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

基于骨转换治疗骨质疏松症的新型精准医学方法

• 批准号: 10493127
• 负责人: Hartmut H Malluche
• 金额: $ 55.33万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10493127
• 关键词: Achievement; Adult; Affect; Age; Age-Related Bone Loss; Age-Related Osteoporosis; Alendronate; American; Anabolic Agents; Biological Assay; Biopsy; Blood; Bone Density; Bone Resorption; Bone marrow biopsy; Complement; Data; Diagnosis; Disease; Dual-Energy X-Ray Absorptiometry; Effectiveness; Elderly; Enrollment; Estrogens; Familiarity; Female; Forteo; Fracture; Gold; Health; Hematologist; Histology; Hospitalization; Life; Measurement; Measures; Medicare; Menopause; Methods; Myocardial Infarction; Osteocalcin; Osteogenesis; Osteoporosis; Osteoporotic; Outcome; Patients; Pharmaceutical Preparations; Physicians; Population; Quality of life; Randomized; Regimen; Serum; Societies; Stroke; Techniques; Testing; Therapeutic; Training; Treatment Protocols; Validation; Woman; age related; aging population; base; bisphosphonate; bone; bone loss; bone mass; bone turnover; burden of illness; carboxylate; comparison group; design; improved; individualized medicine; malignant breast neoplasm; mortality; normal aging; novel; osteoporosis with pathological fracture; personalized approach; precision medicine; prospective; standard of care; success; tool

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.

1. 项目概要/摘要 骨质疏松症是一个重要的健康问题。它影响了超过 4000 万美国人，并导致 仅医疗保险患者中每年就有超过 200 万例骨折。骨质疏松症住院 骨折的发生率超过了心脏病、中风和乳腺癌的总和。骨质疏松症很常见 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 通过高骨转换和增加的吸收而骨形成没有相应的变化。它是在 与年龄相关的骨质流失形成鲜明对比，后者早在四十岁就开始并持续到 年龄增加。年龄相关的骨质流失通常与骨转换率降低和骨量减少有关 形成是主要的异常现象。目前的疗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。这很大程度上是因为困难 与确定骨转换状态所需的骨活检相关。因此，现行标准 治疗依赖于从抗再吸收剂开始，这种药物对于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该人群中的有效性。 我们的研究力求实现两个具体目标： 目标 1) 建立一种新颖的精准医学方法 基于低骨转换认识和初始​​治疗的年龄相关性骨质疏松症的治疗 合成代谢药物，目标 2) 寻找一种非侵入性方法来诊断骨质疏松症患者的低骨转换 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 活检和组织形态计量学。 我们的方法是前瞻性地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。骨转换状态会 采用组织形态计量学进行评估。此外，羧化骨钙素 (1-43/49) 的血液水平将 进行测量以确定其单独或与其他骨标志物组合用于诊断的有效性 骨转换率低是与年龄相关的骨质流失中普遍存在的现象。 患者将根据营业额状态进行分组。低周转率患者将被随机 (1:1) 分配至 使用合成代谢特立帕肽（第 1 组）或标准治疗抗吸收剂阿仑膦酸钠（第 1 组）治疗 2) 为期一年。为了为非侵入性评估营业额提供必要的对照组， 正常-高周转率患者（第 3 组）将接受为期一年的阿仑膦酸钠标准护理治疗。基线时 一年后，将通过 DXA 进行骨矿物质密度测量，并且 BMD 的一年变化将 进行组间比较。我们的中心假设是，低周转率、与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 骨质疏松症治疗范式的转变。