, Volume 42, Issue 6, pp 919–944 | Cite as


Pharmacology and Use in the Treatment of Tumour-Induced Hypercalcaemic and Metastatic Bone Disease
  • Herbert Fleisch
Review Article


The geminal bisphosphonates are a new class of drugs characterised by a P-C-P bond. Consequently, they are analogues of pyrophosphate, but are resistant to chemical and enzymatic hydrolysis. The bisphosphonates bind strongly to hydroxyapatite crystals and inhibit their formation and dissolution. This physicochemical effect leads in vivo to the prevention of soft tissue calcification and, in some instances, inhibition of normal calcification. The main effect is to inhibit bone resorption, but in contrast to the effect on mineralisation, the mechanism involved is cellular. These various effects vary greatly according to the structure of the individual bisphosphonate.

The half-life of circulating bisphosphonates is very brief, in the order of minutes to hours. 20% to 50% of a given dose is taken up by the skeleton, the rest being excreted in the urine. The half-life in bone is far longer and depends upon the turnover rate of the skeleton itself.

Bisphosphonates are very well tolerated; the relatively few adverse events that have been associated with their use are specific for each compound.

Bisphosphonates have been used to treat various clinical conditions, namely ectopic calcification, ectopic bone formation, Paget’s disease, osteoporosis and increased osteolysis of malignant origin. The three compounds commercially available for use in tumour-induced bone disease are in order of increasing potency, etidronate, clodronate and pamidronate. Most data have been obtained with the latter two agents. By inhibiting bone resorption, they correct hypercalcaemia and hypercalciuria, reduce pain, the occurrence of fractures, as well as the development of new osteolytic lesions, and in consequence improve the quality of life.

In view of these actions, of their excellent tolerability and of the fact that they are active for relatively long periods, these compounds are, after rehydration, the drugs of choice in tumour-induced bone disease and an excellent auxiliary to the drugs used in oncology.


Bone Resorption Bisphosphonates Hypercalcemia Pamidronate Calcify Tissue 
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. Adami S, Bhalla AK, Dorizzi R, Montesanti F, Rosini S, et al. The acute-phase response after bisphosphonate administration. Calcified Tissue International 41: 326–331, 1987aPubMedGoogle Scholar
  2. Adami S, Bolzicco GP, Rizzo A, Salvagno G, Bertoldo F, et al. The use of dichloromethylene bisphosphonate and aminobutane bisphosphonate in hypercalcemia of malignancy. Bone and Mineral 2: 395–404, 1987bPubMedGoogle Scholar
  3. Adami S, Mian M. Clodronate therapy of metastatic bone disease in patients with prostatic carcinoma. In Brunner KW, et al. (Eds) Bisphosphonates and tumor osteolysis. Recent Results in Cancer Research 116: 67–72, Springer-Verlag, Berlin/Heidelberg, 1989Google Scholar
  4. Adami S, Salvagno G, Guarrera G, Bianchi G, Dorizzi R, et al. Dichloromethylene-diphosphonate in patients with prostatic carcinoma metastatic to the skeleton. Journal of Urology 134: 1152–1154, 1985PubMedGoogle Scholar
  5. Ahrengart L, Lindgren U. Prevention of ectopic bone formation by local application of ethane-1-hydroxy-1,1-diphosphonate (EHDP): an experimental study in rabbits. Journal of Orthopaedic Research 4: 18–26, 1986PubMedGoogle Scholar
  6. Alden CL, Parker RD, Eastman DF. Development of an acute model for the study of chloromethanediphosphonate nephrotoxicity. Toxicologic Pathology 17: 27–32, 1989PubMedGoogle Scholar
  7. Ascari E, Attardo-Parrinello G, Merlini G. Treatment of painful bone lesions and hypercalcemia. European Journal of Haematology 43(Suppl. 51): 135–139, 1989Google Scholar
  8. Attardo-Parrinello G, Merlini G, Pavesi F, Crema F, Fiorentini ML, et al. Effects of a new aminodiphosphonate (aminohy-droxybutylidene diphosphonate) in patients with osteolytic lesions from metastases and myelomatosis. Archives of Internal Medicine 147: 1629–1633, 1987PubMedGoogle Scholar
  9. Bassani D, Sabatini M, Scanziani E, De Franceso L, Coccioli G, et al. Bone invasion by Walker 256 Carcinoma, line A in young and adult rats: effects of etidronate. Oncology 47: 160–165, 1990PubMedGoogle Scholar
  10. Bevan JA, Franks AF, McOsker JE, Boyce RW, Buckingham KW. Bisphosphonate action in the oophorectomized rat: the effects of 2-(3-pyridinyl)-1-hydroxyethlidene-bis(phosphonate) on skeletal metabolism; comparison with etidronate. Abstract no. 498. Journal of Bone and Mineral Research 3(Suppl. 1): S193, 1988Google Scholar
  11. Bevan JA, Johnson KY, Slough C, Benedict JJ, Fleisch H, et al. Skeletal effects of 2-(2-pyridinyl)-ethylidene-bisphosphonate in acute and subchronic rat studies. Calcified Tissue International 38 (Suppl.): S31, 1986Google Scholar
  12. Bijvoet OLM, Frijlink WB, Jie K, van der Linden H, Meijer CJLM, et al. APD in Paget’s disease of bone. Role of the mononuclear phagocyte system? Arthritis and Rheumatism 23: 1193–1204, 1980PubMedGoogle Scholar
  13. Bijvoet OLM, Hosking DJ, Lemkes HHPJ, Reitsma PH, Frijlink W. Development in the treatment of Paget’s disease. In Copp et al. (Eds) Endocrinology of calcium metabolism 421: 48–54, Excerpta Medica, Amsterdam/Oxford, 1978Google Scholar
  14. Bisaz S, Jung A, Fleisch H. Uptake by bone of pyrophosphate, diphosphonates and their technetium derivatives. Clinical Science and Molecular Medicine 54: 265–272, 1978PubMedGoogle Scholar
  15. Body JJ, Borkowski A, Cleeren A, Bijvoet ALM. Treatment of malignancy-associated hypercalcemia with intravenous aminohydroxypropylidene diphosphonate. Journal of Clinical Oncology 4: 1177–1183, 1986PubMedGoogle Scholar
  16. Body JJ, Magritte A, Seraj F, Sculier JP, Borkowski A. Amino-hydroxypropylidene bisphosphonate (APD) treatment for tumor-associated hypercalcemia: a randomized comparison between a 3-day treatment and single 24-hour infusions. Journal of Bone and Mineral Research 4: 923–928, 1989PubMedGoogle Scholar
  17. Body JJ, Pot M, Borkowski A, Scoulier JP, Klastersky J. Dose/ response study of aminohydroxypropylidene bisphosphonate in tumor-associated hypercalcemia. American Journal of Medicine 82: 563–957, 1987Google Scholar
  18. Boehringer Mannheim (Schweiz) AG. OSTAC. 1986Google Scholar
