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Hypercalcemia of malignancy

Epidemiology and pathogenesis

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References

  1. Mundy GR, Cove DH, Fisken R. 1980 Primary hyperparathyroidism: changes in the pattern of clinical presentation. Lancet 1:1317–1320.

    Article  PubMed  CAS  Google Scholar 

  2. Mundy GR, Martin TJ. 1982 The hypercal cemia of malignancy: pathogenesis and management. Metabolism 31:1247–1277.

    Article  PubMed  CAS  Google Scholar 

  3. Grill V, Martin TJ. 1993 Non-parathyroid hypercalcaemias. In: Metabolic Bone and Stone Disease. Nordin B.E.C., Need A.G., Morris H.A., eds. Churchill Livingstone. New York, 133–145.

    Google Scholar 

  4. Marx SJ, Spiegel AM, Brown EM, Koehler JO, Gardner DG, Brennan MF, et al. 1978 Divalent cation metabolism. Familial hypocalciuric hypercalcemia versus typical primary hyperparathyroidism. Am J Med 65:235–242.

    Article  PubMed  CAS  Google Scholar 

  5. Coombes RC, Ward MK, Greenberg PB, et al. 1976 Calcium metabolism in cancer: studies using calcium isotopes and immunoassay for parathyroid hormone and calcitonin. Cancer 38:2111–2120.

    Article  PubMed  CAS  Google Scholar 

  6. Kimberg DB, Baerg RD, Gerskon E, et al. 1971 Effect of cortisone treatment on the active transport of calcium by the small intestine. J Clin Invest 50:1309–1321.

    PubMed  CAS  Google Scholar 

  7. Walser M. 1961 Calcium clearance is a function of saline clearance in the dog. Am J Physiol 200:1099–1104.

    PubMed  CAS  Google Scholar 

  8. Zondek H, Petrow H, Siebert W. 1924 Die Bedeutung der Calciumbestimmung im Blute fur die Dianose der Niereninsuffizienz. Z Klin Med 99:129–132.

    Google Scholar 

  9. Gutman AB, Tyson TL, Gutman EB. 1936 Serum calcium, inorganic phosphorus, and phosphatase activity in hyperparathyroidism, Paget's disease, multiple myeloma and neoplastic disease of bones. Arch Intern Med 57:379–413.

    CAS  Google Scholar 

  10. Albright F. 1941 Case records of the Massachusetts General Hospital (Case 27401). N Engl J Med 225:789–791.

    Article  Google Scholar 

  11. Berson SA, Yalow RS. 1966 Parathyroid hormone in plasma in adenomatous hyperparathyroidism, uremia and bronchogenic sarcoma. Science 154:907–909.

    Article  PubMed  CAS  Google Scholar 

  12. Knill-Jones RP, Buckle RM, Parsons V, Caine RY, Williams R. 1970 Hypercalcaemia and increased parathyroid hormone activity in a primary hepatoma. Studies before and after hepatic transplantation. N Engl J Med 282:704–708.

    Article  PubMed  CAS  Google Scholar 

  13. Greenberg PB, Martin TJ, Sutcliffe HS. 1973 Synthesis and release of parathyroid hormone by a renal carcinoma in cell culture. Clin Sci Mol Med 45:183–187.

    CAS  PubMed  Google Scholar 

  14. Riggs BL, Arnaud CD, Reynolds JC, Smith LH. 1971 Immunological differentiation of primary hyperparathyroidism from hyperparathyroidism due to non-parathyroid cancer. J Clin Invest 50:2079–2083.

    PubMed  CAS  Google Scholar 

  15. Melick, RA, Martin TJ, Hicks JD. 1972 Parathyroid hormone production and malignancy. Br Med J 1:204–205.

    Google Scholar 

  16. Roof BS, Carpenter B, Fink DJ, Gordan GS. 1971 Some thoughts on the nature of ectopic parathyroid hormones. Am J Med 50:686–691.

    Article  PubMed  CAS  Google Scholar 

  17. Powell D, Singer FR, Murray TM, Minkin C, Potts JT. 1973 Non-parathyroid humoral hypercalcemia in patients with neoplastic disease. N Engl J Med 289:176–181.

    Article  PubMed  CAS  Google Scholar 

  18. Martin TJ, Atkins D. 1979 Biochemical regulators of bone resorption and their significance in cancer. Essays Med Biochem 4:49–82.

