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.
Benzodiazepines (BZDs) are one of the therapeutic groups most widely used, mainly indicated
as hypnotics and anxiolytics. Guidelines recommend treatment courses not exceeding 4-6 weeks.
However, long-term treatment is highly prevalent, particularly in older people with a
prevalence ranging from 15 to 30%. However, treatment is often taken as needed.
Hip/femur fractures are a major cause of morbidity and mortality, impair quality of life and
impose a considerable economic burden. Among people aged 50 years and older, a case-fatality
rate of 20% is associated within the first year.
The relationship between benzodiazepines and hip fractures remains controversial.
Psychotropic medication has been traditionally associated with hip fractures. Among
psychotropic medication, long elimination half-life benzodiazepines were found to increase
the risk of hip fractures in a case-control study published in the late eighties. Since then,
several investigations have been performed, mostly in older patients focusing on the
relationship between benzodiazepines and hip fractures, and between benzodiazepines and falls
as a mechanism underlying this effect. A review performed in 2003, which included 11
epidemiological studies, reported that results were not always consistent. Seven out of eight
cohort and population based case-control studies, found an association, but different results
were reported according to benzodiazepines' half-life. In four hospital-based case-control
studies no association between benzodiazepines use and hip fracture has been described. Data
on dosing was only included in three of the studies, and once more results were not
conclusive. Results ranged from no effect to an increased risk with high dose regimens.
Results from subsequent succeeding studies have also shown contradictions, with no
association reported in one of the studies, and an association described for the short-term
use of short half-life, high-potency benzodiazepines.
Even though there is epidemiological evidence suggesting that the use of benzodiazepines
increases the risk of hip fractures, problems rise with the definition of benzodiazepine
exposure, or biases such as confounding by indication and the control for confounders. These
remain unresolved topics that should be addressed in future studies. In the present protocol,
it is proposed to further asses the risk of hip/femur fractures associated with
benzodiazepines using different study designs in different primary databases, and to compare
the results in order to evaluate the impact of design and population differences on the
outcome of the study association.
The objective of this study is to assess the association between benzodiazepines use and
hip/femur fracture with different study designs (descriptive, cohort, nested case-control,
case crossover and self control case series) across different primary care databases
(Bavarian, Mondriaan, National Databases (Denmark), General Practice Research Database
(GPRD), Base de Datos para la Investigación Farmacoepidemiologica en Atencion Primaria
(BIFAP) and The Health Improvement Network (THIN)) and to compare the results between
databases, across designs to evaluate the impact of design/database/population differences on
the outcome of the studied association.