Markers of bone turnover in the evaluation of the response to GH treatment in GH-deficient children

Abstract

Growth rate and final height are hard end-points when assessing the response to growth hormone (GH) treatment of growth-retarded children. Considering the pronounced variability of height measurements, a 6- to 12-month period of observation is needed to detect a response to GH. Only by employment of the more time-consuming and observer-dependent examination, knemometry (1), can a valid measure of shortterm growth be obtained. Other methods to monitor the effects of GH treatment are therefore sought. Response is known to vary considerably and some children may, in practice, be non-responders, which makes short-term monitoring particularly important. With the prediction of growth response after short-term GH therapy, unnecessary inconvenience for non-responding children and their families, as well as expense for the community, may be avoided. The problem is of particular importance during treatment of children who are not clearly GH deficient (GHD), such as patients with Turner’s syndrome, familial short stature or partial GH deficiency. A study in short non-GHD prepubertal children has reported an inverse relationship between spontaneous GH secretion and growth response (2). Thus, an estimation of GH secretory capacity may help to select probable responders before the start of GH therapy. One of the most commonly used markers of GH therapy is insulin-like growth factor (IGF)-I. Serum IGF-I levels, which increase following GH administration, have been reported to be correlated with growth (3). The effect of GH on bone metabolism could be either direct or mediated through IGFs or IGF-binding proteins (IGFBP), and IGFBP-3 has also been proposed as a marker of the effects of GH in bone. Recently, markers of bone metabolism have been introduced, and changes in their levels during GH treatment, in particular in its early phase, may be valuable indicators of therapeutic efficacy. GH stimulates bone turnover in GHD patients and in healthy subjects, as reflected by simultaneous increments in the levels of markers of bone formation and resorption in serum or urine (4, 5). Positive correlations have been reported between growth velocity and levels of the aminoterminal propeptide of type III collagen (PIIINP) (6), and of the carboxyterminal propeptide of type I procollagen (PICP) (7), which both reflect bone formation. Early phases of the bone remodelling process generate the amino-terminal propeptide of type I collagen (PINP), being involved in the deposition of collagen, and PIIINP, reflecting extraosseus collagen formation. Type I collagen primarily relates to mineralized bone and soft tissue, whereas type III collagen primarily derives from soft connective tissue (8). The reduced bone turnover in GHD children may be causally associated with a diminished bone mineral density (BMD). To what extent changes in bone dynamics can be translated into increased final height, improved BMD or enhanced bone strength in adolescence and adulthood is, however, still uncertain.