Osteonecrosis of the Jaw in Cancer Patients Receiving IV Bisphosphonates

Cases of osteonecrosis of the jaw (ONJ) have been reported with an increasing frequency over the past few years. ONJ is most often identified in patients with cancer who are receiving intravenous bisphosphonate therapy but it has also been diagnosed in patients receiving oral bisphosphonates for nonmalignant conditions. The condition involves exposed bone of the maxilla or mandible. Although it is often associated with a recent dental surgical procedure, spontaneous ONJ can also occur. Patients commonly present with symptoms. Through case reporting and clinical experience, there is a suggestion that the incidence of ONJ in patients with cancer receiving intravenous bisphosphonates ranges between 1% and 10%. Management of ONJ focuses on maximizing oral health, conservative actions with mouth rinses, antibiotics, and avoidance of unnecessary invasive dental procedures. The currently available data on ONJ are reviewed here.

The bisphosphonates are effetive inhibitors of osteoclast-mediated bone resorption. First developed in the early 1970s, bisphosphonates have provided clinical benefit in the treatment of various benign and malignant bone diseases, including postmenopausal osteoporosis, Paget's disease, and tumor-induced osteolytic lesions.[1] Clinical trials have demonstrated that bisphosphonates significantly reduce the incidence of skeletal complications in patients with multiple myeloma and metastatic disease from breast cancer and other solid tumors.[2,3]

Case reports of osteonecrosis of the jaw (ONJ) in patients receiving bisphosphonate therapy have come to attention over the past few years. This condition has also been termed bisphosphonate associated osteo-necrosis[4] and shares some clinical features with neuralgia-inducing cavitational osteonecrosis[5] and osteoradionecrosis.[6] Although the great majority of patients with ONJ were treated with intravenous pamidronate (Aredia) and zoledronic acid (Zometa) for multiple myeloma and metastatic cancer involving the bone, ONJ has also been observed in patients treated with oral alendronate (Fosamax) and risedronate (Actonel) for postmenopausal osteoporosis.[7-10] The pathogenesis of ONJ is undefined and there is no current standard treatment. This article reviews the existing knowledge on ONJ.

Clinical Manifestations

FIGURE 1

Osteonecrosis of the Jaw Presents as Exposed Necrotic Bone

Osteonecrosis of the jaw presents as exposed bone in the maxilla and/or mandible. The bone appears necrotic and nonvital. The surrounding mucosa is often inflamed due to secondary infection. Symptoms may range from mild to severe and include pain, drainage, swelling, and anesthesia/paresthesia. Although most case reports note a history of dentoalveolar surgical procedure prior to the development of ONJ (ie, dental extraction, dental implant placement, periodontal surgery, and endodontic surgical procedure), there are reports of patients who have developed ONJ spontaneously[8,11,12] (Figure 1).

Radiographic Findings

FIGURE 2

Progressive Osteonecrosis of the Jaw May Lead to Pathologic Fracture

The radiographic findings in ONJ are variable. Less advanced ONJ or smaller areas of exposed bone (< 1 cm) is often undetectable on panoramic radiographs but shows faint signals or evidence of bony destruction on bone and CT/MRI scans. Progressive or advanced ONJ shows increased uptake on bone scans and "mottled bone" or areas of lytic changes on CT/MRI scans and panoramic radiographs (Figures 2 and 3).

Histopathologic Findings

FIGURE 3

Advanced Osteonecrosis of the Jaw

Histologically, necrotic bone with associated Actinomyces colonization is often seen. Soft tissue or gingival biopsies reveals inflamed squamous mucosa or granulation tissue. The biopsies show no evidence of malignancy (Figure 4).

Microbiologic Findings

Cultures reveal normal pharyngeal flora or gram positive cocci, gram negative rods, or polymorphonuclear leukocytes. Actinomyces is often present. The presence of Actinomyces species suggests possible osteomyelitis.

Increasing Number of Reports

FIGURE 4

Histologic Presentation of Osteonecrosis of the Jaw

Osteonecrosis of the jaw occurring in patients with a history of exposure to bisphosphonates has come to the attention of medical oncologists, dental specialists, and patients through the recent increase in number of case reports in the medical and dental literature over the past 2 to 3 years. Currently, there is no consensus definition or standard staging system for ONJ and there are no pathognomonic clinical, radiographic, or laboratory characteristics. With only a clinical definition for ONJ, the case reports may be influenced by the authors' expert opinions rather than a scientific criteria for diagnosis.

