The goal of this study was to develop a method that identifies optimal elastic modulus, Poisson’s ratio, porosity and permeability values for mechanically stressed bone substitute. It was hypothesized that porous bone substitute that favors the transport of nutriments, wastes, biochemical signals and cells while keeping the fluid-induced shear stress within a range that stimulates osteoblasts was likely to promote its osteointegration. Two optimization criteria were used: (i) the fluid volume exchange between the artificial bone substitute and its environment must be maximal and (ii) the fluid-induced shear stress must be comprised between 0.03 and 3 Pa. Biot’s poroelastic theory was used to compute the fluid motion due to mechanical stresses. The impact of the elastic modulus, Poisson’s ratio, porosity and permeability on the fluid motion were determined in general and for three different bone substitute sizes used in high tibial osteotomy. It was found that the fluid motion can be optimized in two independent steps. First, the fluid transport was maximized by minimizing the elastic modulus, Poisson’s ratio and porosity. In a second step, the fluid-induced shear stress could be adjusted by tuning the bone substitute permeability so that it stayed within the favorable range of 0.03 to 3Pa. Such method provides clear guidelines to bone substitute developers and to orthopedic surgeons to use bone substitute materials according to its mechanical environment.