Giant cell tumor of bone is a relatively rare benign but locally aggressive tumor.1 The standard treatment is curettage and bone grafting. However, intralesional curettage alone has a high local recurrence rate of 18% to 50%.2,3 Although several adjuvant therapies, including phenol, liquid nitrogen, bone cement, high-speed burr debridement, and argon beam cauterization, have been used to reduce the recurrence rate,4 their effectiveness is controversial. In particular, complete resection of giant cell tumor of bone in the pelvis and spine is difficult.5 Thus, a new adjuvant therapy is required for giant cell tumor of bone.
Bisphosphonates have a characteristic chemical structure that leads to selective accumulation in bone.6 They are selectively taken up by osteoclasts and strongly inhibit bone resorption by inducing apoptosis.7 Furthermore, they have been widely and successfully used in the treatment of several disorders of increased bone resorption, including bone metastasis.8 Nitrogen-containing bisphosphonates, including zoledronic acid, have been 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.9–11
Some reports have shown that intravenous administration of bisphosphonates reduces local recurrence of giant cell tumor of bone.12–14 Although bisphosphonates are generally well tolerated and rarely induce severe side effects, intravenous use has been reported to carry risks of significant complications, including osteonecrosis of the jaw.15–17 Because bisphosphonates have low bioavailability because of their poor lipophilicity and negative charge,18 the authors previously reported the potential use of zoledronic acid for local treatment of giant cell tumor of bone to reduce the risk of side effects and increase the bioavailability of bisphosphonates.19 The goal of this study was to evaluate the effectiveness of locally administered zoledronic acid for giant cell tumor of bone as well as to provide a brief review of the literature.
Materials and Methods
Written informed consent was obtained from patients with giant cell tumor of bone, and the treatment protocol was approved by the ethics committee of Tokushima University. Five patients (4 men and 1 woman) treated with local administration of zoledronic acid for histologically proven giant cell tumor of bone at the authors’ institution from 2008 to 2013 were included in this study (Table). Mean age was 44 years (range, 22–66 years), and mean follow-up was 19 months (range, 3–38 months). Tumors were localized to the proximal tibia, distal tibia, proximal fibula, distal radius, and pelvis, respectively. According to the Campanacci grading system,2 2 tumors were classified as grade II and 3 were classified as grade III.
Demographic Characteristics of Patients Treated With Local Administration of Zoledronic Acid
The authors’ strategy is shown in Figure 1. After intraoperative or definitive pathologic diagnosis was obtained by open biopsy, zoledronic acid was locally administered to the lesion. Definitive surgery, such as curettage or en bloc resection, was performed after a waiting period to achieve the full drug effect. Histologic sections obtained by definitive surgery were evaluated to confirm the effect of local zoledronic acid treatment.
Treatment strategy for giant cell tumor of bone. After open biopsy, zoledronic acid is administered locally, with or without artificial bone. Image evaluation is done during the waiting period, and the necrosis rate of giant cell tumor of bone is evaluated based on histologic findings.
Open biopsy was performed in all patients. After intraoperative diagnosis, 4 patients were treated with local administration of zoledronic acid with artificial bone (hydroxyapatite, Neobone, MMT Co Ltd, Osaka, Japan, in cases 2, 3, and 4; and betatricalcium, Superpore, Pentax, Tokyo, Japan, in case 1) (Figure 2). The remaining patient (case 5) was treated with local administration of zoledronic acid without artificial bone after definitive histologic diagnosis because a malignant bone tumor was suspected based on radiologic findings (Figure 3).
Case 2, a 22-year-old woman. Preoperative anteroposterior radiograph showing a lytic lesion in the distal tibia (a). Preoperative coronal contrast-enhanced magnetic resonance imaging showing gadolinium enhancement of the tumor lesion (b). Histologic diagnosis of the open biopsy specimen showing giant cell tumor of bone (hematoxylin and eosin, original magnification ×200) (c). Plain anteroposterior radiograph after open biopsy showing local administration of zoledronic acid with hydroxyapatite (d). Contrast-enhanced coronal magnetic resonance imaging 2 weeks after biopsy with most of the tumor lesion showing poor gadolinium enhancement (e). Histologic findings showing that both stromal cells and osteoclast-like cells are necrotic (f). Plain anteroposterior radiograph 12 months after resection (g).
