Update in serotonin and bone

Abstract

Context: Serotonin (5-HT) may be an important regulatory agent in bone, and agents that modify 5-HT signaling, such as selective serotonin reuptake inhibitors (SSRIs), are in widespread clinical use.

Evidence acquisition: Evidence was obtained by PubMed search and the author's knowledge of the field.

Evidence synthesis: Recent data suggest that gut-derived 5-HT may mediate the skeletal effects of LDL receptor-related protein 5, stimulating intense interest in a novel mechanism for regulating bone mass. However, the specific biochemical nature of serotonergic pathways influencing bone and their direct and/or indirect effects on bone metabolism are still unclear. The weight of epidemiological evidence suggests that SSRIs are associated with reduced bone mass, increased bone loss, and increased risk of fractures. Interpretation of these studies is complicated by the confounding effects of depression, the usual indication for treatment with SSRIs. The mechanisms for putative SSRI-induced deleterious effects on the skeleton are unknown, and are likely multifactorial.

Conclusions: 5-HT may have regulatory effects on bone. Initial preclinical data suggest that its effects may be deleterious and may be regulated by low-density lipoprotein receptor-related protein 5. These studies need confirmation, as well as elucidation, of the biochemical pathways utilized and the feedback loops involved among bone, gut, and perhaps brain. Paradoxically, targeting of 5-HT synthesis and/or signaling in selective tissues may hold promise as an anabolic intervention for bone. Epidemiological data suggest that clinicians should be vigilant about detection of bone disease in patients who are using SSRIs.

Figure 1

A, 5-HT signaling within the central nervous system. 5-HT is synthesized by presynaptic neurons and stored in vesicles. Released 5-HT activates postsynaptic receptors to stimulate the postsynaptic neuron. Membrane-bound 5-HTTs uptake released 5-HT to control the duration of 5-HT effects and recycle or degrade 5-HT. B, The effects of 5-HTT inhibition using a SSRI on 5-HT signaling. Inhibition of the 5-HTT prevents uptake of 5-HT, resulting in its accumulation within the synaptic cleft and the prolonging of receptor activation. Osteoblasts, osteoclasts, and osteocytes express the 5-HTT, and SSRIs inhibit 5-HT uptake in bone cells in the same manner as in neurons. [Reprinted from S. J. Warden et al.: Bone 46:4–12, 2010 (73), with permission from Elsevier.]

Figure 2

Model of the Lrp5-dependent regulation of bone formation through inhibition of tph1 expression and 5-HT synthesis in enterochromaffin cells. 5-HT binds to Htr_1b in osteoblasts and inhibits cyclic AMP response element binding protein (Creb) expression and function, resulting in reduced osteoblast proliferation. Lrp5 favors bone formation and bone mass accrual through this pathway. [Reprinted from V. K. Yadav et al.: Cell 135:825–837, 2008 (6), with permission from Elsevier.]

Figure 3

Model of the leptin-dependent regulation of bone mass and appetite. Leptin inhibits release of BDS, which favors bone mass accrual. [Reprinted from V. Yadav et al.: Cell 138:976–989, 2009 (28), with permission from Elsevier.]

Figure 4

Mechanisms for the effects of depression and SSRI treatment on bone loss and fracture. Depressed individuals and SSRI users may have several reasons for bone loss, related to either their depression, or their SSRI use, or both. SSRI users may have persistent symptoms of depression, may be in remission from depression, or may be using SSRIs for a nondepressive condition. [Modified from E. M. Haney et al.: Bone 46:13–17, 2010 (74).]