Supportive Care in Cancer

, Volume 14, Issue 5, pp 408–418

Bisphosphonates for malignancy-related bone disease: current status, future developments

Review Article
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Abstract

This review relates to the efficacy and safety of bisphosphonates in metastatic bone disease. It discusses practical recommendations and possible future indications for bisphosphonate therapy. The current aims of bisphosphonates for metastatic bone disease are to prevent skeletal-related events (SREs), reduce bone pain and improve quality of life. Phase III clinical trials of clodronate and pamidronate have established their efficacy against bone complications in patients with breast cancer and multiple myeloma, while randomized trials have shown SRE reductions with zoledronic acid in patients with breast cancer and multiple myeloma, prostate cancer, and lung and other solid tumors. These bisphosphonates also have some effect on metastatic bone pain. Ibandronate is a new aminobisphosphonate, available in more than 40 countries outside of the US as intravenous and oral formulations for the prevention of skeletal events in patients with breast cancer and bone metastases. Phase III studies have shown that both intravenously and orally administered ibandronate have efficacy for the prevention of skeletal events and for the reduction of metastatic bone pain. In addition to efficacy, the long-term tolerability of bisphosphonates in metastatic bone disease influences drug selection. Besides their use in patients with established bone metastases, recent and ongoing research suggests that bisphosphonates also have clinical benefit in the adjuvant setting, and for the treatment of cancer-treatment-induced bone loss. Such interesting new developments may underpin a new era of bisphosphonate use sometime in the near future.

