Comparison of the effects of heparin and the direct factor Xa inhibitor, rivaroxaban, on bone microstructure and metabolism in adult rats

Aim: Deep venous thrombosis is a significant complication following surgery, and is associated with high morbidity and mortality in adults. The direct factor Xa inhibitor, rivaroxaban, is used to prevent venous thromboembolism in patients suffering from trauma and joint arthroplasty. The present study compared the effects of rivaroxaban and heparin on bone microstructure and metabolism in adult rats. Materials and methods: Twenty-four Wistar rats were divided into sham, rivaroxaban and heparin groups. Rivaroxaban ( 1.5mg . kg (-1) . d -1) and heparin ( 2 IU . g - 1 . d - 1) were administered for 4 weeks. To assess changes in bone metabolism, serum calcium and phosphorus levels, and bone formation and resorption markers were examined. Micro- CT analysis was used to examine the microstructure of both trabecular and cortical bone. Dual energy X- ray absorptiometry was employed to detect bone mineral density ( BMD). Results: Serum phosphorus levels were significantly lower in both rivaroxaban ( 1.33 +/- 0.07 mmol/ L) and heparin ( 1.33 +/- 0.21 mmol/ L) rats than in sham rats ( 1.71 +/- 0.14 mmol/ L). Activity and levels of bone formation markers, bone- specific alkaline phosphatase ( BAP) and type I procollagen N- terminal pro- peptide ( PINP), were 32.4 and 38.2% lower in heparin- treated rats than in sham rats. Bone resorption markers, pyridinoline ( PYD) and deoxypyridinoline ( DPD), were 20.1 and 34.3% higher in heparin- treated rats than in sham rats, respectively. By contrast, rivaroxaban only resulted in a decrease PINP levels. Bone volume fraction ( BV/ TV) decreased by 23.5 and 20.5% from those in sham rats, while trabecular separation ( Tb. Sp) increased by 28.2 and 16.3% in trabecular bone of rivaroxaban- and heparintreated rats, respectively. Moreover, the microstructure of cortical bone and BMD were negatively affected by heparin but not by rivaroxaban. Conclusion: Rivaroxaban leads to fewer adverse effects on bone microstructure than heparin.