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Journal ArticleDOI

Bisphosphonates reduce local recurrence in extremity giant cell tumor of bone: A case-control study

01 Jan 2008-Bone (Elsevier)-Vol. 42, Iss: 1, pp 68-73
TL;DR: Clinical use of bisphosphonates as an adjuvant therapy for giant cell tumor of bone demonstrated a lower local recurrence rate and the clinical response seems to be more promising in stage III diseases.
About: This article is published in Bone.The article was published on 2008-01-01. It has received 192 citations till now. The article focuses on the topics: Giant-cell tumor of bone & Bisphosphonate.
Citations
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Journal ArticleDOI
TL;DR: In this article, the potential therapeutic effect of denosumab, a fully human monoclonal antibody against RANKL, on tumour-cell survival and growth in patients with GCT was investigated.
Abstract: Summary Background Giant-cell tumour (GCT) of bone is a primary osteolytic bone tumour with low metastatic potential and is associated with substantial skeletal morbidity. GCT is rich in osteoclast-like giant cells and contains mononuclear (stromal) cells that express RANK ligand (RANKL), a key mediator of osteoclast activation. We investigated the potential therapeutic effect of denosumab, a fully human monoclonal antibody against RANKL, on tumour-cell survival and growth in patients with GCT. Methods In this open-label, single-group study, 37 patients with recurrent or unresectable GCT were enrolled and received subcutaneous denosumab 120 mg monthly (every 28 days), with loading doses on days 8 and 15 of month 1. The primary endpoint was tumour response, defined as elimination of at least 90% of giant cells or no radiological progression of the target lesion up to week 25. Study recruitment is closed; patient treatment and follow-up are ongoing. The study is registered with Clinical Trials.gov, NCT00396279. Findings Two patients had insufficient histology or radiology data for efficacy assessment. 30 of 35 (86%; 95% CI 70–95) of evaluable patients had a tumour response: 20 of 20 assessed by histology and 10 of 15 assessed by radiology. Adverse events were reported in 33 of 37 patients; the most common being pain in an extremity (n=7), back pain (n=4), and headache (n=4). Five patients had grade 3–5 adverse events, only one of which (grade 3 increase in human chorionic gonadotropin concentration not related to pregnancy) was deemed to be possibly treatment related. Five serious adverse events were reported although none were deemed treatment related. Interpretation Further investigation of denosumab as a therapy for GCT is warranted. Funding Amgen, Inc.

575 citations

Journal ArticleDOI
TL;DR: Denosumab treatment of patients with GCTB significantly reduced or eliminated RANK-positive tumor giant cells and reduced the relative content of proliferative, densely cellular tumor stromal cells, replacing them with nonproliferative, differentiated, densely woven new bone.
Abstract: Purpose: Giant cell tumor of bone (GCTB) is a locally aggressive, benign osteolytic tumor in which bone destruction is mediated by RANKL. The RANKL inhibitor denosumab is being investigated for treatment of GCTB. We describe histologic analyses of GCTB tumor samples from a phase 2 study of denosumab in GCTB. Experimental Design: Adult patients with recurrent or unresectable GCTB received subcutaneous denosumab 120 mg every 4 weeks (with additional doses on days 8 and 15). The primary histologic efficacy endpoint was the proportion of patients who had a ≥ 90% elimination of giant cells from their tumor. Baseline and on-study specimens were also evaluated for overall tumor morphology and expression of RANK and RANKL. Results: Baseline tumor samples were typically composed of densely cellular proliferative RANKL-positive tumor stromal cells, RANK-positive rounded mononuclear cells, abundant RANK-positive tumor giant cells, and areas of scant de novo osteoid matrix and woven bone. In on-study samples from 20 of 20 patients (100%), a decrease of ≥ 90% in tumor giant cells and a reduction in tumor stromal cells were observed. In these analyses, thirteen patients (65%) had an increased proportion of dense fibro-osseous tissue and/or new woven bone, replacing areas of proliferative RANKL positive stromal cells. Conclusions: Denosumab treatment of patients with GCTB significantly reduced or eliminated RANK-positive tumor giant cells. Denosumab also reduced the relative content of proliferative, densely cellular tumor stromal cells, replacing them with non-proliferative, differentiated, densely woven new bone. Denosumab continues to be studied as a potential treatment for GCTB.