Keywords

Bisphosphonates Ibandronate Zoledronic acid Bone metastases Adjuvant 

References

  1. 1.
    Rubens RD (2000) Clinical aspects of bone metastases. In: Body JJ (ed) Tumor bone diseases and osteoporosis in cancer patients. Marcel Dekker, New York, pp 85–96Google Scholar
  2. 2.
    Cleeland CS, Janjan NA, Scott CB et al (2000) Cancer pain management by radiotherapists: a survey of radiation therapy oncology group physicians. Int J Radiat Oncol Biol Phys 47:203–208PubMedGoogle Scholar
  3. 3.
    Body JJ (2004) Hypercalcemia of malignancy. Semin Nephrol 24:48−54PubMedCrossRefGoogle Scholar
  4. 4.
    Green JR (2003) Antitumor effects of bisphosphonates. Cancer 97:840–847 (Suppl)PubMedCrossRefGoogle Scholar
  5. 5.
    Fromigue O, Kheddoumi N, Body JJ (2003) Bisphosphonates antagonize bone growth factors effects on human breast cancer cells survival. Br J Cancer 89:178−184PubMedCrossRefGoogle Scholar
  6. 6.
    Santini D, Vespasiani Gentilucci U, Vincenzi B et al (2003) The antineoplastic role of bisphosphonates: from basic research to clinical evidence. Ann Oncol 14:1468−1476PubMedCrossRefGoogle Scholar
  7. 7.
    Kanis JA, Powles T, Paterson AH et al (1996) Clodronate decreases the frequency of skeletal metastases in women with breast cancer. Bone 19:663–667PubMedCrossRefGoogle Scholar
  8. 8.
    Paterson AHG, Powles TJ, Kanis JA et al (1993) Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 11:59–65PubMedGoogle Scholar
  9. 9.
    Body JJ, Dumon JC, Piccart M, Ford J (1995) Intravenous pamidronate in patients with tumor-induced osteolysis: a biochemical dose-response study. J Bone Miner Res 10:1191–1196PubMedCrossRefGoogle Scholar
  10. 10.
    McCloskey BV, Dunn JA, Kanis JA et al (2001) Long-term follow up of a prospective, double-blind, placebo-controlled randomized trial of clodronate in multiple myeloma. Br J Haematol 113:1035–1043PubMedCrossRefGoogle Scholar
  11. 11.
    Tubiana-Hulin M, Beuzeboc P, Mauriac L et al (2001) Double-blinded controlled study comparing clodronate versus placebo in patients with breast cancer bone metastases. Bull Cancer 88:701–707PubMedGoogle Scholar
  12. 12.
    Robertson A, Reed N, Ralston S (1995) Effect of oral clodronate on metastatic bone pain: a double-blind, placebo-controlled study. J Clin Oncol 13:2427–2430PubMedGoogle Scholar
  13. 13.
    Hortobagyi G, Theriault R, Lipton A et al (1998) Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol 16:2038–2044PubMedGoogle Scholar
  14. 14.
    Hillner BE, Weeks JC, Desch CE, Smith TJ (2000) Pamidronate in prevention of bone complications in metastatic breast cancer: a cost-effectiveness analysis. J Clin Oncol 18:72–79PubMedGoogle Scholar
  15. 15.
    Lipton A, Theriault RL, Hortobagyi GN et al (2000) Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases. Cancer 88:1082–1090PubMedCrossRefGoogle Scholar
  16. 16.
    Theriault RL, Lipton A, Hortobagyi GN et al (1999) Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. J Clin Oncol 17:846−854PubMedGoogle Scholar
  17. 17.
    Lipton A (2003) Bisphosphonates and metastatic breast carcinoma. Cancer 97:848–853 (Suppl)PubMedCrossRefGoogle Scholar
  18. 18.
    Jagdev SP, Purohito P, Heatley S, Herling C, Coleman RE (2001) Comparison of the effect of intravenous pamidronate and oral clodronate on symptoms and bone resorption in patients with metastatic bone disease. Ann Oncol 12:1433–1438PubMedCrossRefGoogle Scholar
  19. 19.
    Rosen LS, Gordon D, Kaminski M et al (2001) 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 7:377–387PubMedGoogle Scholar
  20. 20.
    Rosen LS, Gordon D, Kaminski M et al (2003) 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 98:1735–1744PubMedCrossRefGoogle Scholar
  21. 21.
    Rosen LS, Gordon D, Tchekmedyian S et al (2003) Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial − the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 21:3150–3157PubMedCrossRefGoogle Scholar
  22. 22.
    Rosen L, Gordon D, Tchekmediyan S et al (2004) Long-term zoledronic acid therapy is effective and safe for reducing the risk of skeletal complications in patients with non-small cell lung cancer (NSCLC) and bone metastases. Bone 34(Suppl 1):S89 (abstract 73)Google Scholar
  23. 23.
    Saad F, Gleason D, Murray R et al (2002) A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 94:1458–1468PubMedGoogle Scholar
  24. 24.
    Saad F, Gleason DM, Murray R et al (2004) Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 96:879–882PubMedGoogle Scholar
  25. 25.
