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Pharmacy World and Science

, Volume 20, Issue 5, pp 206–213 | Cite as

Bisphosphonates in bone diseases

  • Rolf W. Sparidans
  • Irene M. Twiss
  • Stephanie Talbot
Article

Abstract

Bisphosphonates are a class of drugs which are strongly attracted to the bone where they influence the calcium metabolism, mainly by inhibition of the osteoclast-mediated bone resorption. This property makes these compounds suited for the treatment of several diseases of the bone. In Paget's disease, several bisphosphonates can reduce bone pain and decrease the bone turnover 60‐70%. Cyclical oral etidronate and daily oral alendronate both proved to reduce the vertebral fracture rate for postmenopausal osteoporotic woman, while most investigated bisphosphonates can increase spinal bone mass in osteoporosis. Bisphosphonates can help lowering serum calcium and reverse skeletal complications in malignancy mediated bone diseases. Oral and intravenous administration of therapeutic doses is relatively safe. In general, gastrointestinal disturbances are described most often and the oldest, least potent, bisphosphonate etidronate can induce osteomalacia. The various characteristics of bisphosphonates: physicochemical, biological, therapeutic and toxicological, vary greatly depending on the structure of the individual bisphosphonate. Even small changes in the structure can lead to enormous differences in potency. Overall, this class of drugs offers several prospects for the future.

Bisphosphonates Paget's disease Osteoporosis Hypercalcaemia of malignancy Metastatic bone disease 

