References

rpcardio

Rational Pharmacotherapy in Cardiology

Рациональная Фармакотерапия в Кардиологии

1819-64462225-3653

«SILICEA-POLIGRAF» LLC

10.20996/1819-6446-2020-06-07

rpcardio-2225

Research Article

ASSOCIATED PROBLEMS OF CARDIOLOGY

СМЕЖНЫЕ ВОПРОСЫ КАРДИОЛОГИИ

Clinical and Pathophysiological Aspects of the Effect of Anticoagulants on Bone Tissue

Клинические и патофизиологические аспекты влияния антикоагулянтов на костную ткань

Остроумова

О. Д.

Ostroumova

O. D.

Остроумова Ольга Дмитриевна - доктор медицинских наук, профессор, заведующая кафедрой терапии и полиморбидной патологии, РМАНПО; профессор, кафедра клинической фармакологии и пропедевтики внутренних болезней, Сеченовский университет.

125993, Москва, ул. Баррикадная, 2/1; 119991, Москва, ул. Трубецкая, 8 стр. 2.

Olga D. Ostroumova - MD, PhD, Professor, Head of Chair of Therapy and Polymorbid Pathology, Russian Medical Academy of Continuous Professional Education; Professor, Chair of Clinical Pharmacology and Propaedeutics of Internal Medicine, Sechenov University.

Barrikadnaya ul. 2/1, Moscow, 125993; Trubetskaya ul. 8-2, Moscow, 119991.Trubetskaya ul. 8-2, Moscow, 119991.

ostroumova.olga@mail.ru

Голобородова

И. В.

Goloborodova

I. V.

Голобородова Ирина Васильевна - кандидат медицинских наук, доцент, кафедра факультетской терапии и профболезней, МГМСУ им А.И. Евдокимова.

127423, Москва, ул. Делегатская, 20/1.

Irina V. Goloborodov - MD, PhD, Associate Professor, Chair of Faculty Therapy and Occupational Diseases, A.I. Yevdokimov Moscow State University of Medicine and Dentistry.

Delegatskayaul. 20/1, Moscow, 127423.

Российская медицинская академия непрерывного профессионального образования; Первый Московский государственный медицинский университет им. И.М. Сеченова (Сеченовский Университет)РоссияRussian Medical Academy of Continuous Professional Education; I.M. Sechenov First Moscow State Medical University (Sechenov University)Russian Federation

Московский государственный медико-стоматологический университет им. А.И. ЕвдокимоваРоссияA.I. Yevdokimov Moscow State University of Medicine and DentistryRussian Federation

2020

03072020

163404414

2020

Остроумова О.Д., Голобородова И.В.

Ostroumova O.D., Goloborodova I.V.

Данная работа распространяется под лицензией Creative Commons Attribution 4.0.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://www.rpcardio.online/jour/article/view/2225

Older age is associated with changes in bone metabolism, a loss in its mineral density and volume, and the development of osteoporosis. The high prevalence of atrial fibrillation and osteoporosis in older age groups causes their frequent combination in this category of patients. It is known that some diseases and/or drugs used to treat them, exacerbating the natural violation of bone metabolism, contribute to the progression of osteoporosis and its complications, which in turn can negatively affect the prognosis and quality of life of the patient. Anticoagulants, widely used in the treatment of thromboembolic complications and in the prevention of stroke, can have an adverse effect on bone metabolism. The purpose of this review was to generalize and systematize the available literature data regarding the features of the influence of various representatives of the anticoagulants group on bone tissue. The article analyzes the effects of unfractionated heparin, low molecular weight heparins, vitamin K antagonists, oral anticoagulants on bone metabolism, bone mineral density, and fractures. This review provides data from articles and reviews published through February 2020, inclusive, accumulated in the English-language database of medical and biological publications “PubMed”. The literature data confirm the negative effect of unfractionated heparin on bone tissue, with a violation of bone metabolism, a decreased bone mineral density and the development of fractures. Compared with unfractionated heparin, low molecular weight heparins appear to be safer, and vitamin K antagonists, having a significant effect on bone metabolism, contribute to a decreased bone mineral density, mainly in people who are on long-term (more than 1 year) therapy. Oral anticoagulants, having the mildest effect on bone metabolism, is associated with a lower (compared to other anticoagulants) risk of decreased bone mineral density and the development of fractures, and are recognized as the safest against bone tissue.

