, Volume 18, Issue 4, pp 269–278 | Cite as

Bisphosphonate Effects in Cancer and Inflammatory Diseases

In Vitro and In Vivo Modulation of Cytokine Activities
  • Daniele Santini
  • Maria E. Fratto
  • Bruno Vincenzi
  • Annalisa La Cesa
  • Caterina Dianzani
  • Giuseppe Tonini
Drug Mechanisms and Targets


Bisphosphonates are endogenous pyrophosphate analogs in which a carbon atom replaces the central atom of oxygen. They are indicated in non-neoplastic diseases including osteoporosis, corticosteroid-induced bone loss, Paget disease, and in cancer-related diseases such as neoplastic hypercalcemia, multiple myeloma and bone metastases secondary to breast and prostate cancer. There is now extensive in vitro evidence suggesting a direct antitumor effect of bisphosphonates at different levels of action. Some new in vitro and in vivo studies support the cytostatic effects of bisphosphonates on tumor cells, and the effects on the regulation of cell growth, apoptosis, angiogenesis, cell adhesion, and invasion, with particular attention to biological properties. Well designed clinical trials are necessary to investigate whether the antitumor potential of bisphosphonates may be clinically relevant. On the basis of their effects on macrophages, we may divide bisphosphonates into two distinct categories: aminobisphosphonates, which sensitize macrophages to an inflammatory stimulus inducing an acute-phase response, and non-aminobisphosphonates that can be metabolized into macrophages and that may inhibit the inflammatory response of macrophages. There is evidence of aminobisphosphonate-induced pro-inflammatory response, in particular, related to modifications of the cytokine network. Several in vivo studies have demonstrated an acute-phase reaction after the first administration of aminobisphosphonates, with a significant increase in the main pro-inflammatory cytokines. However, a peculiar aspect concerning the action of non-aminobisphosphonates seems to be an anti-inflammatory activity caused by the inhibition of the release of inflammatory mediators from activated macrophages, such as interleukin (IL)-6, tumor necrosis factor-α and IL-1. The inhibition of inflammatory responses is demonstrated in both in vivo and in vitro models. This activity suggests the use of non-aminobisphosphonates in several inflammatory diseases characterized by macrophage-mediated production of acute-phase cytokines, as prevention of erosions in rheumatoid arthritis, and of loosening of joint prostheses, as well as possibly in osteoarthritis, ankylosing spondylitis, myelofibrosis, and hypertrophic pulmonary osteoarthropathy.


  1. 1.
    Shinoda H, Adamek G, Felix R, et al. Structure-activity relationship of various bisphosphonates. Calcif Tissue Int 1983; 35: 87–99PubMedCrossRefGoogle Scholar
  2. 2.
    Widler L, Jaeggi KA, Glatt M, et al. Highly potent geminal bisphosphonates: from pamidronate disodium (Aredia) to zoledronic acid (Zometa). J Med Chem 2002 Aug 15; 45(17): 3721–38PubMedCrossRefGoogle Scholar
  3. 3.
    VanBeek ER, Lowik CW, Ebetino FH, et al. Binding and antiresorptive properties of heterocycle-containing bisphosphonate analogs: structure-activity relationships. Bone 1998 Nov; 23(5): 437–42PubMedCrossRefGoogle Scholar
  4. 4.
    Schenk R, Eggli P, Fleisch H, et al. Quantitative morphometric evaluation of the inhibitory activity of new amino-bisphosphonates on bone resorption in the rat. Calcif Tissue Int 1986; 38: 342–9PubMedCrossRefGoogle Scholar
  5. 5.
    Sietsema WK, Ebetino FH, Salvagno AM, et al. Antiresorptive dose-response relationship across three generations of bisphosphonates. Drugs Exp Clin Res 1989; 15: 389–96PubMedGoogle Scholar
  6. 6.
    Santini D, Vespasiani Gentilucci U, Vincenzi B, et al. The antineoplastic role of bisphosphonates: from basic research to clinical evidence. Ann Oncol 2003; 14(10): 1468–76PubMedCrossRefGoogle Scholar
  7. 7.
