Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Bone metastasis in prostate cancer: emerging therapeutic strategies

A Correction to this article was published on 30 September 2011

This article has been updated


Metastatic bone disease (MBD) in advanced-stage cancer increases the risk of intractable bone pain, pathological skeletal fracture, spinal-cord compression and decreased survival. The disease manifestation course during MBD is largely driven by homotypic and heterotypic cellular interactions between invading tumor cells, osteoblasts and osteoclasts. The outcome is a sustained vicious cycle of bone matrix remodeling. Osteoclast-mediated bone degradation and subsequent bone loss are the hallmarks of secondary bone metastases from most solid tumors. An additional complication in prostate cancer is the predominance of osteosclerotic lesions typified by inappropriate bone production. Successful therapeutic strategies for the treatment of osteolytic MBD include the administration of intravenous bisphosphonates or subcutaneous inhibitors of receptor activator of nuclear factor κB ligand (RANKL). Inhibitors of SRC and cABL kinases and cathepsin K are under clinical investigation as potential anti-osteolytics. In contrast to the rapid progress being made in the development of anti-osteolytic therapies, the treatment of osteosclerotic MBD remains restricted to palliative radiotherapy for symptomatic solitary lesions and systemic taxane-based chemotherapy for widespread multiple lesions. This Review discusses the complex pathology of bone lesions in metastatic castration-resistant prostate cancer and focuses on new therapeutic strategies and targets that are emerging in preclinical studies.

Key Points

  • Treatment of metastatic bone disease (MBD) in men with castration-resistant prostate cancer (CRPC) is complicated by osteolytic (bone-degrading), osteosclerotic (bone-forming) and mixed osteolytic and osteosclerotic lesions

  • It is essential to study the complex interactions between tumor cells, osteoblasts and osteoclasts in the bone metastatic niche using clinically relevant models to allow development of targeted treatments

  • Bisphosphonates are used as a palliative treatment to protect against the osteolytic effects of MBD; to date, clodronate has been shown to improve survival of CRPC patients with MBD

  • Denosumab, the RANKL inhibitor, has been approved for the treatment of MBD that originate from solid tumors; however, its efficacy in MBD associated with CRPC is unclear

  • Inhibition of Endothelin A receptor and systemic radionuclide therapy target osteoblast activity and are under investigation for their clinical impact in CRPC

  • Improved understanding of the molecular mechanisms of dysregulated type-I collagen deposition in MBD will open up new avenues for therapeutic exploitation

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Bone-targeted therapy in metastatic lesions.
Figure 2: Disruption of the TGF-β1/TGF-βR1/ENDO180 pathway at the osteolytic tumor–bone stromal interface.

Change history

  • 05 August 2011

    In the version of this article initially published online the title of Table 1 should have read "Completed and ongoing trials with bisphosphonates" and it should have stated that trial NCT00330759 excluded patients with prostate cancer. In Table 2, it should have been defined that patients enrolled in trial NCT00089674 did not present with any type of metastases and that the secondary end point was fractures. It should have also stated that trial NCT00321620 assessed denosumab versus zoledronic acid. The errors have been corrected for the HTML and PDF versions of the article.


  1. 1

    Mundy, G. R. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat. Rev. Cancer 2, 584–593 (2002).

    CAS  PubMed  Google Scholar 

  2. 2

    Eisenberger, M. A. & Walsh, P. C. Early androgen deprivation for prostate cancer? N. Engl. J. Med. 341, 1837–1838 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Smith, M. R., Brown, G. A., Saad, F. New opportunities in the management of prostate cancer-related bone complications. Urologic Oncology: Seminars and Original Investigations 27 (Suppl. 1) S1–S20 (2009).

    Google Scholar 

  4. 4

    Janjan, N. et al. Therapeutic guidelines for the treatment of bone metastasis: a report from the American College of Radiology Appropriateness Criteria Expert Panel on Radiation Oncology. J. Palliat. Med. 12, 417–426 (2009).

    PubMed  Google Scholar 

  5. 5

    Tannock, I. F. et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N. Engl. J. Med. 351, 1502–1512 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Berthold, D. R. et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J. Clin. Oncol. 26, 242–245 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Petrylak, D. P. et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N. Engl. J. Med. 351, 1513–1520 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Seruga, B., Ocana, A. & Tannock, I. F. Drug resistance in metastatic castration-resistant prostate cancer. Nat. Rev. Clin. Oncol. 8, 12–23 (2011).

