Bisphosphonates: A New Class of Drugs in Diseases of Bone and Calcium Metabolism

  • H. Fleisch
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 83)


The bisphosphonates are a new class of drugs which have been developed in the past two decades for use in various diseases of bone, tooth, and calcium metabolism. Three are on the market today, while others are under clinical or preclinical investigation. This chapter will cover chemical and experimental aspects as well as clinical applications of these compounds. Literature is essentially limited to one reference, usually the original report. For two recent reviews, weighted somewhat differently and with more extensive references, see Fleisch (1983) and Francis and Martodam (1983).


Heterotopic Ossification Ectopic Calcification Disodium Etidronate Bisphosphonic Acid Dichloromethylene Diphosphonate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Ahrengart L, Lindgren U (1986) Prevention of ectopic bone formation by local application of ethane-1-hydroxy-1,1-diphosphonate (EHDP): an experimental study in rabbits. J Orthop Res 4:18–26PubMedGoogle Scholar
  2. Altman RD, Johnston CC, Khairi MRA, Wellman H, Serafini AN, Sankey RR (1973) Influence of disodium etidronate on clinical and laboratory manifestations of Paget’s disease of bone (osteitis deformans). N Engl J Med 289:1379–1384PubMedGoogle Scholar
  3. Anbar M, Newell GW, St John GA (1973) Fate and toxicity of orally administered polyethylene polyphosphonates. Food Cosmetics Tox 11:1001–1010Google Scholar
  4. Barbier A, Brelière JC, Paul RP, Roncucci R (1985) Comparative study of etidronate and SR 41319, a new diphosphonate, on passive cutaneous anaphylaxis and phospholipase A2 activity. Agents Actions 16:41–42PubMedGoogle Scholar
  5. Barbier A, Brelière JC, Remandet B, Roncucci R (1986) Studies on the chronic phase of adjuvant arthritis: effect of SR 41319, a new diphosphonate. Ann Rheum Dis 45:67–74PubMedGoogle Scholar
  6. Barnett BL, Strickland LC (1979) Structure of disodium dihydrogen 1-hydroxyethylidene-diphosphonate tetrahydrate: a bone growth regulator. Acta Crystall B35:1212–1214Google Scholar
  7. Basle MF, Rebel A, Renier JC, Audran M, Filmon R, Malkani K (1984) Bone tissue in Paget’s disease treated by ethane-1-hydroxy-1,1 diphosphonate (EHDP). Clin Orthop Rel Res 184:281–288Google Scholar
  8. Bassett CAL, Donath A, Macagno F, Preisig R, Fleisch H, Francis MD (1969) Diphosphonates in the treatment of myositis ossificans. Lancet 2:845PubMedGoogle Scholar
  9. Baumann JM, Bisaz S, Fleisch H, Wacker M (1978) Biochemical and clinical effects of ethane-1-hydroxy-1,1-diphosphonate on calcium nephrolithiasis. Clin Sci Mol Med 54:509–516PubMedGoogle Scholar
  10. Baxter LA, DeLuca HF, Bonjour JP, Fleisch H (1974) Inhibition of vitamin D metabolism by ethane-1-hydroxy-1,1-diphosphonate. Arch Biochem Biophys 164:655–662PubMedGoogle Scholar
  11. Beertsen W, Niehof A, Everts V (1985) Effects of 1-hydroxyethylidene-1,1-bisphosphonate (HEBP) on the formation of dentin and the periodontal attachment apparatus in the mouse. Am J Anat 174:83–103PubMedGoogle Scholar
  12. Benedict JJ, Degenhardt CR, Perkins CM, Johnson KY, Bevan JA, Olson HM (1985 a) Cyclic geminal bis(phosphonates) as inhibitors of bone resorption. Calcif Tissue Int 38 [Suppl]:S31Google Scholar
  13. Benedict JJ, Johnson KY, Bevan JA, Perkins CM (1985 b) A structure/activity study of nitrogen heterocycle containing bis(phosphonates) as bone resorption inhibiting agents. Calcif Tissue Int 38 [Suppl]:S31Google Scholar
  14. Bevan JA, Johnson KY, Slough C, Benedict J, Fleisch H, Black J (1985) Skeletal effects of 2-(2-pyridinyl)-ethylidene-bis(phosphonate) in acute and subchronic rat studies. Calcif Tissue Int 38 [Suppl]:S31Google Scholar
  15. Bijvoet OLM, Frijlink WB, Jie K, Linden H van der, Meijer CJLM, Mulder H, Paassen HC van, Reitsma PH, Velde J te, Vries E de, Wey JP van der (1980) APD in Paget’s disease of bone. Role of the mononuclear phagocyte system? Arthritis Rheum 23:1193–1204PubMedGoogle Scholar
  16. Bisaz S, Felix R, Fleisch H (1975 a) Quantitative determination of ethane-1-hydroxy-1,1-diphosphonate in urine and plasma. Clin Chim Acta 65:299–307PubMedGoogle Scholar
  17. Bisaz S, Schenk R, Kunin AS, Russell RGG, Mühlbauer R, Fleisch H (1975 b) The comparative effects of vitamin D deficiency and ethane-1-hydroxy-1,1-diphosphonate administration on the histology and glycolysis of chick epiphyseal and articular cartilage. Calcif Tissue Res 19:139–152PubMedGoogle Scholar
  18. Bisaz S, Jung A, Fleisch H (1978) Uptake by bone of pyrophosphate, diphosphonates and their technetium derivatives. Clin Sci Mol Med 54:265–272PubMedGoogle Scholar
  19. Blaser B, Worms KH, Germscheid HG, Wollmann K (1971) Ueber 1-Hydroxyalkan-1,1-diphosphonsäuren. Z Anorg Allg Chem 381:247–259Google Scholar
  20. Bone HG, Zerwekh JE, Britton F, Pak CYC (1979) Treatment of calcium urolithiasis with diphosphonate: efficacy and hazards. J Urol 121:568–571PubMedGoogle Scholar
  21. Bonjour JP, Russell RGG, Morgan DB, Fleisch H (1973) Intestinal calcium absorption, Ca-binding protein, and Ca-ATPase in diphosphonate-treated rats. Am J Physiol 224:1011–1017Google Scholar
