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Strategies for Management of Prostate Cancer-Related Bone Pain

  • Therapy In Practice
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Abstract

Prostate cancer is one of the most common malignancies and a leading cause of cancer-related death in men worldwide. In the majority of cases, prostate cancer metastasises to the skeleton, in which case cancer-related bone pain becomes a major cause of morbidity. Androgen ablation is the treatment of choice for securing regression of skeletal metastases in the majority of cases. Intermittent androgen ablation is an attractive alternative, aimed at minimising adverse effects of hormone deprivation but also potentially delaying hormone-refractoriness. The development of hormone-refractoriness is heralded by a significant increase in morbidity largely because of escalating bone pain caused by the progression of the metastatic process. Skilful use of analgesics is initially successful but eventually fails to control symptoms. Localised metastases are best treated with local radiotherapy that is rapidly effective. Over the last few years, it has become clear that therapeutic modalities using bone-seeking radionuclides or bisphosphonates have been effective in the palliation of prostate cancer-related bone pain, although not affecting survival. The main limiting factor with the use of radionuclides is bone marrow suppression, also a feature of the very late stages of prostate cancer. Bisphosphonates do not carry this disadvantage. Results of large double-blind, placebo-controlled studies should be awaited, however, before advocating the widespread use of these agents in the management of patients with prostate cancer and skeletal metastases.

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References

  1. Parker SL, Tong T, Bolden S, et al. Cancer statistics 1996. CA Cancer J Clin 1996; 46: 5–27

    Article  PubMed  CAS  Google Scholar 

  2. Dale A. Office of population censuses and survey. Cancer statistics, England and Wales. London: HMSO Series MBI, 1996

    Google Scholar 

  3. Post PN, Straatman H, Kiemeney LA, et al. Increased risk of fatal prostate cancer may explain the rise of mortality in the Netherlands. Int J Epidemiol 1999; 28: 403–8

    Article  PubMed  CAS  Google Scholar 

  4. Visser O, Coebergh JW, Schouten LJ, et al, editors. Incidence of cancer in the Netherlands 1997. Utrecht: Association of Comprehensive Cancer Centres, 2001

    Google Scholar 

  5. Jacobs SC. Spread of prostatic cancer to bone. Urology 1983; 21: 337–44

    Article  PubMed  CAS  Google Scholar 

  6. Franks LM. The spread of prostatic carcinoma. J Pathol Bacte-riol 1956; 72: 603–11

    Article  Google Scholar 

  7. Abrams HL. Skeletal metastases in carcinoma. Radiology 1950; 55: 534–8

    PubMed  CAS  Google Scholar 

  8. Turner JW, Jaffe HL. Metastatic neoplasms. A clinical and roentgenological study of involvement of skeleton and lungs. Am J Roentgenol 1940; 43: 479

    Google Scholar 

  9. Elkin M, Mueller HP. Metastases from cancer of the prostate. Cancer 1954; 7: 1246–8

    Article  PubMed  CAS  Google Scholar 

  10. Orr FW, Lee J, Duivenvoorden WCM, et al. Pathophysiologic interactions in skeletal metastasis. Cancer 2000; 88: 2912–8

    Article  PubMed  CAS  Google Scholar 

  11. Pantel K, Cote RJ, Fodstad O. Detection and clinical importance of micrometastasic disease. J Natl Cancer Inst 1999; 91: 1113–24

    Article  PubMed  CAS  Google Scholar 

  12. Carter RL. Patterns and mechanisms of bone metastases. J R Soc Med 1985; 78 Suppl. 9: 2–6

    PubMed  Google Scholar 

  13. Stoll BA. Natural history, prognosis and staging of bone metastases. In: Stoll BA, Parbhoo S, editors. Bone metastases: monitoring and treatment. New York: Raven, 1983: 1–20

    Google Scholar 

  14. Guise T, Mundy G. Cancer and bone. Endocr Rev 1998; 19: 18–54

    Article  PubMed  CAS  Google Scholar 

  15. Nielsen OS, Munro AJ, Tannock IF. Bone metastases: pathophysiology and management policy. J Clin Oncol 1991; 9(3): 509–24

    PubMed  CAS  Google Scholar 

  16. Galasko CSB. Mechanisms of lytic and blastic metastatic disease of bone. Clin Orthop 1982; 169: 20–7

    PubMed  Google Scholar 

  17. Paterson AHG. Bone metastases in breast cancer, prostate cancer and myeloma. Bone 1987; 8 Suppl. 1: 17–22

    Google Scholar 

  18. Mundy GR. Bone resorption and turnover in health and disease. Bone 1987; 8 Suppl. 1: 9–16

    Google Scholar 

  19. Batson OV. The function of the vertebral veins and their role in the spread of metastases. Ann Surg 1940; 112: 138–49

    Article  PubMed  CAS  Google Scholar 

  20. Manishen JW, Sivananthan K, Orr FW. Resorbing bone stimulates tumor cell growth. Am J Pathol 1986; 123: 39–45

    PubMed  CAS  Google Scholar 

  21. Hauschka PV, Mavrakos AE, Iafrati MD, et al. Growth factors in bone matrix. Isolation of multiple types by affinity chromatography on heparin sepharose. J Biol Chem 1986; 261: 12665–74

    PubMed  CAS  Google Scholar 

  22. Pfeilschifter J, Mundy GR. Modulation of type β transforming growth factor activity in bone cultures by osteotropic hormones. Proc Natl Acad Sci U S A 1987; 84: 2024–8

    Article  PubMed  CAS  Google Scholar 

  23. Powell GJ, Southby J, Danks JA, et al. Localization of parathyroid hormone-related protein in breast cancer metastases: increased incidence in bone compared with other sites. Cancer Res 1991; 51: 3059–61

    PubMed  CAS  Google Scholar 

  24. Vargas SJ, Gillespie MT, Powell GJ, et al. Localization of parathyroid hormone-related protein mRNA expression and metastatic lesions by in situ hybridization. J Bone Miner Res 1992; 7: 971–80

    Article  PubMed  CAS  Google Scholar 

  25. Bouizar Z, Spyratos F, Deytieux S, et al. Polymerase chain reaction analysis of parathyroid hormone-related protein gene expression in breast cancer patients and occurrence of bone metastases. Cancer Res 1993; 53: 5076–8

    PubMed  CAS  Google Scholar 

  26. Asadi F, Farraj M, Sharifi R, et al. Enhanced expression of parathyroid hormone-related protein in prostate cancer as compared with benign prostatic hyperplasia. Hum Pathol 1996; 27: 1319–23

    Article  PubMed  CAS  Google Scholar 

  27. Rabanni SA, Gladu J, Harakidas P, et al. Overproduction of parathyroid hormone-related peptide results in increased osteolytic skeletal metastases by prostate cancer cells in vivo. Int J Cancer 1999; 18: 257–64

    Google Scholar 

  28. Burton DW, Tu S, Smith KC, et al. PTHrP processed peptides regulate prostate cell growth. Bone 1998; 23: 1423

    Google Scholar 

  29. Mundy GR. Mechanisms of bone metastases. Cancer 1997; 80: 1546–56

    Article  PubMed  CAS  Google Scholar 

  30. 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: 102–6

    Article  PubMed  CAS  Google Scholar 

  31. Goltzman D. Mechanisms of the development of osteoblastic metastases. Cancer 1997; 80 Suppl. 8: 1546–56

    Google Scholar 

  32. Deftos LJ. Granin-A, parathyroid hormone related protein, and calcitonin gene products in neuroendocrine prostate cancer. Prostate 1998; 8: 23–31

    Article  PubMed  CAS  Google Scholar 

  33. Urwin G, Percival R, Harris S, et al. Generalised increase in bone resorption in carcinoma of the prostate. Br J Urol 1985; 57: 721–3

    Article  PubMed  CAS  Google Scholar 

  34. Charhon S, Chapuy MC, Delvin EE, et al. Histomorphometric analysis of sclerotic bone metastases from prostatic carcinoma with special reference to osteomalacia. Cancer 1983; 51: 918–24

    Article  PubMed  CAS  Google Scholar 

  35. Percival RC, Urwin GH, Harris S, et al. Biochemical and histological evidence that carcinoma of the prostate is associated with increased bone resorption. Eur J Surg Oncol 1978; 13: 41–9

    Google Scholar 

  36. Goltzman D. Mechanisms of development of osteoblastic metatstases. Cancer 1997; 80 Suppl. 8: 1581S–7S

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  38. Taube T, Kylmälä T, Lamberg-Allardt C, et al. The effect of clodronate on bone in metastatic prostate cancer. Histomorphometric report on double blind randomized placebo-controlled study. Eur J Cancer 1994; 30: 751–8

    Article  Google Scholar 

  39. Thomas RJ, Guise TA, Yin JJ, et al. Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology 1999; 140: 4451–8

    Article  PubMed  CAS  Google Scholar 

  40. Berretoni BA, Carter JR. Mechanisms of Cancer Metastasis to Bone. J Bone and Joint Surg 1986; 68A: 308–12

    Google Scholar 

  41. Willems A. Secondary tumours of bones. In: The spread of tumours in the human body. 3rd ed. London: Butterworth, 1973: 229–250

    Google Scholar 

  42. Lote K, Walloe A, Bjersand A. Bone metastases. Prognosis, diagnosis and treatment. Acta Radiol Oncol 1986; 25: 227–32

    Article  PubMed  CAS  Google Scholar 

  43. Mauch PM, Drew MA. Treatment of metastatic cancer to bone. In: De Vita Jr VT, Helleman S, Rosenberg SA, et al. Cancer, principles & practice of oncology. Philadelphia (PA): Lippincott, 1985: 2132–2141

    Google Scholar 

  44. Malawer MM, Delaney TF. Treatment of metastatic cancer to bone. In: De Vita Jr VT, Hellman S, Rosenberg SA, et al. Cancer, principles & practice of oncology. Philadelphia (PA): Lippincott, 1985: 2298–2317

    Google Scholar 

  45. Miller F, Whitehill R. Carcinoma of the breast metastatic to the skeleton. Clin Orthop 1984; 184: 121–7

    PubMed  Google Scholar 

  46. Bhalla SK. Metastatic disease of the spine. Clin Orthop 1970; 73: 52–60

    PubMed  CAS  Google Scholar 

  47. Drew M, Dickson RB. Osseous complications of malignancy. In: Lokich JJ, editor. Clinical cancer medicine: treatment tactics. Boston: GK Hall, 1980: 97

    Google Scholar 

  48. Enneking WF. Metastatic carcinoma. Musculoskeletal tumor surgery. Vol. 2. New York: Churchill Livingstone, 1983: 1541

    Google Scholar 

  49. Chisholm GD, Rana A, Howard GCW. Management options for painful carcinoma of the prostate. Sem Oncol 1993; 20 (3 Suppl. 2): 34–7

    CAS  Google Scholar 

  50. Tofe AJ, Francis MD, Harvey WJ. Correlations of neoplasms with incidence and localization of bone metastases: an analysis of 1,355 diphosphonate bone scans. J Nucl Med 1975; 16: 986–9

    PubMed  CAS  Google Scholar 

  51. Rubens RD. The nature of metastatic bone disease. In: Rubens Rd, Fogelman I, editors. Bone metastases: diagnosis and treatment. London: Springer-Verlag, 1991: 1–10

    Google Scholar 

  52. Klotz L. Hormone Therapy for patients with prostate carcinoma. Cancer 2000; 88 Suppl. 12: 3009–14

    Article  PubMed  CAS  Google Scholar 

  53. Huggins C, Hodges CV. Studies on prostate cancer: the effect of estrogens and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941; 1: 293–7

    CAS  Google Scholar 

  54. Schroder FH. Endocrine treatment of prostrate cancer. In: Walsh PC, Retik AB, Vaughan ED, et al., editors. Campbell Urology. Vol. 3. Philadelphia: WB Saunders Company, 1998: 2627–44

    Google Scholar 

  55. Daniell HW. Osteoporosis after orchidectomy for prostate cancer. J Urol 1997; 157: 439–44

    Article  PubMed  CAS  Google Scholar 

  56. Fossa SD, Dearnaley DP, Law M. Prognostic factors in hormone-resistant progressing cancer of the prostate. Ann Oncol 1992; 3: 361–6

    PubMed  CAS  Google Scholar 

  57. Goldenberg SL, Bruchovsky N, Gleave ME, et al. Intermittent androgen suppression in the treatment of prostate cancer: a preliminary report. Urology 1995; 45: 839–45

    Article  PubMed  CAS  Google Scholar 

  58. John A, Campa L, Payne R. The management of intractable bone pain: a clinicians perspective. Semin Nucl Med 1992; 22: 3–10

    Google Scholar 

  59. Inturrisi C. Management of cancer pain. Cancer 1989; 63: 2308–20

    Article  PubMed  CAS  Google Scholar 

  60. Benson Jr RC, Hasa SM, Jones AG, et al. External beam radiotherapy for palliation of pain for metastatic carcinoma of the prostate. J Urol 1982; 127: 69–71

    PubMed  Google Scholar 

  61. Kynaston HG, Keen CW, Matthews PN. Radiotherapy for palliation of locally advanced prostatic cancer. Br J Urol 1990; 66: 515–7

    Article  PubMed  CAS  Google Scholar 

  62. Winston MA. Radioisotope therapy in bone and joint disease. Semin Nucl Med 1979; 2: 114–9

    Google Scholar 

  63. Hamdy NAT, Papapoulos SE. The palliative management of skeletal metastases in prostate cancer: use of bone-seeking radionuclides and bisphosphonates. Semin Nucl Med 2001; 31: 62–8

    Article  PubMed  CAS  Google Scholar 

  64. Pauwels EWJ, Stokkel MPM. Radiopharmaceuticals for bone lesions. Imaging and therapy in clinical practise. Q J Nucl Med 2001:45; 18–26

    PubMed  CAS  Google Scholar 

  65. Serafini AN. Therapy of metastatic bone pain. J Nucl Med 2001:42; 895–906

    PubMed  CAS  Google Scholar 

  66. Pecher C. Biological investigations with radioactive calcium and strontium: preliminary report on the use of radioactive strontium in the treatment of metastatic bone cancer. Los Angeles (CA). University of California Publications in Pharmacology 1942; 2: 117–49

    CAS  Google Scholar 

  67. Lawrence JH, Wasserman Jr LR. Multiple myeloma: a study of 24 patients treated with radioactive isotopes (32P and 89Sr). Ann Intern Med 1950; 33: 41–55

    PubMed  CAS  Google Scholar 

  68. Robinson RG, Blake GM, Preston DF, et al. 89Strontium treatment results and kinetics in patients with painful metastatic prostate and breast cancer in bone. Radiographics 1989; 9: 271–81

    PubMed  CAS  Google Scholar 

  69. Blake GM, Zivanovic MA, McEwan AJ, et al. Sr-89 therapy: strontium kinetics in disseminated carcinoma of the prostate. Eur J Nucl Med 1986; 12: 447–54

    PubMed  CAS  Google Scholar 

  70. Robinson RG, Spicer JA, Preston DF, et al. Treatment of metastatic bone pain with 89strontium. Nucl Med Biol 1987; 14: 219–22

    CAS  Google Scholar 

  71. Silberstein EB, Williams C. Strontium-89 therapy for the pain of osseous metastases. J Nucl Med 1985; 26: 345–8

    PubMed  CAS  Google Scholar 

  72. Reddy EK, Robinson RG, Mansfield CM. Strontium-89 for palliation of bone metastases. J Natl Med Assoc 1986; 78: 27–32

    PubMed  CAS  Google Scholar 

  73. Kloiber R, Molnar CP, Barnes M. Sr-89 therapy for metastatic bone disease: scintigraphic and radiographic follow up. Radiology 1987; 163:719–23

    PubMed  CAS  Google Scholar 

  74. Tennvall J, Darte L, Lundgren R, et al. Palliation of multiple bone metastases from prostatic carcinoma with strontium-89. Acta Oncol 1988; 27:365–9

    Article  PubMed  CAS  Google Scholar 

  75. Buchali K, Correns HJ, Schuerer M, et al. Results of a double blind study of 89-strontium therapy of skeletal metastases of prostatic carcinoma. Eur J Nucl Med 1988; 14: 349–51

    Article  PubMed  CAS  Google Scholar 

  76. McEwan AJB, Porter AT, Venner PM, et al. An evaluation of the safety and efficacy of treatment with Strontium-89 in patients who have previously received wide field radiotherapy. Antibody, Immunoconjug Radiopharm 1990; 3: 91–8

    Google Scholar 

  77. Laing AH, Ackery DM, Bayly RJ, et al. Strontium-89 chloride for pain palliation in prostatic skeletal malignancy. Br J Radiol 1991; 64: 816–22

    Article  PubMed  CAS  Google Scholar 

  78. Fossa SD, Paus E, Lochoff M, et al. 89Strontium in bone metastases from hormone resistant prostate cancer: Palliation effect and biochemical changes. Br J Cancer 1992; 66: 177–80

    Article  PubMed  CAS  Google Scholar 

  79. Dearnaly DP, Bayly RJ, A’Hern RP, et al. Palliation of bone metastases in prostate cancer. Hemibody irradiation or Strontium-89? Clin Oncol 1992; 4: 101–7

    Article  Google Scholar 

  80. Mertens WC, Porter AT, Reid RH, et al. Strontium-89 and low-infusion cisplatin for patients with hormone-refractory prostate carcinoma metastatic to bone: a preliminary report. J Nucl Med 1992; 33: 1437–43

    PubMed  CAS  Google Scholar 

  81. Kovner F, Ron IG, Levita M, et al. Strontium-89 therapy in a patient with carcinoma of unknown origin and incurable pain from bone metastases. J Pain Symptom Manage 1993; 8: 47–51

    Article  PubMed  CAS  Google Scholar 

  82. Hansen DV, Holmes ER, Catton G, et al. Strontium-89 therapy for painful osseous metastatic prostate and breast cancer. Am Fam Physician 1993; 47: 1795–800

    PubMed  CAS  Google Scholar 

  83. Guerrieri P, Modoni S, Parisi S, et al. Bone formation markers and pain palliation in bone metastases treated with Strontium-89. Am J Clin Oncol 1994; 17: 77–9

    Article  PubMed  CAS  Google Scholar 

  84. Robinson RG, Preston DF, Schiefelbein M, et al. Strontium-89 therapy for the palliation of pain due to osseous metastases. JAMA 1995; 274: 420–4

    Article  PubMed  CAS  Google Scholar 

  85. Quilty PM, Kirk D, Boiger JJ, et al. A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer. Radiother Oncol 1994; 31: 33–40

    Article  PubMed  CAS  Google Scholar 

  86. Berna L, Carrio I, Alonso C, et al. Bone pain palliation with strontium-89 in breast cancer patients with bone metastases and refractory bone pain. Eur J Nucl Med 1995; 22: 1101–4

    Article  PubMed  CAS  Google Scholar 

  87. Sciuto R, Maini CL, Tofani A, et al. Radiosensitization with low-dose carboplatin enhances pain palliation in radioisotope therapy with strontium-89. Nucl Med Commun 1996; 17: 799–804

    Article  PubMed  CAS  Google Scholar 

  88. Patel BR, Flowers WM. Systemic radionuclide therapy with strontium-89 in skeletal metastases in prostate and breast cancer. South Med J 1997; 90: 506–8

    Article  PubMed  CAS  Google Scholar 

  89. Pons F, Herranz R, Garcia A, et al. Strontium-89 for palliation of pain from bone metastases in patients with prostate and breast cancer. Eur J Nucl Med 1997; 24: 1210–4

    Article  PubMed  CAS  Google Scholar 

  90. Baziotis N, Yakoumakis E, Zissimopoulos A, et al. Strontium-89 chloride in the treatment of bone metastases in breast cancer. Oncology 1998; 55: 377–81

    Article  PubMed  CAS  Google Scholar 

  91. Kasalick J, Krajská V. The effect of repeated strontium-89 chloride therapy on bone palliation in patients with skeletal cancer metastases. Eur J Nucl Med 1998; 25: 1362–7

    Article  Google Scholar 

  92. Jager PL, Mensink HJ, Van den Bergh AC, et al. A Strontium-89 injection: simple treatment of painful bone metastases in patients with prostate cancer unresponsive to hormonal treatment. Ned Tijdschr Geneeskd 1999; 143: 969–73

    PubMed  CAS  Google Scholar 

  93. Nair N. Relative efficacy of 32P and 89Sr in palliation in skeletal metastases. J Nucl Med 1999; 40: 256–61

    PubMed  CAS  Google Scholar 

  94. McEwan AJB. Unsealed source therapy of painful bone metastases: an update. Sem Nucl Med 1997; 27: 165–82

    Article  CAS  Google Scholar 

  95. Turner JH, Martindale AA, Sorby P, et al. Samarium-153-EDTMP therapy of disseminated skeletal metastases. Eur J Nucl Med 1989; 15:784–95

    Article  PubMed  CAS  Google Scholar 

  96. Farhangi M, Holmes RA, Volkert RA, et al. Samarium-153-EDTMP: pharmacokinetic, toxicity and pain response using an escalating dose schedule in treatment of metastatic bone cancer. J Nucl Med 1992; 33: 1451–8

    Google Scholar 

  97. Ahonen A, Joensuu H, Hiltunen J, et al. Samarium-153-EDTMP in bone metastases. J Nucl Biol Med 1994; 38: 123–7

    PubMed  CAS  Google Scholar 

  98. Resche I, Chantal JF, Pecking A, et al. A dose-controlled study Sm-153-EDTMP in the treatment of patients with painful bone metastases. Eur J Cancer 1997; 33: 1583–91

    Article  PubMed  CAS  Google Scholar 

  99. Sartor O, Quick R, Reid R, et al. A double-blinded placebo controlled study of Sm-153-EDTMP for the palliation of bone pain in patients with hormone refractory prostate carcinoma. J Urol 1997; 157: 321

    Google Scholar 

  100. Serafini AN, Houston SJ, Resche I, et al. Palliation of bone pain associated with metastatic bone cancer using Samarium-153 Lexidronam: a double-blind placebo controlled clinical trial. J Clin Oncol 1998; 16: 1574–81

    PubMed  CAS  Google Scholar 

  101. Tian JH, Zhang JM, Hou QT, et al. Multicenter trial on the efficacy and toxicity of single dose samarium-153 ethylenediamine methylene phosphonate as a palliative treatment for painful skeletal metatstases in China. Eur J Nucl Med 1999; 26: 2–7

    Article  PubMed  CAS  Google Scholar 

  102. Olea E, Riccabona G, Tian J, et al. Efficacy and toxicity of 153Sm EDTMPin the palliative treatment of painful skeletal metastases: results of an IAEA international multicenter study. J Nucl Med 2000; 41: 146

    Google Scholar 

  103. Cameron PJ, Klemp PF, Martindale AA, et al. Prospective 153Sm-EDTMP therapy dosimetry by whole-body scintigraphy. Nucl Med Commun 1999; 20: 609–15

    Article  PubMed  CAS  Google Scholar 

  104. Bushneil D, Quick D, Reid D. Multiple administration of sm-153-lexidronam in the treatment of painful bone metastases. J Nucl Med 1998; 39: Al 13

    Google Scholar 

  105. Bushneil DL, Menda Y. Retreatment of patients with metastatic bone disease with multiple doses of samarium. Case Stud Oncol 1999; 1: 1–8

    Google Scholar 

  106. Goeckeler WF, Edwards B, Volkert WA, et al. Skeletal localization of samarium-153 chelates: potential therapeutic bone agents. J Nucl Med 1987; 28: 495–504

    PubMed  Google Scholar 

  107. de Klerk JM, van Dijk A, van het Schip AD, et al. Pharmacokinetics of rhenium-186 after administration of rhenium-186-HEDP to patients with bone metastases. J Nucl Med 1992; 33: 646–51

    PubMed  Google Scholar 

  108. Atkins HL, Mausner LF, Srivastava SC, et al. Biodistribution of Sn-117m(4+)DTPA for palliative therapy of painful osseous metastases. Radiology 1993; 186: 279–83

    PubMed  CAS  Google Scholar 

  109. Tu SM, Delpassand ES, Jones D, et al. Strontium-89 combined with doxorubicin in the treatment of patients with androgenindependent prostate cancer. Urol Oncol 1996; 2: 191–7

    Article  PubMed  CAS  Google Scholar 

  110. Tu SM, Millikan RE, Mengistu B, et al. Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial. Lancet 2001: 357; 336–341

    Article  PubMed  CAS  Google Scholar 

  111. Menschutkin N. Ueber die Einwirkung des Chloracetyls auf phosphorige Sáure. Ann Chem Pharm 1865; 133: 317–20

    Article  Google Scholar 

  112. Fleisch H, Biaz S. Isolation from urine of pyrophosphate, a calcification inhibitor. Am J Physiol 1962; 203: 671–5

    PubMed  CAS  Google Scholar 

  113. Fleisch H, Russell RGG, Bisaz S, et al. The influence of pyrophosphate analogues (diphosphonates) on the precipitation and dissolution of calcium phosphate in vitro and in vivo. Calcif Tissue Res 1968; Suppl. 10: 10A

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  115. Reitsma PH, Bijvoet OLM, Verlinden-Ooms H, et al. Kinetic Studies of bone and mineral metabolism during treatment with (3-amino-l-hydroxypropylidene 0-1, 1-bisphosphonate (APD) in rats. Calcif Tissue Int 1980; 32: 145–57

    Article  PubMed  CAS  Google Scholar 

  116. Sietsema WK, Ebetino FH, Salvagno AM, et al. An tires orptive dose-relationships across three generations of bisphosphonates. Drugs Exp Clin Res 1989; 9: 389–96

    Google Scholar 

  117. Boonekamp PM, Lowik CWGM, van der Wee-Pals LJA, et al. Enhancement of the inhibitory action of APD on the transformation of osteoclast precursors into resorbing cells after dimethylation of the amino-group. Bone Miner 1987; 2: 29–42

    PubMed  CAS  Google Scholar 

  118. Schenk A, Eggli P, Fleisch H, et al. Quantitative morphometric evaluation of the inhibitory activity of new aminobisphosphonates on bone resorption in the rat. Calcif Tissue Int 1986; 38: 342–9

    Article  PubMed  CAS  Google Scholar 

  119. Fleisch H, Russell RGG, Francis MD. Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone-resorption in tissue culture and in vivo. Science 1969; 165: 1262–4

    Article  PubMed  CAS  Google Scholar 

  120. Fleish H. Bisphosphonates in bone disease. London: Academic Press, 2000

    Google Scholar 

  121. Frith JC, Monkkonen J, Blackburn GM, et al. Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosine 5’-β, y-dichloromethylene triphosphate, by mammalian cells in vitro. J Bone Miner Res 1996; 12: 1358–67

    Article  Google Scholar 

  122. Russell RGG, Rogers MJ, Frith JC, et al. The pharmacology of bisphosphonates and new insights into their mechanism of action. J Bone Miner Res 1999; 14 Suppl. 2: 56–65

    Google Scholar 

  123. Rogers MJ, Frith JC, Luckman SP, et al. Molecular mechanism of action of bisphosphonates. Bone 1999; 24: 73S–9S

    Article  PubMed  CAS  Google Scholar 

  124. Luckman SP, Hughes DE, Coxon FP, 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: 581–9

    Article  PubMed  CAS  Google Scholar 

  125. Van Beek E, Löwik C, van der Pluijm G, et al. The role of geranylgeranylation in bone resorption and its suppression by bisphosphonates in fetal bone expiants in vitro: a clue to the mechanism of action of nitrogen-containing bisphosphonates. J Bone Miner Res 1999; 14: 722–9

    Article  Google Scholar 

  126. Fisher JE, Rogers MJ, Halasy JM, et al. Mechanism of action of alendronate: geranylgeraniol, an intermediate of the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption and kinase activity in vitro. Proc Natl Acad Sci USA 1999; 96: 133–8

    Article  PubMed  CAS  Google Scholar 

  127. Van Beek E, Pieterman E, Cohen L, et al. Nitrogen-containing bisphosphonates inhibit isopentyl pyrophosphate isomerase/farnesyl pyrophosphate synthetase activity with relative potencies corresponding to their an tires orptive potencies in vitro and in vivo. Biochem Biophys Res Commun 1999; 255:491–4

    Article  PubMed  Google Scholar 

  128. Reitsma PH, Teitelbaum SL, Bijvoet OLM, et al. Differential action of the bisphosphonates (3 amino-1-hydroxypropy lidene)-1,1-bisphosphonate (APD) and disodium dichloromethyl-idene bisphosphonate (C12MDP) on rat macrophage-mediated bone resorption in vitro. J Clin Invest 1982; 70: 927–33

    Article  PubMed  CAS  Google Scholar 

  129. Schipman CM, Croucher PI, Russell RGR, et al. The bisphosphonate incadronate (YM175) causes apoptosis of human myeloma cells in vitro by inhibiting the mevalonate pathway. Cancer Res 1998; 58: 5294–7

    Google Scholar 

  130. Aparicio A, Gardner A, Tu Y, et al. In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates. Leukemia 1998; 12: 220–9

    Article  PubMed  CAS  Google Scholar 

  131. Busch M, Rave-Fränk M, Hille A, et al. Influence of clodronate on breast cancer cells in vitro. Eur J Med Res 1998; 3: 427–31

    PubMed  CAS  Google Scholar 

  132. Fromigue D, Siwek B, Body JJ. Bisphosphonates inhibit breast cancer cell proliferation [abstract]. Calcif Tissue Int 1999; 64 Suppl. 1: P–261

    Google Scholar 

  133. Van der Pluijm G, Vloedgraven H, van Beek E, et al. Bisphosphonates inhibit the adhesion of breast cancer cells to bone matrices in vitro. J Clin Invest 1996; 98: 698–705

    Article  PubMed  Google Scholar 

  134. Boissier S, Magnetto S, Frappart L, et al. Bisphosphonates inhibit prostate and breast carcinoma cell adhesion to un-mineralized and mineralized bone extracellular matrices. Cancer Res 1997; 57: 3890–4

    PubMed  CAS  Google Scholar 

  135. Maeda H, Koizumi M, Yoshimura K, et al. Correlation between bone metabolic markers and bone scan in prostatic cancer. J Urol 1997; 157:539–43

    Article  PubMed  CAS  Google Scholar 

  136. Kylmälä T, Tammela T, Risteli L, et al. Evaluation of the effect of oral clodronate on skeletal metastases with type 1 collagen metabolites. A controlled trial of the Finnish Prostate Cancer Group. Eur J Cancer 1993; 29A: 821–5

    Article  PubMed  Google Scholar 

  137. Pelger RCM, Hamdy NAT, Zwinderman AH, et al. Effects of the bisphosphonate olpadronate in patients with carcinoma of the prostate metastatic to the skeleton. Bone 1998; 22: 403–8

    Article  PubMed  Google Scholar 

  138. Vinholes JJF, Purohit OP, Abbey ME, et al. Relationships between biochemical and symptomatic response in a double-blind randomised trial of Pamidronate for metastatic bone disease. Ann Oncol 1997; 8: 1243–50

    Article  PubMed  CAS  Google Scholar 

  139. Adami S.Bisphosphonates in prostate carcinoma. Cancer 1997; 80: 1674–9

    Google Scholar 

  140. Papapoulos SE, Hamdy NAT, van der Pluijm G. Bisphosphonates in the management of prostate carcinoma metastatic to the skeleton. Cancer 2000; 88: 3047–53

    Article  PubMed  CAS  Google Scholar 

  141. 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; 141:85–7

    PubMed  Google Scholar 

  142. Carey P, Lippert M. Treatment of painful prostatic bone metastases with oral etidronate disodium. Urology 1988; 32: 403–7

    Article  PubMed  CAS  Google Scholar 

  143. Schnur W. Etidronate for the relief of metastatic bone pain [abstract 424]. J Urol 1984; 131: 209 A

    Google Scholar 

  144. Elomaa I, Blomqvist C, Grohn P, et al. Long-term controlled trial with diphosphonate in patients with osteolytic bone metastases. Lancet 1983; I: 146–9

    Article  Google Scholar 

  145. Paterson A, Powles T, Kanis J, et al. Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 1993; 11: 59–65

    PubMed  CAS  Google Scholar 

  146. Elomaa I, Blomqvist C, Porkka L, et al. Treatment of skeletal disease in breast cancer: a controlled clodronate trial. Bone 1987; 8 Suppl. 1:53–6

    Google Scholar 

  147. Siris ES, Hyman GA, Canfield RE. Effects of dichloro-methylene diphosphonate in women with breast carcinoma metastatic to the skeleton. Am J Med 1983; 74: 401–6

    Article  PubMed  CAS  Google Scholar 

  148. Martoni A, Guaraldi M, Camera P, et al. Controlled clinical study on the use of dichloromethylene diphosphonate in patients with breast carcinoma metastasizing to the skeleton. Oncology 1991; 48: 97–101

    Article  PubMed  CAS  Google Scholar 

  149. Neri B, Gemelli MT, Sambataro S, et al. Subjective and metabolic effects of clodronate in patients with advanced breast cancer and symptomatic bone metastases. Anticancer Drugs 1992;3:87–90

    Article  PubMed  CAS  Google Scholar 

  150. Adami S, Salvagno G, Guarrera G, et al. Dichloromethylene diphosphonate in patients with prostatic carcinoma metastatic to the skeleton. J Urol 1985; 134: 1152–4

    PubMed  CAS  Google Scholar 

  151. Adami S, Mian M. Clodronate therapy of metastatic bone disease in patients with prostatic carcinoma. Cancer Res 1989; 116: 67–72

    CAS  Google Scholar 

  152. Elomaa I, Kylmälä T, Tammela T, et al. Effect of oral clodronate on bone pain. A controlled study in patients with metastatic prostatic cancer. Int Urol Nephrol 1992; 24: 159–66

    Article  PubMed  CAS  Google Scholar 

  153. 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: 792–5

    Article  PubMed  CAS  Google Scholar 

  154. Kylmälä T, Tammela T, Lindholm T, et al. The effect of combined intravenous and oral clodronate treatment on bone pain in patients with metastatic prostate cancer. Ann Chir Gynaecol 1994; 83:316–9

    PubMed  Google Scholar 

  155. 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: 360–5

    Article  PubMed  CAS  Google Scholar 

  156. Heidenreich A, Hofmann R, Engelmann UD. The use of bisphosphonate for the palliative treatment of painful bone metastasis due to refractory prostate cancer. J Urol 2001; 165: 136–40

    Article  PubMed  CAS  Google Scholar 

  157. Lahtinen R, Laakso M, Palva I, et al. Randomised, placebo-controlled multicentre trial of clodronate in multiple myeloma. Finnish Leukaemia Group. Lancet 1992; 340: 1049–52

    Article  PubMed  CAS  Google Scholar 

  158. McCloskey EV, MacLennan IC, Drayson M, et al. Effect of clodronate on skeletal morbidity in myelomatosis. Br J Haematol 1998; 100: 317–25

    Article  PubMed  CAS  Google Scholar 

  159. Delmas PD, Charhon S, Chapuy MC, et al. Long-term effects of dichloromethylene diphosphonate (C12MDP) on skeletal lesions in multiple myeloma. Metab Bone Dis Relat Res 1982; 4: 163–8

    Article  PubMed  CAS  Google Scholar 

  160. Siris ES, Sherman WH, Baquiran DC, et al. Effects of dichloromethylene diphosphonate on skeletal mobilisation of calcium in multiple myeloma. N Engl J Med 1980; 302: 310–5

    Article  PubMed  CAS  Google Scholar 

  161. Heim ME, Clemens MR, Queisser W, et al. Prospective randomized trial of dichloromethylene bisphosphonate (clodronate) in patients with multiple myeloma requiring treatment-A multicenter study. Onkologie 1995; 18: 439–48

    Article  Google Scholar 

  162. Merlini G, Attardo Parrinello G, Piccinini L, et al. Long term effects of parenteral dichloromethylene bisphosphonate on bone disease of myeloma patients treated with chemotherapy. Hematol Oncol 1990; 8: 23–30

    Article  PubMed  CAS  Google Scholar 

  163. O’Rourke N, McCloskey E, Houghton F, et al. Double-blind, placebo-controlled, dose response trial of oral clodronate in patients with bone metastases. J Clin Oncol 1995; 13: 929–34

    PubMed  Google Scholar 

  164. Robertson A, Reed N, Ralston S. Effect of oral clodronate on metastatic bone pain: a double-blind, placebo-controlled study. J Clin Oncol 1995; 13: 2427–30

    PubMed  CAS  Google Scholar 

  165. Francini G, Gonnelli S, Petrioli R, et al. Treatment of bone metastases with dichloromethylene bisphosphonate. J Clin Oncol 1992; 10: 591–8

    PubMed  CAS  Google Scholar 

  166. Jung A, Chantraine A, Donath A, et al. Use of dichloromethylene diphosphonate in metastatic bone disease. N Engl J Med 1983; 308: 1499–501

    Article  PubMed  CAS  Google Scholar 

  167. Delmas PD, Charhon SA, Chapuy MC, et al. Place des diphosphonates dans la thérapeutique de 1’Ostéolyse et des hypercalcémies malignes. Rev Rhum Mal Osteoartic 1984; 51: 663–6

    PubMed  CAS  Google Scholar 

  168. Van Holten-Verzantvoort AFM, Zwinderman AH, Aaronson NH, et al. The effect of supportive Pamidronate treatment on aspects of quality of life of patients with advanced breast cancer. Eur J Cancer 1991; 27: 544–9

    Article  PubMed  Google Scholar 

  169. Purohit OP, Anthony C, Radstone CR, et al. High-dose intravenous Pamidronate for metastatic bone pain. Br J Cancer 1996; 70: 554–8

    Article  Google Scholar 

  170. Glover D, Lipton A, Keller A, et al. Intravenous Pamidronate disodium treatment of bone metastases in patients with breast cancer. A dose-seeking study. Cancer 1994; 74: 2949–55

    Article  PubMed  CAS  Google Scholar 

  171. Van Holten-Verzantvoort AT, Bijvoet OL, Cleton FJ, et al. Reduced morbidity from skeletal metastases in breast cancer patients during long-term bisphosphonate (APD) treatment. Lancet 1987; II: 983–5

    Article  Google Scholar 

  172. Tyrell CJ. On behalf of the Aredia Multinational Cooperative Group: role of Pamidronate in the management of bone metastases from breast cancer: Results of a non-comparative multicenter phase II trial. Ann Oncol 1994; 5 Suppl. 7: S37–40

    Google Scholar 

  173. Thiéband D, Leyvraz S, von Fliedner V, et al. Treatment of bone metastases from breast cancer and myeloma with Pamidronate. Eur J Cancer 1991; 27: 37–41

    Article  Google Scholar 

  174. Coleman RE, Woll PJ, Miles M, et al. Treatment of bone metastases from breast cancer with (3-amino-l-hydroxy-propylidene)-1,1-bisphosphonate (APD). Br J Cancer 1988; 58: 621–5

    Article  PubMed  CAS  Google Scholar 

  175. Coleman RE, Vinholes J, Abbey ME, et al. Double-blind randomized trial of Pamidronate (Aredia) for the palliative treatment of metastases in bone disease [abstract 1706]. Am Soc Clin Oncol Program/Proc 1996; 15: 528

    Google Scholar 

  176. Hultborn R, Gundersen S, Ryden S, et al. Efficacy of Pamidronate in breast cancer with bone metastases: a randomized double-blind placebo-controlled multicenter study. Anticancer Res 1999; 19: 3383–92

    PubMed  CAS  Google Scholar 

  177. Hultborn R, Gundersen S, Ryden S, et al. Efficacy of Pamidronate in breast cancer with bone metastases: a randomized double-blind placebo-controlled multicenter study. Acta Oncol 1996; 35 Suppl. 5: 73–4

    Article  PubMed  Google Scholar 

  178. Millward MJ, Cantwell BMJ, Carmichael J, et al. Arandomised trial of the addition of disodium Pamidronate (APD) to endocrine therapy for advanced breast cancer with bone metastases [abstract 43]. Am Soc Clin Oncol Program/Proc 1991; 10: 42

    Google Scholar 

  179. Radziwill AJ, Thürlimann B. Significant improvement of quality of life in patients with malignancy-related bone disease and bone pain after high dose Pamidronate: a randomised dose finding study. Ann Oncol 1992; 3 (Suppl. 5): A 725

    Google Scholar 

  180. Panagos G, Boukis H, Papadakou M, et al. Treatment of extensive bone metastases due to refractory breast cancer with combination of disodium Pamidronate and epirubicin. Ann Oncol 1992; 3 (Suppl. 5): A352

    Google Scholar 

  181. Thürlimann B, Morant R. Pamidronate for osteolytic bone metastases: is there a dose effect? Eur J Cancer 1991; 27 (Suppl. 2): S284

    Google Scholar 

  182. Bachouchi M, Bruning PF, Soukop M, et al. Intravenous Pamidronate (APD) in the treatment of osteolytic metastases of breast cancer: preliminary results of a multicentre study. In: Bijvoet OLM, Lipton A, editors. Osteoclast inhibition in the management of malignancy-related bone disorders. Lewiston: Hogrefe and Huber, 1991: 38–44

    Google Scholar 

  183. Hacking A, Gudgeon CA, McNaughton D, et al. Pamidronate (APD) as single-infusion monotherapy in the treatment of bone metastases from breast cancer. In: Bijvoet OLM, Lipton A, editors. Osteoclast inhibition in the management of malignancy-related bone disorders. Lewiston: Hogrefe and Huber, 1991:45–53

    Google Scholar 

  184. Dodwell DJ, Howell A, Morton AR, et al. Pamidronate (APD) treatment of skeletal metastases from breast cancer. In Rubens ED, Editor. The management of bone metastases and hypercalcaemia by osteoclast inhibition. Toronto: Huber, 1990: 62–75

    Google Scholar 

  185. Lipton A, Glover D, Harvey H, et al. Disodium Pamidronate (APD) — a dose seeking study in patients with breast and prostate cancer: a preliminary report. In: Bijvoet OLM, Lipton A, editors. Osteoclast inhibition in the management of malignancy-related bone disorders. Lewiston: Hogrefe and Huber, 1991: 33–37

    Google Scholar 

  186. Pelger RCM, Lycklama à Nijeholt AAB, Papapoulos SE. Short-term metabolic effects of Pamidronate in patients with prostatic carcinoma and bone metastases. Lancet 1989; II: 865

    Article  Google Scholar 

  187. Fleisch H. Bisphosphonates —preclinical. In: H. Fleish, editor. Bisphosphonates in bone disease. From laboratory to the patient. San Diego: Academic Press, 2000: 40–41

    Google Scholar 

  188. Gonzalez DC, Mautalen CA. Short-term therapy with oral olpadronate in active paget’s disease of bone. J Bone Miner Res 1999; 14: 2042–7

    Article  PubMed  CAS  Google Scholar 

  189. Soerdjbalie-Maikoe V, Pelger RCM, Lycklama à Nijeholt AAB, et al. Palliation of bone pain by the bisphosphonate olpadronate in hormone-escaped prostate adenocarcinoma metastatic to the skeleton. J Urol 2000; 163: 261

    Google Scholar 

  190. 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: 311–6

    Article  PubMed  CAS  Google Scholar 

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Pelger, R.C.M., Soerdjbalie-Maikoe, V. & Hamdy, N.A.T. Strategies for Management of Prostate Cancer-Related Bone Pain. Drugs Aging 18, 899–911 (2001). https://doi.org/10.2165/00002512-200118120-00002

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