ABSTRACT: Bisphosphonates are a class of agents whose efficacy in treating and preventing the skeletal complications associated with osteoporosis and malignant bone metastases has been well established. Despite this benefit, osteonecrosis of the jaws is a significant complication in a subset of patients receiving these drugs. Based on a growing number of case reports and institutional reviews, bisphosphonate therapy may cause bone to become exposed and necrotic. Currently, this phenomenon is isolated to the jaw. This complication usually presents following simple dentoalveolar surgery. The pathogenesis for this complication appears to be related to the profound inhibition of osteoclast function and bone remodeling. This article serves to alert dentists and dental specialists about the potential complication of jaw necrosis in patients receiving bisphosphonate therapy, and proposes a guideline for diagnosis, staging and management.

Bisphosphonates are a class of agents used to treat osteoporosis and the complications associated with malignant bone metastases (Table 1). Their use has dramatically increased over the past few years as new indications for their use have arisen. Bisphosphonate therapy has made a significant impact in the palliation of cancer morbidity. Its role in decreasing osteoclast-mediated lysis of bone in disease secondary to multiple myeloma, breast cancer, and other solid tumors has been well established in clinical trials.^1,2

Thus bisphosphonates are frequently administered to patients with osteolytic metastases, especially if there is risk for significant morbidity. Based on clinical practice guidelines established by the American Society of Clinical Oncology, the use of bisphosphonates is considered the standard of care for treatment of: (1) moderate to severe hypercal-cemia associated with malignancy; and (2) metastatic osteolytic lesions associated with breast cancer and multiple myeloma in conjunction with antineoplastic chemothera-peutic agents.^1,2

As a potent suppressor of osteoclast activity, bisphosphonates slow the remodeling process and increase bone mineral density, thereby reducing the risk of fracture in women with osteopenia and osteoporosis.^3,4 All bisphosphonates currently approved for osteoporosis treatment have been shown to significantly reduce the risk of osteoporotic fractures. Alendronate has been shown to prevent bone loss at the spine and hip in menopausal women and reduce fractures at these sites by approximately 50%.^5,6 In a large prospective trial, risedronate produced a 30% reduction in hip fractures.⁷ Because of their proven clinical efficacy, bisphosphonates are considered first-line therapy in the treatment of osteoporosis and are the most widely prescribed antiresorptive agents.

Figure 1—Exposed, necrotic alveolar crest in a 61-year-old woman who received IV bisphosphonates for the treatment of metastatic breast cancer.	Figure 2—Exposed, necrotic bone surrounding a dental implant in a patient receiving oral bisphosphonates.
Figure 3—Exposed maxillary torus in a patient receiving oral bisphosphonate therapy.	Figure 4—Osteolysis and sequestrum formation in the region of the left mandibular angle in a patient with Stage 3 BRONJ.

BISPHOSPHONATE-RELATED OSTEONECROSIS OF THE JAWS

Despite the benefits of bisphosphonate therapy, osteonecrosis of the jaws has recently emerged as a significant complication in a subset of patients receiving these drugs.^8-10 In response to a growing number of case reports and institutional reviews, the US Food and Drug Administration issued a broad drug class warning of this complication for all bisphosphonates in 2005.

Although the exact mechanism of bisphosphonate-induced osteonecrosis has not yet been determined, several hypotheses have been proposed. In most cases, the pathogenesis of this process is consistent with a defect in jawbone physiologic remodeling or wound healing. The profound inhibition of osteoclast function also can inhibit normal bone turnover to an extent that local microdamage from normal mechanical loading or injury (tooth extraction) cannot be repaired. Because only a minority of bisphosphonate users develop bone necrosis, it also is possible that individual genetic variations in drug metabolism or skeletal homeostasis may confer susceptibility or resistance to developing bisphosphonate-related osteonecrosis of the jaws (BRONJ). The apparent selective involvement of the maxilla and mandible may be a reflection of the unique environment of the oral cavity. Typically, healing of an open bony wound (eg, extraction socket) in the presence of normal oral microflora occurs quickly and without complication. However, when the healing potential of the mandible or maxilla is compromised either by tumorcidal radiation doses, or some other agent(s) or pathologic process, then minor injury or disease in these sites increases risk for osteonecrosis and possible secondary osteomyelitis. Also, bisphosphonates are deposited preferentially in bones with high turnover rates; given that the maxilla and mandible are sites of significant bone remodeling, it is possible that the levels of bisphosphonate within the jaw are selectively elevated. It is interesting to note that to date this complication has not been reported within bones outside the craniofacial skeleton.

RISK FACTORS AND INCIDENCE

Several retrospective clinical studies have identified potential risk factors associated with the development of BRONJ.^11-14 These include a history of dentoalveolar trauma, duration of bisphosphonate exposure, and the type of bisphosphonate administered. In the majority of BRONJ cases reported to date, recent dentoalveolar trauma was the most prevalent and consistent risk factor.^9,11,15,16 Patients with a history of inflammatory dental disease, such as periodontal and dental abscesses, are at a seven-fold increased risk for developing BRONJ.¹⁷ This underscores the importance of maintaining good oral health and avoiding extractions in this population. The duration of bisphosphonate therapy also appears to be related to the likelihood of developing necrosis, with longer treatment regimens associated with a greater risk of developing disease.^11,17 In addition, the more potent intravenous (IV) bisphosphonates, such as pamidronate and especially zolendronate, appear to be significantly more problematic as compared with the oral bisphosphonate medications. Initially, BRONJ was seen only with the use of the more potent IV forms of the drug; however, there have been reports of osteonecrosis in patients on the less potent oral forms.^8-10 This alarming finding may have significant implications as the number of patients on oral bisphosphonates increases. Though the condition is found in both sexes, the literature reports more cases of BRONJ in women than in men which is likely a reflection of the large number of cases reported in breast cancer patients. With postmenopausal osteoporosis as an indication for bisphosphonate use, a large percentage of the female population also may be at risk for developing BRONJ. Patients receiving oral bisphosphonate therapy for osteoporosis that develop BRONJ have typically been exposed to these agents for a longer period of time (> 3 years) or were receiving concomitant long-term steroid therapy.¹⁸

Current incidence data for BRONJ are limited to retrospective studies with limited sample sizes. The current difficulty in establishing exact incidence data is caused by several factors, which include a nonstandardized definition and inconsistencies in case recognition and reporting. With that understanding, the estimate of cumulative incidence of BRONJ in patients receiving IV bisphosphonates for malignant disease ranges from 0.8% to 12%.¹⁸ For those patients exposed to oral bisphosphonates, the incidence appears to be significantly less.¹⁸ Merck & Co, Inc, the manufacturer of alendronate, calculated the incidence of BRONJ to be 0.7 cases per 100,000 person-years of exposure.¹⁸ This was derived from the number of reported (not confirmed) cases that were deemed likely to represent BRONJ divided by the number of alendronate pills prescribed since approval of the drug, and converted to number of patient-years. However, because these cases were not confirmed, there may be serious problems with this methodology. In a survey study based on prescription data in Australia, the estimated frequency of BRONJ for patients treated weekly with alendronate was 0.01% to 0.04%. When extraction was performed, the calculated frequency increased to 0.09% to 0.34%.¹⁶

CLINICAL PRESENTATION AND STAGING

The American Association of Oral and Maxillofacial Surgeons (AAOMS) established a working definition for BRONJ that is fairly concise and specific.¹⁸ Patients may be considered to have BRONJ if all of the following three characteristics are present: (1) current or previous treatment with a bisphosphonate; (2) exposed, necrotic bone in the maxillofacial region that has persisted for more than 8 weeks; and (3) no history of radiation therapy to the jaws. Patient history and clinical examination are the most sensitive diagnostic tools for this condition. Osteonecrosis lesions are most frequently symptomatic when surrounding tissues become inflamed or there is clinical evidence of exposed bone. Signs and symptoms that may occur before the development of clinically detectable osteonecrosis include pain, tooth mobility, mucosal swelling, erythema, and ulceration. These symptoms may occur spontaneously or more commonly at the site of prior dentoalveolar surgery (Figure 1 through Figure 3). Most cases of osteonecrosis occur at regions of previous dental surgery (ie, extraction sites); however, exposed bone also has been reported in patients with no history of trauma or in edentulous regions of the jaw. Radiographic changes typically are not evident until there is significant bone involvement or demineralization. Therefore, panoramic and periapical radiographs may not reveal significant changes in the early stages of osteonecrosis. When there is extensive bone involvement, regions of mottled bone or sequestrum similar to that of diffuse osteomyelitis have been noted (Figure 4). A clinical staging system (Table 2) has been developed to more accurately categorize patients with BRONJ, direct rational treatment guidelines, and collect data to assess the prognosis in patients who have used either IV or oral bisphosphonates.^10,18

Figure 5—Stage 2 BRONJ with multiple draining mucosal fistulas.	Figure 6—Large section of exposed, necrotic maxillary bone in a patient with long-term oral bisphosphonate exposure.
Figure 7—Grossly displaced pathologic mandibular fracture with exposed bone in a patient with Stage 3 BRONJ and breast cancer.