    Lipton A, Zheng M, Seaman J (2003) Zoledronic acid delays the onset of skeletal-related events and progression of skeletal disease in patients with advanced renal cell carcinoma. Cancer 98:962–969PubMedCrossRefGoogle Scholar
  26. 26.
    Small EJ, Smith MR, Seaman JJ, Petrone S, Kowalski MO (2003) Combined analysis of two multicenter, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer. J Clin Oncol 21:4277–4284PubMedCrossRefGoogle Scholar
  27. 27.
    Lipton A, Seaman J, Zheng M (2004) Long-term efficacy and safety of zoledronic acid in patients with bone metastases from renal cell carcinoma. Bone 24(Suppl 1):S62 (abstract 28)Google Scholar
  28. 28.
    Body JJ, Diel IJ, Lichinitser MR et al (2003) Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. Ann Oncol 14:1399–1405PubMedCrossRefGoogle Scholar
  29. 29.
    Body JJ, Diel IJ, Lichinitzer M et al (2004) Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies. Br J Cancer 90:1133–1137PubMedCrossRefGoogle Scholar
  30. 30.
    Fulfaro F, Casuccio A, Ticozzi C, Ripamonti C (1998) The role of bisphosphonates in the treatment of painful metastatic bone disease: a review of phase III trials. Pain 78:157−169PubMedCrossRefGoogle Scholar
  31. 31.
    Kohno N, Aogi K, Minami H et al (2005) Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial. J Clin Oncol (in press)Google Scholar
  32. 32.
    Diel IJ, Body JJ, Lichinitser MR et al (2004) Improved quality of life after long-term treatment with the bisphosphonate ibandronate in patients with metastatic bone disease due to breast cancer. Eur J Cancer 40:1704–1712PubMedCrossRefGoogle Scholar
  33. 33.
    Body JJ, Diel IJ, Bell R et al (2004) Oral ibandronate improves bone pain and preserves quality of life in patients with skeletal metastases due to breast cancer. Pain 111:306–312PubMedCrossRefGoogle Scholar
  34. 34.
    Coleman R, Rubens R (1987) The clinical course of bone metastases from breast cancer. Br J Cancer 55:61−66PubMedGoogle Scholar
  35. 35.
    Diel IJ, Solomayer EF, Bastert G (2000) Treatment of metastatic bone disease in breast cancer: bisphosphonates. Clin Breast Cancer 1:43–51PubMedCrossRefGoogle Scholar
  36. 36.
    Body J (2001) Dosing regimens and main adverse events of bisphosphonates. Semin Oncol 28(Suppl 11):49–53PubMedCrossRefGoogle Scholar
  37. 37.
    Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL (2004) Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 62:527–534PubMedCrossRefGoogle Scholar
  38. 38.
    Zojer N, Keck AV, Pecherstorfer M (1999) Comparative tolerability of drug therapies for hypercalcaemia of malignancy. Drug Saf 21:389−406PubMedCrossRefGoogle Scholar
  39. 39.
    Chang JT, Green L, Beitz J (2003) Renal failure with the use of zoledronic acid. N Engl J Med 349:1676–1679PubMedCrossRefGoogle Scholar
  40. 40.
    Bell R, Body JJ, Bergström B (2004) Renal safety of intravenous ibandronate for up to 4 years in patients with breast cancer and bone metastases. Breast Cancer Res Treat 88(Suppl 1):S132 (abstract 3058)Google Scholar
  41. 41.
    Neugebauer G, Kohler W, Akinkunmi L et al (2001) Influence of peak ibandronic acid concentrations after 6 mg IV administration with shortened infusion time (15 and 30 minutes) on renal safety in man. Proc Am Soc Clin Oncol 20:122a (abstract 486)Google Scholar
  42. 42.
    Body JJ, Lichinitser M, Andreeva N et al (2004) Safety of an intravenous (i.v.) dose of ibandronate followed by daily oral dosing in metastatic bone disease: results of an open-label study. Proc Am Soc Clin Oncol 23:60 (abstract 735)Google Scholar
  43. 43.
    Body J, Mancini I (2002) Bisphosphonates for cancer patients: why, how, and when? Support Care Cancer 10:399–407PubMedCrossRefGoogle Scholar
  44. 44.
    Kaminski M, Rosen L, Gordon D et al (2004) Zoledronic acid versus pamidronate in patients with breast cancer and multiple myeloma who are at high risk for skeletal complications. Proc Am Soc Clin Oncol 23:90 (abstract 857)Google Scholar
  45. 45.
    Hillner BE, Ingle JN, Chlebowski RT et al (2003) American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21:4042–4057PubMedCrossRefGoogle Scholar
  46. 46.
    Mashiba T, Hirano T, Turner CH et al (2000) Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res 15:613–620PubMedCrossRefGoogle Scholar
  47. 47.
    Vinholes JJF, Prakash Purohit O, Abbey ME, Eastell R, Coleman RE (1997) Relationships between biochemical and symptomatic response in a double-blind randomised trial of pamidronate for metastatic bone disease. Ann Oncol 8:1243−1250PubMedCrossRefGoogle Scholar
  48. 48.
