0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Investigation |

Association of Low Bone Mineral Density With Selective Serotonin Reuptake Inhibitor Use by Older Men FREE

Elizabeth M. Haney, MD; Benjamin K. S. Chan, MS; Susan J. Diem, MD, MPH; Kristine E. Ensrud, MD, MPH; Jane A. Cauley, DrPh; Elizabeth Barrett-Connor, MD; Eric Orwoll, MD; M. Michael Bliziotes, MD; Osteoporotic Fractures in Men Study Group
[+] Author Affiliations

Author Affiliations: Department of Medicine, Oregon Health & Science University, Portland (Drs Haney, Orwoll, and Bliziotes and Mr Chan); University of Minnesota, Minneapolis (Drs Diem and Ensrud); University of Pittsburgh, Pittsburgh, Pa (Dr Cauley); and University of San Diego, La Jolla, Calif (Dr Barrett-Connor).


Arch Intern Med. 2007;167(12):1246-1251. doi:10.1001/archinte.167.12.1246.
Text Size: A A A
Published online

Background  Selective serotonin reuptake inhibitors (SSRIs) are a widely used class of antidepressants that block the serotonin transporter. Osteoblasts and osteocytes express functional serotonin transporters; serotonin transporter gene disruption in mice results in osteopenia; and SSRI use has been associated with increased risk of hip fracture.

Methods  To determine whether SSRI use is associated with lower bone mineral density (BMD) in older men and to compare the results for SSRIs with those of other antidepressants, we performed a cross-sectional analysis of data from 5995 men 65 years and older participating in the prospective cohort Osteoporotic Fractures in Men Study. Main outcome measures included medication use; BMD at the femoral neck, greater trochanter, and lumbar spine measured by dual-energy x-ray absorptiometry; and potential covariates.

Results  In adjusted analyses, mean BMD among SSRI users (n = 160) was 3.9% lower at the total hip and 5.9% lower at the lumbar spine compared with BMD in men reporting no antidepressant use (n = 5708 [P = .002 for total hip; P<.001 for lumbar spine]). There was no significant difference among users of trazodone hydrochloride (n = 52) or tricyclic antidepressants (n = 99) compared with nonusers. Adjusting for variables that could be associated with BMD and/or SSRI use did not significantly alter these results. The observed difference in BMD for SSRIs is similar to that seen with glucocorticoids.

Conclusions  In this population of men, BMD was lower among those reporting current SSRI use, but not among users of other antidepressants. Further research is needed to confirm this finding in light of widespread SSRI use and potentially important clinical implications.

Functional serotonin transporters have been identified in osteoblasts, osteocytes, and osteoclasts.1,2 The functionality of these bone serotonin transporters is suggested by studies in a mouse model of long-term selective serotonin reuptake inhibitor (SSRI) use. In this model, mice with genetic disruption of the serotonin transporter gene have lower bone mineral density (BMD) when compared with wild-type mice.3

Selective serotonin reuptake inhibitors are first-line therapy for depression and account for approximately 62% of all antidepressant prescribing in the United States.4,5 They function by inhibiting the serotonin transporter.6,7 In addition to the cited studies suggesting an association between disruption of the serotonin transporter function and lower BMD in mice, data in humans show that SSRIs are associated with hip fracture independent of falls or fall risk.811 Indeed, depression itself has been shown to be associated with hip fracture in older women, a finding not entirely explained by falls.12 In studies of antidepressants, adjusted odds ratio point estimates for hip fracture are higher among SSRI users compared with users of tricyclic antidepressants (TCAs) or other antidepressants.8,10 It remains unclear whether it is the disease process, the treatment of depression, or the effects of depression on activity, mobility, and weight change that leads to decreased BMD among depressed people.

A large analysis of variables contributing to BMD in the Osteoporotic Fractures in Men (MrOS) Study suggested that SSRI use is a determinant of BMD among men.13 However, that study did not examine how adjustment for potential confounders affected the association between SSRIs and BMD, and it did not examine the association between use of other antidepressants and BMD. We planned the present study to more fully characterize the effect of SSRI use on BMD in men. First, we hypothesized that those taking SSRIs would have lower BMD than those not using SSRIs and that this association would not be fully explained by major confounding variables. Second, we compared the SSRI-BMD association with that of other antidepressants, including trazodone hydrochloride and TCAs, in an attempt to distinguish treatment from disease effects.

