HAART, Acid Loading, and Bone Metabolism

描述（由申请人提供）：本R21支持申请调查hiv感染者中高效抗逆转录病毒治疗（HAART）引起的骨质流失。尽管与年龄匹配、血清阴性的成人相比，HAART治疗的早期HIV患者骨质减少和骨质疏松的患病率增加，但HAART治疗会导致进一步的骨质流失。接受蛋白酶抑制剂治疗的男性患骨质减少症的几率比接受haart治疗的HIV患者高2.2倍。尽管研究尚未证明HIV患者骨折率增加（无论是否接受HAART治疗），但HIV感染者的相对年轻，以及HAART所带来的预期寿命的显著延长，引起了人们对未来可能出现的骨折流行的相当大的担忧。

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.