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Osteonecrosis of the Jaws and Bisphosphonate Therapy
1 Department of Oral and Maxillofacial Surgery, Stony Brook School of Dental Medicine, Long Island Jewish Medical Center, Division of Oral and Maxillofacial Surgery, New Hyde Park, NY; and Correspondence: * corresponding author, sruggie{at}optonline.net
Bisphosphonates are a class of agents used to treat osteoporosis and malignant bone metastases. The efficacy of these agents in treating and preventing the significant skeletal complications associated with these conditions has had a major positive impact for patients and is responsible for their widespread use in medicine. Despite these benefits, osteonecrosis of the jaws has recently emerged as 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 exposed and necrotic bone that is isolated to the jaw. This complication usually presents following simple dento-alveolar surgery, and can cause a significant adverse effect on the quality of life for most patients. The pathogenesis for this complication appears to be related to the profound inhibition of osteoclast function and bone remodeling.
Key Words: bone • bisphosphonate • BRONJ • mandible • osteonecrosis • osteoporosis • jaw
The current widespread use of bisphosphonates as an inhibitor of bone resorption is directly attributable to their efficacy in improving the quality of life for patients with metastatic bone cancer, osteoporosis, and Paget’s disease.
Bone metastasis to the axial skeleton, pelvis, femora, and ribs is a common occurrence for many malignancies (Clain, 1985; Coleman and Rubens, 1987). In a study of 1000 consecutive autopsies of persons who died with metastatic disease, 272 (27.2%) had metastatic osteolytic bone disease (Abrams et al., 1950). The most common tumors associated with bone metastasis are breast (73% of 167 patients), lung (32% of 160 patients), and renal (24% of 34 patients). The primary mechanism responsible for osteolysis in these patients is the excessive resorption of bone by osteoclasts. Cancer cells that have metastasized to bone produce a variety of cytokines, such as interleukins, prostaglandins, parathyroid hormone-related peptide, and tumor necrosis factor. These agents can stimulate osteoclasts to resorb bone in an uncontrolled manner and result in skeletal destruction (Mundy, 1987; Kanis, 1995). Myeloma-related lytic disease is now understood to be secondary to increased osteoclastic activity and impaired osteoblastic activity. Myeloma cells are known to secrete stimulators of both osteoclast activation, such as receptor activator of nuclear- Osteopenia and osteoporosis are diseases that result from an unbalanced level of bone remodeling. The function and activity of osteoblasts and osteocytes are modulated by sex hormones, a variety of cytokines, and physiologic mechanical stress. Age-related changes in physical activity and sex hormones levels result in an increase in the number of osteoclasts and bone resorption sites. This overwhelms the production of new bone by osteoblasts (Lerner, 2006). The end result is an overall decrease in bone mass and bone strength. Osteoporosis is a major clinical problem worldwide and is responsible for over 1.5 million fractures in post-menopausal women each year in the United States, at an annual cost of $18 billion (Gabriel et al., 2002). It is estimated that 35% of post-menopausal Caucasian American women have some degree of osteoporosis in the hip, spine, or forearm, and that 40% of these women will experience some type of osteoporotic fracture (Office of the Surgeon General, 2004). This is in contrast to males over the age of 50, only 13% of whom are estimated to have an osteoporotic fracture (Office of the Surgeon General, 2004). While bone quality cannot be measured directly, bone mineral density is a relatively easy parameter to measure. The US National Institutes of Health consensus conference defined osteoporosis as a disease of increased skeletal fragility and low bone mineral density, where the T-score (number of standard deviations below the normal mean bone density of a young Caucasian female) is below –2.5. Patients with T-scores between –1.0 and –2.5 are considered to be osteopenic, and may be at risk of developing osteoporosis. The pathophysiology of Paget’s disease is also centered on an imbalance of bone remodeling, where the bone-resorbing function of the osteoclast is enhanced. This is due to osteoclastic hyperplasia coupled with an overall increase in osteoclastic bone-resorbing activity. The reciprocal response by the osteoblast is to increase bone formation, but the response is inadequate and disorganized, resulting in a disfigured and structurally weak skeleton (Deftos, 2005). The aforementioned complications associated with metastatic bone disease, osteoporosis, and