Clinical Drug Investigation

, Volume 26, Issue 4, pp 215–222

Effect of Etidronic Acid on Arterial Calcification in Dialysis Patients

  • Tsuneo Ariyoshi
  • Kiyoyuki Eishi
  • Ichiro Sakamoto
  • Seiji Matsukuma
  • Tomohiro Odate
Original Research Article


Background: Bisphosphonate drugs, including etidronic acid, are effective agents for the treatment of osteoporosis and may reduce arterial calcification. The aim of this randomised control trial was to characterise the effect of etidronic acid on arterial calcification in patients undergoing chronic haemodialysis.

Methods: Patients undergoing chronic haemodialysis were assigned to one of two groups by a simple randomisation method: an etidronic acid group (n = 8; 400 mg/day for 24 weeks) and a control group (n = 6; no etidronic acid therapy). Serum calcium, phosphate, calcium-phosphate product, alkaline phosphatase, lactate dehydrogenase, activated colecalciferol and parathyroid hormone levels were measured at baseline and then at 4-weekly intervals thereafter.

Results: Calcification scores of the coronary arteries and the thoracic and abdominal aorta were determined by volume-correcting data collected by a multidetector-row computerised tomographic scanner at baseline, at 6 months and at 1 year. Two patients in the etidronic acid group were excluded from the final analysis because of medical complications. The remainder of the patients (n = 6) showed no significant temporal changes in serum levels of assessed parameters. While no significant temporal changes in coronary calcification score were observed in either group, the mean aortic calcification score significantly decreased over time from 1000 ± 460mm3 at baseline to 970 ± 580mm3 at the completion of treatment and 350 ± 180mm3 at 1 year (p = 0.009), corresponding to a mean percentage decrease of −64.1% (range −86.5% to −50.1%). By contrast, in the control group, the mean aortic calcification score significantly increased with time from 1460 ± 1280mm3 to 1510 ± 1150mm3 at the completion of treatment and 2070 ± 1200mm3 at 1 year (p = 0.006), corresponding to a mean percentage change in the calcification score of +130.0% (range 2.1–414%).

Conclusion: Etidronic acid markedly reduced aortic calcification in patients with end-stage renal disease undergoing chronic haemodialysis. The effect of this agent on aortic calcification may attenuate the increase in aortic stiffness and result in improved long-term outcomes in patients undergoing chronic haemodialysis.


