Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Pathology & Oncology Research
Published in: Pathology & Oncology Research 1/2019

01-01-2019 | Original Article

In Vitro Study of the Effects of Denosumab on Giant Cell Tumor of Bone: Comparison with Zoledronic Acid

Authors: Isao Shibuya, Masamichi Takami, Arei Miyamoto, Akiko Karakawa, Akira Dezawa, Shigeru Nakamura, Ryutaro Kamijo

Published in: Pathology & Oncology Research | Issue 1/2019

Login to get access

Abstract

Giant cell tumor of bone (GCTB) is a locally aggressive primary bone tumor that contains numerous osteoclasts formed from marrow-derived precursors through receptor activator of nuclear factor κ-B ligand (RANKL), an osteoclast differentiation factor expressed in neoplastic cells of GCTB. Denosumab, a fully human monoclonal antibody targeting RANKL, has recently been used for the treatment of GCTB, and superior treatment effects have been reported. The aim of this work was to elucidate the mechanism of action of denosumab, and the differences between denosumab and zoledronic acid at the level of GCTB cells. We isolated GCTB cells from 3 patients and separated them into osteoclasts, osteoclast precursors and proliferating spindle-shaped stromal cells (the true neoplastic component), and examined the action of denosumab on differentiation, survival and bone resorption activity of osteoclasts. Denosumab and zoledronic acid inhibited osteoclast differentiation from mononuclear cells containing osteoclast precursors. Zoledronic acid inhibited osteoclast survival, whereas an inhibitory effect of denosumab on osteoclast survival was not observed. The inhibitory effect on bone resorption by both agents was confirmed in culture on dentin slices. Furthermore, zoledronic acid showed dose-dependent inhibition of cell growth of neoplastic cells whereas denosumab had no inhibitory effect on these cells. Denosumab has an inhibitory effect on osteoclast differentiation, but no inhibitory effects on survival of osteoclasts or growth of neoplastic cells in GCTBs.
Literature
1.
Wulling M, Engels C, Jesse N et al (2001) The nature of giant cell tumor of bone. J Cancer Res Clin Oncol 127:467–474CrossRefPubMed
2.
Stewart MJ, Richardson TR (1952) Giant cell tumor of bone. J Bone Joint Surg (Am Vol) 34-A:272–286
3.
Raskin KA, Schwab JH, Mankin HJ et al (2013) Giant cell tumor of bone. J Am Acad Orthop Surg 21:118–126CrossRefPubMed
4.
Chambers TJ, Fuller K, McSheehy PM et al (1985) The effects of calcium regulating hormones on bone resorption by isolated human osteoclastoma cells. J Pathol 145:297–305CrossRefPubMed
5.
Kanehisa J, Izumo T, Takeuchi M et al (1991) In vitro bone resorption by isolated multinucleated giant cells from giant cell tumour of bone: light and electron microscopic study. Virchows Arch A Pathol Anat Histopathol 419:327–338CrossRefPubMed
6.
Drake FH, Dodds RA, James IE et al (1996) Cathepsin K, but not cathepsins B, L, or S, is abundantly expressed in human osteoclasts. J Biol Chem 271:12511–12516CrossRefPubMed
7.
Huang L, Xu J, Wood DJ et al (2000) Gene expression of osteoprotegerin ligand, osteoprotegerin, and receptor activator of NF-kappaB in giant cell tumor of bone: possible involvement in tumor cell-induced osteoclast-like cell formation. Am J Pathol 156:761–767CrossRefPubMedPubMedCentral
8.
Joyner CJ, Quinn JM, Triffitt JT et al (1992) Phenotypic characterisation of mononuclear and multinucleated cells of giant cell tumour of bone. Bone Miner 16:37–48CrossRefPubMed
9.