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References

  1. 1.
    Rodan GA, Fleisch HA. Bisphosphonates: mechanisms of action. J Clin Invest 1996;97:2692–6.Google Scholar
  2. 2.
    Rosen CJ, Kessenich CR. Comparative clinical pharmacology and therapeutic use of bisphosphonates in metabolic bone diseases. Drugs 1996;51:537–51.Google Scholar
  3. 3.
    Fleisch H. Bisphosphonates: mechanisms of action and clinical use in osteoporosis-an update. Horm Metab Res 1997;29:145–50.Google Scholar
  4. 4.
    Fleisch H. Bisphosphonates: a new class of drugs in diseases of bone and calcium metabolism. In Baker, ed. Handbook of experimental pharmacology. Berlin-Heidelberg: Springer, 1988;83:441–66.Google Scholar
  5. 5.
    Fleisch H. Editorial: prospective use of bisphosphonates in osteoporosis. J Clin Endocrinol Metab 1993;76:1397–8.Google Scholar
  6. 6.
    Recommended INN: List 34. WHO Drug Information, 1994;8:166.Google Scholar
  7. 7.
    van Beek E, Hoekstra M, van der Ruit M, Löwik C, Papapoulos S. Structural requirements for bisphosphonate actions in vitro. J Bone Miner Res 1994;9:1875–82.Google Scholar
  8. 8.
    Rodan GA, Balena R. Bisphosphonates in the treatment of metabolic bone diseases. Ann Med 1993;25:373–8.Google Scholar
  9. 9.
    Ebetino FH, Kaas SM, Crawford RJ. Bisphosphonates: molecular modelling, structure activity relationships and the rational design of new analogs. Phosphorus Sulfur 1993;76:151–4.Google Scholar
  10. 10.
    Fleisch H. New bisphosphonates in osteoporosis. Osteoporosis Int 1993;2:S15–22.Google Scholar
  11. 11.
    Rogers MJ, Xiong X, Brown RJ, Watts DJ, Russell RGG, Bayless AV, et al. Structure-activity relationships of new heterocycle-containing bisphosphonates as inhibitors of bone resorption and as inhibitors of growth of Dictyostelium descoideum Amoebe. Mol Pharmacol 1995;47:398–402.Google Scholar
  12. 12.
    van Beek E, Löwik C, Que I, Papapoulos S. Dissociation of binding and antiresoptive properties of hydroxybisphosphonates by substitution of the hydroxyl with an amino group. Bone Miner Res 11;1996:1492–97.Google Scholar
  13. 13.
    Fleisch H. Bisphosphonates in bone disease. From laboratory to the patient. 2nd ed. New York: The Parthenon Publishing Group, 1995.Google Scholar
  14. 14.
    Adami S, Zamberlan N. Adverse effects of bisphosphonates. A comparative review. Drug Safety 1996;14:158–70.Google Scholar
  15. 15.
    Lin JH. Bisphosphonates: a review of their pharmacokinetic properties. Bone 1996;18:75–85.Google Scholar
  16. 16.
    Fogelman I, Smith L, Mazess R, Wilson MA, Bevan JA. Absorption of oral diphosphonate in normal subjects. Clin Endocr 1986;24:57–62.Google Scholar
  17. 17.
    Recker RR, Saville PD. Intestinal absorption of disodium ethane-1-hydroxy-1,1-diphosphonate (disodium etidronate) using a deconvolution technique. Toxicol Appl Pharmacol 1973;24:580–89.Google Scholar
  18. 18.
    Wiedmer WH, Zbinden AM, Trechsel U, Fleisch H. Ultrafiltrability and chromatographic properties of pyrophosphate, 1-hydroxyethylidene-1,1-bisphosphonate, and dichloromethylenebisphosphonate in aqueous buffers and in human plasma. Calcified Tissue Int 1983;35:397–400.Google Scholar
  19. 19.
    Fleisch H. Bisphosphonates; pharmacology and use in the treatment of tumour-induced hypercalcaemic and metastatic bone disease. Drugs 1991;42:919–44.Google Scholar
  20. 20.
    Saha H, Castren-Kortekangas P, Ojanen S, Juhakoski A, Tuominen J, Tokola O. Pharmacokinetics of clodronate in renal failure. J Bone Miner Res 1994;9:1953–8.Google Scholar
  21. 21.
    Pentikäinen PJ, Elomaa I, Nurmi AK, Kärkkäinen S. Pharmacokinetics of clodronate in patients with metastatic breast cancer. Int J Clin Pharm Th 1989;27:222–8.Google Scholar
  22. 22.
    Hyldstrup L, Flesch G, Hauffe SA. Pharmacokinetic evaluation of pamidronate after oral administration: a study on dose proportionality, absolute bioavailability, and effect of repeated administration. Calcified Tissue Int 1993;53:297–300.Google Scholar
  23. 23.