  22. Bonjour JP, Tröhler U, Preston C, Fleisch H (1978) Parathyroid hormone and renal handling of Pi: effect of dietary Pi and diphosphonates. Am J Physiol 234:F487–F505Google Scholar
  23. Bounameaux HM, Schifferli J, Montani JP, Jung A, Chatelanat F (1983) Renal failure associated with intravenous diphosphonate. Lancet 1:471PubMedGoogle Scholar
  24. Boyce BF, Fogelman I, Ralston S, Smith L, Johnston E, Boyle IT (1984) Focal osteomalacia due to low-dose diphosphonate therapy in Paget’s disease. Lancet 1:821–824PubMedGoogle Scholar
  25. Briner WW, Francis MD, Widder JS (1971) The control of dental calculus in experimental animals. Int Dent J 21:61–73PubMedGoogle Scholar
  26. Canfield R, Rosner W, Skinner J, McWorther J, Resnick L, Feldman F, Kammerman S, Ryan K, Kunigonis M, Bohne W (1977) Diphosphonate therapy of Paget’s disease of bone. J Clin Endocrinol Metab 44:96–106PubMedGoogle Scholar
  27. Casey PA, Casey G, Fleisch H, Russell RGG (1972) The effect of polyphloretin phosphate, polyestradiol phosphate, a diphosphonate and a polyphosphate on calcification induced by dihydrotachysterol in skin, aorta and kidney of rats. Experientia 28:137–138PubMedGoogle Scholar
  28. Cecchini M, Felix R, Cooper PH, Fleisch H (1987) Effect of bisphosphonates on proliferation and viability of mouse bone marrow-derived macrophages. J Bone Min Res 2:135Google Scholar
  29. Cecchini M, Felix R, Cooper PH, Fleisch H (1987) Effect of bisphosphonates on proliferation and viability of mouse bone marrow-derived macrophages. J Bone Min Res 2:142Google Scholar
  30. Chambers TJ (1980) Diphosphonates inhibit bone resorption by macrophages in vitro. J Pathol 132:255–262PubMedGoogle Scholar
  31. Chapuy MC, Meunier PJ, Alexandre CM, Vignon EP (1980) Effects of disodium dichloromethylene diphosphonate on hypercalcemia produced by bone metastases. J Clin Invest 65:1243–1247PubMedGoogle Scholar
  32. Chapuy MC, Charhon SA, Meunier PJ (1983) Sustained biochemical effects of short treatment of Paget’s disease of bone with dichloromethylene diphosphonate. Metab Bone Dis Rel Res 4:325–328Google Scholar
  33. Chester TL, Lewis EC, Benedict JJ, Sunberg RJ, Tettenhorst WC (1981) Determination of (dichloromethylene)diphosphonate in physiological fluids by ion-exchange chromatography with phosphorus-selective detection. J Chromatogr Sci 225:17–25Google Scholar
  34. Conrad KA, Lee SM (1981) Clodronate kinetics and dynamics. Clin Pharmacol Ther 30:114–120PubMedGoogle Scholar
  35. Cram RL, Barmada R, Geho WB, Ray RD (1971) Diphosphonate treatment of calcinosis universalis. N Engl J Med 285:1012–1013PubMedGoogle Scholar
  36. Curry JD, Nicholson DA (1972) Oligophosphonates. In: Griffith J, Grayson M (eds) Topics in phosphorus chemistry, vol 7. Wiley, New York, p 37Google Scholar
  37. Delaissé J-M, Eeckhout Y, Vaes G (1985) Biphosphonates and bone resorption: effects on collagenase and lysosomal enzyme excretion. Life Sci 37:2291–2296PubMedGoogle Scholar
  38. Vries HR De, Bijvoet OLM (1974) Results of prolonged treatment of Paget’s disease of bone with disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP). Neth J Med 17:281–298PubMedGoogle Scholar
  39. Vries E De, Weij JP van der, Veen CJP v d, Paassen HC van, Jager MJ, Sleeboom HP, Bijvoet OLM, Cats A (1982) In vitro effect of (3-amino-1-hydroxypropylidene)-1,1-bisphosphonic acid (APD) on the function of munonuclear phagocytes in lymphocyte proliferation. Immunology 47:157–163PubMedGoogle Scholar
  40. Dewanjee MK, Didisheim P, Kaye MP, Solis E, Zollman PE, Francis MD, Torianni M, Trastek VS, Tago M, Edwards WD (1984) Platlet deposition on and calcification of bovine pericardial valve. Eur Heart J 5 [Suppl D]:1–5PubMedGoogle Scholar
  41. Doty SB, Jones R, Finerman GA (1972) Diphosphonate influence on bone cell structure and lysosomal activity. J Bone Joint Surg 54:1128–1129Google Scholar
  42. Douglas DL, Russell RGG, Preston CJ, Prenton MA, Duckworth T, Kanis JA, Preston FE, Woodhead JS (1980) Effect of dichloromethylene diphosphonate in Paget’s disease of bone and in hypercalcaemia due to primary hyperparathyroidism or malignant disease. Lancet 1:1043–1047PubMedGoogle Scholar
  43. Drake GL, Calamari TA (1983) Industrial uses of phosphonates. In: Hilderbrand RL (ed) The role of phosphonates in living systems. CRC Press, Boca Raton, p 171Google Scholar
  44. Elomaa I, Blomqvist C, Gröhn P, Porkka L, Kairento AL, Seiander K, Lamberg-Allardt C, Holmström T (1983) Long-term controlled trial with diphosphonate in patients with osteolytic bone metastases. Lancet 1:146–149PubMedGoogle Scholar
  45. Emonds-Alt X, Brelière J-C, Roncucci R (1985) Effects of 1-hydroxyethylidene-1,1 bisphosphonate and (chloro-4 phenyl) thiomethylene bisphosphonic acid (SR 41319) on the mononuclear cell factor-mediated release of neutral proteinases by articular chondrocytes and synovial cells. Biochem Pharmacol 34:4043–4049PubMedGoogle Scholar
  46. Ende JJ (1979) Effects of some diphosphonates on the metabolism of bone in vivo and in vitro. Thesis, University of LeidenGoogle Scholar
