Cancer Treatment Reviews
Volume 29, Issue 3 , Pages 189-198 , June 2003

Pathophysiology of bone metastases from prostate cancer and the role of bisphosphonates in treatment

  • Colby L Eaton

      Affiliations

    • Academic Urology Unit, University of Sheffield, Sheffield, UK
    • Corresponding Author InformationCorrespondence to: Colby L. Eaton, Lecturer, Academic Urology Unit, University of Sheffield, Royal Hallamshire Hospital, Sheffield S10 2JF
  • ,
  • R.E Coleman

      Affiliations

    • Professor of Medical Oncology, Academic Unit of Clinical Oncology, Cancer Research Centre, Weston Park Hospital, Sheffield S10 2SJ, UK

References 

  1. Jemal A, Thomas A, Murray T. Cancer statistics. CA Cancer J. Clin. 2002;52:23–47
  2. Kostenuik PJ, Sanchez-Sweatman O, Orr FW, Singh G. Bone cell matrix promotes the adhesion of human prostatic carcinoma cells via the α2 β1 integrin. Clin. Exp. Metastasis. 1996;14:19–26
  3. Lehr JE, Pienta KJ. Preferential adhesion of prostate cancer cells to a human bone marrow endothelial cell line. J. Nat. Cancer Inst. 1998;90:118–123
  4. Bataille R, Chappard D, Basle M. Excessive bone resorption in human plasmacytomas: direct induction by tumour cells in vivo. Br. J. Haematol. 1995;90:721–724
  5. Taube T, Beneton MN, McCloskey EV, Rogers S, Greaves M, Kanis JA. Abnormal bone remodelling in patients with myelomatosis and normal biochemical indices of bone resorption. Eur. J. Haematol. 1992;49(4):192–198
  6. Valentin-Opran A, Charhon SA, Meunier PJ, Edouard CM, Arlot ME. Quantitative histology of myeloma-induced bone changes. Br. J. Haematol. 1982;52:601–610
  7. Mundy GR, Luben RA, Raisz LG, Oppenheim JJ, Buell DN. Bone-resorbing activity in supernatants from lymphoid cell lines. N Engl J. Med. 1974;290:867–871
  8. Mundy GR, Raisz LG, Cooper RA, Schechter GP, Salmon SE. Evidence for the secretion of an osteoclast stimulating factor in myeloma. N Engl J. Med. 1974;291:1041–1046
  9. Cozzolino F, Torcia M, Aldinucci D, Rubartelli A, Miliani A, Shaw AR, et al. Production of interleukin-1 by bone marrow myeloma cells. Blood. 1989;74:380–387
  10. Garrett IR, Durie BG, Nedwin GE, Gillespie A, Bringman T, Sabatini M, et al. Production of lymphotoxin, a bone-resorbing cytokine, by cultured human myeloma cells. N Engl J. Med. 1987;317:526–532
  11. Karadag A, Scutt AM, Croucher PI. Human myeloma cells promote the recruitment of osteoblast precursors: mediation by interleukin-6 and soluble interleukin-6 receptor. J. Bone Miner. Res. 2000;15:1935–1943
  12. Taga T, Hibi M, Hirata Y, Yamasaki K, Yasukawa K, Matsuda T, et al. Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell. 1989;58:573–581
  13. Rose-John S, Ehlers M, Grotzinger J, Mullberg J. The soluble interleukin-6 receptor. Ann. N Y Acad. Sci. 1995;762:207–220 discussion 220–1
  14. Narazaki M, Yasukawa K, Saito T, Ohsugi Y, Fukui H, Koishihara Y, et al. Soluble forms of the interleukin-6 signal-transducing receptor component gp130 in human serum possessing a potential to inhibit signals through membrane-anchored gp130. Blood. 1993;82:1120–1126
  15. Ohtani K, Ninomiya H, Hasegawa Y, Kobayashi T, Kojima H, Nagasawa T, et al. Clinical significance of elevated soluble interleukin-6 receptor levels in the sera of patients with plasma cell dyscrasias. Br. J. Haematol. 1995;91:116–120
  16. Kyrtsonis MC, Dedoussis G, Zervas C, Perifanis V, Baxevanis C, Stamatelou M, et al. Soluble interleukin-6 receptor (sIL-6R), a new prognostic factor in multiple myeloma. Br. J. Haematol. 1996;93:398–400
  17. Gaillard JP, Bataille R, Brailly H, Zuber C, Yasukawa K, Attal M, et al. Increased and highly stable levels of functional soluble interleukin-6* receptor in sera of patients with monoclonal gammopathy. Eur. J. Immunol. 1993;23:820–824
