Acetylcholinesterase inhibitors and the risk of osteoporotic fractures: nested case-control study
The objective of this study was to analyze the effect of acetylcholinesterase inhibitors (AChEIs) on the risk of osteoporotic fractures in Alzheimer patients. A nested case-control study was conducted on 1190 cases and 4760 controls. The use of AChEIs was found to decrease the risk of osteoporotic fractures in these patients.
The objective of this study is to estimate the extent to which the use of AChEIs is associated with a reduction in the risk of osteoporotic fractures.
A nested case-control study was conducted using data from the UK Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES) database (1998–2013). The study cohort consisted of Alzheimer’s Disease (AD) patients aged ≥ 65 years with no previous history of osteoporotic fractures at cohort baseline. Cases were individuals who suffered an osteoporotic fracture during the study period, whereas controls were subject who did not experience any osteoporotic fractures during the same period. Controls were drawn from the population time at risk while being matched to the cases in respect to age, sex, up-to-standard follow-up in the CPRD, calendar time, and duration of AD (control-to-case ratio: 4-to-1). Information on the use of AChEIs and the relevant potential confounders was ascertained from the CPRD database for all the cases and controls.
We identified 1190 cases and 4760 controls. Compared to non-users, any use of AChEIs prior to the fracture was associated with a reduction in the fracture risk [adjusted odds ratio (OR) 0.80 (confidence interval (CI) 95%, 0.70–0.91)]. The use of AChEIs corresponding to a proportion of days covered of 0.8–1.0 was associated with a lower osteoporotic fracture risk compared to non-use [adjusted OR 0.76 (CI 95%, 0.66–0.87)].
In this study using large primary care databases, the use and treatment adherence to AChEIs were associated with a decreased risk of osteoporotic fractures in elderly AD patients.
KeywordsAcetylcholinesterase inhibitors Alzheimer’s disease Mortality Osteoporotic fracture Reintervention Second fracture
We would like to thank the Canadian Institute of Health Research for their financial support. We would also like to thank the patients that participated in this study for their collaboration.
This study was funded by the Canadian Institute of Health Research [MOP-13056x0].
Compliance with ethical standards
Conflicts of interest
The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive license (or non-exclusive for government employees) on a worldwide basis to Osteoporsis International to permit this article (if accepted) to be published in Osteoporsis International editions and any other Osteoporsis International products and sublicenses such use and exploit all subsidiary rights, as set out in our license.
Dr. Tamimi affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
- 5.Elefteriou F, Ahn JD, Takeda S, Starbuck M, Yang X, Liu X, Kondo H, Richards WG, Bannon TW, Noda M, Clement K, Vaisse C, Karsenty G (2005) Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 434(7032):514–520. https://doi.org/10.1038/nature03398 CrossRefPubMedGoogle Scholar
- 9.Sato T, Abe T, Chida D, Nakamoto N, Hori N, Kokabu S, Sakata Y, Tomaru Y, Iwata T, Usui M, Aiko K, Yoda T (2010) Functional role of acetylcholine and the expression of cholinergic receptors and components in osteoblasts. FEBS Lett 584(4):817–824. https://doi.org/10.1016/j.febslet.2010.01.001 CrossRefPubMedGoogle Scholar
- 10.Bajayo A, Bar A, Denes A, Bachar M, Kram V, Attar-Namdar M, Zallone A, Kovacs KJ, Yirmiya R, Bab I (2012) Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual. Proc Natl Acad Sci U S A 109(38):15455–15460. https://doi.org/10.1073/pnas.1206061109 CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Tamimi I, Ojea T, Sanchez-Siles JM, Rojas F, Martin I, Gormaz I, Perez A, Dawid-Milner MS, Mendez L, Tamimi F (2012) Acetylcholinesterase inhibitors and the risk of hip fracture in Alzheimer’s disease patients: a case-control study. J Bone Miner Res Off J Am Soc Bone Miner Res 27(7):1518–1527. https://doi.org/10.1002/jbmr.1616 CrossRefGoogle Scholar
- 17.Hollowell J (1997) The general practice research database: quality of morbidity data. Popul Trends 87:36–40Google Scholar