    Watts NB, Harris ST, Genant HK, et al. Intermittent cyclical etidronate treatment of postmenopausal osteoporosis. N Engl J Med 1990; 323: 73–9PubMedCrossRefGoogle Scholar
  8. 8.
    Reid IR, King AR, Alexander CJ, et al. Prevention of steroid-induced osteoporosis with (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD). Lancet 1988; I: 143–6CrossRefGoogle Scholar
  9. 9.
    Miller PD, Brown JP, Siris ES, et al. A randomized, double blind comparison of risedronate and etidronate in the treatment of Paget’s disease of bone. Paget’s Risedronate/Etidronate Study Group. Am J Med 1999; 106: 513–20PubMedCrossRefGoogle Scholar
  10. 10.
    Reid IR. Bisphosphonates: new indications and methods of administration. Curr Opin Rheumatol 2003 Jul; 15(4): 458–63PubMedCrossRefGoogle Scholar
  11. 11.
    Fleisch H. Bisphosphonates: pharmacology and use in the treatment of tumor-induced hypercalcemic and metastatic bone disease. Drugs 1991; 42: 919–44PubMedCrossRefGoogle Scholar
  12. 12.
    Berenson J, Lichtenstein A, Porter L, 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: 488–93PubMedCrossRefGoogle Scholar
  13. 13.
    Hortobagyi GN, Theriault RL, Porter L, et al. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med 1996; 335: 1785–91PubMedCrossRefGoogle Scholar
  14. 14.
    Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. Natl Cancer Inst 2002 Oct 2; 94(19): 1458–68CrossRefGoogle Scholar
  15. 15.
    Rosen LS, Gordon D, Tchekmedyian S, et al. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial. The Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 2003; 21: 3150–7PubMedCrossRefGoogle Scholar
  16. 16.
    Rogers MJ. New insights into the molecular mechanisms of action of bisphosphonates. Curr Pharm Des 2003; 9: 2643–58PubMedCrossRefGoogle Scholar
  17. 17.
    Luckman SP, Hughes DE, Coxon FP, et al. Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translationalprenylation of GTP-binding proteins, including Ras. J Bone Miner Res 1998; 13: 581–9PubMedCrossRefGoogle Scholar
  18. 18.
    Rogers MJ, Gordon S, Benford HL, et al. Cellular and molecular mechanisms of action of bisphosphonates. Cancer 2000 Jun 15; 88(12 Suppl.): 2961–78PubMedCrossRefGoogle Scholar
  19. 19.
    Russell RG, Rogers MJ. Bisphosphonates: from the laboratory to the clinic and back again. Bone 1999 Jul; 25(1): 97–106PubMedCrossRefGoogle Scholar
  20. 20.
    Sasaki A, Boyce BF, Story B, et al. Bisphosphonate risedronate reduces metastatic human breast cancer burden in nude mice. Cancer Res 1995; 55: 3551–7PubMedGoogle Scholar
  21. 21.
    Green JR, Clezardin P. Mechanisms of bisphosphonate effects on osteoclasts, tumor cell growth, and metastasis. Am J Clin Oncol 2002 Dec; 25(6 Suppl. 1): S3–9PubMedCrossRefGoogle Scholar
  22. 22.
    Green JR. Antitumor effects of bisphosphonates. Cancer 2003 Feb 1; 97(3 Suppl.): 840–7PubMedCrossRefGoogle Scholar
  23. 23.
    Colucci S, Minielli V, Zambonin G, et al. Alendronate reduces adhesion of human osteoclast-like cells to bone and bone protein-coated surfaces. Calcif Tissue Int 1998; 63: 230–5PubMedCrossRefGoogle Scholar
  24. 24.
    Boissier S, Magnetto S, Frappart L, et al. Bisphosphonates inhibit prostate and breast carcinoma cell adhesion to unmineralized and mineralized bone extracellular matrices. Cancer Res 1997; 57: 3890–4PubMedGoogle Scholar
  25. 25.
    Boissier S, Ferreras M, Peyruchaud O, et al. Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res 2000; 60: 2949–54PubMedGoogle Scholar
  26. 26.
    Sawada K, Morishige K, Tahara M, et al. Alendronate inhibits lysophosphatidic acid-induced migration of human ovarian cancer cells by attenuating the activation of rho. Cancer Res 2002 Nov 1; 62(21): 6015–20PubMedGoogle Scholar
  27. 27.
