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，累积和建模的改变，最终导致不可逆转的骨骼缺陷。目前的研究人员对这种疾病中激素的改变如何导致骨髓成分的改变和骨骼的损失有长期的兴趣。拟议的项目建立在最近的一项双盲、安慰剂对照试验的基础上，该试验对患有AN的青少年进行脱氢表雄酮（DHEA）和雌激素替代疗法（ERT）。目前的研究表明，通过脊柱和全身的双能x线吸收仪（DXA）测量，这种合成代谢+抗吸收联合方案减轻了轴骨的骨质流失。人们对这种治疗方案是否也会影响尾骨很感兴趣，这是一个非常重要的临床问题，因为青少年的四肢骨折比中轴骨更常见。目前研究小组的初步数据还显示，患有AN的青少年随着疾病的进展，骨髓从红色转变为黄色（脂肪），骨髓脂肪增加。矛盾的是，这些年轻女性已经消耗了皮下脂肪，却增加了骨髓内的脂肪，这对骨骼形成、青春期的骨骼增生以及最终的终生骨骼健康都有潜在的不利长期后果。需要进一步的研究来确定青少年骨髓红黄转换是否反映了成人骨密度降低和骨折风险增加的相关发现。本研究旨在通过DHEA+ERT联合治疗骨密度（BMD）和骨髓成分的新临床试验来研究这个问题，研究激素因素在红黄骨髓转化中的作用以及结果与阑尾骨密度的关系。在为期一年的试验中，将采用最先进的成像技术，包括外围定量计算机断层扫描（pQCT），磁共振成像（MRI）数据的视觉评估，磁共振松弛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。我们还试图了解在骨密度和骨髓成分中观察到的变化的激素介质，包括肾上腺激素和性腺激素、胰岛素样生长因子、生长激素、饥饿素、脂联素和瘦素。拟议的项目将测试由试点成像数据提出的假设，特别是患有a的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群体中骨骼损失机制的理解，有可能填补关键的知识空白，从而改善对青少年AN患者的护理。从这项研究中获得的知识也可以应用于与骨质流失相关的其他疾病，这些疾病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. PUBLIC HEALTH RELEVANCE: This project seeks to understand the mechanisms behind a promising new therapy, a combined regimen of dehydroepiandrosterone + estrogen replacement therapy, for adolescents with anorexia nervosa, through a randomized controlled trial. The proposal will explore effects of this combined regimen on both bone density of the peripheral skeleton and bone marrow composition, and will examine how hormonal factors mediate skeletal losses and alter marrow composition in this disease. Enhancing understanding of the mechanisms underlying skeletal losses in this young patient population will fill critical knowledge gaps that will potentially improve the care of adolescents with anorexia nervosa.