Features common to the recent case reports on ONJ are exposed, necrotic bone in the mandible or maxilla and exposure to bisphosphonates. Osteoradionecrosis shares similar clinical features with ONJ on physical exam. However, ONJ is generally considered to be a separate entity due to the lack of prior radiation exposure. If patients did have jaw exposure to radiation, the dosage would be expected to be less than the 6,000 cGy that is associated with osteoradio-necrosis.[6,13-15]

The established practice of including bisphosphonate administration in the therapy of osseous lesions for multiple myeloma and solid tumors is based on the results of randomized clinical trials demonstrating the efficacy of the bisphosphonates in decreasing the risk of skeletal related events.[16] The American Society of Clinical Oncology has established guidelines for the inclusion of the intravenous bisphosphonates in both breast cancer and multiple myeloma.[17,18] Pamidronate received US Food and Drug Administration (FDA) approval for hypercalcemia of malignancy in 1991, for multiple myeloma in 1995, and for osteolytic metastases from breast cancer in 1996. Zoledronic acid was first approved for hypercalcemia of malignancy in 2001 and in 2002 gained approval for broad use in bone metastases. It is estimated that approximately 1.9 million people have been treated with pamidronate and 1.0 million with zoledronic acid.[19]

In 2002 the FDA received nine spontaneous reports of ONJ in patients with cancer receiving bisphosphonates as part of their care. In 2003 published reports of ONJ began to appear in the literature.[19-22] In response to the observation that patients with ONJ were receiving bisphosphonates, the package inserts for pamidronate and zoledronic acid were updated in 2003 to include information on ONJ in the Precautions and Adverse Reactions sections. Similarly, the prescribing information on the oral bisphosphonates also addresses the potential association between ONJ and bisphosphonate therapy.

In addition to modifying the labeling, Novartis Pharmaceuticals has sent mailings to physicians and dentists specifically addressing oral health for cancer patients on bisphosphonates. These include the "Dear Doctor" letters from September 2004 and May 2005.[23,24] The International Myeloma Foundation similarly has been active in raising awareness of ONJ and has posted information addressing ONJ on their website.[25] With an increasing number of case reports identifying ONJ, particularly in patients treated with zoledronic acid and/or pamidronate, the Oncologic Drugs Advisory Committee addressed concerns regarding ONJ in the March 4, 2005, meeting. At that time the total number of ONJ cases identified through the FDA spontaneous reporting system was 654.[26]

TABLE 1

Case Reports of Osteonecrosis of the Jaw

Case reports of ONJ have been presented as abstracts at scientific meetings or published as letters to the editor and manuscripts. Case reports are an important source of information for uncommon events such as ONJ. However, the nature of case reports does not allow for insight into the true incidence of the condition or the lead time to diagnosis. Details on risk factors, comorbid diseases, oral hygiene, and all related therapies are usually not available in reports of ONJ. In addition, information regarding the effects of bisphosphonate "de-challenge" and/or "re-challenge" is limited by the small number of patients within the case series. Case reports are subject to underreporting and reporting bias, and there is no controlling for duplication of reporting. Table 1 highlights ONJ case reports and demonstrates the increase in reporting from 2003 through 2005. The number of case reports continues to expand.

Estimates of Incidence

Attempts to estimate the true incidence of ONJ are limited by the difficulty in calculating the denominator of people with cancer who use the bisphosphonates and the lack of a reliable numerator of how many people are affected by ONJ. Therefore, the true incidence of ONJ associated with bisphosphonate use is unknown. A few authors have calculated the incidence of ONJ within a select population. Investigating patients with metastatic breast cancer who had received either pamidronate or zoledronic acid, investigators at Memorial Sloan-Kettering Cancer Center calculated the incidence of ONJ to be 0.6%.[27]

Using a larger database, Hoff et al reported the incidence of ONJ in patients at MD Anderson with breast cancer to be 1.2% and with multiple myeloma 4.5%.[28] Through a web-based survey, Durie et al studied 904 patients with multiple myeloma and 299 with breast cancer and identified 75 patients with ONJ and another 77 with findings suspicious for ONJ.[29] With censoring at 36 months and examining those who were treated only with zoledronic acid or pamidronate, ONJ occurred in 10% of the patients who received only zoledronic acid and in 4% of those who received only pamidronate (P = .002). Without censoring, the mean time to onset of ONJ was 18 months among patients receiving zoledronic acid and 6 years for patients receiving pamidronate.