    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: 698–705PubMedCrossRefGoogle Scholar
  28. 28.
    Ito M, Amizuka N, Nakajima T, et al. Ultrastructural and cytochemical studies on cell death of osteoclasts induced by bisphosphonate treatment. Bone 1999; 25: 447–52PubMedCrossRefGoogle Scholar
  29. 29.
    Selander KS, Monkkonen J, Karhukorpi E, et al. Characteristics of clodronate-induced apoptosis in osteoclasts and macrophages. Mol Pharmacol 1996; 50: 1127–38PubMedGoogle Scholar
  30. 30.
    Senaratne SG, Pirianov G, Mansi JL, et al. Bisphosphonates induce apoptosis in human breast cancer cell lines. Br J Cancer 2000; 82(8): 1459–68PubMedCrossRefGoogle Scholar
  31. 31.
    Shipman CM, Rogers MJ, Apperley JF, et al. Bisphosphonates induce apoptosis of human myeloma cell lines: a novel antitumor activity. Br J Haematol 1997; 98: 665–72PubMedCrossRefGoogle Scholar
  32. 32.
    Riebeling C, Forsea AM, Raisova M, et al. The bisphosphonate pamidronate induces apoptosis in human melanoma cells in vitro. Br J Cancer 2002; 87: 366–71PubMedCrossRefGoogle Scholar
  33. 33.
    Corey E, Brown LG, Quinn JE, et al. Zoledronic acid exhibits inhibitory effects on osteoblastic and osteolytic metastases of prostate cancer. Clin Cancer Res 2003 Jan; 9(1): 295–306PubMedGoogle Scholar
  34. 34.
    Wood J, Bonjean K, Ruetz S, et al. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 2002; 302: 1055–61PubMedCrossRefGoogle Scholar
  35. 35.
    Fournier P, Boissier S, Filleur S, et al. Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 2002 Nov 15; 62(22): 6538–44PubMedGoogle Scholar
  36. 36.
    Bezzi M, Hasmim M, Bieler G, et al. Zoledronate sensitizes endothelial cells to tumor necrosis factor-induced programmed cell death: evidence for the suppression of sustained activation of focal adhesion kinase and protein kinase B/ Akt. J Biol Chem 2003 Oct 31; 278(44): 43603–14PubMedCrossRefGoogle Scholar
  37. 37.
    Santini D, Vincenzi B, Avvisati G, et al. Pamidronate induces modifications of circulating angiogenetic factors in cancer patients. Clin Cancer Res 2002 May; 8(5): 1080–4PubMedGoogle Scholar
  38. 38.
    Santini D, Vincenzi B, Dicuonzo G, et al. Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients. Clin Cancer Res 2003 Aug 1; 9(8): 2893–7PubMedGoogle Scholar
  39. 39.
    Santini D, Vincenzi B, Tonini G, et al. Zoledronic acid exhibits inhibitory effects on osteoblastic and osteolytic metastases of prostate cancer [letter]. Clin Cancer Res 2003 Aug 1;9(8): 3215PubMedGoogle Scholar
  40. 40.
    Kunzmann V, Bauer E, Wilhelm M. γδ T cell stimulation by pamidronate. N Engl J Med 1999; 340: 737–8PubMedCrossRefGoogle Scholar
  41. 41.
    Kunzmann V, Bauer E, Feurle J, et al. Stimulation of γδ T cells by aminobisphosphonates and induction of antiplasma cell activity in multiple myeloma. Blood 2000; 96: 384–92PubMedGoogle Scholar
  42. 42.
    DeLibero G. Sentinel function of broadly reactive human γδ T cells. Immunol Today 1997; 18: 22–6PubMedCrossRefGoogle Scholar
  43. 43.
    Fisch P, Malkovsky M, Kovats S, et al. Recognition by human Vγ9/Vδ2 T cells of a GroEL homolog on Daudi Burkitt’s lymphoma cells. Science 1990; 250: 1269–73PubMedCrossRefGoogle Scholar
  44. 44.
