1. Introduction

Bisphosphonates are inorganic pyrophosphates effective in inhibiting bone resorption and have been approved and used in the past for different indications such as osteoporosis, Paget’s disease, hypercalcemia related to malignancy, multiple myeloma and symptomatic fibrous dysplasia ^[1]. There are 2 types of bisphosphonates: nitrogen containing and non-nitrogen containing. Those containing nitrogen in their structure are more potent and accumulate in maximum concentration in the matrix and osteoclasts.

There are 3 defining components of BRONJ, including exposed bone present for longer than 8 weeks, exposure to bisphosphonates and no history of radiation therapy to the maxilla or mandible ^[2]. The risk of BRONJ is related to the type and duration of exposure to bisphosphonates, with a higher risk associated with IV bisphosphonates (1%-14%) compared with oral bisphosphonates (< 0.3%) ^[3]. Oral bisphosphonates are currently used for treatment of osteoporosis, with the more potent IV bisphosphonates generally reserved for patients with multiple myeloma and bone metastases, with limited use for osteoporosis. Higher risk is also associated with longer duration of exposure. Pamidronate (Aredia) and zoledronic acid (Zometa) are the 2 most widely used IV bisphosphonates. Zoledronic acid is 1000 times more potent than pamidronate, which may account for the higher frequency of BRONJ in patients who receive the drug.

Local risk factors for the development of BRONJ include a history of tooth extraction or other dentoalveolar procedure, the presence of local anatomical structures such as tori or bony exostosis and concomitant inflammatory dental disease. Other risk factors include age, race, and type of underlying malignancy.

The characteristic symptoms of BRONJ are a non-healing extraction sockets or exposed jaw bone with progression to sequestrum formation associated with localised swelling and infection. It is may be associated with localized soft tissue infection, pain, purulent discharge, paresthesia, extraoral fistula formation and pathologic fracture.

The pathogenesis of BRONJ is barely understood and the diagnosis of osteonecrosis is largely based on clinical criteria. Different hypotheses exist for the pathogenesis of BRONJ including infection, loss of blood supply, inhibition of bone turnover and dentoalveolar trauma ^[4].

The jaw is the favored site of involvement by this disorder. This has several possible explanations. First, only a thin layer of mucosa separates the bone in the maxilla and mandible from the oral cavity. Second, the roots of the teeth are separated from the underlying bone by a very thin periodontal ligament, which is frequently affected by caries and periodontal disease. Widening of the periodontal ligament is one of the early signs of BRONJ on panoramic and intraoral radiographs. Poor ossification at a previous extraction site may also be an early radiographic feature of ONJ. The presence of localized or diffuse osteosclerosis or a thickening of the lamina dura on plain film imaging may predict future sites of exposed necrotic bone. In the limited literature on imaging findings of BRONJ, diffuse osseous sclerosis has been described as the predominant finding ^[5]. Presence of sequestra, periosteal reaction and oroantral fistulae encountered in several patients may mimic or suggest an associated osteomyelitis. Gingival ulceration and inflammation are evident in BRONJ specimens along with osteomyelitis caused by actinomyces. In addition, bisphosphonates have not been shown to produce pathologically confirmed aseptic necrosis of normal bone ^[6]. Patients who will be administered the potent aminobisphosphonates should have a dental examination to remove potential and real sources of infection to obviate the need for invasive dental procedures in the future. This is further complicated by the fact that the half-life of these drugs in bone can be quite lengthy (estimated at ≈ 12 years).

BRONJ is primarily diagnosed clinically but imaging is essential for determining the extent of disease, diagnosing early stages, identifying metastatic disease and excluding fractures. The clinical picture does not usually show the full extent and severity of BRONJ sites beneath the mucosa. Imaging modalities used as adjunctive assessment in the evaluation of the ONJ patient may include plain radiographs, computed tomography (CT), magnetic resonance imaging (MRI), cone-beam computed tomography (CBCT), functional imaging with bone scintigraphy and positron emission tomography (PET). Each one of these approaches has advantages and limitations.

