Physiology of Bone Metabolism in an Aging Population

骨质疏松症是一个巨大的公共健康问题。最近的估计表明，约有4400万50岁及以上的美国女性和男性患有骨质疏松症或骨量低，每年导致150万例骨折，其中包括30万例髋部骨折，70万例脊柱骨折，25万例前臂骨折和25万例其他部位骨折。虽然传统上认为骨质疏松症是女性的疾病，但男性也会患上骨质疏松症。因此，在50岁时，女性骨质疏松性骨折的终生风险为40%，而男性的可比数字为13%。考虑到这一问题的范围以及预计随着人口老龄化这一疾病的流行率会增加，合理的预防和治疗方法主要取决于更好地了解这一疾病的发病机制，以及评估其对社区的影响。在上一个资助周期的工作中，现在已经确定雌激素(E)缺乏不仅是女性，而且是男性与年龄相关的骨质流失的关键因素；因此，所有项目的共同主题是E对骨代谢的调节。与过去一样，我们团队的主要优势是将不同学科整合到协同互动中，目前的应用跨越了基于人群的流行病学研究，临床研究中心的密集研究，使用新型小鼠敲除模型的动物研究以及使用最先进的蛋白质组学技术的基础分子研究。这是通过五个项目和一个行政和生物统计核心来完成的：“老年男性骨质疏松病理生理”和“老年女性骨质疏松病理生理”分别利用临床研究中心对男性和女性的深入研究；“老年人髋部骨折的危险因素”利用基于人群的流行病学研究的罗切斯特流行病学项目的资源；“雌激素受体共激活剂和骨代谢”重点关注E作用缺陷的新型小鼠敲除模型；和“雌激素受体共调节因子在成骨细胞中的作用”提出在分子水平上剖析E在骨细胞中的作用。总的来说，这些研究努力提供对这一重要疾病的发病机制和临床影响的全面评估。

Osteoporosis is an enormous public health problem. Recent estimates indicate that about 44 million US women and men aged 50 years and older have osteoporosis or low bone mass, resulting in 1.5 million fractures per year, including 300,000 hip fractures, 700,000 spine fractures, 250,000 forearm fractures, and 250,000 fractures at other sites. While traditionally considered a disease of women, men also develop osteoporosis. Thus, at age 50, the lifetime risk of an osteoporotic fracture in women is 40%, and the comparable figure for men is 13%. Given the scope of this problem and the projected increase in the prevalence of this disease as the population ages, rational approaches to prevention and treatment depend critically on gaining a better understanding the pathogenesis of this disorder, as well as assessing its impact in the community. Work over the previous funding cycle has now identified estrogen (E) deficiency as a key factor in the development of age-related bone loss not only in women, but also in men; hence, a theme common to all projects is E regulation of bone metabolism. As in the past, the major strength of our group is to bring together diverse disciplines into synergistic interactions, and the present application spans the spectrum from population-based epidemiology studies, intensive studies in the clinical research center, animal studies using novel mouse knock out models, and basic molecular studies using state-of-the-art proteomics technology. This is accomplished through five Projects and an Administrative and Biostatistics Core: "Pathophysiology of Osteoporosis in Aging Men" and "Pathophysiology of Osteoporosis in Aging Women" utilize intensive studies in the clinical research center in men and women, respectively; "Risk Factors for Hip Fractures Among the Elderly" utilizes the resources of the Rochester Epidemiology Project in population-based epidemiology studies; "Estrogen Receptor Coactivators and Bone Metabolism" focuses on novel mouse knock out models with defects in E action; and "Actions of Estrogen Receptor Coregulators in Osteoblasts" proposes to dissect E action in bone cells at a molecular level. Collectively, these studies strive to provide a comprehensive assessment of the pathogenesis and clinical impact of this important disorder.