{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T10:51:19Z","timestamp":1774263079138,"version":"3.50.1"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2011,10,28]],"date-time":"2011-10-28T00:00:00Z","timestamp":1319760000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Musculoskelet Disord"],"published-print":{"date-parts":[[2011,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Current treatments for the prevention of thromboembolism include heparin and low-molecular weight heparins (LMWHs). A number of studies have suggested that long term administration of these drugs may adversely affect osteoblasts and therefore, bone metabolism. Xarelto\u2122 (Rivaroxaban) is a new anti-thrombotic drug for the prevention of venous thromboembolism in adult patients undergoing elective hip and knee replacement surgery. The aim of this <jats:italic>in vitro<\/jats:italic> study was to investigate the possible effects of rivaroxaban on osteoblast viability, function and gene expression compared to enoxaparin, a commonly used LMWH.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Primary human osteoblast cultures were treated with varying concentrations of rivaroxaban (0.013, 0.13, 1.3 and 13 \u03bcg\/ml) or enoxaparin (1, 10 and 100 \u03bcg\/ml). The effect of each drug on osteoblast function was evaluated by measuring alkaline phosphatase activity. The MTS assay was used to assess the effect of drug treatments on cell proliferation. Changes in osteocalcin, Runx2 and BMP-2 messenger RNA (mRNA) expression following drug treatments were measured by real-time polymerase chain reaction (PCR).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Rivaroxaban and enoxaparin treatment did not adversely affect osteoblast viability. However, both drugs caused a significant reduction in osteoblast function, as measured by alkaline phosphatase activity. This reduction in osteoblast function was associated with a reduction in the mRNA expression of the bone marker, osteocalcin, the transcription factor, Runx2, and the osteogenic factor, BMP-2.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>These data show that rivaroxaban treatment may negatively affect bone through a reduction in osteoblast function.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1471-2474-12-247","type":"journal-article","created":{"date-parts":[[2011,11,16]],"date-time":"2011-11-16T04:13:55Z","timestamp":1321416835000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["The effect of a new direct Factor Xa inhibitor on human osteoblasts: an in-vitro study comparing the effect of rivaroxaban with enoxaparin"],"prefix":"10.1186","volume":"12","author":[{"given":"Gandhi N","family":"Solayar","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pauline M","family":"Walsh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin J","family":"Mulhall","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2011,10,28]]},"reference":[{"issue":"9 Suppl","key":"1270_CR1","first-page":"11","volume":"36","author":"CW Colwell Jr","year":"2007","unstructured":"Colwell CW: Rationale for thromboprophylaxis in lower joint arthroplasty. American journal of orthopedics (Belle Mead, NJ. 2007, 36 (9 Suppl): 11-13.","journal-title":"American journal of orthopedics (Belle Mead, NJ"},{"issue":"4","key":"1270_CR2","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1016\/0002-9610(91)91126-4","volume":"161","author":"AG Turpie","year":"1991","unstructured":"Turpie AG: Efficacy of a postoperative regimen of enoxaparin in deep vein thrombosis prophylaxis. American journal of surgery. 1991, 161 (4): 532-536. 10.1016\/0002-9610(91)91126-4.","journal-title":"American journal of surgery"},{"issue":"3","key":"1270_CR3","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1016\/j.thromres.2006.10.025","volume":"122","author":"R Rajgopal","year":"2008","unstructured":"Rajgopal R, Bear M, Butcher MK, Shaughnessy SG: The effects of heparin and low molecular weight heparins on bone. Thromb Res. 2008, 122 (3): 293-298. 10.1016\/j.thromres.2006.10.025.","journal-title":"Thromb Res"},{"issue":"2","key":"1270_CR4","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1159\/000073848","volume":"33","author":"L Wawrzynska","year":"2003","unstructured":"Wawrzynska L, Tomkowski WZ, Przedlacki J, Hajduk B, Torbicki A: 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 (2): 64-67. 