  18. Tamura T, Udagawa N, Takahashi N, Miyaura C, Tanaka S, Yamada Y, et al  Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6. Proc. Natl. Acad. Sci. USA. 1993;90:11924–11928
  19. Nishimura R, Kato Y, Chen D, Harris SE, Mundy GR, Yoneda T. Smad5 and DPC4 are key molecules in mediating BMP-2-induced osteoblastic differentiation of the pluripotent mesenchymal precursor cell line C2C12. J. Biol. Chem. 1998;273:1872–1879
  20. Heldin CH, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature. 1997;390:465–471
  21. Hamdy FC, Autzen P, Robinson MC, Horne CH, Neal DE, Robson CN. Immunolocalization and messenger RNA expression of bone morphogenetic protein-6 in human benign and malignant prostatic tissue. Cancer Res. 1997;57:4427–4431
  22. Teicher BA, Kakeji Y, Ara G, Herbst RS, Northey D. Prostate carcinoma response to cytotoxic therapy: in vivo resistance. In Vivo. 1997;11:453–461
  23. Eastham JA, Truong LD, Rogers E, Kattan M, Flanders KC, Scardino PT, et al. Transforming growth factor-β1: comparative immunohistochemical localization in human primary and metastatic prostate cancer. Lab Invest. 1995;73:628–635
  24. Simpson E, Harrod J, Eilon G, Jacobs JW, Mundy GR. Identification of a messenger ribonucleic acid fraction in human prostatic cancer cells coding for a novel osteoblast-stimulating factor. Endocrinology. 1985;117:1615–16120
  25. Kido J, Yamauchi N, Ohishi K, Kataoka M, Nishikawa S, Nakamura T, et al. Inhibition of osteoblastic cell differentiation by conditioned medium derived from the human prostatic cancer cell line PC-3 in vitro. J. Cell. Biochem. 1997;67:248–256
  26. Scutt A, Bertram P, Brautigam M. The role of glucocorticoids and prostaglandin E2 in the recruitment of bone marrow mesenchymal cells to the osteoblastic lineage: positive and negative effects. Calcified Tissue International. 1996;59(3):154–162
  27. Sanders JL, Chattopadhyay N, Kifor O, Yamaguchi T, Brown EM. Ca 2+-sensing receptor expression and PTHrP secretion in PC38 human prostate cancer cells. Am. J. Physiol. – Endocrinol. Metabol. 2001;281(6):E1267–E1274
  28. Iwamura M, Abrahamsson PA, Foss KA, Wu G, Cockett AT, Deftoss LJ. Parathyroid hormone-related protein: a potential autocrine growth regulator in human cancer cell lines. Urology. 1994;43(5):675–679
  29. Thirunavukkarasu K, Miles RR, Halladay DL, Yang X, Galvin RJ, Chandrasekhar S, et al. Stimulation of osteoprotegerin (OPG) gene expression by transforming growth factor-β (TGF-beta). Mapping of the OPG promoter region that mediates TGF-beta effects. J. Biol. Chem. 2001;276(39):36241–36250
  30. Twillie DA, Eisenberger MA, Carducci MA, Hseih WS, Kim WY, Simons JW. Interleukin-6: a candidate mediator of human prostate cancer morbidity. Urology. 1995;45:542–549
  31. Borsellino N, Belldegrun A, Bonavida B. Endogenous interleukin 6 is a resistance factor for cis-diamminedichloroplatinum and etoposide-mediated cytotoxicity of human prostate carcinoma cell lines. Cancer Res. 1995;55:4633–4639
  32. Okamoto M, Lee C, Oyasu R. Interleukin-6 as a paracrine and autocrine growth factor in human prostatic carcinoma cells in vitro. Cancer Res. 1997;57:141–146
  33. Okamoto M, Lee C, Oyasu R. Autocrine effect of androgen on proliferation of an androgen responsive prostatic carcinoma cell line, LNCAP: role of interleukin-6. Endocrinology. 1997;138:5071–5074
  34. Levesque E, Beaulieu M, Guillemette C, Hum DW, Belanger A. Effect of interleukins on UGT2B15 and UGT2B17 steroid uridine diphosphate-glucuronosyltransferase expression and activity in the LNCaP cell line. Endocrinology. 1998;139:2375–2381
  35. Soos G, Jones RF, Haas GP, Wang CY. Comparative intraosseal growth of human prostate cancer cell lines LNCaP and PC-3 in the nude mouse. Anticancer Res. 1997;17:4253–4258