    Lipton A, Costa L, Ali S, Demers L (2001) Use of markers of bone turnover for monitoring bone metastases and the response to therapy. Semin Oncol 28:54–59PubMedCrossRefGoogle Scholar
  49. 49.
    Body JJ, Dumon JC, Gineyts E, Delmas PD (1997) Comparative evaluation of markers of bone resorption in patients with breast-cancer induced osteolysis before and after bisphosphonate therapy. Br J Cancer 75:408–412PubMedGoogle Scholar
  50. 50.
    Brown JE, Thomson CS, Ellis SP, Gutcher SA, Purohit OP, Coleman RE (2003) Bone resorption predicts for skeletal complications in metastatic bone disease. Br J Cancer 89:2031–2037PubMedCrossRefGoogle Scholar
  51. 51.
    Brown JE, Cook RJ, Major P et al (2005) Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst 97:59–69PubMedCrossRefGoogle Scholar
  52. 52.
    Costa L, Demers LM, Gouveia-Oliveira A et al (2002) Prospective evaluation of the peptide bound collagen type 1 cross-links N-telopeptide and C-telopeptide in predicting bone metastases status. J Clin Oncol 20:850–856PubMedCrossRefGoogle Scholar
  53. 53.
    Garnero P (2001) Markers of bone turnover in prostate cancer. Cancer Treat Rev 27:187−192 (discussion 193−196)PubMedCrossRefGoogle Scholar
  54. 54.
    De Cock E, Hutton J, Canney P et al (2005) Cost-effectiveness of oral ibandronate compared with intravenous (i.v.) zoledronic acid or i.v. generic pamidronate in breast cancer patients with metastatic bone disease undergoing i.v. chemotherapy. Support Care Cancer (in press)Google Scholar
  55. 55.
    Berenson J, Hillner B, Kyle R et al (2002) American Society of Clinical Oncology clinical practice guidelines: the role of bisphosphonates in multiple myeloma. J Clin Oncology 20:3719–3736CrossRefGoogle Scholar
  56. 56.
    Berenson JR, Vescio R, Henick K et al (2001) A Phase I, open label, dose ranging trial of intravenous bolus zoledronic acid, a novel bisphosphonate, in cancer patients with metastatic bone disease. Cancer 91:144–154PubMedCrossRefGoogle Scholar
  57. 57.
    Berenson JR, Vescio RA, Rosen LS et al (2001) A phase I dose-ranging trial of monthly infusions of zoledronic acid for the treatment of osteolytic bone metastases. Clin Cancer Res 7:478–485PubMedGoogle Scholar
  58. 58.
    Body JJ, Lichinitser M, Tjulandin SA, Budde M, Bergström B (2005) Effect of oral ibandronate versus intravenous (i.v.) zoledronic acid on markers of bone resorption in patients with breast cancer and bone metastases: results from a comparative phase III trial. Proc Am Soc Clin Oncol 23:12S (abstract 534)Google Scholar
  59. 59.
    Heidenreich A, Elert A, Hofmann R (2002) Ibandronate in the treatment of prostate cancer associated painful osseous metastases. Prostate Cancer Prostatic Dis 5:231–235PubMedCrossRefGoogle Scholar
  60. 60.
    Heidenreich A, Ohlmann C, Olbert P, Hegele A (2003) High-dose ibandronate is effective and well tolerated in the treatment of pain and hypercalcaemia due to metastatic urologic cancer. Eur J Cancer 1(Suppl 5):S270Google Scholar
  61. 61.
    Mancini I, Dumon JC, Body JJ (2004) Efficacy and safety of ibandronate in the treatment of opioid-resistant bone pain associated with metastatic bone disease: a pilot study. J Clin Oncol 22:3587–3592PubMedCrossRefGoogle Scholar
  62. 62.
    Clohisy DR, Mathyh PW (2003) Bone cancer pain. Cancer 97(Suppl 3):866–873PubMedCrossRefGoogle Scholar
  63. 63.
    Yau V, Chow E, Davis L et al (2004) Pain management in cancer patients with bone metastases remains a challenge. J Pain Symptom Manage 27:1–3PubMedCrossRefGoogle Scholar
  64. 64.
    Novartis Pharma. Zometa (zoledronic acid). US prescribing information. November 2004Google Scholar
  65. 65.
    Balla J (2005) The issue of renal safety with zoledronic acid from a nephrologist’s point of view. Oncologist 10:306–368PubMedCrossRefGoogle Scholar
  66. 66.
    Pavlakis N, Stockler M (2002) Bisphosphonates for breast cancer. Cochrane Database System Rev:CD003474Google Scholar
  67. 67.
    Tripathy D, Body JJ, Diel I, Bergstrom B (2004) Intravenous and oral ibandronate reduce the risk of skeletal-related events (SREs) in patients with breast cancer and bone metastases. Eur J Cancer (Suppl 2):138Google Scholar
  68. 68.
    Ernst DS, Brasher P, Hagen N (1997) A randomized, controlled trial of intravenous clodronate in patients with metastatic bone disease and pain. J Pain Symptom Manage 13:319−326Google Scholar
  69. 69.
    Koeberle D, Bacchus L, Thuerlimann B et al (1999) Pamidronate treatment in patients with malignant osteolytic bone disease and pain: a prospective randomized double-blind trial. Support Care Cancer 7:21−27PubMedCrossRefGoogle Scholar
  70. 70.