  1. 1.
    Blacher J, Guerin AP, Pannier B, et al. Impact of aortic stiffness on survival in end-stage renal disease. Circulation 1999; 99: 2434–9PubMedCrossRefGoogle Scholar
  2. 2.
    Wayhs R, Zelinger A, Raggi P. High coronary artery calcium scores pose an extremely elevated risk for hard events. J Am Coll Cardiol 2002; 39: 225–30PubMedCrossRefGoogle Scholar
  3. 3.
    Lindner A, Charra B, Sherrard DJ, et al. Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 1974 Mar 28; 290: 697–701PubMedCrossRefGoogle Scholar
  4. 4.
    Guerin AP, London GM, Marchais SJ, et al. Arterial stiffening and vascular calcifications in end-stage renal disease. Nephrol Dial Transplant 2000; 15: 1014–21PubMedCrossRefGoogle Scholar
  5. 5.
    Fleisch H. Bisphosphonates: mechanisms of action. Endocr Rev 1998; 19: 80–100PubMedCrossRefGoogle Scholar
  6. 6.
    Hollander W, Paddock J, Nagraj S, et al. Effects of anticalcifying and antifibrotic drugs on pre-established atherosclerosis in the rabbit. Atherosclerosis 1979; 33: 111–23PubMedCrossRefGoogle Scholar
  7. 7.
    Rosenblum IY, Flora L, Eisenstein R. The effect of disodium ethane-1-hydroxy-1, 1-diphosphonate (EHDF) on a rabbit model of athero-arteriosclerosis. Atherosclerosis 1975; 22: 411–24PubMedCrossRefGoogle Scholar
  8. 8.
    Daoud AS, Frank AS, Jarmolych J, et al. The effect of ethane-1-hydroxy-1,1-disphosphate (EHDP) on necrosis of atherosclerotic lesions. Atherosclerosis 1987; 67: 41–8PubMedCrossRefGoogle Scholar
  9. 9.
    Ropers D, Baum U, Pohle K, et al. Detection of coronary artery stenoses with thin-slice multi-detector row spiral computed tomography and multiplanar reconstruction. Circulation 2003; 17: 664–7CrossRefGoogle Scholar
  10. 10.
    Kaufmann RB, Sheedy PF, Breen JF, et al. Detection of heart calcification with electron beam CT: interobserver and intraobserver reliability for scoring quantitation. Radiology 1994; 190: 347–52PubMedGoogle Scholar
  11. 11.
    Agatston AS, Janowitz WR, Hildner FJ, et al. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990; 15: 827–32PubMedCrossRefGoogle Scholar
  12. 12.
    Tomson C. Vascular calcification in chronic renal failure. Nephron Clin Pract 2003; 93: 124–30CrossRefGoogle Scholar
  13. 13.
    Pannier B, Guerin AP, Marchais SJ, et al. Stiffness of capacitive and conduit arteries: prognostic significance for end-stage renal disease patients. Hypertension 2005 Apr; 45(4): 592–6PubMedCrossRefGoogle Scholar
  14. 14.
    Green JR, Müller K, Jaeggi KA. Preclinical pharmacology of CGP 42’446, a new, potent, heterocyclic bisphosphonate compound. J Bone Miner Res 1994; 9: 745–51PubMedCrossRefGoogle Scholar
  15. 15.
    Goldsmith DJ, Covic A, Sambrook PA, et al. Vascular calcification in long-term haemodialysis patients in a single unit: a retrospective analysis. Nephron 1997; 77(1): 37–43PubMedCrossRefGoogle Scholar
  16. 16.
    Lantto T, Jarvi K, Toivio I, et al. The visualization of femoral vessels in delayed bone scans — a sign of atherosclerosis? A comparison of 99m-Tc-MDP and 99mTc-DPD. Eur J Nucl Med 1989; 15: 265–8PubMedCrossRefGoogle Scholar
  17. 17.
    Ylitalo R, Monkkonen J, Urtti, et al. Accumulation of bisphosphonates in the aorta and some other tissues of healthy and atherosclerotic rabbits. J Lab Clin Med 1996; 127: 200–6PubMedCrossRefGoogle Scholar
  18. 18.
    Fleisch H, Russell RG, Bisaz S, et al. The inhibitory effect of phosphonates on the formation of calcium phosphate crystals in vitro and on aortic and kidney calcification in vivo. Eur J Clin Invest 1970; 1: 12–8PubMedCrossRefGoogle Scholar
  19. 19.
    Ylitalo R. Bisphosphonates and atherosclerosis. Gen Pharmacol 2000; 35: 287–96PubMedCrossRefGoogle Scholar
  20. 20.
    Ylitalo R, Kalliovalkama J, Wu X, et al. Accumulation of bisphosphonates in human artery and their effects on human and rat arterial function in vitro. Pharmacol Toxicol 1998; 83: 125–31PubMedCrossRefGoogle Scholar
  21. 21.
    Schwarz U, Buzello M, Ritz E, et al. Morphology of coronary atherosclerotic lesions in patients with end-stage renal failure. Nephrol Dial Transplant 2000; 15: 218–23PubMedCrossRefGoogle Scholar
  22. 22.
    Farzaneh-Far A. Morphology of coronary atherosclerotic lesions in patients with end-stage renal failure. Nephrol Dial Transplant 2000; 15: 1710PubMedCrossRefGoogle Scholar
  23. 23.
    Nitta K, Akiba T, Suzuki K, et al. Effects of cyclic intermittent etidronate therapy on coronary artery calcification in patients receiving long-term hemodialysis. Am J Kidney Dis 2004 Oct; 44: 680–8PubMedGoogle Scholar
  24. 24.
    London GM, Guerin AP, Marchais SJ, et al. Cardiac and arterial interactions in end-stage renal disease. Kidney Int 1996 Aug; 50(2): 600–8PubMedCrossRefGoogle Scholar
  25. 25.
    Silberberg JS, Barre PE, Prichard SS, et al. Impact of left ventricular hypertrophy on survival in end-stage renal disease. Kidney Int 1989 Aug; 36(2): 286–90PubMedCrossRefGoogle Scholar
  26. 26.
    Parfrey PS, Foley RN, Harnett JD, et al. Outcome and risk factors of ischemic heart disease in chronic uremia. Kidney Int 1996 May; 49(5): 1428–34PubMedCrossRefGoogle Scholar
  27. 27.
    Iseki K, Miyasato F, Tokuyama K, et al. Low diastolic blood pressure, hypoalbuminemia, and risk of death in a cohort of chronic hemodialysis patients. Kidney Int 1997 Apr; 51: 1212–7PubMedCrossRefGoogle Scholar
  28. 28.
    Jowsey J, Riggs BL, Kelly PJ, et al. The treatment of osteoporosis with disodium ethane-1-hydroxy-1,1-diphosphonate. J Lab Clin Med 1971; 78: 574–84PubMedGoogle Scholar
  29. 29.
    Fujita T, Orimo H, Inoue T, et al. Double-blind Multicenter Comparative Study with Alfacalcidol of Etidronate Disodium (EHDP) in involutional osteoporosis. Clin Eval 1993; 21: 261–302Google Scholar
  30. 30.
    Koshiyama H, Nakamura Y, Tanaka S, et al. Decrease in carotid intima-media thickness after 1-year therapy with Etidronate for Osteopenia Associated with type 2 diabetes. J Clin Endocrinol Metab 2000; 85: 2793–6PubMedCrossRefGoogle Scholar
  31. 31.
    Levy RJ, Schoen FJ, Lund SA, et al. Prevention of leaflet calcification of bioprosthetic heart valves with diphosphonate injection therapy. J Throrac Cardiovasc Surg 1987; 94: 551–7Google Scholar
  32. 32.
    Tanko LB, Qin G, Alexandersen P, et al. Effective doses of ibandronate do not influence the 3-year progression of aortic calcification in elderly osteoporotic women. Osteoporos Int 2005 Feb; 16(2): 184–90PubMedCrossRefGoogle Scholar
  33. 33.
    Price PA, Faus SA, Williamson MK. Bisphosphonates alendronate and ibandronate inhibit artery calcification at doses comparable to those that inhibit bone resorption. Arterioscler Thromb Vasc Biol 2001 May; 21(5): 817–24PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  • Tsuneo Ariyoshi
    • 1
  • Kiyoyuki Eishi
    • 1
  • Ichiro Sakamoto
    • 2
  • Seiji Matsukuma
    • 1
  • Tomohiro Odate
    • 1
  1. 1.Department of Cardiovascular SurgeryNagasaki University School of MedicineNagasakiJapan
  2. 2.Department of RadiologyNagasaki University School of MedicineNagasakiJapan

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