July 6, 2007 — In a large observational study of older women — the Study of Osteoporotic Fractures (SOF) — the use of selective serotonin reuptake inhibitor (SSRI) antidepressants but not tricyclic antidepressants (TCAs) was associated with increased hip bone loss.

The study is published in the June 25 issue of the Archives of Internal Medicine.

Lead study author Susan J. Diem, MD, MPH, from the University of Minnesota in Minneapolis, told Medscape, "It would be premature at this point to conclude that SSRIs definitely have an effect on bone health in humans, but this does suggest that this is an area for more research... Clinically, I think this means physicians who have patients who are depressed or who are on SSRIs might consider testing patients' bone mineral density at some point during their treatment."

The group writes that with the development of SSRIs, prescriptions for antidepressants for the elderly have increased substantially during the past 2 decades. Animal studies have shown that SSRIs inhibit serotonin transporters, and this is linked with reduced bone formation rates. However, TCAs act by a different mechanism. The researchers aimed to determine whether SSRI and TCA use in older women is associated with increased rates of hip bone loss.

They examined data from a cohort of women in the SOF study who had hip bone mineral density (BMD) results from their sixth clinic visit (when they were, on average, age 78.5 years) and their the eighth clinic visit (an average of 4.9 years later) as well as results for the 15-item Geriatric Depression Scale.

From 2844 eligible women, 122 women who were taking antidepressants other than SSRIs or TCAs or who were taking both agents were excluded from the analysis.

The remaining 2722 women were classed into 3 groups based on their medication use at visits 6 and 8: nonusers (no SSRI, TCA, or other antidepressant use; n = 2406; 88.4%), SSRI users (no TCA use; n = 198; 7.3%), and TCA users (no SSRI use; n = 118; 4.3%).

Bone mineral density was measured for the total hip and for 2 subregions: the femoral neck and the trochanter.

Greater Bone Loss in SSRI Users

On average, compared with nonusers of SSRIs, women taking SSRIs but not women taking TCAs had a higher rate of bone loss at the total hip, after adjusting for multiple potential confounding factors including age, race, health status, physical activity, smoking status, body mass index, depression, and use of calcium or vitamin D supplements, estrogen, thiazide, or bisphosphonate.

Table. Mean Annualized Rate of Total Hip Bone Loss*

*Adjusted for multiple potential covariables. SSRI indicates selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.
Source: Arch Intern Med. 2007;167:1240-1245.

Bone loss at the femoral neck and trochanter was similar.

Women not taking SSRIs lost bone density at a rate of about 0.5% per year, and the women taking SSRIs lost bone density at a rate of about 0.8% per year, Dr. Diem summarized, adding that "over time, that difference would accumulate, but what is not known is if that difference in rate will translate into an increased risk of fracture, which is what the real issue is."

She cautioned, "We would not recommend people stop taking their antidepressants based on these findings," since this study cannot definitively say whether the SSRIs are directly responsible for the increased rates of bone loss or whether the association may be caused by other factors.

The study was supported by grants from the National Institute on Aging and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Diem has disclosed participating in trials funded by Pfizer Inc, Eli Lilly and Co, and Merck & Co, Inc in the area of osteoporosis treatment and prevention. The financial disclosures of the other study authors are listed in the original article.

"Mend the Mind, but Mind the Bones"

Kenneth Saag, MD, MSc, at the University of Alabama in Birmingham, author of an editorial that accompanied this article and another article in the same issue about SSRI use and bone health in men, told Medscape that the fact that these 2 studies about SSRI use and bone health reached very similar conclusions, added to animal data that suggest a biological mechanism, while not conclusive, does begin to suggest a possible cause-and-effect relationship.

He added that to establish a causal link would require a randomized clinical trial, since "unmeasured factors relating to depression, co-illnesses, and other conditions that are not being adequately accounted for in the elegant analyses that these investigators did could potentially cause a finding of this type to be spurious."

Regarding the clinical implications he said, "In patients who are at high risk — women over the age of menopause, men over the age of 70, and in particular, people who have other significant osteoporosis risk factors — it may merit further evaluation of their bone health, which might involve tests such as bone density measurement to determine whether they are indeed in a range where potential treatment may be indicated."

Dr. Saag has disclosed serving as a consultant or speaker for or receiving grant funding in the area of osteoporosis from Merck & Co, Inc, Aventis, Eli Lilly and Co, Novartis, Roche, Arngen, and GlaxoSmithKline.

Arch Intern Med. 2007;167:1231-1232, 1240-1245.

Clinical Context

Study Highlights

• Community-dwelling women older than 65 years who were enrolled in the SOF trial were included in this study.
• Of these women, those who completed a medication inventory at 2 visits (visits 6 and 8) and the Geriatric Depression Scale, at visit 6 and who had hip BMD measurements at both visits were included for analysis.
• Excluded were women who took antidepressants other than SSRIs or TCAs, leaving 2722 women who took either medication and who had 2 BMD measurements.
• At visits 6 and 8, women were asked to bring all current prescription and nonprescription medications (any use within the past 2 weeks) and interviewers completed a medication history.
• The average interval between visits 6 and 8 was 4.9 years.
• Nonusers were defined as those not taking an SSRI, a TCA, or any antidepressant at week 6 or 8.
• TCA users were defined as those reporting TCA use but not SSRI use at either visit.
• SSRI users were those reporting SSRI but not TCA or other antidepressant use.
• Women reporting either SSRI or TCA use at only 1 of these visits were classified as partial users of that medication.
• Women reporting use of the same medication at both visits were classified as continuous users.
• BMD at the total hip and 2 subregions (femoral neck and trochanter) were measured at visits 6 and 8 using dual-energy x-ray absorptiometry with bone densitometry scanners.
• Rate of change of BMD was the primary endpoint and defined as an annualized percentage of the difference between follow-up BMD and initial BMD divided by the initial BMD.
• Depressive symptoms were evaluated at visit 6 using the 15-item Geriatric Depression Scale, a self-report scale using yes/no questions.
• A cutoff of 6 or more symptoms on the Geriatric Depression Scale has a sensitivity of 88% and a specificity of 62% for depression.
• Women also completed a questionnaire on health, smoking status, physical activity, and use of oral hormones, thiazides, bisphosphonates, and vitamin D and calcium supplements.
• Dietary intake was assessed using a semiquantitative food frequency questionnaire.
• Functional activity was assessed by asking about 6 independent activities of daily living.
• Mean age was 78.4 years, 8% to 12% were African American, 7.3% were SSRI users, and 4.3% were TCA users.
• 88.4% reported no use of an SSRI, TCA, or other antidepressant at either visit.
• SSRI users were more likely to have a Geriatric Depression Scale score of at least 6 (13.1% vs 5.2%; P < .001).
• Women taking SSRIs had a higher age-adjusted rate of bone loss at the total hip vs nonusers (-0.77% vs -0.49% per year; P = .005).
• Results were not changed after adjustment for multiple confounding factors including Geriatric Depression Scale score.
• At the total hip, femoral, and trochanter sites, the rate of loss of bone was at least 1.6 times higher among SSRI users vs nonusers of antidepressants.
• Compared with nonusers, partial SSRI users and continuous SSRI users showed no difference in rate of bone loss.
• The rate of bone loss was -0.47% for nonusers vs -0.83% for partial users vs -0.76% per year for continuous users.
• Rates of bone loss among TCA users were similar to those of nonusers.
• The authors noted that the indication for TCA use in this population may differ from that for SSRI use and the number of women using TCAs was small. They suggested that more studies may be needed to verify the observation of lack of association between TCA use and bone loss.

Pearls for Practice

• SSRI use in older women is independently associated with an increased rate of bone loss.
• TCA use in older women is not associated with increased rate of bone loss.

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