- 18.Requena G, Huerta C, Gardarsdottir H et al (2016) Hip/femur fractures associated with the use of benzodiazepines (anxiolytics, hypnotics and related drugs): a methodological approach to assess consistencies across databases from the PROTECT-EU project. Pharmacoepidemiol Drug Saf 25(Suppl 1):66–78CrossRefPubMedGoogle Scholar
- 20.Sajjan SG, Barrett-Connor E, McHorney CA, Miller PD, Sen SS, Siris E (2012) Rib fracture as a predictor of future fractures in young and older postmenopausal women: National Osteoporosis Risk Assessment (NORA). Osteoporos Int 23(3):821–828. https://doi.org/10.1007/s00198-011-1757-0 CrossRefPubMedGoogle Scholar
- 28.Moura C, Bernatsky S, Abrahamowicz M, Papaioannou A, Bessette L, Adachi J, Goltzman D, Prior J, Kreiger N, Towheed T, Leslie WD, Kaiser S, Ioannidis G, Pickard L, Fraser LA, Rahme E (2014) Antidepressant use and 10-year incident fracture risk: the population-based Canadian Multicentre Osteoporosis Study (CaMoS). Osteoporos Int 25(5):1473–1481. https://doi.org/10.1007/s00198-014-2649-x CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Eimar H, Perez Lara A, Tamimi I, Marquez Sanchez P, Gormaz Talavera I, Rojas Tomba F, Garcia de la Oliva T, Tamimi F (2013) Acetylcholinesterase inhibitors and healing of hip fracture in Alzheimer’s disease patients: a retrospective cohort study. J Musculoskelet Neuronal Interact 13(4):454–463PubMedGoogle Scholar
- 30.Gill SS, Anderson GM, Fischer HD, Bell CM, Li P, Normand SL, Rochon PA (2009) Syncope and its consequences in patients with dementia receiving cholinesterase inhibitors: a population-based cohort study. Arch Intern Med 169(9):867–873. https://doi.org/10.1001/archinternmed.2009.43 CrossRefPubMedGoogle Scholar
- 32.Ensrud KE, Lipschutz RC, Cauley JA, Seeley D, Nevitt MC, Scott J, Orwoll ES, Genant HK, Cummings SR (1997) Body size and hip fracture risk in older women: a prospective study. Study of Osteoporotic Fractures Research Group. Am J Med 103(4):274–280. https://doi.org/10.1016/S0002-9343(97)00025-9 CrossRefPubMedGoogle Scholar
- 33.Hollinger JO, Schmitt JM, Hwang K, Soleymani P, Buck D (1999) Impact of nicotine on bone healing. J Biomed Mater Res 45(4):294–301. https://doi.org/10.1002/(SICI)1097-4636(19990615)45:4<294::AID-JBM3>3.0.CO;2-1 CrossRefPubMedGoogle Scholar
- 36.Kim DH, Brown RT, Ding EL, Kiel DP, Berry SD (2011) Dementia medications and risk of falls, syncope, and related adverse events: meta-analysis of randomized controlled trials. J Am Geriatr Soc 59(6):1019–1031. https://doi.org/10.1111/j.1532-5415.2011.03450.x CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Homma A, Takeda M, Imai Y, Udaka F, Hasegawa K, Kameyama M, Nishimura T (2000) Clinical efficacy and safety of donepezil on cognitive and global function in patients with Alzheimer’s disease. A 24-week, multicenter, double-blind, placebo-controlled study in Japan. E2020 Study Group. Dement Geriatr Cogn Disord 11(6):299–313. https://doi.org/10.1159/000017259 CrossRefPubMedGoogle Scholar
- 38.Winblad B, Engedal K, Soininen H, Verhey F, Waldemar G, Wimo A, Wetterholm AL, Zhang R, Haglund A, Subbiah P (2001) A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology 57(3):489–495. https://doi.org/10.1212/WNL.57.3.489 CrossRefPubMedGoogle Scholar
- 39.Wilkinson D, Doody R, Helme R, Taubman K, Mintzer J, Kertesz A, Pratt RD (2003) Donepezil in vascular dementia: a randomized, placebo-controlled study. Neurology 61(4):479–486. https://doi.org/10.1212/01.WNL.0000078943.50032.FC CrossRefPubMedGoogle Scholar
- 40.Seeley DG, Browner WS, Nevitt MC, Genant HK, Scott JC, Cummings SR (1991) Which fractures are associated with low appendicular bone mass in elderly women? The Study of Osteoporotic Fractures Research Group. Ann Intern Med 115(11):837–842. https://doi.org/10.7326/0003-4819-115-11-837 CrossRefPubMedGoogle Scholar
- 43.Mendiondo MS, Ashford JW, Kryscio RJ, Schmitt FA (2000) Modelling mini mental state examination changes in Alzheimer’s disease. Stat Med 19(11-12):1607–1616. https://doi.org/10.1002/(SICI)1097-0258(20000615/30)19:11/12<1607::AID-SIM449>3.0.CO;2-O CrossRefPubMedGoogle Scholar
- 44.Ishima T, Nishimura T, Iyo M, Hashimoto K (2008) Potentiation of nerve growth factor-induced neurite outgrowth in PC12 cells by donepezil: role of sigma-1 receptors and IP3 receptors. Prog Neuro-Psychopharmacol Biol Psychiatry 32(7):1656–1659. https://doi.org/10.1016/j.pnpbp.2008.06.011 CrossRefGoogle Scholar