LOW-DOSE DOXYCYCLINE EFFECTS ON OSTEOPENIC BONE LOSS

低剂量多西环素对骨质疏松性骨丢失的影响

• 批准号: 6516519
• 负责人: JEFFREY Bruce PAYNE
• 金额: $ 50.69万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6516519
• 关键词: bone density; bone metabolism; clinical trials; female; human subject; human therapy evaluation; osteoporosis; periodontitis; photon absorptiometry; postmenopause; skeletal disorder chemotherapy; tetracyclines

Osteoporosis represents a major public health problem in the United States. Osteoporosis is associated with decreased systemic bone mineral density (BMD), an increased incidence of vertebrae, wrist and hip fractures, and tooth loss. The dominant pathogenic factor for osteoporosis in postmenopausal women is estrogen (E2) deficiency. In longitudinal NIH-supported clinical trials, we have shown accelerated alveolar crestal bone height and density loss in postmenopausal, E2- deficient women with a periodontitis history relative to E2-sufficient women, and in osteoporotic/osteopenic women versus women with normal lumbar spine BMD. Because of this relationship between E2- deficiency, osteoporosis and oral bone loss, it is desirable to test therapeutic strategies to mitigate alveolar bone loss in postmenopausal women. A recent discovery by Dr. Golub (Co-PI) showed that tetracyclines, including low-dose doxycycline (LDD), by virtue of a non- antimicrobial property, can: a) inhibit host-derived, tissue-destructive matrix metalloproteinases (MMPs), including collagenases, involved in bone resorption; and b) stimulate osteoblast activity and bone formation. These biological properties make tetracyclines compelling candidates for use in postmenopausal women with periodontitis. Therefore, the objective of this research is to investigate the therapeutic potential of LDD in postmenopausal osteopenia and periodontitis, diseases characterized by excess collagen breakdown and bone resorption. The hypothesis of this proposal is that LDD (compared to placebo) can improve radiographic, clinical and biochemical parameters of periodontitis in E2-deficient, osteopenic postmenopausal women with periodontitis. Accordingly, the specific aim of this proposal is to use a 2- year double-blind, placebo-controlled trial of E2-deficient women to determine the effect of LDD on: a) alveolar bone crestal and subcrestal density (measured by computer-assisted densitometric image analysis) and linear alveolar crestal bone height; b) clinical periodontal measurements such as probing depth and relative clinical attachment level; and c) gingival crevicular fluid markers of bone turnover (e.g., C- terminal telopeptide pyridinoline crosslinks [ICTP, a collagen breakdown fragment]). As a secondary aim, the study will evaluate the effect of LDD on systemic bone mineral density at the lumbar spine and femoral neck by dual-energy x-ray absorptiometry (DEXA) and the effect of LDD on serum and urine biochemical markers of bone turnover.

骨质疏松症在美国是一个主要的公共卫生问题。骨质疏松症与全身骨矿物质密度（BMD）降低、椎骨、腕关节和髋部骨折发生率增加以及牙齿脱落有关。绝经后妇女骨质疏松症的主要致病因素是雌激素（E2）缺乏。在NIH支持的纵向临床试验中，我们发现绝经后、E2缺乏且有牙周炎病史的女性的牙槽嵴骨高度和密度损失比E2充足的女性快，而骨质疏松/骨质减少的女性的牙槽嵴骨高度和密度损失比腰椎BMD正常的女性快。由于E2缺乏、骨质疏松症和口腔骨丢失之间的这种关系，需要测试治疗策略以减轻绝经后妇女的牙槽骨丢失。Golu B博士（Co-PI）最近的一项发现表明，四环素类药物，包括低剂量多西环素（LDD），由于其非抗微生物特性，可以：a）抑制宿主来源的组织破坏性基质金属蛋白酶（MMP），包括参与骨吸收的胶原酶;和B）刺激成骨细胞活性和骨形成。这些生物学特性使四环素类药物成为绝经后妇女牙周炎的有力候选药物。因此，本研究的目的是探讨LDD在绝经后骨质减少和牙周炎中的治疗潜力，这些疾病的特征是过度胶原分解和骨吸收。该建议的假设是，LDD（与安慰剂相比）可以改善E2缺乏、骨质减少的绝经后牙周炎妇女的牙周炎的放射学、临床和生化参数。因此，本提案的具体目的是使用E2缺乏女性的2年双盲、安慰剂对照试验来确定LDD对以下方面的影响：a）牙槽骨嵴和嵴下密度（通过计算机辅助光密度图像分析测量）和线性牙槽嵴骨高度; B）临床牙周测量，例如探测深度和相对临床附着水平;和c）骨转换的龈沟液标记物（例如，C-末端肽吡啶啉交联[ICTP，胶原分解片段]）。作为次要目的，本研究将通过双能X线吸收测定法（DEXA）评价LDD对腰椎和股骨颈全身骨密度的影响，以及LDD对骨转换的血清和尿液生化标志物的影响。