Testosterone Therapy and Bone Quality in Men with Diabetes and Hypogonadism

糖尿病和性腺功能减退症男性的睾酮治疗和骨质量

• 批准号: 10217053
• 负责人: REINA C VILLAREAL
• 金额: --
• 依托单位: MICHAEL E DEBAKEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10217053
• 关键词: Age; Androgens; Apoptosis; Area; Aromatase; Bone Density; Bone Diseases; Bone Resorption; Bone remodeling; C-telopeptide; Data; Diabetes Mellitus; Diagnosis; Elderly man; Enrollment; Enzymes; Estradiol; Finite Element Analysis; Fracture; Gel; Health; Hip Fractures; Hip region structure; Hypogonadism; Intervention; Measures; Mediating; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Osteoblasts; Osteocalcin; Osteoclasts; Osteocytes; Osteogenesis; Osteoporosis; Outcome; Patients; Peripheral; Placebos; Population; Production; Quality of life; Radial; Randomized; Recording of previous events; Reporting; Resolution; Risk; Risk Factors; Skeleton; Suggestion; Testing; Testosterone; Veterans; Woman; X-Ray Computed Tomography; base; bone; bone geometry; bone health; bone loss; bone mass; bone metabolism; bone quality; bone strength; bone turnover; diabetic; fracture risk; fragility fracture; glucose metabolism; high risk; impaired glucose tolerance; improved; male; male health; men; non-diabetic; osteoblast differentiation; primary endpoint; progenitor; randomized placebo controlled study; response; skeletal; standard care; tibia; trend; young man

An existing mutual influence between testosterone (T) and glucose metabolism has been suggested by studies showing that men with low T have impaired glucose tolerance, while a significant number of men with type 2 diabetes mellitus (T2D) and obesity have low T. Thus, it is not surprising that as much as 64% of men with T2D were found to have low T. Hypogonadism and diabetes mellitus (DM) each is associated with increased risk for fractures. While hypogonadism is associated with increased bone turnover and bone loss. DM is associated with low bone turnover and normal or high bone mineral density (BMD) but paradoxically a high risk for fractures. Our preliminary data showed that compared to non-diabetic hypogonadal men, men with both conditions have suppressed bone turnover, higher volumetric BMD (vBMD) and smaller bone size. As the effect of T on the male skeleton is mainly mediated by its conversion to estradiol (E2) by the enzyme aromatase, the possibility of further suppression of bone turnover with T therapy in these patients would be a concern. However, our initial data also showed that T therapy in men with both conditions resulted in increased in markers of bone turnover and bone size compared to the decrease in bone turnover and decrease in bone size in men with hypogonadism only, suggesting activation in bone remodeling and improvement in bone geometry in the former. Furthermore, we also found a trend for increase in bone strength (by finite element analysis or FEA) in the limited number of men with both low T and T2D randomized to T compared to placebo. These findings only suggest but do not prove with certainty that T therapy would be beneficial to men with both low T and T2D. The central hypothesis of this study is that T therapy will result in improvement in bone quality in patients who have both hypogonadism and T2D. Thus, the specific aims of this proposal are: 1) to determine the effect of T therapy on bone strength as assessed by finite element analysis (µFEA) using high-resolution peripheral quantitative computer tomography (HR-pQCT), 2) to determine the effect of T therapy on markers of bone turnover, and 3) an exploratory aim, to evaluate the mechanism for improvement in bone quality from T therapy. We hypothesize that because T stimulates osteoblastic proliferation and differentiation, the ensuing increase in osteoblast number will lead to an enhanced cross-talk between osteoblast and osteoclast resulting in activation of bone remodeling and replacement of old with new bone, hence, improvement in bone quality. In this study we will enroll 166 men with T2D and hypogonadism and randomize them to either testosterone gel 1.62% or placebo for 12 months. The following main outcomes will be evaluated: aim# 1) change in the primary endpoint which is µFEA, by HRpQCT, #2) changes in C-telopeptide (CTX) a marker of bone resorption, and aim #3) changes in circulating osteoblast progenitor (COP). We anticipate an increase in µFEA at the tibia and radius suggesting improvement in bone strength, increase CTX and increase in circulating osteoblast progenitors. We further anticipate an increase in other markers of bone turnover (both bone formation and resorption) and osteoclast precursors in men with hypogonadism and T2D randomized to T compared to placebo. Given the suppressed bone turnover at baseline in men with low T and T2D, we hypothesize that the beneficial effect of T is its effect in activating bone remodeling ultimately resulting in improvement in bone quality. Results from this study will provide information on the utility of T not only in improving quality of life but also in improving bone quality in hypogonadal men with T2D. Given the relationship between glucose metabolism and testosterone production, and the increasing number of male patients diagnosed with both hypogonadism and T2D, this study will benefit not only the significant number of male veterans who have both conditions but also men in general.

