, Volume 52, Issue 6, pp 837–848 | Cite as

The Management of Malignant Hypercalcaemia

  • Julie Watters
  • Georgina Gerrard
  • David Dodwell
Disease Management


Malignant hypercalcaemia is a common problem for cancer clinicians. However, the management of this condition has altered substantially over the last 10 years and the condition is usually amenable to modern treatment.

A number of effective pharmacological agents are available in current practice. Bisphosphonate drugs, particularly clodronate and pamidronate, are confirmed as the mainstay of modern management. Bisphosphonates are effective and well tolerated when given intravenously. Many aspects of the actions of bisphosphonates are not well understood, and knowledge of their pharmacokinetics is limited.


Bisphosphonates Calcitonin Pamidronate Etidronate Salmon Calcitonin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Anon. Treating cancer-associated hypercalcaemia. Drug Ther Bull 1990; 20: 85–7Google Scholar
  2. 2.
    Goodwin JS, Atluru D, Sierakowski S, et al. Mechanism of action of glucocorticosteroids: inhibition of T cell proliferation and interleukin 2 production by hydrocortisone is reversed by leukotriene B4. J Clin Invest 1986; 77: 1244–50CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Bilesikian JP. Management of acute hypercalcaemia. N Engl J Med 1992; 326: 1196–203CrossRefGoogle Scholar
  4. 4.
    Percival RC, Yates AJP, Gray RES, et al. Role of glucocorticoids in the management of malignant hypercalcaemia [letter]. BMJ 1984; 289: 287CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ralston SH, Gardner MD, Dryburgh FJ, et al. Comparison of aminohydroxypropylidene diphosphonate, mithramycin and corticosteroids/calcitonin in treatment of cancer-associated hypercalcaemia. Lancet 1985; II: 907–10CrossRefGoogle Scholar
  6. 6.
    Thurlimann B, Waldburger R, Senn HJ, et al. Plicamycin and pamidronate in symptomatic tumour-related hypercalcaemia: a prospective randomized crossover trial. Ann Oncol 1992; 3: 619–23CrossRefPubMedGoogle Scholar
  7. 7.
    Green L, Donehower RC. Hepatic toxicity of low doses of mithramycin in hypercalcemia. Cancer Treat Rep 1984; 68: 1379–81PubMedGoogle Scholar
  8. 8.
    Ostenstad B, Andersen OK. Disodium pamidronate versus mithramycin in the management of tumour-associated hypercalcaemia. Acta Oncol 1992; 31: 861–4CrossRefPubMedGoogle Scholar
  9. 9.
    Clissold SP, Fitton A, Chrisp P. Intranasal salmon calcitonin: a review of its pharmacological properties and potential utility in metabolic bone disorders associated with aging. Drugs Aging 1991; 1: 405–23CrossRefPubMedGoogle Scholar
  10. 10.
    Hosking DJ, Gilson D. Comparison of the renal and skeletal actions of calcitonin in the treatment of severe hypercalcaemia of malignancy. Q J Med 1984; 211: 359–68Google Scholar
  11. 11.
    Wisneski LA. Salmon calcitonin in the acute management of hypercalcaemia. Calcif Tissue Int 1990; 46 Suppl.: S26–30CrossRefPubMedGoogle Scholar
  12. 12.
    Boonekamp PM, van der Wee-Pals LJA, van Wijk-van Lennep MLL, et al. Two modes of action of bisphosphonates on osteoclastic resorption of mineralized matrix. Bone Miner 1986; 1: 27–39PubMedGoogle Scholar
  13. 13.
    Reitsma PH, Bijvoet OLM, Potokar M, et al. Apposition and resorption of bone during oral treatment with (3-amino-1-hydroxypropylidene)-1,1-biphosphonate (APD). Calcif Tissue Int 1983; 35: 357–61CrossRefPubMedGoogle Scholar
  14. 14.
    Dodwell DJ, Howell A, Ford J. Reduction in calcium excretion in women with breast cancer and bone metastases using the oral bisphosphonate pamidronate. Br J Cancer 1990; 61: 123–5CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Thiebaud D, Jaeger Ph, Jacquet AF, et al. Dose-response in the treatment of hypercalcaemia and malignancy by a single infusion of the bisphosphonate AHPrBP. J Clin Oncol 1988; 6: 762–8CrossRefPubMedGoogle Scholar
  16. 16.
    Body JJ, Dumon JC. Treatment of tumour-induced hypercalcaemia with the bisphosphonate pamidronate: dose-response relationship and influence of tumour type. Ann Oncol 1994; 5: 359–63CrossRefPubMedGoogle Scholar
  17. 17.
