Serotonin rising.

To the Editor: Rosen’s Perspective article (March 5 issue)1 highlights recent findings that gut-derived serotonin inhibits bone formation by stimulating serotonin receptors on the preosteoblast.2 A critical question is whether serotonin is delivered to bone in some blood element or as free plasma serotonin. The serum serotonin measurements used by Yadav and colleagues2 reflect an undefined proportion of the platelet pool and say nothing about the minuscule and often mismeasured free plasma concentrations.3 If the platelet is the delivery vehicle, it is paradoxical that increased platelet serotonin levels in Lrp5-knockout animals and patients with osteoporosis pseudoglioma lead to bone loss,2 whereas treatment with selective serotonin-reuptake inhibitors (SSRIs), which lowers platelet serotonin levels by 80 to 95%, also reduces bone mass.4 The apparent requirement for maternally derived serotonin in mammalian embryogenesis5 poses a similar puzzle: How can gestational SSRI treatment markedly reduce maternal platelet serotonin levels without disrupting embryonic development? Perhaps local tissue uptake and release are crucial in regulating exposures. Finally, given the apparent inhibitory role of serotonin (however delivered) in bone formation,1,2 it is puzzling that the carcinoid syndrome has not been commonly associated with osteoporosis.