In Vitro Study of the Effects of Denosumab on Giant Cell Tumor of Bone: Comparison with Zoledronic Acid
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Giant cell tumor of bone (GCTB) is a locally aggressive primary bone tumor that contains numerous osteoclasts formed from marrow-derived precursors through receptor activator of nuclear factor κ-B ligand (RANKL), an osteoclast differentiation factor expressed in neoplastic cells of GCTB. Denosumab, a fully human monoclonal antibody targeting RANKL, has recently been used for the treatment of GCTB, and superior treatment effects have been reported. The aim of this work was to elucidate the mechanism of action of denosumab, and the differences between denosumab and zoledronic acid at the level of GCTB cells. We isolated GCTB cells from 3 patients and separated them into osteoclasts, osteoclast precursors and proliferating spindle-shaped stromal cells (the true neoplastic component), and examined the action of denosumab on differentiation, survival and bone resorption activity of osteoclasts. Denosumab and zoledronic acid inhibited osteoclast differentiation from mononuclear cells containing osteoclast precursors. Zoledronic acid inhibited osteoclast survival, whereas an inhibitory effect of denosumab on osteoclast survival was not observed. The inhibitory effect on bone resorption by both agents was confirmed in culture on dentin slices. Furthermore, zoledronic acid showed dose-dependent inhibition of cell growth of neoplastic cells whereas denosumab had no inhibitory effect on these cells. Denosumab has an inhibitory effect on osteoclast differentiation, but no inhibitory effects on survival of osteoclasts or growth of neoplastic cells in GCTBs.
KeywordsGiant cell tumor of bone Osteoclast Bisphosphonate Denosumab Bone tumor
This work was supported by the Japan Society for the Promotion of Science (Grant Numbers 26293398 and 16 K20655) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
Conception and design: Isao Shibuya, Masamichi Takami.
Analysis and interpretation of data: Isao Shibuya, Masamichi Takami, Arei Miyamoto, Akiko Karakawa.
Drafting the article or revising: Isao Shibuya, Masamichi Takami, Akira Dezawa, Shigeru Nakamura, Ryutaro Kamijo.
GUARANTOR: Isao Shibuya.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
This study has been carried out with the approval of the ethics committee of Teikyo University School of Medicine (approval No: 12–001) and Showa University School of Dentistry (approval No: 2006–12). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
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