Non-osteoporotic Loss of Spinal Bone. Denosumab as a Therapeutic Tool and its Implications
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Published:
Feb 15, 2024
Keywords:
Spine, non-osteoporotic bone loss, tumor, infection
Main Article Content
Abstract
Background: Denosumab is a human monoclonal antibody that acts against RANKL, inhibiting bone destruction mediated by osteoclasts, thus avoiding bone loss. For this reason, it is used in the treatment of osteoporosis as an antiresorptive and is authorized for the treatment of giant cell tumor and multiple myeloma. Our objective is to understand its indications and contraindications for the treatment of non-osteoporotic bone loss.
Materials and Methods: A systematic review of English-language articles published between 2009 and 2023, using PRISMA criteria. Articles indicating or contraindicating the use of denosumab were considered forinclusion.
Results: From a total of 4306 articles, 18 articles were analyzed, which showed consensus on the dose and controls with tomography and indicated or contraindicated the use of denosumab.
Conclusions: Denosumab is recommended as a primary therapeutic option for unresectable spinal tumors, to prevent recurrences or to delay the formation of metastases from primary tumors or solid tumors, primarily breast, prostate, and lung, as well as for multiple myeloma spinal involvement. Denosumab iscurrently contraindicated in infectious lesions.
Materials and Methods: A systematic review of English-language articles published between 2009 and 2023, using PRISMA criteria. Articles indicating or contraindicating the use of denosumab were considered forinclusion.
Results: From a total of 4306 articles, 18 articles were analyzed, which showed consensus on the dose and controls with tomography and indicated or contraindicated the use of denosumab.
Conclusions: Denosumab is recommended as a primary therapeutic option for unresectable spinal tumors, to prevent recurrences or to delay the formation of metastases from primary tumors or solid tumors, primarily breast, prostate, and lung, as well as for multiple myeloma spinal involvement. Denosumab iscurrently contraindicated in infectious lesions.
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How to Cite
Bazán, P. L., Godoy Adaro, A., Hernández Molina, G. L., Blanco Payano, R. Ángel, & Cinalli, M. (2024). Non-osteoporotic Loss of Spinal Bone. Denosumab as a Therapeutic Tool and its Implications. Revista De La Asociación Argentina De Ortopedia Y Traumatología, 89(1), 83-89. https://doi.org/10.15417/issn.1852-7434.2024.89.1.1802
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References
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1976) 2017;42(10):E629-E632. https://doi.org/10.1097/BRS.0000000000001951
2. Ohnishi T, Ogawa Y, Suda K, Komatsu M, Harmon SM, Asukai M, et al. Molecular targeted therapy for the bone
loss secondary to pyogenic spondylodiscitis using medications for osteoporosis: A literature review. Int J Mol Sci
2021;22(9):4453. https://doi.org/10.3390/ijms22094453
3. Zhang RZ, Ma TX, Qi DW, Zhao M, Hu T, Zhang GC. Short-term preoperative denosumab with surgery in
unresectable or recurrent giant cell tumor of bone. Orthop Surg 2019;11(6):1101-8. https://doi.org/10.1111/os.12561
4. Bazán PL, Di Falco R, Borri A, Medina M, Ciccioli N. The use of denosumab in giant cell tumors in the sacrum.
Coluna/Columna 2020;19(2). https://doi.org/10.1590/S1808-185120201902228839
5. Ng VY, Davidson DJ, Kim EY, Pollack SM, Conrad Iii EU, Jones RL. The multidisciplinary management of giant
cell tumor of bone. Expert Rev Anticancer Ther 2014;14(7):783-90. https://doi.org/10.1586/14737140.2014.901891
6. 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. https://doi.org/10.1016/j.ejca.2017.02.021A22
7. 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. https://doi.org/10.1016/S1470-2045(13)70277-8
8. Thomas D, Henshaw R, Skubitz K, Chawla S, Staddon A, Blay JY, et al. Denosumab in patients with giant-cell
tumour of bone: an open-label, phase 2 study. Lancet Oncol 2010;11(3):275-80. https://doi.org/10.1016/S1470-2045(10)70010-3
9. Law GW, Yeo NEM, Howe TS, Tan YZ, Tan SB, Siddiqui MMA. Recommencement of denosumab for unresectable
giant cell tumor of the cervical spine: A case report. Spine (Phila Pa 1976) 2018;43(9):E551-E556. https://doi.org/10.1097/BRS.0000000000002440
10. Lanari F, Godoy AO, Bazán PL. Uso de denosumab para el quiste óseo aneurismático de columna. Reporte de un caso y revisión bibliográfica. Rev Asoc Argent Ortop Traumatol 2021;86(6):821-8. https://doi.org/10.15417/issn.1852-7434.2021.86.6.1121
11. 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):10.1002/pbc.26926.
