Research shows donepezil could be used to prevent bone fractures.
The most common drug used to treat Alzheimer’s disease increases bone mass in mice, according to one of the first research articles published in the new open access journal Heliyon. The authors of the study, from Saitama Medical University in Japan, say this means the drug could also be used to treat bone loss diseases like osteoporosis and periodontitis, following further clinical research.
Alzheimer’s disease is the most common form of dementia and the incidence is increasing in our aging population. In the early stages of Alzheimer’s disease, bone density decreases, putting patients at a higher risk of bone fractures.
The new Heliyon study suggests that treating Alzheimer’s disease with a drug called donepezil not only improves cognitive function but also increases bone density, reducing the risk of fractures.
“We think that donepezil can improve cognitive function and increase bone mass, making it a very useful drug for patients with dementia and osteoporosis,” said lead author Dr. Tsuyoshi Sato, Associate Professor in the Department of Oral and Maxillofacial Surgery, Saitama Medical University. “From the viewpoint of medical economics, this dual purpose could reduce the cost of treating these diseases.”
Two different kinds of cell control the bone mass and density in our bodies: osteoblasts make bone and osteoclasts absorb it. A molecule called acetylcholine causes osteoclasts to die in vitro. Although an enzyme called acetylcholinesterase breaks this molecule down, the effect of this enzyme on osteoclasts remains unclear.
The most common drug used to treat Alzheimer’s disease, donepezil, stops acetylcholinesterase from working, leading to an increase in the amount of acetylcholine in the brain. Recent retrospective clinical studies have suggested that patients being treated with donepezil for Alzheimer’s disease have a lower risk of hip fracture, and that risk was dependent on the dose they were taking.
The researchers wanted to understand how donepezil prevents bone degradation. They looked at the drug’s activity in vitro using mouse bone marrow cells, and found that more acetylcholinesterase is produced when osteoclasts are being made, which leads to even more osteoclasts being made. Donepezil stops acetylcholinesterase from working, therefore preventing osteoclasts from being made.
The team also looked at the effect of the drug in a mouse model with bone loss. They found that donepezil increases bone mass in mice by preventing the production of osteoclasts.
“We were surprised to see that donepezil directly inhibits the production of osteoclasts and subsequently increases bone mass in vivo,” said Dr. Sato. “This is very surprising point – donepezil directly controls the molecule that is responsible for macrophages becoming osteoclasts.”
Previous research has shown that acetylcholinesterase activity increases continuously with age, and may accelerate the risk of bone loss in elderly people. The researchers noted that the concentration of acetylcholinesterase in macrophages was higher when the tissue was inflamed. This suggests that inflammation causes bone to be degraded in part due to acetylcholinesterase production.
“Our findings are very promising and suggest that there is a role for donepezil in increasing bone mass in elderly patients with inflammation and dementia,” said Dr. Sato. “There is still work to be done and we look forward to observing the effect of this drug in patients.”
The team now plans to work with the Department of Neurology at Saitama Medical University on clinical research. They plan to study whether taking donepezil reduces patients’ risk of bone fracture by looking at its effect in a group of patients compared to a control group.
About this neuropharmacology research
Source: Mary Beth O’Leary – Elsevier Image Source: The image is in the public domain Original Research: Full open access research for “Donepezil prevents RANK-induced bone loss via inhibition of osteoclast differentiation by downregulating acetylcholinesterase” by Tsuyoshi Sato, Yuichiro Enoki, Yasushi Sakamoto, Kazuhiro Yokota, Masahiko Okubo, Masahito Matsumoto, Naoki Hayashi, Michihiko Usui, Shoichiro Kokabu, Toshihide Mimura, Yoshihiko Nakazato, Nobuo Araki, Toru Fukuda, Yasushi Okazaki, Tatsuo Suda, Shu Takeda, and etsuya Yoda in Heliyon. Published online September 21 2015 doi:10.1016/j.heliyon.2015.e00013
Donepezil prevents RANK-induced bone loss via inhibition of osteoclast differentiation by downregulating acetylcholinesterase
Donepezil, an inhibitor of acetylcholinesterase (AChE) targeting the brain, is a common medication for Alzheimer’s disease. Interestingly, a recent clinical study found that administration of this agent is associated with lower risk of hip fracture independently of falling, suggesting its direct effect on bone tissues as well. AChE has been reported to be involved in osteoblast function, but the role of AChE on osteoclastogenesis still remains unclear. We analyzed the effect of AChE and donepezil on osteoclastogenesis in vivo and in vitro.
Cell-based assays were conducted using osteoclasts generated in cultures of murine bone marrow macrophages (BMMs) with receptor activator of nuclear factor-kappa B ligand (RANKL). The effect of donepezil was also determined in vivo using a mouse model of RANKL-induced bone loss.
Recombinant AChE in BMMs cultured with RANKL further promoted RANKL-induced tartrate-resistant acid phosphatase (TRAP)-positive osteoclast differentiation. RANKL also upregulated AChE expression in BMMs. RNA interference-mediated knockdown of AChE significantly inhibited RANKL-induced osteoclast differentiation and suppressed gene expression specific for osteoclasts. AChE upregulated expression of RANK, the receptor of RANKL, in BMMs. Donepezil decreased cathepsin K expression in BMMs and the resorptive function of osteoclasts on dentine slices. Donepezil decreased RANK expression in BMMs, resulting in the inhibition of osteoclast differentiation with downregulation of c-Fos and upregulation of Id2. Moreover, administration of donepezil prevented RANKL-induced bone loss in vivo, which was associated with the inhibition of bone resorption by osteoclasts.
AChE promotes osteoclast differentiation in vitro. Donepezil inhibits osteoclast function in vitro and prevents bone loss by suppressing bone resorption in vivo, suggesting the possibility that donepezil reduces fracture risk in patients with Alzheimer’s disease.
“Donepezil prevents RANK-induced bone loss via inhibition of osteoclast differentiation by downregulating acetylcholinesterase” by Tsuyoshi Sato, Yuichiro Enoki, Yasushi Sakamoto, Kazuhiro Yokota, Masahiko Okubo, Masahito Matsumoto, Naoki Hayashi, Michihiko Usui, Shoichiro Kokabu, Toshihide Mimura, Yoshihiko Nakazato, Nobuo Araki, Toru Fukuda, Yasushi Okazaki, Tatsuo Suda, Shu Takeda, and etsuya Yoda in Heliyon. Published online September 21 2015 doi:10.1016/j.heliyon.2015.e00013