Sex steroids and the skeleton

Fuller Albright established in the 1940s that estrogen was a major regulator of bone metabolism in women. Using careful calcium balance studies, he demonstrated that estrogen deficiency was associated with negative calcium balance, which could be reversed with estrogen treatment.

Subsequent studies confirmed his original findings, showing that oophorectomy or menopause in women leads to a marked increase in bone resorption, followed by a coupled increase in bone formation. However, because of estrogen deficiency, bone formation cannot keep pace with bone resorption, leading to rapid bone loss.

Sundeep Khosla, M.D., of the Division of Endocrinology, Diabetes, Metabolism, and Nutrition at Mayo Clinic in Rochester, Minn., says: "While much less was known about sex steroid regulation of the male skeleton, studies in Czech prisoners who were orchiectomized for sexual crimes showed that male castration, which is associated with loss of testosterone, led to a similar pattern of bone loss. Thus, traditional scientific opinion held that, similar to estrogen in women, testosterone was the major regulator of bone metabolism in men."

The pivotal role of testosterone in the male skeleton was challenged, however, by an important experiment of nature. Dr. Khosla explains: "The description in 1994 of a male with mutations in both alleles of the estrogen receptor who had normal testosterone levels but marked osteopenia led to the hypothesis that even in men, estrogen may be the major regulator of the skeleton.

"This hypothesis was rigorously tested by our group using an experimental design in which sex steroid production was suppressed in adult men through a combination of a gonadotropin-releasing hormone agonist and an aromatase inhibitor, followed by the selective replacement of either estrogen or testosterone, both, or neither, by giving the men the respective drug patches.

"After baseline measurements of bone turnover markers, the men were randomly assigned to these four different groups, to define the relative contributions of estrogen and testosterone toward regulating bone turnover. The results demonstrated that estrogen accounted for 70 percent or more of the total effect of sex steroids on bone resorption in men, whereas testosterone could account for no more than 30 percent of the effect."

Dr. Khosla continues: "These findings, combined with observations from numerous other clinical investigative studies, have now established that estrogen is a key hormonal regulator of bone metabolism not only in women, but also in men."

Effects of raloxifene in men

Dr. Khosla says: "In a subsequent study, we tested whether aging men would have skeletal benefits from treatment with the selective estrogen receptor modulator (SERM) raloxifene, which has estrogenlike activity on bone but is nonfeminizing. These studies showed that raloxifene reduced bone resorption in men, but only in those elderly men who had estradiol levels below a threshold for skeletal estrogen deficiency.

"On the basis of these studies, other investigators have demonstrated that men with prostate cancer who are given androgen deprivation therapy (which also leads to estrogen deficiency) do indeed benefit from treatment with a SERM. In addition, epidemiological studies have now found that fracture risk in older men is much more closely related to serum estradiol levels, rather than testosterone levels."

With aging, men have modest decreases in total testosterone levels with little or no change in total estradiol levels. Dr. Khosla notes: "However, due to marked increases in sex hormone-binding globulin (SHBG) concentrations, bioavailable (or non-SHBG bound) testosterone and estradiol levels decrease markedly with aging in men. It is these declining levels of bioavailable estradiol that appear to be most closely related to bone mineral density, bone loss and fracture risk in elderly men."

Bone loss independent of sex steroid levels

Recent studies using standard and high-resolution quantitative computerized tomographic (QCT) imaging of bone are also revealing some important gaps in the understanding of bone loss with aging, independent of changes in sex steroid levels.

Dr. Khosla adds: "Although dual-energy X-ray absorptiometry (DXA) is a very useful clinical tool for assessment of bone mineral density, it cannot separately assess changes in cancellous bone (the spongy bone in the vertebrae, pelvis, and metaphyses of long bones) vs. cortical bone (the compact bone in the diaphyses of long bones and surrounding the cancellous bone in the vertebrae and pelvis).

"The traditional thinking, based on studies using DXA, was that bone mass peaked in the 30s, remained stable until midlife and declined thereafter, following the menopause in women and with aging in men. Using QCT, however, we have found that while cortical bone at multiple sites does follow this pattern, cancellous bone begins to decrease in young women and men, even those in their early 20s. These young individuals are sex-steroid sufficient, a fact that points to other, as-yet unknown mechanisms, leading to the initiation of cancellous bone loss soon after the completion of growth in humans.

"These findings in humans have now been confirmed in mouse models, where cancellous bone loss also begins shortly after skeletal consolidation (at the age of ~3 or 4 months). Collectively, these human and mouse studies are demonstrating that age-related loss of cortical bone is closely tied to estrogen deficiency (in women and in men), whereas age-related loss of cancellous bone, while accentuated by estrogen deficiency, occurs even in the presence of normal estrogen levels."

Dr. Khosla summarizes: "Despite more than 70 years of multiple groups following a line of investigation first initiated by Fuller Albright, we continue to learn more about how sex steroids — and estrogen in particular — regulate bone metabolism. Given the key role of estrogen in the skeleton, unraveling the pathways by which estrogen acts on bone is likely to continue to provide new insights into both the mechanisms of bone loss with aging and the potential molecular targets for new therapies for osteoporosis and age-related bone loss."