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Erschienen in: Current Osteoporosis Reports 2/2021

22.02.2021 | Pediatrics (C Munns and F Rauch, Section Editors)

Denosumab Treatment for Giant Cell Tumors, Aneurysmal Bone Cysts, and Fibrous Dysplasia—Risks and Benefits

verfasst von: Kristen S. Pan, Alison M. Boyce

Erschienen in: Current Osteoporosis Reports | Ausgabe 2/2021

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Abstract

Purpose of Review

This review summarizes current understanding of the role of denosumab, an inhibitor of receptor activator of nuclear kappa-B ligand (RANKL), in the management of 3 skeletal neoplasms: giant cell tumors, aneurysmal bone cysts, and fibrous dysplasia.

Recent Findings

A growing body of literature supports denosumab use in giant cell tumors, a neoplasm in which RANKL plays a clear pathogenic role. Comparatively less data is available in aneurysmal bone cysts and fibrous dysplasia; however, the pathogenic similarity of these disorders to giant cell tumors, as well as encouraging preliminary data, suggests denosumab may be useful. Denosumab’s inhibitory effects on bone turnover are fully reversible after drug discontinuation. This raises important unanswered questions for clinical management, including potential risks of tumor recurrence and bone turnover rebound.

Summary

Denosumab is a promising potential treatment for skeletal neoplasms. However, its clinical use is impacted by ongoing safety concerns related to postdiscontinuation rebound, particularly in children. There is a critical need to understand denosumab treatment and discontinuation effects on tumor recurrence and to develop strategies for long-term treatment in patients who cannot be managed surgically.
Literatur
1.
2.
Zurück zum Zitat Rauch F. Bone accrual in children: adding substance to surfaces. Pediatrics. 2007;119(Suppl 2):S137–40.PubMedCrossRef Rauch F. Bone accrual in children: adding substance to surfaces. Pediatrics. 2007;119(Suppl 2):S137–40.PubMedCrossRef
3.
Zurück zum Zitat Hsu H, Lacey DL, Dunstan CR, Solovyev I, Colombero A, Timms E, et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci U S A. 1999;96(7):3540–5.PubMedPubMedCentralCrossRef Hsu H, Lacey DL, Dunstan CR, Solovyev I, Colombero A, Timms E, et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci U S A. 1999;96(7):3540–5.PubMedPubMedCentralCrossRef
4.
Zurück zum Zitat Ikeda T, Kasai M, Utsuyama M, Hirokawa K. Determination of three isoforms of the receptor activator of nuclear factor-kappaB ligand and their differential expression in bone and thymus. Endocrinology. 2001;142(4):1419–26.PubMedCrossRef Ikeda T, Kasai M, Utsuyama M, Hirokawa K. Determination of three isoforms of the receptor activator of nuclear factor-kappaB ligand and their differential expression in bone and thymus. Endocrinology. 2001;142(4):1419–26.PubMedCrossRef
5.
Zurück zum Zitat Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Lüthy R, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997;89(2):309–19.PubMedCrossRef Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Lüthy R, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997;89(2):309–19.PubMedCrossRef
6.
Zurück zum Zitat Dougall WC, Chaisson M. The RANK/RANKL/OPG triad in cancer-induced bone diseases. Cancer Metastasis Rev. 2006;25(4):541–9.PubMedCrossRef Dougall WC, Chaisson M. The RANK/RANKL/OPG triad in cancer-induced bone diseases. Cancer Metastasis Rev. 2006;25(4):541–9.PubMedCrossRef
7.
Zurück zum Zitat Xgeva (denosumab) [package insert]. Thousand Oaks: Amgen, Inc; 2010. Xgeva (denosumab) [package insert]. Thousand Oaks: Amgen, Inc; 2010.
8.
Zurück zum Zitat Prolia (denosumab) [package insert]. Thousand Oaks: Amgen, Inc; 2010. Prolia (denosumab) [package insert]. Thousand Oaks: Amgen, Inc; 2010.
9.
Zurück zum Zitat Sutjandra L, Rodriguez RD, Doshi S, Ma M, Peterson MC, Jang GR, et al. Population pharmacokinetic meta-analysis of denosumab in healthy subjects and postmenopausal women with osteopenia or osteoporosis. Clin Pharmacokinet. 2011;50(12):793–807.PubMedCrossRef Sutjandra L, Rodriguez RD, Doshi S, Ma M, Peterson MC, Jang GR, et al. Population pharmacokinetic meta-analysis of denosumab in healthy subjects and postmenopausal women with osteopenia or osteoporosis. Clin Pharmacokinet. 2011;50(12):793–807.PubMedCrossRef
10.
Zurück zum Zitat Gibiansky L, Sutjandra L, Doshi S, Zheng J, Sohn W, Peterson MC, et al. Population pharmacokinetic analysis of denosumab in patients with bone metastases from solid tumours. Clin Pharmacokinet. 2012;51(4):247–60.PubMedCrossRef Gibiansky L, Sutjandra L, Doshi S, Zheng J, Sohn W, Peterson MC, et al. Population pharmacokinetic analysis of denosumab in patients with bone metastases from solid tumours. Clin Pharmacokinet. 2012;51(4):247–60.PubMedCrossRef
11.
Zurück zum Zitat • Cummings SR, San Martin J, MR MC, Siris ES, Eastell R, Reid IR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756–65 This seminal phase 3 controlled trial in patients with osteoporosis was the first to show a beneficial effect of denosumab on fracture rate.PubMedCrossRef • Cummings SR, San Martin J, MR MC, Siris ES, Eastell R, Reid IR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756–65 This seminal phase 3 controlled trial in patients with osteoporosis was the first to show a beneficial effect of denosumab on fracture rate.PubMedCrossRef
12.
