Skip to main content
SpringerLink
Log in

The Role of Bisphosphonates in Bone Metastasis

  • Chapter
Bone Metastasis and Molecular Mechanisms

Part of the book series: Cancer Metastasis — Biology and Treatment ((CMBT,volume 6))

Abstract

Bisphosphonates are analogs of pyrophosphate, which is a naturally occurring regulator of bone mineralization with the chemical structure P-O-P (see Figure 1). These compounds were first synthesized in Germany in 1865. Their initial use was industrial (textile, fertilizer and oil industries) and for prevention of mineral scaling (due to their ability to inhibit calcium carbonate precipitation). The biological properties of these compounds, however, were not explored until the 1960’s (1, 2).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Fleisch H, Russel RG, Francis MD. Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone absorption in tissue culture and in vivo. Science, 165: 1262–1264, 1996.

    Article  Google Scholar 

  2. Fliesch H. Bisphosphonates in Bone Disease: From the Laboratory to the Patient. Parthenon Publishing Group Inc. 1997.

    Google Scholar 

  3. Rogers MJ, Gordon S, Benford HL, Coxon FP, Luckman SP, Monkkonen J, Frith JC. Cellular and Molecular Mechanisms of Action of Bisphosphonates. Cancer, 88: 2961–2978, 2000.

    Article  PubMed  CAS  Google Scholar 

  4. Benford HL, McGowan NWA, Helfrich MH, Nuttall ME, Rogers MJ. Visualization of bisphosphonate-induced caspase-3 activity in apoptotic osteoclasts in vitro. Bone. 28: 65–473, 2001.

    Article  Google Scholar 

  5. Dunford JE, Thompson K, Coxon FP, Luckman SP, Hahn FM, Poulter CD, Ebetineo FH, Rogers MJ. Structure-activity relationships for inhibition of farnesyl diphosphonate syntase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther, 296: 235–242, 2001.

    PubMed  CAS  Google Scholar 

  6. Senaratne SG, Colston KW. Direct effects of bisphosphonates on breast cancer cells. Breast Cancer Rev, 4: 18–23. 2002.

    Article  CAS  Google Scholar 

  7. Bergstrom JD, Bostedor RG, Masarachia PJ, Reszka AA, Rodan G. Alendronate is a specific, nanomolar inhibitor of farnesyl disphosphonate synthase. Arch Biochem Biophys, 373: 231–241, 2000.

    Article  PubMed  CAS  Google Scholar 

  8. Coxon FP, Helfrich MH, Van’t Hof R, Sebti S, Ralston SH, Hamilton A, Rogers MJ. Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298. J Bone Miner Res, 15: 1467–1476, 2000.

    Article  PubMed  CAS  Google Scholar 

  9. Hughes DE, Wright KR, Uy HL, Sasaki A, Yoneda T, Roodman GD, Mundy GR, Boyce BF. Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J Bone Miner Res, 10: 1478–1487, 1995.

    Article  PubMed  CAS  Google Scholar 

  10. Hiroi-Furuya E, Kameda T, Hiura K, Mano H, Miyazawa K, Nakamaru Y, Watanabe-Mano M, Okuda N, Shimada J, Yamamoto Y, Hakdea Y, Kumegawa M. Etidronate (EHDP) inhibits osteoclastic-bone resorption, promotes apoptosis and disrupts actin rings in isolate-mature osteoclasts. Calcif Tissue Int, 64: 219–223, 1999.

    Article  PubMed  CAS  Google Scholar 

  11. Ito M, Amizuka N, Nakajima T, Ozawa H. Ultrastructural and cytochemical studies on cell death of osteoclasts induced by bisphosphonate treatment. Bone, 25: 447–452, 1999.

    Article  PubMed  CAS  Google Scholar 

  12. Selander KS, Monkkonen J, Karhukorpi EK, Harkonen P, Hannuniemi R, Vaananen HK. Characteristics of clodronate-induced apoptosis in osteoclasts and macrophages. Mol Pharmacol, 50: 1127–1138, 1996.

    PubMed  CAS  Google Scholar 

  13. Halasy-Nagy JM, Rodan GA, Reska AA. Inhibition of bone resorption by alendronate and risedronate does not require osteoclast apoptosis. Bone, 29: 553–559, 2001.