    Nussbaum SR, Younger J, Vandepol CJ, et al. Single-dose intravenous therapy with pamidronate for the treatment of hypercalcaemia of malignancy: comparison of 30-, 60-, 90-mg dosages. Am J Med 1993; 95: 297–304CrossRefPubMedGoogle Scholar
  18. 18.
    Davis JRE, Health DA. Comparison of different dose regimes of aminohydroxypropylidene-1, 1-bisphosphonate (APD) in hypercalcaemia of malignancy. Br J Clin Pharmacol 1989; 28: 269–74CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Daley-Yates PT, Dodwell DJ, Pongchaidecha M, et al. The clearance and bioavailability of pamidronate in patients with breast cancer and bone metastases. Calcif Tissue Int 1991; 49(6): 37–41CrossRefGoogle Scholar
  20. 20.
    Dodwell DJ, Howell A, Morton AR, et al. Infusion rate and pharmacokinetics of intravenous pamidronate in the treatment of tumour-induced hypercalcaemia. Postgrad Med J 1992; 68: 434–9CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Morton AR, Cantrill JA, Craig AE, et al. Single dose versus daily intravenous aminohydroxypropylidene diphosphonate (APD) for the hypercalcaemia of malignancy. BMJ 1988; 296: 811–4CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Cantwell BMJ, Harris AL. Effect of single high dose infusions of aminohydroxypropylidene diphosphonate on hypercalcaemia caused by cancer. BMJ 1987; 294: 467–9CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Wimalawansa SJ. Optimal frequency of administration of pamidronate in patients with hypercalcaemia of malignancy. Clin Endocrinol Metab 1994; 41: 591–5Google Scholar
  24. 24.
    Body JJ, Borkowski A, Cleeran A, et al. Treatment of malignancy-associated hypercalcaemia with intravenous aminohydroxypropylidine diphosphonate. J Clin Oncol 1986; 4: 1177–83CrossRefPubMedGoogle Scholar
  25. 25.
    Ralston SH, Alzaid AA, Gallacher SJ, et al. Clinical experience with aminohydroxypropylidine bisphosphonate (APD) in the management of cancer associated hypercalcaemia. Q J Med 1988; 69: 825–34Google Scholar
  26. 26.
    Gallacher SJ, Ralston SH, Pael U, et al. Side effects of pamidronate. Lancet 1989; II: 42–3CrossRefGoogle Scholar
  27. 27.
    Jodrell DI, Iveson TJ, Smith IE. Symptomatic hypocalcemia after treatment with high-dose aminohydroxypropylidene diphosphonate [letter]. Lancet 1987; I: 622CrossRefGoogle Scholar
  28. 28.
    Body JJ, Pot M, Borkowski A, et al. Dose/response study of aminohydroxypropylidene bisphosphonate in tumour-associated hypercalcaemia. Am J Med 1987; 82: 957–63CrossRefPubMedGoogle Scholar
  29. 29.
    Pentikainen PJ, Elomaa I, Nurmi AK, et al. Pharmacokinetics of clodronate in patients with metastatic breast cancer. Int J Clin Pharmacol Ther Toxicol 1989; 27: 222–8PubMedGoogle Scholar
  30. 30.
    O’Rourke NP, McCloskey EV, Vasikaran S, et al. Effective treatment of malignant hypercalcaemia with a single intravenous infusion of clodronate. Br J Cancer 1993; 67: 560–3CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Kanis JA, McCloskey EV, Paterson AHG. Use of diphosphonates in hypercalcaemia due to malignancy. Lancet 1990; 335: 170–1CrossRefPubMedGoogle Scholar
  32. 32.
    Bonjour JP, Philippe J, Guelpa G, et al. Bone and renal components in hypercalcaemia of malignancy and responses to a single infusion of clodronate. Bone 1988; 9: 123–30CrossRefPubMedGoogle Scholar
  33. 33.
    Adami S, Bolzicco GP, Rizzo A, et al. The use of dichloromethylene bisphosphonate and aminobutane bisphosphonate in hypercalcaemia of malignancy. Bone Miner 1987; 2: 395–404PubMedGoogle Scholar
  34. 34.
    O’Rourke, McCloskey EV, Neugebauer G, et al. Renal and nonrenal clearance of clodronate in patients with malignancy and renal impairment. Drug Invest 1994; 7(1): 26–33CrossRefGoogle Scholar
  35. 35.
    Ljunghall S, Rastad J, Akerstrom G. Comparative effects of calcitonin and clodronate in hypercalcaemia. Bone 1987; 8 Suppl. 1: S79–83CrossRefPubMedGoogle Scholar
  36. 36.
    Powell JH, DeMark BR. Clinical Pharmacokinetics of diphosphonates. Bone Resorption, Metastasis and Diphosphonates 1985: 41-9Google Scholar
  37. 37.
    Singer FR, Ritch PS, Lad TE, et al. Treatment of hypercalcaemia of malignancy with intravenous etidronate. Arch Intern Med 1991; 151: 471–6CrossRefPubMedGoogle Scholar
  38. 38.