Zurück zum Zitat Bone HG, Wagman RB, Brandi ML, Brown JP, Chapurlat R, Cummings SR, et al. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol. 2017;5(7):513–23.PubMedCrossRef Bone HG, Wagman RB, Brandi ML, Brown JP, Chapurlat R, Cummings SR, et al. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol. 2017;5(7):513–23.PubMedCrossRef
13.
Zurück zum Zitat Smith MR, Egerdie B, Hernández Toriz N, Feldman R, Tammela TL, Saad F, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009;361(8):745–55.PubMedPubMedCentralCrossRef Smith MR, Egerdie B, Hernández Toriz N, Feldman R, Tammela TL, Saad F, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009;361(8):745–55.PubMedPubMedCentralCrossRef
14.
Zurück zum Zitat Ellis GK, Bone HG, Chlebowski R, Paul D, Spadafora S, Smith J, et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol. 2008;26(30):4875–82.PubMedCrossRef Ellis GK, Bone HG, Chlebowski R, Paul D, Spadafora S, Smith J, et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol. 2008;26(30):4875–82.PubMedCrossRef
15.
Zurück zum Zitat Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010;28(35):5132–9.PubMedCrossRef Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010;28(35):5132–9.PubMedCrossRef
17.
Zurück zum Zitat Bone HG, Bolognese MA, Yuen CK, Kendler DL, Miller PD, Yang YC, et al. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J Clin Endocrinol Metab. 2011;96(4):972–80.PubMedCrossRef Bone HG, Bolognese MA, Yuen CK, Kendler DL, Miller PD, Yang YC, et al. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J Clin Endocrinol Metab. 2011;96(4):972–80.PubMedCrossRef
19.
Zurück zum Zitat Tsourdi E, Langdahl B, Cohen-Solal M, Aubry-Rozier B, Eriksen EF, Guañabens N, et al. Discontinuation of denosumab therapy for osteoporosis: a systematic review and position statement by ECTS. Bone. 2017;105:11–7.PubMedCrossRef Tsourdi E, Langdahl B, Cohen-Solal M, Aubry-Rozier B, Eriksen EF, Guañabens N, et al. Discontinuation of denosumab therapy for osteoporosis: a systematic review and position statement by ECTS. Bone. 2017;105:11–7.PubMedCrossRef
20.
Zurück zum Zitat Cummings SR, Ferrari S, Eastell R, Gilchrist N, Jensen JB, McClung M, et al. Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Miner Res. 2018;33(2):190–8.PubMedCrossRef Cummings SR, Ferrari S, Eastell R, Gilchrist N, Jensen JB, McClung M, et al. Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Miner Res. 2018;33(2):190–8.PubMedCrossRef
21.
Zurück zum Zitat Reid IR, Horne AM, Mihov B, Gamble GD. Bone loss after denosumab: only partial protection with Zoledronate. Calcif Tissue Int. 2017;101(4):371–4.PubMedCrossRef Reid IR, Horne AM, Mihov B, Gamble GD. Bone loss after denosumab: only partial protection with Zoledronate. Calcif Tissue Int. 2017;101(4):371–4.PubMedCrossRef
22.
Zurück zum Zitat •• Chawla S, Blay JY, Rutkowski P, Le Cesne A, Reichardt P, Gelderblom H, et al. Denosumab in patients with giant-cell tumour of bone: a multicentre, open-label, phase 2 study. Lancet Oncol. 2019;20(12):1719–29 This phase 2 study of denosumab treatment in GCT showed long-term disease control for patients with unresectable and resectable tumours. Results suggested an increased risk of recurrence after drug discontinuation.PubMedCrossRef •• Chawla S, Blay JY, Rutkowski P, Le Cesne A, Reichardt P, Gelderblom H, et al. Denosumab in patients with giant-cell tumour of bone: a multicentre, open-label, phase 2 study. Lancet Oncol. 2019;20(12):1719–29 This phase 2 study of denosumab treatment in GCT showed long-term disease control for patients with unresectable and resectable tumours. Results suggested an increased risk of recurrence after drug discontinuation.PubMedCrossRef
23.
Zurück zum Zitat Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377(9768):813–22.PubMedPubMedCentralCrossRef Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377(9768):813–22.PubMedPubMedCentralCrossRef
24.
Zurück zum Zitat Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. 2012;379(9810):39–46.PubMedCrossRef Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. 2012;379(9810):39–46.PubMedCrossRef
25.
Zurück zum Zitat Metwally T, Burke A, Tsai JY, Collins MT, Boyce AM. Fibrous dysplasia and medication-related osteonecrosis of the jaw. J Oral Maxillofac Surg. 2016;74(10):1983–99.PubMedPubMedCentralCrossRef Metwally T, Burke A, Tsai JY, Collins MT, Boyce AM. Fibrous dysplasia and medication-related osteonecrosis of the jaw. J Oral Maxillofac Surg. 2016;74(10):1983–99.PubMedPubMedCentralCrossRef
26.
Zurück zum Zitat Body JJ, Lipton A, Gralow J, Steger GG, Gao G, Yeh H, et al. Effects of denosumab in patients with bone metastases with and without previous bisphosphonate exposure. J Bone Miner Res. 2010;25(3):440–6.PubMedCrossRef Body JJ, Lipton A, Gralow J, Steger GG, Gao G, Yeh H, et al. Effects of denosumab in patients with bone metastases with and without previous bisphosphonate exposure. J Bone Miner Res. 2010;25(3):440–6.PubMedCrossRef
27.
Zurück zum Zitat Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999;397(6717):315–23.PubMedCrossRef Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999;397(6717):315–23.PubMedCrossRef
28.