Lau YS, Sabokbar A, Gibbons CL et al (2005) Phenotypic and molecular studies of giant-cell tumors of bone and soft tissue. Hum Pathol 36:945–954CrossRefPubMed
10.
Campanacci M, Baldini N, Boriani S et al (1987) Giant-cell tumor of bone. J Bone Joint Surg Am 69:106–114CrossRefPubMed
11.
Arbeitsgemeinschaft K, Becker WT, Dohle J et al (2008) Local recurrence of giant cell tumor of bone after intralesional treatment with and without adjuvant therapy. J Bone Joint Surg Am 90:1060–1067CrossRef
12.
Mori Y, Tsuchiya H, Karita M et al (2000) Malignant transformation of a giant cell tumor 25 years after initial treatment. Clin Orthop Relat Res 381:185–191CrossRef
13.
Rock MG, Sim FH, Unni KK et al (1986) Secondary malignant giant-cell tumor of bone. Clinicopathological assessment of nineteen patients. J Bone Joint Surg Am 68:1073–1079CrossRefPubMed
14.
Nascimento AG, Huvos AG, Marcove RC (1979) Primary malignant giant cell tumor of bone: a study of eight cases and review of the literature. Cancer 44:1393–1402CrossRefPubMed
15.
Bertoni F, Present D, Sudanese A et al (1988) Giant-cell tumor of bone with pulmonary metastases. Six case reports and a review of the literature. Clin Orthop Relat Res 237:275–285
16.
Kay RM, Eckardt JJ, Seeger LL et al (1994) Pulmonary metastasis of benign giant cell tumor of bone. Six histologically confirmed cases, including one of spontaneous regression. Clin Orthop Relat Res 302:219–230
17.
Nakashima T, Hayashi M, Takayanagi H (2012) New insights into osteoclastogenic signaling mechanisms. Trends Endocrinol Metab 23:582–590CrossRefPubMed
18.
Suda T, Takahashi N, Udagawa N et al (1999) Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev 20:345–357CrossRefPubMed
19.
Blair HC, Athanasou NA (2004) Recent advances in osteoclast biology and pathological bone resorption. Histol Histopathol 19:189–199PubMed
20.
Shiotani A, Takami M, Itoh K et al (2002) Regulation of osteoclast differentiation and function by receptor activator of NFkB ligand and osteoprotegerin. Anat Rec 268:137–146CrossRefPubMed
21.
Blackley HR, Wunder JS, Davis AM et al (1999) Treatment of giant-cell tumors of long bones with curettage and bone-grafting. J Bone Joint Surg Am 81:811–820CrossRefPubMed
22.
XC Y, Xu M, Song RX et al (2010) Long-term outcome of giant cell tumors of bone around the knee treated by en bloc resection of tumor and reconstruction with prosthesis. Orthop Surg 2:211–217CrossRef
23.
Puthoor DK, Puthezhath K (2012) Management of giant cell tumor of bone: computerized tomography based selection strategy and approaching the lesion through the site of cortical break. Orthop Surg 4:76–82CrossRefPubMed
24.
Singh AS, Chawla NS, Chawla SP (2015) Giant-cell tumor of bone: treatment options and role of denosumab. Biologics 9:69–74PubMedPubMedCentral
25.
Tse LF, Wong KC, Kumta SM et al (2008) Bisphosphonates reduce local recurrence in extremity giant cell tumor of bone: a case-control study. Bone 42:68–73CrossRefPubMed
26.
Balke M, Campanacci L, Gebert C et al (2010) Bisphosphonate treatment of aggressive primary, recurrent and metastatic Giant cell tumour of bone. BMC Cancer 10:462CrossRefPubMedPubMedCentral
27.
Yang T, Zheng XF, Lin X et al (2013) Postoperative irrigation with bisphosphonates may reduce the recurrence of giant cell tumor of bone. Med Hypotheses 81:851–852CrossRefPubMed
28.
Gouin F, Rochwerger AR, Di Marco A et al (2014) Adjuvant treatment with zoledronic acid after extensive curettage for giant cell tumours of bone. Eur J Cancer 50:2425–2431CrossRefPubMed
