TNF Receptors Predict Hip Fracture Risk in the WHI Study and Fatty Acid Intake Does Not Modify This Association

Abstract

Context: Chronic inflammation may increase the risk of fracture, and omega-3 polyunsaturated fatty acids (PUFAs) may reduce fracture risk via down-regulation of inflammatory cytokine gene expression and other mechanisms.

Objective: We investigated associations between baseline samples of inflammatory markers, TNFα soluble receptors 1 and 2 (TNFα-sR1 and -sR2), and incident hip fracture. These associations were then tested for effect modification by dietary PUFA intake estimated by a baseline food frequency questionnaire.

Design and setting: A nested case-control study was conducted among participants of the Women's Health Initiative Observational Study (ages, 50-79 y). Multivariable conditional logistic regression models were constructed to account for the paired design.

Participants: This study sampled 400 pairs of hip fracture cases and controls without incident hip fracture, matched on age, year of enrollment, and menopausal hormone use.

Main outcome measures: Odds ratio of hip fracture by quartile of TNF soluble receptors.

Results: The odds ratio of hip fracture comparing the highest to lowest quartiles was 2.24 (95% confidence interval, 1.05-4.79; P for linear trend, .048) for TNFα-sR1 and 2.83 (95% confidence interval, 1.34-5.99; P for linear trend, .011) for TNFα-sR2, adjusted for FRAX hip fracture score, nutritional variables, and selected factors impacting inflammation; there was a gradient of risk by increasing quartile in TNFα-sR1. PUFA intake did not modify these associations.

Conclusions: Women with the highest levels of TNFα-sR1 and TNFα-sR2 had a greater than 2-fold increased hip fracture risk, independent of other fracture risk factors. These associations did not differ by high vs low PUFA intake.

Trial registration: ClinicalTrials.gov NCT00000611.

Figures

Figure 1.

OR of hip fracture by quartiles of TNF-sR1 and TNF-sR2. Quartile 1 is reference strata; OR = 1. Linear trend: *, P < .05; **, P < .01. Error bars denote 95% CI. Data are adjusted for FRAX score, nutritional variables (intake of calcium, vitamin D, total energy, protein, multivitamin use), and factors impacting inflammation (NSAID use, arthritis, depression, body mass index, self-reported general health, comorbidity index, physical function, poor endurance/exhaustion, and physical activity).