  47. Engel R (1983) Phosphonic acids and phosphonates as antimetabolites. In: Hilderbrand RL (ed) The role of phosphonates in living systems. CRC Press, Boca Raton, p 97Google Scholar
  48. Eubank WB, Reeves RE (1982) Analog inhibitors for the pyrophosphate-dependent phosphofructokinase of Entamoeba histolytica and their effect of culture growth. J Parasitol 68:599–602PubMedGoogle Scholar
  49. Evêquoz V, Trechsel U, Fleisch H (1985) Effect of bisphosphonates on production of interleukin 1-like activity by macrophages and its effect on rabbit chondrocytes. Bone 6:439–444PubMedGoogle Scholar
  50. Fast DK, Felix R, Dowse C, Neumann WF, Fleisch H (1978) The effects of diphosphonates on the growth and glycolysis of connective-tissue cells in culture. Biochem J 172:97–107PubMedGoogle Scholar
  51. Felix R, Fleisch H (1979) Increase in alkaline phosphatase activity in calvaria cells cultured with diphosphonates. Biochem J 183:73–81PubMedGoogle Scholar
  52. Felix R, Fleisch H (1981) Increase in fatty acid oxidation in calvaria cells cultured with diphosphonates. Biochem J 196:237–245PubMedGoogle Scholar
  53. Felix R, Russell RGG, Fleisch H (1976) The effect of several diphosphonates on acid phosphohydrolases and other lysosomal enzymes. Biochim Biophys Acta 429:429–438PubMedGoogle Scholar
  54. Felix R, Fast DK, Sallis JD, Fleisch H (1980) Effect of diphosphonate on glycogen content of rabbit ear cartilage cells in culture. Calcif Tissue Int 30:163–166PubMedGoogle Scholar
  55. Felix R, Bettex JD, Fleisch H (1981) Effect of diphosphonates on the synthesis of prostaglandins in cultured calvaria cells. Calcif Tissue Int 33:549–552PubMedGoogle Scholar
  56. Felix R, Guenther HL, Fleisch H (1984) The subcellular distribution of 14C dichloromethylenebisphosphonate and 14C 1-hydroxyethylidene-1,1-bisphosphonate in cultured calvaria cells. Calcif Tissue Int 36:108–113PubMedGoogle Scholar
  57. Finerman GAM, Stover SL (1981) Heterotopic ossification following hip replacement or spinal cord injury. Two clinical studies with EHDP. Metab Bone Dis Rel Res 4:337–342Google Scholar
  58. Fleisch H (1983) Bisphosphonates: mechanisms of action and clinical applications. In: Peck WA (ed) Bone and mineral research, annual 1. Excerpta Medica, Amsterdam, 319–357Google Scholar
  59. Fleisch H, Bisaz S (1962) Isolation from urine of pyrophosphate, a calcification inhibitor. Am J Physiol 203:671–675PubMedGoogle Scholar
  60. Fleisch H, Neuman WF (1961) Mechanisms of calcification: role of collagen, polyphosphates, and phosphatase. Am J Physiol 200:1296–1300Google Scholar
  61. Fleisch H, Russell RGG (1970) Pyrophosphate and polyphosphate. In: Encyclopaedia (Int) of pharmacology and therapeutics, section 51. Pharmacology of the endocrine system and related drugs. Pergamon, Oxford, p 61Google Scholar
  62. Fleisch H, Russell RGG, Straumann F (1966) Effect of pyrophosphate on hydroxyapatite and its implications in calcium homeostasis. Nature 212:901–903Google Scholar
  63. Fleisch H, Russell RGG, Francis MD (1969) Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo. Science 165:1262–1264PubMedGoogle Scholar
  64. Fleisch H, Russell RGG, Bisaz S, Mühlbauer RC, Williams DA (1970) The inhibitory effect of phosphonates on the formation of calcium phosphate crystals in vitro and on aortic and kidney calcification in vivo. Eur J Clin Invest 1:12–18PubMedGoogle Scholar
  65. Flora L (1979) Comparative antiinflammatory and bone protective effects of two diphosphonates in adjuvant arthritis. Arthritis Rheum 4:340–346Google Scholar
  66. Flora L, Hassing GS, Parfitt AM, Villanueva AR (1980) Comparative skeletal effects of two diphosphonates in dogs. Metab Bone Dis Rel Res 2:389–407Google Scholar
  67. Fogelman I, Smith L, Mazess R, Wilson MA, Bevan JA (1986) Absorption of oral disphosphonate in normal subjects. Clin Endocrinol 24:57–62Google Scholar
  68. Francis MD (1969) The inhibition of calcium hydroxyapatite crystal growth by polyphosphates. Calcif Tissue Res 3:151–162PubMedGoogle Scholar
  69. Francis MD, Martodam RR (1983) Chemical, biochemical, and medicinal properties of the diphosphonates. In: Hilderbrand RL (ed) The role of phosphonates in living systems. CRC Press, Boca Raton, Florida, p 55Google Scholar
  70. Francis MD, Slough CL (1984) Acute intravenous infusion of disodium dihydrogen (1-hydroxyethylidene)diphosphonate: mechanism of toxicity. J Pharm Sci 73:1097–1100PubMedGoogle Scholar
  71. Francis MD, Russell RGG, Fleisch H (1969) Diphosphonates inhibit formation of calcium phosphate crystals in vitro and pathological calcification in vivo. Science 165:1264–1266PubMedGoogle Scholar
  72. Francis MD, Flora LF, King WF (1972) The effects of disodium ethane-1-hydroxy-1,1-diphosphonate on adjuvant induced arthritis in rats. Calcif Tissue Res 9:109–121PubMedGoogle Scholar
  73. Fraser D, Russell RGG, Pohler O, Robertson WG, Fleisch H (1972) The influence of disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) on the development of experimentally induced urinary stones in rats. Clin Sci 42:197–207PubMedGoogle Scholar
  74. Frijlink WB, Velde J te, Bijvoet OLM, Heynen G (1979) Treatment of Paget’s disease with (3-amino-1-hydroxypropylidene)-1,1-Bisphosphonate (A.P.D.). Lancet 1:799PubMedGoogle Scholar
