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Characterized human thrombins and two commercial bovine thrombin preparations were examined for their effects on bone resorption and on the cyclic AMP and phosphoinositide second messenger systems in bone. Human α‐ and γ‐thrombins, as well as both bovine thrombin preparations, stimulated bone resorption in vitro, whereas catalytically inactivated human diisopropylfluorophosphate (DIP)‐α‐thrombin did not significantly stimulate resorption. Human α‐thrombin and a commercial bovine thrombin preparation increased cyclic AMP production in fetal rat limb bones, but another bovine commercial thrombin preparation and γ‐thrombin did not. Except for DIP‐α‐thrombin, all thrombins increased production of inositol phosphates in fetal rat limb bones at concentrations that stimulated resorption. In time course studies, bovine thrombin increased label in inositol trisphosphate at 30 s, with decreasing effects at later times. Inositol monophosphate increased progressively over 30 min. Our results are consistent with thrombin‐stimulated bone resorption being mediated at least partially through the inositol phosphate pathway.