Abstract
Bone metastases and their associated morbidities are common in patients with advanced prostate cancer and other genitourinary (GU) malignancies. Zoledronic acid> (a bisphosphonate) has long been the mainstay of treatment for reducing the risk of skeletal-related events in patients with bone metastases from GU cancers, and denosumab (a monoclonal antibody directed against the receptor activator of nuclear factor kappa B ligand [RANKL]) has recently received approval for this indication in the United States. Preclinical data indicate that modifying the bone microenvironment may render it less conducive to metastasis, and emerging clinical findings suggest that the potential benefits from bone-directed therapies are not limited to reducing skeletal morbidity—these agents might help to improve survival and delay bone disease progression or even development of bone metastases (if used earlier in the disease course). This chapter reviews the rationale and recent clinical data supporting an antimetastatic role for bone-directed therapies in patients with GU malignancies.
Keywords
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsAbbreviations
- ADT:
-
Androgen-deprivation therapy
- BALP:
-
Bone-specific alkaline phosphatase
- BMD:
-
Bone mineral density
- BP:
-
Bisphosphonate
- CRPC:
-
Castration-resistant prostate cancer
- CTC:
-
Circulating tumor cell
- DM:
-
Distant metastasis
- DTC:
-
Disseminated tumor cell
- E-E:
-
Patients with elevated baseline and 3-month NTX
- E-N:
-
Patients with elevated baseline and normalized 3-month NTX
- γδ:
-
Gamma-delta (T cells)
- GU:
-
Genitourinary
- HR:
-
Hazard ratio
- MM:
-
Multiple myeloma
- N-BP:
-
Nitrogen-containing bisphosphonate
- NTX:
-
N-telopeptide of type I collagen
- OS:
-
Overall survival
- PC:
-
Prostate cancer
- PO:
-
Oral(ly)
- PSA:
-
Prostate-specific antigen
- RANKL:
-
Receptor activator of nuclear factor kappa B ligand
- RCC:
-
Renal cell carcinoma
- RP:
-
Radical prostatectomy
- SC:
-
Subcutaneous(ly)
- SRE:
-
Skeletal-related event
- ZOL:
-
Zoledronic acid
References
Aapro M, Abrahamsson PA, Body JJ et al (2008) Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol 19:420–432
Amgen Inc (2010a) Xgeva (denosumab) injection [package insert]. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/125320s007lbl.pdf. Accessed 8 Feb 2011
Amgen Inc (2010b) Xgeva™ (denosumab) significantly improved bone metastasis-free survival in men with prostate cancer [press release]. http://wwwext.amgen.com/media/media_pr_detail.jsp?year=2010&releaseID=1507379. Accessed 8 Feb 2011
Amgen Europe BV (2011) XGEVA 120 mg solution for injection [summary of product characteristics]. http://www.ema.europa.eu/docs/en_GB/document.library/EPAR_-_Product_Information/human/002173/WC500110381.pdf. Accessed 21 Oct 2011
Anand A, Scher HI, Beer TM, et al (2010) Circulating tumor cells (CTC) and prostate specific antigen (PSA) as response indicator biomarkers in chemotherapy-naive patients with progressive castration-resistant prostate cancer (CRPC) treated with MDV3100. J Clin Oncol 28(suppl):353 s, Abstract 4546
Berg A, Berner A, Lilleby W et al (2007) Impact of disseminated tumor cells in bone marrow at diagnosis in patients with nonmetastatic prostate cancer treated by definitive radiotherapy. Int J Cancer 120:1603–1609
Bhoopalam N, Campbell SC, Moritz T et al (2009) Intravenous zoledronic acid to prevent osteoporosis in a veteran population with multiple risk factors for bone loss on androgen deprivation therapy. J Urol 182:2257–2264
Body J-J, Cook R, Costa L, et al (2009) Possible survival benefits from zoledronic acid treatment in patients with bone metastases from solid tumors and poor prognostic features [poster]. Presented at: the IX International Meeting on Cancer Induced Bone Disease, Arlington, 28–31 Oct 2009, Poster 71
Boissier S, Ferreras M, Peyruchaud O et al (2000) Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res 60:2949–2954
Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423:337–342
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 97:59–69
