Chronic Alcohol Abuse: Suppression of Bone Remodeling in Non-human Primates

描述（由申请人提供）：慢性重度饮酒者“低创伤”和“全因”骨折的增加大大超过了骨质流失程度所预测的值，表明过度饮酒对骨强度有有害影响，而不是众所周知的降低骨矿物质密度（BMD）的作用。这种与骨密度无关的慢性酒精对骨折风险的影响机制尚不清楚。我们的工作假设是，通过抑制皮质骨重塑，酒精滥用导致骨质量恶化。骨重塑对修复疲劳引起的微损伤至关重要。在啮齿动物模型中，酒精对松质（海绵状）骨重塑的剂量依赖性抑制作用已经得到了很好的证实；然而，关于酒精对皮质骨（致密骨）重塑的影响，我们所知甚少。在人类中，皮质骨占骨量的绝大部分（~80%），在结构支撑中起着至关重要的作用。本应用程序的主要目的是确定慢性重度饮酒在非人类灵长类动物模型中通过抑制皮质内骨重塑而降低骨强度的程度。为了实现这一目标，我们利用了一个独特的机会，从正在niaaa资助的俄勒冈国家灵长类动物研究中心进行的酒精研究项目中研究的恒河猴（Macaca mulatta）身上获得了骨骼标本。与啮齿类动物不同，猕猴的皮质内骨重塑与人类的皮质内骨重塑非常相似。我们的中心假设，部分基于我们在大鼠和猕猴身上的初步数据，是微骨折的积累与慢性重度饮酒引起的骨密度非依赖性骨强度下降密切相关。我们建议通过实现一个具体目标来检验这一假设。具体目的：确定成年雄性恒河猴慢性（1年）重度饮酒与皮质内骨重塑程度、骨微骨折（微损伤）积累和整体骨强度之间的相关关系。根据我们的初步数据，我们预计非人类灵长类动物长期大量饮酒将导致骨强度显著下降，这反过来又与骨质量下降和皮质内骨重塑水平抑制相关。我们预期的研究结果的主要积极影响是为在重度饮酒者中观察到的骨折风险增加的一种新的、与骨密度无关的机制提供了“原理证明”。这些知识有望为未来的R01基金申请奠定基础，以帮助确定大量饮酒对骨骼有害影响的细胞和分子机制。

DESCRIPTION (provided by applicant): The increase in "low trauma," as well as "all cause" fractures in chronic heavy alcohol consumers greatly exceeds values predicted by the extent of bone loss, indicating that excessive drinking has detrimental effects on bone strength independent of its well-known actions to reduce bone mineral density (BMD). The mechanism for this BMD-independent effect of chronic alcohol on fracture risk is unknown. Our working hypothesis is that by inhibiting cortical bone remodeling, alcohol abuse results in deterioration o bone quality. Bone remodeling is essential to repair fatigue-generated microdamage. A dose-dependent inhibitory effect of alcohol on cancellous (spongy) bone remodeling is well established in rodent models; however, significantly less is known concerning the effects of alcohol on remodeling in cortical (compact) bone which, in humans, comprises the great majority (~80%) of bone mass and plays a crucial role in structural support. The primary objective of this application is to determine the extent to which chronic heavy alcohol consumption decreases bone strength by suppressing intracortical bone remodeling in a nonhuman primate model. To accomplish this objective, we have capitalized upon a unique opportunity to obtain bone specimens from rhesus macaque monkeys (Macaca mulatta) being studied in an ongoing NIAAA-sponsored alcohol research project conducted at the Oregon National Primate Research Center. Unlike rodents, which exhibit minimal intracortical bone remodeling, intracortical bone remodeling in macaques closely resembles intracortical bone remodeling in humans. Our central hypothesis, based in part on our preliminary data in rats and macaques, is that accumulation of microfractures will correlate closely with the BMD-independent decrease in bone strength associated with chronic heavy alcohol consumption. We propose to test this hypothesis by accomplishing one specific aim. Specific aim: Define the correlative relationships among chronic (1 year) heavy alcohol consumption, extent of intracortical bone remodeling, accumulation of bone microfractures (microdamage), and overall bone strength in adult male rhesus macaques. Based on our preliminary data, we anticipate that long-term heavy alcohol consumption in the non-human primates will result in significantly decreased bone strength which, in turn, will be correlated with reduced bone quality and suppressed levels of intracortical bone remodeling. The primary positive impact of our anticipated findings is the demonstration of "proof of principle" for a novel, BMD-independent mechanism for the increase in fracture risk observed in heavy drinkers. This knowledge is expected to establish the basis for a future R01 grant application to help define the cellular and molecular mechanisms responsible for the detrimental effects of heavy alcohol consumption on bone.