Elsevier

Bone

Volume 51, Issue 3, September 2012, Pages 606-613
Bone

Review
Antidepressant medications and osteoporosis

https://doi.org/10.1016/j.bone.2012.05.018Get rights and content

Abstract

Use of antidepressant medications that act on the serotonin system has been linked to detrimental impacts on bone mineral density (BMD), and to osteoporosis. This article reviews current evidence for such effects, and identifies themes for future research. Serotonin receptors are found in all major types of bone cell (osteoblasts, osteocytes, and osteoclasts), indicating an important role of the neuroendocrine system in bone. Observational studies indicate a complex relationship between depression, antidepressants, and fracture. First, the presence of depression itself increases fracture risk, in relation with decreased BMD and an increase in falls. A range of aspects of depression may operate, including behavioral factors (e.g., smoking and nutrition), biological changes, and confounders (e.g., comorbidities and concomitant medications). A substantial proportion of depressed patients receive antidepressants, mostly selective serotonin reuptake inhibitors (SSRIs). Some of these have been linked to decreased BMD (SSRIs) and increased fracture risk (SSRIs and tricyclic agents). Current use of SSRIs and tricyclics increases fracture risk by as much as twofold versus nonusers, even after adjustment for potential confounders. While there is a dose–response relationship for SSRIs, the effect does not appear to be homogeneous across the whole class of drugs and may be linked to affinity for the serotonin transporter system. The increase in risk is the greatest in the early stages of treatment, with a dramatic increase after initiation, reaching a peak within 1 month for tricyclics and 8 months for SSRIs. Treatment-associated increased risk diminishes towards baseline in the year following discontinuation. The body of evidence suggests that SSRIs should be considered in the list of medications that are risk factors for osteoporotic fractures.

Highlights

► Current use of selective serotonin reuptake inhibitors (SSRIs) and tricyclics increases fracture risk. ► The increase in risk is the greatest in the early stages of treatment. ► Treatment-associated increased risk diminishes in the year following discontinuation. ► SSRIs should be considered in the list of medications that are risk factors for osteoporotic fractures.

Introduction

Serotonin is well known as a regulator of mood. An increase in synaptic availability of serotonin is known to have an antidepressant effect, and is involved in all or part of the mechanism of action of some of the most widely used antidepressants. However, serotonin also plays an important role centrally in functions such as appetite, sleep, sex, and temperature, and acts peripherally in the cardiovascular and gastrointestinal systems. There is increasing evidence that serotonin may also be an important regulatory agent in bone metabolism [1], notably bone mass.

Antidepressant treatments that act on serotonin pathways may therefore be expected to have some impact on bone, bone mass, and fracture rates. The link between depression, antidepressant use, and osteoporosis is becoming more widely understood, and there is mounting evidence for an effect of depression and antidepressants on fracture rates. This article was prepared by a working group of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO), which reviewed the evidence for an effect of antidepressants on bone mass and fracture, as well as the impact of various confounders, including depression itself.

Section snippets

Methods

Relevant articles, reviews, and abstracts were identified through a PubMed/MEDLINE search of English-language articles published between 1990 and September 2011. The search strategy included the terms antidepressant, serotonin, selective serotonin reuptake inhibitor (SSRIs, fluoxetine, paroxetine, citalopram, escitalopram, sertraline, and fluvoxamine), serotonin and noradrenaline reuptake inhibitor (SNRIs, venlafaxine and duloxetine), tricyclic antidepressants (amitriptyline, clomipramine,

Serotonin and bone pathophysiology

Serotonin (5-hydroxytryptamine, 5-HT) is synthesized in the gut and the brain from tryptophan via the enzyme tryptophan hydroxylase (TPH) [1]. More than 95% of human serotonin is synthesized in the gut (i.e. the duodenum) by enterochromaffin cells via the TPh1 isoform of the enzyme. Gut-derived serotonin is for the most part stored in platelets, and it plays a role in platelet aggregation and blood clotting after injury. The rest of human serotonin (< 5%) is produced in the brainstem, also from

Depression and antidepressants

Depression is a major public health problem and a leading cause of disability. Epidemiological studies suggest that the prevalence of some form of depression is about 22% in the US population, with substantially higher rates in women (26%) than in men (18%) [13]. The lifetime prevalence of major depressive disorder (Diagnostic and Statistical Manual of Mental Disorders IV [DSM-IV] criteria) is estimated at 16% [14]. Similar rates of depression are reported in European populations [15].

According

Depression and risk for fracture

Before considering the impact of any pharmacological modification of the serotonin system on bone, it is necessary to understand the impact of depression itself on bone health. The association between depression and fracture has been known since the late 1990s, and has been the subject of a number of studies. For instance, a prospective study in 7414 elderly white women with depression showed that the presence of depression increased the risk for nonvertebral fracture (adjusted hazard ratio

Antidepressants and BMD

The impact of antidepressants on fracture may be linked to the effects on BMD [28], [29]. There have been a number of cross-sectional and cohort studies exploring the relationship between the use of antidepressants and BMD (Table 3) [30], [31], [32], [33], [34], [35], [36]. A population-based cohort study in 5000 adults reported a significant reduction in hip BMD (− 4%, 95% confidence interval [CI], − 6.6% to − 1.4%) in SSRI users versus nonusers, and a trend towards a reduction in spine BMD (− 

Antidepressants and risk for fracture

The association between antidepressants and fracture has been the subject of a number of observational studies, generally with case–control or cohort designs (Table 4) [27], [34], [35], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56]. The results indicate that current use of SSRIs and tricyclics increases the risk for fracture by as much as twofold versus nonusers. Although there is some variation between the studies, the ORs for increases in

Discussion

There is a complex interaction between depression, the drugs used to treat depression, and osteoporosis. To summarize, patients with depression may have decreased BMD [20], [22], though not all studies have agreed on this finding [21]. This decrease in BMD may be associated with an increased rate of fracture, though part of this elevated risk appears to be independent of BMD, perhaps through increased frequency of falls. The management of depression with antidepressant medications such as SSRIs

Conflict of interest statements

B. Abrahamsen: paid advisory boards for Amgen and Nycomed. Research support from Novartis, NPS Pharmaceuticals, and Amgen. Speakers fees Nycomed, Merck, Eli Lilly, and Amgen. Consulting fees Merck, Sharp and Dohme. J.R. Adachi: consulting and/or speaker fees for Amgen, Eli Lilly, GSK, Merck, Novartis, Pfizer, Procter & Gamble, Roche, Sanofi Aventis, and Warner Chilcott. Research funding (clinical trials) from Amgen, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, Procter & Gamble,

Acknowledgments

This paper was derived from a Working Group meeting on 22 September 2011 supported by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO).

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