The significant number of studies investigating CT and/or MRI for BRONJ imaging, there are considerably fewer papers in the literature that study the use of cone-beam computed tomography (CBCT) as a modality for imaging of BRONJ lesions. The purpose of this article is to investigate the typical CBCT findings of BRONJ and review of the literature.

2. Imaging Techniques and Findings

There are various radiographic findings which may or may not correlate with the clinical symptoms. There are no specific radiographic findings with the clinically exposed bone. A common opinion on account of which method is preferred for BRONJ imaging is not yet available. Nevertheless, conventional radiography and CT scans are frequently used and may show periosteal reaction, sclerotic lesions and mixed bone changes with ill-defined areas of lucency causing sequestrum formation.

The radiological characteristics compromise a diverse pattern of occurrence and progress of BRONJ, starting from the lamina dura and cortical plate to involve the alveolar bone and then progress to enter the medullar bone, and eventually the whole cross-sectional region of the jaw bone. This process is approved in subjects with image follow-up over time; showing that the destructive bone changes are often progressive. Other reported findings include an increase in bone sclerosis, widening of the periodontal membrane space and thickening of the lamina dura.

The radiologic differential diagnosis for BRONJ includes chronic sclerosing osteomyelitis of the jaws, osteoradionecrosis, metastasis and Paget disease. Osteomyelitis of the jaw is characterized by periosteal reaction, sclerosis, osseous expansion/destruction and sequestra. Osteoradionecrosis occurs after radiation therapy to the oral cavity and is radiologically manifested by poorly defined destruction of the mandible. Metastases to the jaws are not common and are most frequently seen in the posterior region of the mandible. They are most commonly lytic lesions with except for prostate and breast cancer metastases that might be sclerotic.

The panoramic radiographs are particularly used to see whether all jaw regions affected by BRONJ could be identified on the image. The extent of sequesters or osteolysis of jaw bone is detected in computed tomography (CT) in individually adapted planes parallel to the hard palate as parameters for evaluation of necrotic bone.

Pathologic fractures, narrowing of the marrow space and involvement of the inferior alveolar canal are also common manifestations at CT and CBCT. When the maxilla is involved, there may be associated patologic conditions in the adjacent maxillary sinus, from mucoperiosteal thickening to air-fluid levels and purulent drainage.

Magnetic resonance imaging (MRI) is free from ionizing radiation and has high soft tissue contrast. MRI provides similar advantages to CT in assessing the osseous ONJ changes, while it appears to be superior in evaluating bone marrow change at the early stage of ONJ, besides the soft tissue changes overlying the osteonecrotic region. One of the most common and earliest MRI findings is a decrease of bone marrow signal intensity on T1-weighted images that may be present prior to clinical manifestations of ONJ ^{[7, 8, 9, 10]}. It is also reported that MRI is very sensitive to osteoradionecrosis and shows the associated soft tissue abnormalities to a much better advantage compared with CT ^[10].

Recent studies show that CT and/or MRI are the most helpful methods for imaging of BRONJ sites ^{[8, 11]}. Besides functional imaging using bone scintigraphy, bone single-photon emission computed tomography or positron emission tomography can also be of diagnostic value ^{[7, 8]}. By the side of the substantial number of studies investigating CT and/or MRI for BRONJ imaging, there are notably fewer papers in the literature that study the use of CBCT as a method for imaging of BRONJ lesions [12-19]^[12].

3. Cone-beam Computed Tomography

Cone-beam computed tomography (CBCT) is widely used by many practitioners because of its ease of use and capacity to generate three-dimensional images of bone. In recent years CBCT has been introduced as a diagnostic tool utilizing cone-beam geometry, flat panel detectors and 3D reconstruction algorithms. CBCT scanners use a square two-dimensional array of detectors to capture the cone-shaped beam providing a volume of data different from the medical scanner which provides a set of consecutive slices.

CBCT was able to provide detailed information about characteristics and extent of the cortical and trabecular bone involvement and the proximity of the alteration in the bony architecture to vital structure such as mandibular canal. It has been reported that CBCT has lower radiation doses than conventional CT scans at high isotropic spatial resolution ^[20]. CBCT is less susceptible to metal-induced artifacts compared with standard multidetector CT and at a lower radiation döşe ^[21].

