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Clodronic Acid Formulations Available in Europe and their Use in Osteoporosis

A Review

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Abstract

Clodronic acid (Cl2-MBP [dichloromethylene bisphosphonic acid], clodronate) is a halogenated non-nitrogen-containing bisphosphonate with antiresorptive efficacy in a variety of diseases associated with excessive bone resorption. The drug is believed to inhibit bone resorption through induction of osteoclast apoptosis, but appears also to possess anti-inflammatory and analgesic properties that contrast with the acute-phase and inflammatory effects seen with nitrogen-containing bisphosphonates.

Clodronic acid has been shown to be effective in the maintenance or improvement of bone mineral density when given orally, intramuscularly or intravenously in patients with osteoporosis. Use of the drug is also associated with reductions in fracture risk. The intramuscular formulation, which is given at a dose of 100 mg weekly or biweekly, is at least as effective as daily oral therapy and appears more effective than intermittent intravenous treatment. Intramuscular clodronic acid in particular has also been associated with improvements in back pain. The drug is well tolerated, with no deleterious effects on bone mineralization, and use of parenteral therapy eliminates the risk of gastrointestinal adverse effects that may be seen in patients receiving bisphosphonate therapy.

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References

  1. Adami S, Guarrera G, Salvagno G, et al. Sequential treatment of Paget’s disease with human calcitonin and dichloromethylene diphosphonate (Cl2MDP). Metab Bone Dis Relat Res 1984; 5(6): 265–7

    PubMed  CAS  Google Scholar 

  2. Atula ST, Tahtela RK, Nevalainen JI, et al. Clodronate as a single-dose intravenous infusion effectively provides short-term correction of malignant hypercalcemia. Acta Oncol 2003; 42(7): 735–40

    PubMed  CAS  Google Scholar 

  3. Douglas DL, Duckworth T, Russell RG, et al. Effect of dichloromethylene diphosphonate in Paget’s disease of bone and in hypercalcaemia due to primary hyperparathyroidism or malignant disease. Lancet 1980 May 17; 1(8177): 1043–7

    PubMed  CAS  Google Scholar 

  4. Gray RE, Yates AJ, Preston CJ, et al. Duration of effect of oral diphosphonate therapy in Paget’s disease of bone. Q J Med 1987 Sep; 64(245): 755–67

    PubMed  CAS  Google Scholar 

  5. Khan SA, McCloskey EV, Eyres KS, et al. Comparison of three intravenous regimens of clodronate in Paget disease of bone. J Bone Miner Res 1996 Feb; 11(2): 178–82

    PubMed  CAS  Google Scholar 

  6. Khan SA, McCloskey EV, Nakatsuka K, et al. Duration of response with oral clodronate in Paget’s disease of bone. Bone 1996 Feb; 18(2): 185–90

    PubMed  CAS  Google Scholar 

  7. O’Rourke NP, McCloskey EV, Vasikaran S, et al. Effective treatment of malignant hypercalcaemia with a single intravenous infusion of clodronate. Br J Cancer 1993 Mar; 67(3): 560–3

    PubMed  Google Scholar 

  8. Yates AJ, Percival RC, Gray RE, et al. Intravenous clodronate in the treatment and retreatment of Paget’s disease of bone. Lancet 1985 Jun 29; 1(8444): 1474–7

    PubMed  CAS  Google Scholar 

  9. Body JJ, Coleman RE, Piccart M. Use of bisphosphonates in cancer patients. Cancer Treat Rev 1996 Jul; 22(4): 265–87

    PubMed  CAS  Google Scholar 

  10. Adami S, Bolzicco GP, Rizzo A, et al. The use of dichloromethylene bisphosphonate and aminobutane bisphosphonate in hypercalcemia of malignancy. Bone Miner 1987 Aug; 2(5): 395–404

    PubMed  CAS  Google Scholar 

  11. Chapuy MC, Meunier PJ, Alexandre CM, et al. Effects of disodium dichloromethylene diphosphonate on hypercalcemia produced by bone metastases. J Clin Invest 1980 May; 65(5): 1243–7

    PubMed  CAS  Google Scholar 

  12. Delmas P, Chapuy MC, Vignon E, et al. Dichloromethylene diphosphonate (Cl2MDP) treatment of hypercalcaemia produced from bone metastases [in French]. Nouv Presse Med 1982 Apr 24; 11(19): 1471–4

    PubMed  CAS  Google Scholar 

  13. Adami S, Salvagno G, Guarrera G, et al. Dichloromethylene-diphosphonate in patients with prostatic carcinoma metastatic to the skeleton. J Urol 1985 Dec; 134(6): 1152–4

    PubMed  CAS  Google Scholar 

  14. Kanis JA, Powles T, Paterson AH, et al. Clodronate decreases the frequency of skeletal metastases in women with breast cancer. Bone 1996 Dec; 19(6): 663–7

    PubMed  CAS  Google Scholar 

  15. Douglas DL, Kanis JA, Paterson AD, et al. Drug treatment of primary hyperparathyroidism: use of clodronate disodium. Br Med J (Clin Res Ed) 1983 Feb 19; 286(6365): 587–90

    CAS  Google Scholar 

  16. Shane E, Baquiran DC, Bilezikian JP. Effects of dichloromethylene diphosphonate on serum and urinary calcium in primary hyperparathyroidism. Ann Intern Med 1981 Jul; 95(1): 23–7

    PubMed  CAS  Google Scholar 

  17. Shane E, Jacobs TP, Siris ES, et al. Therapy of hypercalcemia due to parathyroid carcinoma with intravenous dichloromethylene diphosphonate. Am J Med 1982 Jun; 72(6): 939–44

    PubMed  CAS  Google Scholar 

  18. Hilding M, Aspenberg P. Postoperative clodronate decreases prosthetic migration: 4-year follow-up of a randomized radiostereometric study of 50 total knee patients. Acta Orthop 2006 Dec; 77(6): 912–6

