Selective serotonin-reuptake inhibitors (SSRIs) can cause bone loss, especially if treatment lasts for more than a year. Maria Jose Ortuño, PhD, a postdoctoral fellow at Columbia University in New York, and colleagues sought to better understand the cellular basis underlying the time-dependent effect of SSRIs on bone. To do this, they used bone histomorphometry to examine bone mass accrual in mice treated with fluoxetine (Flx). The researchers published their descriptions of how SSRIs affect bone remodeling on Sept. 5 in Nature Medicine.1 They found that Flx had two distinct effects that shifted over time. The effects could be characterized as those associated with shorter-term use (increased bone mass) and those associated with longer-term use (decreased bone mass).
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To better understand the shorter-term effects, the investigators treated primary osteoclast cultures with SSRIs and noted a decrease in the number of differentiated osteoclasts. Specifically, Flx inhibited the fusion of mononuclear cells that was a required step in the formation of mature, functional osteoclasts. The effect appeared to be independent of serotonin reuptake by the 5-hydroxytryptamine transporter (5HTT). Instead, treatment of cell cultures with Flx directly resulted in decreased expression of the transcription-factor-encoding oncogene Fos, as well as the downstream target of Fos, c-Fos. Likewise, the decrease in Fos expression did not result from signaling through the direct receptor activator of nuclear factor kappa-B ligand (RANKL), but instead appeared to be the result of direct impairment of the Ca2+-calmodulin-CREB-Nfatc1 signaling cascade that is required for the differentiation and function of osteoclasts. All told, the direct effect of Flx on osteoclast formation could explain the higher bone mass observed in mice following a three-week treatment with Flx.
The investigators then searched for an indirect mechanism that might explain the bone loss seen after the mice had been treated for six weeks with Flx. They found that the urine concentrations of epinephrine and norepinephrine were significantly higher after six weeks of treatment with Flx as compared with three weeks of treatment. This suggested to the researchers that there might be a role for sympathetic output in the bone loss. Further experiments led them to conclude that, over time, Flx progressively increases serotonin signaling in the brain, thereby, inducing desensitization of 5-hydroxytryptamine receptor 2C (Htr2c) and increased sympathetic output. This conclusion was further reinforced by the observation that mice that lacked the gene coding for the enzyme necessary for brain serotonin synthesis (Tph2) did not experience the characteristic wild-type reduced bone-formation parameters after treatment with Flx.
“An unexpected finding of our study is the fact that Flx can function directly on osteoclasts through a pathway that is different from its canonical mode of action,” write the authors in their discussion. “Although cells from the osteoclast lineage express 5HTT and the gene encoding Tph1, osteoclasts derived from mice lacking expression of these proteins respond to Flx similarly to WT [wild type] cells. Thus, at least in mice, Flx acts on these cells independently of the serotonin–5HTT system.”
Over time, treatment with Flx triggers a brain-serotonin-dependent rise in sympathetic output that increases bone resorption to a level that counteracts the local anti-resorptive effect of Flx. The investigators were able to block this longer-term systemic effect and prevent Flx-induced bone loss by co-treatment with the β-blocker propranolol.
Lara C. Pullen, PhD, is a medical writer based in the Chicago area.
- Ortuño MJ, Robinson ST, Subramanyam P, et al. Serotonin-reuptake inhibitors act centrally to cause bone loss in mice by counteracting a local anti-resorptive effect. Nat Med. 2016 Oct;22(10):1170-1179. doi: 10.1038/nm.4166. Epub 2016 Sep 5.