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Dentomaxillofacial Radiology (2006) 35, 236–243 q 2006 The British Institute of Radiology http://dmfr.birjournals.org RESEARCH Clinical and diagnostic imaging of bisphosphonate-associated osteonecrosis of the jaws S Chiandussi*,1, M Biasotto1, F Dore2, F Cavalli3, MA Cova4 and R Di Lenarda1 1 Department of Dental Sciences, University of Trieste, Trieste, Italy; 2Department of Nuclear Medicine, Ospedale Maggiore, Trieste, Italy; 3Department of Radiodiagnostic Imaging, Ospedale Maggiore, Trieste, Italy; 4Department of Radiology, Ospedale di Cattinara, Trieste, Italy Objectives: It is important to recognize osteonecrosis of the jaws in patients treated with bisphosphonates because an early diagnosis can make a significant difference to the outcome of the disease. The aim of this study is to describe the radiological features of bisphosphonate osteonecrosis (BON) in order to aid its prompt recognition. Methods: A conventional radiograph, a computed tomograph (CT), a magnetic resonance image (MRI) and a 99Tcm-MDP 3-phase bone scan were carried out for 11 patients with BON. The main imaging findings of osteonecrosis are described. Results: Conventional radiography and CT displayed osteolytic lesions with the involvement of cortical bone. MRI demonstrated the characteristic features of osteonecrosis and the oedema of soft tissues. Both CT and MRI were very useful in defining the extent of the lesions. 99Tcm-MDP threephase bone scan was the most sensitive tool to detect the osteonecrosis at an early stage. Conclusions: 99Tcm-MDP three-phase bone scans who could be used as a screening test to detect subclinical osteonecrosis in patients who have received bisphosphonates. CT scans and MRI are useful in defining the features and extent of osteolytic lesions. Dentomaxillofacial Radiology (2006) 35, 236–243. doi: 10.1259/dmfr/27458726 Keywords: osteonecrosis; bisphosphonates; jaws; imaging Introduction Bisphosphonates act through the inhibition of bone resorption and are used in conjunction with antineoplastic chemotherapy for treatment of hypercalcaemia associated with malignancy, lytic bone metastasis and multiple myeloma.1 Several cases describing a correlation between osteonecrosis of the jaws and intravenous administration of bisphosphonates have been recently reported in the literature.2 – 14 The clinical examination of the patient needs to be accompanied by a careful evaluation of the imaging features of bone lesions to better understand their extent and features. Digital panoramic radiography, computed tomography (CT) scans, magnetic resonance imaging (MRI) and 99Tcm-MDP three-phase bone scans are diagnostic tools that add value to the clinical findings by revealing different aspects of bone involvement. To the best of our knowledge there is no report in the literature *Correspondence to: Silvia Chiandussi, Clinica Stomatologica, Via Stuparich 1, 34100 Trieste, Italy; E-mail: [email protected] Received 28 October 2005; revised 21 February 2006; accepted 13 March 2006 that describes the imaging manifestations of bisphosphonates-associated osteonecrosis of the jaws. The aim of this study is to assess the imaging investigations that better describe the nature, size and features of the bone lesions in a series of 11 patients who attended our clinic with a diagnosis of bisphosphonates osteonecrosis (BON). Materials and methods From January to August 2005, ten oncology patients were referred to the Dental Institute, University of Trieste to investigate non-specific facial swelling accompanied by bone exposure, pain and occasional fever. All patients had previously been diagnosed with extraoral malignant disease. Seven of them had bone metastases (five secondary to breast cancer and two secondary to carcinoma of the lung) and three patients had multiple myeloma with generalized bone lesions. All patients had been treated with intravenous zoledronic acid and were therefore at risk of Bisphosphonate osteonecrosis S Chiandussi et al having developed bisphosphonates osteonecrosis. The diagnosis of BON was confirmed through the histological evaluation of the exposed bone. We documented the patient’s symptoms, the localization of the necrosis, the presence of fistulae or suppuration and the association with previous extractions or traumas as possible triggering factor for the onset of the lesions. Another patient attended our Clinic for a prosthodontic rehabilitation. Her medical history was positive for a multiple myeloma, for which she was on treatment with zoledronic acid. She had a dental extraction 3 months earlier without apparent complications. Despite the fact that at the time of the examination she reported no oral symptoms or discomfort, she was considered at risk for developing either BON or bone metastases. The diagnosis of osteonecrosis was confirmed on the basis of the radiological investigations described below. For every patient, a digital panoramic radiograph was taken as routine diagnostic investigation. The panoramic X-ray was taken using a Kodak 8000C Digital Panoramic & Cephalometric System (Eastman Kodak Company, Rochester, NY) at 73 kV and 12 mA for 13.9 s, and the image was observed with a Trophy Windows 6.0 software (Trophy Radiologie, Croissy Beaubourg, France). In all radiographs an osteolytic lesion was noticed and, to better detect the characteristics of the lytic region, a CT scan and an MRI were performed. CT images were obtained using a Toshiba Aquilion 16 (Toshiba Italia, Milan, Italy) at 120 kV and 200 mA with a slice thickness of 0.5 mm. A three-dimensional reconstruction of the CT images was obtained using the Osirix Medical Imaging Software, MacOs X 10.3 (http://homepage.mac.com/rossetantoine/ osirix/Index2.html). Patients were imaged with MRI using a 1.5 T Super Conductive Magnet (Philips Gyroscan Intera, Best, The Netherlands). The following imaging sequences were obtained with 5 mm thickness in coronal, axial and sagittal planes: turbo spin echo (TSE) T1 weighted spin echo (repetition time (TR) ¼ 598, echo time (TE) ¼ 15), TSE T2 weighted turbo spin echo (TR ¼ 4670, TE ¼ 100), T-short tau inversion recovery (STIR) (TR ¼ 2024, TE ¼ 15) and spectral presaturation with inversion recovery (SPIR) (TR ¼ 513, TE ¼ 12). The images were acquired before and after intravenous administration of gadolinium-containing contrast agent (gadopentate dimeglumine, Magnevist; Schering, Berlin, Germany). Both normal fat intensity areas surrounded by low intensity band and diffuse low intensity areas were defined as osteonecrosis. Our patients were all having regular technetium-99mmethylene diphosphonate (99Tcm-MDP) three-phase bone scans in planar and SPECT technique with gamma camera collimators centred in maxillary and mandibular regions. Moreover, they were undergoing whole-body bone scan to monitor the neoplastic bone involvement. Therefore, we used the data obtained from the existing imaging to determine the bone metabolic activity of the necrotic lesions of the jaws. The bone scan was performed after intravenous injection of technetium99 m labelled methylene diphosphonate (740 MBq) (Osteosol; Amersham Health, Little Chalfont, UK). 237 The 99Tcm-MDP three-phase dynamic procedure allowed examination of perfusion, immediate soft-tissue blood pool and, after 2 – 4 h, bone uptake. Bone scan was performed using a high-resolution low-energy parallel-hole collimator and a large-field-ofview dual-detector g-camera with a mounted CT scanner (Infinia-Hawkeye; General Electric Healthcare, Hayes, UK). SPECT and CT images of the same area were obtained over a 3608 arc, using 120 frames at 20 s per frame and 38 angles. The images were acquired into a 128 £ 128 matrix and reconstructed using a twodimensional ordered-subset expectation maximization iterative technique (10 subsets and 2 iterations), both with and without CT-based attenuation correction and a Hanning three-dimensional post-filter (cut-off frequency ¼ 0.85 cycles cm21). The CT part was acquired at 2.5 mA and 140 kV, with a slice step of 10 mm and a slice time of 14 s. The SPECT acquisition took approximately 25 min, whereas the CT acquisition took approximately 10 min. The maxillary and mandibular areas of abnormal uptake were recorded. Retrospective analysis of the imaging investigations was carried out by an experienced radiologist (panoramic radiograph, CT scan, MRI) and Nuclear Medicine physician. The CT scan, MRI and scintigraphy were reviewed without benefit of clinical and radiological information. The interpretation of the image in accordance with the clinical findings, the possibility of distinguishing between BON and bone metastases and the presence of clear margins were assessed by the examiners. An informed consent was not necessary as our study was based on the assessment of data already available from routine