睾酮（T）和葡萄糖代谢之间存在相互影响， 研究表明，低T的男性葡萄糖耐量受损，而相当数量的男性 2型糖尿病（T2 D）和肥胖者T.因此，这并不奇怪，多达64%的男性 T2 D患者T. 性腺功能减退症和糖尿病（DM）均与骨折风险增加相关。而 性腺机能减退与骨转换增加和骨丢失有关。糖尿病与低骨量有关 骨转换和正常或高骨矿物质密度（BMD），但矛盾的是骨折的高风险。我们 初步数据显示，与非糖尿病性腺功能减退的男性相比， 抑制骨转换，更高的体积BMD（vBMD）和更小的骨大小。T对男性的影响 骨架主要是通过芳香酶将其转化为雌二醇（E2）介导的，进一步 T治疗对这些患者骨转换的抑制是一个值得关注的问题。然而，我们的初步数据也 研究表明，T治疗两种疾病的男性导致骨转换和骨代谢标志物的增加， 与仅有性腺功能减退症的男性中骨转换的减少和骨大小的减少相比， 表明前者的骨重建活化和骨几何形状的改善。而且我们 还发现在有限数量的男性中，骨强度（通过有限元分析或FEA）有增加的趋势 与安慰剂相比，低T和T2 D均随机分配至T组。这些发现只能说明，不能证明 可以肯定的是，T疗法对低T和T2 D的男性都是有益的。这个问题的核心假设是 一项研究表明，试验疗法将改善性腺功能减退症患者骨质量， 2型糖尿病因此，本建议的具体目的是：1）确定T疗法对骨强度的影响， 使用高分辨率外周定量计算机断层扫描进行有限元分析（µFEA）评估 （HR-pQCT），2）确定T治疗对骨转换标志物的影响，3）探索性目的， 评价T疗法改善骨质量的机制。我们假设因为T 刺激成骨细胞增殖和分化，随之而来的成骨细胞数量的增加将导致 增强成骨细胞和破骨细胞之间的相互作用，导致骨重建的激活， 用新骨替换旧骨，从而改善骨质量。在这项研究中，我们将招募166名男性， T2 D和性腺功能减退症，并将他们随机分配至1.62%睾酮凝胶或安慰剂组，持续12个月。 将评价以下主要结局：目标1）主要终点（µFEA）的变化，通过 HRpQCT，#2）C-端肽（CTX）（骨吸收的标志物）的变化，以及目标#3）循环中 成骨细胞祖细胞（COP）。我们预计胫骨和桡骨的µFEA会增加，这表明改善 在骨强度方面，增加CTX和增加循环成骨祖细胞。我们进一步预计， 骨转换（骨形成和吸收）和破骨细胞前体的其他标志物增加， 与安慰剂相比，性腺功能减退和T2 D的男性被随机分配到T组。考虑到骨转换受到抑制 在低T和T2 D的男性中，我们假设T的有益作用是其激活T细胞的作用。 骨重建最终导致骨质量的改善。 这项研究的结果将提供有关T的效用的信息，不仅在改善生活质量， 也可以改善患有T2 D的性腺功能减退男性的骨质量。考虑到葡萄糖代谢和 和睾丸激素的产生，以及越来越多的男性患者被诊断患有性腺功能减退症 和T2 D，这项研究不仅将使大量同时患有这两种疾病的男性退伍军人受益， 也是一般的男人。