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

1.项目总结/摘要 骨质疏松症是一个主要的健康问题。它影响了4000多万美国人， 每年有超过200万例骨折发生在医疗保险患者中。因糖尿病住院 骨折超过了心脏病、中风和乳腺癌的总和。骨质疏松症是常见的 被认为是一种与更年期有关的疾病。这种雌激素缺乏相关的骨质流失的特点是 高骨转换，增加骨吸收，而骨形成没有相应的变化。符合 与年龄相关的骨质流失相反，早在生命的第四个十年就开始了， 年龄增长。骨代谢相关的骨丢失通常与较低的骨转换和骨密度降低有关。 地层是主要的异常。目前的治疗方法不能解决与年龄相关的骨质流失和特殊需求， 与年龄相关的骨质疏松症人群目前被忽视。这在很大程度上是由于困难 与确定骨转换状态所需的骨活检相关。因此，现行标准 的护理依赖于从抗吸收剂开始，这对年龄相关的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， 基于低骨转换的认识和初始治疗的年龄相关性骨质疏松症的治疗 目的2）寻找一种非侵入性的方法来诊断骨质疏松患者的低骨转换 通过测量血清羧化骨钙素（1-43/49），并通过“金标准”骨进行验证 活组织检查和组织形态测定。 我们的方法是在前瞻性研究中招募被诊断患有骨质疏松症的女性患者， 概念验证研究。患者将在基线时接受骨活检和抽血。骨转换状态将 采用组织形态测定法进行评估。此外，血液中羧化骨钙素（1-43/49）的水平将在 测量以确定其有效性-单独或与其他骨标志物组合-用于诊断 低骨转换在年龄相关性骨丢失中普遍存在。 患者将根据转换状态进行分组。低转换患者将随机（1：1）分配至 用合成代谢特立帕肽（第1组）或用标准护理抗吸收剂阿仑膦酸盐（第2组）治疗， 2)一年的为了提供必要的对照组进行非侵入性评估的周转， 正常-高转换患者（第3组）将用标准护理阿仑膦酸盐治疗一年。基线时 在一年时，将通过DXA进行骨矿物质密度测量， 组之间进行比较。我们的中心假设是，低周转，年龄相关的骨质疏松症需要 诊断和治疗与雌激素缺乏相关的骨质疏松症不同。结果将提供一个 治疗骨质疏松症的范式转变

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.