The mechano-biologic environment associated with aseptic loosening of cemented joint replacements is not fully understood. The goal of this study was to use a preclinical rat knee arthroplasty model to explore the changes in cement−bone morphology and micromotion that occur with in vivo service. Narrow gaps between cement and bone under the tibial tray were present at early time points, and with even small magnitude micromotion, resulted in large micromotion-to-gap width ratios. These data were then used to develop models of fluid flow in the cement−bone gaps to estimate potential for high fluid shear stress (FSS). Modeling results revealed supraphysiologic (>4 Pa) FSS were possible, particularly for cases in which eccentric loading applied to the implant and if the fluid in the gap consisted of marrow or synovial fluid. The early, high FSS environment, could cause fluid-induced periprosthetic osteolysis locally, resulting in progressive loss of cement−bone fixation.