativeness in both numbers of articles published and in the quantity of citations received per study. In relation to the authors with the greatest number of publications, two researchers from Germany stand out. With 21 and 17 records in that order, Otto S and Walter C, have the largest number of publications. However, none of these authors remain in articles with more quotations. Ruggiero, in spite of occupying the eleventh position and like unique American representative, is the author with greater production and is the one that has more quantity of citations. As regards the relation between the other articles cited in the Web of Science and those cited by the selected articles (Local Citation Score), between the selection set (2004-2017), we highlight the articles by Ruggiero H [3,6].

Among the 10 most cited in the Global Citation Score, the author has 2 records, the 2 being constructed with the collaboration of coauthors. His article of 2004 is the most cited in the relation among the 10 with the largest number of citations, however the work has this impact factor among the ten articles most cited due to the occurrence of self-citation. The same study published in 2004 [1] gains relevance in relation to the one observed among the 10 most cited articles in the Local Citation Index. In this respect, the study of the author, besides being among the 10 most cited, is one of the two most relevant of the list of citations among the 10 most cited articles, presenting itself as an article of authority. The study published in 2004 [1] is characterized as a pioneering study still seen as a reference, as it is cited by several studies conducted over the years [7,8,10,12,14,15,16]. The other studies are among the 18 articles with the highest impact factor [3,6,8,10,12,14,15,16]. These 18 articles with greater impact identified in the study, whether the origin of articles, periodicals or citations, indicates that the treatment has been well evidenced as an object of relevant study of the health of individuals. These searches for efficient treatments according to Kyle [14] have led various groups and organizations to develop or issue recommendations, position papers, or statements regarding the association of bisphosphonates with osteonecrosis of the jaw. In 2004, a multidisciplinary team was formed to review the literature and clinical evidence and to identify the risk factors of this disease, as well as to develop clinical guidelines for prevention, diagnosis, treatment and with a multidisciplinary effect. The recommendations resulted in a panel, which was distributed as a White Paper in the Annual of 2004 and published later (Table 5). Then the American Academy of Oral Medicine and the American Academy of Oral and Maxillofacial Pathology published position papers, and the American Association of Endodontists issued a statement. All these documents agreed that the prevention of osteonecrosis of the jaw associated with bisphosphonates is the best approach for the treatment of this complication. This table was updated in 2009 [6]. Since then, this document has been influencing behaviors used in several studies, including those most cited in scientific circles. Table 6 shows the list of authors and their respective treatments used by BRONJ for the 10 most cited articles. Authors with similar methods were placed in the same position as happened with Fizazi et al. (2011) and Morgan et al. (2010). In this work it was also possible to access the most recent productions on the subject. In the Jung study [9] involving 17 patients, subjects were first submitted to sequestrectomy under general or local anesthesia and suspension of the bisphosphonate used. The rate of bone regeneration was compared in concomitant computed tomography (CBCT), acquired immediately after the operation and after 3 months. Patients were then divided into groups that based on their treatment regimens, using: teriparatide combined with rhBMP-2 (PTH + BMP), rhBMP-2 (BMP) and control [17-19]. The comparison was made from biochemical markers that were evaluated at baseline (T0), 1 month (T1) and 3 months (T2) after surgery. Significant increase in these values of biochemical markers, osteocalcin and C-terminal telopeptide cross-linking of type I collagen serum was observed within 3 months of surgery in the PTH + BMP group, while the mean value in the BMP group showed no significant change [20,21]. In all groups, the lesions were cured and new bone formation was detected in the CBCT images. The regeneration rate was significantly higher in the 2PTH + BMP group than the BMP and control groups. This has shown that new management possibilities are being tested and have had positive results [22,23]. 

The study allowed to observe the evolution of the publications of more than 15 years on the treatments of BRONJ, as well as contributed to the identification of the most productive authors, as well as institutions with greater collaboration for the theme. There are 875 articles published in 399 different journals indexed in the Web of Science from 2004 to 2017. These articles were written by 3846 authors of 1237 Higher Education Institutions in 59 countries. The 18 articles with the greatest impact were published in the period between 2004 and 2009. It can be seen that research on treatments for BRONJ is developed in several higher education institutions distributed throughout the world, with highlights for the United States, Germany and Italy. The scientific evidence on this subject can contribute to the development of new research to fill knowledge gaps and thus achieve higher success rates for the management of this pathology.