https://doi.org/10.1002/pbc.26926
12. Skubitz KM, Peltola JC, Santos ER, Cheng EY. Response of aneurysmal bone cyst to denosumab. Spine (Phila Pa 1976) 2015;40(22):E1201-E1204. https://doi.org/10.1097/BRS.0000000000001027
13. Dubory A, Missenard G, Domont J, Court C. Interest of denosumab for the treatment of giant-cells tumors and aneurysmal bone cysts of the spine. About nine cases. Spine (Phila Pa 1976) 2016;41(11):E654-E660.
https://doi.org/10.1097/BRS.0000000000001350
14. Kushlinskii NE, Gershtein ES, Solov’ev YN, Timofeev YS, Babkina IV, Dolinkin AO, et al. Receptor activator of
nuclear transcription factor NF-κB (RANK), its ligand RANKL, and natural inhibitor of RANKL osteoprotegerin
(OPG) in the blood serum of patients with primary bone tumors. Bull Exp Biol Med 2017;163(4):478-81.
https://doi.org/10.1007/s10517-017-3832-9
15. Sohn W, Simiens MA, Jaeger K, Hutton S, Jang G. The pharmacokinetics and pharmacodynamics of denosumab in patients with advanced solid tumours and bone metastases: a systematic review. Br J Clin Pharmacol 2014;78(3):477-87. https://doi.org/10.1111/bcp.12355
16. Ford J, Cummins E, Sharma P, Elders A, Stewart F, Johnston R, et al. Systematic review of the clinical effectiveness and cost-effectiveness, and economic evaluation, of denosumab for the treatment of bone metastases from solid tumours. Health Technol Assess 2013;17(29):1-386. https://doi.org/10.3310/hta17290
17. Sun L, Yu S. Efficacy and safety of denosumab versus zoledronic acid in patients with bone metastases: a systematic review and meta-analysis. Am J Clin Oncol 2013;36(4):399-403. https://doi.org/10.1097/COC.0b013e31824be20e
18. Li HS, Lei SY, Li JL, Xing PY, Hao XZ, Xu F, et al. Efficacy and safety of concomitant immunotherapy and
denosumab in patients with advanced non-small cell lung cancer carrying bone metastases: A retrospective chart review. Front Immunol 2022;13:908436. https://doi.org/10.3389/fimmu.2022.908436
19. Diel I, Ansorge S, Hohmann D, Giannopoulou C, Niepel D, Intorcia M. Real-world use of denosumab and
bisphosphonates in patients with solid tumours and bone metastases in Germany. Support Care Cancer
2020;28(11):5223-33. https://doi.org/10.1007/s00520-020-05357-5
20. Li B, Wang P, Jiao J, Wei H, Xu W, Zhou P. Roles of the RANKL-RANK axis in immunity-implications for
pathogenesis and treatment of bone metastasis. Front Immunol 2022;13:824117. https://doi.org/10.3389/fimmu.2022.824117
21. Stopeck A, Brufsky A, Kennedy L, Bhatta S, Bhowmik D, Buchanan J, et al. Cost-effectiveness of denosumab for the prevention of skeletal-related events in patients with solid tumors and bone metastases in the United States. J Medical Econ 2020;23(1):37-47. https://doi.org/10.1080/13696998.2019.1651122
22. Chen J, Zhou L, Liu X, Wen X, Li H, Li W. Meta-analysis of clinical trials to assess denosumab over zoledronic acid in bone metastasis. Int J Clin Pharm 2021;43(1):2-10. https://doi.org/10.1007/s11096-020-01105-1
23. Cadieux B, Coleman R, Jafarinasabian P, Lipton A, Orlowski RZ, Saad F, et al. Experience with denosumab
(XGEVA®) for prevention of skeletal-related events in the 10 years after approval. J Bone Oncol 2022;33:100416.
