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Bisphosphonate-related osteonecrosis of the jaws
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Bisphosphonate-related osteonecrosis of the jaws A report of three cases demonstrating variability in outcomes and morbidity Vandana Kumar, BDS, MDS; Barry Pass, DDS, PhD; Steven A. Guttenberg, DDS, MD; John Ludlow, DDS, MS; Robert W. Emery, DDS; Donald A. Tyndall, DDS, PhD; Ricordo J. Padilla, DDS
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Background. Bisphosphonates are used widely to manage skeletal disorders resulting from maligN C U nancies that destroy bone and from some metabolic A ING EDU 1 bone diseases. A strong association between bisphosRT ICLE phonate treatment and the appearance of painful exposed nonvital bone in the mandible and maxilla after oral surgery has been reported in the last decade. Extensive reviews have appeared in the dental literature regarding bisphosphonate-related osteonecrosis of the jaws (BRONJ), including protocols for diagnosis, management and diagnostic imaging for early detection; feature definition; and determination of extent of the disease. Case Descriptions. The authors provide three case reports to show the contrast in treatment outcomes and morbidity in patients with BRONJ. The cases involved diagnostic imaging modalities commonly used in the practice of dentistry: panoramic radiography and cone-beam volumetric computed tomography. Clinical Implications. These case reports demonstrate the usefulness of dental diagnostic imaging in the detection and management of BRONJ, corroborate the increasing number of reports regarding high levels of morbidity associated with various BRONJ treatments, and underscore the danger of performing invasive dental procedures for patients receiving bisphosphonate therapy. Key Words. Bisphosphonates; osteonecrosis; multiple myeloma; chemotherapy; hypercalcemia; osteoporosis; angiogenesis; cone-beam volumetric computed tomography; panoramic radiography. JADA 2007;138(5):602-9. T
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ABSTRACT CON
ancer patients with metastatic bone lesions often have many complications, including pain, pathological fracture, spinal cord compression and hypercalcemia resulting from pathological bone resorption. Bisphosphonates inhibit bone resorption and are used to treat cancer-related hypercalcemia and bone involvement in multiple myeloma and solid tumors.1 Bisphosphonates also have been used to treat metabolic bone diseases such as Paget’s disease of bone2 and osteoporosis3 in adults and to treat skeletal disorders such as juvenile osteoporosis, osteogenesis imperfecta and polyostotic fibrous dysplasia4 in children. Fifteen years ago, van Persijn van Meerten and colleagues5 reported adverse skeletal effects such as sclerosis of growth plates in children who had been administered bisphosphonates. Twenty-five years ago, Schwartz6 reported chemically induced osteonecrosis of the jaws (ONJ) as a consequence of cancer therapy. In 2005, Hellstein and Marek7 described a new dental-
Dr. Kumar is a resident, Department of Oral and Maxillofacial Radiology, University of North Carolina, Chapel Hill. Dr. Pass is a professor, Department of Diagnostic Services, College of Dentistry, Howard University, 600 W St., NW, Washington, D.C. 20059, e-mail “[email protected]”. Address reprint requests to Dr. Pass. Dr. Guttenberg is in private practice, Washington, and is a senior attending surgeon, Department of Oral and Maxillofacial Surgery, Washington Hospital Center, Washington. Dr. Ludlow is a professor, Department of Oral and Maxillofacial Radiology, University of North Carolina, Chapel Hill. Dr. Emery is in private practice, Washington, and is a senior attending surgeon, Department of Oral and Maxillofacial Surgery, Washington Hospital Center, Washington. Dr. Tyndall is a professor, Department of Oral and Maxillofacial Radiology, University of North Carolina, Chapel Hill. Dr. Padilla is a clinical assistant professor, Department of Diagnostic Sciences and General Dentistry, University of North Carolina, Chapel Hill.
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related complication specifically associated with There was a significant bony depression posterior the use of bisphosphonates: bisphosphonateto the maxillary left first molar. related osteonecrosis of the jaws (BRONJ). The subject’s medical history was significant The knowledge base for the diagnosis and manfor multiple myeloma, type 2 diabetes mellitus, agement of BRONJ is complex and evolving. More anemia and high blood pressure. He did not than 100 new cases of BRONJ were reported in smoke, was a light alcohol user and had no histhe scientific literature in the first one-half of tory of IV drug abuse. At the time he came to the 2006, bringing the number of cases reported to clinic, he was taking amlodipine besylate, thalidobetween 600 and 700.8 Most of these cases were mide, folic acid, aspirin, amoxicillin, dexamethaassociated with the intravenous (IV) administrasone, epoetin alfa and pamidronate. tion of bisphosphonates. However, Nase and The diagnostic imaging we used was computed Suzuki3 reported that BRONJ can be associated tomography image reconstruction from twowith the oral administration of bisphosphonates. dimensional maxillofacial projections using a Recent articles in the dental literature regarding three-dimensional CBCT device. The reformatted BRONJ provide comprehensive literature CBCT scan (Figure 1) shows an extensive radiolureviews,9 definitive protocols for diagnosis and cent region of bone destruction with bony management,8,10 and imaging protocols for early sequestra encompassing the maxillary left first diagnosis and staging.11 Clinical intraoral photomolar and extending to the graphs of BRONJ also are available tuberosity on that side. The maxilin the literature.8 lary sinus had extensive thickening The knowledge base We provide a clinical comparison of the mucosa, and there was posfor the diagnosis of three subjects with BRONJ that sible erosion of the sinus floor and and management demonstrates variability in treatmedial wall. Axial, coronal and ments, outcomes and morbidity. In sagittal sections through the left of bisphosphonateeach case, radiographic modalities sinus (Figure 2) show extensive related osteonecrosis specific to the dental profession— inflammation of the maxillary sinus of the jaws is complex panoramic radiography and coneand possible erosion of the medial and evolving. beam volumetric computed tomogwall. raphy (CBCT)—were used.12 In the literature, patients who had cancer and BRONJ typically had complex medical histories and received treatment with different drugs, but all of them had received bisphosphonate therapy. In our report, the three subjects with malignant disease and BRONJ had received pamidronate or zoledronic acid—two commonly used bisphosphonates administered intravenously. CASE REPORTS
Subject 1. In this case, early recognition of a relatively mild manifestation of the disease and conservative treatment led to a successful outcome. An 86-year-old man came to a private oral surgery office in Washington to have a mobile, periodontally involved maxillary left first molar extracted and to have evaluated an apparently infected painful area in the left posterior maxilla that had been present for two months. Clinical examination showed a mobile maxillary left first molar and an area of denuded, necrotic bone involving the maxillary alveolar ridge from the maxillary left first molar to the tuberosity. The associated mucosa appeared red and inflamed.
