Ms. P, age 44, is concerned about her risk of osteoporosis after her 70-year-old mother is hospitalized for a hip fracture. Ms. P has been taking fluoxetine, 40 mg/d, for 10 years to treat recurrent major depressive episodes that began at age 25. She was diagnosed with anorexia nervosa as a teenager, but recovered after 2 years of psychotherapy. She is lactose intolerant, has mild asthma that does not require steroids, and has no history of thyroid disease or bone fracture. Ms. P smokes 10 cigarettes a day but denies using alcohol or illicit drugs. She does not exercise, and her menses occur every 28 to 30 days.
Osteoporosis is a skeletal disease characterized by low bone mineralization and deteriorating bone architecture that results in increased susceptibility to fracture. Approximately 1 in 2 women and 1 in 5 men in the United States will have an osteoporosis-related fracture.1 Proximal femur and vertebral fractures are most common—1.5 million per year—but other bones may be involved.2
Osteoporosis-related fractures are associated with substantial morbidity and mortality. After a hip fracture, osteoporosis patients have a 10% to 20% risk of death within a year.3 Those who recover from hip fracture have a 2.5-fold increased risk of recurrent fracture and often struggle with chronic pain, disability, and loss of self-esteem and independence.1,3–5
Evidence links osteoporosis and depression
Research has shown that patients with major depression are at higher risk of osteoporosis.6 In one study, bone mineral density among 70 depressed outpatients was 15% lower than among age-matched controls.7 In a cross-sectional study, Michelson et al8 found that compared with nondepressed controls, women with current or past major depression had a lower mean bone mineral density—6.5% lower at the spine and 13.6% lower at the femoral neck.
Fewer prospective studies exist; however, most found depression has some impact on bone health. Whooley et al9 prospectively evaluated changes in bone mineral density among 7,414 Caucasian women age ≥65 for 6 years. Depressed women—those who scored ≥6 on the Geriatric Depression Scale—had a 40% higher risk of nonvertebral fracture after adjusting for history of fracture, weight, physical activity level, smoking, alcohol use, nutritional status, and cognitive function. The depressed cohort also had an increased risk of vertebral fracture. In a prospective study of 21,441 Norwegian female and male subjects, women who reported being depressed at 2 of 3 time points—from 1980 until 1995—had 2.5 times the risk of sustaining a nonvertebral fracture compared with those who did not report depression.10
Depressed women also have greater bone loss over time. Mean hip bone mineral density decreased by 0.69% per year in nondepressed women vs 0.96% in depressed women in a study of 4,177 women age ≥69.11 These findings were significant after adjusting for age, functional status, cognitive function, smoking, calcium intake, vitamin D supplement use, weight, antidepressant use, and bisphosphonate use. These findings have been replicated.12
Behavioral factors such as tobacco use and physical inactivity play a role in the risk of osteoporosis; however, emerging findings suggest a pathophysiologic link between depression and poor bone health. Depression is associated with lower estrogen and testosterone levels, which have been linked to decreased bone formation.6 Similarly, compared with matched controls, depressed women with low bone mineral density have higher urinary cortisol levels, suggesting that hypercortisolemia accelerates bone turnover.6,9,13 Finally, evidence suggests that depression is a pro-inflammatory state associated with production of numerous cytokines. Interleukin-6 and tumor necrosis factor-alpha, for example, inhibit osteoclast apoptosis and accelerate bone turnover.6
Fracture risk and psychotropics
Many psychotropic medications—including anticonvulsants, barbiturates, narcotics, and neuroleptics14–16—are associated with increased risk of falls, fractures, and osteoporosis. In this article we focus on selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) because little data is available on other antidepressants (Table 1).17–22
SSRIs are associated with increased fracture risk. In a cohort of 5,995 men age ≥65, Haney et al23 showed that men taking SSRIs have lower bone mineral density at the hip (3.9% lower) and spine (5.6% lower) compared with non-users after adjusting for age, weight, and race. Current SSRI use carries a greater risk than past use. In a prospective study of 7,983 men and women age ≥55, Ziere et al24 reported that risk of nonvertebral fracture among current SSRI users was 28% higher than among past users over a mean follow-up of 8.4 years. In the same study, the risk ratio of nonvertebral fracture was 2.10 for patients using SSRIs within the previous 6 months and 2.98 for use >6 months.