Skeletal Toxicity Associated with Chronic Ethanol Exposure in a Rat Model Using Total Enteral Nutrition

Abstract

Chronic alcohol abuse decreases bone mass, inhibits osteoblast differentiation and function, increases fracture incidence, and delays fracture healing. Four studies were designed to use intragastric ethanol delivery as part of a total enteral nutrition (TEN) system to determine the negative systemic effects of chronic ethanol on 1) the rat skeleton and 2) local rapid bone formation during limb lengthening (distraction osteogenesis, DO). In study 1, three-point bending tests demonstrated that after 75 days of ethanol exposure, the tibiae had significantly lower load to failure versus control diet (p ϭ 0.0006) or ad libitum chow-fed rats (p ϭ 0.0029). Study 2 examined alcohol's effects on the density and cross-sectional area of the proximal tibial metaphysis using peripheral quantitative computed tomography and found that after 25 days of ethanol exposure the trabecular volumetric bone mineral density (p ϭ 0.011) and cortical cross-sectional area (p ϭ 0.011) were lower compared with controls. In study 3, a comparison of distracted tibial radiographs and histological sections demonstrated ethanolrelated decreases in both gap mineralization (p ϭ 0.03) and bone column formation (p ϭ 0.01). Histological comparisons in study 4 reproduced the ethanol-related deficits in new bone formation during DO (p ϭ 0.001). These results indicate that the TEN system is a viable model to study ethanol's effects on the skeleton and that chronic ethanol delivery via TEN decreases trabecular bone density, cortical area, and mature bone strength. Also, the DO studies demonstrate, for the first time, that chronic ethanol inhibits rapid bone formation during limb lengthening.

Interleukin-1 and Tumor Necrosis Factor Antagonists Attenuate Ethanol-Induced Inhibition of Bone Formation in a Rat Model of Distraction Osteogenesis

“…Relevant herein, patients with alcohol-induced bone disease display marked impairment in bone formation (Crilly et al, 1988). Previous studies by these authors have shown that chronic ethanol exposure via an intragastric dietary delivery system [total enteral nutrition (TEN)] inhibits bone formation during distraction osteogenesis (DO) in the rat (Brown et al, 2002). This model replicates several important aspects of human alcoholic liver disease (Badger et al, 1993).…”

“…There, it was attached to a headpiece secured to the skull by four jeweler's screws and tethered to the top of the cage for infusion of the liquid diet. During the same surgical procedure, stainless steel ring fixators were applied to the left tibia in standardized manner (Aronson, 1994;Brown et al, 2002). All rats received 0.1 mg/kg Buprenex for analgesia and were returned to their cages for observation during recovery.…”

“…These studies were approved by the Institutional Animal Care and Use Committee. All procedures for DO and the TEN system (Badger et al, 1993;Brown et al, 2002) as well as the diet formulations (Lumpkin et al, 1996;Brown et al, 2002) have been described previously in detail.…”

“…Previous studies demonstrate that ethanol exposure decreases bone mineral density (BMD), inhibits bone formation during DO, and increases the expression of IL-1␤ and TNF-␣ in the liver and bone marrow (Fang et al, 1998;Turner et al, 1998;Brown et al, 2002). IL-1␤ and TNF-␣ are known to be potent inhibitors of bone formation in vitro and in vivo (Bertolini et al, 1986;Nguyen et al, 1991).…”

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“…Recent studies concluded that heavy alcohol consumption inhibits bone neo-formation in fracture sites [20,21].…”