Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis

Nat Med. 2010 Mar;16(3):308-12. doi: 10.1038/nm.2098. Epub 2010 Feb 7.


Osteoporosis is a disease of low bone mass most often caused by an increase in bone resorption that is not sufficiently compensated for by a corresponding increase in bone formation. As gut-derived serotonin (GDS) inhibits bone formation, we asked whether hampering its biosynthesis could treat osteoporosis through an anabolic mechanism (that is, by increasing bone formation). We synthesized and used LP533401, a small molecule inhibitor of tryptophan hydroxylase-1 (Tph-1), the initial enzyme in GDS biosynthesis. Oral administration of this small molecule once daily for up to six weeks acts prophylactically or therapeutically, in a dose-dependent manner, to treat osteoporosis in ovariectomized rodents because of an isolated increase in bone formation. These results provide a proof of principle that inhibiting GDS biosynthesis could become a new anabolic treatment for osteoporosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Female
  • Gastrointestinal Tract / physiology
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Osteogenesis / drug effects
  • Osteogenesis / physiology
  • Osteoporosis / drug therapy*
  • Osteoporosis, Postmenopausal / drug therapy
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use*
  • Rats
  • Serotonin / biosynthesis*
  • Serotonin Agents / pharmacology
  • Serotonin Agents / therapeutic use*
  • Tryptophan Hydroxylase / antagonists & inhibitors*


  • LP533401
  • Pyrimidines
  • Serotonin Agents
  • Serotonin
  • Tryptophan Hydroxylase
  • tph1 protein, rat