title: Understanding inconsistency in the results from observational pharmacoepidemiological studies: the case of antidepressant use and risk of hip/femur fractures.
abstract: OBJECTIVE
  Results from observational studies on the same exposure-outcome association may be inconsistent because of variations in methodological factors, clinical factors or health care systems. We evaluated the consistency of results assessing the association between antidepressant use and the risk of hip/femur fractures in three European primary care databases using two different study designs.
  
  
  METHODS
  Cohort and nested case control studies were conducted in three European primary care databases (Spanish BIFAP, Dutch Mondriaan and UK THIN) to assess the association between use of antidepressants and hip/femur fracture. A common protocol and statistical analysis plan was applied to harmonize study design and conduct between data sources.
  
  
  RESULTS
  Current use of antidepressants was consistently associated with a 1.5 to 2.5-fold increased risk of hip/femur fractures in all data sources with both designs, with estimates for SSRIs generally higher than those for TCAs. In general, risk estimates in Mondriaan, the smallest data source, were higher compared to the other data sources. This difference may be partially explained by an interaction between SSRI and age in Mondriaan. Adjustment for GP-recorded lifestyle factors and matching on general practice had negligible impact on adjusted relative risk estimates.
  
  
  CONCLUSIONS
  We found a consistent increased risk of hip/femur fracture with current use of antidepressants across different databases and different designs. Applying similar pharmacoepidemiological study methods resulted in similar risks for TCA use and some variation for SSRI use. Some of these differences may express real (or natural) variance in the exposure-outcome co-occurrences.
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, The Netherlands.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Souverein
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, The Netherlands.
authors.forename: Victoria
authors.initials: V
authors.lastname: Abbing-Karahagopian
authors.affiliation: BIFAP Research Unit, Division of Pharmacoepidemiology and Pharmacovigilance, Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), Madrid, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Martin
authors.affiliation: BIFAP Research Unit, Division of Pharmacoepidemiology and Pharmacovigilance, Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), Madrid, Spain.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Huerta
authors.affiliation: Clinical Pharmacology Unit, University Hospital Príncipe de Asturias, Madrid, Spain.|Department of Biomedical Sciences, School of Medicine and Health Sciences, University of Alcalá, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: de Abajo
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, The Netherlands.|MEB, Medicines Evaluation Board, Utrecht, The Netherlands.
authors.forename: Hubert G M
authors.initials: HG
authors.lastname: Leufkens
authors.affiliation: EMA, European Medicines Agency, London, United Kingdom.
authors.forename: Gianmario
authors.initials: G
authors.lastname: Candore
authors.affiliation: EMA, European Medicines Agency, London, United Kingdom.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Alvarez
authors.affiliation: EMA, European Medicines Agency, London, United Kingdom.
authors.forename: Jim
authors.initials: J
authors.lastname: Slattery
authors.affiliation: Merck KGaA, Geneva, Switzerland.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Miret
authors.affiliation: Department of Biomedical Sciences, School of Medicine and Health Sciences, University of Alcalá, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Requena
authors.affiliation: BIFAP Research Unit, Division of Pharmacoepidemiology and Pharmacovigilance, Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), Madrid, Spain.
authors.forename: Miguel J
authors.initials: MJ
authors.lastname: Gil
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, The Netherlands.|Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Rolf H H
authors.initials: RH
authors.lastname: Groenwold
authors.affiliation: Department of Epidemiology, Pfizer, New York, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Reynolds
authors.affiliation: Global Clinical Epidemiology, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Raymond G
authors.initials: RG
authors.lastname: Schlienger
authors.affiliation: Institute of Population Health, University of Manchester, Manchester, United Kingdom.
authors.forename: John W
authors.initials: JW
authors.lastname: Logie
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, 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: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, The Netherlands.|Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Olaf H
authors.initials: OH
authors.lastname: Klungel
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, The Netherlands.|Worldwide Epidemiology, GlaxoSmithKline, Stockley Park, United Kingdom.
authors.forename: Tjeerd P
authors.initials: TP
authors.lastname: van Staa
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, The Netherlands.|Department of Clinical Pharmacy, Division of Laboratory and Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Toine C G
authors.initials: TC
authors.lastname: Egberts
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, The Netherlands.|Department of Biomedical Sciences, School of Medicine and Health Sciences, University of Alcalá, Spain.
authors.forename: Marie L
authors.initials: ML
authors.lastname: De Bruin
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, The Netherlands.|Department of Clinical Pharmacy, Division of Laboratory and Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Helga
authors.initials: H
authors.lastname: Gardarsdottir
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000928:Antidepressive Agents / Q000009:adverse effects*; D016022:Case-Control Studies; D005260:Female; D005269:Femur / Q000293:injuries; D006620:Hip Fractures / Q000209:etiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D064887:Observational Studies as Topic; D017891:Pharmacoepidemiology / Q000592:standards* / Q000706:statistics & numerical data; D012307:Risk Factors
chemical_list: D000928:Antidepressive Agents
keywords: adjustment; antidepressants; confounding; electronic healthcare record databases; hip/femur fracture; methodology; observational studies; pharmacoepidemiology