Estrogen (E) deficiency causes both the early and late forms of osteoporosis in postmenopausal women and contributes to the development of osteoporosis in elderly men (1). It is associated with large increases in bone resorption caused by increased osteoclast (OC) numbers (due to enhanced OC formation and reduced OC apoptosis) and by increased OC activity (2). Since the demonstration in 1988 that bone cells contain functional E receptors, progress on elucidating the molecular basis of E action has been rapid, albeit controversial and incomplete.Early studies on E's role in bone metabolism focused on the role of the proinflammatory cytokines -IL-1, IL-6, TNF-α, granulocyte macrophage colony-stimulating factor, macrophage colony-stimulating factor (M-CSF), and prostaglandin-E 2 (PGE 2 ). These factors increase bone resorption, mainly by increasing the pool size of pre-OCs in bone marrow (2, 3), and are downregulated by E. Moreover, ovariectomyinduced increases in OCs are attenuated or prevented by measures that impair the synthesis of or response to IL-1, IL-6, TNF-α, or PGE 2 (2, 3). Other studies have found that E upregulates TGF-β, an inhibitor of bone resorption that acts directly on OC to decrease activity and increase apoptosis (2).However, E regulation of bone resorption must now be re-evaluated in the light of the recent discovery of three new members of the TNF ligand and receptor signaling family that serve as the final effectors of OC differentiation and function (4, 5). The long-sought osteoblast-derived paracrine effector of OC differentiation has been identified as the receptor activator of NF-κB ligand (RANKL, also called OPG ligand or OC differentiating factor), which is expressed by stromal-osteoblast lineage cells. Contact between these cells and cells of the OC lineage allows RANKL to bind its physiologic receptor, RANK, potently stimulating all aspects of OC function: In response to RANKL signaling, OC differentiation and activity increase, and OC apoptosis decreases. Indeed, RANKL is both necessary and sufficient for OC formation, provided that permissive concentrations of M-CSF are present. The stromalosteoblast lineage cells also secrete osteoprotegerin (OPG), a soluble decoy receptor that neutralizes RANKL. E increases OPG (5) and decreases M-CSF (3) and RANK (6). Part of the effect on this signaling system may be indirect, acting through E-responsive intermediaries. Thus, IL-1 and TNF-α increase RANKL, OPG, and M-CSF, whereas PGE 2 increases RANKL and decreases OPG (3, 5). E has not yet been shown to regulate RANKL directly.In elegant studies published in this issue of the JCI, Cenci et al. (7) report that increased production of TNF-α by T cells in bone marrow mediates the increased bone resorption and bone loss in ovariectomized (OVX) mice. These authors show that ovariectomyinduced bone loss can be prevented by administering either E, TNF-α binding protein, or an inactivating antibody specific for TNF-α, and that bone loss does not occur in OVX, T cell-deficient animals. OVX mice also i...

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Serum concentrations of insulin-like growth factors (IGF) were measured by RIA in 57 normal women, ages 30 - 90 yr, and in 29 untreated women with postmenopausal osteoporosis and vertebral compression fractures, ages 55 - 75 yr. These values were correlated with bone mineral density (BMD) of the distal and midradius assessed by single photon absorptiometry and of the lumbar spine assessed by dual photon absorptiometry as well as serum and urinary calcium, phosphorus, creatinine, alkaline phosphatase, immunoreactive PTH, urinary hydroxyproline, and creatinine clearance. Serum IGF-I levels declined markedly with age (r = -0.47, P less than 0.001). Serum IGF-II levels decreased only slightly with age, and this decrease was not statistically significant. Although BMD at all three scanning sites also declined significantly with age, neither serum IGF-I nor II concentrations correlated with BMD when age was held constant. In women with postmenopausal osteoporosis, serum IGF-I and II did not differ from the concentrations in normal women of similar age and did not correlate with BMD. In neither group was a correlation between serum IGF-I or II and serum or urinary proteins or cations found. Thus, there was no evidence that impaired synthesis of IGF-I and II contributes to pathogenesis of the syndrome of Type I (postmenopausal) osteoporosis, which is characterized by accelerated loss of trabecular bone and vertebral compression fractures. The possibility remains, however, that decreasing concentrations of serum IGF-I play a role in the more gradual loss of bone with aging (Type II osteoporosis) in which impared bone formation at the cellular level has been demonstrated.