Burr David B, Liu Ziyue, Allen Matthew R
Department of Anatomy and Cell Biology, Indiana University School of Medicine, USA.
Department of Biostatistics, Indiana University School of Medicine, USA.
Bone. 2015 Feb;71:58-62. doi: 10.1016/j.bone.2014.10.010. Epub 2014 Oct 23.
Bisphosphonates (BPs) have been shown to significantly reduce bone toughness in vertebrae within one year when given at clinical doses to dogs. Although BPs also reduce toughness in the cortical bone when given at high doses, their effect on cortical bone material properties when given at clinical doses is less clear. In part, this may be due to the use of small sample sizes that were powered to demonstrate differences in bone mineral density rather than the bone's material properties. Our lab has conducted several studies in which dogs were treated with alendronate at a clinically relevant dose. The goal of this study was to examine these published and unpublished data collectively to determine whether there is a significant time-dependent effect of alendronate on toughness of the cortical bone. This analysis seemed particularly relevant given the recent occurrence of atypical femoral fractures in humans. Differences in the toughness of ribs taken from dogs derived from five separate experiments were measured. The dogs were orally administered saline (CON, 1ml/kg/day) or alendronate (ALN) at a clinical dose (0.2mg/kg/day). Treatment duration ranged from 3months to 3years. Groups were compared using ANOVA, and time trends analyzed with linear regression analysis. Linear regressions of the percent difference in toughness between CON and ALN at each time point revealed a significant reduction in toughness with longer exposure to ALN. The downward trend was primarily driven by a downward trend in post-yield toughness, whereas toughness in the pre-yield region was not changed relative to CON. These data suggest that a longer duration of treatment with clinical doses of ALN results in deterioration of cortical bone toughness in a time-dependent manner. As the duration of treatment is lengthened, the cortical bone exhibits increasingly brittle behavior. This may be important in assessing the role that long-term BP treatments play in the risk of atypical fractures of the femoral cortical bone in humans.
双膦酸盐（BPs）已被证明，以临床剂量给予犬类时，可在一年内显著降低椎骨的骨韧性。尽管高剂量给予双膦酸盐时也会降低皮质骨的韧性，但临床剂量下其对皮质骨材料特性的影响尚不清楚。部分原因可能是使用的样本量较小，这些样本旨在证明骨矿物质密度的差异，而非骨的材料特性。我们实验室进行了多项研究，用阿仑膦酸钠以临床相关剂量治疗犬类。本研究的目的是综合分析这些已发表和未发表的数据，以确定阿仑膦酸钠对皮质骨韧性是否存在显著的时间依赖性影响。鉴于近期人类非典型股骨骨折的发生，这种分析显得尤为重要。测量了来自五个独立实验的犬类肋骨韧性差异。犬类口服生理盐水（对照组，1ml/kg/天）或临床剂量（0.2mg/kg/天）的阿仑膦酸钠（ALN）。治疗持续时间为3个月至3年。使用方差分析比较各组，并通过线性回归分析时间趋势。每个时间点对照组和阿仑膦酸钠组之间韧性百分比差异的线性回归显示，随着暴露于阿仑膦酸钠的时间延长，韧性显著降低。下降趋势主要由屈服后韧性的下降趋势驱动，而屈服前区域的韧性相对于对照组没有变化。这些数据表明，临床剂量的阿仑膦酸钠治疗时间延长会导致皮质骨韧性随时间推移而恶化。随着治疗时间的延长，皮质骨表现出越来越脆的行为。这对于评估长期双膦酸盐治疗在人类股骨皮质骨非典型骨折风险中所起的作用可能很重要。