    Daley-Yates PT, Cal JC, Cockshott A, Pongchaidecha M, Gilchrist K. Plasma protein binding of APD: role of calcium and transferrin. Chem-Biol Interactions 1992;81:79–89.Google Scholar
  24. 24.
    Sansom LN, Necciari J, Thiercelin JF. Human pharmacokinetics of tiludronate. Bone 1995;17:S479–83.Google Scholar
  25. 25.
    Gertz BJ, Holland SD, Kline WF, Matuszewski BK, Freeman A, Quan H, et al. Studies of oral bioavailability of alendronate. Clin Pharmacol Ther 1995;58:288–98.Google Scholar
  26. 26.
    Gertz BJ, Holland SD, Kline WF, Matuszewski BK, Porras AG. Clinical pharmacology of alendronate sodium. Osteoporosis Int 1993;3:S13–6.Google Scholar
  27. 27.
    Lin JH, Chen I, Deluna FA. Nonlinear kinetics of alendronate; plasma protein binding and bone uptake. Drug Metab Dispos 1994;22:400–5.Google Scholar
  28. 28.
    Kanis JA. Osteoporosis. London: Blackwell Science, 1994.Google Scholar
  29. 29.
    Lombardi A, Santora AC. Clinical trials with bisphosphonates. Ann Ital Med Int 1992;7:S158–65.Google Scholar
  30. 30.
    Harinck HIJ, Papapoulos SE, Blanksma HJ, Molenaar AJ, Vermeij P, Bijvoet OLM, et al. Paget's Disease of the bone: early and late responses of three different modes of treatment with aminohydroxypropylidene bisphosphonate (APD). Br Med J 1987;295:1301–5.Google Scholar
  31. 31.
    Lufkin EG, Arqueta R, Withaker MD, Cameron AL, Wong VH, Egan KS, et al. Pamidronate: an unrecognized problem in gastro intestinal tolerability. Osteoporosis Int 1994;4:320–2.Google Scholar
  32. 32.
    de Groen PC, Lubbe DF, Hirsch LJ, Daifotis A, Stephenson W, Freedholm D, et al. Esophagitis associated with the use of alendronate. New Engl J Med 1996;335:1016–21.Google Scholar
  33. 33.
    Fosamax (alendronate sodium tablets). West Point, PA: Merck, 1996 (package insert).Google Scholar
  34. 34.
    Hosking DJ. Advances in the management of Paget's disease of bone. Drugs 1990;40:829–40.Google Scholar
  35. 35.
    Axelrod DW, Teitelbaum SL. Results of long-term cyclical etidronate therapy: bone histomorphometric and clinical correlates.J. Bone Miner Res 1994;9:S136.Google Scholar
  36. 36.
    Papapoulos SE, Lockefeer JHM. Bisfosfonaten bij osteoporose; een herbeoordeling. Ned Tijdschr Geneeskd 1996;140:2394–8.Google Scholar
  37. 37.
    Watts NB, Miller PD, Licata AA, Jackson RD, Wasnich RD, Ross PD, et al. Seven years of cyclical etidronate: continues improvement in spine BMD and progressive decline in vertebral fracture incidence. Bone 1995;17:597.Google Scholar
  38. 38.
    Singer FR, Ritch PS, Lad TE, Ringenberg QS, Schiller JH. Treatment of hypercalcemia of malignancy with intravenous etidronate. Arch Int Med 1991;151:471–6.Google Scholar
  39. 39.
    Bijvoet OLM, Frijlink WB, Jie K, van der Linden H, Meyer CJLN, Mulder H, et al. APD in Paget's disease of bone. Role of mononuclear phagocyte system? Arthr Rheum 1980;23:1193–204.Google Scholar
  40. 40.
    Harinck HIJ, Bijvoet OLM, Blanksma HJ, Dahlinghaus-Nienhuys AJ. Efficacious management with aminobisphosphonate (APD) in Paget's disease of bone. Clin Orthop 1987;217:79–98.Google Scholar
  41. 41.
    Schweitzer DH, Oostendorp-van der Ruit M, van de Pluijm G, Löwik CWGM, Papapoulos SE. 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;6:956–62.Google Scholar
  42. 42.
    Macarol V, Fraunfelder FT. Pamidronate disodium and possible ocular adverse drug reactions. Am J Ophtalmol 1994;118:220–4.Google Scholar
  43. 43.
    Reid IR, Mills DAJ, Wattie DJ. Ototoxicity associated with intravenous bisphosphonate administration. Calc Tissue Int 1995;56:584–5.Google Scholar
  44. 44.
    Siris ES. Bisphosphonates and iritis. Lancet 1993;341:4367.Google Scholar
  45. 45.
    Delmas PD, Meunier PJ. The management of Paget's disease of bone. New Engl J Med 1997;336:558–66.Google Scholar
  46. 46.
    Hosking D, Meunier PJ, Ringe JD, Reginster J-Y, Gennari C. Paget's disease of bone: diagnosis and management. Brit Med J 1996;312:491–4.Google Scholar
  47. 47.
    Patel S, Lyons AR, Hosking DJ. Drugs used in the treatment of metabolic bone disease; clinical pharmacology and therapeutic use. Drugs 1993;46:594–617.Google Scholar
  48. 48.
