Hypercalcemia of Malignancy: Diagnostic and Therapeutic Challenges
DOI:
https://doi.org/10.12775/JEHS.2026.88.68240Keywords
Hypercalcemia, Neoplasms, Bisphosphonates, Parathyroid Hormone-Related Protein, Prognosis, TherapeuticsAbstract
Background.
Malignancy-associated hypercalcemia (HHM) is a frequent metabolic complication in advanced cancer, often leading to neurological deterioration, cardiovascular disturbances, reduced functional status, and shorter survival. In palliative care, timely diagnosis and management of HHM are essential to improve symptom control and patient comfort.
Aim.
To present a comprehensive, evidence-based review of current diagnostic and therapeutic approaches to hypercalcemia of malignancy, with a focus on palliative care settings.
Material and methods.
A narrative review was conducted using databases such as PubMed, MEDLINE, Google Scholar, and Europe PMC. Fifty-six articles published between 1994 and 2024 were selected based on clinical relevance and scientific quality.
Results.
Hypercalcemia in malignancy arises predominantly from PTHrP secretion, calcitriol overproduction, or local osteolysis. Diagnostic workup includes calcium profile, PTH/PTHrP levels, and imaging. Management involves intravenous hydration, bisphosphonates, denosumab, glucocorticosteroids, and—occasionally—calcitonin or hemodialysis. Timely treatment improves symptoms and may enable continuation of oncologic therapies. In palliative patients, hypercalcemia often necessitates a shift toward comfort-focused care and underscores the importance of interdisciplinary management.
Conclusions.
Malignancy-associated hypercalcemia significantly worsens prognosis and quality of life in advanced cancer. Individualized treatment—including rehydration, anti-resorptive agents, and symptom control—is essential. Effective calcium regulation alleviates suffering, facilitates supportive care, and should be integrated into comprehensive palliative strategies.
References
1. Jick S, Li L, Gastanaga VM, Liede A. Prevalence of hypercalcemia of malignancy among cancer patients in the UK: analysis of the Clinical Practice Research Datalink database. Cancer Epidemiol. 2015;39: 901–907. doi:10.1016/j.canep.2015.10.012
2. Mousseaux C, Dupont A, Rafat C, Ekpe K, Ghrenassia E, Kerhuel L, et al. Epidemiology, clinical features, and management of severe hypercalcemia in critically ill patients. Ann Intensive Care. 2019;9: 133. doi:10.1186/s13613-019-0606-8
3. Gupta S, Rastogi A, Singh P, Chophy A, Roushan R, Krishnan AS, et al. Treatment outcomes and survival in hypercalcemia of malignancy: A grave metabolic emergency. Cureus. 2023;15: e35783. doi:10.7759/cureus.35783
4. Mirrakhimov AE. Hypercalcemia of malignancy: An update on pathogenesis and management. N Am J Med Sci. 2015;7: 483–493. doi:10.4103/1947-2714.170600
5. Asonitis N, Angelousi A, Zafeiris C, Lambrou GI, Dontas I, Kassi E. Diagnosis, pathophysiology and management of hypercalcemia in malignancy: A review of the literature. Horm Metab Res. 2019;51: 770–778. doi:10.1055/a-1049-0647
6. Goldner W. Cancer-related hypercalcemia. J Oncol Pract. 2016;12: 426–432. doi:10.1200/JOP.2016.011155
7. Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med. 2005;352: 373–379. doi:10.1056/NEJMcp042806
8. Reagan P, Pani A, Rosner MH. Approach to diagnosis and treatment of hypercalcemia in a patient with malignancy. Am J Kidney Dis. 2014;63: 141–147. doi:10.1053/j.ajkd.2013.06.025
9. Zagzag J, Hu MI, Fisher SB, Perrier ND. Hypercalcemia and cancer: Differential diagnosis and treatment. CA Cancer J Clin. 2018;68: 377–386. doi:10.3322/caac.21489
10. Rosner MH, Dalkin AC. Onco-nephrology: the pathophysiology and treatment of malignancy-associated hypercalcemia. Clin J Am Soc Nephrol. 2012;7: 1722–1729. doi:10.2215/CJN.02470312
11. Almuradova E, Cicin I. Cancer-related hypercalcemia and potential treatments. Front Endocrinol (Lausanne). 2023;14: 1039490. doi:10.3389/fendo.2023.1039490
12. Basso U, Maruzzo M, Roma A, Camozzi V, Luisetto G, Lumachi F. Malignant hypercalcemia. Curr Med Chem. 2011;18: 3462–3467. doi: https://doi.org/10.2174/157340612801216382
