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Osteoporosis in Depression: Which Patients Are at Risk?

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Osteoporosis in Depression: Which Patients Are at Risk? Med/Psych Update Osteoporosis in depression: Which patients are at risk? Psychotropics increase fracture risk; depression compounds poor bone health s. P, age 44, is concerned about her risk of osteoporosis after her 70-year-old mother is Mhospitalized 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. Ap- proximately 1 in 2 women and 1 in 5 men in the United © 2010 BRANDTNER & STAEDELI / GETTY 1 States will have an osteoporosis-related fracture. Proxi- Charles Hebert, MD mal femur and vertebral fractures are most common—1.5 Chief resident million per year—but other bones may be involved.2 Combined internal medicine and psychiatry residency Osteoporosis-related fractures are associated with Melanie McKean, DO, PhD substantial morbidity and mortality. After a hip frac- Resident Combined internal medicine and psychiatry residency ture, osteoporosis patients have a 10% to 20% risk of 3 Bezalel Dantz, MD death within a year. Those who recover from hip frac- Assistant professor of internal medicine and psychiatry ture 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 Rush University Medical Center Chicago, IL Evidence links osteoporosis and depression Research has shown that patients with major depres- Current Psychiatry sion are at higher risk of osteoporosis.6 In one study, Vol. 9, No. 4 9 Table 1 eral density decreased by 0.69% per year in nondepressed women vs 0.96% in de- Psychotropic medications pressed women in a study of 4,177 women associated with osteoporosis risk age ≥69.11 These findings were significant Odds ratio (95% after adjusting for age, functional status, Medication/class confidence interval) cognitive function, smoking, calcium in- Selective serotonin 1.45 (1.32 to 1.59) take, vitamin D supplement use, weight, Depression and reuptake inhibitors antidepressant use, and bisphosphonate bone health (SSRIs) use. These findings have been replicated.12 Carbamazepine 1.18 (1.10 to 1.26) Behavioral factors such as tobacco use Non-SSRIs (eg, 1.15 (1.07 to 1.24) and physical inactivity play a role in the tricyclics, atypicals) risk of osteoporosis; however, emerging Valproate 1.15 (1.05 to 1.26) findings suggest a pathophysiologic link Oxcarbazepine 1.14 (1.03 to 1.26) between depression and poor bone health. Benzodiazepines 1.10 (1.04 to 1.16) Depression is associated with lower estro- Lamotrigine 1.04 (0.91 to 1.19) gen and testosterone levels, which have Clinical Point Typical antipsychotics 1.01 (0.86 to 1.19) been linked to decreased bone forma- 6 Depression is Atypical antipsychotics 0.96 (0.79 to 1.17) tion. Similarly, compared with matched controls, depressed women with low associated with Lithium 0.63 (0.43 to 0.93) Source: References 17-22 bone mineral density have higher urinary lower estrogen and cortisol levels, suggesting that hypercor- testosterone levels, tisolemia accelerates bone turnover.6,9,13 Fi- which have been bone mineral density among 70 depressed nally, evidence suggests that depression is linked to decreased outpatients was 15% lower than among a pro-inflammatory state associated with age-matched controls.7 In a cross-sectional production of numerous cytokines. Inter- bone formation study, Michelson et al8 found that com- leukin-6 and tumor necrosis factor-alpha, pared with nondepressed controls, women for example, inhibit osteoclast apoptosis with current or past major depression had and accelerate bone turnover.6 a lower mean bone mineral density—6.5% lower at the spine and 13.6% lower at the femoral neck. Fracture risk and psychotropics Fewer prospective studies exist; howev- Many psychotropic medications—includ- er, most found depression has some impact ing anticonvulsants, barbiturates, narcotics, on bone health. Whooley et al9 prospective- and neuroleptics14-16—are associated with ly evaluated changes in bone mineral den- increased risk of falls, fractures, and osteo- sity among 7,414 Caucasian women age porosis. In this article we focus on selective ≥65 for 6 years. Depressed women—those serotonin reuptake inhibitors (SSRIs) and who scored ≥6 on the Geriatric Depression tricyclic antidepressants (TCAs) because Scale—had a 40% higher risk of nonverte- little data is available on other antidepres- bral fracture after adjusting for history of sants (Table 1).17-22 fracture, weight, physical activity level, smoking, alcohol use, nutritional status, SSRIs are associated with increased frac- and cognitive function. The depressed co- ture risk. In a cohort of 5,995 men age ≥65, hort also had an increased risk of vertebral