Bisphosphonates May Reduce Recurrence in Giant Cell Tumor by Inducing Apoptosis Seong Sil Chang, MD, PhD*; Sanjeev J. Suratwala, MD*; Kwang Mook Jung, PhD†; Jason D. Doppelt, BS*; Hui Zhu Zhang, MD‡; Theodore A. Blaine, MD*; Tae Wan Kim, PhD†; Robert J. Winchester, MD‡; and Francis Young-In Lee, MD* Giant cell tumor of bone is an aggressive tumor character- ized by extensive bone destruction and high recurrence rates. This tumor consists of stromal cells and hematopoietic cells that interact in an autocrine manner to produce tumoral osteoclastogenesis and bone resorption. This autocrine regu- lation may be disrupted by novel therapeutic agents. Non- specific local adjuvant therapies such as phenol or liquid nitrogen have been used in the treatment of giant cell tumor, but specific adjuvant therapies have not been described. The bisphosphonates pamidronate and Zoledronate can induce apoptosis in giant cell tumor culture in a dose-dependent manner. We established giant cell tumor cultures from pa- tients with extensive destruction of bone. One of the four cultures formed osteoclastlike giant cells in vitro after more than six passages without exogenous receptor activator of NF-kB ligand or macrophage colony stimulating factor. An- nexin V staining, presence of active cleaved form of caspase- 3, and disappearance of poly (ADP-ribose) polymerase on Western blotting indicated activation of apoptosis by bis- phosphonates in giant cell tumor. These results indicate that topical or systemic use of pamidronate or zoledronate can be a novel adjuvant therapy for giant cell tumor by targeting osteoclastlike giant cells, mononuclear giant cell precursor cells, and the autocrine loop of tumor osteoclastogenesis. Giant cell tumor (GCT) is a locally aggressive, benign bone lesion which shows extensive bone destruction that often leads to pain and pathologic fracture. It usually occurs in the epiphysis and metaphysis of bone near the joint. The destruction of subchondral bone impairs joint function. 7,14,26 In rare instances, the tumor can spread to the lungs or can present as multifocal disease. 5,27 On histologic examina- tion, the tumor shows a mixture of cells consisting of osteoclastlike multinucleated giant cells, mononuclear cells, and stromal cells. 7,26 This unique composition of different cell types has been the subject of the study of osteoclast biology. 3,19,38 The preferred treatment options include surgical treat- ment such as curettage, in conjunction with chemical or physical adjuvant therapy, or extensive resection followed by major reconstructive surgery. 7,13,26 The outcome after surgical resection has been affected negatively by tumor recurrence and additional bone destruction. 6 Many topical adjuvant therapies such as phenol, hydrogen peroxide, or liquid nitrogen have been used in an attempt to decrease local recurrence by inducing physical or chemical damage to the remaining GCT cells after curettage, but a specific adjuvant therapy that directly targets osteoclasts and GCT cells has not been described. 10,25 To decrease the local recurrence and additional destruction of bone by GCT, it is necessary to understand the pathophysiology of GCT. A medical or pharmacologic treatment that targets the osteolytic process may lower the recurrence rates of GCT and avoid major reconstructive surgery with its associ- ated morbidity and mortality. Furthermore, this kind of therapy may be able to control other osteolytic bone le- sions that share the common mechanism of osteoclastic activation. Bisphosphonates are known to bind to bone in vivo and in vitro, to inhibit osteoclastic bone resorption, and to inhibit osteoclastogenesis. 18,32 Multinucleated giant cells in GCT have the capacity to resorb bone and express From the *Center for Orthopaedic Research, Department of Orthopaedic Surgery; †Department of Pathology; ‡Department of Pediatrics, Institute of Autoimmune and Molecular Diseases; Columbia University, New York, NY. Each author certifies that he or she has no commercial associations (consul- tancies, stock ownership, equity interest, patent/licensing arrangements) that might pose a conflict of interest in connection with the submitted article. Each author certifies that his or her institution has approved the reporting of this patient report, and that all investigations were conducted in conformity with ethical principles of research. The study was supported by NIH Training Grant (JDD), Department of Orthopaedic Surgery and Woman At Risk grant (FYL). Correspondence to: Francis Y. Lee, MD, Center for Orthopaedic Research, Department of Orthopaedic Surgery, Columbia University, 622 W 168th PH 11, New York, NY 10032. Phone: 212-305-3293; Fax: 212-305-8271; E-mail: fl127@columbia.edu. DOI: 10.1097/01.blo.0000141372.54456.80 CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Number 426, pp. 103–109 © 2004 Lippincott Williams & Wilkins 103