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Growth hormone and adult bone remodelling

The importance of growth hormone for normal skeletal growth during childhood and adolescence is long established, but much less is known about its effect on the adult skeleton. Children with untreated growth hormone deficiency, whether isolated or as a component of panhypopituitarism, have low serum levels of osteocalcin (an index of bone formation) that return to normal with replacement therapy (Johansen et al., 1990b; Sartorio et al., 1991). When such patients are studied as adults after withdrawal of growth hormone for at least 6 months, serum osteocalcin levels are normal, but increase to supranormal levels 4 months after treatment is resumed (Johansen et al., 1990a). This is not evidence for selective stimulation of bone formation, as may occur as a component of increased skeletal growth, since there was a concomitant increase in urinary excretion of hydroxyproline, an index of bone resorption (Johansen ef al., 1990a). In this issue, further data are reported from the same study that confirm the increase in bone resorption with a more specific index, the urinary excretion of collagen cross-links (Schlemmer et al., 1991). Bone remodelling in vivo can be studied by histologic, radiokinetic or biochemical methods (Charles et al., 1985, 1987). Histologic methods require an invasive procedure and are subject to substantial sampling variation in individuals, and so are most useful for the study of pathogenetic or therapeutic mechanisms in groups of subjects. Radiokinetic methods are cumbersome, subject to regulatory restriction, and need simultaneous measurement of external calcium balance in order to obtain separate measurements of bone resorption and formation. Not surprisingly, the biochemical methods are by far the most commonly used. Measurements on blood and/or urine samples can provide independent assessment of bone resorption and bone formation. Such measurements are commonly referred to as ‘markers’ of bone turnover, but this term is more appropriate for a feature that is present or absent rather than for a continuous variable. The indices available are of two general kinds: those that relate directly to the rate of bone matrix production or destruction and those that depend more on the total number of forming or resorbing cells, or on some other aspect of their functional capacity (Parfitt & Kleerekoper, 1984). The proper interpretation of biochemical indices requires an understanding of the organization of bone remodelling at the histologic level (Parfitt & Kleerekoper, 1984; Parfitt, 1990a, b). In the adult skeleton remodelling is a cyclical phenomenon, each cycle being initiated by the event of activation that marks the conversion of a quiescent region of bone surface to one where remodelling is active. A cavity excavated by a team of osteoclasts is subsequently refilled, completely or (more commonly) incompletely, by a subsequently appearing team of osteoblasts. The whole body rates of resorption and formation that influence the levels of the biochemical indices represent the product of two quantities that are partly independent: the frequency of remodelling activation, which varies over a wide range, and the amounts of bone resorbed and formed during each cycle, which vary over a narrow range. Consequently, all biochemical indices, whether ostensibly of resorption or formation, are influenced mainly by the whole body rate of remodelling activation, and give little information about the function of individual teamspf osteoclasts and osteoblasts, and none at all about the activity of individual cells (Parfitt, 1990b). Until recently, the most commonly used index of whole body bone resorption was the urinary excretion of hydroxyproline (Kivirikko, 1970). This occurs in the form of small peptides containing hydroxyproline that are derived mainly from the breakdown of collagen. Urinary total hydroxyproline excretion has provided a great deal of useful information during the last 30 years but suffers from several disadvantages (Beardsworth et al., 1990). Approximately 15% is derived from the amino-terminal extension peptide of procollagen, and so is a by-product of bone formation rather than resorption. Type I collagen catabolism in skin also contributes to urinary hydroxyproline, which is increased in certain skin diseases. Only about 10% of the hydroxyproline liberated from collagen appears in the urine, the remainder being catabolized in the liver. Hydroxyproline excretion is influenced by diet, and if measured over a period of 24 hours or longer, requires a low gelatin diet beginning several days earlier. However, this can be circumvented by measuring the hydroxyproline/creatinine ratio in an early morning specimen obtained after an overnight fast (Wilson et al., 1990). During the extracellular maturation of secreted collagen, both intramolecular and intermolecular cross-links develop between adjacent a chains. Two of these cross-links, both derivatives of 3-hydroxypyridinium, have been recently introduced as indices of bone resorption. Hydroxylysylpyridinoline occurs in cartilage and other skeletal connective tissues as well as in bone, whereas lysyl-pyridinoline occurs