10.1159\/000073848.","journal-title":"Pathophysiol Haemost Thromb"},{"issue":"3","key":"1270_CR5","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1016\/S0025-7125(05)70015-8","volume":"82","author":"JM Walenga","year":"1998","unstructured":"Walenga JM, Bick RL: Heparin-induced thrombocytopenia, paradoxical thromboembolism, and other side effects of heparin therapy. Med Clin North Am. 1998, 82 (3): 635-658. 10.1016\/S0025-7125(05)70015-8.","journal-title":"Med Clin North Am"},{"issue":"22","key":"1270_CR6","doi-asserted-by":"publisher","first-page":"2417","DOI":"10.1001\/jama.1979.03290480051024","volume":"241","author":"JW Squires","year":"1979","unstructured":"Squires JW, Pinch LW: Heparin-induced spinal fractures. Jama. 1979, 241 (22): 2417-2418. 10.1001\/jama.241.22.2417.","journal-title":"Jama"},{"issue":"4","key":"1270_CR7","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1016\/0002-9378(93)90378-V","volume":"168","author":"TC Dahlman","year":"1993","unstructured":"Dahlman TC: 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 (4): 1265-1270.","journal-title":"Am J Obstet Gynecol"},{"issue":"2","key":"1270_CR8","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1055\/s-0038-1650255","volume":"75","author":"JD Douketis","year":"1996","unstructured":"Douketis JD, Ginsberg JS, Burrows RF, Duku EK, Webber CE, Brill-Edwards P: The effects of long-term heparin therapy during pregnancy on bone density. A prospective matched cohort study. Thromb Haemost. 1996, 75 (2): 254-257.","journal-title":"Thromb Haemost"},{"key":"1270_CR9","unstructured":"European Commission approval for Xarelto. [http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/EPAR_-_Public_assessment_report\/human\/000944\/WC500057122.pdf]"},{"issue":"5","key":"1270_CR10","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1302\/0301-620X.91B5.21691","volume":"91","author":"BI Eriksson","year":"2009","unstructured":"Eriksson BI, Kakkar AK, Turpie AG, Gent M, Bandel TJ, Homering M, Misselwitz F, Lassen MR: Oral rivaroxaban for the prevention of symptomatic venous thromboembolism after elective hip and knee replacement. J Bone Joint Surg Br. 2009, 91 (5): 636-644. 10.1302\/0301-620X.91B5.21691.","journal-title":"J Bone Joint Surg Br"},{"issue":"3","key":"1270_CR11","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1111\/j.1538-7836.2005.01166.x","volume":"3","author":"E Perzborn","year":"2005","unstructured":"Perzborn E, Strassburger J, Wilmen A, Pohlmann J, Roehrig S, Schlemmer KH, Straub A: In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939--an oral, direct Factor Xa inhibitor. J Thromb Haemost. 2005, 3 (3): 514-521. 10.1111\/j.1538-7836.2005.01166.x.","journal-title":"J Thromb Haemost"},{"issue":"4","key":"1270_CR12","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1111\/j.1365-2125.2006.02776.x","volume":"63","author":"D Kubitza","year":"2007","unstructured":"Kubitza D, Becka M, Mueck W, Zuehlsdorf M: Rivaroxaban (BAY 59-7939)--an oral, direct Factor Xa inhibitor--has no clinically relevant interaction with naproxen. Br J Clin Pharmacol. 2007, 63 (4): 469-476. 10.1111\/j.1365-2125.2006.02776.x.","journal-title":"Br J Clin Pharmacol"},{"issue":"1","key":"1270_CR13","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1093\/nar\/gkn910","volume":"37","author":"PM Wilson","year":"2009","unstructured":"Wilson PM, Fazzone W, LaBonte MJ, Lenz HJ, Ladner RD: Regulation of human dUTPase gene expression and p53-mediated transcriptional repression in response to oxaliplatin-induced DNA damage. Nucleic Acids Res. 2009, 37 (1): 78-95. 10.1093\/nar\/gkn910.","journal-title":"Nucleic Acids Res"},{"issue":"12","key":"1270_CR14","doi-asserted-by":"publisher","first-page":"1521","DOI":"10.1089\/aid.2007.0112","volume":"23","author":"EJ Cotter","year":"2007","unstructured":"Cotter EJ, Malizia AP, Chew N, Powderly WG, Doran PP: HIV proteins regulate bone marker secretion and transcription factor activity in cultured human osteoblasts with consequent potential implications for osteoblast function and development. AIDS Res Hum Retroviruses. 2007, 23 (12): 1521-1530. 10.1089\/aid.2007.0112.","journal-title":"AIDS Res Hum Retroviruses"},{"issue":"3","key":"1270_CR15","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1016\/S0002-9378(94)70299-3","volume":"170","author":"LA Barbour","year":"1994","unstructured":"Barbour LA, Kick SD, Steiner JF, LoVerde ME, Heddleston LN, Lear JL, Baron AE, Barton PL: A prospective study of heparin-induced osteoporosis in pregnancy using bone densitometry. Am J Obstet Gynecol. 1994, 170 (3): 862-869.","journal-title":"Am J Obstet Gynecol"},{"issue":"1","key":"1270_CR16","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1055\/s-0038-1642376","volume":"71","author":"M Monreal","year":"1994","unstructured":"Monreal M, Lafoz E, Olive A, del Rio L, Vedia C: 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 (1): 7-11.","journal-title":"Thromb Haemost"},{"issue":"4","key":"1270_CR17","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/S0049-3848(99)00110-3","volume":"96","author":"V Pettila","year":"1999","unstructured":"Pettila V, Kaaja R, Leinonen P, Ekblad U, Kataja M, Ikkala E: Thromboprophylaxis with low molecular weight heparin (dalteparin) in pregnancy. Thromb Res. 1999, 96 (4): 275-282. 10.1016\/S0049-3848(99)00110-3.","journal-title":"Thromb Res"},{"issue":"4","key":"1270_CR18","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1007\/s00223-002-2091-5","volume":"73","author":"G Matziolis","year":"2003","unstructured":"Matziolis G, Perka C, Disch A, Zippel H: Effects of fondaparinux compared with dalteparin, enoxaparin and unfractionated heparin on human osteoblasts. Calcified tissue international. 2003, 73 (4): 370-379. 10.1007\/s00223-002-2091-5.","journal-title":"Calcified tissue international"},{"issue":"2","key":"1270_CR19","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1002\/bjs.4809","volume":"92","author":"AE Handschin","year":"2005","unstructured":"Handschin AE, Trentz OA, Hoerstrup SP, Kock HJ, Wanner GA, Trentz O: Effect of low molecular weight heparin (dalteparin) and fondaparinux (Arixtra) on human osteoblasts in vitro. Br J Surg. 2005, 92 (2): 177-183. 10.1002\/bjs.4809.","journal-title":"Br J Surg"},{"issue":"1-2","key":"1270_CR20","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/S0009-8981(02)00248-6","volume":"325","author":"P Magnusson","year":"2002","unstructured":"Magnusson P, Sharp CA, Farley JR: Different distributions of human bone alkaline phosphatase isoforms in serum and bone tissue extracts. Clin Chim Acta. 2002, 325 (1-2): 59-70. 10.1016\/S0009-8981(02)00248-6.","journal-title":"Clin Chim Acta"},{"issue":"3","key":"1270_CR21","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1055\/s-0037-1615222","volume":"80","author":"M Bhandari","year":"1998","unstructured":"Bhandari M, Hirsh J, Weitz JI, Young E, Venner TJ, Shaughnessy SG: The effects of standard and low molecular weight heparin on bone nodule formation in vitro. Thrombosis and haemostasis. 1998, 80 (3): 413-417.","journal-title":"Thrombosis and haemostasis"},{"issue":"4","key":"1270_CR22","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1160\/TH04-03-0199","volume":"92","author":"SL Osip","year":"2004","unstructured":"Osip SL, Butcher M, Young E, Yang L, Shaughnessy SG: Differential effects of heparin and low molecular weight heparin on osteoblastogenesis and adipogenesis in vitro. Thrombosis and haemostasis. 2004, 92 (4): 803-810.","journal-title":"Thrombosis and haemostasis"},{"issue":"11","key":"1270_CR23","first-page":"1673","volume":"17","author":"S Wada","year":"2007","unstructured":"Wada S, Fukawa T, Kamiya S: Osteocalcin and bone. Clinical calcium. 2007, 17 (11): 1673-1677.","journal-title":"Clinical calcium"},{"issue":"3","key":"1270_CR24","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1002\/1097-4644(20010301)80:3<424::AID-JCB160>3.0.CO;2-6","volume":"80","author":"M Prince","year":"2001","unstructured":"Prince M, Banerjee C, Javed A, Green J, Lian JB, Stein GS, Bodine PV, Komm BS: Expression and regulation of Runx2\/Cbfa1 and osteoblast phenotypic markers during the growth and differentiation of human osteoblasts. J Cell Biochem. 2001, 80 (3): 424-440. 10.1002\/1097-4644(20010301)80:3<424::AID-JCB160>3.0.CO;2-6.","journal-title":"J Cell Biochem"},{"key":"1270_CR25","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1196\/annals.1346.003","volume":"1068","author":"PS Leboy","year":"2006","unstructured":"Leboy PS: Regulating bone growth and development with bone morphogenetic proteins. Ann N Y Acad Sci. 2006, 1068: 14-18. 10.1196\/annals.1346.003.","journal-title":"Ann N Y Acad Sci"},{"issue":"4","key":"1270_CR26","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1359\/jbmr.060109","volume":"21","author":"M Phimphilai","year":"2006","unstructured":"Phimphilai M, Zhao Z, Boules H, Roca H, Franceschi RT: BMP signaling is required for RUNX2-dependent induction of the osteoblast phenotype. J Bone Miner Res. 2006, 21 (4): 637-646. 