Smoking effects on bone microstructure, mechanical strength, and fracture healing

 描述（由申请人提供）：吸烟是癌症相关死亡的众所周知的原因，但也可能对长期骨骼健康产生可怕的影响。骨折和随后的死亡风险已经是老年人的一个重要问题，吸烟可以使65岁以上女性的骨折风险增加近1.5倍。在临床上，据观察，吸烟者骨折修复后骨不连和延迟愈合的发生率更高，导致护理费用更高。虽然对生物学机制有所了解，但仍不清楚吸烟如何导致骨骼差异，导致骨折风险增加和骨折愈合受损，从而导致观察到的临床结果。迄今为止，研究吸烟对骨骼的宏观影响的研究大多集中在骨骼结构和强度的不精确测量上，结果不一致。表征由于吸烟导致的骨微观结构的差异，这在骨强度中起作用，以及骨强度的功能结果的差异，将进一步提高我们对吸烟对骨骼系统影响的理解。本申请的目的是：（目的1）使用横断面研究设计表征吸烟者和非吸烟者（既往有骨折和无骨折）之间骨微观结构和机械强度的体内差异;（目的2）使用前瞻性研究设计表征吸烟者和非吸烟者急性桡骨远端骨折之间的骨折愈合差异。对于目标1，将从所有受试者中采集非优势前臂的高分辨率外周定量计算机断层扫描（HR-pQCT）图像，以确定皮质和小梁微结构参数。此外，将根据HR-pQCT图像构建多尺度微观有限元（FE）模型，以评价刚度和断裂强度。将使用双因素方差分析比较吸烟者和非吸烟者之间以及骨折状态之间的这些参数。对于目标2，将在骨折后2周内（基线）和4个月后（间隔1个月）采集骨折和对侧肢体的HR-pQCT图像。骨折愈合阶段的多尺度微观有限元模型也将被创建 时间点。将使用混合线性模型比较吸烟者和非吸烟者的骨折愈合状态的微观结构、刚度和临床结局。长期目标是开发特定于受试者的工具，以确定导致临床损伤的吸烟量或持续时间，并根据当前的吸烟习惯预测骨折修复干预的成功或失败。这项工作将允许准确预测导致骨折风险增加的受试者特定吸烟阈值，并客观识别导致骨折愈合不良的吸烟阈值。术前干预（如戒烟、尼古丁替代疗法等）的有效性充分改善骨质量，导致成功的术后结果也可以确定，进一步改善生活质量。

 DESCRIPTION (provided by applicant): Smoking is a well-known cause of cancer related death, but could also have a dire impact on long-term skeletal health. Risk for fracture and subsequent mortality is already a significant problem among the elderly, and smoking can increase fracture risk almost 1.5 times in women over 65. In the clinic, it is observed that smokers have greater incidences of non-unions and delayed healing after fracture repair, resulting in higher care expenses. While the biological mechanism is somewhat understood, it is still not clear how smoking causes skeletal differences that result in increased fracture risk and impaired fracture healing, leading to the observed clinical outcomes. Studies to-date looking at the macro-scale effects of smoking on bone have mostly focused on imprecise measures of bone structure and strength, with inconsistent results. Characterizing differences due to smoking in bone microstructure, which plays a role in bone strength, and also differences in functional outcomes of bone strength, will further improve our understanding of effects of smoking on the skeletal system. The objectives of this application are to: (Aim 1) characterize in vivo differences in bone microstructure and mechanical strength between smokers and non-smokers (both with and without a previous fracture) using a cross-sectional study design; and, (Aim 2) characterize differences in fracture healing between smokers and non-smokers who present with acute distal radius fractures using a longitudinal-prospective study design. For Aim 1, high-resolution peripheral quantitative computed tomography (HR-pQCT) images of non-dominant forearms will be acquired from all subjects to determine cortical and trabecular microstructure parameters. Also, multiscale micro-finite element (FE) models will be constructed from the HR-pQCT images to evaluate stiffness and fracture strength. These parameters will be compared between smokers and non- smokers and between fracture status using a two-way analysis of variance. For Aim 2, HR-pQCT images of both fractured and contralateral limbs will be acquired within two weeks of fracture (baseline) and following 4 months, at one month intervals. Multiscale micro-FE models of the stages of fracture healing will also be created at all time-points. Microstructure, stiffness and clinical outcomes of fracture healing status will be compared between smokers and non-smokers using mixed linear models. The long-term goal is to develop subject-specific tools to determine quantity or duration of smoking that leads to clinical impairment, and to predict the success or failure of interventions for fracture repair based on current smoking habits. This work will allow for accurate predictions of subject-specific thresholds of smoking that result in increased fracture risk, and objective identification of smoking thresholds that cause poor fracture healing. The effectiveness of preoperative interventions (such as smoking cessation, nicotine replacement therapies etc.) to adequately improve bone quality resulting in successful postoperative outcomes can also be determined, further improving quality of life.