STUDY DESIGN AND PARTICIPANTS

We performed a cross-sectional analysis using data from participants in the MrOS Study. The MrOS Study includes 5995 men 65 years or older who were recruited from 6 regions of the United States (Birmingham, Ala; Minneapolis, Minn; Monongahela Valley near Pittsburgh, Pa; Palo Alto, Calif; Portland, Ore; and San Diego, Calif) between March 1, 2000, and April 30, 2002. The institutional review boards at each site approved the study. Written informed consent was obtained from all participants.14,15

BONE MINERAL DENSITY

The main outcome variables were BMD for the total hip (and subregions: the greater trochanter and femoral neck) and lumbar spine. Bone mineral density at baseline was measured using fan-beam dual-energy x-ray absorptiometry (QDR-4500W; Hologic Inc, Bedford, Mass). All measurements at the hip were performed on the right hip unless a participant reported a right hip replacement or metal objects in the right leg, in which case the measurement was performed on the left hip. Standardized procedures for participant positioning and scan analysis were executed for all scans. Spine and hip phantom scan results were assessed for longitudinal and cross-sectional quality control. The intraclinic coefficients of variation for spine phantoms (0.34% to 0.42%) and hip phantoms (0.37% to 0.58%) were within acceptable limits. The interclinic coefficients of variation were 0.6% (spine) and 0.9% (hip), and the maximum difference between means was 1.4% (spine) and 2.2% (hip).1416 All dual-energy x-ray absorptiometry operators at the different clinic sites were centrally certified on the basis of an evaluation of scanning and analysis techniques. To adjust for interclinic differences, statistical models included a variable for clinic site. Body size measurements, including total lean and fat mass, were also obtained from dual-energy x-ray absorptiometry.

MEDICATION USE

Participants brought all medications to their baseline clinic visit, where interviewers recorded all prescription medications used daily or almost daily for at least the past month. Medications were coded by class according to a standardized computerized study-specific medication dictionary, based on product brand or generic names from the containers. Antidepressant information was used to sort the participants into the following categories: SSRI users, trazodone users, TCA users, combination users (any 2 categories of antidepressant), and nonusers (no use of any antidepressant).

POTENTIAL COVARIATE MEASURES

Potential covariate measures for BMD were obtained from the baseline questionnaire, interview, and examination. These included demographic characteristics such as age, race/ethnicity, and clinic site; anthropometric measurements, including height, weight, body mass index, lean and fat mass, and self-reported height and weight change since age 25 years; medical conditions, including hypertension, Parkinson disease, hypothyroidism, diabetes, and stroke; lifestyle factors such as physical activity, history of heavy alcohol use, current smoking, and marital status; family history of fracture; and any history of falls. Race and/or ethnicity was ascertained by self-declaration as white, black or African American, Asian, Hispanic or Latino, and other. Any participant who indicated Hispanic background, regardless of the race category, was classified as Hispanic; those not meeting any of the descriptions listed were classified as other. Physical activity was assessed using the Physical Activity Scale for the Elderly.17 Perceived health status was obtained from the Medical Outcomes Study 12-Item Short-Form Health Survey (SF-12)18 scored for physical and mental well-being. The mental component summary (MCS) scale of the SF-12 is a reliable measure that has been shown to distinguish between major depressive disorder, depressive symptoms, and no depression.19,20 In addition, the individual questions, as surrogates for depressed mood, were tested for correlation with BMD and use of SSRIs. Accomplishment of independent activities of daily living was self-reported. Dietary calcium and vitamin D intake was calculated using a modified food frequency questionnaire developed specifically for the MrOS Study by Block Dietary Data Systems, Berkeley, Calif (http://www.nutritionquest.com). As part of the clinic visit, participants completed tests of neuromuscular function, including walking speed, grip strength, and completion of 5 chair stands (rising from a seated position without using the chair's arms).

STATISTICAL ANALYSIS

We compared the characteristics of men using SSRIs with those of men not using any antidepressant, using unpaired, 2-tailed t tests for continuous variables and contingency tables for categorical variables. We conducted descriptive analyses to understand the associations between medication use and all other potential covariates.

MULTIVARIABLE MODELS

To test the hypothesis that SSRI use was associated with decreased BMD, we used age-adjusted linear regression models. We included clinic site and race in all models to account for sampling method. Because of the large effect of body weight on BMD,21 we also added body weight to the models. We then systematically assessed potential confounding variables using a list of variables that have been found to be significant predictors of BMD in this population13 or that might be associated with both BMD and use of SSRIs. For the most parsimonious model, we retained only the variables that influenced the parameter estimate for SSRI use (P<.05). All final models included clinic site, age, race, and body weight. Because none of the other variables confounded the association between SSRI use and BMD, we did not retain them in the models. We estimated the mean BMD according to medication use from the linear models (PROC GLM in SAS; SAS Institute Inc, Cary, NC).

Our analyses also included an assessment of whether the association between BMD and use of SSRIs could be explained by mood. The baseline MrOS data do not contain a rigorous measure of depression or depressive symptoms but do contain the SF-12 findings, from which an MCS score can be calculated. Also, there are specific SF-12 questions about feeling “downhearted and blue,” having “accomplished less than you would like because of emotional problems (being depressed or anxious),” or not doing “work or activities as carefully as usual because of emotional problems.” Thus, to evaluate the influence of mood on the association between SSRI use and BMD, we compared these models with those including the SF-12 MCS score and individual mental health questions from the SF-12.

