We provide a clinical comparison of three subjects with BRONJ that demonstrates variability in treatments, outcomes and morbidity. In each case, radiographic modalities specific to the dental profession—panoramic radiography and cone-beam volumetric computed tomography (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

TOP ABSTRACT CASE REPORTS DISCUSSION CONCLUSION REFERENCES

 
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. There was a significant bony depression posterior to the maxillary left first molar.

The subject’s medical history was significant for multiple myeloma, type 2 diabetes mellitus, anemia and high blood pressure. He did not smoke, was a light alcohol user and had no history of IV drug abuse. At the time he came to the clinic, he was taking amlodipine besylate, thalidomide, folic acid, aspirin, amoxicillin, dexamethasone, epoetin alfa and pamidronate.

The diagnostic imaging we used was computed tomography image reconstruction from two-dimensional maxillofacial projections using a three-dimensional CBCT device. The reformatted CBCT scan (Figure 1) shows an extensive radiolucent region of bone destruction with bony sequestra encompassing the maxillary left first molar and extending to the tuberosity on that side. The maxillary sinus had extensive thickening of the mucosa, and there was possible erosion of the sinus floor and medial wall. Axial, coronal and sagittal sections through the left sinus (Figure 2) show extensive inflammation of the maxillary sinus and possible erosion of the medial wall.

View larger version (83K): [in this window] [in a new window]   Figure 1. Subject 1: preoperative cone-beam volumetric computed tomography reformatted panoramic view (A) and cross-sections perpendicular to the axis (B) showing an 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 extensive thickening of the mucosa and possible erosion of the sinus floor and medial wall. Cross hairs in each frame indicate level of slices.

View larger version (74K): [in this window] [in a new window]   Figure 2. Subject 1: preoperative cone-beam volumetric computed tomography cross-sectional slices (axial [A], coronal [B] and sagittal [C]) through the left sinus showing extensive inflammation of the maxillary sinus and possible erosion of the medial wall. Cross hairs in each frame indicate level of slices.

We treated the lesion two days after the subject came to the private oral surgery office; we extracted the maxillary left first molar with basic curettage and irrigation of the necrotic defect without penetrating into the sinus, and closed the surgical site. Antibiotic coverage began two days 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 four-month 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 the sinus floor corresponding to the clinically evident area of denuded bone (Figure 4). The subject was free of pain.

View larger version (108K): [in this window] [in a new window]   Figure 3. Intraoral image of subject 1 taken eight months postoperatively showing noninflamed regenerated mucosa with a small, quiescent area of denuded bone.

View larger version (83K): [in this window] [in a new window]   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 residual bony defect in the maxilla, opacity of the sinus with indications of regeneration of bone resulting in an intact medial wall, and residual small defect in the sinus floor. Cross hairs in each frame indicate level of slices.

Subject 2. This case started with a more extensive presentation of the disease than in the case for subject 1. Then, complications ensued, requiring wide-ranging, comprehensive treatments.

A 54-year-old woman with a history of adenocarcinoma of the breast treated with mastectomy, chemotherapy and IV paclitaxel came to the Department of Oral and Maxillofacial Surgery, University of North Carolina School of Dentistry, Chapel Hill, for evaluation of a painful and non-healing 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.

A panoramic radiograph of the subject showed multiple sequestra and a nonhealing deep bony defect (Figure 5). In addition to zoledronic acid, she also took granisetron, dexamethasone sodium phosphate, diphenhydramine and cimetidine. Her local oral and maxillofacial surgeon had previously removed multiple teeth and operated several times to remove sequestra.

View larger version (33K): [in this window] [in a new window]   Figure 5. Panoramic radiograph of subject 2 showing a bony defect with ill-defined margins and multiple irregular radiopacities interspersed within the lesion, indicating multiple sequestra posterior to the mandibular right second premolar.

Five months postoperatively, the reconstruction bar eroded through her skin, showing a visible area of erosion, pus drainage, an oral fistula and exposed bone at the right anterior lingual surface. We performed additional surgery to remove involved bone and to stabilize the bone plates (Figure 6). She received another regimen of antibiotics (cephalexin), and we advised her to maintain oral hygiene and to use fluoride rinses.

View larger version (31K): [in this window] [in a new window]   Figure 6. Panoramic radiograph of subject 2 showing the second surgical resection of the anterior mandible and restabilization with a titanium bar.

View larger version (30K): [in this window] [in a new window]   Figure 7. Most recent panoramic radiograph of subject 2 showing apparently healthy and stabilized bone and no evidence of infection’s having spread along fascial planes.

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.

