What Is the Role of Positron Emission Tomography in Osteonecrosis of the Jaws?

PATHOLOGY

What Is the Role of Positron Emission Tomography in Osteonecrosis of the Jaws? Ryan Belcher, MD,* Jennings Boyette, MD,y Tiffany Pierson, MD,z Eric Siegel, MS,x Twyla B. Bartel, DO, MBA,k Elias Aniasse, MD,{ and Brendan Stack Jr, MD# Purpose:

Bisphosphonate-related osteonecrosis of the jaw (BP-ONJ) has become an associated side effect of BP therapy and several imaging modalities have been studied to show an ability to detect clinical disease. Because most patients at the authors’ university hospital who develop BP-ONJ also undergo concurrent positron emission tomographic (PET) scanning, the authors investigated the utility of PET scans for diagnosis of BP-ONJ.

Patients and Methods:

A retrospective chart review was performed of patients whose PET scans were acquired within 1 year of their BP-ONJ diagnosis (1998 through 2006). BP-ONJ was defined as intraoral exposure of the maxilla or mandible in patients on BPs and not given radiation to that area. This was performed at a university hospital with oncologic patients treated with BPs. All PET scans in this study were secondarily reviewed by a single expert reader for internal consistency (T.B.B.). A detailed timeline of the course of BP-ONJ was constructed by the review of medical records for each patient and the relation of each patient’s PET scan results to that patient’s BP-ONJ disease was evaluated. Data analysis was a descriptive analysis of PET scan findings in this patient population.

Results:

Of the 25 patients studied, 5 were excluded for insufficient clinical or radiologic data. Of the 20 remaining patients (16 male, 4 female), 46 PET scans were performed and showed 53 areas of enhancement. Many patients had multiple PET scans performed while experiencing exposed bone, and 5 of these patients had alternating positive and negative scans with exposed bone, resulting in 13 patients with positive enhancement on a scan with exposed bone and 9 patients with no enhancement on a scan with exposed bone. Of the 13 patients with PET enhancement, 4 had signs of clinical infection documented at the time of examination. Sensitivity, specificity, and accuracy of PET scanning for BP-ONJ were 43%, 19%, and 62%, respectively. There were 7 patients with PET scans performed after clinical resolution of their exposed bone and 6 of those had no enhancement.

Conclusion:

The purpose of this study was to report findings on PET scanning for patients with BP-ONJ. Although PET scans are useful in oncology, the present findings do not support their routine use for exclusively diagnosing or following cases of BP-ONJ. Ó 2014 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 72:306-310, 2014

*Medical Student, University of Arkansas College of Medicine,

Conflict of Interest Disclosures: None of the authors reported any

Little Rock, AR. yAssistant Professor, Department of Otolaryngology-Head and Neck

disclosures. Address correspondence and reprint requests to Dr Stack: 4301

Surgery, University of Arkansas for Medical Sciences, Little Rock, AR.

West Markham St, #543, Little Rock, AR 72205; e-mail: Bcstackjr@

zMedical Student, University of Arkansas College of Medicine, Little

gmail.com

Rock, AR.

Received April 12 2013

xConsultant, Department of Biostatistics, University of Arkansas for

Accepted July 31 2013 Ó 2014 American Association of Oral and Maxillofacial Surgeons

Medical Sciences, Little Rock, AR. kResident, Department of Radiology, University of Arkansas for

0278-2391/13/00950-6$36.00/0

Medical Sciences, Little Rock, AR. {Professor, University of Cincinnati Cancer Institute, Cincinnati, OH.

http://dx.doi.org/10.1016/j.joms.2013.07.038

#Professor, Department of Otolaryngology-Head and Neck Surgery, University of Arkansas for Medical Sciences; University of Arkansas College of Medicine, Little Rock, AR.

