Unhealthy lifestyles and chronic metabolic stress are key contributors to obesity and the increased risk of osteoporotic fractures, both of which are significant global health concerns. This study aimed to evaluate the time-dependent effects of exercise and caloric restriction (CR) on bone homeostasis and quality in high-fat diet (HFD)-induced obesity. Seven-week-old male Wistar rats were fed either a normal diet (ND; n=6) or an HFD (n=30) for 28 weeks to induce obesity. At week 13, the HFD-fed rats were further divided into five groups (n=6/group): (1) HFD without intervention (HFNI), (2) six weeks of exercise followed by ND for 10 weeks (HFEX-S), (3) 16 weeks of continuous exercise (HFEX-L), (4) 40% CR for six weeks followed by ad libitum ND for 10 weeks (HFCR-S), and (5) 40% CR for 16 weeks (HFCR-L). Metabolic parameters were reassessed, and samples from serum, tibia, and femur were collected for analysis. Compared to ND, HFNI rats exhibited significantly elevated serum CTX-I, TRAP5b, bone malondialdehyde levels, and increased expression of p16, p21, p53, IL1-β, tnfrsf11a, tnfsf11, ctsk, fgf23, and Sost mRNA (p <0.05). Conversely, markers of antioxidant defense (GSH-Px), Wnt signaling (Wnt1, LRP5), and bone strength were reduced (p <0.05). Both exercise and CR improved bone parameters by reducing oxidative stress and inflammatory markers (p <0.05). Notably, long-term exercise provided the greatest benefit by enhancing bone strength, cortical quality, and trabecular microarchitecture (p <0.05). These findings suggest that sustained lifestyle changes, particularly long-term exercise, are effective strategies for mitigating obesity-induced bone fragility.
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