Старший возраст ассоциирован с развитием изменений метаболизма костной ткани, снижением ее минеральной плотности и объема, развитием остеопороза. Высокая распространенность фибрилляции предсердий и остеопороза в старших возрастных группах обуславливает их частое сочетание у этой категории пациентов. Известно, что некоторые заболевания и/или лекарственные средства, используемые для их лечения, усугубляя естественное нарушение костного метаболизма, способствуют прогрессированию остеопороза и его осложнений, что может оказать негативное влияние на прогноз и качество жизни пациента. Антикоагулянты, широко используемые в терапии тромбоэмболических осложнений и в профилактике инсульта, способны оказывать неблагоприятное действие на костный метаболизм. Целью настоящего обзора явилось обобщение и систематизация имеющихся данных литературы, касающихся особенностей влияния различных антикоагулянтов на костную ткань. Анализируется влияние нефракционированного гепарина (НФГ), низкомолекулярных гепаринов (НМГ), антагонистов витамина К (АВК), прямых пероральных антикоагулянтов (ПОАК) на костный метаболизм, минеральную плотность костной ткани (МПК) и ос-теопоретические переломы. Приведены данные статей и обзоров, опубликованных до февраля 2020 г. включительно, аккумулированных в англоязычной базе данных медицинских и биологических публикаций «PubMed». Данные литературы подтверждают негативное влияние НФГ на костную ткань, с нарушением костного метаболизма, снижением МПК и развитием переломов. НМГ по сравнению с НФГ представляются более безопасными, а АВК, оказывая значительное влияние на костный метаболизм, способствуют снижению МПК, преимущественно у лиц, находящихся на длительной (более 1 года) терапии. ПОАК, оказывая наиболее мягкое влияние на костный метаболизм, ассоциированы с меньшим (в сравнении с другими антикоагулянтами) риском снижения МПК и развития переломов, и признаны наиболее безопасными в отношении костной ткани.

остеопорозостеопоретический переломфибрилляция предсердийвенозные тромбоэмболииантикоагулянтыгепариннизкомолекулярный гепаринварфаринпрямые оральные антикоагулянтыапиксабан

osteoporosisosteoporetic fractureatrial fibrillationvenous thromboembolismanticoagulantsheparinlow molecular weight heparinwarfarindirect oral anticoagulantsapixaban

Статья опубликована при финансовой поддержке компании Пфайзер.

The article was published with the financial support of the Pfizer company .

References1

Piran S., Schulman S. Management of venous thromboembolism: An update. Thromb J. 2016;14:107-15. DOI:10.1186/s12959-016-0107-z.

Granger C.B., Alexander J.H., McMurray J.J., et al. ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-92. DOI:10.1056/NE-JMoa1107039.

Connolly S.J., Eikelboom J., Joyner C., et al. AVERROES Steering Committee Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364:806-17. DOI:10.1056/NEJMoa1007432.

Hylek E.M., Held C., Alexander J.H., et al. Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: The ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation): Predictors, Characteristics, and Clinical Outcomes. J Am Coll Cardiol. 2014;63:2141-7. DOI:10.1016/j.jacc.2014.02.549.

Flaker G.C., Eikelboom J.W., Shestakovska O., et al. Bleeding during treatment with aspirin versus apix-aban in patients with atrial fibrillation unsuitable for warfarin: the apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment (AVERROES) trial. Stroke. 2012;43:3291-7. DOI:10.1161/STROKEAHA.112.664144.

Brandjes D.P., Heijboer H., Buller H.R., et al. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl J Med. 1992;327:1485-9. DOI:10.1056/NEJM199211193272103.

Kelman A., Lane N.E. The management of secondary osteoporosis. Best Pract Res Clin Rheumatol. 2005;19:1021-37. DOI:10.1016/j.berh.2005.06.005.

Borgelt L.M., Fixen D.R. Osteoporosis and Osteomalacia. In: Tisdale J.E., Miller D.A., eds. Drug-Induced Diseases: Prevention, Detection, and Management. 3rd ed. Bethesda: American Society of Health-System Pharmacists; 2018: 1119-33.

Jamal S.A., Browner W.S., Bauer D.C., Cummings S.R. Study of Osteoporotic Fractures Research Group. Warfarin use and risk for osteoporosis in elderly women. Ann Intern Med. 1998;128:829-32. DOI:10.7326/0003-4819-128-10-199805150-00006.

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; 41:382-8. DOI:10.1055/s-0034-1543999.

Nelson-Piercy C. Hazards of heparin: Allergy, Heparin-Induced thrombocytopenia and osteoporosis. Baillieres Clin Obstet Gynaecol. 1997;11:489-509. DOI:10.1016/S0950-3552(97)80024-7.

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

Schulman S., Hellgren-Wаngdahl M. Pregnancy, heparin and osteoporosis. Thromb Haemost. 2002;87:180-1.

Barbour L.A., Kick S.D., Steiner J.F., et al. A prospective study of Heparin-Induced osteoporosis in pregnancy using bone densitometry. Am. J. Obstet. Gynecol. 1994;170:862-9. DOI:10.1016/S0002-9378(94)70299-3.

Muir J.M., Andrew M., Hirsh J., et al. Histomorphometric analysis of the effects of standard heparin on trabecular bone in vivo. Blood. 1996;88:1314-20. DOI:10.1182/blood.V88.4.1314.bloodjournal8841314.

Muir J.M., Hirsh J., Weitz J.I., 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. DOI:10.1182/blood.V89.9.3236.

Shaughnessy S.G., Young E., Deschamps P., Hirsh J. The effects of low molecular weight and standard heparin on calcium loss from fetal rat calvaria. Blood. 1995;86:1368-73. DOI:10.1182/blood.V86.4.1368.bloodjournal8641368.

Handschin A.E., Trentz O.A., Hoerstrup S.P., et al. Effect of low molecular weight heparin (dalteparin) and fondaparinux (Arixtra) on human osteoblasts in vitro. Br J Surg. 2005;92:177-83. DOI:10.1002/bjs.4809.

Osip S.L., Butcher M., Young E., et al. Differential effects of heparin and low molecular weight heparin on osteoblastogenesis and adipogenesis in vitro. Thromb Haemost. 2004;92:803-10. DOI:10.1160/TH04-03-0199.

Bhandari M., Hirsh J., Weitz J.I., et al. The effects of standard and low molecular weight heparin on bone nodule formation in vitro. Thromb Haemost. 1998;80:413-7. DOI:10.1055/s-0037-1615222.

Irie A., Takami M., Kubo H., et al. Heparin enhances osteoclastic bone resorption by inhibiting osteoprotegerin activity. Bone. 2007;41:165-74. DOI:10.1016/j.bone.2007.04.190.

Melissari E., Parker C.J., Wilson N.V., et al. Use of low molecular weight heparin in pregnancy. Thromb Haemost. 1992;68: 652-6.

Vik A., Brodin E., Sveinbjornsson B., Hansen J.B. Heparin induces mobilization of osteoprotegerin into the circulation. Thromb Haemost. 2007;98:148-54.

Dahlman T.C., Sjoberg H.E., Ringertz H. Bone mineral density during long-term prophylaxis with heparin in pregnancy. Am J Obstet Gynecol. 1994;170:1315-20. DOI:10.1016/S0002-9378(13)90457-9.

Douketis J.D., Ginsberg J.S., Burrows R.F., 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.

Nelson-Piercy C., Letsky E.A., 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. DOI:10.1016/S0002-9378(97)70403-4.

Casele H.L., Laifer S.A. Prospective evaluation of bone density in pregnant women receiving the low molecular weight heparin enoxaparin sodium. J Matern Fetal Med. 2000;9:122-5.

