Fatty Acids and Risk of Fracture in Postmenopausal Women

Polyunsaturated fatty acids of the omega-3 (n-3) and omega-6 (n-6) families may differentially modulate osteoporotic fracture risk. This research uses the Women’s Health Initiative (WHI) cohort to examine dietary intake, as well as red blood cell (RBC) FAs, in relation to bone mineral density (BMD) and fracture risk.

The objective of the first research project was to examine FA intake, specifically n-3 and n-6 FAs, as well as the type of n-3 FA (marine versus non-marine sources) relative to osteoporotic fractures. Participants were 137,486 postmenopausal women enrolled in the WHI Clinical Trials and Observational Study. Total fractures were identified by self-report; hip fractures were confirmed by medical record review. FA intake was estimated from baseline food frequency questionnaires and standardized to total caloric intake. No data on n-3 FA supplementation was available. Cox proportional hazard models were constructed to estimate risk of fracture.

Women in the highest quartile of saturated FA (SFA) intake had a 31% increase in relative risk for hip fracture. Both higher monounsaturated FA (MUFA) and polyunsaturated FA (PUFA) were associated with a small decrease (5–6%) in total fracture risk. Unexpectedly, higher consumption of marine n-3 FAs was associated with a 7% increase in total fracture risk whereas higher n-6 FA intake was associated with 6% lower total fracture risk. These results suggest SFA intake may increase hip fracture risk, while MUFA and PUFA may decrease total fracture risk. In postmenopausal women with low intake of marine n-3 FAs, higher intake of n-6 FAs may modestly decrease total fracture risk.

To address limitations of this project such as inability to capture n-3 FA supplement use and error associated with self-reported intake, we examined RBC FAs in relation to hip fractures using a nested case/control design (n=400 pairs) within WHI. Frozen RBCs collected at baseline were analyzed for FA content using gas chromatography. Hip fractures were confirmed by medical record review. Cox proportional hazard models were constructed to estimate hip fracture risk. The association of FAs to previously analyzed inflammatory markers, bone markers, and serial BMD was estimated using generalized linear models.

After exclusion of 212 samples due to potential RBC degradation, 294 matched pairs were included in statistical analysis. The n-3 index [eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) in RBCs] was a significant indicator of dietary intake of EPA+DHA. There were weak, though statistically significant associations of total n-6 FAs and linoleic acid in RBCs with dietary intake. Higher α-linolenic acid (ALA) was associated with a 61% lower hip fracture risk, potentially related to more favorable bone turnover markers. Women with a higher n-3 index and total n-3 FAs had lower inflammatory markers predictive of fracture risk. Although bone turnover markers tended to be less favorable with higher total n-6 FAs, n-6 FAs were not associated with hip fracture. PUFAs in RBCs had no impact on total hip BMD. These results suggest that n-3 FAs may improve the skeletal environment via modulation of inflammatory and bone turnover markers, thus positively impacting hip fracture risk.