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

肾上腺和性腺激素对骨髓和四肢 BMD 的影响

• 批准号: 8509337
• 负责人: CATHERINE M. GORDON
• 金额: $ 29.6万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8509337
• 关键词: Adipocytes; Adolescence; Adolescent; Adrenal Glands; Adrenal hormone preparation; Adult; Affect; Age; Anorexia Nervosa; Body Composition; Bone Density; Bone Marrow; Bone Resorption; C-telopeptide; Caring; Clinical; Clinical Trials; Data; Dehydroepiandrosterone Sulfate; Development; Dimensions; Disease; Disease Progression; Elderly; Estradiol; Estrogen Replacement Therapy; Exhibits; Fatty acid glycerol esters; Female Adolescents; Fracture; Functional disorder; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Health; Height; Hematopoietic; Hormonal; Hydrocortisone; Image; Imaging Techniques; Insulin-Like Growth Factor I; Knowledge; Lead; Leptin; Life; Limb structure; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Maintenance; Marrow; Measurement; Measures; Mediating; Mediator of activation protein; Mesenchymal Stem Cells; Modeling; Osteoblasts; Osteogenesis; Osteoporosis; Participant; Patient Care; Patients; Peripheral; Placebos; Radial; Randomized; Randomized Controlled Trials; Red Marrow; Regimen; Research; Research Personnel; Risk; Role; Skeleton; Somatomedins; Somatotropin; Testing; Testosterone; Therapeutic; Vertebral column; Visual; Weight; X-Ray Computed Tomography; Yellow Marrow; adiponectin; adverse outcome; bone; bone health; bone loss; bone mass; bone strength; bone turnover; clinical care; critical period; dehydroepiandrosterone; double-blind placebo controlled trial; emerging adult; ghrelin; girls; improved; interest; novel; patient population; prevent; response; restoration; skeletal; subcutaneous; tibia; young woman

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.

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荷尔蒙异常，容易导致骨转换、累积​​和建模发生变化，最终导致不可逆转的骨骼缺陷。目前的研究人员长期以来一直对这种疾病中的激素变化如何导致骨髓成分变化和骨骼损失感兴趣。拟议的项目建立在最近对患有 AN 的青少年进行的脱氢表雄酮 (DHEA) 和雌激素替代疗法 (ERT) 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+抗骨吸收相结合的方案可以减轻中轴骨骼的骨质流失，脊柱和全身的双能 X 射线吸收测定法 (DXA) 测量结果证明了这一点。人们对这种治疗方案是否也会影响附肢骨骼感兴趣，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中轴骨骼骨折更常见。当前研究组的初步数据还表明，患有 AN 的青少年随着疾病的进展，骨髓会从红色变为黄色（脂肪）骨髓，并且骨髓脂肪增加。这些年轻女性虽然皮下脂肪已被消耗殆尽，但骨髓内的脂肪却增加了，这可能对骨形成、青春期骨增生以及最终终生骨骼健康产生潜在的不利长期影响。需要进一步的研究来确定青少年中红骨髓向黄骨髓的转变是否反映了成年人的研究结果，表明相关的骨密度降低和骨折风险增加。本提案旨在通过一项新的临床试验来研究这个问题，即 DHEA+ERT 联合治疗对骨矿物质密度 (BMD) 和骨髓成分的影响，检查激素因子在红骨髓转化为黄骨髓中的作用以及研究结果与阑尾骨密度。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 松弛测量和磁共振波谱来测量骨矿物质密度并分别评估骨髓成分。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、生长素释放肽、脂联素和瘦素。拟议的项目将测试试点成像数据提出的假设，特别是患有 AN 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。加强对年轻患者群体骨骼损失机制的了解有可能填补关键的知识空白，从而改善患有 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与骨质流失相关并涉及骨髓成分改变的跨年龄段的其他疾病。