investigations. Results Among the patients with bone metastases (six females and one male), the mean age was 72 years (range 61 – 84 years). The four patients with multiple myeloma were equally distributed in terms of gender (two females and two male) and had a mean age of 71.5 years, with a range between 57 years and 82 years. Seven patients had BON in the mandible, while three subjects showed maxillary involvement. One patient had lesions affecting both upper and lower jaws. In ten subjects, the osteonecrosis was associated with severe pain, swelling and exposed bone, but only one patient developed cutaneous fistula with suppuration. In four cases the necrosis was triggered by previous dental extractions, and in one subject the BON was diagnosed following a perimplantitis. Another patient developed the osteonecrosis after pre-prosthodontic surgery and, in one case, the BON followed a bone biopsy. For the remaining subjects it was not possible to associate the onset of the necrosis with any procedure. Table 1 summarizes the clinical features of BON in our series of patients. Dentomaxillofacial Radiology Bisphosphonate osteonecrosis S Chiandussi et al 238 Table 1 Clinical features of our series of patients Patients Age (years) Gender Reason for taking Zometa 1 84 F 2 69 F 3 4 57 71 M F 5 6 71 71 F F 7 61 F 8 9 10 76 82 70 F M F 11 78 M Bone metastases secondary breast cancer Bone metastases secondary breast cancer Multiple myeloma Bone metastases secondary breast cancer Multiple myeloma Bone metastases secondary breast cancer Bone metastases secondary lung cancer Multiple myeloma Multiple myeloma Bone metastases secondary breast cancer Bone metastases secondary lung cancer Site of necrosis Pain Bone sequestrum Fever Possible associated factor to Mandible Yes Yes Yes Not known to Maxilla Yes Yes Yes Not known Maxilla and mandible Yes to Mandible Yes Yes Yes Yes Yes Not known Perimplantitis Mandible to Mandible Yes Yes Yes Yes Yes Yes Dental extraction Dental extraction to Maxilla Yes Yes Yes Not known Mandible Mandible to Mandible No Yes Yes No Yes Yes No Yes No Dental extraction Biopsy Dental extraction to Maxilla Yes Yes No Pre-prosthodontic surgery Panoramic radiography In all symptomatic patients, areas of bone destruction were present in correspondence with the regions of clinical involvement. The radiolucent areas were patchy, with occasional evidence of radiopaque sequestra of necrotic bone and little evidence of healing. The border between the necrotic and normal bone was not sharply defined and subperiosteal new bone formation was not usually evident (Figures 1 and 2). The radiographic imaging of the asymptomatic patient showed a radiolucent lesion corresponding to an empty socket. The 99Tcm-MDP three-phase bone scan aroused the suspicion of an area of increased activity in the mandible of the asymptomatic patient. The presence of increased uptake was confirmed through the SPECT (Figures 8 and 9). Discussion Bisphosphonates are non-metabolic synthetic analogues of pyrophosphate synthase. They bind to osteoclasts, particularly in areas where bone resorption and formation is taking place, causing reduction in the recruitment, life span CT scan Imaging evaluation of CT scan disclosed abnormalities in all symptomatic patients. The images showed a moderate irregularity of the cortical margins and, in all symptomatic patients, destruction of cortical bone was noticed. Both clear areas of osteolysis and osteosclerosis were noticed (Figures 3 and 4). The CT scan did not add significant data to the panoramic radiograph of the asymptomatic subject. MRI In all cases, it was possible to identify the involvement of the cancellous bone, which produced low signal intensity on T1 weighted images and a mild hyperintensity on T2 weighted and T-STIR images. A mild and irregular enhancement of the lytic areas was noticed after injection of the contrast agent. Where the bone sequestrum was evident, it presented as a well-defined dark area (Figure 5). In patients with evident swelling, an area of oedema of soft tissues was clearly visible on T-STIR images as high signal intensity. Scintigraphy In all cases, the bone scan was judged positive for the presence of bone lesions and showed abnormal localized activity in the jaws in comparison with the surrounding regions. In three cases, a central or adjacent spot of decreased uptake was observed within the area of uptake of the radionuclide (Figures 