    CAS  PubMed  Google Scholar 

  9. 9

    Zaidi, M. Skeletal remodeling in health and disease. Nat. Med. 13, 791–801 (2007).

    CAS  PubMed  Google Scholar 

  10. 10

    Ory, S., Brazier, H., Pawlak, G. & Blangy, A. Rho GTPases in osteoclasts: orchestrators of podosome arrangement. Eur. J. Cell Biol. 87, 469–477 (2008).

    CAS  PubMed  Google Scholar 

  11. 11

    Heckel, T. et al. Src-dependent repression of ARF6 is required to maintain podosome-rich sealing zones in bone-digesting osteoclasts. Proc. Natl Acad. Sci. USA 106, 1451–1456 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Garnero, P. et al. The collagenolytic activity of cathepsin K is unique among mammalian proteinases. J. Biol. Chem. 273, 32347–32352 (1998).

    CAS  PubMed  Google Scholar 

  13. 13

    Coxon, F. P. & Taylor, A. Vesicular trafficking in osteoclasts. Semin. Cell Dev. Biol. 19, 424–433 (2008).

    CAS  PubMed  Google Scholar 

  14. 14

    Leblond, C. P. Synthesis and secretion of collagen by cells of connective tissue, bone, and dentin. Anat. Rec. 224, 123–138 (1989).

    CAS  PubMed  Google Scholar 

  15. 15

    Rohde, M. & Mayer, H. Exocytotic process as a novel model for mineralization by osteoblasts in vitro and in vivo determined by electron microscopic analysis. Calcif. Tissue Int. 80, 323–336 (2007).

    CAS  PubMed  Google Scholar 

  16. 16

    Lacey, D. L. et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93, 165–176 (1998).

    CAS  Google Scholar 

  17. 17

    Boyle, W. J., Simonet, W. S. & Lacey, D. L. Osteoclast differentiation and activation. Nature 423, 337–342 (2003).

    CAS  Google Scholar 

  18. 18

    Honore, P. et al. Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord. Nat. Med. 6, 521–528 (2000).

    CAS  PubMed  Google Scholar 

  19. 19

    Clines, G. A. & Guise, T. A. Molecular mechanisms and treatment of bone metastasis. Expert Rev. Mol. Med. 10, e7 (2008).

    PubMed  Google Scholar 

  20. 20

    Rose, A. A. & Siegel, P. M. Breast cancer-derived factors facilitate osteolytic bone metastasis. Bull. Cancer 93, 931–943 (2006).

    CAS  PubMed  Google Scholar 

  21. 21

    Cereceda, L. E., Flechon, A. & Droz, J. P. Management of vertebral metastases in prostate cancer: a retrospective analysis in 119 patients. Clin. Prostate Cancer 2, 34–40 (2003).

    PubMed  Google Scholar 

  22. 22

    Cheville, J. C. et al. Metastatic prostate carcinoma to bone: clinical and pathologic features associated with cancer-specific survival. Cancer 95, 1028–1036 (2002).

    PubMed  Google Scholar 

  23. 23

    Brown, J. E. et al. Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J. Natl Cancer Inst. 97, 59–69 (2005).

    CAS  PubMed  Google Scholar 

  24. 24

    Coleman, R. E. et al. 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 (2005).

    CAS  Google Scholar 

  25. 25

    Atley, L. M., Mort, J. S., Lalumiere, M. & Eyre, D. R. Proteolysis of human bone collagen by cathepsin K: characterization of the cleavage sites generating by cross-linked N.-telopeptide neoepitope. Bone 26, 241–247 (2000).

    CAS  PubMed  Google Scholar 

  26. 26

    Brown, J. E. & Sim, S. Evolving role of bone biomarkers in castration-resistant prostate cancer. Neoplasia 12, 685–696 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Saad, F. & Sternberg, C. N. Multidisciplinary management of bone complications in prostate cancer and optimizing outcomes of bisphosphonate therapy. Nat. Clin. Pract. Urol. 4, S3–S13 (2007).

    CAS  PubMed  Google Scholar 

  28. 28

    Drake, M. T., Clarke, B. L. & Khosla, S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin. Proc. 83, 1032–1045 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Bellido, T. & Plotkin, L. I. Novel actions of bisphosphonates in bone: Preservation of osteoblast and osteocyte viability. Bone, doi:10.1016/j.bone.2010.08.008 (2010).

  30. 30

    Roelofs, A. J., Thompson, K., Gordon, S. & Rogers, M. J. Molecular mechanisms of action of bisphosphonates: current status. Clin. Cancer Res. 12, 6222s–6230s (2006).