https://doi.org/10.1016/j.jbo.2022.100416
24. Raje N, Terpos E, Willenbacher W, Shimizu K, García-Sanz R, Durie B, et al. Denosumab versus zoledronic acid
in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy,
randomised, controlled, phase 3 study. Lancet Oncol 2018;19(3):370-81. https://doi.org/10.1016/S1470-2045(18)30072-X
25. Lam FC, Arle JE, Glazer PA, Kasper EM. Primary extradural tumors of the spine - Case review with evidenceguided management. Surg Neurol Int 2014;5(Suppl 7):S373-5. https://doi.org/10.4103/2152-7806.139673
26. 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.
https://doi.org/10.3171/2014.10.SPINE13937
27. Boriani S, Cecchinato R, Cuzzocrea F, Bandiera S, Gambarotti M, Gasbarrini A. Denosumab in the treatment
of giant cell tumor of the spine. Preliminary report, review of the literature and protocol proposal. Eur Spine J
2019;29(2):257-71. https://doi.org/10.1007/s00586-019-05997-0
28. Xará‐Leite F, Coutinho L, Fleming C, Magalhães M, Oliveira V, Rodrigues-Pinto R, et al. Can denosumab cure giant cell tumors of the spine? A case report and literature review. Eur J Orthop Surg Traumatol 2020;30(1):19-23.
https://doi.org/10.1007/s00590-019-02554-9
29. Leggett A, Berg A, Hullinger H, Benevenia J. Diagnosis and treatment of lumbar giant cell tumor of the spine:
Update on current management strategies. Diagnostics (Basel) 2022;12(4):857. https://doi.org/10.3390/diagnostics12040857
30. Bazán PL, Cinalli M, Lanari Zabiaur, F, Castelli R, Silveri C, Monayer JL, et al. Long-term use of denosumab in
giant cell tumors and vertebral aneurysmal bone cysts. Coluna/Columna 2022;21(1). https://doi.org/10.1590/S1808-185120222101253789
31. Yayama T, Mori K, Nakamura A, Mimura T, Imai S. Denosumab therapy for giant-cell tumor of the lumbar spine: A case report and immunohistochemical examination. J Orthop Case Rep 2020;10(2):76-9.
https://doi.org/10.13107/jocr.2020.v10.i02.1706
32. Kajiwara D, Kamoda H, Yonemoto T, Iwata S, Ishii T, Tsukanishi T, et al. Denosumab for treatment of a recurrent cervical giant-cell tumor. Asian Spine J 2016;10(3):553-7. https://doi.org/10.4184/asj.2016.10.3.553
33. Guelman R, Larroude MS, Mansur JL, Sánchez A, Vega E, Zanchetta MB, et al. Osteonecrosis de los maxilares
asociada a medicamentos (ONMM). Guía redactada por expertos invitados de la Asociación Argentina de Osteología y Metabolismo Mineral y por la Sociedad Argentina de Osteoporosis. Actual Osteol 2020;16(3):232-52.
Disponible en: http://www.osteologia.org.ar
34. Bansal K, Singh S, Mallepally AR, Shahi P. Rapid recurrence of giant cell tumour of C2 vertebra after long-term
denosumab following surgical resection. Cureus 2022;14(2):e22000. https://doi.org/10.7759/cureus.22000
35. Bukata SV, Blay JY, Rutkowski P, Skubitz K, Henshaw R, Seeger L, et al. Denosumab treatment for giant cell tumor of the spine including the sacrum. Spine (Phila Pa 1976) 2021;46(5):277-84. https://doi.org/10.1097/BRS.0000000000003728
1976) 2017;42(10):E629-E632. https://doi.org/10.1097/BRS.0000000000001951
2. Ohnishi T, Ogawa Y, Suda K, Komatsu M, Harmon SM, Asukai M, et al. Molecular targeted therapy for the bone
loss secondary to pyogenic spondylodiscitis using medications for osteoporosis: A literature review. Int J Mol Sci
2021;22(9):4453. https://doi.org/10.3390/ijms22094453
3. Zhang RZ, Ma TX, Qi DW, Zhao M, Hu T, Zhang GC. Short-term preoperative denosumab with surgery in
unresectable or recurrent giant cell tumor of bone. Orthop Surg 2019;11(6):1101-8. https://doi.org/10.1111/os.12561