Patients who are considered At risk have no evidence of exposed or necrotic bone but have been exposed to either IV or oral bisphosphonates. The potency of the bisphosphonate used, the duration of exposure, and dental surgery appear to be the main determinates in assessing those patients at risk. Patients with Stage 1 disease have exposed bone, but are asymptomatic. There is no evident significant adjacent or regional soft-tissue inflammatory swelling or infection. Stage 2 disease is characterized by exposed bone associated with infection evidenced by pain and adjacent or regional soft-tissue inflammatory swelling (Figure 5 and Figure 6). Patients with Stage 3 disease have exposed bone with pain and infection as well as one or more of the following: pathologic fracture, extraoral fistula, or radi-ographic evidence of osteolysis extending to the inferior border (Figure 7).

PREVENTION AND MANAGEMENT

It is important for patients and clinicians to realize that a cure may not be a realistic expectation. The goal of treatment for patients at risk of developing BRONJ or those who have active disease is to preserve the quality of life by controlling pain, managing infection, and preventing the development of new areas of necrosis. This has to be balanced with the oncologic management of the patient with oste-olytic metastases. The main emphasis at this time is to minimize the risk of developing BRONJ. Although a small percentage of patients receiving bisphosphonates develop osteonecrosis of the jaws spontaneously, the majority of affected patients experience this complication following simple dentoalveolar surgery (ie, extraction, dental implant placement, or apical surgery). Therefore, prevention strategies that optimize dental health have been the main directive in managing patients who will receive or are receiving bisphosphonate therapy. For those patients who are about to start bisphosphonate therapy, the degree of risk will likely depend on the type of bisphosphonate and the duration of exposure. Management strategies similar to osteoradio-necrosis prevention protocols should be implemented for those patients who are about to initiate IV bisphosphonate therapy for cancer metastasis. The initiation of monthly IV bisphosphonate therapy should be delayed, if possible, until dental health is optimized. Specifically, nonrestorable teeth and those with a poor prognosis should be extracted before the initiation of therapy.

For those patients with established BRONJ, treatment is basically directed by the symptoms (Table 3). Patients with Stage 1 disease are, by definition, asymptomatic and therefore require no intervention other than periodic oral rinses and close clinical follow up. Patients with symptomatic disease (Stage 2 and Stage 3) will require antibiotic therapy and/or surgical debridement. All patients with established BRONJ are likely at high risk of developing BRONJ at any future site of dentoalveolar surgery and therefore should be educated on the benefits of prophylactic dental care and should avoid dentoalveolar surgery.

Regardless of the clinical scenario or disease stage, dental prophylaxis, caries control, and restorative dentistry should be continued indefinitely for all patients receiving bisphosphonates. While it does not appear necessary for patients to initiate prophylactic dental treatment before initiating oral bisphosphonate therapy for osteoporosis, it would be prudent to encourage these patients to maintain an optimal level of dental health because they are likely to be maintained on a bisphosphonate for a prolonged period of time.

CONCLUSION

Osteonecrosis of the jaws is a new and emerging complication of bisphosphonate therapy that is associated with significant morbidity and often requires symptomatic management for palliation in certain patients. Despite the strong clinical correlation between jaw necrosis and bisphospho-nate therapy, a definitive causal relationship has yet to be established. Retrospective studies have established an association, but prospective clinical trials and basic science research are needed to elucidate the pathogenesis of this process and to define more accurately the clinical and perhaps genetic risk factors. The efficacy of these agents in treating and preventing the significant skeletal complications associated with osteoporosis and bone metastases has had a major positive impact for patients. A more complete understanding of BRONJ will allow clinicians to predict who will benefit most from bisphosphonate therapy, and to make more accurate judgments about risk, prognosis, treatment selection, and outcome.

ABOUT THE AUTHOR

Salvatore L. Ruggiero, DMD, MD, is a surgeon at the New York Center for Orthognathic and Maxillary Surgery in Lake Success, New York. He is an Associate Professor at the State University of New York at Stony Brook, School of Dental Medicine, Department of Oral and Maxillofacial Surgery in Stony Brook, New York, and an attending physician at the Long Island Jewish Medical Center, Division of Oral and Maxillofacial Surgery, in New Hyde Park, New York.

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