Savvy Psychopharmacology

Serotonergic antidepressants’ effects on bone health

Current Psychiatry. 2021 September;20(9):45-49 | doi:10.12788/cp.0162

References

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Mrs. D, age 67, has a history of major depressive disorder. She has had adequate treatment trials with duloxetine, mirtazapine, and sertraline; each failed to produce remission. She is currently prescribed paroxetine, 40 mg/d, and aripiprazole, 10 mg/d, with good efficacy. She also has a history of hypertension and seasonal allergies, for which she receives amlodipine, 10 mg/d, and loratadine, 10 mg/d, respectively.

Mrs. D’s depressive symptoms were well controlled until 2 months ago, when she fell and fractured her hip. With encouragement from her prescriber, she enrolled in a partial hospitalization program for more intensive psychotherapy. During a medication education session, she is surprised to learn that antidepressants may affect bone health.

During a medication management meeting with her prescriber, Mrs. D asks about the risk of osteoporosis, and whether her antidepressant could have contributed to her hip fracture.

Bone is a dynamic tissue that undergoes a continuous process of remodeling. Osteoblasts are responsible for bone formation, whereas osteoclasts are responsible for bone resorption. Osteocytes—the predominant cell type in bone—along with cytokines, hormones, and growth factors help to orchestrate these actions.¹ Serotonin is increasingly recognized as a factor in bone homeostasis. Bone synthesizes serotonin, expresses serotonin transporters, and contains a variety of serotonin receptors.²

Serotonin serves many physiologic functions outside of the CNS, and it appears to have opposing actions on bone metabolism (Table 1^1,3). Peripheral (gut-derived) serotonin inhibits bone formation through its effects on osteoblasts, whereas the actions of serotonin in the CNS promote bone growth through inhibitory effects on sympathetic output.²Selective serotonin reuptake inhibitor (SSRI) enhancement of peripheral serotonin and its negative effect on bone may outweigh the benefits caused by SSRI enhancement of central serotonin neurotransmission.¹ In vitro data suggest SSRIs inhibit osteoblast and osteoclast function, theoretically decreasing bone turnover and increasing fracture risk.⁴ Other data indicate SSRI treatment may decrease procollagen type 1 N-terminal propeptide, a peripheral marker of bone formation.⁵ Both SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been associated with lower cortical bone mineral density (BMD).⁶Table 2^7,8details the relative affinity of select antidepressants for the serotonin transporter.

Both serotonergic antidepressants and depression have been associated with decreased BMD and increased fracture risk.^1,9 Behavioral aspects of depression, such as inadequate nutrition or physical inactivity, overlap with risk factors for poor bone health. In addition, elevated levels of circulating cortisol and proinflammatory cytokines in patients with depressive symptoms may contribute to decreased bone mass.^10,11 Modifiable risk factors for osteoporosis and fractures include low calcium and vitamin D intake, low body weight, and a sedentary lifestyle. Nonmodifiable risk factors include advancing age, female sex, Asian or White ethnicity, malabsorptive conditions, and chronic corticosteroid use.¹²

What the evidence says

Evidence for the correlation between fractures and serotonergic antidepressant use is mixed. One meta-analysis found a significant association between SSRIs and fractures, suggesting a 1.62-fold increased risk.¹³Another meta-analysis investigated SSRIs and SNRIs and the risk of fracture.¹⁴ The SSRIs had a 1.67-fold increased risk; however, a lack of studies prohibited making conclusions about SNRIs. The number needed to harm was calculated at 85, 46, and 19 with 1, 2, and 5 years of SSRI exposure, respectively. A third meta-analysis found increased fracture risk related to depression and reported a hazard ratio of 1.26 after adjusting for confounders.⁹ This analysis suggests depression affects fracture risk and may limit the interpretation of causation from SSRI use. Studies included in these meta-analyses had significant heterogeneity.

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