Caroline Helwick

May 27, 2010

May 27, 2010 (New Orleans, Louisiana) —The use of certain psychotropic medications enhances an already high underlying risk for osteoporosis, according to several studies presented here at the American Psychiatric Association 2010 Annual Meeting.

Psychotropic agents have been linked to fractures and antidepressants have been associated with low bone mineral density (BMD). Studies presented at this meeting validate these earlier findings and suggest that many patients may already be at high risk for bone disease.

In a large study from Canada, osteoporosis was found to be associated with the use of selective serotonin reuptake inhibitors (SSRIs), mood stabilizers other than lithium, and benzodiazepines. Use of tricyclic antidepressants was protective, he reported.

"We found a 40% increased risk for low BMD with SSRIs and a 37% reduced risk with tricyclic antidepressants," said James Bolton, MD, of the University of Manitoba in Winnipeg, Canada.

Data were derived from Manitoba's healthcare database that captures all physician contacts and diagnoses, all medication prescriptions, all hospitalizations, and census data, which was linked to data from the Manitoba Bone Density Program, a clinical database of information from dual-energy X-ray absorptiometry scans.

From the databases of 2000 to 2007, investigators identified 7994 osteoporosis cases, which were defined as persons with a T-score of −2.5 or lower at 1 of 4 sites (trochanter, femoral neck, total hip, or lumbar spine). Controls were 23,928 subjects matched for sex, age, and ethnicity but with normal BMD at 4 sites. Three controls were matched for each case.

"We assessed all psychotropic medications prescribed, all mental disorders diagnosed, and nearly 20 confounders (body mass index, medical comorbidity, estrogen use, bisphosphonate use, and so forth)," Dr. Bolton said.

The adjusted odds ratios were 1.39 for SSRIs (95% confidence interval [CI], 1.21 – 1.59), 1.35 for nonlithium mood stabilizers (ie, anticonvulsants) (95% CI, 1.10 – 1.66), 1.10 for benzodiazepines (95% CI, 1.01 – 1.20), and 0.63 for tricyclic antidepressants (95% CI, 0.56 – 0.72).

Probably because sample sizes were smaller, Dr. Bolton suggested, the odds ratio for lithium was 0.57 but the CI crossed 1.0 (95% CI, 0.29 – 1.12) and, therefore, the suggestion of protection with this agent was not significant. The same was true for typical antipsychotics, for which the odds ratio was 1.20 (95% CI, 0.81 – 1.77), and for atypical antipsychotics, whose odds ratio was 1.55 (95% CI, 0.87 – 1.97). Other antidepressants had an odds ratio of 1.08 (95% CI, 0.91 – 1.27).

Mental Disorders Also Have an Impact

Mental disorders themselves also had statistically significant osteoporotic effects, he added. Odds ratios were 1.34 for dementia (95% CI, 1.04 – 1.72), 1.92 for schizophrenia (95% CI, 1.11 – 3.33), and 1.53 for alcohol dependence (95% CI, 1.01 – 2.32), whereas risk was reduced, interestingly, with depression, which carried an odds ratio of 0.85 (95% CI, 0.75 – 0.95). Bipolar disorder and drug abuse or dependence was not significantly associated with osteoporosis.

"SSRIs, anticonvulsant mood stabilizers, and benzodiazepines are associated with osteoporotic changes in bone, independent of the effects of mental disorders and other confounders, and tricyclic antidepressants appear to be protective," Dr. Bolton concluded.

He acknowledged that the investigators were not able to assess medication compliance, use of supplements (vitamin D, calcium), and lifestyle risk factors or interventions.

"There are clinical implications in that physicians may choose tricyclic antidepressants ahead of SSRIs for treating depression in patients deemed at risk of osteoporosis," he suggested.

"Similarly, lithium may be a preferred option in bipolar disorder patients at risk, while anticonvulsants may be better suited as second-line options. But most importantly, psychiatrists should maintain an awareness that many of their patients are at risk for osteoporosis and should investigate and manage this appropriately."

Average Patient Has Many Risk Factors

A study from the University of Rochester Medical Center in New York suggested that women treated for depression — and presumably receiving SSRIs in many cases — have an underlying risk for osteoporosis that may be neglected.

Dr. Barbara Gracious

"Most of the subjects in our study were disabled by depression and had been maintained on SSRIs for years. The majority also had exposure to prolactin-elevating antipsychotic medications [associated with reduced estrogen and testosterone]. We found the risk factor burden of these patients was huge," said principal investigator Barbara Gracious, MD.

Her project systematically examined osteoporosis risk factors via personalized screening to determine whether osteoporosis prevention is warranted in midlife mood-disordered patients. The 19 patients (mean age, 47 years; 94% female) were recruited from a university psychiatric partial hospitalization program and an urban university neighborhood family medical center.

The Mini-International Neuropsychiatric Interview confirmed the primary Axis I diagnosis of major depression and captured comorbid mental disorders. Structured interviews provided demographics, history, lifestyle, and medication risk.

The average patient was found to have 19 risk factors for osteoporosis. The most prevalent iatrogenic risk factors were history of SSRI use (89%), history of major surgery (89%), and history of prolactin-elevating antipsychotic exposure (68%). Prevalent lifestyle factors were decreased weight-bearing exercise (76%), low vitamin D levels (64%), alcohol use (59%), cigarette smoking (53%), and excess salt use (41%).

Many had a family history of fractures (53%) or osteoporosis (29%) and irregular periods (35%). Only about half the subjects were postmenopausal.

Lifestyle Interventions Appropriate

The investigators concluded that midlife patients treated for major depression have many lifestyle, iatrogenic, and historical risk factors that raise the likelihood for poor bone quality and osteoporotic fractures at younger ages.

"We believe that lifestyle interventions are appropriate for this population, including calcium and vitamin D supplementation and enhanced weight-bearing physical activity. In addition, coordinated primary care follow-up should be a priority, and heavy smokers and alcohol abusers should receive substance abuse treatment," Dr. Gracious said.

"These interventions may also reduce the risk and burden of comorbid physical disorders and improve the mental health of depressed adults," she added.

Dr. Gracious also added that BMD is not the only factor to consider for bone health. "We should also consider bone quality. We don't have good quality indicators of this, but we think these women are going headlong into menopause and may have poor bone quality."

Iqbal Ahmed MD, professor of psychiatry at the University of Hawaii, Honolulu, and a geriatric psychiatrist, commented on the studies' findings for Medscape Psychiatry. "There is reason to be concerned about bone health in these patients. Several studies have shown that SSRIs may affect BMD and may increase osteoporosis and fracture risk, perhaps through serotonin's impact on deposition of calcium in the bone. SSRIs may also increase the risk of falls and therefore fractures by upsetting balance mechanisms. The dilemma is that depression itself is also associated with increased risk, so risk of fracture and injuries could be from the factors related to depression or from the treatment of depression," he said in an interview.

Clinicians should be cognizant of the potential risks of SSRIs and in some cases perhaps monitor BMD and nutritional intake, which should not be a problem for geriatric psychiatrists, who understood the need for care for the whole patient, he said.

Dr. Ahmed added that he would not take Dr. Bolton's suggestion and prescribe tricyclic antidepressants to older women deemed at risk for osteoporosis. He speculated that the reduced risk associated with them in the Manitoba database may have been observed because these agents were prescribed to a younger, healthier subset.

"In older persons, they are associated with risks. This is not good advice in older patients," he maintained.

Dr. Bolton and Dr. Ahmed have disclosed no relevant financial relationships.

American Psychiatric Association (APA) 2010 Annual Meeting: Abstract NR4-5. Presented May 25, 2010.


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