Simon Ryan R, Beaudin Suzanne M, Johnston Marilyn, Walton Kimberly J, Shaughnessy Stephen G
Department of Pathology and Molecular Medicine, McMaster University and Hamilton Civic Hospitals Research Centre, Hamilton, ON, Canada.
Thromb Res. 2002 Feb 15;105(4):353-8. doi: 10.1016/s0049-3848(02)00035-x.
The issue of whether long-term sodium warfarin therapy results in decreased bone density is controversial. To address this question, we randomized rats to once daily subcutaneous injections of either sodium warfarin (0.20 or 0.25 mg/kg) or saline for 28 days and monitored the effects on bone, both biomechanically and by histomorphometric analysis. In addition, the anticoagulant status of both saline- and warfarin-treated rats were monitored throughout the course of the experiment by measuring the prothrombin time, expressed as international normalized ratios (INRs). Rats treated with 0.25 mg/kg warfarin demonstrated INRs of approximately 2.6, while rats treated with either 0.20 mg/kg warfarin or saline were found to have INRs of 1.3 and 1.0, respectively. Biomechanical testing of the right femur of rats treated with 0.25 mg/kg warfarin demonstrated that warfarin caused an 8% reduction in bone strength as measured by maximum tolerated load. A similar reduction in the biomechanical parameters of energy to break (P<.0001) and force at break point (P<.005) was also observed. Histomorphometric analysis of the left femur of warfarin-treated rats revealed a 17% reduction in cancellous bone volume. This was accompanied by a 60% decrease in osteoblast surface, as well as an 80% reduction in osteoid surface. In contrast, warfarin treatment had the opposite effect on osteoclast surface, which was 35% higher following warfarin treatment. Based on these observations, we conclude that clinically relevant doses of warfarin decrease femoral bone strength and cancellous bone volume, both by decreasing the rate of bone formation and increasing the rate of bone resorption.
长期使用华法林钠治疗是否会导致骨密度降低这一问题存在争议。为解决这个问题，我们将大鼠随机分为两组，一组每天皮下注射一次华法林钠（0.20或0.25毫克/千克），另一组每天皮下注射一次生理盐水，持续28天，并通过生物力学和组织形态计量学分析监测对骨骼的影响。此外，在整个实验过程中，通过测量凝血酶原时间（以国际标准化比值（INR）表示）来监测用生理盐水和华法林治疗的大鼠的抗凝状态。用0.25毫克/千克华法林治疗的大鼠的INR约为2.6，而用0.20毫克/千克华法林或生理盐水治疗的大鼠的INR分别为1.3和1.0。对用0.25毫克/千克华法林治疗的大鼠的右股骨进行生物力学测试表明，根据最大耐受负荷测量，华法林导致骨强度降低了8%。还观察到断裂能量（P<0.0001）和断裂点力（P<0.005）的生物力学参数有类似的降低。对华法林治疗的大鼠的左股骨进行组织形态计量学分析显示，松质骨体积减少了17%。这伴随着成骨细胞表面减少60%，以及类骨质表面减少80%。相比之下，华法林治疗对破骨细胞表面有相反的影响，华法林治疗后破骨细胞表面增加了35%。基于这些观察结果，我们得出结论，临床相关剂量的华法林通过降低骨形成速率和增加骨吸收速率来降低股骨骨强度和松质骨体积。
