Elevated ceramides 18:0 and 24:1 with aging are associated with hip fracture risk through increased bone resorption.

We assessed whether circulating ceramides, which play a role in a number of degenerative changes with aging, significantly differed according to fragility hip fracture (HF) status. We also performed a human study using bone marrow (BM) aspirates, directly reflecting the bone microenvironment, in addition to in vitro experiments. Peripheral blood and BM samples were simultaneously collected from 74 patients 65 years or older at hip surgery for either HF (n = 28) or for other causes (n = 46). Ceramides were measured by liquid chromatography-tandem mass spectrometry. Age was correlated positively with circulating C16:0, C18:0, and C24:1 ceramide levels. Patients with fragility HF had 21.3%, 49.5%, 34.3%, and 22.5% higher plasma C16:0, C18:0, C18:1, and C24:1 ceramide levels, respectively, than those without HF. Higher C16:0, C18:0, C18:1, and C24:1 ceramide levels were positively related to bone resorption markers in both blood and BM samples. Furthermore, in vitro studies showed that C18:0 and C24:1 ceramides directly increased osteoclastogenesis, bone resorption, and expression levels of osteoclast differentiation markers. These results suggested that the association of increased ceramides, especially C18:0 and C24:1, with adverse bone phenotypes in elderly people could be explained mainly by the increase in osteoclastogenesis and bone resorption.