ANTICANCER RESEARCH 33: 3917-3924 (2013)

Incidence of -related Osteonecrosis of the Jaw in Consideration of Primary Diseases and Concomitant Therapies

ALEXANDRE T. ASSAF1*, RALF SMEETS1, BJÖRN RIECKE1, EVA WEISE2, ALEXANDER GRÖBE1, MARCO BLESSMANN1, TIM STEINER2, JOHANNES WIKNER1, REINHARD E. FRIEDRICH1, MAX HEILAND1, FRANK HOELZLE2 and FRANK GERHARDS2

1Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg Eppendorf, University of Hamburg, Hamburg, Germany; 2Department of Oral and Maxillofacial Surgery, University Hospital Aachen, Aachen, Germany

Abstract. Background: Since its first description by Marx in analysis did show a significant correlation concerning 2003, the etiology of bisphosphonate-related osteonecrosis of monocytostatic (p=0.0215) and triple-cytostatic therapy the jaw (BRONJ) is the subject of numerous scientific (p=0.0137). The majority of patients with BRONJ (60%) discussions for oral and maxillofacial surgeons. Many received a bisphosphonate therapy including zoledronate. retrospective studies on its etiology and pathogenesis have Single application with one bisphosphonate was administered been carried out to explain pathological mechanisms; most in 28 cases; 44 patients had a medical history of different use of them just take a close look at the issue of dosage and of bisphosphonate. Concomitant medication did not suggest application. Recently, attempts have been made, to identify possible correlation, nor did accompanying diseases, arterial co-factors which might promote the development of BRONJ. hypertension (33.33%) or arterial microcirculatory Patients and Methods: The present study is based on data of disturbances (20%). Conclusion: The evaluation of our 169 patients with osseous metastatic malignancies. All results is pioneering. The influence of cytostatics and patients received intravenous bisphosphonate therapy. On the combined therapy of cytotoxic drugs on the pathogenesis of basis of medical history, malignancy, and primary treatment, BRONJ is demonstrated here statistically. We confirmed a the modality of bisphosphonate therapy, and existing co- drug- and dose-dependent occurrence of BRONJ. Further morbidities and medication were analyzed. The role of prospective studies should be performed to elucidate the role immunosuppressive drugs, influence of underlying diseases, of tissue perfusion and oxygen saturation, and the influence and general factors such as age and gender were examined. of immunosuppressive drugs in relation to the occurrence of The predictability of necrotic involvement, influenced by the BRONJ, as well as on wound healing of initial lesions. underlying malignancy and its specific therapy, e.g. radiation and cytostatic therapy were analyzed and statistically Currently, non-neoplastic diseases, such as osteoporosis (1, 2), evaluated. Results: A total of 8.9% (n=15) of patients osteitis deformans (Paget’s disease) (1, 3) and arthritis (4) are developed BRONJ. The average time between diagnosis of treated by , as are neoplastic diseases, such as malignancy and BRONJ was 80 months. Nine patients tumor-associated hypercalcemia (1, 4-6), suffered from breast cancer, five had prostate cancer and one and skeletally metastatic carcinomas (1, 5, 7, 8), e.g. breast renal cancer. Separation into stage and histological subtype cancer. In 2003, more than 20 million oral applications of did not show any significant correlation, nor did age or bisphosphonates and, in 2005 about 2.9 million intravenous gender, to the occurrence of BRONJ. However statistical applications of bisphosphonates were recorded (9). Most frequently used bisphosphonates are zoledronate, pamidronate and ibandronate. Zoledronate is considered to be the most effective antiresorptive bisphosphonate (5, 10) and is used in Correspondence to: Dr. Alexandre Thomas Assaf, MD, DMD, therapy of tumor-induced hypercalcemia since 2001, osteolytic Department of Oral and Maxillofacial Surgery, University Medical processes since 2002 (9, 10) and postmenopausal osteoporosis Center Hamburg Eppendorf, Martinistrasse 52, 20246 Hamburg, since 2007 (11). Pamidronate was firstly permitted for Germany. Tel: +49 40741053259, Fax: +49 40741055467, Mobile: +49 15222815057, e-mail: [email protected] treatment of tumor-induced hypercalcemia in 1991, later for osteolytic lesions in multiple myelomas in 1995, and Key Words: Bisphosphonate, osteonecrosis, mandible, cytostatic osteolytic bone metastases of solid tumors (9) and Paget’s therapy, risk factors. disease in 1996 (12). Ibandronate was firstly permitted in 1996

