HAART, Acid Loading, and Bone Metabolism

描述(由申请人提供)：这份R21支持申请书调查了高效抗逆转录病毒疗法(HAART)在HIV感染者中引起的骨丢失。尽管HAART初治的HIV患者与年龄匹配、血清阴性的成年人相比，骨量减少和骨质疏松的发生率增加，但HAART会导致进一步的骨丢失。接受蛋白酶抑制剂治疗的男性骨量减少的患病率是未服用HAART的HIV患者的2.2倍。虽然研究尚未证明艾滋病毒患者的骨折发生率增加(无论是否接受HAART治疗)，但艾滋病毒感染者的相对年轻，以及HAART提供的预期寿命显著延长，引起了人们对未来可能出现的骨折流行的相当大的担忧。 HIV中骨质丢失的病因仍不清楚，但危险因素包括细胞因子激活、性腺功能减退、营养不良、缺乏运动、肠道吸收不良和体重减轻。考虑到酸导致骨丢失的先前报道，腹泻引起的和HAART引起的代谢酸负荷也值得考虑。在人类和动物中，NH4Cl诱导的代谢酸负荷会导致高钙尿和钙负平衡；我们团队最近的研究表明，减少饮食中蛋白质诱导的酸负荷可以减少尿钙和骨吸收。这些观察结果可能是通过引用骨骼缓冲液(由碱性钙盐组成)的概念来解释的，该缓冲液是以骨骼为代价动员起来的，以保护pH动态平衡。在这份R21拨款申请中，我们假设HIV患者的骨丢失部分是由于(A)腹泻导致的碳酸氢盐消耗和(B)HAART造成的乳酸酸血症/乳酸负荷造成的大量代谢酸负荷所致。我们还预测，口服KHCO3缓冲液将减轻酸诱导的骨吸收，并将减少骨丢失。 我们将首先对130名感染艾滋病毒的成年人进行横断面分析，以评估代谢酸负荷和骨骼重塑之间的相关性。然后，我们将90名不同种族的酸血症HIV患者(血清HCO3和Lt；24mEq/L)分成服用和不服用HAART的患者，然后独立随机地将每组患者分别服用安慰剂(2周)，然后服用碳酸氢钾、氯化钾或安慰剂(另外2周)。每周将采集血液和尿液，以评估(A)HIV患者的代谢酸负荷(净肾酸排泄量)的大小，(B)尿钙和骨吸收标志物，以及(C)外源性KHCO3是否减轻钙尿症和骨吸收(与Kc1和安慰剂对照)。最后，我们将检验慢性KHCO3是否延缓了随机服用KHCO3或安慰剂的HIV患者的骨丢失(通过连续骨密度测量评估)。如果成功，这些探索性的“R21”研究可以为一种新的方法提供基础，以改善HAART治疗和HAART初治患者的骨丢失。

DESCRIPTION (provided by applicant): This application for R21 support investigates bone loss caused by highly active antiretroviral therapy (HAART) in HIV-infected individuals. Although prevalences of osteopenia and osteoporosis are increased in HAART-naive HIV patients vs. age-matched, seronegative adults, HAART causes further bone loss. Men receiving protease inhibitors have a 2.2 fold higher prevalence of osteopenia than do HAART-naive HIV patients. Although studies are yet to demonstrate increased fracture rates in HIV patients (HAART-treated or not), the relative youth of HIV-infected individuals, and the dramatically increased life expectancy afforded by HAART, give rise to considerable concern about a possible fracture epidemic in the future. The etiology of bone loss in HIV remains poorly understood but risk factors include cytokine activation, hypogonadism, malnutrition, physical inactivity, intestinal malabsorption and weight loss. Given prior reports of acid-induced bone loss, diarrhea-induced and HAART-induced metabolic acid loading also deserve consideration. In humans and animals, metabolic acid loads induced by NH4C1 result in hypercalciuria and negative calcium balance; recent studies by our group show that reductions in dietary protein-induced acid loads decrease both urine calcium and bone resorption. These observations are potentially explained by invoking the notion of a skeletal buffer (consisting of alkaline salts of calcium) which is mobilized, at the expense of the skeleton, in defense of pH homeostasis. In this R21 grant submission, we hypothesize that bone loss in HIV patients results partly from large metabolic acid loads due to (a) bicarbonate wasting from diarrhea and (b) lactic acidemia / lactic acid burdens from HAART. We also predict that orally administered KHCO3 buffer will mitigate acid-induced bone resorption and will reduce bone loss. We will initially perform a cross-sectional analysis on 130 HIV-infected adults to assess the correlation between metabolic acid loads and skeletal remodelling. We will then stratify 90 ethnically diverse, acidemic HIV patients (serum HCO3 <24 mEq/L) into those taking and not taking HAART, and will then independently randomize each group to take placebo (2 weeks) followed by one of KHCO3, KC1, or placebo (2 additional weeks). Blood and urine will be collected weekly to assess (a) the magnitude of metabolic acid burdens (net renal acid excretion) in HIV patients, (b) urine calcium and bone resorption markers, and (c) whether exogenous KHCO3 mitigates calciuria and bone resorption (vs KC1 and placebo controls). Lastly, we will examine whether chronic KHCO3 retards bone loss (assessed by serial bone densitometry) in HIV patients randomized to KHCO3 or placebo. If successful, these exploratory "R21" studies could provide the basis for a novel approach to ameliorating bone loss in HAART-treated and HAART-naive patients.