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，容易导致骨转换、骨积累和骨造型改变，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的荷尔蒙变化如何导致骨髓成分变化和骨骼丢失有着长期的兴趣。拟议的项目建立在最近一项脱氢表雄酮(DHEA)和雌激素替代疗法(ERT)在患有AN的青少年中的双盲、安慰剂对照试验的基础上。目前的研究人员已经表明，这种合成代谢+抗吸收联合方案减轻了脊柱和全身的双能X射线吸收测量(DXA)所证明的中轴骨的骨丢失。人们感兴趣的是，这种治疗方案是否也会影响附件骨骼，这是一个具有高度临床重要性的问题，因为青少年四肢骨折比轴骨骨折更常见。来自当前小组的初步数据还显示，随着疾病的进展，青少年的骨髓从红色转变为黄色(脂肪)，并发展出更多的骨髓脂肪。这些年轻女性自相矛盾地消耗了皮下脂肪，却增加了骨髓中的脂肪，对骨形成、青春期骨积累以及最终终生骨骼健康产生了潜在的长期不利影响。需要进一步的研究来确定青少年的红骨髓到黄骨髓的转换是否反映了成年人的发现，即骨密度降低和骨折风险增加。这项建议试图通过一项新的临床试验来探讨这一问题，该试验通过DHEA+ERT联合治疗对骨密度(BMD)和骨髓成分的影响，检查激素因素在红骨髓向黄骨髓转化中的作用，以及所发现的结果与附件骨密度的关系。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、MR松弛测量法和磁共振光谱学，分别用于测量骨密度和评估骨髓成分。我们还试图了解骨密度和骨髓成分变化的激素介质，包括肾上腺和性腺类固醇、胰岛素样生长因子、生长激素、生长激素以及生长激素、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，特别是患有骨髓间充质干细胞的女孩的激素异常是否会影响骨髓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潜在的骨骼丢失机制的了解，有可能填补关键的知识空白，从而改善对患有AN的青少年的护理。从这项研究中获得的知识也可能适用于年龄范围内的其他疾病，这些疾病与骨丢失有关，并涉及骨髓成分的变化。

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.