Treatments in Endocrinology

, Volume 2, Issue 4, pp 273–292 | Cite as

Current Management Strategies for Hypercalcemia

  • Martin Pecherstorfer
  • Karin Brenner
  • Niklas Zojer
Review Article

Abstract

The two most common causes of hypercalcemia are primary hyperparathyroidism and neoplastic disease. Parathyroidectomy is the only curative intervention for the former condition. In the rare cases of patients with primary hyperparathyroidism who present with clinical symptoms due to their hypercalcemia, pharmacological treatment may be required. Fluid repletion and intravenous (IV) administration of bisphosphonates are recommended in the literature. Calcium receptor agonists (calcimimetic agents) are at the present time only available for use within clinical trials.

Cancer patients usually present with symptoms of hypercalcemia. Rapid institution of antihypercalcemic treatment is essential in preventing life-threatening deterioration. Fluid repletion and administration of bisphosphonates are the treatment mainstays in hypercalcemia of malignancy. Five bisphosphonates are currently licensed in Europe for treatment of tumor-associated hypercalcemia: etidronate, clodronate, pamidronate, ibandronate, and zoledronate. In the US, pamidronate and zoledronate are licensed for use in this indication.

Bisphosphonates containing nitrogen atoms (e.g. pamidronate, ibandronate, and zoledronate) are more potent than those without (e.g. etidronate, clodronate, and tiludronate). In patients with malignant hypercalcemia, the efficacy of the individual bisphosphonate depends on dose administered and initial serum calcium concentration. At present, pamidronate has been studied in the greatest number of investigations and in the largest number of patients. In the literature, the efficacy of pamidronate in restoring normocalcemia ranges between 40% and 100%, depending on the dose used and baseline serum calcium concentration. More recently, one study reported that pamidronate was inferior to zoledronate. In this study, the duration of response was also longer in the two zoledronate groups (30 and 40 days) than in the pamidronate group (17 days).

The most serious adverse events of bisphosphonates concern renal function. Increases in serum creatinine levels have been more frequently reported following treatment of tumor-associated hypercalcemia with etidronate (8%) and clodronate (5%) than with the nitrogen-containing bisphosphonates pamidronate (2%) and ibandronate (1%). The frequency of increases in serum creatinine levels following treatment with zoledronate is difficult to estimate. Administration of the nitrogen-containing bisphosphonates has been associated with transient (usually mild) fever, lymphocytopenia, malaise, and myalgias. These events occur within 36 hours of the first dose and are self-limiting. Hypocalcemia occurs in up to 50% of patients treated with bisphosphonates for hypercalcemia of malignancy, although symptomatic hypocalcemia is rare.

The toxicity and low efficacy of plicamycin (mithramycin) mean that use of this agent should be restricted to patients with hypercalcemia of malignancy who fail to respond to IV bisphosphonates. Calcitonin is characterized by good tolerability but poor efficacy in normalizing the serum calcium level. However, a major advantage of calcitonin is the acute onset of the hypocalcemic effect, which contrasts with the delayed but more pronounced effect of bisphosphonates. Combination calcitonin and bisphosphonate treatment may therefore be of value when rapid reduction of serum calcium is warranted. Gallium nitrate may be a valuable treatment for hypercalcemia of malignancy. It is characterized by high efficacy and few adverse events apart from renal toxicity (10% of cases). However, data are very limited and further trials are necessary.

Keywords

Serum Calcium Hypercalcemia Pamidronate Primary Hyperparathyroidism Ibandronate 

References

  1. 1.
    Laposata M. SI unit conversion guide. Boston (MA): NEJM Books, 1992Google Scholar
  2. 2.
    Shane E. Hypercalcemia: pathogenesis, clinical manifestations, differential diagnosis, and management. In: Farus MJ, editor. Primer on the metabolic bone disease and disorders of mineral metabolism: an official publication of The American Society for Bone and Mineral Research. 4th ed. Philadelphia (PA): Lippincott, 1999: 183–7Google Scholar
  3. 3.
    Heath DA. Primary hyperparathyroidism: clinical presentation and factors influencing clinical management. Endocrinol Metab Clin North Am 1989; 18: 631–46PubMedGoogle Scholar
  4. 4.
    Mundy GR, Cove DH, Fisken R, et al. Primary hyperparathyroidism: changes in the pattern of clinical presentation. Lancet 1980; I: 1317–20CrossRefGoogle Scholar
  5. 5.
    Vassilopoulou-Sellin R, Newman BM, Taylor SH, et al. Incidence of hypercalcemia in patients with malignancy referred to a comprehensive cancer center. Cancer 1993; 71(4): 1309–12PubMedCrossRefGoogle Scholar
  6. 6.
    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(5): 1268–70PubMedCrossRefGoogle Scholar
  7. 7.
    Ralston SH, Gallacher SJ, Patel U, et al. Cancer-associated hypercalcemia: morbidity and mortality: clinical experience in 126 treated patients. Ann Intern Med 1990; 112: 499–504PubMedGoogle Scholar
  8. 8.
    Otsuka F, Hayakawa N, Ogura T, et al. A case of primary hyperparathyroidism accompanying multiple myeloma. Endocr J 1997; 44: 105–9PubMedCrossRefGoogle Scholar
  9. 9.