    Adami S, Mian M, Gatti P, Rossini M, Zamberlan N, Bertoldo F, et al. Effects of two oral doses of alendronate in the treatment of Paget's disease of bone. Bone 1994;15:415–7.Google Scholar
  49. 49.
    Adami S, Zamberlan N, Mian M, Dorizzi R, Rossini M, Bragga B, et al. Duration of the effects of intravenous alendronate in postmenopausal women and in patients with primary hyperparathyroidism and Paget's disease of bone. Bone Miner 1994;25:75–82.Google Scholar
  50. 50.
    Altman RD, Johnston CC, Khairi MRA, Wellman H, Serafini AN, Sankey RR. Influence of disodium etidronate on clinical and laboratory manifestations of Paget's disease of bone (osteitis deformans). New Engl J Med 1973;289:1379–84.Google Scholar
  51. 51.
    Altman RD. Long term follow up of therapy with intermittent etidronate disodium in Paget's disease of bone. Am J Med 1985;79:583–90.Google Scholar
  52. 52.
    Johnson CC Jr, Altman RD, Canfield RE, Finerman GAM, Taulbee JD, Ebert ML. Review of fracture experience during treatment of Paget's disease of bone with etidronate disodium (EHDP). Clin Orthop 1983;172:186–94.Google Scholar
  53. 53.
    Yates AJP, Gray RES, Urwin GH, Preston CJ, Russell RGG, Percival RC, et al. Intravenous clodronate in the treatment and retreatment of Paget's disease of bone. Lancet 1985(I):1474–7.Google Scholar
  54. 54.
    Reginster J-YL, Lecart M-O. Efficacy and safety of drugs for Paget's disease of bone. Bone 1995;17:S485–8.Google Scholar
  55. 55.
    Gutteridge DH, Retallack RW, Ward LC, Stuckey BGA, Steward GO, Prince RL, et al. Clinical, biochemical, hematologic, and radiographic responses in Paget's disease following intravenous pamidronate disodium: a 2-year study. Bone 1996;19:387–94.Google Scholar
  56. 56.
    Aredia (pamidronate disodium injection concentrate). Summit, NJ: Ciba-Geigy, 1994 (package insert).Google Scholar
  57. 57.
    McClung MR, Tou CKP, Goldstein NH, Picot C. Tiludronate therapy for Paget's disease of bone. Bone 1995;17:S493–6.Google Scholar
  58. 58.
    Roux C, Gennari C, Farrerons J, Devogelaar JP, Mulder H, Kruse HP, et al. Comparative prospective double blind multicentre study of the efficacy of tiludronate and etidronate in the treatment of Paget's disease of bone. Arthr Rheum 1995;38:851–8.Google Scholar
  59. 59.
    Reid IR, Nicholson GC, Weinstein RS, Hosking DJ, Cundy T, Kotowicz MA, et al. Biochemical and radiological improvement in Paget's disease of bone treated with alendronate: a randomized placebo-controlled trial. Am J Med 1996;101:341–8.Google Scholar
  60. 60.
    Filipponi P, Pedetti M, Beghe F, Giovagnini B, Miam M, Cristallini S. Effects of two different bisphosphonates on Paget's disease of bone: ICTP assessed. Bone 1994;15:261–7.Google Scholar
  61. 61.
    Schweitzer DH, Zwinderman AH, Vermeij P, Bijvoet OLM, Papapoulos SE. Improved treatment of Paget's disease with dimethylaminohydroxypropylidene bisphosphonate (dimethyl-APD). J Bone Miner Res 1993;8:175–82.Google Scholar
  62. 62.
    Pak CYC, Zerwekh JE, Antich PP, Bell NH, Singer FR. Slow-release sodium fluoride in osteoporosis. J Bone Miner Res 1996;11:561–4.Google Scholar
  63. 63.
    Furner CH. Fluoride and the FDA. J Bone Miner Res 1996;11:1369–70 [Reply: Zerwekh JE, Antich P, Pak CYC. J Bone Miner Res 1996;11:1370-1].Google Scholar
  64. 64.
    Lufkin EG, Wahner HW, O'Fallon WM, Hodgson SF, Kotowics MA, Lane AW, et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med 1992;117:1–9.Google Scholar
  65. 65.
    Lindsay R, Tohme JF. Estrogen treatment of patients with established postmenopausal osteoporosis. Obstet Gynecol 1990;76:290–5.Google Scholar
  66. 66.
    Colditz GA, Hankinson SE, Hunter DJ, Willet WC, Manson JE, Stampfer MJ, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. New Eng J Med 1995;332:1589–93.Google Scholar
  67. 67.
    Lindsay R. Criteria for succesful estrogen therapy in osteoporosis. Osteoporosis Int 1993; (supp C2):S9–13.Google Scholar
  68. 68.
    Overgaard K, Riis BJ, Christiansen C, Hansen MA. Effect of salcatonin given intranassally on early postmenopausal bone loss. Br Med J 1989;299:477–9.Google Scholar