Brown JE, Lipton A, Cook RJ, et al (2009) N-telopeptide of type I collagen (NTX) correlates with survival and fractures in patients (pts) with bone metastases from renal cell carcinoma (RCC) [poster]. Presented at: American Society of Clinical Oncology 2009 Genitourinary Cancers Symposium, Orlando, 26–28 Feb 2009, Poster A66
Casey R, Gesztesi Z, Rochford J (2010) Long term zoledronic acid during androgen blockade for prostate cancer. Can J Urol 17:5170–5177
Choueiri TK, Duh MS, Clement J et al (2010) Angiogenesis inhibitor therapies for metastatic renal cell carcinoma: effectiveness, safety and treatment patterns in clinical practice-based on medical chart review. BJU Int 105:1247–1254
Clezardin P, Massaia M (2010) Nitrogen-containing bisphosphonates and cancer immunotherapy. Curr Pharm Des 16:3007–3014
Clines GA, Guise TA (2008) Molecular mechanisms and treatment of bone metastasis. Expert Rev Mol Med 10:e7
Clyburn RD, Reid P, Evans CA et al (2010) Increased anti-tumour effects of doxorubicin and zoledronic acid in prostate cancer cells in vitro: supporting the benefits of combination therapy. Cancer Chemother Pharmacol 65:969–978
Coleman RE (2001) Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 27:165–176
Coleman RE, Major P, Lipton A et al (2005) Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol 23:4925–4935
Cook RJ, Coleman R, Brown J et al (2006) Markers of bone metabolism and survival in men with hormone-refractory metastatic prostate cancer. Clin Cancer Res 12:3361–3367
Costa L, Cook R, Body JJ, et al (2009) Zoledronic acid treatment delays disease progression and improves survival in patients with bone metastases from solid tumors and elevated levels of bone resorption [poster]. Presented at: the IX International Meeting on Cancer Induced Bone Disease, Arlington, 28–31 Oct 2009, Poster 50
Coxon JP, Oades GM, Kirby RS et al (2004) Zoledronic acid induces apoptosis and inhibits adhesion to mineralized matrix in prostate cancer cells via inhibition of protein prenylation. BJU Int 94:164–170
Danila DC, Heller G, Gignac GA et al (2007) Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer. Clin Cancer Res 13:7053–7058
Danila DC, Anand A, Sung CC, et al (2010) Molecular profiling of circulating tumor cells (CTC) in patients with castrate metastatic prostate cancer (CMPC) receiving abiraterone acetate (AA) after failure of docetaxel-based chemotherapy [abstract]. J Clin Oncol 28(suppl): 375 s, Abstract 4635
Dearnaley DP, Mason MD, Parmar MK, et al (2009a) Survival benefit with oral sodium clodronate in metastatic but not localised prostate cancer: long-term results of MRC PR04 & PR05 [poster]. Presented at: American Society of Clinical Oncology 2009 Genitourinary Cancers Symposium, Orlando, 26–28 Feb 2009, Abstract 6
Dearnaley DP, Mason MD, Parmar MKB et al (2009b) Adjuvant therapy with oral sodium clodronate in locally advanced and metastatic prostate cancer: long-term overall survival results from the MRC PR04 and PR05 randomised controlled trials. Lancet Oncol 10:872–876
Diamond TH, Higano CS, Smith MR et al (2004) Osteoporosis in men with prostate carcinoma receiving androgen-deprivation therapy: recommendations for diagnosis and therapies. Cancer 100:892–899
Dieli F, Vermijlen D, Fulfaro F et al (2007) Targeting human gd T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer. Cancer Res 67:7450–7457
Donat DA, Pesic JM, Tesanovic SM, et al (2006) Low-dose clodronate as adjunctive therapy in prostate cancer patients with painful bone metastases [abstract]. Ann Oncol 17(suppl 9):ix156 Abstract 484
Ernst DS, Tannock IF, Winquist EW et al (2003) Randomized, double-blind, controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone and placebo in patients with hormone-refractory prostate cancer and pain. J Clin Oncol 21:3335–3342
Facchini G, Caraglia M, Morabito A et al (2010) Metronomic administration of zoledronic acid and Taxotere combination in castration resistant prostate cancer patients: phase I ZANTE trial. Cancer Biol Ther 10:543–548
Fizazi K, Carducci M, Smith M, et al (2011) Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377:813–822