    Albes B, Bazex J, Bayle-Lebey P, et al. Primary hyperparathyroidism and cutaneous T-cell lymphoma: fortuitous association? Dermatology 2001; 203: 162–4PubMedCrossRefGoogle Scholar
  10. 10.
    Hutchesson AC, Bundred NJ, Ratcliffe WA. Survival in hypercalcemic cancer patients with co-existing primary hyperparathyroidism. Postgrad Med J 1995; 71: 28–31PubMedCrossRefGoogle Scholar
  11. 11.
    Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998; 93(2): 165–76PubMedCrossRefGoogle Scholar
  12. 12.
    Yasuda H, Shima N, Nakagawa N, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis: inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A 1998; 95(7): 3597–602PubMedCrossRefGoogle Scholar
  13. 13.
    Aubin JE, Bonnelye E. Osteoprotegerin and its ligand: a new paradigm for regulation of osteoclastogenesis and bone resorption. Osteoporos Int 2000; 11: 905–13PubMedCrossRefGoogle Scholar
  14. 14.
    Kong YY, Yoshida H, Sarosi I, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 1999; 397(6717): 315–23PubMedCrossRefGoogle Scholar
  15. 15.
    Hsu H, Lacey DL, Dunstan CR, et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci U S A 1999; 96(7): 3540–5PubMedCrossRefGoogle Scholar
  16. 16.
    Goltzmann D. Osteolysis and cancer. J Clin Invest 2001; 107: 1219–20CrossRefGoogle Scholar
  17. 17.
    Hofbauer LC, Neubauer A, Heufelder AE. Receptor activator of nuclear factor-?.B ligand and osteoprotegerin: potential indications for the pathogenesis and treatment of malignant bone disease. Cancer 2001; 92: 460–70PubMedCrossRefGoogle Scholar
  18. 18.
    Suda T, Takahashi N, Udagawa N, et al. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev 1999; 20: 345–57PubMedCrossRefGoogle Scholar
  19. 19.
    Simonet WS, Lacey DL, Dunstan CR, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997; 89(2): 309–19PubMedCrossRefGoogle Scholar
  20. 20.
    Kong YY, Boyle WJ, Penninger JM. Osteoprotegerin ligand: a common link between osteoclastogenesis, lymph node formation and lymphocytic development. Immunol Cell Biol 1999; 77: 188–93PubMedCrossRefGoogle Scholar
  21. 21.
    Hofbauer LC, Khosla S, Dunstan CR, et al. The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Mineral Res 2000; 15: 2–12CrossRefGoogle Scholar
  22. 22.
    Roodman DG. Advances in bone biology: the osteoclast. Endocr Rev 1996; 17(4): 308–32PubMedGoogle Scholar
  23. 23.
    Parfitt AM, Mundy GR, Roodman GD, et al. A new model for the regulation of bone resorption, with particular reference to the effects of bisphosphonates. J Bone Miner Res 1996; 11(2): 150–9PubMedCrossRefGoogle Scholar
  24. 24.
    Jüppner H, Brown M, Kronenberg H. Parathyroid hormone. In: Farus MJ, editor. Primer on the metabolic bone disease and disorders of mineral metabolism: an official publication of The American Society for Bone and Mineral Research. 4th ed. Philadelphia (PA): Lippincott, 1999: 80–7Google Scholar
  25. 25.
    Kovacs CS, Lanske B, Hunzelman JL, et al. Parathyroid hormone-related peptide (PTHrP) regulates fetal-placental calcium transport through a receptor distinct from the PTH/PTHrP receptor. Proc Natl Acad Sci U S A 1996; 93(26): 15233–8PubMedCrossRefGoogle Scholar
  26. 26.
    Uemura H, Yasui T, Yoneda N, et al. Measurement of N- and C-terminal-region fragments of parathyroid hormone-related peptide in milk from lactating women and investigation of the relationship of their concentrations to calcium in milk. J Endocrinol 1997; 153(3): 445–51PubMedCrossRefGoogle Scholar
  27. 27.
    Thiebaud D, Janisch S, Koelbl H, et al. Direct evidence of a parathyroid related protein gradient between the mother and the newborn in humans. Bone Miner 1993; 23(3): 213–21PubMedCrossRefGoogle Scholar
  28. 28.
    Wysolmerski JJ, Stewart AF. The physiology of parathyroid hormone-related protein: an emerging role as a developmental factor. Annu Rev Physiol 1998; 60: 431–60PubMedCrossRefGoogle Scholar
  29. 29.
    Bilezikian JP. Primary hyperparathyroidism. In: Farus MJ, editor. Primer on the metabolic bone disease and disorders of mineral metabolism: an official publication of The American Society for Bone and Mineral Research. 4th ed. Philadelphia (PA): Lippincott, 1999: 187–91Google Scholar
  30. 30.
    Hobbs MR, Heath III H. Familial hyperparathyroid syndromes. In: Farus MJ, editor. Primer on the metabolic bone disease and disorders of mineral metabolism: an official publication of The American Society for Bone and Mineral Research. 4th ed. Philadelphia (PA): Lippincott, 1999: 192–5Google Scholar
  31. 31.