Other investigators have noted the median time to ONJ in patients with metastatic breast cancer or multiple myeloma to be 39 months in those treated with pamidronate and 18 months in those treated with zoledronic acid.[30] In a prospective study of patients with cancer receiving bisphosphonates, the incidence of ONJ was 9.9% in patients with multiple myeloma and 2.9% in breast cancer patients. This prospective study suggested that the risk of developing ONJ increased with longer exposure to bisphosphonate therapy.[31] These calculated incidences suggest that ONJ is not common, but given the wide use of bisphosphonate therapy for both cancer and nonmalignant conditions, it is likely that most clinicians caring for patients with cancer will see individuals affected by ONJ.

Potential Contributing Factors to the Development of ONJ

TABLE 2

Factors Associated With Osteonecrosis

The mechanism behind ONJ has not yet been defined. Osteonecrosis in bones such as the hip may be referred to as aseptic necrosis, avascular necrosis, or ischemic necrosis. The phenomenon of ONJ may differ from the classic forms of avascular necrosis, ie, avascular necrosis of the hip in a patients with sickle cell anemia, in part due to the mircoenvironment of the oral cavity and its microorganisms. Table 2 illustrates factors associated with osteonecrosis and ONJ. The observation that ONJ occurs in patients with cancer treated with bisphosphonates has led to hypothetical mechanisms involving the action of bisphosphosphonate therapy. The following discussion addresses potential factors that may contribute to the development of ONJ; however, none have been prospectively tested or validated for causality of ONJ.

Osteoclast Inhibition and Delayed Bone Remodeling

The bisphosphonates are potent inhibitors of osteoclast activity.[32] Bone resorption by osteoclast activity is a component of normal bone metabolism. It is possible that disturbing osteoclast function may predispose bone to delayed bone remodeling. Odvina et al have reported a small case series of patients where bisphosphonates may have contributed to a hypodynamic state.[33] Similarly, it is possible that after a traumatic event such as a dental extraction, delay in healing in the tooth socket and jaw could occur in the setting of profound osteoclast inhibition. Woo et al put forth the suggestion that ONJ probably results from a hypodynamic state whereby the bone is unable to adequately respond to demands for repair and remodeling owing to physiologic stress of mastication or trauma such as dental extraction or infection.[34] Marx et al have likened ONJ to osteopetrosis with impaired osteoclastic bone remodeling and repair.[12]

Microarchitectural Changes

There are concerns that the highly potent bisphosphonates used over a long period of time may alter the bone microachitecture and predispose it to microcracks that could coalesce to form clinically relevant, overt fractures. Changes in bone microarchetitecure has been demonstrated in dogs exposed to high-dose bisphosphonate therapy.[35,36] However, the increases in microdamage accumulation did not produce an increase in bone fragility because of compensation in bone mass and mineralization.[35,37] Changes in jaw microarchitecture may be an influence on the development of ONJ. Although fractures within the jaw have been identified in patients with ONJ (Figure 4), the histology of ONJ lesions reported to date does not specifically address or support this hypothesis.

Inflammation and Infection

The oral cavity is an environment rich in microorganisms. When the bone becomes exposed, the surrounding mucosa can become inflamed and thus vulnerable to infection. The inflammation associated with infection as well as preexisting dental disease could potentially trigger cytokines to insult the bone microenvironment and promote osteonecrosis. Actinomyces colonization had been identified[8,38] within ONJ lesions, although the role of Actinomyces and other microorganisms in the development or course of ONJ has not yet been identified. Clinical experience has noted an element of soft-tissue irritation and the improvement of symptoms with antibiotics, supporting the theory that ONJ may involve an infection and/or an inflammatory component.

