Med/Psych Update

Osteoporosis in depression: Which patients are at risk?

Current Psychiatry. 2010 April;9(4):9-25

References

1. National Osteoporosis Foundation. Clinician’s guide to prevention and treatment of osteoporosis. Washington, DC: National Osteoporosis Foundation; 2008.

2. Lane NE. Epidemiology, etiology, and diagnosis of osteoporosis. Amer J Obstet Gynecol. 2006;194(2 suppl):S3-11.

3. Sambrook P, Cooper C. Osteoporosis. Lancet. 2006;367:2010-2018.

4. Salaffi F, Cimmino MA, Malavolta N, et al. The burden of prevalent fractures on health-related quality of life in postmenopausal women with osteoporosis: the IMOF study. J Rheumatol. 2007;34(7):1551-1560.

5. Gold DT, Stegmaier K, Bales CW, et al. Psychosocial functioning and osteoporosis in late life: results of a multidisciplinary intervention. Journal of Women’s Health. 1993;2:149-155.

6. Mezuk B, Eaton WW, Golden SH. Depression and osteoporosis: epidemiology and potential mediating pathways. Osteoporos Int. 2008;19:1-12.

7. Schweiger U, Deuschle M, Korner A, et al. Low lumbar bone mineral density in patients with major depression. Am J Psychiatry. 1994;151:1691-1693.

8. Michelson D, Stratakis C, Hill L, et al. Bone mineral density in women with depression. N Engl J Med. 1996;335:1176-1181.

9. Whooley MA, Kip KE, Cauley JA, et al. Depression, falls, and risk of fracture in older women. Arch Intern Med. 1999;159:484-490.

10. Søgaard AJ, Joakimsen RM, Tverdal A, et al. Long-term mental distress, bone mineral density, and non-vertebral fractures. The Tromsø Study. Osteoporos Int. 2005;16(8):887-897.

11. Diem SJ, Blackwell TL, Stone KL, et al. Depressive symptoms and rates of bone loss at the hip in older women. J Am Geriatr Soc. 2007;55:824-831.

12. Eskandari F, Martinez PE, Torvik S, et al. Low bone mass in premenopausal women with depression. Arch Intern Med. 2007;167:2329-2336.

13. Yirmiya R, Goshen I, Bajayo A, et al. Depression induces bone loss through stimulation of the sympathetic nervous system. Proc Natl Acad Sci U S A. 2006;103(45):16876-16881.

14. French DD, Campbell R, Spehar A, et al. Outpatient medications and hip fractures in the US: a national veterans study. Drugs Aging. 2005;22(10):877-885.

15. Ensrud KE, Blackwell T, Mangione CM, et al. Central nervous system active medications and risk for fractures in older women. Arch Intern Med. 2003;163:949-957.

16. O’Keane V. Antipsychotic-induced hyperprolactinemia, hypogonadism, and osteoporosis in the treatment of schizophrenia. J Psychopharmacol. 2008;22(2 suppl):70-75.

17. Bolton JM, Metge C, Lix L, et al. Fracture risk from psychotropic medications: a population-based analysis. J Clin Psychopharmacol. 2008;28:384-391.

18. Heidrich FE, Stergachis A, Gross KM. Diuretic drug use and the risk for hip fracture. Ann Intern Med. 1991;115(1):1-6.

19. Yang YX, Lewis JD, Epstein S, et al. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006;296(24):2947-2953.

20. Schoofs MW, van der Klift M, Hofman A, et al. Thiazide diuretics and the risk for hip fracture. Ann Intern Med. 2003;139(6):476-482.

21. Schlienger RG, Kraenzlin ME, Jick SS, et al. Use of beta blockers and risk of fractures. JAMA. 2004;292(11):1326-1332.

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Table 1

Psychotropic medications associated with osteoporosis risk

Medication/class	Odds ratio (95% confidence interval)
Selective serotonin reuptake inhibitors (SSRIs)	1.45 (1.32 to 1.59)
Carbamazepine	1.18 (1.10 to 1.26)
Non-SSRIs (eg, tricyclics, atypicals)	1.15 (1.07 to 1.24)
Valproate	1.15 (1.05 to 1.26)
Oxcarbazepine	1.14 (1.03 to 1.26)
Benzodiazepines	1.10 (1.04 to 1.16)
Lamotrigine	1.04 (0.91 to 1.19)
Typical antipsychotics	1.01 (0.86 to 1.19)
Atypical antipsychotics	0.96 (0.79 to 1.17)
Lithium	0.63 (0.43 to 0.93)
Source: References 17-22

Increased fracture risk with SSRIs may be partially explained by the greater risk of osteoporosis in major depression.²⁵ SSRI use has been linked to higher risk of fracture in the absence of depressive symptoms, however.²⁶ Bolton et al¹⁷ revealed a trend of increasing fracture risk with higher SSRI dose. In this study, SSRI users had 45% greater likelihood of fracture than controls after adjusting for a diagnosis of depression.

