The ideal bone graft substitute should have certain properties and there are many studies dealing with mixture of polymethylmetacrilate (PMMA) and β-tricalciumphospate (β-TCP) presenting the best characteristics of both. Scanning Electron Microscopy (SEM), for ultra-structural data, resulted a very reliable in vivo model to better understand the bioactivity of a cement and to properly evaluate its suitability for a particular purpose. The present study aims to further improve the knowledge on osteointegration development, using both parameters obtained with the Environmental Scanning Electron Microscopy (ESEM) and focused histological examination. Two hybrid bone graft substitute were designed among ceramic and polymer-based bone graft substitutes. Based on β-TCP granules sizes, they were created with theoretical different osteoconductive properties. An acrylic standard cement was chosen as control. Cements were implanted in twelve New Zealand White (NZW) rabbits, which were sacrificed at 1, 2, 3, 6, 9 and 12 months after cement implantation. Histological samples were prepared with an infiltration process of LR white resin and then specimens were studied by X-rays, histology and Environmental Scanning Electron Microscopy (ESEM). Comparing the resulting data, it was possible to follow osteointegration’s various developments resulting from different sizes of β-TCP granules. In this paper, we show that this evaluation process, together with ESEM, provides further important information that allows to follow any osteointegration at every stage of develop.