Antiangiogenesis

Preclinically, the bisphosphonates have demonstrated antiangiogenic properties.[39-42] Although a clinically relevant antiangiogenic tumor effect has not been noted, it has been postulated that antiangiogenic effects of bisphosphonate therapy may decrease the healing of oral lesions and thereby predispose patients to ONJ.[7,34] Delayed healing due to antiangiogenesis and hypovascularization could impede healing after mucosal or dental trauma, thereby leaving exposed bone vulnerable to the microorganisms of the oral cavity.

Coagulopathy

Osteonecrosis in bones such as the hip may be referred to as aseptic necrosis, avascular necrosis, or ischemic necrosis. Approximately 15,000 new cases of avascular necrosis of the femoral head are reported annually in the United States.[43] The mechanism of osteonecrosis of the hip is not fully understood but is believed to involve compromise of the bone vasculature leading to mechanical failure.[44] In patients with multiple myeloma with a median follow-up of 33 months, 9% of patients developed avascular necrosis of the femoral head.[45] A condition referred to as neuralgia-inducing cavitational osteonecrosis (NICO) appears to be a form of jaw bone necrosis with minimal regenerating capabilities; NICO may result from hypercoagulopathy.[5] Patients with advanced cancer may be in a hypercoagulable state due to their disease or therapy. How ONJ relates to avascular necrosis of the long bone or NICO is not clear; however, these conditions may share hypercoagulability as an insult to bone.

Genetic Predisposition

Osteonecrosis of the jaw appears to occur in a minority of patients receiving bisphosphonate therapy; most cases have been identified in individuals with cancer receiving the high-potency intravenous bisphosphonates over long periods of time. It is possible that ONJ occurs in those with a genetic predisposition to this phenomenon either due to polymorphisms in bone or drug metabolism. Alternatively, a defect may exist in a cellular repair mechanism.

Anatomy: The Jaw as a Distinctive Site

The jaw bone is unique in that it is exposed to the external environment by the presence of teeth. Dental and periodontal disease, as well as the biomechanical stresses during normal function, exert high demands for metabolic remodeling. It is possible that ONJ preferentially occurs in cancer patients on bisphosphonates due to characteristics distinctive to the jaw related to structural anatomy and physiology and surrounding tissues, blood flow, and rate of bone turnover.

Management Strategies

Oral health is an important component of the patient's overall care. Prior to initiating cancer therapy, including bisphosphonates, a dental assessment is generally recommended. Dental assessment may include a medical history and review of all medications, comprehensive oral examination with imaging, assessment for and management of periodontal disease, restorative dentistry, and prophylaxis given with instruction to maximize oral hygiene.[4] Teeth requiring extraction and other dental surgical procedures should be performed and sites should be well-healed prior to initiating bisphosphonate therapy. The focus is on maximizing oral health; dental follow-up is recommended. In patients receiving bisphosphonate therapy, dental surgical procedures (eg, dental extraction, periodontal surgery, and dental implant placement) should be avoided, if possible. If dental surgery is necessary, the patient should be informed of the potential complication.

When ONJ is suspected, a dental evaluation by a professional team, ideally familiar with treating patients with cancer and the same team that evaluated the patient prior to initiation of therapy, may be considered the first step in managing ONJ. Referral to an oral and maxillofacial surgeon may be appropriate. Open communication between the dental and medical oncology teams is critical to maximize efforts in managing the cancer and the ONJ simultaneously. The patient also plays a significant role in maintaining this dialog.

TABLE 3

Approaches to Maximizing Oral Hygiene in Patients With Cancer

There is no standard treatment for ONJ. Efforts are directed toward alleviation of symptoms and prevention of infection. General approaches to managing ONJ include the use of antibacterial rinses (eg, chlorhexidine gluconate), conservative and minimal debridement with focus on removing sharp edges of bone, and antibiotic therapy if superinfection is present. Specific antibiotic regimens should be tailored to the clinical situation and general approaches have been suggested in recent dental publications.[4,12] Attempts to manage ONJ with hyperbaric oxygen have not yielded improvement in the condition.[8,12] Aggressive surgical debridement and resection of the necrotic bone is not recommended as this may exacerbate the condition.[8-12] Throughout the course of patient therapy, monitoring of oral health by both the dental and the medical oncology team should be ongoing, at a level of intensity appropriate for each subspecialty. Table 3 illustrates approaches to maximize oral health in patients with cancer receiving intravenous bisphosphonates.

