Bone is a hierarchically organized biological material, and its strength is usually attributed to overt factors such as mass, density, and composition. Here we investigate a covert factor – the topological blueprint, or the network organization pattern of trabecular bone. This generally conserved metric of an edge-and-node simplified presentation of trabecular bone relates to the average coordination/valence of nodes and the equiangular 3D offset of trabeculae emanating from these nodes. We compare the topological blueprint of trabecular bone in presumably normal, fractured osteoporotic, and osteoarthritic samples (all from human femoral head, cross-sectional study). We show that bone topology is altered similarly in both fragility fracture and in joint degeneration. Decoupled from the morphological descriptors, the topological blueprint subjected to simulated loading associates with an abnormal distribution of strain, local stress concentrations and lower resistance to the standardized load in pathological samples, in comparison with normal samples. These topological effects show no correlation with classic morphological descriptors of trabecular bone. The negative effect of the altered topological blueprint may, or may not, be partly compensated for by the morphological parameters. Thus, naturally occurring optimization of trabecular topology, or a lack thereof in skeletal disease, might be an additional, previously unaccounted for, contributor to the biomechanical performance of bone, and might be considered as a factor in the life-long pathophysiological trajectory of common bone ailments.