    Gober HJ, Kistowska M, Angman L, et al. Human T cell receptor gamma delta cells recognize endogenous mevalonate metabolites in tumor cells. J Exp Med 2003; 197: 163–8PubMedCrossRefGoogle Scholar
  45. 45.
    Schweitzer DH, Oostendorp-van de Ruit M, Van der Pluijm G, et al. Interleukin-6 and the acute phase response during treatment of patients with Paget’s disease with the nitrogen-containing bisphosphonate dimethylaminohydroxypropylidene bisphosphonate. J Bone Miner Res 1995 Jun; 10(6): 956–62PubMedCrossRefGoogle Scholar
  46. 46.
    Thiébaud D, Sauty A, Burckhardt P, et al. An in vitro and in vivo study of cytokines in the acute-phase response associated with bisphosphonates. Calcif Tissue Int 1997 Nov; 61(5): 386–92PubMedCrossRefGoogle Scholar
  47. 47.
    Lissoni P, Cazzaniga M, Barni S, et al. Acute effects of pamidronate administration on serum levels of interleukin-6 in advanced solid tumour patients with bone metastases and their possible implications in the immunotherapy of cancer with interleukin-2. Eur J Cancer 1997 Feb; 33(2): 304–6PubMedCrossRefGoogle Scholar
  48. 48.
    Sauty A, Pecherstorfer M, Zimmer-Roth I, et al. Interleukin-6 and tumor necrosis factor alpha levels after bisphosphonates treatment in vitro and in patients with malignancy. Bone 1996 Feb; 18(2): 133–9PubMedCrossRefGoogle Scholar
  49. 49.
    Rendina D, Postiglione L, Vuotto P, et al. Clodronate treatment reduces serum levels of interleukin-6 soluble receptor in Paget’s disease of bone. Clin Exp Rheumatol 2002 May–Jun; 20(3): 359–64PubMedGoogle Scholar
  50. 50.
    Dicuonzo G, Vincenzi B, Santini D, et al. Fever after zoledronic acid administration is due to increase in TNF-alpha and IL-6. J Interferon Cytokine Res 2003; 23: 649–54PubMedCrossRefGoogle Scholar
  51. 51.
    Zysk SP, Durr HR, Gebhard HH, et al. Effects of ibandronate on inflammation in mouse antigen-induced arthritis. Inflamm Res 2003 May; 52(5): 221–6PubMedGoogle Scholar
  52. 52.
    Richards PJ, Amos N, Williams AS, et al. Pro-inflammatory effects of the aminobisphosphonate ibandronate in vitro and in vivo. Rheumatology (Oxford) 1999 Oct; 38(10): 984–91CrossRefGoogle Scholar
  53. 53.
    Monkonnen J, Simila J, Rogers MJ. Effects of tiludronate and ibandronate on the secretion of proinflammatory cytokines and nitric oxide from macrophages in vitro. Life Sci 1998; 62(8): 95–102Google Scholar
  54. 54.
    Pietschmann P, Stohlawetz P, Brosch S, et al. The effect of alendronate on cytokine production, adhesion molecule expression, and transendothelial migration of human peripheral blood mononuclear cells. Calcif Tissue Int 1998 Oct; 63(4): 325–30PubMedCrossRefGoogle Scholar
  55. 55.
    Rogers MJ, Ji X, Russell RG, et al. Incorporation of bisphosphonates into adenine nucleotides by amoebae of the cellular slime mould Dictyostelium discoideum. Biochem J 1994; 303 (Pt 1): 303–11PubMedGoogle Scholar
  56. 56.
    Pelorgeas S, Martin JB, Satre M. Cytotoxicity of dichloromethane diphosphonate and of 1-hydroximethane-1,1-diphosphonate in the amoebae of the slime mould Dictyostelium discoideum: a 31P NMR study. Biochem Pharmacol 1992; 44: 2157–63PubMedCrossRefGoogle Scholar
  57. 57.
    Rogers MJ, Brown RG, Hodkin V, et al. Bisphosphonates are incorporated into adenine nucleotides by human aminoacil-tRNA synthetases enzymes. Biochem Biophys Res Commun 1996; 224: 863–9PubMedCrossRefGoogle Scholar
  58. 58.