  75. Gallagher JA, Guenther HL, Fleisch H (1982) Rapid intracellular degradation of newly synthesized collagen by bone cells. Effect of dichloromethylenebisphosphonate. Biochim Biophys Acta 719:349–355PubMedGoogle Scholar
  76. Garattini S (1985) Bone resorption, metastasis, and diphosphonates. Monographs of the Mario Negri Institute for pharmacological research. Raven, New YorkGoogle Scholar
  77. Gasser AB, Morgan DB, Fleisch HA, Richelle LJ (1972) The influence of two diphosphonates on calcium metabolism in the rat. Clin Sci 43:31–45PubMedGoogle Scholar
  78. Gebauer U, Russell RGG, Touabi M, Fleisch H (1976) Effect of diphosphonates on adenosine 3′:5′ cyclic monophosphate in mouse calvaria after stimulation by parathyroid hormone in vitro. Clin Sci Mol Med 50:473–478PubMedGoogle Scholar
  79. Geho WB, Whiteside JA (1973) Experience with disodium etidronate in diseases of ectopic calcification. In: Frame B, Parfitt AM, Duncan H (eds) Clinical aspects of metabolic bone disease. Excerpta Medica, Amsterdam, p 506Google Scholar
  80. Grabenstetter RJ, Cilley WA (1971) Polynuclear complex formation in solutions of calcium ion and ethane-1-hydroxy-1,1-diphosphonic acid. I. Complexometric and pH titrations. J Phys Chem 75:676–682Google Scholar
  81. Guenther HL, Guenther HE, Fleisch H (1979) Effects of 1-hydroxyethane-1,1-diphosphonate and dichloromethane-diphosphonate on rabbit articular chondrocytes in culture. Biochem J 184:203–214PubMedGoogle Scholar
  82. Guenther HL, Guenther HE, Fleisch H (1981 a) The effects of 1-hydroxyethane-1,1-di-phosphonate and dichloromethanediphosphonate on collagen synthesis by rabbit articular chondrocytes and rat bone cells. Biochem J 196:293–301PubMedGoogle Scholar
  83. Guenther HL, Guenther HE, Fleisch H (1981 b) The influence of 1-hydroxyethane-1,1-diphosphonate and dichloromethanediphosphonate on lysine hydroxylation and crosslink formation in rat bone, cartilage and skin collagen. Biochem J 196:303–310PubMedGoogle Scholar
  84. Guilland DF, Sallis JD, Fleisch H (1974) The effect of two diphosphonates on the handling of calcium by rat kidney mitochondria in vitro. Calcif Tissue Res 15:303–314PubMedGoogle Scholar
  85. Guilland D, Trechsel U, Bonjour JP, Fleisch H (1975) Stimulation of calcium absorption and apparent increased intestinal, 1,25-dihydroxycholecalciferol in rats treated with low doses of ethane-1-hydroxy-1,1-diphosphonate. Clin Sci Mol Med 48:157–160PubMedGoogle Scholar
  86. Guncaga J, Lauffenburger R, Lentner C, Dambacher MA, Haas HG, Fleisch H, Olah AJ (1974) Diphosphonate treatment of Paget’s disease of bone. A correlated metabolic, calcium kinetic and morphometric study. Horm Metab Res 6:62–69PubMedGoogle Scholar
  87. Gural RP (1975) Pharmacokinetics and gastrointestinal absorption behavior of etidronate. Dissertation, University of KentuckyGoogle Scholar
  88. Hähnel H, Mühlbach R, Lindenhayn K, Schaetz P, Schmidt UJ (1973) Zum Einfluss von Diphosphonat auf die experimentelle Heparinosteopathie. Z Altersforsch 27:289–292Google Scholar
  89. Hansen NM Jr, Felix R, Bisaz S, Fleisch H (1976) Aggregation of hydroxyapatite crystals. Biochim Biophys Acta 451:549–559PubMedGoogle Scholar
  90. Harvey RG, Sombre ER De (1964) The Michaelis-Arbuzov and related reactions. In: Grayson M, Griffith EJ (eds) Topics in phosphorus chemistry, vol I. 3. Wiley, New York, p 57Google Scholar
  91. Heaney RP, Saville PD (1976) Etidronate disodium in postmenopausal osteoporosis. Clin Pharmacol Ther 20:593–604PubMedGoogle Scholar
  92. Hendlin D, Stapley EO, Jackson M, Wallick H, Miller AK, Wolf FJ, Miller TW, Chaiet L, Kahan FM, Foltz EL (1969) Phosphonomycin, a new antibiotic produced by strains of streptomyces. Science 166:122–123PubMedGoogle Scholar
  93. Henley JW, Croxson RS, Ibbertson HK (1979) The cardiovascular system in Paget’s disease of bone and the response to therapy with calcitonin and diphosphonate. Aust NZ J Med 9:390–397Google Scholar
  94. Heynen G, Delwaide P, Bijvoet OLM, Franchimont P (1982) Clinical and biological effects of low doses of (3 amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) in Paget’s disease of bone. Eur J Clin Invest 11:29–35Google Scholar
  95. Hilderbrand RL (1983) The effects of synthetic phosphonates on living systems. In: Hilderbrand RL (ed) The role of phosphonates in living systems. CRC Press, Boca Raton, p 139Google Scholar
  96. Hilderbrand RL, Henderson TO (1983) Phosphonic acids in nature. In: Hilderbrand RL (ed) The role of phosphonates in living systems. CRC Press, Boca Raton, p 5Google Scholar
  97. Hill LF, Lumb GA, Mawer EB, Stanbury SW (1973) Indirect inhibition of the biosynthesis of 1,25-dihydroxycholecalciferol in rats treated with a diphosphonate. Clin Sci 44:335–347PubMedGoogle Scholar
  98. Hollander W, Prusty S, Nagraj S, Kirkpatrick B, Paddock J, Colombo M (1978) Comparative effects of cetaben (PHB) and dichloromethylene diphosphonate (Cl2MBP) on the development of atherosclerosis in the cynomolgus monkey. Atherosclerosis 31:307–325PubMedGoogle Scholar
