Takahata Masahiko, Maher Jason R, Juneja Subhash C, Inzana Jason, Xing Lianping, Schwarz Edward M, Berger Andrew J, Awad Hani A
University of Rochester, New York, USA.
Arthritis Rheum. 2012 Nov;64(11):3649-59. doi: 10.1002/art.34639.
Glucocorticoid (GC) therapy is associated with increased risk of fracture in patients with rheumatoid arthritis (RA). To elucidate the cause of this increased risk, we examined the effects of chronic erosive inflammatory arthritis and GC treatment on bone quality, structure, and biomechanical properties in a murine model.
Mice with established arthritis and expressing human tumor necrosis factor α (TNFα) transgene (Tg) and their wild-type (WT) littermates were continually treated with GC (prednisolone 5 mg/kg/day via subcutaneous controlled-release pellet) or placebo for 14, 28, or 42 days. Microstructure, biomechanical properties, chemical composition, and morphology of the tibiae and lumbar vertebral bodies were assessed by micro-computed tomography, biomechanical testing, Raman spectroscopy, and histology, respectively. Serum markers of bone turnover were also determined.
TNF-Tg and GC treatment additively decreased mechanical strength and stiffness in both the tibiae and the vertebral bodies. GC treatment in the TNF-Tg mice increased the ductility of tibiae under torsional loading. These changes were associated with significant alterations in the biochemical and structural composition of the mineral and organic components of the bone matrix, a decrease in osteoblast activity and bone formation, and an increase in osteoclast activity.
Our findings indicate that the concomitant decrease in bone strength and increase in bone ductility associated with chronic inflammation and GC therapy, coupled with the significant changes in the bone quality and structure, may increase the susceptibility of the bone to failure under low-energy loading. This may explain the mechanism of symptomatic insufficiency fractures in patients with RA receiving GC therapy who do not have radiographic manifestations of fracture.
糖皮质激素（GC）治疗与类风湿关节炎（RA）患者骨折风险增加相关。为阐明这种风险增加的原因，我们在小鼠模型中研究了慢性侵蚀性炎症性关节炎和GC治疗对骨质量、结构及生物力学特性的影响。
患有已确诊关节炎且表达人肿瘤坏死因子α（TNFα）转基因（Tg）的小鼠及其野生型（WT）同窝小鼠持续接受GC（通过皮下控释微丸给予泼尼松龙5 mg/kg/天）或安慰剂治疗14、28或42天。分别通过微计算机断层扫描、生物力学测试、拉曼光谱和组织学评估胫骨和腰椎椎体的微观结构、生物力学特性、化学成分和形态。还测定了骨转换的血清标志物。
TNF-Tg和GC治疗叠加性降低了胫骨和椎体的机械强度和刚度。TNF-Tg小鼠接受GC治疗增加了胫骨在扭转负荷下的延展性。这些变化与骨基质矿物质和有机成分的生化及结构组成的显著改变、成骨细胞活性和骨形成的降低以及破骨细胞活性的增加有关。
我们的研究结果表明，与慢性炎症和GC治疗相关的骨强度降低和骨延展性增加，再加上骨质量和结构的显著变化，可能会增加骨骼在低能量负荷下发生骨折的易感性。这可能解释了接受GC治疗的RA患者出现症状性不全骨折但无骨折影像学表现的机制。
