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Mechanisms of acute hypercalcemia in pediatric patients following the interruption of Denosumab

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Abstract

Purpose

Denosumab is a fully human monoclonal anti-RANK-L antibody that is clinically used to counteract the bone loss induced by exacerbated osteoclast activity. Indeed, its binding to RANK-L prevents the interaction RANK-L/receptor RANK that is essential for osteoclastogenesis and bone resorbing activity. Although there are many medications available to treat bone loss diseases, including bisphosphonates, Denosumab is highly effective since it reduces the bone erosion. The use in pediatric patients is safe. However, some concerns are related to the interruption of the treatment. Indeed, in this study, we reported hypercalcemia in two pediatric patients and alterations of circulating osteoclast precursors.

Methods

Peripheral Blood Mononuclear Cells (PBMC) were isolated from two pediatric patients with hypercalcemia after Denosumab interruption and from 10 controls. Cytofluorimetric analysis and in vitro osteoclastogenesis experiments were performed.

Results

Increase of CD16−CD14+CD11b+ cells was revealed in PBMC from patients reflecting the enhanced in vitro osteoclastogenesis.

Conclusion

Our data suggest that precautions must be taken when Denosumab therapy is interrupted and gradual decrease of dose and/or timing of treatment should be performed. To prevent the onset of hypercalcemia that could be in the discontinuation phase, cytofluorimetric analysis of PBMC should be performed to evaluate osteoclast precursors.

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References

  1. Hofbauer LC, Heufelder AE (2001) Role of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin in bone cell biology. J Mol Med (Berl) 79(5–6):243–253. https://doi.org/10.1007/s001090100226

    Article  CAS  Google Scholar 

  2. Kearns AE, Khosla S, Kostenuik PJ (2008) Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev 29(2):155–192. https://doi.org/10.1210/er.2007-0014

    Article  CAS  PubMed  Google Scholar 

  3. Ono T, Hayashi M, Sasaki F, Nakashima T (2020) RANKL biology: bone metabolism, the immune system, and beyond. Inflamm Regen 40:2. https://doi.org/10.1186/s41232-019-0111-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ahern E, Smyth MJ, Dougall WC, Teng MWL (2018) Roles of the RANKL-RANK axis in antitumour immunity—implications for therapy. Nat Rev Clin Oncol 15(11):676–693. https://doi.org/10.1038/s41571-018-0095-y

    Article  PubMed  Google Scholar 

  5. Xiong J, Cawley K, Piemontese M, Fujiwara Y, Zhao H, Goellner JJ, O’Brien CA (2018) Soluble RANKL contributes to osteoclast formation in adult mice but not ovariectomy-induced bone loss. Nat Commun 9(1):2909. https://doi.org/10.1038/s41467-018-05244-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wilson C (2011) Osteocytes, RANKL and bone loss. Nat Rev Endocrinol 7(12):693. https://doi.org/10.1038/nrendo.2011.176

    Article  PubMed  Google Scholar 

  7. Sobacchi C, Menale C, Villa A (2019) The RANKL-RANK axis: a bone to thymus round trip. Front Immunol 10:629. https://doi.org/10.3389/fimmu.2019.00629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chen X, Zhi X, Wang J, Su J (2018) RANKL signaling in bone marrow mesenchymal stem cells negatively regulates osteoblastic bone formation. Bone Res 6:34. https://doi.org/10.1038/s41413-018-0035-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kostenuik PJ, Nguyen HQ, McCabe J, Warmington KS, Kurahara C, Sun N, Chen C, Li L, Cattley RC, Van G et al (2009) Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL. J Bone Miner Res 24(2):182–195. https://doi.org/10.1359/jbmr.081112

    Article  CAS  PubMed  Google Scholar 

  10. Dubois EA, Rissmann R, Cohen AF (2011) Denosumab. Br J Clin Pharmacol 71(6):804–806. https://doi.org/10.1111/j.1365-2125.2011.03969.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. An SY (2012) Aneurysmal bone cyst of the mandible managed by conservative surgical therapy with preoperative embolization. Imaging Sci Dent 42(1):35–39. https://doi.org/10.5624/isd.2012.42.1.35

