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One would like to express the results of crosslink marker assays as a function of an individual's bone mass. Since bone mass cannot be directly measured, inferences are made from body height, and circulating crosslink markers are expressed in relation to body height raised to a certain power. There is some discussion on what is the most appropriate power factor to use. Unfortunately the scientific literature does not contain a lot of information on the skeletal mass of children. It is very likely that, as for a height-independent measure of body weight, the optimal factor changes with age. If one had a very large series of normal values for skeletal mass at different ages, one could transform it into SD scores and make a regression model, but the baseline data for that are not available yet. Preliminary data from a longitudinal study using bone mass data obtained by dual energy X-ray absorptiometry (DEXA) suggests that an exponent of 3 can be used for normal children (Branca). In a study of malnourished children, whose skeletal mass per unit height was lower than in normal children, Golden found an exponent of 2 most appropriate.
Crosslinks are the end product of different processes (diurnal cycles in hormone production, etc., and perhaps small growth spurts). The day-to-day variation of crosslink secretion is about 15%, which one would like to interpret as actual variation in growth, but at present it is not yet possible to distinguish within this variation the experimental error from a biological response. Better growth measures, as will perhaps be obtained by knemometry, may contribute to the solution of this problem.
A question was put about the marker for the turnover of collagen in soft tissues. The main collagen pool is skin, which accounts for about 25% of body weight and which contains both type I and type III collagen. In the experiment of Dickerson and Widdowson, skin collagen was more labile than that of either muscle or bone (Cabak, Dickerson & Widdowson, 1963). Part of the reason for that is that there are differences in cross-linking pathways, but this has nothing to do with differences in turnover rate. In experiments in which a radio-label was incorporated into the skin of malnourished animals and the animals were then refed to produce catch-up growth, the total amount of label stayed the same. Therefore, although there was a large amount of growth of the skin, what seemed to happen was that the lattice-work expanded and filled in with more collagen, rather than the collagen being resorbed and replaced.
Part of the discussion dealt with the usefulness of osteocalcin as an indicator, for instance of growth velocity. In his paper, Robins had mentioned its use as an early outcome measure of growth hormone therapy. The main problems seem to be a persisting uncertainty as to whether or not serum levels reflect production levels, and the lack of systematic information on the osteocalcin content of different bones at different ages. It does not seem to be stoichometrically related to mineralization. In Senegal, Ndiaye et al. (in press) found reduced osteocalcin levels in malnourished children suffering from kwashiorkor which increased during recovery and became normal in half of them, but no differences in osteocalcin levels between stunted and non-stunted marasmic children.
Several discussants would like to
know what the different markers are indicative of and under what circumstances one should
use one or the other. It does not seem possible yet to answer such questions, and in most
situations it is recommended to use several markers in an attempt to further clarify their
diagnostic value.
Cabak V, Dickerson, JWT & Widdowson EM (1963): Response of young rats to deprivation of protein and of calories. Br. J. Nutr. 17, 601-616.