Paget’s disease are all related to perturbations in osteoclast function. Therefore, it is not surprising that bisphosphonates, which are potent inhibitors of osteoclast function, have demonstrated clinical efficacy in all of these diseases. Bisphosphonate use has dramatically increased over the past few years, as new indications for their use continue to be identified. Bisphosphonate therapy has made a significant impact on the palliation of cancer morbidity by reducing bone pain, hypercalcemia, and skeletal complications, such as pathologic fractures. The efficacy of intravenous bisphosphonates in decreasing osteoclast-mediated lysis of bone in disease secondary to multiple myeloma, advanced breast cancer, and other solid tumors has been well-established in clinical trials (van Holten-Verzantvoort et al., 1993; Berenson et al., 1996, 1998; Hortobagyi et al., 1996, 1998; Theriault et al., 1999; Conte and Coleman, 2004; Michaelson and Smith, 2005). Thus, intravenous 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 the treatment of: (1) moderate to severe hypercalcemia associated with malignancy; and (2) metastatic osteolytic lesions associated with breast cancer and multiple myeloma in conjunction with antineoplastic chemotherapeutic agents (Hillner et al., 2000; Berenson et al., 2002). Recently, the US Food and Drug Administration has broadened the indications for intravenous bisphosphonates to include bone metastases from any solid tumor. In 2005, it was estimated that over 2.8 million cancer patients worldwide had received intravenous bisphosphonates since their introduction to the marketplace (United States Food and Drug Administration, 2005). 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 (Chesnut et al., 2001; Guyatt et al., 2002). All bisphosphonates currently approved for osteoporosis treatment have been shown to reduce the risk of osteoporotic fractures significantly. Alendronate has been shown to prevent bone loss at the spine and hip in menopausal women, and to reduce fractures at these sites by approximately 50% (Black et al., 1996; Hosking et al., 1998; Ravn et al., 1999). In a large prospective trial, risedronate produced a 30% reduction in hip fractures (Miller et al., 1999; McClung et al., 2001). Due to their proven clinical efficacy, bisphosphonates are considered first-line therapy in the treatment of osteoporosis, and are the most widely prescribed anti-resorptive agent. By 2006, over 190 million oral bisphosphonate prescriptions were dispensed worldwide (American Dental Association, 2006).
Despite these benefits, osteonecrosis of the jaws has recently emerged as 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 exposed and necrotic bone that is isolated to the jaw. Since 2003, numerous reports have been published highlighting the adverse-effect profile of this class of agents, including the development of osteonecrosis of the jaw in patients treated with bisphosphonates (Mehrotra et al., 2003; Rosenberg et al., 2003; Ruggiero et al., 2004, 2006; Greenberg, 2004; Gibbs et al., 2005; Marx et al., 2005; Mehrotra and Ruggiero, 2005; Melo and Obeid, 2005; Migliorati et al., 2005b; Purcell and Boyd, 2005; Vannucchi et al., 2005; Bilezikian, 2006; Van Poznak and Ward, 2006). 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 can also inhibit normal bone turnover to an extent that local microdamage from normal mechanical loading or injury (tooth extraction) cannot be repaired. This can ultimately results in bone necrosis. Consideration must also be given to the anti-angiogenic properties of certain bisphosphonates. Zolendronic acid has been demonstrated to exert an inhibitory effect on circulating levels of vascular endothelial growth factor (a potent stimulator of angiogenesis) (Santini et al., 2002; Wood et al., 2002). These properties may affect the local bone blood supply, contributing to the apparent ischemic changes noted in the affected patients’ jawbones, or may operate in concert with the metabolic changes mediated by osteoclast suppression to produce local jawbone necrosis. Since only a minority of bisphosphonate users develop bone necrosis, it is also possible that individual genetic variations in drug metabolism or skeletal homeostasis may confer susceptibility or resistance to developing BRONJ. These theories and suppositions need to be validated by evidence-based clinical and basic science research. 