ABSTRACT
Although it has been recognized for a number of years that a deficiency in estrogen results in increased bone fragility, the mechanism of the effect has been elusive. It is only within the past 10 years that investigators have had the cellular models and analytical methodologies to establish that bone cells of several types possess high affinity receptors for estrogens. This was first reported in 1988 by Komm and colleagues in two osteoblast cell lines, rat ROS 17/2.8 and human HOS TE85’ and by Ericksen and co- workers in cultured osteoblastic cells from human surgical specimens 2 . Receptors for estrogens or genes for estrogen receptors were subsequently reported in other osteoblastic cell lines 3–5 , as well as in normal osteoblasts and preosteoblastic cells from other species 6–9 , osteoclastic and preosteoclastic cells 10–14 , osteocytes 15 and a bone endothelial cell line 16 . The density of the receptors is generally lower than in reproductive tissues, although the affinities are comparable to those in typical estrogen target tissues. This widespread presence of estrogen receptors allows for multiple options in terms of how estrogens might directly affect bone, and also for the possibility of multifaceted effects. This is especially true since normal bone remodeling requires direct actions of osteoclasts on the bone matrix, which can involve acute activation of these osteoclasts by osteoblasts, and more delayed effects on differentiation of osteoblasts and osteoclasts. Studies in the past several years have revealed a number of effects of estrogens on bone, which include effects on proliferation, on phenotypic responses and on the secretion of local factors that could be mediators of the action of estrogens. Estrogens have been observed to have inconsistent and often opposite effects on osteoblast proliferation and phenotypic responses, such as alkaline phosphatase and osteocalcin, in different studies 17–19 . Since a wide range of culture conditions, cell lines and passage numbers are represented in the data, the diversity of response may be indicative that the effects are limited to a subpopulation of the bone cells. Alternatively, the lack of a consistent response may indicate that these are not critical phenomena in the actions of estrogen to preserve bone. In osteoclasts and osteoclastic cells, the effects of estrogens on functions related to the bone resorbing activity of the cells are in the direction of inhibition, with decreased osteoclast- mediated resorption and decreases in several osteoclast lysosomal enzymes 20 . However, other investigations have failed to show effects of physiological concentrations of estrogen on osteoclastic formation 21 .
