ORL 2014;76:199–206 DOI: 10.1159/000365930 Received: December 19, 2013 Accepted after revision: July 11, 2014 Published online: August 28, 2014
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Original Paper
Sinus Mucosal Thickening in Bisphosphonate-Related Osteonecrosis of the Jaws: A Case-Control Study Lorena Gallego a Luis Junquera b Alejandro Pelaz a Luis García-Consuegra a Ángel Alvarez-Arenal c Serafín Costilla d a Department of Oral and Maxillofacial Surgery, Cabueñes Hospital, Gijón, b Department of Oral and Maxillofacial Surgery, Central University Hospital, University of Oviedo Dental School, c University of Oviedo Dental School, and d Department of Radiology, Central University Hospital, University of Oviedo Dental School, Oviedo, Spain
Key Words Bisphosphonates · Osteonecrosis · Sinus mucosa · Radiographic signs Abstract Osteonecrosis of the jaws is a clinically significant complication of bisphosphonate (BP) medications. Otherwise, the effects of BPs on oral soft tissue or cells remain unknown. The main objective of the present study was to determine whether the presence of sinus mucosal thickening was significantly related to BP-related osteonecrosis of the jaw (BRONJ). A case-control study was conducted on 32 patients who underwent treatment of BRONJ with conventional radiological investigations (panoramic radiographs) and computed tomography. The results indicated that patients with BRONJ had a 5.57-fold greater probability of presenting sinus mucosal thickening than controls. Although the existence of this thickening was more common in patients with advanced-stage disease or low levels of C-telopeptide-cross-linked type I collagen, no significant difference was observed between cases and controls. While considering the limitations inherent in the design and number of cases analyzed in our study, patients with osteonecrosis of the jaw were found to have a 5.57-fold greater probability of presenting sinus mucosal thickening (>3 mm) than healthy subjects. © 2014 S. Karger AG, Basel
Introduction
Osteonecrosis of the jaws is an increasingly common and clinically significant complication of bisphosphonate (BP) medications. Since 2003, more than 1,000 cases of BP-associated osteonecrosis of the jaw have been documented in the literature, and more than 3,500 Lorena Gallego Cabueñes Hospital Cabueñes s/n ES–33394 Gijón (Spain) E-Mail lorenagallegolopez @ gmail.com
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cases have been reported to the Food and Drug Administration in the US alone [1–5]. BP-related osteonecrosis of the jaw (BRONJ) is defined by (1) a positive history of BP intake, (2) no history of irradiation in the head and neck region, and (3) exposed bone over a period of 8 weeks [6]. In some cases, the clinical hallmark of the disease (exposed bone) is not present in the early stages (stage 0) or even advanced stages [7]. Patients with stage 0 disease have no evidence of necrotic bone but (1) nonspecific symptoms such as pain or odontalgia not explained by odontogenic causes; (2) clinical findings including loosening of teeth not explained by chronic periodontal disease and/or periapical/periodontal fistula not associated with pulpal necrosis, or (3) radiographic findings including alveolar bone loss not attributable to chronic periodontal disease, trabecular bone alterations including dense woven bone, and persistent unremodeled bone in extraction sites, thickening of the lamina dura, and inferior alveolar canal narrowing [8]. A timely diagnosis and initiation of therapy are of crucial importance as the therapy outcome results of early BRONJ stages are good; however, in some cases, BRONJ can be hidden and the diagnosis may be delayed. Thus, characterizing clinical and radiographic features that precede stages 1–3 BRONJ is extremely important. Although defective wound healing of soft tissue is frequently, if not always, observed in BRONJ, the effects of BPs on oral soft tissue or cells remain unknown. Several in vitro and in vivo studies suggest that BP results in higher levels of apoptosis and premature senescence of oral mucosal cells, supporting the idea that BP treatment affects the oral mucosa [9, 10]. Soft tissue wound healing might be partly responsible for the development of BRONJ in individuals taking BPs. There are few studies investigating the role of an involvement of the maxillary sinus in BRONJ, and those studies associated maxillary sinusitis and oroantral fistulae with BRONJ located on the maxilla [11]. The purpose of this study was to characterize radiographic signs of maxillary sinus disease in a group of patients with BRONJ and investigate with the help of clinical symptoms and imaging features whether BP induces alterations in the sinus mucosa and may anticipate the development of BRONJ. We hypothesized that sinus mucosal thickening is a nonspecific but characteristic sign of BRONJ. Our secondary aim included the relation between local or demographical variables and radiographic signs of maxillary sinus disease in BRONJ patients. Materials and Methods Study Design The investigators designed and implemented an observational case-control study, which was reviewed and approved by the Institutional Review Boards of the Central University Hospital (Oviedo, Spain). This study followed the Declaration of Helsinki on medical protocol and ethics, and the regional Ethical Review Board of the Central University Hospital approved the study. Sample Eligible cases were patients with a working diagnosis of BRONJ who had been treated at the Oral and Maxillofacial Surgery Unit of the Central University Hospital, a tertiary health care hospital for a population of 1,110,000 inhabitants. To allow inclusion into the study, the patients had to meet the definition for BRONJ as defined by the American Association of Oral and Maxillofacial Surgeons [8]. A complete medical history including indication for BP therapy, type, dose, frequency, therapy duration and discontinuation, primary disease, comorbidities, and dental history was collected and analyzed along with BRONJ signs, symptoms, location, stage, treatment and evolution as well as radiographic data (table 1). Special attention was given as to whether or not there was any evidence of an involvement of the maxillary sinus, namely for maxillary sinusitis or mucosal thickening occurring in the course of the disease. With regard to the radiological data, conventional radiological
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Table 1. Clinical and radiological variables
Radiological variables
Clinical variables
Sinus condition Sinus sign FSS (sinus sign without underlying osteonecrosis) Dentition status
Age Sex Systemic disease BP BP dose Time of exposure to BP Localization Stage CTx value Evolution
investigations (panoramic radiographs) and computed tomography (CT) scans were available in all 32 cases with BRONJ. For each case, a control matching the selection criteria (including sex and age), who had not received BP treatment, had no oncologic or bone metabolism pathology, and had CT studies involving the maxillary sinus, was selected. All images corresponding to patients and controls were assessed by a single expert who did not know the origin (patient/control) of the image. Study Variables Special attention was given as to whether or not there was any evidence of an involvement of the maxillary sinus. Based on previous classifications [12], this involvement was classified as: (1) normal sinus, (2) mucosal thickening, (3) mucous cyst, and (4) occupation of the entire maxillary sinus (fig. 1). The information provided by the orthopantomographs was used to define the variable corresponding to the ‘state of dentition’. For this purpose, both the maxilla and mandible were divided into four quadrants, which were classified as completely edentulous, partially edentulous or dentate. The primary study variable was mucosal thickening and relation with BP treatment. Increased thickening of the mucosa greater than 3 mm was considered as ‘positive sinus sign’ (PSS). If thickening of the mucosa of the maxillary sinus was described without involvement of the underlying bone (BRONJ areas in the jaw or contralateral upper maxillary), it was considered as ‘final sinus sign’ (FSS). Other variables included age, gender, primary disease, dose, number of infusions, BRONJ location and stage, radiologic signs and serum C-telopeptide-cross-linked type I collagen (CTx) as well as evolution (table 1). The follow-up time varied between 6 and 42 months, with a mean duration of 14.375 months. Statistical Analysis The qualitative and quantitative variables were analyzed using χ2 tests or Student’s t distribution. Associations of possible predictor variables with the dependent variable sinus mucosal thickening were determined using logistic regression analysis. p values were two-sided and subjected to a global significance level of 0.05. The data were analyzed with SPSS version 20.0 software (SPSS Inc., Chicago, Ill., USA).