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 bone wound (e.g., 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 tumoricidal radiation doses or some other agent(s) or pathologic process, then minor injury or disease in these sites increases the risk for osteonecrosis and possible secondary osteomyelitis. Also, bisphosphonates are preferentially deposited 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. Several retrospective clinical studies have identified potential risk factors associated with the development of BRONJ (Cafro et al., 2005; Dimopoulos et al., 2005; Durie et al., 2005; Gallucci et al., 2005; Migliorati et al., 2005a; Pozzi et al., 2005; Tosi et al., 2005; Badros et al., 2006; Woo et al., 2006). These include a history of dento-alveolar trauma, duration of bisphosphonate exposure, and the type of bisphosphonate. In the majority of BRONJ cases reported to date, recent dento-alveolar trauma was the most prevalent and consistent risk factor (Durie et al., 2005; Marx et al., 2005; Badros et al., 2006). Patients with a history of inflammatory dental disease, e.g., periodontal and dental abscesses, are at a seven-fold increased risk for developing BRONJ (Hoff et al., 2006). In a case series, the use of chronic steroids in conjunction with bisphosphonates has also been identified as a potential risk factor (American Association of Oral and Maxillofacial Surgeons, 2007). The duration of bisphosphonate therapy also appears to be related to the likelihood of an individual’s developing necrosis, with longer treatment regimens associated with a greater risk of developing disease (Badros et al., 2006; Hoff et al., 2006). In addition, the more potent intravenous bisphosphonates, such as pamidronate and especially zolendronic acid, 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 intravenous forms of the drug; however, there have been reports of osteonecrosis in patients on the less potent oral forms (Ruggiero et al., 2004; Marx et al., 2005; Mavrokokki et al., 2007). This alarming finding may have significant implications as the number of patients on oral bisphosphonates increases. Though BRONJ is found in both sexes, the literature reports more cases in females than in males, which is likely a reflection of the large number of cases reported in breast cancer patients. With post-menopausal osteoporosis as an indication for bisphosphonate use, a large percentage of the female population may also be at risk for developing BRONJ. Patients who develop BRONJ after receiving oral bisphosphonate therapy for osteoporosis have typically been exposed to these agents for a longer period of time (greater than 3 years), or were also exposed to steroid therapy (American Association of Oral and Maxillofacial Surgeons, 2007). Current incidence data for BRONJ are limited to retrospective studies with limited sample sizes. The current difficulty in establishing exact incidence data is due to several factors, which include a non-standardized definition and inconsistencies in case recognition and reporting. With that understanding, the estimate of cumulative incidence of BRONJ in patients receiving intravenous bisphosphonates for malignant disease ranges from 0.8% to 12% (American Association of Oral and Maxillofacial Surgeons, 2007). For those patients exposed to oral bisphosphonates, the incidence appears to be significantly less (American Association of Oral and Maxillofacial Surgeons, 2007). Merck, the manufacturer of alendronate, calculated the incidence of BRONJ to be 0.7 cases per 100,000 person-years of exposure (American Association of Oral and Maxillofacial Surgeons, 2007). This was derived from the number of reported (not confirmed) cases that were deemed to likely represent BRONJ, divided by the number of alendronate pills prescribed since approval of the drug, and converted to number of patient-years. However, since 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 0.01–0.04%. If extractions were performed, the calculated frequency increased to 0.09%–0.34% (Mavrokokki et al., 2007). In 2005, the US Food and Drug Administration responded to the growing number of BRONJ cases by issuing a broad drug-class warning of this complication for all bisphosphonates. This has also prompted a change in clinical practice. With the benefit of bisphosphonate therapy beyond 5 years coming into question for patients with low-to-moderate risk of an osteoporotic fracture (Odvina et al., 2005; Black et al., 2006), coupled with the growing concern about long-term suppression of bone turnover (Ott, 2005; Colon-Emeric, 2006), some clinicians have emphasized the importance of a ’drug holiday’. Bisphosphonate treatment algorithms for the oncology patient have also been modified in some institutions. In a consensus statement from the Mayo Clinic, the use of bisphosphonates in the treatment of multiple myeloma was modified to limit the exposure of intravenous bisphosphonates and minimize the potential for developing BRONJ (Lacy et al., 2006). The efficacy of these new treatment strategies in decreasing the incidence of BRONJ remains to be determined. In the patient group receiving oral bisphosphonates, the benefit will be especially difficult to establish, given the low incidence of BRONJ.