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Intravenous bisphosphonate (BP) use was first introduced in the mid-1990s and quickly became a standard for the management of many osteopathies, including multiple myeloma, malignant hypercalcemia, and metastatic malignant disease (ie, breast, prostate, lung, and kidney cancers, Hodgkin lymphoma, and nonHodgkin lymphoma). It was not until the early 2000s that BP-related osteonecrosis of the jaw (BP-ONJ) began to be reported in the literature and the Food and Drug Administration has since produced several warnings for this side effect, specifically with pamidronate and zoledronate.1 As more information has been gathered about BP-ONJ, the investigation and use of imaging modalities have been of interest to dentists and physicians for possible early diagnosis and accurate estimation of its extent and to help manage BP-ONJ.1 F-18–fluorodeoxyglucose positron emission tomography (FDG-PET) has emerged at many institutions as the premier imaging modality for the diagnosis and surveillance of malignant disease. As such, PET scan findings of BP-ONJ have recently been described because these 2 patient populations overlap.2 In 2007, Catalano et al3 reported on a study of 4 patients with clinically evident BP-ONJ and enhancement on PET scans. All 4 patients had exposed bone, but without signs of clinical infection. In addition to PET scans, technetium-99m (Tc99m) scans were performed, but did not show increased mandibular enhancement. Based on these results, it was concluded that PET scans would be a better diagnostic tool than Tc99m scans in diagnosing BP-ONJ.3 Several other studies have reported focal enhancement on PET scans at sites of BP-ONJ.2,4,5 The authors previously published a study of BP-ONJ and recognized a need for increased diagnostic capability before the development of severe clinical necrotic disease.6 They found that many of their patients with BP-ONJ had PET scans performed on a routine basis for their myeloma care and that many of these scans showed evidence of focal enhancement at BP-ONJ sites. Because they had such a large patient population with reliable clinical and imaging data, the authors investigated PET imaging capabilities further. The aim of this study was to better characterize PET finding in cases of BP-ONJ. The authors hypothesized that PET scan enhancement would show areas of concern for BP-ONJ. The purpose of this study was to report findings on PET scanning for patients with BP-ONJ.

tients who presented to the University of Arkansas for Medical Sciences (UAMS) for the evaluation and management of multiple myeloma or metastatic solid tumors to the skeleton from 1998 through 2006.6 To be eligible for study enrollment, patients met the case definition of BP-ONJ that existed during the study period, in the setting of BP exposure, and had a PET scan within 1 year of the diagnosis of BP-ONJ. BPONJ was defined as a history of BP use and at least 8 weeks of exposed bone that occurred spontaneously or after a dental procedure. UAMS institutional review board approval was obtained for this study. Patients were excluded if they had a history of head and neck cancer surgery or therapy, including radiation therapy to the jaws. PET data from 1998 until 2003 came from the GE Advance NXI Whole-Body PET Scanner (GE Medical Systems, Milwaukee, WI). From 2004 to 2006, a CTI-Reveal (16-slice) or Biograph 6 (6-slice) system (Siemens Medical Systems, Malvern, PA) was used.

Patients and Methods

Results

STUDY DESIGN AND SAMPLE

To address the study purpose, the authors designed and implemented a retrospective cohort study. The study sample was derived from the population of pa-

VARIABLES

The primary predictor variable was the PET scan result in a patient with the diagnosis of ONJ. Demographic data, including age, gender and cancer comorbidity, also were collected.7 DATA COLLECTION METHODS

Data were collected from a list maintained by the UAMS Myeloma Institute for Research and Therapy and searches of institutional electronic medical records, based on the diagnostic code for intraoral exposed bone and a history of intravenous BP administration. For each patient who qualified for inclusion in this study, a detailed timeline of the course of ONJ was constructed. Close attention was paid to the development and resolution of exposed bone, oral and maxillofacial surgical procedures performed, antibiotic treatments administered, and any documentation of signs of complication at ONJ sites. DATA ANALYSES

All PET scans initially read clinically for the patients in this study were secondarily reviewed by a single expert reader (T.B.B.). The reviewing radiologist’s interpretation of each PET scan was used as the primary source of data regarding evidence of enhancement and standardized uptake value for each location reported.

Twenty-five records initially qualified for inclusion into this study. Five patients had insufficient clinical or radiologic follow-up to draw reliable conclusions and they were excluded. Twenty

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Table 1. DESCRIPTIVE DATA AND OUTCOME VARIABLES (PET SCAN RESULTS) FOR THE STUDY POPULATION

Sample size, n Total patients with ONJ Evaluable patients PET scans reviewed Sites of PET enhancement Men, n (%) Location of ONJ, n Mandible Maxillary Multifocal Age (yr), mean (range) Drug treatment, n IV bisphosphonate Pamidronate Zoledronate Both Pamidronate/Zoledronate

25 20 46 53 16 (80) 19 3 2 61 (44-77) 20 10 4 6

Abbreviations: IV, intravenous; ONJ, osteonecrosis of the jaw; PET, positron emission tomographic. Belcher et al. Positron Emission Tomography in Osteonecrosis. J Oral Maxillofac Surg 2014.

