Skip to main content

Thank you for visiting nature.com. 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.

  • Review
  • Published:

The potential role of bisphosphonates in prostate cancer

Prostate Cancer and Prostatic Diseases volume 5, pages 264–272 (2002)Cite this article

Abstract

Skeletal morbidity secondary to metastases and osteoporosis is common in patients with advanced prostate cancer. Despite the typically sclerotic nature of prostate cancer metastases, osteoclast mediated osteolysis may play a significant role. This review addresses the newly recognised antitumour effects of bisphosphonates in addition to their role in inhibiting osteoclast mediated bone resorption. Both preclinical and clinical evidence of a role for bisphosphonates in the treatment and prevention of bone metastases secondary to prostate cancer is assessed.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Cancer in South East England 1998 Thames Cancer Registry 2001

  2. Murphy M et al.. Changing trends in prostatic cancer BJU Int 1999 83: 786–791

    Article  CAS  PubMed  Google Scholar 

  3. Bubendorf L et al.. Metastatic patterns of prostate cancer: an autopsy study of 1589 patients Hum Pathol 2000 31: 578–583

    Article  CAS  PubMed  Google Scholar 

  4. Denis L . Prostate cancer. Primary hormonal treatment Cancer 1993 71: 1050–1058

    Article  CAS  PubMed  Google Scholar 

  5. Oh WK, Kantoff PW . Management of hormone refractory prostate cancer: current standards and future prospects J Urol 1998 160: 1220–1229

    Article  CAS  PubMed  Google Scholar 

  6. Berruti A 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

    Article  CAS  PubMed  Google Scholar 

  7. Benford H et al.. Farnesol and geranylgeraniol prevent activation of caspases by aminobisphosphonates: biochemical evidence for two distinct pharmacological classes of bisphosphonate drugs Mol Pharmacol 1999 56: 131–140

    Article  CAS  PubMed  Google Scholar 

  8. Bisaz S, Jung A, Fleisch H . Uptake by bone of pyrophosphate, diphosphonates and their technetium derivatives Clin Sci Mol Med 1978 54: 265–272

    CAS  PubMed  Google Scholar 

  9. Jung A, Bisaz S, Fleisch H . The binding of pyrophosphate and two diphosphonates by hydroxyapatite crystals Calcif Tissue Res 1973 11: 269–280

    Article  CAS  PubMed  Google Scholar 

  10. Kasting GB, Francis MD . Retention of etidronate in human, dog, and rat J Bone Miner Res 1992 7: 513–522

    Article  CAS  PubMed  Google Scholar 

  11. Rogers MJ, Watts DJ, Russell RG . Overview of bisphosphonates Cancer 1997 80: 1652–1660

    Article  CAS  PubMed  Google Scholar 

  12. Fleisch H . Bisphosphonates: mechanisms of action Endocr Rev 1998 19: 80–100

    Article  CAS  PubMed  Google Scholar 

  13. Garnero P et al.. Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment J Clin Endocrinol 1994 79: 1693–1700

    CAS  Google Scholar 

  14. Balena R et al.. The effects of 2-y treatment with the aminobisphosphonate alendronate on bone metabolism, bone histomorphometry, and bone strength in ovariectomized nonhuman primates J Clin Invest 1993 92: 2577–2586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rodan GA . Mechanisms of action of bisphosphonates Ann Rev Pharmacol Toxicol 1998 38: 375–388

    Article  CAS  Google Scholar 

  16. Guise TA, Mundy GR . Cancer and bone Endocr Rev 1998 19: 18–54

    CAS  PubMed  Google Scholar 

  17. Taube T et al.. Histomorphometric evidence for osteoclast-mediated bone resorption in metastatic breast cancer Bone 1994 15: 161–166

    Article  CAS  PubMed  Google Scholar 

  18. Bundred NJ et al.. Parathyroid hormone related protein and hypercalcaemia in breast cancer BMJ 1991 303: 1506–1509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Deftos LJ . Prostate carcinoma: production of bioactive factors Cancer 2000 88: 3002–3008

    Article  CAS  PubMed  Google Scholar 

  20. Teitelbaum SL . Bone resorption by osteoclasts Science 2000 289: 1504–1508

    Article  CAS  PubMed  Google Scholar 

  21. Suda T et al.. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families Endocr Rev 1999 20: 345–357

    Article  CAS  PubMed  Google Scholar 

  22. Simonet WS et al.. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density Cell 1997 89: 309–319

    Article  CAS  PubMed  Google Scholar 

  23. Thomas RJ et al.. Breast cancer cells interact with osteoblasts to support osteoclast formation Endocrinology 1999 140: 4451–4458

