Zoledronic acid is a potent, third generation, nitrogen-containing bisphosphonate, licensed for the management of skeletal metastases and hypercalcaemia of malignancy, both of which cause considerable morbidity. In the preclinical setting, zoledronic acid has demonstrated superior potency regarding inhibition of osteolysis and reduction of hypercalcaemia as compared with other bisphosphonates. Clinical trials have indicated that zoledronic acid is superior to pamidronate in suppressing osteolysis and in reducing hypercalcaemia of malignancy. Its main mechanism of action is induction of osteoclast apoptosis through inhibition of the mevalonate pathway. Zoledronic acid has also demonstrated direct anti-tumour activity both in vitro and in animal models, suggesting it may be of benefit in preventing the formation of bone metastases. Clinical trials are in progress, assessing the benefit of zoledronic acid in the adjuvant setting in both breast and prostate cancer.
Theriault RLLipton A, Hortobagyi GN, et al. 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 Oncol1999; 17: 846–854.
3.
Hortobagyi GN, Theriault R, Lipton A, et al. Aredia Breast Cancer Study Group. Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. J Clin Oncol1998; 16: 2038–2044.
4.
Berenson JR, Lichtenstein A, Porter L, et al. Myeloma Aredia Study Group. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. N Engl J Med1996; 334: 488–493.
5.
Berenson JR, Lichtenstein A, Porter L, et al. Myeloma Aredia Study Group. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. J Clin Oncol1998; 16: 593–602.
6.
Guise TA. Molecular mechanisms of osteolytic bone metastases. Cancer2000; 88:2892–2898.
7.
Thomas RJ, Guise TA, Yin JJ, et al. Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology1999; 140: 4451–4458.
8.
Hofbauer LC, Khosla S, Dunstan CR, Lacey DL, Boyle WJ, Riggs BL. The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res2000; 15: 2–12.
9.
Chikatsu N, Takeuchi Y, Tamura Y, et al. Interactions between cancer and bone marrow cells induce osteoblas differentiation factor expression and osteoclast-like cell formation in vitro. Biochem Biophys Res Commun2000; 267: 632–637.
10.
Zhang J, Dai J, Qi Y, et al. Osteoprotegerin inhibits prostate cancer-induced osteoclastogenesis and prevents prostate tumour growth in the bone. J Clin Invest2001; 107: 1235–1244.
11.
Nelson JB, Hedican SP, George DJ, et al. Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nat Med1995; 1: 944–949.
12.
Takuwa Y, Masaki T, Yamashita K. The effects of the endothelin family peptides on cultured osteoblastic cells from rat calvariae. Biochem Biophys Res Commun1990; 170: 998–1005.
13.
Chiao JW, Moonga BS, Yang YM, et al. Endothelin-1 from prostate cancer cells is enhanced by bone contact which blocks osteoclastic bone resorption. Br J Cancer2000; 83: 360–365.
14.
Granchi S, Brocchi S, Bonaccorsi L, et al. Endothelin-1 production by prostate cancer cell lines is up-regulated by factors involved in cancer progression and down-regulated by androgens. Prostate2001; 49: 267–277.
15.
Bryden AA, Hoyland JA, Freemont AJ, Clarke NW, George NJ. Parathyroid hormone related peptide and receptor expression in paired primary prostate cancer and bone metastases. Br J Cancer2002; 86: 322–325.
16.
Clarke NW, McClure J, George NJ. Morphometric evidence for bone resorption and replacement in prostate cancer. Br J Urol1991; 68: 74–80.
17.
Lee YP, Schwarz EM, Davies M, et al. Use of zoledronate to treat osteoblastic versus osteolytic lesions in a severe-combined-immunodeficient mouse model. Cancer Res2002; 62: 5564–5570.
18.
Reinholz GG, Getz B, Pederson L, et al. Bisphosphonates directly regulate cell proliferation, differentiation, and gene expression in human osteoblasts. Cancer Res2000; 60: 6001–6007.