6 and 7). Dentomaxillofacial Radiology Figure 1 Panoramic radiograph that shows wide areas of bilateral bone destruction in a patient with multiple myeloma. On the left side, the patient experienced swelling with bone exposure. The histological examination of the exposed bone revealed the presence of avascular osteonecrosis Figure 2 bone Osteolysis of the right mandible with damage to the cortical Bisphosphonate osteonecrosis S Chiandussi et al Figure 5 Figure 3 Computed tomography of a mandibular bone defect due to osteonecrosis and activity of osteoclasts and modulation of the osteoclast – osteoblast interrelation.1,15,16 They also show potent antiangiogenetic properties due to their ability to significantly decrease circulating levels of vascular endothelial growth factor in breast cancer patients with bone metastases.17 In our series of patients, the initial symptoms corresponded to the typical presentation already described in the literature: the patients were complaining of a painful “non-healing” extraction socket or exposed bone with progression to sequestrum formation associated with localized swelling. In accordance with the literature, in our series of patients the osteonecrosis was preceded by traumas or surgical procedures of the involved bone.2 – 13 To the best of our knowledge, this correlation is not based on scientific evidence and it can not be excluded that a surgical procedure merely exposes some bone which was already necrotic. Figure 4 Figure 3 Three-dimensional reconstruction of the bone defect shown in 239 MRI showing bone sequestrum in the right maxilla The diagnosis of BON is generally established in a late stage of the disease since patients usually present to the attention of the clinician when the osteonecrosis is already symptomatic. It is essential that the medical and dental professions are able to recognize subclinical signs of this condition early, as a timely diagnosis can make a significant Figure 6 99Tcm-MDP three-phase bone scan showing increased uptake of the radionuclide in correspondence with an osteonecrotic area Dentomaxillofacial Radiology Bisphosphonate osteonecrosis S Chiandussi et al 240 Figure 7 SPECT-CT image of the same patient shown in Figure 6 difference to the outcome of the disease. BON may remain asymptomatic for many weeks or months and is usually recognized exclusively by exposed bone in the oral cavity. These lesions typically become symptomatic following a secondary infection or trauma to adjacent and/or opposing healthy soft tissues from irregular surfaces of the exposed bone.18 Radiological and nuclear medicine imaging can be of crucial value in helping the recognition and definition of bone lesions in patients on therapy with bisphosphonates. Nuclear medicine scans of the jaws are usually available for patients receiving bisphosphonates since they undergo Dentomaxillofacial Radiology regular bone scans as routine investigations for metastatic diseases. 99Tcm-MDP uptake is associated with both osteoblastic metabolism and blood flow, and is much more sensitive than radiography in detecting early and subclinical osteonecrosis. During the early stages of BON, areas of reduced uptake are consistent with the decreased level of vascularity of the bone. However, as the disease progresses, the scintigraphy is able to show areas of radionuclide uptake representative of osteoblastic hyperactivity in a subchondral distribution. Among our patients, in three cases the centre of the osteonecrosis showed a Bisphosphonate osteonecrosis S Chiandussi et al Figure 8 99 241 Tcm-MDP three-phase bone scan of the asymptomatic patient significant decrease of radionuclide activity or even complete lack of activity. This feature can be interpreted as a sign of decreased metabolism in the necrotic focus due to the absence of blood supply. Limitations of the use of scintigraphy in such patients include low resolution and a difficulty in differentiating between inflammation and metastasis during the late stages of the disease. However, increased uptake of technetium-99 in the scintigraphy of the jaws of patients who receive bisphosphonates should always be considered as an indicator of probable BON. A bone scan is therefore recommended as a screening technique for all patients taking bisphosphonates. The management of BON also remains extremely difficult, and at the moment there are no scientific data to support a universally accepted