    Article  CAS  PubMed  Google Scholar 

  24. Takai H et al.. Transforming growth factor-beta stimulates the production of osteoprotegerin/osteoclastogenesis inhibitory factor by bone marrow stromal cells J Biol Chem 1998 273: 27091–27096

    Article  CAS  PubMed  Google Scholar 

  25. Urwin GH et al.. Generalised increase in bone resorption in carcinoma of the prostate Br J Urol 1985 57: 721–723

    Article  CAS  PubMed  Google Scholar 

  26. Clarke NW, McClure J, George NJ . Morphometric evidence for bone resorption and replacement in prostate cancer Br J Urol 1991 68: 74–80

    Article  CAS  PubMed  Google Scholar 

  27. Papapoulos SE, Hamdy NA, van der Pluijm G . Bisphosphonates in the management of prostate carcinoma metastatic to the skeleton Cancer 2000 88: 3047–3053

    Article  CAS  PubMed  Google Scholar 

  28. Yi B et al.. Tumor-derived platelet-derived growth factor-BB plays a critical role in osteosclerotic bone metastasis in an animal model of human breast cancer Cancer Res 2002 62: 917–923

    CAS  PubMed  Google Scholar 

  29. Ikeda I, Miura T, Kondo I . Pyridinium cross-links as urinary markers of bone metastases in patients with prostate cancer Br J Urol 1996 77: 102–106

    Article  CAS  PubMed  Google Scholar 

  30. Hughes DE et al.. Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo J Bone Miner Res 1995 10: 1478–1487

    Article  CAS  PubMed  Google Scholar 

  31. Selander KS et al.. Characteristics of clodronate-induced apoptosis in osteoclasts and macrophages Mol Pharmacol 1996 50: 1127–1138

    CAS  PubMed  Google Scholar 

  32. Frith JC et al.. Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosine 5′-(beta, gamma-dichloromethylene) triphosphate, by mammalian cells in vitro J Bone Miner 1997 12: 1358–1367

    Article  CAS  Google Scholar 

  33. Goldstein JL, Brown MS . Regulation of the mevalonate pathway Nature 1990 343: 425–430

    Article  CAS  PubMed  Google Scholar 

  34. Luckman et al.. Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras J Bone Miner Res 1998 13: 581–589

    Article  CAS  PubMed  Google Scholar 

  35. Cox AD . Farnesyltransferase inhibitors: potential role in the treatment of cancer Drugs 1902 61: 723–732

    Article  Google Scholar 

  36. Danesi R et al.. Phenylacetate inhibits protein isoprenylation and growth of the androgen-independent LNCaP prostate cancer cells transfected with the T24 Ha-ras oncogene Mol Pharmacol 1996 49: 972–979

    CAS  PubMed  Google Scholar 

  37. Shipman CM et al.. The bisphosphonate incadronate (YM175) causes apoptosis of human myeloma cells in vitro by inhibiting the mevalonate pathway Cancer Res 1998 58: 5294–5297

    CAS  PubMed  Google Scholar 

  38. Aparicio A et al.. In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates Leukaemia 1998 12: 220–229

    Article  CAS  Google Scholar 

  39. Senaratne SG et al.. Bisphosphonates, induce apoptosis in human breast cancer cell lines Br J Cancer 2000 82: 1459–1468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Senaratne SG, Colston KW . Mechanisms involved in aminobisphosphonate-induced apoptosis in breast cancer cells Proc Am Assoc Cancer Res 2001 Abstract 2377

  41. Lee MV, Fong EM, Singer FR, Guenette RS . Bisphosphonate treatment inhibits the growth of prostate cancer cells Cancer Res 2001 61: 2602–2608

    CAS  PubMed  Google Scholar 

  42. Oades GM et al.. Mechanisms of bisphosphonate induced apoptosis in prostate cancer Eur Urol (supplements) 2002 1: Abstract

  43. Nemoto R et al.. Effects of a new bisphosphonate (AHBuBP) on osteolysis induced by human prostate cancer cells in nude mice J Urol 1990 144: 770–774

    Article  CAS  PubMed  Google Scholar 

  44. Sun YC, Geldof AA, Newling DW, Rao BR . Progression delay of prostate tumor skeletal metastasis effects by bisphosphonates J Urol 1992 148: 1270–1273

    Article  CAS  PubMed  Google Scholar 

  45. Wood J, Schnell JR, Green JR . Zoledronic acid (Zometa), a potent inhibitor of bone resorption, inhibits proliferation and induces apoptosis in human endothelial cells in vitro and is anti-angiogenic in a murine growth factor implant model ASCO 2000 Abstract 2620

  46. Boissier S et al.. Bisphosphonates inhibit breast and prostate carcinoma cell invasion an early event in the formation of bone metastases Cancer 2000 60: 2949–2954

