Locally Administered Zoledronic Acid Therapy for Giant Cell Tumor of Bone

Case Report

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.

Discussion

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, ^3,4 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%. ^2,5 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 rate, ² severe functional impairment is often observed because giant cell tumor of bone occurs close to a joint. ⁶ Hence, local adjuvants such as liquid nitrogen, phenol, and alcohol are recommended. ⁷

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. ⁸ 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. ^9–11 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. ^12,13 Additionally, these agents have low bioavailability due to their poor lipophilicity and negative charge. ¹⁴ 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. ^15,16 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. ^17,18 Cheng et al ¹⁰ showed the apoptotic effect of bisphosphonates on giant cell tumors of bone in both stromal cells and giant cells. Zwolak et al ¹⁹ 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 antitumor effect.

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. ²⁰ 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.