Donepezil for Alzheimer's Effects on Bone Metabolism

Overseen By Connie Thacker

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Duke University

Must not be taking: Acetylcholinesterase inhibitors, Osteoporosis meds

Disqualifiers: Osteoporosis, Hip fracture, Parkinson's, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: 12 months

45 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

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 placebo 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.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as acetylcholinesterase inhibitors, osteoporosis medications, and some hormone therapies, among others. If you are on any of these, you may need to stop them before participating.

Is Donepezil safe for humans?

Donepezil, commonly used for Alzheimer's disease, has been shown to improve bone quality in patients with hip fractures and may lower the risk of hip fractures. However, in animal studies, it showed slightly negative effects on bone and muscle in rats with normal estrogen levels. ^{1 2 3 4 5}

How is the drug Donepezil unique in treating Alzheimer's disease?

Donepezil is unique because it is a highly selective acetylcholinesterase inhibitor, which means it helps improve memory and thinking by increasing levels of a chemical in the brain called acetylcholine. It is also convenient to use because it only needs to be taken once a day. ^{6 7 8 9 10}

What data supports the effectiveness of the drug Donepezil for Alzheimer's disease?

Research shows that Donepezil (Aricept) helps improve memory and daily function in people with mild to moderate Alzheimer's disease. It is effective in delaying the need for nursing home care and works well across different ethnic groups, even in older patients. ^{6 8 9 10 11}

Who Is on the Research Team?

Richard H Lee, MD, MPH

Principal Investigator

Duke University

Are You a Good Fit for This Trial?

This trial is for people with Alzheimer's who are at risk of osteoporosis. Women over 55 or postmenopausal, men over 50, and those willing to start treatment can join. Exclusions include current use of certain bone-related drugs, recent hormone treatments, severe liver disease or kidney impairment, and other specific health conditions.

Inclusion Criteria

I am willing to start treatment for Alzheimer's or related dementia.

My cognitive test score is below 24.

I am a woman over 55 or under 55 and haven't had a period in 12 months.

Exclusion Criteria

I am taking medication for osteoporosis.

I haven't used hormones, seizure meds, blood thinners, or diabetes drugs in the last 6 months.

I have a condition linked to weak bones, like severe liver disease or thyroid issues.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomly assigned to donepezil or placebo, taken daily by mouth for 12 months. Blood samples and bone density tests are conducted.

12 months

Baseline, 6 months, 12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including bone density and turnover markers.

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Donepezil

Trial Overview The study tests if Donepezil affects bone health in Alzheimer's patients compared to a placebo. Participants will take the drug or placebo for a year with blood tests and bone density scans at the beginning, middle, and end to measure changes in their bones.

How Is the Trial Designed?

Group I: Donepezil Experimental Treatment 1 Intervention

Group II: Placebo Placebo Group 1 Intervention

Donepezil is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Aricept for:

• Alzheimer's disease

Approved in United States as Aricept for:

• Alzheimer's disease
• Mild to moderate dementia of the Alzheimer's type

Approved in Canada as Aricept for:

• Alzheimer's disease

Approved in Japan as Aricept for:

• Alzheimer's disease

Who Is Running the Clinical Trial?

Duke University

Lead Sponsor

Trials

2,495

Recruited

5,912,000+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Published Research Related to This Trial

Donepezil is rapidly absorbed after oral administration, with most of the drug remaining unchanged in the brain, indicating that it effectively crosses the blood-brain barrier while its metabolites do not.

The drug is primarily excreted through feces, with extensive metabolism occurring in the body, but no significant accumulation of its metabolites in the brain or other tissues, suggesting a low risk of toxicity from these byproducts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Absorption, distribution, metabolism, and excretion of donepezil (Aricept) after a single oral administration to Rat. Matsui, K., Mishima, M., Nagai, Y., et al.[2018]

A small dose of donepezil (2.5 mg daily) significantly improved cognitive function in patients with amnestic mild cognitive impairment (aMCI), as evidenced by better scores in memory IQ tests and the mini-mental state examination after 3 months of treatment.

Magnetic resonance spectroscopy (MRS) results suggest that donepezil may enhance memory by activating astrocytes and stabilizing neurons, despite no significant changes in certain metabolite ratios in the hippocampus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[An interventional study on amnestic mild cognitive impairment with small dose donepezil]. Wang, LN., Wang, W., Zhang, XH., et al.[2018]

In a 12-week study involving 468 patients with mild to moderately severe Alzheimer disease, donepezil hydrochloride significantly improved cognitive function and clinical outcomes compared to placebo, with notable improvements in ADAS-cog and CIBIC plus scores.

Donepezil was well-tolerated, with a similar incidence of side effects compared to placebo, and did not show the hepatotoxic effects seen with other cholinesterase inhibitors, making it a safe option for treating Alzheimer's symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Rogers, SL., Doody, RS., Mohs, RC., et al.[2022]

Donepezil, a selective acetylcholinesterase inhibitor, has been shown to consistently improve cognitive function, global clinical ratings, and daily living activities in patients with mild to moderately severe Alzheimer's disease, based on extensive clinical trial data.

