American Journal of Cancer

, Volume 4, Issue 5, pp 293–305 | Cite as

Bisphosphonates in Oncology

Focus on Clinical Experience with Pamidronate
Review Article


Pamidronate (pamidronic acid) is an aminobisphosphonate that interferes with the mevalonate pathway inducing osteoclast-apoptotic cell death. A 90mg dose of pamidronate administered in a 2- to 24-hour infusion achieves normocalcemia in >90% of unselected patients. Zoledronate (zoledronic acid) is more effective than pamidronate in normalising calcium levels in patients with tumor-induced hypercalcemia, at least in patients without bone metastases; however, zoledronate should be used with caution in patients with renal insufficiency. Pamidronate can be safely administered in hypercalcemic patients with renal insufficiency. Clinically meaningful bone pain relief occurs in about half of patients treated with pamidronate.

Pamidronate also achieved significantly better pain control than placebo in patients with breast cancer (bone metastases) or myeloma, in 2-year placebo-controlled trials. Pamidronate 90mg administered over 2 hours every 3–4 weeks for 2 years has been shown to reduce the frequency of skeletal-related events in patients with bone metastases from breast cancer by up to 40% and in patients with multiple myeloma by nearly 50%. In the largest randomized double-blind trial that compared zoledronate 4 or 8mg with pamidronate 90mg every 3–4 weeks in patients with breast cancer or myeloma, the primary efficacy endpoint (proportion of patients experiencing at least one skeletal-related event) was similar in all three treatment groups. The 8mg dose of zoledronate had to be lowered to 4mg during the trial because of renal toxicity. Indeed, concern about the renal toxicity of zoledronate has led authorities to recommend controlling serum creatinine levels before each infusion. When the data were analyzed by a complex multiple-event analysis, the hazard ratio for developing a bone complication was reduced by about 16% in patients treated with zoledronate compared with pamidronate after 2 years of therapy. This superiority of zoledronate was observed in the breast cancer subgroup but not in myeloma patients. However, multiple-event analyses rely on assumptions that are not unanimously accepted. The short duration of zoledronate infusion (15 minutes compared with 1.5–2 hours for pamidronate) is its most evident advantage, but cost savings have not been confirmed so far in limited micro-costing analyses.

Positive effects of pamidronate therapy on bone mass have been shown in patients with prostate cancer who are undergoing androgen-blockade therapy; antineoplastic therapy-induced bone loss was prevented. Studies with bisphosphonates are ongoing in breast cancer patients receiving aromatase inhibitors for the prevention of cancer treatment-induced bone loss. Zoledronate appears to be more potent than pamidronate for the prevention of endocrine therapy-induced bone loss.


  1. 1.
    Fleisch H. Bisphosphonates in bone disease: from the laboratory to the patient. 2nded. New York and London: Parthenon Publishing Group Ltd, 1995Google Scholar
  2. 2.
    Fleisch H, Russel RG, Francis MD. Diphosphonates inhibit hydroxy apatite dissolution in vitro and bone resorption in tissue culture and in vivo. Science 1969; 165: 1262–4PubMedCrossRefGoogle Scholar
  3. 3.
    Frith JC, Mönkkönen J, Blackburn GM, et al. Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosine 5′-(-dichloromethylene) triphosphate, by mammalian cells in vitro. J Bone Miner Res 1997; 12: 1358–67PubMedCrossRefGoogle Scholar
  4. 4.
    Luckman SP, Hughes DE, Coxon FP, et al. Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including ras. J Bone Miner Res 1998; 13: 581–9PubMedCrossRefGoogle Scholar
  5. 5.
    Fromigue O, Kheddoumi N, Body JJ. Bisphosphonates antagonize bone growth factors effects on human breast cancer cells survival. Br J Cancer 2003; 89: 178–84PubMedCrossRefGoogle Scholar
  6. 6.
    Fromigué O, Lagneaux L, Body JJ. Bisphosphonates induce breast cancer cell death in vitro. J Bone Miner Res 2000; 15: 2211–21PubMedCrossRefGoogle Scholar
  7. 7.
    Body JJ. Bisphosphonates as chemotherapeutic agents. Curr Opin Investig Drugs 2000; 2: 155–61Google Scholar
  8. 8.
    Body JJ. Zoledronic acid: an advance in tumour bone disease and a new hope for osteoporosis. Expert Opin Pharmacother 2003; 4: 567–80PubMedCrossRefGoogle Scholar
  9. 9.
