Giant cell tumor of bone is locally aggressive and occurs in the meta-epiphyseal region of long bones. Because of its high
recurrence rate, local adjuvant therapies such as phenol or liquid nitrogen have been recommended. In the present study, zoledronic
acid, a nitrogen-containing bisphosphonate, was administered locally as an adjuvant during a biopsy. An otherwise healthy
43-year-old man presented with pain and swelling in the right knee. Plain radiographs showed an osteolytic lesion of the right
proximal tibia. An open biopsy was performed and the intraoperative pathologic diagnosis was giant cell tumor of bone. Following
biopsy, the defect was filled with betatricalcium phosphate, and 4 mg of zoledronic acid was locally administered into the
tumor lesion. Two months after the biopsy, curettage and bone grafting were performed. Sections were obtained during the curettage
for histology to evaluate the response to bisphosphonate treatment. Histologic examination revealed massive tumor cell death
in the lesion in which both stromal cells and osteoclast-like giant cells were necrotic. Curettage was performed and the defect
was filled with a commercial preshaped hydroxyapatitetricalcium phosphate bone substitute. Eighteen months after curettage,
the patient had regained full range of motion and good function of the knee, and radiographs at 18 months after curettage
revealed no recurrence of giant cell tumor of bone.
Drs Nishisho, Hanaoka, Endo, Takahashi, and Yasui are from the Department of Orthopedics, Institute of Health Biosciences,
University of Tokushima Graduate School, Tokushima, Japan.
Drs Nishisho, Hanaoka, Endo, Takahashi, and Yasui have no relevant financial relationships to disclose.
Correspondence should be addressed to: Toshihiko Nishisho, MD, Department of Orthopedics, Institute of Health Biosciences,
University of Tokushima Graduate School, 3-18-15 Kuramoto, Tokushima 770-8503, Japan (email@example.com).
Giant cell tumor of bone is locally aggressive and occurs in the meta-epiphyseal region of long bones.
Intralesional curettage alone has a high local recurrence rate (18%–50%).
In the present study, zoledronic acid, a nitrogen-containing bisphosphonate, was administered locally as an adjuvant during
a biopsy. This article presents a case of giant cell tumor of bone in the proximal tibia, in which local administration of
zoledronic acid showed antitumor effects.
An otherwise healthy 43-year-old man presented with pain and swelling in the right knee following a fall 1 month earlier.
Plain radiographs showed an osteolytic lesion of the right proximal tibia, which had a thin cortex and showed no signs of
fracture or calcification (Figure ). Magnetic resonance imaging (MRI) demonstrated a low-intensity lesion on T1-weighted images and presented as a low- to isointensity
lesion on T2-weighted images. The lesion showed substantial gadolinium enhancement (Figure ). No extraosseous expansion was observed.
Figure 1:. Preoperative radiograph showing a lytic lesion in the proximal tibia (A). Contrast-enhanced MRI showing gadolinium enhancement
of the tumor lesion (B).
An open biopsy was performed and the intraoperative pathologic diagnosis was giant cell tumor of bone (Figure ). Following biopsy, the defect was filled with beta-tricalcium phosphate, and 4 mg of zoledronic acid was locally administered
into the tumor lesion directly by a syringe (Figure ).
Figure 2:. Photomicrograph demonstrating numerous osteoclast-like, multinucleated giant cells and spindle to polygonal mononuclear cells;
the diagnosis was giant cell tumor of bone (hematoxylin-eosin, ×200) (A). Following biopsy, the defect was filled with beta-tricalcium
phosphate, and 4 mg of zoledronic acid was locally administered into the tumor lesion (B).
Magnetic resonance imaging 2 months after biopsy demonstrated poor gadolinium enhancement of the residual tumor, although
strong gadolinium enhancement of the peripheral tumor lesion was seen (Figure ). Subsequently, curettage and bone grafting were performed. Sections were obtained during the curettage for histology to
evaluate the response to bisphosphonate treatment (Figure ). Histologic examination revealed massive tumor cell death in the lesion in which both stromal cells and osteoclast-like
giant cells were necrotic (Figure ). The peripheral tumor lesion, which showed gadolinium enhancement on MRI, presented marked fibrosis with infiltration of
inflammatory cells, and no tumor cells were found in this lesion (Figure ). Curettage was performed and the defect was filled with a commercial preshaped hydroxyapatite-tricalcium phosphate bone
substitute (Ceratite, Kobayashi Medical, Osaka, Japan). No serious complications directly associated with curettage or the
local administration of zoledronic acid was present. Eighteen month after curettage, the patient regained full range of motion
and good function of the knee, and radiographs at 18 months after curettage revealed no recurrence of giant cell tumor of
bone (Figure ). Additionally, no side effects were observed during the treatment.