368 citations


Cites background from "Bisphosphonates reduce local recurr..."

  • ...Tibia 4/18 (22) 2/11 (18) Sacrum 3/18 (17) 2/11 (18) Femur distal 2/18 (11) 1/11 (9) Fibula 2/18 (11) 1/11 (9) Other 1/18 (6) 2/11 (18) Pubis 2/18 (11) 1/11 (9) Ulna 2/18 (11) 1/11 (9) Thoracic vertebrae 1/18 (6) 1/11 (9) Radius 1/18 (6) 0/11 (0) Previous surgery, n (%) None 6 (30) 1 4 (20) >1 10 (50) Other previous therapies received Chemotherapy 2 (10) Radiation 4 (20) Oral bisphosphonates 0 (0) Intravenous bisphosphonates 1 (5) Calcitonin 0 (0) IFN 0 (0)...

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  • ...Female sex, n (%) 11 (55) Ethnic or racial group, n (%) White or Caucasian 13 (65) Black or African American 2 (10) Hispanic or Latino 3 (15) Asian 2 (10) Age, y, mean (SD) 33 (10) GCTB disease type, n (%) Primary unresectable 8 (40) Recurrent unresectable 8 (40) Recurrent resectable 4 (20) ECOG performance status 0 7 (35) 1 10 (50) 2 1 (5) Missing 2 (10) Anatomic site of biopsy/resection, n (%) Baseline On-study...

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  • ...In one study, no change in the morphologic structure of the tumor was observed; however, several patients showed an increase in radiologic density and bone mineral content (50)....

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Journal ArticleDOI
TL;DR: This work considers how osteoclast signals may contribute to bone formation by osteoblasts and to the pathology of bone lesions such as fibrous dysplasia and giant cell tumors and reviews the interaction of osteoclasts with the hematopoietic system, including the stem cell niche and adaptive immune cells.

302 citations

Journal ArticleDOI
TL;DR: Intralesional surgery with polymethylmethacrylate is recommended for the majority of primary GCTs and the potential for metastases should not by itself create an indication for wide resection of primary tumors.
Abstract: Background Many surgeons treat giant cell tumor of bone (GCT) with intralesional curettage. Wide resection is reserved for extensive bone destruction where joint preservation is impossible or when expendable sites (eg, fibular head) are affected. Adjuvants such as polymethylmethacrylate and phenol have been recommended to reduce the risk of local recurrence after intralesional surgery. However, the best treatment of these tumors and risk factors for recurrence remain controversial.

299 citations


Cites result from "Bisphosphonates reduce local recurr..."

  • ...This hypothesis is supported by studies showing inhibition of bone turnover with bisphosphonates reduced the risk of recurrence of GCT [7, 9, 17, 48]....

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Journal ArticleDOI
TL;DR: Osteonecrosis of the jaws incidence correlation with BP potency suggests that inhibition of osteoclast function and differentiation might be a key factor in the pathophysiology of the disease.

242 citations

References
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Journal ArticleDOI
TL;DR: Of the fifty-one local recurrences that were seen after treatment at the Istituto Rizzoli, 90 per cent appeared in the first three years after surgery, and these results did not correlate with the radiographic grade of the lesion.
Abstract: Of 327 patients who had a giant-cell tumor of bone and were seen at the Istituto Rizzoli, 293 were treated at the Institute, and 280 of these were followed for two to forty-four years. The distribution according to sex and age of the patient and site of the tumor was similar to the distributions in major reports of large series. The tumor usually involved the metaphysis and the epiphysis, but was occasionally limited to the metaphysis, and in only 2 per cent of the patients was it adjacent to an open growth plate. The tumor on occasion invaded the articular space, also involving the ligaments and the synovial membrane. Extension to an adjacent bone through the joint occurred in 5 per cent of the tumors. Our radiographic grading, which is roughly comparable with the staging system of Enneking et al., was Grade I in 4 per cent, II in 74 per cent, and III in 22 per cent of 266 patients before treatment. A pathological fracture was apparent on the first radiograph in 9 per cent of the patients. In the 280 patients with adequate follow-up, 331 surgical procedures were performed. The rate of local recurrence was 27 per cent in the 151 intralesional procedures, 8 per cent in the 122 marginal excisions, and zero in the fifty-eight wide or radical procedures. These results did not correlate with the radiographic grade of the lesion. Of the fifty-one local recurrences that were seen after treatment at our institution, 90 per cent appeared in the first three years after surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