The gray appearance of the avascular, nonvital bone we saw during surgery and the subject’s history of pamidronate therapy indicated a diagnosis of bisphosphonaterelated osteonecrosis of the maxilla. The subject was in remission and clinically free of malignancy; therefore, we ruled out that the osteolytic lesion could be secondary to multiple myeloma. The absence of purulence suggested that the jaw lesions were not due to acute osteomyelitis. Further, the subject had type 2 diabetes mellitus, as opposed to type 1 diabetes mellitus. His blood glucose levels were under moderately good control without medication. A patient with diabetes such as this ordinarily is not at a significantly greater risk of experiencing infections resulting from compromised immune systems than are other patients. According to recommended treatment protocols for BRONJ,8,10 we did not perform a pretreatment biopsy, as the results would not have ABBREVIATION KEY. BRONJ: Bisphosphonaterelated osteonecrosis of the jaws. CBCT: Cone-beam volumetric computed tomography. IV: Intravenous. ONJ: Osteonecrosis of the jaws.
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before the surgical procedures and continued, with variable patient compliance, for several months. At the three-week postoperative visit, the subject had no complaints. Healing in the affected area was progressing well and no bleeding or purulent exudate were present. The subject failed to report for a fourmonth checkup. At the eight-month postoperative visit, clinical examination showed there was a small area of denuded bone protruding through otherwise healthy alveolar mucosa (Figure 3). CBCT imaging showed a large residual bony defect in the maxilla, opacity of the sinus with indications of regeneration of bone resulting in an intact medial wall, and a residual small defect in Figure 1. Subject 1: preoperative cone-beam volumetric computed tomography reforthe sinus floor corresponding to the matted panoramic view (A) and cross-sections perpendicular to the axis (B) showing an clinically evident area of denuded extensive radiolucent region of bone destruction with bony sequestra encompassing the maxillary left first molar and extending to the tuberosity on that side, as well as extenbone (Figure 4). The subject was sive thickening of the mucosa and possible erosion of the sinus floor and medial wall. free of pain. Cross hairs in each frame indicate level of slices. The slow postoperative period during which bone in the posterior maxilla remained exposed for approximately nine months until it was almost completely covered by the mucosa supported the diagnosis of bisphosphonate-related osteonecrosis of the maxilla. The B lack of advanced periodontal disease in other areas of the oral cavity and the close proximity of the maxillary left first molar to the dead or necrotic bone indicated that the tooth was floating because of the destruction of its bony support C caused by the progressing BRONJ. We do not know if the antiangioFigure 2. Subject 1: preoperative cone-beam volumetric computed tomography crosssectional slices (axial [A], coronal [B] and sagittal [C]) through the left sinus showing genic thalidomide used as an extensive inflammation of the maxillary sinus and possible erosion of the medial wall. antimyeloma agent by this subject Cross hairs in each frame indicate level of slices. contributed to bone necrosis. altered the treatment and any form of maxilloSubject 2. This case started with a more facial surgery would constitute an additional risk extensive presentation of the disease than of inducing ONJ. in the case for subject 1. Then, complications We treated the lesion two days after the subensued, requiring wide-ranging, comprehensive ject came to the private oral surgery office; we treatments. extracted the maxillary left first molar with basic A 54-year-old woman with a history of adenocurettage and irrigation of the necrotic defect carcinoma of the breast treated with mastectomy, without penetrating into the sinus, and closed the chemotherapy and IV paclitaxel came to the surgical site. Antibiotic coverage began two days Department of Oral and Maxillofacial Surgery, 604
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University of North Carolina School of Dentistry, Chapel Hill, for evaluation of a painful and nonhealing mandibular right molar extraction. She also had undergone a regimen of bisphosphonates. She began with zoledronic acid 4 milligrams intravenously for six months in 1991 when she was first diagnosed with breast cancer. She began taking bisphosphonates again in 1998 when she was diagnosed with liver metastasis from the primary adenocarcinoma of the breast. The zoledronic acid therapy continued weekly up to the time she came to the department of oral surgery. Zoledronic acid is available in vials as a sterile liquid concentrate solution for IV infusion. Each 5-milliliter vial contains 4.264 mg of zoledronic acid monohydrate, corresponding to 4 mg zoledronic acid on an anhydrous basis. Figure 3. Intraoral image of subject 1 taken eight months postopA panoramic radiograph of the subject showed eratively showing noninflamed regenerated mucosa with a small, multiple sequestra and a nonhealing deep bony quiescent area of denuded bone. defect (Figure 5). In addition to zoledronic acid, she also took granisetron, dexamethasone sodium with sterile, petrolatum-impregnated gauze, and phosphate, diphenhydramine and cimetidine. Her we advised her against heavy chewing in that local oral and maxillofacial surgeon had previarea. ously removed multiple teeth and operated sevFive months postoperatively, the reconstruceral times to remove sequestra. tion bar eroded through her skin, showing a visThe subject had been taking various antibiotics ible area of erosion, pus drainage, an oral fistula to treat the multiple sequestra and nonhealing and exposed bone at the right anterior lingual bony defects typical of osteomyelitis, though they surface. We performed additional surgery to had done little to help her situation. When we conducted a clinical examination, we found a large segment of exposed necrotic bone in the right mandibular angle and body. The subject had developed sevB eral fistulas that were painful, tender and swollen. The biopsy showed no evidence of metastatic disease. Débridement and irrigation of the area at the time of clinical examination did not help. After three weeks, we surgically resected the right mandibular body from the angle to the canine region and placed a titanium reconstruction bar. We placed three screws in the proximal segment A C and four screws in the distal segment of the reconstruction Figure 4. Eight-month postoperative cone-beam volumetric computed tomography cross-sectional slices (axial [A], coronal [B] and sagittal [C]) of subject 1 showing a large bar. We instructed the subject bony defect in the maxilla, opacity of the sinus with indications of regeneration of to irrigate the surgical site with residual bone resulting in an intact medial wall, and residual small defect in the sinus floor. Cross hairs normal saline and to pack it in each frame indicate level of slices. JADA, Vol. 138 http://jada.ada.org Copyright ©2007 American Dental Association. All rights reserved.