    Pecherstorfer M, Zimmer-Roth I, Schilling T, et al. The diagnostic value of urinary pyridinium cross-links of collagen, serum total alkaline phosphatase, and urinary calcium excretion in neoplastic bone disease. J Clin Endocrinol Metab 1995; 80(1): 97–103PubMedCrossRefGoogle Scholar
  32. 32.
    Mundy GR, Guise TA. Hypercalcemia of malignancy. Am J Med 1997; 103: 134–45PubMedCrossRefGoogle Scholar
  33. 33.
    Kremer R, Shustik C, Tabak T, et al. Parathyroid hormone-related peptide in hematologic malignancies. Am J Med 1996; 100(4): 406–11PubMedCrossRefGoogle Scholar
  34. 34.
    Grill V, Martin TJ. Hypercalcemia. In: Rubens RD, Mundy GR, editors. Cancer and the skeleton. London: Martin Dunitz, 2000: 75–89Google Scholar
  35. 35.
    Schilling T, Pecherstorfer M, Blind E, et al. Parathyroid hormone-related protein (PTHrP) does not regulate 1,25 Dihydroxy vitamin D levels in hypercalcemia of malignancy. J Clin Endocrinol Metab 1993; 76: 801–3PubMedCrossRefGoogle Scholar
  36. 36.
    Croucher PI, Shipman CM, Lippitt J, et al. Osteoprotegerin inhibits the development of osteolytic bone disease in multiple myeloma. Blood 2001; 98: 3534–40PubMedCrossRefGoogle Scholar
  37. 37.
    Zhang J, Dai J, Qi Y, et al. Osteoprotegerin inhibits prostate cancer-induced osteoclastogenesis and prevents prostate tumor growth in the bone. J Clin Investig 2001; 107: 1235–44PubMedCrossRefGoogle Scholar
  38. 38.
    Nosaka K, Miyamoto T, Sakai T, et al. Mechanism of hypercalcemia in adult T-cell leukemia: overexpression of receptor activator of nuclear factor? B ligand on adult T-cell leukemia cells. Blood 2002; 99: 634–40PubMedCrossRefGoogle Scholar
  39. 39.
    Mundy GR. Calcium homeostasis: hypercalcemia and hypocalcemia. 2nd ed. London: Martin Dunitz, 1990Google Scholar
  40. 40.
    Insogna KL, Dreyer BE, Mitnich M, et al. Enhanced production rate of 1,25 hydroxyvitamin D in sarcoidosis. J Clin Endocrinol Metab 1988; 66: 72–5PubMedCrossRefGoogle Scholar
  41. 41.
    Playford EG, Bansal AS, Looke DFM, et al. Hypercalcemia and elevated 1,25(OH)2D3 levels associated with disseminated mycobacterium avis infection in AIDS. J Infect 2001; 42: 157–8PubMedCrossRefGoogle Scholar
  42. 42.
    D’Souza-Li L, Yang B, Canaff L, et al. Identification and functional characterization of novel calcium-sensing receptor mutations in familial hypocalcuric hypercalcemia and autosomal dominant hypocalcemia. J Clin Endocrinol Metab 2002; 87: 1309–18PubMedCrossRefGoogle Scholar
  43. 43.
    El-Hajj Fuleihan G. Familial benign hypocalciuric hypercalcemia. Proceedings of the National Institute of Diabetes and Digestive and Kidney Diseases Workshop: asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Bone Mineral Res 2002; 17Suppl. 2: N51–6Google Scholar
  44. 44.
    Heath III H. Familial benign (hypocalcuric) hypercalcemia: a troublesome mimic of hyperparathyroidism. Endocrinol Metab Clin North Am 1989; 18: 723–40PubMedGoogle Scholar
  45. 45.
    Bell NH. Osteomalacia and rickets. In Becker KL, editor. Principles and practice of endocrinology. 2nd ed. Philadelphia (PA): JB Lippincott, 1995: 566Google Scholar
  46. 46.
    Hatake K, Uwai M, Ohtsuki T, et al. Rare but important adverse effects of all-trans retinoic acid in acute promyelocytic leukemia and their management. Int J Hematol 1997; 66: 13–9PubMedCrossRefGoogle Scholar
  47. 47.
    Nikolic-Tomasevic Z, Jelic S, Popov I, et al. Tumor “flare” hypercalcemia-an additional indication for bisphosphonates? Oncology 2001; 60: 123–6PubMedCrossRefGoogle Scholar
  48. 48.
    Takata S, Yasui N. Disuse osteoporosis. J Med Invest 2001; 48: 147–56PubMedGoogle Scholar
  49. 49.
    Ziegler R. Hypercalcemic crisis. J Am Soc Nephrol 2001; 12Suppl. 17: S3–9PubMedGoogle Scholar
  50. 50.
    Proceedings of the National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Bone Miner Res 2002; 17Suppl. 2: N1–162Google Scholar
  51. 51.
    Tal A, Graves L. Intravenous pamidronate for hypercalcemia of primary hyperparathyroidism. South Med J 1996; 89: 637–40PubMedCrossRefGoogle Scholar
  52. 52.
    Tisell LE, Hedback G, Jansson S, et al. Management of hyperparathyroid patients with grave hypercalcemia. World J Surg 1991; 15: 730–7PubMedCrossRefGoogle Scholar
  53. 53.