    CAS  PubMed  Google Scholar 

  31. 31

    Roelofs, A. J., Thompson, K., Ebetino, F. H., Rogers, M. J. & Coxon, F. P. Bisphosphonates: molecular mechanisms of action and effects on bone cells, monocytes and macrophages. Curr. Pharm. Des. 16, 2950–2960 (2010).

    CAS  PubMed  Google Scholar 

  32. 32

    Corey, E. et al. Zoledronic acid exhibits inhibitory effects on osteoblastic and osteolytic metastases of prostate cancer. Clin. Cancer Res. 9, 295–306 (2003).

    CAS  PubMed  Google Scholar 

  33. 33

    Berry, S., Waldron, T., Winquist, E. & Lukka, H. The use of bisphosphonates in men with hormone-refractory prostate cancer: a systematic review of randomized trials. Can. J. Urol. 13, 3180–3188 (2006).

    PubMed  Google Scholar 

  34. 34

    Dearnaley, D. P., Mason, M. D., Parmar, M. K., Sanders, K. & Sydes, M. R. 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 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Saad, F. et al. 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 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Saad, F. et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J. Natl Cancer Inst. 94, 1458–1468 (2002).

    CAS  PubMed  Google Scholar 

  37. 37

    Sydes, M. R. et al. Issues in applying multi-arm multi-stage methodology to a clinical trial in prostate cancer: the MRC STAMPEDE trial. Trials 10, 39 (2009).

    PubMed  PubMed Central  Google Scholar 

  38. 38

    James, N. D. et al. STAMPEDE: Systemic Therapy for Advancing or Metastatic Prostate Cancer—a multi-arm multi-stage randomised controlled trial. Clin. Oncol. (R. Coll. Radiol) 20, 577–581 (2008).

    CAS  Google Scholar 

  39. 39

    James, N. D. et al. Systemic therapy for advancing or metastatic prostate cancer (STAMPEDE): a multi-arm, multistage randomized controlled trial. BJU Int. 103, 464–469 (2009).

    CAS  PubMed  Google Scholar 

  40. 40

    Ishizaka, K. et al. Preventive effect of risedronate on bone loss in men receiving androgen-deprivation therapy for prostate cancer. Int. J. Urol. 14, 1071–1075 (2007).

    CAS  PubMed  Google Scholar 

  41. 41

    Izumi, K. et al. Risedronate recovers bone loss in patients with prostate cancer undergoing androgen-deprivation therapy. Urology 73, 1342–1346 (2009).

    PubMed  Google Scholar 

  42. 42

    Taxel, P. et al. 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 (2010).

    CAS  PubMed  Google Scholar 

  43. 43

    Greenspan, S. L. et al. Skeletal health after continuation, withdrawal, or delay of alendronate in men with prostate cancer undergoing androgen-deprivation therapy. J. Clin. Oncol. 26, 4426–4434 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Stopeck, A. T. 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. 28, 5132–5139 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Fizazi, K. 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. 27, 1564–1571 (2009).

    CAS  Google Scholar 

  46. 46

    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. 182, 509–515; discussion 515–516 (2009).

    CAS  PubMed  Google Scholar 

  47. 47

    Body, J. J. et al. Effects of denosumab in patients with bone metastases with and without previous bisphosphonate exposure. J. Bone Miner. Res. 25, 440–446 (2010).

    CAS  PubMed  Google Scholar 

  48. 48

    Saftig, P. et al. Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc. Natl Acad. Sci. USA 95, 13453–13458 (1998).

    CAS  PubMed  Google Scholar 

  49. 49

    Podgorski, I. et al. Bone marrow-derived cathepsin K cleaves SPARC in bone metastasis. Am. J. Pathol. 175, 1255–1269 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Le Gall, C. et al. A cathepsin K inhibitor reduces breast cancer induced osteolysis and skeletal tumor burden. Cancer Res. 67, 9894–9902 (2007).

    CAS  PubMed  Google Scholar 

  51. 51

    Brubaker, K. D., Vessella, R. L., True, L. D., Thomas, R. & Corey, E. Cathepsin K mRNA and protein expression in prostate cancer progression. J. Bone Miner. Res. 18, 222–230 (2003).

    CAS  PubMed  Google Scholar 

  52. 52

    Seals, D. F. et al. The adaptor protein Tks5/Fish is required for podosome formation and function, and for the protease-driven invasion of cancer cells. Cancer Cell 7, 155–165 (2005).

