LOW-DOSE DOXYCYCLINE EFFECTS ON OSTEOPENIC BONE LOSS

骨质疏松症是美国的一个主要公共卫生问题。骨质疏松症与全身骨密度(BMD)降低、椎骨、手腕和髋部骨折的发生率增加以及牙齿脱落有关。雌激素缺乏是绝经后妇女骨质疏松症的主要致病因素。在NIH支持的纵向临床试验中，我们发现绝经后、有牙周炎病史的E2缺乏女性与E2充足的女性相比，以及骨质疏松/骨量减少的女性与腰椎BMD正常的女性相比，牙槽骨顶高度和密度的损失加速。由于雌激素缺乏、骨质疏松症和口腔骨丢失之间的这种关系，有必要测试减少绝经后妇女牙槽骨丢失的治疗策略。Golub博士(Co-Pi)最近的一项发现表明，四环素类药物，包括低剂量的强力霉素(LDD)，由于其非抗菌特性，可以：a)抑制宿主来源的、组织破坏性的基质金属蛋白酶(MMPs)，包括胶原酶，参与骨吸收；以及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患有牙周炎的女性的首选药物。因此，本研究的目的是探讨LDD对绝经后骨质疏松症和牙周炎的治疗潜力，这些疾病的特征是过度的胶原分解和骨吸收。这项建议的假设是，LDD(与安慰剂相比)可以改善患有牙周炎的E2缺乏、骨量减少的绝经后妇女的牙周炎的放射学、临床和生化参数。因此，这项建议的具体目的是利用一项为期两年的双盲安慰剂对照试验，对E2缺乏的妇女进行研究，以确定LDD对以下各项的影响：a)牙槽骨冠和顶下密度(通过计算机辅助密度图像分析测量)和线性牙槽骨顶高度；b)临床牙周测量，如探诊深度和相对临床附着水平；c)牙龈沟液中骨转换的标志物(如C-末端端肽吡啶交联物[ICTP，一种胶原分解片段])。作为第二个目标，本研究将通过双能X线骨密度仪(DEXA)评估LDD对腰椎和股骨颈全身骨密度的影响，以及LDD对血清和尿骨转换生化标志物的影响。

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.