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。项目摘要/摘要 骨质疏松症是主要比例的健康问题。它影响了超过4000万美国人，并导致 仅在医疗保险患者中，每年超过200万个骨折。骨质疏松的医院入院 骨折超过了心脏病发作，中风和乳腺癌的骨折。骨质疏松症通常是 被认为是一种与更年期相关的疾病。这种与雌激素缺乏相关的骨质流失的特征 通过高骨转换，分辨率增加而没有骨形成的变化。它在 与年龄有关的骨质流失形成对比，与年龄相关的骨质流失早在生命的第四个十年开始就开始 年龄增加。与年龄相关的骨质流失通常与较低的骨转换和增加的骨骼有关 形成是主要异常。当前疗法不能满足与年龄相关的骨质流失和特殊需求 目前忽略了与年龄相关的骨质疏松症的人群中。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。那，当前的标准 护理依赖于从抗吸毒者开始的，该抗吸毒者在与年龄有关的骨质疏松症方面效果较差，实际上 阻碍了适当的合成代谢药物的有效性。 我们的研究旨在实现两个具体目标：目标1）建立一种新颖的精确医学方法 根据对低骨转换和初始治疗的认识，治疗与年龄有关的骨质疏松症 合成代谢和目标2）找到一种非侵入性方法来诊断骨质疏松患者的骨骼更新。 通过测量血清羧化骨钙素（1-43/49），并通过“金标准”骨骼进行验证 活检和组织形态计。 我们的方法是招募被诊断为骨质疏松症的女性患者 概念验证研究。患者将进行骨活检，并在基线时吸血。骨转换状态将 使用组织形态计量法评估。此外，羧化骨钙素的血液水平（1-43/49）将是 为了确定其有效性（单独或与其他骨标记）的有效性来衡量 - 用于诊断 与年龄相关的骨质流失占主导地位。 患者将根据失误状态进行分组。低转变的患者将被随机分配（1：1） 用合成代谢teriparatide（第1组）或护理标准抗吸毒者alendronate治疗（组） 2）一年。为了提供对不侵入性评估营业额评估的必要比较组， 正常流动率患者（第3组）将用标准的护理甲酸盐治疗一年。基线 DXA将进行一年的骨矿物质密度测量，BMD的1年变化将 在组之间进行比较。我们的核心假设是，离职率低，与年龄相关的骨质疏松症必须是 与雌激素缺乏相关的骨质疏松症的诊断和治疗不同。结果将提供 骨质疏松症治疗的范式转移。