    CAS  PubMed  Google Scholar 

  53. 53

    Berdeaux, R. L., Diaz, B., Kim, L. & Martin, G. S. Active Rho is localized to podosomes induced by oncogenic Src and is required for their assembly and function. J. Cell Biol. 166, 317–323 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Schramp, M., Ying, O., Kim, T. Y. & Martin, G. S. ERK5 promotes Src-induced podosome formation by limiting Rho activation. J. Cell Biol. 181, 1195–1210 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Mandal, S., Johnson, K. R. & Wheelock, M. J. TGF-β induces formation of F-actin cores and matrix degradation in human breast cancer cells via distinct signaling pathways. Exp. Cell Res. 314, 3478–3493 (2008).

    CAS  PubMed  Google Scholar 

  56. 56

    Tu, C. et al. Lysosomal cathepsin B participates in the podosome-mediated extracellular matrix degradation and invasion via secreted lysosomes in v-Src fibroblasts. Cancer Res. 68, 9147–9156 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Peroni, A. et al. Drug-induced morphea: report of a case induced by balicatib and review of the literature. J. Am. Acad. Dermatol. 59, 125–129 (2008).

    PubMed  Google Scholar 

  58. 58

    Bromme, D. & Lecaille, F. Cathepsin K inhibitors for osteoporosis and potential off-target effects. Expert Opin. Investig Drugs 18, 585–600 (2009).

    PubMed  PubMed Central  Google Scholar 

  59. 59

    Jensen, A. B. 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 10, 452–458 (2010).

    CAS  Google Scholar 

  60. 60

    Migliaccio, A. et al. Steroid-induced androgen receptor-oestradiol receptor beta-Src complex triggers prostate cancer cell proliferation. EMBO J. 19, 5406–5417 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Slack, J. K. et al. Alterations in the focal adhesion kinase/Src signal transduction pathway correlate with increased migratory capacity of prostate carcinoma cells. Oncogene 20, 1152–1163 (2001).

    CAS  PubMed  Google Scholar 

  62. 62

    Asim, M., Siddiqui, I. A., Hafeez, B. B., Baniahmad, A. & Mukhtar, H. Src kinase potentiates androgen receptor transactivation function and invasion of androgen-independent prostate cancer C4–2 cells. Oncogene 27, 3596–3604 (2008).

    CAS  PubMed  Google Scholar 

  63. 63

    Xia, W., Unger, P., Miller, L., Nelson, J. & Gelman, I. H. The Src-suppressed C kinase substrate, SSeCKS, is a potential metastasis inhibitor in prostate cancer. Cancer Res. 61, 5644–5651 (2001).

    CAS  PubMed  Google Scholar 

  64. 64

    Marzia, M. et al. Decreased c-Src expression enhances osteoblast differentiation and bone formation. J. Cell Biol. 151, 311–320 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Soriano, P., Montgomery, C., Geske, R. & Bradley, A. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 64, 693–702 (1991).

    CAS  PubMed  Google Scholar 

  66. 66

    Lee, Y. C. et al. Src family kinase/abl inhibitor dasatinib suppresses proliferation and enhances differentiation of osteoblasts. Oncogene 29, 3196–3207 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Id Boufker, H. et al. The Src inhibitor dasatinib accelerates the differentiation of human bone marrow-derived mesenchymal stromal cells into osteoblasts. BMC Cancer 10, 298 (2010).

    PubMed  PubMed Central  Google Scholar 

  68. 68

    Koreckij, T. et al. Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis. Br. J. Cancer 101, 263–268 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Yang, J. C. et al. Effect of the specific Src family kinase inhibitor saracatinib on osteolytic lesions using the PC-3 bone model. Mol. Cancer Ther. 9, 1629–1637 (2010).

    CAS  PubMed  Google Scholar 

  70. 70

    Rabbani, S. A., Valentino, M. L., Arakelian, A., Ali, S. & Boschelli, F. SKI-606 (Bosutinib) blocks prostate cancer invasion, growth, and metastasis in vitro and in vivo through regulation of genes involved in cancer growth and skeletal metastasis. Mol. Cancer Ther. 9, 1147–1157 (2010).

    CAS  PubMed  Google Scholar 

  71. 71

    Janssens, K., ten Dijke, P., Janssens, S. & Van Hul, W. Transforming growth factor-β1 to the bone. Endocr. Rev. 26, 743–774 (2005).

    CAS  PubMed  Google Scholar 

  72. 72

    Blobe, G. C., Schiemann, W. P. & Lodish, H. F. Role of transforming growth factor-β in human disease. N. Engl. J. Med. 342, 1350–1358 (2000).

