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

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, TNF alpha soluble receptors 1 and 2 (TNF alpha-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 TNF alpha-sR1 and 2.83 (95% confidence interval, 1.34-5.99; P for linear trend,.011) for TNF alpha-sR2, adjusted for FRAX hip fracture score, nutritional variables, and selected factors impacting inflammation; there was a gradient of risk by increasing quartile in TNF alpha-sR1. PUFA intake did not modify these associations. Conclusions: Women with the highest levels of TNF alpha-sR1 and TNF alpha-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.