    Kotzmann H, Svoboda T, Bernecker P, et al.Disodium pamidronate (APD) in therapy of hypercalcemia in primary hyperparathyroidism. Wien Klin Wochenschr 1994; 106: 422–5PubMedGoogle Scholar
  54. 54.
    Ishimura E, Miki T, Harada K, et al. Effect of aminohydroxypropylidene diphosphonate on the bone metabolism of patients with parathyroid adenoma. Horm Metab Res 1993; 25: 493–7PubMedCrossRefGoogle Scholar
  55. 55.
    Christensen JH, Kristiansen JH. Combination therapy with pamidronate and calcitonin in hypercalcemic crisis caused by primary hyperparathyroidism. Ugeskr Laeger 1992; 16: 3341–2Google Scholar
  56. 56.
    Janson S, Tisell LE, Linstedt G, et al. Disodium pamidronate in the preoperative management of hypercalcemia in patients with primary hyperparathyroidism. Surgery 1991; 110: 480–6Google Scholar
  57. 57.
    Evans RA. Aminohydroxypropylidene diphosphonate treatment of hypercalcemic crisis due to primary hyperparathyroidism. Aust N Z J Med 1987; 17: 58–9PubMedCrossRefGoogle Scholar
  58. 58.
    Mundy GR, Wilkinson R, Heath DA. Comparative study of medical therapy for hypercalcemia of malignancy. Am J Med 1983; 74: 421–32PubMedCrossRefGoogle Scholar
  59. 59.
    Van Breukelen FJ, Bijvoet OL, Frijlink WB, et al. Efficacy of amino-hydroxypropylidene bisphosphonate in hypercalcemia: observations on regulation of serum calcium. Calcif Tissue Int 1982; 34: 321–7PubMedCrossRefGoogle Scholar
  60. 60.
    Hamdy NA, Gray RE, McCloskey E, et al. Clodronate in the medical management of hyperparathyroidism. Bone 1987; 8Suppl. 1: S69–77PubMedGoogle Scholar
  61. 61.
    Shane E, Jacobs TP, Siris ES, et al. Therapy of hypercalcemia due to parathyroid carcinoma with intravenous dichloromethylene diphosphonate. Am J Med 1982; 72: 939–44PubMedCrossRefGoogle Scholar
  62. 62.
    Silverberg SJ, Bone III HG, Marriott TB, et al. Short term inhibition of parathyroid hormone secretion by a calcium-receptor agonist in patients with primary hyperparathyroidism. N Engl J Med 1997; 337: 1506–10PubMedCrossRefGoogle Scholar
  63. 63.
    Antoniucci DM, Shoback D. Calcimimetics in the treatment of primary hypeparathyroidism. In: Proceedings of the National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Bone Miner Res 2002; 17Suppl. 2: N141–5Google Scholar
  64. 64.
    Peacock M, Bilezikian JP, Turner SA, et al. Long-term treatment with the calcimimetic AMG 073 in patients with primary hyperparathyroidism [abstract]. Proceedings of the Annual Meeting of The Endocrine Society; San Francisco; 2002 Jun 19–22: 92, OR 21-1Google Scholar
  65. 65.
    Sleeboom HP, Bijvoet OLM, Van Oosterom AT, et al. Comparison of intravenous (3-amino-1-hydroxypropylidene)-1-1-bisphosphonate and volume repletion in tumour-induced hypercalcemia. Lancet 1983; II: 239–43CrossRefGoogle Scholar
  66. 66.
    Fleisch H. Bisphosphonates: pharmacology and use in the treatment of tumor-induced hypercalcemia and metastatic bone loss. Drugs 1991; 42(6): 919–44PubMedCrossRefGoogle Scholar
  67. 67.
    Zojer N, Keck AV, Pecherstorfer M. Comparative tolerability of drug therapies for hypercalcemia of malignancy. Drug Saf 1999; 21: 389–406PubMedCrossRefGoogle Scholar
  68. 68.
    Flores JF, Singer FR, Rude RK. Effectiveness of a 24-hour infusion of etidronate disodium in the treatment of hypercalcemia of malignant disease. Miner Electrolyte Metab 1991; 17: 390–5PubMedGoogle Scholar
  69. 69.
    Body JJ, Lortholary A, Romieu G, et al. A dose-finding study of zoledronate in hypercalcemic cancer patients. J Bone Miner Res 1999; 14: 1557–61PubMedCrossRefGoogle Scholar
  70. 70.
    Major P, Lortholary J, Hon J, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol 2001; 19: 558–67PubMedGoogle Scholar
  71. 71.
    Hasling C, Charles P, Mosekilde L. Etidronate disodium in the management of malignancy related hypercalcemia. Am J Med 1987; 82Suppl. 2A: 51–4PubMedCrossRefGoogle Scholar
  72. 72.
    Singer FR, Ritch PS, Lad TE, et al. Treatment of hypercalcemia of malignancy with intravenous etidronate: a controlled multicenter study. Arch Intern Med 1991; 151: 471–6PubMedCrossRefGoogle Scholar
  73. 73.
    Warrell RP, Murphy WK, Schulman P, et al. A randomized double-blind study of gallium nitrate compared with etidronate for acute control of cancer-related hypercalcemia. J Clin Oncol 1991; 9(8): 1467–75PubMedGoogle Scholar
  74. 74.