    Article  PubMed  PubMed Central  Google Scholar 

  12. Yu X, Guo R, Fan C, Liu H, Zhang B, Nie T, Tu YI, Dai M (2016) Aneurysmal bone cyst secondary to a giant cell tumor of the patella: a case report. Oncol Lett 11(2):1481–1485. https://doi.org/10.3892/ol.2016.4080

    Article  PubMed  PubMed Central  Google Scholar 

  13. Boyce AM (2017) Denosumab: an emerging therapy in pediatric bone disorders. Curr Osteoporos Rep 15(4):283–292. https://doi.org/10.1007/s11914-017-0380-1

    Article  PubMed  PubMed Central  Google Scholar 

  14. Colia V, Provenzano S, Hindi N, Casali PG, Stacchiotti S (2016) Systemic therapy for selected skull base sarcomas: Chondrosarcoma, chordoma, giant cell tumour and solitary fibrous tumour/hemangiopericytoma. Rep Pract Oncol Radiother 21(4):361–369. https://doi.org/10.1016/j.rpor.2015.12.005

    Article  PubMed  PubMed Central  Google Scholar 

  15. Marcucci G, Beltrami G, Tamburini A, Body JJ, Confavreux CB, Hadji P, Holzer G, Kendler D, Napoli N, Pierroz DD et al (2019) Bone health in childhood cancer: review of the literature and recommendations for the management of bone health in childhood cancer survivors. Ann Oncol 30(6):908–920. https://doi.org/10.1093/annonc/mdz120

    Article  CAS  PubMed  Google Scholar 

  16. Lipplaa A, Dijkstra S, Gelderblom H (2019) Challenges of denosumab in giant cell tumor of bone, and other giant cell-rich tumors of bone. Curr Opin Oncol 31(4):329–335. https://doi.org/10.1097/CCO.0000000000000529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Leithner A, Windhager R, Lang S, Haas OA, Kainberger F, Kotz R (1999) Aneurysmal bone cyst. A population based epidemiologic study and literature review. Clin Orthop Relat Res 363:176–179

    Article  Google Scholar 

  18. Park HY, Yang SK, Sheppard WL, Hegde V, Zoller SD, Nelson SD, Federman N, Bernthal NM (2016) Current management of aneurysmal bone cysts. Curr Rev Musculoskelet Med 9(4):435–444. https://doi.org/10.1007/s12178-016-9371-6

    Article  PubMed  PubMed Central  Google Scholar 

  19. Wang Y, Le A, El Demellawy D, Shago M, Odell M, Johnson-Obaseki S (2019) An aggressive central giant cell granuloma in a pediatric patient: case report and review of literature. J Otolaryngol Head Neck Surg 48(1):32. https://doi.org/10.1186/s40463-019-0356-5

    Article  PubMed  PubMed Central  Google Scholar 

  20. Bredell M, Rordorf T, Kroiss S, Rucker M, Zweifel DF, Rostetter C (2018) Denosumab as a treatment alternative for central giant cell granuloma: a long-term retrospective cohort study. J Oral Maxillofac Surg 76(4):775–784. https://doi.org/10.1016/j.joms.2017.09.013

    Article  PubMed  Google Scholar 

  21. Jeyaraj P (2019) Management of central giant cell granulomas of the jaws: an unusual case report with critical appraisal of existing literature. Ann Maxillofac Surg 9(1):37–47. https://doi.org/10.4103/ams.ams_232_18

    Article  PubMed  PubMed Central  Google Scholar 

  22. McClung MR (2017) Denosumab for the treatment of osteoporosis. Osteoporos Sarcopenia 3(1):8–17. https://doi.org/10.1016/j.afos.2017.01.002