    Lambert LE, Paulnock DM. Differential induction of activation markers in macrophage cell lines by interferon-gamma. Cell Immunol1989; 120: 401–18PubMedCrossRefGoogle Scholar
  59. 59.
    Flanagan AM, Chambers TJ. Dichloromethylenebisphosphonate (Cl2MBP) inhibits bone resorption through injury to osteoclasts that resorb Cl2MBP-coated bone. Bone Miner 1989; 6: 33–43PubMedCrossRefGoogle Scholar
  60. 60.
    Monkonnen J, Pennanen N, Lapinjoki S, et al. Clorodronate inhibits LPS-stimulated IL-6 and TNF production by RAW 264 cells. Life Sci 1994; 54(14): 229–34Google Scholar
  61. 61.
    Monkonnen N, Hirvonen MR, Teravainen T, et al. Different effects of three bisphosphonates on nitric oxide production by RAW 264-macrophages cell line in vitro. J Pharmacol Exp Ther 1996; 277: 1097–102Google Scholar
  62. 62.
    Monkonnen J, Monkonnen N. Effects of alendronate on macrophage growth and pro-inflammatory cytokine production. Bone 1995; 17(6): 597–618Google Scholar
  63. 63.
    Pennanen N, Lapinjoki S, Urtti A, et al. Effects of liposomial and free bisphosphonates on the IL-1beta, IL-6 and TNF-alpha secretion from RAW 264 cells in vitro. Pharm Res 1995; 12(6): 916–22PubMedCrossRefGoogle Scholar
  64. 64.
    Monkonnen N, Salminem A, Rogers MJ, et al. Contrasting effects of alendronate and clorodronate on RAW 264 macrophages: the role of a bisphosphonate metabolite. Eur J Pharm Sci 1999; 8: 109–18CrossRefGoogle Scholar
  65. 65.
    Engel E, Serrano S, Marinoso ML, et al. Alendronate and etidronate do not regulate Interleukin 6 and 11 synthesis in normal osteoblast in culture. Calcif Tissue Int 2003; 72: 228–35PubMedCrossRefGoogle Scholar
  66. 66.
    Giuliani N, Pedrazzoni M, Passeri G, et al. Bisphosphonates inhibit IL-6 production by human osteoblast-like cells. Scand J Rheumatol 1998; 27: 38–41PubMedCrossRefGoogle Scholar
  67. 67.
    Sanders JL, Tarjan G, Foster SA, et al. Alendronate/Interleukine-1beta cotreatment increases interleukin-6 in bone and UMR-106 cells: dose dependence and relationship to the antiresorptive effect of alendronate. J Bone Miner Res 1998; 13(5): 786–92PubMedCrossRefGoogle Scholar
  68. 68.
    Dunn CJ, Galinet LA, Wu H, et al. Demonstration of novel antiarthritic and antiinflammatory effects of diphosphonates. J Pharmacol Exp Ther 1993; 266: 1691–8PubMedGoogle Scholar
  69. 69.
    Flora L. Comparative antiinflammatory and bone protective effects of two diphosphonates in adjuvant arthritis. Arthritis Rheum 1979; 22: 340–6PubMedCrossRefGoogle Scholar
  70. 70.
    Ostermann T, Kippo K, Lauren L, et al. Effect of clorodronate on established adjuvant arthritis. Rheumatol Int 1994; 14: 139–47CrossRefGoogle Scholar
  71. 71.
    Cantatore FP, Introsso AM, Carrozzo M. Effects of bisphosphosphonates on interleukin-1, tumor necrosis factor alpha, and beta 2 microglobulin in rheumatoid arthritis. J Rheumatol 1996; 23: 1117–8PubMedGoogle Scholar
  72. 72.
    Mossetti G, Rendina D, Nurnis PG, et al. Biochemical markers of bone turnover, serum levels of interleukin-6/interleukin-6 soluble receptor and bisphosphonate treatment in Erdheim-Chester disease. Clin Exp Rheumatol 2003; 21: 232–6PubMedGoogle Scholar
  73. 73.
    Bauerle PA, Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol 1994; 12: 141–79CrossRefGoogle Scholar
  74. 74.