    Gucalp R, Ritch P, Wiernik PH, et al. Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcemia. J Clin Oncol 1992; 10(1): 134–42PubMedGoogle Scholar
  75. 75.
    Cohen AI, Koeller J, Davis TE, et al. IV dichloromethylene diphosphonate in cancer associated hypercalcemia: a phase I–II evaluation. Cancer Treat Rep 1981; 65(7–8): 651–3PubMedGoogle Scholar
  76. 76.
    Jacobs TP, Siris ES, Bilezikian JP, et al. Hypercalcemia of malignancy: treatment with intravenous dichloromethylene diphosphonate. Ann Intern Med 1981; 94: 312–6PubMedGoogle Scholar
  77. 77.
    Urwin GH, Yates AJP, Gray RES, et al. Treatment of hypercalcemia of malignancy with intravenous clodronate. Bone 1987; 8Suppl. 1: S43–51PubMedGoogle Scholar
  78. 78.
    Harjung H, Fritze D. Results of treating tumour-induced hypercalcemia with clodronate alone. Dtsch Med Wochenschr 1990; 115: 48–52PubMedCrossRefGoogle Scholar
  79. 79.
    Rotstein S, Glas U, Eriksson M, et al. Intravenous clodronate for the treatment of hypercalcemia in breast cancer patients with bone metastases: a prospective randomised placebo-controlled study. Eur J Cancer 1992; 28A(4/5): 890–3PubMedCrossRefGoogle Scholar
  80. 80.
    O’Rourke NP, McCloskey EV, Vasikaran S, et al. Effective treatment of malignant hypercalcemia with a single intravenous infusion of clodronate. Br J Cancer 1993; 67(3): 560–3PubMedCrossRefGoogle Scholar
  81. 81.
    Purohit OP, Radstone CR, Anthony C, et al. A randomized double-blind comparison of intravenous pamidronate and clodronate in the hypercalcemia of malignancy. Br J Cancer 1995; 72: 1289–93PubMedCrossRefGoogle Scholar
  82. 82.
    Ralston SH, Dryburgh FJ, Cowan RA, et al. Comparison of aminohydroxypropylidene diphosphonate, mithramycin, and corticosteroids/calcitonin in the treatment of cancer-associated hypercalcemia. Lancet 1985; II: 907–10CrossRefGoogle Scholar
  83. 83.
    Thiebaud D, Jaeger P, Jacquet AF, et al. A single day treatment of tumor-induced hypercalcemia by intravenous amino-hydroxypropylidene bisphosphonate. J Bone Miner Res 1986; 1(6): 555–62PubMedCrossRefGoogle Scholar
  84. 84.
    Body JJ, Pot M, Borkowski A, et al. Dose/response study of aminohydroxypropylidene bisphosphonate in tumor-associated hypercalcemia. Am J Med 1987; 82: 957–63PubMedCrossRefGoogle Scholar
  85. 85.
    Cantwell BM, Harris AL. Effect of single high dose infusions of aminohydroxypropylidene diphosphonate on hypercalcemia caused by cancer. BMJ 1987; 294: 467–9PubMedCrossRefGoogle Scholar
  86. 86.
    Coleman RE, Rubens RD. 3(amino-1,1-hydroxypropylidene) bisphosphonate (APD) for hypercalcemia of breast cancer. Br J Cancer 1987; 56: 465–9PubMedCrossRefGoogle Scholar
  87. 87.
    Yates AJP, Murray RML, Jerums GJ, et al. A comparison of single and multiple intravenous infusions of 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (APD) in the treatment of hypercalcemia of malignancy. Aust N Z J Med 1987; 17: 387–91PubMedCrossRefGoogle Scholar
  88. 88.
    Morton AR, Cantrill JA, Craig AE, et al. Single dose versus daily intravenous aminohydroxypropylidene bisphosphonate (APD) for the hypercalcemia of malignancy. BMJ 1988; 296: 811–4PubMedCrossRefGoogle Scholar
  89. 89.
    Thiebaud D, Jaeger P, Jacquet AF, et al. Dose-response in the treatment of hypercalcemia of malignancy by a single infusion of the bisphosphonate AHPrBP. J Clin Oncol 1988; 6(5): 762–8PubMedGoogle Scholar
  90. 90.
    Body JJ, Magritte A, Seraj F, et al. Aminohydroxypropylidene bisphosphonate (APD) treatment for tumor-associated hypercalcemia: a randomized comparison between a 3-day treatment and single 24-hour infusions. J Bone Miner Res 1989; 4(6): 923–8PubMedCrossRefGoogle Scholar
  91. 91.
    Davis JRE, Heath DA. Comparison of different dose regimens of aminohydroxypropylidene-1, 1-bisphosphonate (APD) in hypercalcemia of malignancy. Br J Clin Pharmacol 1989; 28: 269–74PubMedCrossRefGoogle Scholar
  92. 92.
    Gallacher SJ, Ralston SH, Patel U, et al. Side effects of pamidronate. Lancet 1989; II: 42–3CrossRefGoogle Scholar
  93. 93.