29.
Bekker PJ, Holloway DL, Rasmussen AS et al (2004) A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res 19:1059–1066CrossRefPubMed
30.
Lacey DL, Boyle WJ, Simonet WS et al (2012) Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab. Nat Rev Drug Discov 11:401–419CrossRefPubMed
31.
Thomas D, Henshaw R, Skubitz K et al (2010) Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study. Lancet Oncol 11:275–280CrossRefPubMed
32.
Lewiecki EM (2010) Clinical use of denosumab for the treatment for postmenopausal osteoporosis. Curr Med Res Opin 26:2807–2812CrossRefPubMed
33.
Morgan T, Atkins GJ, Trivett MK et al (2005) Molecular profiling of giant cell tumor of bone and the osteoclastic localization of ligand for receptor activator of nuclear factor kappaB. Am J Pathol 167:117–128CrossRefPubMedPubMedCentral
34.
Roux S, Amazit L, Meduri G et al (2002) RANK (receptor activator of nuclear factor kappa B) and RANK ligand are expressed in giant cell tumors of bone. Am J Clin Pathol 117:210–216CrossRefPubMed
35.
36.
Hakozaki M, Tajino T, Yamada H et al (2014) Radiological and pathological characteristics of giant cell tumor of bone treated with denosumab. Diagn Pathol 9:111CrossRefPubMedPubMedCentral
37.
Yamagishi T, Kawashima H, Ogose A et al (2016) Disappearance of giant cells and presence of newly formed bone in the pulmonary metastasis of a sacral giant-cell tumor following denosumab treatment: a case report. Oncol Lett 11:243–246CrossRefPubMed
38.
van Beek E, Pieterman E, Cohen L et al (1999) Farnesyl pyrophosphate synthase is the molecular target of nitrogen-containing bisphosphonates. Biochem Biophys Res Commun 264:108–111CrossRefPubMed
39.
Martin M, Bell R, Bourgeois H et al (2012) Bone-related complications and quality of life in advanced breast cancer: results from a randomized phase III trial of denosumab versus zoledronic acid. Clin Cancer Res 18:4841–4849CrossRefPubMed
40.
Lipton A, Fizazi K, Stopeck AT et al (2012) Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer 48:3082–3092CrossRefPubMed
41.
Scagliotti GV, Hirsh V, Siena S et al (2012) Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study. J Thorac Oncol 7:1823–1829CrossRefPubMed
42.
Branstetter DG, Nelson SD, Manivel JC et al (2012) Denosumab induces tumor reduction and bone formation in patients with giant-cell tumor of bone. Clin Cancer Res 18:4415–4424CrossRefPubMed
43.
Cheng YY, Huang L, Lee KM et al (2004) Bisphosphonates induce apoptosis of stromal tumor cells in giant cell tumor of bone. Calcif Tissue Int 75:71–77CrossRefPubMed
44.
Nishisho T, Hanaoka N, Miyagi R et al (2015) Local administration of zoledronic acid for giant cell tumor of bone. Orthopedics 38:e25–e30CrossRefPubMed
45.
46.
Avnet S, Salerno M, Zini N et al (2013) Sustained autocrine induction and impaired negative feedback of osteoclastogenesis in CD14(+) cells of giant cell tumor of bone. Am J Pathol 182:1357–1366CrossRefPubMed
47.
Takami M, Takahashi N, Udagawa N et al (2000) Intracellular calcium and protein kinase C mediate expression of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin in osteoblasts. Endocrinology 141:4711–4719CrossRefPubMed
48.
Agarwal A, Larsen BT, Buadu LD et al (2013) Denosumab chemotherapy for recurrent giant-cell tumor of bone: a case report of neoadjuvant use enabling complete surgical resection. Case Rep Oncol Med 2013:496351PubMedPubMedCentral
49.
Akaike K, Suehara Y, Takagi T et al (2014) An eggshell-like mineralized recurrent lesion in the popliteal region after treatment of giant cell tumor of the bone with denosumab. Skelet Radiol 43:1767–1772CrossRef