13. Sternlicht H, Glezerman IG. Hypercalcemia of malignancy and new treatment options. Ther Clin Risk Manag. 2015;11: 1779–1788. doi:10.2147/TCRM.S83681
14. Bartkiewicz P, Kunachowicz D, Filipski M, Stebel A, Ligoda J, Rembiałkowska N. Hypercalcemia in cancer: Causes, effects, and treatment strategies. Cells. 2024;13: 1051. doi:10.3390/cells13121051
15. Peacock M. Calcium metabolism in health and disease. Clin J Am Soc Nephrol. 2010;5 Suppl 1: S23–30. doi:10.2215/CJN.05910809
16. Kim W, Takyar FM, Swan K, Jeong J, VanHouten J, Sullivan C, et al. Calcium-sensing receptor promotes breast cancer by stimulating intracrine actions of parathyroid hormone-related protein. Cancer Res. 2016;76: 5348–5360. doi:10.1158/0008-5472.CAN-15-2614
17. Levine BS, Rodríguez M, Felsenfeld AJ. Serum calcium and bone: effect of PTH, phosphate, vitamin D and uremia. Nefrologia. 2014;34: 658–669. doi:10.3265/Nefrologia.pre2014.Jun.12379
18. Chukir T, Liu Y, Hoffman K, Bilezikian JP, Farooki A. Calcitriol elevation is associated with a higher risk of refractory hypercalcemia of malignancy in solid tumors. J Clin Endocrinol Metab. 2020;105: e1115–e1123. doi:10.1210/clinem/dgz278
19. Tebben PJ, Singh RJ, Kumar R. Vitamin D-mediated hypercalcemia: Mechanisms, diagnosis, and treatment. Endocr Rev. 2016;37: 521–547. doi:10.1210/er.2016-1070
20. Sheehan MT, Li Y-H, Doi SA, Onitilo AA. Evaluation of diagnostic workup and etiology of hypercalcemia of malignancy in a cohort of 167 551 patients over 20 years. J Endocr Soc. 2021;5: bvab157. doi:10.1210/jendso/bvab157
21. Tonon CR, Silva TAAL, Pereira FWL, Queiroz DAR, Junior ELF, Martins D, et al. A review of current clinical concepts in the pathophysiology, etiology, diagnosis, and management of hypercalcemia. Med Sci Monit. 2022;28: e935821. doi:10.12659/MSM.935821
22. Maurizi A, Rucci N. The osteoclast in bone metastasis: Player and target. Cancers (Basel). 2018;10. doi:10.3390/cancers10070218
23. Soki FN, Park SI, McCauley LK. The multifaceted actions of PTHrP in skeletal metastasis. Future Oncol. 2012;8: 803–817. doi:10.2217/fon.12.76
24. Neves A, Mendonça I, Cunha Marques JA, Costa J, Almeida JS. Malignant hypercalcemia induced by the ectopic production of intact parathyroid hormone (PTH). Cureus. 2023;15: e34770. doi:10.7759/cureus.34770
25. Cheng C, Kuzhively J, Baim S. Hypercalcemia of malignancy in thymic carcinoma: Evolving mechanisms of hypercalcemia and targeted therapies. Case Rep Endocrinol. 2017;2017: 2608392. doi:10.1155/2017/2608392
26. Solimando DA. Overview of hypercalcemia of malignancy. Am J Health Syst Pharm. 2001;58 Suppl 3: S4–7. doi:10.1093/ajhp/58.suppl_3.S4
27. Song L. Calcium and bone metabolism indices. Adv Clin Chem. 2017;82: 1–46. doi:10.1016/bs.acc.2017.06.005
28. Bushinsky DA, Monk RD. Electrolyte quintet: Calcium. Lancet. 1998;352: 306–311. doi:10.1016/s0140-6736(97)12331-5
29. Fischer M, Schmutzhard E. Posterior reversible encephalopathy syndrome. J Neurol. 2017;264: 1608–1616. doi:10.1007/s00415-016-8377-8
30. Moussawi K, Meltzer EI, Levin SN, Prasad S. Paraneoplastic PRES from lymphoma induced hypercalcemia: Case report and review of the literature. eNeurologicalSci. 2018;13: 24–25. doi:10.1016/j.ensci.2018.11.003
31. Nishi SPE, Barbagelata NA, Atar S, Birnbaum Y, Tuero E. Hypercalcemia-induced ST-segment elevation mimicking acute myocardial infarction. J Electrocardiol. 2006;39: 298–300. doi:10.1016/j.jelectrocard.2005.10.015
32. Chang W-TW, Radin B, McCurdy MT. Calcium, magnesium, and phosphate abnormalities in the emergency department. Emerg Med Clin North Am. 2014;32: 349–366. doi:10.1016/j.emc.2013.12.006
33. Yang L, Lin Y, Zhang X-Q, Liu B, Wang J-Y. Acute pancreatitis with hypercalcemia caused by primary hyperparathyroidism associated with paraneoplastic syndrome: A case report and review of literature. World J Clin Cases. 2021;9: 8906–8914. doi:10.12998/wjcc.v9.i29.8906
34. Clines GA. Mechanisms and treatment of hypercalcemia of malignancy. Curr Opin Endocrinol Diabetes Obes. 2011;18: 339–346. doi:10.1097/MED.0b013e32834b4401
35. Inzucchi SE. Understanding hypercalcemia. Postgrad Med. 2004;115: 69–76. doi:10.3810/pgm.2004.04.1486
36. Duminuco A, Del Fabro V, De Luca P, Leotta D, Limoli MC, Longo E, et al. Emergencies in hematology: Why, when and how I treat? J Clin Med. 2024;13. doi:10.3390/jcm13247572