A universally accepted term for this new condition has yet to be established, and this has resulted in some degree of confusion. This complication has been referred to in the literature by several acronyms, including BRONJ (bisphosphonate-related osteonecrosis of the jaw), BRON (bisphosphonate-related osteonecrosis), BON (bisphosphonate osteonecrosis), BAONJ (bisphosphonate-associated osteonecrosis of the jaw), and simply ONJ (osteonecrosis of the jaw). Based on the pattern of association between bisphosphonate therapy and jaw necrosis that has been established in numerous retrospective clinical case studies, the American Association of Oral and Maxillofacial Surgeons (AAOMS) has decided to adopt the term ’BRONJ’ for this entity. Standardization of diagnostic criteria for this new clinical entity is important to facilitate future clinical and epidemiological research. In addition, a uniform definition for BRONJ will serve to distinguish this new clinical entity from other delayed intra-oral healing conditions. Various organizations have proposed clinical definitions for BRONJ, all of which are analogous to each other. The American Association of Oral and Maxillofacial Surgeons (AAOMS) established a working definition for BRONJ that is fairly concise and specific (American Association of Oral and Maxillofacial Surgeons, 2007). 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.
The differential diagnosis of BRONJ should exclude other common clinical conditions that may include, but are not limited to, alveolar osteitis, sinusitis, gingivitis/periodontitis, periapical pathology, and temporomandibular joint disorders. The patient history and clinical examination remain as the most sensitive diagnostic tools for this condition. Areas of exposed and necrotic bone may remain asymptomatic for weeks, months, or even years. These 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 may occur spontaneously or, more commonly, at the site of prior dento-alveolar surgery (Fig. 1A
It has been observed that lesions are found more commonly in the mandible than the maxilla (2:1 ratio). It is also more prevalent in areas with thin mucosa overlying bone prominences, such as tori, exostoses, and the mylohyoid ridge (Ruggiero et al., 2004, 2006; Marx et al., 2005). The size of the affected area can be variable and range from a non-healing extraction site to exposure and necrosis of large sections of the jawbone (Fig. 1D  ). The area of exposed bone is typically surrounded by inflamed erythematous soft tissue. Purulent discharge at the site of the exposed bone will be present when these sites become secondarily infected. Microbial cultures from areas of exposed bone will usually isolate normal oral microbes, and therefore are not always helpful. However, in cases where there is extensive soft tissue involvement, microbial culture data may define co-morbid oral infections that may facilitate the selection of an appropriate antibiotic regimen. Microscopic examination of debrided specimens of exposed bone will typically reveal necrotic bone with associated bacterial debris and granulation tissue. The necrotic bone specimens have not demonstrated any microscopic features that are unique or diagnostic for BRONJ.
Radiographic changes are typically 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, and thus are poor screening tools for this condition. Little or no ossification at a previous extraction site may represent an early radiographic sign. Early or late radiographic changes may mimic classic periapical pathology or osteomyelitis, or, in cancer patients, may raise the suspicion of primary (myeloma) or metastatic bone disease. If there is a strong clinical suspicion of metastatic disease within the jaw, and if the diagnosis of such will alter clinical treatment decisions, then a bone biopsy should be considered. Otherwise, bone biopsies should not be performed, given the potential for the creation of a non-healing bone wound. When there is extensive bone involvement, regions of mottled bone or sequestrum similar to that of diffuse osteomyelitis are noted (Fig. 1E ). Widening of the periodontal ligament space may also be noted radiographically. After prolonged exposure to the intravenous bisphosphonates, osteosclerosis of the bone may be noted radiographically, especially osteosclerotic lamina dura. In more advanced stages of BRONJ, the osteolytic changes can extend to the inferior border of the mandible and result in a pathologic fracture (Fig. 1F). Computerized tomography (CT) scans can provide more accurate three-dimensional information about the extent of the necrosis and are often useful for planning surgical debridement procedures. However, CT has not proved helpful with early identification of this process in asymptomatic individuals. Magnetic resonance imaging (MRI) has the ability to detect marrow edema, which may be an early sign of bone ischemia and necrosis, but it is associated with a high rate of false-positive results. Radionucleotide bone scans are the most sensitive modality for detecting changes in bone vascularity, and may be helpful if vascular changes prove to be part of the early phase of BRONJ. In general, all imaging modalities have proved helpful in determining the extent of the existing necrotic process, but have yet to demonstrate any efficacy in assessing patients at risk for BRONJ.
