Bone-targeted therapies like bisphosphonates (zoledronic acid or pamidronate) or denosumab are recommended in all patients with metastatic breast cancer and bone metastases, whether they are symptomatic or not. The choice between these 2 different agents, however, remains open. In this review, we critically discuss the emerging evidence for direct anti-tumor activity of bone-targeting agents, the utility of bone turnover markers for treatment decision and efficacy prediction, as well as the safety and financial aspects of bisphosphonates and denosumab. Furthermore, we provide a possible therapeutic algorithm, and present new pharmacologic agents which are being investigated for the treatment of meta-static bone disease.

Keywords:
Metastatic breast cancer, Bone metastasis, Bone-targeted therapy, Bisphosphonates, Denosumab
1.
Coleman RE: Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 2001;27:165-176.
2.
Delea T, McKiernan J, Brandman J, et al.: Retrospective study of the effect of skeletal complications on total medical care costs in patients with bone metastases of breast cancer seen in typical clinical practice. J Support Oncol 2006;4:341-347.
3.
Costa L, Badia X, Chow E, et al.: Impact of skeletal complications on patients' quality of life, mobility, and functional independence. Support Care Cancer 2008;16:879-889.
4.
Norgaard M, Jensen AO, Jacobsen JB, et al.: Skeletal related events, bone metastasis and survival of prostate cancer: a population based cohort study in Denmark (1999 to 2007). J Urol 2010;184:162-167.
5.
Coleman RE: Bisphosphonates in breast cancer. Ann Oncol 2005;16:687-695.
6.
Russell RG: Bisphosphonates: the first 40 years. Bone 2011;49:2-19.
7.
Brown JE, Coleman RE: Denosumab in patients with cancer-a surgical strike against the osteoclast. Nat Rev Clin Oncol 2012;9:110-118.
8.
Lipton A, Fizazi K, Stopeck AT, et al.: Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer 2012;48:3082-3092.
9.
Body JJ, Diel IJ, Lichinitzer M, et al.: 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 2004;90:1133-1137.
10.
Kohno N, Aogi K, Minami H, et al.: 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 2005;23:3314-3321.
11.
Lipton A, Theriault RL, Hortobagyi GN, et al.: Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer 2000;88:1082-1090.
12.
Theriault RL, Lipton A, Hortobagyi GN, et al.: Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol 1999;17:846-854.
13.
Tripathy D, Lichinitzer M, Lazarev A, et al.: Oral ibandronate for the treatment of metastatic bone disease in breast cancer: efficacy and safety results from a randomized, double-blind, placebo-controlled trial. Ann Oncol 2004;15:743-750.
14.
Wong MH, Stockler MR, Pavlakis N: Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst Reviews 2012;2:CD003474.
15.
Green JR, Muller K, Jaeggi KA: Preclinical pharmacology of CGP 42'446, a new, potent, heterocyclic bisphosphonate compound. J Bone Miner Res 1994;9:745-751.
16.
Barrett-Lee P, Casbard A, Abraham J, et al.: Oral ibandronic acid versus intravenous zoledronic acid in treatment of bone metastases from breast cancer: a randomised, open label, non-inferiority phase 3 trial. Lancet Oncol 2014;15:114-122.
17.
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;19:558-567.
18.
Rosen LS, Gordon D, Kaminski M, et al.: 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 2003;98:1735-1744.
19.
Rosen LS, Gordon DH, Dugan W Jr, et al.: Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 2004;100:36-43.
20.
Coleman RE: Efficacy of zoledronic acid and pamidronate in breast cancer patients: a comparative analysis of randomized phase III trials. Am J Clin Oncol 2002;25:S25-31.
21.
Hortobagyi GN, Lipton A, Chew HK, et al.: Efficacy and safety of continued zoledronic acid every 4 weeks versus every 12 weeks in women with bone metastases from breast cancer: results of the optimize-2 trial. J Clin Oncol 2014;32:5s.
22.
Dougall WC, Chaisson M: The RANK/RANKL/OPG triad in cancer-induced bone diseases. Cancer Metastasis Rev 2006;25:541-549.
23.
Coleman R, Gnant M, Morgan G, Clezardin P: Effects of bone-targeted agents on cancer progression and mortality. J Natl Cancer Inst 2012;104: 1059-1067.
24.