Garcia M, Jemal A, Ward EM, et al (2007) Global cancer facts and figures 2007. American Cancer Society. http://www.cancer.org/acs/groups/content/@nho/documents/document/globalfactsandfigures2007rev2p.pdf. Accessed 8 Feb 2011
Greenspan SL, Bone HG, Ettinger MP et al (2007) Effect of recombinant human parathyroid hormone (1–84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann Intern Med 146:326–339
Guise TA (2008) Antitumor effects of bisphosphonates: promising preclinical evidence. Cancer Treat Rev 34:S19–S24
Harper S, Dansey R (2010) Amgen investor meeting: 2010 ASCO annual meeting. http://phx.corporate-ir.net/External.File?item=UGFyZW50SUQ9NDkyMTh8Q2hpbGRJRD0tMXxUeXBlPTM=&t=1. Accessed 8 Feb 2011
Hatoum HT, Lin SJ, Guo A et al (2011) Zoledronic acid therapy impacts risk and frequency of skeletal complications and follow-up duration in prostate cancer patients with bone metastasis. Curr Med Res Opin 27:55–62
Heidenreich A, Bolla M, Joniau S et al (2009) Guidelines on prostate cancer. European Association of Urology. http://www.uroweb.org/fileadmin/tx_eauguidelines/2009/Full/Prostate_Cancer.pdf. Accessed 8 Feb 2011
Henry DH, Costa L, Goldwasser F et al (2011) Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 29:1125–1132
Hering F, Rodrigues PRT, Lipay M (2003) Clodronate for treatment of bone metastases in hormone refractory prostate cancer. Int Braz J Urol 29:228–233
Hirsh V, Major PP, Lipton A et al (2008) Zoledronic acid and survival in patients with metastatic bone disease from lung cancer and elevated markers of osteoclast activity. J Thorac Oncol 3:228–236
Israeli RS, Rosenberg SJ, Saltzstein DR et al (2007) The effect of zoledronic acid on bone mineral density in patients undergoing androgen deprivation therapy. Clin Genitourin Cancer 5:271–277
Izumi K, Mizokami A, Sugimoto K et al (2009) Risedronate recovers bone loss in patients with prostate cancer undergoing androgen-deprivation therapy. Urology 73:1342–1346
Izumi K, Mizokami A, Narimoto K, et al (2010) The role of bone turnover markers in patients with bone metastatic prostate cancer receiving zoledronate infusion [poster]. Presented at: American Society of Clinical Oncology 2010 Genitourinary Cancers Symposium, San Francisco, 5–7 March 2010, Abstract 196
Josson S, Matsuoka Y, Chung LW et al (2010) Tumor-stroma co-evolution in prostate cancer progression and metastasis. Semin Cell Dev Biol 21:26–32
Kollermann J, Weikert S, Schostak M et al (2008) Prognostic significance of disseminated tumor cells in the bone marrow of prostate cancer patients treated with neoadjuvant hormone treatment. J Clin Oncol 26:4928–4933
Koul HK, Koul S, Kumar B, et al (2010) Direct effects of zoledronic acid on hormone-responsive and hormone-refractory prostate cancer cells [poster]. Presented at: American Society of Clinical Oncology 2010 Genitourinary Cancers Symposium, San Francisco, 5–7 March 2010, Abstract 184
Lee RJ, Stott SL, Nagrath S, et al (2009) Analyses of circulating tumor cell (CTC) dynamics and treatment response in prostate cancer using CTC-chip microfluidic device [abstract]. J Clin Oncol 27(suppl):271 s Abstract 5149
Lipton A, Small E, Saad F et al (2002) The new bisphosphonate, zometa (zoledronic acid), decreases skeletal complications in both osteolytic and osteoblastic lesions: a comparison to pamidronate. Cancer Invest 20(suppl 2):45–54
Lipton A, Seaman J, Zheng M (2004) Efficacy and safety of zoledronic acid in patients with bone metastases from renal cell carcinoma [poster]. Presented at: What is New in Bisphosphonates? Seventh Workshop on Bisphosphonates--From the Laboratory to the Patient, Davos, Switzerland, 24–26 Mar 2004 Abstract 28
Lipton A, Cook RJ, Major P et al (2007) Zoledronic acid and survival in breast cancer patients with bone metastases and elevated markers of osteoclast activity. Oncologist 12:1035–1043
Lipton A, Cook R, Saad F et al (2008) Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid. Cancer 113:193–201
Meads MB, Hazlehurst LA, Dalton WS (2008) The bone marrow microenvironment as a tumor sanctuary and contributor to drug resistance. Clin Cancer Res 14:2519–2526