  99. Horiguchi M, Kandatsu M (1959) Isolation of 2-aminoethane phosphonic acid from rumen Protozoa. Nature 184:901–902PubMedGoogle Scholar
  100. Jacobs TP, Siris ES, Bilezikian JP, Baquiran DC, Shane E, Canfield RE (1981) Hypercalcemia of malignancy: treatment with intravenous dichloromethylene diphosphonate. Ann Intern Med 94:312–316PubMedGoogle Scholar
  101. Jee WSS, Black HE, Gotcher JE (1981) Effect of dichloromethane disphosphonate on cortisol-induced bone loss in young adult rabbits. Clin Orthop Rel Res 156:39–51Google Scholar
  102. Johnson KY, Wesseler MA, Olson HM, Martodam RR, Poser JW (1982) The effects of diphosphonates on tumor-induced hypercalcemia and osteolysis in Walker carcinosarcoma 256 (W-256) of rats. In: Donath A, Courvoisier B (eds) Diphosphonates and bone. Editions Médecine et Hygiène, Genève, p 386Google Scholar
  103. Johnston CC Jr, Altman RD, Canfield RE, Finerman GAM, Taulbee JD, Ebert ML (1983) Review of fracture experience during treatment of Paget’s disease of bone with etidronate disodium (EHDP). Clin Orthop 172:186–194PubMedGoogle Scholar
  104. Jowsey J, Holley KE, Linman JW (1970) Effect of sodium etidronate in adult cats. J Lab Clin Med 76:126–133PubMedGoogle Scholar
  105. Jowsey J, Riggs BL, Kelly PJ, Hoffman DL, Bordier P (1971) The treatment of osteoporosis with disodium ethane-1-hydroxy-1,1-diphosphonate. J Lab Clin Med 78:574–584PubMedGoogle Scholar
  106. Jung A (1982) Comparison of two parenteral diphosphonates in hypercalcemia of malignancy. Am J Med 72:221–226PubMedGoogle Scholar
  107. Jung A, Bisaz S, Fleisch H (1973) The binding of pyrophosphate and two diphosphonates on hydroxyapatite crystals. Calciv Tissue Res 11:269–280Google Scholar
  108. Jung A, Bornand J, Mermillod B, Edouard C, Meunier PJ (1984) Inhibition by diphosphonates of bone resorption induced by the Walker tumor of the rat. Cancer Res 44:3007–3011PubMedGoogle Scholar
  109. Kaplan RA, Geho WB, Pointdexter C, Haussier M, Dietz GW, Pak CYC (1977) Metabolic effects of diphosphonate in primary hyperparathyroidism. J Clin Pharmacol 17:410–419PubMedGoogle Scholar
  110. King WR, Francis MD, Michael WR (1971) Effect of disodium ethane-1-hydroxy-1,1-diphosphonate on bone formation. Clin Orthop 78:251–270PubMedGoogle Scholar
  111. Komissarenko SV, Zhuravskii NI, Karlova NP, Gulyi MF (1977) Inhibition of hypersensitivity of delayed and immediate types in guinea pigs by methylenediphosphonic acid. Bull Exp Biol Med 84:1322–1323Google Scholar
  112. Kramsch DM, Chan CT (1978) The effect of agents interfering with soft tissue calcification and cell proliferation on calcific fibrous fatty plaques in rabbits. Circ Res 42:562–571PubMedGoogle Scholar
  113. Labat ML, Tzehoval E, Moricard Y, Feldmann M, Milhaud G (1983) Lack of a T-cell dependent subpopulation of macrophages in (dichloromethylene) diphosphonate-treated mice. Biomed Pharmacother 37:270–276PubMedGoogle Scholar
  114. Labat ML, Florentin I, Davigny M, Moricard Y, Milhaud G (1984) Dichloromethylene diphosphonate (Cl2MDP) reduces natural killer (NK) cell activity in mice. Metab Bone Dis Rel Res 5:281–287Google Scholar
  115. Lamson ML, Fox JL, Huguchi WI (1984) Calcium and 1-hydroxyethylidene-1,1-bisphos-phonic acid: polynuclear complex formation in the physiological range of pH. Int J Pharmaceut 21:143–154Google Scholar
  116. Larsson A (1974) The short-term effects of high doses of ethylene-1-hydroxy-1,1-diphosphonates upon early dentin formation. Calcif Tissue Res 16:109–127PubMedGoogle Scholar
  117. Larsson SE (1976) The metabolic heterogeneity of glycosaminoglycans of the different zones of the epiphyseal growth plate and the effect of ethane-1-hydroxy-1,1-diphosphonate (EHDP) upon glycosaminoglycan synthesis in vivo. Calcif Tissue Res 21:67–82PubMedGoogle Scholar
  118. Lenehan TM, Balligand M, Nunamaker DM, Wood FE Jr (1985) Effect of EHDP on fracture healing in dogs. J Orthop Res 3:499–507PubMedGoogle Scholar
  119. Leonard EP, Reese WV, Mandel EJ (1979) Comparison of the effects of ethane-1-hydroxy-1,1-diphosphonate and dichloromethane diphosphonate upon periodontal bone resorption in rice rats. Arch Oral Biol 24:707–708PubMedGoogle Scholar
  120. Levy RJ, Wolfrum J, Schoen FJ, Hawley MA, Lund SA (1985) Inhibition of calcification of bioprosthetic heart valves by local controlled-release diphosphonate. Science 228:190–192PubMedGoogle Scholar
  121. Liggett SJ (1973) Determination of ethane-1-hydroxy-1,1-diphosphonic acid (EHDP) in human feces and urine. Biochem Med 7:68–77PubMedGoogle Scholar
  122. Lockwood DR, Vogel JM, Schneider VS, Hulley SB (1975) Effect of the diphosphonate EHDP on bone mineral metabolism during prolonged bed rest. J Clin Endocrinol Metab 41:533–541PubMedGoogle Scholar
  123. Martodam RR, Thornton KS, Sica DA, Souza SM, Flora L, Mundy GR (1983) The effects of dichloromethylene diphosphonate on hypercalcemia and other parameters of the humoral hypercalcemia of malignancy in the rat Leydig cell tumor. Calcif Tissue Int 35:512–519PubMedGoogle Scholar
  124. Metzger AL, Singer FR, Bluestone R, Pearson CM (1974) Failure of disodium etidronate in calcinosis due to dermatomyositis and scleroderma. N Engl J Med 291:1294–1296PubMedGoogle Scholar