We next evaluated whether the BMD-SSRI association was common to other antidepressants (trazodone, TCAs, or combined antidepressants). We compared the mean BMDs for each of the antidepressant user groups with the nonuser group. Finally, to understand the relative effect of SSRIs on BMD, we compared the parameter estimates and estimated means for BMD among users of antidepressants and glucocorticoids. Glucocorticoids were chosen because they represent a category of medication with a well-documented detrimental effect on BMD.

CHARACTERISTICS OF THE STUDY POPULATION

At baseline, the mean age of the 5995 study participants was 73.7 (SD, 5.9) years; 89.4% were white; and 39.4% had a college education. Overall, 160 men (2.7%) reported current SSRI use; 99 (1.7%) reported TCA use; and 52 (0.9%) reported trazodone use. Table 1 shows the demographic characteristics for SSRI users compared with the users of other antidepressants and those who used no antidepressants (nonusers). There were no significant differences among the groups in terms of education (college degree or higher), height, height loss since age 25 years, current tobacco use, glucocorticoid use, total daily calcium intake, and history of nontraumatic fracture after age 50 years. The group that reported using more than 1 type of antidepressant consisted mainly of SSRI users who were also taking trazodone or a TCA (95.8%). Overall, those reporting any SSRI use (alone or in combination with other antidepressants) did not differ significantly from SSRI nonusers by age, race/ethnicity, height, weight, body mass index, reported weight change, or current tobacco or glucocorticoid use. The SSRI users were more likely to have been heavy drinkers at some time in their lives (P<.001). All antidepressant users had lower physical activity scores compared with nonusers (P<.001).

Table Graphic Jump LocationTable 1. Demographics of the MrOS Cohort by Antidepressant Use*

Table 2 shows the estimated least square mean BMD at the total hip, femoral neck, trochanter, and lumbar spine for users of the 3 antidepressants (SSRIs, TCAs, and trazodone), users of multiple antidepressants, and nonusers. Total hip BMD was 3.9% lower among SSRI users compared with nonusers (0.92 vs 0.96 g/cm2 [P = .002]). There were no significant differences in BMD among TCA and trazodone users compared with nonusers. Adjusted spine BMD was 5.9% lower among SSRI users compared with nonusers of antidepressants (1.01 vs 1.07 g/cm2 [P<.001]). There were no significant differences at the spine among TCA and trazodone users compared with nonusers of antidepressants. Results for the femoral neck and greater trochanter were similar, ie, adjusted BMDs were lower by 4.7% (P<.001) and 3.6% (P = .01), respectively.

Table Graphic Jump LocationTable 2. Estimated Least Square Mean BMD for Users vs Nonusers of Antidepressants*

We conducted additional analyses including different variables in the model. The associations between SSRI use and BMD were not significantly altered by educational or marital status, weight change, height or height loss, body mass index, lean or fat mass, pack-years of tobacco history, current smoking, SF-12 physical score or Physical Activity Scale for the Elderly score, heavy alcohol use, vitamin D and calcium intake, number or type of medical conditions (including chronic obstructive pulmonary disease, diabetes mellitus, nephrolithiasis, hypertension, prostate cancer, and osteoarthritis), personal or family history of fracture, grip strength, ability to complete 5 chair stands, and use of bisphosphonates, glucocorticoids, benzodiazepines, cyclooxygenase 2 inhibitors, statins, or diuretics. None of these variables significantly changed the parameter estimate for SSRIs.

Finally, for comparison with the magnitude of SSRI medication effects, Table 3 shows the estimated least square mean BMD at the total hip, femoral neck, trochanter, and lumbar spine for glucocorticoid users and nonusers, adjusted for age, body weight, clinic site, and race. Total hip BMD was 2.4% lower among the 334 men who were glucocorticoid users compared with nonusers (P<.001), and spine BMD was 3.9% lower among glucocorticoid users compared with nonusers (P<.001).

Table Graphic Jump LocationTable 3. Estimated Least Square Mean BMD for Glucocorticoid Users and Nonusers*

In this large cross-sectional study, SSRI use was consistently associated with lower BMD at the hip (3.9% lower) and spine (5.6% lower). This association remained consistent in several separate models when adjusted for major potential confounding variables and was unique to SSRIs among the antidepressants studied. In this population, a decrease of 0.1 g/cm2 in age-adjusted total hip BMD results in a 3.2% increase in fracture risk. Measured BMD of 0.897 g/cm2 corresponds to a T score of −1.22

Lower BMD among men using SSRIs is supported by in vitro and animal data. Osteoblastic and osteocytic cells express a functional serotonin transporter system, with mechanisms for responding to and regulating uptake of serotonin.1 Serotonin regulates prostaglandin E2 activity in osteocytic cells.23 Serotonin induces murine osteoblast proliferation and human osteoclast differentiation in vitro.24 In cultured cells, the serotonin receptor (5-HT2B) contributes in an autocrine manner to osteogenic differentiation.25 Mice with disruption of the serotonin transporter gene have reduced bone mass, altered bone geometry, and reduced mechanical strength.3 Wild-type mice treated with fluoxetine hydrochloride (an SSRI) have reduced bone mineral content and reduced bone formation rates.3 These studies support the hypothesis that serotonin transporters expressed in bone cells have a functional role in determining bone mass, architecture, and strength. Our findings are similar to results from another clinical study26 wherein SSRI use was associated with increased rates of bone loss among elderly women.