50.
Mattei TA, Ramos E, Rehman AA et al (2014) Sustained long-term complete regression of a giant cell tumor of the spine after treatment with denosumab. Spine J 14:e15–e21CrossRefPubMed
51.
Atkins J, Kostakis P, Vincent C et al (2006) RANK expression as a cell surface marker of human osteoclast precursors in peripheral blood, bone marrow, and giant cell tumors of bone. J Bone Miner Res 21:1339–1349CrossRefPubMed
52.
Liverani C, Mercatali L, Spadazzi C et al (2014) CSF-1 blockade impairs breast cancer osteoclastogenic potential in co-culture systems. Bone 66:214–222CrossRefPubMed
53.
Cheng YY, Huang L, Kumta SM et al (2003) Cytochemical and ultrastructural changes in the osteoclast-like giant cells of giant cell tumor of bone following bisphosphonate administration. Ultrastruct Pathol 27:385–391CrossRefPubMed
54.
Lau CP, Huang L, Wong KC et al (2013) Comparison of the anti-tumor effects of denosumab and zoledronic acid on the neopastic cells of giant cell tumor of bone. Connect Tissue Res 54:439–449CrossRefPubMed
55.
Ueda T, Morioka H, Nishida Y et al (2015) Objective tumor response to denosumab in patients with giant cell tumor of bone: a multicenter phase II trial. Ann Oncol 26:2149–2154CrossRefPubMedPubMedCentral
56.
Akiyama T, Choong PF, Dass CR (2010) RANK-fc inhibits malignancy via inhibiting ERK activation and evoking caspase-3-mediated anoikis in human osteosarcoma cells. Clin Exp Metastasis 27:207–215CrossRefPubMed
57.
James IE, Dodds RA, Olivera DL et al (1996) Human osteoclastoma-derived stromal cells: correlation of the ability to form mineralized nodules in vitro with formation of bone in vivo. J Bone Miner Res 11:1453–1460CrossRefPubMed
58.
Murata A, Fujita T, Kawahara N et al (2005) Osteoblast lineage properties in giant cell tumors of bone. J Orthop Sci 10:581–588CrossRefPubMed
Metadata
Title
In Vitro Study of the Effects of Denosumab on Giant Cell Tumor of Bone: Comparison with Zoledronic Acid
Authors
Isao Shibuya
Masamichi Takami
Arei Miyamoto
Akiko Karakawa
Akira Dezawa
Shigeru Nakamura
Ryutaro Kamijo
Publication date
01-01-2019
Publisher
Springer Netherlands
Published in
Pathology & Oncology Research / Issue 1/2019
Print ISSN: 1219-4956
Electronic ISSN: 1532-2807
DOI
https://doi.org/10.1007/s12253-017-0362-8

Other articles of this Issue 1/2019

Pathology & Oncology Research 1/2019 Go to the issue

Original Article

Efficacy of Iodine-125 Seed Implantation in Locoregionally Recurrent and Unresectable Breast Cancer: a Retrospective Study

Original Article

Suppression of Angiotensin-(1–7) on the Disruption of Blood-Brain Barrier in Rat of Brain Glioma

Original Article

Development of Response Classifier for Vascular Endothelial Growth Factor Receptor (VEGFR)-Tyrosine Kinase Inhibitor (TKI) in Metastatic Renal Cell Carcinoma

Original Article

Cancer-Specific Survival Stratification Derived from Tumor Expression of Tissue Inhibitor of Metalloproteinase-2 in Non-Metastatic Renal Cell Carcinoma

Original Article

The Results of Stricter Inclusion Criteria in an Immunomagnetic Detection Study of Micrometastatic Cells in Bone Marrow of Uveal Melanoma Patients - Relevance for Dormancy

Original Article

RETRACTED ARTICLE: Effects of microRNA-708 on Epithelial-Mesenchymal Transition, Cell Proliferation and Apoptosis in Melanoma Cells by Targeting LEF1 through the Wnt Signaling Pathway
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits