Novel precision medicine approach to treatment of osteoporosis based on bone turnover

1.项目摘要/摘要 骨质疏松症是一个严重的健康问题。它影响了4000多万美国人，并导致 仅在医疗保险患者中，每年就有200多万人骨折。骨质疏松症住院治疗 骨折超过了心脏病、中风和乳腺癌的总和。骨质疏松是常见的 被认为是一种与更年期有关的疾病。这种雌激素缺乏导致的骨丢失的特征是 由于骨的高周转率，骨吸收增加，骨形成没有相应的变化。它很流行 相比之下，与年龄相关的骨质流失早在生命的第四个十年就开始了，并持续到 年龄越来越大。与年龄相关的骨丢失通常与骨转换率降低和骨减少有关。 地层是主要异常。目前的治疗方法没有解决与年龄相关的骨丢失和特殊需求 与年龄相关的骨质疏松症人口的一部分目前被忽视。这在很大程度上是由于困难。 与确定骨周转状态所需的骨活检有关。因此，目前的标准 治疗依赖于从抗吸收药物开始，这种药物对年龄相关性骨质疏松症效果较差，事实上 阻碍了适当的合成代谢药物在这一人群中的有效性。 我们的研究旨在实现两个具体目标：目标1)建立一种新的精准医学方法，以 老年骨质疏松症的治疗--基于对低骨转换的认识和早期治疗 目的2)寻找一种诊断骨质疏松患者骨转换低下的非侵入性方法。 通过测量血清中的羧化骨钙素(1-43/49)并通过“金标准”骨进行验证 活检和组织形态计量学。 我们的方法将是招募已被诊断为骨质疏松症的女性患者， 概念验证研究。患者将在基线水平上接受骨活检和抽血。骨周转状态将 采用组织形态计量学方法进行评估。此外，血液中的羧化骨钙素水平(1-43/49)将 测量以确定它们的有效性-单独或与其他骨标记物结合-诊断 低骨转换普遍存在于与年龄相关的骨丢失。 患者将根据周转情况进行分组。低周转率的患者将随机(1：1) 使用合成代谢药物(组1)或使用标准护理标准的抗吸收药物阿仑磷酸钠(组)治疗 2)为期一年。为了为营业额的非侵入性评估提供必要的对照组， 正常-高周转患者(第3组)将接受标准护理阿仑磷酸钠治疗一年。在基线上 在一年后，用DXA进行骨密度测量，一年后骨密度的变化将 在不同的组之间进行比较。我们的中心假设是低周转率、年龄相关性骨质疏松症需要 诊断和治疗与雌激素缺乏性骨质疏松症不同。结果将提供一个 骨质疏松症治疗的范式转变。

1. Project Summary/Abstract Osteoporosis is a health problem of major proportions. It affects more than 40 million Americans and results in more than 2 million fractures annually among Medicare patients alone. Hospital admissions for osteoporotic fractures exceed those of heart attacks, strokes and breast cancer combined. Osteoporosis is commonly considered a disease associated with menopause. This estrogen deficiency related bone loss is characterized by high bone turnover with increased resorption without commensurate changes in bone formation. It is in contrast to age-related bone loss, which starts as early as in the fourth decade of life and continues with increasing age. Age-related bone loss is usually associated with lower bone turnover and decreased bone formation is the main abnormality. Current therapies do not address age-related bone loss and the special needs of the age-related osteoporosis population is currently ignored. This is to a great degree due to difficulties associated with the bone biopsy necessary for determination of bone turnover status. Thus, the current standard of care relies on starting with an antiresorber, which is less effective in age-related osteoporosis, and in fact impedes the effectiveness in this population of the appropriate anabolic medication. Our study seeks to achieve two specific aims: Aim 1) to establish a novel precision medicine approach to treatment of age-related osteoporosis based on recognition of low bone turnover and initial treatment with anabolics, and Aim 2) to find a non-invasive method for diagnosing low bone turnover in osteoporotic patients by measurements of serum carboxylated osteocalcin (1-43/49) with validation via the “gold standard” bone biopsy and histomorphometry. Our approach will be to enroll female patients who have been diagnosed with osteoporosis in a prospective, proof of concept study. Patients will undergo bone biopsy and blood draws at baseline. Bone turnover status will be assessed employing histomorphometry. In addition, blood levels of carboxylated osteocalcin (1-43/49) will be measured in order to determine their validity - alone or in combination with other bone markers - for diagnosing low bone turnover prevailing in age-related bone loss. Patients will be grouped according to turnover status. Low-turnover patients will be randomized (1:1) either to treatment with the anabolic teriparatide (Group 1) or with the standard of care antiresorber alendronate (Group 2) for one year. In order to provide the necessary comparison group for the non-invasive assessment of turnover, normal-high turnover patients (Group 3) will be treated with standard of care alendronate for one year. At baseline and at one-year bone mineral density measurements will be performed by DXA and 1-year changes in BMD will be compared between groups. Our central hypothesis is that low turnover, age-related osteoporosis needs to be diagnosed and treated differently from estrogen deficiency related osteoporosis. The results will provide a paradigm shift in the treatment of osteoporosis.