    Mannix KA, Carmichael J, Harris AL, et al. Single high-dose (45mg) infusions of aminohydroxypropylidene diphosphonate for severe malignant hypercalcemia. Cancer 1989; 64: 1358–61PubMedCrossRefGoogle Scholar
  94. 94.
    Sawyer N, Newstead C, Drummond A, et al. One-shot high-dose pamidronate disodium (APD): effective, simple treatment for hypercalcemia in haematological malignancy. Clin Lab Haematol 1989; 11: 179–84PubMedCrossRefGoogle Scholar
  95. 95.
    Sawyer N, Newstead C, Drummond A, et al. Fast (4-h) or slow (24-h) infusions of pamidronate disodium (aminohydroxypropylidene diphosphonate (APD)) as single shot treatment for hypercalcemia. Bone Miner 1990; 9: 122–8CrossRefGoogle Scholar
  96. 96.
    Pecherstorfer M, Janisch S, Marosi C, et al. Treatment of cancer-associated hypercalcemia with pamidronate. Klin Wochenschr 1991; 69: 690–5PubMedCrossRefGoogle Scholar
  97. 97.
    Gallacher SJ, Ralston SH, Fraser WD, et al. A comparison of low versus high dose pamidronate in cancer-associated hypercalcemia. Bone Miner 1991; 15(3): 249–56PubMedCrossRefGoogle Scholar
  98. 98.
    Dodwell DJ, Howell A, Morton AR, et al. Infusion rate and pharmacokinetics of intravenous pamidronate in the treatment of tumour-induced hypercalcemia. Postgrad Med J 1992; 68: 434–9PubMedCrossRefGoogle Scholar
  99. 99.
    Ostenstad B, Andersen OK. Disodium pamidronate versus mithramycin in the management of tumour-associated hypercalcemia. Acta Oncol 1992; 31(8): 861–4PubMedCrossRefGoogle Scholar
  100. 100.
    Thürlimann B, Waldburger R, Senn HJ, et al. Plicamycin and pamidronate in symptomatic tumor-related hypercalcemia: a prospective randomized crossover trial. Ann Oncol 1992; 3: 619–23PubMedGoogle Scholar
  101. 101.
    Nussbaum SR, Younger J, Vandepol CJ, et al. Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy: comparison of 30-, 60-, and 90-mg dosages. Am J Med 1993; 95: 297–304PubMedCrossRefGoogle Scholar
  102. 102.
    Gucalp R, Theriault R, Gill I, et al. Treatment of cancer-associated hypercalcemia: double blind comparison of rapid and slow intravenous infusion regimens of pamidronate disodium and saline alone. Arch Intern Med 1994; 154: 1935–44PubMedCrossRefGoogle Scholar
  103. 103.
    Zysset E, Ammann P, Jenzer A, et al. Comparison of a rapid (2-h) versus a slow (24-h) infusion of alendronate in the treatment of hypercalcemia of malignancy. Bone Miner 1992; 18: 237–49PubMedCrossRefGoogle Scholar
  104. 104.
    Nussbaum SR, Warrell RP, Rude R, et al. Dose-response study of alendronate sodium for the treatment of cancer-associated hypercalcemia. J Clin Oncol 1993; 11(8): 1618–23PubMedGoogle Scholar
  105. 105.
    Wüster C, Schöter KH, Thiebaud D, et al. Methylpentylaminopropylidenebisphosphonate (BM 21.0955): a new potent and safe bisphosphonate for the treatment of cancer-associated hypercalcemia. Bone Miner 1993; 22: 77–85PubMedCrossRefGoogle Scholar
  106. 106.
    Pecherstorfer M, Herrmann Z, Body JJ, et al. Randomized phase II trial comparing different doses of the bisphosphonate ibandronate in the treatment of hypercalcemia of malignancy. J Clin Oncol 1996; 14(1): 268–76PubMedGoogle Scholar
  107. 107.
    Ralston SH, Thiebaud D, Herrmann Z, et al. Dose-response study of ibandronate in the treatment of cancer-associated hypercalcemia. Br J Cancer 1997; 75(2): 295–300PubMedCrossRefGoogle Scholar
  108. 108.
    Dumon JC, Magritte A, Body JJ. Efficacy and safety of the bisphosphonate tiludronate for the treatment of tumor-associated hypercalcemia. Bone Miner 1991; 15: 257–66PubMedCrossRefGoogle Scholar
  109. 109.
    O’Rourke NP, McCloskey EV, Rosini S, et al. Treatment of malignant hypercalcemia with aminohexane bisphosphonate (neridronate). Br J Cancer 1994; 69: 914–7PubMedCrossRefGoogle Scholar
  110. 110.
    Van Breukelen FJM, Bijovoet OLM, Frijlink WB, et al. Efficacy of aminohydroxypropylidene bisphosphonate in hypercalcemia: observations on regulation of serum calcium. Calcif Tissue Int 1982; 34: 321–7PubMedCrossRefGoogle Scholar
  111. 111.
    Thiebaud D, Portmann L, Jaeger P, et al. Oral versus intravenous AHPrBP (APD) in the treatment of hypercalcemia of malignancy. Bone 1986; 7(4): 247–53PubMedCrossRefGoogle Scholar
  112. 112.
    Ziegler R, Scharla SH. Treatment of tumor hypercalcemia with clodronate. Recent Results Cancer Res 1989; 116: 47–53Google Scholar
  113. 113.
