Osteoporosis International

, Volume 29, Issue 4, pp 849–857 | Cite as

Acetylcholinesterase inhibitors and the risk of osteoporotic fractures: nested case-control study

  • I. Tamimi
  • B. Nicolau
  • H. Eimar
  • S. Arekunnath Madathil
  • A. Kezouh
  • I. Karp
  • F. TamimiEmail author
Original Article



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.


Acetylcholinesterase 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.

Financial support

This study was funded by the Canadian Institute of Health Research [MOP-13056x0].

Compliance with ethical standards

Conflicts of interest


Copyright statement

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.

Transparency statement

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.


  1. 1.
    Eimar H, Tamimi I, Murshed M, Tamimi F (2013) Cholinergic regulation of bone. J Musculoskelet Neuronal Interact 13(2):124–132PubMedGoogle Scholar
  2. 2.
    Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker KL, Armstrong D, Ducy P, Karsenty G (2002) Leptin regulates bone formation via the sympathetic nervous system. Cell 111(3):305–317. CrossRefPubMedGoogle Scholar
  3. 3.
    Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen JH, Vinson C, Rueger JM, Karsenty G (2000) Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 100(2):197–207. CrossRefPubMedGoogle Scholar
  4. 4.
    Karsenty G (2006) Convergence between bone and energy homeostases: leptin regulation of bone mass. Cell Metab 4(5):341–348. CrossRefPubMedGoogle Scholar
  5. 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. CrossRefPubMedGoogle Scholar
  6. 6.
    Pasco JA, Henry MJ, Sanders KM, Kotowicz MA, Seeman E, Nicholson GC (2004) Beta-adrenergic blockers reduce the risk of fracture partly by increasing bone mineral density: Geelong Osteoporosis Study. J Bone Miner Res Off J Am Soc Bone Miner Res 19:19–24CrossRefGoogle Scholar
  7. 7.
    Schlienger RG, Kraenzlin ME, Jick SS, Meier CR (2004) Use of beta-blockers and risk of fractures. Jama-J Am Med Assoc 292(11):1326–1332. CrossRefGoogle Scholar
  8. 8.
    Liu PS, Chen YY, Feng CK, Lin YH, Yu TC (2011) Muscarinic acetylcholine receptors present in human osteoblast and bone tissue. Eur J Pharmacol 650(1):34–40. CrossRefPubMedGoogle Scholar
  9. 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. CrossRefPubMedGoogle Scholar
  10. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Shi Y, Oury F, Yadav VK, Wess J, Liu XS, Guo XE, Murshed M, Karsenty G (2010) Signaling through the M3 muscarinic receptor favors bone mass accrual by decreasing sympathetic activity. Cell Metab 11(3):231–238. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Eimar H, Alebrahim S, Manickam G, Al-Subaie A, Abu-Nada L, Murshed M, Tamimi F (2016) Donepezil regulates energy metabolism and favors bone mass accrual. Bone 84:131–138. CrossRefPubMedGoogle Scholar
  13. 13.
    Pepeu G, Giovannini MG (2009) Cholinesterase inhibitors and beyond. Curr Alzheimer Res 6(2):86–96. CrossRefPubMedGoogle Scholar
  14. 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. CrossRefGoogle Scholar
  15. 15.
    Garcia Rodriguez LA, Perez Gutthann S (1998) Use of the UK general practice research database for pharmacoepidemiology. Br J Clin Pharmacol 45(5):419–425CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Lawrenson R, Williams T, Farmer R (1999) Clinical information for research; the use of general practice databases. J Public Health Med 21(3):299–304. CrossRefPubMedGoogle Scholar
  17. 17.
    Hollowell J (1997) The general practice research database: quality of morbidity data. Popul Trends 87:36–40Google Scholar
  18. 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
  19. 19.
    Imfeld P, Brauchli Pernus YB, Jick SS, Meier CR (2013) Epidemiology, co-morbidities, and medication use of patients with Alzheimer’s disease or vascular dementia in the UK. J Alzheimers Dis 35(3):565–573. PubMedGoogle Scholar
  20. 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. CrossRefPubMedGoogle Scholar
  21. 21.
    Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A (2007) Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025. J Bone Miner Res Off J Am Soc Bone Miner Res 22(3):465–475. CrossRefGoogle Scholar
  22. 22.
    Meier CR, Schlienger RG, Kraenzlin ME, Schlegel B, Jick H (2000) HMG-CoA reductase inhibitors and the risk of fractures. JAMA 283(24):3205–3210. CrossRefPubMedGoogle Scholar
  23. 23.
    Lubin JH, Gail MH (1984) Biased selection of controls for case-control analyses of cohort studies. Biometrics 40(1):63–75. CrossRefPubMedGoogle Scholar
  24. 24.
    Arsura EL, Brunner NG, Namba T, Grob D (1987) Adverse cardiovascular effects of anticholinesterase medications. Am J Med Sci 293(1):18–23. CrossRefPubMedGoogle Scholar
  25. 25.
    Berdot S, Bertrand M, Dartigues J-F, Fourrier A, Tavernier B, Ritchie K, Alpérovitch A (2009) Inappropriate medication use and risk of falls—a prospective study in a large community-dwelling elderly cohort. BMC Geriatr 9:1–10CrossRefGoogle Scholar
  26. 26.
    Franklin JM, Shrank WH, Pakes J, Sanfelix-Gimeno G, Matlin OS, Brennan TA, Choudhry NK (2013) Group-based trajectory models: a new approach to classifying and predicting long-term medication adherence. Med Care 51(9):789–796. CrossRefPubMedGoogle Scholar
  27. 27.
    Yang YX, Lewis JD, Epstein S, Metz DC (2006) Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 296(24):2947–2953. CrossRefPubMedGoogle Scholar
  28. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 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. 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. CrossRefPubMedGoogle Scholar
  31. 31.
    Friedman SM, Menzies IB, Bukata SV, Mendelson DA, Kates SL (2010) Dementia and hip fractures: development of a pathogenic framework for understanding and studying risk. Geriatr Orthop Surg Rehabil 1(2):52–62. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 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. CrossRefPubMedGoogle Scholar
  33. 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.<294::AID-JBM3>3.0.CO;2-1 CrossRefPubMedGoogle Scholar
  34. 34.
    Stevenson FH (1952) The osteoporosis of immobilisation in recumbency. J Bone Joint Surg Br 34-b:256–265CrossRefPubMedGoogle Scholar
  35. 35.
    Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT (1998) A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Donepezil Study Group. Neurology 50(1):136–145. CrossRefPubMedGoogle Scholar
  36. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 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. CrossRefPubMedGoogle Scholar
  38. 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. CrossRefPubMedGoogle Scholar
  39. 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. CrossRefPubMedGoogle Scholar
  40. 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. CrossRefPubMedGoogle Scholar
  41. 41.
    Davies NM, Kehoe PG, Ben-Shlomo Y, Martin RM (2011) Associations of anti-hypertensive treatments with Alzheimer’s disease, vascular dementia, and other dementias. J Alzheimers Dis 26(4):699–708. PubMedGoogle Scholar
  42. 42.
    Tamimi F, Wu X (2017) Osseointegration pharmacology. JDR Clin Transl Res 2(3):211–213. CrossRefGoogle Scholar
  43. 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.<1607::AID-SIM449>3.0.CO;2-O CrossRefPubMedGoogle Scholar
  44. 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. CrossRefGoogle Scholar
  45. 45.
    Woodruff-Pak DS, Vogel RW 3rd, Wenk GL (2001) Galantamine: effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning. Proc Natl Acad Sci U S A 98(4):2089–2094. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Cummings SR, Melton LJ (2002) Epidemiology and outcomes of osteoporotic fractures. Lancet (London, England) 359(9319):1761–1767. CrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2017

Authors and Affiliations

  • I. Tamimi
    • 1
  • B. Nicolau
    • 2
  • H. Eimar
    • 3
  • S. Arekunnath Madathil
    • 4
  • A. Kezouh
    • 5
  • I. Karp
    • 6
  • F. Tamimi
    • 7
    Email author
  1. 1.Hospital Regional Universitario de MalagaMalagaSpain
  2. 2.Division of Oral Health and Society Research, Faculty of DentistryMcGill UniversityMontrealCanada
  3. 3.Faculty of Medicine and DentistryUniversity of AlbertaEdmontonCanada
  4. 4.Division of Oral Health and Society Research, Faculty of DentistryMcGill UniversityMontrealCanada
  5. 5.Department of Epidemiology and Biostatistics, Centre for Clinical EpidemiologyLady Davis InstituteMontrealCanada
  6. 6.Department of Epidemiology and Biostatistics, Kresge Building K214Western UniversityLondonCanada
  7. 7.Faculty of DentistryMcGill UniversityMontrealCanada

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