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Spotlight on Zoledronic Acid in the Management of Bone Metastases and Hypercalcemia of Malignancy

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American Journal of Cancer

Abstract

Zoledronic acid (Zometa®) is an effective inhibitor of osteoclast-mediated bone resorption. Zoledronic acid demonstrated efficacy in the reduction of skeletal-related events (SREs) in patients with multiple myeloma or bone metastases secondary to breast cancer, prostate cancer or other solid tumors, or hypercalcemia of malignancy.

Zoledronic acid was effective in patients with multiple myeloma or metastatic breast cancer with osteolytic or mixed bone lesions. The proportion of patients who experienced an SRE was similar during 12 months of treatment with zoledronic acid 4mg or pamidronic acid 90mg, but significantly fewer patients receiving zoledronic acid required radiotherapy to bone. Furthermore, in patients with breast cancer and osteolytic lesions, median time to a first SRE was more than 4 months longer with zoledronic acid than with pamidronic acid. In the multiple event analysis in a 12-month extension study (total study duration was 25 months) in patients with breast cancer, zoledronic acid was superior to pamidronic acid, with an 18% reduction in the risk of experiencing an SRE. Both drugs were associated with a slight reduction in pain.

Zoledronic acid 4mg, compared with placebo, significantly reduced the proportion of patients with prostate cancer bone metastases experiencing an SRE, particularly pathological fractures, after 15 months’ treatment. The drug also significantly delayed the onset of skeletal complications compared with placebo in patients with prostate cancer or other solid tumors including non-small cell lung cancer.

When administered as a single 15-minute intravenous infusion, zoledronic acid 4mg was significantly more effective than pamidronic acid administered as a 2-hour infusion in the treatment of severe hypercalcemia of malignancy, as assessed by complete responses measuring normalized serum calcium concentrations at day 10 after a single dose. Furthermore, zoledronic acid normalized serum calcium concentrations significantly faster than pamidronic acid, and the duration of response and median time to relapse were approximately twice as long in zoledronic acid recipients than in pamidronic acid recipients.

Zoledronic acid is well tolerated and has a similar tolerability profile to pamidronic acid. The most commonly reported adverse events included flu-like symptoms (fever, arthralgias, myalgias, and bone pain), fatigue, gastrointestinal reactions, anemia, weakness, dyspnea, and edema.

Conclusion: In conjunction with antitumor therapy, zoledronic acid should be considered for routine use to reduce skeletal complications in patients with advanced malignancies involving bone. In patients with hypercalcemia of malignancy, zoledronic acid is expected to become the treatment of choice.

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References

  1. Fromigué O, Body JJ. Bisphosphonates influence the proliferation and the maturation of normal human osteoblasts. J Endocrinol Invest 2002 Jun; 25(6): 539–46

    PubMed  Google Scholar 

  2. Dunford JE, Thompson K, Coxon FP, et al. Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther 2001 Feb; 296(2): 235–42

    PubMed  CAS  Google Scholar 

  3. Evans CE, Braidman IP. Effects of two novel bisphosphonates on bone cells in vitro. Bone Miner 1994; 26: 95–107

    Article  PubMed  CAS  Google Scholar 

  4. Coxon FP, Helfrich MH, Van’t Hof RJ, et al. Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298. J Bone Miner Res 2000 Aug; 15(8): 1467–76

    Article  PubMed  CAS  Google Scholar 

  5. Pataki A, Müller K, Green JR, et al. Effects of short-term treatment with the bisphosphonates zoledronate and pamidronate on rat bone: a comparative histomorphometric study on the cancellous bone formed before, during, and after treatment. Anat Rec 1997; 249: 458–68

    Article  PubMed  CAS  Google Scholar 

  6. Reinholz GG, Getz B, Pederson L, et al. Bisphosphonates directly regulate cell proliferation, differentiation, and gene expression in human osteoblasts. Cancer Res 2000 Nov 1; 60(21): 6001–7

