Effects of alcohol on bone remodeling balance in male and female non-human primates and humans - PROJECT SUMMARY Chronic heavy alcohol consumption contributes to high rates of low trauma fractures in middle-aged and elderly populations, especially men. However, low trauma fracture rates in chronic alcohol abusers exceed levels predicted by age, sex, and bone mineral density, suggesting that alcohol negatively impacts bone quality. Without understanding the precise effects of alcohol on bone quality, it will be difficult to appropriately target interventions. Rhesus macaques are a valuable animal model for alcohol studies because of their similar physiology to humans and because they exhibit drinking behavior that mimics the full range observed in humans. We have shown that male rhesus macaques (Macaca mulatta) offered free access to alcohol for 12 months had lower cancellous bone turnover in lumbar vertebra, where a negative turnover balance led to bone loss. The alcohol consuming monkeys also had lower initiation of intracortical bone remodeling (tibia), a process critical for repair of fatigue-induced microdamage. These findings suggest that excessive alcohol consumption could lower cancellous bone mass due to a negative turnover balance and decrease bone quality in cortical bone by suppressing repair of microdamage. These intriguing effects of alcohol in monkeys require verification by comparison to humans. The objective of this R03 application is to assess bone response (quantity and quality) to alcohol in male and female rhesus macaques at a skeletal site (iliac crest) typically biopsied in humans. We propose to test the hypothesis that chronic alcohol consumption will result in dose, bone compartment (cancellous versus cortical), and sex-specific changes in bone architecture and remodeling balance, and that the changes will be similar to those in humans. Specifically, alcohol will reduce cancellous bone mass and lower cortical porosity in both species. The rationale for this project is that the results will increase understanding of the actions of alcohol on the skeleton and will rigorously assess translatability of the nonhuman primate model to humans. To accomplish our objective, we propose two Specific Aims. Specific Aim 1: Assess bone mass, density, microarchitecture, and turnover in iliac crest biopsies from male and female rhesus macaques given free access to alcohol for 7 or 15 months. Specific Aim 2: Assess bone mass, density, and microarchitecture in iliac crest biopsies obtained from sudden death human males and females who chronically abused alcohol for the previous 5 years. The proposed studies are important because 1) they will rigorously test our hypothesis that chronic heavy alcohol consumption alters bone architecture and turnover balance independent of comorbidities, and 2) validate the translatability of the animal model to humans. Additionally, the results have the potential to guide treatment to prevent or reverse the detrimental skeletal effects of alcohol abuse. 1 2/14/2024
