Steven Dubovsky, MD reviewing Ortuño MJ et al. Nat Med 2016 Sep 5.

An animal study reveals the complicated effects of fluoxetine on bone resorption and suggests a possible future solution.

Chronic use of some selective serotonin reuptake inhibitors (SSRIs) causes bone loss and predisposes to fractures. To determine why, investigators conducted a series of in vitro experiments and in vivo studies of mice exposed to therapeutic levels of fluoxetine for 3 or 6 weeks.

After the shorter period of exposure, the authors identified a nonserotonergic mechanism involving alteration of a calcium–calmodulin cascade that led to altered activity of a transcription factor. This cascade resulted in decreased osteoclast production and less preservation of bone. After 6 weeks, increased synaptic serotonin in the hypothalamus desensitized 5-HT2 receptors, with the result that hypothalamic activation of the sympathetic nervous system was disinhibited and systemic norepinephrine and epinephrine were increased. These catecholamines then promoted bone loss, which eventually predominated over the 5-HT–independent effect in bone. Propranolol blocked the peripheral noradrenergic effect and prevented bone loss.

CITATION(S):

Ortuño MJ et al. Serotonin-reuptake inhibitors act centrally to cause bone loss in mice by counteracting a local anti-resorptive effect. Nat Med 2016 Sep 5; [e-pub].

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