The presentation and symptomatology of BRONJ can vary in patients, despite similar disease processes, bisphosphonate dosage regimens, and treatment durations. A clinical staging system (Fig. 2  ) has been developed to categorize patients with BRONJ more accurately, direct rational treatment guidelines, and collect data to assess the prognosis in patients who have used either IV or oral bisphosphonates (Ruggiero et al., 2006). In a broad sense, patients can be categorized into those at risk and those with established disease. Patients who are considered ’at risk’ according to the AAOMS criteria 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 whether dento-alveolar surgery has been performed appear to be the main determinants in assessing an individual’s risk of developing BRONJ.
Patients with Stage 1 disease have exposed bone, but are asymptomatic. There is no evidence of significant adjacent or regional soft-tissue inflammatory swelling or infection. It is possible that patients may have symptoms of pain prior to the development of radiographic changes suspicious for osteonecrosis or clinical evidence of exposed bone. Stage 2 disease is characterized by exposed bone with associated pain, adjacent or regional soft-tissue inflammatory swelling, or secondary infection. Patients with Stage 3 disease have exposed bone associated with pain, adjacent or regional soft-tissue inflammatory swelling, or secondary infection, in addition to a pathologic fracture or an extra-oral fistula or radiographic evidence of osteolysis extending to the inferior border. The likelihood of a patient with Stage 1 or 2 disease progressing to a more advanced stage has not been determined, but may be dependent on several variables, such as the duration of bisphosphonate exposure and whether the patient is still receiving bisphosphonate therapy.
The BRONJ treatment algorithms that have been published are either a consensus of expert opinions or based on case series data (Marx et al., 2005; Ruggiero et al., 2006; American Association of Oral and Maxillofacial Surgeons, 2007). These management strategies have varied according to the risk of developing BRONJ or the stage of disease. Nonetheless, the main emphasis at this time is to minimize the individual’s risk of developing BRONJ. Although a small percentage of patients receiving bisphosphonates develop osteonecrosis of the jaw spontaneously, the majority of affected patients experience this complication following simple dento-alveolar surgery (i.e., extraction, dental implant placement, or apical surgery). Therefore, the rationale for the current treatment strategies is to optimize dental health for those patients who will receive or are receiving bisphosphonate therapy (Table ).
Management and prevention strategies can be segregated into 3 distinct clinical scenarios: (1) those patients who are about to initiate bisphosphonate therapy; (2) asymptomatic, disease-free patients who are currently receiving bisphosphonate therapy; and (3) those patients with established BRONJ. In broad terms, managing patients with BRONJ can be very challenging, since most surgical and medical interventions do not eradicate this process. In fact, except for those patients with Stage 3 disease who require surgical resections for palliation, most surgical interventions have resulted in an increase in the area of exposed bone. 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 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 must be balanced with the oncologic management of the patient with osteolytic metastases. 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 osteoradionecrosis prevention protocols should be implemented for those patients who are about to initiate intravenous bisphosphonate therapy for cancer metastasis. The initiation of monthly intravenous bisphosphonate should be delayed, if possible, until the dental health is optimized. Specifically, non-restorable teeth and those with a poor prognosis should be extracted before the initiation of therapy. Bisphosphonate therapy may begin once there is clinical evidence of bone healing at the surgical sites. Regardless of the clinical scenario, dental prophylaxis, caries control, and conservative restorative dentistry should be continued indefinitely for all patients receiving bisphosphonates. While it does not appear necessary for patients to initiate prophylactic dental treatment prior to initiating oral bisphosphonate therapy for osteoporosis, it would be prudent to encourage these patients to maintain an optimal level of dental health, since they are likely to be maintained on a bisphosphonate for a prolonged period of time. Consideration must also be given to those patients who are disease-free, but are receiving oral or intravenous bisphosphonates. The concern is greatest for those patients receiving monthly intravenous infusions of zolendronic acid or pamidronate. The estimate of the cumulative incidence of BRONJ in this group ranges from 0.8% to 12%, where dento-alveolar trauma was a major factor contributing to the development of necrosis. In some studies, patients receiving intravenous bisphosphonates