    PubMed  CAS  Google Scholar 

  7. Rosen LS, Gordon D, Antonio BS, 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 Sep 31; 7(5): 377–87

    PubMed  CAS  Google Scholar 

  8. Coleman RE, Rosen LS, Gordon D, et al. Zoledronic acid (4mg) significantly reduces the relative risk of developing a skeletal-related event compared with pamidronate (90mg) in patients with breast cancer and bone metastasis [abstract 355]. Breast Cancer Res Treat 2002; 76Suppl. 1: S95

    Google Scholar 

  9. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. Zoledronic Acid Prostate Cancer Study Group. J Natl Cancer Inst 2002 Oct 2; 94(19): 1458–68

    Article  PubMed  CAS  Google Scholar 

  10. Berenson JR, Vescio R, Henick K, et al. A phase I, open label, dose ranging trial of intravenous bolus zoledronic acid, a novel bisphosphonate, in cancer patients with metastatic bone disease. Cancer 2001; 91(1): 144–54

    Article  PubMed  CAS  Google Scholar 

  11. Berenson JR, Vescio RA, Rosen LS, et al. A phase I dose-ranging trial of monthly infusions of zoledronic acid for the treatment of osteolytic bone metastases. Clin Cancer Res 2001 Mar; 7(3): 478–85

    PubMed  CAS  Google Scholar 

  12. Berenson JR, Rosen LS, Howell A, et al. Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases: a double-blind, randomized doseresponse study. Cancer 2001 Apr 1; 91(7): 1191–200

    Article  PubMed  CAS  Google Scholar 

  13. Green JR, Müller K, Jaeggi KA. Preclinical pharmacology of CGP 42’446, a new, potent, heterocyclic bisphosphonate compound. J Bone Miner Res 1994; 9: 745–51

    Article  PubMed  CAS  Google Scholar 

  14. Body JJ, Lortholary A, Romieu G, et al. A dose-finding study of zoledronate in hypercalcemic cancer patients. J Bone Miner Res 1999; 14(9): 1557–61

    Article  PubMed  CAS  Google Scholar 

  15. Aparicio A, Gardner A, Tu Y, et al. In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates. Leukemia 1998 Feb; 12(2): 220–9

    Article  PubMed  CAS  Google Scholar 

  16. Derenne S, Amiot M, Barillé S, et al. Zoledronate is a potent inhibitor of myeloma cell growth and secretion of IL-6 and MMP-1 by the tumoral environment. J Bone Miner Res 1999 Dec; 14(12): 2048–56

    Article  PubMed  CAS  Google Scholar 

  17. Gordon S, Helfrich MH, Sati HIA, et al. Pamidronate causes apoptosis of plasma cells in vivo in patients with multiple myeloma. Br J Haematol 2002 Nov; 119(2): 475–83

    Article  PubMed  CAS  Google Scholar 

  18. Fromigué O, Lagneaux L, Body J-J. Bisphosphonates induce breast cancer cell death in vitro. J Bone Miner Res 2000 Nov; 15(11): 2211–21

    Article  PubMed  Google Scholar 

  19. Witters L, Javeed M, Crispino J, et al. Inhibition of growth of human breast cancer cell lines with the combination of zoledronic acid and a COX-2 inhibitor. Eur J Cancer 2001 Oct; 37Suppl. 6: 78

    Article  Google Scholar 

  20. Jagdev SP, Coleman RE, Shipman CM, et al. The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel. Br J Cancer 2001 Apr 20; 84(8): 1126–34

    Article  PubMed  CAS  Google Scholar 

  21. Senaratne SG, Mansi JL, Colston KW. The bisphosphonate zoledronic acid impairs membrane localisation and induces cytochrome c release in breast cancer cells. Br J Cancer 2002 May 6; 86(9): 1479–86

    Article  PubMed  CAS  Google Scholar 

  22. Corey E, Brown LG, Quinn JE, et al. Effects of zoledronic acid on prostate cancer in vitro and in vivo [abstract 1148 plus poster]. 92nd Annual Scientific Meeting of the American Association for Cancer Researsh; 2001 Mar 24–28; New Orleans, (LA). Proc Am Assoc Cancer Res 2001; 42: 214

