Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study

Thomas, David M.; Henshaw, Robert M.; Skubitz, Keith M.; Chawla, Sant P.; Staddon, Arthur P.; Blay, Jean‐Yves; Roudier, Martine P.; Smith, Judy; Ye, Zhishen; Sohn, Winnie; Dansey, Roger; Jun, Susie

doi:10.1016/s1470-2045(10)70010-3

Cited by 637 publications

(556 citation statements)

References 23 publications

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“…However, the safety of denosumab and adverse events with higher doses (beginning with a 360-mg dose and then 120-mg monthly every 28 days), as used in treating patients with giant cell tumor of bone, has not been well defined. The effectiveness of denosumab regarding disease and symptom control in patients with an unresectable or recurrent giant cell tumor of bone has been seen, without severe adverse effects [22]; however, Thomas et al [22] reported, in a Phase 2 study, that the reason for two of their four patients discontinuing the denosumab regimen before completion of planned treatment was because of disease progression of a malignant giant cell tumor of bone. Additionally although five patients had serious adverse events, none were deemed to be treatmentrelated.…”

Section: Discussionmentioning

confidence: 99%

“…Owing to the local aggressiveness of the tumor and the belief that a radical resection was not feasible, in May 2013 we decided to initiate treatment with denosumab as an adjuvant to avoid future recurrences. The administration began with a 360 mg subcutaneous dose, then 120 mg subcutaneously monthly (every 28 days) according to current FDA-approved protocol [22]. By October 2013, we observed clearly demarcated osteosclerosis of the recurrent mass located in the popliteal region (Fig.…”

Section: Case Reportmentioning

confidence: 94%

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A High-grade Sarcoma Arising in a Patient With Recurrent Benign Giant Cell Tumor of the Proximal Tibia While Receiving Treatment With Denosumab

Aponte-Tinao

Piuzzi

Roitman

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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Background A giant cell tumor of bone is a primary benign but locally aggressive neoplasm. Malignant transformation in a histologically typical giant cell tumor of bone, without radiotherapy exposure, is an uncommon event, occurring in less than 1% of giant cell tumors of bone. Although surgery is the standard initial treatment, denosumab, a monoclonal antibody drug that inhibits receptor activator of nuclear factor-jB ligand (RANKL), has shown considerable activity regarding disease and control of symptoms in patients with recurrence, unresectable, and metastatic giant cell tumors of bone. Case Description We report the case of a 20-year-old woman with a recurrent benign, giant cell tumor of bone, who had a bone sarcoma develop while receiving denosumab treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Case Reportmentioning

confidence: 94%

A High-grade Sarcoma Arising in a Patient With Recurrent Benign Giant Cell Tumor of the Proximal Tibia While Receiving Treatment With Denosumab

Aponte-Tinao

Piuzzi

Roitman

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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“…Denosumab has been used with excellent results in the treatment of osteoporosis, skeletal metastases, and GCTs [8,15,18]. Concerns about patient safety with denosumab have also been answered by studies evaluating its side effects [17].…”

Section: Discussionmentioning

confidence: 99%

“…RANKL inhibition blocks osteoclast maturation and function [16], and denosumab has been successfully used in the treatment of osteoporosis [15] and skeletal metastases [8], and more recently in GCT therapy as well [18]. The satisfactory results with denosumab in the treatment of GCTs and the clear immunohistochemical similarity and relationship between GCTs and ABCs [19] justify the hypothesis that denosumab may also have positive effects on ABCs.…”

Section: Introductionmentioning

confidence: 99%

Denosumab: a potential new and innovative treatment option for aneurysmal bone cysts

et al. 2013

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Introduction Aneurysmal bone cysts (ABCs) are expansive and destructive lesions positive for osteoclast markers, resembling benign giant cell tumors (GCTs). Treatment options include surgical resection, curettage and cavity filling, embolization, injection of fibrosing agents, or radiotherapy. Particularly in children and adolescents with spinal ABCs, these options may be unsatisfactory, and innovative forms of treatment are needed. Denosumab is a human monoclonal antibody that inhibits osteoclast function by blocking the cytokine receptor activator of the nuclear factor-kappa B ligand. Satisfactory results with denosumab in treating GCTs and immunohistochemical similarities suggest that it may also have positive effects on ABCs. Methods and ResultsThis report is the first description of the therapeutic use of denosumab in two patients with spinal ABCs. Two boys (aged 8 and 11) had recurrent ABCs at C5 after surgery with intralesional tumor resection. Treatment options were discussed by the interdisciplinary tumor board. Arterial embolization was attempted, but failed due to an absence of appropriate afferent arteries. After the families had received extensive information and provided written consent, denosumab therapy was initiated as an individualized treatment, despite the absence as yet of scientific evidence. After the start of denosumab therapy, both patients recovered from pain and neurologic symptoms significantly and are now in a healthy condition with no severe side effects. Magnetic resonance imaging check-ups after 2 or 4 months of denosumab treatment, respectively, showed tumor regression in both patients. Discussion Longer follow-up and clinical studies are warranted to establish the value of denosumab in the treatment of ABCs.