1,255 citations

Journal Article
TL;DR: Zoledronic acid (4 mg) via 15-minute intravenous infusion was as effective and well tolerated as 90 mg of pamidronate in the treatment of osteolytic and mixed bone metastases/lesions in patients with advanced breast cancer or multiple myeloma.
Abstract: PURPOSE Zoledronic acid, a new and more potent bisphosphonate, was compared with pamidronate, the current standard treatment for patients with osteolytic or mixed bone metastases/lesions. PATIENTS AND METHODS A total of 1,648 patients with either Durie-Salmon stage III multiple myeloma or advanced breast cancer and at least one bone lesion were randomly assigned to treatment with either 4 or 8 mg of zoledronic acid via 15-minute intravenous infusion or 90 mg of pamidronate via 2-hour intravenous infusion every 3 to 4 weeks for 12 months. The primary efficacy endpoint was the proportion of patients experiencing at least one skeletal-related event over 13 months. RESULTS The proportion of patients with at least one skeletal-related event was similar in all treatment groups. Median time to the first skeletal-related eventwas approximately 1 year in each treatment group. The skeletal morbidity rate was slightly lower in patients treated with zoledronic acid than in those treated with pamidronate, and zoledronic acid (4 mg) significantly decreased the incidence and event rate for radiation therapy to bone, both overall and in breast cancer patients receiving hormonal therapy. Pain scores decreased in all treatment groups in the presence of stable or decreased analgesic use. Zoledronic acid (4 mg) and pamidronate were equally well tolerated; the most common adverse events were bone pain, nausea, fatigue, and fever and < 5% of serious adverse events were related to the study drug. The incidence of renal impairment among patients treated with 4 mg of zoledronic acid via 15-minute infusion was similar to that among patients treated with pamidronate. CONCLUSIONS Zoledronic acid (4 mg) via 15-minute intravenous infusion was as effective and well tolerated as 90 mg of pamidronate in the treatment of osteolytic and mixed bone metastases/lesions in patients with advanced breast cancer or multiple myeloma. (Can-

891 citations


"Bisphosphonates reduce local recurr..." refers background in this paper

  • ...Given the encouraging response of anti-osteoclastic agents such as bisphosphonates in the management of osteolytic metastatic bone disease [12–14], their use to mitigate bone destruction and prevent local recurrence in yet another osteolytic neoplasm (GCT) seems to be a novel but a rational concept....

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Journal ArticleDOI
01 Mar 2000-Cancer
TL;DR: Pamidronate therapy has been shown to reduce skeletal complications effectively for up to 12 months in breast carcinoma patients with bone metastases as discussed by the authors, and the results of two randomized, multicenter, randomized, double-blind, placebo-controlled intervention trials conducted at academic and community oncology centers were combined to provide a large data set with which to evaluate the long term efficacy and safety of pamidroneate therapy.
Abstract: BACKGROUND Pamidronate therapy previously has been shown to reduce skeletal complications effectively for up to 12 months in breast carcinoma patients with bone metastases. The current study data provide further follow-up results regarding the effects of long term (up to 24 months) pamidronate treatment in women with breast carcinoma and osteolytic metastases. METHODS Follow-up results from two prospective, multicenter, randomized, double-blind, placebo-controlled intervention trials conducted at academic and community oncology centers were combined to provide a large data set with which to evaluate the long term efficacy and safety of pamidronate therapy. Seven hundred fifty-four women with Stage IV breast carcinoma and osteolytic metastases were randomized to the 2 treatment arms of the trial. Three patients were excluded from the intent-to-treat population for the analysis. A total of 751 evaluable patients were randomized to receive either a 90-mg intravenous pamidronate infusion (367 patients) or a placebo infusion (384 patients) every 3–4 weeks. The primary outcome measures were skeletal morbidity rate (events/year), proportion of patients developing a skeletal complication, and time to first skeletal complication. RESULTS Of the 367 women receiving pamidronate, 115 (31.3%) completed the trial and 81 (22.1%) discontinued the study due to adverse events. Of the 384 women who received placebo, 100 (26.0%) completed the study and 76 (19.8%) discontinued the study due to adverse events. The skeletal morbidity rate was 2.4 in the pamidronate group and 3.7 in the placebo group (P < 0.001). In the pamidronate group, 186 of the 367 patients (51%) had skeletal complications compared with 246 of the 384 patients in the placebo group (64%) (P < 0.001). The median time to first skeletal complication was 12.7 months in the pamidronate group and 7 months in the placebo group (P < 0.001). Six patients treated with pamidronate discontinued treatment due to drug-related adverse events. Pain and analgesic scores were significantly worse in the placebo group compared with those patients in the pamidronate group. CONCLUSIONS In the current study, monthly infusions of 90 mg of pamidronate as a supplement to antineoplastic therapy were found to be well tolerated and superior to antineoplastic therapy alone in preventing skeletal complications and palliating symptoms for at least 24 months in breast carcinoma patients with osteolytic bone metastases. Cancer 2000;88:1082–90. © 2000 American Cancer Society.

