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.

Correlates of bone quality in older persons

“…Since estrogens enhance the osteoclastpromoting activity of PTH and all the women in our study population were postmenopausal, we speculated that the inverse association between PTH and vBMDc might be also mediated by estrogen deficiency. This is also in accordance with findings reported by Riggs et al, indicating that estrogen deficiency is indirectly responsible for the secondary hyperparathyroidism observed in late postmenopausal women [35]. Our data are also in agreement with Neer et al who suggested that PTH prevent a proximal femur and total body bone loss in young women with induced estrogen deficiency [36].…”

Estrogen and the selective estrogen receptor modulator (SERM) protection against cell death in estrogen receptor alpha and beta expressing U2OS cells

“…The ability of estrogen to decrease the expression of these cytokines in osteoblastic cells has previously been shown by several researchers (Spelsberg et al, 1999;Brady et al, 2002Khosla et al, 2002. Transfected U2OS cells were incubated overnight with 0,1nM or 1 nM E 2, after which cells were either treated for one hour with 5ng/ml TNFα or left untreated.…”

“…It is believed that the major action of estrogen on the skeleton in vivo is through the inhibition of bone resorption (Riggs et al, 2002). Although some of the anti-resorptive effects of estrogen are via direct actions on bone-resorbing osteoclasts, estrogen has also been shown to have indirect effects by regulating bone-forming osteoblasts and bone marrow stromal cells (Zallone 2006).…”

Modulation of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptors in a human osteoclast model in vitro

“…Studies in animals suggest that estrogen acts by altering either the production or activity of local factors that regulate osteoblast and osteoclast precursors (Trivedi et al, 2010). A number of cytokines and growth factors are released in response to estrogenic stimulation; M-CSF, IL-1 and -6, TNF, prostaglandins, and IGF-1, all of which have effects on bone cells in vitro and in vivo (Riggs et al, 2002). Most, but not all of these cytokines can be produced by the bone cells, so some are produced by other cells in the bone microenvironment, inducing both paracrine and autocrine effects on remodeling.…”