Testosterone Therapy and Bone Quality in Men with Diabetes and Hypogonadism

研究表明，睾酮(T)和葡萄糖代谢之间存在着相互影响 研究表明，睾酮过低的男性糖耐量受损，而有相当数量的男性 2型糖尿病(T2D)和肥胖症患者的总睾酮水平较低，因此，也就难怪有高达%的男性患有 T2D的T值较低。 性腺功能减退症和糖尿病(DM)都与骨折风险增加有关。而当 性腺功能减退与骨转换增加和骨丢失有关。糖尿病与骨质疏松有关 周转率和正常或高骨密度(BMD)，但矛盾的是，骨折的风险很高。我们的 初步数据显示，与非糖尿病性腺功能减退的男性相比，患有这两种疾病的男性 抑制骨转换，较高的体积骨密度(VBMD)和较小的骨大小。因为T对雄性的影响 骨骼主要是通过芳香酶转化为雌二醇(E_2)来调节的，进一步 在这些患者中，使用T疗法抑制骨转换将是一个令人担忧的问题。然而，我们的初始数据也 结果显示，在患有这两种疾病的男性中，T疗法导致骨转换和骨标记物增加 与仅有性腺功能减退男性的骨转换减少和骨大小减少相比， 提示前者在骨重塑和骨几何结构改善方面具有激活作用。此外，我们 在有限数量的男性中，也发现了骨骼强度(通过有限元分析或FEA)增加的趋势 与安慰剂相比，低T和T2D都被随机分为T组。这些发现只是暗示，但并不能证明 可以肯定的是，T疗法对低T和T2D的男性都是有益的。这一点的中心假设是 研究表明，T疗法将改善性腺功能减退和骨质疏松症患者的骨质量。 T2D。因此，这项建议的具体目标是：1)确定T疗法对骨强度的影响，如 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，以及3)探索性目的，以 评价T疗法改善骨质量的机制。我们假设是因为T 刺激成骨细胞的增殖和分化，随之而来的成骨细胞数量的增加将导致 成骨细胞和破骨细胞之间的相互作用增强，从而激活骨重建和 以新骨替代旧骨，从而提高骨质量。在这项研究中，我们将招募166名男性 T2D和性腺功能减退症，并随机给予1.62%睾丸酮凝胶或安慰剂治疗12个月。 将评估以下主要结果：目标1)主要终点的变化，即通过 HRpQCT，#2)骨吸收标志物C-端肽(CTX)的变化，以及目的#3)循环的变化 成骨细胞前体细胞(COP)。我们预计胫骨和桡骨的微有限元分析将有所增加，这表明情况有所改善 在骨强度方面，增加CTX和增加循环中的成骨细胞前体细胞。我们进一步预计， 骨转换的其他标志(骨形成和骨吸收)和破骨细胞前体的增加 性腺功能减退和T2D的男性被随机分成T组和安慰剂组。考虑到骨骼转换受到抑制 在低T和T2D男性的基线上，我们假设T的有益作用是它在激活 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方面，而且 在改善患有T2D的性腺功能减退男性的骨质量方面也是如此。考虑到葡萄糖代谢之间的关系 和睾丸素的产生，以及越来越多的男性患者被诊断为性腺功能减退 和T2D，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，而且 一般来说，男性也是如此。

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.