Sex Steroids and the Construction and Conservation of the Adult Skeleton

Abstract

Here we review and extend a new unitary model for the pathophysiology of involutional osteoporosis that identifies estrogen (E) as the key hormone for maintaining bone mass and E deficiency as the major cause of age-related bone loss in both sexes. Also, both E and testosterone (T) are key regulators of skeletal growth and maturation, and E, together with GH and IGF-I, initiate a 3- to 4-yr pubertal growth spurt that doubles skeletal mass. Although E is required for the attainment of maximal peak bone mass in both sexes, the additional action of T on stimulating periosteal apposition accounts for the larger size and thicker cortices of the adult male skeleton. Aging women undergo two phases of bone loss, whereas aging men undergo only one. In women, the menopause initiates an accelerated phase of predominantly cancellous bone loss that declines rapidly over 4-8 yr to become asymptotic with a subsequent slow phase that continues indefinitely. The accelerated phase results from the loss of the direct restraining effects of E on bone turnover, an action mediated by E receptors in both osteoblasts and osteoclasts. In the ensuing slow phase, the rate of cancellous bone loss is reduced, but the rate of cortical bone loss is unchanged or increased. This phase is mediated largely by secondary hyperparathyroidism that results from the loss of E actions on extraskeletal calcium metabolism. The resultant external calcium losses increase the level of dietary calcium intake that is required to maintain bone balance. Impaired osteoblast function due to E deficiency, aging, or both also contributes to the slow phase of bone loss. Although both serum bioavailable (Bio) E and Bio T decline in aging men, Bio E is the major predictor of their bone loss. Thus, both sex steroids are important for developing peak bone mass, but E deficiency is the major determinant of age-related bone loss in both sexes.

Association between bone mineral density and metabolic syndrome in pre- and postmenopausal women

“…This may be attributed to the protective effect of estrogen on bone. In addition, the onset of estrogen deficiency in women is associated with rapid bone loss, particularly in trabecular bone as in the vertebrae [23]. Cortical bone, as in the long bones, also decreases due to estrogen deficiency, but at a slow rate.…”

High aromatase activity in hypogonadal men is associated with higher spine bone mineral density, increased truncal fat and reduced lean mass

“…Prior studies have suggested a skeletal threshold for serum E 2 in men (34,35,36,37,38). In a review by Rochira et al (37), the authors identified a threshold between 15 and 25 pg/ml, whereas Khosla et al (38) suggested a threshold between 20 and 25 pg/ml using immunoassays and 16 pg/ml using mass spectroscopy.…”

Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-γ-induced class II transactivator

“…strogen deficiency causes osteoporosis, a major source of morbidity and disability in the occidental world (1). Genotropic and nongenotropic effects of estrogen lead to preservation of bone mass through modulation of bone cell lifespan (2) and decreased cytokine-driven osteoclastogenesis (3).…”