  19. Bonjour JP, Philippe J, Guelpa G, Bisetti A, Rizzoli R, et al. Bone and renal components in hypercalcemia of malignancy and responses to a single infusion of clodronate. Bone 9: 123–130, 1988PubMedGoogle Scholar
  20. Bonjour JP, Rizzoli R. Clodronate in hypercalcemia of malignancy. Calcified Tissue International 46 (Suppl.): S20–S25, 1990PubMedGoogle Scholar
  21. Bonjour JP, Troehler U, Preston C, Fleisch H. Parathyroid hormone and renal handling of Pi: effect of dietary Pi and diphosphonates. American Journal of Physiology 234: F497–F505, 1978PubMedGoogle Scholar
  22. Boonekamp PM, Löwik CWGM, van der Wee-Pals LJA, van Wijk-van Lennep MLL, Bijvoet OLM. Enhancement of the inhibitory action of APD on the transformation of osteoclast precursors into resorbing cells after dimethylation of the amino group. Bone and Mineral 2: 29–42, 1987PubMedGoogle Scholar
  23. Boonekamp PM, van der Wee-Pals LJA, van Wijk-van-Lennep MML, Thesing CW, Bijvoet OLM. Two models of action of bisphosphonates on osteoclastic resorption of mineralized matrix. Bone and Mineral 1: 27–39, 1986PubMedGoogle Scholar
  24. Bounameaux HM, Schifferli J, Montani JP, Jung A, Chatelanat F. Renal failure associated with intravenous diphosphonate. Lancet 1: 471, 1983PubMedGoogle Scholar
  25. Briner WW, Francis MD, Widder JS. The control of dental calculus in experimental animals. International Dental Journal 21: 61–73, 1971PubMedGoogle Scholar
  26. Broadus AE, Mangin M, Ikeda K, Insogna KL, Weir EC, et al. Humoral hypercalcemia of malignancy: identification of a novel parathyroid hormone-like peptide. New England Journal of Medicine 319: 556–563, 1988PubMedGoogle Scholar
  27. Brunner KW, Fleisch H, Senn HJ (Eds) Bisphosphonates and tumor osteolysis. Recent Results in Cancer Research 116, Springer Verlag, Berlin/Heidelberg, 1989Google Scholar
  28. Budayr AA, Thiébaud D, Amman P, Rizzoli R, Bonjour JP, et al. Effects of treatment of malignancy-associated hypercalcemia on serum levels of parathyroid hormone-related peptide. Abstract no. 789. Journal of Bone and Mineral Research 5(Suppl. 2): S271, 1990Google Scholar
  29. Burckhardt P (Ed.) Disodium pamidronate (APD) in the treatment of malignancy-related disorders. Hans Huber Publishers, Bern, 1989Google Scholar
  30. Burtis WJ, Wu J, Bunch CM, Sysolmerski JJ, Isogna KL, et al. Identification of a novel 17,000-dalton parathyroid hormone-like adenylate cyclase-stimulating protein from a tumor associated with humoral hypercalcemia of malignancy. Journal of Biological Chemistry 162: 151–156, 1987Google Scholar
  31. Canfield RE. Etidronate disodium: a new therapy for hypercalcemia of malignancy. American Journal of Medicine 82: 1–78, 1987PubMedGoogle Scholar
  32. Carano A, Teitelbaum SL, Konsek JD, Schlesinger PH, Blair HC. Bisphosphonates directly inhibit the bone resorption activity of isolated avian osteoclasts in vitro. Journal of Clinical Investigation 85: 461–465, 1990Google Scholar
  33. Carey PO, Lippert MC. Treatment of painful prostatic bone metastases with oral etidronate disodium. Urology 32: 403–407, 1988PubMedGoogle Scholar
  34. Cecchini MG, Castagna M, Schenk R, Fleisch H. A new ‘in vivo’ model for studying ‘de novo’ osteoclastogenesis: the post-natal mouse caudal vertebrae. Abstract no. 595. Journal of Bone and Mineral Research 5(Suppl. 2): S223, 1990Google Scholar
  35. Cecchini MG, Felix R, Fleisch H, Cooper PH. Effects of bis-phosphonates on proliferation and viability of mouse bone marrow-derived macrophages. Journal of Bone and Mineral Research 2: 135–142, 1987PubMedGoogle Scholar
  36. Cecchini MG, Fleisch H. Bisphosphonates in vitro specifically inhibit, among the hematopoietic series, the development of the mouse mononuclear phagocyte lineage. Journal of Bone and Mineral Research 5: 1019–1027, 1990PubMedGoogle Scholar
  37. Chambers TJ. Diphosphonates inhibit bone resorption by macrophages in vitro. Journal of Pathology 132: 255–262, 1980PubMedGoogle Scholar
  38. Chapuy MC, Meunier PJ, Alexandre CM, Vignon EP. Effects of disodium dichloromethylene diphosphonate on hypercalcemia produced by bone metastases. Journal of Clinical Investigation 65: 1243–1247, 1980PubMedGoogle Scholar
  39. Charhon S, Chapuy MC, Valentin-Opran A, Edpuard C, Rosini S, et al. Traitement de l’hypercalcémie d’origine myélomateuse par les diphosphonates intraveineux. La Presse Médicale 12: 2983–2986, 1983PubMedGoogle Scholar
  40. Cleton FJ, van Holten-Verzantvoort AT, Zwinderman A, Kroon HM, Hermans J, et al. Long-term bisphosphonate treatment of bone metastases in breast cancer patients–effects on morbidity and quality of life. In Burckhardt P, et al. (Eds) Disodium pamidronate (APD) in the treatment of malignancy-related disorders, pp. 113–119, Hans Huber Publishers, Bern, 1989Google Scholar
  41. Coleman RE, Rubens RD. 3 (amino-1,1-hydroxypropylidene)bis-phosphonate (APD) for hypercalcaemia of breast cancer. British Journal of Cancer 56: 465–469, 1987PubMedGoogle Scholar
  42. Coleman RE, Woll PJ, Miles M, Scrivener W, Rubens RD. Treatment of bone metastases from breast cancer with (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD). British Journal of Cancer 58: 621–625, 1988PubMedGoogle Scholar
  43. Conrad KA, Lee SM. Godronate kinetics and dynamics. Clinical Pharmacology and Therapeutics 30: 114–120, 1981PubMedGoogle Scholar
  44. Conte N, Di Virgilio R, Roiter I, Caberlotto L. Hypercalcemia in malignancies: treatment with dichloromethylene diphosphate (C12MDP). Tumori 71: 51–54, 1985PubMedGoogle Scholar
  45. Davis JRE, Heath DA. Comparison of different dose regimes of aminohydroxypropylidene-1,1-bisphosphonate (APD) in hypercalcaemia of malignancy. British Journal of Clinical Pharmacology 28: 269–274, 1989PubMedGoogle Scholar
  46. Delmas P, Chapuy MC, Vignon E, Briançon D, Charhon S, et al. Traitement de l’hypercalcémie de’origine métastatique osseuse par le dichlorométhylène disphosphonate. Nouvelle Presse Médicale 11: 1471–1474, 1982aPubMedGoogle Scholar
  47. Delmas PD, Charhon S, Chapuy MC, Vignon E, Briançon D, et al. Long-term effects of dichloromethylene diphosphonate (Cl2MDP) on skeletal lesions in multiple myeloma. Metabolic Bone Disease and Related Research 4: 163–168, 1982bGoogle Scholar