Greer I.A., Nelson-Piercy C. Low-Molecular-Weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: A systematic review of safety and efficacy. Blood. 2005;106:401-7. DOI:10.1182/blood-2005-02-0626.

Lefkou E., Khamashta M., Hampson G., Hunt B.J. Review: Low-Molecular-Weight Heparin-Induced osteoporosis and osteoporotic fractures: A myth or an existing entity? Lupus. 2010;19:3-12. DOI:10.1177/0961203309353171.

Carlin A.J., Farquharson R.G., Quenby S.M., et al. Prospective observational study of bone mineral density during pregnancy: Low molecular weight heparin versus control. Hum Reprod. 2004;19:1211-4. DOI:10.1093/humrep/deh115.

Pettila V., Leinonen P., Markkola A., et al. Postpartum bone mineral density in women treated for thromboprophylaxis with unfractionated heparin or LMW heparin. Thromb Haemost. 2002;87:182-96. DOI:10.1055/s-0037-1612970.

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

Wawrzynska L., Tomkowski W.Z., Przedlacki J., et al. Changes in bone density during Long-Term administration of Low-Molecular-Weight heparins or acenocoumarol for secondary prophylaxis of venous thromboembolism. Pathophysiol Haemost Thromb. 2003;33:64-7. DOI:10.1159/000073848.

Bernis C. Mineral bone density variation in hemodialysis patients: Nonfractioned heparin (NFH) versus low molecular weight heparin (LMWH). Nephrol Dial Transplant. 1997;12:1789.

Lai K.N., Ho K., Cheung R.C., et al. Effect of low molecular weight heparin on bone metabolism and hyperlipidemia in patients on maintenance hemodialysis. Int J Artif Organs. 2001;24:447-55. DOI:10.1177/039139880102400708.

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;26:190-7. DOI:10.1016/j.avsg.2011.04.008.

Grassman E.D., Leya F., Fareed J. et al. A randomized trial of the low Molecular-Weight heparin certoparin to prevent restenosis following coronary angioplasty. J Invasive Cardiol. 2001;13:723-8.

Monreal M., Olive A., Lafoz E., del Rio L. Heparins, coumarin, and bone density. Lancet. 1991;338:706. DOI:10.1016/0140-6736(91)91292-3.

Grzegorzewska A.E., Mlot-Michalska M. Low molecular weight heparins and antiplatelet drugs, and bone mineral density in dialysis patients. Adv Perit Dial. 2008;24:125-31.

Pettila V., Kaaja R., Leinonen P., et al. Thromboprophylaxis with low molecular weight heparin (dalteparin) in pregnancy. Thromb Res. 1999;96:275-82. DOI:10.1016/S0049-3848(99)00110-3.

Dahlman T.C. Osteoporotic fractures and the recurrence of thromboembolism during pregnancy and the puerperium in 184 women undergoing thromboprophylaxis with heparin. Am J Obstet Gynecol. 1993;168:1265-70. DOI:10.1016/0002-9378(93)90378-V.

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. DOI:10.1055/s-0038-1642376.

Gajic-Veljanoski O., Chai W., Prakesh S., Cheung A.M. Effects of Long-Term Low- Molecular-Weight Heparin on Fractures and Bone Density in Non-Pregnant Adults: A Systematic Review with MetaAnalysis. J Gen Intern Med. 2016;31:947-57. DOI:10.1007/s11606-016-3603-8.

Karsenty G., Olson E.N. Bone and Muscle Endocrine Functions: Unexpected Paradigms of Inter-Organ Communication. Cell. 2016;164:1248-56. DOI:10.1016/j.cell.2016.02.043.

Price P.A., Williamson M.K. Effects of warfarin on bone. Studies on the vitamin K-dependent protein of rat bone. J Biol Chem. 1981;256:12754-9.

Ferriеre K., Rizzoli R. Anticoagulants and osteoporosis [in French]. Rev Med Suisse. 2007;3: 1508-11.

Pearson D.A. Bone health and osteoporosis: The role of vitamin K and potential antagonism by anticoagulants. Nutr Clin Pract. 2007;22:517-44. DOI:10.1177/0115426507022005517.

