Остеопороз и антитромботическая терапия

Антикоагулянтные и антитромбоцитарные препараты применяются для профилактики инсульта, тромбоэмболических осложнений. Недостаточно данных о влиянии на костную ткань этих препаратов, а имеющиеся данные неоднозначны, что повышает настороженность при применении их у лиц с риском развития остеопороза. В статье приводятся данные по действию антикоагулянтных и антитромбоцитарных препаратов на метаболизм кости, минеральную плотность костной ткани и риск переломов. Данные литературы свидетельствуют об отрицательном эффекте гепарина на костную ткань, заключающемся в увеличении риска переломов. Низкомолекулярные гепарины более нейтральны в отношении действия на костную ткань в сравнении с гепарином. Известно, что антагонисты витамина К существенно влияют на метаболизм костной ткани и маркеры костеобразования, однако данные о влиянии на минеральную плотность кости и риск переломов противоречивы. Относительно безопасны в отношении костной ткани новые прямые оральные антикоагулянты. Данные о влиянии антитромбоцитарных препаратов на кость неоднозначны.

1. Signorelli SS, Scuto S, Marino E, et al. Anticoagulants and Osteoporosis. Int J Mol Sci. 2019;20(21):5275. doi:10.3390/ijms20215275.

2. Lazrak HH, René É, Elftouh N, et al. Safety of low-molecular-weight heparin compared to unfractionated heparin in hemodialysis: a systematic review and meta-analysis. BMC Nephrol. 2017;18(1):187. doi:10.1186/s12882-017-0596-4.

3. Cosmi B. Management of idiopathic venous thromboembolism. Expert Rev Cardiovasc Ther. 2016;14(12):1371-84. doi:10.1080/14779072.2016.1248406.

4. Thaler J, Pabinger I, Ay C. Anticoagulant Treatment of Deep Vein Thrombosis and Pulmonary Embolism: The Present State of the Art. Front Cardiovasc Med. 2015;2:30. doi:10.3389/fcvm.2015.00030.

5. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e44S-e88S. doi:10.1378/chest.11-2292.

6. Riva N, Bellesini M, Di Minno MN, et al. Poor predictive value of contemporary bleeding risk scores during long-term treatment of venous thromboembolism. A multicentre retrospective cohort study. Thromb Haemost. 2014;112(3):511-21. doi:10.1160/TH14-01-0081.

7. Julia S, James U. Direct Oral Anticoagulants: A Quick Guide. Eur Cardiol. 2017;12(1):40-5. doi:10.15420/ecr.2017:11:2.

8. Dadwal G, Schulte-Huxel T, Kolb G. Effect of antithrombotic drugs on bone health. Auswirkung von Antithrombotika auf den Knochen. Z Gerontol Geriatr. 2020;53(5):457-62. doi:10.1007/s00391-019-01590-8.

9. Alban S. Adverse effects of heparin. Handb Exp Pharmacol. 2012;(207):211-63. doi:10.1007/978-3-642-23056-1_10.

10. 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(9):3236-42.

11. 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.

12. Li B, Lu D, Chen Y, et al. Unfractionated Heparin Promotes Osteoclast Formation in Vitro by Inhibiting Osteoprotegerin Activity. Int J Mol Sci. 2016;17(4):613. doi:10.3390/ijms17040613.

13. Panday K, Gona A, Humphrey MB. Medication-induced osteoporosis: screening and treatment strategies. Ther Adv Musculoskelet Dis. 2014;6(5):185-202. doi:10.1177/1759720X14546350.

14. Lefkou E, Khamashta M, Hampson G, et al. Review: Low-molecular-weight heparininduced osteoporosis and osteoporotic fractures: a myth or an existing entity? Lupus. 2010;19(1):3-12. doi:10.1177/0961203309353171.