    CAS  PubMed  Google Scholar 

  73. 73

    Gordon, K. J. & Blobe, G. C. Role of transforming growth factor-β superfamily signaling pathways in human disease. Biochim. Biophys. Acta 1782, 197–228 (2008).

    CAS  PubMed  Google Scholar 

  74. 74

    Tang, Y. et al. TGF-β1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat. Med. 15, 757–765 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Mohammad, K. S. et al. Pharmacologic inhibition of the TGF-β type I receptor kinase has anabolic and anti-catabolic effects on bone. PLoS One 4, e5275 (2009).

    PubMed  PubMed Central  Google Scholar 

  76. 76

    Alliston, T., Choy, L., Ducy, P., Karsenty, G. & Derynck, R. TGF-β-induced repression of CBFA1 by Smad3 decreases cbfa1 and osteocalcin expression and inhibits osteoblast differentiation. EMBO J. 20, 2254–2272 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Qiu, T. et al. TGF-β type II receptor phosphorylates PTH receptor to integrate bone remodelling signalling. Nat. Cell Biol. 12, 224–234 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Kang, Y. et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3, 537–549 (2003).

    CAS  Google Scholar 

  79. 79

    Kang, Y. et al. Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proc. Natl Acad. Sci. USA 102, 13909–13914 (2005).

    CAS  PubMed  Google Scholar 

  80. 80

    Korpal, M. et al. Imaging transforming growth factor-β signaling dynamics and therapeutic response in breast cancer bone metastasis. Nat. Med. 15, 960–966 (2009).

    CAS  PubMed  Google Scholar 

  81. 81

    Ganapathy, V. et al. Targeting the transforming growth factor-β pathway inhibits human basal-like breast cancer metastasis. Mol. Cancer 9, 122 (2010).

    PubMed  PubMed Central  Google Scholar 

  82. 82

    Nam, J. S. et al. An anti-transforming growth factor-β antibody suppresses metastasis via cooperative effects on multiple cell compartments. Cancer Res. 68, 3835–3843 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Mohammad, K. S. et al. TGF-β-RI kinase inhibitor SD-208 reduces the development and progression of melanoma bone metastases. Cancer Res. 71, 175–184 (2011).

    CAS  PubMed  Google Scholar 

  84. 84

    Hu, Z., Zhang, Z., Guise, T. & Seth, P. Systemic delivery of an oncolytic adenovirus expressing soluble transforming growth factor-β receptor II-Fc fusion protein can inhibit breast cancer bone metastasis in a mouse model. Hum. Gene Ther. 21, 1623–1629 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Hu, Z. et al. A modified hTERT promoter-directed oncolytic adenovirus replication with concurrent inhibition of TGFβ signaling for breast cancer therapy. Cancer Gene Ther. 17, 235–243 (2010).

    CAS  PubMed  Google Scholar 

  86. 86

    Criswell, T. L., Dumont, N., Barnett, J. V. & Arteaga, C. L. Knockdown of the transforming growth factor-beta type III receptor impairs motility and invasion of metastatic cancer cells. Cancer Res. 68, 7304–7312 (2008).

    CAS  PubMed  Google Scholar 

  87. 87

    Ikushima, H. & Miyazono, K. TGFβ signalling: a complex web in cancer progression. Nat. Rev. Cancer 10, 415–424 (2010).

    CAS  PubMed  Google Scholar 

  88. 88

    Jansen, D. R., Krijger, G. C., Kolar, Z. I., Zonnenberg, B. A. & Zeevaart, J. R. Targeted Radiotherapy of Bone Malignancies. Curr. Drug Discov. Technol. 7 233–246 (2010).

    CAS  PubMed  Google Scholar 

  89. 89

    Bauman, G., Charette, M., Reid, R. & Sathya, J. Radiopharmaceuticals for the palliation of painful bone metastasis-a systemic review. Radiother Oncol. 75, 258–270 (2005).

    CAS  PubMed  Google Scholar 

  90. 90

    Tu, S. M. et al. Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial. Lancet 357, 336–341 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Collins, C. et al. Samarium-153-EDTMP in bone metastases of hormone refractory prostate carcinoma: a phase I/II trial. J. Nucl. Med. 34, 1839–1844 (1993).

    CAS  PubMed  Google Scholar 

  92. 92

    Nilsson, S. et al. Radium-223 chloride, a first-in-class alpha-pharmaceutical with a benign safety profile for patients with castration-resistant prostate cancer (CRPC) and bone metastases: Combined analysis of phase I and II clinical trials. ASCO Meeting Abstracts 28, 4678 (2010).