19.
Derenne S, Amiot M, Barille 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 Res1999; 14: 2048–2056.
20.
Barille S, Akhoundi C, Collette M, et al. Metalloproteinases in multiple myeloma: production of matrix metal-loproteinase-9 (MMP-9), activation of pro-M MP-2, and induction of MMP-1 by myeloma cells. Blood1997; 90: 1649–1655.
21.
Yoneda T, Michigami T, Yi B, Williams PJ, Niewolna M, Hiraga T. Actions of bisphospho nate on bone metastasis in animal models of breast carcinoma. Cancer2000; 88: 2979–2988.
22.
Mundy GR, Yoneda T, Hiraga T. Preclinical studies with zoledronic acid and other bisphosphonates: impact on the bone microenvironment. Semin Oncol2001; 28: 35–44.
23.
Ralston SH, Gallacher SJ, Patel U, Campbell J, Boyle IT. Cancer-associated hypercalcaemia: morbidity and mortality-clinical experience in 126 treated patients. Ann Intern Med1990; 112: 499–504.
24.
Green JR. Chemical and biological pre-requisites for novel bisphosphonate molecules: results of comparative preclinical studies. Semin Oncol2001; 28 (suppl 6): 4–10.
25.
Jung A, Bisaz S, Fleisch H. The binding of pyrophosphate and two diphosphonates by hydroxyapatite crystals. Calcif Tissue Res1973; 11: 269–280.
26.
Russell RGG, Rogers MJ. Bisphosphonates: from the laboratory to the clinic and back again. Bone1999; 25: 97–106.
27.
Amin D, Cornell SA, Gustafson SK, et al. Bisphosphonates used for the treatment of bone disorders inhibit squalene synthase and cholesterol biosynthesis. J Lipid Res1992; 33:1657–1653.
28.
Jagdev SP, Coleman RE, Shipman CM, Rostami-H A, Croucher PI. The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel. Br J Cancer2001; 84: 1126–1134.
29.
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 amino bisphospho nates. J Pharm Exp Therapeut2001; 296: 235–234.
30.
Rogers MJ, Gordon S, Benford HL, et al. Cellular and molecular mechanisms of action of bisphosphonates. Cancer2000; 88: 2961–2978.
31.
Benford HL, McGowan NW, Helfrich MH, Nutall ME, Rogers MJ. Visualisation of bisphosphonate-induced caspase-3 activity in apoptotic osteoclasts in vitro. Bone2001; 28: 465–467.
32.
Senaratne SG, Mansi JL, Colston KW. The bisphosphonate zoledronic acid impairs membrane localisation and induces cytochrome c release in breast cancer cells. Br J Cancer2002; 86: 1479–1486.
33.
Mundy GR, Yoneda T, Hiraga T. Preclinical studies with zoledronic acid and other bisphosphonates: impact on the bone microenvironment. Semin Oncol2001; 28: 35–44.
34.
Krempien B, Manegold C. Prophyla ctic treatment of skeletal metastases, tumour-induced osteolysis, and hypercalcaemia in rats with the bisphosphonate Cl2MBP. Cancer1993; 72: 91–98.
35.
Kostenuik PJ, Orr W, Suyama K, Singh G. Increased growth rate and tumour burden of spontaneously metastatic Walker 256 cancer cells in the skeleton of bisphosphonate-treated rats. Cancer Res1993; 53: 5452–5457.
36.
Neville-Webbe HL, Holen I, Coleman RE. The anti-tumour activity and potential of bisphosphonates. Cancer Treat Rev2002; 28: 305–319.
37.
Boissier S, Ferreras M, Peyruchaud O, et al. Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res2000; 60: 2949–2954.
38.
Macdougall JR, Matrisian LM. Contributions of tumour and stromal matrix metalloproteinases to tumour progression, invasion, and metastases. Cancer Metastases Rev1995; 14: 351–362.
39.
Saadeh SP, Mehrara BJ, Steinbrech DS, et al. Mechanisms of fibroblastic growth factor-2 modulation of vascular endothelial growth factor expression by osteoblastic cells. Endocrinology2000; 141: 2075–2083.
40.
Wood J, Bonjean K, Ruetz S, et al. Novel anti-angiogenic effects of the bisphosphonates compound zoledronic acid. JPET2002; 302: 1055–1061.
41.
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 Res2001; 7: 478–485.
42.
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. Cancer2001; 91: 144–154.
43.
Berenson JR, Rosen LS, Howell A, et al. Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases. A double-blind, randomized dose-response study. Cancer2001; 91: 1191–1200.
44.
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 J2001; 7: 377–387.
45.
Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst2002; 94: 1458–1468.
46.
Rosen L, Gorden D, Tchelmedyian S, et al. Zoledronic acid significantly reduces skeletal-related events (SREs) in patients with bone metastases from solid tumours. Proc Am Soc Clin Oncol2002, Abstract number 1179.
47.
Lipton A, Demers L, Curley E, et al. Markers of bone resorption in patients treated with pamidronate. Eur J Cancer1998; 34: 2021–2026.
48.
Garnero P, Buchs N, Zekri J, Rizzoli R, Coleman RE, Delmas PD. Markers of bone turnover for the management of patients with bone metastases from prostate cancer. Br J Cancer2000; 82: 858–864.
49.
Vinholes J, Guo CY, Purohit OP, Eastell R, Coleman RE. Evaluation of new bone resorption markers in a randomized comparison of pamidronate or clodronate for hypercalcaemia of malignancy. J Clin Oncol1997; 15: 131–138.
50.
Coleman RE, Rosen LS, Gordon D, et al. Zoledronic acid (4 mg) significantly reduces the relative risk of developing a skeletal-related event compared with pamidronate (90 mg) in patients with breast cancer and bone metastasis. Breast Cancer Res Treat2002; 76 (suppl 1): 95–95.
51.
Powles TJ, Patterson S, Kanis SA, et al. Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol2002; 20: 3219–3224.
52.
Diel IJ, Solomayer EF, Costa SD, et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med1998; 339: 357–363.
53.
Saarto T, Blomqvist C, Virkkunen P, Elomaa I. Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomised controlled trial. J Clin Oncol2001; 19: 10–17.
54.
Diel IJ, Solomayer E-F, Gollan C, Schutz F, Bastert G. Bisphosphon ates in the reduction of metastases in breast cancer-results of the extended follow-up of the first study population. Proc Am Soc Clin Oncol2000, Abstract 314-314.
55.
Coleman RE, Seaman JJ. The role of zoledronic acid in cancer: clinical studies in the treatment and prevention of bone metastases. Semin Oncol2001; 28 (suppl 6): 11–16.
56.
Body JJ, Lortholaary A, Romieu G, Vigneron AM, Ford J. A dose-finding study of zoledronate in hypercalcaemic cancer patients. J Bone Miner Res1999; 14: 1557–1561.
57.
Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcaemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol2001; 19: 558–567.
58.
Nussbaum J, Warrell RP, Rude R, et al. Single-dose intravenous therapy with pamidronate for the treatment of hypercalcaemia of malignancy: comparison of 30-, 60-, and 90-mg dosages. Am J Med1993; 95: 297–304.
59.
Purohit OP, Radstone SH, Anthony C, Kanis JA, Coleman RE. A randomized double-blind comparison of intravenous pamidronate and clodronate in the hypercalcaemia of malignancy. Br J Cancer1995; 72: 1289–1293.
60.
Ralston SH, Thiebaud D, Herrmann Z, et al. Dose-response study of ibandronate in the treatment of cancer-associated hypercalcaemia. Br J Cancer1997; 75: 295–300.
61.
Nussbaum SR, Warrell RP Jr, Rude R, et al. Dose-response study of alendronate sodium for the treatment of cancer-associated hypercalcaemia. J Clin Oncol1993; 11: 1618–1623.
