Low-Dose Doxycycline Effects on Osteopenic Bone Loss

描述(由申请人提供)：本申请是R01DE12872-05的竞争性延续，标题为“小剂量多西环素对骨质疏松性骨丢失的影响”。在一项为期两年的随机临床试验中，128名患有慢性牙周炎的绝经后骨质疏松症(PM)妇女随机接受亚抗菌剂量(低剂量；LDD)多西环素或安慰剂对照。这项试验正在进行中，正在检验LDD将减少牙周组织和骨骼组织(股骨颈和腰椎)骨丢失的假设。除了骨质丢失，心血管疾病(CVD)是更年期的另一种临床后遗症，最近的证据表明全身炎症在CVD的发病机制中起着重要作用。重要的是，我们最近证明了LDD降低了急性冠脉综合征患者全身炎症的生物标志物。NIDCR和数据与安全监测委员会在我们2004年3月的会议之后批准了一份附录同意书；这些签署的同意书允许我们检查LDD反应的血清炎性生物标记物。然而，没有资金可用于进行这些额外的化验；因此，我们正在申请继续进行这种竞争性的检测。目前正在我们的临床试验中收集基线的血清，一年和两年的访问和骨吸收/形成的血清生物标记物正在测量中。这项应用的假设是，LDD可以减少PM女性全身炎症的生物标志物和与心血管疾病风险相关的MMPs。这一假设将通过追求以下具体目标来验证：确定在患有慢性牙周炎的PM骨质疏松女性中，LDD治疗是否有益地改变了已经在我们目前的临床试验中登记的患者的全身炎症和心血管疾病的血清生物标志物(C-反应蛋白、IL-6、髓过氧化物酶、基质金属蛋白酶-2和基质金属蛋白酶-9)。不需要为这项研究收集额外的血清，这将使我们能够扩大我们目前资助的R01的意义。这项工作意义重大，因为如果LDD最终被发现可以降低更年期两大并发症(即骨质疏松症和心血管疾病发病率增加)的严重程度，LDD可以为PM妇女提供激素替代疗法的替代方案。这项工作与公众健康相关，因为LDD可能提供一种安全有效的治疗方法，以减少与更年期相关的并发症。骨丢失和心血管疾病发病率的减少将代表着公共健康的显著改善。

DESCRIPTION (provided by applicant): This application is a competing continuation of R01DE12872-05 entitled, "Low-Dose Doxycycline Effects on Osteopenic Bone Loss." For the currently-funded grant, 128 postmenopausal (PM) osteopenic women with chronic periodontitis were randomized to receive either subantimicrobial dose (low-dose; LDD) doxycycline or a placebo control in a two-year randomized clinical trial. This trial is ongoing and is testing the hypothesis that LDD will reduce bone loss in the periodontium and skeletal tissues (femoral neck and lumber spine). In addition to bone loss, cardiovascular disease (CVD) is an additional clinical sequelae of menopause and recent evidence suggests that systemic inflammation plays an important role in CVD pathogenesis. Importantly, we recently demonstrated that LDD reduces biomarkers of systemic inflammation in acute coronary syndromes patients. The NIDCR and Data and Safety Monitoring Board approved an addendum consent form subsequent to our March 2004 meeting; these signed consent forms give us permission to examine serum inflammatory biomarkers in response to LDD. However, no funds are available to conduct these additional assays; hence, we are applying for this competing continuation. Serum is currently being collected in our clinical trial at baseline, one-year and two-year visits and serum biomarkers of bone resorption/formation are being measured. The hypothesis for this application is that LDD can reduce biomarkers of systemic inflammation and MMPs associated with CVD risk in PM women. This hypothesis will be tested by pursuing the following specific aim: determine whether LDD therapy, in PM osteopenic women with chronic periodontitis, beneficially alters serum biomarkers of systemic inflammation and CVD (C-reactive protein, IL-6, myeloperoxidase, MMP-2 and MMP-9) in patients already enrolled in our current clinical trial. No additional serum will need to be collected for this study which will enable us to expand the significance of our currently-funded R01. This work is significant because, if LDD ultimately is found to reduce the severity of two major complications of menopause (namely, osteoporosis and increased incidence of CVD), LDD could provide an alternative to hormone replacement therapy in PM women. This work is relevant to public health as LDD may provide a safe and effective therapy to reduce complications associated with menopause. Reduced bone loss and CVD incidence would represent significant public health improvements.