HAART, Acid Loading, and Bone Metabolism

描述（由申请人提供）：本R21支持申请研究了HIV感染者接受高效抗逆转录病毒治疗（HAART）引起的骨丢失。尽管与年龄匹配的血清阴性成人相比，HAART初治HIV患者的骨质减少和骨质疏松症患病率增加，但HAART会导致进一步的骨质流失。接受蛋白酶抑制剂治疗的男性骨质减少的患病率是HAART初治HIV患者的2.2倍。尽管研究尚未证明HIV患者（HAART治疗或未治疗）的骨折率增加，但HIV感染者的相对年轻以及HAART提供的预期寿命显著增加，引起了对未来可能发生骨折流行病的相当大的担忧。 艾滋病毒引起骨丢失的病因仍然知之甚少，但风险因素包括细胞因子激活、性腺功能减退、营养不良、缺乏体力活动、肠道吸收不良和体重减轻。考虑到酸诱导骨丢失的既往报告，也值得考虑黄芪诱导和HAART诱导的代谢性酸负荷。在人类和动物中，NH 4C 1诱导的代谢性酸负荷导致高钙尿和负钙平衡;我们小组最近的研究表明，饮食蛋白诱导的酸负荷减少会降低尿钙和骨吸收。这些观察结果可能通过调用骨骼缓冲液（由钙的碱性盐组成）的概念来解释，该缓冲液以骨骼为代价被动员，以防御pH稳态。在本R21授权申请中，我们假设HIV患者的骨丢失部分是由于（a）腹泻引起的碳酸氢盐消耗和（B）HAART引起的乳酸血症/乳酸负荷导致的大量代谢酸负荷。我们还预测，口服KHCO 3缓冲液将减轻酸诱导的骨吸收，并减少骨丢失。 我们将首先对130名HIV感染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名种族多样的酸血症HIV患者（血清HCO 3 <24 mEq/L）分层为接受和不接受HAART的患者，然后将每组独立随机接受安慰剂（2周），随后接受KHCO 3，KCl或安慰剂（另外2周）。每周采集血液和尿液，以评估（a）HIV患者代谢酸负荷（净肾脏酸排泄）的程度，（B）尿钙和骨吸收标志物，以及（c）外源性KHCO 3是否减轻钙尿和骨吸收（与KCl和安慰剂对照相比）。最后，我们将研究慢性KHCO 3是否延缓随机接受KHCO 3或安慰剂的HIV患者的骨丢失（通过连续骨密度测定法评估）。如果成功的话，这些探索性的“R21”研究可以为改善HAART治疗和HAART初治患者的骨丢失提供新的方法。

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.