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 Zoledronic Acid

Description of zoledronic acid: zoledronic acid is a synthetic imidazole bisphosphonate analog of pyrophosphate with anti-bone-resorption activity. A third-generation bisphosphonate, zoledronic acid binds to hydroxyapatite crystals in the bone matrix, slowing their dissolution and inhibiting the formation and aggregation of these crystals. This agent also inhibits farnesyl pyrophosphate synthase, an enzyme involved in terpenoid biosynthesis. Inhibition of this enzyme prevents the biosynthesis of isoprenoid lipids, donor substrates of farnesylation and geranylgeranylation during the post-translational modification of small GTPase signalling proteins, which are important in the process of osteoclast turnover. Decreased bone turnover and stabilization of the bone matrix contribute to the analgesic effect of zoledronic acid with respect to painful osteoblastic lesions. The agent also reduces serum calcium concentrations associated with hypercalcemia. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

According to http://en.wikipedia.org/wiki/Zoledronic_acid, Reclast is a single 5 mg infusion for the treatment of Paget's disease of bone. In 2007, the U.S. Food and Drug Administration (FDA) also approved Reclast for the treatment of postmenopausal osteoporosis. Washington University in St. Louis researchers at the Alvin Siteman Cancer Center, under Dr. Rebecca Aft, M.D., Ph.D., discerned in May 2010 that zoledronic acid reduces the number of disseminated tumor cells (DTCs) in breast cancer that go to lodge metastatically in the bone marrow, which often proves fatal to the patient. They also observed that the drug could directly impede the breast cancer tumor itself by slowing the rate of angiogenesis or by boosting the immune system.

DRUG DESCRIPTION

Reclast contains zoledronic acid, a bisphosphonic acid which is an inhibitor of osteoclastic bone resorption. Zoledronic acid is designated chemically as (1-Hydroxy-2imidazol-1-yl-phosphonoethyl) phosphonic acid monohydrate Zoledronic acid monohydrate is a white crystalline powder. Its molecular formula is C5H10N2O7P2•H2O and a molar mass of 290.1 g/Mol. Zoledronic acid monohydrate is highly soluble in 0.1N sodium hydroxide solution, sparingly soluble in water and 0.1N hydrochloric acid, and practically insoluble in organic solvents. The pH of the Reclast solution for infusion is approximately 6.0 – 7.0. Reclast Injection is available as a sterile solution in bottles for intravenous infusion. One bottle with 100 mL solution contains 5.330 mg of zoledronic acid monohydrate, equivalent to 5 mg zoledronic acid on an anhydrous basis. Inactive Ingredients: 4950 mg of mannitol, USP; and 30 mg of sodium citrate, USP.

Mechanism of Action

Reclast is a bisphosphonate and acts primarily on bone. It is an inhibitor of osteoclast-mediated bone resorption. The selective action of bisphosphonates on bone is based on their high affinity for mineralized bone. Intravenously administered zoledronic acid rapidly partitions to bone and localizes preferentially at sites of high bone turnover. The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate synthase. The relatively long duration of action of zoledronic acid is attributable to its high binding affinity to bone mineral.

Review articles about Zoledronic acid

1: Bosch-Barrera J, Merajver SD, Menéndez JA, Van Poznak C. Direct antitumour activity of zoledronic acid: preclinical and clinical data. Clin Transl Oncol. 2011 Mar;13(3):148-55. Review. PubMed PMID: 21421459.

2: Recknor C. Zoledronic acid for prevention and treatment of osteoporosis. Expert Opin Pharmacother. 2011 Apr;12(5):807-15. Epub 2011 Mar 9. Review. PubMed PMID: 21385149.

3: Costa L, Harper P, Coleman RE, Lipton A. Anticancer evidence for zoledronic acid across the cancer continuum. Crit Rev Oncol Hematol. 2011 Feb;77 Suppl 1:S31-7. Review. PubMed PMID: 21353179.

