Objective　To　explore　the　effects　of　disuse-induced　architectural　changes　in　the　osteocytic　lacunar-canalicular　system　(LCS)　on　the　fluid　dynamic　microenvironment　of　osteocytes　under　mechanical　stimulus.　Methods　First,　taking　the　axially　loaded　mice　tibia　as　the　object,　a　multi-scale　model　of　‘whole　bone-single　osteocyte　LCS’　was　established.　Subsequently,　pressure　gradients　and　other　results　obtained　from　the　whole-bone　poroelastic　finite　element　model　were　used　as　boundary　conditions　for　the　single-osteocyte　LCS　model　to　calculate　the　flow　velocity　and　shear　stress　around　osteocytes.　Finally,　a　design　of　experiment　(DOE)　method　was　used　to　determine　the　individual　and　interactive　effects　of　the　LCS　architectural　parameters　(lacunar　volume,　lacunar　shape,　and　canalicular　diameter)　on　the　osteocytic　fluid　dynamic　microenvironment　within　the　LCS.　Results　When　the　lacunar　volume,　lacunar　shape,　and　canalicular　diameter　changed　from　normal　to　disused,　the　flow　velocity　increased　by　5.　3%,　39.　3%,　and　37.　0%,　respectively.　The　DOE　results　showed　that　the　lacunar　shape　and　canalicular　diameter　had　a　significant　effect　on　fluid　velocity　and　shear　stress　(P　＜　0.　05),　with　a　contribution　ratio　of　0.　38　∶　0.　62,　whereas　the　lacunar　volume　and　interaction　of　architectural　parameters　had　no　significant　effects.　Conclusions　Disuse-induced　changes　in　canalicular　diameter　and　lacunar　shape　were　the　main　factors　affecting　the　osteocytic　fluid　dynamic　environment　within　the　LCS　under　mechanical　stimulus.　Appropriate　exercise　methods　are　expected　to　prevent　disuse-induced　bone　loss　caused　by　space　weightlessness　and　other　conditions.　©　2024　Editorial　Department　of　Journal　of　Shanghai　Second　Medical　University.　All　rights　reserved.