  48. de Vries HR, Bijvoet OLM. Results of prolonged treatment of Paget’s disease of bone with disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP). Netherlands Journal of Medicine 17: 281–298, 1974PubMedGoogle Scholar
  49. Dodwell DJ, Howell A, Ford J. Reduction in calcium excretion in women with breast cancer and bone metastases using the oral bisphosphonate pamidronate. British Journal of Cancer 61: 123–125, 1990PubMedGoogle Scholar
  50. Douglas DL, Russell RGG, Preston CJ, Preston MA, Duckworth T, et al. Effect of dichloromethylene diphosphonate in Paget’s disease of bone and in hypercalcaemia due to primary hyperparathyroidism or malignant disease. Lancet 1: 1043–1047, 1980PubMedGoogle Scholar
  51. Elomaa I, Blomqvist C, Gröhn P, Porkka L, Kairento AL, et al. Long-term controlled trial with diphosphonate in patients with osteolytic bone metastases. Lancet 1: 146–149, 1983PubMedGoogle Scholar
  52. Elomaa I, Blomqvist C, Porkka L, Lamberg-Allardt C, Borgström GH. Treatment of skeletal disease in breast cancer: a controlled clodronate trial. Bone 8(Suppl. 1): S53–S56, 1987PubMedGoogle Scholar
  53. Fast DK, Felix R, Dowse C, Neuman WF, Fleisch H. The effects of diphosphonates on the growth and glycolysis of connective-tissue cells in culture. Biochemical Journal 172: 97–107, 1978PubMedGoogle Scholar
  54. Felix R, Bettex JD, Fleisch H. Effect of diphosphonates on the synthesis of prostaglandins in cultured calvaria cells. Calcified Tissue International 33: 549–552, 1981PubMedGoogle Scholar
  55. Felix R, Guenther HL, Fleisch H. The subcellular distribution of 14C dichloromethylenebisphosphonate and 14C 1-hydroxy-ethylidene-1,1-bisphosphonate in cultured calvaria cells. Calcified Tissue International 36: 108–113, 1984PubMedGoogle Scholar
  56. Felix R, Russell RGG, Fleisch H. The effect of several diphosphonates on acid phosphohydrolases and other lysosomal enzymes. Biochimica et Biophysica Acta 429: 429–438, 1976PubMedGoogle Scholar
  57. Fitton A, McTavish D. Pamidronate: a review of its pharmacological properties and therapeutic efficacy in resorptive bone disease. Drugs 41: 289–318, 1991PubMedGoogle Scholar
  58. Flanagan AM, Chambers TJ. Dichloromethylenebisphosphonate (Cl2MBP) inhibits bone resorption through injury to osteoclasts that resorb Cl2MBP-coated bone. Bone and Mineral 6: 33–43, 1989PubMedGoogle Scholar
  59. Fleisch H. Bisphosphonates: a new class of drugs in diseases of bone and Calcium metabolism. In Baker (Ed.) Handbook of experimental pharmacology 83: 441–466, Springer, Berlin/Heidelberg, 1988Google Scholar
  60. Fleisch H, Bisaz S. Isolation from urine of pyrophosphate, a calcification inhibitor. American Journal of Physiology 203: 671–675, 1962PubMedGoogle Scholar
  61. Fleisch H, Neuman WF. Mechanisms of calcification: role of collagen polyphosphates, and phosphatase. American Journal of Physiology 200: 1296–1300, 1961Google Scholar
  62. Fleisch H, Russell RG, Bisaz S, Casey PA, Mühlbauer RC. The influence of pyrophosphate analogues (diphosphonates) on the precipitation and dissolution of calcium phosphate in vitro and in vivo. Calcified Tissue Research 2 (Suppl.): 10–10A, 1968Google Scholar
  63. Fleisch H, Russell RGG, Bisaz S, Mühlbauer RC, Williams DA. The inhibitory effect of phosphonates on the formation of calcium phosphate crystals in vitro and on aortic and kidney calcification in vivo. European Journal of Clinical Investigation 1: 12–18, 1970PubMedGoogle Scholar
  64. Fleisch H, Russell RGG, Francis MD. Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo. Science 165: 1262–1264, 1969PubMedGoogle Scholar
  65. Fleisch H, Russell RGG, Straumann F. Effect of pyrophosphate on hydroxyapatite and its implications in calcium homeostasis. Nature 212: 901–903, 1966Google Scholar
  66. Flora L, Hassing GS, Cloyd GG, Bevan JA, Parfitt AM, et al. The long-term skeletal effects of EHDP in dogs. Metabolic Bone Disease and Related Research 3: 289–300, 1981Google Scholar
  67. Flora L, Hassing GS, Parfitt AM, Villanueva AR. Comparative skeletal effects of two diphosphonates in dogs. Metabolic Bone Disease and Related Research 2: 389–407, 1980Google Scholar
  68. Francis MD. The inhibition of calcium hydroxyapatite crystal growth by polyphosphates. Calcified Tissue Research 3: 151–162, 1969PubMedGoogle Scholar
  69. Francis MD, Martodam RR. Chemical, biochemical and medicinal properties of the diphosphonates. In Hilderbrand (Ed.) The role of phosphonates in living systems, pp. 55–96, CRC Press, Boca Raton, Florida, 1983Google Scholar
  70. Francis MD, Russell RGG, Fleisch H. Diphosphonates inhibit formation of calcium phosphate crystals in vitro and pathological calcification in vitro and pathological calcification in vivo. Science 165: 1264–1266, 1969PubMedGoogle Scholar
  71. Francis MD, Slough CL. Acute intravenous infusion of disodium dihydrogen (1-hydroxyethylidene) diphosphonate: mechanism of toxicity. Journal of Pharmaceutical Sciences 73: 1097–1100, 1984PubMedGoogle Scholar
  72. Galasko CSB, Samuel AW, Rushton S, Lacey E. The effect of prostaglandin synthesis inhibitors and diphosphonates on tumour-mediated osteolysis. British Journal of Surgery 67: 493–496, 1980PubMedGoogle Scholar
  73. Gallacher SJ, Ralston S, Patel U, Boyle IT. Side-effects of pamidronate. Lancet 2: 42–43, 1989PubMedGoogle Scholar
  74. Garattini S, Guaitani A, Mantovani A. Effect of etidronate disodium on the interactions between malignancy and bone. American Journal of Medicine 82(Suppl. 2A): 29–33, 1987PubMedGoogle Scholar
  75. Gasser AB, Morgan DB, Fleisch HA, Richelle LJ. The influence of two diphosphonates on calcium metabolism in the rat. Clinical Science 43: 31–45, 1972PubMedGoogle Scholar
  76. Guaitani A, Polentarutti N, Filippeschi S, Marmonti L, Corti F, et al. Effects of disodium etidronate in murine tumor models. European Journal of Cancer and Clinical Oncology 20: 685–693, 1984Google Scholar
  77. Guaitani A, Sabatini M, Coccioli G, Cristina S, Garattini S, et al. An experimental rat model of local bone cancer invasion and its responsiveness to ethane-1-hydroxy-1,1bis(phosphonate). Cancer Research 45: 2206–2209, 1985PubMedGoogle Scholar
  78. Guncaga J, Lauffenburger R, Lentner C, Dambacher MA, Haas HG, et al. Diphosphonate treatment of Paget’s disease of bone. A correlated metabolic, calcium kinetic and morphometric study. Hormone and Metabolic Research 6: 62–69, 1974PubMedGoogle Scholar