10.1359\/jbmr.060109.","journal-title":"J Bone Miner Res"},{"issue":"5-6","key":"1270_CR27","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1016\/j.cytogfr.2009.10.018","volume":"20","author":"V Rosen","year":"2009","unstructured":"Rosen V: BMP2 signaling in bone development and repair. Cytokine & growth factor reviews. 2009, 20 (5-6): 475-480. 10.1016\/j.cytogfr.2009.10.018.","journal-title":"Cytokine & growth factor reviews"},{"issue":"5","key":"1270_CR28","first-page":"809","volume":"16","author":"M Nakamura","year":"2006","unstructured":"Nakamura M, Udagawa N, Yamamoto Y, Nakamura H: BMP and osteoclastogenesis. Clinical calcium. 2006, 16 (5): 809-815.","journal-title":"Clinical calcium"},{"issue":"11","key":"1270_CR29","doi-asserted-by":"publisher","first-page":"6972","DOI":"10.1074\/jbc.274.11.6972","volume":"274","author":"H Harada","year":"1999","unstructured":"Harada H, Tagashira S, Fujiwara M, Ogawa S, Katsumata T, Yamaguchi A, Komori T, Nakatsuka M: Cbfa1 isoforms exert functional differences in osteoblast differentiation. J Biol Chem. 1999, 274 (11): 6972-6978. 10.1074\/jbc.274.11.6972.","journal-title":"J Biol Chem"},{"issue":"9","key":"1270_CR30","doi-asserted-by":"publisher","first-page":"3339","DOI":"10.1128\/MCB.23.9.3339-3351.2003","volume":"23","author":"J Sierra","year":"2003","unstructured":"Sierra J, Villagra A, Paredes R, Cruzat F, Gutierrez S, Javed A, Arriagada G, Olate J, Imschenetzky M, Van Wijnen AJ: Regulation of the bone-specific osteocalcin gene by p300 requires Runx2\/Cbfa1 and the vitamin D3 receptor but not p300 intrinsic histone acetyltransferase activity. Mol Cell Biol. 2003, 23 (9): 3339-3351. 10.1128\/MCB.23.9.3339-3351.2003.","journal-title":"Mol Cell Biol"},{"issue":"3","key":"1270_CR31","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1002\/jcp.21468","volume":"216","author":"S Kanzaki","year":"2008","unstructured":"Kanzaki S, Takahashi T, Kanno T, Ariyoshi W, Shinmyouzu K, Tujisawa T, Nishihara T: Heparin inhibits BMP-2 osteogenic bioactivity by binding to both BMP-2 and BMP receptor. J Cell Physiol. 2008, 216 (3): 844-850. 10.1002\/jcp.21468.","journal-title":"J Cell Physiol"},{"issue":"4","key":"1270_CR32","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1182\/blood.V88.4.1314.bloodjournal8841314","volume":"88","author":"JM Muir","year":"1996","unstructured":"Muir JM, Andrew M, Hirsh J, Weitz JI, Young E, Deschamps P, Shaughnessy SG: Histomorphometric analysis of the effects of standard heparin on trabecular bone in vivo. Blood. 1996, 88 (4): 1314-1320.","journal-title":"Blood"},{"issue":"7","key":"1270_CR33","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1002\/jbmr.5650070707","volume":"7","author":"MH Chowdhury","year":"1992","unstructured":"Chowdhury MH, Hamada C, Dempster DW: Effects of heparin on osteoclast activity. J Bone Miner Res. 1992, 7 (7): 771-777.","journal-title":"J Bone Miner Res"},{"issue":"2","key":"1270_CR34","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/j.bone.2007.04.190","volume":"41","author":"A Irie","year":"2007","unstructured":"Irie A, Takami M, Kubo H, Sekino-Suzuki N, Kasahara K, Sanai Y: Heparin enhances osteoclastic bone resorption by inhibiting osteoprotegerin activity. Bone. 2007, 41 (2): 165-174. 10.1016\/j.bone.2007.04.190.","journal-title":"Bone"}],"container-title":["BMC Musculoskeletal Disorders"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2474-12-247.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/1471-2474-12-247\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2474-12-247","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2474-12-247.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T17:31:47Z","timestamp":1630517507000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcmusculoskeletdisord.biomedcentral.com\/articles\/10.1186\/1471-2474-12-247"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,10,28]]},"references-count":34,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2011,12]]}},"alternative-id":["1270"],"URL":"https:\/\/doi.org\/10.1186\/1471-2474-12-247","relation":{},"ISSN":["1471-2474"],"issn-type":[{"value":"1471-2474","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,10,28]]},"assertion":[{"value":"23 January 2011","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 October 2011","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 October 2011","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"247"}}