Antidepressants Increase Fracture Risk for Older Patients

MONTREAL, Jan. 22 -- Commonly used antidepressants may increase the risk of osteoporotic fractures among patients 50 and older, researchers here found.

Daily use of the selective serotonin reuptake inhibitors (SSRIs) doubled the risk of a minimal-trauma fracture, reported David Goltzman, M.D., of Royal Victoria Hospital and McGill University here, and colleagues, in the Jan. 22 issue of the Archives of Internal Medicine.

The prospective population-based study confirmed the link that had been found in previous database studies t, which had limited ability to control for confounding factors.

The researchers said these findings may have important public health consequences because about 10% of older patients in the U.S. suffer from depression. SSRIs, because of their "presumed favorable adverse effect profile," are considered the first-line therapy for these patients.

Physicians should balance the risk of fracture against the benefits of treating depression with SSRIs, Dr. Goltzman and colleagues wrote.

The researchers analyzed 137 patients ages 50 and older (average 65.1) who reported daily SSRI use in the much larger Canadian Multicentre Osteoporosis Study of community-dwelling adults. The SSRIs in the study-- those on the market at baseline--included Celexa (citalopram), Prozac (fluoxetine), Luvox (fluvoxamine), Paxil (paroxetine), and Zoloft (sertraline).

Participants were sent yearly questionnaires for five years regarding incident clinical fragility fractures, defined as clinically reported minimal trauma fractures (such as falling from bed, chair, or standing height).

All fractures were radiographically confirmed, and tended to occur at clinically relevant sites (40% forearm, 21% ankle and foot, 13% hip, 13% rib, 9% femur, and 4% back).

Daily SSRI use was associated with substantially increased risk of fragility fracture (hazard rate 2.1, 95% confidence interval 1.3 to 3.4) even after adjusting for age, total hip bone mineral density, modified Charlson index, prevalent vertebral deformity, prevalent fragility fractures at baseline, and cumulative estrogen use.

The researchers also found a dose effect. A one unit increase in the daily SSRI dose, effectively doubling the starting dose, increased the adjusted risk of fragility fracture 1.5-fold (95% CI 1.1 to 2.1).

Participants with probable long-term use--those who reported daily SSRI use at baseline and at the five-year follow-up though duration of use was unknown--did not appear to have higher risk than the overall group who reported taking antidepressants at baseline. The adjusted hazard rate for these patients with recurrent use was 2.1 (95% CI 1.1 to 4.0).

Daily SSRI use was associated with 2.2-fold increased odds of falling in the month before the baseline interview (95% CI 1.4 to 3.5). This relationship was also dose dependent with 1.5-fold increased odds of falling for each one-unit increase in daily SSRI dose (95% CI 1.1 to 2.0).

Controlling for the other potentially confounding factors, daily SSRI use was associated with lower bone mineral density at the total hip (-4.0% difference versus nonusers, 95% CI -6.6% to -1.4%) and the lumbar spine (-2.4% difference versus nonusers, 95% CI -5.5% to 0.9%). This association was also dose dependent and similar for recurrent users.

Although lower bone mineral density and increased likelihood of falls would increase the risk of fracture, both factors were controlled for in the analysis and so cannot entirely explain the effect of SSRI use on fracture risk, the researchers said.

"Our results suggest that bone mineral density and falls may be affected adversely by daily SSRI use but that fracture rates remain elevated despite adjustment for these two risk factors," they wrote, "indicating that other pathways, such as impaired bone quality leading to reduced bone strength, may be of particular relevance."

Other studies have shown that serotonin plays a potentially important role in bone physiology by modulating the skeletal effects of parathyroid hormone and mechanical stimulation, they said.

Depressive symptoms were also unlikely to have been responsible for the link between fracture and SSRIs because the researchers found no association between symptoms and fractures in univariate or multivariate regression models.

While the study focused on SSRI antidepressants, there was a small increase in adjusted fracture risk for tricyclic antidepressants among the 162 participants reporting daily use of this class of antidepressants (HR 1.2, 95% CI 0.7 to 2.2). However, "the wide 95% CI precludes any conclusions," Dr. Goltzman and colleagues said.

Participants in the study had "almost normal" dementia scores assessed with the Mini-Mental State Examination (mean 29.1). The researchers said that SSRIs may further elevate fractures among patients with dementia since dementia is known to be an independent risk factor for fracture.

The researchers concluded that prospective, controlled trials will be needed to confirm the findings.