Figure 3:. Contrast-enhanced MRI 2 months after open biopsy (A). Most of the tumor lesion, except for the periphery, demonstrated poor
gadolinium enhancement. Histologic examination revealed that both stromal cells and osteolcast-like giant cells were necrotic
(B). The peripheral tumor lesion, which showed strong gadolinium enhancement on MRI, presented marked fibrosis with infiltration
of inflammatory cells but no viable tumor cells (hematoxylin-eosin, ×200) (C).
Figure 4:. Radiograph of the right knee 18 months after intralesional curettage with bone graft substitute showing no recurrence of giant
cell bone tumor.
In the present case, the local administration of zoledronic acid-induced tumor cell death may also have suppressed recurrence.
Although a few studies have demonstrated that local administration of bisphosphonate is effective for the treatment of bone
disorders in animal models,
to our knowledge, this is the first clinical report of local administration of zoledronic acid.
Although giant cell tumor of bone is generally considered a benign tumor that rarely metastasizes, it tends to recur locally
in 10% to 50% of cases with a meta-static rate of approximately 2%.
The standard treatment for giant cell tumor of bone is extended curettage combined with bone grafting or cement-augmented
stabilization. Although wide resection of the tumor, followed by major reconstructive surgery, results in a low recurrence
severe functional impairment is often observed because giant cell tumor of bone occurs close to a joint.
Hence, local adjuvants such as liquid nitrogen, phenol, and alcohol are recommended.
Bisphosphonates have a characteristic chemical structure that leads to selective accumulation in bone. Bisphosphonates are
selectively taken up by osteoclasts and inhibit bone resorption by inducing apoptosis.
They have been widely and successfully used in the treatment of several disorders of increased bone resorption, including
osteoporosis, Paget’s disease, fibrous dysplasia, myeloma, and bone metastasis. Studies have shown that intravenous administration
of bisphosphonates is effective for preventing local recurrence of giant cell tumor of bone.
In addition, bisphosphonates are well tolerated and have few severe side effects. However, intravenous bisphosphonate treatments
have been reported to cause significant complications, including osteonecrosis of the jaw bones.
Additionally, these agents have low bioavailability due to their poor lipophilicity and negative charge.
To reduce the risk of side effects and increase bioavailability, we attempted local administration of the bisphosphonate
zoledronic acid for the treatment of giant cell tumor of bone.
Giant cell tumor of bone is composed of a stromal population of cells of osteoblastic origin and a distinctive osteoclast-like
population of probable monocytic origin.
The interplay between these 2 cell populations is critical to the pathogenesis of giant cell tumor of bone. Multinucleated
giant cells have phenotypic features of osteoclasts and mediate bone destruction. Stromal cells are considered as primary
neoplastic cells of this tumor and interact with multinucleated giant cells. In the present case, histologic examination revealed
that both multinucleated giant cell death and stromal cell death occurred following treatment with local bisphosphonates.
Nitrogen-containing bisphosphonates, including zoledronic acid, were reported to promote apoptosis of not only osteoclasts
but also tumor cells by inhibiting the action of the enzyme farnesyl pyrophosphate synthase in the mevalonate pathway.
Cheng et al
showed the apoptotic effect of bisphosphonates on giant cell tumors of bone in both stromal cells and giant cells. Zwolak
reported the cytotoxic effect on giant cell tumor cell lines in vitro of zoledronic acid released from bone cement. Taken
together, these findings demonstrate the possibility that the local administration of bisphosphonates caused a strong direct
To understand the effect of local bisphosphonates, it is important to determine the pharmacokinetics of local administration
of zoledronic acid. This drug has a high affinity for mineralized bone, and when intravenously administered, zoledronic acid
rapidly localizes to bone and displays a rapid elimination from the systemic circulation.
Therefore, it is possible that local administration of zoledronic acid results in greater accumulation of bisphosphonate
in the bone matrix than intravenous administration, and will therefore result in fewer side effects. However, in future, we
need to examine the drug distribution using an animal model.
To our knowledge, this is the first report of local administration of bisphosphonates for the treatment of giant cell tumor
of bone. This method of bisphosphonate administration may be suitable for other bone disorders such as metastatic bone disease.
Studies including more patients, however, are needed to confirm the clinical effect of this treatment.
- 1. Thomas DM, Skubitz KM. Giant cell tumour of bone.
Curr Opin Oncol. 2009; 21(4):338–344. doi: 10.1097/CCO.0b013e32832c951d
- 2. Becker WT, Dohle J, Arbeitsgemeinschaft Knochentumoren et al. Local recurrence of giant cell tumor of bone after intralesional treatment with and without adjuvant therapy.