0250-7005/2013 $2.00+.40 3917 ANTICANCER RESEARCH 33: 3917-3924 (2013) for treatment of tumor-induced hypercalcemia, skeletal metastatic carcinomas and postmenopausal osteoporosis. A prophylactic and analgesic effect of bisphosphonates has been reported, thus increasing the quality of life (13). In patients with breast cancer, a strong -induced resorption is detectable, which is why bisphosphonates can reduce osteolytic lesions (14). However, osseous metastases of prostate cancer mainly occur as osteoblastic lesions, which is why there was no positive effect after application of pamidronate in 643 patients (15). Zoledronate was found to be the only bisphosphonate that exhibits an analgesic effect as well as a reduction of skeletal complications in patients with prostate cancer. Additionally, zoledronate interacts with malignant plasma cells of Figure 1. Exposed necrotic bone in the right maxilla in a patient who multiple myeloma by causing a disturbance of the received zoledronate therapy over a period of 23 months. Exposed bone interaction between connective tissue cells and plasma cells initiated by teeth removal. in the bone marrow (10). In addition zoledronate has an analgesic effect and prevents fractures in patients with non- small cell lung cancer (16). Typical features of patients suffering from BRONJ are exposed necrotic bone areas in the maxilla (Figure 1) or mandibula (Figure 2). Initial diagnostics include a panoramic view (Figure 3), cone beam computed tomography, computed tomography scans, magnetic resonance imaging and scintigraphy. Next to intraoral affections of exposed necrotic areas, extraoral fistulas, resulting from necrotic bone lesions can be found (Figure 4). The clinical presentation and the course of BRONJ is similar to the one of osteoradionecrosis (ORN) (17-19). The risk of developing intraoral radiogenically-induced mucositis or osteitis of the jaw is mentioned only for the radiation field of head and neck tumors (5, 20). Radiation therapy in the head and neck area causes avascular osteonecrosis followed Exposed necrotic bone in the mandible in a patient who was by high linear energy impacting on osteoblasts, , Figure 2. treated with zoledronate. Exposed bone occurred spontaneously. osteoprogenitor cells, and endothelial cells (21, 22). Radiation therapy hypoxia causes hypovascularity and hypocellularity, which result in the clinical image of a non- healing wound (17). after intravenous application (1, 5, 24, 26). Co-factors for the BRONJ is related to the presence of a high number of development of BRONJ are traumata of the oral mucosa, e.g. osteoclasts with active re-absorbed bone. This accumulation prosthesis pressure marks, and iatrogenic lesions after dental seems to simulate a healing process. A similarly high number treatment or extraction wounds (12). Furthermore, there of osteoclasts are also seen in ORN but in this case, seems to be a relation between BRONJ and high expression accumulation is defined by sequestration and resolution (17). of nuclear factor Κ-B ligands (RANKL) in human gingival Both for ORN and BRONJ, obliteration of blood vessels of fibroblasts (HGF) and human periodontal ligament cells the jaw has been demonstrated; however, in patients with (HPDL), which can be found in the periodontal tissue (27- BRONJ this occurred only in very few samples (20). 29). However, spontaneous cases of BRONJ have been The etiology of BRONJ is considered to be multifactorial. described (1), according to Katz, particularly in the posterior Several prospective and retrospective studies have reported lingual mandible (30). Marx reported BRONJ to occur the frequency of occurrence of BRONJ to be 6.7-28% (1, 24- spontaneously in 22.3% of cases, and Ruggiero et al. in 14% 26). Zoledronate and pamidronate use represent the highest of cases (31, 32). As a pathophysiological mechanism of risk factors for the occurrence of BRONJ (12). The length of BRONJ, a lack of repair stimuli of osteocytes and osteoclasts duration of therapy seems to be decisive for the development arises. This should lead to a summation of microfractures (33, of BRONJ; the average period ranges from 25 to 40 months 34). Other authors support the theory of the angiogenic effect

