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 formation1. As gut-derived serotonin (GDS) inhibits bone formation2, 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.