  36. Robbins SE, Shu WP, Kirschenbaum A, Levine AC, Miniati DN, Liu BC. Bone extracellular matrix induces homeobox proteins independent of androgens: possible mechanism for androgen-independent growth in human prostate cancer cells. Prostate. 1996;29:362–367
  37. Thompson SW, Tonge D. Bone cancer gain without the pain. Nat. Med. 2000;6:504–505
  38. Yano K, Tsuda E, Washida N, Kobayashi F, Goto M, Harada A, et al. Immunological characterization of circulating osteoprotegerin/osteoclastogenesis inhibitory factor: increased serum concentrations in postmenopausal women with osteoporosis. J. Bone Miner. Res. 1999;14:518–527
  39. Seidel C, Hjertner O, Abildgaard N, Heickendorff L, Hjorth M, Westin J, et al. Nordic Myeloma Study Group. Serum osteoprotegerin levels are reduced in patients with multiple myeloma with lytic bone disease. Blood. 2001;98:2269–2271
  40. Sezer O, Heider U, Jakob C, Eucker J, Possinger K. Human bone marrow myeloma cells express RANKL. J. Clin. Oncol. 2002;20:353–354
  41. Roux S, Meignin V, Quillard J, Meduri G, Guiochon-Mantel A, Fermand JP, et al. RANK (receptor activator of nuclear factor-κB) and RANKL expression in multiple myeloma. Br. J. Haematol. 2002;117:86–92
  42. Croucher PI, Shipman CM, Lippitt J, Perry M, Asosingh K, Hijzen A, et al. Osteoprotegerin inhibits the development of osteolytic bone disease in multiple myeloma. Blood. 2001;98:3534–3540
  43. Brown JM, Vessella RL, Kostenuik PJ, Dunstan CR, Lange PH, Corey E. Serum osteoprotegerin levels are increased in patients with advanced prostate cancer. Clin. Cancer Res. 2001;7:2977–2983
  44. Holen I, Croucher PI, Hamdy FC, Eaton CL. Osteoprotegerin (OPG) is a survival factor for human prostate cancer cells. Cancer Res. 2002;62:1619–1623
  45. Morony S, Capparelli C, Sarosi I, Lacey DL, Dunstan CR, Kostenuik PJ. Osteoprotegerin inhibits osteolysis and decreases skeletal tumor burden in syngeneic and nude mouse models of experimental bone metastasis. Cancer Res. 2001;61:4432–4436
  46. Honore P, Luger NM, Sabino MA, Schwei MJ, Rogers SD, Mach DB, et al. Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord. Nat. Med. 2000;6:521–528 erratum appears in Nat Med 2000 Jul; 6: 838
  47. Nagata S. Steering anti-cancer drugs away from the TRAIL. Nat. Med. 2000;6:502–503
  48. Koeneman KS, Yeung F, Chung LW. Osteomimetic properties of prostate cancer cells: a hypothesis supporting the predilection of prostate cancer metastasis and growth in the bone environment. Prostate. 1999;39:246–261
  49. Carlin BI, Andriole GL. The natural history, skeletal complications, and management of bone metastases in patients with prostate carcinoma. Cancer. 2000;88:2989–2994
  50. Daniell HW. Osteoporosis after orchiectomy for prostate cancer. J. Urol. 1997;157:439–444
  51. Coleman RE. Skeletal complications of malignancy. Cancer. 1997;80(suppl):1588–1594
  52. Saad F, Gleason DM, Murray R, et al. Zoledronic acid reduces skeletal complications in patients with hormone-refractory prostate carcinoma metastatic to bone: a randomized, placebo-controlled trial. J Natl Cancer Inst 2002; xxxxx
  53. Poor G, Atkinson EJ, Lewallen DG, et al.  Age-related hip fractures in men: clinical spectrum and short-term outcomes. Osteoporos. Int. 1995;5:419–426
  54. Urwin GH, Percival RC, Harris S, et al.  Generalised increase in bone resorption in carcinoma of the prostate. Br. J. Urol. 1985;57:721–723
  55. Clarke NW, McClure J, George NJR. Morphometric evidence for bone resorption and replacement in prostate cancer. Br. J. Urol. 1991;68:74–80