remaining patients had BP-ONJ and PET scans. Eighty percent of the patients were men, and the mean age was 61 years. Forty-six PET scans were reviewed, with most patients having multiple PET scans performed over a period of months to years surrounding their jaw complaint. There were 53 areas of enhancement. The details of these patients are listed in Table 1. Focal enhancement was found in 13 of 20 patients during a period of exposed bone (Table 2). In 9 of the 20 patients, there were PET scans performed during periods of exposed bone that did not depict any focal enhancement. Included in these 9 patients were 5 patients who had alternating enhancing and nonenTable 2. CLINICAL BP-ONJ (EXPOSED BONE) AND PET RESULTS WITH STATISTICAL ANALYSIS

Exposed Bone

Yes

No

Total

Positive PET finding Yes No Total

23 12 35

8 10 18

31 22 53

Note: True positive, 65.7%; true negative, 55.6%; false positive, 25.8%; false negative, 54.5%; sensitivity, 43.4%; specificity, 18.9%; accuracy, 62.3% (odds ratio = 2.40, c2 = 2.21, df = 1, P = .14). Abbreviations: BP-ONJ, bisphosphonate-related osteonecrosis of the jaw; PET, positron emission tomographic. Belcher et al. Positron Emission Tomography in Osteonecrosis. J Oral Maxillofac Surg 2014.

hancing scans, and this explains why the numbers reported exceed the total number of patients. Of the 13 patients with enhancement, 4 had clinical signs of infection at the time of the PET scan (Table 3). There were 7 patients who underwent PET imaging after clinical resolution of their disease; 2 of them had PET scans performed only after their mucosa had healed over the exposed bone. Of these 7 patients, 6 had nonenhancing PET scans at that time. These data are presented in Table 4. Five patients had PET scans performed within months before their BP-ONJ diagnosis. Four of these patients had enhancing PET scans, and 3 of these 4 patients had documented dental infection at that time. They proceeded to have a dental extraction and subsequently developed BP-ONJ. Dental extraction was documented in 6 patients before their development of BP-ONJ.

Discussion The purpose of this study was to report findings and better characterize PET findings in cases of BP-ONJ. The authors hypothesized that infected bone would enhance on PET images, whereas dead bone would not enhance. This difference in PET enhancement also might distinguish osteomyelitis from osteonecrosis. The specific aim of this study was to examine the relation between PET findings and BP-ONJ in patients with known BP-ONJ. There have been several studies on the relation of PET imaging to BP-ONJ but, to the authors’ knowledge, the present study contains the largest number of patients (n = 20) with BP-ONJ and concordant PET scans (n = 46). The authors investigated the use of PET scans in the evaluation of BPONJ and whether PET could help guide treatment or detect subclinical (early) disease. Upon review of the present BP-ONJ patient population, nonenhancing PET scans were common with exposed bone; enhancing PET scans were seen in those with clinical signs of local infection. Of the 20 evaluable patients in this study with BPONJ, 18 had PET scans performed with exposed bone. Thirteen of these patients had enhancing PET scans, with 4 having a reported active infection before the scan. Nine of the 18 patients had nonenhancing PET scans with exposed bone. Five patients in this group had alternating enhancing and nonenhancing scans, which is the reason the scan numbers exceed the total number of patients. Five patients had PET scans performed before their BP-ONJ diagnosis, which provides some indication as to the scans’ possible usefulness to detect subclinical disease or to predict future clinical outcome. Four of these patients had enhancing PET scans that were presumed to be due to a dental infection, with 3 of the 4 requiring a dental

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Table 3. POSITRON EMISSION TOMOGRAPHIC SUVS FOR EXPOSED NONINFECTED VERSUS CLINICALLY INFECTED BONE

Group Documented infection No documented infection

Patients, n

Patients Who Contributed $1 SUV, n

SUVs Contributed, n

Group Mean

Group SD

4 10

4 6

5 11

9.76 6.46

5.80 3.69

Abbreviations: SD, standard deviation; SUV, standardized uptake value. Belcher et al. Positron Emission Tomography in Osteonecrosis. J Oral Maxillofac Surg 2014.

