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Beta blockers: Answer to osteoporosis?

by Ruth SoRelle, MPH

Gerard Karsenty, MD, PhD

Background on Osteoporosis

Solving the problem of osteoporosis may involve no more than a special adaptation of drugs that already exist -- beta blockers, said a researcher at Baylor College of Medicine, who has spent more than five years unraveling the relationship between a protein known to control appetite and the formation of bone.

Gerard Karsenty, MD, PhD, BCM professor of molecular and human genetics, has been pursuing a link between leptin, a protein usually associated with appetite control, and the formation and resorption or destruction of bone. In a report in a recent issue of the journal Nature, he and his colleagues show that in mice that the sympathetic nervous system mediates the resorption or destruction of bone through a special receptor on bone cells.

This effect is required for development of osteoporosis after menopause, said Karsenty. Blocking the sympathetic nervous system from interaction with that receptor could prevent osteoporosis.

Currently, he and colleagues at The University of Texas M.D. Anderson Cancer Center, a BCM affiliate, hope to study the effects of beta blockers in men who have undergone removal of their gonads as part of treatment for prostate cancer. This sets up a situation that is conducive to development of osteoporosis. If the beta blockers lower the rate of bone problems in this group, it would show that they are as effective in people as they have proven in mice.

Impact of osteoporosis

An estimated 10 million Americans over the age of 50 and 30 million people worldwide have osteoporosis, a disease in which there is less bone mass and a high risk of fracture. Each year, 1.5 million Americans suffer a fracture because of the disease. In a report last October, the U.S. Surgeon General estimated that the cost of caring for people with osteoporosis-related factures cost $18 billion per year, a figure that will increase unless prevention efforts increase.

Until recently, women in the Western World warded off osteoporosis with hormone replacement therapy that literally replaced the estrogen they lost at menopause. However, the Women's Health Initiative, the largest study of women ever undertaken, demonstrated that the risks of such treatment far outweighed the benefits, particularly long term. That left menopausal women with few alternatives for preventing osteoporosis.

If beta blockers work and a pill that does not affect the heart can be developed, it will provide an answer to millions of women.

History of research

Karsenty began his work more than five years ago when he and members of his groups showed that one of the main functions of leptin is to regulate bone formation. In a subsequent paper, they showed that the sympathetic nervous system mediates this action of leptin.

In the most recent study in Nature, their experiments demonstrate that leptin also affects bone destruction or resorption through this special receptor on bone cells. When mice lack this receptor, they do not develop osteoporosis.

"They have what every woman at the time of menopause would like to experience," said Karsenty. "They make more bone, they destroy less bone and they do not lose bone when their ovaries are removed. This is the first demonstration that nerve cells are involved in osteoporosis development. This has tremendous clinical implications, especially since these mice are not obese."

Inhibiting the sympathetic nervous system would block bone destruction. Beta blockers do this, and it should be possible to develop one that works specifically with the bone cells. Current beta blockers are designed to work with receptors on many kinds of cells, a factor that is crucial to lowering blood pressure.

A study in the Journal of the American Medical Association (JAMA. 2004 Sep 15;292(11):1326-32) buttresses Karsenty's hypothesis by demonstrating that older patients with osteoporosis who took beta blockers had fewer fractures than those who did not.

The task ahead

"The task now is to develop beta blockers that are specific to bone and do not affect cells in the heart muscle. Then you would have the prevention of osteoporosis with a safe drug and no heart effect. There is a lot of reason to believe it can be done," said Karsenty.

Once a pill is developed, he said, pharmaceutical firms will have to study its effects in variety of animals and, eventually, people.

Karsenty plans to continue his studies of leptin. His studies indicate that leptin's role in bone formation and resorption extends back to the development of skeletons.

"Regulation of bone mass may have been an ancestral function of leptin," he said. "Three million years ago, it was more important to repair a fracture than to prevent obesity."

Others who participated in the research include: Drs. Florent Elefteriou, Jong Deok Ahn, Shu Takeda, Michael Starbuck, Xiangli Yang, and Xiuyun Liu, all of BCM; Hisataka Kondo and Masaki Noda of Tokyo Medical and Dental University in Japan; William G. Richards and Tony W. Bannon of Amgen Inc., in Thousand Oaks, California; Karine Clement of INSERM Avenir team; University Paris, and Christian Vaisse of the University of California, San Francisco.

The citation for the paper: Nature. 2005 Feb 20; [Epub ahead of print]

This work was supported by grants from the National Institutes of Health, the National Space Biomedical Research Institute, the Children's Nutrition Research Center, the Arthritis Foundation and the Children's Brittle Bone Foundation.

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