    Body JJ, Diel IJ, Lichinitser MR, et al. Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. Annals Oncol 2003; 14: 1399–405CrossRefGoogle Scholar
  10. 10.
    Hillner BE, Ingle JN, Berenson JR, et al. American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. American Society of Clinical Oncology Bisphosphonates Expert Panel. J Clin Oncol 2000; 18: 1378–91PubMedGoogle Scholar
  11. 11.
    Body JJ. Hypercalcemia of malignancy. Semin Nephrol 2004; 24: 48–54PubMedCrossRefGoogle Scholar
  12. 12.
    Body JJ, Bartl R, Burckhardt P, et al. Current use of bisphosphonates in oncology. International Bone and Cancer Study Group. J Clin Oncol 1998; 16: 3890–9PubMedGoogle Scholar
  13. 13.
    DeWit S, Cleton F. Hypercalcemia in patients with breast cancer: a survival study. J Cancer Res Clin Oncol 1994; 120: 610–4PubMedCrossRefGoogle Scholar
  14. 14.
    Body JJ, Delmas PD. Urinary pyridinium cross-links as markers of bone resorption in tumor-associated hypercalcemia. J Clin Endocrinol Metab 1992; 74: 471–5PubMedCrossRefGoogle Scholar
  15. 15.
    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: 1309–15PubMedCrossRefGoogle Scholar
  16. 16.
    Dumon JC, Wantier H, Mathieu F, et al. Technical and clinical validation of a new immunoradiometric assay for human osteocalcin. Eur J Endocrinol 1996; 135: 231–7PubMedCrossRefGoogle Scholar
  17. 17.
    Nussbaum S, Younger J, Vandepol C, 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
  18. 18.
    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: 359–63PubMedGoogle Scholar
  19. 19.
    Gurney H, Grill V, Martin TJ. Parathyroid hormone-related protein and response to pamidronate in tumour-induced hypercalcaemia. Lancet 1993; 341: 1611–3PubMedCrossRefGoogle Scholar
  20. 20.
    Body JJ, Louviaux I, Dumon JC. Decreased efficacy of bisphosphonates for recurrences of tumor-induced hypercalcemia. Support Care Cancer 2000; 8: 398–404PubMedCrossRefGoogle Scholar
  21. 21.
    Ralston SH, Thiebaud D, Herrmann Z, et al. Dose-response study of ibandronate in the treatment of cancer-associated hypercalcaemia. Br J Cancer 1997; 75: 295–300PubMedCrossRefGoogle Scholar
  22. 22.
    Major P, Lortholary A, 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
  23. 23.
    Rosen LS, Gordon D, Kaminski M, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J 2001; 7: 377–87PubMedGoogle Scholar
  24. 24.
    Machado CE, Flombaum CD. Safety of pamidronate in patients with renal failure and hypercalcemia. Clin Nephrol 1996; 45: 175–9PubMedGoogle Scholar
  25. 25.
    Berenson JR, Rosen L, Vescio R, et al. Pharmacokinetics of pamidronate disodium in patients with cancer with normal or impaired renal function. J Clin Pharmacol 1997; 37: 285–90PubMedGoogle Scholar
  26. 26.
    Body JJ. Bisphosphonates for metastatic bone pain. Support Care Cancer 1999; 7: 1–3PubMedCrossRefGoogle Scholar
  27. 27.
    Hillner BE, Ingle JN, Chlebowski RT, et al. American Society of Clinical Oncology. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 2003; 21: 4042–57PubMedCrossRefGoogle Scholar
  28. 28.
    Robertson AG, Reed NS, Ralston SH. Effect of oral clodronate on metastatic bone pain: a double-blind, placebo-controlled study. J Clin Oncol 1995; 13: 2427–30PubMedGoogle Scholar
  29. 29.
    Ernst DS, Brasher P, Hagen N, et al. A randomized, controlled trial of intravenous clodronate in patients with metastatic bone disease and pain. J Pain Symptom Manage 1997; 13: 319–26PubMedCrossRefGoogle Scholar
  30. 30.
    Purohit OP, Anthony C, Radstone CR, et al. High-dose intravenous pamidronate for metastatic bone pain. Br J Cancer 1994; 70: 554–8PubMedCrossRefGoogle Scholar
  31. 31.