The use of donepezil is associated with significant benefits, including a reduced risk of nursing home placement, highlighting its effectiveness in managing long-term outcomes of Alzheimer's disease despite some prescribers' perceptions of limited efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Donepezil (Aricept) for treatment of Alzheimer's disease and other dementing conditions. Geldmacher, DS.[2018]

A retrospective analysis of 41 elderly Alzheimer's patients from various ethnic backgrounds showed that Donepezil (Aricept) is clinically effective for treating mild to moderate Alzheimer's disease.

The study suggests that Donepezil's efficacy is consistent across different ethnicities, including a significant number of Asian and Hawaiian patients, even in older age groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of donepezil in elderly patients with Alzheimer's disease--a Hawaii based study. Alagiakrishnan, K., Wong, W., Blanchette, PL.[2022]

Donepezil, a medication that inhibits acetylcholinesterase (AChE), significantly decreased AChE activity in mesenchymal stroma cells (MSC) from an osteoporosis sheep model, suggesting a potential mechanism for improved bone quality.

While donepezil did not increase MSC proliferation, it did enhance the mRNA expression of collagen, indicating that AChE inhibition may promote osteogenic activity rather than cell growth.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Application of donepezil increased collagen 1 expression in mesenchymal stroma cells of an ovine osteoporosis model. Nachlinger, RJ., Kauschke, V., Trinkaus, K., et al.[2019]

In a study of 45,006 older patients with Alzheimer's disease, the use of acetylcholinesterase inhibitors (AChEIs) was associated with a mild increased risk of osteoporotic fractures, with an adjusted odds ratio of 1.18.

This suggests that AChEIs do not reduce the risk of fractures and may actually contribute to them, highlighting the need for clinicians to consider this risk when prescribing these medications to older patients with Alzheimer's.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association Between Acetylcholinesterase Inhibitors and Osteoporotic Fractures in Older Persons With Alzheimer's Disease. Won, DY., Byun, SJ., Jeong, JS., et al.[2021]

In a study involving mature female rats, donepezil, an Alzheimer's drug, showed slightly negative effects on the musculoskeletal system, particularly in rats with normal estrogen levels, by decreasing bone volume and potentially reducing muscle strength.

In ovariectomized rats, which simulate post-menopausal conditions, donepezil did not show significant adverse effects on bone health, suggesting that its impact may vary depending on estrogen status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Donepezil on the Musculoskeletal System in Female Rats. Londzin, P., Trawczyński, M., Cegieła, U., et al.[2023]

Treatments for postmenopausal osteoporosis, while generally safe, can lead to rare but serious side effects such as gastrointestinal issues, musculoskeletal pain, and osteonecrosis of the jaw, particularly with bisphosphonates and denosumab.

The management of osteoporosis requires careful consideration of the potential adverse reactions against the benefits of therapy, primarily the reduction of fracture risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse drug reactions to osteoporosis treatments. Rizzoli, R., Reginster, JY.[2019]

Donepezil, a medication for Alzheimer's disease, not only inhibits acetylcholinesterase but also reduces osteoclast differentiation and function, which may help prevent bone loss and lower fracture risk in patients.

In both in vitro and in vivo studies, donepezil was shown to inhibit RANKL-induced bone resorption, suggesting a direct protective effect on bone health beyond its cognitive benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Donepezil prevents RANK-induced bone loss via inhibition of osteoclast differentiation by downregulating acetylcholinesterase. Sato, T., Enoki, Y., Sakamoto, Y., et al.[2020]

In a 24-week study involving 30 adults with Down syndrome and mild to moderate Alzheimer's disease, donepezil was found to be generally safe and well-tolerated, with no life-threatening side effects reported.

While the results showed some potential efficacy, with 50% of donepezil patients improving in dementia scores compared to 31% on placebo, the small sample size limited the statistical significance of these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Down syndrome and Alzheimer's disease--pilot study. Prasher, VP., Huxley, A., Haque, MS.[2019]

Citations

1. United States pubmed.ncbi.nlm.nih.gov

Absorption, distribution, metabolism, and excretion of donepezil (Aricept) after a single oral administration to Rat. [2018]

2. China pubmed.ncbi.nlm.nih.gov

[An interventional study on amnestic mild cognitive impairment with small dose donepezil]. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Donepezil (Aricept) for treatment of Alzheimer's disease and other dementing conditions. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Use of donepezil in elderly patients with Alzheimer's disease--a Hawaii based study. [2022]

6. Greece pubmed.ncbi.nlm.nih.gov

Application of donepezil increased collagen 1 expression in mesenchymal stroma cells of an ovine osteoporosis model. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Association Between Acetylcholinesterase Inhibitors and Osteoporotic Fractures in Older Persons With Alzheimer's Disease. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Effects of Donepezil on the Musculoskeletal System in Female Rats. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Adverse drug reactions to osteoporosis treatments. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Donepezil prevents RANK-induced bone loss via inhibition of osteoclast differentiation by downregulating acetylcholinesterase. [2020]

11. England pubmed.ncbi.nlm.nih.gov

A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Down syndrome and Alzheimer's disease--pilot study. [2019]