    Patel S, Lyons AR, Hosking DJ. Drugs used in the treatment of metabolic bone disease: clinical pharmacology and therapeutic use. Drugs 1993; 46(4): 594–617CrossRefPubMedGoogle Scholar
  39. 39.
    Flores JF, Rude RK, Chapman RA, et al. Evaluation of a 24-hour infusion of etidronate disodium for the treatment of hypercalcaemia of malignancy. Cancer 1994; 73: 2527–34CrossRefPubMedGoogle Scholar
  40. 40.
    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 hypercalcaemia. J Clin Oncol 1991; 9: 1467–75CrossRefPubMedGoogle Scholar
  41. 41.
    Ralston SH, Gallacher SJ, Patel U, et al. Comparison of three intravenous bisphosphonates in cancer-related hypercalcaemia. Lancet 1989; I: 1180–2CrossRefGoogle Scholar
  42. 42.
    Gucalp R, Ritch P, Wiernik PH, et al. Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcaemia. J Clin Oncol 1992; 10: 134–42CrossRefPubMedGoogle Scholar
  43. 43.
    Warrell Jr RP. Clinical trials of gallium nitrate in patients with cancer-related hypercalcaemia. Semin Oncol 1991; 18 Suppl. 5: 26–31PubMedGoogle Scholar
  44. 44.
    Blumenthal NC, Cosma V, Levine S. Effect of gallium on the in vitro formation, growth and solubility of hydroxyapatite. Calcif Tissue Int 1989; 45: 81–7CrossRefPubMedGoogle Scholar
  45. 45.
    Repo MA, Bockman RS, Betts F, et al. Effect of gallium on bone mineral properties. Calcif Tissue Int 1988; 43: 300–6CrossRefPubMedGoogle Scholar
  46. 46.
    Warrell RP, Bockman RS. Gallium in the treatment of hypercalcaemia and bone metastasis. Important Adv Oncol 1989: 205-20Google Scholar
  47. 47.
    Warrell Jr RP, Alcock NW, Bockman RS. Gallium nitrate inhibits accelerated bone turnover in patients with bone metastases. J Clin Oncol 1987; 5: 292–8CrossRefPubMedGoogle Scholar
  48. 48.
    Bockman RS, Boskey A, Blumenthal NC, et al. Gallium increases bone calcium and crystallite perfection of hydroxy-apatite. Calcif Tissue Int 1986; 39: 376–81CrossRefPubMedGoogle Scholar
  49. 49.
    Guidon PT, Bockman RS. Gallium nitrate initiates expression of early and late genes responsible for bone formation [abstract]. J Bone Miner Res 1990; Suppl.2: S91Google Scholar
  50. 50.
    Bockman RS. Studies on the mechanism of action of gallium nitrate. Semin Oncol 1991; 18 Suppl. 5: 21–5PubMedGoogle Scholar
  51. 51.
    Wakeley GK, Brown D, Garant J, et al. Gallium inhibits not only bone resorption but also bone formation in vivo, possibly by an indirect mechanism [abstract]. Clin Res 1986; 34: 689AGoogle Scholar
  52. 52.
    Ho DH, Lin JR, Brown NS, et al. Bioavailability of gallium nitrate [abstract]. Eur J Pharmacol 1990; 183: 1200CrossRefGoogle Scholar
  53. 53.
    Kinirons MT. Newer agents for the treatment of malignant hypercalcaemia. Am J Med Sci 1993; 305: 403–6CrossRefPubMedGoogle Scholar
  54. 54.
    Hall SW, Yeung K, Benjamin RS, et al. Kinetics of gallium nitrate, a new anticancer agent. Clin Pharmacol Ther 1979; 25: 82–7CrossRefPubMedGoogle Scholar
  55. 55.
    Krakoff IH, Newman RA, Goldbert RS. Clinical toxicologic and pharmacologic studies of gallium nitrate. Cancer 1979; 44: 1722–7CrossRefPubMedGoogle Scholar
  56. 56.
    Kelsen DP, Alcock N, Yeh S, et al. Pharmacokinetics of gallium nitrate in man. Cancer 1980; 46: 2009–13CrossRefPubMedGoogle Scholar
  57. 57.
    Warrell RP, Skelos A, Alcock NW, et al. Gallium nitrate for acute treatment of cancer-related hypercalcemia: clinicopharmacological and dose response analysis. Cancer Res 1986; 46: 4208–12PubMedGoogle Scholar
  58. 58.
    Warrell RP, Israel R, Frisone M, et al. Gallium nitrate for acute treatment of cancer-related hypercalcemia — a randomized, double-blind comparison of calcitonin. Ann Intern Med 1988; 108: 669–74CrossRefPubMedGoogle Scholar
  59. 59.
    Fleisch H. Chemistry and mechanisms of action of bisphosphonates. In: Garattini S, editor. Bone resorption, metastasis and diphosphonates. New York: Raven Press, 1985: 33–40Google Scholar

Copyright information

© Adis International Limited 1996

Authors and Affiliations

  • Julie Watters
    • 1
  • Georgina Gerrard
    • 1
  • David Dodwell
    • 1
  1. 1.Yorkshire Regional Centre for Cancer TreatmentCookridge HospitalCookridge, West YorkshireEngland

Personalised recommendations