    CAS  Google Scholar 

  19. Stewart AF, Horst R, Deftos LJ, Cadman EC, Lang R, Broadus AE. 1980 Biochemical evaluatgion of patients with cancer-associated hypercalcemia. Evidence for humoral and non-humoral groups. N Engl J Med 303:1377–1381.

    Article  PubMed  CAS  Google Scholar 

  20. Kukreja SC, Shermerdiak WP, Lad TE, Johnson PA. 1980 Elevated nephrogenous cyclic AMP-with normal serum parathyroid hormone levels in patients with lung cancer. J Clin Endocrinol Metab 51:167–169.

    PubMed  CAS  Google Scholar 

  21. Rude RK, Sharp CF Jr, Fredericks RS et al. 1981 Urinary and nephrogenous adenosine 3′5′-monophosphate in the hypercalcemia of malignancy. J Clin Invest 52:765–771.

    CAS  Google Scholar 

  22. Stewart AF, Insogna KL, Goltzman D, Broadus AE. 1983 Identification of adenylate cyclase-stimulating activity and cytochemical glucose-6 phosphatedehydrogenasestimulating activity in extracts of tumours from patients with humoral hypercalcemia of malignancy. Proc Natl Acad Sci USA 80:1454–1458.

    Article  PubMed  CAS  Google Scholar 

  23. Gotzman D, Stewart AF, Broaus AE. 1981 Malignancyassociated hyperaclecmai evaluation with a cytochemial bioassay for parathyroid hormone. J Clin Endocrinol Metab 53:899–904.

    Google Scholar 

  24. Rodan SB, Insogna KL, Vignery AM-C, Stewart AF, Broadus AE, D'Souza S, et al. 1983 Factors associated with humoral hypercalcemia of malignancy stimulate adenylate cyclase in osteoblastic cells. J Clin Invest 72:1511–1515.

    PubMed  CAS  Google Scholar 

  25. Simpson EL, Mundy GR, D'Souza SM, Ibbotson KJ, Bockman R, Jacobs JW. 1983 Absence of parathyroid hormone messenger RNA in non-parathyroid tumors associated with hypercalcemia. N Engl J Med 309:325–330.

    Article  PubMed  CAS  Google Scholar 

  26. Moseley JM, Kubota M, Diefenbach-Jagger H, et al. 1987 Parathyroid hormone-related protein purified from a human lung cancer cell line. Proc Natl Acad Sci USA 84:5048–5052.

    Article  PubMed  CAS  Google Scholar 

  27. Suva LJ, Winslow GA, Wettenhall REH, et al. 1987 A parathyroid hormone-related protein implicated in malignant hypercalcemia: Cloning and expression. Science 237:893–896.

    Article  PubMed  CAS  Google Scholar 

  28. Strewler JG, Stern PH, Jacobs JW, et al. 1987. Parathyroid jhormone-like protein from human renal carcinoma cells Structural and functional hormology with parathyroid hormone. J Clin Inwest 80:1803–1807.

    CAS  Google Scholar 

  29. Burtis WJ, Wu J, Bunch CM, et al. 1987 Indentification of a novel 17,000-dalton parathyroid hormone-like adenylate cyclase-stimulating protein from a tumor associated with humoral hypercalcemia of malignancy. J Biol Chem 262:7151–7156.

    PubMed  CAS  Google Scholar 

  30. Moseley JM, Gillespie MT. Parathyroid hormone-related protein. 1995. Crit Rev Clin Lab Sci 32:299–343.

    PubMed  CAS  Google Scholar 

  31. Shaw G, Karmen R. 1986 A conserved AU sequence from the 3′ untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell 46:659–667.

    Article  PubMed  CAS  Google Scholar 

  32. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, et al. 1997 Osteoprotogerin: a novel secreted proteion involved in the regulation of bone density. Cell 89:309–319.

    Article  PubMed  CAS  Google Scholar 

  33. Tsuda E, Goto M, Mochizuki S, Yano K, Kobayashi F, Morinaga, T., et al. 1997 Isolation of a novel cytokine from human fibrob lasts that specifically inhibits osteoclaso genesis. Biochem Biophys Res Commun 234:137–142.

    Article  PubMed  CAS  Google Scholar 

  34. Yasuda H, Shima, N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S-I, et al. 1998 Osteoclast differentiation factor is a ligand for osteoproteogerin/osteoclastogenesis inhibitory factor and identical to TRANCE/RANKL. Proc Natl Acad Sci USA 95:3597–3602.