Neurohormonal signaling in bone is an area of growing interest and investigation, but the effects of serotonin transporters in bone are not yet well understood. One potential mechanism to explain our findings is a reduction in osteoblast activity as a result of serotonin transporter inhibition leading to lower BMD, as documented in the mice with disruption of the serotonin transporter gene. We did not measure bone formation rates in our population and cannot be certain that this is the explanation for the observed associations. Alternatively, a reduction in overall remodeling (coupled osteoclast/osteoblast activity) leading to a decrease in osteoblast bone formation is possible given the negative effects of SSRIs on osteoclast differentiation in vitro.

An alternative mechanism to explain lower BMD among SSRI users is an association between BMD and depression per se or a depression-associated comorbidity such as tobacco use, alcohol excess, weight loss, or low physical activity. Depression has been associated with lower BMD in some studies2733 but not all.12,3436 Many of these studies used select psychiatric populations27,29,30,33 or failed to adjust for medication use. Indirect effects on bone such as changes in cortisol metabolism or physical activity among depressed individuals are other possible mechanisms for an association. Neither of these proposed mechanisms has consistently explained associations with lower BMD in depressed people.29,33

The SSRI-BMD association reported herein is consistent with other literature, not explained by major covariates, and likely to be clinically important because of the percent difference in BMD. The observed effect size is similar to the well-known detrimental effect of corticosteroids on bone loss.37 However, we did not have information on the dose and duration of glucocorticoid therapy, and the degree of change we observed for SSRIs, although similar to that for glucocorticoids in this population, may be somewhat lower than other observational studies of glucocorticoids have reported and may not correspond to the same fracture risk.37

The strengths of this study include its size, the population-based recruitment of a multicentered cohort of men, the reliability of our BMD measurements, and the many covariates and potential confounders evaluated.

There are several important limitations to this study. One limitation is the relatively small number of men using antidepressants (which was less than the rate expected on the basis of data from the general population4) compatible with a healthy volunteer effect in observational studies. Cross-sectional studies do not demonstrate a cause-and-effect association, although it is hard to imagine how a low BMD could lead to SSRI use. Furthermore, the consistency of the observed association with published results in women, who have a much higher SSRI use, supports a true association. Unfortunately, data were not collected on the dose or the duration of SSRI use, and therefore we were unable to assess for a dose effect. Trazodone and TCAs are used in low doses to treat insomnia and neuropathic pain, at lower doses than those used for antidepressant effect. Diagnosed depression may have been less common among participants using trazodone or TCAs. Most TCAs and trazodone have some blocking effect at the serotonin transporter, but this effect is much weaker than that of SSRIs.

Because no standard instrument for depression or depressed mood was obtained, we could not adjust for depression or depressive symptoms. However, results were not altered by adjustment for the SF-12 MCS score, which captures depressed mood with several items. These analyses do not take into consideration cortisol or sex steroid levels, which also have a potential effect on depression and bone mass. A final caveat is the possibility of residual confounding, based on the inability to correct for etiologic variables that were not considered or not measured well. Reported diet and physical activity are examples of such variables considered herein but with well-known limitations in self-report and a potential to be associated with BMD, depression, and SSRI use.

These findings need confirmation in prospective studies. Additional clinical studies should include longitudinal studies of antidepressants, BMD, bone turnover markers, and fracture outcomes. More rigorous evaluation of the influence of SSRI use on BMD adjusting for depressive symptoms, diagnoses of major depression, and other variables that could explain this association is warranted. Studies of bone quality using metrics other than BMD will also be important. Although the effect of SSRIs on BMD observed herein would contribute to fracture risk, the effects of SSRIs on measures of bone quality, rather than density, have been investigated only in a study of fluoxetine-treated growing rats.38 Fluoxetine significantly reduced trabecular thickness, ultimate stress, and Young's modulus, indicating that less force per area is needed to deform and subsequently break the bone. For further understanding of the mechanism, it will be important to investigate the neurohormonal signaling pathways in bone, with particular attention to the serotonin transporter.

In conclusion, in this cohort of community-dwelling older men, femoral neck and lumbar spine BMD measurements were significantly lower among men using SSRIs compared with men not using any antidepressant or using a non-SSRI antidepressant; these associations were independent of multiple covariates. These associations are biologically plausible and clinically important. Because SSRI use is prevalent in the general population, our findings have a potentially important public health impact. If confirmed, people using SSRIs might be targeted for osteoporosis screening and preventive intervention.

Correspondence: Elizabeth M. Haney, MD, Division of General Internal Medicine and Geriatrics, Oregon Health & Science University, Mailcode L-475, 3181 SW Sam Jackson Park Rd, Portland, OR 97239 (haneye@ohsu.edu).

Accepted for Publication: January 13, 2007.

Author Contributions: Dr Haney had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Haney, Cauley, and Orwoll. Acquisition of data: Ensrud, Cauley, Barrett-Connor, and Orwoll. Analysis and interpretation of data: Haney, Chan, Diem, Ensrud, Barrett-Connor, and Bliziotes. Drafting of the manuscript: Haney and Chan. Critical revision of the manuscript for important intellectual content: Haney, Diem, Ensrud, Cauley, Barrett-Connor, Orwoll, and Bliziotes. Statistical analysis: Chan and Barrett-Connor. Obtained funding: Ensrud, Cauley, Barrett-Connor, and Orwoll. Administrative, technical, and material support: Cauley and Orwoll. Study supervision: Orwoll.

Financial Disclosure: Dr Haney has participated in trials funded by Sanofi-Synthelabo and Pfizer Inc that did not involve treatments for depression or osteoporosis. Dr Diem has participated in trials funded by Pfizer Inc, Eli Lilly and Company, and Merck & Co Inc in the area of osteoporosis treatment and prevention. Dr Ensrud reports research funding from Pfizer Inc, Eli Lilly and Company, and Bionovo. Dr Cauley has received research grants from Merck & Co Inc, Eli Lilly and Company, Pfizer Inc, and Novartis Pharmaceuticals; has received honoraria from Merck & Co Inc, Novaritis Pharmaceuticals, and Eli Lilly and Company; and has been on the speakers' bureau of Merck & Co Inc. Dr Barrett-Connor is a paid investigator for Eli Lilly and Company in the area of cardiovascular disease, cancer, and fracture, but has no research funding related to SSRIs. Dr Orwoll recieves research support or honoraria from Amgen Inc, Aventis, Imaging Therapeutics, Eli Lilly and Company, Merck & Co Inc, Novartis Pharmaceuticals, Pfizer Inc, and Zelos Therapeutics. Dr Bliziotes has acted as a consultant for and received research grants and honoraria from Merck & Co Inc and Proctor & Gamble.

Funding/Support: This study was supported by National Institutes of Health funding from National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute on Aging, and the National Cancer Institute under the following grant numbers: U01 AG18197, U01 AR45580, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654, U01 AR45583, M01 RR00334, R01 AR052018, and K23 AR051926.

Group Information: A list of members of the Osteoporotic Fractures in Men Study Group was published in Arch Intern Med. 2006;166:2130.

Role of the Sponsors: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.

Previous Presentation: This paper was presented at the 26th Annual Meeting of the American Society for Bone and Mineral Research; October 2, 2004; Seattle, Wash.

Acknowledgment: We thank Lori Lambert, MA, Lynn M. Marshall, ScD, and Janet Babich Blank, MPA, CCRA, for their assistance and the staff at each clinical center and the Coordinating Center for their efforts in data collection.

Bliziotes  MMEshleman  AZhang  XWiren  K Neurotransmitter action in osteoblasts: expression of a functional system for serotonin receptor activation and reuptake. Bone 2001;29477- 486
PubMed Link to Article
Battaglino  RFu  JSpate  U  et al.  Serotonin regulates osteoclast differentiation through its transporter. J Bone Miner Res 2004;191420- 1431
PubMed Link to Article
Warden  SJRobling  AGSanders  MSBliziotes  MMTurner  CH Inhibition of the serotonin (5-hydroxytryptamine) transporter reduces bone accrual during growth. Endocrinology 2005;146685- 693
PubMed Link to Article
Pirraglia  PAStafford  RSSinger  DE Trends in prescribing of selective serotonin reuptake inhibitors and other newer antidepressant agents in adult primary care. Prim Care Companion J Clin Psychiatry 2003;5153- 157
PubMed Link to Article
Anderson  IM Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. J Affect Disord 2000;5819- 36
PubMed Link to Article
Sauer  WHBerlin  JAKimmel  SE Effect of antidepressants and their relative affinity for the serotonin transporter on the risk of myocardial infarction. Circulation 2003;10832- 36
PubMed Link to Article
Rausch  JLJohnson  MEFei  Y-J  et al.  Initial conditions of serotonin transporter kinetics and genotype: influence on SSRI treatment trial outcome. Biol Psychiatry 2002;51723- 732
PubMed Link to Article
Liu  BAnderson  GMittmann  NTo  TAxcell  TShear  N Use of selective serotonin-reuptake inhibitors or tricyclic antidepressants and risk of hip fractures in elderly people. Lancet 1998;3511303- 1307
PubMed Link to Article
Ensrud  KEBlackwell  TMangione  CM  et al.  Central nervous system active medications and risk for fractures in older women. Arch Intern Med 2003;163949- 957
PubMed Link to Article
Hubbard  RFarrington  PSmith  CSmeeth  LTattersfield  A Exposure to tricyclic and selective serotonin reuptake inhibitor antidepressants and the risk of hip fracture. Am J Epidemiol 2003;15877- 84
PubMed Link to Article
Schneeweiss  SWang  PS Association between SSRI use and hip fractures and the effect of residual confounding bias in claims database studies. J Clin Psychopharmacol 2004;24632- 638
PubMed Link to Article
Whooley  MAKip  KECauley  JAEnsrud  KENevitt  MCBrowner  WS Depression, falls, and risk of fracture in older women. Arch Intern Med 1999;159484- 490
PubMed Link to Article
Cauley  JAFullman  RStone  K  et al. Mr. OS Research Group, Factors associated with the lumbar spine and proximal femur bone mineral density in older men. Osteoporos Int 2005;161525- 1537
PubMed Link to Article
Orwoll  EBlank  JBBarrett-Connor  E  et al.  Design and baseline characteristics of the osteoporotic fractures in men (MrOS) study: a large observational study of the determinants of fracture in older men. Contemp Clin Trials 2005;26569- 585
PubMed Link to Article
Blank  JBCawthon  PMCarrion-Petersen  ML  et al.  Overview of recruitment for the Osteoporotic Fractures in Men Study (MrOS). Contemp Clin Trials 2005;26557- 568
PubMed Link to Article
Cauley  JStone  KFullman  R  et al.  Determinants of bone mineral density are similar in older men and women. J Bone Miner Res 2003;18 ((supp 2)) S355
Washburn  RAMcAuley  EKatula  JMihalko  SLBoileau  RA The Physical Activity Scale for the Elderly (PASE): evidence for validity. J Clin Epidemiol 1999;52643- 651
PubMed Link to Article
Ware  JKosinski  MKeller  S SF-12: How to Score the SF-12 Physical and Mental Health Summary Scores. 3rd ed. Lincoln, RI Quality Metric Inc1998;
Amir  MLewin-Epstein  NBecker  GBuskila  D Psychometric properties of the SF-12 (Hebrew version) in a primary care population in Israel. Med Care 2002;40918- 928
PubMed Link to Article
Ware  J  JrKosinski  MKeller  SD A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care 1996;34220- 233
PubMed Link to Article
Orwoll  ESBauer  DCVogt  TMFox  KMStudy of Osteoporotic Fractures Research Group, Axial bone mass in older women. Ann Intern Med 1996;124187- 196
PubMed Link to Article
Cummings  SRCawthon  PMEnsrud  KE  et al.  BMD and risk of hip and non-vertebral fractures in older men: a prospective study and comparison with older women. J Bone Miner Res 2006;211550- 1556
PubMed Link to Article
Bliziotes  MMEshleman  ABurt-Pichat  B  et al.  Serotonin transporter and receptor expression in osteocytic MLO-Y4 cells. Bone 2006;391313- 1321
PubMed Link to Article
Gustafsson  BIThommesen  LStunes  AK  et al.  Serotonin and fluoxetine modulate bone cell function in vitro. J Cell Biochem 2006;98139- 151
PubMed Link to Article
Locker  MBitard  JCollet  C  et al.  Stepwise control of osteogenic differentiation by 5-HT2B receptor signaling: nitric oxide production and phospholipase A2 activation. Cell Signal 2006;18628- 639
PubMed Link to Article
Diem  SJBlackwell  TLStone  KL  et al.  Use of antidepressants and rates of hip bone loss in older women: the Study of Osteoporotic Fractures. Arch Intern Med 2007;1671240- 1245
Link to Article
Cizza  GEskandari  FMartinez  P  et al. P.O.W.E.R. (Premenopausal, Osteoporosis Women, Alendronate, Depression) Study Group, 21 to 45 year old premenopausal women suffering from major depression are at increased risk for osteoporosis: role of endocrine and life style factors. J Bone Miner Res 2003;18 ((supp 2)) S87
Coelho  RSilva  CMaia  APrata  JBarros  H Bone mineral density and depression: a community study in women. J Psychosom Res 1999;4629- 35
PubMed Link to Article
Halbreich  URojansky  NPalter  S  et al.  Decreased bone mineral density in medicated psychiatric patients. Psychosom Med 1995;57485- 491
PubMed Link to Article
Michelson  DStratakis  CHill  L  et al.  Bone mineral density in women with depression. N Engl J Med 1996;3351176- 1181
PubMed Link to Article
Robbins  JHirsch  CWhitmer  RCauley  JHarris  T The association of bone mineral density and depression in an older population. J Am Geriatr Soc 2001;49732- 736
PubMed Link to Article
Wong  SYSLau  EMCLynn  H  et al.  Depression and bone mineral density: is there a relationship in elderly Asian men? results from Mr. Os (Hong Kong). Osteoporos Int 2005;16610- 615
PubMed Link to Article
Yazici  KMAkinci  ASutcu  AOzcakar  L Bone mineral density in premenopausal women with major depressive disorder. Psychiatry Res 2003;117271- 275
PubMed Link to Article
Whooley  MACauley  JAZmuda  JMHaney  EMGlynn  NW Depressive symptoms and bone mineral density in older men. J Geriatr Psychiatry Neurol 2004;1788- 92
PubMed Link to Article
Reginster  JYDeroisy  RPaul  IHansenne  MAnsseau  M Depressive vulnerability is not an independent risk factor for osteoporosis in postmenopausal women. Maturitas 1999;33 (2) 133- 137
PubMed Link to Article
Kinjo  MSetoguchi  SSchneeweiss  SSolomon  DH Bone mineral density in subjects using central nervous system-active medications. Am J Med 2005;1181414
PubMed Link to Article
Saag  KG Low-dose corticosteroid therapy in rheumatoid arthritis: balancing the evidence. Am J Med 1997;103 (6A) 31S- 39S
PubMed Link to Article
Westbroek  IWaarsing  JHva Leeuwen  JP Long-term fluoxetine administration does not result in major changes in bone architecture and strength in growing rats. doi:10.1002/jcb.21177 J Cell Biochem 2006;101360- 368[Published Online Ahead Of Print December 12, 2006]
PubMed Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Demographics of the MrOS Cohort by Antidepressant Use*
Table Graphic Jump LocationTable 2. Estimated Least Square Mean BMD for Users vs Nonusers of Antidepressants*
Table Graphic Jump LocationTable 3. Estimated Least Square Mean BMD for Glucocorticoid Users and Nonusers*

References

Bliziotes  MMEshleman  AZhang  XWiren  K Neurotransmitter action in osteoblasts: expression of a functional system for serotonin receptor activation and reuptake. Bone 2001;29477- 486
PubMed Link to Article
Battaglino  RFu  JSpate  U  et al.  Serotonin regulates osteoclast differentiation through its transporter. J Bone Miner Res 2004;191420- 1431
PubMed Link to Article
Warden  SJRobling  AGSanders  MSBliziotes  MMTurner  CH Inhibition of the serotonin (5-hydroxytryptamine) transporter reduces bone accrual during growth. Endocrinology 2005;146685- 693
PubMed Link to Article
Pirraglia  PAStafford  RSSinger  DE Trends in prescribing of selective serotonin reuptake inhibitors and other newer antidepressant agents in adult primary care. Prim Care Companion J Clin Psychiatry 2003;5153- 157
PubMed Link to Article
Anderson  IM Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. J Affect Disord 2000;5819- 36
PubMed Link to Article
Sauer  WHBerlin  JAKimmel  SE Effect of antidepressants and their relative affinity for the serotonin transporter on the risk of myocardial infarction. Circulation 2003;10832- 36
PubMed Link to Article
Rausch  JLJohnson  MEFei  Y-J  et al.  Initial conditions of serotonin transporter kinetics and genotype: influence on SSRI treatment trial outcome. Biol Psychiatry 2002;51723- 732
PubMed Link to Article
Liu  BAnderson  GMittmann  NTo  TAxcell  TShear  N Use of selective serotonin-reuptake inhibitors or tricyclic antidepressants and risk of hip fractures in elderly people. Lancet 1998;3511303- 1307
PubMed Link to Article
Ensrud  KEBlackwell  TMangione  CM  et al.  Central nervous system active medications and risk for fractures in older women. Arch Intern Med 2003;163949- 957
PubMed Link to Article
Hubbard  RFarrington  PSmith  CSmeeth  LTattersfield  A Exposure to tricyclic and selective serotonin reuptake inhibitor antidepressants and the risk of hip fracture. Am J Epidemiol 2003;15877- 84
PubMed Link to Article
Schneeweiss  SWang  PS Association between SSRI use and hip fractures and the effect of residual confounding bias in claims database studies. J Clin Psychopharmacol 2004;24632- 638
PubMed Link to Article
Whooley  MAKip  KECauley  JAEnsrud  KENevitt  MCBrowner  WS Depression, falls, and risk of fracture in older women. Arch Intern Med 1999;159484- 490
PubMed Link to Article
Cauley  JAFullman  RStone  K  et al. Mr. OS Research Group, Factors associated with the lumbar spine and proximal femur bone mineral density in older men. Osteoporos Int 2005;161525- 1537
PubMed Link to Article
Orwoll  EBlank  JBBarrett-Connor  E  et al.  Design and baseline characteristics of the osteoporotic fractures in men (MrOS) study: a large observational study of the determinants of fracture in older men. Contemp Clin Trials 2005;26569- 585
PubMed Link to Article
Blank  JBCawthon  PMCarrion-Petersen  ML  et al.  Overview of recruitment for the Osteoporotic Fractures in Men Study (MrOS). Contemp Clin Trials 2005;26557- 568
PubMed Link to Article
Cauley  JStone  KFullman  R  et al.  Determinants of bone mineral density are similar in older men and women. J Bone Miner Res 2003;18 ((supp 2)) S355
Washburn  RAMcAuley  EKatula  JMihalko  SLBoileau  RA The Physical Activity Scale for the Elderly (PASE): evidence for validity. J Clin Epidemiol 1999;52643- 651
PubMed Link to Article
Ware  JKosinski  MKeller  S SF-12: How to Score the SF-12 Physical and Mental Health Summary Scores. 3rd ed. Lincoln, RI Quality Metric Inc1998;
Amir  MLewin-Epstein  NBecker  GBuskila  D Psychometric properties of the SF-12 (Hebrew version) in a primary care population in Israel. Med Care 2002;40918- 928
PubMed Link to Article
Ware  J  JrKosinski  MKeller  SD A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care 1996;34220- 233
PubMed Link to Article
Orwoll  ESBauer  DCVogt  TMFox  KMStudy of Osteoporotic Fractures Research Group, Axial bone mass in older women. Ann Intern Med 1996;124187- 196
PubMed Link to Article
Cummings  SRCawthon  PMEnsrud  KE  et al.  BMD and risk of hip and non-vertebral fractures in older men: a prospective study and comparison with older women. J Bone Miner Res 2006;211550- 1556
PubMed Link to Article
Bliziotes  MMEshleman  ABurt-Pichat  B  et al.  Serotonin transporter and receptor expression in osteocytic MLO-Y4 cells. Bone 2006;391313- 1321
PubMed Link to Article
Gustafsson  BIThommesen  LStunes  AK  et al.  Serotonin and fluoxetine modulate bone cell function in vitro. J Cell Biochem 2006;98139- 151
PubMed Link to Article
Locker  MBitard  JCollet  C  et al.  Stepwise control of osteogenic differentiation by 5-HT2B receptor signaling: nitric oxide production and phospholipase A2 activation. Cell Signal 2006;18628- 639
PubMed Link to Article
Diem  SJBlackwell  TLStone  KL  et al.  Use of antidepressants and rates of hip bone loss in older women: the Study of Osteoporotic Fractures. Arch Intern Med 2007;1671240- 1245
Link to Article
Cizza  GEskandari  FMartinez  P  et al. P.O.W.E.R. (Premenopausal, Osteoporosis Women, Alendronate, Depression) Study Group, 21 to 45 year old premenopausal women suffering from major depression are at increased risk for osteoporosis: role of endocrine and life style factors. J Bone Miner Res 2003;18 ((supp 2)) S87
Coelho  RSilva  CMaia  APrata  JBarros  H Bone mineral density and depression: a community study in women. J Psychosom Res 1999;4629- 35
PubMed Link to Article
Halbreich  URojansky  NPalter  S  et al.  Decreased bone mineral density in medicated psychiatric patients. Psychosom Med 1995;57485- 491
PubMed Link to Article
Michelson  DStratakis  CHill  L  et al.  Bone mineral density in women with depression. N Engl J Med 1996;3351176- 1181
PubMed Link to Article
Robbins  JHirsch  CWhitmer  RCauley  JHarris  T The association of bone mineral density and depression in an older population. J Am Geriatr Soc 2001;49732- 736
PubMed Link to Article
Wong  SYSLau  EMCLynn  H  et al.  Depression and bone mineral density: is there a relationship in elderly Asian men? results from Mr. Os (Hong Kong). Osteoporos Int 2005;16610- 615
PubMed Link to Article
Yazici  KMAkinci  ASutcu  AOzcakar  L Bone mineral density in premenopausal women with major depressive disorder. Psychiatry Res 2003;117271- 275
PubMed Link to Article
Whooley  MACauley  JAZmuda  JMHaney  EMGlynn  NW Depressive symptoms and bone mineral density in older men. J Geriatr Psychiatry Neurol 2004;1788- 92
PubMed Link to Article
Reginster  JYDeroisy  RPaul  IHansenne  MAnsseau  M Depressive vulnerability is not an independent risk factor for osteoporosis in postmenopausal women. Maturitas 1999;33 (2) 133- 137
PubMed Link to Article
Kinjo  MSetoguchi  SSchneeweiss  SSolomon  DH Bone mineral density in subjects using central nervous system-active medications. Am J Med 2005;1181414
PubMed Link to Article
Saag  KG Low-dose corticosteroid therapy in rheumatoid arthritis: balancing the evidence. Am J Med 1997;103 (6A) 31S- 39S
PubMed Link to Article
Westbroek  IWaarsing  JHva Leeuwen  JP Long-term fluoxetine administration does not result in major changes in bone architecture and strength in growing rats. doi:10.1002/jcb.21177 J Cell Biochem 2006;101360- 368[Published Online Ahead Of Print December 12, 2006]
PubMed Link to Article

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 124

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Collections
PubMed Articles
JAMAevidence.com

The Rational Clinical Examination
Evidence Summary and Review 2

The Rational Clinical Examination
Evidence Summary and Review 2