Zurück zum Zitat Hoyer-Kuhn H, Franklin J, Allo G, Kron M, Netzer C, Eysel P, et al. Safety and efficacy of denosumab in children with osteogenesis imperfect—a first prospective trial. J Musculoskelet Neuronal Interact. 2016;16(1):24–32.PubMedPubMedCentral Hoyer-Kuhn H, Franklin J, Allo G, Kron M, Netzer C, Eysel P, et al. Safety and efficacy of denosumab in children with osteogenesis imperfect—a first prospective trial. J Musculoskelet Neuronal Interact. 2016;16(1):24–32.PubMedPubMedCentral
29.
Zurück zum Zitat Wang HD, Boyce AM, Tsai JY, Gafni RI, Farley FA, Kasa-Vubu JZ, et al. Effects of denosumab treatment and discontinuation on human growth plates. J Clin Endocrinol Metab. 2014;99(3):891–7.PubMedPubMedCentralCrossRef Wang HD, Boyce AM, Tsai JY, Gafni RI, Farley FA, Kasa-Vubu JZ, et al. Effects of denosumab treatment and discontinuation on human growth plates. J Clin Endocrinol Metab. 2014;99(3):891–7.PubMedPubMedCentralCrossRef
30.
Zurück zum Zitat Boyce AM, Kelly MH, Brillante BA, Kushner H, Wientroub S, Riminucci M, et al. A randomized, double blind, placebo-controlled trial of alendronate treatment for fibrous dysplasia of bone. J Clin Endocrinol Metab. 2014;99(11):4133–40.PubMedPubMedCentralCrossRef Boyce AM, Kelly MH, Brillante BA, Kushner H, Wientroub S, Riminucci M, et al. A randomized, double blind, placebo-controlled trial of alendronate treatment for fibrous dysplasia of bone. J Clin Endocrinol Metab. 2014;99(11):4133–40.PubMedPubMedCentralCrossRef
31.
Zurück zum Zitat Whyte MP, McAlister WH, Novack DV, Clements KL, Schoenecker PL, Wenkert D. Bisphosphonate-induced osteopetrosis: novel bone modeling defects, metaphyseal osteopenia, and osteosclerosis fractures after drug exposure ceases. J Bone Miner Res. 2008;23(10):1698–707.PubMedCrossRef Whyte MP, McAlister WH, Novack DV, Clements KL, Schoenecker PL, Wenkert D. Bisphosphonate-induced osteopetrosis: novel bone modeling defects, metaphyseal osteopenia, and osteosclerosis fractures after drug exposure ceases. J Bone Miner Res. 2008;23(10):1698–707.PubMedCrossRef
32.
Zurück zum Zitat Mendenhall WM, Zlotecki RA, Scarborough MT, Gibbs CP, Mendenhall NP. Giant cell tumor of bone. Am J Clin Oncol. 2006;29(1):96–9.PubMedCrossRef Mendenhall WM, Zlotecki RA, Scarborough MT, Gibbs CP, Mendenhall NP. Giant cell tumor of bone. Am J Clin Oncol. 2006;29(1):96–9.PubMedCrossRef
33.
Zurück zum Zitat Zheng MH, Robbins P, Xu J, Huang L, Wood DJ, Papadimitriou JM. The histogenesis of giant cell tumour of bone: a model of interaction between neoplastic cells and osteoclasts. Histol Histopathol. 2001;16(1):297–307.PubMed Zheng MH, Robbins P, Xu J, Huang L, Wood DJ, Papadimitriou JM. The histogenesis of giant cell tumour of bone: a model of interaction between neoplastic cells and osteoclasts. Histol Histopathol. 2001;16(1):297–307.PubMed
34.
Zurück zum Zitat Cowan RW, Singh G. Giant cell tumor of bone: a basic science perspective. Bone. 2013;52(1):238–46.PubMedCrossRef Cowan RW, Singh G. Giant cell tumor of bone: a basic science perspective. Bone. 2013;52(1):238–46.PubMedCrossRef
35.
Zurück zum Zitat Al-Ibraheemi A, Inwards CY, Zreik RT, Wenger DE, Jenkins SM, Carter JM, et al. Histologic spectrum of giant cell tumor (GCT) of bone in patients 18 years of age and below: a study of 63 patients. Am J Surg Pathol. 2016;40(12):1702–12.PubMedCrossRef Al-Ibraheemi A, Inwards CY, Zreik RT, Wenger DE, Jenkins SM, Carter JM, et al. Histologic spectrum of giant cell tumor (GCT) of bone in patients 18 years of age and below: a study of 63 patients. Am J Surg Pathol. 2016;40(12):1702–12.PubMedCrossRef
36.
Zurück zum Zitat Noh BJ, Park YK. Giant cell tumor of bone: updated molecular pathogenesis and tumor biology. Hum Pathol. 2018;81:1–8.PubMedCrossRef Noh BJ, Park YK. Giant cell tumor of bone: updated molecular pathogenesis and tumor biology. Hum Pathol. 2018;81:1–8.PubMedCrossRef
37.
Zurück zum Zitat Jaffe HL, Lichtenstein L, Portis RB. Giant cell tumor of bone: its pathologic appearance, grading, supposed variants and treatment. Arch Pathol. 1940;30:993–1031. Jaffe HL, Lichtenstein L, Portis RB. Giant cell tumor of bone: its pathologic appearance, grading, supposed variants and treatment. Arch Pathol. 1940;30:993–1031.
38.
Zurück zum Zitat Campanacci M, Baldini N, Boriani S, Sudanese A. Giant-cell tumor of bone. J Bone Joint Surg Am. 1987;69(1):106–14.PubMedCrossRef Campanacci M, Baldini N, Boriani S, Sudanese A. Giant-cell tumor of bone. J Bone Joint Surg Am. 1987;69(1):106–14.PubMedCrossRef
39.