and undergoing dento-alveolar surgery were reported to be at least 7 times more likely to develop BRONJ than patients who had no dento-alveolar surgery (Hoff et al., 2006). This has been the basis for the recommendation that procedures that involve direct osseous injury should be avoided in these patients. More specifically, non-surgical endodontic therapy is the preferred treatment for teeth that are symptomatic. Patients with symptomatic non-restorable teeth that would otherwise require extraction may be treated by removal of the crown and endodontic treatment of the remaining roots (American Association of Endodontists, 2005; Katz, 2005; Sarathy et al., 2005). Similarly, the placement of dental implants or performance of any type of periodontal flap surgery that would expose or injure bone should be avoided in patients who were exposed to the more potent intravenous bisphosphonate medications. Stopping the intravenous bisphosphonate therapy provides no short-term benefit, given the fact that these agents remain incorporated within the bone for an extended period of time. The benefit of long-term cessation of bisphosphonate treatment remains to be determined. Although the risk of BRONJ in patients receiving oral bisphosphonates is low, cases of BRONJ have been reported in patients exposed to oral bisphosphonates (Ruggiero et al., 2004; Cheng et al., 2005; Marx et al., 2005; Ruggiero et al., 2006). Data on the incidence of BRONJ in this group are slowly emerging. Based on the number of reported cases and the total number of prescriptions dispensed, the manufacturer of alendronate has calculated the incidence of BRONJ and estimated it to be 0.7 cases per 100,000 person-years of exposure (American Association of Oral and Maxillofacial Surgeons, 2007). Mavrokokki et al.(2007) reported on the frequency of BRONJ in the Australian population. In osteoporosis patients receiving weekly alendronate, the frequency of BRONJ ranged from 0.01% to 0.04%. If extractions were performed, the calculated frequency increased (0.09% to 0.34%). Similar to patients exposed to intravenous bisphosphonates, the duration of oral bisphosphonates therapy appears to be an important factor, with most cases of BRONJ occurring after 3 years of exposure. Shorter exposure times have been reported in those patients who were also receiving chronic steroid therapy (Marx et al., 2005; Ruggiero et al., 2006). Unlike patients who are receiving intravenous bisphosphonates, discontinuation of the oral agents may have short-term benefits that relate to risk reduction. With certain modifications, dento-alveolar surgery is indicated in this group. Based on the AAOMS guidelines, patients who have taken an oral bisphosphonate for more than 3 years (or less if they were exposed to chronic steroid medication), discontinuation of the oral bisphosphonate for 3 months prior to oral surgery may reduce the risk. The bisphosphonate can be restarted once osseous healing has occurred. The rationale for this approach is based on data extrapolated from a study by Bone et al.(2004), in which markers for bone remodeling began to increase within months following withdrawal of oral bisphosphonate medications in osteoporotic women. This suggests that osteoclastic function was also returning. However, the validity of using surrogate markers of bone resorption to determine BRONJ risk is questionable, for several reasons. These markers are a reflection of total bone turnover throughout the entire skeleton. They are not specific to the maxilla or mandible, where it is suspected that the bone turnover rate may be more severely depressed from prolonged bisphosphonate exposure. From a more practical perspective, using bone turnover markers to estimate the level of bone turnover suppression is meaningful only when compared with baseline pre-treatment levels, and these are rarely obtained in clinical practice. In addition, using bone resorption marker levels to assess BRONJ risk can be misleading for the small cohort of patients who develop osteoporosis, despite a normal baseline level of bone resorption. For individuals who have taken an oral bisphosphonate for less than 3 years and have no other risk factors for BRONJ, no alteration or delay in the planned surgery is typically necessary (Marx et al., 2005; Ruggiero et al., 2006). For those patients with established BRONJ, treatment is basically focused on preserving the quality of life by controlling the pain and secondary infection, while supporting the ongoing oncologic or osteoporotic treatment. It is also important to prevent the extension of existing areas of necrosis and the development of new lesions. Patients with an established diagnosis of BRONJ are certainly at the highest risk of developing osteonecrosis following any type of dento-alveolar surgery. Therefore, the guidelines for dental treatment and oral surgery mentioned in the previous section certainly apply to this group of patients. It is important that patients with established BRONJ avoid elective dento-alveolar surgical procedures, since these surgical sites are the most likely to result in areas of exposed necrotic bone.
