Endocrine Abstracts

In contrast to traditional ideas that loss of estrogens at menopause is the seminal mechanism of osteoporosis, bone loss begins as early as the early part of the third decade in both women and men; substantial trabecular bone loss occurs in sex steroid sufficient young adult women and men; and after the first few years of accelerated bone loss in postmenopausal women, bone mass and strength decline in both sexes at the same rate. Consistent with these clinical observations, mechanistic studies in mice show that aging, and specifically increased oxidative stress, rather than age-associated failure of other organs, is a fundamental pathogenetic mechanism of age-related bone loss and strength, leading to, among other changes, a decrease in osteoblast lifespan and bone formation. Loss of estrogens or androgens accelerates the effects of aging on bone by decreasing defense against oxidative stress. Oxygen radical-induced activation of the FoxO family of transcription factors defends against such an increase by up regulating free radical scavenging and DNA repair enzymes, thereby representing an indispensable homeostatic mechanism for skeletal health. Consistent with this, loss or gain of function of FoxOs decreases and increases bone mass respectively. Albeit, excessive or protracted FoxO activation diverts ß-catenin away from Wnt signaling, leading to a decreased osteoblastogenesis. Excessive FoxO activation may also lead to a decrease in bone strength, independently of bone mass, by compromising the bone vasculature and the hydration of the aging skeleton. Fascinatingly, attenuation of Wnt-mediated transcription, resulting from an autosomal dominant missense mutation in LRP6 or LRP5 -co-receptors for the Wnt-signaling pathway has been linked recently genetically not only to premature osteoporosis, but also to coronary artery disease as well as several features of the metabolic syndrome including hyperlipidemia, hypertension, and diabetes, but not obesity. Hence, antagonism of Wnt-signaling by oxidative stress—induced activation of FoxOs with increasing age may be a common molecular mechanism contributing to the development not only of involutional osteoporosis, but several pathologies like atherosclerosis, insulin resistance, and hyperlipidemia – all of which become more prevalent with advancing age (Manolagas & Almeida Mol. Endocrinol. 2007 21 2605–14).