Zurück zum Zitat McDonald DJ, Sim FH, McLeod RA, Dahlin DC. Giant-cell tumor of bone. J Bone Joint Surg Am. 1986;68(2):235–42.PubMedCrossRef McDonald DJ, Sim FH, McLeod RA, Dahlin DC. Giant-cell tumor of bone. J Bone Joint Surg Am. 1986;68(2):235–42.PubMedCrossRef
40.
Zurück zum Zitat van der Heijden L, Dijkstra PDS, Blay JY, Gelderblom H. Giant cell tumour of bone in the denosumab era. Eur J Cancer. 2017;77:75–83.PubMedCrossRef van der Heijden L, Dijkstra PDS, Blay JY, Gelderblom H. Giant cell tumour of bone in the denosumab era. Eur J Cancer. 2017;77:75–83.PubMedCrossRef
41.
Zurück zum Zitat Becker WT, Dohle J, Bernd L, Braun A, Cserhati M, Enderle A, 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):1060–7.PubMedCrossRef Becker WT, Dohle J, Bernd L, Braun A, Cserhati M, Enderle A, 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):1060–7.PubMedCrossRef
42.
Zurück zum Zitat Errani C, Ruggieri P, Asenzio MA, Toscano A, Colangeli S, Rimondi E, et al. Giant cell tumor of the extremity: a review of 349 cases from a single institution. Cancer Treat Rev. 2010;36(1):1–7.PubMedCrossRef Errani C, Ruggieri P, Asenzio MA, Toscano A, Colangeli S, Rimondi E, et al. Giant cell tumor of the extremity: a review of 349 cases from a single institution. Cancer Treat Rev. 2010;36(1):1–7.PubMedCrossRef
43.
Zurück zum Zitat Balke M, Schremper L, Gebert C, Ahrens H, Streitbuerger A, Koehler G, et al. Giant cell tumor of bone: treatment and outcome of 214 cases. J Cancer Res Clin Oncol. 2008;134(9):969–78.PubMedCrossRef Balke M, Schremper L, Gebert C, Ahrens H, Streitbuerger A, Koehler G, et al. Giant cell tumor of bone: treatment and outcome of 214 cases. J Cancer Res Clin Oncol. 2008;134(9):969–78.PubMedCrossRef
44.
Zurück zum Zitat Mak IW, Evaniew N, Popovic S, Tozer R, Ghert M. A translational study of the neoplastic cells of giant cell tumor of bone following neoadjuvant denosumab. J Bone Joint Surg Am. 2014;96(15):e127.PubMedCrossRef Mak IW, Evaniew N, Popovic S, Tozer R, Ghert M. A translational study of the neoplastic cells of giant cell tumor of bone following neoadjuvant denosumab. J Bone Joint Surg Am. 2014;96(15):e127.PubMedCrossRef
45.
Zurück zum Zitat Chawla S, Henshaw R, Seeger L, Choy E, Blay JY, Ferrari S, et al. Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study. Lancet Oncol. 2013;14(9):901–8.PubMedCrossRef Chawla S, Henshaw R, Seeger L, Choy E, Blay JY, Ferrari S, et al. Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study. Lancet Oncol. 2013;14(9):901–8.PubMedCrossRef
46.
Zurück zum Zitat Rutkowski P, Ferrari S, Grimer RJ, Stalley PD, Dijkstra SP, Pienkowski A, et al. Surgical downstaging in an open-label phase II trial of denosumab in patients with giant cell tumor of bone. Ann Surg Oncol. 2015;22(9):2860–8.PubMedPubMedCentralCrossRef Rutkowski P, Ferrari S, Grimer RJ, Stalley PD, Dijkstra SP, Pienkowski A, et al. Surgical downstaging in an open-label phase II trial of denosumab in patients with giant cell tumor of bone. Ann Surg Oncol. 2015;22(9):2860–8.PubMedPubMedCentralCrossRef
47.
Zurück zum Zitat Luengo-Alonso G, Mellado-Romero M, Shemesh S, Ramos-Pascua L, Pretell-Mazzini J. Denosumab treatment for giant-cell tumor of bone: a systematic review of the literature. Arch Orthop Trauma Surg. 2019;139(10):1339–49.PubMedCrossRef Luengo-Alonso G, Mellado-Romero M, Shemesh S, Ramos-Pascua L, Pretell-Mazzini J. Denosumab treatment for giant-cell tumor of bone: a systematic review of the literature. Arch Orthop Trauma Surg. 2019;139(10):1339–49.PubMedCrossRef
48.
Zurück zum Zitat Goldschlager T, Dea N, Boyd M, Reynolds J, Patel S, Rhines LD, et al. Giant cell tumors of the spine: has denosumab changed the treatment paradigm? J Neurosurg Spine. 2015;22(5):526–33.PubMedCrossRef Goldschlager T, Dea N, Boyd M, Reynolds J, Patel S, Rhines LD, et al. Giant cell tumors of the spine: has denosumab changed the treatment paradigm? J Neurosurg Spine. 2015;22(5):526–33.PubMedCrossRef
49.
Zurück zum Zitat Muller DA, Beltrami G, Scoccianti G, Campanacci DA, Franchi A, Capanna R. Risks and benefits of combining denosumab and surgery in giant cell tumor of bone-a case series. World J Surg Oncol. 2016;14(1):281.PubMedPubMedCentralCrossRef Muller DA, Beltrami G, Scoccianti G, Campanacci DA, Franchi A, Capanna R. Risks and benefits of combining denosumab and surgery in giant cell tumor of bone-a case series. World J Surg Oncol. 2016;14(1):281.PubMedPubMedCentralCrossRef
50.