    Handel ML, McMorrow LB, Gravallese EM. Nuclear factor-kappa B in rheumatoid synovium. Arthritis Rheum 1995; 38: 1762–70PubMedCrossRefGoogle Scholar
  75. 75.
    Koj A. Initiation of acute phase response and synthesis of cytokines. Biochim Biophys Acta 1996; 1317: 84–94PubMedCrossRefGoogle Scholar
  76. 76.
    Asahara H, Fujisawa K, Kobata T, E. Direct evidence of high DNA binding activity of transcription factor AP-1 in the rheumatoid arthritis synovium. Arthritis Rheum 1997; 40: 912–8PubMedCrossRefGoogle Scholar
  77. 77.
    Baldwin AS. The NF-kappa B and I kappa B proteins: a new discoveries and insight. Annu Rev Immunol 1996; 14: 649–81PubMedCrossRefGoogle Scholar
  78. 78.
    Khurihara N, Civin C, Roodman GD. Osteotropic factor responsiveness of a novel purified population of early and late precursors for human and multinucleated cells expressing the osteoclastic phenotype. J Bone Miner Res 1991; 6: 257–81CrossRefGoogle Scholar
  79. 79.
    Ohsaki Y, Takahashi S, Scarcez S, et al. Evidence for an autocrine/paracrine role for IL-6 in bone resorption by giant cells from giant cells tumors of bone. Endocrinology 1992; 131(5): 2229–34PubMedCrossRefGoogle Scholar
  80. 80.
    Freeman GJ, Fredman AS, Rabinowe SN, et al. Interleukin 6 gene expression in normal and neoplastic B cells. J Clin Invest 1989; 81: 1512–8CrossRefGoogle Scholar
  81. 81.
    Kishimoto T, Akira S, Taga T. Interleukin 6 and its receptor: a paradigm for cytokines. Science 1992; 258: 593–7PubMedCrossRefGoogle Scholar
  82. 82.
    Baumann H, Schendel P. Interleukin 11 regulates the hepatic expression of the same plasma protein genes as interleukin 6. J Biol Chem 1991; 266: 20424–7PubMedGoogle Scholar
  83. 83.
    Bruno E, Bridell RA, Cooper RJ, et al. Effects of recombinant interleukin 11 on human megakaryocyte progenitor cells. Exp Hematol 1991; 19: 378–81PubMedGoogle Scholar
  84. 84.
    Quesniaux FFJ. Interleukins 9,10, 11 and 12 and kit ligand: a brief overview. Res Immunol 1992; 143: 385–400PubMedCrossRefGoogle Scholar
  85. 85.
    Girasole G, Passeri G, Jilka RL, et al. Interleukin 11: a new cytokine critical for osteoclast development. J Clin Invest 1994; 93: 1516–24PubMedCrossRefGoogle Scholar
  86. 86.
    Girasoli G, Passeri G, Knutson S, et al. A distinct and hierarchically central role of interleukin 11 among other cytokines in osteoclast development [abstract]. J Bone Miner Res 1993; 8: S1117Google Scholar
  87. 87.
    Elias JA, Tang W, Horowitz MC. Cytokine and hormonal stimulation of human osteosarcoma interleukin 11 production. Endocrinology 1995; 136: 489–98PubMedCrossRefGoogle Scholar
  88. 88.
    VanRooijen N. The liposome-mediated macrophage suicide technique. J Immunol Methods 1989; 124: 1–6PubMedCrossRefGoogle Scholar
  89. 89.
    Van Lent PLEM, Van den Bersselaar L, Van den Hoek AEM, et al. Reversible depletion of synovial lining cells after intra-articular treatment with liposome-encapsulated dichloromethylene diphosphonate. Rheumatol Int 1993; 13: 21–30CrossRefGoogle Scholar
  90. 90.
    Egeler RM. More on pamidronate in Langerhans cell histiocytosis. N Engl J Med 2001; 345: 1502–3PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  • Daniele Santini
    • 1
  • Maria E. Fratto
    • 1
  • Bruno Vincenzi
    • 1
  • Annalisa La Cesa
    • 1
  • Caterina Dianzani
    • 1
  • Giuseppe Tonini
    • 1
  1. 1.Oncology DepartmentCampus Bio-Medico UniversityRomeItaly

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