J Bone Joint Surg Am. 2008; 90(5):1060–1067. doi: 10.2106/JBJS.D.02771
- 3. Amanat N, Brown R, Bilston LE, Little DG. A single systemic dose of pamidronate improves bone mineral content and accelerates restoration of strength in a rat model
of fracture repair [published online ahead of print April 19, 2005].
J Orthop Res. 2005; 23(5):1029–1034. doi: 10.1016/j.orthres.2005.03.004
- 4. Omi H, Kusumi T, Kijima H, Toh S. Locally administered low-dose alendronate increases bone mineral density during distraction osteogenesis in a rabbit model.
J Bone Joint Surg Br. 2007; 89(7):984–988. doi: 10.1302/0301-620X.89B7.18980
- 5. Ladanyi M, Traganos F, Huvos AG. Benign metastasizing giant cell tumors of bone. A DNA flow cytometric study.
Cancer. 1989; 64(7):1521–1526. doi: 10.1002/1097-0142(19891001)64:7<1521::AID-CNCR2820640727>3.0.CO;2-7
- 6. Turcotte RE, Wunder JS, Isler MH, et al. Giant cell tumor of long bone: a Canadian Sarcoma Group study.
Clin Orthop Relat Res. 2002; (397):248–258. doi: 10.1097/00003086-200204000-00029
- 7. Errani C, Ruggieri P, Asenzio MA, et al. Giant cell tumor of the extremity: A review of 349 cases from a single institution [published online ahead of print October
Cancer Treat Rev. 2010; 36(1):1–7. doi: 10.1016/j.ctrv.2009.09.002
- 8. Hughes DE, Wright KR, Uy HL, et al. Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo.
J Bone Miner Res. 1995; 10(10):1478–1487. doi: 10.1002/jbmr.5650101008
- 9. Arpornchayanon O, Leerapun T. Effectiveness of intravenous bisphosphonate in treatment of giant cell tumor: a case report and review of the literature.
J Med Assoc Thai. 2008; 91(10):1609–1612.
- 10. Cheng YY, Huang L, Lee KM, Xu JK, Zheng MH, Kumta SM. Bisphosphonates induce apoptosis of stromal tumor cells in giant cell tumor of bone.
Calcif Tissue Int. 2004; 75(1):71–77. doi: 10.1007/s00223-004-0120-2
- 11. Tse LF, Wong KC, Kumta SM, Huang L, Chow TC, Griffith JF. Bisphosphonates reduce local recurrence in extremity giant cell tumor of bone: a case-control study [published online ahead
of print September 6, 2007].
Bone. 2008; 42(1):68–73. doi: 10.1016/j.bone.2007.08.038
- 12. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases.
J Oral Maxillofac Surg. 2004; 62(5):527–534. doi: 10.1016/j.joms.2004.02.004
- 13. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic.
J Oral Maxillofac Surg. 2003; 61(9):1115–1117. doi: 10.1016/S0278-2391(03)00720-1
- 14. Ezra A, Golomb G. Administration routes and delivery systems of bisphosphonates for the treatment of bone resorption.
Adv Drug Deliv Rev. 2000; 42(3):175–195. doi: 10.1016/S0169-409X(00)00061-2
- 15. Goldring SR, Roelke MS, Petrison KK, Bhan AK. Human giant cell tumors of bone identification and characterization of cell types.
J Clin Invest. 1987; 79(2):483–491. doi: 10.1172/JCI112838
- 16. Wulling M, Engels C, Jesse N, Werner M, Delling G, Kaiser E. The nature of giant cell tumor of bone.
J Cancer Res Clin Oncol. 2001; 127(8):467–474. doi: 10.1007/s004320100234
- 17. Fromigue O, Lagneaux L, Body JJ. Bisphosphonates induce breast cancer cell death in vitro.
J Bone Miner Res. 2000; 15(11):2211–2221. doi: 10.1359/jbmr.2000.15.11.2211
- 18. Tassone P, Tagliaferri P, Viscomi C, et al. Zoledronic acid induces antiproliferative and apoptotic effects in human pancreatic cancer cells in vitro.
Br J Cancer. 2003; 88(12):1971–1978. doi: 10.1038/sj.bjc.6600986
- 19. Zwolak P, Manivel JC, Jasinski P, et al. Cytotoxic effect of zoledronic acid-loaded bone cement on giant cell tumor, multiple myeloma, and renal cell carcinoma cell
J Bone Joint Surg Am. 2010; 92(1):162–168. doi: 10.2106/JBJS.H.01679
- 20. Weiss HM, Pfaar U, Schweitzer A, Wiegand H, Skerjanec A, Schran H. Biodistribution and plasma protein binding of zoledronic acid [published online ahead of print July 14, 2008].
Drug Metab Dispos. 2008; 36(10):2043–2049. doi: 10.1124/dmd.108.021071