660 citations

Journal ArticleDOI
TL;DR: The nine-year experience with sixty patients who had had a giant-cell tumor of a long bone was reviewed to determine the rate of recurrence after treatment with curettage and packing with polymethylmethacrylate cement.
Abstract: The nine-year experience with sixty patients who had had a giant-cell tumor of a long bone was reviewed to determine the rate of recurrence after treatment with curettage and packing with polymethylmethacrylate cement. The demographic characteristics, including the age and sex of the patient and the site of the tumor, were similar to those that have been reported for other large series. An average of four years (range, two to ten years) after the operation, the over-all rate of initial local recurrence was 25 per cent (fifteen of sixty patients). Patients who had had a tumor of the distal aspect of the radius had a higher rate of recurrence (five of ten) than those who had had a tumor of the proximal aspect of the tibia (seven [28 per cent] of twenty-five) or of the distal part of the femur (three [13 per cent] of twenty-three). Higher rates of recurrence were also noted for patients who had had a pathological fracture (three of six), those who had had a Stage-III tumor according to the classification of Campanacci et al. (six of sixteen), and those who had not had adjuvant treatment with either a high-speed burr or phenol (eight of nineteen). Patients who had had an initial recurrence after packing with cement had a low rate of secondary recurrence when the initial recurrence had been treated with a wide resection or a second intralesional procedure (zero of ten and one of five patients, respectively), after an average of three years (range, ten months to eight years). No patient had a multicentric tumor or metastasis.(ABSTRACT TRUNCATED AT 250 WORDS)

406 citations

Journal ArticleDOI
H W Sung, D P Kuo, W P Shu, Y B Chai, C C Liu, S M Li 
TL;DR: This work proposes excision and curettage with bone-grafting as the most suitable method of treatment in the majority of patients with giant-cell tumor of bone.
Abstract: Giant-cell tumor of bone seems to occur more frequently in Chinese people than in those residing in Western countries. The estimated incidence is about 20 per cent of all primary tumors of bone. Of 208 surgically treated and pathologically proved giant-cell tumors, 194 were benign. We excluded patients with primary or secondary amputation unrelated to recurrence and those followed for less than two years or lost to follow-up. Of the remaining 111 patients who were followed for more than two years, twenty-nine had a recurrence, giving a recurrence rate of 26.1 per cent. The rate of recurrence was highest following curettage and bone-grafting (41.2 per cent) and was much lower in patients who were treated by resection and fusion (7.1 per cent). Since resection of this tumor with reconstructive procedures, either by massive homogenous bone-grafting or artificial joint replacement, is complicated and might cripple the patient if it fails, we propose excision and curettage with bone-grafting as the most suitable method of treatment in the majority of patients with giant-cell tumor of bone.

385 citations


"Bisphosphonates reduce local recurr..." refers background in this paper

  • ...It is a common neoplasm in Chinese patients, constituting 20% of all benign bone tumors [1], and tends to occur in young adults adjacent to the joint surface, commonly around the knee, shoulder and wrist [2]....

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  • ...5 to 45% with the majority in the 25 to 35% [1]....

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  • ...It is usually treated by local curettage and sometimes wide excision yet it tends to recur locally in 10 to 50% of patients as reported in some clinical series [1]....

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