    CAS  Google Scholar 

  47. Bae SN et al.. Molecular and cellular analysis of basement membrane invasion by human breast cancer cells in Matrigel-based in vitro assays Breast Cancer Res Treat 1993 24: 241–255

    Article  CAS  PubMed  Google Scholar 

  48. Orr FW, Lee J, Duivenvoorden WC, Singh G . Pathophysiologic interactions in skeletal metastasis Cancer 2000 88: 2912–2918

    Article  CAS  PubMed  Google Scholar 

  49. Teronen O et al.. Inhibition of matrix metalloproteinase-1 by dichloromethylene bisphosphonate (clodronate) Calcif Tissue Int 1997 61: 59–61

    Article  CAS  PubMed  Google Scholar 

  50. van der Pluijm G et al.. Bisphosphonates inhibit the adhesion of breast cancer cells to bone matrices in vitro. J Clin Invest 1996 98: 698–705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Boissier S et al.. Bisphosphonates inhibit prostate and breast carcinoma cell adhesion to unmineralized and mineralized bone extracellular matrices Cancer Res 1997 57: 3890–3894

    CAS  PubMed  Google Scholar 

  52. Pavlakis N, Stockler M . Bisphosphonates in breast cancer (Cochrane Review) Cochrane Database Syst 1902 CD003474

  53. Adami S et al.. Dichloromethylene-diphosphonate in patients with prostatic carcinoma metastatic to the skeleton J Urol 1985 134: 1152–1154

    Article  CAS  PubMed  Google Scholar 

  54. Kylmala T, Tammela TL, Lindholm TS, Seppanen J . 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

    CAS  PubMed  Google Scholar 

  55. Cresswell SM 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

    Article  CAS  PubMed  Google Scholar 

  56. Elomaa I et al.. Effect of oral clodronate on bone pain. A controlled study in patients with metastic prostatic cancer Int Urol Nephrol 1992 24: 159–166

    Article  CAS  PubMed  Google Scholar 

  57. Strang P 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

    CAS  PubMed  Google Scholar 

  58. Kylmala T 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

    Article  CAS  PubMed  Google Scholar 

  59. Carey PO, Lippert MC . Treatment of painful prostatic bone metastases with oral etidronate disodium Urology 1988 32: 403–407

    Article  CAS  PubMed  Google Scholar 

  60. Smith JAJ . 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

    Article  PubMed  Google Scholar 

  61. Clarke NW, Holbrook IB, McClure J, George NJ . Osteoclast inhibition by pamidronate in metastatic prostate cancer: a preliminary study Br J Cancer 1991 63: 420–423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Pelger RC, Lycklama, Papapoulos SE . Short-term metabolic effects of pamidronate in patients with prostatic carcinoma and bone metastases Lancet 1989 2: 865

    Article  CAS  PubMed  Google Scholar 

  63. Lipton A et al.. Pamidronate in the treatment of bone metastases: results of 2 dose-ranging trials in patients with breast or prostate cancer Ann 1994 5: (Suppl 7) S3–S35

    Google Scholar 

  64. Haegerstam GA . Pathophysiology of bone pain: a review Acta Orthop Scand 2001 72: 308–317

    Article  CAS  PubMed  Google Scholar 

  65. Daniell HW . Osteoporosis after orchiectomy for prostate cancer J Urol 1997 157: 439–444

    Article  CAS  PubMed  Google Scholar 

  66. Townsend MF, Sanders WH, Northway RO, Graham SDJ . Bone fractures associated with luteinizing hormone-releasing hormone agonists used in the treatment of prostate carcinoma Cancer 1997 79: 545–550

    Article  CAS  PubMed  Google Scholar 

  67. Lipton A et al.. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials Cancer 2000 88: 1082–1090

    Article  CAS  PubMed  Google Scholar 

  68. Berenson JR et al.. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group N Engl J Med 1996 334: 488–493

    Article  CAS  PubMed  Google Scholar 

  69. Dearnaley DP, Sydes MR . Preliminary evidence that oral clodronate delays symptomatic progression of bone metastasis from prostate cancer: First results of the MRC Pr05 trial ASCO 2001 Abstract 693

  70. Lipton A, Small E, Saad F . The new bisphosphonate, Zometa (zoledronic acid), decreases skeletal complications in both lytic and blastic lesions: a comparison to pamidronate Chemotherapy Foundation Symposium XIX 2001 Abstract 34

  71. Percival RC, Watson ME, Williams JL, Kanis JA . Carcinoma of the prostate: remission of paraparesis with inhibitors of bone resorption Postgrad Med J 1985 61: 551–553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Diel IJ et al.. Reduction in new metastases in breast cancer with adjuvant clodronate treatment N Engl J Med 1998 339: 357–363

