By Laura L. Tosi, MD; Mary I. O’Connor, MD; and Annie Hayashi

Is there a link between SSRIs and bone loss?

NIH/NIAMS and AAOS
This is the first in a series of articles featuring orthopaedic-related research funded by the National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS).

During the past 2 decades, an increasing number of older women have been taking antidepressants. That fact may have an impact on orthopaedic practices. A recent study, funded by the National Institutes of Health, demonstrated an association between a class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs) and hip bone loss.

According to the study, led by Susan J. Diem, MD, MPH, an assistant professor of internal medicine at the University of Minnesota, SSRIs­—which include fluoxetine, paroxetine, and sertraline—appear to be associated with higher rates of bone loss in older women. Dr. Diem also found that depression itself seemed to have an even greater association with lower bone density.

This study underscores the complexity of this potential association, the imperative for orthopaedic surgeons to increase their awareness of this issue, and the need for more research to further clarify the association.

“Certainly, no one should stop taking antidepressant medication as a result of our findings,” said Dr. Diem. She also emphasized that the finding of an association between SSRI use and higher rates of bone loss does not mean a causal relationship exists between use of the medications and bone loss.

Serotonin transporters: The link between SSRIs and bone loss?
SSRIs are designed to combat depression by inhibiting the reuptake of serotonin by certain nerve receptor sites in the brain.

Research in this area has led to the discovery of serotonin transporters on bone cells, osteoblasts, and osteocytes. The discovery of serotonin transporters on bone prompted researchers to examine whether blocking those serotonin transporters—the mechanism of action of the SSRIs—might have an impact on bone density.

To examine the potential association of SSRIs with higher rates of bone loss, Dr. Diem and her colleagues used data from the Study of Osteoporotic Fractures, a long-term observational, prospective study of older women.

More than 2,700 women participated in the study. Bone mineral density (BMD) at the hip was measured between January 1997 and February 1999, and again between January 2002 and April 2004. Participants also completed a medication inventory, several questionnaires, and an interview. Due to the older average age of the participants (78.5 years), more than 15 percent of the participants died between the two evaluation periods.

Are SSRIs really the problem?
To understand the potential impact of SSRIs, researchers divided the participants into three groups based on their use of antidepressants: SSRI users, tricyclic antidepressant (TCAs—an older class that inhibits uptake of norepinephrine and serotonin to a lesser degree than SSRIs) users, and nonusers of antidepressants. Individuals taking both an SSRI and a TCA as well as those taking an antidepressant other than an SSRI or a TCA were not included.

Each woman was asked to complete the Geriatric Depression Scale (GDS)—a 15-question, self-reported assessment of depression. A score of 6 or higher was an indicator of depression.

Participants were asked to complete questionnaires and were interviewed about several factors that could influence BMD, including their level of physical activity; smoking status; use of oral estrogen, bisphosphonates, and diuretics; and intake of vitamin D supplements, calcium supplements, and dietary calcium.

Independent living skills, as well as cognitive and neuromuscular function, were evaluated, and body mass index was calculated for each participant.

“As we considered all these factors, we identified many potential confounders,” explained Dr. Diem. “People who had more chronic medical conditions were more likely to have depression and be on SSRIs, as well as have higher rates of bone loss.”

“Because women with low BMD tended to be sicker, factors other than SSRIs could be responsible for a low BMD finding. Women who were depressed tended to get less physical exercise, which affected bone density. They were more likely to be smokers, which also lowered bone density,” she noted.

SSRIs and hip bone loss
Dr. Diem clearly acknowledged the numerous and complex potential confounders when analyzing all of the data. However, the researchers were able to control for many of the confounders through a series of statistical analyses.

“Even after we were able to control for many of the potential confounders,” she said, “we still saw a significantly higher rate of bone loss in SSRI users than in nonusers. In comparison, we did not see a higher rate of bone loss in the TCA group.”

“At any site, the adjusted rate of loss among SSRI users was at least 1.6-fold higher than that among nonusers of antidepressants.”

A secondary analysis, conducted on rates of change in BMD in nonusers, partial SSRI users, and continuous SSRI users, showed no difference in the rate of bone loss between partial and continuous users. Women who took antidepressants at one of their two visits were considered partial users.

The absence of such a dose effect—higher rates of bone loss with longer duration of use—speaks against a causal relationship between SSRI use and rates of bone loss, according to Dr. Diem. One potential explanation for this finding may be that partial users had preexisting depression, which contributed to their bone loss.

Depression and hip bone loss
As part of the Study of Osteo­porotic Fractures, Dr. Diem and her associates also examined the potential association of symptoms of depression with increased rates of hip bone loss among older women.

Researchers evaluated 3,977 older women who completed the GDS questionnaire as well as all of the survey and measurement instruments used in the SSRI study. Participants taking any antidepressant medication were excluded from the analysis.

Women who had GDS scores of 6 or higher—indicative of depression—tended to be older than women who scored lower than 6. High scorers also were more likely to report being in poor health, less likely to walk for exercise, and more likely to smoke.

Even when the analysis was adjusted for confounders, high scorers (13.3 percent) had a higher rate of bone loss at the hip than low-scoring women in age-adjusted models. More bone was lost at the femoral neck than at the greater trochanter.

Dr. Diem and her associates also found a correlation between the number of depressive symptoms and rates of bone loss. Women with more depressive symptoms had higher rates of bone loss at the hip in age-adjusted and multivariable models.

How orthopaedic surgeons can help
Orthopaedic surgeons should be aware of the association between depression and bone loss, as well as the higher rate of bone loss in patients on SSRI medication for their depression. In patients with depression and those on SSRIs, attention should be directed to the heightened risk of fragility fracture.

These patients need to be strongly counseled to adopt bone health strategies, including use of calcium and vitamin D supplements, quitting smoking, limiting alcohol consumption to fewer than two glasses a day, and participating in weight-bearing exercises and fall-prevention programs.

If a patient has been diagnosed with osteoporosis, she should be referred to her primary care physician so the appropriate pharmacotherapy can be started and follow-up can proceed.

Diem SJ, Blackwell TL, Stone KL, et al: Use of antidepressants and rates of hip bone loss in older women. Arch Intern Med 2007;167:1240-1245.

Dr. Diem has participated in trials funded by Pfizer, Eli Lilly and Company, and Merck.

Laura L. Tosi, MD, is director of the bone health program at Children’s National Medical Center. She can be reached at ltosi@cnmc.org

Mary I. O’Connor is chair of the AAOS Women’s Health Issues Advisory Board. She can be reached at oconnor.mary@mayo.edu

Annie Hayashi is senior science writer for AAOS Now. She can be reached at hayashi@aaos.org

Disclosure Information:
Susan J. Diem, MD, MPH, has participated in trials funded by Pfizer, Eli Lilly and Company, and Merck. Kristine E. Ensrud, MD, MPH, reports research funding from Pfizer, Eli Lilly and Company, and Bionovo. Elizabeth M. Haney, MD, has participated in trials funded by Sanofi-Synthelabo and Pfizer that did not involve treatments for depression or osteoporosis. Michael M. Bliziotes, MD, has acted as a consultant for and received research grants and honoraria from Merck and Proctor & Gamble.