Abstract
Denosumab delays and prevents skeletal related events in patients with malignancy-related bony metastases. Rarely, denosumab discontinuation can lead to rebound hypercalcemia in the setting of increased bone resorption. We describe the case of a 49-year-old breast cancer survivor who developed rebound hypercalcemia after cessation of long-term denosumab. She had been treated with 42 doses of denosumab between August 2013 and March 2020 and 8 months after her last dose of denosumab developed symptomatic hypercalcemia. Parathyroid hormone levels were suppressed, and active malignancy was excluded based on biochemical and radiological testing. She required treatment with intravenous bisphosphonates on three separate occasions in order to achieve long-term normalization of her hypercalcemia. Rebound hypercalcemia post-denosumab cessation is a rare but serious complication that clinicians should be aware of.
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References
Stewart AF (2005) Clinical practice. Hypercalcemia associated with cancer. N Engl J Med. 352(4):373–9. https://doi.org/10.1056/NEJMcp042806
Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, Lichinitser M, Fujiwara Y, Yardley DA, Viniegra M, Fan M, Jiang Q, Dansey R, Jun S, Braun A (2010) 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 28(35):5132–5139. https://doi.org/10.1200/JCO.2010.29.7101
Anastasilakis AD, Makras P, Yavropoulou MP, Tabacco G, Naciu AM, Palermo A (2021) Denosumab discontinuation and the rebound phenomenon: a narrative review. J Clin Med 10(1):152. https://doi.org/10.3390/jcm10010152
Van Poznak C, Somerfield MR, Barlow WE, Biermann JS, Bosserman LD, Clemons MJ, Dhesy-Thind SK, Dillmon MS, Eisen A, Frank ES, Jagsi R, Jimenez R, Theriault RL, Vandenberg TA, Yee GC, Moy B (2017) role of bone-modifying agents in metastatic breast cancer: an American Society of Clinical Oncology-Cancer Care Ontario Focused Guideline Update. J Clin Oncol 35(35):3978–3986. https://doi.org/10.1200/JCO.2017.75.4614
Coleman R, Hadji P, Body JJ, Santini D, Chow E, Terpos E, Oudard S, Bruland Ø, Flamen P, Kurth A, Van Poznak C, Aapro M, Jordan K, ESMO Guidelines Committee (2020) Electronic address: clinicalguidelines@esmo.org. Bone health in cancer: ESMO Clinical Practice Guidelines. Ann Oncol 31(12):1650–1663. https://doi.org/10.1016/j.annonc.2020.07.019
Camponovo C, Aubry-Rozier B, Lamy O, Gonzalez RE (2020) Hypercalcemia upon denosumab withdrawal in primary hyperparathyroidism: a case report and literature review. Osteoporos Int 31(12):2485–2491. https://doi.org/10.1007/s00198-020-05676-7
Maugars Y, Guillot P, Glémarec J, Berthelot JM, Le Goff B, Darrieutort-Laffite C (2020) Long-term follow up after denosumab treatment for osteoporosis - rebound associated with hypercalcemia, parathyroid hyperplasia, severe bone mineral density loss, and multiple fractures: a case report. J Med Case Rep 14(1):130. https://doi.org/10.1186/s13256-020-02401-0
Uday S, Gaston CL, Rogers L, Parry M, Joffe J, Pearson J, Sutton D, Grimer R, Högler 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
Chawla S, Blay JY, Rutkowski P, Le Cesne A, Reichardt P, Gelderblom H, Grimer RJ, Choy E, Skubitz K, Seeger L, Schuetze SM, Henshaw R, Dai T, Jandial D, Palmerini E (2019) Denosumab in patients with giant-cell tumour of bone: a multicentre, open-label, phase 2 study. Lancet Oncol 20(12):1719–1729. https://doi.org/10.1016/S1470-2045(19)30663-1
Uchida T, Yamaguchi H, Kushima C, Yonekawa T, Nakazato M (2020) Elevated levels of circulating fibroblast growth factor 23 with hypercalcemia following discontinuation of denosumab. Endocr J 67(1):31–35. https://doi.org/10.1507/endocrj.EJ19-0198
Roux S, Massicotte MH, Huot Daneault A, Brazeau-Lamontagne L, Dufresne J (2019) Acute hypercalcemia and excessive bone resorption following anti-RANKL withdrawal: case report and brief literature review. Bone 120:482–486. https://doi.org/10.1016/j.bone.2018.12.012
Koldkjær Sølling AS, Harsløf T, Kaal A, Rejnmark L, Langdahl B (2016) Hypercalcemia after discontinuation of long-term denosumab treatment. Osteoporos Int 27(7):2383–2386. https://doi.org/10.1007/s00198-016-3535-5
Tjelum L, Eiken P (2018) [Multiple vertebral fractures after denosumab discontinuation]. Ugeskr Laeger. 180(45):V12170948. Danish
Boyce AM, Chong WH, Yao J, Gafni RI, Kelly MH, Chamberlain CE, Bassim C, Cherman N, Ellsworth M, Kasa-Vubu JZ, Farley FA, Molinolo AA, Bhattacharyya N, Collins MT (2012) Denosumab treatment for fibrous dysplasia. J Bone Miner Res 27(7):1462–1470. https://doi.org/10.1002/jbmr.1603
Grasemann C, Schündeln MM, Hövel 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
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
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
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
Trejo P, Rauch F, Ward L (2018) Hypercalcemia and hypercalciuria during denosumab treatment in children with osteogenesis imperfecta type VI. J Musculoskelet Neuronal Interact 18(1):76–80
Dürr HR, Grahneis F, Baur-Melnyk A, Knösel T, Birkenmaier C, Jansson V, Klein A (2019) Aneurysmal bone cyst: results of an off label treatment with Denosumab. BMC Musculoskelet Disord 20(1):456. https://doi.org/10.1186/s12891-019-2855-y
Upfill-Brown A, Bukata S, Bernthal NM, Felsenfeld AL, Nelson SD, Singh A, Wesseling-Perry K, Eilber FC, Federman NC (2019) Use of denosumab in children with osteoclast bone dysplasias: report of three cases. JBMR Plus 3(10):e10210. https://doi.org/10.1002/jbm4.10210
Tsourdi E, Langdahl B, Cohen-Solal M, Aubry-Rozier B, Eriksen EF, Guañabens 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
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Wang, R., Renouf, D.A. Rebound hypercalcemia post-denosumab cessation in metastatic breast cancer. Osteoporos Int 33, 1625–1629 (2022). https://doi.org/10.1007/s00198-022-06369-z
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DOI: https://doi.org/10.1007/s00198-022-06369-z