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症 (ADRD) 的老年人出现临床症状的风险增加 2 倍 骨折，骨折后的发病率和死亡率高出 33%。我们之前的研究表明临床 服用乙酰胆碱酯酶抑制剂 (AchEI) 的患者骨折发生率减少了 18%。两者都有 认知和非认知益处，多奈哌齐等 AchEI 对于预防骨折很有价值 针对患有 ADRD 的老年人的计划，具有多个互补和协同组成部分。然而， AchEI 降低骨折风险的途径存在巨大的知识空白。合并前 将 AchEIs 纳入多组分方案后，必须了解 AchEIs 对骨代谢的具体影响。 本应用的目的是测量 AchEI 治疗 ADRD 对骨折危险因素的影响 包括骨矿物质密度 (BMD)、骨转换标志物和骨质量。我们的中心假设是 AchEI 通过刺激成骨细胞直接影响骨代谢，从而降低骨折风险 破骨细胞骨吸收的形成和减少。我们将从记忆中招募年龄>50岁的成年人 患有轻度至中度 ADRD 的疾病诊所 (N = 45) 将按 2:1 随机分配至 AchEI 多奈哌齐 分别为每日 10 毫克或安慰剂。来自这个生物标志物诊断的轻度至中度老年人队列 ADRD，我们将实现以下具体目标：1) 确定 12 个月内骨矿物质的变化 通过双 X 射线吸收法测量与多奈哌齐起始相关的密度； 2）确定变更 通过 (A) 骨吸收标记 C-端肽 (CTX) 测量的 6 个月和 12 个月的骨转换率以及 (B) 与起始相关的骨形成标志物前胶原 1 完整 N 末端前肽 (P1NP) 多奈哌齐； 3) 通过骨小梁评分确定 12 个月内骨质量的变化 与多奈哌齐的启动有关。在解决这一重要领域时，当前的应用重点是 NIA 的多个优先事项，包括多种合并症和 ADRD 成人护理。拟议的研究是 其对成年人骨代谢进行全面、前瞻性评估的创新性生物标志物 ADRD 引发 AchE 的基础诊断。