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“…25 Our findings suggest that pharmacological inhibitors of osteoclast formation and activity may be useful in the treatment of ABC. It is possible that bisphosphonates and the anti-RANKL antibody denosumab, both of which have been used to treat GCTB, 26,27 may also be useful in inhibiting osteoclast formation and osteolysis in ABC. …”

Section: Discussionmentioning

confidence: 99%

CD14− mononuclear stromal cells support (CD14+) monocyte–osteoclast differentiation in aneurysmal bone cyst

Taylor

Kashima

Hemingway

et al. 2012

Laboratory Investigation

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Aneurysmal bone cyst (ABC) is a benign osteolytic bone lesion in which there are blood-filled spaces separated by fibrous septa containing giant cells. The nature of the giant cells in this lesion and the mechanism of bone destruction in ABC is not certain. In this study, we have analysed several characteristics of mononuclear and multinucleated cells in the ABC and examined the cellular and molecular mechanisms of ABC osteolysis. The antigenic and functional phenotype of giant cells in ABC was determined by histochemistry/immunohistochemistry using antibodies to macrophage and osteoclast markers. Giant cells and CD14 þ and CD14À mononuclear cells were isolated from ABC specimens and cultured on dentine slices and coverslips with receptor activator of nuclear factor kB ligand (RANKL) þ /À macrophage-colony stimulating factor (M-CSF) and functional and cytochemical evidence of osteoclast differentiation sought. Giant cells in ABC expressed an osteoclast-like phenotype (CD51 þ , CD14À, cathepsin K þ , TRAP þ ) and were capable of lacunar resorption, which was inhibited by zoledronate, calcitonin and osteoprotegerin (OPG). When cultured with RANKL ± M-CSF, CD14 þ , but not CD14À, mononuclear cells differentiated into TRAP þ multinucleated cells that were capable of lacunar resorption. M-CSF was not necessary for osteoclast formation from CD14 þ cell cultures. CD14À cells variably expressed RANKL, OPG and M-CSF but supported osteoclast differentiation. Our findings show that the giant cells in ABC express an osteoclast-like phenotype and are formed from CD14 þ macrophage precursors. CD14À mononuclear stromal cells express osteoclastogenic factors and most likely interact with CD14 þ cells to form osteoclast-like giant cells by a RANKL-dependent mechanism.Laboratory Investigation (2012) 92, 600-605; doi:10.1038/labinvest.2012.5; published online 13 February 2012 KEYWORDS: aneurysmal bone cyst (ABC); bisophosphonate; bone resorption; giant cell; osteoclast Benign and malignant tumours that contain numerous osteoclast-like giant cells frequently arise in bone and are categorised on the basis of tissue location and histomorphology. 1,2 The mechanism whereby giant cells accumulate and contribute to the osteolysis that accompanies growth of these tumours in bone is not certain. Primary aneurysmal bone cyst (ABC) is a benign cystic giant cell-rich tumour that arises most commonly in the metaphyseal region of a long bone; 1,2 the cysts are filled with blood and the fibrous cyst wall contains fibroblast-like stromal cells, scattered macrophages and osteoclast-like giant cells. The lesion most commonly arises in the first two decades of life and is a clonal proliferation associated with a characteristic rearrangement of the short arm of chromosome 17. [3][4][5] Osteoclasts are formed from marrow-derived circulating precursors, which express a monocyte/macrophage phenotype. 6,7 These mononuclear phagocyte precursors express the receptor activator of nuclear factor kB (RANK) and, in the presence of macrophage-colony stimulating...

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Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study

Cited by 637 publications

References 23 publications

A High-grade Sarcoma Arising in a Patient With Recurrent Benign Giant Cell Tumor of the Proximal Tibia While Receiving Treatment With Denosumab

A High-grade Sarcoma Arising in a Patient With Recurrent Benign Giant Cell Tumor of the Proximal Tibia While Receiving Treatment With Denosumab

Denosumab: a potential new and innovative treatment option for aneurysmal bone cysts

CD14− mononuclear stromal cells support (CD14+) monocyte–osteoclast differentiation in aneurysmal bone cyst

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