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In the past 10 years, millions of patients with cancers, bone disorders, and osteoporosis have taken bisphosphonates (BPs) to combat the bone weakening and related problems that come with these conditions.
   Recently, reports in popular and medical literature have cast a shadow over the medical success of BPs, especially the high-dose, intravenous therapy used to treat bone complications of certain cancers. This has been linked in rare cases to osteonecrosis of the jaw (ONJ), a sometimes painful and potentially debilitating condition in which areas of the jaw bone can become exposed and necrotic.
   At CUMC, a multidisciplinary research effort spearheaded by Regina Landesberg, D.M.D., Ph.D., an associate professor in the Division of Oral & Maxillofacial Surgery at the College of Dental Medicine, is under way to study the phenomenon. The research encompasses several departments, including endocrinology, oncology, and radiology. The goal of the research is to more clearly define what ONJ is, to better understand the frequency with which it occurs in association with BP therapy, and to determine the risk factors involved in developing ONJ.
   Bisphosphonate therapy works by slowing the breakdown of bone. Throughout life, bones are constantly being reformed, due to the action of cells called osteoblasts and osteoclasts. Like construction and demolition workers laboring side-by-side, osteoblasts build bone while osteoclasts break it down, ensuring a constant supply of new, strong bone. When the pace of demolition outstrips construction, however, bones can become porous, fragile and prone to fracture and other serious complications. BPs inhibit the action of osteoclasts, tipping the balance toward bone replacement, allowing osteoblasts to repair damage already done. BP therapy is used in cancer patients to prevent hypercalcemia and bone fractures.

A Multidisciplinary Team
John Bilezikian, M.D., professor of medicine and pharmacology, head of endocrinology and director of the metabolic bone diseases program, says that ONJ is more likely to occur, if at all, when BPs are used intravenously in high doses with cancer patients. Dr. Bilezikian and his team will study potential predisposing skeletal characteristics of breast cancer patients.
   Dawn Hershman, M.D., assistant professor in the medical oncology division, has long studied BPs related to bone health in cancer. While typically only patients with advanced breast cancer that has spread to the bone receive BP therapy, Dr. Hershman is investigating whether earlier intervention may help prevent bone metastases or enhance survival rates.
   John Grbic, D.M.D., professor of clinical dentistry and director of the division of oral biology and the Center for Clinical Research in Dentistry, is working to establish diagnostic criteria for which oral lesions should be characterized as ONJ. The lack of clear diagnostic criteria has led to wide variations in reported incidence of this lesion in cancer patients. Without such criteria, it is impossible to study the incidence and frequency of the disease and its risk factors, or to understand its epidemiology.
   Dr. Landesberg believes the vast majority of patients on BP therapy have little cause for concern. Among cancer patients, who account for about one-half million of the more than 20 million patients on BP therapy, the risk of developing ONJ is estimated to range from less than .8 percent to 20 percent. For the millions of patients who are on the most common form of BP therapy – for osteoporosis – the risks are even rarer; only 40 cases of ONJ associated with oral BP therapy have been reported in the literature and the drug manufacturers have estimated that the incidence is less than 1/100,000 patient years. “It’s extremely rare in this population,” says Dr. Bilezikian. “In our practice we have not seen anyone with osteoporosis who has ONJ.”
   While it is unknown precisely how BPs cause ONJ, one clear risk factor is trauma to oral tissues, such as occurs in dental surgery or tooth extraction. Now that this problem has been identified, it is considered extremely important for cancer patients to achieve optimal dental health before starting chemotherapy. Those about to take the more common forms of BP therapy for osteoporosis are also advised to have a comprehensive dental exam.
   Dr. Landesberg hopes that her NIH funding for this two-year multi-disciplinary clinical study will lead to answers about any ONJ-breast cancer link. “Our major goal is to identify markers that would help predict which patients are at a higher risk for developing this condition,” she says.

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