TABLE 4

Suggested Staging and Management of Osteonecrosis of the Jaw

Osteonecrosis of the jaw may range from mild to significantly problematic; similarly, there is a range of outcomes from resolution to progression. The evolving data on ONJ do not yet give the clinician the ability to reliably predict which individuals with ONJ are likely to have a better or worse outcome.[11] Withholding bisphosphonate therapy does not appear to alter the course of established ONJ.[7,8] However, when an individual has been diagnosed with ONJ, consideration may be given to holding bisphosphonate and cancer related therapy if clinically indicated.[12,25,46] The recently proposed staging system for severity of ONJ[47] is outlined in Table 4. Staging offers the opportunity for standardization of disease severity and ultimately quantifying response to therapy. A staging system could be incorporated into clinical trials investigating ONJ.

Discussion

Osteonecrosis of the jaw is a phenomenon that has gained attention through the case reporting of both community care givers and academicians. Case reports are an important means of identifying adverse events, particularly when dealing with an uncommon problem. Many of the ONJ case reports have been made public in abstract format and presented at scientific meetings. Although communication in this fashion is a classic and an important form of distributing information on an unusual diagnosis, presentations of this type often have significant limitations. Voluntary ONJ case reports may underestimate ONJ due to the possibility of missed cases, either due to underreporting or perhaps misclassification of the patients' oral lesion. It is possible that not all cases of ONJ are reported either to the FDA through Medwatch, or to industry.

Another possibility is that there may be duplication of case reports to agencies, as cases may have been reported by multiple health-care providers. Similarly, the reports in the literature may have duplication as the authors' case series grow; ie, patients that may have been part of an early case report are included in the later, larger case series.

Most cases of ONJ appear to occur in patients with advanced cancer receiving intravenous bisphosphonate therapy to reduce the risk of skeletal complications from the cancer, but ONJ has also been reported in patients treated with the oral bisphosphonates.[7,9,10] The frequency of ONJ in patients on oral bisphosphonate therapy for benign conditions appears to be lower then with the intravenous bisphosphonates. It is possible that cancer and/or its therapies may play a significant role in the incidence of ONJ development.

Patients with advanced cancer are a complex population, often with significant comorbid conditions. These patients frequently require polypharmacy treatments including antineoplastic regimens, supportive agents such antiemetics, steroids, growth factor support, and pain medication. Risk factors for ONJ may be multifactorial and the possibility that drug interactions could increase the risk of ONJ must be acknowledged. To date, no reliable, predictive pattern has been clearly identified to allow for calculations of risk for of ONJ in a particular patient. ONJ has been identified in patients with or without recent prior dental manipulation, and it has been observed in patients with the full range of oral hygiene from good to poor.

Clearly, maximizing oral hygiene is a worthy goal for all populations, and it certainly applies to patients with cancer receiving bisphosphonate therapy. It has been suggested that ONJ may be prevented through systematic measures to eliminate infections and prevent the need for invasive dental procedures.[4,12] However, there are no data demonstrating that oral health practices alter the risk of ONJ, although maximizing oral health is sound advice in general.

Once ONJ has been diagnosed, optimal management appears to be conservative with gentle debridement, antibiotics, chlorhexidine rinses, and pain control. Reports to date have not demonstrated resolution of ONJ by withholding the intravenous bisphosphonate.[7,8] Whether some patients would benefit from de-challenge and possible subsequent re-challenge has yet to be defined.

The bisphosphonates are potent inhibitors of osteoclast function and despite the large number of patients treated with bisphosphonates, the effects of these drugs on fracture healing in osteoporosis or pathologic fractures has not been sufficiently investigated and remains a topic for debate.[48,49] On the basis of preclinical data, it may be reasonable to suggest that at doses used to treat osteoporosis, fracture healing is not delayed, although the remodeling of the callus may be slightly delayed.[48] Without conclusive data on continuing bisphosphonates in the setting of common events such as fracture, it difficult to extrapolate risks and benefits associated with ONJ.