  69. 69.
    Lyretis GP, Tsakalokos N, Magrass B, Karachalios T, Tiatrides A. Analgesic effect of salmon cacitonin in osteoporotic vertebral fractures: a double blind, placebo-controlled clinical study. Calcified Tissue Int 1991;49:368–72.Google Scholar
  70. 70.
    Heany RP, Saville PD. Etidronate disodium in postmenopausal osteoporosis. Clin Pharmacol Ther 1976;20:593–604.Google Scholar
  71. 71.
    Bijvoet OLM, Valkema R, Löwik CWGM, Papapoulos SE. The use of bisphosphonates in osteoporosis. In DeLuca HF, Mazess R, eds. Osteoporosis: physiological basis, assessment and treatment. Amsterdam: Elsevier, 1990:331–8.Google Scholar
  72. 72.
    Liberman UA, Weiss SR, Bröll J, Minne HW, Quan H, Bell NH, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. New Engl J Med 1995;333:1437–43.Google Scholar
  73. 73.
    Storm T, Thamborg G, Steiniche T, Genant HK, Helmer Sørensen O. Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis. New Eng J Med 1990;322:1265–71.Google Scholar
  74. 74.
    Harris ST, Watts NB, Jackson RD, Genant HK, Wasnich RD, Ross P, et al. Four-year study of intermittent cyclic etidronate treatment of postmenopausal osteoporosis: three years of blinded therapy followed by one year of open therapy. Am J Med 1993;95:556–67.Google Scholar
  75. 75.
    Reid IR, Wattie DJ, Evans MC, Gamble GD, Stapleton JP, Carnish J. Continuous therapy with pamidronate, a potent bisphosphonate in postmenopausal osteoporosis. J Clin Endocr Metab 1994;79:1595–9.Google Scholar
  76. 76.
    Orr-Walker B, Wattie DJ, Evans MC, Reid IR. Effects of prolonged bisphosphonate therapy and its discontinuation on bone mineral density in post-menopausal osteoporosis. Clin Endocrinol 46;1997:87–92.Google Scholar
  77. 77.
    Landman JO. Long-term effects of bisphosphonate (pamidronate) therapy in osteoporosis. Leiden: thesis, 1996.Google Scholar
  78. 78.
    Reginster JY, Deroisy R, Denis D, Colette J, Lecart MP, Sarlet N, et al. Prevention of postmenopausal bone loss by tiludronate. Lancet 1989(II):1469–71.Google Scholar
  79. 79.
    Chesnut CH, III. Tiludronate: development as an osteoporosis therapy. Bone 1995;17:S517–9.Google Scholar
  80. 80.
    Sambrook PN. The treatment of postmenopausal osteoporosis. New Engl J Med 1995;333:1495–6.Google Scholar
  81. 81.
    Black BM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, et al. Randomised trial of effect of alendronate on risk of fracture in woman with existing vertebral fractures. Lancet 1996;348:1535–41.Google Scholar
  82. 82.
    Ravn P, Clemmensen B, Riis BJ, Christiansen C. The effect on bone mass and bone markers of different doses of ibandronate: a new bisphosphonate for prevention and treatment of postmenopausal osteoporosis: a 1-year, randomized, double-blind, placebo-controlled, dose-finding study. Bone 1996;19:527–33.Google Scholar
  83. 83.
    Fisken RA, Heath DA, Bold AM. Hypercalcaemia-a hospital survey. Q J Med 1980;49:405–18.Google Scholar
  84. 84.
    Scher HI, Yagonda A. Bone metastasis pathogenesis, treatment and rationale for the use of resorption inhibitors. Am J Med 1987;82, suppl. 2a:6–28.Google Scholar
  85. 85.
    Coleman RE, Rubens RA. The clinical course of bone metastasis from breast cancer. Br J Cancer 1987;55:61–6.Google Scholar
  86. 86.
    Mundy GR. Calciumhomeostasis: hypercalcemia an hypocalcemia. London: Martin Dunitz, 1990.Google Scholar
  87. 87.
    Verzantvoort ATM. Palliative bisphosphonate treatment of metastatic bone disease. Leiden: thesis, 1993.Google Scholar
  88. 88.
    Harinck HIJ, Bijvoet OLM, Plantingh AST, Body JJ, Elte JWF, Sleeboom HP, et al. Role of bone and kidney in tumour-induced hypercalcemia and its treatment with bisphosphonate and sodium chloride. Am J Med 1987;82:1133–42.Google Scholar
  89. 89.
    Nakashima L. Guidelines for the treatment of hypercalcemia associated with malignancy. J Oncol Pharm Practice 1997;3:31–7.Google Scholar
  90. 90.
    Rizzoli R, Buchs B, Bonjour JP. Effect of a single infusion of alendronate in malignant hypercalcaemia: dose dependency and comparison with clodronate. Int J Cancer 1992;50:706–12.Google Scholar