extraction that subsequently resulted in BP-ONJ. These findings suggest that abnormal mandibular enhancement on PET scan is not necessarily an indicator of BP-ONJ, but rather a reflection of an inflammatory process. Therefore, PET scanning did not appear to be a reliable diagnostic tool in diagnosing BP-ONJ. Panorex radiography, computed tomography (CT), and magnetic resonance imaging (MRI) have been used as modalities to diagnose BP-ONJ.4 All 3 imaging modalities have been shown effective at depicting the anatomic breakdown and necrotic sequestrum of BPONJ, with CT and MRI showing greater diagnostic capability and sensitivity over plain film radiography.8 CT and MRI are not specific for this disease and, although they show the osteonecrotic pattern, they are unsuitable for analysis of the osteoblastic or inflammatory activity of BP-ONJ.1 Thus, none of these modalities can reliably show bone abnormalities before clinically demonstrable disease. For this reason, nuclear bone scanning has been investigated. Tc99m methoxy-isobutyl-isonitrile scans are useful in patients with a neoplastic process because methoxy-isobutyl-isonitrile coupled with radiolabeled technetium has been found to accumulate in neoplastic tissues.9 Traditionally used in the surveillance of multiple myeloma, Tc99m scans also have been found to display abnormal enhancement of the jaw before clinically or otherwise radiologically evident bone disease. Chiandussi et al10 investigated Tc99m scans of 11 patients receiving BPs with active clinical infectious symptoms of pain, fever, and edema. In all patients, they found decreased mandibular enhancement early Table 4. RESOLUTION OF ENHANCEMENT ON PET IN CASES OF BP-ONJ

PET scans Enhancing PET scans with exposed bone Resolved BP-ONJ with nonenhancing PET Resolved BP-ONJ with enhancing PET

53 23 6 1

Abbreviations: BP-ONJ, bisphosphonate-related osteonecrosis of the jaw; PET, positron emission tomographic. Belcher et al. Positron Emission Tomography in Osteonecrosis. J Oral Maxillofac Surg 2014.

in the disease process and increased enhancement in later stages. This was thought to be due to increased osteoblastic activity later in the disease. In contrast, Catalano et al3 described 4 patients with BP-ONJ who had Tc99m scans performed with no apparent active infection and did not show mandibular enhancement. They concluded that because Tc99m is specific for a neoplastic process, the imaging modality can be used in patients with multiple myeloma in distinguishing a plasma cell bone lesion from BP-ONJ, thus obviating a biopsy and avoiding the risk of biopsy.3,9 FDG-PET has become a valuable imaging tool in oncology.11 Specifically in multiple myeloma, PET imaging is useful to evaluate disease activity, to detect extraosseous disease involvement, to direct local therapy such as radiation, to assess patients with nonsecretory myeloma, and to evaluate response to therapy by measuring visually and semiquantitatively the FDG enhancement in each neoplastic lesion.3,12 The mechanism of BP-ONJ remains unclear. Many theories have been proposed, such as inhibition of osteoclast function by BPs, mucosal toxicity, biofilm formation, and possibly the antiangiogenic effects of BPs.1,4,9,10,13,14 Possibly a combination of all these mechanisms result in that the lack of repair from physiologic microdamage from masticatory forces, the demand placed on bone remodeling because of infection, and exposure of the tooth socket after extraction to a contaminated environment.4 The role of infection has led to much speculation. Does necrosis occur as a result of chronic osteomyelitis or does the necrotic bone serve as a nidus for a secondary infection? Many cases of clinical resolution in response to antibiotics have prompted the American Association of Oral and Maxillofacial Surgeons to recommend antibiotic therapy in all stages of BP-ONJ.7 This infectious association may help to explain the repeated findings of enhancement at nuclear medicine imaging. PET enhancement is dependent on blood flow and hypermetabolism, which by definition would be absent in necrotic tissue. PET uptake in BP-ONJ may be indicative of hypermetabolism caused by superimposing infection and may not necessarily be indicative of