    PubMed  Google Scholar 

  19. Priano F, Adravanti A, Castellacci E, et al. Bone loss prevention after hip arthroplasty: effect of intramuscular clodronate. Italian multicenter study [abstract]. Osteoporos Int 2004; 15Suppl. 1: S95

    Google Scholar 

  20. Resch H, Cavalieri L. A randomised, double-blind, placebo controlled study to evaluate the efficacy of clodronate in preventing local bone loss after total hip arthroplasty [abstract]. Clin Cases Miner Bone Metab 2007; 4(3): 361

    Google Scholar 

  21. Cherie-Ligniere G, Tamborini U, Grosso P. Algodystrophy in conjunction with van der Hoeve’s syndrome. Clin Exp Rheumatol 1995 May–Jun; 13(3): 361–5

    PubMed  CAS  Google Scholar 

  22. Di Battista L, Verrocchio A, Grasso I, et al. Trattamento del morbo di Sudeck con clodronate. EV Atti del IV Congresso Nazionale GIBIS, 41

  23. Donelli F. Post-traumatic algo-distrophic syndrome of the lower limb [abstract P156SU]. Osteoporos Int 2002; Suppl. 1: S51

  24. Monteforte P, Rovetta G. Sindrome dolorosa regionale complessa migrante mineralometria per la diagnosi, clodronate per la terapia. Algos 1999; 1: 32–6

    Google Scholar 

  25. Varenna M, Zucchi F, Ghiringhelli D, et al. Intravenous clodronate in the treatment of reflex sympathetic dystrophy syndrome: a randomized, double blind, placebo controlled study. J Rheumatol 2000 Jun; 27(6): 1477–83

    PubMed  CAS  Google Scholar 

  26. Zucchi F, Varenna M, Binelli L, et al. Reflex sympathetic dystrophy syndrome following acute gouty arthritis. Clin Exp Rheumatol 1996 Jul–Aug; 14(4): 417–20

    PubMed  CAS  Google Scholar 

  27. Montonen M, Kalso E, Pylkkaren L, et al. Disodium clodronate in the treatment of diffuse sclerosing osteomyelitis (DSO) of the mandible. Int J Oral Maxillofac Surg 2001 Aug; 30(4): 313–7

    PubMed  CAS  Google Scholar 

  28. Sugata T, Fujita Y, Myoken Y, et al. Successful management of severe facial pain in patients with diffuse sclerosing osteomyelitis (DSO) of the mandible using disodium clodronate. Int J Oral Maxillofac Surg 2003 Oct; 32(5): 574–5

    PubMed  Google Scholar 

  29. Monteforte P, Molfetta L, Grillo G, et al. Disodium clodronate in painful nonresponsive periarthropathy of the hip. Int J Tissue React 2000; 22(4): 111–5

    PubMed  CAS  Google Scholar 

  30. Saviola G, Santoro L. Clodronate in erosive osteoarthrosis of the hand: efficacy for pain and function recovery [in Italian]. G Ital Med Lav Ergon 2000 Oct–Dec; 22(4): 328–31

    PubMed  CAS  Google Scholar 

  31. Rovetta G, Monteforte P. Efficacy of disodium-clodronate in the management of joint pain in rheumatoid arthritis: six months open study. Minerva Med 2003 Oct; 94(5): 353–7

    PubMed  CAS  Google Scholar 

  32. Monteforte P, Rovetta G. Changes in size of periarthritis calcifications in patients with painful shoulder treated with injectable disodium-clodronate. Int J Clin Pharmacol Res 2002; 22(1): 7–12

    PubMed  CAS  Google Scholar 

  33. Ashford RU, Dey A, Kayan K, et al. Oral clodronate as treatment of osteogenesis imperfecta [letter]. Arch Dis Child 2003 Oct; 88(10): 945

    PubMed  CAS  Google Scholar 

  34. Varenna M, Sinigaglia L, Binelli L, et al. Transient osteoporosis of the hip: a densitometric study. Clin Rheumatol 1996 Mar; 15(2): 169–73

    PubMed  CAS  Google Scholar 

  35. Filipponi P, Cristallini S, Policani G, et al. Intermittent versus continuous clodronate administration in postmenopausal women with low bone mass. Bone 2000 Mar; 26(3): 269–74

    PubMed  CAS  Google Scholar 

  36. Filipponi P, Pedetti M, Fedeli L, et al. Cyclical clodronate is effective in preventing postmenopausal bone loss: a comparative study with transcutaneous hormone replacement therapy. J Bone Miner Res 1995 May; 10(5): 697–703

    PubMed  CAS  Google Scholar 

  37. Giannini S, D’Angelo A, Malvasi L, et al. Effects of one-year cyclical treatment with clodronate on postmenopausal bone loss. Bone 1993 Mar–Apr; 14(2): 137–41

    PubMed  CAS  Google Scholar 

  38. Giannini S, D’Angelo A, Sartori L, et al. Continuous and cyclical clodronate therapies and bone density in postmenopausal bone loss. Obstet Gynecol 1996 Sep; 88(3): 431–6

    PubMed  CAS  Google Scholar 

  39. Rossini M, Braga V, Gatti D, et al. Intramuscular clodronate therapy in postmenopausal osteoporosis. Bone 1999 Feb; 24(2): 125–9

    PubMed  CAS  Google Scholar 

  40. Wang CY, Bruder JM, Rubin CD. Evaluation and treatment of postmenopausal osteoporosis. Am J Manag Care 2001 Sep 25; 7 Spec. No.: SP5-S16

  41. Dominguez LJ, Galioto A, Ferlisi A, et al. Intermittent intramuscular clodronate therapy: a valuable option for older osteoporotic women. Age Ageing 2005 Nov; 34(6): 633–6

    PubMed  Google Scholar 

  42. Gnudi S, Lisi L, Fini M, et al. Effect of intramuscular clodronate on bone mass and metabolism in osteoporotic women. Int J Tissue React 2001; 23(1): 33–7

    PubMed  CAS  Google Scholar 

  43. Frediani B, Falsetti P, Baldi F, et al. Effects of 4-year treatment with once-weekly clodronate on prevention of corticosteroid-induced bone loss and fractures in patients with arthritis: evaluation with dual-energy X-ray absorptiometry and quantitative ultrasound. Bone 2003 Oct; 33(4): 575–81

    PubMed  CAS  Google Scholar 

  44. Ghinoi V, Brandi ML. Clodronate: mechanisms of action on bone remodelling and clinical use in osteometabolic disorders. Expert Opin Pharmacother 2002 Nov; 3(11): 1643–56

    PubMed  CAS  Google Scholar 

  45. Diel IJ, Fogelman I, Al-Nawas B, et al. Pathophysiology, risk factors and management of bisphosphonateassociated osteonecrosis of the jaw: is there a diverse relationship of amino- and non-aminobisphosphonates? Crit Rev Oncol Hematol 2007 Dec; 64(3): 198–207

    PubMed  Google Scholar 

  46. Reszka AA, Rodan GA. Mechanism of action of bisphosphonates. Curr Osteoporos Rep 2003 Sep; 1(2): 45–52

    PubMed  Google Scholar 

  47. Benford HL, McGowan NW, Helfrich MH, et al. Visualization of bisphosphonate-induced caspase-3 activity in apoptotic osteoclasts in vitro. Bone 2001 May; 28(5): 465–73

    PubMed  CAS  Google Scholar 

  48. Solomon CG. Bisphosphonates and osteoporosis. N Engl J Med 2002 Feb 28; 346(9): 642

    PubMed  Google Scholar 

  49. Schindeler A, Little DG. Bisphosphonate action: revelations and deceptions from in vitro studies. J Pharm Sci 2007 Aug; 96(8): 1872–8

    PubMed  CAS  Google Scholar 

  50. Duque G, Rivas D. Alendronate has an anabolic effect on bone through the differentiation of mesenchymal stem cells. J Bone Miner Res 2007 Oct; 22(10): 1603–11

    PubMed  CAS  Google Scholar 

  51. Follet H, Li J, Phipps RJ, et al. Risedronate and alendronate suppress osteocyte apoptosis following cyclic fatigue loading. Bone 2007 Apr; 40(4): 1172–7

    PubMed  CAS  Google Scholar 

  52. Giuliani N, Pedrazzoni M, Negri G, et al. Bisphosphonates stimulate formation of osteoblast precursors and mineralized nodules in murine and human bone marrow cultures in vitro and promote early osteoblastogenesis in young and aged mice in vivo. Bone 1998 May; 22(5): 455–61

    PubMed  CAS  Google Scholar 

  53. Mathov I, Plotkin LI, Sgarlata CL, et al. Extracellular signal-regulated kinases and calcium channels are involved in the proliferative effect of bisphosphonates on osteoblastic cells in vitro. J Bone Miner Res 2001 Nov; 16(11): 2050–6

    PubMed  CAS  Google Scholar 

  54. Sahni M, Guenther HL, Fleisch H, et al. Bisphosphonates act on rat bone resorption through the mediation of osteoblasts. J Clin Invest 1993 May; 91(5): 2004–11

    PubMed  CAS  Google Scholar 

  55. Van Beek ER, Lowik CW, Papapoulos SE. Bisphosphonates suppress bone resorption by a direct effect on early osteoclast precursors without affecting the osteoclastogenic capacity of osteogenic cells: the role of protein geranylgeranylation in the action of nitrogen-containing bisphosphonates on osteoclast precursors. Bone 2002 Jan; 30(1): 64–70

    PubMed  Google Scholar 

  56. Reinholz GG, Getz B, Pederson L, et al. Bisphosphonates directly regulate cell proliferation, differentiation, and gene expression in human osteoblasts. Cancer Res 2000 Nov 1; 60(21): 6001–7

    PubMed  CAS  Google Scholar 

  57. Fast DK, Felix R, Dowse C, et al. The effects of diphosphonates on the growth and glycolysis of connective-tissue cells in culture. Biochem J 1978 Apr 15; 172(1): 97–107

    PubMed  CAS  Google Scholar 

  58. Reitsma PH, Teitelbaum SL, Bijvoet OL, et al. 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 1982 Nov; 70(5): 927–33

    PubMed  CAS  Google Scholar 

  59. Twiss IM, Pas O, Ramp-Koopmanschap W, et al. The effects of nitrogen-containing bisphosphonates on human epithelial (Caco-2) cells, an in vitro model for intestinal epithelium. J Bone Miner Res 1999 May; 14(5): 784–91

    PubMed  CAS  Google Scholar 

  60. Adami S, Bhalla AK, Dorizzi R, et al. The acute-phase response after bisphosphonate administration. Calcif Tissue Int 1987 Dec; 41(6): 326–31

    PubMed  CAS  Google Scholar 

  61. Itoh F, Aoyagi S, Kusama H, et al. Effects of clodronate and alendronate on local and systemic changes in bone metabolism in rats with adjuvant arthritis. Inflammation 2004 Feb; 28(1): 15–21

    PubMed  CAS  Google Scholar 

  62. Endo Y, Shibazaki M, Yamaguchi K, et al. Inhibition of inflammatory actions of aminobisphosphonates by dichloromethylene bisphosphonate, a non-aminobisphosphonate. Br J Pharmacol 1999 Feb; 126(4): 903–10

    PubMed  CAS  Google Scholar 

  63. Frith JC, Monkkonen J, Auriola S, et al. The molecular mechanism of action of the antiresorptive and antiinflammatory drug clodronate: evidence for the formation in vivo of a metabolite that inhibits bone resorption and causes osteoclast and macrophage apoptosis. Arthritis Rheum 2001 Sep; 44(9): 2201–10

    PubMed  CAS  Google Scholar 

  64. Makkonen N, Hirvonen MR, Teravainen T, et al. Different effects of three bisphosphonates on nitric oxide production by RAW 264 macrophage-like cells in vitro. J Pharmacol Exp Ther 1996 May; 277(2): 1097–102

    PubMed  CAS  Google Scholar 

  65. Makkonen N, Salminen A, Rogers MJ, et al. Contrasting effects of alendronate and clodronate on RAW 264 macrophages: the role of a bisphosphonate metabolite. Eur J Pharm Sci 1999 May; 8(2): 109–18

  66. Monkkonen J, Pennanen N, Lapinjoki S, et al. Clodronate (dichloromethylene bisphosphonate) inhibits LPS-stimulated IL-6 and TNF production by RAW 264 cells. Life Sci 1994; 54(14): PL229–34

    PubMed  CAS  Google Scholar 

  67. Toyras A, Ollikainen J, Taskinen M, et al. Inhibition of mevalonate pathway is involved in alendronate-induced cell growth inhibition, but not in cytokine secretion from macrophages in vitro. Eur J Pharm Sci 2003 Jul; 19(4): 223–30

    PubMed  CAS  Google Scholar 

  68. Coxon FP, Thompson K, Rogers MJ. Recent advances in understanding the mechanism of action of bisphosphonates. Curr Opin Pharmacol 2006 Jun; 6(3): 307–12

    PubMed  CAS  Google Scholar 

  69. Funayama H, Mayanagi H, Takada H, et al. Elevation of histidine decarboxylase activity in the mandible of mice by Prevotella intermedia lipopolysaccharide and its augmentation by an aminobisphosphonate. Arch Oral Biol 2000 Sep; 45(9): 787–95

    PubMed  CAS  Google Scholar 

  70. Sugawara S, Shibazaki M, Takada H, et al. Contrasting effects of an aminobisphosphonate, a potent inhibitor of bone resorption, on lipopolysaccharide-induced production of interleukin-1 and tumour necrosis factor alpha in mice. Br J Pharmacol 1998 Oct; 125(4): 735–40

    PubMed  CAS  Google Scholar 

  71. Yamaguchi K, Motegi K, Iwakura Y, et al. Involvement of interleukin-1 in the inflammatory actions of aminobisphosphonates in mice. Br J Pharmacol 2000 Aug; 130(7): 1646–54

    PubMed  CAS  Google Scholar 

  72. Oelzner P, Kunze A, Henzgen S, et al. High-dose clodronate therapy prevents joint destruction in chronic antigen-induced arthritis of the rat but inhibits bone formation at the axial skeleton. Inflamm Res 2000 Aug; 49(8): 424–33

    PubMed  CAS  Google Scholar 

  73. Osterman T, Kippo K, Lauren L, et al. Effect of clodronate on established collagen-induced arthritis in rats. Inflamm Res 1995 Jun; 44(6): 258–63

    PubMed  CAS  Google Scholar 

  74. Sims NA, Green JR, Glatt M, et al. Targeting osteoclasts with zoledronic acid prevents bone destruction in collagen-induced arthritis. Arthritis Rheum 2004 Jul; 50(7): 2338–46

    PubMed  CAS  Google Scholar 

  75. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007 May 3; 356(18): 1809–22

    PubMed  CAS  Google Scholar 

  76. Heckbert SR, Li G, Cummings SR, et al. Use of alendronate and risk of incident atrial fibrillation in women. Arch Intern Med 2008 Apr 28; 168(8): 826–31

    PubMed  CAS  Google Scholar 

  77. Cummings SR, Schwartz AV, Black DM. Alendronate and atrial fibrillation. N Engl J Med 2007 May 3; 356(18): 1895–6

    PubMed  CAS  Google Scholar 

  78. Sorensen HT, Christensen S, Mehnert F, et al. Use of bisphosphonates among women and risk of atrial fibrillation and flutter: population based case-control study [see comment]. BMJ 2008 Apr 12; 336(7648): 813–6

    PubMed  Google Scholar 

  79. Abrahamsen B, Eiken P, Brixen K. Atrial fibrillation in fracture patients treated with oral bisphosphonates. J Intern Med. Epub 2009 Jan 6

  80. Deng X, Yu Z, Funayama H, et al. Mutual augmentation of the induction of the histamine-forming enzyme, histidine decarboxylase, between alendronate and immunostimulants (IL-1, TNF, and LPS), and its prevention by clodronate. Toxicol Appl Pharmacol 2006 May 15; 213(1): 64–73

    PubMed  CAS  Google Scholar 

  81. Yu Z, Funayama H, Deng X, et al. Comparative appraisal of clodronate, aspirin and dexamethasone as agents reducing alendronate-induced inflammation in a murine model. Basic Clin Pharmacol Toxicol 2005 Oct; 97(4): 222–9

    PubMed  CAS  Google Scholar 

  82. Hewitt RE, Lissina A, Green AE, et al. The bisphosphonate acute phase response: rapid and copious production of proinflammatory cytokines by peripheral blood gd T cells in response to aminobisphosphonates is inhibited by statins. Clin Exp Immunol 2005 Jan; 139(1): 101–11

    PubMed  CAS  Google Scholar 

  83. Liu L, Igarashi K, Kanzaki H, et al. Clodronate inhibits PGE(2) production in compressed periodontal ligament cells. J Dent Res 2006 Aug; 85(8): 757–60

    PubMed  CAS  Google Scholar 

  84. Bonabello A, Galmozzi MR, Bruzzese T, et al. Analgesic effect of bisphosphonates in mice. Pain 2001 Apr; 91(3): 269–75

    PubMed  CAS  Google Scholar 

  85. Bonabello A, Galmozzi MR, Canaparo R, et al. Long-term analgesic effect of clodronate in rodents. Bone 2003 Oct; 33(4): 567–74

    PubMed  CAS  Google Scholar 

  86. Rovetta G, Monteforte P, Molfetta L. Parenteral disodiumclodronate in patients with rheumatoid arthritis: a two-month open clinical study [Italian]. Minerva Med 2001 Dec; 92(6): 417–9

    PubMed  CAS  Google Scholar 

  87. Meunier PJ, Chapuy MC, Alexandre C, et al. Effects of disodium dichloromethylene diphosphonate on Paget’s disease of bone. Lancet 1979 Sep 8; 2(8141): 489–92

    PubMed  CAS  Google Scholar 

  88. Delmas PD, Chapuy MC, Vignon E, et al. Long term effects of dichloromethylene diphosphonate in Paget’s disease of bone. J Clin Endocrinol Metab 1982 Apr; 54(4): 837–44

    PubMed  CAS  Google Scholar 

  89. Muratore M, Calcagnile F, Quarta E. Antalgic efficacy of the bisphosphonates in vertebral fractures of recent onset [abstract]. Osteoporos Int 2004; 15Suppl. 1: S121

    Google Scholar 

  90. Muratore M, Canaparo R, Della Pepa C, et al. Bisphosphonates antalgic activity in recent vertebral fracture: a clodronate vs neridronate comparison [abstract]. Osteoporos Int 2004; 15Suppl. 1: S1 19

    Google Scholar 

  91. Rovetta G, Maggiani G, Molfetta L, et al. One-month follow-up of patients treated by intravenous clodronate for acute pain induced by osteoporotic vertebral fracture. Drugs Exp Clin Res 2001; 27(2): 77–81

    PubMed  CAS  Google Scholar 

  92. Rovetta G, Monteforte P, Balestra V. Intravenous clodronate for acute pain induced by osteoporotic vertebral fracture. Drugs Exp Clin Res 2000; 26(1): 25–30

    PubMed  CAS  Google Scholar 

  93. Ernst DS, Brasher P, Hagen N, et al. A randomized, controlled trial of intravenous clodronate in patients with metastatic bone disease and pain. J Pain Symptom Manage 1997 Jun; 13(6): 319–26

    PubMed  CAS  Google Scholar 

  94. Ernst DS, MacDonald RN, Paterson AH, et al. A doubleblind, crossover trial of intravenous clodronate in metastatic bone pain. J Pain Symptom Manage 1992 Jan; 7(1): 4–11

    PubMed  CAS  Google Scholar 

  95. Heidenreich A, Hoffman R, Engelmann UH. The use of bisphosphonate for the palliative treatment of painful bone metastasis due to hormone refractory prostate cancer. J Urol 1985; 134(6): 1152–4

    Google Scholar 

  96. Merlini G, Parrinello GA, Piccinini L, et al. Long-term effects of parenteral dichloromethylene bisphosphonate (CL2MBP) on bone disease of myeloma patients treated with chemotherapy. Hematol Oncol 1990 Jan–Feb; 8(1): 23–30

    PubMed  CAS  Google Scholar 

  97. Santangelo A, Testai M, Barbagallo P, et al. The use of bisphosphonates in palliative treatment of bone metastases in a terminally ill, oncological elderly population. Arch Gerontol Geriatr 2006 Sep–Oct; 43(2): 187–92

    PubMed  CAS  Google Scholar 

  98. Siden H. The boy who refused an IV: a case report of subcutaneous clodronate for bone pain in a child with Ewing sarcoma. J Med Case Reports 2007; 1: 7

    Google Scholar 

  99. Tubiana-Hulin M, Beuzeboc P, Mauriac L, et al. Doubleblinded controlled study comparing clodronate versus placebo in patients with breast cancer bone metastases. Bull Cancer 2001 Jul; 88(7): 701–7

    PubMed  CAS  Google Scholar 

  100. Jones DG, Savage R, Highton J. Synovitis induced by alendronic acid can present as acute carpal tunnel syndrome [letter]. BMJ 2005 Jan 8; 330(7482): 74

    PubMed  Google Scholar 

  101. Young-Min SA, Herbert L, Dick M, et al. Weekly alendronate-induced acute pseudogout. Rheumatology (Oxford) 2005 Jan; 44(1): 131–2

    CAS  Google Scholar 

  102. Wysowski DK, Chang JT. Alendronate and risedronate: reports of severe bone, joint, and muscle pain. Arch Intern Med 2005 Feb 14; 165(3): 346–7

    PubMed  Google Scholar 

  103. Haworth CS, Selby PL, Webb AK, et al. Severe bone pain after intravenous pamidronate in adult patients with cystic fibrosis. Lancet 1998 Nov 28; 352(9142): 1753–4

    PubMed  CAS  Google Scholar 

  104. Haworth CS, Selby PL, Webb AK, et al. Oral corticosteroids and bone pain after pamidronate in adults with cystic fibrosis [letter]. Lancet 1999 May 29; 353(9167): 1886

    PubMed  CAS  Google Scholar 

  105. Teramoto S, Matsuse T, Ouchi Y. Increased cytokines and pamidronate-induced bone pain in adults with cystic fibrosis [letter]. Lancet 1999 Feb 27; 353(9154): 750

    PubMed  CAS  Google Scholar 

  106. Bonefos. Summary of product characteristics. Revised 2003 Apr 11

  107. Roemer-Becuwe C, Vigano A, Romano F, et al. Safety of subcutaneous clodronate and efficacy in hypercalcemia of malignancy: a novel route of administration. J Pain Symptom Manage 2003 Sep; 26(3): 843–8

    PubMed  CAS  Google Scholar 

  108. Walker P, Watanabe S, Lawlor P, et al. Subcutaneous clodronate. Lancet 1996 Aug 3; 348(9023): 345–6

    PubMed  CAS  Google Scholar 

  109. Walker P, Watanabe S, Lawlor P, et al. Subcutaneous clodronate: a study evaluating efficacy in hypercalcemia of malignancy and local toxicity. Ann Oncol 1997 Sep; 8(9): 915–6

    PubMed  CAS  Google Scholar 

  110. Barrera P, Blom A, van Lent PL, et al. Synovial macrophage depletion with clodronate-containing liposomes in rheumatoid arthritis. Arthritis Rheum 2000 Sep; 43(9): 1951–9

    PubMed  CAS  Google Scholar 

  111. Cocco R, Tofi C, Fioravanti A, et al. Effects of clodronate on synovial fluid levels of some inflammatory mediators, after intra-articular administration to patients with synovitis secondary to knee osteoarthritis. Boll Soc Ital Biol Sper 1999 Nov–Dec; 75(11-12): 71–6

    PubMed  CAS  Google Scholar 

  112. Pentikainen PJ, Elomaa I, Nurmi AK, et al. Pharmacokinetics of clodronate in patients with metastatic breast cancer. Int J Clin Pharmacol Ther Toxicol 1989 May; 27(5): 222–8

    PubMed  CAS  Google Scholar 

  113. Conrad KA, Lee SM. Clodronate kinetics and dynamics. Clin Pharmacol Ther 1981 Jul; 30(1): 114–20

    PubMed  CAS  Google Scholar 

  114. Hanhijarvi H, Elomaa I, Karlsson M, et al. Pharmacokinetics of disodium clodronate after daily intravenous infusions during five consecutive days. Int J Clin Pharmacol Ther Toxicol 1989 Dec; 27(12): 602–6

    PubMed  CAS  Google Scholar 

  115. Yakatan GJ, Poynor WJ, Talbert RL, et al. Clodronate kinetics and bioavailability. Clin Pharmacol Ther 1982 Mar; 31(3): 402–10

    PubMed  CAS  Google Scholar 

  116. Castren-Kortekangas P, Loyttyniemi E, Liukko-Sipi S, et al. Pooling of clodronate urinary excretion data: a new pharmacokinetic method to study drugs with highly variable gastrointestinal absorption. J Bone Miner Res 1997 Jan; 12(1): 66–71

    PubMed  CAS  Google Scholar 

  117. Saha H, Castren-Kortekangas P, Ojanen S, et al. Pharmacokinetics of clodronate in renal failure. J Bone Miner Res 1994 Dec; 9(12): 1953–8

    PubMed  CAS  Google Scholar 

  118. Ylitalo P, Holli K, Monkkonen J, et al. Comparison of pharmacokinetics of clodronate after single and repeated doses. Int J Clin Pharmacol Ther 1999 Jun; 37(6): 294–300

    PubMed  CAS  Google Scholar 

  119. Muntoni E, Canaparo R, Della Pepa C, et al. Determination of disodium clodronate in human plasma and urine using gas-chromatography-nitrogen-phosphorus detections: validation and application in pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci 2004 Jan 5; 799(1): 133–9

    PubMed  CAS  Google Scholar 

  120. Filipponi P, Cristallini S, Rizzello E, et al. Cyclical intravenous clodronate in postmenopausal osteoporosis: results of a long-term clinical trial. Bone 1996 Feb; 18(2): 179–84

    PubMed  CAS  Google Scholar 

  121. McCloskey E, Selby P, Davies M, et al. Clodronate reduces vertebral fracture risk in women with postmenopausal or secondary osteoporosis: results of a double-blind, placebocontrolled 3-year study. J Bone Miner Res 2004 May; 19(5): 728–36

    PubMed  CAS  Google Scholar 

  122. McCloskey EV, Beneton M, Charlesworth D, et al. Clodronate reduces the incidence of fractures in communitydwelling elderly women unselected for osteoporosis: results of a double-blind, placebo-controlled randomized study. J Bone Miner Res 2007 Jan; 22(1): 135–41

    PubMed  CAS  Google Scholar 

  123. Tanakol R, Yarman S, Bayraktaroglu T, et al. Clodronic acid in the treatment of postmenopausal osteoporosis. Clin Drug Invest 2007; 27(6): 419–33

    CAS  Google Scholar 

  124. D’Amelio P, Muratore M, Tinelli F, et al. Effect of raloxifene and clodronate on bone density in postmenopausal osteoporotic women. Int J Tissue React 2003; 25(2): 73–8

    PubMed  Google Scholar 

  125. Muscoso E, Puglisi N, Mamazza C, et al. Antiresorption therapy and reduction in fracture susceptibility in the osteoporotic elderly patient: open study. Eur Rev Med Pharmacol Sci 2004 Mar–Apr; 8(2): 97–102

    PubMed  CAS  Google Scholar 

  126. Reid IR, Brown JP, Burckhardt P, et al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 2002 Feb 28; 346(9): 653–61

    PubMed  CAS  Google Scholar 

  127. del Puente A, Scognamiglio A, Itto E, et al. Intramuscular clodronate in nonresponders to oral alendronate therapy for osteoporosis. J Rheumatol 2000 Aug; 27(8): 1980–3

    PubMed  Google Scholar 

  128. Abitbol V, Briot K, Roux C, et al. A double-blind placebocontrolled study of intravenous clodronate for prevention of steroid-induced bone loss in inflammatory bowel disease. Clin Gastroenterol Hepatol 2007 Oct; 5(10): 1184–9

    PubMed  Google Scholar 

  129. Herrala J, Puolijoki H, Liippo K, et al. Clodronate is effective in preventing corticosteroid-induced bone loss among asthmatic patients. Bone 1998 May; 22(5): 577–82

    PubMed  CAS  Google Scholar 

  130. Kristensen B, Ejlertsen B, Groenvold M, et al. Oral clodronate in breast cancer patients with bone metastases: a randomized study. J Intern Med 1999 Jul; 246(1): 67–74

    PubMed  CAS  Google Scholar 

  131. McCloskey EV, MacLennan IC, Drayson MT, et al. A randomized trial of the effect of clodronate on skeletal morbidity in multiple myeloma. MRC Working Party on Leukaemia in Adults. Br J Haematol 1998 Feb; 100(2): 317–25

    PubMed  CAS  Google Scholar 

  132. Paterson AH, Powles TJ, Kanis JA, et al. Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 1993 Jan; 11(1): 59–65

    PubMed  CAS  Google Scholar 

  133. Nguyen ND, Eisman JA, Nguyen TV. Anti-hip fracture efficacy of bisphosphonates: a Bayesian analysis of clinical trials. J Bone Miner Res 2006 Feb; 21(2): 340–9

    PubMed  CAS  Google Scholar 

  134. Epstein S. The roles of bone mineral density, bone turnover, and other properties in reducing fracture risk during antiresorptive therapy. Mayo Clin Proc 2005 Mar; 80(3): 379–88

    PubMed  Google Scholar 

  135. Sarkar S, Mitlak BH, Wong M, et al. Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy. J Bone Miner Res 2002 Jan; 17(1): 1–10

    PubMed  CAS  Google Scholar 

  136. Watts NB, Cooper C, Lindsay R, et al. Relationship between changes in bone mineral density and vertebral fracture risk associated with risedronate: greater increases in bone mineral density do not relate to greater decreases in fracture risk. J Clin Densitom 2004; 7(3): 255–61

    PubMed  Google Scholar 

  137. Watts NB, Geusens P, Barton IP, et al. Relationship between changes in BMD and nonvertebral fracture incidence associated with risedronate: reduction in risk of nonvertebral fracture is not related to change in BMD. J Bone Miner Res 2005 Dec; 20(12): 2097–104

    PubMed  Google Scholar 

  138. Delmas PD, Seeman E. Changes in bone mineral density explain little of the reduction in vertebral or nonvertebral fracture risk with anti-resorptive therapy. Bone 2004 Apr; 34(4): 599–604

    PubMed  CAS  Google Scholar 

  139. Genant HK, Delmas PD, Chen P, et al. Severity of vertebral fracture reflects deterioration of bone microarchitecture. Osteoporos Int 2007 Jan; 18(1): 69–76

    PubMed  CAS  Google Scholar 

  140. Anastasilakis AD, Goulis DG, Kita M, et al. Oral bisphosphonate adverse effects in 849 patients with metabolic bone diseases. Hormones (Athens) 2007 Jul–Sep; 6(3): 233–41

    Google Scholar 

  141. Ettinger B, Pressman A, Schein J. Clinic visits and hospital admissions for care of acid-related upper gastrointestinal disorders in women using alendronate for osteoporosis. Am J Manag Care 1998 Oct; 4(10): 1377–82

    PubMed  CAS  Google Scholar 

  142. Suri S, Monkkonen J, Taskinen M, et al. Nitrogencontaining bisphosphonates induce apoptosis of Caco-2 cells in vitro by inhibiting the mevalonate pathway: a model of bisphosphonate-induced gastrointestinal toxicity. Bone 2001 Oct; 29(4): 336–43

    PubMed  CAS  Google Scholar 

  143. de Groen PC, Lubbe DF, Hirsch LJ, et al. Esophagitis associated with the use of alendronate. N Engl J Med 1996 Oct 3; 335(14): 1016–21

    PubMed  Google Scholar 

  144. Kikendall JW. Pill esophagitis. J Clin Gastroenterol 1999 Jun; 28(4): 298–305

    PubMed  CAS  Google Scholar 

  145. Lanza F, Schwartz H, Sahba B, et al. An endoscopic comparison of the effects of alendronate and risedronate on upper gastrointestinal mucosae. Am J Gastroenterol 2000 Nov; 95(11): 3112–7

    PubMed  CAS  Google Scholar 

  146. Graham DY, Malaty HM. Alendronate gastric ulcers. Aliment Pharmacol Ther 1999 Apr; 13(4): 515–9

    PubMed  CAS  Google Scholar 

  147. Graham DY, Malaty HM. Alendronate and naproxen are synergistic for development of gastric ulcers. Arch Intern Med 2001 Jan 8; 161(1): 107–10

    PubMed  CAS  Google Scholar 

  148. Aihara E, Hayashi S, Amagase K, et al. Prophylactic effect of rebamipide against the irritative and healing impairment actions of alendronate in rat stomachs. Inflammopharmacology 2007 Oct; 15(5): 196–202

    PubMed  CAS  Google Scholar 

  149. Iseri SO, Sener G, Yuksel M, et al. Ghrelin against alendronate-induced gastric damage in rats. J Endocrinol 2005 Dec; 187(3): 399–406

    PubMed  CAS  Google Scholar 

  150. Sener G, Goren FO, Ulusoy NB, et al. Protective effect of melatonin and omeprazole against alendronate-induced gastric damage. Dig Dis Sci 2005 Aug; 50(8): 1506–12

    PubMed  CAS  Google Scholar 

  151. Sener G, Kapucu C, Cetinel S, et al. Gastroprotective effect of leukotriene receptor blocker montelukast in alendronate-induced lesions of the rat gastric mucosa. Prostaglandins Leukot Essent Fatty Acids 2005 Jan; 72(1): 1–11

    PubMed  CAS  Google Scholar 

  152. Sener G, Paskaloglu K, Kapucu C, et al. Octreotide ameliorates alendronate-induced gastric injury. Peptides 2004 Jan; 25(1): 115–21

    PubMed  CAS  Google Scholar 

  153. Sener G, Sehirli O, Cetinel S, et al. Protective effect of taurine against alendronate-induced gastric damage in rats. Fundam Clin Pharmacol 2005 Feb; 19(1): 93–100

    PubMed  CAS  Google Scholar 

  154. Bounameaux HM, Schifferli J, Montani JP, et al. Renal failure associated with intravenous diphosphonates [letter]. Lancet 1983 Feb 26; 1(8322): 471

    PubMed  CAS  Google Scholar 

  155. Chang JT, Green L, Beitz J. Renal failure with the use of zoledronic acid. N Engl J Med 2003 Oct 23; 349(17): 1676–9

    PubMed  CAS  Google Scholar 

  156. Tanvetyanon T, Stiff PJ. Management of the adverse effects associated with intravenous bisphosphonates. Ann Oncol 2006 Jun; 17(6): 897–907

    PubMed  CAS  Google Scholar 

  157. Pecherstorfer M, Jilch R, Sauty A, et al. Effect of first treatment with aminobisphosphonates pamidronate and ibandronate on circulating lymphocyte subpopulations. J Bone Miner Res 2000 Jan; 15(1): 147–54