15. Tsvetov G, Levy S, Benbassat C, et al. Influence of number of deliveries and total breastfeeding time on bone mineral density in premenopausal and young postmenopausal women. Maturitas. 2014;77(3):249-54. doi:10.1016/j.maturitas.2013.11.003.

16. 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(2):64- 7. doi:10.1159/000073848.

17. Serra R, Buffone G, de Franciscis A, et al. Skin grafting followed by low-molecular-weight heparin long-term therapy in chronic venous leg ulcers. Ann Vasc Surg. 2012;26(2):190-7. doi:10.1016/j.avsg.2011.04.008.

18. Gajic-Veljanoski O, Phua CW, Shah PS, et al. Effects of Long-Term Low-Molecular-Weight Heparin on Fractures and Bone Density in Non-Pregnant Adults: A Systematic Review With Meta-Analysis. J Gen Intern Med. 2016;31(8):947-57. doi:10.1007/s11606-016-3603-8.

19. Akbari S, Rasouli-Ghahroudi AA. Vitamin K and Bone Metabolism: A Review of the Latest Evidence in Preclinical Studies. Biomed Res Int. 2018;2018:4629383. doi:10.1155/2018/4629383.

20. Rodríguez-Olleros Rodríguez C, Díaz Curiel M. Vitamin K and Bone Health: A Review on the Effects of Vitamin K Deficiency and Supplementation and the Effect of NonVitamin K Antagonist Oral Anticoagulants on Different Bone Parameters. J Osteoporos. 2019:2069176. doi:10.1155/2019/2069176.

21. Ferron M, Wei J, Yoshizawa T, et al. Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell. 2010;142(2):296-308. doi:10.1016/j.cell.2010.06.003.

22. Karsenty G, Olson EN. Bone and Muscle Endocrine Functions: Unexpected Paradigms of Inter-organ Communication. Cell. 2016;164(6):1248-56. doi:10.1016/j.cell.2016.02.043.

23. Hao G, Zhang B, Gu M, et al. Vitamin K intake and the risk of fractures: A meta-analysis. Medicine (Baltimore). 2017;96(17):e6725. doi:10.1097/MD.0000000000006725.

24. Rejnmark L, Vestergaard P, Charles P, et al. No effect of vitamin K1 intake on bone mineral density and fracture risk in perimenopausal women. Osteoporos Int. 2006;17(8):1122-32. doi:10.1007/s00198-005-0044-3.

25. Akhtar T, Hajra A, Bhyan P, et al. Association between direct-acting oral anticoagulants vs. warfarin with the risk of osteoporosis in patients with non-valvular atrial fibrillation. Int J Cardiol Heart Vasc. 2020;27:100484. doi:10.1016/j.ijcha.2020.100484.

26. Gage BF, Birman-Deych E, Radford MJ, et al. Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2. Arch Intern Med. 2006;166(2):241-6. doi:10.1001/archinte.166.2.241.

27. Fiordellisi W, White K, Schweizer M. A Systematic Review and Meta-analysis of the Association Between Vitamin K Antagonist Use and Fracture. J Gen Intern Med. 2019;34(2):304-11. doi:10.1007/s11606-018-4758-2.

28. Beaubrun AC, Kilpatrick RD, Freburger JK, et al. Temporal trends in fracture rates and postdischarge outcomes among hemodialysis patients. J Am Soc Nephrol. 2013;24(9):1461-9. doi:10.1681/ASN.2012090916.

29. Tufano A, Coppola A, Contaldi P, et al. Oral anticoagulant drugs and the risk of osteoporosis: new anticoagulants better than old? Semin Thromb Hemost. 2015;41(4):382-8. doi:10.1055/s-0034-1543999.

30. Somjen D, Katzburg S, Gigi R, et al. Rivaroxaban, a direct inhibitor of the coagulation factor Xa interferes with hormonal-induced physiological modulations in human female osteoblastic cell line SaSO2. J Steroid Biochem Mol Biol. 2013;135:67-70. doi:10.1016/j.jsbmb.2013.01.006.