37. Walker MD, Shane E. Hypercalcemia: A review. JAMA. 2022;328: 1624–1636. doi:10.1001/jama.2022.18331
38. Endres DB. Investigation of hypercalcemia. Clin Biochem. 2012;45: 954–963. doi:10.1016/j.clinbiochem.2012.04.025
39. Kc O, Dahal PH, Koirala M, Al Zaghal E. Unusual case of dehydration leading to severe symptomatic hypercalcemia. Am J Case Rep. 2022;23: e936204. doi:10.12659/AJCR.936204
40. Meng QH, Wagar EA. Laboratory approaches for the diagnosis and assessment of hypercalcemia. Crit Rev Clin Lab Sci. 2015;52: 107–119. doi:10.3109/10408363.2014.970266
41. Wysolmerski JJ, Broadus AE. Hypercalcemia of malignancy: the central role of parathyroid hormone-related protein. Annu Rev Med. 1994;45: 189–200. doi:10.1146/annurev.med.45.1.189
42. Markowitz ME, Underland L, Gensure R. Parathyroid disorders. Pediatr Rev. 2016;37: 524–535. doi:10.1542/pir.2015-0076
43. Xie R, Tang B, Yong X, Luo G, Yang S-M. Roles of the calcium sensing receptor in digestive physiology and pathophysiology (review). Int J Oncol. 2014;45: 1355–1362. doi:10.3892/ijo.2014.2560
44. Vahe C, Benomar K, Espiard S, Coppin L, Jannin A, Odou MF, et al. Diseases associated with calcium-sensing receptor. Orphanet J Rare Dis. 2017;12: 19. doi:10.1186/s13023-017-0570-z
45. Body J-J, Niepel D, Tonini G. Hypercalcaemia and hypocalcaemia: finding the balance. Support Care Cancer. 2017;25: 1639–1649. doi:10.1007/s00520-016-3543-1
46. Reid IR, Green JR, Lyles KW, Reid DM, Trechsel U, Hosking DJ, et al. Zoledronate. Bone. 2020;137: 115390. doi:10.1016/j.bone.2020.115390
47. Abrahamsen B. Adverse effects of bisphosphonates. Calcif Tissue Int. 2010;86: 421–435. doi:10.1007/s00223-010-9364-1
48. Coleman RE, Winter MC, Cameron D, Bell R, Dodwell D, Keane MM, et al. The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer. Br J Cancer. 2010;102: 1099–1105. doi:10.1038/sj.bjc.6605604
49. Maier JD, Levine SN. Hypercalcemia in the intensive care unit: A review of pathophysiology, diagnosis, and modern therapy. J Intensive Care Med. 2015;30: 235–252. doi:10.1177/0885066613507530
50. Lim D, Oliva E. Gynecological neoplasms associated with paraneoplastic hypercalcemia. Semin Diagn Pathol. 2019;36: 246–259. doi:10.1053/j.semdp.2019.01.003
51. Shivnani SB, Shelton JM, Richardson JA, Maalouf NM. Hypercalcemia of malignancy with simultaneous elevation in serum parathyroid hormone--related peptide and 1,25-dihydroxyvitamin D in a patient with metastatic renal cell carcinoma. Endocr Pract. 2009;15: 234–239. doi:10.4158/EP.15.3.234
52. Marcocci C, Chanson P, Shoback D, Bilezikian J, Fernandez-Cruz L, Orgiazzi J, et al. Cinacalcet reduces serum calcium concentrations in patients with intractable primary hyperparathyroidism. J Clin Endocrinol Metab. 2009;94: 2766–2772. doi:10.1210/jc.2008-2640
53. Dellay B, Groth M. Emergency management of malignancy-associated hypercalcemia. Adv Emerg Nurs J. 2016;38: 15–25. doi:10.1097/tme.0000000000000093
54. Delgado-Guay MO, Yennurajalingam S, Bruera E. Delirium with severe symptom expression related to hypercalcemia in a patient with advanced cancer: an interdisciplinary approach to treatment. J Pain Symptom Manage. 2008;36: 442–449. doi:10.1016/j.jpainsymman.2007.11.004
55. Faiman BM, Mangan P, Spong J, Tariman JD, The International Myeloma Foundation Nurse Leadership Board. Renal complications in multiple myeloma and related disorders: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board. Clin J Oncol Nurs. 2011;15 Suppl: 66–76. doi:10.1188/11.CJON.S1.66-76
56. Cherny NI, ESMO Guidelines Working Group. ESMO Clinical Practice Guidelines for the management of refractory symptoms at the end of life and the use of palliative sedation. Ann Oncol. 2014;25 Suppl 3: iii143–52. doi:10.1093/annonc/mdu238
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Dominika Bachurska, Zuzanna Czach, Magdalena Ignarska, Justyna Ignarska, Oliwia Grygorczuk

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
The periodical offers access to content in the Open Access system under the Creative Commons Attribution-NonCommercial-ShareAlike 4.0
Stats
Number of views and downloads: 2
Number of citations: 0