Results
Seventy potential cases of BRONJ were initially identified. Electronic medical records were reviewed for each potential case. Thirty-eight BRONJ cases had incomplete radiographic information and were excluded from the study. The final sample of cases was composed of 32 subjects with BRONJ diagnosed in 96 months. Complete radiological investigations (panoramic radiographs) and CT scans were available in all cases. A total of 32 patients suffering from BRONJ were identified. Ten males and 22 females, and their age ranged from 47 to 89 years (mean: 69.03; 95% CI: 65.3–73.5). In the control group, there were 10 males and 22 females, and their age ranged from 46 to 84 years (mean: 68.5; 95% CI: 65.3–71.8).
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a
b
Fig. 1. Classification used to define the radiographic findings of the maxillary sinus on CT coronal sections. a No sign of pathology. b Maxillary sinus mucocele. c Mucosal thickening greater than 3 mm. d Maxillary sinusitis.
c
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ORL 2014;76:199–206 © 2014 S. Karger AG, Basel www.karger.com/orl
DOI: 10.1159/000365930
Gallego et al.: Sinus Mucosal Thickening in Bisphosphonate-Related Osteonecrosis of the Jaws: A Case-Control Study
Fig. 2. CT image showing bilateral sinus mucosal thickening greater than 3 mm in a BRONJ patient.
Table 2. Number of teeth in each quadrant of the jaws in the two study groups
Dentition status
I
II
III
IV
Full dentition
Cases Controls
5 8
4 9
2 5
2 6
Partial edentulism
Cases Controls
16 19
17 15
21 20
22 20
Complete edentulism
Cases Controls
12 5
12 8
9 7
8 6
Intravenous zoledronate was administered in 20 patients (62.5%), a combination of pamidronate and zoledronate in 1 patient (3.1%), ibandronate in 5 patients (15.6%), and alendronate in 6 patients (18.8%). The mean period of intake of intravenous BP was 17.9 months (range 1–45; 95% CI: 12.4–23.4), and for oral BPs it was 50.9 months (range 36–84; 95% CI: 39–62.8). Diagnoses indicating the intake of BPs were carcinoma of the breast in 5 cases (15.6%), multiple myeloma in 7 cases (21.9%), prostate cancer in 5 cases (15.6%), kidney cancer in 2 cases (6.3%), cervix cancer in 1 case (3.1%), and osteoporosis in 12 cases (37.5%). The mandible (26 lesions in 19 patients) was affected more commonly than the maxilla (13 lesions in 12 patients), and the most frequent sign at presentation was bone exposure (24 patients). One patient presented bone exposure in the maxilla and mandible. According to the 2009 update classification of the American Association of Oral and Maxillofacial Surgeons (AAOMS), stage 1 was found in 4 patients (12.5%), stage 2 in 18 patients (56.2%), and stage 3 in 10 patients (31.3%). The different types of edentulism in the BRONJ and control groups are shown in table 2. Eight control subjects were completely dentate (25%) versus 5 BRONJ patients (15.6%). Sinus involvement was observed in the CT images of 21 patients (65.6%) of the BRONJ group and in 11 control subjects (34.4%). PSS was observed in the CT images in 20 maxillary sinuses of 18 BRONJ patients (56.3%). We found FSS in 13 patients (40.6%) of those 18 patients. In the BRONJ group, 6 patients showed entire sinus occupation (18.8%) (fig. 2, 3), 3
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Gallego et al.: Sinus Mucosal Thickening in Bisphosphonate-Related Osteonecrosis of the Jaws: A Case-Control Study
Fig. 3. CT image demonstrating maxillary bone sequestra of 8.9 mm in a BRONJ patient with ipsilateral sinus mucosal thickening.