31. Morishima Y, Kamisato C, Honda Y, et al. The effects of warfarin and edoxaban, an oral direct factor Xa inhibitor, on gammacarboxylated (Gla-osteocalcin) and undercarboxylated osteocalcin (uc-osteocalcin) in rats. Thromb Res. 2013;131(1):59-63. doi:10.1016/j.thromres.2012.08.304.

32. Solayar GN, Walsh PM, Mulhall KJ. The effect of a new direct Factor Xa inhibitor on human osteoblasts: an in-vitro study comparing the effect of rivaroxaban with enoxaparin. BMC Musculoskelet Disord. 2011;12:247. doi:10.1186/1471-2474-12-247.

33. Somjen D, Sharfman ZT, Katzburg S, et al. Rivaroxaban significantly inhibits the stimulatory effects of bone-modulating hormones: In vitro study of primary female osteoblasts. Connect Tissue Res. 2017;58(2):215-20. doi:10.1080/03008207.2016.1220942.

34. Namba S, Yamaoka-Tojo M, Kakizaki R, et al. Effects on bone metabolism markers and arterial stiffness by switching to rivaroxaban from warfarin in patients with atrial fibrillation. Heart Vessels. 2017;32(8):977-82. doi:10.1007/s00380-017-0950-2.

35. Dalle Carbonare L, Mottes M, Brunelli A, et al. Effects of Oral Anticoagulant Therapy on Gene Expression in Crosstalk between Osteogenic Progenitor Cells and Endothelial Cells. J Clin Med. 2019;8(3):329. doi:10.3390/jcm8030329.

36. Lau WC, Chan EW, Cheung CL, et al. Association Between Dabigatran vs Warfarin and Risk of Osteoporotic Fractures Among Patients With Nonvalvular Atrial Fibrillation. JAMA. 2017;317(11):1151-8. doi:10.1001/jama.2017.1363.

37. Gigi R, Salai M, Dolkart O, et al. The effects of direct factor Xa inhibitor (Rivaroxaban) on the human osteoblastic cell line SaOS2. Connect Tissue Res. 2012;53(6):446-50. doi:10.3109/03008207.2012.711867.

38. Winkler T, Perka C, Matziolis D, et al. Effect of a direct thrombin inhibitor compared with dalteparin and unfractionated heparin on human osteoblasts. Open Orthop J. 2011;5:52-8. doi:10.2174/1874325001105010052.

39. Treceño-Lobato C, Jiménez-Serranía MI, Martínez-García R, et al. New Anticoagulant Agents: Incidence of Adverse Drug Reactions and New Signals Thereof. Semin Thromb Hemost. 2019;45(2):196-204. doi:10.1055/s-0038-1657783.

40. Jørgensen NR, Schwarz P, Iversen HK, et al. P2Y12 Receptor Antagonist, Clopidogrel, Does Not Contribute to Risk of Osteoporotic Fractures in Stroke Patients. Front Pharmacol. 2017;8:821. doi:10.3389/fphar.2017.00821.

41. Syberg S, Brandao-Burch A, Patel JJ, et al. Clopidogrel (Plavix), a P2Y12 receptor antagonist, inhibits bone cell function in vitro and decreases trabecular bone in vivo. J Bone Miner Res. 2012;27(11):2373-86. doi:10.1002/jbmr.1690.

42. Jørgensen NR, Grove EL, Schwarz P, et al. Clopidogrel and the risk of osteoporotic fractures: a nationwide cohort study. J Intern Med. 2012;272(4):385-93. doi:10.1111/j.1365-2796.2012.02535.x.

43. Mediero A, Wilder T, Reddy VS, et al. Ticagrelor regulates osteoblast and osteoclast function and promotes bone formation in vivo via an adenosine-dependent mechanism. FASEB J. 2016;30(11):3887-900. doi:10.1096/fj.201600616R.