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Use of Antidepressants and Rates of Hip Bone Loss in Older Women
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The Study of Osteoporotic Fractures
Susan J. Diem, MD, MPH; Terri L. Blackwell, MA; Katie L. Stone, PhD; Kristine Yaffe, MD; Elizabeth M. Haney, MD; Michael M. Bliziotes, MD; Kristine E. Ensrud, MD, MPH
Arch Intern Med. 2007;167(12):1240-1245.
"One potential explanation for our findings is that SSRI use may have a direct deleterious effect on bone. This theory is supported by findings of in vitro and in vivo laboratory investigations. Functional receptors for serotonin and serotonin transporter systems have been identified in osteoblasts, osteoclasts, and osteocytes.4-5,23 Serotonin has been shown to induce murine osteoblast proliferation and human osteoclast differentiation in vitro.24 Other in vitro data suggest that fluoxetine hydrochloride inhibits osteoblast formation24 and reduces osteoclast differentiation.4, 24 These findings suggest that a reduction in osteoblast activity or a reduction in coupled osteoclast/osteoblast activity owing to serotonin transporter inhibition could be a potential mechanism by which SSRIs may influence BMD"
ABSTRACT
Background Serotonin transporters have recently been described in bone, raising the possibility that medications that block serotonin reuptake could affect bone metabolism.
Methods We assessed current use of selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) and obtained serial bone mineral density (BMD) measurements in a cohort of 2722 older women (mean age, 78.5 years) participating in the Study of Osteoporotic Fractures, a prospective cohort study of community-dwelling women. Hip BMD was measured at the sixth examination and an average of 4.9 years later at the eighth examination. We categorized women as nonusers (used no SSRIs or TCAs at either examination; n = 2406), SSRI users (used SSRIs but no TCAs at either examination; n = 198), or TCA users (used TCAs but no SSRIs at either examination; n = 118). Depressive symptoms were identified using a cutoff score of at least 6 on the Geriatric Depression Scale.
Results After adjustment for potential confounders, including the Geriatric Depression Scale score, mean total hip BMD decreased 0.47% per year in nonusers compared with 0.82% in SSRI users (P<.001) and 0.47% in TCA users (P = .99). Higher rates of bone loss were also observed at the 2 hip subregions for SSRI users. Results were not substantially altered when women who scored at least 6 on the Geriatric Depression Scale were excluded from the analysis.
Conclusion Use of SSRIs but not TCAs is associated with an increased rate of bone loss at the hip in this cohort of older women.
INTRODUCTION
Antidepressants are one of the most commonly prescribed classes of pharmacologic agents in the United States; in 2002, 8.5% of Americans used antidepressants.1 With the development of the selective serotonin reuptake inhibitors (SSRIs), prescriptions for antidepressants for the elderly have increased substantially during the past 2 decades.2
Selective serotonin reuptake inhibitors function by inhibiting the serotonin transporter.3 An older class of antidepressants, the tricyclic antidepressants (TCAs), inhibit uptake of norepinephrine and serotonin to varying degrees.3 The recent description of functional serotonin transporters in osteoblasts, osteoclasts, and osteocytes4-5 raises the possibility that serotonin transporters may play a role in bone metabolism and that medications that affect these transporter systems may also affect bone metabolism.
To determine whether SSRI and TCA use among older women is associated with increased rates of hip bone loss, we ascertained use of antidepressants, assessed evidence of depressive symptoms, and performed hip bone mineral density (BMD) measurements at 2 examinations in a cohort of 2722 women 65 years and older who were enrolled in the Study of Osteoporotic Fractures.
COMMENT
We found that use of SSRIs in our cohort of older women was independently associated with an increased rate of hip bone loss. Use of a TCA was not similarly associated with increased rates of hip bone loss in our cohort.
One potential explanation for our findings is that SSRI use may have a direct deleterious effect on bone. This theory is supported by findings of in vitro and in vivo laboratory investigations. Functional receptors for serotonin and serotonin transporter systems have been identified in osteoblasts, osteoclasts, and osteocytes.4-5,23 Serotonin has been shown to induce murine osteoblast proliferation and human osteoclast differentiation in vitro.24 Other in vitro data suggest that fluoxetine hydrochloride inhibits osteoblast formation24 and reduces osteoclast differentiation.4, 24 These findings suggest that a reduction in osteoblast activity or a reduction in coupled osteoclast/osteoblast activity owing to serotonin transporter inhibition could be a potential mechanism by which SSRIs may influence BMD.
In vivo, both young and adult mice with a null mutation in the gene encoding for the serotonin transporter had reduced bone mass, altered skeletal architecture, and inferior mechanical properties,25 suggesting a role for the serotonin transporter in bone metabolism. Growing mice treated with an SSRI demonstrated reduced bone mineral accrual.25 In both models (genetic disruption of the serotonin transporter and pharmacologic inhibition of it), bone formation rates were reduced, indicating that osteoblast function is significantly reduced in vivo, with inhibition of serotonin transporter function.
On the other hand, evidence in humans that blockade of serotonin reuptake has a negative effect on bone metabolism is limited. Recently, Haney et al26 reported an association between SSRI use and decreased BMD in older men. In other cross-sectional analyses,8-9,27-28 use of antidepressants has not been associated with reduced BMD, although these other analyses have generally not separated TCA use from SSRI use. Use of antidepressants has been linked to an increased risk of fractures,27, 29-30 although the mechanisms underlying this association remain unclear. Owing to their limitations, cross-sectional studies might underestimate or overestimate any association between antidepressant use and bone density.
Observational studies examining possible associations among antidepressant use, bone density, and fractures are subject to confounding, which may also explain our findings. In particular, confounding by indication may be an important issue. Antidepressants are often prescribed for depressive symptoms, and depression itself has been associated with a lower BMD.8-10 Depression has been postulated to have a direct effect on bone density, through such pathways as alterations in the hypothalamic-pituitary-adrenal system and up-regulation of the proinflammatory cytokines interleukin 6 and tumor necrosis factor {alpha}.9, 31-32 In our study, when women with a GDS score of at least 6 were excluded, the magnitude of the difference in rates of hip bone loss between SSRI users and nonusers was attenuated, suggesting that confounding by indication at least partially explains our findings. The GDS measurement was only available at the clinic examinations; thus, we cannot account for depressive symptoms that may have been present between visits. In addition, although the GDS is a useful screening tool for depression, it cannot substitute for a clinical diagnosis of depression based on established diagnostic criteria.
Medical conditions associated with increased loss of bone density, such as chronic obstructive pulmonary disease, liver disease, and diabetes mellitus,33 may also predispose to depression; thus, patients with these conditions may be more likely to be prescribed antidepressants. In addition, depression is associated with decreased mobility and weight loss, both of which have effects on bone. Owing to concerns about the adverse effects of TCAs, SSRIs may be preferentially prescribed to participants perceived to be at higher risk for falls because of comorbidities; these comorbidities may also predispose them to higher rates of bone loss, another potential source of confounding. To address these potential confounders, we adjusted for health status, functional status, and weight change, although unmeasured factors might explain our results.
Because our cohort consists of elderly women, we cannot extrapolate our findings to other populations. Because we have limited information on dose and duration of use of antidepressants in the cohort, we were limited in our ability to look for evidence of a dose effect of antidepressants on the rate of change of BMD. We did not find evidence that continuous users had higher rates of bone loss than partial users. In addition, the small number of SSRI users at visit 6 was insufficient to determine whether SSRI use was prospectively associated with subsequent rates of bone loss. We observed an increase in the prevalence of SSRI use in our cohort between visit 6, which occurred in 1997 through 1998, and visit 8, which occurred in 2002 through 2004, consistent with other data.1 Future research with larger numbers of SSRI users will be important to determine whether SSRI use is prospectively associated with increased rates of bone loss.
We did not find that use of TCAs, which also have an effect on serotonin reuptake, was associated with an increased rate of hip bone loss. There are several potential explanations for this finding. Tricyclic antidepressants are often prescribed for reasons other than depression, such as sleep disorders or chronic pain. As a result, fewer subjects receiving TCAs than the number receiving SSRIs may have underlying depression. When prescribed for treatment of insomnia or chronic pain, TCAs are often prescribed at lower doses than those used to treat depression; as a result, the degree of serotonin blockade may be lower than that associated with SSRI use. Alternatively, we may not have observed an association between TCA use and rates of bone loss because the degree of serotonin transporter inhibition differs among the many TCAs; for example, desipramine's potency at the serotonin transporter is lower than that of fluoxetine in osteoblasts.5
Our findings suggest that, in this cohort, use of SSRIs is associated with increased rates of hip bone loss. Although some of this association is likely due to confounding by indication, further investigation of SSRI use and rates of change in BMD in other populations with longer follow-up is warranted given the recent description of serotonin transporters in bone.
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