Case 5, a 56-year-old man. Preoperative anteroposterior radiograph showing a lytic lesion in the ischium expanding to the acetabulum (a). Preoperative axial contrast-enhanced axial magnetic resonance imaging showing gadolinium enhancement of the tumor lesion (b). Histologic findings showing giant cell tumor of bone (hematoxylin and eosin, original magnification ×200) (c). Plain anteroposterior radiograph after open biopsy with local administration of zoledronic acid with a syringe (arrow, drug administration route) (d). Contrast-enhanced axial magnetic resonance imaging before definitive surgery. No significant antitumor effect was observed after local zoledronic acid administration (e). Histologic findings showing no tumor cell necrosis (f). Axial magnetic resonance imaging 18 months after definitive surgery showing local recurrence (arrow) in soft tissue (g).
Initially, the authors used zoledronic acid (4 mg) for local administration, according to the standard for intravenous zoledronic acid use.20,21 In case 5, an additional 4 mg zoledronic acid was administered because no effect of the initial 4 mg zoledronic acid was observed on preoperative needle biopsy. To minimize the risk of side effects, a lower dose of zoledronic acid was used for cases 3 and 4, based on clinical experience.
The waiting period from open biopsy to definitive surgery was 10 weeks, 3 weeks, 1 week, 3 weeks, and 6 weeks for cases 1 to 5, respectively. In case 1, the authors used a waiting period of 10 weeks to ensure effective treatment with zoledronic acid.19 Thereafter, the authors changed the standard waiting period to 3 weeks for intravenous zoledronic acid administration in patients with bone metastasis.20,21 In case 3, definitive surgery was performed before the end of the waiting period because of peroneal nerve palsy.
For definitive surgery, 3 patients (cases 1, 2, and 4) underwent curettage and debridement with a high-speed burr and bone grafting. Artificial bone was used in cases 1 and 2, and autograft bone was used in case 4. En bloc resection was performed for the other 2 patients (cases 3 and 5). In case 5, the patient had a huge pelvic tumor that was reconstructed with polymethylmethacrylate followed by en bloc resection of the ischium and extended curettage of the acetabular lesion with a high-speed burr after cementing.
Four patients underwent gadolinium-enhanced magnetic resonance imaging (MRI) during the waiting period. Only 1 patient (case 3), who had a fibular head tumor, did not undergo MRI because of peroneal nerve palsy that required emergent surgery. The necrosis rate for giant cell tumor of bone was evaluated with histologic specimens stained with hematoxylin and eosin.
Two types of artificial bone material, hydroxyapatite and betatricalcium phosphate, were used as the zoledronic acid carrier in 4 patients (cases 1–4). However, no apparent differences were noted between these 2 types of artificial bone with regard to the effectiveness of local zoledronic acid administration. Three patients (cases 1, 2, and 4) showed poor gadolinium enhancement on MRI after local administration of zoledronic acid.
Cases 1 and 2, classified as Campanacci grade II, showed a 90% histologic tumor necrosis rate. Cases 3 and 4, classified as Campanacci grade III, showed a 50% and 10% histologic tumor necrosis rate, respectively. These 4 patients were disease-free during the follow-up period. Case 5, classified as Campanacci grade III, was an exception in this case series (Figure 3). Because preoperative radiologic findings suggested malignancy, the patient underwent only tissue extraction by open biopsy and no local zoledronic acid administration. Between open biopsy and definitive surgery, the patient was administered zoledronic acid locally with a syringe at the outpatient clinic. An additional 4 mg zoledronic acid was administered because no tumor necrosis was apparent on preoperative needle biopsy after initial administration of 4 mg zoledronic acid. However, gadolinium-enhanced MRI before definitive surgery showed no significant changes. Despite administration of a double dose, no histologic tumor necrosis was observed. Further, a postoperative pubic fracture occurred 5 months after the definitive operation, resulting in nonunion. The patient had local recurrence in soft tissue that required recurettage 18 months later.
Delayed wound healing after biopsy occurred in 2 patients and was controlled with antibiotics and debridement (Figure 4). Because the peroneal palsy in case 3 occurred just before open biopsy, the authors believe that there was no connection between nerve palsy and zoledronic acid treatment. No other complications were observed during treatment.
Two cases showing delayed wound healing and superficial infection after open biopsy. Frontal view of the ankle (case 2) (a). Inner aspect of the proximal thigh (case 5) (b). Both healed after definitive surgery with subcutaneous tissue debridement.
