A diet rich in omega-3s has previously been suggested to prevent bone loss. However, evidence for this has been limited by short exposure to omega-3 fatty acids (FM). We investigated whether a diet enriched in eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) for the entire adult life of mice could improve bone microstructure and strength. Thirty female mice received a diet enriched in DHA or EPA or an isocaloric control diet from 3 to 17 months of age. Changes in bone microstructure were analyzed longitudinally and biomechanical properties were analysed by a three-point bending test. Bone remodelling was evaluated by markers of bone turnover and histomorphometry. Trabecular bone volume in caudal vertebrae was improved by EPA or DHA at 8 months (+26.6% and +17.2%, respectively, compared to +3.8% in controls, P=.01), but not thereafter. Trabecular bone loss in the tibia was not prevented by omega-3 FAs (BV/TV -94%, -93% and -97% in EPA. DHA and controls, respectively). EPA improved femur cortical bone volume (+8.1%. P<.05) and thickness (+4.4%, P<.05) compared to controls. EPA, but not DHA, reduced age-related decline of osteocalcin (-70% vs. -83% in controls, P<.05). EPA and DHA increased leptin levels (7.3 +/- 0.7 and 8.5 +/- 0.5 ng ml(-1), respectively, compared to 4.5 +/- 0.9 ng ml(-1) in controls, P=.001); however, only EPA further increased IGF-1 levels (739 +/- 108 ng ml(-1), compared to 417 +/- 58 ng ml(-1) in controls, P=.04). These data suggest that long-term intake of omega-3 FA, particularly EPA, may modestly improve the structural and mechanical properties of cortical bone by an increase in leptin and IGF-1 levels, without affecting trabecular bone loss. (C) 2011 Elsevier Inc. All rights reserved.