title: 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.
abstract: BACKGROUND
  Results from observational studies may be inconsistent because of variations in methodological and clinical factors that may be intrinsically related to the database (DB) where the study is performed.
  
  
  OBJECTIVE
  The objectives of this paper were to evaluate the impact of applying a common study protocol to study benzodiazepines (BZDs) (anxiolytics, hypnotics, and related drugs) and the risk of hip/femur fracture (HFF) across three European primary care DBs and to investigate any resulting discrepancies.
  
  
  METHODS
  To measure the risk of HFF among adult users of BZDs during 2001-2009, three cohort and nested case control (NCC) studies were performed in Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP) (Spain), Clinical Practice Research Datalink (CPRD) (UK), and Mondriaan (The Netherlands). Four different models (A-D) with increasing levels of adjustment were analyzed. The risk according to duration and type of BZD was also explored. Adjusted hazard ratios (cohort), odds ratios (NCC), and their 95% confidence intervals were estimated.
  
  
  RESULTS
  Adjusted hazard ratios (Model C) were 1.34 (1.23-1.47) in BIFAP, 1.66 (1.54-1.78) in CPRD, and 2.22 (1.55-3.29) in Mondriaan in cohort studies. Adjusted odds ratios (Model C) were 1.28 (1.16-1.42) in BIFAP, 1.60 (1.49-1.72) in CPRD, and 1.48 (0.89-2.48) in Mondriaan in NCC studies. A short-term effect was suggested in Mondriaan, but not in CPRD or BIFAP. All DBs showed an increased risk with the concomitant use of anxiolytic and hypnotic drugs.
  
  
  CONCLUSIONS
  Applying similar study methods to different populations and DBs showed an increased risk of HFF in BZDs users but differed in the magnitude of the risk, which may be because of inherent differences between DBs.
authors.affiliation: Pharmacology Section, Department of Biomedical Sciences, School of Medicine and Health Sciences, University of Alcalá, Madrid, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Requena
authors.affiliation: BIFAP Research Unit, Division of Pharmacoepidemiology and Pharmacovigilance, Medicines for Human Use Department, Spanish Agency for Medicines and Medical Devices (AEMPS), Madrid, Spain.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Huerta
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands.|Department of Clinical Pharmacy, Division Laboratory and Pharmacy, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
authors.forename: Helga
authors.initials: H
authors.lastname: Gardarsdottir
authors.affiliation: Worldwide Epidemiology, GlaxoSmithKline Research and Development, Uxbridge, Middlesex, UK.
authors.forename: John
authors.initials: J
authors.lastname: Logie
authors.affiliation: BIFAP Research Unit, Division of Pharmacoepidemiology and Pharmacovigilance, Medicines for Human Use Department, Spanish Agency for Medicines and Medical Devices (AEMPS), Madrid, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: González-González
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands.
authors.forename: Victoria
authors.initials: V
authors.lastname: Abbing-Karahagopian
authors.affiliation: Merck KGaA, Geneva, Switzerland.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Miret
authors.affiliation: Division of Clinical Pharmacy & Epidemiology, University of Basel, Basel, Switzerland.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Schneider
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Souverein
authors.affiliation: Worldwide Epidemiology, GlaxoSmithKline Research and Development, Uxbridge, Middlesex, UK.
authors.forename: Dave
authors.initials: D
authors.lastname: Webb
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands.
authors.forename: Ana
authors.initials: A
authors.lastname: Afonso
authors.affiliation: Worldwide Epidemiology, GlaxoSmithKline Research and Development, Uxbridge, Middlesex, UK.
authors.forename: Nada
authors.initials: N
authors.lastname: Boudiaf
authors.affiliation: BIFAP Research Unit, Division of Pharmacoepidemiology and Pharmacovigilance, Medicines for Human Use Department, Spanish Agency for Medicines and Medical Devices (AEMPS), Madrid, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Martin
authors.affiliation: BIFAP Research Unit, Division of Pharmacoepidemiology and Pharmacovigilance, Medicines for Human Use Department, Spanish Agency for Medicines and Medical Devices (AEMPS), Madrid, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Oliva
authors.affiliation: BIFAP Research Unit, Division of Pharmacoepidemiology and Pharmacovigilance, Medicines for Human Use Department, Spanish Agency for Medicines and Medical Devices (AEMPS), Madrid, Spain.
authors.forename: Arturo
authors.initials: A
authors.lastname: Alvarez
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands.
authors.forename: Mark C H
authors.identifier: http://orcid.org/0000-0002-5764-5788
authors.initials: MC
authors.lastname: De Groot
authors.affiliation: Epidemiology, Pfizer Ltd, Tadworth, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bate
authors.affiliation: AstraZeneca AB, Mölndal, Sweden.
authors.forename: Saga
authors.initials: S
authors.lastname: Johansson
authors.affiliation: Global Clinical Epidemiology, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Raymond
authors.initials: R
authors.lastname: Schlienger
authors.affiliation: Epidemiology, Medical Division, Pfizer, New York, NY, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Reynolds
authors.affiliation: Department of Clinical Pharmacy, Division Laboratory and Pharmacy, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.|Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
authors.forename: Olaf H
authors.initials: OH
authors.lastname: Klungel
authors.affiliation: Pharmacology Section, Department of Biomedical Sciences, School of Medicine and Health Sciences, University of Alcalá, Madrid, Spain.|Clinical Pharmacology Unit, University Hospital Príncipe de Asturias, Madrid, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: de Abajo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014151:Anti-Anxiety Agents / Q000009:adverse effects; D001569:Benzodiazepines / Q000009:adverse effects*; D016022:Case-Control Studies; D015331:Cohort Studies; D016208:Databases, Factual / Q000592:standards*; D005062:European Union; D005260:Female; D006620:Hip Fractures / Q000209:etiology*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000009:adverse effects; D008297:Male; D008875:Middle Aged
chemical_list: D014151:Anti-Anxiety Agents; D006993:Hypnotics and Sedatives; D001569:Benzodiazepines
keywords: benzodiazepines; cohort; databases; hip fractures; nested case control; pharmacoepidemiology