of them with oroantral communication; 2 patients showed mucous cysts and 12 patients (37.5%) presented a normal sinus. In the control group, PSS was observed in seven maxillary sinuses of 6 subjects (18.8%), 2 patients showed sinus occupation, and 3 patients presented mucous cysts. Statistically significant differences were found between BRONJ and control patients with respect to the presence of PSS (p = 0.002) and FSS (p = 0.05). A positive history of BP use was associated with an increased risk of PSS in regression analysis (OR: 5.57; 95% CI: 1.8006– 17.2392). We found no significant association between PSS and BP dose or type, primary disease, route of administration or BRONJ evolution. Otherwise, we observed that patient age (p = 0.02) and male gender (p = 0.02) were correlated with FSS. The mean level of CTx for patients with FSS was 138.33 pg/ml, whereas the mean level of CTx for patients without FSS was 108.38 pg/ml, with no statistically significant differences (p > 0.05). FSS was present in 1 of 4 patients in stage 1 (25%), 6 of 17 patients in stage 2 (35.3%) and 6 of 10 patients in stage 3 (60%). Considering stage 1 as reference, we obtained a nonsignificant trend (p = 0.34). Discussion
Direct mucosal toxicity from high BP concentrations in the bone has been considered the primary event for jawbone exposure and necrosis [13, 14]. The aim of the present study was to investigate the effects of a high concentration of BP in oral mucosa and to determine whether thickening of the Schneider membrane could be related to BP treatment. The presence of sinus mucosal thickening varies significantly depending on the series and the imaging technique employed, generally ranging between 12 and 38.1% [15–17]. The methods described by Maestre-Ferrin et al. [12] were partially modified for the collection of radiological information in our study. Using CT, these authors identified mucosal thickening in 33.3% of the 30 patients included in their study. At present, CT is considered the ‘gold standard’ for the diagnosis of sinus pathology due to its ability to obtain different spatial
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projections and to differentiate between bone and soft tissue [18]. Most authors agree that the ability to identify mucoceles (or mucosal thickening) using orthopantomographs is limited, as this rate of detection ranges from 5.2 to 14% [19–21]. Harar et al. [22] reviewed 500 maxillary sinus CTs and identified the presence of mucoceles in 110 sinus scans (22%). Thus, mucosal thickening observed in CT images was used for evaluation, and we also assessed the images on orthopantomographs for the classification of the dentition status in both patients with BRONJ and controls. Positive sinus CT findings in our series were present in 56.3% of the 32 patients investigated, and such findings were found in 13 of these patients even when the clinical osteonecrosis was located in the contralateral mandible or maxilla. The presence of positive findings was significantly lower in the control subjects (18.8%). Some authors have proposed the potential for odontogenic origin as a cause of positive sinus CT findings in the general population, as this condition is more common in dentate patients than edentulous patients [15]. Although this association was not observed in other studies [12, 23], its potential influence was excluded in the present study, as the number of dentate subjects in our series was slightly higher among controls than patients with osteonecrosis. Nevertheless, the presence of positive sinus CT findings was higher in patients with osteonecrosis. To our knowledge, few articles published in the literature have analyzed sinus disease of patients with osteonecrosis or those receiving BP therapy. Mast et al. [11] published a multicenter study on 170 cases of chemical osteonecrosis, among which the disease process was located in the maxilla in 53 patients (31.2%). These authors reported the presence of at least one clinical symptom of maxillary sinusitis in 23 patients (43.6%), and over the course of the disease, they recognized the clinical presence of orosinusal communication in 19 patients (35.8%). A comparison with the radiographic findings in our study was not possible, as those results were not discussed in detail. In our study, we observed an association between the presence of mucosal thickening and male sex in BRONJ cases. Although unexpected, this relationship was also reported in various previous studies [12, 20, 21]. However, unlike previously published studies reporting no relationship between age and mucosal thickening in patients without osteonecrosis, our study revealed that patients with osteonecrosis and positive sinus CT findings were 8 years older that those who showed no signs of mucosal thickening. In support of this finding, Phothikhun et al. [24] reported this association in subjects older than 49 years. While considering the limitations inherent in the design and number of cases analyzed in our study, patients with osteonecrosis of the jaw were found to have a 5.57-fold greater probability of presenting sinus mucosal thickening (>3 mm) than healthy subjects. Although this thickening was more common in patients with advanced-stage disease and low levels of CTx, as reported by Ruggiero et al. [8], we could not rule out the possibility that these associations were the result of chance. Obviously, these preliminary findings need to be confirmed in larger populations. This is a preliminary study, and we are planning more research to confirm the preliminary conclusions reached in the present investigation. Disclosure Statement The authors have no conflicts of interest to disclose.
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