Henry DH, Costa L, Goldwasser F, et al.: 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 2011;29:1125-1132.
25.
Stopeck AT, Lipton A, Body JJ, et al.: Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 2010;28:5132-5139.
26.
Fizazi K, Carducci M, Smith M, et al.: Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011;377:813-822.
27.
Henry D, Vadhan-Raj S, Hirsh V, et al.: Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: an analysis of data from patients with solid tumors. Support Care Cancer 2014;22:679-687.
28.
Coleman RE, Major P, Lipton A, et al.: Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol 2005; 23:4925-4935.
29.
Lipton A, Cook R, Saad F, et al.: 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 2008;113:193-201.
30.
Fizazi K, Lipton A, Mariette X, et al.: Randomized phase ii trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol 2009;27:1564-1571.
31.
Clezardin P: Bisphosphonates' antitumor activity: an unravelled side of a multifaceted drug class. Bone 2011;48:71-79.
32.
Neville-Webbe HL, Gnant M, Coleman RE: Potential anticancer properties of bisphosphonates. Seminars in oncology 2010;37 Suppl 1:S53-65.
33.
Stresing V, Fournier PG, Bellahcene A, et al.: Nitrogen-containing bisphosphonates can inhibit angiogenesis in vivo without the involvement of farnesyl pyrophosphate synthase. Bone 2011;48: 259-266.
34.
Stresing V, Daubine F, Benzaid I, et al.: Bisphosphonates in cancer therapy. Cancer Lett 2007;257: 16-35.
35.
Tang X, Zhang Q, Shi S, et al.: Bisphosphonates suppress insulin-like growth factor 1-induced angiogenesis via the HIF-1alpha/VEGF signaling pathways in human breast cancer cells. Int J Cancer 2010;126:90-103.
36.
Gallo M, De Luca A, Lamura L, Normanno N: Zoledronic acid blocks the interaction between mesenchymal stem cells and breast cancer cells: implications for adjuvant therapy of breast cancer. Ann Oncol 2012;23:597-604.
37.
Fata JE, Kong YY, Li J, et al.: The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 2000; 103:41-50.
38.
Gonzalez-Suarez E, Jacob AP, Jones J, et al.: Rank ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 2010;468:103-107.
39.
Tan W, Zhang W, Strasner A, et al.: Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 2011;470:548-553.
40.
Santini D, Schiavon G, Vincenzi B, et al.: Receptor activator of NF-kB (RANK) expression in primary tumors associates with bone metastasis occurrence in breast cancer patients. PloS One 2011;6:e19234.
41.
Misso G, Porru M, Stoppacciaro A, et al.: Evaluation of the in vitro and in vivo antiangiogenic effects of denosumab and zoledronic acid. Cancer Biol Ther 2012;13:1491-1500.
42.
Chlebowski RT, Chen Z, Cauley JA, et al.: Oral bisphosphonate use and breast cancer incidence in postmenopausal women. J Clin Oncol 2010;28: 3582-3590.
43.
Rennert G, Pinchev M, Rennert HS: Use of bisphosphonates and risk of postmenopausal breast cancer. J Clin Oncol 2010;28:3577-3581.
44.
Aft R, Naughton M, Trinkaus K, et al.: Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial. Lancet Oncol 2010;11:421-428.
45.
Rack B, Juckstock J, Genss EM, et al.: Effect of zoledronate on persisting isolated tumour cells in patients with early breast cancer. Anticancer Res 2010;30:1807-1813.
46.
Solomayer EF, Gebauer G, Hirnle P, et al.: Influence of zoledronic acid on disseminated tumor cells in primary breast cancer patients. Ann Oncol 2012;23:2271-2277.
47.
Banys M, Solomayer EF, Gebauer G, et al.: Influence of zoledronic acid on disseminated tumor cells in bone marrow and survival: results of a prospective clinical trial. BMC Cancer 2013;13:480.
48.
Coleman R, Gnant M, Paterson A, et al.: Effects of bisphosphonate treatment on recurrence and cause-specific mortality in women with early breast cancer: a meta-analysis of individual patient data from randomised trials. Cancer Res 2013;73(24 suppl):abstr S4-07.
49.
Cook RJ, Hirsh V, Major PP, et al.: Meta-analysis of effects of zoledronic acid (ZOL) on survival in metastatic bone disease (MBD): survival in patients with high bone turnover. J Clin Oncol 2008;26:abstr 20562.
50.
Dearnaley DP, Mason MD, Parmar MK, et al.: 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 2009;10:872-876.
51.
Zarogoulidis K, Boutsikou E, Zarogoulidis P, et al.: The impact of zoledronic acid therapy in survival of lung cancer patients with bone metastasis. Int J Cancer 2009;125:1705-1709.
52.
Smith MR, Saad F, Coleman R, et al.: Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 2012;379:39-46.
53.
Mortimer JE, Pal SK: Safety considerations for use of bone-targeted agents in patients with cancer. Semin Oncol 2010;37(suppl 1):S66-72.
54.
Saad F, Brown JE, Van Poznak C, et al.: Incidence, risk factors, and outcomes of osteonecrosis of the jaw: ntegrated analysis from three blinded active-controlled phase iii trials in cancer patients with bone metastases. Ann Oncol 2012;23:1341-1347.
55.
Weitzman R, Sauter N, Eriksen EF, et al.: Critical review: updated recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in cancer patients - May 2006. Crit Rev Oncol Hematol 2007;62:148-152.
56.
Block GA, Bone HG, Fang L, et al.: A single-dose study of denosumab in patients with various degrees of renal impairment. J Bone Miner Res 2012; 27:1471-1479.
57.
Wang W, Wang EQ, Balthasar JP: Monoclonal antibody pharmacokineticsf and pharmacodynamics. Clin Pharmacol Ther 2008;84:548-558.
58.
Kreutle V, Blum C, Meier C, et al.: Bisphosphonate induced hypocalcaemia - report of six cases and review of the literature. Swiss Med Wkly 2014;144: w13979.
59.
Milat F, Goh S, Gani LU, et al.: Prolonged hypocalcemia following denosumab therapy in metastatic hormone refractory prostate cancer. Bone 2013;55:305-308.
60.
Paul D, Vukelja SJ, Holmes FA, et al.: Letrozole plus dasatinib improves progression-free survival (PFS) in hormone receptor-positive, HER2-negative postmenopausal metastatic breast cancer (MBC) patients receiving first-line aromatase inhibitor (AI) therapy. Cancer Res 2013;73(24 suppl):abstr S3-07.
61.
Campone M, Bondarenko I, Brincat S, et al.: Phase II study of single-agent bosutinib, a Src/Abl tyrosine kinase inhibitor, in patients with locally advanced or metastatic breast cancer pretreated with chemotherapy. Ann Oncol 2012;23:610-617.
62.
Jensen AB, Wynne C, Ramirez G, et al.: The cathepsin K inhibitor odanacatib suppresses bone resorption in women with breast cancer and established bone metastases: results of a 4-week, double-blind, randomized, controlled trial. Clin Breast Cancer 2010;10:452-458.
63.
Hadji P, Coleman R, Gnant M: Bone effects of mammalian target of rapamycin (mTOR) inhibition with everolimus. Crit Rev Oncol Hematol 2013;87:101-111.
64.
Onishi T, Hayashi N, Theriault RL, et al.: Future directions of bone-targeted therapy for metastatic breast cancer. Nat Rev Clin Oncol 2010;7:641-651.
65.
Deng X, He G, Liu J, et al.: Recent advances in bone-targeted therapies of metastatic prostate cancer. Cancer Treat Rev 2014;40:730-738.
66.
Parker C, Nilsson S, Heinrich D, et al.; ALSYMPCA Investigators: Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013;369:213-223.
67.
Coleman R, Aksnes AK, Naume B, et al.: A phase IIa, nonrandomized study of radium-223 dichloride in advanced breast cancer patients with bone-dominant disease. Breast Cancer Res Treat 2014;145: 411-418.
68.
Rubini G, Nicoletti A, Rubini D, Asabella AN: Radiometabolic treatment of bone-metastasizing cancer: from 186rhenium to 223radium. Cancer Biother Radiopharm 2014;29:1-11.
69.
Coleman R, Body JJ, Aapro M, et al.; on behalf of the EGWG: Bone health in cancer patients: ESMO clinical practice guidelines. Ann Oncol 2014;25 (suppl 3):iii124-iii137.
70.
Van Poznak CH, Temin S, Yee GC, et al.; American Society of Clinical Oncology: American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol 2011;29:1221-1227.
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2014
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