    PubMed  CAS  Google Scholar 

  158. Pecherstorfer M, Steinhauer EU, Rizzoli R, et al. Efficacy and safety of ibandronate in the treatment of hypercalcemia of malignancy: a randomized multicentric comparison to pamidronate. Support Care Cancer 2003 Aug; 11(8): 539–47

    PubMed  CAS  Google Scholar 

  159. Bock O, Boerst H, Thomasius FE, et al. Common musculoskeletal adverse effects of oral treatment with once weekly alendronate and risedronate in patients with osteoporosis and ways for their prevention. J Musculoskelet Neuronal Interact 2007 Apr–Jun; 7(2): 144–8

    PubMed  CAS  Google Scholar 

  160. Federal Drug Administration Alert. Information on bisphosphonates: released January 7, 2008 [online]. Available from URL: http://www.fda.gov/cder/drug/infopage/bisphosphonates/default.htm [Accessed 2008 Feb 25]

  161. Allen MR, Burr DB. Mandible matrix necrosis in beagle dogs after 3 years of daily oral bisphosphonate treatment. J Oral Maxillofac Surg 2008 May; 66(5): 987–94

    PubMed  Google Scholar 

  162. Adamson BB, Gallacher SJ, Byars J, et al. Mineralisation defects with pamidronate therapy for Paget’s disease. Lancet 1993 Dec 11; 342(8885): 1459–60

    PubMed  CAS  Google Scholar 

  163. Armamento-Villareal R, Napoli N, Panwar V, et al. Suppressed bone turnover during alendronate therapy for high-turnover osteoporosis. N Engl J Med 2006 Nov 9; 355(19): 2048–50

    PubMed  CAS  Google Scholar 

  164. Boyce BF, Smith L, Fogelman I, et al. Focal osteomalacia due to low-dose diphosphonate therapy in Paget’s disease. Lancet 1984 Apr 14; 1(8381): 821–4

    PubMed  CAS  Google Scholar 

  165. Goh SK, Yang KY, Koh JS, et al. Subtrochanteric insufficiency fractures in patients on alendronate therapy: a caution. J Bone Joint Surg Br 2007 Mar; 89(3): 349–53

    PubMed  Google Scholar 

  166. Imai K, Yamamoto S, Anamizu Y, et al. Pelvic insufficiency fracture associated with severe suppression of bone turnover by alendronate therapy. J Bone Miner Metab 2007; 25(5): 333–6

    PubMed  Google Scholar 

  167. Karsdal MA, Qvist P, Christiansen C, et al. Optimising antiresorptive therapies in postmenopausal women: why do we need to give due consideration to the degree of suppression? Drugs 2006; 66(15): 1909–18

    PubMed  Google Scholar 

  168. Kwek EB, Goh SK, Koh JS, et al. An emerging pattern of subtrochanteric stress fractures: a long-term complication of alendronate therapy? Injury 2008 Feb; 39(2): 224–31

    PubMed  Google Scholar 

  169. Lee P, van der Wall H, Seibel MJ. Looking beyond low bone mineral density: multiple insufficiency fractures in a woman with post-menopausal osteoporosis on alendronate therapy. J Endocrinol Invest 2007 Jul–Aug; 30(7): 590–7

    PubMed  CAS  Google Scholar 

  170. Lugassy G, Shaham R, Nemets A, et al. Severe osteomyelitis of the jaw in long-term survivors of multiple myeloma: a new clinical entity. Am J Med 2004 Sep 15; 117(6): 440–1

    PubMed  Google Scholar 

  171. Odvina CV, Zerwekh JE, Rao DS, et al. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 2005 Mar; 90(3): 1294–301

    PubMed  CAS  Google Scholar 

  172. Senel FC, Saracoglu Tekin U, Durmus A, et al. Severe osteomyelitis of the mandible associated with the use of non-nitrogen-containing bisphosphonate (disodium clodronate): report of a case. J Oral Maxillofac Surg 2007 Mar; 65(3): 562–5

    PubMed  Google Scholar 

  173. Anonymous. Diphosphonates: ocular risks. Prescrire Int 2005 Oct; 14 (79): 179

  174. Mian M, Beghe F, Caprio A, et al. Tolerability and safety of clodronate therapy in bone diseases. Int J Clin Pharmacol Res 1991; 11(2): 107–14

    PubMed  CAS  Google Scholar 

  175. Borgstrom GH, Elomaa I, Blomqvist C, et al. Cytogenetic investigations of patients on clodronate therapy for Paget’s disease of bone. Bone 1987; 8Suppl. 1: S85–6

    PubMed  Google Scholar 

  176. Poli G, Mariotti F, Corrado ME, et al. A tolerability and pharmacokinetic study of a new injectable formulation of disodium clodronate in healthy female volunteers. Eur J Drug Metab Pharmacokinet 2004 Apr–Jun; 29(2): 145–52

    PubMed  CAS  Google Scholar 

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Acknowledgements

The preparation of the manuscript was financially supported by Chiesi Farmaceutici SpA. Dr Frediani has no conflicts of interest that are directly relevant to the content of this review. Dr Cavalieri is an employee of Promedica Srl and Chiesi Farmaceutici SpA. Dr Cremonesi is an employee of Chiesi Farmaceutici SpA. Medical writing services were provided by Wolters Kluwer Health.

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  1. Istituto di Reumatologia, Universita’ di Siena, Siena, Italy

    Bruno Frediani

  2. Promedica Srl, Parma, Italy

    Luca Cavalieri

  3. Medical Department, Chiesi Farmaceutici SpA, Parma, Italy

    Luca Cavalieri & Giovanni Cremonesi

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  1. Bruno Frediani
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Correspondence to Bruno Frediani.

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Frediani, B., Cavalieri, L. & Cremonesi, G. Clodronic Acid Formulations Available in Europe and their Use in Osteoporosis. Clin. Drug Investig. 29, 359–379 (2009). https://doi.org/10.2165/00044011-200929060-00001

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