  56. Berruti A, Dogliotti L, Bitossi R, et al.  Incidence of skeletal complications in patients with bone metastatic prostate cancer and hormone refractory disease: predictive role of bone resorption and formation markers evaluated at baseline. J. Urol. 2000;164:1248–1253
  57. Garnero P, Buchs N, Zekri J, et al.  Markers of bone turnover for the management of patients with bone metastases from prostate cancer. Br. J. Cancer. 2000;82:858–864
  58. Adami S, Salvagno G, Guarrera G, et al.  Dichloromethylene-diphosphonate in patients with prostatic carcinoma metastatic to the skeleton. J. Urol. 1985;134:1152–1154
  59. Adami S, Mian M. Clodronate therapy of metastatic bone disease in patients with prostatic carcinoma. Recent Results Cancer Res. 1989;116:67–72
  60. Vorreuther R. Bisphosphonates as an adjunct to palliative therapy of bone metastases from prostatic carcinoma. A pilot study on clodronate. Br. J. Urol. 1993;72:792–795
  61. Cresswell SM, English PJ, Hall RR, et al.  Pain relief and quality-of-life assessment following intravenous and oral clodronate in hormone-escaped metastatic prostate cancer. Br. J. Urol. 1995;76:360–365
  62. Papapoulos SE, Hamdy NA, van der Pluijm G. Bisphosphonates in the management of prostate carcinoma metastatic to the skeleton. Cancer. 2000;88(suppl):3047–3053
  63. Coleman RE, Purohit OP, Black C, et al.  Double-blind, randomised, placebo-controlled, dose-finding study of oral ibandronate in patients with metastatic bone disease. Ann. Oncol. 1999;10:311–316
  64. Pelger RC, Hamdy NA, Zwinderman AH, et al.  Effects of the bisphosphonate olpadronate in patients with carcinoma of the prostate metastatic to the skeleton. Bone. 1998;22:403–408
  65. Heidenreich A, Elert A, Hofmann R. Ibandronate in the treatment of prostate cancer associated painful osseus metastases. Prostate Cancer Prostat. Dis. 2002;5:231–235
  66. Kylmala T, Tammela TL, Lindholm TS, et al.  The effect of combined intravenous and oral clodronate treatment on bone pain in patients with metastatic prostate cancer. Ann. Chir. Gynaecol. 1994;83:316–319
  67. Elomaa I, Kylmala T, Tammela T, et al.  Effect of oral clodronate on bone pain. A controlled study in patients with metastatic prostate cancer. Int. Urol. Nephrol. 1992;24:159–166
  68. Kylmala T, Taube T, Tammela TL, et al.  Concomitant i.v. and oral clodronate in the relief of bone pain—a double-blind placebo-controlled study in patients with prostate cancer. Br. J. Cancer. 1997;76:939–942
  69. Strang P, Nilsson S, Brandstedt S, et al.  The analgesic efficacy of clodronate compared with placebo in patients with painful bone metastases from prostatic cancer. Anticancer Res. 1997;17:4717–4721
  70. Smith JA. Palliation of painful bone metastases from prostate cancer using sodium etidronate: results of a randomized, prospective, double-blind, placebo-controlled study. J. Urol. 1989;141:85–87
  71. Ernst DS, Tannock IF, Venner PM, et al. Randomized placebo controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone alone in patients with hormone refractory prostate cancer (HRPC) and pain: National Cancer Institute of Canada Clinical Trials Group study [abstract]. Proc Am Soc Clin Oncol 2002; 21: abs 705, 177a
  72. Dearnaley DP, Sydes MR on behalf of the MRC PR05 collaborators. Preliminary evidence that oral clodronate delays symptomatic progression of bone metastases from prostate cancer: First results of the MRC PR05 trial. Proc Am Soc Clin Oncol 2001; 20: abs 693, 174a
  73. Lipton A, Small E, Saad F, Gleason D, et al.  The new bisphosphonate, Zometa (zoledronic acid), decreases skeletal complications in both osteolytic and osteoblastic lesions: a comparison to pamidronate. Cancer Invest. 2002;20(Suppl 2):45–54

PII: S0305-7372(03)00071-9

doi: 10.1016/S0305-7372(03)00071-9

Cancer Treatment Reviews
Volume 29, Issue 3 , Pages 189-198 , June 2003