Nutritional and Hormonal Determinants of Peak Bone Mass

描述(由申请人提供)： 青春期骨矿积累量最大，90%的峰值骨量在18岁时达到。因此，青春期遭受的侮辱会导致永久性缺陷，并增加日后骨折的风险。神经性厌食症(AN)与骨形成减少、严重的骨量减少和骨质疏松有关。骨量减少在青春期开始时也比成年时更严重。然而，骨丢失的发病机制尚不清楚，到目前为止，还没有任何治疗方法被证明对患有AN的青少年低骨密度(BMD)有效。随着体重的恢复，骨密度有所改善，但三分之一的受试者仍患有骨质疏松症。补充钙和维生素D不能改善AN患者的骨密度。患有AN的成年人生长激素(GH)水平较高，而IGF-I水平较低，提示存在营养获得性‘GH抵抗’。GH直接或通过IGF-I在成骨细胞分化过程中发挥重要作用。然而，生长激素抵抗在不同青春期阶段的AN青少年中的存在，以及这种“抵抗”对低BMD的贡献还没有被研究。AN与雌激素水平非常低有关，但尽管已知雌激素对骨吸收有抑制作用，但口服雌激素对成人AN患者的骨密度改善并不有效。口服雌激素抑制IGF-I，这可能会阻止雌激素抗吸收作用所带来的骨量改善。相反，经皮雌激素不会降低IGF-I，而且经皮给药雌激素对AN骨转换的影响还没有被研究过。该提案的目的之一是确定患有AN的青少年是否对生长激素具有抵抗力，以及这种抵抗力是否导致AN的骨形成减少和骨密度降低。为了研究这一假设，我们将检查AN和匹配对照组的GH分泌模式，并确定GH分泌的变化是否预测全身新陈代谢、身体成分、骨形成标志物和BMD的变化。我们还假设，对患有AN的成年青春期女孩服用经皮雌激素将导致减少骨丢失和增加骨形成(通过增加IGF-I水平)。为了研究这一假说，我们将检查服用经皮雌激素前和服用后6个月的青春期女孩的骨代谢。雌激素在体重恢复和未恢复体重的AN中的作用也将被研究。

DESCRIPTION (provided by applicant): Bone mineral accrual is maximum in adolescence and 90% of peak bone mass is achieved by 18 y of age. Insults suffered in adolescence can thus result in permanent deficits with increasd fracture risk in later life. Anorexia nervosa (AN) is associated with decreased bone formation and signifiant osteopenia and osteoporosis. Osteopenia is also more severe when AN begins in adolescence than in adult life. The pathogenesis of bone loss, however, is not well understood and no treatment has so far proven effective in treating low bone density (BMD) in adolescents with AN. Some improvement in BMD occurs with weight recovery, but a third of AN subjects remain osteoporotic. Calcium and vitamin D supplementation does not improve BMD in AN. Adults with AN have have high growth hormone (GH) and low IGF-I levels, suggestive of a nutritionally acquired 'GH resistance'. GH, both directly and through IGF-I, plays an important role in osteoblast differentiation. However, the presence of GH resistance in adolescents with AN in different pubertal stages, and the contribution of this 'resistance' to low BMD has not been examined. AN is associated with very low estrogen levels, but despite the known inhibitory effect of estrogen on bone resorption, oral estrogen was not effective in improving bone density in adults with AN. Oral estrogen suppresses IGF-I, and this may prevent the improvement in bone mass expected from anti-resorptioe effects of estrogen. Conversely, transdermal estrogen does not lower IGF-I, and the effects of transdermally administered estrogen on bone turnover in AN have not been examined. One aim of the proposal is to determine whether adolescents with AN are GH resistant, and whether this 'resistance' contributes to decreased bone formation and low bone density in AN. To investigate this hypothesis, we will examine GH secretory patterns in AN and matched controls, and determine if alterations in GH secretion predict changes in whole body metabolism, body composition, bone formation markers and BMD. We also hypothesize that administration of transdermal estrogen to mature adolescent girls with AN will result in decreased bone loss and increased bone formation (by increasing IGF-I levels). To investigate this hypothesis, we will examine bone metabolism in adolescent girls with AN before and six months after administration of transdermal estrogen. The effects of estrogen in weight recovered vs. non-weight recovered AN will also be studied.