Zurück zum Zitat Rutkowski P, Gaston L, Borkowska A, Stacchiotti S, Gelderblom H, Baldi GG, et al. Denosumab treatment of inoperable or locally advanced giant cell tumor of bone—multicenter analysis outside clinical trial. Eur J Surg Oncol. 2018;44(9):1384–90.PubMedCrossRef Rutkowski P, Gaston L, Borkowska A, Stacchiotti S, Gelderblom H, Baldi GG, et al. Denosumab treatment of inoperable or locally advanced giant cell tumor of bone—multicenter analysis outside clinical trial. Eur J Surg Oncol. 2018;44(9):1384–90.PubMedCrossRef
51.
Zurück zum Zitat Chinder PS, Hindiskere S, Doddarangappa S, Pal U. Evaluation of local recurrence in giant-cell tumor of bone treated by neoadjuvant denosumab. Clin Orthop Surg. 2019;11(3):352–60.PubMedPubMedCentralCrossRef Chinder PS, Hindiskere S, Doddarangappa S, Pal U. Evaluation of local recurrence in giant-cell tumor of bone treated by neoadjuvant denosumab. Clin Orthop Surg. 2019;11(3):352–60.PubMedPubMedCentralCrossRef
52.
Zurück zum Zitat Agarwal MG, Gundavda MK, Gupta R, Reddy R. Does denosumab change the giant cell tumor treatment strategy? Lessons learned from early experience. Clin Orthop Relat Res. 2018;476(9):1773–82.PubMedPubMedCentralCrossRef Agarwal MG, Gundavda MK, Gupta R, Reddy R. Does denosumab change the giant cell tumor treatment strategy? Lessons learned from early experience. Clin Orthop Relat Res. 2018;476(9):1773–82.PubMedPubMedCentralCrossRef
53.
Zurück zum Zitat Errani C, Tsukamoto S, Leone G, Righi A, Akahane M, Tanaka Y, et al. Denosumab may increase the risk of local recurrence in patients with giant-cell tumor of bone treated with curettage. J Bone Joint Surg Am. 2018;100(6):496–504.PubMedCrossRef Errani C, Tsukamoto S, Leone G, Righi A, Akahane M, Tanaka Y, et al. Denosumab may increase the risk of local recurrence in patients with giant-cell tumor of bone treated with curettage. J Bone Joint Surg Am. 2018;100(6):496–504.PubMedCrossRef
54.
Zurück zum Zitat Urakawa H, Mizusawa J, Tanaka K, Eba J, Hiraga H, Kawai A, et al. A randomized phase III trial of denosumab before curettage for giant cell tumor of bone: Japan Clinical Oncology Group Study JCOG1610. Jpn J Clin Oncol. 2019;49(4):379–82.PubMedCrossRef Urakawa H, Mizusawa J, Tanaka K, Eba J, Hiraga H, Kawai A, et al. A randomized phase III trial of denosumab before curettage for giant cell tumor of bone: Japan Clinical Oncology Group Study JCOG1610. Jpn J Clin Oncol. 2019;49(4):379–82.PubMedCrossRef
55.
Zurück zum Zitat Alaqaili SI, Abduljabbar AM, Altaho AJ, Khan AA, Alherabi JA. Malignant sarcomatous transformation of benign giant cell tumor of bone after treatment with denosumab therapy: a literature review of reported cases. Cureus. 2018;10(12):e3792.PubMedPubMedCentral Alaqaili SI, Abduljabbar AM, Altaho AJ, Khan AA, Alherabi JA. Malignant sarcomatous transformation of benign giant cell tumor of bone after treatment with denosumab therapy: a literature review of reported cases. Cureus. 2018;10(12):e3792.PubMedPubMedCentral
56.
Zurück zum Zitat Muratori F, Mondanelli N, Rizzo AR, Beltrami G, Giannotti S, Capanna R, et al. Aneurysmal bone cyst: a review of management. Surg Technol Int. 2019;35:325–35.PubMed Muratori F, Mondanelli N, Rizzo AR, Beltrami G, Giannotti S, Capanna R, et al. Aneurysmal bone cyst: a review of management. Surg Technol Int. 2019;35:325–35.PubMed
57.
Zurück zum Zitat Lichtenstein L. Aneurysmal bone cyst. A pathological entity commonly mistaken for giant-cell tumor and occasionally for hemangioma and osteogenic sarcoma. Cancer. 1950;3(2):279–89.CrossRef Lichtenstein L. Aneurysmal bone cyst. A pathological entity commonly mistaken for giant-cell tumor and occasionally for hemangioma and osteogenic sarcoma. Cancer. 1950;3(2):279–89.CrossRef
58.
Zurück zum Zitat Buraczewski J, Dabska M. Pathogenesis of aneurysmal bone cyst. Relationship between the aneurysmal bone cyst and fibrous dysplasia of bone. Cancer. 1971;28(3):597–604.PubMedCrossRef Buraczewski J, Dabska M. Pathogenesis of aneurysmal bone cyst. Relationship between the aneurysmal bone cyst and fibrous dysplasia of bone. Cancer. 1971;28(3):597–604.PubMedCrossRef
59.
Zurück zum Zitat Martinez V, Sissons HA. Aneurysmal bone cyst. A review of 123 cases including primary lesions and those secondary to other bone pathology. Cancer. 1988;61(11):2291–304.PubMedCrossRef Martinez V, Sissons HA. Aneurysmal bone cyst. A review of 123 cases including primary lesions and those secondary to other bone pathology. Cancer. 1988;61(11):2291–304.PubMedCrossRef
60.