  125. Meunier P, Chapuy MC, Courpron P, Vignon E, Edouard C, Bernard J (1975) Effets cliniques, biologiques et histologiques de l’éthane-1-hydroxy-1,1-diphosphonate (EHDP) dans la maladie de Paget. Rev Rhum Mat Osteoartic 42:699–705Google Scholar
  126. Meunier PJ, Alexandre C, Edouard C, Mathieu L, Chapuy MC, Bressot C, Vignon E, Trechsel U (1979) Effects of disodium dichloromethylenediphosphonate on Paget’s disease of bone. Lancet 2:489–492PubMedGoogle Scholar
  127. Meyer JL, Nancollas GH (1973) The influence of multidentate organic phosphonates on the crystal growth of hydroxyapatite. Calcif Tissue Res 13:295–303PubMedGoogle Scholar
  128. Meyer JL, Lee KE, Bergert JH (1977) The inhibition of calcium oxalate crystal growth by multidentate organic phosphonates. Calcif Tissue Res 23:83–86PubMedGoogle Scholar
  129. Michael WR, King WR, Wakim JM (1972) Metabolism of disodium ethane-1-hydroxy-1,1-diphosphonate (disodium etidronate) in the rat, rabbit, dog and monkey. Toxicol Appl Pharmacol 21:503–515PubMedGoogle Scholar
  130. Milhaud G, Labat ML, Moricard Y (1983) (Dichloromethylene) diphosphonate-induced impairment of T-lymphocyte function. Proc Natl Acad Sci USA 80:4469–4473PubMedGoogle Scholar
  131. Miller SC, Jee WSS (1979) The effect of dichloromethylenediphosphonate, a pyrophosphate analog, on bone and bone cell structure in the growing rat. Anat Rec 193:439–462PubMedGoogle Scholar
  132. Minaire P, Bérard E, Meunier PJ, Edouard C, Goedert G, Pilonchéry G (1981) Effects of disodium dichloromethylene diphosphonate on bone loss in paraplegic patients. J Clin Invest 68:1086–1092PubMedGoogle Scholar
  133. Morgan DB, Monod A, Russell RGG, Fleisch H (1973) Influence of dichloromethylene diphosphonate (Cl2MDP) and calcitonin on bone resorption, lactate production and phosphatase and pyrophosphatase content of mouse calvaria treated with parathyroid hormone in vitro. Calcif Tissue Res 13:287–294PubMedGoogle Scholar
  134. Mühlbauer RC, Russell RGG, Williams DA, Fleisch H (1971) The effects of diphosphonates, polyphosphates, and calcitonin on immobilisation osteoporosis in rats. Eur J Clin Invest 1:336–344PubMedGoogle Scholar
  135. Mühlemann HR, Bowles D, Schatt A, Bernimoulin JP (1970) Effect of diphosphonate on human supragingival calculus. Helv Odont Acta 14:31–33Google Scholar
  136. Nagant de Deuxchaisnes C, Rombouts-Lindemans C, Huaux JP, Devogelaer JP, Malghem J, Madlague B (1979) Roentgenologic evaluation of the action of the diphosphonate EHDP and of combined therapy (EHDP and calcitonin) in Paget’s disease of bone. Mol Endocrinol 1:405–433Google Scholar
  137. Nixon GA, Buehler EV, Newmann EA (1972) Preliminary safety assessment of disodium etidronate as an additive to experimental oral hygiene products. Toxicol Appl Pharmacol 22:661–671PubMedGoogle Scholar
  138. Nolen GA, Buehler EV (1971) The effects of disodium etidronate on the reproductive functions and embryogeny of albino rats and New Zealand rabbits. Toxicol Appl Pharmacol 18:548–561PubMedGoogle Scholar
  139. Ohata M, Pak CY (1974) Preliminary study of the treatment of nephrolithiasis (calcium stones) with diphosphonate. Metabolism 23:1167–1173Google Scholar
  140. Ohya K, Yamada S, Felix R, Fleisch H (1985) Effect of bisphosphonates on prostaglandin synthesis by rat bone cells and mouse calvaria in culture. Clin Sci 69:403–411PubMedGoogle Scholar
  141. Pilczyk R, Sutcliffe H, Martin TJ (1972) Effects of pyrophosphate and diphosphonates on parythyroid hormone- and fluoride-stimulated adenylate cyclase activity. FEBS Lett 24:225–228PubMedGoogle Scholar
  142. Plasmans CMT, Kuypers W, Slooff TJJH (1978) The effect of ethane-1-hydroxy-1,1-diphosphonic acid (EHDP) on matrix induced ectopic bone formation. Clin Orthop Rel Res 132:233–243Google Scholar
  143. Plasmans CMT, Jap PHK, Kujipers W, Slooff TJJH (1980) Influence of diphosphonate on the cellular aspect of young bone tissue. Calcif Tissue Int 32:247–256PubMedGoogle Scholar
  144. Pollard M, Luckert PH (1985) Effects of dichloromethylene diphosphonate on the osteolytic and osteoplastic effects of rat prostate adenocarcinoma cells. JNCI 75:949–954PubMedGoogle Scholar
  145. Preston CJ, Yates AJP, Beneton MNC, Russell RGG, Gray RES, Smith R, Kanis JA (1986) Effective short term treatment of Paget’s disease with oral etidronate. Br Med J 292:79–80Google Scholar
  146. Rabens SF, Bethune JE (1975) Disodium etidronate therapy for dystrophic cutaneous calcification. Arch Dermatol 111:357–361PubMedGoogle Scholar
  147. Radl J, Croese JW, Zurcher C, Enden-Vieveen MHM Van Den, Brondijk RJ, Kazil M, Haaijman JJ, Reitsma PH, Bijvoet OLM (1985) Influence of treatment with ADP-bisphosphonate on the bone lesions in the mouse 5T2 multiple myeloma. Cancer 55:1030–1040PubMedGoogle Scholar
  148. Recker RR, Saville PD (1973) Intestinal absorption of disodium ethane-1-hydroxy-1,1-diphosphonate (disodium etidronate) using a deconvolution technique. Toxicol Appl Pharmacol 24:580–589PubMedGoogle Scholar
  149. Recker RR, Hassing GS, Lau JR, Saville PD (1973) The hyperphosphatemic effect of disodium ethane-1-hydroxy-1,1-diphosphonates (EHDP™): renal handling of phosphorus and the renal response to parathyroid hormone. J Lab Clin Med 81:258–266PubMedGoogle Scholar