    Article  PubMed  CAS  Google Scholar 

  35. Lacey DM, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, et al. 1998 Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–176.

    Article  PubMed  CAS  Google Scholar 

  36. Quinn J MW, Elliott J, Gillespie MT, Martin TJ 1998 A combination of osteoclast differention factor and macrophage-colony stimulating factor is sufficient for both human and mouse osteclast formation in vitro. Endocrinology 139:4424–4427.

    Article  PubMed  CAS  Google Scholar 

  37. Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, et al. 1997 TRANCE is a novel ligand of the tumor mecrosis factor receptor family that activates c-Jun N-terminal kinasein T-cells. J Biol Chem 272:25,190–25,194.

    CAS  Google Scholar 

  38. Horwood NJ, Kartsogiannis V, Quinn JMW, Romas E, Martin TJ, Gillespie MT, et al. 1999 Activated T lymphocytes support osteoclast formation in vitro. Biochem Biophys Res Commun 265:144–150.

    Article  PubMed  CAS  Google Scholar 

  39. Horwood NJ, Elliott J, Martin TJ, and Gillespie MT. 1998 Osteotropic agents regulate the expression of osteoclast differentiation factor and osteoprotegerin in osteoblastic stromal cells. Endocrinology 139:4743–4746.

    Article  PubMed  CAS  Google Scholar 

  40. Thomas RJ, Guise TA, Yin JJ, Eliot J, Horwood NJ, Martin TJ, et al. 1999 Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology 140:4451–4458.

    Article  PubMed  CAS  Google Scholar 

  41. Danks JA, Ebeling PR, Hayman JA, Chou ST, Moseley JM, Dunlop J, et al. 1989 Parathyroid hormone-related protein: immunohistochemical localization in cancers and in normal skin. J Bone Miner Res 4:273–278.

    PubMed  CAS  Google Scholar 

  42. Kukreja SC, Schavin DH, Wimbuscus S, et al. 1998 Antibodies to parathyroid hormone-related protein lower serum calcium in athymic mouse models of, malignancy associated hypercalcenia due to human tumors. J Clin Invest 82:1798–1802.

    Google Scholar 

  43. Grill V, Ho P, Body JJ, Lee SC, Moseley JM, et al. 1991 Parathyroid hormone-related protein: elevated levels in both humoral hypercalcemia of malignancy and hypercalcemia complicating metastatic breast cancer. J Clin Endocrinol Metab 73:1309–1315.

    PubMed  CAS  Google Scholar 

  44. Ralston SH, Fogelman I, Gardner MD, Boyle IT. 1984 Relative contribution of humoral and metastatic factors to the pathogenesis of hypercalcemia of malignancy. Br Med J 288:1405–1408.

    Article  CAS  Google Scholar 

  45. Coleman RE, Rubens RD. 1987 The clinical course of bone metastases from breast cancer. Br J Cancer 55:61–66.

    PubMed  CAS  Google Scholar 

  46. Southby J, Kissin MW, Danks JA, Hayman JA, Moseley JM, Henderson MA, et al. 1990 Immunohistochemical human breast cancer. Cancer Res 50:7710–7716.

    PubMed  CAS  Google Scholar 

  47. Powell GJ, Southby J, Danks IA, Stillwell RG, Hayman JA, Henderson MA, et al. 1991 Localization of parathyroid hormone-related protein in breast cancer metastases: increased incidence in bone compared with other sites. Cancer Res 51:3059–3061.

    PubMed  CAS  Google Scholar 

  48. Vargas SJ, Gillespie MT, Powell GJ, Southby J, Danks JA, Moseley JM, et al. 1992 20Localization of parathyroid hormone-related protein mRNA in breast cancer and metastatic lesions by in situ hybridization. J Bone Miner Research 7:971–979.

    CAS  Google Scholar 

  49. Guise TA, Yin JJ, Taylor SD, Kumagai Y, Dallas M, Boyce BF, et al. 1996 Evidence for a casual role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. J Clin Invest 98:1544–1549.

    PubMed  CAS  Google Scholar 

  50. Martin TJ, Moseley JM. 2000 Mechanisms in the skeletal complications of breast cancer. Endocrine-Related Cancer 7:271–284.

    Article  PubMed  CAS  Google Scholar 

  51. Smith DC, Tucker JA, Trump DL. 1992 Hypercalcemia and neuroendocrine carcinoma of the prostate: a report of three cases and a review of the literature. J Clin Oncol 10:499–505.