Zurück zum Zitat Vergel De Dios AM, Bond JR, Shives TC, McLeod RA, Unni KK. Aneurysmal bone cyst. A clinicopathologic study of 238 cases. Cancer. 1992;69(12):2921–31.PubMedCrossRef Vergel De Dios AM, Bond JR, Shives TC, McLeod RA, Unni KK. Aneurysmal bone cyst. A clinicopathologic study of 238 cases. Cancer. 1992;69(12):2921–31.PubMedCrossRef
61.
Zurück zum Zitat Baumhoer D, Amary F, Flanagan AM. An update of molecular pathology of bone tumors. Lessons learned from investigating samples by next generation sequencing. Genes Chromosomes Cancer. 2019;58(2):88–99.PubMedCrossRef Baumhoer D, Amary F, Flanagan AM. An update of molecular pathology of bone tumors. Lessons learned from investigating samples by next generation sequencing. Genes Chromosomes Cancer. 2019;58(2):88–99.PubMedCrossRef
62.
Zurück zum Zitat Lau AW, Pringle LM, Quick L, Riquelme DN, Ye Y, Oliveira AM, et al. TRE17/ubiquitin-specific protease 6 (USP6) oncogene translocated in aneurysmal bone cyst blocks osteoblastic maturation via an autocrine mechanism involving bone morphogenetic protein dysregulation. J Biol Chem. 2010;285(47):37111–20.PubMedPubMedCentralCrossRef Lau AW, Pringle LM, Quick L, Riquelme DN, Ye Y, Oliveira AM, et al. TRE17/ubiquitin-specific protease 6 (USP6) oncogene translocated in aneurysmal bone cyst blocks osteoblastic maturation via an autocrine mechanism involving bone morphogenetic protein dysregulation. J Biol Chem. 2010;285(47):37111–20.PubMedPubMedCentralCrossRef
63.
Zurück zum Zitat Ye Y, Pringle LM, Lau AW, Riquelme DN, Wang H, Jiang T, et al. TRE17/USP6 oncogene translocated in aneurysmal bone cyst induces matrix metalloproteinase production via activation of NF-kappaB. Oncogene. 2010;29(25):3619–29.PubMedPubMedCentralCrossRef Ye Y, Pringle LM, Lau AW, Riquelme DN, Wang H, Jiang T, et al. TRE17/USP6 oncogene translocated in aneurysmal bone cyst induces matrix metalloproteinase production via activation of NF-kappaB. Oncogene. 2010;29(25):3619–29.PubMedPubMedCentralCrossRef
64.
Zurück zum Zitat Oliveira AM, Chou MM, Perez-Atayde AR, Rosenberg AE. Aneurysmal bone cyst: a neoplasm driven by upregulation of the USP6 oncogene. J Clin Oncol. 2006;24(1):e1; author reply e2.PubMedCrossRef Oliveira AM, Chou MM, Perez-Atayde AR, Rosenberg AE. Aneurysmal bone cyst: a neoplasm driven by upregulation of the USP6 oncogene. J Clin Oncol. 2006;24(1):e1; author reply e2.PubMedCrossRef
65.
Zurück zum Zitat Park HY, Yang SK, Sheppard WL, Hegde V, Zoller SD, Nelson SD, et al. Current management of aneurysmal bone cysts. Curr Rev Musculoskelet Med. 2016;9(4):435–44.PubMedPubMedCentralCrossRef Park HY, Yang SK, Sheppard WL, Hegde V, Zoller SD, Nelson SD, et al. Current management of aneurysmal bone cysts. Curr Rev Musculoskelet Med. 2016;9(4):435–44.PubMedPubMedCentralCrossRef
66.
Zurück zum Zitat Pelle DW, Ringler JW, Peacock JD, Kampfschulte K, Scholten DJ 2nd, Davis MM, et al. Targeting receptor-activator of nuclear kappaB ligand in aneurysmal bone cysts: verification of target and therapeutic response. Transl Res. 2014;164(2):139–48.PubMedCrossRef Pelle DW, Ringler JW, Peacock JD, Kampfschulte K, Scholten DJ 2nd, Davis MM, et al. Targeting receptor-activator of nuclear kappaB ligand in aneurysmal bone cysts: verification of target and therapeutic response. Transl Res. 2014;164(2):139–48.PubMedCrossRef
67.
Zurück zum Zitat • Alhumaid I, Abu-Zaid A. Denosumab therapy in the management of aneurysmal bone cysts: a comprehensive literature review. Cureus. 2019;11(1):e3989 This review summarizes the most current clinical experience with denosumab treatment of ABCs.PubMedPubMedCentral • Alhumaid I, Abu-Zaid A. Denosumab therapy in the management of aneurysmal bone cysts: a comprehensive literature review. Cureus. 2019;11(1):e3989 This review summarizes the most current clinical experience with denosumab treatment of ABCs.PubMedPubMedCentral
68.
Zurück zum Zitat Ntalos D, Priemel M, Schlickewei C, Thiesen DM, Rueger JM, Spiro AS. Therapeutic management of a substantial pelvic aneurysmatic bone cyst Including the off-label use of denosumab in a 35-year-old female patient. Case Rep Orthop. 2017;2017:9125493.PubMedPubMedCentral Ntalos D, Priemel M, Schlickewei C, Thiesen DM, Rueger JM, Spiro AS. Therapeutic management of a substantial pelvic aneurysmatic bone cyst Including the off-label use of denosumab in a 35-year-old female patient. Case Rep Orthop. 2017;2017:9125493.PubMedPubMedCentral
69.
Zurück zum Zitat Kurucu N, Akyuz C, Ergen FB, Yalcin B, Kosemehmetoglu K, Ayvaz M, et al. Denosumab treatment in aneurysmal bone cyst: evaluation of nine cases. Pediatr Blood Cancer. 2018;65(4). Kurucu N, Akyuz C, Ergen FB, Yalcin B, Kosemehmetoglu K, Ayvaz M, et al. Denosumab treatment in aneurysmal bone cyst: evaluation of nine cases. Pediatr Blood Cancer. 2018;65(4).
