Current evidence indicates that achieving optimal bone mass during childhood may be a significant factor in the prevention of osteoporosis. Since the rate of childhood bone mineral accumulation is maximal during puberty, it is essential to understand the factors associated with mineral metabolism during this period of time. Using stable isotope techniques, we have found that, in girls, dietary calcium absorption and the kinetically determined bone calcium accretion rate are maximal in early puberty and decline to near adult values by 2-3 years postmenarche. This proposed study will evaluate the relationships among the hormonal and biochemical changes associated with female puberty and kinetically determined measures of bone calcium turnover. Our purpose is to identify the hormonal and biochemical factors associated with the onset and peak rates of the pubertal increases in bone mineral metabolism. Differences in bone mineral metabolism among Caucasian, Black, and hispanic girls and between normal girls and those with central precocious puberty will be identified. Healthy 8.5- to 9.0-year old girls will be enrolled. Their growth and pubertal development will be assessed by anthropometry, physical examination, and bone age determination. Subjects will have comprehensive mineral metabolism studies performed every 6 months from the time of enrollment until 6 months after reaching menarche. With each of these studies, pubertal development will be defined by physical examination and hormonal markers including the FSH and LH responses to gonadotropin releasing hormone (GnRH), as well as other hormonal markers of puberty, including DHEA-S and IGF-1. Serum estradiol will be measured using a novel recombinant cell bioassay method which is capable of measuring the very low levels of this hormone which are present in prepubertal girls. Bone density will be evaluated by total body and regional dual-energy X-ray absorptiometry. Calcium absorption, bone calcium deposition, bone calcium resorption and calcium metabolic pool size will be measured using a stable isotope technique in which one calcium stable isotope is given orally and a second is given intravenously. In this technique, changes in serum and urinary isotopic enrichments during the 120 hours after isotope administration are used to calculate calcium absorption and kinetics. Biochemical and hormonal markers of mineral metabolism, including serum osteocalcin, vitamin D metabolites, intact parathyroid hormone, and urinary N-telopeptide, will be measured and correlated to the bone densitometric and calcium kinetic results. As a corollary to these studies, a group of 4.0- 6.9-year-old girls with precocious puberty will have calcium isotope studies performed once before and twice after puberty is inhibited using a GnRH analogue. A third group of girls, with the established diagnosis of precocious puberty will be studied while receiving a GnRH analogue and twice after its discontinuation. These studies will provide novel information regarding the relationship between pubertal development in girls of different races and bone formation and metabolism.
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