Hypercalcemia of malignancy: Mechanisms
- Mara J Horwitz, MD
Mara J Horwitz, MD
- Assistant Professor of Medicine
- University of Pittsburgh
Hypercalcemia is relatively common in patients with cancer, occurring in approximately 20 to 30 percent of cases . It is the most common cause of hypercalcemia in the inpatient setting. It occurs in patients with both solid tumors and hematologic malignancies. The most common cancers associated with hypercalcemia are breast and lung cancer and multiple myeloma. Malignancy is often evident clinically by the time it causes hypercalcemia, and patients with hypercalcemia of malignancy often have a poor prognosis. The mechanisms of hypercalcemia will be reviewed here. The clinical manifestations, diagnosis, and treatment of hypercalcemia are reviewed in detail separately.
●(See "Treatment of hypercalcemia".)
MECHANISMS OF HYPERCALCEMIA
- Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med 2005; 352:373.
- 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.
- Mirrakhimov AE. Hypercalcemia of Malignancy: An Update on Pathogenesis and Management. N Am J Med Sci 2015; 7:483.
- Ratcliffe WA, Hutchesson AC, Bundred NJ, Ratcliffe JG. Role of assays for parathyroid-hormone-related protein in investigation of hypercalcaemia. Lancet 1992; 339:164.
- Ikeda K, Ohno H, Hane M, et al. Development of a sensitive two-site immunoradiometric assay for parathyroid hormone-related peptide: evidence for elevated levels in plasma from patients with adult T-cell leukemia/lymphoma and B-cell lymphoma. J Clin Endocrinol Metab 1994; 79:1322.
- Horwitz MJ, Tedesco MB, Sereika SM, et al. Direct comparison of sustained infusion of human parathyroid hormone-related protein-(1-36) [hPTHrP-(1-36)] versus hPTH-(1-34) on serum calcium, plasma 1,25-dihydroxyvitamin D concentrations, and fractional calcium excretion in healthy human volunteers. J Clin Endocrinol Metab 2003; 88:1603.
- Horwitz MJ et al. Non-Parathryoid Hypercalcemia. In: Primer on the metabolic bone diseases and disorders of mineral metabolism, 8th ed, Rosen CJ (ed), Wiley –Blackwell and The American Society for Bone and Mineral Research. 2013. 562.
- Wimalawansa SJ. Significance of plasma PTH-rp in patients with hypercalcemia of malignancy treated with bisphosphonate. Cancer 1994; 73:2223.
- Pecherstorfer M, Schilling T, Blind E, et al. Parathyroid hormone-related protein and life expectancy in hypercalcemic cancer patients. J Clin Endocrinol Metab 1994; 78:1268.
- Roodman GD. Mechanisms of bone lesions in multiple myeloma and lymphoma. Cancer 1997; 80:1557.
- Seymour JF, Grill V, Martin TJ, et al. Hypercalcemia in the blastic phase of chronic myeloid leukemia associated with elevated parathyroid hormone-related protein. Leukemia 1993; 7:1672.
- Nakamura Y, Bando H, Shintani Y, et al. Serum parathyroid hormone-related protein concentrations in patients with hematologic malignancies or solid tumors. Acta Endocrinol (Copenh) 1992; 127:324.
- Inoue D, Matsumoto T, Ogata E, Ikeda K. 22-Oxacalcitriol, a noncalcemic analogue of calcitriol, suppresses both cell proliferation and parathyroid hormone-related peptide gene expression in human T cell lymphotrophic virus, type I-infected T cells. J Biol Chem 1993; 268:16730.
- Ishibashi K, Ishitsuka K, Chuman Y, et al. Tumor necrosis factor-beta in the serum of adult T-cell leukemia with hypercalcemia. Blood 1991; 77:2451.
- Burtis WJ, Brady TG, Orloff JJ, et al. Immunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer. N Engl J Med 1990; 322:1106.
- Rizzoli R, Ferrari SL, Pizurki L, et al. Actions of parathyroid hormone and parathyroid hormone-related protein. J Endocrinol Invest 1992; 15:51.
- Fraher LJ, Hodsman AB, Jonas K, et al. A comparison of the in vivo biochemical responses to exogenous parathyroid hormone-(1-34) [PTH-(1-34)] and PTH-related peptide-(1-34) in man. J Clin Endocrinol Metab 1992; 75:417.
- Esbrit P, Egido J. The emerging role of parathyroid hormone-related protein as a renal regulating factor. Nephrol Dial Transplant 2000; 15:1109.
- Schilling T, Pecherstorfer M, Blind E, et al. Parathyroid hormone-related protein (PTHrP) does not regulate 1,25-dihydroxyvitamin D serum levels in hypercalcemia of malignancy. J Clin Endocrinol Metab 1993; 76:801.
- Schweitzer DH, Hamdy NA, Frölich M, et al. Malignancy-associated hypercalcaemia: resolution of controversies over vitamin D metabolism by a pathophysiological approach to the syndrome. Clin Endocrinol (Oxf) 1994; 41:251.
- Nakayama K, Fukumoto S, Takeda S, et al. Differences in bone and vitamin D metabolism between primary hyperparathyroidism and malignancy-associated hypercalcemia. J Clin Endocrinol Metab 1996; 81:607.
- 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 Miner Res 2005; 20:1792.