    Article  PubMed  PubMed Central  Google Scholar 

  23. Tsourdi E, Langdahl B, Cohen-Solal M, Aubry-Rozier B, Eriksen EF, Guanabens N, Obermayer-Pietsch B, Ralston SH, Eastell R, Zillikens MC (2017) Discontinuation of Denosumab therapy for osteoporosis: a systematic review and position statement by ECTS. Bone 105:11–17. https://doi.org/10.1016/j.bone.2017.08.003

    Article  PubMed  Google Scholar 

  24. Hoyer-Kuhn H, Franklin J, Allo G, Kron M, Netzer C, Eysel P, Hero B, Schoenau E, Semler O (2016) Safety and efficacy of denosumab in children with osteogenesis imperfect–a first prospective trial. J Musculoskelet Neuronal Interact 16(1):24–32

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Sydlik C, Durr HR, Pozza SB, Weissenbacher C, Roeb J, Schmidt H (2020) Hypercalcaemia after treatment with denosumab in children: bisphosphonates as an option for therapy and prevention? World J Pediatr 16(5):520–527. https://doi.org/10.1007/s12519-020-00378-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Grasemann C, Schundeln MM, Hovel M, Schweiger B, Bergmann C, Herrmann R, Wieczorek D, Zabel B, Wieland R, Hauffa BP (2013) Effects of RANK-ligand antibody (denosumab) treatment on bone turnover markers in a girl with juvenile Paget’s disease. J Clin Endocrinol Metab 98(8):3121–3126. https://doi.org/10.1210/jc.2013-1143

    Article  CAS  PubMed  Google Scholar 

  27. Setsu N, Kobayashi E, Asano N, Yasui N, Kawamoto H, Kawai A, Horiuchi K (2016) Severe hypercalcemia following denosumab treatment in a juvenile patient. J Bone Miner Metab 34(1):118–122. https://doi.org/10.1007/s00774-015-0677-z

    Article  PubMed  Google Scholar 

  28. Uday S, Gaston CL, Rogers L, Parry M, Joffe J, Pearson J, Sutton D, Grimer R, Hogler W (2018) Osteonecrosis of the jaw and rebound hypercalcemia in young people treated with denosumab for giant cell tumor of bone. J Clin Endocrinol Metab 103(2):596–603. https://doi.org/10.1210/jc.2017-02025

    Article  PubMed  Google Scholar 

  29. Del Fattore A, Peruzzi B, Rucci N, Recchia I, Cappariello A, Longo M, Fortunati D, Ballanti P, Iacobini M, Luciani M et al (2006) Clinical, genetic, and cellular analysis of 49 osteopetrotic patients: implications for diagnosis and treatment. J Med Genet 43(4):315–325. https://doi.org/10.1136/jmg.2005.036673

    Article  CAS  PubMed  Google Scholar 

  30. Palmerini E, Ruggieri P, Angelini A, Boriani S, Campanacci D, Milano GM, Cesari M, Paioli A, Longhi A, Abate ME et al (2018) Denosumab in patients with aneurysmal bone cysts: a case series with preliminary results. Tumori 104(5):344–351. https://doi.org/10.1177/0300891618784808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Auron A, Alon US (2018) Hypercalcemia: a consultant’s approach. Pediatr Nephrol 33(9):1475–1488. https://doi.org/10.1007/s00467-017-3788-z

    Article  PubMed  Google Scholar 

  32. Komano Y, Nanki T, Hayashida K, Taniguchi K, Miyasaka N (2006) Identification of a human peripheral blood monocyte subset that differentiates into osteoclasts. Arthritis Res Ther 8(5):R152. https://doi.org/10.1186/ar2046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. McClung MR, Wagman RB, Miller PD, Wang A, Lewiecki EM (2017) Observations following discontinuation of long-term denosumab therapy. Osteoporos Int 28(5):1723–1732. https://doi.org/10.1007/s00198-017-3919-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Martin J, Amg Bone Loss Study G (2008) Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone 43(2):222–229. https://doi.org/10.1016/j.bone.2008.04.007