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mandibular region. The skin was erythematous around the fistula and some pus could be expressed from the area. However, there was no evidence of the infection’s having spread along the fascial plane of the neck. No clinical photographs for this subject are available. The subject claimed that she was comfortable and refused any further surgical treatment; however, we advised her to report to the University of North Carolina School of Dentistry oral surgery clinic if Figure 5. Panoramic radiograph of subject 2 showing a bony defect with illsymptoms developed and the infection defined margins and multiple irregular radiopacities interspersed within the spread. lesion, indicating multiple sequestra posterior to the mandibular right second premolar. Subject 3. In this case, a moderately severe case of BRONJ responded to an array of treatments that are not always effective. A 63-year-old man with diabetes came to the Department of Oral and Maxillofacial Surgery, University of North Carolina School of Dentistry, Chapel Hill, with chief complaints of pain in the right mandible, swelling and difficulty opening his mouth. After he had undergone extraction of his mandibular right first and second molars, the tooth sockets did not heal. Figure 6. Panoramic radiograph of subject 2 showing the second surgical The subject had a medical history of mulresection of the anterior mandible and restabilization with a titanium bar. tiple myeloma, hypertension and hypercholesterolemia. He initially received chemotherapy and then an autologous stem cell transplant. He had been receiving bisphosphonate therapy for four years (pamidronate disodium by injection), and then he received zoledronic acid at the time of the extractions. His other medications included olmesartan and doxazosin mesylate for hypertension, and glipizide, metformin and rosiglitazone maleate for diabetes. A panoramic radiograph taken at the Figure 7. Most recent panoramic radiograph of subject 2 showing apparsubject’s first visit showed a deep bony ently healthy and stabilized bone and no evidence of infection’s having defect in the extraction site (Figure 8). spread along fascial planes. Clinical evaluation showed an area of remove involved bone and to stabilize the bone exposed bone in the subject’s right posterior plates (Figure 6). She received another regimen of mandible. Staff members at the University of antibiotics (cephalexin), and we advised her to North Carolina School of Dentistry oral surgery maintain oral hygiene and to use fluoride rinses. clinic recommended that he undergo treatment Nine months after we performed the first consisting of antibiotics, hyperbaric oxygen and surgery, the subject appeared to be doing well. surgical débridement. We prescribed a course of The reconstruction bar seemed to be maintaining metronidazole and penicillin at the time of clinthe positions of the jaw segments well (Figure 7). ical examination, which helped reduce his pain. There was no evidence of infection or drainage The subject then received hyperbaric oxygen when we noticed another fistula in the subtreatment at 2 atmospheres absolute with 606
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100 percent oxygen for 30 sessions. During the surgical débridement procedure, we raised a mucoperiosteal flap to allow access to the necrotic bone, and we removed overlying granulation tissue and submitted it for pathological evaluation. After débriding the necrotic bone and removing granulation tissue, we closed the surgical site with resorbable sutures and allowed it to heal by first intention (fibrous adhesion without suppuration or granulation tissue formation). We took a panoramic radiograph at four months and noticed appreciable healing of the affected site (Figure 9). The pathological report indicated osteonecrosis and filamentous bacteria consistent with actinomycotic osteomyelitis (Figure 10). Whether this represented true primary actinomycotic infection or superinfection of necrotic bone with Actinomyces was not clear. The subject underwent 10 additional sessions of hyperbaric oxygen therapy. All 40 sessions took approximately two and one-half months. At postoperative visits over six months, the soft tissues surrounding the surgical site no longer were erythematous or edematous. No clinical photographs are available for this subject.
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Figure 8. Panoramic radiograph of subject 3 showing a deep bony defect posterior to the mandibular right second premolar, indicating a nonhealing extraction socket.
Figure 9. Panoramic radiograph of subject 3 taken at four months, showing healing of the bony defect posterior to the mandibular right second premolar.
DISCUSSION
Bisphosphonate therapy effectively controls bone resorption that occurs with certain diseases, but its use has significant implications for dentistry. Bisphosphonates can concentrate in bone and inhibit osteoclast-mediated bone resorption, affecting bone turnover at the cellular and molecular levels.13,14 They also have been shown to have potent antiangiogenic properties owing to their ability to significantly decrease circulating levels of vascular endothelial growth factor (a potent angiogenic factor) in patients who have breast cancer with bone metastases.15,16 Thus, it is believed by a consensus of experts reporting in the literature that the major factors in BRONJ are the inhibition of osteoclastic activity and bone remodeling by bisphosphonates. Additionally, bisphosphonates’ inhibition of endothelial proliferation may result in
Figure 10. Photomicrograph of subject 3 showing necrotic or dead bone (DB) with an absence of osteocytes, and bacterial colonies (BC) (hematoxylin and eosin stain, magnification ✕10 low power).