70.
Zurück zum Zitat Pauli C, Fuchs B, Pfirrmann C, Bridge JA, Hofer S, Bode B. Response of an aggressive periosteal aneurysmal bone cyst (ABC) of the radius to denosumab therapy. World J Surg Oncol. 2014;12:17.PubMedPubMedCentralCrossRef Pauli C, Fuchs B, Pfirrmann C, Bridge JA, Hofer S, Bode B. Response of an aggressive periosteal aneurysmal bone cyst (ABC) of the radius to denosumab therapy. World J Surg Oncol. 2014;12:17.PubMedPubMedCentralCrossRef
71.
Zurück zum Zitat Lange T, Stehling C, Frohlich B, Klingenhofer M, Kunkel P, Schneppenheim R, et al. Denosumab: a potential new and innovative treatment option for aneurysmal bone cysts. Eur Spine J. 2013;22(6):1417–22.PubMedPubMedCentralCrossRef Lange T, Stehling C, Frohlich B, Klingenhofer M, Kunkel P, Schneppenheim R, et al. Denosumab: a potential new and innovative treatment option for aneurysmal bone cysts. Eur Spine J. 2013;22(6):1417–22.PubMedPubMedCentralCrossRef
72.
Zurück zum Zitat Durr HR, Grahneis F, Baur-Melnyk A, Knosel T, Birkenmaier C, Jansson V, et al. Aneurysmal bone cyst: results of an off label treatment with denosumab. BMC Musculoskelet Disord. 2019;20(1):456.PubMedPubMedCentralCrossRef Durr HR, Grahneis F, Baur-Melnyk A, Knosel T, Birkenmaier C, Jansson V, et al. Aneurysmal bone cyst: results of an off label treatment with denosumab. BMC Musculoskelet Disord. 2019;20(1):456.PubMedPubMedCentralCrossRef
73.
Zurück zum Zitat Boyce AM, Collins MT. Fibrous dysplasia/McCune–Albright syndrome: a rare, mosaic disease of Galphas activation. Endocr Rev. 2020;41(2):345–70.CrossRef Boyce AM, Collins MT. Fibrous dysplasia/McCune–Albright syndrome: a rare, mosaic disease of Galphas activation. Endocr Rev. 2020;41(2):345–70.CrossRef
74.
Zurück zum Zitat Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCune–Albright syndrome. N Engl J Med. 1991;325(24):1688–95.PubMedCrossRef Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCune–Albright syndrome. N Engl J Med. 1991;325(24):1688–95.PubMedCrossRef
75.
Zurück zum Zitat Riminucci M, Liu B, Corsi A, Shenker A, Spiegel AM, Robey PG, et al. The histopathology of fibrous dysplasia of bone in patients with activating mutations of the Gs alpha gene: site-specific patterns and recurrent histological hallmarks. J Pathol. 1999;187(2):249–58.PubMedCrossRef Riminucci M, Liu B, Corsi A, Shenker A, Spiegel AM, Robey PG, et al. The histopathology of fibrous dysplasia of bone in patients with activating mutations of the Gs alpha gene: site-specific patterns and recurrent histological hallmarks. J Pathol. 1999;187(2):249–58.PubMedCrossRef
76.
Zurück zum Zitat de Castro LF, Burke AB, Wang HD, Tsai J, Florenzano P, Pan KS, et al. Activation of RANK/RANKL/OPG pathway is involved in the pathophysiology of fibrous dysplasia and associated with disease burden. J Bone Miner Res. 2019;34(2):290–4.PubMedCrossRef de Castro LF, Burke AB, Wang HD, Tsai J, Florenzano P, Pan KS, et al. Activation of RANK/RANKL/OPG pathway is involved in the pathophysiology of fibrous dysplasia and associated with disease burden. J Bone Miner Res. 2019;34(2):290–4.PubMedCrossRef
77.
Zurück zum Zitat Kushchayeva YS, Kushchayev SV, Glushko TY, Tella SH, Teytelboym OM, Collins MT, et al. Fibrous dysplasia for radiologists: beyond ground glass bone matrix. Insights Imaging. 2018;9(6):1035–56.PubMedPubMedCentralCrossRef Kushchayeva YS, Kushchayev SV, Glushko TY, Tella SH, Teytelboym OM, Collins MT, et al. Fibrous dysplasia for radiologists: beyond ground glass bone matrix. Insights Imaging. 2018;9(6):1035–56.PubMedPubMedCentralCrossRef
78.
Zurück zum Zitat Burke AB, Collins MT, Boyce AM. Fibrous dysplasia of bone: craniofacial and dental implications. Oral Dis. 2017;23(6):697–708.PubMedCrossRef Burke AB, Collins MT, Boyce AM. Fibrous dysplasia of bone: craniofacial and dental implications. Oral Dis. 2017;23(6):697–708.PubMedCrossRef
79.
Zurück zum Zitat Kelly MH, Brillante B, Collins MT. Pain in fibrous dysplasia of bone: age-related changes and the anatomical distribution of skeletal lesions. Osteoporos Int. 2008;19(1):57–63.PubMedCrossRef Kelly MH, Brillante B, Collins MT. Pain in fibrous dysplasia of bone: age-related changes and the anatomical distribution of skeletal lesions. Osteoporos Int. 2008;19(1):57–63.PubMedCrossRef
80.