    Google Scholar 

  93. 93

    Morris, M. J. et al. Phase I study of samarium-153 lexidronam with docetaxel in castration-resistant metastatic prostate cancer. J. Clin. Oncol. 27, 2436–2442 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Fizazi, K. et al. Phase II trial of consolidation docetaxel and samarium-153 in patients with bone metastases from castration-resistant prostate cancer. J. Clin. Oncol. 27, 2429–2435 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Tu, S. M. et al. Phase I study of concurrent weekly docetaxel and repeated samarium-153 lexidronam in patients with castration-resistant metastatic prostate cancer. J. Clin. Oncol. 27, 3319–3324 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Lam, M. G. et al. Combined use of zoledronic acid and 153Sm-EDTMP in hormone-refractory prostate cancer patients with bone metastases. Eur. J. Nucl. Med. Mol. Imaging 35, 756–65 (2008).

    CAS  PubMed  Google Scholar 

  97. 97

    Lam, M. G., de Klerk, J. M. & Zonnenberg, B. A. Treatment of painful bone metastases in hormone-refractory prostate cancer with zoledronic acid and samarium-153-ethylenediaminetetramethylphosphonic acid combined. J. Palliat. Med. 12, 649–651 (2009).

    PubMed  Google Scholar 

  98. 98

    Nelson, J. B. et al. Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nat. Med. 1, 944–949 (1995).

    CAS  PubMed  Google Scholar 

  99. 99

    Yin, J. J. et al. A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases. Proc. Natl Acad. Sci. USA 100, 10954–10959 (2003).

    CAS  PubMed  Google Scholar 

  100. 100

    Drake, J. M., Danke, J. R. & Henry, M. D. Bone-specific growth inhibition of prostate cancer metastasis by atrasentan. Cancer Biol. Ther. 9, 607–614 (2010).

    CAS  PubMed  Google Scholar 

  101. 101

    Guise, T. A., Yin, J. J. & Mohammad, K. S. Role of endothelin-1 in osteoblastic bone metastases. Cancer 97, 779–784 (2003).

    PubMed  Google Scholar 

  102. 102

    Carducci, M. A. et al. Effect of endothelin-A receptor blockade with atrasentan on tumor progression in men with hormone-refractory prostate cancer: a randomized, phase II, placebo-controlled trial. J. Clin. Oncol. 21, 679–689 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Cella, D. et al. Role of quality of life in men with metastatic hormone-refractory prostate cancer: how does atrasentan influence quality of life? Eur. Urol. 49, 781–789 (2006).

    PubMed  Google Scholar 

  104. 104

    Nelson, J. B. et al. Suppression of prostate cancer induced bone remodeling by the endothelin receptor A antagonist atrasentan. J. Urol. 169, 1143–1149 (2003).

    CAS  PubMed  Google Scholar 

  105. 105

    Carducci, M. A. et al. A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer 110, 1959–1966 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Vogelzang, N. J. et al. Meta-analysis of clinical trials of atrasentan 10 mg in metastatic hormone-refractory prostate cancer. J. Clin. Oncol. (Meeting Abstracts) 23, Suppl. 4563 (2005).

    Google Scholar 

  107. 107

    Michaelson, M. D., Kaufman, D. S., Kantoff, P., Oh, W. K. & Smith, M. R. Randomized phase II study of atrasentan alone or in combination with zoledronic acid in men with metastatic prostate cancer. Cancer 107, 530–535 (2006).

    CAS  PubMed  Google Scholar 

  108. 108

    Nelson, J. B. Phase III study of the efficacy and safety of zibotentan (ZD4054) in patients with bone metastatic castration-resistant prostate cancer (CRPC) [abstract]. J. Clin. Oncol. 29 (Suppl. 7), a117 (2011).

    Google Scholar 

  109. 109

    James, N. D. et al. Final safety and efficacy analysis of the specific endothelin A receptor antagonist zibotentan (ZD4054) in patients with metastatic castration-resistant prostate cancer and bone metastases who were pain-free or mildly symptomatic for pain: a double-blind, placebo-controlled, randomized phase II trial. BJU Int. 106, 966–973 (2010).

    CAS  PubMed  Google Scholar 

  110. 110

    Day, T. F., Guo, X., Garrett-Beal, L. & Yang, Y. Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev. Cell 8, 739–750 (2005).