The mechanisms of bone destruction in giant cell tumor of bone are similar to those of bone metastasis in carcinoma. Two different cell types are involved in giant cell tumor of bone, osteoclast-like giant cells and fibroblast-like stromal tumor cells.22,23 Osteoclast-like giant cells mainly destroy bone, and fibroblast-like stromal cells behave similarly to neoplastic cells and activate these giant cells through expressing receptor activator of nuclear factor kappa-B ligand.24 Several studies of the use of bisphosphonates to prevent local recurrence or for systemic treatment of giant cell tumor of bone have been reported.12–14,25 When local administration of bisphosphonates for giant cell tumor of bone is possible, bioavailability is greater than with intravenous administration. A case of giant cell tumor of bone that was treated successfully with local administration of zoledronic acid was reported.19
In this case series, the rate of local control was 80%; only 1 patient did not achieve control. Artificial bone is considered necessary for zoledronic acid to be effective because it accumulates in the bone matrix to exhibit its effect. In an animal study by Kumar et al,26 pamidronate mixed with saline produced inconsistent bone uptake and therefore was not used. For the same reason, Campanacci grading is important to predict the effect of local zoledronic acid administration.2
In case 5, local recurrence occurred in soft tissue, and zoledronic acid is known to have a high affinity for mineralized bone. Its concentration declines rapidly in plasma and noncalcified tissue when administered intravenously.27 Locally administered zoledronic acid may accumulate strongly in the bone matrix and poorly in soft tissue. The characteristics of zoledronic acid may be a reason for soft tissue recurrence.
The optimal waiting period has not been elucidated. From the authors’ experience, the different waiting periods in case 1 (10 weeks) and case 2 (3 weeks) had no effect on the histologic necrosis rate. Furthermore, the histologic necrosis rate was 50% in case 3, with a waiting period of only 1 week. Therefore, a waiting period of as little as 2 weeks may be sufficient. In addition, intravenous zoledronic acid for bone metastasis is administered once every 3 to 4 weeks as standard therapy.20,21 Taken together, a 3-week waiting period between biopsy and zoledronic acid treatment appears reasonable.
In 2 cases, delayed wound healing occurred. Several studies reported that zoledronic acid inhibits angiogenesis,28–30 and Kobayashi et al31 showed that zoledronic acid delays wound healing of the tooth extraction socket, inhibits oral epithelial cell migration, and promotes proliferation. Therefore, a certain degree of technique is needed to prevent leakage of zoledronic acid into soft tissue. Because the direct effect of zoledronic acid on nerve tissue is unclear, local administration is likely unsuitable for lesions at sites such as the sacrum.
The current study had several limitations, including the small sample size and the heterogeneity of zoledronic acid regimens. Nevertheless, the findings suggest that locally administered zoledronic acid is a candidate for adjuvant therapy for giant cell tumor of bone. Further studies are needed to verify these results.
- Becker WT, Dohle J, Bernd L, 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 [CrossRef]
- Campanacci M, Baldini N, Boriani S, Sudanese A. Giant-cell tumor of bone. J Bone Joint Surg Am. 1987; 69(1):106–114.
- McDonald DJ, Sim FH, McLeod RA, Dahlin DC. Giant-cell tumor of bone. J Bone Joint Surg Am. 1986; 68(2):235–242.
- Jones KB, DeYoung BR, Morcuende JA, Buckwalter JA. Ethanol as a local adjuvant for giant cell tumor of bone. Iowa Orthop J. 2006; 26:69–76.
- Martin C, McCarthy EF. Giant cell tumor of the sacrum and spine: series of 23 cases and a review of the literature. Iowa Orthop J. 2010; 30:69–75.
- Rogers MJ, Watts DJ, Russell RG. Overview of bisphosphonates. Cancer. 1997; 80(8 suppl):1652–1660. doi:10.1002/(SICI)1097-0142(19971015)80:8+<1652::AID-CNCR15>3.0.CO;2-Z [CrossRef]
- 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 [CrossRef]
- Costa L, Major PP. Effect of bisphosphonates on pain and quality of life in patients with bone metastases. Nat Clin Pract Oncol. 2009; 6(3):163–174. doi:10.1038/ncponc1323 [CrossRef]
- 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 [CrossRef]
- Shipman CM, Rogers MJ, Apperley JF, Russell RG, Croucher PI. Bisphosphonates induce apoptosis in human myeloma cell lines: a novel anti-tumour activity. Br J Haematol. 1997; 98(3):665–672. doi:10.1046/j.1365-2141.1997.2713086.x [CrossRef]
- 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 [CrossRef]
- 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. Bone. 2008; 42(1):68–73. doi:10.1016/j.bone.2007.08.038 [CrossRef]
- 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.
