Donepezil for Alzheimer's Effects on Bone Metabolism

Overseen By Susanne Danus

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

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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?

This trial investigates how donepezil, a medication commonly used for Alzheimer's disease, affects bone health. People with Alzheimer's have a higher risk of bone fractures, and the study aims to determine if donepezil can reduce that risk by improving bone strength and quality. Participants will take either donepezil or memantine for a year, with regular check-ins to test bone density and collect blood samples. The trial seeks individuals diagnosed with cognitive impairment who are not currently on certain medications, such as osteoporosis treatments. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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 there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that donepezil is generally well-tolerated by people with Alzheimer's disease. The FDA has approved it for treating Alzheimer's, indicating it has passed safety tests for this purpose. Common side effects include nausea, diarrhea, and trouble sleeping, while serious side effects are rare.

Memantine also has FDA approval for treating Alzheimer's and is generally well-tolerated. Common side effects include dizziness and headaches. Both treatments have been used extensively, offering a wealth of safety information. For concerns about side effects, consulting a healthcare professional is advisable. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Alzheimer's?

Unlike the standard treatments for Alzheimer's, which primarily focus on cognitive symptoms, Donepezil in this trial is being explored for its effects on bone metabolism. Researchers are excited about this treatment because Donepezil is known for its role in enhancing neurotransmitter function, but it may also influence bone health in Alzheimer's patients. This dual action—cognitive support and potential bone metabolism improvement—sets Donepezil apart from current options like cholinesterase inhibitors and NMDA receptor antagonists, offering a more comprehensive approach to patient care.

What evidence suggests that this trial's treatments could be effective for Alzheimer's-related bone metabolism issues?

This trial will compare Donepezil, an experimental treatment, with Memantine, an active comparator. Studies have shown that Donepezil, a medication for Alzheimer's disease, might also improve bone health. Research indicates that people taking Donepezil have a lower risk of hip fractures. Early findings suggest this might result from its positive effects on bone health, including bone strength and the natural process of bone renewal. Although this effect is still under investigation, the connection between Donepezil and better bone health appears promising. While Donepezil does not alter Alzheimer's progression, it helps manage symptoms and may also benefit bones. ^{1 2 3 6 7}

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: Memantine Active Control 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

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 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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39566720/

Effect of donepezil on bone metabolism among older adults ... We have designed this randomized, double-blind, placebo-controlled clinical trial to investigate the effect of AD treatment with donepezil on bone metabolism.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2654795/

Donepezil in Alzheimer's disease: From conventional trials to ... Although donepezil represents a non cost-effective treatment, most studies convey that this drug can provide a modest benefit on cognition, behavior, and ...

3. withpower.com withpower.com/trial/phase-2-osteoporosis-8-2023-b834b

Donepezil for Alzheimer's Effects on Bone Metabolism 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.

4. go.drugbank.com go.drugbank.com/drugs/DB00843

Donepezil: Uses, Interactions, Mechanism of Action Though it does not alter the progression of Alzheimer's disease, donepezil is effective in managing the symptoms of its associated dementia.

5. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2012/020690s035,021720s008,022568s005lbl.pdf

Aricept (donepezil hydrochloride) Label - accessdata.fda.gov The effectiveness of ARICEPT as a treatment for Alzheimer's disease is demonstrated by the results of randomized, double-blind, placebo- controlled clinical ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2010/022568s000lbl.pdf

022568s000lbl.pdf - accessdata.fda.gov ARICEPT (donepezil hydrochloride) is a reversible inhibitor of the enzyme ... ARICEPT does not cure Alzheimer's disease. All patients with Alzheimer's.

7. mayoclinic.org mayoclinic.org/drugs-supplements/donepezil-oral-route/description/drg-20063538

Donepezil (oral route) - Side effects & dosage Donepezil will not cure Alzheimer's disease, and it will not stop the disease from getting worse. ... Safety and efficacy have not been established.