4: Green JR, Guenther A. The backbone of progress--preclinical studies and innovations with zoledronic acid. Crit Rev Oncol Hematol. 2011 Feb;77 Suppl 1:S3-S12. Review. PubMed PMID: 21353178.

5: Mahtani R, Khan R, Jahanzeb M. The potential application of zoledronic acid as anticancer therapy in patients with non-small-cell lung cancer. Clin Lung Cancer. 2011 Jan;12(1):26-32. Review. PubMed PMID: 21273176.

6: Coleman R, Cook R, Hirsh V, Major P, Lipton A. Zoledronic acid use in cancer patients: more than just supportive care? Cancer. 2011 Jan 1;117(1):11-23. Review. PubMed PMID: 21235033.

7: Hamdy RC. Zoledronic acid: clinical utility and patient considerations in osteoporosis and low bone mass. Drug Des Devel Ther. 2010 Nov 18;4:321-35. Review. PubMed PMID: 21151620; PubMed Central PMCID: PMC2998805.

8: Coleman R, Burkinshaw R, Winter M, Neville-Webbe H, Lester J, Woodward E, Brown J. Zoledronic acid. Expert Opin Drug Saf. 2011 Jan;10(1):133-45. Epub 2010 Nov 29. Review. PubMed PMID: 21114419.

9: Leszczyński P. [Zoledronic acid reduces risk of any new clinical fracture and risk of death after surgical repair of a low-trauma hip fracture]. Chir Narzadow Ruchu Ortop Pol. 2010 May-Jun;75(3):168-71. Review. Polish. PubMed PMID: 21038635.

10: Tonyali O, Arslan C, Altundag K. The role of zoledronic acid in the adjuvant treatment of breast cancer: current perspectives. Expert Opin Pharmacother. 2010 Nov;11(16):2715-25. Review. PubMed PMID: 20977404.

11: Kuriyama DK, McElligott SC, Glaser DW, Thompson KS. Treatment of Gorham-Stout disease with zoledronic acid and interferon-α: a case report and literature review. J Pediatr Hematol Oncol. 2010 Nov;32(8):579-84. Review. PubMed PMID: 20962674.

12: Green J, Lipton A. Anticancer properties of zoledronic acid. Cancer Invest. 2010 Nov;28(9):944-57. Review. PubMed PMID: 20879838.

13: Saad F, Eastham JA. Zoledronic acid use in patients with bone metastases from renal cell carcinoma or bladder cancer. Semin Oncol. 2010 Jun;37 Suppl 1:S38-44. Review. PubMed PMID: 20682371.

14: Reid DM. Update on the use of zoledronic acid in the management of osteoporosis. Curr Osteoporos Rep. 2010 Sep;8(3):145-50. Review. PubMed PMID: 20556671.

15: Maricic M. The role of zoledronic acid in the management of osteoporosis. Clin Rheumatol. 2010 Oct;29(10):1079-84. Epub 2010 Jun 11. Review. PubMed PMID: 20544246.

16: Weide R, Koppler H, Antras L, Smith M, Chang MP, Green J, Wintfeld N, Neary MP, Duh MS. Renal toxicity in patients with multiple myeloma receiving zoledronic acid vs. ibandronate: a retrospective medical records review. J Cancer Res Ther. 2010 Jan-Mar;6(1):31-5. Review. PubMed PMID: 20479544.

17: John Camm A. Review of the cardiovascular safety of zoledronic acid and other bisphosphonates for the treatment of osteoporosis. Clin Ther. 2010 Mar;32(3):426-36. Review. PubMed PMID: 20399982.

18: Sugie T, Tanaka Y, Toi M. [New development in breast cancer therapy. III. Zoledronic acid and anti-tumor immunity in breast cancer]. Gan To Kagaku Ryoho. 2009 Dec;36(13):2555-9. Review. Japanese. PubMed PMID: 20104681.

19: Santini D, Virzi V, Fratto ME, Bertoldo F, Sabbatini R, Berardi R, Calipari N, Ottaviani D, Ibrahim T. Can we consider zoledronic acid a new antitumor agent? Recent evidence in clinical setting. Curr Cancer Drug Targets. 2010 Feb;10(1):46-54. Review. PubMed PMID: 20088792.

