Diagnosis, Pathophysiology and Management of Hypercalcemia in Malignancy: A Review of the Literature

Abstract

Hypercalcemia of malignancy is the most common life-threatening metabolic disorder in patients with advanced stage cancers and is a sign of poor prognosis. It usually presents with markedly elevated calcium level and is severely symptomatic. It is associated with hematological malignancies, such as multiple myeloma, non-Hodgkin lymphoma, leukemias and solid cancers, particularly renal and breast carcinomas as well as squamous cell carcinomas of any organ. Several mechanisms have been implicated in the development of hypercalcemia of malignancy amongst them the osteolytic related hypercalcemia, parathyroid hormone-related peptide (PTHrP) mediated hypercalcemia, extrarenal 1,25 dixydroxyvitamin D (calcitriol) mediated hypercalcemia and parathyroid hormone (PTH) related hypercalcemia either ectopic in origin or in patients with parathyroid carcinoma. Clinical history and and physical examination could point towards the correct diagnosis confirmed by the above-mentioned biochemical mediators of hypercalcemia. Early diagnosis and treatment lowering calcium levels in the blood can improve symptoms and the quality of life of these patients and avoid delays for further antitumor therapy.

Key words

calcium - cancer - hypercalcemia - parathyroid hormone (PTH) - parathyroid hormone related peptide (PTHrP) - malignancy - bisphosphonates

• References

• 1 Dalemo S, Eggertsen R, Hjerpe P. et al. Long-term follow-up of patients with elevated serum calcium concentrations in Swedish primary care. Scand J Prim Health Care 2013; 31: 248-254
• 2 Lindner G, Felber R, Schwarz C. et al. Hypercalcemia in the ED: Prevalence, etiology, and outcome. Am J Emerg Med 2013; 31: 657-660
• 3 Turner JJO. Hypercalcaemia - presentation and management. Clin Med (London, England) 2017; 17: 270-273
• 4 Sargent JT, Smith OP. Haematological emergencies managing hypercalcaemia in adults and children with haematological disorders. Br J Haematol 2010; 149: 465-477
• 5 Zagzag J, Hu MI, Fisher SB. et al. Hypercalcemia and cancer: Differential diagnosis and treatment. CA-Cancer J Clin 2018; 68: 377-386
• 6 Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Eng J Med 2005; 352: 373-379
• 7 Dellay B, Groth M. Emergency management of malignancy-associated hypercalcemia. Adv Emerg Nurs J 2016; 38: 15-25 quiz E11
• 8 Mhaskar R, Kumar A, Miladinovic B. et al. Bisphosphonates in multiple myeloma: An updated network meta-analysis. Cochrane Database System Rev 2017; 12: CD003188
• 9 Williams J, Seelamanthula V, Loon K. Parathyroid hormone-related peptide mediated hypercalcaemia with squamous cell carcinoma of the anus. ANZ J Surg 2018; 88: 516-517
• 10 Trisal D, Kumar N, Sundriyal D. et al. Hypercalcaemia of malignancy: Two primaries in the same patient. BMJ Case Rep. 2014; 2014 pii bcr2014204368 doi:10.1136/bcr-2014-204368
• 11 Hua J, Ide S, Ohara S. et al. Hypercalcemia and osteolytic bone lesions as the major symptoms in a chronic lymphocytic leukemia/small lymphocytic lymphoma patient: A rare case. J Clin Exp Hematopathol 2018; 58: 171-174
• 12 Rujirachun P, Junyavoraluk A, Owattanapanich W. et al. Leukemic arthritis and severe hypercalcemia in a man with chronic myeloid leukemia: A case report and review of the literature. J Med Case Rep 2018; 12: 257
• 13 Toro-Tobon D, Agosto S, Ahmadi S. et al. Chronic myeloid leukemia associated hypercalcemia: A case report and literature review. Am J Case Rep 2017; 18: 203-207
• 14 Chang WT, Radin B, McCurdy MT. Calcium, magnesium, and phosphate abnormalities in the emergency department. Emerg Med Clin North Am 2014; 32: 349-366
• 15 Lumachi F, Brunello A, Roma A. et al. Cancer-induced hypercalcemia. Anticancer Res 2009; 29: 1551-1555
• 16 Inzucchi SE. Understanding hypercalcemia. Its metabolic basis, signs, and symptoms. Postgrad Med 2004; 115: 69-70 73–66
• 17 Clines GA. Mechanisms and treatment of hypercalcemia of malignancy. Curr Opin Endocrinol Diabetes Obesity 2011; 18: 339-346
• 18 Clines GA, Guise TA. Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone. Endocr Relat Cancer 2005; 12: 549-583
• 19 Maier JD, Levine SN. Hypercalcemia in the intensive care unit: A review of pathophysiology, diagnosis, and modern therapy. J Intens Care Med 2015; 30: 235-252
• 20 Zheng H, Li W, Kang Y. Tumor-stroma interactions in bone metastasis: Molecular mechanisms and therapeutic implications. Cold Spring Harbor Symp Quant Biol 2016; 81: 151-161
• 21 Santarpia L, Koch CA, Sarlis NJ. Hypercalcemia in cancer patients: Pathobiology and management. Horm Metab Res 2010; 42: 153-164
• 22 Wysolmerski JJ. Parathyroid hormone-related protein: An update. J Clin Endocrinol Metab 2012; 97: 2947-2956
• 23 Bandyopadhyay A, Tsuji K, Cox K. et al. Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis. PLoS Genet 2006; 2: e216
• 24 Miao D, Su H, He B. et al. Severe growth retardation and early lethality in mice lacking the nuclear localization sequence and C-terminus of PTH-related protein. Proc Natl Acad Sci USA 2008; 105: 20309-20314
• 25 Datta NS, Abou-Samra AB. PTH and PTHrP signaling in osteoblasts. Cell Signal 2009; 21: 1245-1254
• 26 Sternlicht H, Glezerman IG. Hypercalcemia of malignancy and new treatment options. Therap Clinical. Risk Manage 2015; 11: 1779-1788
• 27 Acikgoz Y, Sendur MA, Aksoy S. et al. Metastatic parenchymal renal squamous cell carcinoma with hypercalcemia. Med Oncol (Northwood, London, England) 2014; 31: 169
• 28 Ngo N, Edriss H, Figueroa JA. et al. Squamous cell carcinoma of the sigmoid colon presenting with severe hypercalcemia. Clin Colorect Cancer 2014; 13: 251-254
• 29 Rossi RE, Naik K, Navalkissoor S. et al. Case report of multimodality treatment for metastatic parathyroid hormone-related peptide-secreting pancreatic neuroendocrine tumour. Tumori 2014; 100: 153e-156e
• 30 Motilal Nehru V, Garcia G, Ding J. et al. Humoral hypercalcemia in uterine cancers: A case report and literature review. Am J Case Rep 2017; 18: 22-25
• 31 Chen Y, Xu G, Yang F. Effect of neoadjuvant chemotherapy on the serum levels of bone turnover markers in women with early-stage breast cancer. PloS One 2015; 10: e0126053
• 32 Chevalier N, Udi J, Sigler M. et al. Interplay of parathyroid hormone-related peptide (PTHrP), renal insufficiency and bulky disease in the pathogenesis of hypercalcemia in Hodgkin's lymphoma (HL). Eur J Haematol 2010; 85: 368-369
• 33 Shallis RM, Rome RS, Reagan JL. Mechanisms of hypercalcemia in non-hodgkin lymphoma and associated outcomes: A retrospective review. Clin Lymp Myel Leuke 2018; 18: e123-e129
• 34 Mundy GR, Edwards JR. PTH-related peptide (PTHrP) in hypercalcemia. J Am Soc Nephrol 2008; 19: 672-675
• 35 Wei CH, Harari A. Parathyroid carcinoma: Update and guidelines for management. Curr Treat Opt. Oncol 2012; 13: 11-23
• 36 Soki FN, Park SI, McCauley LK. The multifaceted actions of PTHrP in skeletal metastasis. Future Oncol (London, England) 2012; 8: 803-817
• 37 Dean T, Vilardaga JP, Potts JT. et al. Altered selectivity of parathyroid hormone (PTH) and PTH-related protein (PTHrP) for distinct conformations of the PTH/PTHrP receptor. Mol Endocrinol (Baltimore, Md) 2008; 22: 156-166
• 38 Pioszak AA, Parker NR, Gardella TJ. et al. Structural basis for parathyroid hormone-related protein binding to the parathyroid hormone receptor and design of conformation-selective peptides. J Biol Chem 2009; 284: 28382-28391
• 39 Mirrakhimov AE. Hypercalcemia of malignancy: An update on pathogenesis and management. North Am J Med Sci 2015; 7: 483-493
• 40 Johnson RW, Nguyen MP, Padalecki SS. et al. TGF-beta promotion of Gli2-induced expression of parathyroid hormone-related protein, an important osteolytic factor in bone metastasis, is independent of canonical Hedgehog signaling. Cancer Res 2011; 71: 822-831
• 41 Goldner W. Cancer-related hypercalcemia. J Oncol Pract 2016; 12: 426-432
• 42 Ikushima H, Miyazono K. TGFbeta signalling: A complex web in cancer progression. Nat Rev Cancer 2010; 10: 415-424
• 43 Roodman GD. Pathogenesis of myeloma bone disease. J Cell Biochem 2010; 109: 283-291
• 44 Cheng C, Kuzhively J, Baim S. Hypercalcemia of malignancy in thymic carcinoma: Evolving mechanisms of hypercalcemia and targeted therapies. Case Rep Endocrinol 2017; 2608392
• 45 Hibi M, Hara F, Tomishige H. et al. 1,25-dihydroxyvitamin D-mediated hypercalcemia in ovarian dysgerminoma. Pediatr Hematol Oncol 2008; 25: 73-78
• 46 Kallas M, Green F, Hewison M. et al. Rare causes of calcitriol-mediated hypercalcemia: A case report and literature review. J Clin Endocrinol Metab 2010; 95: 3111-3117
• 47 Christakos S, Ajibade DV, Dhawan P. et al. Vitamin D: Metabolism. Endocrinol Metab Clin North Am 2010; 39: 243-253. Table of contents
• 48 Rosner MH, Dalkin AC. Onco-nephrology: The pathophysiology and treatment of malignancy-associated hypercalcemia. Clin J Am Soc Nephrol 2012; 7: 1722-1729
• 49 Wong K, Tsuda S, Mukai R. et al. Parathyroid hormone expression in a patient with metastatic nasopharyngeal rhabdomyosarcoma and hypercalcemia. Endocrine 2005; 27: 83-86
• 50 Nakajima K, Tamai M, Okaniwa S. et al. Humoral hypercalcemia associated with gastric carcinoma secreting parathyroid hormone: A case report and review of the literature. Endocr J 2013; 60: 557-562
• 51 Nussbaum SR, Gaz RD, Arnold A. Hypercalcemia and ectopic secretion of parathyroid hormone by an ovarian carcinoma with rearrangement of the gene for parathyroid hormone. N Eng. J Med 1990; 323: 1324-1328
• 52 Yoshimoto K, Yamasaki R, Sakai H. et al. Ectopic production of parathyroid hormone by small cell lung cancer in a patient with hypercalcemia. J Clin Endocrinol Metab 1989; 68: 976-981
• 53 Behl D, Hendrickson AW, Moynihan TJ. Oncologic emergencies. Crit Care Clin 2010; 26: 181-205
• 54 Horwitz MJ, Tedesco MB, Sereika SM. et al. Continuous PTH and PTHrP infusion causes suppression of bone formation and discordant effects on 1,25(OH)₂ vitamin D. J Bone Mineral Res 2005; 20: 1792-1803
• 55 Alperstein A, Bhayani R. Parathyroid carcinoma, a rare cause of primary hyperparathyroidism. BMJ Case Rep. 2014; pii bcr2014204279 doi:10.1136/bcr-2014-204279
• 56 Endres DB. Investigation of hypercalcemia. Clin Biochem 2012; 45: 954-963
• 57 Lafferty FW. Differential diagnosis of hypercalcemia. J Bone Mineral Res 1991; (6 Suppl 2) S51-S59. discussion S61
• 58 Meng QH, Wagar EA. Laboratory approaches for the diagnosis and assessment of hypercalcemia. Crit Rev Clin Lab Sci 2015; 52: 107-119
• 59 Savvari P, Peitsidis P, Alevizaki M. et al. Paraneoplastic humorally mediated hypercalcemia induced by parathyroid hormone-related protein in gynecologic malignancies: a systematic review. Onkologie 2009; 32: 517-523
• 60 Soyfoo MS, Brenner K, Paesmans M. et al. Non-malignant causes of hypercalcemia in cancer patients: A frequent and neglected occurrence. Support Care Cancer 2013; 21: 1415-1419
• 61 Bilezikian JP. Primary hyperparathyroidism. Endocr Pract 2012; 18: 781-790
• 62 McCurdy MT, Shanholtz CB. Oncologic emergencies. Crit Care Med 2012; 40: 2212-2222
• 63 LeGrand SB, Leskuski D, Zama I. Narrative review: Furosemide for hypercalcemia: An unproven yet common practice. Ann Intern Med 2008; 149: 259-263
• 64 Tsavaris N, Kopterides P, Kosmas C. et al. Analgesic activity of high-dose intravenous calcitonin in cancer patients with bone metastases. Oncol Rep 2006; 16: 871-875
• 65 Drake MT, Clarke BL, Lewiecki EM. The pathophysiology and treatment of osteoporosis. Clin Therap 2015; 37: 1837-1850
• 66 Dunford JE. Molecular targets of the nitrogen containing bisphosphonates: The molecular pharmacology of prenyl synthase inhibition. Curr Pharmaceut Design 2010; 16: 2961-2969
• 67 Sabry NA, Habib EE. Zoledronic acid and clodronate in the treatment of malignant bone metastases with hypercalcaemia; efficacy and safety comparative study. Med Oncol (Northwood, London, England) 2011; 28: 584-590
• 68 Teixeira S, Branco L, Fernandes MH. et al. Bisphosphonates and Cancer: A relationship beyond the antiresorptive effects. Mini Rev Med Chem 2019; 19: 988-998
• 69 von Moos R, Costa L, Gonzalez-Suarez E. et al. Management of bone health in solid tumours: From bisphosphonates to a monoclonal antibody. Cancer Treat Rev 2019; 76: 57-67
• 70 Kommalapati A, Tella SH, Esquivel MA. et al. Evaluation and management of skeletal disease in cancer care. Crit Rev Oncol/Hematol 2017; 120: 217-226
• 71 Macherey S, Monsef I, Jahn F. et al. Bisphosphonates for advanced prostate cancer. The Cochrane Database System Rev 2017; 12: CD006250
• 72 Henrich D, Hoffmann M, Uppenkamp M. et al. Ibandronate for the treatment of hypercalcemia or nephrocalcinosis in patients with multiple myeloma and acute renal failure: Case reports. Acta haematologica 2006; 116: 165-172
• 73 Body JJ, Diel IJ, Tripathy D. et al. Intravenous ibandronate does not affect time to renal function deterioration in patients with skeletal metastases from breast cancer: Phase III trial results. Eur J Cancer Care 2006; 15: 299-302
• 74 Khan A, Morrison A, Cheung A. et al. Osteonecrosis of the jaw (ONJ): Diagnosis and management in 2015. Osteopor Int 2016; 27: 853-859
• 75 Walsh J, Gittoes N, Selby P. et al. Emergency management of acute hypercalcaemia in adult patients. Endocr Connect 2016; 5: G9-G11
• 76 Fardet L, Flahault A, Kettaneh A. et al. Corticosteroid-induced clinical adverse events: Frequency, risk factors and patient's opinion. Br J Dermatol 2007; 157: 142-148
• 77 Castellano D, Sepulveda JM, Garcia-Escobar I. et al. The role of RANK-ligand inhibition in cancer: The story of denosumab. Oncologist 2011; 16: 136-145
• 78 Stopeck AT, Lipton A, Body JJ. 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: 5132-5139
• 79 Hu MI, Glezerman IG, Leboulleux S. et al. Denosumab for treatment of hypercalcemia of malignancy. J Clin Endocrinol Metab 2014; 99: 3144-3152
• 80 Salahudeen AA, Gupta A, Jones JC. et al. PTHrP-Induced refractory malignant hypercalcemia in a patient with chronic lymphocytic leukemia responding to denosumab. Clin Lymph Myel Leuk 2015; 15: e137-e140
• 81 Diel IJ, Body JJ, Stopeck AT. et al. The role of denosumab in the prevention of hypercalcaemia of malignancy in cancer patients with metastatic bone disease. Eur J Cancer (Oxford, England: 1990) 2015; 51: 1467-1475
• 82 Cicci JD, Buie L, Bates J. et al. Denosumab for the management of hypercalcemia of malignancy in patients with multiple myeloma and renal dysfunction. Clin Lymph Myel Leuk. 2014; 14: e207-e211
• 83 Hanley DA, Adachi JD, Bell A. et al. Denosumab: Mechanism of action and clinical outcomes. Int J Clin Pract 2012; 66: 1139-1146
• 84 Saad F, Brown JE, Van Poznak C. et al. Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol 2012; 23: 1341-1347
• 85 Brown EM. Mechanisms underlying extracellular calcium homeostasis. In: Handbook of Parathyroid Diseases. Berlin: Springer; 2012: 1-18
• 86 Schwarz P, Body JJ, Cap J. et al. The PRIMARA study: A prospective, descriptive, observational study to review cinacalcet use in patients with primary hyperparathyroidism in clinical practice. Eur J Endocrinol 2014; 171: 727-735
• 87 Khan A, Grey A, Shoback D. Medical management of asymptomatic primary hyperparathyroidism: Proceedings of the third international workshop. J Clin Endocrinol Metab 2009; 94: 373-381
• 88 Takeuchi Y, Takahashi S, Miura D. et al. Cinacalcet hydrochloride relieves hypercalcemia in Japanese patients with parathyroid cancer and intractable primary hyperparathyroidism. J Bone Mineral Metab 2017; 35: 616-622
• 89 Valdes-Socin H, Almanza MR, Fernandez-Ladreda MT. et al. Use of cinacalcet and sunitinib to treat hypercalcaemia due to a pancreatic neuroendocrine tumor. Archiv Endocrinol Metab 2017; 61: 506-509
• 90 Asonitis N, Kassi E, Kokkinos M. et al. Hypercalcemia of malignancy treated with cinacalcet. Endocrinol Diabetes Metab Case Rep. 2017; pii: 17-0118 eCollection 2017
• 91 Kindgen-Milles D, Kram R, Kleinekofort W. et al. Treatment of severe hypercalcemia using continuous renal replacement therapy with regional citrate anticoagulation. ASAIO J 2008; 54: 442-444
• 92 Cvitkovic F, Armand JP, Tubiana-Hulin M. et al. Randomized, double-blind, phase II trial of gallium nitrate compared with pamidronate for acute control of cancer-related hypercalcemia. Cancer J (Sudbury, Mass) 2006; 12: 47-53