3918 Assaf et al: Incidence of BRONJ - Clinical Evaluation of 169 Patients

Figure 3. Preoperative orthopantomographic image showing a typical osteolytic lesion in the right mandibule after bisphosphonate therapy with zoledronate.

of bisphosphonates (30, 35-38), e.g. lower capillary formation, inhibition of endothelial growth factor and of endothelial cell function (39). The findings of Allegra et al. support the theory of suppressive angiogenic activity by bisphosphonates on circulating endothelial cells in patients with BRONJ (36). In addition, in vitro studies showed an inhibition of vascular endothelial growth factor after zoledronate and pamidronate therapy, thus inducing a reduction of vascular sprouting (40, 41). Nevertheless, there is no clinical study to prove that the bisphosphonate-related inhibition of angiogenic activity causes osteonecrosis of the jaw (40, 42), which is why this theory is still controversially discussed (43, 44). Migliorati suspected that genetic disposition could be a co-factor for the development of BRONJ, as some patients were affected and others not (45). Figure 4. Extraoral fistula resulting from a necrotic bone lesion of the The aim of this study was to investigate retrospective the left mandible in a patient who received pamidronate (Aredia) therapy over a period of 19 months. incidence of BRONJ in patients treated for osseous lesions induced by cancer or metastases, taking into account further underlying diseases and concomitant therapies, which can lead to wound-healing disorders and associated Patients’ data were collected at the Department of Oral and hypoperfusion of maxillofacial tissues. Maxillofacial Surgery at the University Hospital of Aachen. Data collection included retrospective evaluation of the patients’ medical history and dental examination during outpatient cytostatic therapy Patients and Methods or intravenous bisphosphonate therapy. Inclusion criteria for this study were intravenous administration of a bisphosphonate due to a The evaluation of clinical data of this retrospective cohort study was primary or secondary bone malignancy. carried out through the investigation and data analysis of patients Evaluation of the patient data took place regarding previous who underwent adjuvant therapy with aminobisphosphonates due to bisphosphonate therapies (preparation, application time and dosage), a primary osseous metastatic malignancy. This data collection took the malignancy of primary diagnosis; present tumor stage according place over a period between February 2006 and April 2008. to classification of the Union Internationale de Cancer (UICC);