It has been hypothesized that the increase in case reports of ONJ in 2003 coincides with the increased use of zoledronic acid. The approximate time to onset of ONJ in patients treated with zoledronic acid appears to 18 months while it may be longer (39 to 72 months) in patients treated with pamidronate.[29,30] The life expectancy of patients with metastatic breast cancer and multiple myeloma is estimated to be approximately 2 to 3 years.[50] It is conceivable that ONJ came to medical attention with the use of zoledronic acid due to the shorter time to onset of ONJ. Of note, zoledronic acid has been shown to demonstrate efficacy in reducing skeletal related complications in a variety of tumor types and is a clinically relevant therapy in managing osseous metastases.[16] Although case reports have suggested an association between ONJ and all bisphosphonates, it is noteworthy that the bisphosphonates have been used to treat avascular necrosis of the hip preclinically[51] and clinically.[52,53] This underscores our need to define the mechanism behind ONJ.

Osteonecrosis of the jaw may not be the optimal term for this phenomenon; "bisphosphonate-associated osteonecrosis" is an emerging term for the condition.[4] Also evolving is a case definition of ONJ. The American Association of Oral and Maxillofacial Surgeons (AAOMS) gives the case definition as "Any patient who has not received radiation therapy to the oral cavity or neck, and who has exposed bone in the maxillofacial area that occurred spontaneously or following dental surgery and has no evidence of healing for more then 3-6 weeks after appropriate care".[54] Using this definition AAOMS is conducting an internet based survey to obtain information regarding the frequency of patients evaluated or treated for ONJ. AAOMS may use the survey to develop a registry of Oral and Maxillofacial Surgeons interested in participating in ONJ research.

Similarly, the medical oncology community is rallying to develop formal methods to study ONJ. Reporting presently includes use of the FDA Medwatch system. The Medwatch forms can be downloaded from http://www.fda.gov/medwatch/getforms.htm. Upcoming randomized clinical trials investigating zoledronic acid will incorporate monitoring for ONJ, including CZOL446E2352, which will explore long-term use of zoledronic acid in patients with metastatic breast cancer, and the Southwest Oncology Group clinical trial investigating three different bisphosphonates for their ability to alter the risk of relapse in the adjuvant breast cancer setting (SWOG 0307).

In treating patients with any disease it is critical that clinicians weigh the risks and benefits of each therapeutic intervention. Similarly, the toxicities associated with therapy for cancer require evaluation for both short-term and long-term effects. Osteonecrosis of the jaw could potentially become more prevalent as the use of bisphosphonates expands for both malignant and nonmalignant conditions. New therapies targeting bone are in development, and may offer a different risk profile for the development of ONJ; examples include denosumab (AMG 162, monoclonal antibody to RANKL) and inhibitors of cathepsin. As clinical trials evolve exploring bone-targeting therapies it is anticipated that data on ONJ will be prospectively collected.

Conclusions

Osteonecrosis of the jaw may be a treatment complication in patients with cancer receiving intravenous bisphosphonates; the pathogenesis and true incidence of ONJ are not yet defined. It is likely that most medical oncologists will be involved in the care of patients with ONJ as the condition appears to occur in 1% to 10% of patients with advanced cancer on intravenous bisphosphonate therapy.

Maximizing oral hygiene before initiating bisphosphonate therapy and continuing with dental care throughout treatment is a prudent action. Osteonecrosis appears to be best managed conservatively with minimal debridement, chlorhexidine rinses, pain management, and consideration for antibiotics. There are no specific prognostic or predictive factors to gauge which patients will have a better outcome once ONJ is diagnosed; reports to date have demonstrated that ONJ may resolve, stabilize, or progress irrespective of discontinuing bisphosphonate therapy. Optimal management of ONJ is still being defined.

A staging system has been proposed with the interventions escalating with increasing exposure of bone or symptoms.[47] The utility of this grading and management system needs to be tested prospectively. Creation of a centralized ONJ registry could be a potential mechanism to track the course of ONJ, through the changes in care that patients may require due to disease progression, geographic relocation, changes in insurance, or other reasons for alterations of the health-care regimens or providers.

Upcoming prospective randomized clinical trials using bisphosphonates will include monitoring for ONJ as part of the study evaluation. It is anticipated that data generated through these studies and others will lend insight into ways to manage, and perhaps prevent, ONJ.

Financial Disclosure:Dr. Van Poznak has served as a consultant for Amgen, Berlex, Novartis, and Roche.

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