    CAS  PubMed  Google Scholar 

  111. 111

    Hill, T. P., Später, D., Taketo, M. M., Birchmeier, W. & Hartmann, C. Canonical Wnt/β-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev. Cell 8, 727–738 (2005).

    CAS  PubMed  Google Scholar 

  112. 112

    Bennett, C. N. et al. Wnt10b increases postnatal bone formation by enhancing osteoblast differentiation. J. Bone Miner. Res. 22, 1924–1932 (2007).

    CAS  PubMed  Google Scholar 

  113. 113

    Morvan, F. et al. Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. J. Bone Miner. Res. 21, 934–945 (2006).

    CAS  PubMed  Google Scholar 

  114. 114

    ten Dijke, P., Krause, C., de Gorter, D. J., Löwik, C. W. & van Bezooijen, R. L. Osteocyte-derived sclerostin inhibits bone formation: its role in bone morphogenetic protein and Wnt signaling. J. Bone Joint Surg. Am. 90 (Suppl. 1), 31–35 (2008).

    PubMed  Google Scholar 

  115. 115

    Hall, C. L., Bafico, A., Dai, J., Aaronson, S. A. & Keller, E. T. Prostate cancer cells promote osteoblastic bone metastases through Wnts. Cancer Res. 65, 7554–7560 (2005).

    CAS  PubMed  Google Scholar 

  116. 116

    Dai, J. et al. Prostate cancer induces bone metastasis through Wnt-induced bone morphogenetic protein-dependent and independent mechanisms. Cancer Res. 68, 5785–5794 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Schwaninger, R. et al. Lack of noggin expression by cancer cells is a determinant of the osteoblast response in bone metastases. Am. J. Pathol. 170, 160–175 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Rentsch, C. A., Cecchini, M. G. & Thalmann, G. N. Loss of inhibition over master pathways of bone mass regulation results in osteosclerotic bone metastases in prostate cancer. Swiss Med. Wkly 139, 220–225 (2009).

    CAS  PubMed  Google Scholar 

  119. 119

    Hall, C. L. & Keller, E. T. The role of Wnts in bone metastases. Cancer Metastasis Rev. 25, 551–558 (2006).

    CAS  PubMed  Google Scholar 

  120. 120

    Smith, H. W. & Marshall, C. J. Regulation of cell signalling by uPAR. Nat. Rev. Mol. Cell Biol. 11, 23–36 (2010).

    CAS  Google Scholar 

  121. 121

    Shariat, S. F. et al. Association of the circulating levels of the urokinase system of plasminogen activation with the presence of prostate cancer and invasion, progression, and metastasis. J. Clin. Oncol. 25, 349–355 (2007).

    CAS  PubMed  Google Scholar 

  122. 122

    Thomas, C. et al. Urokinase-plasminogen-activator receptor expression in disseminated tumour cells in the bone marrow and peripheral blood of patients with clinically localized prostate cancer. BJU Int. 104, 29–34 (2009).

    CAS  PubMed  Google Scholar 

  123. 123

    Rabbani, S. A. et al. An amino-terminal fragment of urokinase isolated from a prostate cancer cell line (PC-3) is mitogenic for osteoblast-like cells. Biochem. Biophys. Res. Commun. 173, 1058–1064 (1990).

    CAS  PubMed  Google Scholar 

  124. 124

    Rabbani, S. A., Gladu, J., Mazar, A. P., Henkin, J. & Goltzman, D. Induction in human osteoblastic cells (SaOS2) of the early response genes fos, jun, and myc by the amino terminal fragment (ATF) of urokinase. J. Cell Physiol. 172, 137–145 (1997).

    CAS  PubMed  Google Scholar 

  125. 125

    Koutsilieris, M., Sourla, A., Pelletier, G. & Doillon, C. J. Three-dimensional type I collagen gel system for the study of osteoblastic metastases produced by metastatic prostate cancer. J. Bone Miner. Res. 9, 1823–1832 (1994).

    CAS  PubMed  Google Scholar 

  126. 126

    Mitsiades, C., Sourla, A., Doillon, C., Lembessis, P. & Koutsilieris, M. Three-dimensional type I collagen co-culture systems for the study of cell-cell interactions and treatment response in bone metastases. J. Musculoskelet. Neuronal Interact. 1, 153–155 (2000).

    CAS  PubMed  Google Scholar 

  127. 127

    Achbarou, A. et al. Urokinase overproduction results in increased skeletal metastasis by prostate cancer cells in vivo. Cancer Res. 54, 2372–2377 (1994).

