Interferon gamma (IFN-γ)-mediated inflammation and the kynurenine pathway in relation to risk of hip fractures: the Hordaland Health Study

Osteoporos Int. 2014 Aug;25(8):2067-75. doi: 10.1007/s00198-014-2720-7. Epub 2014 May 10.


The cytokine interferon gamma (IFN-γ) stimulates neopterin release and tryptophan degradation into kynurenines through the kynurenine pathway. High levels of neopterin were associated with increased hip fracture risk, as were some of the kynurenines, suggesting a role of IFN-γ-mediated inflammation in the processes leading to hip fracture.

Introduction: Low-grade systemic inflammation has been associated with bone loss and risk of fractures. Interferon gamma (IFN-γ) initiates macrophage release of neopterin and also stimulates degradation of tryptophan along the kynurenine pathway as part of cell-mediated immune activation. Plasma neopterin and the kynurenine/tryptophan ratio (KTR) are thus markers of IFN-γ-mediated inflammation. Risk of hip fracture was investigated in relation to markers of inflammation and metabolites in the kynurenine pathway (kynurenines).

Methods: Participants (71 to 74 years, N = 3,311) in the community-based Hordaland Health Study (HUSK) were followed for hip fractures from enrolment (1998-2000) until 31 December 2009. Plasma C-reactive protein (CRP), neopterin, KTR, and six kynurenines were investigated as predictors of hip fracture, using Cox proportional hazards regression analyses.

Results: A hazard ratio (HR) of 1.9 (95% confidence interval (CI) 1.3-2.7) for hip fracture was found in the highest compared to the lowest quartile of neopterin (p trend across quartiles <0.001). CRP and KTR were not related to hip fracture risk. Among the kynurenines, a higher risk of fracture was found in the highest compared to the lowest quartiles of anthranilic acid and 3-hydroxykynurenine. For subjects in the highest quartiles of neopterin, CRP, and KTR compared to those in no top quartiles, HR was 2.5 (95% CI 1.6-4.0).

Conclusions: This may indicate a role for low-grade immune activation in the pathogenic processes leading to hip fracture.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biomarkers / blood
  • C-Reactive Protein / metabolism
  • Female
  • Follow-Up Studies
  • Hip Fractures / blood*
  • Hip Fractures / epidemiology
  • Humans
  • Inflammation Mediators / blood*
  • Interferon-gamma / blood*
  • Kaplan-Meier Estimate
  • Kynurenine / blood*
  • Male
  • Neopterin / blood
  • Norway / epidemiology
  • Risk Assessment / methods
  • Signal Transduction / physiology


  • Biomarkers
  • Inflammation Mediators
  • Kynurenine
  • Neopterin
  • Interferon-gamma
  • C-Reactive Protein