    Rastad J, Benson L, Johansson H, et al. Clodronate treatment in patients with malignancy-associated hypercalcemia. Acta Med Scand 1987; 221: 489–94PubMedCrossRefGoogle Scholar
  114. 114.
    Percival RC, Paterson AD, Yates AJP, et al. Treatment of malignant hypercalcemia with clodronate. Br J Cancer 1985; 51: 665–9PubMedCrossRefGoogle Scholar
  115. 115.
    Schiller JH, Rasmussen P, Benson AB, et al. Maintenance etidronate in the prevention of malignancy-associated hypercalcemia. Arch Intern Med 1987; 147: 963–6PubMedCrossRefGoogle Scholar
  116. 116.
    Ebetino FH, Dansereau SM. Bisphosphonate antiresorptive structure-activity relationship. In: Bijvoet OLM, Fleisch HA, Canfield RE, et al., editors. Bisphosphonates on bones. Amsterdam: Elsevier, 1995: 139–53Google Scholar
  117. 117.
    Green JR, Müller K, Jaeggi KA. Preclinical pharmacology of CGP 42′446, a new potent, heterocyclic bisphosphonate compound. J Bone Miner Res 1994; 9: 745–51PubMedCrossRefGoogle Scholar
  118. 118.
    Walls J, Ratcliffe WA, Howell A, et al. Response to intravenous bisphosphonate therapy in hypercalcaemic patients with and without bone metastases: the role of parathyroid hormone-related protein. Br J Cancer 1994; 70: 169–72PubMedCrossRefGoogle Scholar
  119. 119.
    Gurney H, Grill V, Martin TJ. Parathyroid hormone-related protein and response to pamidronate in tumour-induced hypercalcemia. Lancet 1993; 341: 1611–3PubMedCrossRefGoogle Scholar
  120. 120.
    Body JJ, Dumon JC, Thirion M, et al. Circulating PTHrP concentrations in tumor-induced hypercalcemia: influence on the response to bisphosphonate and changes after therapy. J Bone Miner Res 1993; 8: 701–6PubMedCrossRefGoogle Scholar
  121. 121.
    Pecherstorfer M, Thiebaud D. Treatment of tumor-induced hypercalcemia with escalating doses of pamidronate (APD). Ann Oncol 1992; 3(8): 661–3PubMedGoogle Scholar
  122. 122.
    Thiébaud D, Jaeger P, Burckhardt P. Response to retreatment of malignant hypercalcemia with the bisphosphonate AHPrBP (APD): respective role of kidney and bone. J Bone Miner Res 1990; 5: 221–6PubMedCrossRefGoogle Scholar
  123. 123.
    Pecherstorfer M, Steinhauser EU, Rizzoli R, et al. Efficacy and safety of ibandronate in the treatment of hypercalcemia of malignancy: a randomized multicentric comparison to pamidronate. Support Care Cancer. In pressGoogle Scholar
  124. 124.
    Bounameaux HM, Schifferli J, Montani JP, et al. Renal failure associated with intravenous bisphosphonates [letter]. Lancet 1983; I: 471CrossRefGoogle Scholar
  125. 125.
    Machado CE, Flombaum CD. Safety of pamidronate in patients with renal failure and hypercalcemia. Clin Nephrol 1996; 45(3): 175–9PubMedGoogle Scholar
  126. 126.
    Adami S, Zamberlan N. Adverse effects of bisphosphonates. Drug Saf 1996; 14(3): 158–70PubMedCrossRefGoogle Scholar
  127. 127.
    Pecherstorfer M, Jilch R, Horn E, et al. Effect of first treatment with the aminobisphosphonatespamidronate and ibandronate on circulating lymphocyte subpopulations. J Bone Miner Res 2000, 154Google Scholar
  128. 128.
    Kunzmann V, Bauer E, Wilhelm M. Gamma/delta T-cell stimulation by pamidronate. N Engl J Med 1999; 340: 737–8PubMedCrossRefGoogle Scholar
  129. 129.
    Kunzmann V, Bauer E, Feurle J, et al. Stimulation of gammadelta T cells by aminobisphosphonates and induction of antiplasma cell activity in multiple myeloma. Blood 2000; 96: 384–92PubMedGoogle Scholar
  130. 130.
    Sauty A, Pecherstorfer M, Zimmer-Roth I, et al. Interleukin-6 and tumor necrosis factor alpha levels after bisphosphonate treatment in vitro and in patients with malignancy. Bone 1996; 18(2): 133–9PubMedCrossRefGoogle Scholar
  131. 131.
    Schweitzer DH, Oostendorp-Van de Ruit M, Van der Pluijm G, et al. Interleukin-6 and the acute phase response during treatment of patients with Paget’s disease with the nitrogen-containing bisphosphonate dimethylaminohydroxypropylidene bisphosphonate. J Bone Miner Res 1995; 10(6): 956–62PubMedCrossRefGoogle Scholar
  132. 132.
    Stewart GO, Stuckey BG, Ward LC, et al. Iritis following intravenous pamidronate. Aust N Z J Med 1996; 26(3): 414–5PubMedCrossRefGoogle Scholar
  133. 133.
