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: 6893841
• 负责人: JEFFREY Bruce PAYNE
• 金额: $ 53.14万
• 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/6893841
• 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.

骨质疏松症是美国一个主要的公共健康问题。骨质疏松症与全身骨密度（BMD）降低、椎骨、手腕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。在美国国立卫生研究院支持的纵向临床试验中，我们发现绝经后、有牙周炎史的E2缺乏的女性与E2充足的女性相比，以及骨质疏松/骨质减少的女性与腰椎骨密度正常的女性相比，牙槽嵴骨高度和密度的下降速度加快。由于E2-缺乏、骨质疏松和口腔骨质流失之间存在这种关系，因此有必要测试缓解绝经后妇女牙槽骨流失的治疗策略。Golub博士（Co-PI）最近的一项发现表明，四环素，包括低剂量强力霉素（LDD），由于其非抗菌特性，可以：A)抑制宿主来源的组织破坏基质金属蛋白酶（MMPs），包括参与骨吸收的胶原酶；b)刺激成骨细胞活动和骨形成。这些生物学特性使四环素成为绝经后牙周炎妇女的有力候选药物。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，这些疾病的特征是胶原蛋白过量分解和骨吸收。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牙周炎的放射学、临床和生化参数。因此，本建议的具体目的是对e2缺乏的女性进行为期2年的双盲、安慰剂对照试验，以确定LDD对以下方面的影响：a)牙槽骨嵴和牙槽骨下密度（通过计算机辅助密度图像分析测量）和牙槽骨嵴线性高度；B)临床牙周测量，如探诊深度和相对临床附着水平；c)龈沟液骨转换标志物（例如，c -末端末端肽吡啶啉交联[ICTP，胶原分解片段]）。作为次要目的，本研究将通过双能x线吸收仪（DEXA）评估LDD对腰椎和股骨颈全身骨密度的影响，以及LDD对血清和尿液骨转换生化指标的影响。