The pathophysiologic role of liver in bone metabolism remains largely unknown. Here, we uncover a novel liver-bone axis regulated by hepatocyte SIRT2. We firstly demonstrated that liver-specific SIRT2 deficiency (SIRT2-KOhep) obviously inhibits osteoclastogenesis and alleviates osteoporosis in aged and postmenopausal osteoporosis mouse models. Mechanistically, leucine-rich alpha-2-glycoprotein 1 (LRG1) was identified as the functional cargo in hepatocyte-derived small extracellular vesicles (sEVs), which is required for the protection of SIRT2-KOhep against osteoclastogenesis. In hepatocytes, SIRT2-KOhep up-regulates the expression of LRG1 in hepatocyte-derived sEVs (sEVs-LRG1) through increasing acetylation of H4K16. The sEVs-LRG1 is transfered to bone marrow-derived monocytes (BMDMs) to suppress osteoclast differentiation through directly inhibiting nuclear translocation of NF-κB p65. Therapeutically, treating ovariectomized mice with SIRT2 pharmacological inhibitor AGK2 or sEVs purified from LRG1-overexpressed AML12 hepatocytes obviously attenuated osteoclastogenesis and bone loss. In accordance, sEVs derived from either human LRG1high plasma or hepatocytes with SIRT2 inhibition may markedly inhibit human osteoclast differentiation. Importantly, the clinical data showed that the plasma sEVs-LRG1 was positively correlated with bone mineral density and negatively related with bone resorption marker in patients. Therefore, drugs targeting the hepatocyte-osteoclast communication, including hepatocyte SIRT2 and sEVs-LRG1, should be considered as promising therapeutic strategy for primary osteoporosis.