Osteonecrosis of the Jaw in Cancer Patients Receiving IV Bisphosphonates
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. 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 and shares some clinical features with neuralgia-inducing cavitational osteonecrosis and osteoradionecrosis. 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.
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).
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).
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).
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
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. 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.
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. 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.
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.