3919 ANTICANCER RESEARCH 33: 3917-3924 (2013) histopathological results; the aubsequent cytostatic therapy, including (n=10; 66.67%), ibandronate (n=3; 20%) or pamidronate the initial cytostatic subclassifications and special treatment (n=2; 13.33%). In all 147 patients (87%) treated by regimens; and any further resulting mono- or polycytostatic therapy, monotherapy (p=0.7795), and all 22 patients (13%) treated as well as local or distant radiation therapy; concomitant medications by combined therapy, no statistical significance regarding the according to their mechanism of action, and the prevailing comorbidities. Due to the large number of different application occurrence of BRONJ was found (p=0.5352). schemes of cytostatic substance classes, the statistical analysis was In patients without BRONJ, the median number of limited to the calculation enclosing mono- and polycytostatics, as administrations was 13, in those with BRONJ, the median was well as their combinations. Radiation therapy was categorized in 28. In patients without BRONJ, the interquartile range (IQR) head-local and head-distant treatment, with appropriate classification was five to 28 administrations (minimum one, maximum 99). of applied radiation dose and frequency of radiation. In the group of patients with BRONJ, the frequency of Statistical analysis was performed in collaboration with the administrations was higher, with IQR of 9.5 to 45.5 (minimum Institute of Medical Statistics at the University Aachen (RWTH) using Fisher’s exact test and Wilcoxon test. For statistical analysis 2, maximum 70), without statistical significance (p=0.8353). SAS 9.1 (SAS Institute Inc., Cary, USA) was used. In the group without BRONJ treated with alternating bisphosphonates, the IQR of single applications was 21.5 and Results 52.25 (median=34.5), and for patients with BRONJ it was 26 to 67.25 applications (median=44). The minimum number of The study cohort included 169 patients treated with administrations was two in patients without BRONJ, and 17 bisphosphonates, 121 women (71.6%) and 48 men (28.4%). in those with BRONJ, with maximums of 88 and 92, The prevalence of BRONJ in this study group was 8.9% (n=15 respectively. There was no statistical significance correlated patients), consisting of 9 female (60%) and 6 male patients to the sum of single applications with bisphosphonate- (40%); 154 patients did not show any signs of BRONJ changing therapy and the occurrence of BRONJ (p=0.2685). (91.1%), in total, 112 females (72.73%) and 42 males Fifty-nine patients without BRONJ received corticosteroids (27.27%). The mean age at the BRONJ-group was 62 years (51 as concomitant therapy. Cortisone was applied in 14 patients to 76 years), and that in the group without BRONJ 65 years (9.1%), prednisone in 12 (7.8%), and dexamethasone in 33 (37 to 81 years). According to Fisher’s exact test, there is no (21.4%). Four patients with BRONJ received dexamethasone statistically significant relationship between sex (p=0.3682), or (26.7%), one cortisone (6.7%), and one prednisone (6.7%). age of patients (p=0.3974) and the occurrence of BRONJ. There was no statistical significance between very short The median time for the development of BRONJ was 80 impact of corticosteroid therapy and the occurrence of months; the earliest diagnosis of BRONJ was 11 months and BRONJ (p=0.1214), nor after short impact (p=1), or long the latest 157 months after the initial diagnosis of malignancy. impact (p=0.2410). Furthermore, there was no statistical The median ranged from 61.25 to 140.75 months after the significance between other concomitant medications such as initial diagnosis of malignancy. The study cohort of 169 beta blockers or calcium channel blockers, and the occurrence patients consisted of 95 female patients with breast cancer of BRONJ (p=0.1701). (56.2%), 42 patients with multiple myeloma (24.3%), nine The prevalence of concomitant diseases, such as arterial males with prostate cancer (5.3%), four patients with rectal hypertension, diabetes mellitus, lung diseases or adiposity cancer (2.4%), four with renal cancer (2.4%), three with lung was high (n=129), but did not show any statistical cancer (1.8%), and 13 with miscellaneous malignancies, e.g. significance for the occurrence of BRONJ (p=0.05). thyroid cancer or sarcomas (7.6%). Among the 15 patients Another group of 123 patients received concomitant with BRONJ, the most common malignancy was breast cancer radiotherapy, 108 patients were without BRONJ (71%), and (n=9; 60%), followed by multiple myeloma (n=5; 33.33%) all 15 patients (100%) who suffered from BRONJ. Twenty- and renal cancer (n=1; 6.67%). All patients related to this five patients received head-near radiotherapy (20.3%) study were suffering from malignancies with . (p=0.2936), and 98 patients head-distant radiotherapy Twenty patients (13%) out of the initial study group and none (79.7%) (p=0.5776), without any statistical correlation to the of the 15 patients with BRONJ developed secondary occurrence of BRONJ for either group. Both groups that malignancies. There is no statistical relationship between the received head-distant radiotherapy were treated with a median incidence of a secondary malignancy and BRONJ (p=0.2209). dose of 40 Gy. No statistical significance was detected in the The bisphosphonates applied in this study cohort were group without BRONJ (IQR 19-72 Gy) (p=0.3498), nor in pamidronate in 49 patients (29%), ibandronate in 49 (29%), the group with BRONJ (IQR 30-50.4 Gy) (p=0.5436). zoledronate in 49 (29%), combined therapy including A total of 56 patients without BRONJ (36.4%) and nine zoledronate and ibandronate in 19 (11.2%), and combined patients with BRONJ (60%) received cytostatic monotherapy therapy of pamidronate and ibandronate in three patients with a frequency of five administrations. Statistical (1.8%). Patients suffering from BRONJ were most often evaluation points to a significant correlation between the treated with zoledronate or combined zoledronate therapies number of monocytostatic applications (p=0.0215) and the

