Effect of Acetylcholinesterase inhibitors on Bone Metabolism and Fracture Risk Factors among older adults with mild to moderate Alzheimer's Disease

乙酰胆碱酯酶抑制剂对患有轻至中度阿尔茨海默病的老年人骨代谢和骨折危险因素的影响

• 批准号: 10739853
• 负责人: Richard Hsang-Yang Lee
• 金额: $ 23.94万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739853
• 关键词: Acetylcholinesterase Inhibitors; Ache; Address; Adult; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease related dementia; Apoptosis; Area; Biological Markers; Bone Density; Bone Resorption; C-telopeptide; Capsicum; Caring; Cholinergic Receptors; Clinic; Clinical; Cognitive; Diagnosis; Dose; Elderly; Epidemiology; Fracture; Goals; Harm Reduction; Intervention; Knowledge; Measures; Memory Disorders; Morbidity - disease rate; Muscarinics; N-terminal; Newly Diagnosed; Osteoblasts; Osteoclasts; Osteogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Actions; Physical Function; Pilot Projects; Placebos; Prevention program; Probability; Procollagen; Public Health; Publishing; Quality of life; Randomized; Regimen; Resources; Risk Factors; Roentgen Rays; Side; Trabecular Bone Score; Work; aged; bone; bone metabolism; bone quality; bone turnover; clinical risk; clinically significant; cohort; comorbidity; design; donepezil; fracture risk; hip bone; improved; innovation; mortality; older men; osteoblast proliferation; pharmacologic; preclinical study; prevent; programs; prospective; rational design; recruit

Project Abstract Older adults with Alzheimer's disease and related dementias (ADRD) have a 2-fold increased risk of clinical bone fracture, and 33% higher rate of morbidity and mortality following fracture. Our prior study showed clinical fractures were reduced by 18% among those prescribed an acetylcholinesterase inhibitor (AchEI). With both cognitive and non-cognitive benefits, AchEIs such as donepezil would be valuable in a fracture prevention program, for older adults with ADRD, with multiple complementary and synergistic components. However, the pathways by which AchEIs reduce fracture risk represent a significant gap in knowledge. Before incorporating AchEIs into a multicomponent program, the specific effects of AchEIs on bone metabolism must be understood. The objective of this application is to measure the effect of ADRD treatment with AchEIs on fracture risk factors including bone mineral density (BMD), bone turnover markers, and bone quality. Our central hypothesis is that AchEIs reduce fracture risk through direct effects on bone metabolism via stimulation of osteoblastic bone formation and reduction in osteoclastic bone resorption. We will recruit adults aged >50 years from the Memory Disorders Clinic with mild to moderate ADRD (N = 45) who will be randomized 2:1 to either the AchEI donepezil 10 mg daily or placebo, respectively. From this biomarker-diagnosed cohort of older adults with mild to moderate ADRD, we will address the following Specific Aims: 1) Determine change over 12-months in Bone Mineral Density measured by dual x-ray absorptiometry associated with the initiation of donepezil; 2) Determine change over 6- and 12-months in Bone Turnover measured by (A) the Bone Resorption Marker C-telopeptide (CTX) and (B) the Bone Formation Marker Procollagen 1 intact N-terminal Pro-peptide (P1NP) associated with the initiation of donepezil; 3) Determine change over 12-months in Bone Quality measured by Trabecular Bone Score associated with the initiation of donepezil. In addressing this significant area, the current application focuses on several NIA priorities including multiple comorbidities and care for adults with ADRD. The proposed study is innovative in its comprehensive, prospective assessment of bone metabolism among adults with biomarker- based diagnosis of ADRD initiating AchE.

项目摘要 患有阿尔茨海默病和相关痴呆（ADRD）的老年人的临床风险增加2倍， 骨折，骨折后的发病率和死亡率高33%。我们之前的研究显示， 在服用乙酰胆碱酯酶抑制剂（AchEI）的患者中，骨折减少了18%。与两 认知和非认知方面的益处，乙酰胆碱酯酶抑制剂如多奈哌齐在预防骨折方面是有价值的。 计划，为老年人与ADRD，与多个互补和协同作用的组成部分。但 乙酰胆碱酯酶抑制剂降低骨折风险的途径代表了知识上的重大空白。在合并之前 为了将AchEIs纳入一个多组分的程序中，必须了解AchEIs对骨代谢的具体作用。 本申请的目的是测量使用AchEI治疗ADRD对骨折风险因素的影响 包括骨矿物质密度（BMD）、骨转换标志物和骨质量。我们的核心假设是， 乙酰胆碱酯酶抑制剂通过刺激成骨细胞骨直接影响骨代谢降低骨折风险 骨形成和骨吸收减少。我们将从记忆中招募年龄>50岁的成年人 门诊轻度至中度ADRD患者（N = 45），将以2：1的比例随机接受AchEI多奈哌齐治疗 每天10 mg或安慰剂。从这个生物标志物诊断的老年人队列中， ADRD，我们将解决以下具体目标：1）确定12个月内骨矿物质的变化 通过与多奈哌齐的开始相关的双X射线吸收测定法测量的密度; 2）确定变化 通过（A）骨吸收标志物C-端肽（CTX）和 (B)骨形成标志物前胶原1完整的N-末端前肽（P1 NP）与骨形成起始相关， 3）通过骨小梁评分测定12个月内骨质量的变化 与多奈哌齐的起始有关。在解决这一重要领域时，本申请关注 几个NIA优先事项，包括多种合并症和成人ADRD护理。拟定研究 创新性地采用生物标志物对成人骨代谢进行全面的前瞻性评估， 基于ADRD的诊断启动AchE。