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osteonecrosis. Mahfouz et al15 reported in 2005 that PET scans frequently enhanced with BP-ONJ, but did not enhance when osteonecrosis occurred in other parts of the body. This could be explained by the inflammatory susceptibility of the contaminated oral cavity compared with other sterile deep tissue structures.15 Raje et al4 also suggested that PET enhancement at BP-ONJ sites may simply be a representation of the surrounding healing process. In their study, however, not all patients showed enhancement at sites of exposed bone; 5 of 17 BP-ONJ sites on FDG-PET images and 3 of 16 sites on F18 sodium fluoride PET images did not enhance.4 PET scans depicting enhancement before the development of exposed bone could indicate bacterial seeding of necrotic bone before gingival loss. In these cases, independent of symptoms, one may suspect early or impending BP-ONJ. Treatment, such as discontinuation of BPs, avoidance of dental trauma, improved oral hygiene, or empiric antibiotics, might be recommended. Limitations to this study include the retrospective approach. In addition, staging and reporting of BPONJ were incomplete owing to a nonexistent staging system. Moreover, medical practitioners are not as meticulous at documenting their oral examination findings as their dental colleagues. Previous studies have indicated that PET imaging may be of diagnostic utility in BP-ONJ because enhancement at BP-ONJ sites has been observed. Upon review of the present BP-ONJ population, nonenhancing PET scans were common with exposed bone; enhancing PET scans were seen for patients with clinical signs of local infection. Although more studies are needed to determine the utility of PET scanning in the diagnosis and treatment of BP-ONJ, the present study shows that an enhancing PET scan is not a reliable indicator of BP-ONJ and that a nonenhancing scan does not necessarily exclude the disease. However, PET scans in conjunction with physical examination may be of use in monitoring the need for further antibiotic treatment in cases of clinical infection. Certainly a review of these scans for jaw abnormalities, in a setting

of BP exposure, when they are obtained for other clinical indications is recommended.

References 1. Package insert revisions re: Osteonecrosis of the jaw: Zometa (zoledronic acid) injection and Aredia (pamidronate disodium) injection. Oncologic Drugs Advisory Committee Meeting, 2005 2. Wilde F, Steinhoff K, Frerich B, et al: Positron-emission tomography imaging in the diagnosis of bisphosphonate-related osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 107:412, 2009 3. Catalano L, Del Vecchio S, Petruzziello F, et al: Sestamibi and FDG-PET scans to support diagnosis of jaw osteonecrosis. Ann Hematol 86:415, 2007 4. Raje N, Woo SB, Hande K, et al: Clinical, radiographic, and biochemical characterization of multiple myeloma patients with osteonecrosis of the jaw. Clin Cancer Res 14:2387, 2008 5. Ho L, Quan V, Henderson R: Zoledronate-related osteonecrosis of the mandible. Clin Nucl Med 33:68, 2008 6. Clarke BM, Boyette J, Vural E, et al: Bisphosphonates and jaw osteonecrosis: The UAMS experience. Otolaryngol Head Neck Surg 136:397, 2007 7. Ruggiero SL, Dodson TB, Assael LA, et al: American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonaterelated osteonecrosis of the jaws—2009 update. J Oral Maxillofac Surg 67(5 Suppl):2, 2009 8. Stockmann P, Hinkmann FM, Lell MM, et al: Panoramic radiograph, computed tomography or magnetic resonance imaging. Which imaging technique should be preferred in bisphosphonate-associated osteonecrosis of the jaw? A prospective clinical study. Clin Oral Investig 14:311, 2010 9. Arce K, Assael LA, Weissman JL, et al: Imaging findings in bisphosphonate-related osteonecrosis of jaws. J Oral Maxillofac Surg 67(5 Suppl):75, 2009 10. Chiandussi S, Biasotto M, Dore F, et al: Clinical and diagnostic imaging of bisphosphonate-associated osteonecrosis of the jaws. Dentomaxillofac Radiol 35:236, 2006 11. Terpos E, Moulopoulos LA, Dimopoulos MA: Advances in imaging and the management of myeloma bone disease. J Clin Oncol 29:1907, 2011 12. Bredella MA, Steinbach L, Caputo G, et al: Value of FDG PET in the assessment of patients with multiple myeloma. AJR Am J Roentgenol 184:1199, 2005 13. Reid IR, Bolland MJ, Grey AB: Is bisphosphonate-associated osteonecrosis of the jaw caused by soft tissue toxicity? Bone 41:318, 2007 14. Sedghizadeh PP, Kumar SK, Gorur A, et al: Identification of microbial biofilms in osteonecrosis of the jaws secondary to bisphosphonate therapy. J Oral Maxillofac Surg 66:767, 2008 15. Mahfouz T, Miceli MH, Saqhafifar F, et al: 18F-fluorodeoxyglucose positron emission tomography contributes to the diagnosis and management of infections in patients with multiple myeloma: A study of 165 infectious episodes. J Clin Oncol 23:7857, 2005