3920 Assaf et al: Incidence of BRONJ - Clinical Evaluation of 169 Patients occurrence of BRONJ. Polycytostatic applications including The small sample size of 169 cancer patients, with only two different cytostatics were given to 73 patients without 15 patients (8.9%) with BRONJ, provides only limited BRONJ (47.4%) and in none of the patients with BRONJ, information. This prevalence confirms the results of Bamias with a frequency of one to three applications, and was not et al. with prevalence of 6.7% of BRONJ in their study statistically significantly correlated to the occurrence of group (24). In contrast, Boonyapakorn et al. presented a BRONJ (p=0.4771). Application of three cytostatics, with a four-fold higher prevalence of 28%, which may be due to the frequency of one or two administrations, took place for 25 fact that 46% suffered from multiple myeloma with highly- patients (16.2%) without BRONJ and six patients (40%) with dosed cytostatics and corticosteroids, and 82% of all patients BRONJ. Similar to the statistical results for monocytostatic with BRONJ received bisphosphonate therapy containing use, a significant correlation with the occurrence of BRONJ zoledronate (1). was found (p=0.0137). In most study groups, the majority of patients with Finally, the relationship between tumor stage, BRONJ have breast cancer or multiple myeloma (7, 18, 32). histopathological classifications of each malignant disease A possible correlation between the frequency distribution and occurrence of BRONJ was evaluated. As an example, with BRONJ and patients with breast cancer may be seen in patients with breast cancer (n=95) were divided into four the high prevalence of this malignancy within the female subgroups: 47 patients without BRONJ (49.5%) and five population. In addition, patients with breast cancer receive patients with BRONJ (5.3%) had an invasive ductal immunosuppressive cytostatic therapies, which may be risk carcinoma. Invasive lobular carcinoma was found in 10 factors for the development of BRONJ. The incidence of women (10.5%) without BRONJ, but in no women with multiple myelomas is lower, but primary manifestation of BRONJ. Likewise a mixed form of breast cancer was found numerous neoplastic proliferations, introduced by plasma in only one woman (1.05%) without BRONJ. The final group cells, requires early bisphosphonate therapy. Furthermore, had tunor of an uncertain histology: 28 women (29.5%) there is a prothrombotic effect of malignant diseases, which without BRONJ and four women (4.2%) with BRONJ. No is additionally treated by high-risk therapies, such as statistical correlation was found between the different corticosteroids and high-dose cytostatics. histological types of breast cancer and the occurrence of Over a period of 60 to 141 months, our patients were BRONJ (p=0.9112) in any of the groups. Even the staging treated, according to their malignancy, by several tumor- (UICC) of all patients with breast cancer (with and without specific therapies, e.g. cytostatic or radiation therapy BRONJ) did not show any statistically significant correlation combined with concomitant therapies, such as (p=0.2037). In all other groups with malignancies, e.g. corticosteroids. In every therapeutic cycle, patients are prostate cancer (p=0.4429), multiple myeloma (p=0.4782), repeatedly exposed to immunocompromising systemic and and lung cancer (p=0.4429), no statistical significance local factors (neutropenia, oral mucositis), which enhance the concerning the occurrence of BRONJ was found. probability of BRONJ occurrence (17, 36). Zoledronate is currently the most potent and effective of Discussion all bisphosphonates (5, 10). In our study, 46.6% of patients that received zoledronate as single medication developed The aim of this retrospective cohort study was to determine BRONJ; 66.7% received zoledronate in combined therapy. possible correlations between patient-related examination This high percentage supports the conclusion of a correlation parameters and the occurrence of BRONJ. Most publications between the use of zoledronate and the occurrence of concerning BRONJ are retrospective studies or case reports. BRONJ. In the literature we found many results that are Only few prospective studies are reported related to possible similar to ours, with 41.2-64% of patients with BRONJ being pathogenesis of BRONJ by means of selected generic treated by single administration of zoledronate and 22.7- parameters, e.g. different application forms of 58.8% in combined therapy (1, 24, 25, 35). A significant bisphosphonates, underlying malignancies, cytostatics, and age correlation between the occurrence of BRONJ and the and sex of patients (1, 24). Several concomitant diseases and application of zoledronate was found. Similar to our findings medications have been discussed as influencing factors for the (13.33%), only 14% of patients with BRONJ in the study of occurrence of BRONJ, however, without proven statistical Boonyapakorn et al. received pamidronate (1). In contrast to connections (17, 42, 46). In addition, tumor-specific therapies the studies of Bamias et al. and Boonyapakorn et al., in have been described, such as cytostatic or radiation therapy of which no patient that was treated with ibandronate developed the head and neck region with undesirable immunosuppressive BRONJ, in our study group, three patients receiving side-effects, associated with the occurrence of BRONJ (12, ibandronate (20%) suffered from BRONJ (1, 24). 46). There is no prospective study with a closed group of The question as to whether there is a significant influence patients in regard to the prevalence of all possible relevant concerning the means of treatment for the purposes of mono- factors that may be related to the occurrence of BRONJ. or polycytostatic therapy and the occurrence of BRONJ