20: Ricciardi S, de Marinis F. Treatment of bone metastases in lung cancer: the actual role of zoledronic acid. Rev Recent Clin Trials. 2009 Sep;4(3):205-11. Review. PubMed PMID: 20028333.

21: Caraglia M, Marra M, Naviglio S, Botti G, Addeo R, Abbruzzese A. Zoledronic acid: an unending tale for an antiresorptive agent. Expert Opin Pharmacother. 2010 Jan;11(1):141-54. Review. PubMed PMID: 20001436.

22: Tamási L. [Antitumor activity of zoledronic acid]. Magy Onkol. 2009 Sep;53(3):269-71. Review. Hungarian. PubMed PMID: 19793692.

23: Doggrell SA. Clinical efficacy and safety of zoledronic acid in prostate and breast cancer. Expert Rev Anticancer Ther. 2009 Sep;9(9):1211-8. Review. PubMed PMID: 19761424.

24: Piper PK Jr, Gruntmanis U. Management of osteoporosis in the aging male: focus on zoledronic acid. Clin Interv Aging. 2009;4:289-303. Epub 2009 Jun 29. Review. PubMed PMID: 19750231; PubMed Central PMCID: PMC2739630.

25: Silverman SL. New therapies for osteoporosis: zoledronic acid, bazedoxifene, and denosumab. Curr Osteoporos Rep. 2009 Sep;7(3):91-5. Review. PubMed PMID: 19723467.

26: Demontiero O, Duque G. Once-yearly zoledronic acid in hip fracture prevention. Clin Interv Aging. 2009;4:153-64. Epub 2009 May 14. Review. PubMed PMID: 19503777; PubMed Central PMCID: PMC2685236.

27: Bertoldo F, Tonini G, Vincenzi B, Santini D. Medical oncology: zoledronic acid prevents bone loss in early-stage breast cancer. Nat Rev Clin Oncol. 2009 Apr;6(4):191-2. Review. PubMed PMID: 19333223.

28: Lyseng-Williamson KA. Zoledronic acid: a review of its use in breast cancer. Drugs. 2008;68(18):2661-82. doi: 10.2165/0003495-200868180-00010. Review. PubMed PMID: 19093706.

29: BMJ Group. Annual zoledronic acid for osteoporosis. Drug Ther Bull. 2008 Dec;46(12):93-6. Review. PubMed PMID: 19056701.

30: Lambrinoudaki I, Vlachou S, Galapi F, Papadimitriou D, Papadias K. Once-yearly zoledronic acid in the prevention of osteoporotic bone fractures in postmenopausal women. Clin Interv Aging. 2008;3(3):445-51. Review. PubMed PMID: 18982915; PubMed Central PMCID: PMC2682377.

31: Deeks ED, Perry CM. Zoledronic acid: a review of its use in the treatment of osteoporosis. Drugs Aging. 2008;25(11):963-86. doi: 10.2165/0002512-200825110-00007. Review. PubMed PMID: 18947264.

32: Lewiecki EM. A clinician's perspective on the use of zoledronic acid in the treatment of postmenopausal osteoporosis. J Clin Densitom. 2008 Oct-Dec;11(4):478-84. Epub 2008 Aug 30. Review. PubMed PMID: 18757222.

33: Lewiecki EM. Intravenous zoledronic acid for the treatment of osteoporosis. Curr Osteoporos Rep. 2008 Mar;6(1):17-23. Review. PubMed PMID: 18430396.

34: Brufsky AM. Zoledronic acid for cancer therapy--induced and postmenopausal bone loss. Expert Opin Pharmacother. 2008 Apr;9(6):1013-28. Review. PubMed PMID: 18377343.

35: Dhillon S, Lyseng-Williamson KA. Zoledronic acid : a review of its use in the management of bone metastases of malignancy. Drugs. 2008;68(4):507-34. Review. PubMed PMID: 18318568.