CBCT imaging provided high resolution hard tissue diagnosis when offering a field of view, covering both jaws, affected areas could be easily compared to non-affected areas. Furthermore, the CBCT data can also be considered valuable for volumetry which helps to determine the extent of the lesion. As such it can serve as a guide towards management planning. Indeed, cross-sectional slices allowed identification of the true extent of affected marrow and thus facilitated transfer from the three-dimensional images to the surgical topographical landmarks.

A major disadvantage of CBCT is the low contrast resolution and poor soft tissue detail. However, the ability of CBCT to image bony structures is similar to that of CT ^[22].

As CBCT has been popular in recent years because of the presumably reduced radiation dose when compared to standard multidetector CT, it has become more important to assess its diagnostic performance in the detection and quantification of BRONJ, particularly when surgical therapy is planned. The radiological signs destruction of the trabecular structure of the cancellous bone and erosion of the cortical bone are the 2 most frequent and most typical findings for BRONJ in CBCT scans ^[17]. Early stages of BRONJ are related with nonspecific clinical symptoms and imaging is often delayed or may not be diagnostic. CBCT may be able to detect early findings like periosteal thickening or bone density changes, before necrotic bone is seen on visual inspection. This should be the focus of future studies because early detection may play an important role for the efficient therapy. CBCT imaging findings of the osteonecrotic areas are similar to those with CT and include increased bone density, osteolysis, cortical erosions, sequestration and periosteal bone reaction ^{[17, 19]}.

There are small number of studies in the recent literature including CBCT to image BRONJ sites [12-19]^[12] and in these studies; Barragan- Adjemian et al ^[15] and Olutayo et al ^[16] describe changing radiological findings in CBCT according to the progression of BRONJ lesions. Barragan- Adjemian et al ^[15] suggested that the sagittal slices of CBCT may allow detection of subclinical, small involucrums and also allow progression of the lesions to be monitored over time. Olutayo et al ^[16] reported that cross-sectional slices of CBCT scans allow the identification of the true extent of the affected marrow and thus facilitate the transfer from 3D images to surgical topographic landmarks.

Some other authors describe the radiological findings of BRONJ lesions in CBCT ^{[13, 14, 16]} and/or used CBCT as an imaging modality before surgery ^[12]. The radiological signs of BRONJ in CBCT scans correspond to the signs that have been described for multislice computed tomography (MSCT) scans by several authors ^{[8, 11]}. BRONJ has been reported without exposed bone, suggesting a larger need for inclusion of radiographic criteria ^[23].

In general, diagnosis of BRONJ in CBCT is based on subjective image parameters, such as the detection of periosteal thickening, sclerosis or bone lucencies, necrosis ^[17]. Furthermore, changes in bone density cause changes in x-ray attenuation that can be quantified by calculating mean bone density values (BDV) of a certain region or volume. This can either be measured by 2D regions of interest (ROI) on multiplanar reformations or 3D volumes of interest (VOI) generated from a 3D CBCT data set. However, CBCT using flat-panel detector technology is known to be vulnerable to certain gray level discrepancies, variation of x-ray attenuation ^[24]. Thus, adequate VOIs and cutoff attenuation values may be influenced by these discrepancies but have to be applied for the purpose of reliable detection of BRONJ.

ROIs are placed in the center of each region excluding cortical bone. Guggenberger et al ^[25] stated that whether a region was affected by BRONJ with concomitant locally altered anatomy, volume loss or density changes in the centrally positioned ROI could have been inadvertently placed in the peripheral, mostly sclerotic area of a BRONJ. Therefore, BDVs of ROIs in BRONJ-affected regions are likely higher than in standardized VOI segmentations. Although much care was taken to crop teeth, including radices, minimal radicular remnants may have slightly increased the mean BDVs of VOIs, thereby reducing discrimination of healthy from pathologic conditions. Guggenberger et al ^[25] also reported that BRONJ can effectively and reliably be diagnosed and quantified with CBCT and qualitative image parameters yield a higher diagnostic performance than quantitative BDV, among which ROI-based attenuation measurements are more accurate than VOI-based measurements.

Cankaya et al ^[18] stated that both CBCT and the Hounsfield Units (HU) evaluations together are thought to be efficient in the diagnosis of BRONJ. Attenuation measurements in CBCT using Hounsfield units (HU) to be efficient in the diagnosis of BRONJ. Furthermore the extent of the BRONJ lesions assessed from CBCT scans did not differ significantly from the intraoperative situation, and a significant correlation between CBCT measurements and intraoperative measurements was found.

On CBCT images fractal dimension (FD) assesments might be a helpful diagnostic tool for early bone alterations associated with bisphosphonates. The study by Torres et al ^[19] demonstrated that the regions close to the alveolar bone show the most promise for detection of differences in the FD of the bony structure associated with bisphosphonates.

Stockmann et al ^[7] studied that detectability of osteonecrosis was calculated for the different imaging techniques. The results of the study revealed that the panoramic radiographs have a poor detectability for the determination of the extent of BRONJ and CT scans had the highest detectability for BRONJ lesions. MRI as well as CT have a high detectability for BRONJ lesions that exceeds that of panoramic radiographs and both techniques show problems with the exact evaluation of the extent of BRONJ lesions in the individual patients. Therefore, the relevance of MRI and CT for the preoperative assessment of the extent of BRONJ lesions is limited. Furthermore, there was a significant correlation of the intra-operative extent of the BRONJ lesions with the extent in the CT scans. However, the extent of the BRONJ lesions measured intra-operatively and the extent assessed on the CT scans showed a statistically significant difference. The extent of the lesions on the CT scans was only in the range of approximately 50% of the intra-operative extent of the BRONJ lesions. Consequently, when CT scans are used to estimate the extent of BRONJ lesions, it should be kept in mind that there is a high probability that the intra-operative situation will present a significantly larger BRONJ lesion.

It is concluded that even with cross-sectional slices and substantial experience in assessing such images it is not possible to determine the exact margins of the BRONJ lesion using any mode of imaging ^[17]. This is for CT scans, as stated by Stockmann et al ^[7] during surgical therapy, the exact resection margins are determined from intraoperative clinical findings. For this reason, CBCT imaging and CT of BRONJ offer only the possibility of estimating the extent of the BRONJ lesion and depicting the involvement of anatomical structures, for instance, the mandibular nerve, the maxillary sinus, or the teeth ^{[13, 16]}. This information is essential if surgical therapy is considered. It is suggested that 3D imaging should be taken for follow-up of conservative therapy ^[26]. Wilde et al ^[27] determined clinical staging of bisphosphonate-associated osteonecrosis of the jaw (Table 1). A comprehensive study by Wilde et al ^[17] reported that sequestration and osteosclerosis were less frequent and could be seen across all stages. Periosteal bone formation occurred in high-stage BRONJ only. Osteosclerosis of the jaws as a radiological sign of BRONJ in CBCT can be seen across all stages as well and is again represented by an irregular distribution across all 4 stages. Cortical bone erosion, cancellous bone destruction, osteosclerosis and sequestration can be seen across all 4 stages and prevalence seems to decrease with decreasing severity of BRONJ. However, osteosclerosis tends to be rarer in stage 1 than in the other stages.

Table 1. Clinical staging of bisphosphonate-related osteonecrosis of the jaw according to Wilde et al [27]

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4. Conclusions

In conclusion, imaging is of value in diagnosing BRONJ. Radiographic evaluation can be very useful in determining the extent of bony changes, the size and location of sequestra, proximity of changes to the important anatomic structures like inferior alveolar and mental nerves as well as the maxillary sinus, and presence of and/or risk for pathologic fracture. It is possible to assess bone mineral distribution or bone density by using CBCT which can give us information about bone quality. CBCT might better contribute to the prevention of BRONJ as well to disease management. The recent advances in CBCT techniques have led to its use in surgical and postoperative planning especially for head and neck procedures and for detection and quantification of BRONJ. Future researches should focus on the identification of imaging techniques that allow assessing the extent of BRONJ lesions with a higher accuracy.

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