3921 ANTICANCER RESEARCH 33: 3917-3924 (2013) cannot be answered on the basis of the available data. The Marx discussed a negative effect on local wound healing fact that there were also patients who developed BRONJ after radiation therapy (31). The clinical features of BRONJ following low-dose therapy supports the assumption of a seem to be similar to the ones of ORN, characterized by multi-causal event. tissue hypoxia, hypovascularization, and hypocellularity (17, Patients of our study group were treated monthly with 21, 22). Both BRONJ and ORN appear predominantly after intravenous application of bisphosphonates. The average months to years; differently from the effect of duration of administrations in our study group was 36 bisphosphonates, radiation therapy impairs stem cells of late- months; this was close to that of other studies who describe reacting tissues, fibroblasts, and vessels (18, 20, 47). The 25-39 months (1, 5, 26). current study did not show any correlation between direct or Increased incidence of BRONJ at an advanced age is indirect head distant radiation therapy and the occurrence of marked by the prevalence of treatment-indicated BRONJ. The applied radiation dose, divided into low-, malignancies between the sixth and eighth decade of life medium-, and high-dosage groups, did not confirm any (48); this becomes apparent in the results of multiple studies significant correlation, similarly to the results of other (1, 4, 24, 25). studies (4, 5, 12, 21, 53). As also presented in our study, most patients with BRONJ Cytostatic therapy is discussed as a co-factor for the suffer from breast cancer (60%) at an average of 62-63 years development of BRONJ (10). A possible etiology could be (48). An existing relationship between the age of patients and cytostatic-associated myelosuppression (17) and the resulting malignant disease is strengthened by the results of immunosuppression (36). Attributable to the cytotoxicity of Vahtsevanos et al., who presented a significant correlation in cytostatics, local occurrence of oral mucositis is probable, a study group of 1621 patients (49). thus allowing gateways for bacteria through epithelial Sixty percent of patients who suffer from BRONJ are lesions, supporting local infection and reducing females. This reflects to the fact that 56.2% of all patients immunotolerance. The dose of cytostatics and their had breast cancer, which is similar to the results of O’Ryan combinations have an additive effect on the incidence of et al., who reported 57.6% of female patients with BRONJ, unsolicited effects (47). Statistical calculation showed a with 44.1% patients with breast cancer (50). The results of correlation of the occurrence of BRONJ and the frequency Boonyapakorn et al. and Bamias et al. revealed a higher of monocytostatic therapy (p=0.0215). In patients treated by fraction of male patients with BRONJ (58.8-64%), whereas polycytostatic therapy with two substances, a significance in their study groups, patients suffered from prostate cancer, was not found; however, in patients receiving three or more and multiple myeloma, which is 1.5-times more frequently cytostatics, a statistical correlation was found (p=0.0137). found in males (1, 24). The retrospective study results Based on our results, we confirm the opinion that the risk of presented in the literature demonstrate that occurrence of adverse reactions increases with accelerated individual BRONJ is not gender-specific, but depends on malignancies application rates of cytostatics (47). Many authors grade included in the study and their gender-specific prevalence. cytostatic therapy as a possible correlating risk factor of As part of a multifactorial cause complex, concomitant BRONJ (5, 12, 31, 53). Similar to the studies of Ficarra et medications are discussed; above all immunosuppressant al. and Capalbo et al., most of our patients with BRONJ have corticosteroids (17, 40, 43, 47). The similar distribution in been treated with alkylants (18, 54). Some cases, as also our two populations (26.6% with and 21.43% without reported by Migliorati et al., were treated with cytostatics BRONJ) show, similarly to the results of Boonyapakorn et from the antibiotic group (5). Due to the small amount of al., that the duration of corticosteroid action is apparently not data and a high variation in cytostatic regimens, a possible a predisposing factor for the development of BRONJ (1); correlation cannot be considered. Larger prospective cohort even the statistical analysis did not show a significant studies are necessary to prove any correlation between the correlation. different cytostatic substances and the occurrence of BRONJ. Numerous publications discuss the risk of increasing the occurrence of BRONJ by concomitant diseases, such as Conclusion diabetes mellitus, peripheral vascular diseases (17, 43, 51), hypertension (52) and hypercholesterolemia (38). Local The available data set in this study group was not sufficient predisposing factors are seen in the context of orally to address all our questions regarding finding significant manifesting complications, e.g. mucositis, gingivitis and correlations for the occurrence of BRONJ. Further questions periodontitis (17). In our study, hypertension was the remain concerning start and stop therapy with complaint with the highest prevalence, both in patients with bisphosphonates, correlation in the occurrence of BRONJ, BRONJ (33.33%) and those without BRONJ (20.78%). surgical treatment of patients with BRONJ at convenient time Nevertheless, statistical evaluation did not prove a significant or most effective conservative and surgical treatment correlation for the occurrence of BRONJ. depending on the stage of BRONJ and associated diseases.