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subjects 2 and 3 did not respond well. Discontinuischemia and avascular necrosis of bone. ation of bisphosphonate therapy did not ensure Migliorati and colleagues10 identified dental healing. A physician treated subject 1 for extractions and other surgical procedures as preosteomyelitis-type symptoms before he was cipitants in many cases. The apparent selective referred to the private oral surgery office. He then involvement of the maxilla and mandible in these began a new course of antibiotic coverage, which patients may be a reflection of the unique envihe followed inconsistently. We treated subjects ronment of the oral cavity. Typically, an open 2 and 3 according to a protocol for osteomyelitis. bony wound such as an extraction socket heals The subjects’ positive responses to therapy varied quickly and without infection in the presence of from several weeks to many months, but their oral microflora. However, when the vascular conditions required repeated surgical intervensupply of the mandible or maxilla is compromised tions (curettage or sequestrectomy). by radiation therapy or other therapies, the minor The case reports we include in this article proinjury or disease in these sites is more likely to vide a detailed comparison—revealed using develop into a nonhealing wound. That, in turn, imaging modalities readily available to the dental can progress to widespread necrosis and profession—that demonstrates the wide variation osteomyelitis. in treatments and outcomes reported in the literBecause bisphosphonates do not metabolize, ature for BRONJ. the bone maintains high concentrations for long periods, with a half-life of 10 years. Accordingly, CONCLUSION discontinuation of bisphosphonate therapy does not appear to hasten the recovery of the Bisphosphonates are effective in reducing the osteonecrosis. Treatments including mouthrinses, symptoms and complications of metastatic bone systemic antibiotics, hyperbaric disease. The scientific literature oxygen and surgical débridement indicates, however, that bisphoshave been tried, but none have phonates contribute to the pathoThe outcomes and proven effective consistently.8-10 genesis of the oral lesions of ONJ.3 morbidity associated Treatment of the disease is a conunThis condition is accepted as an with bisphosphonate- oral complication in patients with drum, in that intervention involving related osteonecrosis débridement of neighboring healthy cancer. The risk factors for and prebone can result in further spread of cise mechanism involved in the forof the jaws vary necrosis. As this condition and its mation of BRONJ are known only markedly, and complications can result in signifipartially. Furthermore, the outtreatment protocols cant and difficult-to-treat chronic comes and morbidity associated and predictability pain, dysfunction and disfigurewith BRONJ vary markedly, and are understood only ment, the focus should be on pretreatment protocols and prepartially. vention. dictability are understood only The three subjects we describe partially. had histories of multiple myeloma Marx and colleagues13 reported or adenocarcinoma of the breast and had received cases of ONJ with the oral administration of biszoledronic acid or pamidronate by IV for more phosphonates for the prevention of osteoporosis. than three years, but they had varied responses to Because ONJ has been reported in patients dental extractions. Subject 1 received minimal undergoing treatment with bisphosphonates for treatment for BRONJ and recovered without disosteoporosis, and because of the 10-year half-life figurement and remained free of pain. Subject 3 of bisphosphonates, there is a need for further received more extensive treatment, including studies of this extensive population. hyperbaric oxygen therapy, and he appeared to Health professionals, especially dentists, oncolrecover fully. Subject 2, however, had severe morogists and oral surgeons, should be aware of the bidity after tooth extractions, which necessitated possibility that patients being considered for extensive treatment involving a series of ostecdental extractions or other oral surgical protomies without relief of symptoms. Despite surcedures might be undergoing bisphosphonate gical intervention, antibiotic therapy, hyperbaric therapy.17 Because of the extensive use of oral bisoxygen therapy (for subject 3) and topical use of phosphonates, the likelihood of a dentist treating chemotherapeutic mouthrinses, the lesions for a patient using these drugs to prevent osteo608
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porosis is high. Dentists should obtain good medical histories from and inform their patients about the risk of experiencing complications from bisphosphonate therapy so they can assess the need for dental treatment before starting therapy. The American Dental Association has published guidelines for dental management of these patients.18 Health professionals should stay current with the evolving body of knowledge regarding BRONJ, as it is not possible to predict what new and useful information will emerge regarding the etiology and management of this disease, as well as the optimal management of dental patients taking bisphosphonates. ■ 1. Hortobagyi GN. Novel approaches to the management of bone metastases in patients with breast cancer. Semin Oncol 2002;29(3 supplement 11):134-44. 2. Cacace E, Ruggiero V, Matulli C, Uras L, Perpignano G. Markers of bone resorption in bisphosphonate therapy of Paget’s disease. Clin Exp Rheumatol 2004;22(4):502. 3. Nase JB, Suzuki JB. Osteonecrosis of the jaw and oral bisphosphonate treatment. JADA 2006;137(8):1115-9. 4. Speiser PW, Clarson CL, Eugster EA, et al. Bisphosphonate treatment of pediatric bone disease. Pediatr Endocrinol Rev 2005;3(2): 87-96. 5. van Persijn van Meerten EL, Kroon HM, Papapoulos SE. Epi- and metaphyseal changes in children caused by administration of bisphosphonates. Radiology 1992;184(1):249-54. 6. Schwartz HC. Osteonecrosis of the jaws: a complication of cancer chemotherapy. Head Neck Surg 1982;4(3):251-3.
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7. Hellstein JW, Marek CL. Bisphosphonate osteochemonecrosis (bisphossy jaw): is this phossy jaw of the 21st century? J Oral Maxillofac Surg 2005;63(5):682-9. 8. Ruggiero SL, Fantasia J, Carlson E. Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;102(4):433-41. 9. Leite AF, Figueiredo PT, Melo NS, et al. Bisphosphonateassociated osteonecrosis of the jaws: report of a case and literature review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;102(1):14-21. 10. Migliorati CA, Casiglia J, Epstein J, Jacobsen PL, Siegel MA, Woo SB. Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper (published correction appears in JADA 2006;137([1]):26.). JADA 2005;136(12):1658-68. 11. Chiandussi S, Biasotto M, Dore F, Cavalli F, Cova MA, Di Lenarda R. Clinical and diagnostic imaging of bisphosphonateassociated osteonecrosis of the jaws. Dentomaxillofac Radiol 2006;35 (4):236-43. 12. Scarfe WC, Farman AG, Sukovic P. Clinical applications of conebeam computed tomography in dental practice. J Can Dent Assoc 2006;72(1):75-80. 13. Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonateinduced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 2005;63(11):1567-75. 14. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62(5):527-34. 15. Fournier P, Boissier S, Filleur S, et al. Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 2002;62(22):6538-44. 16. Wood J, Bonjean K, Ruetz S, et al. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 2002;302(3):1055-61. 17. Expert panel recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaws. LDA J 2005;64(3):21-4. 18. Dental management of patients receiving oral bisphosphonate therapy: expert panel recommendations. JADA 2006;137(8):1144-50.