Clinical Point

Investigations suggest that SSRIs are concentrated in bone and impact fibroblast formation and osteoblast activity

Researchers are studying the mechanism by which SSRIs affect bone mineralization. Serotonin receptors—including 5-HT2A, 5-HT2B, and 5-HT2C—are present in bone.²⁷ Preliminary investigations suggest SSRIs are concentrated in bone and impact fibroblast formation and osteoblast activity. High bone marrow concentrations of fluoxetine inhibit human osteoblast proliferation. Osteoblasts contribute to bone production.²⁸ Fluoxetine concentrations in bone marrow can be up to 100-fold higher than serum levels, and the drug can be detected in bone up to 3 months after discontinuation.

TCAs. U.S. veterans with prior hip fracture are twice as likely to have received TCAs than age- and sex-matched controls.¹⁴In prospective studies, the risk of hip fracture among men and women age ≥65 is 50% higher in patients exposed to TCAs.³⁰ Other investigations have revealed a dose-response relationship between TCA use and risk of fracture.³¹ A direct comparison of TCAs and SSRIs has found an equivalent increase in fracture risk in these 2 classes.³⁰

A direct effect of TCAs on bone metabolism has not been elucidated. However, side effects of TCAs include orthostatic hypotension, impaired cognition, dizziness, and altered balance, all of which increase the risk of falls and fractures, particularly in elderly patients.³¹ Most studies of TCAs, however, do not account for depression’s role in fracture risk. Some patients in these studies may have received TCAs for disorders other than major depression, such as peripheral neuropathy or prophylaxis of migraine headaches.

Benzodiazepine use is associated with confusion, ataxia, and vertigo, which may increase the incidence of falls. Even low doses pose a risk. In one case-control study of 1,222 hip fracture patients age ≥65, use of >3 mg/d diazepam equivalents increased risk of hip fracture by 50% after adjusting for confounding factors.³⁰ Although the data are mixed, benzodiazepines with shorter half-lives (eg, lorazepam) might not be safer than those with longer half-lives (eg, clonazepam).^31,32

Clinical Point

The mechanism by which antipsychotics accelerate bone turnover has not been described, but hyperprolactinemia likely plays a role

Other psychotropics. Some anticonvulsants may lead to bone demineralization via induction of the cytochrome P450 hepatic enzyme system, which accelerates conversion of vitamin D to an inactive metabolite that cannot adequately facilitate absorption of ingested calcium. The subsequent release of parathyroid hormone causes bone resorption.³³ Patients taking anticonvulsants have nearly double the serum parathyroid hormone level of matched controls.³⁴ Carbamazepine, oxcarbazepine, and valproate have been associated with increased risk of fracture.³² Although lamotrigine has not been widely studied, evidence suggests that its impact on bone metabolism is negligible.³⁵

Clinical Point

Recommend bone density testing for depressed patients with predisposing risk factors and long-term psychotropic use

Many antipsychotics, including risperidone and haloperidol, have been associated with osteoporosis. The mechanism by which antipsychotics accelerate bone turnover has not been described; hyperprolactinemia likely plays a role.³⁶

Screening and treatment

Effective pharmacotherapy for osteoporosis includes bisphosphonates (eg, alendronate), selective estrogen receptor modulators (eg, raloxifene), recombinant parathyroid hormone (eg, teriparatide), as well as calcium and vitamin D supplementation. Consider recommending bone density evaluation for depressed patients who have predisposing risk factors (Table 2)¹ and those with long-term exposure to psychotropic agents. Dual energy X-ray absorptiometry is the preferred screening method. Refer patients whose results indicate osteopenia or osteoporosis to primary care. Although pharmacotherapy for osteoporosis should be managed by primary care practitioners, psychiatrists can serve an important role by promoting healthy lifestyle behaviors—such as regular exercise and adequate dietary vitamin D and calcium intake (Table 3).¹

Table 2

Risk factors for osteoporosis-related fracture*

Clinical factors
Age >50 Female sex Amenorrhea Cognitive impairment Family history of osteoporosis-related fracture Malnutrition Poor visual acuity Previous falls Low body mass index Glucocorticoid use (prednisone >5 mg/d for ≥3 months)
Secondary medical conditions
Hyperprolactinemia Anorexia nervosa Postmenopausal status Adrenal insufficiency Diabetes mellitus Hyperparathyroidism Celiac disease Inflammatory bowel disease Malabsorption syndromes Multiple myeloma End-stage renal disease
Behavioral factors
Low calcium intake Tobacco abuse Physical inactivity Excessive alcohol intake (>3 drinks per day) Vitamin D deficiency Immobilization
Italics indicate conditions commonly encountered in psychiatric patients Source:* Reference 1