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

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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.