Osteoporosis in HIV-infected Postmenopausal Women

描述(由申请者提供)：美国艾滋病毒感染的发病率在妇女中增长最快，特别是非洲裔美国人和西班牙裔妇女。此外，向疾控中心报告的艾滋病病例中，约有11%是50岁以上的女性。有效的抗逆转录病毒疗法(ART)的引入，特别是艾滋病毒蛋白酶抑制剂的引入，延长了艾滋病毒感染患者的生存时间。然而，它们的使用伴随着几种代谢并发症的出现，其中包括低骨量。尽管绝经后妇女骨质丢失和骨折的风险很高，但已发表的关于艾滋病毒/艾滋病患者骨量和矿物质代谢的研究并未包括老年妇女。我们观察到，超过40%的少数民族绝经后HIV+妇女患有骨质疏松症。因此，未来的研究必须专门针对这一群体。与HIV感染相关的过度骨丢失的发病机制很复杂。低体重、慢性病、营养不良、吸收不良、钙和维生素D缺乏，尤其是在绝经后女性，可能是导致雌激素缺乏的原因。骨丢失也可能是HIV感染和ART与破骨细胞、成骨细胞和骨微环境中其他元素之间的病理生理相互作用造成的。在这项建议中，我们将：1.建立骨质疏松症的患病率和骨丢失率；2.阐明骨丢失的发病机制；3.描述ART对HIV阳性的非裔美国人和西班牙裔绝经后妇女骨结构和骨转换的影响。我们将使用标准和新的方法：双能X射线吸收测量法，血清骨转换标志物和细胞因子的测量，利用外周血和骨髓单个核细胞进行破骨细胞生成的体外分析，定量骨组织形态计量学和显微计算机断层扫描，在ART开始前后获得的髂骨活组织检查。我们将证明，在HIV+中，骨质疏松比正常绝经后女性更普遍，骨丢失速度更快，RANK/RANKL/OPG破骨细胞信号系统的变化是骨质疏松症发病机制的核心，ART，特别是包括利托那韦在内的治疗方案，在导致骨丢失方面起着重要作用。这些研究的结果将对管理越来越多的患有艾滋病毒/艾滋病的绝经后妇女具有重要的治疗意义。

DESCRIPTION (provided by applicant): The incidence of HIV infection in the United States iincreasing fastest in women, particularly those of African American and Hispanic descent. Moreover, approximately 11% of AIDS cases reported to the CDC are women over the age of 50. The introduction of potent antiretroviral therapy (ART), particularly HIV protease inhibitors, has extended survival of HIV-infected patients. However, their use has been accompanied by the emergence of several metabolic complications, among them low bone mass. Although postmenopausal women are at high risk for bone loss and fractures, published studies of bone mass and mineral metabolism in HIV/AIDS patients have not included older women. We have observed that over 40% of minority postmenopausal HIV+ women have osteoporosis. It is therefore essential that future research specifically target this group. The pathogenesis of excess bone loss associated with HIV infection is complex. Low body weight, chronic illness, malnutrition, malabsorption, calcium and vitamin D deficiency, and especially in postmenopausal women, estrogen deficiency, may contribute. Bone loss may also result from pathophysiologic interactions between HIV infection and ART and osteoclasts, osteoblasts and other elements within the bone microenvironment. In this proposal, we will: 1. Establish the prevalence of osteoporosis and rates of bone loss; 2. Elucidate the pathogenesis of bone loss; and 3. Delineate the effects of ART on bone structure and turnover in HIV+ African American and Hispanic postmenopausal women. We will use standard and novel methods: dual energy X-ray absorptiometry, serum measurements of bone turnover markers and cytokines, in vitro assays of osteoclastogenesis utilizing peripheral blood mononuclear cells and marrow mononuclear cells, quantitative bone histomorphometry and micro-computed tomography of iliac crest bone biopsies obtained before and after initiation of ART. We will demonstrate that osteoporosis is more prevalent and rates of bone loss more rapid in HIV+ than normal postmenopausal women, that alterations in the RANK/RANKL/OPG osteoclast signaling system are central to the pathogenesis of the osteoporosis, and that ART, particularly regimens that include ritonavir, is important in causing the bone loss. The results of these studies will have important therapeutic implications for the management of the growing number of postmenopausal women with HIV/AIDS.