    Article  CAS  Google Scholar 

  35. Iranikhah M, Deas C, Murphy P, Freeman MK (2018) Effects of denosumab after treatment discontinuation: a review of the literature. Consult Pharm 33(3):142–151. https://doi.org/10.4140/TCP.n.2018.142

    Article  PubMed  Google Scholar 

  36. Bone HG, Bolognese MA, Yuen CK, Kendler DL, Miller PD, Yang YC, Grazette L, San Martin J, Gallagher JC (2011) 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 96(4):972–980. https://doi.org/10.1210/jc.2010-1502

    Article  CAS  PubMed  Google Scholar 

  37. Anastasilakis AD, Evangelatos G, Makras P, Iliopoulos A (2020) Rebound-associated vertebral fractures may occur in sequential time points following denosumab discontinuation: need for prompt treatment re-initiation. Bone Rep 12:100267. https://doi.org/10.1016/j.bonr.2020.100267

    Article  PubMed  PubMed Central  Google Scholar 

  38. Choe M, Smith V, Okcu MF, Wulff J, Gruner S, Huisman T, Venkatramani R (2020) Treatment of central giant cell granuloma in children with denosumab. Pediatr Blood Cancer. https://doi.org/10.1002/pbc.28778

    Article  PubMed  Google Scholar 

  39. Anastasilakis AD, Yavropoulou MP, Makras P, Sakellariou GT, Papadopoulou F, Gerou S, Papapoulos SE (2017) Increased osteoclastogenesis in patients with vertebral fractures following discontinuation of denosumab treatment. Eur J Endocrinol 176(6):677–683. https://doi.org/10.1530/EJE-16-1027

    Article  CAS  PubMed  Google Scholar 

  40. Gossai N, Hilgers MV, Polgreen LE, Greengard EG (2015) Critical hypercalcemia following discontinuation of denosumab therapy for metastatic giant cell tumor of bone. Pediatr Blood Cancer 62(6):1078–1080. https://doi.org/10.1002/pbc.25393

    Article  PubMed  Google Scholar 

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Funding

The present study received funding from Ministero della Salute (Ricerca Corrente 2020) to ADF.

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Authors and Affiliations

  1. Endocrinology Unit, University Pediatric Clinical Department, Bambino Gesù Children’s Hospital, IRCCS, 00146, Rome, Italy

    A. Deodati, D. Fintini, G. Ubertini & M. Cappa

  2. Department of Pediatrics, University Hospitals Leuven, 3000, Leuven, Belgium

    E. Levtchenko & H. Segers

  3. Bone Physiopathology Research Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children’s Hospital, IRCCS, Viale San Paolo 15, 00146, Rome, Italy

    M. Rossi, G. Battafarano & A. Del Fattore

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  1. A. Deodati
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  2. D. Fintini
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  4. M. Rossi
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  9. A. Del Fattore
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Contributions

Study design: AD and DF. Study conduct: MR, GB and HS. Data collection: AD, DF, EL, GU, and ADF. Data analysis and interpretation: ADF, DF, MC and AD. Drafting manuscript: AD, DF, MC, and ADF. Approving final version of manuscript: AD, DF, EL, MR, GU, HS, GB, MC and ADF. ADF take responsibility for the integrity of the data analysis.

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Correspondence to A. Del Fattore.

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The authors have no conflict of interest to declare.

Ethical approval

All the procedures performed in this study involving human participants were in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Ethical approval for the study was granted by ethical committee of Bambino Gesù Children’s Hospital.

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Informed consent was obtained from all individual participants included in the study.

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Deodati, A., Fintini, D., Levtchenko, E. et al. Mechanisms of acute hypercalcemia in pediatric patients following the interruption of Denosumab. J Endocrinol Invest 45, 159–166 (2022). https://doi.org/10.1007/s40618-021-01630-4

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  • DOI: https://doi.org/10.1007/s40618-021-01630-4

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