treatment protocol. Surgical debridements are not completely effective in eradicating the necrotic areas, as it is extremely difficult to obtain surgical margins with good quality vital bone. Even though bleeding is able to distinguish between necrotic and vital tissues, no intraoperative technique can help the clinician in determining whether the surgical margins consist of really healthy bone. This is why it is important to identify the clinical image that better defines the border between the lesion and surrounding good quality tissues. Conventional radiographs are widely used in the evaluation of osteonecrosis and it is therefore recommended to take a panoramic radiograph as first routine radiological investigation. In our series of patients, ten out of 11 subjects presented to our Clinic during a late stage of their condition. In all cases, the panoramic radiographs were able to demonstrate clear signs of osteolytic lesions, but the margins between necrotic areas and healthy bone Dentomaxillofacial Radiology Bisphosphonate osteonecrosis S Chiandussi et al 242 Figure 9 SPECT-CT image of the same patient shown in Figure 7 were not always well-defined. On the basis of conventional radiography, the ability to distinguish between metastatic lesions and osteonecrosis is good, mainly when radiopaque sequestra are present or when osteolysis is combined with Dentomaxillofacial Radiology osteosclerosis. However, an osteonecrosis presenting as an osteolytic lesion can occasionally be difficult to distinguish from malignancy. The specificity of panoramic radiography is therefore high, but early lesions are often missed. Bisphosphonate osteonecrosis S Chiandussi et al Another inconvenience of this technique is the limit of showing a two-dimensional image of three-dimensional structures, preventing the clinician from understanding the real extent of the lesion. This disadvantage is overcome by both CT and MRI as they show axial, sagittal and coronal sections, allowing a three-dimensional reconstruction of the osteolysis. CT and MRI are also very helpful in differentiating osteonecrosis from other causes of osteolysis. CT is useful in providing detailed information about both cortical and trabecular bone. On the other hand, MRI is not able to show destruction of the cortical bone, but is useful in detecting the involvement of soft tissues. The contrast agent in MRI can differentiate between the bone sequestrum, where there is no enhancement, and areas of hyperaemia where the contrast medium reaches high concentrations. As to diagnostic imaging, it has to be underlined that although panoramic radiography, and especially CT and MRI, have a good specificity in distinguishing osteonecrosis from other pathologies, these techniques are not able to distinguish bisphosphonate-induced osteonecrosis of the jaws from other known causes of exposed bone in the jaws such as 243 osteoradionecrosis, osteonecrosis of the jaws related to osteomyelitis, or steroid-induced osteonecrosis, which is rarely found in the jaws. In this study, the small number of patients available for assessment is a limitation and it may reflect the rate of reported occurrence, which is actually low. However, awareness of imaging features of this condition is very important in establishing the correct diagnosis and could help in the recognition of osteonecrotic lesions of the jaws in patients being treated with bisphosphonates. In conclusion, conventional radiography that shows a lesion with the characteristic imaging features of osteonecrosis in patients receiving bisphosphonates should alert the clinician to the diagnosis of BON. A CT scan is extremely useful in defining the features and extent of the lesions and, in selected cases, an MRI can add value to the radiological findings by showing the soft tissue involvement. Scintigraphy is a very sensitive investigation and therefore could be used as a screening test to detect subclinical osteonecrosis in patients receiving bisphosphonates. References 1. Fleisch H. 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Pamidronate induces modifications of circulating angiogenetic factors in cancer patients. Clin Cancer Res 2002; 8: 1080– 1084. 18. Ruggiero S, Gralow J, Marx RE, Hoff AO, Schubert MM, Huryn JM, et al. Practical guidelines for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in patients with cancer. J Oncol Practice 2006; 2: 7– 14. Dentomaxillofacial Radiology