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