title: Bisphosphonates may reduce recurrence in giant cell tumor by inducing apoptosis.
abstract: Giant cell tumor of bone is an aggressive tumor characterized 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 regulation may be disrupted by novel therapeutic agents. Nonspecific 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 patients 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-kappaB ligand or macrophage colony stimulating factor. Annexin 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 bisphosphonates 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.
authors.affiliation: Center for Orthopaedic Research, Department of Orthopaedic Surgery, Columbia University, New York, NY 10032, USA.
authors.forename: Seong Sil
authors.initials: SS
authors.lastname: Chang
authors.forename: Sanjeev J
authors.initials: SJ
authors.lastname: Suratwala
authors.forename: Kwang Mook
authors.initials: KM
authors.lastname: Jung
authors.forename: Jason D
authors.initials: JD
authors.lastname: Doppelt
authors.forename: Hui Zhu
authors.initials: HZ
authors.lastname: Zhang
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Blaine
authors.forename: Tae Wan
authors.initials: TW
authors.lastname: Kim
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Winchester
authors.forename: Francis Young-In
authors.initials: FY
authors.lastname: Lee
mesh_terms: D017304:Annexin A5 / Q000032:analysis; D017209:Apoptosis / Q000187:drug effects*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3; D020169:Caspases / Q000032:analysis; D004164:Diphosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D018212:Giant Cell Tumor of Bone / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D007150:Immunohistochemistry; D000077268:Pamidronate; D011064:Poly Adenosine Diphosphate Ribose / Q000032:analysis; D014407:Tumor Cells, Cultured; D000077211:Zoledronic Acid
chemical_list: D017304:Annexin A5; D004164:Diphosphonates; D007093:Imidazoles; D011064:Poly Adenosine Diphosphate Ribose; D000077211:Zoledronic Acid; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D000077268:Pamidronate