The association of red blood cell n-3 and n-6 fatty acids to dietary fatty acid intake, bone mineral density and hip fracture risk in the Women's Health Initiative.

Omega 3 (n3) and omega-6 (n6) polyunsaturated fatty acids (PUFA) in red blood cells (RBC) are an objective indicator of PUFA status and may be related to hip fracture risk. The primary objective of this study was to examine RBC PUFAs as predictors of hip fracture risk in postmenopausal women.  A nested case-control study (n of 400 pairs) was completed within the Women’s Health Initiative (WHI) using 201 incident hip fracture cases from the Bone Mineral Density (BMD) cohort, along with 199 additional incident hip fracture cases randomly selected from the WHI Observational Study. Cases were 1 to 1 matched on age, race, and hormone use with non hip fracture controls.  Stored baseline RBCs were analyzed for fatty acids using gas chromatography. After removing degraded samples, 324 matched pairs were included in statistical analyses. Stratified Cox proportional hazard models were constructed according to case-control pair status; risk of fracture was estimated for tertiles of RBC PUFA.  In adjusted hazard models, lower hip fracture risk was associated with higher RBC alpha linolenic acid [Hazard ratio (HR) Tertile 3 (T3): 0.44; 95 percent CI: 0.23 to 0.85; p for linear trend 0.0154)], eicosapentaenoic acid (HR T3: 0.46; 95percent CI: 0.24 to 0.87; p for linear trend 0.0181) and total n3 PUFAs (HR T3: 0.55; 95percent CI: 0.30 to1.01; p for linear trend 0.0492). Conversely, hip fracture nearly doubled with the highest RBC n6/n3 ratio (HR T3: 1.96; 95percent CI: 1.03 to 3.70; p for linear trend 0.0399). RBC PUFAs were not associated with BMD. RBC PUFAs were indicative of dietary intake of marine n3 PUFAs (Spearman’s rho 0.45, p<0.0001), total n6 PUFAs (rho 0.17, p<0.0001) and linoleic acid (rho= 0.09, p<0.05).  These results suggest that higher RBC alpha linolenic acid, as well as eicosapentaenoic acid and total n3 PUFAs, may predict lower hip fracture risk. Contrastingly, a higher RBC n6/n3 ratio may predict higher hip fracture risk in postmenopausal women. (Authors abstract)

Determining the relation of various nutritional components to fracture outcomes is an important step in developing dietary recommendations to decrease the burden of postmenopausal osteoporosis. Chronic inflammation leads to uncoupling of bone formation and bone resorption, which is central to the pathogenesis of osteoporosis. Recently, investigators from the Framingham Osteoporosis Study reported that higher intakes of alpha linolenic acid (ALA) in older men and women were associated with lower risk of hip fracture. In contrast, researchers in the Cardiovascular Health Study reported that neither fish intake nor eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) intake were associated with risk for hip. Analysis of PUFA levels in biological samples may more objectively assess the relationship of these fatty acids to skeletal outcomes. Thus based upon data suggesting that RBC samples are useful surrogates reflecting PUFA exposure, and because hip fracture is associated with the greatest morbidity and mortality of all osteoporotic fractures, the primary goal of this study was to investigate n3 and n6 FAs in RBCs as predictors of hip fracture risk in postmenopausal women. Secondary goals were to examine the association between major classes of fatty acids (saturated, monounsaturated and polyunsaturated) in RBCs and hip fracture risk, and investigate the relationship between serial 5 measures of BMD across varying levels of RBC n3 and n6 FAs, and examine the correlation of RBC FAs to self reported dietary intake of FAs in this cohort. RBC ALA, EPA, and total n3 FAs were significantly inversely associated with risk of hip fracture in these WHI participants. Conversely, women with an n6/n3 FA ratio in the highest tertile had nearly twice the risk of hip fracture compared to those in the lowest tertile. In this nested case-control study within WHI, there was no significant relation of total RBC n6 FAs to hip fracture. Total RBC n3 FAs were significantly inversely associated with risk of hip fracture in these postmenopausal women. A similar significant inverse linear trend was noted for individual RBC ALA and EPA. Women in the highest tertile of RBC ALA had a 56 percent lower risk of hip fracture than women in the lowest tertile. Higher dietary intake of ALA in older men and women in the Framingham Osteoporosis Study was associated with a 54 percent decreased risk of hip fracture. It has been proposed that the balance between n3 and n6 FAs may impact skeletal health more than individual classes of PUFAs. (Editors comments)