    Macarol V, Fraunfelder F. Pamidronate disodium and possible ocular adverse drug reactions. Am J Ophtalmol 1994; 118: 220–4Google Scholar
  134. 134.
    Pedersen-Bjergaard U, Myhre J. Severe hypocalcemia after treatment with diphosphonate and aminoglycoside [letter]. BMJ 1991; 302: 295PubMedCrossRefGoogle Scholar
  135. 135.
    Pecherstorfer M, Schilling T, Janisch S, et al. Effect of clodronate treatment on bone scintigraphy in metastatic breast cancer. J Nucl Med 1993; 34: 1039–44PubMedGoogle Scholar
  136. 136.
    Warrell RP, Israel R, Frisone M, et al. Gallium nitrate for acute treatment of cancer-related hypercalcemia: a randomized, double-blind comparison to calcitonin. Ann Intern Med 1988; 108: 669–74PubMedGoogle Scholar
  137. 137.
    Bockman RS, Repo MA, Warrell RP, et al. Distribution of trace levels of therapeutic gallium in bone as mapped by synchroton x-ray microscopy. Proc Natl Acad Sci U S A 1990; 87(11): 4149–53PubMedCrossRefGoogle Scholar
  138. 138.
    Bockman RS, Boskey AL, Blumenthal NC, et al. Gallium increases bone calcium and crystallite perfection of hydroxyapatite. Calcif Tissue Int 1986; 39(6): 376–81PubMedCrossRefGoogle Scholar
  139. 139.
    Bockman RS, Guidon Jr PT, Pan LC, et al. Gallium nitrate increases type I collagen and fibronectin mRNA and collagen protein levels in bone and fibroblast cells. J Cell Biochem 1993; 52(4): 396–403PubMedCrossRefGoogle Scholar
  140. 140.
    Kiang DT, Loken MK, Kennedy BJ. Mechanism of the hypocalcemic effect of mithramycin. J Clin Endocrinol Metab 1979; 48(2): 341–4PubMedCrossRefGoogle Scholar
  141. 141.
    Slayton RE, Shnider BI, Elias E, et al. New approach to the treatment of hypercalcemia: the effect of short-term treatment with mithramycin. Clin Pharmacol Ther 1971; 12(5): 833–7PubMedGoogle Scholar
  142. 142.
    Elias EG, Evans JT. Hypercalcemic crisis in neoplastic disease: management with mithramycin. Surgery 1972; 71(4): 631–5PubMedGoogle Scholar
  143. 143.
    Gasser AB, Flury R, Senn HJ. Therapie des Hyperkalzämiesyndroms mit Mithramyzin. Schweiz Med Wochenschr 1974; 104: 1792–4PubMedGoogle Scholar
  144. 144.
    Fillastre JP, Maitrot J, Canonne MA, et al. Renal function and alterations in plasma electrolyte levels in normocalcemic and hypercalcemic patients with malignant diseases, given an intravenous infusion of mithramycin. Chemotherapy 1974; 20: 280–95PubMedCrossRefGoogle Scholar
  145. 145.
    Green L, Donehower RC. Hepatic toxicity of low doses of mithramycin in hypercalcemia. Cancer Treat Rep 1984; 68(11): 1379–81PubMedGoogle Scholar
  146. 146.
    Silva OL, Becker KL. Salmon calcitonin in the treatment of hypercalcemia. Arch Intern Med 1973; 132: 337–9PubMedCrossRefGoogle Scholar
  147. 147.
    Wisneski LA, Croom WP, Silva OL, et al. Salmon calcitonin in hypercalcemia. Clin Pharmacol Ther 1978; 24(2): 219–22PubMedGoogle Scholar
  148. 148.
    Geley S, Fiegl M, Hartmann BL, et al. Genes mediating glucocorticoid effects and mechanisms of their regulation. Rev Physiol Biochem Pharmacol 1996; 128: 1–97PubMedGoogle Scholar
  149. 149.
    Takahashi S, Goldring S, Katz M, et al. Downregulation of calcitonin receptor mRNA expression by calcitonin during human osteoclast-like differentiation. J Clin Invest 1995; 95(1): 167–71PubMedCrossRefGoogle Scholar
  150. 150.
    Ralston SH, Alzaid AA, Gardner MD, et al. Treatment of cancer-associated hypercalcemia with combined aminohydroxypropylidene diphosphonate and calcitonin. BMJ 1986; 292: 1549–50PubMedCrossRefGoogle Scholar
  151. 151.
    Bower M, Stein RC, Hedley A, et al. The use of nasal calcitonin spray in the treatment of hypercalcemia of malignancy. Cancer Chemother Pharmacol 1991; 28: 311–2PubMedGoogle Scholar
  152. 152.
    Leyland-Jones B. Pharmacokinetics and therapeutic index of gallium nitrate. Semin Oncol 1991; 18(4 Suppl. 5): 16–20PubMedGoogle Scholar
  153. 153.
    Ahr DJ, Scialla SJ, Kimball DB. Acquired platelet dysfunction following mithramycin therapy. Cancer 1978; 41: 448–54PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  • Martin Pecherstorfer
    • 1
  • Karin Brenner
    • 1
  • Niklas Zojer
    • 1
  1. 1.First Department of Medicine and Medical OncologyWilhelminenspitalViennaAustria

Personalised recommendations