    Article  PubMed  CAS  Google Scholar 

  14. Murakami H, Takahashi N, Sasaki T, Udagawa N, Tanaka S, Nakamura I, Zhang D, Barbier A, Suda A. A possible mechanism of the specific action of bisphosphonates on osteoclasts: tiludronate preferentially affects polarized osteoclasts having ruffled borders. Bone, 17: 137–144, 1995.

    Article  PubMed  CAS  Google Scholar 

  15. Miller SC, Jee WS. The effect of dichloromethylene diphosphonate, a pyrophosphate analog, on bone and bone cell structure in the growing rat. Anat Rec, 193: 439–462, 1979.

    Article  PubMed  CAS  Google Scholar 

  16. Sato M, Grasser W, Endo N, Akins R, Simmons H, Thompson DD, Golub E, Rodan GA. Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure. Clin Invest, 88: 2095–2105, 1991.

    Article  CAS  Google Scholar 

  17. Ito M, Amizuka N, Nakajima T, Ozawa H. Bisphosphonate acts on osteoclasts independent of ruffled borders in osteosclerotic (oc/oc) mice. Bone, 28: 609–616, 2001.

    Article  PubMed  CAS  Google Scholar 

  18. Alakangas A, Selander K, Mulari M, Helleen J, Lehenkari P, Monkkonen J, Salo J, Vaanenen K. Alendronate disturbs vesicular trafficking in osteoclasts. Calcif Tissue, 70: 40–47, 2002.

    Article  CAS  Google Scholar 

  19. Sezar O, Heider U, Zavrski I, Kuhne CA, Hofbauer LC. RANK ligand and osteoprotegerin in myeloma bone disease. Blood, 10: 2094–2098, 2003.

    Article  Google Scholar 

  20. Evans CE, Braidman IP. Effects of two novel bisphosphonates on bone cells in vitro. Bone Miner, 26: 95–107, 1994.

    Article  PubMed  CAS  Google Scholar 

  21. Lowik CW, van der Pluijm G, van der Wee-Pals LJ, Van Treslong-De Groot HB, Bijvoet OL. Migration and phenotypic transformation of osteoclast precursors into mature osteoclasts: the effect of a bisphosphonate. Bone Miner Res, 3: 185–192, 1998.

    Article  Google Scholar 

  22. Nishikawa M, Yamamoto M, Murakami T, Akatsu T, Kugai N, Nagata N. A third-generation bisphosphonate, YM175, inhibits osteoclast formation in murine cocultures by inhibiting proliferation of precursor cells via support cell-dependent mechanisms. J Bone Miner Res, 13: 986–995, 1998.

    Article  PubMed  CAS  Google Scholar 

  23. Clohisy DR, O’Keefe PF, Ramnaraine ML. Pamidronate decreases tumor-induced osteoclastogenesis in osteopetrotic mice. J Orthop Res, 19: 554–558, 2001.

    Article  PubMed  CAS  Google Scholar 

  24. Viereck V, Emons G, Lauck V. Bisphosphonates pamidronate and zoledronic acid stimulate osteoprotegerin production by primary human osteoblasts. Biochem Res Commun, 291: 680–686, 2002.

    Article  CAS  Google Scholar 

  25. Breuil V, Cosman F, Stein L, Hobart W, Nieves J, Shen V. Human osteoclast formation and activity in vitro: effects of alendronate. J Bone Miner Res, 13: 1721–1729, 1998.

    Article  PubMed  CAS  Google Scholar 

  26. Reinholz GG, Getz B, Pederson L, Sanders ES, Subramaniam M, Ingle JN, Spelsberg TC. Bisphosphonates directly regulate cell proliferation, differentiation, and gene expression in human osteoblasts. Cancer Res, 60: 6001–6007, 2000.

    PubMed  CAS  Google Scholar 

  27. Reinholz GG, Getz B, Sanders ES, Karpeisky MY, Padyukova NSh, Mikhailov SN, Ingle JN, Spelsberg TC. Distinct mechanisms of bisphosphonate action between osteoblasts and breast cancer cells: identity of a potent new bisphosphonate analogue. Breast Cancer Res, 71: 257–268, 2002.

    Article  CAS  Google Scholar 

  28. Vitte C, Fleisch H, Guenther HL. Bisphosphonates induce osteoblasts to secrete an inhibitor of osteoclast-mediated resorption. Endocrinology, 137: 2324–2333, 1996.

    Article  PubMed  CAS  Google Scholar 

  29. Yu X, Scholler J, Foged NT. Interaction between effects of parathyroid hormone and bisphosphonate on regulation of osteoclast activity by the osteoblast-like cell line UMR106. Bone, 19: 339–345, 1996.

    Article  PubMed  CAS  Google Scholar 

  30. Gomez-Garcia L, Esbrit P, Carreno L, Sabando P, Garcia-Flores M, Martinez ME. Alendronate interacts with the inhibitory effect of 1,25(OH)2D3 on parathyroid hormone-related protein expression in human osteoblastic cells. J Bone Miner Res, 18: 78–87, 2003.

    Article  PubMed  CAS  Google Scholar 

  31. Clezardin P, Fournier P, Boissier S, Peyruchaud O. In vitro and in vivo antitumor effects of bisphosphonates. Curr Med Chem, 10: 173–180, 2003.

    Google Scholar 

  32. van der Pluijm G, Vloedgraven H, van Beek E, van der Wee-Pals L, Lowik C, Papapoulos S. Bisphosphonates inhibit the adhesion of breast cancer cells to bone matrices in vitro. J Clin Invest, 98: 698–705, 1996.

    Article  PubMed  Google Scholar 

  33. Boissier S, Ferreras M, Payruchaud O, Magnetto S, Ebetino FH, Colombel M, Delmas P, Delaisse JM, Clezardin P. Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res, 60: 2949–2054, 2000.

    PubMed  CAS  Google Scholar 

  34. Neville-Webbe HL, Holen I, Coleman RE. The anti-tumor activity of bisphosphonates. Cancer Treat Rev, 28: 305–319, 2000.

    Article  Google Scholar 

  35. Teronen O, Heikkila P, Konttinen YT, Laitinen M, Salo T, Hanemaaijer R, Teronen A, Maisi P, Sorsa T. MMP inhibition and downreguation by bisphosphonates. Ann NY Acad Sci, 878: 453–465, 1999.

    Article  PubMed  CAS  Google Scholar 

  36. Derenne S, Amiot M, Barille S, Collette M, Robillard N, Berthaud P, Harousseau JL, Bataille R. Zoledronate is a potent inhibitor of myeloma cell growth and secretion of IL-6 and MMP-1 by the tumoral environment. J Bone Miner Res, 14: 2048–2056, 1999.

    Article  PubMed  CAS  Google Scholar 

  37. Ichinose Y, Migita K, Nakashima T, Kawakami A, Aoyagi T, Eguchi K. Effects of bisphosphonate on the release of MMP-2 from cultured human osteoblasts. Tohuko J Exp Med, 192: 111–118, 2000

    Article  CAS  Google Scholar 

  38. Green J. Bisphosphonates in cancer therapy. Curr Opin Oncol, 14: 609–615, 2002.

    Article  PubMed  CAS  Google Scholar 

  39. Corey E, Brown LG, Quinn JE, Poot M, Roudier MP, Higano CS, Vessella RL. Zoledronic acid exhibits inhibitory effects on osteoblastic and osteolytic metastases of prostate cancer. Clin Cancer Res, 9: 295–306, 2003.

    PubMed  CAS  Google Scholar 

  40. Wood J, Bonjean K, Ruetz S, Bellahcene A, Devy L, Foidart JM, Castronovo V, Green JR. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther, 302: 1055–1061, 2002.

    Article  PubMed  CAS  Google Scholar 

  41. Fournier P, Boissier S, Filleur S, Guglielmi J, Cabon F, Colombel M, Clezardin P. Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res, 62: 6538–6544, 2002.

    PubMed  CAS  Google Scholar 

  42. Croucher PI, De Hendrick R, Perry MJ, Hijzen A, Shipman CM, Lippitt J, Green J, Van Marck E, Van Camp B, Vanderkerken K. Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease: evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival. J Bone Miner Res, 18: 483–492, 2003.

    Article  Google Scholar 

  43. Santini D, Vicenzi B, Avvisati G, Dicuonzo G, Battistoni F, Gavasci M. Salerno A, Denaro V, Tonini G. Pamidronate induces modifications of circulating angiogenetic factors in cancer patients. Clin Cancer Res; 8: 1080–1084, 2002.