The subject had a medical history of multiple 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 subject’s first visit showed a deep bony defect in the extraction site (Figure 8).

View larger version (31K): [in this window] [in a new window]   Figure 8. Panoramic radiograph of subject 3 showing a deep bony defect posterior to the mandibular right second premolar, indicating a nonhealing extraction socket.

View larger version (35K): [in this window] [in a new window]   Figure 9. Panoramic radiograph of subject 3 taken at four months, showing healing of the bony defect posterior to the mandibular right second premolar.

View larger version (136K): [in this window] [in a new window]   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 x10 low power).

	DISCUSSION

TOP ABSTRACT CASE REPORTS DISCUSSION CONCLUSION REFERENCES

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 ischemia and avascular necrosis of bone.

Migliorati and colleagues¹⁰ identified dental extractions and other surgical procedures as precipitants in many cases. The apparent selective involvement of the maxilla and mandible in these patients may be a reflection of the unique environment of the oral cavity. Typically, an open bony wound such as an extraction socket heals quickly and without infection in the presence of oral microflora. However, when the vascular supply of the mandible or maxilla is compromised by radiation therapy or other therapies, the minor injury or disease in these sites is more likely to develop into a nonhealing wound. That, in turn, can progress to widespread necrosis and osteomyelitis.

Because bisphosphonates do not metabolize, the bone maintains high concentrations for long periods, with a half-life of 10 years. Accordingly, discontinuation of bisphosphonate therapy does not appear to hasten the recovery of the osteonecrosis. Treatments including mouthrinses, systemic antibiotics, hyperbaric oxygen and surgical débridement have been tried, but none have proven effective consistently.^8–10 Treatment of the disease is a conundrum, in that intervention involving débridement of neighboring healthy bone can result in further spread of necrosis. As this condition and its complications can result in significant and difficult-to-treat chronic pain, dysfunction and disfigurement, the focus should be on prevention.

The outcomes and morbidity associated with bisphosphonate-related osteonecrosis of the jaws vary markedly, and treatment protocols and predictability are understood only partially.

The three subjects we describe had histories of multiple myeloma or adenocarcinoma of the breast and had received zoledronic acid or pamidronate by IV for more than three years, but they had varied responses to dental extractions. Subject 1 received minimal treatment for BRONJ and recovered without disfigurement and remained free of pain. Subject 3 received more extensive treatment, including hyperbaric oxygen therapy, and he appeared to recover fully. Subject 2, however, had severe morbidity after tooth extractions, which necessitated extensive treatment involving a series of ostectomies without relief of symptoms. Despite surgical intervention, antibiotic therapy, hyperbaric oxygen therapy (for subject 3) and topical use of chemotherapeutic mouthrinses, the lesions for subjects 2 and 3 did not respond well. Discontinuation of bisphosphonate therapy did not ensure healing. A physician treated subject 1 for osteomyelitis-type symptoms before he was referred to the private oral surgery office. He then began a new course of antibiotic coverage, which he followed inconsistently. We treated subjects 2 and 3 according to a protocol for osteomyelitis. The subjects’ positive responses to therapy varied from several weeks to many months, but their conditions required repeated surgical interventions (curettage or sequestrectomy).

The case reports we include in this article provide a detailed comparison—revealed using imaging modalities readily available to the dental profession—that demonstrates the wide variation in treatments and outcomes reported in the literature for BRONJ.

	CONCLUSION

TOP ABSTRACT CASE REPORTS DISCUSSION CONCLUSION REFERENCES

 
Bisphosphonates are effective in reducing the symptoms and complications of metastatic bone disease. The scientific literature indicates, however, that bisphosphonates contribute to the pathogenesis of the oral lesions of ONJ.³ This condition is accepted as an oral complication in patients with cancer. The risk factors for and precise mechanism involved in the formation of BRONJ are known only partially. Furthermore, the outcomes and morbidity associated with BRONJ vary markedly, and treatment protocols and predictability are understood only partially.

Marx and colleagues¹³ reported cases of ONJ with the oral administration of bisphosphonates for the prevention of osteoporosis. Because ONJ has been reported in patients undergoing treatment with bisphosphonates for osteoporosis, and because of the 10-year half-life of bisphosphonates, there is a need for further studies of this extensive population.

Health professionals, especially dentists, oncologists and oral surgeons, should be aware of the possibility that patients being considered for dental extractions or other oral surgical procedures might be undergoing bisphosphonate therapy.¹⁷ Because of the extensive use of oral bisphosphonates, the likelihood of a dentist treating a patient using these drugs to prevent osteoporosis 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.