N-Acetyl Cysteine Treatment Restores Early Phase Fracture Healing in Ethanol-Fed Rats

Alcohol Clin Exp Res. 2018 Jul;42(7):1206-1216. doi: 10.1111/acer.13765. Epub 2018 May 27.


Background: Fracture healing in alcoholics is delayed and often associated with infections resulting in prolonged rehabilitation. It has been reported that binge drinking of alcohol increases oxidative stress and delays fracture healing in rats, which is prevented by treatment with the antioxidant n-acetyl cysteine (NAC). Oxidative stress is a significant factor in pathologies of various organs resulting from chronic alcoholism. Therefore, we hypothesize that treatment with NAC reduces oxidative stress and restores fracture healing in chronic alcoholics.

Methods: Rats (10 months old) were pair-fed the Lieber-DeCarli ethanol (EtOH) diet or control diet for 16 weeks. A closed fracture was performed and rats allowed to recover for 72 hours. Rats were divided into 4 groups-control, control + NAC, EtOH, and EtOH + NAC-and injected intraperitoneally with 200 mg/kg of NAC daily for 3 days. Serum and bone fracture callus homogenates were collected and assayed for traditional markers of inflammation, oxidative stress, and bone regeneration.

Results: The oxidative stress marker malondialdehyde (MDA) was increased in both serum and bone tissue in EtOH-fed animals compared to controls. NAC treatment significantly (p < 0.01) reduced MDA to near normal levels and dramatically increased the index of antioxidant efficacy (catalase/MDA ratio) (p < 0.01). Inflammatory markers tumor necrosis factor-α, interferon-γ, and interleukin-6 were significantly decreased in serum and callus following NAC treatment. NAC treatment reduced EtOH-induced bone resorption as evidenced by significant decreases in C-telopeptide of type-I-collagen levels (p < 0.05) and band-5 tartrate-resistant acid phosphatase levels in the tissue (p < 0.001).

Conclusions: Oxidative stress and excessive inflammation are involved in the inhibition of fracture healing by EtOH. In this study, early short-term treatment of EtOH-fed animals with the antioxidant NAC reduced oxidative stress and normalized the innate immune response to fracture in the early phase of fracture healing, thereby restoring the normal onset of bone regeneration.

Keywords: Alcoholic Liver Disease; Antioxidants; Ethanol; Fracture Model; Inflammation; N-Acetyl Cysteine; Rat Model; Reactive Oxygen Species.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetylcysteine / pharmacology*
  • Animals
  • Dose-Response Relationship, Drug
  • Ethanol / administration & dosage
  • Ethanol / toxicity*
  • Femur / drug effects*
  • Femur / injuries*
  • Femur / metabolism
  • Fracture Healing / drug effects*
  • Fracture Healing / physiology
  • Inflammation Mediators / antagonists & inhibitors
  • Inflammation Mediators / metabolism
  • Male
  • Rats
  • Rats, Wistar
  • Treatment Outcome


  • Inflammation Mediators
  • Ethanol
  • Acetylcysteine