Introduction: Osteoporosis (OP), osteoarthrosis (OA), and rheumatoid arthritis (RA) are the most common age-related degenerative bone diseases, and major public health problems in terms of enormous amount of economic cost. RA is considered as a major cause of secondary osteoporosis. At late stage, OP often leads to skeletal fractures, and OA and RA result in severe joint disability. Over the last a few decades, much significant research on the properties has been carried out on these diseases, however, a detailed comparison of the microarchitecture of cancellous bones of these diseases is not available. In this study, we investigated three-dimensional (3-D) microarchitectural properties of OP, OA and RA cancellous bone. We hypothesized that there were significant differences in microarchitecture among OP, OA and RA bone tissues that might lead to different bone quality. Materials and Method Twenty OP, fifty OA, and twelve RA femur heads were harvested from patients undergone total hip replacement surgery. Cubic cancellous bone samples (8*8*8 mm3) were prepared and scanned with a high resolution microtomographic system (vivaCT 40, Scanco Medical AG., Brüttisellen, Switzerland). Then micro-CT images were segmented using individual thresholds to obtain accurate 3-D data sets. Detailed microarchitectural properties were evaluated based on novel unbiased, model-free 3-D methods. For statistical analysis, one-way ANOVA was used, and a p<0.05 was considered significant. Results Significant differences in the microarchitecture of cancellous bone were observed among the OP, OA and RA groups. Compared with the other groups, OP cancellous bone had lowest density, thinner, typical rod-like structure and less connectivity (all p<0.01). Interestingly, there were no significant differences in the microarchitectural properties measured between the OA and RA cancellous bones. Both OA and RA cancellous bones had significant higher bone volume fraction and were thicker, typical plate-like structure compared with the OP group (all p<0.01), even though there was clearly bone erosion observed in RA cancellous bone. Discussion Quantification of the alterations in bone properties and quality will help to gain more insights into the pathogenesis of degenerative bone diseases and to target and develop novel approaches for the intervention and treatment, and for the design, fixation and durability of total joint prosthesis. Our study demonstrated that there were significant differences in the microarchitecture of the OP, OA and RA femur head cancellous bone. The OA and RA cancellous bone had similar bone density and microarchitecture despite apparent bone erosion in the RA cancellous bone. These results from femur head did not support the traditional notion that RA and OP had similar low bone density. Thus, whether femur head bone tissues from these diseases have similar bone collagen, mineral and mechanical properties, more importantly bone quality, should be clarified in the future.