36: McKeage K, Plosker GL. Zoledronic acid: a pharmacoeconomic review of its use in the management of bone metastases. Pharmacoeconomics. 2008;26(3):251-68. Review. PubMed PMID: 18282018.

37: Abelson A. A review of Paget's disease of bone with a focus on the efficacy and safety of zoledronic acid 5 mg. Curr Med Res Opin. 2008 Mar;24(3):695-705. Epub 2008 Jan 25. Review. PubMed PMID: 18226324.

38: Maricic M. Zoledronic acid for Paget's disease of bone. Drugs Today (Barc). 2007 Dec;43(12):879-85. Review. PubMed PMID: 18174973.

39: Saad F. New research findings on zoledronic acid: survival, pain, and anti-tumour effects. Cancer Treat Rev. 2008 Apr;34(2):183-92. Epub 2007 Dec 3. Review. PubMed PMID: 18061356.

40: Devogelaer JP, Manicourt DH. Zoledronic acid for treatment of Paget's disease of bone. Expert Opin Pharmacother. 2007 Nov;8(16):2863-9. Review. PubMed PMID: 17956205.

41: Yuasa T, Kimura S, Ashihara E, Habuchi T, Maekawa T. Zoledronic acid - a multiplicity of anti-cancer action. Curr Med Chem. 2007;14(20):2126-35. Review. PubMed PMID: 17691952.

42: Lipton A. The safety of zoledronic acid. Expert Opin Drug Saf. 2007 May;6(3):305-13. Review. PubMed PMID: 17480179.

43: Keating GM, Scott LJ. Zoledronic acid: a review of its use in the treatment of Paget's disease of bone. Drugs. 2007;67(5):793-804. Review. PubMed PMID: 17385948.

44: Santini D, Fratto ME, Vincenzi B, Galluzzo S, Tonini G. Zoledronic acid in the management of metastatic bone disease. Expert Opin Biol Ther. 2006 Dec;6(12):1333-48. Review. PubMed PMID: 17223741.

45: Sakurai T. [Therapeutic agents for disorders of bone and calcium metabolism: Zoledronic acid]. Clin Calcium. 2007 Jan;17(1):24-8. Review. Japanese. PubMed PMID: 17211090.

46: Griz L, Colares V, Bandeira F. [Treatment of Paget's disease of bone: importance of the zoledronic acid]. Arq Bras Endocrinol Metabol. 2006 Oct;50(5):845-51. Review. Portuguese. PubMed PMID: 17160207.

47: Benderson D, Karakunnel J, Kathuria S, Badros A. Scleritis complicating zoledronic acid infusion. Clin Lymphoma Myeloma. 2006 Sep;7(2):145-7. Review. PubMed PMID: 17026827.

48: Saad F. Zoledronic acid: past, present and future roles in cancer treatment. Future Oncol. 2005 Apr;1(2):149-59. Review. PubMed PMID: 16555985.

49: Maricic M. The use of zoledronic acid for Paget's disease of bone. Curr Osteoporos Rep. 2006 Mar;4(1):40-4. Review. PubMed PMID: 16527007.

50: Caffo O. [Zoledronic acid and bone pathology in the course of neoplasia. Part I]. Tumori. 2005 Sep-Oct;91(5):22-6. Review. Italian. PubMed PMID: 16459649.

51: Caffo O. [Zoledronic acid and osseous pathologies in the course of neoplasia. Part II]. Tumori. 2005 Nov-Dec;91(6):suppl 23-7. Review. Italian. PubMed PMID: 16457163.

52: Body JJ, Sternon J. [Treatment of Paget's disease of bone with zoledronic acid]. Rev Med Brux. 2005 Nov-Dec;26(6):513-7. Review. French. PubMed PMID: 16454155.

53: Saad F, McKiernan J, Eastham J. Rationale for zoledronic acid therapy in men with hormone-sensitive prostate cancer with or without bone metastasis. Urol Oncol. 2006 Jan-Feb;24(1):4-12. Review. PubMed PMID: 16414486.

