LITTLE ROCK — Scientists at the University of Arkansas for Medical Sciences (UAMS) and Central Arkansas Veterans Healthcare System (CAVHS) report in the prestigious journal Science today that they may have found a safer, more effective alternative to hormone replacement therapy to prevent or reverse bone loss.

Stavros C. Manolagas, M.D., Ph.D., professor and director of endocrinology in the College of Medicine at UAMS, and his research team describe a synthetic drug called “estren” that reverses bone loss like conventional hormone replacement therapy, without the possible damage to reproductive organs of that therapy.
 

Stavroula Kousteni, Ph.D., lead author of the Oct. 24, 2002, article in Science, with Stavros Manolagas, M.D., Ph.D. (UAMS) Click on image
for print-quality resolution.

His findings are especially timely because of recent federal concern about the risks of hormone replacement therapy (HRT). That therapy, which has involved a combination of the hormones estrogen and progestin, provides some protection from bone fractures in women but increases women’s risk for breast cancer, uterine cancer, heart attack, stroke, and blood clots.

The UAMS researchers found that estren reverses loss in bone mass and strength that occurs after menopause in women. They propose in Science that the drug merits more study as an alternative to hormone replacement for the purpose of preventing osteoporosis. (The article, “Reversal of Bone Loss in Mice by Nongenotropic Signaling of Sex Steroids,” is available to subscribers at Science.)

The new drug may also be beneficial for preventing bone loss in men.

“It’s very exciting that this may be a gender-neutral therapy. This is a brand new page of pharmacology,” Dr. Manolagas commented recently.

Hormones like estrogen operate in two ways in the body, launching separate cascades of signals, Dr. Manolagas and his colleagues have found in previous studies. The so-called “genotropic” signaling pathway regulates the expression of genes in the cell nucleus. This pathway has been linked to cancer development in reproductive tissues. The “non-genotropic” pathway promotes bone growth by extending the lives of bone-building cells, called osteoblasts, and shortening the lives of bone-destroying cells called osteoclasts.

Dr. Manolagas and his colleagues at UAMS and CAVHS in Little Rock tested estren in mice to see if it could activate only the non-genotropic pathway. Estren belongs to a group of compounds called “ANGELS,” for Activators of Non-Genomic Estrogen-Like Signaling.

The article in Science follows the UAMS group’s earlier report in the journal Cell in March 2001.

Dr. Manolagas is director of the Division of Endocrinology in the Department of Internal Medicine of the UAMS College of Medicine and chief of the section of endocrinology at the Central Arkansas Veterans Healthcare System. He directs the UAMS Center for Osteoporosis and Metabolic Bone Diseases.

His colleagues in the study are S. Kousteni, J-R. Chen, T. Bellido, L. Han, A.A. Ali, C.A. O’Brien, L. Plotkin, Q. Fu, A.T. Mancino, Y. Wen, A.M. Vertino, C.C. Powers, S.A. Stewart, R. Ebert, A.M. Parfitt, R.S. Weinstein, and R.L. Jilka.

The UAMS research team recently made the greatest number of oral presentations of any national or international group at the annual meeting of the American Society for Bone and Mineral Research. The group delivered 12 presentations at the meeting in San Antonio, Texas, Sept. 20-24. Two members, Lilian Plotkin, Ph.D., and Jin Ran Chen, M.D., PH.D., received “young investigator” awards at the conference. Scientists with the center at UAMS have been among the busiest presenters at the annual scientific meeting for each of the last 10 years.

Dr. Manolagas received his doctorate of medicine from the University of Athens Medical School in Athens, Greece. He served his residency at Stepping Hill Hospital in Stockport, England, and was a fellow in endocrinology at Manchester Royal Infirmary, University of Manchester, England. Prior to his present position, he was on the faculty of the University of California at San Diego for nine years, and Indiana University for six years.

Author of more than 200 articles and book chapters, and more than 300 abstracts, Dr. Manolagas has conducted research on the pathophysiology of osteoporosis and other disorders of bone and mineral metabolism, and the interactions of the endocrine and the immune system.

He is a member of the highly prestigious Association of American Physicians, the recipient of the Founder’s award of the American Society for Bone and Mineral research for his fundamental contributions to the field, the winner (among 52 contestants across the nation) of the highly prestigious AlliedSignal award for research on aging for studies on the new drugs in 1999, and the UAMS Distinguished Faculty Scholar in 2000.

The study was funded by the National Institutes of Health, the Department of Veterans Affairs, and Anabonix, Inc., which has a licensing agreement with UAMS, through the business accelerator UAMS Arkansas BioVentures, to develop and commercialize anabolic drugs, including estren, for osteoporosis.