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: 8664813
• 负责人: CATHERINE M. GORDON
• 金额: $ 29.32万
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8664813
• 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）：具有神经性厌食症（AN）的青春期女孩表现出荷尔蒙异常，这些异常会易于骨化，应计和建模的改变，最终会导致不可逆的骨骼缺陷。目前的研究人员对这种疾病的激素改变如何导致骨髓组成和骨骼损失的变化具有长期的兴趣。拟议的项目建立在最近的双盲，安慰剂对照试验的脱氢表甲酮（DHEA）和雌激素替代疗法（ERT）的基础上，该试验是An的青少年。目前的研究人员表明，这种合成代谢 +抗吸收方案减轻了轴向骨骼的骨骼损失，这是通过双能X射线吸收仪（DXA）测量的脊柱和整个身体的测量所证明的。这种治疗方案是否还会影响阑尾骨骼感兴趣，这是年轻的青少年肢体肢体比轴向骨骼更常见的临床重要性问题。来自当前组的初步数据还表明，具有疾病进展并增加骨髓脂肪的青少年从红色向黄色（脂肪）骨髓转移。这些年轻女性自相矛盾的是皮下脂肪，在骨髓内增加了脂肪，对骨骼形成，青春期骨骼积聚以及最终终生骨骼健康的长期不利影响。需要进一步的研究来确定青少年中红色向黄骨髓的转化是否反映了成年人的发现，表明相关的骨密度降低和骨折风险增加。该建议旨在通过一项与DHEA+ERT联合治疗在骨矿物质密度（BMD）和骨髓组成上的新型临床试验来研究这个问题，研究了激素因子在红骨髓转化为黄骨髓中的转化以及发现与附录BMD的关系中的作用。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松弛计和磁共振光谱，以分别测量骨矿物质密度和评估骨骨髓组成。我们还寻求了解骨密度和骨髓组成中观察到的变化的激素介体，包括肾上腺和性腺类固醇，胰岛素样生长因子，生长激素和生长素蛋白，脂联素和瘦素。拟议的项目将测试通过试验成像数据提出的假设，特别是在具有影响间充质干细胞的女孩的激素异常是否优先区分成骨细胞的脂肪细胞。增强对这个年轻患者群体骨骼损失的机制的理解有可能填补关键的知识差距，从而改善AN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频谱中的其他疾病，并涉及骨髓组成的改变。