    Koeberle D, Bacchus L, Thuerlimann B, et al. Pamidronate treatment in patients with malignant osteolytic bone disease and pain: a prospective randomized double-blind trial. Support Care Cancer 1999; 7: 21–7PubMedCrossRefGoogle Scholar
  32. 32.
    Tyrrell CT, Bruning PF, May-Levin F, et al. Pamidronate infusions as single-agent therapy for bone metastases: a phase II trial in patients with breast cancer. Eur J Cancer 1995; 31A: 1976–80PubMedCrossRefGoogle Scholar
  33. 33.
    Vinholes JJF, Purohit OP, Abbey ME, et al. Relationships between biochemical and symptomatic response in a double-blind randomised trial of pamidronate for metastatic bone disease. Ann Oncol 1997; 8: 1243–50PubMedCrossRefGoogle Scholar
  34. 34.
    Mancini I, Dumon JC, Body JJ. Short-term treatment with the bisphosphonate ibandronate for opioid-resistant metastatic bone pain. J Clin Oncol 2004; 22: 3587–92PubMedCrossRefGoogle Scholar
  35. 35.
    Hortobagyi GN, Theriault RL, Porter L, et al. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. N Engl J Med 1996; 335: 1785–91PubMedCrossRefGoogle Scholar
  36. 36.
    Hortobagyi GN, Theriault RL, Lipton A, et al., on behalf of the Protocol 19 Aredia Breast Cancer Study Group. Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. J Clin Oncol 1998; 16: 2038–44PubMedGoogle Scholar
  37. 37.
    Theriault RL, Lipton A, Hortobagyi GN, et al., on behalf of the Protocol 18 Aredia breast cancer study group. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. J Clin Oncol 1999; 17: 846–54PubMedGoogle Scholar
  38. 38.
    Berenson JR, Lichtenstein A, Porter L, et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. N Engl J Med 1996; 334: 488–93PubMedCrossRefGoogle Scholar
  39. 39.
    Conte PF, Latrellie J, Mauriac L, et al., on behalf of the Aredia Multinational Cooperative Group. Delay in progression of bone metastases in breast cancer patients teated with intravenous pamidronate: results from a multinational randomised controlled trial. J Clin Oncol 1996; 14: 2552–9PubMedGoogle Scholar
  40. 40.
    Lipton A, Theriault RL, Hortobagyi GN, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer 2000; 88: 1082–109PubMedCrossRefGoogle Scholar
  41. 41.
    Berenson JR, Lichtenstein A, Porter L, et al. Long-term treatment of advanced multiple myeloma patients reduces skeletal events. J Clin Oncol 1998; 16: 593–602PubMedGoogle Scholar
  42. 42.
    Berenson JR, Rosen LS, Howell A, et al. Zoledronaic acid reduces skeletal-related events in patients with osteolytic metastases. Cancer 2001; 91: 1191–200PubMedCrossRefGoogle Scholar
  43. 43.
    Rosen LS, Gordon DH, Dugan Jr W, et al. Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 2004; 100: 36–43PubMedCrossRefGoogle Scholar
  44. 44.
    Major PP, Cook R. Efficacy of bisphosphonates in the management of skeletal complications of bone metastases and selection of clinical endpoints. Am J Clin Oncol 2002; 26Suppl. 1: S10–8CrossRefGoogle Scholar
  45. 45.
    Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 2003; 98: 1735–44PubMedCrossRefGoogle Scholar
  46. 46.
    Body JJ, Diel IJ, Lichinitzer M, et al. Oral ibandronate significantly reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomized, placebo-controlled phase III studies. Br J Cancer 2004; 90: 1133–7PubMedCrossRefGoogle Scholar
  47. 47.
    Diel IJ, Body JJ, Tripathy D, et al. Oral daily ibandronate in women with metastatic breast cancer: a pooled safety analysis [abstract no. 186]. Proc Am Soc Clin Oncol 2003; 22: 47Google Scholar
  48. 48.
    Body JJ. Effectiveness and cost of bisphosphonate therapy in tumor bone disease. Cancer 2003; 97: 859–65PubMedCrossRefGoogle Scholar
  49. 49.
    Bruce NJ, McCloskey EV, Kanis JA, et al. Economic impact of using clodronate in the management of patients with multiple myeloma. Br J Haematol 1999; 104: 358–64PubMedCrossRefGoogle Scholar
  50. 50.
    Hillner BE, Weeks JC, Desch CE, et al. Pamidronate in prevention of bone complications in metastatic breast cancer: a cost-effectiveness analysis. J Clin Oncol 2000; 18: 72–9PubMedGoogle Scholar
  51. 51.