  150. Reiner M, Sautter V, Olah A, Bossi A, Largiadèr U, Fleisch H (1980) Diphosphonate treatment in myositis ossificans progressiva. In: Caniggia A (ed) Etidronate. Institute Gentili, Pisa, p 237Google Scholar
  151. Reitsma PH, Bijvoet OLM, Verlinden-Ooms H, Wee-Pals LJA van der (1980) Kinetic studies of bone and mineral metabolism during treatment with (3-amino-1-hydroxy-propylidene)-1,1-bisphosphonate (APD) in rats. Calcif Tissue Int 32:145–147PubMedGoogle Scholar
  152. Reitsma PH, Teitelbaum SL, Bijvoet OLM, Kahn AJ (1982) Differential action of the bisphosphonates (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) and disodium dichloromethylidene bisphosphonate (Cl2MDP) on rat macrophage-mediated bone resorption in vitro. J Clin Invest 70:927–933PubMedGoogle Scholar
  153. Reynolds JJ, Minkin C, Morgan DB, Spycher D, Fleisch H (1972) The effect of two diphosphonates on the resorption of mouse calvaria in vitro. Calcif Tissue Res 10:302–313PubMedGoogle Scholar
  154. Reynolds JJ, Murphy H, Mühlbauer RC, Morgan DB, Fleisch H (1973) Inhibition by diphosphonates of bone resorption in mice and comparison with grey lethal osteopetrosis. Calcif Tissue Res 12:59–71PubMedGoogle Scholar
  155. Robertson WG, Peacock M, Nordin BEC (1973) Inhibitors of the growth and aggregation of calcium oxalate crystals in vitro. Clin Chim Acta 43:31–37PubMedGoogle Scholar
  156. Rosenblum IY, Black HE, Ferrell JF (1977) The effects of various diphosphonates on a rat model of cardiac calciphylaxis. Calcif Tissue Res 23:151–159PubMedGoogle Scholar
  157. Russell RGG, Mühlbauer RC, Bisaz S, Williams DA, Fleisch H (1970) The influence of pyrophosphate, condensed phosphates, phosphonates and other phosphate compounds on the dissolution of hydroxyapatite in vitro and on bone resorption induced by parathyroid hormone in tissue culture and in thyroparathyroidectomised rats. Calcif Tissue Res 6:183–196PubMedGoogle Scholar
  158. Russell RGG, Bisaz S, Donath A, Morgan DB, Fleisch H (1971) Inorganic pyrophosphate in plasma in normal persons and in patients with hypophosphatasia, osteogenesis imperfecta and other disorders of bone. J Clin Invest 50:961–969PubMedGoogle Scholar
  159. Russell RGG, Smith R, Preston C, Walton RJ, Woods CG (1974) Diphosphonates in Paget’s disease. Lancet 1:894–898PubMedGoogle Scholar
  160. Ryzen E, Martodam RR, Troxell M, Benson A, Paterson A, Shepard K, Hicks R (1985) Intravenous etidronate in the management of malignant hypercalcemia. Arch Intern Med 145:449–452PubMedGoogle Scholar
  161. Schenk R, Merz WA, Mühlbauer R, Russell RGG, Fleisch H (1973) Effect of ethane-1-hydroxy-1,1-diphosphonate (EHDP) and dichloromethylene diphosphonate (Cl2MDP) on the calcification and resorption of cartilage and bone in the tibial epiphysis and metaphysis of rats. Calcif Tissue Res 11:196–214PubMedGoogle Scholar
  162. Schenk R, Eggli P, Felix R, Fleisch H, Rosini S (1986) Quantitative morphometric evaluation of the inhibitory activity of new aminobisphosphonates on bone resorption in the rat. Calcif Tissue Int 38:342–349PubMedGoogle Scholar
  163. Schibler D, Russell RGG, Fleisch H (1968) Inhibition of pyrophosphate and polyphosphate of aortic calcification induced by vitamin D3 in rats. Clin Sci 35:363–372PubMedGoogle Scholar
  164. Shane E, Baquiran DC, Bilezikian JP (1981) Effect of dichloromethylene diphosphonate on serum and urinary calcium in primary hyperparathyroidism. Ann Intern Med 95:23–27PubMedGoogle Scholar
  165. Shindoa H, Adamek G, Felix R, Fleisch H, Schenk R, Hagan P (1983) Structure-activity relationship of various bisphosphonates. Calcif Tissue Int 35:87–99Google Scholar
  166. Siris ES, Canfield RE, Jacobs TP, Baquiran DC (1980 a) Long-term therapy of Paget’s disease of bone with EHDP. Arthritis Rheum 23:1177–1183PubMedGoogle Scholar
  167. Siris ES, Sherman WH, Baquiran DC, Schlatterer JP, Osserman EF, Canfield RE (1980 b) Effects of dichloromethylene diphosphonate on skeletal mobilization of calcium in multiple myeloma. N Engl J Med 302:310–315PubMedGoogle Scholar
  168. Siris ES, Hyman GA, Canfield R (1983) Effects of dichloromethylene diphosphonate in woman with breast carcinoma metastatic to the skeleton. Am J Med 74:401–406PubMedGoogle Scholar
  169. Sleeboom HP, Bijvoet OLM, van Oosterom AT, Gleed JH, O’Riordan JLH (1983) Comparison of intravenous (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate and volume repletion in tumor-induced hypercalcemia. Lancet 2:239–243PubMedGoogle Scholar
  170. Slooff TJJH, Feith R, Bijvoet OLM, Nollen AJG (1974) The use of a disphosphonate in para-articular ossification after total hip replacement. A clinical study. Acta Orthop Belg 40:820–828PubMedGoogle Scholar
  171. Smith JD (1983) Metabolism of phosphonates. In: Hilderbrand RL (ed) The role of phos-phonates in living systems. CRC Press, Boca Raton, p 31Google Scholar
  172. Smith R, Russell RGG, Bishop M (1971) Diphosphonates and Paget’s disease of bone. Lancet 1:945–947PubMedGoogle Scholar