    Article  CAS  PubMed  Google Scholar 

  73. Powles TJ, Paterson AHG, Nevantaus A, Legault S . Adjuvant clodronate reduces the incidence of bone metastases in patients with primary operable breast cancer Proc Am Soc Clin Oncol 1998 17: 123, Abstract 468

    Google Scholar 

  74. Saarto T, Blomqvist C, Virkkunen P, Elomaa I . Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-y results of a randomized controlled trial J Clin Oncol 2001 19: 10–17

    Article  CAS  PubMed  Google Scholar 

  75. Vassilopoulou-Sellin R, Newman BM, Taylor SH, Guinee VF . Incidence of hypercalcemia in patients with malignancy referred to a comprehensive cancer center Cancer 1993 71: 1309–1312

    Article  CAS  PubMed  Google Scholar 

  76. Cramer SD, Chen Z, Peehl DM . Prostate specific antigen cleaves parathyroid hormone-related protein in the PTH-like domain: inactivation of PTHrP-stimulated cAMP accumulation in mouse osteoblasts J Urol 1996 156: 526–531

    Article  CAS  PubMed  Google Scholar 

  77. Riancho JA et al.. The clinical spectrum of hypocalcaemia associated with bone metastases J Intern Med 1989 226: 449–452

    Article  CAS  PubMed  Google Scholar 

  78. Szentirmai M, Constantinou C, Rainey JM, Loewenstein JE . Hypocalcemia due to avid calcium uptake by osteoblastic meta-stases of prostate cancer West J Med 1995 163: 577–578

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Rico H et al.. Hyperparathyroidism in metastases of prostatic carcinoma: a biochemical, hormonal and histomorphometric study Eur Urol 1990 17: 35–39

    Article  CAS  PubMed  Google Scholar 

  80. Murray et al.. Hypocalcemic and normocalcemic hyperparathyroidism in patients with advanced prostatic cancer J Clin Endocrinol Metab 2001 86: 4133–4138

    Article  CAS  PubMed  Google Scholar 

  81. Yoneda T . Cellular and molecular mechanisms of breast and prostate cancer metastasis to bone Eur J Cancer 1998 34: 240–245

    Article  CAS  PubMed  Google Scholar 

  82. Grill V et al.. Circulating PTH and PTHrP levels before and after treatment of tumor induced hypercalcemia with pamidronate disodium (APD) J Clin Endocrinol Metab 1992 74: 1468–1470

    CAS  PubMed  Google Scholar 

  83. Berruti A et al.. Pamidronate administration improves the secondary hyperparathyroidism due to ‘Bone Hunger Syndrome’ in a patient with osteoblastic metastases from prostate cancer Prostate 1997 33: 252–255

    Article  CAS  PubMed  Google Scholar 

  84. The Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial Br J Urol 1997 79: 235–246

  85. Bolla M et al.. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin N Engl J Med 1997 337: 295–300

    Article  CAS  PubMed  Google Scholar 

  86. Pilepich MV et al.. Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: report of radiation Therapy Oncology Group Protocol 85–31 J Clin Oncol 1997 15: 1013–1021

    Article  CAS  PubMed  Google Scholar 

  87. Messing EM et al.. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer N Engl J Med 1999 341: 1781–1788

    Article  CAS  PubMed  Google Scholar 

  88. Daniell HW et al.. Progressive osteoporosis during androgen deprivation therapy for prostate cancer J Urol 2000 163: 181–186

    Article  CAS  PubMed  Google Scholar 

  89. Maillefert JF et al.. Bone mineral density in men treated with synthetic gonadotropin-releasing hormone agonists for prostatic carcinoma J Urol 1999 161: 1219–1222

    Article  CAS  PubMed  Google Scholar 

  90. Smith MR et al.. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer N Engl J Med 2001 345: 948–955

    Article  CAS  PubMed  Google Scholar 

  91. Diamond TH et al.. The antiosteoporotic efficacy of intravenous pamidronate in men with prostate carcinoma receiving combined androgen blockade: a double blind, randomized, placebo-controlled crossover study Cancer 2001 92: 1444–1450

    Article  CAS  PubMed  Google Scholar 

  92. Rodan GA, Martin TJ . Therapeutic approaches to bone diseases Science 2000 289: 1508–1514

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Urology, St George's Hospital and Medical School, London, UK

    G M Oades

  2. Department of Oncology, Gastroenterology, Endocrinology and Metabolism, St George's Hospital and Medical School, London, UK

    J Coxon & K W Colston

Authors
  1. G M Oades
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Coxon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K W Colston
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G M Oades.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Oades, G., Coxon, J. & Colston, K. The potential role of bisphosphonates in prostate cancer. Prostate Cancer Prostatic Dis 5, 264–272 (2002). https://doi.org/10.1038/sj.pcan.4500607

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.pcan.4500607

Keywords

This article is cited by

Search

Advanced search

Quick links