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Bisphosphonate-related osteonecrosis of the jaws A report of three cases demonstrating variability in outcomes and morbidity Vandana Kumar, BDS, MDS; Barry Pass, DDS, PhD; Steven A. Guttenberg, DDS, MD; John Ludlow, DDS, MS; Robert W. Emery, DDS; Donald A. Tyndall, DDS, PhD; Ricordo J. Padilla, DDS
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Background. Bisphosphonates are used widely to manage skeletal disorders resulting from maligN C U nancies that destroy bone and from some metabolic A ING EDU 1 bone diseases. A strong association between bisphosRT ICLE phonate treatment and the appearance of painful exposed nonvital bone in the mandible and maxilla after oral surgery has been reported in the last decade. Extensive reviews have appeared in the dental literature regarding bisphosphonate-related osteonecrosis of the jaws (BRONJ), including protocols for diagnosis, management and diagnostic imaging for early detection; feature definition; and determination of extent of the disease. Case Descriptions. The authors provide three case reports to show the contrast in treatment outcomes and morbidity in patients with BRONJ. The cases involved diagnostic imaging modalities commonly used in the practice of dentistry: panoramic radiography and cone-beam volumetric computed tomography. Clinical Implications. These case reports demonstrate the usefulness of dental diagnostic imaging in the detection and management of BRONJ, corroborate the increasing number of reports regarding high levels of morbidity associated with various BRONJ treatments, and underscore the danger of performing invasive dental procedures for patients receiving bisphosphonate therapy. Key Words. Bisphosphonates; osteonecrosis; multiple myeloma; chemotherapy; hypercalcemia; osteoporosis; angiogenesis; cone-beam volumetric computed tomography; panoramic radiography. JADA 2007;138(5):602-9. T
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ABSTRACT CON
ancer patients with metastatic bone lesions often have many complications, including pain, pathological fracture, spinal cord compression and hypercalcemia resulting from pathological bone resorption. Bisphosphonates inhibit bone resorption and are used to treat cancer-related hypercalcemia and bone involvement in multiple myeloma and solid tumors.1 Bisphosphonates also have been used to treat metabolic bone diseases such as Paget’s disease of bone2 and osteoporosis3 in adults and to treat skeletal disorders such as juvenile osteoporosis, osteogenesis imperfecta and polyostotic fibrous dysplasia4 in children. Fifteen years ago, van Persijn van Meerten and colleagues5 reported adverse skeletal effects such as sclerosis of growth plates in children who had been administered bisphosphonates. Twenty-five years ago, Schwartz6 reported chemically induced osteonecrosis of the jaws (ONJ) as a consequence of cancer therapy. In 2005, Hellstein and Marek7 described a new dental-
Dr. Kumar is a resident, Department of Oral and Maxillofacial Radiology, University of North Carolina, Chapel Hill. Dr. Pass is a professor, Department of Diagnostic Services, College of Dentistry, Howard University, 600 W St., NW, Washington, D.C. 20059, e-mail “[email protected]”. Address reprint requests to Dr. Pass. Dr. Guttenberg is in private practice, Washington, and is a senior attending surgeon, Department of Oral and Maxillofacial Surgery, Washington Hospital Center, Washington. Dr. Ludlow is a professor, Department of Oral and Maxillofacial Radiology, University of North Carolina, Chapel Hill. Dr. Emery is in private practice, Washington, and is a senior attending surgeon, Department of Oral and Maxillofacial Surgery, Washington Hospital Center, Washington. Dr. Tyndall is a professor, Department of Oral and Maxillofacial Radiology, University of North Carolina, Chapel Hill. Dr. Padilla is a clinical assistant professor, Department of Diagnostic Sciences and General Dentistry, University of North Carolina, Chapel Hill.
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related complication specifically associated with There was a significant bony depression posterior the use of bisphosphonates: bisphosphonateto the maxillary left first molar. related osteonecrosis of the jaws (BRONJ). The subject’s medical history was significant The knowledge base for the diagnosis and manfor multiple myeloma, type 2 diabetes mellitus, agement of BRONJ is complex and evolving. More anemia and high blood pressure. He did not than 100 new cases of BRONJ were reported in smoke, was a light alcohol user and had no histhe scientific literature in the first one-half of tory of IV drug abuse. At the time he came to the 2006, bringing the number of cases reported to clinic, he was taking amlodipine besylate, thalidobetween 600 and 700.8 Most of these cases were mide, folic acid, aspirin, amoxicillin, dexamethaassociated with the intravenous (IV) administrasone, epoetin alfa and pamidronate. tion of bisphosphonates. However, Nase and The diagnostic imaging we used was computed Suzuki3 reported that BRONJ can be associated tomography image reconstruction from twowith the oral administration of bisphosphonates. dimensional maxillofacial projections using a Recent articles in the dental literature regarding three-dimensional CBCT device. The reformatted BRONJ provide comprehensive literature CBCT scan (Figure 1) shows an extensive radiolureviews,9 definitive protocols for diagnosis and cent region of bone destruction with bony management,8,10 and imaging protocols for early sequestra encompassing the maxillary left first diagnosis and staging.11 Clinical intraoral photomolar and extending to the graphs of BRONJ also are available tuberosity on that side. The maxilin the literature.8 lary sinus had extensive thickening The knowledge base We provide a clinical comparison of the mucosa, and there was posfor the diagnosis of three subjects with BRONJ that sible erosion of the sinus floor and and management demonstrates variability in treatmedial wall. Axial, coronal and ments, outcomes and morbidity. In sagittal sections through the left of bisphosphonateeach case, radiographic modalities sinus (Figure 2) show extensive related osteonecrosis specific to the dental profession— inflammation of the maxillary sinus of the jaws is complex panoramic radiography and coneand possible erosion of the medial and evolving. beam volumetric computed tomogwall. raphy (CBCT)—were used.12 In the literature, patients who had cancer and BRONJ typically had complex medical histories and received treatment with different drugs, but all of them had received bisphosphonate therapy. In our report, the three subjects with malignant disease and BRONJ had received pamidronate or zoledronic acid—two commonly used bisphosphonates administered intravenously. CASE REPORTS
Subject 1. In this case, early recognition of a relatively mild manifestation of the disease and conservative treatment led to a successful outcome. An 86-year-old man came to a private oral surgery office in Washington to have a mobile, periodontally involved maxillary left first molar extracted and to have evaluated an apparently infected painful area in the left posterior maxilla that had been present for two months. Clinical examination showed a mobile maxillary left first molar and an area of denuded, necrotic bone involving the maxillary alveolar ridge from the maxillary left first molar to the tuberosity. The associated mucosa appeared red and inflamed.