3922 Assaf et al: Incidence of BRONJ - Clinical Evaluation of 169 Patients

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Swiss Med Wkly 136(31-32): 504-509, 2006. Factors associated with osteonecrosis of the jaw among 37 Koka S, Clarke BL, Amin S, Gertz M and Ruggiero SL: Oral bisphosphonate users. Am J Med 121(6): 475-483, 2008. bisphosphonate therapy and osteonecrosis of the jaw: What to 53 Dimitrakopoulos I, Magopoulos C and Karakasis D: tell the concerned patient. Int J Prosthodont 20(2): 115-122, Bisphosphonate-induced avascular osteonecrosis of the jaws: A 2007. clinical report of 11 cases. Int J Oral Maxillofac Surg 35(7): 38 Yarom N, Yahalom R, Shoshani Y, Hamed W, Regev E and Elad 588-593, 2006. S: Osteonecrosis of the jaw induced by orally administered 54 Capalbo S, Delia M, Diomede D, Dargenio M, Chiefa A, Favia bisphosphonates: Incidence, clinical features, predisposing G and Liso V: Jaw osteonecrosis associated with use of factors and treatment outcome. Osteoporos Int 18(10): 1363- bisphosphonates and chemotherapy: Paradoxical complication of 1370, 2007. treatment of bone lesions in multiple myeloma patients. Int J 39 Merigo E, Manfredi M, Meleti M, Corradi D and Vescovi P: Jaw Hematol 83(5): 439-442, 2006. bone necrosis without previous dental extractions associated with the use of bisphosphonates (pamidronate and zoledronate): A four-case report. J Oral Pathol & Med 34(10): 613-617, 2005. 40 Thakkar SG, Isada C, Smith J, Karam MA, Reed J, Tomford JW, Englund K, Richmond M, Licata A, Hatch C and Hussein MA: Received June 11, 2013 Jaw complications associated with bisphosphonate use in patients Revised July 1, 2013 with plasma cell dyscrasias. Med Oncol 23(1): 51-56, 2006. Accepted July 3, 2013

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