Inflammatory Markers and the Risk of Hip and Vertebral Fractures in Men: the Osteoporotic Fractures in Men (MrOS)

Abstract

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.

Plasma proteomic signature of age in healthy humans

“…TNFR1 (TNFRSF1A) has both activating and death receptor functions and can affect cell metabolism, differentiation, and proliferation (Li, Yin, & Wu, 2013). Soluble TNF receptor 1 (TNFRSF1A) and 2 (TNFRSF1B) have been associated with advance age and aging pathologies such as kidney function, fractures, and cognitive performance (Cauley et al., 2016; Gao et al., 2016; Schei et al., 2017). Our study results would suggest that there may be a more coordinate change in the TNF receptor family with age that may be important determinant of healthy aging.…”

Pain at Multiple Sites Is Associated With Prevalent and Incident Fractures in Older Adults

“…The mechanisms underlying the link of MSP to vertebral fractures are not clear, but systemic inflammation caused by pain is one of the suggested explanations. Systemic inflammation has been suggested to play a crucial role in bone remodeling with human studies showing increased risk of fractures associated with proinflammatory cytokines . There is some evidence that participants with widespread pain (eg, fibromyalgia), have modestly elevated levels of systemic inflammation, reduced anti‐inflammatory markers, and enhanced innate immune response .…”

Patterns and Predictors of Frailty Transitions in Older Men: The Osteoporotic Fractures in Men Study

“…Based on knowledge of the pathogenesis of frailty, it was hypothesized that the following variables would be associated with frailty transitions: comorbidities, sociodemographic characteristics, physical function, lifestyle, and blood markers of inflammation or organ dysfunction . To assess systemic inflammation, a composite inflammatory burden score was calculated, as has been done previously with this dataset . Variables included within each category are listed in the Appendix .…”