New Drug May Reverse Bone Loss Without Estrogen’s Side Effects, Science Study Says

Thursday, 24 October 2002 A synthetic compound called “estren” helped build bone, without affecting the reproductive organs of both female and male mice, a new study reports. These findings may suggest an alternative to standard hormone replacement therapy for treating osteoporosis, the authors say. The study appears in the journal Science, published by the American Association for the Advancement of Science.

Osteoporosis affects millions of people worldwide, many of them post-menopausal women.

“For a long time we have been giving hormone replacement to women, based on the evidence that estrogens are effective in preventing osteoporosis. The big assumption was that estrogen worked the same way in all the tissues,” said study author Stavros Manolagas of the University of Arkansas for Medical Sciences and Central Arkansas Veterans Health Care System

Along with their bone-related benefits, however, estrogen supplements can also have unwanted effects in the body’s reproductive tissues, according to Manolagas. For example, they can modestly increase the risk of breast and uterine cancer. Several months ago, a major clinical study on the long-term use of estrogen plus progesterone found that these risks, as well as others, outweighed the therapy’s benefits. The news left many women in a quandary about whether to continue their therapy.

“Our study shows you can have the benefits [of estrogen] on non-reproductive tissues, without having the side effects,” Manolagas said. “This is a brand new page of pharmacology.”

Estren may be useful for preventing osteoporosis in men as well as women. Because androgen stimulates prostate cancer, men with the disease typically have their prostate removed or take androgen-inhibiting drugs, leaving them vulnerable to osteoporosis.

“It’s very exciting that this may be a gender-neutral therapy,” said Manolagas.

Hormones like estrogen operate in two different ways in the body, launching two separate cascades of signals, Manolagas and his colleagues have found in previous studies.

The so-called “genotropic” signaling pathway regulates the expression of genes in the cell nucleus, and it is this pathway that has been linked to cancer development in reproductive tissue. The “non-genotropic” pathway promotes bone growth, by extending the lives of bone-building cells called osteoblasts and shortening the lives of bone-destroying osteoclasts.

Manolagas and his colleagues tested a synthetic compound called 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.

First the researchers removed the mice’s ovaries and testes, the major sources of estrogen and testosterone. The animals then lost bone density and strength. The surgery also led to the shrinking of the uterus in female mice, and of a male sex gland called the seminal vesicle, the researchers report. Both types of shrinkage are typical signs of the loss of estrogen or androgen in those tissues, Manolagas explained.

The researchers then compared the effects of treating the mice with either normal hormones or estren. Overall, estrogen brought the females’ bone density back to around normal, improved bone strength only slightly, and actually increased the uterine weight above normal.

In contrast, estren improved bone density and strength over their initial levels, and left the uterine weight low. The results in the male mice were generally similar, although estren and testosterone were equally effective in restoring bone strength. The improvements in bone density, whether produced by estren or the hormone, were smaller in males than in females, the authors report.

Estren might be able to mimic estrogen’s beneficial effects in other tissues besides bone, Manolagas speculated, such as the heart and nervous system. This has not been tested, however. (The harmful side effects on these tissues in the recent hormone replacement trials were likely related to using the combination of progesterone and estrogen, according to Manolagas.)

Thus, further experiments on the drug’s non-genotropic effects might reveal additional benefits in the body, making estren an alternative to standard hormone replacement therapy for fighting the effects of menopause and aging in women and men, Manolagas said.

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The other authors of 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, at the University of Arkansas for Medical Sciences, in Little Rock, AR. A T. Mancino, Y. Wen, A. M. Vertino, R. S. Weinstein, and R. L. Jilka are also at the Central Arkansas Veterans Health Care System, in Little Rock, AR. The study was funded by the National Institutes of Health, the Department of Veterans Affairs, and Anabonix, Inc, which has a licensing agreement with the University of Arkansas for Medical sciences to develop and commercialize anabolic drugs for osteoporosis, including estren.

 
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