THE EFFECT OF RIVAROXABAN ON OSTEOBLASTIC PROLIFERATION, FUNCTION AND GENE EXPRESSION

Abstract

Introduction: Low-molecular-weight heparin is commonly used for thromboprophylactic therapy post orthopaedic surgery. Studies in the past have suggested that it may have a negative effect on osteoblasts and some have implicated its use with the risk of developing osteoporosis. Recently, Rivaroxaban, an oral Factor Xa inhibitor is gaining impetus for antithrombotic therapy over the last year and has been recommended for licensing by the FDA for this purpose. The effect of Rivaroxa-ban on bone and osteoblasts, if any, remains to be seen.

Methods: In a standardized in vitro model, human osteoblasts were cultured and exposed to a range of Enoxaparin and Rivaroxaban concentrations including their therapeutic dose. We evaluated the effects of these drugs on osteoblastic proliferation and activity using CellTiter 96 AQueous non-radioactive cell proliferation (MTS) and alkaline phosphatase assays respectively. Gene expression of Runt-related transcription factor 2 (Runx2), osteocalcin and bone morphogenetic protein 2 (BMP-2) were evaluated using Real time-polymerase chain reaction (RT-PCR) studies. Statistical analyses (t-test) were conducted using Microsoft Excel 2007.

Results: Rivaroxaban and Enoxaparin significantly reduced alkaline phosphatase activity (p< 0.05) however, no negative effects on osteoblastic proliferation was seen at all concentrations of both drugs. Rivaroxaban decreased Osteocalcin and Runx2 mRNA expression levels at 24 hours at therapeutic concentrations (p< 0.05). This effect was similarly found at therapeutic levels of Enoxaparin. Both Rivaroxaban and Enoxaparin significantly reduced BMP-2 mRNA expression both at 24 hours and 7 days at therapeutic concentrations. (p< 0.05).

Conclusion: Our study suggests that Rivaroxaban has similar negative effects on osteoblasts compared to Enoxaparin in the early stages. The increased duration of recommended Rivaroxaban therapy (2 and 5 weeks) post arthroplasty compared to Enoxaparin therapy (around 1 week) may have a more pronounced effect on bone homeostasis.