Vermeer C. Vitamin K: The effect on health beyond coagulation - An overview. Food Nutr Res. 2012;56:5329. DOI:10.3402/fnr.v56i0.5329.

Cranenburg E.C., Schurgers L.J., Vermeer C. Vitamin K: The coagulation vitamin that became omnipotent. Thromb Haemost. 2007;98:120-5. DOI:10.1160/TH07-04-0266.

Szulc P., Arlot M., Chapuy M.C., et al. Serum undercarboxylated osteocalcin correlates with hip bone mineral density in elderly women. J Bone Miner Res. 1994;9:1591-5. DOI:10.1002/jbmr.5650091012.

Avgeri M., Papadopoulou A., Platokouki H., et al. Assessment of bone mineral density and markers of bone turnover in children under Long-Term oral anticoagulant therapy. J Pediatr Hematol Oncol. 2008;30:592-7. DOI:10.1097/MPH.0b013e31817541a8.

Rezaieyazdi Z., Falsoleiman H., Khajehdaluee M. et al. Reduced bone density in patients on longterm warfarin. Int J Rheum Dis. 2009;12:130-5. DOI:10.1111/j.1756-185X.2009.01395.x.

Caraballo P.J., Heit J.A., Atkinson E.J., et al. Long-Term use of oral anticoagulants and the risk of fracture. Arch Intern Med. 1999;159:1750-6. DOI:10.1001/archinte.159.15.1750.

Gage B.F., Birman-Deych E., Radford M.J., et al. Risk of osteoporotic fracture in elderly patients taking warfarin: Results from the National Registry of Atrial Fibrillation 2. Arch Intern Med. 2006;166:241-6. DOI:10.1001/archinte.166.2.241.

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;34:304-11. DOI:10.1007/s11606-018-4758-2.

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;53:446-50. DOI:10.3109/03008207.2012.711867.

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.

Winkler T., Perka C., Matziolis D., Matziolis G. 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.

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-os-teocalcin) in rats. Thromb Res. 2013;131:59-63. DOI:10.1016/j.thromres.2012.08.304.

Solayar G.N., Walsh P.M., Mulhall K.J. 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.

Pilge H., Frobel J., Mrotzek S.J. et al. Effects of thromboprophylaxis on mesenchymal stromal cells during osteogenic differentiation: An in-vitro study comparing enoxaparin with rivaroxaban. BMC Musculoskelet. Disord 2016;17:108. DOI:10.1186/s12891-016-0966-2.

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;32:977-82. DOI:10.1007/s00380-017-0950-2.

Abd El Ghafar O.A.M.A., Helal G.K., Abo-Yousef A.M. Apixaban exhibits anti-arthritic effects by inhibiting activated factor X-mediated JAK2/STAT3 and MAPK phosphorylation pathways. Inflam-mopharmacol 2020. DOI:10.1007/s10787-020-00693-8.

Huang H.K., Liu P.P.S., Hsu J.Y et al. Risk of Osteoporosis in Patients ^th Atrial Fibrillation Using NonVitamin K Antagonist Oral Anticoagulants or Warfarin. J Am Heart Assoc 2020;9:e013845. DOI:10.1161/JAHA.119.013845.

Treceno-Lobato C., Jimenez-Serrania M.I., Martinez-Garcia R. et al. New Anticoagulant Agents: Incidence of Adverse Drug Reactions and New Signals Thereof. Semin. Thromb. Hemost 2019;45:196-204.

Lau W.C., Chan E.W., Cheung C.L. et al. Association Between Dabigatran vs Warfarin and Risk of Osteoporotic Fractures Among Patients with Nonvalvular Atrial Fibrillation. JAMA 2017;317:1151-8. DOI:10.1001/jama.2017.1363.

Huang H.-K., Liu P.P.-S., Hsu J.-Y. et al. Fracture risks among patients with atrial fibrillation receiving different oral anticoagulants: a real-world nationwide cohort study. European Heart Journal. 2020;0:1-9. DOI:10.1093/eurheartj/ehz952.

The authors declare that there are no conflicts of interest present.