SAFETY, EFFICACY, & OPTIMAL DOSAGE OF SOY ISOFLAVONES TO PREVENT OSTEOPOROSIS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。绝经后女性骨折的风险急剧增加。雌激素替代疗法通过减少骨质流失来降低这种风险，但引入了潜在的副作用和增加的癌症风险。在短期研究中，大豆异黄酮已被证明可以减少围绝经期和绝经后妇女腰椎的骨质流失，而且没有任何有害影响。大豆异黄酮预防绝经期妇女骨质流失的长期安全性、有效性和最佳剂量尚不清楚。我们假设长期补充大豆异黄酮可以安全地减少绝经后妇女的骨质流失，并且有益效果是剂量依赖性的。为了验证这一假设，400名处于更年期早期的健康绝经后妇女将在美国四个研究地点（贝勒医学院、乔治亚大学、爱荷华州立大学和加州大学戴维斯分校）参加一项为期2年的随机、双盲、安慰剂对照研究。其中三分之一的女性将服用安慰剂；三分之一的人接受80毫克/天的异黄酮补充；剩下的三分之一每天补充120毫克异黄酮。在研究期间，所有女性都将补充钙和维生素D。将在基线、6个月、12个月和24个月进行临床访问，以监测异黄酮补充的安全性。为监测安全性，每次就诊时将进行临床血液化学检查和全面体检。乳房x光检查、巴氏涂片检查和大便愈创木试验将在基线和每年进行一次。为了监测疗效，将在基线和每年间隔测量全身和局部骨矿物质含量（BMC）和骨矿物质密度（BMD）以及骨代谢的生化指标。BMC和BMD将通过双能x射线吸收仪（DXA）测量。异黄酮及其代谢物的血液浓度将在基线和每年间隔测量，以监测依从性、肠道吸收效率和剂量反应性。每组约133名女性的样本量将使我们能够检测腰椎BMC和BMD每年分别增加4.1%和2.2%，α水平为0.05，幂为0.8。样本量也将使我们能够检测血清骨钙素1.0 ng/mL，血清骨特异性碱性磷酸酶（BAP） 2.0 U/L和血清脱氧吡啶啉交联（Dpd） 5.9 nmol/L的差异。这将是第一个确定天然大豆异黄酮补充剂预防绝经后妇女骨质流失的安全性、有效性和最佳剂量的国家研究。如果我们的假设是正确的，大豆异黄酮可能为治疗和预防女性骨质疏松症提供一种安全的雌激素替代疗法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Risk for bone fracture increases dramatically in women after menopause. Estrogen replacement therapy reduces this risk by reducing bone loss but introduces potential side effects and increased risk of cancer. Soy isoflavones have been shown to reduce lumbar spine bone loss in peri- and postmenopausal women in short-term studies with no harmful effects. The long-term safety, efficacy, and optimal dosage of soy isoflavones to prevent bone loss in menopausal women are not known. We hypothesize that long-term soy isoflavone supplementation safely reduce bone loss in postmenopausal women and the beneficial effect is dose dependent. To test this hypothesis, 400 healthy postmenopausal women in their early years of menopause will be enrolled in a 2-year follow-up, randomized, double-blind, placebo-controlled study at four U.S. study sites (Baylor College of Medicine, University of Georgia, Iowa State University, and University of California @ Davis). One-third of these women will receive a placebo; one-third will receive isoflavone supplementation at 80 mg/day; and the remaining one-third will receive isoflavone supplementation at 120 mg/day. All women will receive calcium and vitamin D supplementation during the study. Clinic visits at baseline, 6, 12, and 24 months will be carried out to monitor the safety of isoflavone supplementation. To monitor safety, clinical blood chemistries and complete physical examinations will be performed at each clinic visit. Mammograms, Pap smears, and stool guaiac tests will be performed at baseline and at annual intervals. To monitor efficacy, total-body and regional bone mineral content (BMC) and bone mineral density (BMD) as well as biochemical markers of bone metabolism will be measured at baseline and at annual intervals. BMC and BMD will be measured by dual-energy x-ray absorptiometry (DXA). Blood concentrations of isoflavones and their metabolites will be measured at baseline and at annual intervals to monitor compliance, intestinal absorption efficiency, and dose responsiveness. The sample size of ~133 women per group will allow us to detect increases in lumbar spine BMC and BMD of 4.1% per year and 2.2% per year, respectively with an alpha level of 0.05 and a power of 0.8. The sample size also will allow us to detect differences in serum osteocalcin of 1.0 ng/mL, in serum bone-specific alkaline phosphatase (BAP) of 2.0 U/L, and in serum deoxypyrindinoline crosslink (Dpd) of 5.9 nmol/L. This will represent the first National study to determine the safety, efficacy, and optimal dosage of natural soy isoflavone supplementation to prevent bone loss in postmenopausal women. If our hypothesis is correct, soy isoflavones may provide a safe alternative to estrogen replacement therapy for the treatment and prevention of osteoporosis in women.