No 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.

ABSTRACT

In a population-based, cross-sectional study, we assessed age-and sex-specific changes in bone structure by QCT. Over life, the cross-sectional area of the vertebrae and proximal femur increased by ϳ15% in both sexes, whereas vBMD at these sites decreased by 39 -55% and 34 -46%, respectively, with greater decreases in women than in men.Introduction: The changes in bone structure and density with aging that lead to fragility fractures are still unclear. Materials and Methods: In an age-and sex-stratified population sample of 373 women and 323 men (age, 20 -97 years), we assessed bone geometry and volumetric BMD (vBMD) by QCT at the lumbar spine, femoral neck, distal radius, and distal tibia. Results: In young adulthood, men had 35-42% larger bone areas than women (p Ͻ 0.001), consistent with their larger body size. Bone area increased equally over life in both sexes by ϳ15% (p Ͻ 0.001) at central sites and by ϳ16% and slightly more in men at peripheral sites. Decreases in trabecular vBMD began before midlife and continued throughout life (p Ͻ 0.001), whereas cortical vBMD decreases began in midlife. Average decreases in trabecular vBMD were greater in women (Ϫ55%) than in men (Ϫ46%, p Ͻ 0.001) at central sites, but were similar (Ϫ24% and Ϫ26%, respectively) at peripheral sites. With aging, cortical area decreased slightly, and the cortex was displaced outwardly by periosteal and endocortical bone remodeling. Cortical vBMD decreased over life more in women (ϳ25%) than in men (ϳ18%, p Ͻ 0.001), consistent with menopausal-induced increases in bone turnover and bone porosity. Conclusions: Age-related changes in bone are complex. Some are beneficial to bone strength, such as periosteal apposition with outward cortical displacement. Others are deleterious, such as increased subendocortical resorption, increased cortical porosity, and, especially, large decreases in trabecular vBMD that may be the most important cause of increased skeletal fragility in the elderly. Our findings further suggest that the greater age-related decreases in trabecular and cortical vBMD and perhaps also their smaller bone size may explain, in large part, why fragility fractures are more common in elderly women than in elderly men.

No abstract

We propose here a new unitary model for the pathophysiology of involutional osteoporosis that identifies estrogen (E) deficiency as the cause of both the early, accelerated and the late, slow phases of bone loss in postmenopausal women and as a contributing cause of the continuous phase of bone loss in aging men. The accelerated phase in women is most apparent during the first decade after menopause, involves disproportionate loss of cancellous bone, and is mediated mainly by loss of the direct restraining effects of E on bone cell function. The ensuing slow phase continues throughout life in women, involves proportionate losses of cancellous and cortical bone, and is associated with progressive secondary hyperparathyroidism. This phase is mediated mainly by loss of E action on extraskeletal calcium homeostasis which results in net calcium wasting and increases in the level of dietary calcium intake required to maintain bone balance. Because elderly men have low circulating levels of both bioavailable E and bioavailable testosterone (T) and because recent data suggest that E is at least as important as T in determining bone mass in aging men, E deficiency may also contribute substantially to the continuous bone loss of aging men. In both genders, E deficiency increases bone resorption and may also impair a compensatory increase in bone formation. For the most part, this unitary model is well supported by observational and experimental data and provides plausible explanations to traditional objections to a unitary hypothesis. (J Bone Miner Res 1998;13:763-773)

he selective estrogen-receptor modulators (serm s ) represent a major therapeutic advance for clinical practice. Unlike estrogens, which are uniformly agonists, and antiestrogens, which are uniformly antagonists, the SERMs exert selective agonist or antagonist effects on various estrogen target tissues. The SERMs are chemically diverse compounds that lack the steroid structure of estrogens ( Fig. 1) but possess a tertiary structure that allows them to bind to the estrogen receptor. Although some members of this class of drugs have been available for decades, their tissue-specificity in humans has only recently been recognized. Certain phytoestrogens, such as genistein, also appear to have SERM-like properties.In this article we review the emerging understanding of the molecular basis of action of SERMs, summarize their tissue-selective agonist-antagonist effects, and place in perspective their therapeutic uses as compared with estrogen or nonestrogen alternatives.In the classic model of estrogen action, the unoccupied nuclear estrogen receptor resides in the nuclei of target cells in an inactive form. Binding to an agonist, such as estradiol, alters the physicochemical properties of the estrogen receptor, allowing the receptor dimer to interact with specific DNA sequences (estrogen response elements) within the promoters of responsive genes. 1 The DNA-bound estrogen receptor then regulates target-gene transcription, either positively or negatively (Fig. 2). However, the recognition that tamoxifen and other SERMs have tissue-specific agonist-antagonist activity led to the realization that the classic model was incomplete and that estrogen action was more complex than had been thought. 2,3 The mechanisms of the tissueselective, mixed agonist-antagonist action of SERMs, although still only partly understood, are gradually becoming clearer.Most of the unique pharmacology of SERMs can be explained by three interactive mechanisms: differential estrogen-receptor expression in a given target tissue, differential estrogen-receptor conformation on ligand binding, and differential expression and binding to the estrogen receptor of coregulator proteins (Fig. 2).First, target cells for estrogen action contain varying concentrations of homodimers of one or both of two species of estrogen receptors -estrogen receptor a and estrogen receptor b -as well as estrogen receptor a -estrogen receptor b heterodimers. Mice with genetic disruptions of estrogen receptor a and estrogen receptor b display different phenotypes, demonstrating that each receptor has a distinct action. 4,5 Estrogen receptor a is almost always an activator, whereas estrogen receptor b can inhibit the action of estrogen receptor a by forming a heterodimer with it. Moreover, microarray analysis in mice with deletions of estrogen receptor a or estrogen receptor b showed t mechanisms of action A correction has been published: N Engl J Med 348(12):1192. See last page of this PDF.

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.