Effects of heparin and low-molecular-weight heparins on bone mechanical properties in rats

Summary

Long-term administration of heparin can be associated with development of osteoporosis. The present study was carried out to compare the effects of standard heparin and two low-molecular-weight heparins (nadroparin and enoxaparin) on bone mechanical properties in rats. The experiment was conducted on 3-month-old female Wistar rats. Standard heparin was administered in doses of 1000 or 2000 IU/kg sc daily, nadroparin and enoxaparin were administered in doses of 1000 or 2000 anti-Xa IU/kg sc daily, for 28 days. Bone mass, length, diameter, mineral content and mechanical properties of the whole femur (extrinsic stiffness, ultimate and breaking load, deformation caused by the applied load) and the femoral neck (load at fracture) were examined. Standard heparin (2000 IU/kg sc daily) weakened the femoral neck. Enoxaparin and the higher doses of standard heparin and nadroparin induced similar unfavourable changes in mechanical properties of the whole femur; the changes were noticeable the most after administration of enoxaparin.

Keywords

Heparin - nadroparin - enoxaparin - bones - rats

• References

• 1 Ginsberg JS, Kowalchuk G, Hirsh J. et al. Heparin effect on bone density. Thromb Haemost 1990; 64: 286-9.
• 2 Dahlman TC, Sjöberg HE, Ringertz H. Bone mineral density during long-term prophylaxis with heparin in pregnancy. Am J Obstet Gynecol 1994; 170: 1315-20.
• 3 Barbour LA, Kick SD, Steiner JF. et al. A prospective study of heparin-induced osteoporosis in pregnancy using bone densitometry. Am J Obstet Gynecol 1994; 170: 862-9.
• 4 Douketis JD, Ginsberg JS, Burrows RF. et al. The effects of long-term heparin therapy during pregnancy on bone density. A prospective matched cohort study. Thromb Haemost 1996; 75: 254-7.
• 5 Mätzsch T, Bergqvist D, Hedner U. et al. Effects of low molecular weight heparin and unfragmented heparin on induction of osteoporosis in rats. Thromb Haemost 1990; 63: 505-9.
• 6 Muir JM, Andrew M, Hirsh J. et al. Histomorphometric analysis of the effects of standard heparin on trabecular bone in vivo. Blood 1996; 88: 1314-20.
• 7 Muir JM, Hirsh J, Weitz JI. et al. A histomorphometric comparison of the effects of heparin and low-molecular-weight heparin on cancellous bone in rats. Blood 1997; 89: 3236-42.
• 8 Murray WJ, Lindo VS, Kakkar VV. et al. Long-term administration of heparin and heparin fractions and osteoporosis in experimental animals. Blood Coagul Fibrinolysis 1995; 06: 113-8.
• 9 Mutoh S, Takeshita N, Yoshino T. et al. Characterization of heparin-induced osteopenia in rats. Endocrinology 1993; 133: 2743-8.
• 10 Monreal M, Viñas L, Monreal L. et al. Heparin-related osteoporosis in rats. A comparative study between unfractioned heparin and a low-molecular-weight heparin. Haemostasis 1990; 20: 204-7.
• 11 Martineau P, Tawil N. Low-molecular-weight heparins in the treatment of deep-vein thrombosis. Ann Pharmacother 1998; 32: 588-98 601..
• 12 Hirsh J, Warkentin TE, Shaughnessy SG. et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 2001; 119 (01) 64S-94S.
• 13 Laurent P, Dussarat GV, Bonal J. et al. Low molecular weight heparins: a guide to their optimum use in pregnancy. Drugs 2002; 62: 463-77.
• 14 Backos M, Rai R, Thomas E. et al. Bone density changes in pregnant women treated with heparin: a prospective, longitudinal study. Hum Reprod 1999; 14: 2876-80.
• 15 Shefras J, Farquharson RG. Bone density studies in pregnant women receiving heparin. Eur J Obstet Gynecol Reprod Biol 1996; 65: 171-4.
• 16 Casele HL, Laifer SA. Prospective evaluation of bone density in pregnant women receiving the low molecular weight heparin enoxaparin sodium. J Matern Fetal Med 2000; 09: 122-5.
• 17 Monreal M, Lafoz E, Olive A. et al. Comparison of subcutaneous unfractionated heparin with a low molecular weight heparin (Fragmin) in patients with venous thromboembolism and contraindications to coumarin. Thromb Haemost 1994; 71: 7-11.
• 18 Nelson-Piercy C, Letsky EA, de Swiet M. Low-molecular-weight heparin for obstetric thromboprophylaxis: experience of sixty-nine pregnancies in sixty-one women at high risk. Am J Obstet Gynecol 1997; 176: 1062-8.
• 19 Pettila V, Leinonen P, Markkola A. et al. Postpartum bone mineral density in women treated for thromboprophylaxis with unfractioned heparin or LMW heparin. Thromb Haemost 2002; 87: 182-6.
• 20 Wawrzyńska L, Tomkowski WZ, Przedlacki J. et al. Changes in bone density during longterm administration of low-molecular-weight heparins or acenocoumarol for secondary prophylaxis of venous thromboembolism. Pathophysiol Haemost Thromb 2003; 33: 64-7.
• 21 Shaughnessy SG, Young E, Deschamps P. et al. The effects of low molecular weight and standard heparin on calcium loss from fetal rat calvaria. Blood 1995; 86: 1368-73.
• 22 Bhandari M, Hirsh J, Weitz JI. et al. The effects of standard and low molecular weight heparin on bone nodule formation in vitro. Thromb Haemost 1998; 80: 413-7.
• 23 Nishiyama M, Itoh F, Ujiie A. Low-molecularweight heparin (dalteparin) demonstrated a weaker effect on rat bone metabolism compared with heparin. Jpn J Pharmacol 1997; 74: 59-68.
• 24 Folwarczna J, Janiec W, Barej M, Cegie-la U, Pytlik M, Kaczmarczyk-Sedlak I. Effects of nadroparin on bone histomorphometric parameters in rats. Pol J Pharmacol 2004; 56: 337-43.
• 25 Eikelboom JW, Hankey GJ. Low molecular weight heparins and heparinoids. Med J Aust 2002; 177: 379-83.
• 26 Pytlik M, Folwarczna J, Janiec W. Effect of doxycycline on mechanical properties of bones in rats with ovariectomy-induced osteopenia. Calcif Tissue Int 2004; 75: 225-30.
• 27 Mätzsch T, Bergqvist D, Hedner U. et al. Heparin-induced osteoporosis in rats. Thromb Haemost 1986; 56: 293-4.
• 28 Walenga JM, Bick RL. Heparin-induced thrombocytopenia, paradoxical thromboembolism, and other side effects of heparin therapy. Med Clin North Am 1998; 82: 635-58.
• 29 Akkas N, Yeni YN, Turan B. et al. Effect of medication on biomechanical properties of rabbit bones: heparin induced osteoporosis. Clin Rheumatol 1997; 16: 585-95.
• 30 Turner CH, Burr DB. Basic biomechanical measurements of bone: a tutorial. Bone 1993; 14: 595-608.
• 31 Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 2000; 21: 115-37.
• 32 Folwarczna J, Janiec W, Gawor M. et al. Effects of enoxaparin on histomorphometric parameters of bones in rats. Pol J Pharmacol. 2004 56. accepted for publication.
• 33 Kock HJ, Handschin AE. Osteoblast growth inhibition by unfractionated heparin and by low molecular weight heparins: an in-vitro investigation. Clin Appl Thromb Hemost 2002; 08: 251-5.
• 34 Matziolis G, Perka C, Disch A. et al. Effects of fondaparinux compared with dalteparin, enoxaparin and unfractionated heparin on human osteoblasts. Calcif Tissue Int 2003; 73: 370-9.