4. Bazán PL, Di Falco R, Borri A, Medina M, Ciccioli N. The use of denosumab in giant cell tumors in the sacrum.
Coluna/Columna 2020;19(2). https://doi.org/10.1590/S1808-185120201902228839
5. Ng VY, Davidson DJ, Kim EY, Pollack SM, Conrad Iii EU, Jones RL. The multidisciplinary management of giant
cell tumor of bone. Expert Rev Anticancer Ther 2014;14(7):783-90. https://doi.org/10.1586/14737140.2014.901891
6. 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. https://doi.org/10.1016/j.ejca.2017.02.021A22
7. 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. https://doi.org/10.1016/S1470-2045(13)70277-8
8. Thomas D, Henshaw R, Skubitz K, Chawla S, Staddon A, Blay JY, et al. Denosumab in patients with giant-cell
tumour of bone: an open-label, phase 2 study. Lancet Oncol 2010;11(3):275-80. https://doi.org/10.1016/S1470-2045(10)70010-3
9. Law GW, Yeo NEM, Howe TS, Tan YZ, Tan SB, Siddiqui MMA. Recommencement of denosumab for unresectable
giant cell tumor of the cervical spine: A case report. Spine (Phila Pa 1976) 2018;43(9):E551-E556. https://doi.org/10.1097/BRS.0000000000002440
10. Lanari F, Godoy AO, Bazán PL. Uso de denosumab para el quiste óseo aneurismático de columna. Reporte de un caso y revisión bibliográfica. Rev Asoc Argent Ortop Traumatol 2021;86(6):821-8. https://doi.org/10.15417/issn.1852-7434.2021.86.6.1121
11. 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):10.1002/pbc.26926.
https://doi.org/10.1002/pbc.26926
12. Skubitz KM, Peltola JC, Santos ER, Cheng EY. Response of aneurysmal bone cyst to denosumab. Spine (Phila Pa 1976) 2015;40(22):E1201-E1204. https://doi.org/10.1097/BRS.0000000000001027
13. Dubory A, Missenard G, Domont J, Court C. Interest of denosumab for the treatment of giant-cells tumors and aneurysmal bone cysts of the spine. About nine cases. Spine (Phila Pa 1976) 2016;41(11):E654-E660.
https://doi.org/10.1097/BRS.0000000000001350
14. Kushlinskii NE, Gershtein ES, Solov’ev YN, Timofeev YS, Babkina IV, Dolinkin AO, et al. Receptor activator of
nuclear transcription factor NF-κB (RANK), its ligand RANKL, and natural inhibitor of RANKL osteoprotegerin
(OPG) in the blood serum of patients with primary bone tumors. Bull Exp Biol Med 2017;163(4):478-81.
https://doi.org/10.1007/s10517-017-3832-9
15. Sohn W, Simiens MA, Jaeger K, Hutton S, Jang G. The pharmacokinetics and pharmacodynamics of denosumab in patients with advanced solid tumours and bone metastases: a systematic review. Br J Clin Pharmacol 2014;78(3):477-87. https://doi.org/10.1111/bcp.12355
16. Ford J, Cummins E, Sharma P, Elders A, Stewart F, Johnston R, et al. Systematic review of the clinical effectiveness and cost-effectiveness, and economic evaluation, of denosumab for the treatment of bone metastases from solid tumours. Health Technol Assess 2013;17(29):1-386. https://doi.org/10.3310/hta17290
17. Sun L, Yu S. Efficacy and safety of denosumab versus zoledronic acid in patients with bone metastases: a systematic review and meta-analysis. Am J Clin Oncol 2013;36(4):399-403. https://doi.org/10.1097/COC.0b013e31824be20e
18. Li HS, Lei SY, Li JL, Xing PY, Hao XZ, Xu F, et al. Efficacy and safety of concomitant immunotherapy and
denosumab in patients with advanced non-small cell lung cancer carrying bone metastases: A retrospective chart review. Front Immunol 2022;13:908436. https://doi.org/10.3389/fimmu.2022.908436
19. Diel I, Ansorge S, Hohmann D, Giannopoulou C, Niepel D, Intorcia M. Real-world use of denosumab and
bisphosphonates in patients with solid tumours and bone metastases in Germany. Support Care Cancer
2020;28(11):5223-33. https://doi.org/10.1007/s00520-020-05357-5
20. Li B, Wang P, Jiao J, Wei H, Xu W, Zhou P. Roles of the RANKL-RANK axis in immunity-implications for
pathogenesis and treatment of bone metastasis. Front Immunol 2022;13:824117. https://doi.org/10.3389/fimmu.2022.824117
21. Stopeck A, Brufsky A, Kennedy L, Bhatta S, Bhowmik D, Buchanan J, et al. Cost-effectiveness of denosumab for the prevention of skeletal-related events in patients with solid tumors and bone metastases in the United States. J Medical Econ 2020;23(1):37-47. https://doi.org/10.1080/13696998.2019.1651122
22. Chen J, Zhou L, Liu X, Wen X, Li H, Li W. Meta-analysis of clinical trials to assess denosumab over zoledronic acid in bone metastasis. Int J Clin Pharm 2021;43(1):2-10. https://doi.org/10.1007/s11096-020-01105-1
23. Cadieux B, Coleman R, Jafarinasabian P, Lipton A, Orlowski RZ, Saad F, et al. Experience with denosumab
(XGEVA®) for prevention of skeletal-related events in the 10 years after approval. J Bone Oncol 2022;33:100416.
