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.
Heavy alcohol consumption is a well-established risk factor for bone loss, predisposing individuals to osteoporotic fractures. The proposed studies will test the novel hypothesis that chronic alcohol abuse increases fracture risk by impairing bone quality. This research is significant because it will lead to a better understanding of the mechanism for the detrimental skeletal effects of heavy alcohol consumption and suggest interventions to reverse them.