Sci. Aging Knowl. Environ., 23 July 2003
The Manly Route to Strong Bones
Testosterone is tough enough to build the skeleton without an estrogen go-between
Key Words: osteopenia estradiol osteoblast osteoclast
Macho men can breathe a sigh of relief. The strength of their bones doesn't depend just on the female hormone estrogen. New work supports the view that androgens such as testosterone also beef up the skeleton by tweaking the cycle of bone demolition and restoration. The results suggest that androgen treatments might bolster the weakening bones of elderly men, if researchers can avert possible side effects.
Cells continually tear down and rebuild bone, and its strength reflects a balance between these processes. Sex hormones influence whether destruction or construction predominates (see "The Plot Thickens on Thin Bones"). In women, estrogen spurs bone building, and dwindling amounts of the hormone after menopause can provoke osteoporosis, a drastic thinning of the skeleton. Estrogen also hardens the male skeleton: Men lacking an operational estrogen receptor have fragile bones. Whether androgens also bulk up the male skeleton has vexed researchers because cells can transform testosterone into estrogen. For example, prostate cancer patients suffer bone thinning after being treated to remove the testosterone that feeds the tumor, but the weakening could stem from loss of so-called crossover estrogen. Several studies, including one that manipulated testosterone and estrogen concentrations in elderly men, also implicated testosterone, but none established whether androgens bolster bone directly by stimulating the androgen receptor.
To find out, molecular geneticist Shigeaki Kato of the University of Tokyo and colleagues disabled the receptor in mice. The leg bones of altered male mice were thinner and less dense than those of control males. The researchers then compared the rate of bone remodeling in normal and altered mice. Although the rate of bone-building was higher in the receptor-deficient male mice, the rate of bone breakdown was even higher. These observations suggest that curtailing androgen signaling weakens bones by speeding their dissolution. However, the altered mice had withered testes that produced little testosterone, and their flimsy bones could have resulted from a scarcity of converted estrogen. To eliminate this possibility, the researchers castrated normal and receptor-disabled mice and implanted animals with either testosterone or dihydrotestosterone (DHT), a similar molecule that cells can't transform into estrogen. DHT boosted bone density only in mice with the androgen receptor. Testosterone fortified the skeleton twice as much in nonengineered males, in which both pathways were working. These results indicate that maintaining maximal bone strength requires the direct as well as the indirect pathway, the researchers conclude.
It's a convincing paper that answers a stubborn question, says bone expert Deborah Novack of Washington University in St. Louis, Missouri. Sundeep Khosla, a bone biologist at the Mayo Medical School in Rochester, Minnesota, says that "the study indicates clearly that the androgen receptor is important in bone metabolism." Sex hormone concentrations in men decline gradually with age--and so does bone strength. However, doses of androgen can increase the risk of heart attack and possibly cancer, says Kato. Anti-osteoporosis drugs for women reduce side effects by targeting bone, and it might be possible to develop something similar for men, he says. To have strong bones, it seems, men need to rely on more than their feminine side.
July 23, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150