Exposure to diets high in fat and sucrose can induce hyperinsulinaemia, affect Ca and Mg metabolism, and alter bone mineralisation and mechanical properties. The present study assessed morphological and mechanical changes in a murine model exposed to a high-fat/sucrose (HFS) diet, as well as corresponding molecular and endocrine markers of bone turnover. Female C57BL/6 mice (aged 9 weeks) consumed either a low-fat, complex carbohydrate diet or an HFS diet for 10 weeks. At the end of the 10 weeks, serum was collected for biochemical analysis. Tibiae from half the mice (n 15) were randomly selected to be micro-computed tomography scanned and tested to failure in cantilever bending, while the remaining half were prepared for real-time PCR analysis. Serum tartrate-resistant acid phosphatase was significantly elevated in HFS mice, while osteocalcin remained unchanged. Both body mass and percentage body fat were greater in mice fed HFS diet. After adjusting for body mass, tibial structural and morphological properties were adversely affected in the HFS cohort. Cortical thickness, cross-sectional area, and load at maximum were all significantly lower in mice fed HFS diet. Receptor activator of nuclear factor kappabeta ligand (RANKL) mRNA was significantly upregulated in HFS mice, but osteoprotegerin/RANKL mRNA ratio remained unchanged between cohorts. Moreover, cyclo-oxygenase-2 mRNA tended to be increased in HFS. Thus, ingestion of an HFS diet had a significant adverse effect on mouse bone morphology and mechanics, and these effects were likely due to elevated osteoclast activity associated with the inflammatory state of obesity, and not necessarily osteoclast recruitment/proliferation.