    PubMed  CAS  Google Scholar 

  52. Iwamura M, di Sant'Agnese PA, Wu G, Benning CM, Cockett ATK, Deftos LJ, et al. 1993 Immunohistochemical localization of parathyroid hormone-related protein in human prostate cancer. Cancer Res 53:1724–1726.

    PubMed  CAS  Google Scholar 

  53. Cramer SD, Peehl DM, Edgar MG, Wong ST, Deftos LJ, Feldman D, 1996 Parathyroid hormone-related protein (PTHrP) is an epidermal growth factor-regulated secretory product of human prostatic epithelial cells. Prostate 29:20–29.

    Article  PubMed  CAS  Google Scholar 

  54. Iwamura M, Wu G, Abrahamsson P-A, di Sant'Agnese PA, Cockett ATK, Deftos LJ. 1994 Parathyroid hormone-related protein is expressed by prostatic neuroendocrine cells. Urology 43:667–674.

    Article  PubMed  CAS  Google Scholar 

  55. Iwamura M, Abrahamsson P-A, Schoen S, Cockett ATK, Deftos LJ. 1994 Immunoreactive parathyroid hormonerelated protein is present in human seminal plasma and is of prostate origin. J Androl 15:410–414.

    PubMed  CAS  Google Scholar 

  56. Iwamura M, Abrahamsson P-A, Foss KA, Wu G, Cockett ATK, Deftos LJ. 1994 Parathyroid hormone related protein: a potential autocrine growth regulator in human prostate cancer cell lines. Urology 43:675–679.

    Article  PubMed  CAS  Google Scholar 

  57. Iwamura M, Gershagen S, Lapets O, Moynes R, Arahamsson P-A, Cockett ATK, et al. 1995 Immunohistochemical localization of parathyroid hormonerelated protein in prostatic intraepithelial neoplasia. Hum Pathol 26:797–801.

    Article  PubMed  CAS  Google Scholar 

  58. Firkin F, Seymour JF, Watson AM, Grill V, Martin TJ. 1996 Parathyroid hormone-related protein in hypercalcaemia associated with haematological malignancy. Br J Haematol 94:486–492.

    Article  PubMed  CAS  Google Scholar 

  59. Breslau NA, McGuire JL, Zerwekh JE, Frenkel EP, Pak CYC. 1984 Hypercalcemia associated with increased serum calcitriol levels in three patients with lymphoma. Ann Intern Med 100:1–7.

    PubMed  CAS  Google Scholar 

  60. Rosenthal N, Insogna KL, Godsall JW, Smaldone L, Waldron JA, Stewart AF. 1985 Elevations in circulating 1,25-dihydroxyvitamin D in three patients with lymphoma-associated hypercalcemia. J Clin Endocrinol Metab 60:29–33.

    Article  PubMed  CAS  Google Scholar 

  61. Fukumoto S, Matsumoto T, Ikeda K, Yamashita T, Watanabe T, Yamaguchi K, et al. 1988 Clinical evaluation of calcium metabolism in adult T-cell leukemia/lymphoma. Arch Intern Med 148:921–925.

    Article  PubMed  CAS  Google Scholar 

  62. Mundy GR, Raisz LG, Cooper RA, Schechter GP, Salmon SE. 1974 Evidence for the secretion of an osteoclast stimulating factor in myeloma. N Engl J 291:1041–1046.

    Article  CAS  Google Scholar 

  63. Roodman GD. 1995 Osteoclast function in Paget's disease and multiple myeloma. Bone 17:57S-61S.

    Article  PubMed  CAS  Google Scholar 

  64. Schneider H-G, Kartsogiannis V, Zhou H, Chou ST, Martin TJ, Grill V. 1998 Parathyroid hormone-related protein mRNA and protein expression in multiple myeloma: a case report. J Bone Miner Res 13:1–4.

    Article  Google Scholar 

  65. Schneider HG, Cheng MH, Cole-Sinclair M, Gillespie MT, Grill VM. 2000 RANKL and OPG are expressed in malignant plasma cells of patients with multiple myeloma. J Bone Min Res 15(Suppl 1):S480 (abstract).

    Google Scholar 

  66. Budayr AA, Nissenson RA, Klein RF, Pun KK, Clark OH, Diep D, et al. 1989 Increased serum levels of a parathyroid hormone-like, protein in malignancy-associated hyperacalcemia. Ann Intern Med 111:807–812.