    CAS  PubMed  Google Scholar 

  128. 128

    Fritz, V. et al. Antitumoral activity and osteogenic potential of mesenchymal stem cells expressing the urokinase-type plasminogen antagonist amino-terminal fragment in a murine model of osteolytic tumor. Stem Cells 26, 2981–2990 (2008).

    CAS  PubMed  Google Scholar 

  129. 129

    Sturge, J., Wienke, D., East, L., Jones, G. E. & Isacke, C. M. GPI-anchored uPAR requires Endo180 for rapid directional sensing during chemotaxis. J. Cell Biol. 162, 789–794 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Thomas, E. K. et al. Endo180 binds to the C-terminal region of type I collagen. J. Biol. Chem. 280, 22596–22605 (2005).

    CAS  PubMed  Google Scholar 

  131. 131

    Sturge, J., Wienke, D. & Isacke, C. M. Endosomes generate localized Rho-ROCK-MLC2-based contractile signals via Endo180 to promote adhesion disassembly. J. Cell Biol. 175, 337–347 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Wu, K., Yuan, J. & Lasky, L. A. Characterization of a novel member of the macrophage mannose receptor type C lectin family. J. Biol. Chem. 271, 21323–21330 (1996).

    CAS  PubMed  Google Scholar 

  133. 133

    Fasquelle, C. et al. Balancing selection of a frame-shift mutation in the MRC2 gene accounts for the outbreak of the Crooked Tail Syndrome in Belgian Blue Cattle. PLoS Genet. 5, e1000666 (2009).

    PubMed  PubMed Central  Google Scholar 

  134. 134

    Wagenaar-Miller, R. A. et al. Complementary roles of intracellular and pericellular collagen degradation pathways in vivo. Mol. Cell Biol. 27, 6309–6322 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Huijbers, I. J. et al. A role for fibrillar collagen deposition and the collagen internalization receptor Endo180 in glioma invasion. PLoS One 5, e9808 (2010).

    PubMed  PubMed Central  Google Scholar 

  136. 136

    Wienke, D. et al. The collagen receptor Endo180 (CD280) is expressed on basal-like breast tumor cells and promotes tumor growth in vivo. Cancer Res. 67, 10230–10240 (2007).

    CAS  PubMed  Google Scholar 

  137. 137

    Caley, M. et al. Osteoblasts orchestrate collagen remodelling via tumour cell-dependent regulation of Endo180 in metastatic bone disease. 2010 Nature - CNIO Cancer Symposium: Frontiers in Tumour Progression,

  138. 138

    Kogianni, G., Walker, M. M., Waxman, J. & Sturge, J. Endo180 expression with cofunctional partners MT1-MMP and uPAR-uPA is correlated with prostate cancer progression. Eur. J. Cancer 45, 685–693 (2009).

    CAS  PubMed  Google Scholar 

  139. 139

    Wang, G. et al. Osteoblast-derived factors induce an expression signature that identifies prostate cancer metastasis and hormonal progression. Cancer Res. 69, 3433–3442 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Hikita, A. et al. Identification of an alternatively spliced variant of Ca2+-promoted Ras inactivator as a possible regulator of RANKL shedding. J. Biol. Chem. 280, 41700–41706 (2005).

    CAS  PubMed  Google Scholar 

  141. 141

    Hikita, A. et al. Negative regulation of osteoclastogenesis by ectodomain shedding of receptor activator of NFκB ligand. J. Biol. Chem. 281, 36846–36855 (2006).

    CAS  Google Scholar 

  142. 142

    Lynch, C. C. et al. MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. Cancer Cell 7, 485–496 (2005).

    CAS  Google Scholar 

Download references


The authors would like to acknowledge funding support from The Prostate Cancer Charity (Grant 110632), The Prostate Cancer Charity and the Milly Apthorp Charitable Trust (Grant 110854), The Association of International Cancer Research (Grant 08-0803), The Rosetrees Trust (Grant JS16/M59), Tony & Rita Gallagher, Imperial College NHS Healthcare Trust Special Trustees and The Fundação para a Ciência e Tecnologia. We thank A. V. Fonseca for her help in the schematic design.

Author information




J. Sturge and M. P. Caley contributed to researching the data for the article. J. Sturge made a substantial contribution to the discussion and writing of the content. All authors contributed to reviewing and editing of the manuscript before submission.

Corresponding author

Correspondence to Justin Sturge.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sturge, J., Caley, M. & Waxman, J. Bone metastasis in prostate cancer: emerging therapeutic strategies. Nat Rev Clin Oncol 8, 357–368 (2011).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing