Skip to main navigation menu Skip to main content Skip to site footer

Review article: Biomedical intelligence

Vol. 147 No. 2526 (2017)

Bone targeted therapies in advanced breast cancer

DOI
https://doi.org/10.4414/smw.2017.14440
Cite this as:
Swiss Med Wkly. 2017;147:w14440
Published
23.06.2017

Abstract

Bone targeted therapies are of increasing importance, not only for bone health in the clinical course of breast cancer, but recently also in the adjuvant setting as preventative, anticancer and prognosis-improving agents. It is well established that women with advanced breast cancer receive bisphosphonates or denosumab to prevent therapy-related osteoporosis. As many as 70% of these patients suffer from bone metastases and receive bone targeted agents in order to prevent skeletal related events (SREs), which are debilitating or diminish the quality of life.

A number of trials provided guidance, identifying zoledronic acid as the most efficient bisphosphonate, showing that intravenous bisphosphonate administration is superior to oral intake and illustrating the different safety profile of denosumab, which has been reported to be more beneficial than zoledronic acid in delaying the time to first and subsequent (multiple) SREs. New studies have suggested that bone targeted therapies improve rates of overall survival and contribute to preventing recurrence of breast cancer at all sites. Increased bone turnover is both a consequence and a driving factor for tumour growth, expansion, formation of bone lesions and potentially also activation of disseminated tumour cells, leading to bone relapses. We review the current knowledge of bone targeted therapies in advanced breast cancer, with a focus on new insights into their bone-preserving and antitumor activity. Current guidelines, pathology of bone metastasis, mode of action and common side effects have been summarised. We also elaborate on the use of bisphosphonates and denosumab in early breast cancer, during adjuvant therapy with aromatase inhibitors.

References

  1. Van Poznak CH. The use of bisphosphonates in patients with breast cancer. Cancer Contr. 2002;9(6):480–9.
  2. Coleman R. The use of bisphosphonates in cancer treatment. Ann N Y Acad Sci. 2011;1218(1):3–14. https://doi.org/10.1111/j.1749-6632.2010.05766.x
  3. Fizazi K, Bosserman L, Gao G, Skacel T, Markus R. Denosumab treatment of prostate cancer with bone metastases and increased urine N-telopeptide levels after therapy with intravenous bisphosphonates: results of a randomized phase II trial. J Urol. 2009;182(2):509–15, discussion 515–6. https://doi.org/10.1016/j.juro.2009.04.023
  4. Milat F, Goh S, Gani LU, Suriadi C, Gillespie MT, Fuller PJ, et al. Prolonged hypocalcemia following denosumab therapy in metastatic hormone refractory prostate cancer. Bone. 2013;55(2):305–8. https://doi.org/10.1016/j.bone.2013.04.012
  5. Siderova MV, Hristozov KH. Tolerability of once yearly intravenous infusion of Zolendronic acid in the treatment of postmenopausal osteporosis. Osteoporos Int. 2010;21:S365. Available at: http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L70226391%5Cnhttp://dx.doi.org/10.1007/s00198-010-1247-9%5Cnhttp://findit.library.jhu.edu/resolve?sid=EMBASE&issn=0937941X&id=doi:10.1007/s00198-010-1247-9&atitle=Tolerability+of+once+ye. [Internet].
  6. Povoroznyuk V, Grygorieva N, Vayda V, Dzerovych N, Balatska N. Effect of zolendronic acid in treatment of postmenopausal women with osteoporosis. Osteoporos Int. 2010;21:S759–60. Available at: http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L70338275%5Cnhttp://dx.doi.org/10.1007/s00198-010-1433-9. [Internet].
  7. Palombaro KM, Black JD, Buchbinder R, Jette DU. Effectiveness of exercise for managing osteoporosis in women postmenopause. Phys Ther. 2013;93(8):1021–5. https://doi.org/10.2522/ptj.20110476
  8. Gnant M, Pfeiler G, Dubsky P, Hubalek M, Greil R, Jakesz R, et al. Abstract S2-02: The impact of adjuvant denosumab on disease-free survival: Results from 3,425 postmenopausal patients of the ABCSG-18 trial. Cancer Res. 2016;76(4 Supplement):S2-02. https://doi.org/10.1158/1538-7445.SABCS15-S2-02
  9. Hillner BE, Ingle JN, Berenson JR, Janjan NA, Albain KS, Lipton A, et al.; American Society of Clinical Oncology Bisphosphonates Expert Panel. American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. J Clin Oncol. 2000;18(6):1378–91. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10715310. https://doi.org/10.1200/JCO.2000.18.6.1378
  10. Van Poznak CH, Temin S, Yee GC, Janjan NA, Barlow WE, Biermann JS, 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(9):1221–7. https://doi.org/10.1200/JCO.2010.32.5209
  11. NCCN. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Breast Cancer. Version 2.2013. 2013. p. 1–174.
  12. NCCN. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Breast Cancer. Version 1.2014. 2014. p. 1–74.
  13. Wood DE. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for Lung Cancer Screening. Thorac Surg Clin. 2015;25(2):185–97. https://doi.org/10.1016/j.thorsurg.2014.12.003
  14. NCCN. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Breast Cancer [Internet]. Version 1.2016. 2016. p. 1–191. Available from www.nccn.org/patients
  15. Breast G. Osteoonkologie und Knochengesundheit Osteoonkologie und. Osteoonkologie und Knochengesundheit Osteoonkologie u. 2015.
  16. Winter MC, Coleman RE. Bisphosphonates in the adjuvant treatment of breast cancer. Clin Oncol (R Coll Radiol). 2013;25(2):135–45. https://doi.org/10.1016/j.clon.2012.10.010
  17. Mathew A, Brufsky AM. The use of adjuvant bisphophonates in the treatment of early-stage breast cancer. Clin Adv Hematol Oncol. 2014;12(11):749–56.
  18. Theriault RL. Bisphosphonates: ready for use as adjuvant therapy of breast cancer? Curr Opin Obstet Gynecol. 2010;22(1):61–6. https://doi.org/10.1097/GCO.0b013e328334e43b
  19. Theriault RL. The role of bisphosphonates in breast cancer. J Natl Compr Canc Netw. 2003;1(2):232–41. doi:.https://doi.org/10.1677/erc.0.0110207
  20. Kreienberg R, Albert U-S, Follmann M, Kopp I, Kühn T, Wöckel A, et al. Interdisziplinäre S3-Leitlinie für die Diagnostik, Therapie und Nachsorge des Mammakarzinoms. Ger Cancer Soc [Internet]. 2012; 32–45. doi: https://doi.org/10.1055/s-0033-1355476
  21. Salmen J, Banys-Paluchowski M, Fehm T. Bone-Targeted Therapy. Geburtshilfe Frauenheilkd. 2015;75(6):584–7. https://doi.org/10.1055/s-0035-1546151
  22. Wilson C, Coleman RE. Adjuvant therapy with bone-targeted agents. Curr Opin Support Palliat Care. 2011;5(3):241–50. https://doi.org/10.1097/SPC.0b013e3283499c93
  23. Rosol TJ, Tannehill-Gregg SH, LeRoy BE, Mandl S, Contag CH. Animal models of bone metastasis. Cancer. 2003;97(3, Suppl):748–57. https://doi.org/10.1002/cncr.11150
  24. Virk MS, Lieberman JR. Tumor metastasis to bone. Arthritis Res Ther. 2007;9(Suppl 1):S5. https://doi.org/10.1186/ar2169
  25. Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350(16):1655–64. https://doi.org/10.1056/NEJMra030831
  26. Kingsley LA, Fournier PG, Chirgwin JM, Guise TA. Molecular biology of bone metastasis. Mol Cancer Ther. 2007;6(10):2609–17. https://doi.org/10.1158/1535-7163.MCT-07-0234
  27. Jacob K, Webber M, Benayahu D, Kleinman HK. Osteonectin promotes prostate cancer cell migration and invasion: a possible mechanism for metastasis to bone. Cancer Res. 1999;59(17):4453–7.
  28. Mercadante S. Malignant bone pain: pathophysiology and treatment. Pain. 1997;69(1):1–18. https://doi.org/10.1016/S0304-3959(96)03267-8
  29. Sabino MAC, Mantyh PW. Pathophysiology of bone cancer pain. J Support Oncol. 2005;3(1):15–24. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20637323. [Internet].
  30. Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordón-Cardo C, et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell. 2003;3(6):537–49. https://doi.org/10.1016/S1535-6108(03)00132-6
  31. Blair JM, Zhou H, Seibel MJ, Dunstan CR. Mechanisms of disease: roles of OPG, RANKL and RANK in the pathophysiology of skeletal metastasis. Nat Clin Pract Oncol. 2006;3(1):41–9. https://doi.org/10.1038/ncponc0381
  32. Weilbaecher KN, Guise TA, McCauley LK. Cancer to bone: a fatal attraction. Nat Rev Cancer. 2011;11(6):411–25. https://doi.org/10.1038/nrc3055
  33. Twycross R, Harcourt J, Bergl S. A survey of pain in patients with advanced cancer. J Pain Symptom Manage. 1996;12(5):273–82. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8942122. https://doi.org/10.1016/S0885-3924(96)00149-2
  34. Twycross RG, Lack SA. Symptom control in far advanced cancer: pain relief. Symptom Control Far Adv Cancer Pain Reli Twycross Rg, Lack Sa, London, Pitman Publ. 1983.
  35. Grond S, Zech D, Diefenbach C, Radbruch L, Lehmann KA. Assessment of cancer pain: a prospective evaluation in 2266 cancer patients referred to a pain service. Pain. 1996;64(1):107–14. https://doi.org/10.1016/0304-3959(95)00076-3
  36. Falk S, Bannister K, Dickenson AH. Cancer pain physiology. Br J Pain. 2014;8(4):154–62. https://doi.org/10.1177/2049463714545136
  37. Schwei MJ, Honore P, Rogers SD, Salak-Johnson JL, Finke MP, Ramnaraine ML, et al. Neurochemical and cellular reorganization of the spinal cord in a murine model of bone cancer pain. J Neurosci. 1999;19(24):10886–97.
  38. Honore P, Mantyh PW. Bone cancer pain: from mechanism to model to therapy. Pain Med. 2000;1(4):303–9. https://doi.org/10.1046/j.1526-4637.2000.00047.x
  39. Russell RGG. Bisphosphonates: mode of action and pharmacology. Pediatrics. 2007;119(Suppl 2):S150–62. https://doi.org/10.1542/peds.2006-2023H
  40. Rogers MJ, Frith JC, Luckman SP, Coxon FP, Benford HL, Mönkkönen J, et al. Molecular mechanisms of action of bisphosphonates. Bone. 1999;24(5, Suppl):73S–9S. https://doi.org/10.1016/S8756-3282(99)00070-8
  41. Roelofs AJ, Ebetino FH, Reszka AA, Russell RGG, Rogers MJ. Chapter 81 - Bisphosphonates: Mechanisms of Action. Principles of Bone Biology (Third Edition) [Internet]. 2008. p. 1737–67. doi: http://dx.doi.org/https://doi.org/10.1016/B978-0-12-373884-4.00095-1
  42. Coxon FP, Helfrich MH, Van’t Hof R, Sebti S, Ralston SH, Hamilton A, et al. Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298. J Bone Miner Res. 2000;15(8):1467–76. https://doi.org/10.1359/jbmr.2000.15.8.1467
  43. Roodman GD. Cell biology of the osteoclast. Exp Hematol. 1999;27(8):1229–41. https://doi.org/10.1016/S0301-472X(99)00061-2
  44. Diel IJ. Bisphosphonates in breast cancer patients with bone metastases. Breast Care (Basel). 2010;5(5):306–11. https://doi.org/10.1159/000322043
  45. Green JR. Chemical and biological prerequisites for novel bisphosphonate molecules: results of comparative preclinical studies. Semin Oncol. 2001;28(2, Suppl 6):4–10. https://doi.org/10.1016/S0093-7754(01)90259-3
  46. Boissier S, Ferreras M, Peyruchaud O, Magnetto S, Ebetino FH, Colombel M, et al. Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res. 2000;60(11):2949–54.
  47. Reinholz GG, Getz B, Pederson L, Sanders ES, Subramaniam M, Ingle JN, et al. Bisphosphonates directly regulate cell proliferation, differentiation, and gene expression in human osteoblasts. Cancer Res. 2000;60(21):6001–7.
  48. Hofmann A, Ritz U, Hessmann MH, Schmid C, Tresch A, Rompe JD, et al. Cell viability, osteoblast differentiation, and gene expression are altered in human osteoblasts from hypertrophic fracture non-unions. Bone. 2008;42(5):894–906. https://doi.org/10.1016/j.bone.2008.01.013
  49. Russell RGG. Bisphosphonates: the first 40 years. Bone. 2011;49(1):2–19. https://doi.org/10.1016/j.bone.2011.04.022
  50. Bellido T, Plotkin LI. Novel actions of bisphosphonates in bone: preservation of osteoblast and osteocyte viability. Bone. 2011;49(1):50–5. https://doi.org/10.1016/j.bone.2010.08.008
  51. Clézardin P, Benzaïd I, Croucher PI. Bisphosphonates in preclinical bone oncology. Bone. 2011;49(1):66–70. https://doi.org/10.1016/j.bone.2010.11.017
  52. Boyce BF, Xing L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys. 2008;473(2):139–46. https://doi.org/10.1016/j.abb.2008.03.018
  53. Anandarajah AP, Schwarz EM. Anti-RANKL therapy for inflammatory bone disorders: Mechanisms and potential clinical applications. J Cell Biochem. 2006;97(2):226–32. https://doi.org/10.1002/jcb.20674
  54. Stopeck AT, Lipton A, Body J-J, Steger GG, Tonkin K, de Boer RH, 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(35):5132–9. https://doi.org/10.1200/JCO.2010.29.7101
  55. Thiébaud D, Sauty A, Burckhardt P, Leuenberger P, Sitzler L, Green JR, et al. An in vitro and in vivo study of cytokines in the acute-phase response associated with bisphosphonates. Calcif Tissue Int. 1997;61(5):386–92. https://doi.org/10.1007/s002239900353
  56. Lin JH. Bisphosphonates: a review of their pharmacokinetic properties. Bone. 1996;18(2):75–85. https://doi.org/10.1016/8756-3282(95)00445-9
  57. Moshage H. Cytokines and the hepatic acute phase response. J Pathol. 1997;181(3):257–66. https://doi.org/10.1002/(SICI)1096-9896(199703)181:3<257::AID-PATH756>3.0.CO;2-U
  58. Wark JD, Bensen W, Recknor C, Ryabitseva O, Chiodo J, 3rd, Mesenbrink P, et al. Treatment with acetaminophen/paracetamol or ibuprofen alleviates post-dose symptoms related to intravenous infusion with zoledronic acid 5 mg. Osteoporos Int. 2012;23(2):503–12. https://doi.org/10.1007/s00198-011-1563-8
  59. Abrahamsen B. Adverse effects of bisphosphonates. Calcif Tissue Int. 2010;86(6):421–35. https://doi.org/10.1007/s00223-010-9364-1
  60. Diel IJ, Bergner R, Grötz KA. Adverse effects of bisphosphonates: current issues. J Support Oncol. 2007;5(10):475–82. Available at: https://www.researchgate.net/publication/5610810_Adverse_effects_of_bisphosphonates_current_issues_J_Support_Oncol_5475-482. [Internet].
  61. Kennel KA, Drake MT. Adverse effects of bisphosphonates: implications for osteoporosis management. Mayo Clin Proc. 2009;84(7):632–7, quiz 638. https://doi.org/10.1016/S0025-6196(11)60752-0
  62. Nieto JE, Maher O, Stanley SD, Knych HK, Snyder JR. Pharmacokinetics, pharmacodynamics, and safety of zoledronic acid in horses. Am J Vet Res. 2013;74(4):550–6. https://doi.org/10.2460/ajvr.74.4.550
  63. Weiss HM, Pfaar U, Schweitzer A, Wiegand H, Skerjanec A, Schran H. Biodistribution and plasma protein binding of zoledronic acid. Drug Metab Dispos. 2008;36(10):2043–9. https://doi.org/10.1124/dmd.108.021071
  64. Perazella MA, Markowitz GS. Bisphosphonate nephrotoxicity. Kidney Int. 2008;74(11):1385–93. https://doi.org/10.1038/ki.2008.356
  65. Edwards BJ, Usmani S, Raisch DW, McKoy JM, Samaras AT, Belknap SM, et al. Acute kidney injury and bisphosphonate use in cancer: a report from the research on adverse drug events and reports (RADAR) project. J Oncol Pract. 2013;9(2):101–6. https://doi.org/10.1200/JOP.2011.000486
  66. Markowitz GS, Fine PL, Stack JI, Kunis CL, Radhakrishnan J, Palecki W, et al. Toxic acute tubular necrosis following treatment with zoledronate (Zometa). Kidney Int. 2003;64(1):281–9. https://doi.org/10.1046/j.1523-1755.2003.00071.x
  67. Markowitz GS, Nasr SH, Stokes MB, D’Agati VD. Treatment with IFN-alpha, -beta, or -gamma is associated with collapsing focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2010;5(4):607–15. https://doi.org/10.2215/CJN.07311009
  68. Markowitz GS, Appel GB, Fine PL, Fenves AZ, Loon NR, Jagannath S, et al. Collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate. J Am Soc Nephrol. 2001;12(6):1164–72.
  69. Jackson GH. Renal safety of ibandronate. Oncologist. 2005;10(Suppl 1):14–8. https://doi.org/10.1634/theoncologist.10-90001-14
  70. Berenson JR, Vescio RA, Rosen LS, VonTeichert JM, Woo M, Swift R, 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;7(3):478–85.
  71. Scott LJ, Muir VJ. Denosumab: in the prevention of skeletal-related events in patients with bone metastases from solid tumours. Drugs. 2011;71(8):1059–69. https://doi.org/10.2165/11207370-000000000-00000
  72. Body J-J, Bone HG, de Boer RH, Stopeck A, Van Poznak C, Damião R, et al. Hypocalcaemia in patients with metastatic bone disease treated with denosumab. Eur J Cancer. 2015;51(13):1812–21. https://doi.org/10.1016/j.ejca.2015.05.016
  73. Kreutle V, Blum C, Meier C, Past M, Müller B, Schütz P, et al. Bisphosphonate induced hypocalcaemia - report of six cases and review of the literature. Swiss Med Wkly. 2014;144:w13979. doi:.https://doi.org/10.4414/smw.2014.13979
  74. Do W-S, Park J-K, Park M-I, Kim H-S, Kim S-H, Lee D-H. Bisphosphonate-induced Severe Hypocalcemia - A Case Report -. J Bone Metab. 2012;19(2):139–45. https://doi.org/10.11005/jbm.2012.19.2.139
  75. Buonerba C, Caraglia M, Malgieri S, Perri F, Bosso D, Federico P, et al. Calcitriol: a better option than vitamin D in denosumab-treated patients with kidney failure? Expert Opin Biol Ther. 2013;13(2):149–51. https://doi.org/10.1517/14712598.2012.756470
  76. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic [1]. J Oral Maxillofac Surg. 2003;61(9):1115–7. https://doi.org/10.1016/S0278-2391(03)00720-1
  77. Junquera L, Gallego L. Nonexposed bisphosphonate-related osteonecrosis of the jaws: another clinical variant? J Oral Maxillofac Surg. 2008;66(7):1516–7. https://doi.org/10.1016/j.joms.2008.02.012
  78. Campisi G, Fedele S, Fusco V, Pizzo G, Di Fede O, Bedogni A. Epidemiology, clinical manifestations, risk reduction and treatment strategies of jaw osteonecrosis in cancer patients exposed to antiresorptive agents. Future Oncol. 2014;10(2):257–75. https://doi.org/10.2217/fon.13.211
  79. Sun L, Yu S. Efficacy and safety of denosumab versus zoledronic acid in patients with bone metastases: a systematic review and meta-analysis. Am J Clin Oncol. 2013;36(4):399–403. https://doi.org/10.1097/COC.0b013e31824be20e
  80. Hoff AO, Toth BB, Altundag K, Johnson MM, Warneke CL, Hu M, et al. Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res. 2008;23(6):826–36. https://doi.org/10.1359/jbmr.080205
  81. Ibrahim T, Barbanti F, Giorgio-Marrano G, Mercatali L, Ronconi S, Vicini C, et al. Osteonecrosis of the jaw in patients with bone metastases treated with bisphosphonates: a retrospective study. Oncologist. 2008;13(3):330–6. https://doi.org/10.1634/theoncologist.2007-0159
  82. Coleman RE. Bisphosphonates in breast cancer. Ann Oncol. 2005;16(5):687–95. https://doi.org/10.1093/annonc/mdi162
  83. Wong MH, Stockler MR, Pavlakis N. Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst Rev. 2012;2(2):CD003474. doi:. [Internet].https://doi.org/10.1002/14651858.CD003474.pub3
  84. Prommer EE. Toxicity of bisphosphonates. J Palliat Med. 2009;12(11):1061–5. https://doi.org/10.1089/jpm.2009.9936
  85. Colucci A, Modorati G, Miserocchi E, Di Matteo F, Rama P. Anterior uveitis complicating zoledronic acid infusion. Ocul Immunol Inflamm. 2009;17(4):267–8. https://doi.org/10.1080/09273940902916111
  86. Fraunfelder FW, Fraunfelder FT. Adverse ocular drug reactions recently identified by the National Registry of Drug-Induced Ocular Side Effects. Ophthalmology. 2004;111(7):1275–9. https://doi.org/10.1016/j.ophtha.2003.12.052
  87. Tanvetyanon T, Stiff PJ. Management of the adverse effects associated with intravenous bisphosphonates. Ann Oncol. 2006;17(6):897–907. https://doi.org/10.1093/annonc/mdj105
  88. Steger GG, Bartsch R. Denosumab for the treatment of bone metastases in breast cancer: evidence and opinion. Ther Adv Med Oncol. 2011;3(5):233–43. https://doi.org/10.1177/1758834011412656
  89. Lenart BA, Lorich DG, Lane JM. Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. N Engl J Med. 2008;358(12):1304–6. https://doi.org/10.1056/NEJMc0707493
  90. Gartrell BA, Coleman RE, Fizazi K, Miller K, Saad F, Sternberg CN, et al. Toxicities following treatment with bisphosphonates and receptor activator of nuclear factor-κB ligand inhibitors in patients with advanced prostate cancer. Eur Urol. 2014;65(2):278–86. https://doi.org/10.1016/j.eururo.2013.05.015
  91. Hadji P, Body JJ, Aapro MS, Brufsky A, Coleman RE, Guise T, et al. Practical guidance for the management of aromatase inhibitor-associated bone loss. Ann Oncol. 2008;19(8):1407–16. https://doi.org/10.1093/annonc/mdn164
  92. Hadji P, Aapro MS, Body JJ, Bundred NJ, Brufsky A, Coleman RE, et al. Management of aromatase inhibitor-associated bone loss in postmenopausal women with breast cancer: practical guidance for prevention and treatment. Ann Oncol. 2011;22(12):2546–55. https://doi.org/10.1093/annonc/mdr017
  93. Van Poznak C, Hannon RA, Mackey JR, Campone M, Apffelstaedt JP, Clack G, et al. Prevention of aromatase inhibitor-induced bone loss using risedronate: the SABRE trial. J Clin Oncol. 2010;28(6):967–75. https://doi.org/10.1200/JCO.2009.24.5902
  94. Lester JE, Dodwell D, Brown JE, Purohit OP, Gutcher SA, Ellis SP, et al. Prevention of anastrozole induced bone loss with monthly oral ibandronate: Final 5 year results from the ARIBON trial. J Bone Oncol. 2012;1(2):57–62. https://doi.org/10.1016/j.jbo.2012.06.002
  95. Brufsky A, Bundred N, Coleman R, Lambert-Falls R, Mena R, Hadji P, et al.; Z-FAST and ZO-FAST Study Groups. Integrated analysis of zoledronic acid for prevention of aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole. Oncologist. 2008;13(5):503–14. Available at: http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L351872868%5Cnhttp://theoncologist.alphamedpress.org/cgi/reprint/13/5/503%5Cnhttp://dx.doi.org/10.1634/theoncologist.2007-0206%5Cnhttp://resolver.ebscohost.com/openurl?custid=s3733374&auth. https://doi.org/10.1634/theoncologist.2007-0206
  96. Brufsky A, Harker WG, Beck JT, Carroll R, Tan-Chiu E, Seidler C, et al. Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopausal women with early breast cancer. J Clin Oncol. 2007;25(7):829–36. https://doi.org/10.1200/JCO.2005.05.3744
  97. Pritchard KI, Goss PE, Shepherd L. The extended adjuvant NCIC CTG MA.17 trials: initial and rerandomization studies. Breast. 2006;15(Suppl 1):S14–20. https://doi.org/10.1016/j.breast.2006.01.002
  98. Chlebowski RT, Chen Z, Cauley JA, Anderson G, Rodabough RJ, McTiernan A, et al. Oral bisphosphonate use and breast cancer incidence in postmenopausal women. J Clin Oncol. 2010;28(22):3582–90. https://doi.org/10.1200/JCO.2010.28.2095
  99. Prentice RL, Anderson GL. The women’s health initiative: lessons learned. Annu Rev Public Health. 2008;29(1):131–50. https://doi.org/10.1146/annurev.publhealth.29.020907.090947
  100. Aft R, Naughton M, Trinkaus K, Watson M, Ylagan L, Chavez-MacGregor M, 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(5):421–8. https://doi.org/10.1016/S1470-2045(10)70054-1
  101. Clézardin P. Bisphosphonates’ antitumor activity: an unravelled side of a multifaceted drug class. Bone. 2011;48(1):71–9. https://doi.org/10.1016/j.bone.2010.07.016
  102. Stresing V, Fournier PG, Bellahcène A, Benzaïd I, Mönkkönen H, Colombel M, et al. Nitrogen-containing bisphosphonates can inhibit angiogenesis in vivo without the involvement of farnesyl pyrophosphate synthase. Bone. 2011;48(2):259–66. https://doi.org/10.1016/j.bone.2010.09.035
  103. Stresing V, Daubiné F, Benzaid I, Mönkkönen H, Clézardin P. Bisphosphonates in cancer therapy. Cancer Lett. 2007;257(1):16–35. https://doi.org/10.1016/j.canlet.2007.07.007
  104. Tang X, Zhang Q, Shi S, Yen Y, Li X, Zhang Y, 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(1):90–103. https://doi.org/10.1002/ijc.24710
  105. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3(10):721–32. https://doi.org/10.1038/nrc1187
  106. Lee J-W, Bae S-H, Jeong J-W, Kim S-H, Kim K-W. Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions. Exp Mol Med. 2004;36(1):1–12. https://doi.org/10.1038/emm.2004.1
  107. Neville-Webbe HL, Gnant M, Coleman RE. Potential anticancer properties of bisphosphonates. Semin Oncol. 2010;37(Suppl 1):S53–65. https://doi.org/10.1053/j.seminoncol.2010.06.008
  108. Gnant M, Clézardin P. Direct and indirect anticancer activity of bisphosphonates: a brief review of published literature. Cancer Treat Rev. 2012;38(5):407–15. https://doi.org/10.1016/j.ctrv.2011.09.003
  109. Santini D, Schiavon G, Vincenzi B, Gaeta L, Pantano F, Russo A, 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(4):e19234. https://doi.org/10.1371/journal.pone.0019234
  110. Fata JE, Kong Y-Y, Li J, Sasaki T, Irie-Sasaki J, Moorehead RA, et al. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell. 2000;103(1):41–50. https://doi.org/10.1016/S0092-8674(00)00103-3
  111. Gonzalez-Suarez E, Jacob AP, Jones J, Miller R, Roudier-Meyer MP, Erwert R, et al. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature. 2010;468(7320):103–7. https://doi.org/10.1038/nature09495
  112. Tan W, Zhang W, Strasner A, Grivennikov S, Cheng JQ, Hoffman RM, et al. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature. 2011;470(7335):548–53. https://doi.org/10.1038/nature09707
  113. Weigelt B, Peterse JL, van ’t Veer LJ. Breast cancer metastasis: markers and models. Nat Rev Cancer. 2005;5(8):591–602. https://doi.org/10.1038/nrc1670
  114. Guise TA. Breast cancer bone metastases: it’s all about the neighborhood. Cell. 2013;154(5):957–9. https://doi.org/10.1016/j.cell.2013.08.020
  115. Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 2006;12(20 Pt 2):6243s–9s. https://doi.org/10.1158/1078-0432.CCR-06-0931
  116. Clézardin P. Therapeutic targets for bone metastases in breast cancer. Breast Cancer Res. 2011;13(2):207. https://doi.org/10.1186/bcr2835
  117. Costelloe CM, Rohren EM, Madewell JE, Hamaoka T, Theriault RL, Yu TK, et al. Imaging bone metastases in breast cancer: techniques and recommendations for diagnosis. Lancet Oncol. 2009;10(6):606–14. https://doi.org/10.1016/S1470-2045(09)70088-9
  118. Clemons M, Gelmon KA, Pritchard KI, Paterson AHG. Bone-targeted agents and skeletal-related events in breast cancer patients with bone metastases: the state of the art. Curr Oncol. 2012;19(5):259–68. https://doi.org/10.3747/co.19.1011
  119. Yong M, Jensen AÖ, Jacobsen JB, Nørgaard M, Fryzek JP, Sørensen HT. Survival in breast cancer patients with bone metastases and skeletal-related events: a population-based cohort study in Denmark (1999-2007). Breast Cancer Res Treat. 2011;129(2):495–503. https://doi.org/10.1007/s10549-011-1475-5
  120. Body JJ, Diel IJ, Lichinitzer M, Lazarev A, Pecherstorfer M, Bell R, 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(6):1133–7. https://doi.org/10.1038/sj.bjc.6601663
  121. Kohno N, Aogi K, Minami H, Nakamura S, Asaga T, Iino Y, 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(15):3314–21. https://doi.org/10.1200/JCO.2005.05.116
  122. Lipton A, Theriault RL, Hortobagyi GN, Simeone J, Knight RD, Mellars K, 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(5):1082–90. https://doi.org/10.1002/(SICI)1097-0142(20000301)88:5<1082::AID-CNCR20>3.0.CO;2-Z
  123. Theriault RL, Lipton A, Hortobagyi GN, Leff R, Glück S, Stewart JF, 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(3):846–54. https://doi.org/10.1200/JCO.1999.17.3.846
  124. Tripathy D, Lichinitzer M, Lazarev A, MacLachlan SA, Apffelstaedt J, Budde M, et al.; MF 4434 Study Group. 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(5):743–50. https://doi.org/10.1093/annonc/mdh173
  125. Barrett-Lee P, Casbard A, Abraham J, Hood K, Coleman R, Simmonds P, 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(1):114–22. https://doi.org/10.1016/S1470-2045(13)70539-4
  126. Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, Mackey J, 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;7(5):377–87. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11693896. [Internet].
  127. Rosen LS, Gordon DH, Dugan W, Jr, Major P, Eisenberg PD, Provencher L, 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(1):36–43. https://doi.org/10.1002/cncr.11892
  128. 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(6, Suppl 1):S25–31. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12562048. https://doi.org/10.1097/00000421-200212001-00005
  129. Vadhan-Raj S, von Moos R, Fallowfield LJ, Patrick DL, Goldwasser F, Cleeland CS, et al. Clinical benefit in patients with metastatic bone disease: results of a phase 3 study of denosumab versus zoledronic acid. Ann Oncol. 2012;23(12):3045–51. https://doi.org/10.1093/annonc/mds175
  130. Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, 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(9):1125–32. https://doi.org/10.1200/JCO.2010.31.3304
  131. Rosen LS, Gordon D, Tchekmedyian NS, Yanagihara R, Hirsh V, Krzakowski M, et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors. Cancer. 2004;100(12):2613–21. https://doi.org/10.1002/cncr.20308
  132. Scagliotti GV, Hirsh V, Siena S, Henry DH, Woll PJ, Manegold C, et al. Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study. J Thorac Oncol. 2012;7(12):1823–9. https://doi.org/10.1097/JTO.0b013e31826aec2b
  133. Saad F, Brown JE, Van Poznak C, Ibrahim T, Stemmer SM, Stopeck AT, et al. Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol. 2012;23(5):1341–7. https://doi.org/10.1093/annonc/mdr435
  134. Ellis GK, Bone HG, Chlebowski R, Paul D, Spadafora S, Smith J, et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol. 2008;26(30):4875–82. https://doi.org/10.1200/JCO.2008.16.3832
  135. Fontana A, Delmas PD. Markers of bone turnover in bone metastases. Cancer. 2000;88(12, Suppl):2952–60. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10898339. https://doi.org/10.1002/1097-0142(20000615)88:12+<2952::AID-CNCR11>3.0.CO;2-M
  136. Delmas PD. Biochemical markers of bone turnover. J Bone Miner Res. 1993;8(S2, Suppl 2):S549–55. Available at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8122526. https://doi.org/10.1002/jbmr.5650081323
  137. Naylor K, Eastell R. Bone turnover markers: use in osteoporosis. Nat Rev Rheumatol. 2012;8(7):379–89. https://doi.org/10.1038/nrrheum.2012.86
  138. Szulc P, Bauer DC, Eastell R. Biochemical Markers of Bone Turnover in Osteoporosis. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism [Internet]. 2013. p. 297–306. doi: https://doi.org/10.1002/9781118453926.ch35
  139. Szulc P. The role of bone turnover markers in monitoring treatment in postmenopausal osteoporosis. Clin Biochem. 2012;45(12):907–19. https://doi.org/10.1016/j.clinbiochem.2012.01.022
  140. Vasikaran S, Eastell R, Bruyère O, Foldes AJ, Garnero P, Griesmacher A, et al.; IOF-IFCC Bone Marker Standards Working Group. Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int. 2011;22(2):391–420. https://doi.org/10.1007/s00198-010-1501-1
  141. Garnero P. Markers of bone turnover in prostate cancer. Cancer Treat Rev. 2001;27(3):187–92, discussion 193–6. https://doi.org/10.1053/ctrv.2000.0213
  142. Eastell R, Christiansen C, Grauer A, Kutilek S, Libanati C, McClung MR, et al. Effects of denosumab on bone turnover markers in postmenopausal osteoporosis. J Bone Miner Res. 2011;26(3):530–7. https://doi.org/10.1002/jbmr.251
  143. Seibel MJ. Biochemical markers of bone turnover: part I: biochemistry and variability. Clin Biochem Rev. 2005;26(4):97–122.
  144. Seibel MJ. Biochemical markers of bone turnover part II: clinical applications in the management of osteoporosis. Clin Biochem Rev. 2006;27(3):123–38. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1579289&tool=pmcentrez&rendertype=abstract. [Internet].
  145. Coleman R, Costa L, Saad F, Cook R, Hadji P, Terpos E, et al. Consensus on the utility of bone markers in the malignant bone disease setting. Crit Rev Oncol Hematol. 2011;80(3):411–32. https://doi.org/10.1016/j.critrevonc.2011.02.005
  146. Kanis JA, McCloskey EV. Bone turnover and biochemical markers in malignancy. Cancer. 1997;80(8, Suppl):1538–45. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9362420. https://doi.org/10.1002/(SICI)1097-0142(19971015)80:8+<1538::AID-CNCR3>3.0.CO;2-G
  147. Hlaing TT, Compston JE. Biochemical markers of bone turnover - uses and limitations. Ann Clin Biochem. 2014;51(2):189–202. https://doi.org/10.1177/0004563213515190
  148. Lipton A, Cook R, Saad F, Major P, Garnero P, Terpos E, 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(1):193–201. https://doi.org/10.1002/cncr.23529
  149. Berenson JR, Vescio R, Henick K, Nishikubo C, Rettig M, Swift RA, 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. https://doi.org/10.1002/1097-0142(20010101)91:1<144::AID-CNCR19>3.0.CO;2-Q
  150. Lipton A. Implications of bone metastases and the benefits of bone-targeted therapy. Semin Oncol. 2010;37(Suppl 2):S15–29. https://doi.org/10.1053/j.seminoncol.2010.10.002
  151. Singer FR, Eyre DR. Using biochemical markers of bone turnover in clinical practice. Cleve Clin J Med. 2008;75(10):739–50. https://doi.org/10.3949/ccjm.75.10.739
  152. Fizazi K, Lipton A, Mariette X, Body JJ, Rahim Y, Gralow JR, 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(10):1564–71. https://doi.org/10.1200/JCO.2008.19.2146
  153. Talreja DB. Importance of antiresorptive therapies for patients with bone metastases from solid tumors. Cancer Manag Res. 2012;4:287–97. https://doi.org/10.2147/CMAR.S33983
  154. Jacob L, Hadji P, Kostev K. Age-related differences in persistence with bisphosphonates in women with metastatic breast cancer. J Bone Oncol. 2016;5(2):63–6. https://doi.org/10.1016/j.jbo.2016.02.006
  155. Partridge AH, Wang PS, Winer EP, Avorn J. Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol. 2003;21(4):602–6. https://doi.org/10.1200/JCO.2003.07.071
  156. Gallagher AM, Rietbrock S, Olson M, van Staa TP. Fracture outcomes related to persistence and compliance with oral bisphosphonates. J Bone Miner Res. 2008;23(10):1569–75. https://doi.org/10.1359/jbmr.080510
  157. Penning-van Beest FJA, Goettsch WG, Erkens JA, Herings RMC. Determinants of persistence with bisphosphonates: a study in women with postmenopausal osteoporosis. Clin Ther. 2006;28(2):236–42. https://doi.org/10.1016/j.clinthera.2006.01.002
  158. Balkrishnan R. Predictors of medication adherence in the elderly. Clin Ther. 1998;20(4):764–71. https://doi.org/10.1016/S0149-2918(98)80139-2
  159. He W, Fang F, Varnum C, Eriksson M, Hall P, Czene K. Predictors of Discontinuation of Adjuvant Hormone Therapy in Patients With Breast Cancer. J Clin Oncol. 2015;33(20):2262–9. https://doi.org/10.1200/JCO.2014.59.3673
  160. Sidwell AI, Wilkinson TJ, Hanger HC. Secondary prevention of fractures in older people: evaluation of a protocol for the investigation and treatment of osteoporosis. Intern Med J. 2004;34(3):129–32. https://doi.org/10.1111/j.1444-0903.2004.00554.x
  161. Bell JS, Blacker N, Edwards S, Frank O, Alderman CP, Karan L, et al. Osteoporosis - pharmacological prevention and management in older people. Aust Fam Physician. 2012;41(3):110–8.