Stage-specific treatment strategies (Fig. 3
Patients with Stage 2 BRONJ will have exposed necrotic bone that is painful and now secondarily infected. These patients benefit from the use of oral antimicrobial rinses in combination with antibiotic therapy. If reliable culture data are obtainable, they can be utilized to direct the appropriate antibiotic regimen. In general, most of the isolated microbes have been sensitive to the penicillin group of antibiotics. Quinolones, metronidazole, clindamycin, doxycycline, and erythromycin have been used with success in those patients who are allergic to penicillin. In some refractory cases, patients may require combination antibiotic therapy, long-term antibiotic maintenance, or a course of intravenous antibiotic therapy. In special circumstances, where patients with multiple myelomas are being considered for stem cell transplantation, the maintenance of an ’infection-free’ oral environment is important. However, despite aggressive therapy, some patients will have persistent infection and exposed bone. The risks and benefits of proceeding with the transplantation in this scenario must be considered on a case-by-case basis. Patients with Stage 3 disease have pain and infection that significantly affect the quality of life. The large burden of necrotic bone that results in extra-oral fistulization, pathologic fracture, or extensive sinusitis is typically refractory to antibiotic therapy. At this stage, aggressive surgical management is indicated, so that palliation with resolution of acute infection and pain can be achieved. Persistent regions of exposed bone may remain or develop at the periphery of the resection/debridement, due to the generalized effects of the bisphosphonate and the compromised bone healing throughout the jaw. For patients with mandibular necrosis associated with a pathologic fracture or osteolysis extending to the inferior border, segmental resection is indicated. Stabilization of the residual mandibular segments with a reconstruction plate is preferred, since immediate reconstruction with non-vascularized or vascularized bone may be problematic, given the potential for poor bone healing at the surgical margins. Soft-tissue coverage of the hardware and surrounding bone should be accomplished with local or distant flaps. Patients with Stage 3 maxillary disease, characterized by large areas of exposed bone with facial swelling and/or sinusitis, will require a maxillary resection. In cases where chronic sinusitis exists, resection of the infected maxillary alveolar bone, with creation of an oral antral communication, will serve to reduce or eliminate the infected bone and provide immediate and long-term drainage of the sinus. In this instance, reconstruction of maxillary defects can be immediate or delayed with fabrication of a partial denture or maxillary obturator.
Osteonecrosis of the jaw 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. This has caused individual clinicians and certain institutions to re-evaluate the indications for and the duration of bisphosphonate therapy for osteopenia/osteoporosis and cancer patients. Despite the strong clinical correlation between jaw necrosis and bisphosphonate therapy, a definitive causal relationship has yet to be established. Retrospective and prospective case studies have certainly established an association between bisphosphonates and jaw necrosis, but the true incidence of this complication remains unknown. Clinical studies in the form of practitioner surveys or retrospective and prospective cohort investigations are needed to establish a more meaningful assessment of the associated risk factors and incidence of this problem in the population at risk. In addition, basic science research, with the development of an animal model system, is needed to elucidate the cellular, molecular, and genetic mechanisms responsible for this process. Ideally, this would include studies that examine the role of regional differences in bisphosphonate bioavailability, wound healing, and bone metabolism of the jaw in the presence of bisphosphonates, and the efficacy of systemic or preferably local jawbone markers in monitoring disease and assessing risk. Also, the development of an animal model for this disease process is important to establish treatment strategies that are evidence-based and associated with valid outcome data. 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 and is responsible for their widespread use in medicine. 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.
Received for publication May 4, 2007. Revision received August 21, 2007. Accepted for publication August 22, 2007.
Journal of Dental Research, Vol. 86, No. 11,
1013-1021 (2007) This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
B ligand (RANKL), and soluble molecules, such as dickkopf 1 (DKK), that inhibit osteoblastic activity (
