The effect of a new direct Factor Xa inhibitor on human osteoblasts: an in-vitro study comparing the effect of rivaroxaban with enoxaparin.
BACKGROUND
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™ (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 in vitro study was to investigate the possible effects of rivaroxaban on osteoblast viability, function and gene expression compared to enoxaparin, a commonly used LMWH.


METHODS
Primary human osteoblast cultures were treated with varying concentrations of rivaroxaban (0.013, 0.13, 1.3 and 13 μg/ml) or enoxaparin (1, 10 and 100 μg/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).


RESULTS
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.


CONCLUSIONS
These data show that rivaroxaban treatment may negatively affect bone through a reduction in osteoblast function.
UCD Clinical Research Centre, UCD School of Medicine and Medical Sciences, Mater Misericordiae University Hospital, Dublin, Ireland.
Gandhi N
GN
Solayar
Pauline M
PM
Walsh
Kevin J
KJ
Mulhall
D000368:Aged; D000469:Alkaline Phosphatase / Q000378:metabolism; D000925:Anticoagulants / Q000494:pharmacology*; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D017984:Enoxaparin / Q000494:pharmacology*; D065427:Factor Xa Inhibitors; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D009025:Morpholines / Q000494:pharmacology*; D010006:Osteoblasts / Q000187:drug effects* / Q000201:enzymology; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000069552:Rivaroxaban; D013876:Thiophenes / Q000494:pharmacology*
D000925:Anticoagulants; C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D050659:Core Binding Factor Alpha 1 Subunit; D017984:Enoxaparin; D065427:Factor Xa Inhibitors; D009025:Morpholines; D012333:RNA, Messenger; C493709:RUNX2 protein, human; D013876:Thiophenes; D015675:Osteocalcin; D000069552:Rivaroxaban; D000469:Alkaline Phosphatase