Objectives-Osteoporosis is associated epidemiologically with atherosclerosis and hyperlipidemia. We previously found that atherogenic lipids regulate bone formation. To determine whether hyperlipidemia also affects bone resorption, we compared osteoclastogenesis in marrow preosteoclasts derived from hyperlipidemic versus control mice. Methods-Nonadherent marrow cells from low-density lipoprotein receptorϪ/Ϫ (LDLRϪ/Ϫ)and C57BL/6J mice were cultured with M-CSF and ligand for receptor activator of

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... nuclear factor-kappaB (RANKL). Functional osteoclastic activity, measured as number of resorption pits, was significantly greater in 12-month-old LDLRϪ/Ϫ. Similar results were obtained in 5-and 10-month-old LDLRϪ/Ϫ versus C57BL/6J mice on a high-fat diet. Osteoclastic differentiation, indicated by tartrate resistant acid phosphatase (TRAP) activity, was significantly greater in the 12-month-old LDLRϪ/Ϫ, and there was a trend toward increased TRAP activity in LDLRϪ/Ϫ on a high-fat diet, at ages 5 and 10 months. Osteoclastic parameters correlated with total serum lipoproteins with a possible threshold effect. Osteoporotic human cortical bone stained positive for lipids in the perivascular space of Haversian canals by oil red O. The presence of lipid hydroperoxides was detected in bone marrow from hyperlipidemic mice. Conclusions-Hyperlipidemia may contribute to osteoporosis via increased osteoclastic bone resorption.(Arterioscler Thromb Vasc Biol. 2004;24:e6 -e10.)