- Syed MA, Horwitz MJ, Tedesco MB, et al. Parathyroid hormone-related protein-(1--36) stimulates renal tubular calcium reabsorption in normal human volunteers: implications for the pathogenesis of humoral hypercalcemia of malignancy. J Clin Endocrinol Metab 2001; 86:1525.
- Mundy GR, Edwards JR. PTH-related peptide (PTHrP) in hypercalcemia. J Am Soc Nephrol 2008; 19:672.
- Gurney H, Grill V, Martin TJ. Parathyroid hormone-related protein and response to pamidronate in tumour-induced hypercalcaemia. Lancet 1993; 341:1611.
- Ling PJ, A'Hern RP, Hardy JR. Analysis of survival following treatment of tumour-induced hypercalcaemia with intravenous pamidronate (APD). Br J Cancer 1995; 72:206.
- Quinn JM, Matsumura Y, Tarin D, et al. Cellular and hormonal mechanisms associated with malignant bone resorption. Lab Invest 1994; 71:465.
- Grill V, Ho P, Body JJ, et al. Parathyroid hormone-related protein: elevated levels in both humoral hypercalcemia of malignancy and hypercalcemia complicating metastatic breast cancer. J Clin Endocrinol Metab 1991; 73:1309.
- Legha SS, Powell K, Buzdar AU, Blumenschein GR. Tamoxifen-induced hypercalcemia in breast cancer. Cancer 1981; 47:2803.
- Arumugam GP, Sundravel S, Shanthi P, Sachdanandam P. Tamoxifen flare hypercalcemia: an additional support for gallium nitrate usage. J Bone Miner Metab 2006; 24:243.
- Valentin-Opran A, Eilon G, Saez S, Mundy GR. Estrogens and antiestrogens stimulate release of bone resorbing activity by cultured human breast cancer cells. J Clin Invest 1985; 75:726.
- Kuroi K, Yamashita T, Aruga T, et al. Flare hypercalcemia after letrozole in a patient with liver metastasis from breast cancer: a case report. J Med Case Rep 2011; 5:495.
- Roodman GD. Pathogenesis of myeloma bone disease. J Cell Biochem 2010; 109:283.
- Silbermann R and Roodman GD. Hematologic malignancies and Bone. In: Primer on the metabolic bone diseases and disorders of mineral metabolism, 8th ed, Rosen CJ (ed), Wiley-Blackwell and The American Society for Bone and Mineral Research, Washington, DC. 2013. 694.
- Seymour JF, Gagel RF. Calcitriol: the major humoral mediator of hypercalcemia in Hodgkin's disease and non-Hodgkin's lymphomas. Blood 1993; 82:1383.
- Henderson JE, Shustik C, Kremer R, et al. Circulating concentrations of parathyroid hormone-like peptide in malignancy and in hyperparathyroidism. J Bone Miner Res 1990; 5:105.
- Hibi M, Hara F, Tomishige H, et al. 1,25-dihydroxyvitamin D-mediated hypercalcemia in ovarian dysgerminoma. Pediatr Hematol Oncol 2008; 25:73.
- Scheinman SJ, Kelberman MW, Tatum AH, Zamkoff KW. Hypercalcemia with excess serum 1,25 dihydroxyvitamin D in lymphomatoid granulomatosis/angiocentric lymphoma. Am J Med Sci 1991; 301:178.
- 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.
- 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.
- 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 Engl J Med 1990; 323:1324.
- Strewler GJ, Budayr AA, Clark OH, Nissenson RA. Production of parathyroid hormone by a malignant nonparathyroid tumor in a hypercalcemic patient. J Clin Endocrinol Metab 1993; 76:1373.
- Nielsen PK, Rasmussen AK, Feldt-Rasmussen U, et al. Ectopic production of intact parathyroid hormone by a squamous cell lung carcinoma in vivo and in vitro. J Clin Endocrinol Metab 1996; 81:3793.
- Wong K, Tsuda S, Mukai R, et al. Parathyroid hormone expression in a patient with metastatic nasopharyngeal rhabdomyosarcoma and hypercalcemia. Endocrine 2005; 27:83.
- VanHouten JN, Yu N, Rimm D, et al. Hypercalcemia of malignancy due to ectopic transactivation of the parathyroid hormone gene. J Clin Endocrinol Metab 2006; 91:580.
- Vacher-Coponat H, Opris A, Denizot A, et al. Hypercalcaemia induced by excessive parathyroid hormone secretion in a patient with a neuroendocrine tumour. Nephrol Dial Transplant 2005; 20:2832.
- Kandil E, Noureldine S, Khalek MA, et al. Ectopic secretion of parathyroid hormone in a neuroendocrine tumor: a case report and review of the literature. Int J Clin Exp Med 2011; 4:234.
- Hutchesson AC, Bundred NJ, Ratcliffe WA. Survival in hypercalcaemic patients with cancer and co-existing primary hyperparathyroidism. Postgrad Med J 1995; 71:28.
- Strodel WE, Thompson NW, Eckhauser FE, Knol JA. Malignancy and concomitant primary hyperparathyroidism. J Surg Oncol 1988; 37:10.
- Casez J, Pfammatter R, Nguyen Q, et al. Diagnostic approach to hypercalcemia: relevance of parathyroid hormone and parathyroid hormone-related protein measurements. Eur J Intern Med 2001; 12:344.
- Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357:266.