- 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 [CrossRef]
- Gutta R, Louis PJ. Bisphosphonates and osteonecrosis of the jaws: science and rationale. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007; 104(2):186–193. doi:10.1016/j.tripleo.2006.12.004 [CrossRef]
- 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 [CrossRef]
- Ruggiero SL. Bisphosphonate-related osteonecrosis of the jaws. Compend Contin Educ Dent. 2008; 29(2):96–98.
- Ezra A, Golomb G. Administration routes and delivery systems of bisphosphonates for the treatment of bone resorption: advanced drug delivery reviews. Adv Drug Deliv Rev. 2000; 42(3):175–195. doi:10.1016/S0169-409X(00)00061-2 [CrossRef]
- Nishisho T, Hanaoka N, Endo K, Takahashi M, Yasui N. Locally administered zoledronic acid therapy for giant cell tumor of bone. Orthopedics. 2011; 34(7):e312–e315.
- Rosen LS, Gordon D, Kaminski M, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J. 2001; 7(5):377–387.
- Rosen LS, Gordon D, Tchekmedyian NS, et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with non-small cell lung carcinoma and other solid tumors: a randomized, phase III, double-blind, placebo-controlled trial. Cancer. 2004; 100(12):2613–2621. doi:10.1002/cncr.20308 [CrossRef]
- 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 [CrossRef]
- 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 [CrossRef]
- Kim Y, Nizami S, Goto H, Lee FY. Modern interpretation of giant cell tumor of bone: predominantly osteoclastogenic stromal tumor. Clin Orthop Surg. 2012; 4(2):107–116. doi:10.4055/cios.2012.4.2.107 [CrossRef]
- Balke M, Campanacci L, Gebert C, et al. Bisphosphonate treatment of aggressive primary, recurrent and metastatic giant cell tumour of bone. BMC Cancer. 2010; 10:462. doi:10.1186/1471-2407-10-462 [CrossRef]
- Kumar D, Kumar V, Little DG, Howman-Giles RB, Wong E, Ali SO. Evaluation of biodistribution by local versus systemic administration of 99mTc-labeled pamidronate. J Orthop Sci. 2006; 11(5):512–520. doi:10.1007/s00776-006-1046-5 [CrossRef]
- Weiss HM, Pfaar U, Schweitzer A, Wiegand H, Skerjanec A, Schran H. Biodistribution and plasma protein binding of zoledronic acid. Drug Metab Dispos. 2008; 36(10):2043–2049. doi:10.1124/dmd.108.021071 [CrossRef]
- Muller S, Migianu E, Lecouvey M, Kraemer M, Oudar O. Alendronate inhibits proliferation and invasion of human epidermoid carcinoma cells in vitro. Anticancer Res. 2005; 25(4):2655–2660.
- Ribatti D, Nico B, Mangieri D, et al. Neridronate inhibits angiogenesis in vitro and in vivo. Clin Rheumatol. 2007; 26(7):1094–1098. doi:10.1007/s10067-006-0455-3 [CrossRef]
- Yamagishi S, Abe R, Inagaki Y, et al. Minodronate, a newly developed nitrogen-containing bisphosphonate, suppresses melanoma growth and improves survival in nude mice by blocking vascular endothelial growth factor signaling. Am J Pathol. 2004; 165(6):1865–1874. doi:10.1016/S0002-9440(10)63239-7 [CrossRef]
- Kobayashi Y, Hiraga T, Ueda A, et al. Zoledronic acid delays wound healing of the tooth extraction socket, inhibits oral epithelial cell migration, and promotes proliferation and adhesion to hydroxyapatite of oral bacteria, without causing osteonecrosis of the jaw, in mice. J Bone Miner Metab. 2010; 28(2):165–175. doi:10.1007/s00774-009-0128-9 [CrossRef]
Demographic Characteristics of Patients Treated With Local Administration of Zoledronic Acid
|Case No./Sex/Age, y
||Zoledronic Acid, mg
||Waiting Period, wk
||Histologic Necrosis Rate, %
||Complication After Biopsy
||Curettage and bone grafting
||Curettage and bone grafting
||Delaying wound healing
||En bloc resection
||Curettage and bone grafting
||En bloc resection, curettage, and cementing
||Delaying wound healing