    Beusterien KM, Hill MC, Ackerman SJ, et al. The impact of pamidronate on inpatient and outpatient services among metastatic breast cancer patients. Support Care Cancer 2001; 9: 169–76PubMedCrossRefGoogle Scholar
  52. 52.
    DesHarnais Castel L, Bajwa K, Markle JP, et al. A Microcosting analysis of zoledronic acid and pamidronate therapy in patients with metastatique bone disease. Support Care Cancer 2001; 9: 545–51CrossRefGoogle Scholar
  53. 53.
    53.Guest F,Clegg P,Davie M, et al. Costs and consequences of using pamidronate compared with zoledronic acid in the management of breast cancer patients in the UK. Curr Med Res Opin 2005May; 21(5): 805–15PubMedCrossRefGoogle Scholar
  54. 54.
    DeCock E, HuttonJ, CanneyP, eaet al. Cost-effectivenes of oral ibandronate versus intravenous (i.V.) zolendronic acid or i.V. pamidronate for breast cancer and bone metastases patients receiving oral hormonal therapy in the UK. Clin Ther. In pressGoogle Scholar
  55. 55.
    Mashiba T, Hirano T, Turner CH, et al. Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res 2000; 15: 613–20PubMedCrossRefGoogle Scholar
  56. 56.
    Berenson JR, Hillner BE, Kyle RA, et al. American Society of Clinical Oncology clinical practice guidelines: the role of bisphosphonates in multiple myeloma. J Clin Oncol 2002; 20: 3719–36PubMedCrossRefGoogle Scholar
  57. 57.
    Lipton A, Demers L, Curley E, et al. Markers of bone resorption in patients treated with pamidronate. Eur J Cancer 1998; 34: 2021–6PubMedCrossRefGoogle Scholar
  58. 58.
    Peretz A, Body JJ, Dumon JC, et al. Cyclical pamidronate infusions in osteoporosis: effects on bone metabolism and bone mineral density. Maturitas 1996; 25: 69–75PubMedCrossRefGoogle Scholar
  59. 59.
    Peretz A, Siderova V, Body J, et al. Response to alendronate in osteoporotic women previously treated with pamidronate. Maturitas 2003; 44: 111–5PubMedCrossRefGoogle Scholar
  60. 60.
    Dodidou P, Bruckner T, Hosch S, et al. Better late than never? Experience with intravenous pamidronate treatment in patients with low bone mass or fractures following cardiac or liver transplantation. Osteoporos Int 2003; 14: 82–9PubMedCrossRefGoogle Scholar
  61. 61.
    Chan SS, Nery LM, McElduff A, et al. Intravenous pamidronate in the treatment and prevention of osteoporosis. Intern Med J 2004; 34: 162–6PubMedCrossRefGoogle Scholar
  62. 62.
    Heijckmann AC, Juttmann JR, Wolffenbuttel BH. Intravenous pamidronate compared with oral alendronate for the treatment of postmenopausal osteoporosis. Neth J Med 2002; 60: 315–9PubMedGoogle Scholar
  63. 63.
    Krieg MA, Seydoux C, Sandini L, et al. Intravenous pamidronate as treatment for osteoporosis after heart transplantation: a prospective study. Osteoporos Int 2001; 12: 112–6PubMedCrossRefGoogle Scholar
  64. 64.
    Boutsen Y, Jamart J, Esselinckx W, et al. Primary prevention of glucocorticoid-induced osteoporosis with intravenous pamidronate and calcium: a prospective controlled 1-year study comparing a single infusion, an infusion given once every 3 months, and calcium alone. J Bone Miner Res 2001; 16(1): 104–12PubMedCrossRefGoogle Scholar
  65. 65.
    Glorieux EH, Bishop NJ, Plotkin H, et al. Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med 1998; 339: 947–52PubMedCrossRefGoogle Scholar
  66. 66.
    Zeitlin L, Rauch F, Plotkin H, et al. Height and weight development during four years of therapy with cyclical intravenous pamidronate in children and adolescents with osteogenesis imperfecta types I, III, and IV. Pediatrics 2003; 111: 1030–6PubMedCrossRefGoogle Scholar
  67. 67.
    Montpetit K, Plotkin H, Rauch F. Rapid increase in grip force after start of pamidronate therapy in children and adolescents with severe osteogenesis imperfecta. Pediatrics 2003; 111: 601–3CrossRefGoogle Scholar
  68. 68.