The gray appearance of the avascular, nonvital bone we saw during surgery and the subject’s history of pamidronate therapy indicated a diagnosis of bisphosphonaterelated osteonecrosis of the maxilla. The subject was in remission and clinically free of malignancy; therefore, we ruled out that the osteolytic lesion could be secondary to multiple myeloma. The absence of purulence suggested that the jaw lesions were not due to acute osteomyelitis. Further, the subject had type 2 diabetes mellitus, as opposed to type 1 diabetes mellitus. His blood glucose levels were under moderately good control without medication. A patient with diabetes such as this ordinarily is not at a significantly greater risk of experiencing infections resulting from compromised immune systems than are other patients. According to recommended treatment protocols for BRONJ,8,10 we did not perform a pretreatment biopsy, as the results would not have ABBREVIATION KEY. BRONJ: Bisphosphonaterelated osteonecrosis of the jaws. CBCT: Cone-beam volumetric computed tomography. IV: Intravenous. ONJ: Osteonecrosis of the jaws.
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before the surgical procedures and continued, with variable patient compliance, for several months. At the three-week postoperative visit, the subject had no complaints. Healing in the affected area was progressing well and no bleeding or purulent exudate were present. The subject failed to report for a fourmonth checkup. At the eight-month postoperative visit, clinical examination showed there was a small area of denuded bone protruding through otherwise healthy alveolar mucosa (Figure 3). CBCT imaging showed a large residual bony defect in the maxilla, opacity of the sinus with indications of regeneration of bone resulting in an intact medial wall, and a residual small defect in Figure 1. Subject 1: preoperative cone-beam volumetric computed tomography reforthe sinus floor corresponding to the matted panoramic view (A) and cross-sections perpendicular to the axis (B) showing an clinically evident area of denuded extensive radiolucent region of bone destruction with bony sequestra encompassing the maxillary left first molar and extending to the tuberosity on that side, as well as extenbone (Figure 4). The subject was sive thickening of the mucosa and possible erosion of the sinus floor and medial wall. free of pain. Cross hairs in each frame indicate level of slices. The slow postoperative period during which bone in the posterior maxilla remained exposed for approximately nine months until it was almost completely covered by the mucosa supported the diagnosis of bisphosphonate-related osteonecrosis of the maxilla. The B lack of advanced periodontal disease in other areas of the oral cavity and the close proximity of the maxillary left first molar to the dead or necrotic bone indicated that the tooth was floating because of the destruction of its bony support C caused by the progressing BRONJ. We do not know if the antiangioFigure 2. Subject 1: preoperative cone-beam volumetric computed tomography crosssectional slices (axial [A], coronal [B] and sagittal [C]) through the left sinus showing genic thalidomide used as an extensive inflammation of the maxillary sinus and possible erosion of the medial wall. antimyeloma agent by this subject Cross hairs in each frame indicate level of slices. contributed to bone necrosis. altered the treatment and any form of maxilloSubject 2. This case started with a more facial surgery would constitute an additional risk extensive presentation of the disease than of inducing ONJ. in the case for subject 1. Then, complications We treated the lesion two days after the subensued, requiring wide-ranging, comprehensive ject came to the private oral surgery office; we treatments. extracted the maxillary left first molar with basic A 54-year-old woman with a history of adenocurettage and irrigation of the necrotic defect carcinoma of the breast treated with mastectomy, without penetrating into the sinus, and closed the chemotherapy and IV paclitaxel came to the surgical site. Antibiotic coverage began two days Department of Oral and Maxillofacial Surgery, 604
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University of North Carolina School of Dentistry, Chapel Hill, for evaluation of a painful and nonhealing mandibular right molar extraction. She also had undergone a regimen of bisphosphonates. She began with zoledronic acid 4 milligrams intravenously for six months in 1991 when she was first diagnosed with breast cancer. She began taking bisphosphonates again in 1998 when she was diagnosed with liver metastasis from the primary adenocarcinoma of the breast. The zoledronic acid therapy continued weekly up to the time she came to the department of oral surgery. Zoledronic acid is available in vials as a sterile liquid concentrate solution for IV infusion. Each 5-milliliter vial contains 4.264 mg of zoledronic acid monohydrate, corresponding to 4 mg zoledronic acid on an anhydrous basis. Figure 3. Intraoral image of subject 1 taken eight months postopA panoramic radiograph of the subject showed eratively showing noninflamed regenerated mucosa with a small, multiple sequestra and a nonhealing deep bony quiescent area of denuded bone. defect (Figure 5). In addition to zoledronic acid, she also took granisetron, dexamethasone sodium with sterile, petrolatum-impregnated gauze, and phosphate, diphenhydramine and cimetidine. Her we advised her against heavy chewing in that local oral and maxillofacial surgeon had previarea. ously removed multiple teeth and operated sevFive months postoperatively, the reconstruceral times to remove sequestra. tion bar eroded through her skin, showing a visThe subject had been taking various antibiotics ible area of erosion, pus drainage, an oral fistula to treat the multiple sequestra and nonhealing and exposed bone at the right anterior lingual bony defects typical of osteomyelitis, though they surface. We performed additional surgery to had done little to help her situation. When we conducted a clinical examination, we found a large segment of exposed necrotic bone in the right mandibular angle and body. The subject had developed sevB eral fistulas that were painful, tender and swollen. The biopsy showed no evidence of metastatic disease. Débridement and irrigation of the area at the time of clinical examination did not help. After three weeks, we surgically resected the right mandibular body from the angle to the canine region and placed a titanium reconstruction bar. We placed three screws in the proximal segment A C and four screws in the distal segment of the reconstruction Figure 4. Eight-month postoperative cone-beam volumetric computed tomography cross-sectional slices (axial [A], coronal [B] and sagittal [C]) of subject 1 showing a large bar. We instructed the subject bony defect in the maxilla, opacity of the sinus with indications of regeneration of to irrigate the surgical site with residual bone resulting in an intact medial wall, and residual small defect in the sinus floor. Cross hairs normal saline and to pack it in each frame indicate level of slices. JADA, Vol. 138 http://jada.ada.org Copyright ©2007 American Dental Association. All rights reserved.
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mandibular region. The skin was erythematous around the fistula and some pus could be expressed from the area. However, there was no evidence of the infection’s having spread along the fascial plane of the neck. No clinical photographs for this subject are available. The subject claimed that she was comfortable and refused any further surgical treatment; however, we advised her to report to the University of North Carolina School of Dentistry oral surgery clinic if Figure 5. Panoramic radiograph of subject 2 showing a bony defect with illsymptoms developed and the infection defined margins and multiple irregular radiopacities interspersed within the spread. lesion, indicating multiple sequestra posterior to the mandibular right second premolar. Subject 3. In this case, a moderately severe case of BRONJ responded to an array of treatments that are not always effective. A 63-year-old man with diabetes came to the Department of Oral and Maxillofacial Surgery, University of North Carolina School of Dentistry, Chapel Hill, with chief complaints of pain in the right mandible, swelling and difficulty opening his mouth. After he had undergone extraction of his mandibular right first and second molars, the tooth sockets did not heal. Figure 6. Panoramic radiograph of subject 2 showing the second surgical The subject had a medical history of mulresection of the anterior mandible and restabilization with a titanium bar. tiple myeloma, hypertension and hypercholesterolemia. He initially received chemotherapy and then an autologous stem cell transplant. He had been receiving bisphosphonate therapy for four years (pamidronate disodium by injection), and then he received zoledronic acid at the time of the extractions. His other medications included olmesartan and doxazosin mesylate for hypertension, and glipizide, metformin and rosiglitazone maleate for diabetes. A panoramic radiograph taken at the Figure 7. Most recent panoramic radiograph of subject 2 showing apparsubject’s first visit showed a deep bony ently healthy and stabilized bone and no evidence of infection’s having defect in the extraction site (Figure 8). spread along fascial planes. Clinical evaluation showed an area of remove involved bone and to stabilize the bone exposed bone in the subject’s right posterior plates (Figure 6). She received another regimen of mandible. Staff members at the University of antibiotics (cephalexin), and we advised her to North Carolina School of Dentistry oral surgery maintain oral hygiene and to use fluoride rinses. clinic recommended that he undergo treatment Nine months after we performed the first consisting of antibiotics, hyperbaric oxygen and surgery, the subject appeared to be doing well. surgical débridement. We prescribed a course of The reconstruction bar seemed to be maintaining metronidazole and penicillin at the time of clinthe positions of the jaw segments well (Figure 7). ical examination, which helped reduce his pain. There was no evidence of infection or drainage The subject then received hyperbaric oxygen when we noticed another fistula in the subtreatment at 2 atmospheres absolute with 606
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100 percent oxygen for 30 sessions. During the surgical débridement procedure, we raised a mucoperiosteal flap to allow access to the necrotic bone, and we removed overlying granulation tissue and submitted it for pathological evaluation. After débriding the necrotic bone and removing granulation tissue, we closed the surgical site with resorbable sutures and allowed it to heal by first intention (fibrous adhesion without suppuration or granulation tissue formation). We took a panoramic radiograph at four months and noticed appreciable healing of the affected site (Figure 9). The pathological report indicated osteonecrosis and filamentous bacteria consistent with actinomycotic osteomyelitis (Figure 10). Whether this represented true primary actinomycotic infection or superinfection of necrotic bone with Actinomyces was not clear. The subject underwent 10 additional sessions of hyperbaric oxygen therapy. All 40 sessions took approximately two and one-half months. At postoperative visits over six months, the soft tissues surrounding the surgical site no longer were erythematous or edematous. No clinical photographs are available for this subject.
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Figure 8. Panoramic radiograph of subject 3 showing a deep bony defect posterior to the mandibular right second premolar, indicating a nonhealing extraction socket.
Figure 9. Panoramic radiograph of subject 3 taken at four months, showing healing of the bony defect posterior to the mandibular right second premolar.
DISCUSSION
Bisphosphonate therapy effectively controls bone resorption that occurs with certain diseases, but its use has significant implications for dentistry. Bisphosphonates can concentrate in bone and inhibit osteoclast-mediated bone resorption, affecting bone turnover at the cellular and molecular levels.13,14 They also have been shown to have potent antiangiogenic properties owing to their ability to significantly decrease circulating levels of vascular endothelial growth factor (a potent angiogenic factor) in patients who have breast cancer with bone metastases.15,16 Thus, it is believed by a consensus of experts reporting in the literature that the major factors in BRONJ are the inhibition of osteoclastic activity and bone remodeling by bisphosphonates. Additionally, bisphosphonates’ inhibition of endothelial proliferation may result in
Figure 10. Photomicrograph of subject 3 showing necrotic or dead bone (DB) with an absence of osteocytes, and bacterial colonies (BC) (hematoxylin and eosin stain, magnification ✕10 low power).