  91. 91.
    Dodwell DJ, Howell A, Morton AR, Daley-Yates PT, Hoggarth CR. Infusion rate and pharmacokinetics of intravenous pamidronate in the treatment of tumour-induced hypercalcaemia. Postgrad Med J 1992;68:434–9.Google Scholar
  92. 92.
    Wimalawansa SJ. Optimal frequency of administration of pamidronate in patients with hypercalcaemia of malignancy. Clin Endocrinol 1994;41:591–5.Google Scholar
  93. 93.
    Purohit OP, Radstone CR, Anthony C, Kanis JA, Coleman RE. A randomised double-blind comparison of intravenous pamidronate and clodronate in the hypercalcaemia of malignancy. Br J Cancer 1995;72:1289–93.Google Scholar
  94. 94.
    Vinholes J, Guo C-Y, Purohit OP, Eastell R, Coleman RE. Evaluation of new bone resorption markers in a randomized comparison of pamidronate or clodronate for hypercalcemia of malignancy. J Clin Oncol 1997;15:131–8.Google Scholar
  95. 95.
    Nussbaum SR, Warrell RP Jr, Rude R, Glusman J, Bilezikian JP, Stewart AF, et al. Dose-response study of alendronate sodium for the treatment of cancer associated hypercalcaemia. J Clin Oncol 1993;11:1618–23.Google Scholar
  96. 96.
    Wüster C, Schöter KH, Thiébaud D, Manegold C, Krahl D, Clemens MR, et al. Methylpentylaminopropylidenebisphosphonate (BM 21.0955): a new potent and safe bisphosphonate for the treatment of cancer-associated hypercalcemia. Bone Miner 1993;22:77–85.Google Scholar
  97. 97.
    Pecherstorfer M, Herrmann Z, Body J-J, Manegold C, Degardin M, Clemens MR, et al. Randomized phase II trial comparing different doses of the bisphosphonate ibandronate in the treatment of hypercalcemia of malignancy. J Clin Oncol 1996;14:268–76.Google Scholar
  98. 98.
    Ralston SH, Thiébaud D, Herrmann Z, Steinhauer EU, Thürlimann B, Walls J, et al. Dose-response study of ibandronate in the treatment of cancer-associated hypercalcaemia. Br J Cancer 1997;75:295–300.Google Scholar
  99. 99.
    Belch AR, Bersagel DE, Wilson K, O'Reilly S, Wilson J, Sutton D, et al. Effect of daily etidronate on the osteolysis of multiple myeloma. J Clin Oncol 1991;9:1397–402.Google Scholar
  100. 100.
    van Holten-Verzantvoort ATM, Kroon HM, Bijvoet OLM, Cleton FJ, Beex LVAM, Blijham G, et al. Palliative pamidronate treatment in patients with bone metastases from breast cancer. J Clin Oncol 1993;11:491–3.Google Scholar
  101. 101.
    van Holten-Verzantvoort ATM, Zwinderman AH, Aaronson NK, Hermans J, van Emmerik B, van Dam FSAM, 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.Google Scholar
  102. 102.
    Conte PF, Latreille J, Mauriac L, Calabresi F, Santos R, Campos D, et al. Delay in progression of bone metastases in breast cancer patients treated with intravenous pamidronate: results from a multinational randomized controlled trial. J Clin Oncol 1996;14:2552–9.Google Scholar
  103. 103.
    Hortobagyi GN, Theriault RL, Porter L, Blayney D, Lipton A, Sinoff C, et al. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. New Eng J Med 1996;335:1785–91.Google Scholar
  104. 104.
    Berenson JR, Lichtenstein A, Porter L, Dimopoulos MA, Bordoni R, George S, et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. New Engl J Med 1996;334:488–93.Google Scholar
  105. 105.
    Lahtinen R, Laakso M, Palva I, Virkkunen P, Elomaa I. Randomised, placebo-controlled multicentre trial of clodronate in multiple myeloma. Lancet 1992;340:1049–52.Google Scholar
  106. 106.
    van der Pluijm G, Vloedgraven H, van Beek E, van der Wee-Pals L, Löwik C, Papapoulos S. Bisphosphonates inhibit the adhesion of breast cancer cells to bone matrices in vitro. J Clin Invest 1996;98:698–705.Google Scholar
  107. 107.
    Sparidans RW, den Hartigh J. Chromatography of bisphosphonates. Pharm World Sci. (In press.)Google Scholar

Copyright information

© Kluwer Academic Publishers 1998

Authors and Affiliations

  • Rolf W. Sparidans
    • 1
  • Irene M. Twiss
    • 1
  • Stephanie Talbot
    • 1
  1. 1.Department of Clinical Pharmacy and ToxicologyLeiden University Medical CentreLeidenThe Netherlands

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