Merck & Co. Inc (2010) Fosamax (alendronate sodium) tablets and oral solution [package insert]. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020560s051s055s057,021575s012s016s018lbl.pdf. Accessed 8 Feb 2011
Michaelson MD, Marujo RM, Smith MR (2004) Contribution of androgen deprivation therapy to elevated osteoclast activity in men with metastatic prostate cancer. Clin Cancer Res 10:2705–2708
Morgan C, Lewis PD, Jones RM et al (2007) The in vitro anti-tumour activity of zoledronic acid and docetaxel at clinically achievable concentrations in prostate cancer. Acta Oncol 46:669–677
Morgan TM, Lange PH, Porter MP et al (2009) Disseminated tumor cells in prostate cancer patients after radical prostatectomy and without evidence of disease predicts biochemical recurrence. Clin Cancer Res 15:677–683
Mundy GR (2002) Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2:584–593
Naoe M, Ogawa Y, Takeshita K et al (2010) Zoledronate stimulates gamma delta T cells in prostate cancer patients. Oncol Res 18:493–501
Neville-Webbe HL, Rostami-Hodjegan A, Evans CA et al (2005) Sequence- and schedule-dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells. Int J Cancer 113:364–371
Noguchi M, Yahara J, Noda S (2003) Serum levels of bone turnover markers parallel the results of bone scintigraphy in monitoring bone activity of prostate cancer. Urology 61:993–998
Norton L, Massague J (2006) Is cancer a disease of self-seeding? Nat Med 12:875–878
Novartis Pharmaceuticals Corporation (2008) Reclast (zoledronic acid) injection [package insert]. http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021817s001lbl.pdf. Accessed 8 Feb 2011
Novartis Pharmaceuticals Corporation (2009) Zometa (zoledronic acid) injection [package insert]. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021223s018lbl.pdf. Accessed 8 Feb 2011
Olmos D, Arkenau HT, Ang JE et al (2009) Circulating tumour cell (CTC) counts as intermediate end points in castration-resistant prostate cancer (CRPC): a single-centre experience. Ann Oncol 20:27–33
Oudard S, Smith MR, Karsh L et al (2011) Denosumab and bone metastases-free survival in men with castration-resistant prostate cancer: Subgroup analyses from an international, double-blind, randomized phase 3 trial. Presented at: The European Multidisciplinary Cancer Congress. Stockholm, Sweden, 23–27 Sept 2011. Abstract 7003 [oral]
Padalecki SS, Carreon MR, Grubbs B, et al (2002) Androgen deprivation causes bone loss and increased prostate cancer metastases to bone: prevention by zoledronic acid [abstract]. Presented at: 24th annual meeting of the American Society for Bone and Mineral Research, San Antonio, 20–24 Sept 2002, Abstract SU072
Paget S (1889) The distribution of secondary growths in cancer of the breast. Lancet 1:571–573
Planas J, Trilla E, Raventos C et al (2009) Alendronate decreases the fracture risk in patients with prostate cancer on androgen-deprivation therapy and with severe osteopenia or osteoporosis. BJU Int 104:1637–1640
Procter & Gamble Pharmaceuticals Inc (2009) Actonel (risedronate sodium) tablets [package insert]. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020835s036lbl.pdf. Accessed 8 Feb 2011
Rodrigues P, Hering F, Campagnari JC (2004) Use of bisphosphonates can dramatically improve pain in advanced hormone-refractory prostate cancer patients. Prostate Cancer Prostatic Dis 7:350–354
Rogers MJ, Gordon S, Benford HL et al (2000) Cellular and molecular mechanisms of action of bisphosphonates. Cancer 88:2961–2978
Rucci N, Teti A (2010) Osteomimicry: how tumor cells try to deceive the bone. Front Biosci (Schol Ed) 2:907–915
Ryan CW, Huo D, Demers LM, et al (2006) Zoledronic acid initiated during the first year of androgen deprivation therapy increases bone mineral density in patients with prostate cancer. J Urol 176:972–978, discussion follows
Saad F (2008) New research findings on zoledronic acid: survival, pain, and anti-tumour effects. Cancer Treat Rev 34:183–192
Saad F, Lipton A (2005) Zoledronic acid is effective in preventing and delaying skeletal events in patients with bone metastases secondary to genitourinary cancers. BJU Int 96:964–969
Saad F, Lipton A (2007) Clinical benefits and considerations of bisphosphonate treatment in metastatic bone disease. Semin Oncol 34(4):S17–S23
Saad F, Gleason DM, 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 94:1458–1468
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 96:879–882
Saad F, Lipton A, Cook R et al (2007) Pathologic fractures correlate with reduced survival in patients with malignant bone disease. Cancer 110:1860–1867
Shiozawa Y, Havens AM, Pienta KJ et al (2008) The bone marrow niche: habitat to hematopoietic and mesenchymal stem cells, and unwitting host to molecular parasites. Leukemia 22:941–950
Smith MR, McGovern FJ, Zietman AL et al (2001) Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 345:948–955
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 169:2008–2012
Smith MR, Cook RJ, Coleman R et al (2007) Predictors of skeletal complications in men with hormone-refractory metastatic prostate cancer. Urology 70:315–319
Smith MR, Egerdie B, Hernandez Toriz N et al (2009) Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 361:745–755
Smith MR, Saad F, Coleman R, et al (2009) Denosumab to prolong bone metastases-free survival in men with castrate-resistant prostate cancer: Results of a global phase 3, randomized, double-blind trial. Presented at: American Urological Association Annual Meeting. Washington, DC, 14–19 May 2011. Late Breaking News
Soltau J, Zirrgiebel U, Esser N et al (2008) Antitumoral and antiangiogenic efficacy of bisphosphonates in vitro and in a murine RENCA model. Anticancer Res 28:933–941
Taxel P, Dowsett R, Richter L et al (2010) Risedronate prevents early bone loss and increased bone turnover in the first 6 months of luteinizing hormone-releasing hormone-agonist therapy for prostate cancer. BJU Int 106:1473–1476
US National Institutes of Health (2008) Zoledronate plus standard therapy compared with placebo plus standard therapy to prevent bone metastases in patients with recurrent prostate cancer that has no symptoms. http://clinicaltrials.gov/ct2/show/NCT00005073. Accessed 8 Feb 2011
US National Institutes of Health (2009) RADAR trial—randomised androgen deprivation and radiotherapy. http://clinicaltrials.gov/ct2/show/NCT00193856. Accessed 8 Feb 2011
Ullen A, Schwarz S, Lennartsson L et al (2009) Zoledronic acid induces caspase-dependent apoptosis in renal cancer cell lines. Scand J Urol Nephrol 43:98–103
Weckermann D, Polzer B, Ragg T et al (2009) Perioperative activation of disseminated tumor cells in bone marrow of patients with prostate cancer. J Clin Oncol 27:1549–1556
Yuasa T, Sato K, Ashihara E et al (2009) Intravesical administration of gammadelta T cells successfully prevents the growth of bladder cancer in the murine model. Cancer Immunol Immunother 58:493–502
Zaghloul MS, Boutrus R, El-Hossieny H et al (2010) A prospective, randomized, placebo-controlled trial of zoledronic acid in bony metastatic bladder cancer. Int J Clin Oncol 15:382–389
Acknowledgments
Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. We thank Shalini Murthy, PhD, ProEd Communications, Inc., for her medical editorial assistance with this manuscript.
Conflict of Interest
Dr. Saad has served as an advisor and conducted research for Novartis and Amgen and has received funding for medical editorial assistance from Novartis. Dr. Lattouf has served as a consultant for and received research funding from Novartis and Amgen.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2012 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Saad, F., Lattouf, JB. (2012). Bisphosphonates: Prevention of Bone Metastases in Prostate Cancer. In: Joerger, M., Gnant, M. (eds) Prevention of Bone Metastases. Recent Results in Cancer Research, vol 192. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-21892-7_5
Download citation
DOI: https://doi.org/10.1007/978-3-642-21892-7_5
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-21891-0
Online ISBN: 978-3-642-21892-7
eBook Packages: MedicineMedicine (R0)