Bone as a Target Organ: Toward a Better Definition of Osteoporosis

BONE AS A TARGET ORGAN: TOWARD A BETTER DEFINITION OF OSTEOPOROSIS FREDERIC C. BARTTER, M.D.* Introduction The endocrine system is generally described as a set of feedback loops, where a stimulus affects a target gland, the target gland responds by production of a substance that bears no chemical relationship to the stimulus, and this substance, directly or indirectly, operates to limit the further production of the initial stimulating hormone . Bone occupies a central position in such a feedback loop in at least three ways; doubtless more of them will be found as the knowledge of bone physiology at the molecular level is expanded. The simplest "loop," for example, involves the secretion of parathyroid hormone which leads to resorption of bone and thus to an increase in circulating calcium ion, which in turn limits the further production of parathyroid hormone [I]. It is likely that this hormonal relationship shares with many other feedback loops the intervention of one or more messengers. As parathyroid hormone causes production of 3',5'-cyclic adenosine monophosphate (cyclic AMP) from osteocytes, the sequence of events leading to bone resorption by osteoclasts may involve cyclic AMP as an intermediate. A second type of loop is apparent in the relationship between bone resorption and the secretion of thyrocalcitonin from the thyroid or the ultimobranchial or neural crest anläge. In this case, the loop operates "in reverse ," in that a rise of plasma calcium ion concentration stimulates the production of thyrocalcitonin [2], and this in turn limits the rate of resorption of bone, thus ultimately limiting the release of calcium ions. As far as is known, these systems operate on the resorption of complete bone (mineralized matrix). Bone may represent a target * Endocrinology Branch, National Heart and Lung Institute, National Institutes of Health, Bethesda, Maryland 20014. Perspectives in Biology and Medicine · Winter 1973 | 215 gland for the action of hormones in a manner bearing no known relationship to their action on formed bone by affecting the maturation of collagen destined to become bone matrix. Mature tropocollagen extruded from osteoblasts to assume such a role has approximately half of its proline residues hydroxylated; there is evidence to suggest that poorly hydroxylated matrix collagen is inadequate as a nidus for deposition of apatite. Accordingly, parathyroid hormone (perhaps, through an action on protocollagen proline hydroxylase) could serve to control the formation of calcifiable bone matrix and thus, ultimately , of bone. We have studied bone as the ultimate target of some systems of hormonal interplay with the hope that we could better understand metabolic bone diseases. Virtually all advances in the understanding of bone physiology stem from the pioneering works of Albright [3], who started by considering bone formation and bone resorption separately. Figure la shows his schema, wherein many osteoblasts are shown laying down a sizable osteoid border. With deposition of apatite, this becomes bone, and finally osteoclasts operate to remove bone, but without prior removal of apatite. This model is useful for the understanding of two of the metabolic bone diseases in which the total bone mass OSTEOBLASTS (p'TAsoru ED r MATRIX FORMATION - (a) OSTEOCLASTS !T ____? m BONE t DESTRUCTION U MATRIX CALCIFICATION NORMAL ADULT GD GD GD CZl GD (C) ? OSTEOMALCI A GD (e) V, W OSTEITIS FIBROSA CYSTICA OSTEOPOROSIS Fig. 1.—a, Schema for physiology of bone, after Albright, b, Realistic schema for normal, adult bone, c, Bone in osteomalacia, d, Bone in osteitis fibrosa cystica, e, Bone in osteoporosis. 216 I Frederic C. Bartter · Bone as a Target Organ is inadequate, osteomalacia and osteitis fibrosa cystica. Because there is obvious histological evidence for enormous overproduction of osteoid borders in the former and equally impressive evidence for increased osteoclastic resorption in the latter, we shall consider these disorders as interactions of hormones with bone as a target organ. First, however, we should note a very important limitation of this model for the understanding of normal bone physiology. Normal bone appears, at the magnification available for light microscopy, to be almost inert. Thus, a more faithful schema (fig. ) would represent normal bone as the product of very few osteoblasts laying down what appears at any one time to be very little osteoid; similarly, a very...