Zurück zum Zitat Majoor BCJ, Traunmueller E, Maurer-Ertl W, Appelman-Dijkstra NM, Fink A, Liegl B, et al. Pain in fibrous dysplasia: relationship with anatomical and clinical features. Acta Orthop. 2019;90(4):401–5.PubMedPubMedCentralCrossRef Majoor BCJ, Traunmueller E, Maurer-Ertl W, Appelman-Dijkstra NM, Fink A, Liegl B, et al. Pain in fibrous dysplasia: relationship with anatomical and clinical features. Acta Orthop. 2019;90(4):401–5.PubMedPubMedCentralCrossRef
81.
Zurück zum Zitat Stanton RP, Ippolito E, Springfield D, Lindaman L, Wientroub S, Leet A. The surgical management of fibrous dysplasia of bone. Orphanet J Rare Dis. 2012;7 Suppl 1(Suppl 1):S1.PubMedCrossRef Stanton RP, Ippolito E, Springfield D, Lindaman L, Wientroub S, Leet A. The surgical management of fibrous dysplasia of bone. Orphanet J Rare Dis. 2012;7 Suppl 1(Suppl 1):S1.PubMedCrossRef
82.
Zurück zum Zitat Florenzano P, Pan KS, Brown SM, Paul SM, Kushner H, Guthrie LC, et al. Age-related changes and effects of bisphosphonates on bone turnover and disease progression in fibrous dysplasia of Bone. J Bone Miner Res. 2019;34(4):653–60.PubMedPubMedCentralCrossRef Florenzano P, Pan KS, Brown SM, Paul SM, Kushner H, Guthrie LC, et al. Age-related changes and effects of bisphosphonates on bone turnover and disease progression in fibrous dysplasia of Bone. J Bone Miner Res. 2019;34(4):653–60.PubMedPubMedCentralCrossRef
83.
Zurück zum Zitat Plotkin H, Rauch F, Zeitlin L, Munns C, Travers R, Glorieux FH. Effect of pamidronate treatment in children with polyostotic fibrous dysplasia of bone. J Clin Endocrinol Metab. 2003;88(10):4569–75.PubMedCrossRef Plotkin H, Rauch F, Zeitlin L, Munns C, Travers R, Glorieux FH. Effect of pamidronate treatment in children with polyostotic fibrous dysplasia of bone. J Clin Endocrinol Metab. 2003;88(10):4569–75.PubMedCrossRef
84.
Zurück zum Zitat Majoor BC, Appelman-Dijkstra NM, Fiocco M, van de Sande MA, Dijkstra PS, Hamdy NA. Outcome of long-term bisphosphonate therapy in McCune–Albright syndrome and polyostotic fibrous dysplasia. J Bone Miner Res. 2017;32(2):264–76.PubMedCrossRef Majoor BC, Appelman-Dijkstra NM, Fiocco M, van de Sande MA, Dijkstra PS, Hamdy NA. Outcome of long-term bisphosphonate therapy in McCune–Albright syndrome and polyostotic fibrous dysplasia. J Bone Miner Res. 2017;32(2):264–76.PubMedCrossRef
85.
Zurück zum Zitat Collins MT, de Castro LF, Boyce AM. Denosumab for fibrous dysplasia: promising, but questions remain. J Clin Endocrinol Metab. 2020;105(11):e4179–80.CrossRef Collins MT, de Castro LF, Boyce AM. Denosumab for fibrous dysplasia: promising, but questions remain. J Clin Endocrinol Metab. 2020;105(11):e4179–80.CrossRef
86.
Zurück zum Zitat Palmisano B, Spica E, Remoli C, Labella R, Di Filippo A, Donsante S, et al. RANKL inhibition in fibrous dysplasia of bone: a preclinical study in a mouse model of the human disease. J Bone Miner Res. 2019;34(12):2171–82.PubMedCrossRef Palmisano B, Spica E, Remoli C, Labella R, Di Filippo A, Donsante S, et al. RANKL inhibition in fibrous dysplasia of bone: a preclinical study in a mouse model of the human disease. J Bone Miner Res. 2019;34(12):2171–82.PubMedCrossRef
87.
Zurück zum Zitat Boyce AM, Chong WH, Yao J, Gafni RI, Kelly MH, Chamberlain CE, et al. Denosumab treatment for fibrous dysplasia. J Bone Miner Res. 2012;27(7):1462–70.PubMedPubMedCentralCrossRef Boyce AM, Chong WH, Yao J, Gafni RI, Kelly MH, Chamberlain CE, et al. Denosumab treatment for fibrous dysplasia. J Bone Miner Res. 2012;27(7):1462–70.PubMedPubMedCentralCrossRef
88.
Zurück zum Zitat Majoor BCJ, Papapoulos SE, Dijkstra PDS, Fiocco M, Hamdy NAT, Appelman-Dijkstra NM. Denosumab in patients with fibrous dysplasia previously treated with bisphosphonates. J Clin Endocrinol Metab. 2019;104(12):6069–78.PubMedCrossRef Majoor BCJ, Papapoulos SE, Dijkstra PDS, Fiocco M, Hamdy NAT, Appelman-Dijkstra NM. Denosumab in patients with fibrous dysplasia previously treated with bisphosphonates. J Clin Endocrinol Metab. 2019;104(12):6069–78.PubMedCrossRef
Metadaten
Titel
Denosumab Treatment for Giant Cell Tumors, Aneurysmal Bone Cysts, and Fibrous Dysplasia—Risks and Benefits
verfasst von
Kristen S. Pan
Alison M. Boyce
Publikationsdatum
22.02.2021
Verlag
Springer US
Erschienen in
Current Osteoporosis Reports / Ausgabe 2/2021
Print ISSN: 1544-1873
Elektronische ISSN: 1544-2241
DOI
https://doi.org/10.1007/s11914-021-00657-z

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