Clinical, Radiographic, and Biochemical Characterization of Multiple Myeloma Patients with Osteonecrosis of the Jaw Noopur Raje, 1,2 Sook-Bin Woo, 3 Karen Hande, 1 JeffreyT. Yap, 1 Paul G. Richardson, 1 Sonia Vallet, 1 Nathaniel Treister, 3 Teru Hideshima, 1 Niall Sheehy, 1 Shweta Chhetri, 1 Brendan Connell, 1 Wanling Xie, 1 Yu-TzuTai, 1 Agnieszka Szot-Barnes, 1 Mei Tian, 1 Robert L. Schlossman, 1 Edie Weller, 1 Nikhil C. Munshi, 1 Annick D.Van Den Abbeele, 1 and Kenneth C. Anderson 1 Abstract Purpose: Osteonecrosis of the jaw (ONJ) has been reported in patients with a history of aminobisphosphonate use. This study was conducted in order to define ONJ clinically and radio- graphically and gain insights into its pathophysiology. Experimental Design: Eleven multiple myeloma (MM) patients with ONJ were included in the study. Patients underwent clinical, biochemical, radiographic, and molecular profiling. Ten MM patients on aminobisphosphonates without ONJ and five healthy volunteers were used as controls for biochemical and molecular studies. Results: MM patients with ONJ were treated with either pamidronate ( n = 3), zoledronate ( n = 4), or both agents sequentially ( n = 4) for a mean of 38.7 months. Radiographic studies showed bone sclerosis and fragmentation on plain films and computerized tomography. Quanti- tative regional analysis of NaF-PET and FDG-PET scans confirmed an increased standardized uptake value (SUVmax) in areas of ONJ. The target to background ratio of SUVmax was signifi- cantly greater for NaF-PET compared with FDG-PET scan. Biochemical bone marker data and transcriptional profiling studies showed that genes and proteins involved in osteoblast and oste- oclast signaling cascades were significantly down-regulated in patients with ONJ. Conclusions: ONJ was associated with a mean duration of 38.7 months of aminobisphospho- nate exposure. Radiographic and functional imaging confirmed sites of clinically established ONJ. Gene and protein studies are consistent with altered bone remodeling, evidenced by suppression of both bone resorption and formation. Bone disease encompasses a broad range of conditions including postmenopausal osteoporosis, Paget’s disease, bone metastasis in breast, lung, prostate, and other cancers, and primary tumor cell involvement in multiple myeloma (MM). Postmenopausal osteoporosis results in 1.5 million fractures per year (1). Although the exact incidence of bone metastases from cancer is unknown, it is estimated that >350,000 Americans die with the presence of skeletal metastasis annually (2). Morbidity from bone disease includes skeletal-related events (SRE) such as pain, pathologic fractures, the need for radiation and its associated complications, hypercalcemia, spinal cord compression, surgical interventions, and compro- mised quality of life (3). Bisphosphonates have potent antiresorptive activity that have remarkably reduced bone disease – related morbidity. Prospective randomized placebo-controlled studies in patients with cancer, osteoporosis, and Paget’s disease have shown that bisphosphonates decrease SREs (4 – 6). Both pamidronate and zoledronic acid are second-generation nitrogen-containing aminobisphosphonates with the additional nitrogen side chain conferring greater potency with respect to bone resorptive effects. Alendronate, risedronate, and ibandronate are other aminobisphosphonates commonly used to prevent and/or treat osteoporosis and Paget’s disease (7). Clinical trials have validated the use of intravenous pamidronate or zoledronic acid in patients with breast cancer and MM (8, 9), and have provided the basis for guidelines for their use by the American Society of Clinical Oncology. For patients with MM, current revised American Society of Clinical Oncology guidelines recommend the use of either pamidronate or zoledronic acid for the treatment of bone disease for up to 2 years (10). This is largely based on increasing concerns of osteonecrosis of the jaw (ONJ). The recommendations for the use of bisphosphonates in MM stem from two pivotal studies. Imaging, Diagnosis, Prognosis Authors’ Affiliations: 1 The Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, 2 Massachusetts General Hospital, and 3 Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts Received 6/11/07; revised 11/7/07; accepted 11/28/07. Grant support: Novartis Pharmaceuticals, East Hanover, NJ, Multiple Myeloma Research Foundation Senior Award (N. Raje), NIH grant Specialized Programs of Research Excellence, IP50 CA10070-01, PO-1 78378, and RO-1CA 50947; the Doris Duke Distinguished Clinical Research Scientist Award (K.C. Anderson); the LeBow Fund to Cure Myeloma (K.C. Anderson); and theVA Merit Review (N.C. Munshi). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Presented at The American Society of Hematology 2006. Requests for reprints: Noopur Raje, Massachusetts General Hospital and Dana- Farber Cancer Institute, P.O. Box 218, 55 Fruit Street, Boston, MA 02114. Phone: 617-726-0711; Fax: 617-724-3166; E-mail: nraje@partners.org. F 2008 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-07-1430 www.aacrjournals.org Clin Cancer Res 2008;14(8) April 15, 2008 2387 Research. on June 8, 2020. © 2008 American Association for Cancer clincancerres.aacrjournals.org Downloaded from