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: 10578646
• 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 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578646
• 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; Proliferating; Quality of life; Radial; Randomized; Recommendation; Recording of previous events; Reporting; Resolution; Risk; Risk Factors; Skeleton; Suggestion; Testing; Testosterone; Veterans; Woman; X-Ray Computed Tomography; 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，T 值低的男性糖耐量受损，而相当多的男性 T 值低 2 型糖尿病 (T2D) 和肥胖症患者的 T 值较低。因此，高达 64% 的男性患有 2 型糖尿病 (T2D) 和肥胖症的 T 值较低也就不足为奇了。 发现 T2D 的 T 值较低。 性腺功能减退症和糖尿病 (DM) 均与骨折风险增加相关。 性腺功能减退症与骨转换增加有关，而骨丢失则与骨量减少有关。 骨密度 (BMD) 正常或较高，但骨折风险却很高。 初步数据显示，与非糖尿病性性腺功能减退男性相比，患有这两种疾病的男性 由于 T 对男性的影响，骨转换受到抑制，体积骨密度 (vBMD) 更高，骨尺寸更小。 骨架主要是通过芳香酶转化为雌二醇（E2）介导的，进一步的可能性 然而，我们的初始数据也令人担忧。 表明对患有这两种疾病的男性进行 T 疗法会导致骨转换和骨标志物增加 与仅患有性腺功能减退症的男性骨转换减少和骨大小减少相比， 表明前者激活了骨重塑并改善了骨几何形状。 还发现有限数量的男性骨强度有增加的趋势（通过有限元分析或 FEA） 与安慰剂相比，低 T 和 T2D 均随机分配至 T。这些结果仅表明但并未证明。 可以肯定的是，T 疗法对患有低 T 和 T2D 的男性都有益。 研究表明，T 疗法将改善患有性腺功能减退症和 因此，该提案的具体目标是： 1) 确定 T 疗法对骨强度的影响： 使用高分辨率外围定量计算机断层扫描通过有限元分析 (µFEA) 进行评估 (HR-pQCT)，2) 确定 T 疗法对骨转换标志物的影响，以及 3) 探索性目标， 评估 T 疗法改善骨质量的机制，因为 T 疗法我们勇敢地面对这一点。 刺激成骨细胞增殖和分化，随后成骨细胞数量的增加将导致 成骨细胞和破骨细胞之间的串扰增强，导致骨重塑的激活 用新骨替代旧骨，从而改善骨质量。在这项研究中，我们将招募 166 名患有此病的男性。 T2D 和性腺功能减退症，并将他们随机分配到 1.62% 睾酮凝胶或安慰剂组，为期 12 个月。 将评估以下主要结果：目标＃1）主要终点（μFEA）的变化，通过 HRpQCT，#2) C-端肽 (CTX) 的变化（骨吸收的标志物），以及目标 #3) 循环的变化 我们预计胫骨和桡骨处的 µFEA 会增加，表明有所改善。 骨强度，增加 CTX 和循环成骨细胞祖细胞的增加，我们预计会进一步增加。 其他骨转换标志物（骨形成和骨吸收）和破骨细胞前体的增加 考虑到骨转换受到抑制，患有性腺功能减退症和 T2D 的男性被随机分配至 T 组和安慰剂组。 在低 T 和 T2D 男性的基线时，我们发现 T 的有益作用是其激活 骨重塑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，不仅可以提高生活质量，而且可以提高生活质量。 鉴于葡萄糖代谢之间的关系，还可以改善患有 T2D 的性腺功能减退男性的骨质量。 和睾酮的产生，以及越来越多的男性患者被诊断患有性腺功能减退症 和 T2D，这项研究不仅将使大量患有这两种疾病的男性退伍军人受益， 也包括一般男性。