Cytokines play major roles in regulating bone remodeling, but their relationship to incident fractures in older men is uncertain. We tested the hypothesis that men with higher concentrations of pro-inflammatory markers have a higher risk of fracture. We used a case-cohort design and measured inflammatory markers in a random sample of 961 men and in men with incident fractures including 120 clinical vertebral, 117 hip, and 577 non-spine fractures; average follow-up 6.13 years (7.88 years for vertebral fractures). We measured interleukin (IL)-6, C-reactive protein (CRP), tumor necrosis factor alpha (TNFα), soluble receptors (SR) of IL-6 (IL-6SR) and TNF (TNFαSR1 and TNFαSR2), and IL-10. The risk of non-spine, hip, and clinical vertebral fracture was compared across quartiles (Q) of inflammatory markers using Cox proportional hazard models with tests for linear trend. In multivariable-adjusted models, men with the highest (Q4) TNFa cytokine concentrations and their receptors had a 2.0–4.2-fold higher risk of hip and clinical vertebral fracture than men with the lowest (Q1). Results were similar for all non-spine fractures, but associations were smaller. There was no association between CRP and IL-6SR and fracture. Men in the highest Q of IL-10 had a 49% lower risk of vertebral fracture compared with men in Q1. Among men with ≥3 inflammatory markers in the highest Q, the hazard ratio (HR) for hip fractures was 2.03 (95% confidence interval [CI] 1.11–3.71) and for vertebral fracture 3.06 (1.66–5.63). The HRs for hip fracture were attenuated by 27%, 27%, and 15%, respectively, after adjusting for appendicular lean mass (ALM), disability, and bone density, suggesting mediating roles. ALM also attenuated the HR for vertebral fractures by 10%. There was no association between inflammation and rate of hip BMD loss. We conclude that inflammation may play an important role in the etiology of fractures in older men.
- FRACTURE RISK ASSESSMENT
- GENERAL POPULATION STUDIES