In 2003, reports came about that identified cases of osteonecrosis of the jaws in patients being treated with bisphosphonate medications, such as zoledronic acid (Zometa, Novartis, East Hanover, NJ), pamidronate (Aredia, Novartis, East Hanover, NJ), alendronate (Fosamax, Merck and Co., Whitehouse Station, NJ), and risedronate (Actonel, Proctor & Gamble Pharmaceuticals, Cincinnati, Ohio) for a variety of diagnoses, typically metastatic breast cancer, multiple myeloma, and osteoporosis. The first report, an abstract presented by a member of the division of oral and maxillofacial surgery at Long Island Jewish Medical Center in New York, reviewed 26 cases of osteonecrosis of the maxilla and mandible noted in these patients receiving bisphosphonate therapy for metastatic bone disease.1 These cases were referred for evaluation and management of refractory osteomyelitis of varying duration, an old disease well known to dentists and physicians. The typical presentation was a nonhealing extraction socket, or exposed jawbone with progression to sequestrum formation, localized swelling, and purulent discharge. The second report involved a letter to the editor of the Journal of Oral and Maxillofacial Surgery that reviewed 36 cases of painful bone exposure in the jaws.2 The author of this letter to the Editor indicated that the difficulty in treating this disease was that debridement could not be carried out to uninvolved bone for fear of causing further exposure of bone. In addition, this author indicated that the dentist or oral and maxillofacial surgeon was likely the responsible party in creating this disease.
The first peer reviewed paper published on the topic of osteonecrosis of the jaws in patients exposed to bisphosphonate medications was authored by Ruggiero et al.,3 in the Journal of Oral and Maxillofacial Surgery in 2004. Since that time to the present, hundreds of papers have been published on this subject. What has followed can only be described as unnecessary panic on the part of members of the dental profession who treat these patients, medical oncologists and other physicians who prescribe these medications, and patients who develop osteonecrosis of the jaws. Specifically, non-evidenced-based comments were published regarding a cause and effect relationship between bisphosphonate exposure and the subsequent development of osteonecrosis of the jaws, and the inability to treat patients who develop this disease. In 2010, neither issue is scientifically valid.
Bisphosphonates have a broad array of indications, including the use of intravenous bisphosphonate medications in the management of hypercalcemia of malignancy, skeletal related events associated with bone metastases from solid tumors, and in the management of bone lesions in the setting of multiple myeloma. A significant prolongation in the length and quality of life has been realized by the use of the intravenous bisphosphonate medications in patients with cancer. Newer indications for the intravenous bisphosphonate medications include their use in osteoporosis as alternatives to the oral bisphosphonates. Oral bisphosphonates are approved to treat osteoporosis and prevent from 40-70% of fractures of the hip and spine that have been shown to be fatal in 50% of patients within five years.4,5 Clearly, bisphosphonate medications help many otherwise hopeless patients each year.
In 2010, numerous questions persist regarding bisphosphonate medications in patients who develop osteo-necrosis of the jaws. In particular, two issues related to these medications are worthy of discussion, including an assessment of causation with regard to osteonecrosis of the jaws, and the best form of treatment for that condition. With regard to causation, close scrutiny of these patients, in fact, indicates that most patients are old; have cancer that has been treated with chemotherapy and corticosteroid medications; have metastatic disease or other major medical diagnoses; are diabetic, anemic, hypercoagulable, or immunosuppressed; are alcoholics or smokers with periodontal disease or other inflammatory dental disorders; or have undergone the removal of a tooth or the placement of a dental implant, all of which represent risk factors for the development of osteonecrosis of the jaws in general. Specifically, many of these diagnoses or social habits have also been noted in other patients with osteonecrosis of the jaws who have notbeen treated with bisphosphonate therapy. It is significant how clinically and radiographically similar these cases of osteonecrosis of the jaws in patients taking bisphosphonate medications are to cases of osteomyelitis of the jaws in patients not taking bisphosphonate medications that were managed decades ago. Moreover, the incidence of osteonecrosis of the jaws in patients taking intravenous bisphosphonate medications is exceedingly low, 1.5% and 1.4% in two American studies.6,7 Finally, the risk of osteonecrosis in patients taking an oral bisphosphonate medication is between one in 10,000 and one in 100,000.8 These statistics point out the unlikelihood of the development of osteonecrosis of the jaws exclusively due to exposure to bisphosphonate medications. For all of these reasons, a cause and effect relationship between exposure to bisphosphonate medications and the subsequent development of osteonecrosis of the jaws cannot be established scientifically.
Treatment of osteonecrosis of the jaws in patients taking bisphosphonate medications is also a source of contention and great debate. The most appropriate treatment for bisphosphonate-related osteonecrosis of the jaws has been discussed nearly as long as the entity has been described. The perceived limitations of surgical therapy, in particular, have been discussed extensively in the literature in an anecdotal fashion, and recommendations have largely been made to offer conservative therapy to patients, with aggressive surgery offered only to symptomatic patients, such as those with refractory infections or advanced disease. One author has suggested that attempts to accomplish debridements and other bone-contouring procedures have mostly been counterproductive and have led to further exposed bone with worse symptoms, such that patients must and can live with some exposed bone.9 A recent report challenged this opinion and specifically investigated the utility and success of resection of osteonecrosis of the jaws with the premise that dead bone is a surgical problem that must be treated by its removal.10 This protocol has been proposed so as to treat patients with early stage disease, thereby resolving the osteonecrotic process and avoiding the need for aggressive surgery for late stage disease.
In the final analysis, bisphosphonate-related osteonecrosis of the jaws might be a variant of osteo-myelitis of the jaws—an old disease quite familiar to the medical and dental communities, associated with a new class of drugs. Regardless of its cause, patients should be counseled as to the great benefit associated with these bisphosphonate medications and the successful treatment that may be offered when osteonecrosis of the jaws is diagnosed, preferably in early stages. To this end, the medical and dental communities should be vigilant in the early diagnosis of this event so as to treat patients in an expedient fashion.
Eric R. Carlson, D.M.D., M.D.
Professor and Chairman
Department of Oral and Maxillofacial Surgery
University of Tennessee Graduate School of Medicine
The University of Tennessee Cancer Institute
Knoxville, Tennessee
E-mail: ecarlson@mc.utmck.edu
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