54: Tomoo T, Suzuki M. [Preclinical and clinical profile of zoledronic acid (Zometa) for hypercalcemia of malignancy]. Nihon Yakurigaku Zasshi. 2005 Nov;126(5):353-7. Review. Japanese. PubMed PMID: 16394581.

55: Conti G. [Zoledronic acid in the treatment of prostate cancer]. Minerva Urol Nefrol. 2005 Dec;57(4):313-7. Review. Italian. PubMed PMID: 16247352.

56: Smith MR. Zoledronic acid to prevent skeletal complications in cancer: corroborating the evidence. Cancer Treat Rev. 2005;31 Suppl 3:19-25. Epub 2005 Oct 14. Review. PubMed PMID: 16229955.

57: Clézardin P. Anti-tumour activity of zoledronic acid. Cancer Treat Rev. 2005;31 Suppl 3:1-8. Epub 2005 Oct 12. Review. PubMed PMID: 16225995.

58: Saad F, Lipton A. Zoledronic acid is effective in preventing and delaying skeletal events in patients with bone metastases secondary to genitourinary cancers. BJU Int. 2005 Nov;96(7):964-9. Review. PubMed PMID: 16225510.

59: Olson KB, Hellie CM, Pienta KJ. Osteonecrosis of jaw in patient with hormone-refractory prostate cancer treated with zoledronic acid. Urology. 2005 Sep;66(3):658. Review. PubMed PMID: 16140106.

60: Corso A, Ferretti E, Lazzarino M. Zoledronic acid exerts its antitumor effect in multiple myeloma interfering with the bone marrow microenvironment. Hematology. 2005 Jun;10(3):215-24. Review. PubMed PMID: 16019470.

61: Berenson JR. Recommendations for zoledronic acid treatment of patients with bone metastases. Oncologist. 2005 Jan;10(1):52-62. Review. PubMed PMID: 15632252.

62: Lipton A, Colombo-Berra A, Bukowski RM, Rosen L, Zheng M, Urbanowitz G. Skeletal complications in patients with bone metastases from renal cell carcinoma and therapeutic benefits of zoledronic acid. Clin Cancer Res. 2004 Sep 15;10(18 Pt 2):6397S-403S. Review. PubMed PMID: 15448038.

63: Berenson J, Hirschberg R. Safety and convenience of a 15-minute infusion of zoledronic acid. Oncologist. 2004;9(3):319-29. Review. PubMed PMID: 15169987.

64: Perry CM, Figgitt DP. Zoledronic acid: a review of its use in patients with advanced cancer. Drugs. 2004;64(11):1197-211. Review. PubMed PMID: 15161327.

65: Saad F. Zoledronic acid significantly reduces pathologic fractures in patients with advanced-stage prostate cancer metastatic to bone. Clin Prostate Cancer. 2002 Dec;1(3):145-52. Review. PubMed PMID: 15046689.

66: Li EC, Davis LE. Zoledronic acid: a new parenteral bisphosphonate. Clin Ther. 2003 Nov;25(11):2669-708. Review. PubMed PMID: 14693298.

67: Croucher P, Jagdev S, Coleman R. The anti-tumor potential of zoledronic acid. Breast. 2003 Aug;12 Suppl 2:S30-6. Review. PubMed PMID: 14659141.

68: Cameron D. Proven efficacy of zoledronic acid in the treatment of bone metastases in patients with breast cancer and other malignancies. Breast. 2003 Aug;12 Suppl 2:S22-9. Review. PubMed PMID: 14659140.

69: Lacerna L, Hohneker J. Zoledronic acid for the treatment of bone metastases in patients with breast cancer and other solid tumors. Semin Oncol. 2003 Oct;30(5 Suppl 16):150-60. Review. PubMed PMID: 14613036.

70: Neville-Webbe H, Coleman RE. The use of zoledronic acid in the management of metastatic bone disease and hypercalcaemia. Palliat Med. 2003 Sep;17(6):539-53. Review. PubMed PMID: 14526888.

71: Theriault RL. Zoledronic acid (Zometa) use in bone disease. Expert Rev Anticancer Ther. 2003 Apr;3(2):157-66. Review. PubMed PMID: 12722875.

72: Body JJ. Zoledronic acid: an advance in tumour bone disease therapy and a new hope for osteoporosis. Expert Opin Pharmacother. 2003 Apr;4(4):567-80. Review. PubMed PMID: 12667119.

73: Rosen LS. Efficacy and safety of zoledronic acid in the treatment of bone metastases associated with lung cancer and other solid tumors. Semin Oncol. 2002 Dec;29(6 Suppl 21):28-32. Review. PubMed PMID: 12584692.

74: Saad F. Treatment of bone complications in advanced prostate cancer: rationale for bisphosphonate use and results of a phase III trial with zoledronic acid. Semin Oncol. 2002 Dec;29(6 Suppl 21):19-27. Review. PubMed PMID: 12584691.

75: Green JR. Preclinical pharmacology of zoledronic acid. Semin Oncol. 2002 Dec;29(6 Suppl 21):3-11. Review. PubMed PMID: 12584689.

76: Gilbert SM, Olsson CA, Benson MC, McKiernan JM. The role of intravenous zoledronic acid in the management of high-risk prostate cancer. Curr Opin Urol. 2003 Mar;13(2):133-5. Review. PubMed PMID: 12584473.

77: Rosen L, Harland SJ, Oosterlinck W. Broad clinical activity of zoledronic acid in osteolytic to osteoblastic bone lesions in patients with a broad range of solid tumors. Am J Clin Oncol. 2002 Dec;25(6 Suppl 1):S19-24. Review. PubMed PMID: 12562047.

78: Wellington K, Goa KL. Zoledronic acid: a review of its use in the management of bone metastases and hypercalcaemia of malignancy. Drugs. 2003;63(4):417-37. Review. PubMed PMID: 12558465.

79: Major P. The use of zoledronic acid, a novel, highly potent bisphosphonate, for the treatment of hypercalcemia of malignancy. Oncologist. 2002;7(6):481-91. Review. PubMed PMID: 12490736.

80: Lipton A, Small E, Saad F, Gleason D, Gordon D, Smith M, Rosen L, Kowalski MO, Reitsma D, Seaman J. The new bisphosphonate, Zometa (zoledronic acid), decreases skeletal complications in both osteolytic and osteoblastic lesions: a comparison to pamidronate. Cancer Invest. 2002;20 Suppl 2:45-54. Review. PubMed PMID: 12442349.

81: Cheer SM, Noble S. Zoledronic acid. Drugs. 2001;61(6):799-805; discussion 806. Review. PubMed PMID: 11398911.

82: Fleisch H. Zoledronic acid: an evolving role in the treatment of cancer patients with bone disease. Semin Oncol. 2001 Apr;28(2 Suppl 6):45-7. Review. PubMed PMID: 11346864.

83: Mundy GR, Yoneda T, Hiraga T. Preclinical studies with zoledronic acid and other bisphosphonates: impact on the bone microenvironment. Semin Oncol. 2001 Apr;28(2 Suppl 6):35-44. Review. PubMed PMID: 11346863.

84: Berenson JR. Zoledronic acid in cancer patients with bone metastases: results of Phase I and II trials. Semin Oncol. 2001 Apr;28(2 Suppl 6):25-34. Review. PubMed PMID: 11346862.

85: Major PP, Coleman RE. Zoledronic acid in the treatment of hypercalcemia of malignancy: results of the international clinical development program. Semin Oncol. 2001 Apr;28(2 Suppl 6):17-24. Review. PubMed PMID: 11346861.

86: Coleman RE, Seaman JJ. The role of zoledronic acid in cancer: clinical studies in the treatment and prevention of bone metastases. Semin Oncol. 2001 Apr;28(2 Suppl 6):11-6. Review. PubMed PMID: 11346860.