    Ohlmann C, Heidenreich A (2003) Ibandronate in the palliative management of urological malignancies with compensated renal insufficiency. Support Care Cancer 11:413 (abstract A-97)Google Scholar
  71. 71.
    Body JJ, Mancini I, Dumon JC (2004) Intensive intravenous ibandronate treatment significantly relieves opioid-resistant bone pain and improves quality of life in patients with skeletal metastases. Eur J Cancer (Suppl 2):133Google Scholar
  72. 72.
    Diel IJ, Solomayer EF, Costa SD et al (1998) Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 339:357–363PubMedCrossRefGoogle Scholar
  73. 73.
    Saarto T, Blomqvist C, Virkkunen P, Elomaa I (2001) Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial. J Clin Oncol 19:10–17PubMedGoogle Scholar
  74. 74.
    Saarto T, Vehmanen L, Blomqvist C et al (2004) Ten-year follow-up of a randomized controlled trial of adjuvant clodronate treatment. Proc Am Soc Clin Oncol 23:8 (abstract 527)Google Scholar
  75. 75.
    Powles T, Paterson S, Kanis J et al (2002) Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol 20:3219–3224PubMedCrossRefGoogle Scholar
  76. 76.
    Powles T, Paterson A, McCloskey E et al (2004) Oral clodronate for adjuvant treatment of operable breast cancer: results of a randomized, double-blind, placebo-controlled multicenter trial. Proc Am Soc Clin Oncol 23:9 (abstract 528)Google Scholar
  77. 77.
    Jaschke A, Bastert G, Solomayer EF et al (2004) Adjuvant clodronate treatment improves the overall survival of primary breast cancer patients with micrometastases to bone marrow—a longtime follow-up. Proc Am Soc Clin Oncol 23:9 (abstract 529)Google Scholar
  78. 78.
    Kokufu I, Kohno N, Takao S et al (2004) Adjuvant pamidronate therapy for the prevention of bone metastasis in breast cancer patients with four or more positive nodes. Proc Am Soc Clin Oncol 23:8 (abstract 530)Google Scholar
  79. 79.
    Coleman R, Gralow J, Bell R et al (2004) Zoledronic acid is being investigated for the prevention of bone metastases in patients with early stage breast cancer. Bone 34(Suppl 1):S85Google Scholar
  80. 80.
    Bauss F, Russell RGG (2004) Ibandronate in osteoporosis: preclinical data and rationale for intermittent dosing. Osteoporos Int 15:423–433PubMedCrossRefGoogle Scholar
  81. 81.
    Powles TJ, McCloskey E, Paterson AH et al (1998) Oral clodronate and reduction in loss of bone mineral density in women with operable primary breast cancer. J Natl Cancer Inst 90:704–708PubMedCrossRefGoogle Scholar
  82. 82.
    Vehmanen L, Saarto T, Elomaa I et al (2001) Long-term impact of chemotherapy-induced ovarian failure on bone mineral density (BMD) in premenopausal breast cancer patients. The effect of adjuvant clodronate treatment. Eur J Cancer 37:2373–2378PubMedCrossRefGoogle Scholar
  83. 83.
    Rizzoli R, Forni M, Schaad MA et al (1996) Effects of oral clodronate on bone mineral density in patients with relapsing breast cancer. Bone 18:531–537PubMedCrossRefGoogle Scholar
  84. 84.
    Delmas PD, Balena R, Confravreux E et al (1997) Bisphosphonate risedronate prevents bone loss in women with artificial menopause due to chemotherapy of breast cancer: a double-blind, placebo-controlled study. J Clin Oncol 15:955–962PubMedGoogle Scholar
  85. 85.
    Gant M, Hausmaninger H, Samonigg H et al (2002) Changes in bone mineral density caused by anastrazole or tamoxifen in combination with goserelin (+/− zoledronate) as adjuvant treatment for hormone receptor positive premenopausal breast cancer: results of a randomised multicenter trial. Breast Cancer Res Treat 76(Suppl 1):S31Google Scholar
  86. 86.
    Theriault R, Jakesz R, Gnant M et al (2004) The evolving role of bisphosphonates for the prevention of cancer treatment-induced bone loss in patients with breast cancer. Bone 34(Suppl 1):S90Google Scholar
  87. 87.
    Smith MR, McGovern FJ, Zietman AL et al (2001) Pamidronate to prevent bone loss in men receiving gonadotropin releasing hormone agonist therapy for prostate cancer. N Engl J Med 345:948–955PubMedCrossRefGoogle Scholar
  88. 88.
    Smith MR, Eastham J, Gleason DM et al (2003) Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol 169:2008–2012PubMedCrossRefGoogle Scholar
  89. 89.
    Smith M (2003) Bisphosphonates to prevent osteoporosis in men receiving androgen deprivation therapy for prostate cancer. Drugs Aging 20:175–183PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  1. 1.Department of Internal Medicine, Institut Jules BordetUniversité Libre de BruxellesBrusselsBelgium

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