Army-funded effort examines androgen's role in bone loss

November 16, 2004

PORTLAND, Ore. - An extensive, Oregon Health & Science University-led research effort examining the role of the male sex hormone androgen in bone formation has piqued the interest of the United States military.

The U.S. Army Medical Research and Materiel Command, looking to reduce stress fractures and preserve bone health among its young recruits, is funding a four-year, $1.72 million project through the Department of Defense Peer Reviewed Medical Research Program that scientists hope will lead to a better understanding of the molecular and cellular events by which androgen influences the skeleton.

"It turns out that one of the most common injuries sustained in basic training in both men and women is stress fracture in long bones. In this population, there's also anabolic steroid abuse," said the study's lead investigator, Kristine Wiren, Ph.D., associate professor of medicine (endocrinology, diabetes and clinical nutrition) and behavioral neuroscience, OHSU School of Medicine, and research biologist, Portland Veterans Affairs Medical Center.

"The goal of the Army in funding this grant is to identify factors that promote a healthy skeleton, that influence stress fractures, and to treat and prevent bone-weakening osteoporosis in the aging population."

Of the 1.3 million bone fractures attributed to osteoporosis each year, 150,000 are hip fractures that occur in men with a 15 percent lifetime risk for the development of fracture. Hip fractures tend to occur over the age of 70; nearly a fourth of the patients who suffer a hip fracture die within the first year; half of patients are unable to walk without assistance; and a third are totally dependent.

Osteoporosis is characterized by a relative decrease in bone formation, mediated by osteoblast cells, versus bone resorption, mediated by osteoclast cells. Androgen - testosterone is best-known type - and estrogen both contribute to adult bone mass maintenance: Androgen is an anabolic agent that stimulates bone formation, and estrogen is thought to have a protective effect on bone by inhibiting resorption.

"In osteoporosis, you have more resorption than formation," Wiren said.

Aging, glucocorticoid therapy for asthma, alcoholism, chronic smoking and bone marrow malignancies are believed to cause androgen deficiency. All - in addition to reduced hormone secretion from the testes, a condition called hypogonadism - are associated with osteoporosis development in men.

The disease also is a side effect of androgen deprivation therapy, a common treatment for prostate cancer that wipes out most male hormones found in the body.

"Women and estrogen have been targets for a lot of osteoporosis research because estrogen is effective at stopping bone loss," Wiren said. "We understand a lot more about estrogen than we do androgen. But both genders have androgen and both genders have estrogen and both are at risk for the development of osteoporosis. It's also clear in intervention studies that you can effectively treat osteoporotic women with androgen."

One option being studied for treating osteoporosis in men and women is androgen therapy, either through androgen replacement using hormone drugs, or androgen replacement combined with estrogen replacement.

"You get a better response with combined treatment than with either steroid alone, which suggests they're doing different things," Wiren said.

Selective androgen receptor modulators, or SARMs, are among a class of drugs that also are being studied as an alternative to androgen therapy. Like selective estrogen receptor modulators, SARMs activate the hormone's signaling pathway, but only in a tissue-specific manner. By targeting androgen receptors in bone, SARMs are thought to curb potential risks for prostate cancer progression and other side effects that can result from androgen replacement.

The Army grant, which began in November, comes on the heels of a study Wiren published in July in the journal Endocrinology. In it, she describes her research team's development of a transgenic mouse group with overexpressed androgen receptors in bone-forming osteoblast cells.

"There's a whole superfamily of receptors for steroid hormones; steroids require a receptor for biologic actions," Wiren said. "By overexpressing the receptor, we get a more sensitive response to androgen."

Using collagen DNA cloned from rats as a promoter, Wiren was able to drive overexpression of the androgen receptor DNA in the skeleton and at a high level. "When we characterized how much of the receptor was present, it was four-fold higher. It's higher than what you usually have in bone, but at a level you'd find in the prostate or other androgen target tissues," she said.

The result was a mouse group with enhanced androgen responsiveness in bone, particularly among males. Their skulls were thicker, they had increased formation on the outside of long bones, such as the femur, decreased formation on the marrow surface inside the bone, reduced bone loss and low bone "turnover." Biomechanical analysis showed that the bones were not stronger, however, with reduced load capability and different material properties.

The study also demonstrated that androgen receptors are important to the development of the sexually distinct skeletons of men and women.

"There are receptors everywhere, but these mice demonstrate proof of concept that the androgen receptor in bone is responsible for sexually dimorphic skeletons. In other words, that male bones are wider than female," she said. "This is an important model to look at the influence of gender on bone development and skeletal maintenance."
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