  79. Gural RP. Pharmacokinetics and gastrointestinal absorption behaviour of etidronate. Dissertation, University of Kentucky, 1975Google Scholar
  80. Hähnel H, Mühlbach R, Lindenhayn K, Schätz P, Schmidt UJ. Zum Einfluss von Diphosphonat auf die experimentelle Heparinosteopathie. Zeitschrift für Alternforschung 27: 289–292, 1973Google Scholar
  81. Hanhijärvi H, Elomaa I, Karlsson M, Lauren L. Pharmacokinetics of disodium clodronate after daily intravenous infusions during five consecutive days. International Journal of Clinical Pharmacology, Therapy and Toxicology 27: 602–606, 1989Google Scholar
  82. Hansen Jr NM, Felix R, Bisaz S, Fleisch H. Aggregation of hydroxyapatite crystals. Biochimica et Biophysica Acta 451: 549–559, 1976PubMedGoogle Scholar
  83. Harinck HIJ, Bijvoet OLM, Plantingh AST, Body JJ, Elte JWF, et al. Role of bone and kidney in tumor-induced hypercalcemia and its treatment with bisphosphonate and sodium chloride. American Journal of Medicine 82: 1133–1142, 1987aPubMedGoogle Scholar
  84. Harinck HIJ, Papapoulos SE, Blanksma HJ, Moolenaar AJ, Vermeij P, et al. Paget’s disease of bone: early and late responses to three different modes of treatment with aminohydroxypropylidene bisphosphonate (APD). British Medical Journal 295: 1301–1305, 1987bPubMedGoogle Scholar
  85. Hasling C, Charles P, Mosekilde L. Etidronate disodium for treating hypercalcaemia of malignancy: a double blind, placebo-controlled study. European Journal of Clinical Investigation 16: 433–437, 1986PubMedGoogle Scholar
  86. Hosking DJ. Assessment of renal and skeletal components of hypercalcemia. Calcified Tissue International 46 (Suppl.): SUS19, 1990aGoogle Scholar
  87. Hosking DJ. Advances in the management of Paget’s disease of bone. Drugs 40: 829–840, 1990bPubMedGoogle Scholar
  88. Hughes DE, MacDonald BR, Russell RGG, Gowen M. Inhibition of osteoclast-like cell formation by bisphosphonates in long-term cultures of human bone marrow. Journal of Clinical Investigation 83: 1930–1935, 1989PubMedGoogle Scholar
  89. Jacobs TP, Gordon AC, Silverberg SJ, Shane E, Reich L, et al. Neoplastic hypercalcemia: physiologic response to intravenous etidronate disodium. American Journal of Medicine 82(Suppl. 2A): 42–50, 1987PubMedGoogle Scholar
  90. Jacobs TP, Siris ES, Bilezikian JP, Baquiran DC, Shane E, et al. Hypercalcemia of malignancy: treatment with intravenous dichloromethylene diphosphonate. Annals of Internal Medicine 94: 312–316, 1981PubMedGoogle Scholar
  91. Jee WSS, Black HE, Gotcher JE. Effect of dichloromethane diphosphonate on cortisol-induced bone loss in young adult rabbits. Clinical Orthopaedics and Related Research 156: 39–51, 1981PubMedGoogle Scholar
  92. Johnson KY, Wesseler MA, Olson HM, Martodam RR, Poser JW. The effects of diphosphonates on tumor-induced hypercalcaemia and osteolysis in Walker carcinosarcoma 256 (W-256) of rats. In Donath A, et al. (Eds) Diphosphonates and Bone 4: 386–389, Editions Médecine et Hygiène, 1982Google Scholar
  93. Jowsey J, Holley KE, Linman JW. Effect of sodium etidronate in adult cats. Journal of Laboratory and Clinical Medicine 76: 126–133, 1970PubMedGoogle Scholar
  94. Jowsey J, Riggs BL, Kelly PJ, Hoffman DL, Bordier P. The treatment of osteoporosis with disodium ethane-1-hydroxy-1,1-diphosphonate. Journal of Laboratory and Clinical Medicine 78: 574–584, 1971PubMedGoogle Scholar
  95. Jung A. Comparison of two parenteral diphosphonates in hypercalcemia of malignancy. American Journal of Medicine 72: 221–226, 1982PubMedGoogle Scholar
  96. Jung A, Bisaz S, Fleisch H. The binding of pyrophosphate and two diphosphonates on hydroxyapatite crystals. Calcified Tissue Research 11: 269–280, 1973PubMedGoogle Scholar
  97. Jung A, Bornand J, Mermillod B, Edouard C, Meunier PJ. Inhibition by diphosphonates of bone resorption induced by the Walker tumor of the rat. Cancer Research 44: 3007–3011, 1984PubMedGoogle Scholar
  98. Jung A, Chantraine A, Donath A, van Ouwenaller C, Turnill D, et al. Use of dichloromethylene diphosphonate in metastatic bone disease. New England Journal of Medicine 308: 1499–1501, 1983PubMedGoogle Scholar
  99. Jung A, Mermillod B, Barras C, Baud M, Courvoisier B. Inhibition by two diphosphonates of bone lysis in tumor-conditioned media. Cancer Research 41: 3233–3237, 1981PubMedGoogle Scholar
  100. Jung A, van Ouwenaller C, Chantraine A, Courvoisier B. Traitement par deux diphosphonates des hypercalcémies d’origine tumorale. Schweizerische Medizinische Wochenschrift 110: 1822–1824, 1980PubMedGoogle Scholar
  101. Kanis JA, Cundy T, Heynen G, Russell RGG. The pathophysiology of hypercalcaemia. Metabolic Bone Disease and Related Research 2: 151–159, 1980Google Scholar
  102. Kanis JA, McCloskey EV. The use of clodronate in disorders of calcium and skeletal metabolism. In Kanis JA (Ed.) Calcium metabolism, pp. 89–136, Karger AG, Basel, 1990Google Scholar
  103. Kanis JA, Percival RC, Urwin GH, Murray SA, Hamdy NAT, et al. Renal handling of calcium and sodium in metastatic and non-metastatic malignancy. British Medical Journal 292: 1273, 1986PubMedGoogle Scholar
  104. Kanis JA, Urwin GH, Gray RES, Beneton MNC, McCloskey EV, et al. Effects of intravenous etidronate disodium on skeletal and calcium metabolism. American Journal of Medicine 82(Suppl. 2A): 55–70, 1987PubMedGoogle Scholar
  105. King WR, Francis MD, Michael WR. Effect of disodium ethane-1-hydroxy-1,1-diphosphonate on bone formation. Clinical Orthopaedics 78: 251–270, 1971Google Scholar
  106. Kozak ST, Rizzoli R, Trechsel U, Fleisch H. Effect of a single injection of two new bisphosphonates on the hypercalcemia and hypercalciuria induced by Walker carcinosarcoma 256/B in thyroparathyroidectomized rats. Cancer Research 47: 6193–6197, 1987PubMedGoogle Scholar
  107. Krempien B, Wingen F, Eichmann T, Müller M, Schmähl D. Protective effects of a prophylactic treatment with the bisphosphonate 3-amino-1-hydroxypropane-1,1-bisphosphonic acid on the development of tumor osteopathies in the rat: experimental studies with the Walker carcinosarcoma 256. Oncology 45: 41–46, 1988PubMedGoogle Scholar
  108. Labat ML, Florentin I, Davigny M, Moricard J, Milhaud G. Dichloromethylene diphosphonate (Cl2MDP) reduces natural killer (NK) cell activity in mice. Metabolic Bone Disease and Related Research 5: 281–287, 1984Google Scholar
  109. Labat ML, Tzehoval E, Moricard Y, Feldmann M, Milhaud G. Lack of a T-cell dependent subpopulation of macrophages in (dichloromethylene) diphosphonate-treated mice. Biomedicine and Pharmacotherapy 3.7: 270–276, 1983Google Scholar
  110. Larsson A. The short-term effects of high doses of ethylene-1-hydroxy-1,1-diphosphonates upon early dentine formation. Calcified Tissue Research 16: 109–127, 1974PubMedGoogle Scholar
  111. Larsson A, Rohlin M. In vivo distribution of 14C-labeled ethylene-1-hydroxy-1,1-diphosphonate in normal and treated young rats. An autoradiographic and ultrastructural study. Toxicology and Applied Pharmacology 52: 391–399, 1980PubMedGoogle Scholar
  112. Ljunghall S, Rastad J, Akerström G. Comparative effects of calcitonin and clodronate in hypercalcaemia. Bone 8(Suppl. 1): S79–S83, 1987PubMedGoogle Scholar
  113. Löwik CWGM, van der Pluijm G, van der Wee-Pals LJA, Bloys van Treslong-de Groot H, Bijvoet OLM. Migration and phenotypic transformation of osteoclast precursors into mature osteoclasts: the effect of a bisphosphonate. Journal of Bone and Mineral Research 3: 185–191, 1988PubMedGoogle Scholar
  114. Marie PJ, Hott M, Garba MT. Inhibition by aminohydroxypropylidene bisphosphonate (AHPrBP) of 1,25 (OH)2 vitamin D3-induced stimulated bone turnover in the mouse. Calcified Tissue International 37: 268–275, 1985PubMedGoogle Scholar
  115. Markkula R, Repo H, Leirisalo M, Blomqvist C, Elomaa I. Effect of dichloromethylene diphosphonate (Cl2MDP) on immune function in breast cancer patients with bone metastases. Cancer Immunology and Immunotherapy 15: 159–161, 1983PubMedGoogle Scholar
  116. Martin TJ. Hypercalcemia–solid tumors. In Kleerekoper M et al. (Eds) Clinical disorders of bone and mineral metabolism, pp. 509–516, Mary Ann Liebert, Inc., New York, 1989Google Scholar
  117. Martodam RR, Thornton KS, Sica DA, D’Souza SM, Flora L, et al. The effects of dichloromethylene diphosphonate on hypercalcemia and other parameters of the humoral hypercalcemia of malignancy in the rat Leydig cell tumor. Calcified Tissue International 35: 512–519, 1983PubMedGoogle Scholar
  118. Maxon III HR, Schroder LE, Thomas SR, Hertzberg VS, Deutsch EA, et al. Re-186 (Sn) HEDP for treatment of painful osseous metastases: initial clinical experience in 20 patients with hormone-resistant prostate cancer. Radiology 176: 155–159, 1990PubMedGoogle Scholar
  119. McCloskey EV, Paterson AHG, Powles T, Kanis JA. Clodronate decreases the incidence of hypercalcaemia and major vertebral fractures in metastatic breast cancer. Abstract no. 670. Journal of Bone and Mineral Research 5(Suppl. 2): S241, 1990Google Scholar
  120. Meunier PJ, Chapuy MC, Delmas P, Charhon S, Edouard C, et al. Intravenous disodium etidronate therapy in Paget’s disease of bone and hypercalcemia of malignancy. American Journal of Medicine 82(Suppl. 2A): 71–78, 1987PubMedGoogle Scholar
  121. Meyer JL, Nancollas GH. The influence of multidentate organic phosphonates on the crystal growth of hydroxyapatite. Calcified Tissue Research 13: 295–703, 1973PubMedGoogle Scholar
  122. Michael WR, King WR, Wakim JM. Metabolism of disodium ethane-1-hydroxy-1,1-diphosphonate (disodium etidronate) in the rat, rabbit, dog and monkey. Toxicology and Applied Pharmacology 21: 503–515, 1972PubMedGoogle Scholar
  123. Milhaud G, Labat ML, Moricard Y. (Dichloromethylene) diphosphonate-induced impairment of T-lymphocyte function. Proceedings of the National Academy of Sciences of the United States of America 80: 4469–4473, 1983PubMedGoogle Scholar
  124. Miller SC, Jee WSS. The effect of dichlormethylene-diphosphonate, a pyrophosphate analog, on bone and bone cell structure in the growing rat. Anatomical Record 193: 439–462, 1979PubMedGoogle Scholar
  125. Mönkkönen J. A one year follow-up study of the distribution of 14C-clodronate in mice and rats. Pharmacology and Toxicology 62: 51–53, 1988PubMedGoogle Scholar
  126. Mönkkönen J, Koponen HM, Ylitalo P. Comparison of the distribution of three bisphosphonates in mice. Pharmacology and Toxicology 65: 294–298, 1989aGoogle Scholar
  127. Mönkkönen J, Urtti A, Paronen P, Elo HA, Ylitalo P. The uptake of clodronate (dichloromethylene bisphosphonate) by macrophages in vivo and in vitro. Drug Metabolism and Disposition 17: 690–693, 1989bPubMedGoogle Scholar
  128. Mönkkönen J, Ylitalo P. The tissue distribution of clodronate (dichloromethylene bisphosphonate) in mice. The effects of vehicle and the route of administration. European Journal of Drug Metabolism and Pharmacokinetics 15: 239–243, 1990PubMedGoogle Scholar
  129. Mönkkönen J, Ylitalo P, Elo HA, Airaksinen MM. Distribution of 14C-clodronate (dichloromethylene bisphosphonate) disodium in mice. Toxicology and Applied Pharmacology 89: 287–292, 1987PubMedGoogle Scholar
  130. Morgan DB, Monod A, Rüssel RGG, Fleisch H. Influence of dichlormethylene diphosphonate (Cl2MDP) and calcitonin on bone resorption, lactate production and phosphatase and pyrophosphatase content of mouse calvaria treated with parathyroid hormone in vitro. Calcified Tissue Research 13: 287–294, 1973PubMedGoogle Scholar
  131. Morton AR, Cantilli JA, Craig AE, Howell A, Davies M, et al. Single dose versus daily intravenous aminohydroxypropylidene biphosphonate (APD) for the hypercalcaemia of malignancy. British Medical Journal 296: 811–814, 1988PubMedGoogle Scholar
  132. Moseley JM, Kubota M, Diefenba Ch, Jagger H, Wettenhall REH, Kemp BE, et al. Parathyroid hormone-related protein purified from a human lung cancer cell line. Proceedings of the National Academy of Sciences of the United States of America 84: 5048–5052, 1987PubMedGoogle Scholar
  133. Mühlbauer RC, Bauss F, Schenk R, Janner M, Bosies E, et al. BM 21.0955 a potent new bisphosphonate to inhibit bone resorption. Endocrinology, in press, 1991Google Scholar
  134. Mühlbauer RC, Fleisch H. A method for continual monitoring of bone resorption in rats: evidence for a diurnal rhythm. American Journal of Physiology 259: R679–R689, 1990PubMedGoogle Scholar
  135. Mühlbauer RC, Rüssel RGG, Williams DA, Fleisch H. The effects of diphosphonates, polyphosphates, and calcitonin on immobilisation osteoporosis in rats. European Journal of Clinical Investigation 1: 336–344, 1971PubMedGoogle Scholar
  136. Mühlbauer RC, Stutzer A, Schenk R, Janner M, Fleisch H, et al. 1-hydroxy-3-(methylpentylamino) propylidene-bisphosphonate (BM 21.0955), a potent new inhibitor of bone resorption. Abstract no. 201. Journal of Bone and Mineral Research 4(Suppl. 1): S168, 1989Google Scholar
  137. Mundy GR. Hypercalcemia in hematologic malignancies and in solid tumors associated with extensive localized bone destruction. In Favus MJ (Ed.) Primer on the metabolic bone diseases and disorders of mineral metabolism, pp. 118–120, American Society for Bone and Mineral Research, Kelseyville, 1990Google Scholar
  138. Mundy GR. Pathophysiological aspects of tumour-induced hypercalcaemia and bone metastases. In Burckhardt P (Ed.) Disodium pamidronate (APD) in the treatment of malignancy-related disorders, pp. 12–20, Huber Publishers, Toronto, 1989Google Scholar
  139. Nemoto R, Sato S, Nishijima Y, Miyakawa I, Koiso K, et al. Effects of a new bisphosphonate (AHBuBP) on osteolysis induced by human prostate cancer cells in nude mice. Journal of Urology 144: 770–774, 1990PubMedGoogle Scholar
  140. Nemoto R, Uchida K, Tsutsumi M, Koiso K, Satou S, et al. A model of localized osteolysis induced by the MBT-2 tumor in mice and its responsiveness to etidronate disodium. Journal of Cancer Research Clinical Oncology 113: 539–543, 1987Google Scholar
  141. Nixon GA, Buehler EV, Newmann EA. Preliminary safety assessment of disodium etidronate as an additive to experimental oral hygiene products. Toxicology and Applied Pharmacology 22: 661–671, 1972PubMedGoogle Scholar
  142. Nolen GA, Buehler EV. The effects of disodium etidronate on the reproductive functions and embryogeny of albino rats and New Zealand rabbits. Toxicology and Applied Pharmacology 18: 548–561, 1971PubMedGoogle Scholar
  143. Ostrowski K, Wojtowicz A, Dziedzic-Goclawska A, Rozycka M. Effect of 1-hydroxyethylidene-1,1-bisphosphonate(HEBP) and dichloromethylidene-bisphosphonate (Cl2MBP) on the structure of the organic matrix of heterotopically induced bone tissue. Histochemistry 88: 207–212, 1988PubMedGoogle Scholar
  144. Paterson AD, Kanis JA, Cameron EC, Douglas DL, Beard DJ, et al. The use of dichloromethylene diphosphonate for the management of hypercalcaemia in multiple myeloma. British Journal of Haematology 54: 121–132, 1983PubMedGoogle Scholar
  145. Percival RC, Paterson AD, Yates AJP, Beard DJ, Douglas DL, et al. Treatment of malignant hypercalcaemia with clodronate. British Journal of Cancer 51: 665–669, 1985aPubMedGoogle Scholar
  146. Percival RC, Yates AJP, Gray RES, Galloway J, Rogers K, et al. Mechanisms of malignant hypercalcaemia in carcinoma of the breast. British Medical Journal 291: 776–779, 1985bPubMedGoogle Scholar
  147. Plasmans CMT, Kuypers W, Slooff TJJH. The effect of ethane-1-hydroxy-1,1-diphosphonic acid (EHDP) on matrix induced ectopic bone formation. Clinical Orthopaedics and Related Research 132: 233–243, 1978PubMedGoogle Scholar
  148. Pollard M, Luckert PH. Effects of dichloromethylene diphosphonate on the osteolytic and osteoplastic effects of rat prostate adenocarcinoma cells. Journal of the National Cancer Institute 75: 949–954, 1985PubMedGoogle Scholar
  149. Pollard M, Luckert PH, Scheu J. Effects of diphosphonate and x-rays on bone lesions induced in rats by prostate cancer cells. Cancer 61: 2027–2032, 1988PubMedGoogle Scholar
  150. Portmann L, Häfliger JM, Bill G, Burckhardt P. Un traitement simple de l’hypercalcémie tumorale: l’amino-hydroxypropylidène bisphosphonate (APD) i.v. Schweizerische Medizinische Wochenschrift 113: 1960–1963, 1983PubMedGoogle Scholar
  151. Powell JH, DeMark BR. Clinical pharmacokinetics of diphosphonates. In Garattini S (Ed.) Bone resorption, metastasis, and diphosphonates, pp. 41–49, Raven Press, New York, 1985Google Scholar
  152. Radl J, Croese JW, Zurcher C, van den Enden-Vieveen MH, Brondijk RJ, et al. Influence of treatment with APD-bisphosphonate on the bone lesions in the mouse 5T2 multiple myeloma. Cancer 55: 1030–1040, 1985PubMedGoogle Scholar
  153. Ralston SH, Alzaid AA, Gallacher SJ, Gardner MD, Cowan RA, et al. Clinical experience with aminohydroxypropylidene bisphosphonate (APD) in the management of cancer-associated hypercalcaemia. Quarterly Journal of Medicine 258: 825–834, 1988Google Scholar
  154. Ralston SH, Alzaid AA, Gardner MD, Boyle IT. Treatment of cancer associated hypercalcaemia with combined aminohydroxypropylidene diphosphonate and calcitonin. British Medical Journal 292: 1549–1550, 1986PubMedGoogle Scholar
  155. Ralston SH, Fogelman I, Gardner MD, Dryburgh FJ, Cowan RA, et al. Hypercalcaemia of malignancy: evidence for a non-parathyroid humoral agent with an effect on renal tubular handling of calcium. Clinical Science 66: 187–191, 1984PubMedGoogle Scholar
  156. Ralston SH, Gallacher SJ, Patel U, Dryburgh FJ, Fraser WD, et al. Comparison of three intravenous bisphosphonates in cancer-associated hypercalcaemia. Lancet 2: 1180–1182, 1989PubMedGoogle Scholar
  157. Ralston SH, Gardner MD, Dryburgh FJ, Jenkins AS, Cowan RA, et al. Comparison of aminohydroxypropylidene diphosphonate, mithramycin, and corticosteroids/calcitonin in treatment of cancer-associated hypercalcaemia. Lancet 2: 907–910, 1985PubMedGoogle Scholar
  158. Rastad J, Benson L, Johansson H, Knuutila M, Pettersson B, et al. Clodronate treatment in patients with malignancy-associated hypercalcemia. Acta Medica Scandinavica 221: 489–494, 1987PubMedGoogle Scholar
  159. Recker RR, Hassing GS, Lau JR, Saville PD. The hyperphosphatemic effect of disodium ethane-1-hydroxy-1,1-diphosphonates (EHDP TM): renal handling of phosphorus and the renal response to parathyroid hormone. Journal of Laboratory and Clinical Medicine 81: 258–266, 1973PubMedGoogle Scholar
  160. Recker RR, Saville PD. Intestinal absorption of disodium ethane-1-hydroxy-1,1-diphosphonate (disodium etidronate) using a deconvolution technique. Toxicology and Applied Pharmacology 24: 580–589, 1973PubMedGoogle Scholar
  161. Reiner M, Sautter V, Olah A, Bossi E, Largiader U, et al. Diphosphonate treatment in myositis ossificans progressiva. In Caniggia A (Ed.) Etidronate, p. 237, Istituto Gentili, Pisa, 1980Google Scholar
  162. Reitsma PH, Bijvoet OLM, Potokar M, van der Wee-Pals LJA, van Wijk-van Lennep MML. Apposition and resorption of bone during oral treatment with (3-amino-1-hydroxypropylidene)-1,1 -bisphosphonate (APD). Calcified Tissue International 35: 357–361, 1983PubMedGoogle Scholar
  163. Reitsma PH, Bijvoet OLM, Verlinden Ooms H, van der Wee-Pals LJA. Kinetic studies of bone and mineral metabolism during treatment with (3-amino-1-hydroxy-propylidene)-1,1-bisphosphonate (APD) in rats. Calcified Tissue International 32: 145–147, 1980PubMedGoogle Scholar
  164. Reynolds JJ, Minkin C, Morgan DB, Spycher D, Fleisch H. The effect of two diphosphonates on the resorption of mouse calvaria in vitro. Calcified Tissue Research 10: 302–313, 1972PubMedGoogle Scholar
  165. Reynolds JJ, Murphy H, Mühlbauer RC, Morgan DB, Fleisch H. Inhibition by diphosphonates of bone resorption in mice and comparison with grey-lethal osteoporosis. Calcified Tissue Research 12: 59–71, 1973PubMedGoogle Scholar
  166. Ringenberg QS, Riten PS. Efficacy of oral administration of etidronate disodium in maintaining normal serum calcium levels in previously hypercalcemic cancer patients. Clinical Therapeutics 9: 318–325, 1987PubMedGoogle Scholar
  167. Rizzoli R, Bonjour JP. High extracellular calcium increases the production of a parathyroid hormone-like activity by cultured Leydig tumor cells associated with humoral hypercalcemia. Journal of Bone and Mineral Research 4: 839–844, 1989PubMedGoogle Scholar
  168. Rizzoli R, Caverzasio J, Chapuy MC, Martin TJ, Bonjour JP. Role of bone and kidney in parathyroid hormone-related peptide-induced hypercalcemia in rats. Journal of Bone and Mineral Research 4: 759–765, 1989PubMedGoogle Scholar
  169. Rizzoli R, Caverzasio J, Fleisch H, Bonjour JP. Parathyroid hormone-like changes of renal calcium and phosphate reabsorption induced by Leydig cell tumor in thyroparathyroid-ectomized rats. Endocrinology 119: 1004–1009, 1986PubMedGoogle Scholar
  170. Rizzoli R, Fleisch H. The Walker 256/B carcinosarcoma in thyroparathyroidectomized rats: a model to evaluate. Calcified Tissue International 41: 202–207, 1987PubMedGoogle Scholar
  171. Russell RGG, Bisaz S, Donath A, Morgan DB, Fleisch H. Inorganic pyrophosphate in plasma in normal persons and in patients with hypophosphatasia, osteogenesis imperfecta and other disorders of bone. Journal of Clinical Investigation 50: 961–969, 1971PubMedGoogle Scholar
  172. Russell RGG, Mühlbauer RC, Bisaz S, Williams DA, Fleisch H. 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. Calcified Tissue Research 6: 183–196, 1970PubMedGoogle Scholar
  173. Russell RGG, Smith R, Preston C, Walton RJ, Woods CG. Diphosphonates in Paget’s disease. Lancet 1: 894–898, 1974PubMedGoogle Scholar
  174. Ryzen E, Martodam RR, Troxell M, Benson A, Paterson A, et al. Intravenous etidronate in the management of malignant hypercalcemia. Archives of Internal Medicine 145: 449–452, 1985PubMedGoogle Scholar
  175. Sato M, Grasser W. Effects of bisphosphonates on isolated rat osteoclasts as examined by reflected light microscopy. Journal of Bone and Mineral Research 5: 31–40, 1990PubMedGoogle Scholar
  176. Sawyer N, Newstead C, Drummond A, Cunningham J. Fast (4-h) or slow (24-h) infusions of pamidronate disodium (aminohydroxypropylidene diphosphonate) [APD] as single shot treatment of hypercalcaemia. Bone and Mineral 9: 122–128, 1990Google Scholar
  177. Scharia SH, Minne HW, Sattar P, Mende U, Blind E, et al. Therapie der Tumorhypercalciämie mit Clodronat. Deutsche Medizinische Wochenschrift 112: 1121–1125, 1987Google Scholar
  178. Schenk R, Eggli P, Felix R, Heisch H, Rosini S. Quantitative morphometric evaluation of the inhibitory activity of new aminobisphosphonates on bone resorption in the rat. Calcified Tissue International 38: 342–349, 1986PubMedGoogle Scholar
  179. Schenk R, Merz WA, Mühlbauer R, Russell RGG, Fleisch H. 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. Calcified Tissue Research 11: 196–214, 1973PubMedGoogle Scholar
  180. Schibler D, Russell RGG, Fleisch H. Inhibition of pyrophosphate and polyphosphate on aortic calcification induced by vitamin D3, in rats. Clinical Science 35: 363–372, 1968PubMedGoogle Scholar
  181. Schiller JH, Rasmussen P, Benson AB, Witte RS, Bockman RS, et al. Maintenance etidronate in the prevention of malignancy-associated hypercalcemia. Archives of Internal Medicine 147: 963–966, 1987PubMedGoogle Scholar
  182. Schnur W. Relief of metastatic bone pain with etidronate disodium. Ohio State Medical Journal 83: 62–65, 1987PubMedGoogle Scholar
  183. Shane E, Jacobs TP, Siris ES, Steinberg SF, Stoddart K, et al. Therapy of hypercalcemia due to parathyroid carcinoma with intravenous dichloromethylene diphosphonate. American Journal of Medicine 72: 939–944, 1982PubMedGoogle Scholar
  184. Shinoda H, Adamek G, Felix R, Fleisch H, Schenk R, et al. Structure-activity relationship of various bisphosphonates. Calcified Tissue International 35: 87–99, 1983PubMedGoogle Scholar
  185. Shiota E. Effects of diphosphonate on osteoporosis induced in rats. Fukuoka Acta Medica 76: 317–342, 1985Google Scholar
  186. Sietsema WK, Ebetino FH, Salvagno AM, Bevan JA. Antiresorptive dose-response relationship across three generations of bisphosphonates. Drugs Under Experimental and Clinical Research 15: 389–396, 1989PubMedGoogle Scholar
  187. Singer FR, Ritch PS, Lad TE, Ringenberg QS, Schiller JH, et al. Treatment of hypercalcemia of malignancy with intravenous etidronate. Archives of Internal Medicine 151: 471–476, 1991PubMedGoogle Scholar
  188. Siris ES, Sherman WH, Baquiran DC, Schlatterer JP, Osserman EF, et al. Effects of dichloromethylene diphosphonate on skeletal mobilization of calcium in multiple myeloma. New England Journal of Medicine 302: 310–315, 1980PubMedGoogle Scholar
  189. Sleeboom HP, Bijvoet OLM, van Oosterom AT, Gleed JH, O’Riordan JLH. Comparison of intravenous (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate and volume repletion in tumour-induced hypercalcaemia. Lancet 2: 239–243, 1983PubMedGoogle Scholar
  190. Smirnova IN, Kudryavtseva NA, Korhissarenko SV, Tarusova NB, Baykov AA. Diphosphonates are potent inhibitors of mammalian inorganic pyrophosphatase. Archives of Biochemistry and Biophysics 267: 280–284, 1988PubMedGoogle Scholar
  191. Smith JA. Pallation of painful bone metastases from prostate cancer using sodium etidronate: results of a randomized, prospective double-blind, placebo-controlled study. Journal of Urology 141: 85–87, 1989PubMedGoogle Scholar
