Use of antidepressant drugs and risk of osteoporotic and non-osteoporotic fractures
Introduction
Osteoporotic fractures (especially fractures of the femur, vertebrae and distal forearm) are a major health problem in the elderly, and the annual costs for this type of fractures are high. Osteoporosis is a skeletal disease which is characterized by low bone mass and disruption of the micro-architecture of bone, resulting in increased bone fragility and increased risk of fractures [1], [2], [3]. Several drug classes have been associated with an increased risk of falls and fractures, including antidepressants [4], [5], [6], [7], [8], [9], [10], [11], [12]. Several pharmacological mechanisms have been proposed to explain this adverse effect of antidepressant drug treatment. TCAs may cause orthostatic hypotension, sedation and confusion/dizziness by blocking the α-adrenergic, histaminic H1, and cholinergic (muscarinic) M3 receptors, and thereby increase the risk of falls and subsequent fractures. Although it was expected that SSRIs would cause fewer problems in this respect, given their weak affinity for the α-, H1- and M3-receptors, they also have been associated with an increased risk of falls and fractures [5], [13]. Long-term use of SSRIs has been linked with a reduction of bone mass and may affect bone micro architecture [14], [15], [16]. The underlying mechanism has been related to the selective blockade of the serotonin (5-hydroxytryptamine, 5-HT) reuptake transporter (5-HTT). The 5-HTT and several functional 5-HT-receptors have been found in osteoblastic cell lines [17], [18], as well as in osteoclasts [19] and may therefore be important in bone physiology.
However, among antidepressants, not only SSRIs block the 5-HTT. For instance, within the group of TCAs, clomipramine has more pharmacological similarities with SSRIs than with other TCAs. Imipramine has a high affinity for the 5-HTT as well. This raises the question whether the therapeutical classification of antidepressants (TCAs versus SSRIs), which is mainly based on molecular structure (tricyclic) and mechanism of action (interference with the serotonergic neurotransmitter system), is an appropriate way to evaluate the association between antidepressant use and the occurrence of fractures. Recently, two studies evaluated the effect of antidepressants' affinity for the 5-HTT on hip/femur fractures and any fracture [10], [12]. In both studies, fracture risk increased with an increasing degree of affinity for the 5-HTT. Currently, there is no information available whether this association applies also for other types of fractures.
Therefore, the aim of this study was to assess the association between the use of antidepressant drugs, categorized both in a therapeutical-based way (SSRIs, TCAs) as well as on their affinity for the 5-HTT, and the risk of both osteoporotic and non-osteoporotic fractures.
Section snippets
Setting
Data for this study were obtained from the PHARMO record linkage system (http://www.pharmo.nl). The PHARMO RLS includes the demographic details and complete medication history of more than two million community-dwelling residents of more than twenty-five population-defined areas in the Netherlands from 1985 onwards, further linked to hospital admission records as well as several other health registries, including pathology, clinical laboratory findings and general practitioner data. Since
Results
The study population consisted of 16,717 patients with a hospitalization for any type of fracture and 61,517 matched controls. Osteoporotic fractures were most frequent (n = 9943, 59.5%). The characteristics of the patients with osteoporotic and non-osteoporotic fractures are shown in Table 2. The majority of the patients with an osteoporotic fracture were older than 60 years (71.6%) (mean age 67.8 years, SD ± 19.3) and were females (66.0%) in contrast to patients with a non-osteoporotic fracture
Discussion
The main finding of this study was the association between the degree of 5-HTT inhibition of antidepressants and the risk of osteoporotic fracture. This association was absent when the risk of non-osteoporotic fracture was evaluated. Current use of antidepressant drugs with a high affinity for the 5-HTT was associated with a higher risk of osteoporotic fractures compared to use of antidepressants with a medium or low affinity. The 5-HTT has been located in osteoclasts, osteoblasts and
Acknowledgments
The division of Pharmacoepidemiology and Pharmacotherapy employing authors BMV, PCS, TCGE, TS, HGML and FV has received unrestricted funding for pharmacoepidemiological research from GlaxoSmithKline, Novo Nordisk, the private-public funded Top Institute Pharma (www.tipharma.nl, includes co-funding from universities, government, and industry), the Dutch Medicines Evaluation Board, and the Dutch Ministry of Health.
TS and FV also work for the General Practice Research Database (GPRD). GPRD is
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