Effect of Adrenal and Gonadal Hormones on Bone Marrow and Appendicular BMD

描述（由申请人提供）：患有神经性厌食症（AN）的青春期女孩表现出激素异常，易导致骨转换、骨累积和骨塑形的改变，最终导致不可逆的骨骼缺陷。目前的研究人员长期以来一直对这种疾病中激素的改变如何导致骨髓成分和骨骼损失的变化感兴趣。该项目建立在最近的双盲，安慰剂对照试验的脱氢表雄酮（DHEA）和雌激素替代疗法（ERT）的青少年与AN。目前的研究人员已经表明，这种结合合成代谢+抗吸收方案减轻了中轴骨骼的骨丢失，这一点可以通过脊柱和全身的双能X线吸收测定法（DXA）测量得到证明。人们感兴趣的是，这种治疗方案是否也会影响approxial骨骼，一个具有高度临床重要性的问题，因为年轻的青少年四肢骨折比中轴骨骼更常见。目前研究组的初步数据还表明，随着疾病的进展，AN青少年的骨髓从红色变为黄色（脂肪），并出现骨髓脂肪增加。这些年轻女性，谁矛盾地耗尽了皮下脂肪，增加了骨髓内的脂肪，对骨形成，骨增生在青春期，并最终终身骨骼健康的潜在不利的长期后果。需要进一步的研究来确定青少年红骨髓向黄骨髓的转化是否反映了成年人的发现，表明骨密度降低和骨折风险增加。该提案旨在通过DHEA+ERT联合治疗对骨矿物质密度（BMD）和骨髓成分的新临床试验来研究这一问题，检查激素因素在红骨髓向黄骨髓转化中的作用以及结果与非骨矿物质BMD的关系。在为期一年的试验中，将采用最先进的成像技术，包括外周定量计算机断层扫描（pQCT）、磁共振成像（MRI）数据的视觉评估、MR弛豫测量和磁共振波谱，分别测量骨矿物质密度和评估骨髓成分。我们还试图了解激素介质的骨密度和骨髓组成的变化，包括肾上腺和性腺类固醇，胰岛素样生长因子，生长激素，生长激素，和ghrelin，脂联素，瘦素。拟议的项目将测试由试点成像数据提出的假设，特别是AN女孩的激素异常是否会影响间充质干细胞优先分化为脂肪细胞而不是成骨细胞。加强对这一年轻患者人群骨骼丢失机制的理解，有可能填补关键的知识空白，改善AN青少年的护理。从这项研究中获得的知识也可能适用于与骨质流失相关的年龄范围内的其他疾病，并涉及骨髓成分的改变。

DESCRIPTION (provided by applicant): Adolescent girls with anorexia nervosa (AN) exhibit hormonal abnormalities that predispose to alterations in bone turnover, accrual, and modeling that can ultimately lead to irreversible skeletal deficits. The current investigators have a longtime interest in how hormonal alterations in this disease lead to changes in bone marrow composition and skeletal losses. The proposed project builds on a recent double-blind, placebo- controlled trial of dehydroepiandrosterone (DHEA) and estrogen replacement therapy (ERT) in adolescents with AN. The current investigators have shown that this combined anabolic + antiresorptive regimen mitigated bone loss of the axial skeleton as evidenced by dual-energy x-ray absorptiometry (DXA) measures of the spine and whole body. There is interest in whether this therapeutic regimen also affects the appendicular skeleton, a question of high clinical importance as young adolescents fracture extremities much more commonly than the axial skeleton. Preliminary data from the current group have also shown that adolescents with AN exhibit shifts from red to yellow (fatty) marrow with progression of disease and develop increased marrow fat. These young women, who paradoxically have depleted subcutaneous fat, have increased fat within bone marrow, with potential adverse long-term consequences for bone formation, bone accretion during adolescence, and ultimately, lifetime skeletal health. Further research is needed to determine whether this conversion of red to yellow marrow in adolescents mirrors findings in adults indicating an associated decreased bone density and increased fracture risk. This proposal seeks to investigate this question through a novel clinical trial of combined therapy with DHEA+ERT on bone mineral density (BMD) and bone marrow composition, examining the role of hormonal factors in the conversion of red to yellow marrow and relation of findings to appendicular BMD. Over the one-year trial, state-of-the-art imaging techniques will be employed, including peripheral quantitative computed tomography (pQCT), visual assessments of magnetic resonance imaging (MRI) data, MR relaxometry and magnetic resonance spectroscopy to measure bone mineral density and evaluate bone marrow composition, respectively. We also seek to understand hormonal mediators of the changes observed in both bone density and bone marrow composition, including adrenal and gonadal steroids, insulin-like growth factors, growth hormone, and ghrelin, adiponectin, and leptin. The proposed project will test hypotheses raised by the pilot imaging data, in particular whether hormonal abnormalities in girls with AN influence mesenchymal stem cells to differentiate preferentially into adipocytes over osteoblasts. Enhancing understanding of the mechanisms underlying skeletal losses in this young patient population has the potential to fill critical knowledge gaps that will improve the care of adolescents with AN. Knowledge gained from this study may also have application to other diseases across the age spectrum that are associated with bone loss and involve alterations in bone marrow composition.