Stimulation of Osteogenic Differentiation in Stromal Cells of Giant Cell Tumour of Bone by Zoledronic Acid

  • Yang, Tao (Department of Orthopaedics, Guangzhou Liu Hua Qiao Hospital) ;
  • Zheng, Xiao-Fei (Department of Orthopaedics, Guangzhou Liu Hua Qiao Hospital) ;
  • Li, Mei (Department of Orthopaedics, Guangzhou Liu Hua Qiao Hospital) ;
  • Lin, Xi (Southern Medical University) ;
  • Yin, Qing-Shui (Department of Orthopaedics, Guangzhou Liu Hua Qiao Hospital)
  • Published : 2013.09.30


Therapeutic effects of zoledronic acid (ZOL) on giant cell tumour of bone (GCT) have been proven. Apoptosis induction was considered to be one of the mechanisms of ZOL tumour inhibition. In this study, we presented the possibility of an osteogenic differentiation stimulation mechanism of ZOL and further investigated dosage and time effects. We treated stromal cells of GCT (GCTSC) with ZOL for 48 hours at different concentrations ($0{\mu}M$, $0.01{\mu}M$, $0.1{\mu}M$, $1{\mu}M$, 5${\mu}M$, $30{\mu}M$) and assessed apoptotic and osteogenic differentiation markers with immunohistochemical techniques and real-time quantitative RT-PCR. Our results suggested that ZOL enhanced mRNA expression of Cbfa-1, osterix and osteocalcin genes with a maximum effect at $1{\mu}M$ in GCTSC. Time course experiments indicated a time dependent osteogenic differentiation effect. In conclusion, ZOL may be considered as an adjuvant in the treatment of GCT not only by inducing apoptosis but also by stimulating osteogenic differentiation of remaining tumor stromal cells after surgery.


Giant cell tumour of bone;zoledronic acid;apoptosis;osteogenic differentiation


  1. Arpornchayanon O, Leerapun T (2008). Effectiveness of intravenous bisphosphonate in treatment of giant cell tumor: a case report and review of the literature. J Med Assoc Thai, 91, 1609-12.
  2. Balke M, Campanacci L, Gebert C, et al (2010). Bisphosphonate treatment of aggressive primary, recurrent and metastatic Giant Cell Tumour of Bone. BMC Cancer, 10, 462.
  3. Boissier S, Ferreras M, Peyruchaud O, et al (2000). Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res, 60, 2949-54.
  4. Boonekamp PM, van der Wee-Pals LJ, van Wijk-van Lennep MM, Thesing CW, Bijvoet OL (1986). Two modes of action of bisphosphonates on osteoclastic resorption of mineralized matrix. Bone Miner, 1, 27-39.
  5. Chang SS, Suratwala SJ, Jung KM, et al (2004). Bisphosphonates may reduce recurrence in giant cell tumor by inducing apoptosis. Clin Orthop Relat Res, 426, 103-9.
  6. Gibbs CP, Lewis VO, Peabody T (2005). Beyond bone grafting: techniques in the surgical management of benign bone tumors. Instr Course Lect, 54, 497-503.
  7. Cheng YY, Huang L, Lee KM, et al (2004). Bisphosphonates induce apoptosis of stromal tumor cells in giant cell tumor of bone. Calcif Tissue Int, 75, 71-7.
  8. Cowan RW, Singh G (2013). Giant cell tumor of bone: a basic science perspective. Bone, 52, 238-46.
  9. Fu L, Tang T, Miao Y, et al (2008). Stimulation of osteogenic differentiation and inhibition of adipogenic differentiation in bone marrow stromal cells by alendronate via ERK and JNK activation. Bone, 43, 40-7.
  10. Gille O, Oliveira BA, Guerin P, et al (2012). Regression of giant cell tumor of the cervical spine with bisphosphonate as single therapy. Spine (Phila Pa 1976), 37, E396-9.
  11. Huang L, Teng XY, Cheng YY, Lee KM, Kumta SM (2004). Expression of preosteoblast markers and Cbfa-1 and Osterix gene transcripts in stromal tumour cells of giant cell tumour of bone. Bone, 34, 393-401.
  12. Luckman SP, Hughes DE, Coxon FP, et al (1998). Nitrogencontaining bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res, 13, 581-9.
  13. Mendenhall WM, Zlotecki RA, Scarborough MT, Gibbs CP, Mendenhall NP (2006). Giant cell tumor of bone. Am J Clin Oncol, 29, 96-9.
  14. Nishisho T, Hanaoka N, Endo K, Takahashi M, Yasui N (2011). Locally administered zoledronic Acid therapy for giant cell tumor of bone. Orthopedics, 34, e312-5.
  15. Reid IR, Brown JP, Burckhardt P, et al (2002). Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med, 346, 653-61.
  16. Turcotte RE (2006). Giant cell tumor of bone. Orthop Clin North Am, 37, 35-51.
  17. Sung HW, Kuo DP, Shu WP, et al (1982). Giant-cell tumor of bone: analysis of two hundred and eight cases in Chinese patients. J Bone Joint Surg Am, 64, 755-61.
  18. Szendroi M (2004). Giant-cell tumour of bone. J Bone Joint Surg Br, 86, 5-12.
  19. Tse LF, Wong KC, Kumta SM, et al (2008). Bisphosphonates reduce local recurrence in extremity giant cell tumor of bone: a case-control study. Bone, 42, 68-73.
  20. Wang CZ, Chen SM, Chen CH, et al (2010). The effect of the local delivery of alendronate on human adipose-derived stem cell-based bone regeneration. Biomaterials, 31, 8674-83.
  21. Werner M (2006). Giant cell tumour of bone: morphological, biological and histogenetical aspects. Int Orthop, 30, 484-9.
  22. Zheng MH, Robbins P, Xu J, et al (2001). The histogenesis of giant cell tumour of bone: a model of interaction between neoplastic cells and osteoclasts. Histol Histopathol, 16, 297-307.
  23. Zwolak P, Manivel JC, Jasinski P, et al (2010). Cytotoxic effect of zoledronic acid-loaded bone cement on giant cell tumor, multiple myeloma, and renal cell carcinoma cell lines. J Bone Joint Surg Am, 92, 162-8.

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