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subjects 2 and 3 did not respond well. Discontinuischemia and avascular necrosis of bone. ation of bisphosphonate therapy did not ensure Migliorati and colleagues10 identified dental healing. A physician treated subject 1 for extractions and other surgical procedures as preosteomyelitis-type symptoms before he was cipitants in many cases. The apparent selective referred to the private oral surgery office. He then involvement of the maxilla and mandible in these began a new course of antibiotic coverage, which patients may be a reflection of the unique envihe followed inconsistently. We treated subjects ronment of the oral cavity. Typically, an open 2 and 3 according to a protocol for osteomyelitis. bony wound such as an extraction socket heals The subjects’ positive responses to therapy varied quickly and without infection in the presence of from several weeks to many months, but their oral microflora. However, when the vascular conditions required repeated surgical intervensupply of the mandible or maxilla is compromised tions (curettage or sequestrectomy). by radiation therapy or other therapies, the minor The case reports we include in this article proinjury or disease in these sites is more likely to vide a detailed comparison—revealed using develop into a nonhealing wound. That, in turn, imaging modalities readily available to the dental can progress to widespread necrosis and profession—that demonstrates the wide variation osteomyelitis. in treatments and outcomes reported in the literBecause bisphosphonates do not metabolize, ature for BRONJ. the bone maintains high concentrations for long periods, with a half-life of 10 years. Accordingly, CONCLUSION discontinuation of bisphosphonate therapy does not appear to hasten the recovery of the Bisphosphonates are effective in reducing the osteonecrosis. Treatments including mouthrinses, symptoms and complications of metastatic bone systemic antibiotics, hyperbaric disease. The scientific literature oxygen and surgical débridement indicates, however, that bisphoshave been tried, but none have phonates contribute to the pathoThe outcomes and proven effective consistently.8-10 genesis of the oral lesions of ONJ.3 morbidity associated Treatment of the disease is a conunThis condition is accepted as an with bisphosphonate- oral complication in patients with drum, in that intervention involving related osteonecrosis débridement of neighboring healthy cancer. The risk factors for and prebone can result in further spread of cise mechanism involved in the forof the jaws vary necrosis. As this condition and its mation of BRONJ are known only markedly, and complications can result in signifipartially. Furthermore, the outtreatment protocols cant and difficult-to-treat chronic comes and morbidity associated and predictability pain, dysfunction and disfigurewith BRONJ vary markedly, and are understood only ment, the focus should be on pretreatment protocols and prepartially. vention. dictability are understood only The three subjects we describe partially. had histories of multiple myeloma Marx and colleagues13 reported or adenocarcinoma of the breast and had received cases of ONJ with the oral administration of biszoledronic acid or pamidronate by IV for more phosphonates for the prevention of osteoporosis. than three years, but they had varied responses to Because ONJ has been reported in patients dental extractions. Subject 1 received minimal undergoing treatment with bisphosphonates for treatment for BRONJ and recovered without disosteoporosis, and because of the 10-year half-life figurement and remained free of pain. Subject 3 of bisphosphonates, there is a need for further received more extensive treatment, including studies of this extensive population. hyperbaric oxygen therapy, and he appeared to Health professionals, especially dentists, oncolrecover fully. Subject 2, however, had severe morogists and oral surgeons, should be aware of the bidity after tooth extractions, which necessitated possibility that patients being considered for extensive treatment involving a series of ostecdental extractions or other oral surgical protomies without relief of symptoms. Despite surcedures might be undergoing bisphosphonate gical intervention, antibiotic therapy, hyperbaric therapy.17 Because of the extensive use of oral bisoxygen therapy (for subject 3) and topical use of phosphonates, the likelihood of a dentist treating chemotherapeutic mouthrinses, the lesions for a patient using these drugs to prevent osteo608
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porosis is high. Dentists should obtain good medical histories from and inform their patients about the risk of experiencing complications from bisphosphonate therapy so they can assess the need for dental treatment before starting therapy. The American Dental Association has published guidelines for dental management of these patients.18 Health professionals should stay current with the evolving body of knowledge regarding BRONJ, as it is not possible to predict what new and useful information will emerge regarding the etiology and management of this disease, as well as the optimal management of dental patients taking bisphosphonates. ■ 1. Hortobagyi GN. Novel approaches to the management of bone metastases in patients with breast cancer. Semin Oncol 2002;29(3 supplement 11):134-44. 2. Cacace E, Ruggiero V, Matulli C, Uras L, Perpignano G. Markers of bone resorption in bisphosphonate therapy of Paget’s disease. Clin Exp Rheumatol 2004;22(4):502. 3. Nase JB, Suzuki JB. Osteonecrosis of the jaw and oral bisphosphonate treatment. JADA 2006;137(8):1115-9. 4. Speiser PW, Clarson CL, Eugster EA, et al. Bisphosphonate treatment of pediatric bone disease. Pediatr Endocrinol Rev 2005;3(2): 87-96. 5. van Persijn van Meerten EL, Kroon HM, Papapoulos SE. Epi- and metaphyseal changes in children caused by administration of bisphosphonates. Radiology 1992;184(1):249-54. 6. Schwartz HC. Osteonecrosis of the jaws: a complication of cancer chemotherapy. Head Neck Surg 1982;4(3):251-3.
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7. Hellstein JW, Marek CL. Bisphosphonate osteochemonecrosis (bisphossy jaw): is this phossy jaw of the 21st century? J Oral Maxillofac Surg 2005;63(5):682-9. 8. Ruggiero SL, Fantasia J, Carlson E. Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;102(4):433-41. 9. Leite AF, Figueiredo PT, Melo NS, et al. Bisphosphonateassociated osteonecrosis of the jaws: report of a case and literature review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;102(1):14-21. 10. Migliorati CA, Casiglia J, Epstein J, Jacobsen PL, Siegel MA, Woo SB. Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper (published correction appears in JADA 2006;137([1]):26.). JADA 2005;136(12):1658-68. 11. Chiandussi S, Biasotto M, Dore F, Cavalli F, Cova MA, Di Lenarda R. Clinical and diagnostic imaging of bisphosphonateassociated osteonecrosis of the jaws. Dentomaxillofac Radiol 2006;35 (4):236-43. 12. Scarfe WC, Farman AG, Sukovic P. Clinical applications of conebeam computed tomography in dental practice. J Can Dent Assoc 2006;72(1):75-80. 13. Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonateinduced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 2005;63(11):1567-75. 14. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62(5):527-34. 15. Fournier P, Boissier S, Filleur S, et al. Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 2002;62(22):6538-44. 16. Wood J, Bonjean K, Ruetz S, et al. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 2002;302(3):1055-61. 17. Expert panel recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaws. LDA J 2005;64(3):21-4. 18. Dental management of patients receiving oral bisphosphonate therapy: expert panel recommendations. JADA 2006;137(8):1144-50.
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