    Rauch F, Travers R, Plotkin H, et al. The effects of intravenous pamidronate on the bone tissue of children and adolescents with osteogenesis imperfecta. J Clin Invest 2002; 110: 1293–9PubMedGoogle Scholar
  69. 69.
    Smith MR. Bisphosphonates to prevent skeletal complications in men with meta-static prostate cancer. J Urol 2003; 170: S55–7PubMedCrossRefGoogle Scholar
  70. 70.
    Smith MR, McGovem FJ, Zietman AL, et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 2001; 345: 948–55PubMedCrossRefGoogle Scholar
  71. 71.
    Diamond TH, Winters J, Smith A, et al. The antiosteoporotic efficacy of intravenous pamidronate in men with prostate carcinoma receiving combined androgen blockade: a double blind, randomized, placebo-controlled crossover study. Cancer 2001; 92: 1444–50PubMedCrossRefGoogle Scholar
  72. 72.
    Smith MR. Bisphosphonates to prevent osteoporosis in men receiving androgen deprivation therapy for prostate cancer. Drugs Aging 2003; 20: 175–83PubMedCrossRefGoogle Scholar
  73. 73.
    Kim SH, Lim SK, Hahn S. Effect of pamidronate on new vertebral fractures and bone mineral density in patients with malignant lymphoma receiving chemotherapy. Am J Med 2004; 116: 524–8PubMedCrossRefGoogle Scholar
  74. 74.
    Coukell AJ, Markham A. Pamidronate: a review of its use in the management of osteolytic bone metastases, tumour-induced hypercalcaemia and Paget’s disease of bone. Drugs Aging 1998; 12: 149–68PubMedCrossRefGoogle Scholar
  75. 75.
    Fitton A, McTavish D. Pamidronate: a review of its pharmacological properties and therapeutic efficacy in resorptive bone disease. Drugs 1991; 41: 289–318PubMedCrossRefGoogle Scholar
  76. 76.
    Macarol V, Fraunfelder FT. Pamidronate disodium and possible ocular adverse drag reactions. Am J Ophthalmol 1994; 118: 220–4PubMedGoogle Scholar
  77. 77.
    Banerjee D, Asif A, Striker L, et al. Short-term, high-dose pamidronate-induced acute tubular necrosis: the postulated mechanisms of bisphosphonate nephrotoxicity. Am J Kidney Dis 2003; 41: E18PubMedCrossRefGoogle Scholar
  78. 78.
    Chang JT. Renal failure with the use of zoledronic acid. N Engl J Med 2003; 349: 1676–9PubMedCrossRefGoogle Scholar
  79. 79.
    Johnson KB, Gable P, Kaime EM, et al. Significant deterioration in renal function with the new bisphosphonate, zoledronic acid [abstract]. Proc Am Soc Clin Oncol 2003; 22:738: 2968Google Scholar
  80. 80.
    Markowitz GS, Fine PL, Stack JI, et al. Toxic acute necrosis following treatment with zoledronate (Zometa). Kidney Int 2003; 64: 281–9PubMedCrossRefGoogle Scholar
  81. 81.
    Zometa® (zolendronic acid) US prescribing information. East Hanover (NJ): Norvartis Pharma, 2004 NovGoogle Scholar
  82. 82.
    Markowitz GS, Appel GB, Fine PL, et al. Collapsing focal segmental glomeralos-clerosis following treatment with high-dose pamidronate. J Am Soc Nephrol 2001; 12: 1164–72PubMedGoogle Scholar
  83. 83.
    Smetana S, Michlin A, Rosenman E, et al. Pamidronate-induced nephrotoxic tubular necrosis: a case report. Clin Nephrol 2004; 61: 63–7PubMedGoogle Scholar
  84. 84.
    Glover D, Lipton A, Keller A, et al. Intravenous pamidronate disodium treatment of bone metastases in patients with breast cancer: a dose-seeking study. Cancer 1994; 74: 2949–55PubMedCrossRefGoogle Scholar
  85. 85.
    Body JJ, Dumon JC, Piccart M, et al. Intravenous pamidronate in patients with tumor-induced osteolysis: a biochemical dose-response study. J Bone Miner Res 1995: 10: 1191–6PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  1. 1.Department of Internal Medicine and Unit of Endocrinology and Bone DiseasesInstitut J. Bordet, Université Libre de BruxellesBrusselsBelgium

Personalised recommendations