    PubMed  CAS  Google Scholar 

  44. Jagdev SP, Coleman RE, Shipman CM, Rostami A, Croucher PI. The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel. Br J Cancer; 84: 1126–1134, 2001.

    Article  PubMed  CAS  Google Scholar 

  45. Yoneda T, Michigami T, Yi B, Williams PJ, Niewlona M, Hiraga T. Actions of bisphosphonate on bone metastasis in animal models of breast carcinoma. Cancer, 88: 2979–2988, 2000.

    Article  PubMed  CAS  Google Scholar 

  46. Witters L, Crispino J, Javeed M. Inhibition of growth of a human prostate cancer cell line with the combination of zoledronic acid and a COX-2 inhibitor. (Abst) Proc Am Soc Clin Oncol, 1827, 2002.

    Google Scholar 

  47. Brown JE, Coleman RE. The present and future role of bisphosphonates in the management of patients with breast cancer. Breast Cancer Res, 4: 24–29, 2002.

    Article  PubMed  CAS  Google Scholar 

  48. Pavlakis N, Stockler M. Bisphosphonates for breast cancer. Cochrane Database Syst Rev, (1):CD003474, 2002.

    Google Scholar 

  49. Diel I, Solomayer ER, Costa SD, Gollan C, Goener R. eduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med, 339: 357–363, 1998.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  51. DeVita VT, Hellman S, Rosenburg S. Cancer: Principles and Practice of Oncology Sixth Edition. Lippincott, Williams and Wilkins 2002.

    Google Scholar 

  52. Djulbegovic B, Wheatly K, Ross J, Clark O, Bos G, Goldschmidt H, Cremer F, Alsina M, Glasmacher A. Bisphosphonates in multiple myeloma. The Cochrane Library 2002.

    Google Scholar 

  53. Saad F, Gleason DM, Marray R, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goas J, Chen B. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory prostate carcinoma. J Natl Cancer Inst, 94: 1458–1468, 2002.

    Article  PubMed  CAS  Google Scholar 

  54. Smith MR, Eastham J, Gleason DM, Shasha D, Tchekmedyian S, Zinner N. Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol, 169: 2008–2012, 2003.

    Article  PubMed  CAS  Google Scholar 

  55. Paterson AHG, Powles TJ, Kanis JA. Double blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol, 11: 59–65, 1993.

    PubMed  CAS  Google Scholar 

  56. Kanis JA, Powles T, Paterson AHG. Clodronate decreases the frequency of skeletal metastases in women with breast cancer. Bone, 19: 663–667, 1996.

    Article  PubMed  CAS  Google Scholar 

  57. Hortobagyi GN, Theriault RL, Porter L, Blaney D, Lipton A, Sinoff C. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. N Engl J Med, 335: 1785–1791, 1996.

    Article  PubMed  CAS  Google Scholar 

  58. Kristensen B, Ejlertsen B, Groenvold M, Hein S, Loft H, Mouridsen HT. Oral clodronate in breast cancer patients with bone metastases: a randomised study. J Intern Med, 246: 67–74, 1999.

    Article  PubMed  CAS  Google Scholar 

  59. Theriault RL, Lipton A, Hortobagyi GN, Leff R, Gluck S, Stewart JF, Costello S, Kennedy I. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: A randomised placebo-controlled trial. J Clin Oncol, 17: 846–854, 1999.

    PubMed  CAS  Google Scholar 

  60. Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, Mackey JA 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, 7: 377–87, 2001.

    CAS  Google Scholar 

  61. Powles T, Paterson S, Kanis JA, McCloskey E, Ashley S, Tidy A. Randomised placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol, 20: 3219–3224, 2002.

    Article  PubMed  CAS  Google Scholar 

  62. Belch AR, Bergsagel DE, Wilson K, O’Reilly S, Wilson J, Sutton D, Pater J, Johnston D, Zee B. Effect of daily etidronate on the osteolysis of multiple myeloma. J Clin Oncol, 9: 1397–1402, 1991.

    PubMed  CAS  Google Scholar 

  63. Lahtinen R, Laasko M, Palva I, Virkkunen P, Elomaa I. Randomised, placebo-controlled multicentre trial of clodronate in multiple myeloma. Lancet, 340: 1049–1052, 1992.

    Article  PubMed  CAS  Google Scholar 

  64. Brinker H, Westin J, Abildgaard N, Gimsing P, Turesson I, Hedenus M, Ford J, Kandra A. Failure of oral pamidronate to reduce skeletal morbidity in multiple myeloma: a double-blind placebo-controlled trial. Br J Haematol, 101: 280–286, 1998.

    Article  Google Scholar 

  65. Berenson JR, Lichtenstein A, Porter L, Dimopoulos MA, Bordoni R, George S, Lipton A, Keller A. Long term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. J Clin Oncol, 16: 593–602, 1998.

    PubMed  CAS  Google Scholar 

  66. Terpos E, Palermos J, Tsionos K, Anargyrou K, Vinious N Effect of pamidronate administration on markers of bone turnover and disease activity in multiple myeloma. Eur J Haematol, 65: 331–336, 2000.

    CAS  Google Scholar 

  67. Mccloskey EV, Dunn JA, Kanis JA, MacLennan IC, Drayson MT. Long-term follow-up of a prospective, double-blind, placebo-controlled randomised trial of clodronate in multiple myeloma. Br J Haematol, 113: 1035–43, 2001.

    Article  PubMed  CAS  Google Scholar 

  68. Menssen HD, Sakalova A, Fontana A, Herrmann Z, Boewer C, Facon T, Lichinitser MR, Singer CR. Effects of long-term intravenous ibandronate therapy on skeletal-related events, survival, and bone resorption markers in patients with advanced multiple myeloma. J Clin Oncol, 20: 2353–2359, 2002.

    Article  PubMed  CAS  Google Scholar 

  69. 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, 141: 85–87, 1989.

    PubMed  Google Scholar 

  70. Strang P, Nilsson S, Brandstedt S, Sehlin J, Borghede G, Varenhorst E, Bandman U, Borck L, EnglundG, Selin L. The analgesic efficacy of clodronate compared with placebo in patients with painful bone metastases from prostatic cancer. Anticancer Res, 17: 4717–4721, 1997.

    PubMed  CAS  Google Scholar 

  71. Pelger RC, Hamdy NA, Zwinderman AH, Lycklama a Nijeholt AA, Papapoulos SE. Effect of the bisphosphonate olpadronate in patient with carcinoma of the prostate metastatic to the skeleton. Bone, 22: 403–408, 1998.

    Article  PubMed  Google Scholar 

  72. Heidenreich A, Hofmann R, Engelmann UH. The use of bisphosphonate for the palliative treatment of painful bone metastases due to hormone refractory prostate cancer. J Urol, 165: 136–140, 2001.

    Article  PubMed  CAS  Google Scholar 

  73. Heidenreich A, Elert A, Hofmann R. Ibandronate in the treatment of prostate cancer associated with painful osseous metastases. Prostate Cancer Prostatic Dis, 5: 231–235, 2002.

    Article  PubMed  CAS  Google Scholar 

  74. Ernst DS, Tannock IF, Venner PM, Winquist EW, Reyno L, Walker H, Ding K, Elliot C, Parulekar W. Randomized placebo controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone alone in patients with hormone refractory prostate cancer. (Abst) Proc Am Soc Cin Oncol 21: 705, 177a, 2002.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Juravinski Cancer Centre, Hamilton, Ontario, Canada

    Mary MacKenzie & Pierre Major

Authors
  1. Mary MacKenzie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pierre Major
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Juravinski Cancer Centre, McMaster University, Hamilton, Ontario, Canada

    Gurmit Singh (Director of Research, Professor of Pathology & Molecular Medicine) (Director of Research, Professor of Pathology & Molecular Medicine)

  2. Department of Pathology, University of Manitoba, Winnipeg, Manitoba, Canada

    William Orr (Chair) (Chair)

Rights and permissions

Reprints and permissions

Copyright information

© 2004 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

MacKenzie, M., Major, P. (2004). The Role of Bisphosphonates in Bone Metastasis. In: Singh, G., Orr, W. (eds) Bone Metastasis and Molecular Mechanisms. Cancer Metastasis — Biology and Treatment, vol 6. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-2036-0_13

Download citation

  • DOI: https://doi.org/10.1007/978-1-4020-2036-0_13

  • Publisher Name: Springer, Dordrecht

  • Print ISBN: 978-90-481-6563-6

  • Online ISBN: 978-1-4020-2036-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation