By Laura Gehrig, MD, and Mary I. O’Connor, MD

Estrogen, men, and hip fractures

Morbidity and mortality after hip fracture continue to be concerns, particularly for the elderly. Recently, a nationwide cohort study from Denmark showed a decrease in crude 1-year survival rates following hip fracture and an interesting sex-specific fact: the proportion of men with hip fractures had increased.

Hip fractures and osteoporosis leading to hip fractures have long been associated with postmenopausal women. As women age and go though menopause, their ovaries shut down and reproductive function ceases. During menopause, the ovaries almost completely stop producing estrogens, which are critical for bone formation and regulation of bone remodeling. With men now sustaining nearly 30 percent of hip fractures in some population groups, the influence of estrogen on the bone health of elderly men becomes a significant question.

Normal growth and development of bone
Normal growth and development of bone during childhood, puberty, and adolescence involve a complicated array of hormones, growth factors, and their action on cell receptors. Estrogen affects bone by binding to receptors in osteoblasts. These bone-forming cells then produce factors that control osteoclast activity, coupling bone formation with resorption.

As people age, resorption exceeds bone formation. For normal bone to model and remodel, the estrogen level must be normal and appropriate for the sex of the individual. The estrogen receptor must not have defective binding, and the mechanism of signal transduction in the cell must carry out the programmed function.

Estrogen functions to regulate osteoblast proliferation and the expression of genes that code for enzymes, bone matrix proteins, and hormone receptors, as well as growth factors and cytokines involved in bone. Additionally, estrogen affects the epiphyseal closure at the end of puberty for both males and females, having direct effects on the growth plate cartilage cells. This occurs later in males due to their lower levels of circulating estrogen and differences in how male cells respond to estrogen.

While bone size increases in males during puberty due to increased periosteal apposition, the higher levels of estrogen in females have an inhibitory effect on bone size. The growth plate closes earlier in females than in males. The end result is that men have greater bone length, larger outer and inner bone perimeters, and a larger cortical volume than women.

Estrogen receptors
Estrogen receptors are expressed by both osteoblasts and osteocytes. The number of receptors varies from 60 to 4,500 per cell. The implication is that estrogen at a physiologic concentration will bind to the receptor and transduce the signal with the resultant effect. Osteoclasts have not been found to express estrogen receptors, but preosteoclasts do, and evidence exists that estrogen inhibits the development of osteoclasts.

Although estrogen receptors are found predominantly in females, a number of cells and organ systems in males also have estrogen receptors and estrogen signaling.

Menopause: For men and women?
The withdrawal of estrogen and subsequent development of postmenopausal osteoporosis in women has historically led research efforts to primarily, and almost exclusively, concentrate on women. Moreover, most research efforts to explore skeletal effects of sex hormones have focused on estrogens. Because men produce estrogen and have estrogen receptors, however, estrogen withdrawal and its consequences may contribute to their developing osteoporosis with aging as well.

Research also suggests that the genes that mediate estrogen action (ER-α and ER-β) are important candidates for the determination of osteoporotic risk. A disruptive mutation of the ER-α gene may result in osteoporosis. With this notion in mind, the allelic variations of ER-α gene may cause differential responsiveness to estrogen binding. High levels of estrogen can initially overcome the resistance, resulting in a normal phenotype. As estrogen levels decrease, however, the genetic difference may become phenotypically apparent. Moreover, some women are not responsive to their estrogen, possibly due to inadequate number of estrogen receptors or to the estrogen receptor genotype. Whether a similar situation could exist for some men is unknown.

If high estrogen levels can compensate for allelic differences in binding affinities, this compensatory balance may also display itself with reduced levels of estrogen production when menopause occurs, or with aging. Not only could this explain what happens in postmenopausal women and the rapidity with which some women lose bone, but it could also explain cases of men with hip fractures who are found to have osteoporosis.

In addition, new information indicates that osteoblasts can produce estrogen from testosterone locally. Female cells produce more estrogen than male cells, whereas male cells convert testosterone to a more biologically active form of testosterone. The impact on bone health is not yet known.

Future significance
Our understanding of the sex-specific role of estrogen and estrogen receptors on the risk of hip fracture is still in its infancy. Historically, most research on hip fractures has been focused on white women, who, through menopause, have an increased risk of rapid bone loss, osteoporosis, and hip fracture. Estrogen has a prominent, contributory role in this.

As people live longer, healthier lives, the risk of fragility and hip fracture increases for everyone—regardless of sex or racial/ethnic background. It is reasonable to predict that fragility fractures, including hip fractures, will continue to increase until more effective sex- and gender-focused prevention and treatment occurs.

The role of estrogen and the effects of estrogen/receptor interaction, bone remodeling, and aging remain areas of active research for both sexes. Although estrogen withdrawal in women during menopause causes a distinct decrease in bone mineral density and a corresponding increase in osteoporosis and fracture risk, the role that estrogen plays in men is still unclear. It is reasonable to assume that estrogen/receptor interaction does occur and would have an effect, but the extent and amount of this effect in men is unknown. Three things are certain: men do have estrogen receptors, men do age, and men do have increased comorbidities and mortality after hip fracture.

Laura Gehrig, MD, is a member of the Women’s Health Issues Advisory Board (WHIAB); she can be reached at laura.gehrig@gmail.com

Mary I. O’Connor, MD, chairs the WHIAB; she can be reached at oconnor.mary@mayo.edu