https://doi.org/10.1016/j.jbo.2022.100416
24. Raje N, Terpos E, Willenbacher W, Shimizu K, García-Sanz R, Durie B, et al. Denosumab versus zoledronic acid
in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy,
randomised, controlled, phase 3 study. Lancet Oncol 2018;19(3):370-81. https://doi.org/10.1016/S1470-2045(18)30072-X
25. Lam FC, Arle JE, Glazer PA, Kasper EM. Primary extradural tumors of the spine - Case review with evidenceguided management. Surg Neurol Int 2014;5(Suppl 7):S373-5. https://doi.org/10.4103/2152-7806.139673
26. 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.
https://doi.org/10.3171/2014.10.SPINE13937
27. Boriani S, Cecchinato R, Cuzzocrea F, Bandiera S, Gambarotti M, Gasbarrini A. Denosumab in the treatment
of giant cell tumor of the spine. Preliminary report, review of the literature and protocol proposal. Eur Spine J
2019;29(2):257-71. https://doi.org/10.1007/s00586-019-05997-0
28. Xará‐Leite F, Coutinho L, Fleming C, Magalhães M, Oliveira V, Rodrigues-Pinto R, et al. Can denosumab cure giant cell tumors of the spine? A case report and literature review. Eur J Orthop Surg Traumatol 2020;30(1):19-23.
https://doi.org/10.1007/s00590-019-02554-9
29. Leggett A, Berg A, Hullinger H, Benevenia J. Diagnosis and treatment of lumbar giant cell tumor of the spine:
Update on current management strategies. Diagnostics (Basel) 2022;12(4):857. https://doi.org/10.3390/diagnostics12040857
30. Bazán PL, Cinalli M, Lanari Zabiaur, F, Castelli R, Silveri C, Monayer JL, et al. Long-term use of denosumab in
giant cell tumors and vertebral aneurysmal bone cysts. Coluna/Columna 2022;21(1). https://doi.org/10.1590/S1808-185120222101253789
31. Yayama T, Mori K, Nakamura A, Mimura T, Imai S. Denosumab therapy for giant-cell tumor of the lumbar spine: A case report and immunohistochemical examination. J Orthop Case Rep 2020;10(2):76-9.
https://doi.org/10.13107/jocr.2020.v10.i02.1706
32. Kajiwara D, Kamoda H, Yonemoto T, Iwata S, Ishii T, Tsukanishi T, et al. Denosumab for treatment of a recurrent cervical giant-cell tumor. Asian Spine J 2016;10(3):553-7. https://doi.org/10.4184/asj.2016.10.3.553
33. Guelman R, Larroude MS, Mansur JL, Sánchez A, Vega E, Zanchetta MB, et al. Osteonecrosis de los maxilares
asociada a medicamentos (ONMM). Guía redactada por expertos invitados de la Asociación Argentina de Osteología y Metabolismo Mineral y por la Sociedad Argentina de Osteoporosis. Actual Osteol 2020;16(3):232-52.
Disponible en: http://www.osteologia.org.ar
34. Bansal K, Singh S, Mallepally AR, Shahi P. Rapid recurrence of giant cell tumour of C2 vertebra after long-term
denosumab following surgical resection. Cureus 2022;14(2):e22000. https://doi.org/10.7759/cureus.22000
35. Bukata SV, Blay JY, Rutkowski P, Skubitz K, Henshaw R, Seeger L, et al. Denosumab treatment for giant cell tumor of the spine including the sacrum. Spine (Phila Pa 1976) 2021;46(5):277-84. https://doi.org/10.1097/BRS.0000000000003728