An international team led by researchers from Columbia University Medical Center was able to cure osteoporosis in mice and rats through a daily dose of an experimental compound that inhibits serotonin synthesis in the gut.
Recent research has already shown that serotonin in the gut stalls bone formation. This latest finding could lead to novel therapies that build new bone; most current osteoporosis drugs can only prevent the breakdown of old bone. The research results were published in the Feb. 7 issue of Nature Medicine.
“New therapies that inhibit the production of serotonin in the gut have the potential to become a novel class of drugs to be added to the therapeutic arsenal against osteoporosis,” said Gerard Karsenty, M.D., Ph.D., chair of the Department of Genetics and Development at Columbia UniversityCollege of Physicians and Surgeons, lead author of the paper.
Osteoporosis is a disease in which bones become fragile and porous, increasing the risk of breaks. It is diagnosed when bone mass drops below a certain level. It is a growing health concern that affects tens of millions of people worldwide given the aging population, and a particular issue for women because of the rising incidence of post-menopausal osteoporosis.
Bone constantly undergoes renovation, with some cells responsible for removing old material and other cells responsible for creating new bone. In humans, the balance between bone formation and breakdown tips toward breakdown after age 20, and bone mass starts to decline. The rate of decline for women increases after menopause, when estrogen levels drop and cells that tear down old bone become overactive.
“There is an urgent need for new treatments that not only stop bone loss, but also build new bone,” Karsenty said. “Using these findings, we are working hard to develop this type of treatment for human patients.”
The Nature Medicine paper follows on another major discovery by Karsenty’s group in 2008 (and published in the journal Cell) that serotonin released by the gut inhibits bone formation, and that regulating the production of serotonin within the gut affects the formation of bone. Prior to that discovery, serotonin was primarily known as a neurotransmitter acting in the brain. Yet, 95 percent of the body’s serotonin is found in the gut, where its major function is to inhibit bone formation.
Based on their findings reported in the Cell paper, the Karsenty team postulated that an inhibitor of serotonin synthesis should be an effective treatment for osteoporosis. Shortly thereafter, they read about an investigational drug, known as LP533401, which is able to inhibit serotonin in the gut. “When we learned of this compound, we thought that it was important to test it as proof of principle that there could be novel ways to treat osteoporosis with therapies that can be taken orally and regulate the formation of serotonin,” said Karsenty.
Karsenty and his team tested their theory by administering a small daily dose of the compound orally for up to six weeks to rodents experiencing post-menopausal osteoporosis. Results demonstrated that osteoporosis was prevented from developing, or if present, could be fully cured. Of critical importance, levels of serotonin were normal in the brain, which indicated that the compound did not enter the general circulation and did not cross the blood-brain barrier, thereby avoiding many potential side effects.
“There is an urgent need to identify new, safe therapies that can increase bone formation on a long term basis and to such an extent that they compensate for the increase in bone resorption caused by menopause,” said Karsenty. “Furthermore, it is important to note that since this study was conducted in rodents, it will need further confirmation in human subjects.”
This research was supported by grants from the National Institutes of Health and a Gideon and Sevgi Rodan fellowship from the International Bone and Mineral Society.
Co-authors on this paper include Vijay K. Yadav from the Department of Genetics and Development at Columbia University Medical Center (CUMC); Santhanam Balaji and Marc Vidal, Department of Genetics, Harvard Medical School; P.S. Suresh and R. Medhamurthy, Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, India; X. Sherry Liu, Xin Lu andEdward Guo, Department of Biomedical Engineering (Columbia); Zhishan Li and Michael D. Gershon, Department of Cell Biology (CUMC); J. John Mann, Department of Psychiatry (CUMC); Anil K. Balapure, Tissue and Cell Culture Unit, Central Drug Research Institute, India; and Patricia Ducy, Department of Pathology (CUMC).