Effect of Acetylcholinesterase Inhibitors on Bone Metabolism

Effect of Acetylcholinesterase Inhibitors on Bone Metabolism and Fracture Risk Factors Among Older Adults With Mild to Moderate Alzheimer's Disease

People with Alzheimer's disease are at an increased risk of bone fracture. Some studies have shown that those taking donepezil have a lower rate of bone fractures, but the reasons for this are unknown. The purpose of this study is to measure the effect of donepezil treatment on bone metabolism factors including bone mineral density, bone turnover markers, and bone quality.

Participants in this study will have a bone density test and have blood samples collected at the baseline study visit. Participants will then be randomly assigned to donepezil or matching memantine to be taken daily by mouth for 12 months. Blood samples will be collected at 6 and 12 months. A repeat bone density test will be performed at 12 months. Participants will also complete questionnaires at each study visit.

Study Overview

• Status: Recruiting
• Conditions: Osteoporosis
• Intervention / Treatment: Drug: Donepezil; Drug: Memantine

• Study Type: Interventional
• Enrollment (Estimated): 45
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Susanne Danus; Phone Number: (919) 681-9807; Email: susanne.danus@duke.edu

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Recruiting
      • Duke Memory Disorders Clinic
      • Contact: Connie Thacker

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Diagnosis of cognitive impairment, including clinical assessment, radiographic or laboratory biomarker assessment
2. Willing to initiate treatment for cognitive impairment
3. A) For females: either age > 55 years, or Age < 55 years and at least 12 months since last menstrual period B) For males, age > 50 years
4. Geriatric Depression Scale score < 6
5. English-speaking

Exclusion Criteria:

1. Currently on acetylcholinesterase inhibitor or memantine
2. History of bradycardia, heart block, long QT, unexplained syncope, or other contraindication for donepezil; subject with ECG showing HR < 50, PR interval > 200 ms, QTc > 440 ms in men or > 460 ms in women, or evidence of atrioventricular block
3. Currently on osteoporosis medication (e.g., bisphosphonate, SERM, denosumab, teriparatide, abaloparatide, romozosumab, calcitonin)
4. Use of bisphosphonate within last 5 years
5. Use within last 6 months of estrogens or testosterone, androgen deprivation therapy or aromatase inhibitors, antiepileptic, heparin therapy, thiazolidinediones
6. History of disorders associated with secondary osteoporosis: collagen vascular diseases, malabsorption, inflammatory bowel disease, severe liver disease/cirrhosis, hyperthyroidism (endogenous or exogenous)
7. History of fracture of the humerus, wrist, or vertebra due to fall from standing height or less
8. History of hip fracture, hip replacement, or non-ambulatory
9. Long-term use (>6 months) of corticosteroids
10. History of Parkinson's, HIV, Huntington's disease
11. History of solid organ transplantation
12. History of bariatric surgery or intending to lose weight by bariatric surgery or weight loss medication (e.g. GLP-1 agonist) in the next 12-months
13. Severe kidney impairment (eGFR < 30 ml/min),
14. Active malignancy currently undergoing chemotherapeutic, surgical, or radiation therapy, except non-melanomatous skin cancer
15. 1-year mortality > 25%, measured by ePrognosis calculator
16. Planning to move out of the area in the next 12-months
17. Planning surgery in the next 12-months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Donepezil	Drug: Donepezil; 10 mg tablet
Active Comparator: Memantine	Drug: Memantine; 10 mg tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in bone mineral density, as measured by dual x-ray absorptiometry (DXA)	baseline, 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in bone resorption marker C-terminal telopeptide (CTX)	measured using commercially available ELISA test on serum	baseline, 6 months, 12 months
Change in bone formation marker amino-terminal propeptide of type I procollagen (P1NP)	measured using commercially available ELISA test on serum	baseline, 6 months, 12 months
Change in Trabecular Bone score	measure of bone quality, using DXA spine images	baseline, 12 months

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Richard H Lee, MD, MPH, Duke University

Study record dates

Study Major Dates

• Study Start (Actual): February 3, 2025
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): November 1, 2026

Study Registration Dates

• First Submitted: September 11, 2023
• First Submitted That Met QC Criteria: September 11, 2023
• First Posted (Actual): September 18, 2023

Study Record Updates

• Last Update Posted (Estimated): September 11, 2025
• Last Update Submitted That Met QC Criteria: September 5, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Bone Diseases, Metabolic; Nutritional and Metabolic Diseases; Osteoporosis; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Hydrocarbons; Hydrocarbons, Cyclic; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Piperidines; Adamantane; Bridged-Ring Compounds; Amantadine; Indans; Indenes; Donepezil; Memantine
• Other Study ID Numbers: Pro00111080; R21AG078982 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No