    Google Scholar 

  23. Novartis Pharmaceuticals Corporation. Zometa® (zoledronic acid for injection) prescribing information [online]. Available from URL: http://www.zometa.com [Accessed 2002 Nov 20]

  24. Rosen L, Gordon DH, Dugan Jr W, et al. Zoledronic acid (4 mg) is more effective than pamidronate (90 mg) for treating bone metastases in breast cancer patients with at least one osteolytic lesion [abtract 629]. 27th European Society for Medical Oncology Congress; 2002 Oct 18–22; Nice. Ann Oncol 2002; 13(Suppl.5): 171

    Google Scholar 

  25. Rosen L, Gordon D, Tchekmedyian S, et al. Zometa significantly increased the median time to first skeletal related event (SRE) in patients with osteolytic bone metastases from non-small cell lung cancer (NSCLC) and other solid tumours (OST). Lung Cancer 2001; 34Suppl. 1: S67

    Google Scholar 

  26. Rosen L, Gordon D, Tchekmedyian S, et al. Zoledronic acid (Zol) significantly reduces skeletal-related events (SREs) in patients with bone metastases from solid tumours [abstract online 1179] 38th Annual Meeting of the American Society of Clinical Oncology; 2002 May 18–21; Orlando, (FL). Available from URL: http://www.asco.org [Accessed 2002 Sep 26]

  27. Weinfurt KP, Li Y, Castel LD, et al. The impact of skeletal-related events on health-related quality of life of patients with metastatic prostate cancer [abstract 662]. 27th European Society for Medical Oncology Congress; 2002 Oct 18–22; Nice. Ann Oncol 2002 13Suppl. 5: 180

    Google Scholar 

  28. 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(2): 558–67

    PubMed  CAS  Google Scholar 

  29. Novartis Pharmaceuticals Corporation. The Zometa international site: European summary of product characteristics [online]. Available from URL: http://www.zometa.com/eu_spc.html [Accessed 2002 Nov 20]

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Acknowledgements

The full text article in Drugs 2003; 63 (4): 417–437 was reviewed by: J. Brown, Oncology Research Centre, Prince of Wales Hospital, Randwick, New South Wales, Australia; R.E. Coleman, Cancer Research Centre, Weston Park Hospital, Sheffield, England; D.R. Dearnaley, Department of Radiotherapy and Oncology, Institute of Cancer Research and the Royal Marsden Hospital, Sutton, England; H. Fleisch, Department of Pathophysiology, University of Berne, Berne, Switzerland; S.J. Hotte, Department of Medicine, McMaster University, Hamilton Regional Cancer Centre, Hamilton, Ontario, Canada; A. Howell, CRC Department of Medical Oncology, University of Manchester, Christie Hospital, Manchester, England; M.A. Rosenthal, Department of Clinical Haematology and Medical Oncology, Royal Melbourne Hospital, Parkville, Victoria, Australia; F. Saad, Uro-Oncology Clinic, Centre Hospitalier de l’Université de Montréal, Hôpital Notre-Dame, Montréal, Quebec, Canada; S. Thongprasert, Division of Oncology, Chiang Mai University, Chiang Mai, Thailand.

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  1. Adis International Inc., 770 Township Line Road, Suite 300, Yardley, PA, 19067, USA

    Keri Wellington & Karen L. Goa

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  1. Keri Wellington
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  2. Karen L. Goa
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Correspondence to Keri Wellington.

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This Spotlight is derived from abstract and summary text of an Adis Drug Evaluation originally published in full in Drugs 2003; 63 (4): 417–437

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Wellington, K., Goa, K.L. Spotlight on Zoledronic Acid in the Management of Bone Metastases and Hypercalcemia of Malignancy. Am J Cancer 2, 223–226 (2003). https://doi.org/10.2165/00024669-200302030-00006

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