The studies described in this protocol are all performed within the framework of PROTECT
(Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium)
Workpackage 2 and Workgroup 1. Primary aim of these studies is to develop, test and
disseminate methodological standards for the design, conduct and analysis of
Pharmacoepidemiological (PE) studies applicable to different safety issues and using
different data sources. To achieve this, results from PE studies on five key adverse events
(AEs) performed in different databases will be evaluated. Therefore, emphasis will be on the
methodological aspects of the studies in this protocol and not on the clinical consequences
of the association under investigation.
Fracture of the proximal end of the femur or hip is associated with considerable morbidity
and mortality. Hip/femur fractures impair quality of life and impose a considerable economic
burden, and occur with 20% mortality rate within the first year. Antidepressants (AD), mainly
tricyclic AD (TCAs) and selective serotonin re-uptake inhibitors (SSRIs) have been associated
with fractures in several studies. A review of 13 observational studies showed risk ratios
ranging from 1.2 to 3.7 for current TCA users and a wide range of 1.5 to 8.6 for SSRI users.
The majority of the studies in the aforementioned review reported increased risks of
fractures in general with SSRIs use and more mixed risk outcomes for TCA use. Several
mechanisms underlying this adverse effect have been postulated in the literature: e.g.
through decrease in bone mineral density (BMD) or through blocking the serotonin transporter
activity (5-hydroxytryptamine re-uptake) and hence affecting bone metabolism and structure or
simply by falling or through co-morbidities such as depression itself. Previous observational
studies differ in design, conduct and analysis of the considered association with varying
degree of accounting for confounders. Confounding factors such as depression and other
co-morbidities, previous fractures, concomitant drug use and lifestyle factors such as
smoking have usually not been accounted for in most of the studies. In addition, small sample
size, different methods used to ascertain exposure, selection bias and lack of data on
compliance as well as important covariates limit the use of these results in benefit-risk
analyses. Furthermore, studies evaluating different types of SSRI and TCA are few and
dose-response relationship for most of the AD remains to be studied. We will study effects of
cumulative exposure focusing on acute (less than 6 months) and long term exposure (at least 5
years) and doses of exposure.
The objective of the study is to assess the association between AD use and hip/femur fracture
using different study designs (descriptive, cohort, nested case-control and case crossover)
across different databases and to compare the results between and across databases and
designs. This is to evaluate the impact of design/database /population difference in the
outcome of the studies association.
Data will be collected from the following databases: The Health Improvement Network [(THIN]),
a UK-based primary care electronic medical record database, the Dutch Mondriaan project (a
primarily general physician based database with some linkage to survey data from the
Netherlands), Base de Datos para la Investigación Farmacoepidemiológica en Atencion Primaria
[(BIFAP] (Spanish primary care database)), and the Bavarian statutory health insurance
physicians' association database (German health insurance database from primary and secondary
care).