Haney et al23 showed that men taking fracture. In a prospective study of 21,441 SSRIs have lower bone mineral density at Norwegian female and male subjects, the hip (3.9% lower) and spine (5.6% lower) women who reported being depressed at compared with non-users after adjusting 2 of 3 time points—from 1980 until 1995— for age, weight, and race. Current SSRI use had 2.5 times the risk of sustaining a non- carries a greater risk than past use. In a pro- vertebral fracture compared with those spective study of 7,983 men and women age who did not report depression.10 ≥55, Ziere et al24 reported that risk of non- Depressed women also have greater vertebral fracture among current SSRI us- Current Psychiatry 10 April 2010 bone loss over time. Mean hip bone min- ers was 28% higher than among past users Med/Psych Update over a mean follow-up of 8.4 years. In the Table 2 same study, the risk ratio of nonvertebral fracture was 2.10 for patients using SSRIs Risk factors for osteoporosis- within the previous 6 months and 2.98 for related fracture* use >6 months. Clinical factors Increased fracture risk with SSRIs may Age >50 be partially explained by the greater risk of Female sex osteoporosis in major depression.25 SSRI use Amenorrhea has been linked to higher risk of fracture in Cognitive impairment the absence of depressive symptoms, how- Family history of osteoporosis-related fracture 26 17 Malnutrition ever. Bolton et al revealed a trend of in- Poor visual acuity creasing fracture risk with higher SSRI dose. Previous falls In this study, SSRI users had 45% greater Low body mass index likelihood of fracture than controls after ad- Glucocorticoid use (prednisone >5 mg/d for justing for a diagnosis of depression. ≥3 months) Researchers are studying the mecha- Secondary medical conditions nism by which SSRIs affect bone miner- Hyperprolactinemia Clinical Point alization. Serotonin receptors—including Anorexia nervosa Investigations 5-HT2A, 5-HT2B, and 5-HT2C—are present Postmenopausal status Adrenal insufficiency suggest that SSRIs in bone.27 Preliminary investigations sug- Diabetes mellitus are concentrated in gest SSRIs are concentrated in bone and Hyperparathyroidism impact fibroblast formation and osteoblast Celiac disease bone and impact activity. High bone marrow concentrations Inflammatory bowel disease fibroblast formation Malabsorption syndromes of fluoxetine inhibit human osteoblast pro- and osteoblast liferation. Osteoblasts contribute to bone Multiple myeloma End-stage renal disease production.28 Fluoxetine concentrations in activity Behavioral factors bone marrow can be up to 100-fold higher Low calcium intake than serum levels, and the drug can be de- Tobacco abuse tected in bone up to 3 months after discon- Physical inactivity 29 tinuation. Excessive alcohol intake (>3 drinks per day) Vitamin D deficiency TCAs. U.S. veterans with prior hip fracture Immobilization are twice as likely to have received TCAs *Italics indicate conditions commonly encountered in psychiatric patients 14 than age- and sex-matched controls. In Source: Reference 1 prospective studies, the risk of hip frac- ture among men and women age ≥65 is peripheral neuropathy or prophylaxis of 50% higher in patients exposed to TCAs.30 migraine headaches. Other investigations have revealed a dose- response relationship between TCA use Benzodiazepine use is associated with and risk of fracture.31 A direct comparison confusion, ataxia, and vertigo, which may of TCAs and SSRIs has found an equivalent increase the incidence of falls. Even low increase in fracture risk in these 2 classes.30 doses pose a risk. In one case-control study A direct effect of TCAs on bone metabo- of 1,222 hip fracture patients age ≥65, use of lism has not been elucidated. However, >3 mg/d diazepam equivalents increased side effects of TCAs include orthostatic hy- risk of hip fracture by 50% after adjust- potension, impaired cognition, dizziness, ing for confounding factors.30 Although and altered balance, all of which increase the data are mixed, benzodiazepines with the risk of falls and fractures, particularly shorter half-lives (eg, lorazepam) might in elderly patients.31 Most studies of TCAs, not be safer than those with longer half- however, do not account for depression’s lives (eg, clonazepam).31,32 role in fracture risk. Some patients in these studies may have received TCAs for disor- Other psychotropics. Some anticonvul- Current Psychiatry ders other than major depression, such as sants may lead to bone demineralization Vol. 9, No. 4 11 Table 3 with long-term exposure to psychotropic agents. Dual energy X-ray absorptiometry Reducing osteoporosis risk: is the preferred screening method.
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