  173. Spielman G, Gennarelli TA, Rogers CR (1983) Disodium etidronate: its role in preventing heterotopic ossification in severe head injury. Arch Phys Med Rehabil 64:539–542PubMedGoogle Scholar
  174. Steber J, Wierich P (1986) Properties of hydroxyethane disphosphonate affecting its environmental fate: degradability, sludge adsorption, mobility in soils, and bioconcentration. Chemosphere 15:929–945Google Scholar
  175. Steiner RM, Glassman L, Schwartz MW, Vanace P (1974) The radiological findings in dermatomyositis of childhood. Pediatr Radiol 111:385–393Google Scholar
  176. Stevenson PH, Stevenson JR (1986) Cytotoxic and migration inhibitory effects of bisphosphonates on macrophages. Calcif Tissue Int 38:227–233PubMedGoogle Scholar
  177. Stronski St A, Trechsel U, Fleisch H (1985) Plasma osteocalcin: lack of relation with bone resorption and effect of bisphosphonates in rats. Calcif Tissue Int 38 [Suppl]:S39Google Scholar
  178. Sturzenberger OP, Swancar JR, Reiter G (1971) Reduction of dental calculus in humans through the use of a dentifrice containing a crystal-growth inhibitor. J Periodontol 42:416–419PubMedGoogle Scholar
  179. Stutzer A, Fleisch H, Trechsel U (1987 a) Long and short term effects of a single administration of bisphosphonates on retinoid induced bone resorption. J Bone Min Res 2 Suppl 1:416Google Scholar
  180. Stutzer A, Trechsel U, Fleisch H, Schenk R (1987 b) Effect of bisphosphonates on osteoclast number and bone resorption in the rat. J Bone Min Res 2 Suppl 1:266Google Scholar
  181. Thiébaud D, Jaeger P, Jacquet AF, Burckhardt P (1986) A single-day treatment of tumor-induced hypercalcemia by intravenous amino-hydroxypropylidene bisphosphonate. J Bone Min Res 1:555–562Google Scholar
  182. Thomas BJ, Amstutz HC (1985) Results of the administration of diphosphonate for the prevention of heterotopic ossification after total hip arthroplasty. J Bone Joint Surg 67A:400–403Google Scholar
  183. Trechsel U, Schenk R, Bonjour JP, Russell RGG, Fleisch H (1977) Relation between bone mineralization, Ca absorption, and plasma Ca in phosphonate-treated rats. Am J Physiol 232:E298–E305PubMedGoogle Scholar
  184. Troehler U, Bonjour JP, Fleisch H (1975) Renal secretion of diphosphonates in rats. Kidney Int 8:6–13PubMedGoogle Scholar
  185. Van Breukelen FJM, Bijovet OLM, Oosterom AT (1979) Inhibition of osteolytic bone lesions by (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (A.P.D.). Lancet 1:803–805PubMedGoogle Scholar
  186. Van Breukelen FJM, Bijvoet OLM, Frijlink WB, Sleebloom HP, Mulder H, von Oosterom AT (1982) Efficacy of amino-hydroxypropylidene bisphosphonate in hypercalcemia: observations on regulation of serum calcium. Calcif Tissue Int 34:321–327PubMedGoogle Scholar
  187. Van Rooijen N, van Nieuwmegen R, Kamperdijk EWA (1985) Elimination of phagocytic cells in the spleen after intravenous injection of liposome-encapsulated dichloromethylene diphosphonate. Virchows Arch (Zel) 49:375–383Google Scholar
  188. Walton RJ, Russell RGG, Smith R (1975) Changes in the renal and extrarenal handling of phosphate induced by disodium etidronate (EHDP) in man. J Clin Sci Mol Med 49:45–56Google Scholar
  189. Wasserman RH, Bonjour JP, Fleisch H (1973) Ileal absorption of disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) and disodium dichloromethylene diphosphonate (Cl2MDP) in the chick. Experientia 29:1110–1111PubMedGoogle Scholar
  190. Wiedmer WH, Zbinden AM, Trechsel U, Fleisch H (1983) Ultrafiltrability and chromatographic properties of pyrophosphate, 1-hydroxyethylidene-1,1-bisphosphonate, and dichloromethylenebisphosphonate in aqueous buffers and in human plasma. Calcif Tissue Int 35:397–400PubMedGoogle Scholar
  191. Wingen F, Schmähl D (1985) Distribution of 3-amino-1-hydroxypropane-1,1-diphosphonic acid in rats and effects on rat osteosarcoma. Arzneimittelforsch 35:1565–1571PubMedGoogle Scholar
  192. Wink CS, Onge MSt, Parker B (1985) The effects of dichloromethylene bisphosphonate on osteoporotic femora of adult castrate male rats. Acta Anat 124:117–121PubMedGoogle Scholar
  193. Worms KH, Blum H (1979) Umsetzungen von 1-Aminoalkal-1,1-diphosphonsäuren mit salpetriger Säure. Z Anorg Allg Chem 457:209–213Google Scholar
  194. Worms KH, Schmidt-Dunker M (1976) Phosphonic acids and derivatives. In: Kosolapoff GM, Maier L (eds) Organic phosphorus compounds, vol 7. Wiley, New York, p 1Google Scholar
  195. Yakatan GJ, Poynor WJ, Talbert RL, Floyd BF, Slough CL, Ampulski RS, Benedict JJ (1982) Clodronate kinetics and bioavailability. Clin Pharmacol Ther 31:402–410PubMedGoogle Scholar
  196. Yates AJP, Percival RC, Gray RES, Urwin GH, Hamdy NAT, Preston CJ, Beneton MNC, Russell RGG, Kanis JA (1985) Intravenous clodronate in the treatment and retreatment of Paget’s disease of bone. Lancet 1:1474–1477PubMedGoogle Scholar
  197. Zernov IM, Stefani DV, Vel’tischev YE (1979) Assessment of the protective action of diphosphonate compound against damage to T-lymphocytes by antilymphocytic serum. Bull Exp Biol Med 87:253–254Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1988

Authors and Affiliations

  • H. Fleisch

There are no affiliations available

Personalised recommendations