    PubMed  CAS  Google Scholar 

  67. Henderson JE, Shustik C, Kremer R, Rabbani SA, Hendy GN, Goltzman D. 1990 Circulating concentrations of parathyroid hormone-like peptide in malignancy and in hyperparathyroidism. J Bone Miner Res 5:105–113.

    Article  PubMed  CAS  Google Scholar 

  68. Kao PC, Klee GG, Taylor RL, Heath H. 1990 Parathyroid hormone-related peptide in plasma of patients with hypercalcemia and malignant lesions. Mayo Clin Proc 65:1399–1407.

    PubMed  CAS  Google Scholar 

  69. Burtis WJ, Brady TG, Orloff JJ, Ersbak JB, Warrell RP, Olson BR, et al. 1990 Immunochemical characterisation of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer. N Engl J Med 322:1106–1112.

    Article  PubMed  CAS  Google Scholar 

  70. Ratcliffe WA, Norbury S, Heath DA, Ratcliffe JG. 1991 Development and validation of an immunoradiometric assay of parathyrin-related protein in unextracted plasma. Clin Chem 37:678–685.

    PubMed  CAS  Google Scholar 

  71. Ikeda K, Ohno H, Hane M, Yokoi H, Okada M, Honma T, et al. 1994 Development of a sensitive tow-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 79:1322–1327.

    Article  PubMed  CAS  Google Scholar 

  72. Gurney H, Grill V, Martin TJ. 1993 Parathyroid hormone-related protein level predicts response to pamidronate in the treatment of tumor-induced hypercalcemia. Lancet 2:241–244.

    Google Scholar 

  73. Murayama E, Miyamoto K, Kubodera N, Mori T, Matsunaga I. 1986 Synthetic studies of Vitamin D3 analogues. VIII. Synthesis of 22-oxavitamin D3 analogues. Chem Pharm Bull (Tokyo) 34:4410–4413.

    CAS  Google Scholar 

  74. Brown AJ, Ritter CR, Finch JL, Morrissey J, Martin KJ, Murayama E, et al. 1989 The noncalcemic analogue of vitamin D, 22-oxacalcitriol, supresses parthyroid hormone synthesis and secretion. J Clin invest 84:728–732.

    Article  PubMed  CAS  Google Scholar 

  75. Ikeda K, Lu C, Weir EC, Mangin M, Broadus AE. 1989 Transcriptional regulation of the parathyroid hormone-related protein gene by glucocorticoids and vitamin D in a human C-cell line. J Biol Chem 264:15,743–15,746.

    CAS  Google Scholar 

  76. Falzon M, Zong J. 1998 The noncalcemic vitamin D analogs EB1089 and 22-oxacalcitriol suppress serum-induced parathyroid hormone-related peptide gene expression in a lung cancer cell line. Endocrinology 139:1046–1053.

    Article  PubMed  CAS  Google Scholar 

  77. Akatsu T, Murakami T, Ono K, Nishikawa M, Tsuda E, Mochizuki SI, et al. 1998 Osteoclastogensis inhibitory factor exhibits hypocalcemic effects in normal mice and in hypercalcemic nude mice carrying tumors associated with humoral hypercalcemia of malignancy. Bone 23:495–498.

    Article  PubMed  CAS  Google Scholar 

  78. Capparelli C, Kostenuik PJ, Morony S, Starnes C, Weimann B, Van G, et al. 2000 Osteoprotegerin prevents and reverses hypercalcemia in a murine model of humoral hypercalcemia of malignancy. Cancer Res 15:783–787.

    Google Scholar 

  79. Oyajob BO, Anderson DM, Traiandes K, Williams PJ, Yoneda T, Mundy GR, 2001 Therapeutic efficacy of a soluble receptor activator of nuclear factor kappaB-IgG Fc fusion protein in suppressing bone resorption and hypercalcemia in a model of humoral hypercalcemia of malignancy. Cancer Res 15:2572–2578.

    Google Scholar 

  80. Rodan GA, Martin TJ. 2000. Therapeutic approaches to bone disease. Science 289:1508–1514.

    Article  PubMed  CAS  Google Scholar 

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Martin, T.J. Hypercalcemia of malignancy. Clinic Rev Bone Miner Metab 1, 51–63 (2002). https://doi.org/10.1385/BMM:1:1:51

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