  192. Stewart AF. Humoral hypercalcemia of malignancy. In Favus MJ (Ed.) Primer on the metabolic bone diseases and disorders of mineral metabolism, pp. 115–118, American Society for Bone and Mineral Research, Kelseyville, 1990Google Scholar
  193. Strewler GJ, Stern PH, Jacobs JW, Eveloff J, Klein RF, et al. Parathyroid hormone-like protein from human renal carcinoma cells. Journal of Clinical Investigation 80: 1803–1807, 1987PubMedGoogle Scholar
  194. Stutzer A, Fleisch H, Trechsel U. Short- and long-term effects of a single dose of bisphosphonates on retinoid-induced bone resorption in thyroparathyroidectomized rats. Calcified Tissue International 43: 294–299, 1988PubMedGoogle Scholar
  195. Stutzer A, Trechsel U, Fleisch H, Schenk R. Effect of bisphosphonates on osteoclast number and bone resorption in the rat. Calcified Tissue International 41(Suppl. 2): 50–102, 1987Google Scholar
  196. Suva LJ, Winslow GA, Wettenhall REH, Kemp BE, Hudson PJ, et al. Molecular cloning and expression of a novel hormone cDNA encoding a parathyroid hormone-like protein in human lung cancer cells. Science 237: 893–896, 1987PubMedGoogle Scholar
  197. Thiébaud D, Jaeger P, Burckhardt P. Response to retreatment of malignant hypercalcemia with the bisphosphonate AHPrBP (ABD): respective role of kidney and bone. Journal of Bone and Mineral Research 5: 221–226, 1990PubMedGoogle Scholar
  198. Thiébaud D, Jaeger P, Jacquet AF, Burckhardt P. A single-day treatment of tumor-induced hypercalcemia by intravenous amino-hydroxypropylidene bisphosphonate. Journal of Bone and Mineral Research 1: 555–562, 1986aPubMedGoogle Scholar
  199. Thiébaud D, Jaeger P, Jacquet AF, Burckhardt P. Dose-response in the treatment of hypercalcemia of malignancy by a single infusion of the bisphosphonate AHPrBP. Journal of Clinical Oncology 6: 762–768, 1988PubMedGoogle Scholar
  200. Thiébaud D, Leyvraz S, von Fliedner V, Perey L, Cornu P, et al. Treatment of bone metastases from breast cancer and myeloma with pamidronate. European Journal of Cancer 27: 37–41, 1991PubMedGoogle Scholar
  201. Thiébaud D, Portmann L, Jaeger PH, Jacquet AF, Burckhardt P. Oral versus intravenous AHPrBP (APD) in the treatment of hypercalcemia of malignancy. Bone 7: 247–253, 1986bPubMedGoogle Scholar
  202. Trechsel U, Stutzer A, Fleisch H. Hypercalcemia induced with an arotinoid in thyroparathyroidectomized rats: a new model to study bone resorption in vivo. Journal of Clinical Investigation 80: 1679–1686, 1987PubMedGoogle Scholar
  203. Troehler U, Bonjour JP, Fleisch H. Interference of dichloromethylene diphosphonate with parathyroid hormone effects at the bone but not at the kidney level. Mineral and Electrolyte Metabolism 7: 122–126, 1982PubMedGoogle Scholar
  204. Troehler U, Bonjour JP, Fleisch H. Renal secretion of diphosphonates in rats. Kidney International 8: 6–13, 1975PubMedGoogle Scholar
  205. Tubiana-Hulin M, de Vernejoul MC, Brière M, Miravet L, Clavel B. Traitement des hypercalcémies des metastases ostéolytiques par l’amino-hydroxypropylidene-diphosphonate par voie orale. La Presse Médicale 8: 483–486, 1984Google Scholar
  206. Urwin GH, Yates AJP, Gray RES, Hamdy NAT, McCloskey EV, et al. Treatment of the hypercalcaemia of malignancy with intravenous clodronate. Bone 8(Suppl. 1): S43–S51, 1987PubMedGoogle Scholar
  207. Van Breukelen FJM, Bijvoet OLM, Frijlink WB, Sleeboom HP, Mulder H, et al. Efficacy of amino-hydroxypropylidene bisphosphonate in hypercalcemia: observations on regulation of serum calcium. Calcified Tissue International 34: 321–327, 1982PubMedGoogle Scholar
  208. Van Breukelen FJM, Bijvoet OLM, Oosterom AT. Inhibition of osteolytic bone lesions by (3-amino-1-hydroxpropylidene)-1,1-bisphosphonate (APD). Lancet 1: 803–805, 1979PubMedGoogle Scholar
  209. Van den Bos T, Beertsen W. Effects of 1-hydroxyethylidene-1,1-bisphosphonate (HEBP) on the synthesis of dentine matrix proteins in the mouse. Collagen Related Research 7: 135–147, 1987Google Scholar
  210. Van Holten-Verzantvoort AT, Bijvoet OLM, Cleton FJ, Hermans J, Kroon DM, et al. Reduced morbidity from skeletal metastases in breast cancer patients during long-term bisphosphonate (APD) treatment. Lancet 2: 983–985, 1987PubMedGoogle Scholar
  211. Walton RJ, Russell RGG, Smith R. Changes in the renal and extrarenai handling of phosphate induced by disodium-etidronate (EHDP) in man. Journal of Clinical Science and Molecular Medicine 49: 45–56, 1975Google Scholar
  212. Wasserman RH, Bonjour JP, Fleisch H. Ileal absorption of disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) and disodium dichloromethylene diphosphonate (Cl2MDP) in the chick. Experientia 29: 1110–1111, 1973PubMedGoogle Scholar
  213. Wingen F, Eichmann T, Manegold C, Krempien B. Effects of new bisphosphonic acids on tumor-induced bone destruction in the rat. Journal of Cancer Research and Clinical Oncology 111: 35–41, 1986PubMedGoogle Scholar
  214. Wingen F, Schmähl D. Distribution of 3-amino-1-hydroxy-propane-1,1-diphosphonic acid in rats and effects on rat osteosarcoma. Arzneimittel-Forschung 35: 1565–1571, 1985PubMedGoogle Scholar
  215. Wingen F, Schmähl D. Pharmacokinetics of the osteotropic diphosphonate 3-amino-1-hydroxypropane-1,1-diphosphonic acid in mammals. Arzneimittel-Forschung 37: 1037–1042, 1987PubMedGoogle Scholar
  216. Wink CS, Onge MST, Parker B. The effects of dichloromethylene biphosphonate on osteoporotic femora of adult castrate male rats. Acta Anatomica 124: 117–121, 1985PubMedGoogle Scholar
  217. Wüster C, Scharia SH, Schmidt J, Ziegler R. Efficacy and safety of BM 21.0955, a new bisphosphonate in patients with humoral hypercalcemia of malignancy. Abstract no. 113. Journal of Bone and Mineral Research 5(Suppl. 2): S102, 1990Google Scholar
  218. Yakatan GJ, Poynor WJ, Talbert RL, Floyd BF, Slough CL, et al. Clodronate kinetics and bioavailability. Clinical Pharmacology and Therapeutics 31: 402–410, 1982PubMedGoogle Scholar
  219. Yates AJP, Murray RML, Jerums GJ, Martin TJ. A comparison of single and multiple intravenous infusions of 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (APD) in the treatment of hypercalcemia of malignancy. Australian and New Zealand Journal of Medicine 17: 387–391, 1987PubMedGoogle Scholar

Copyright information

© Adis International Limited 1991

Authors and Affiliations

  • Herbert Fleisch
    • 1
  1. 1.Department of PathophysiologyUniversity of BerneBerneSwitzerland

Personalised recommendations