We investigated if time between injury and surgery affects cancellous bone properties in patients suffering tibial plateau fractures (TPF), in terms of structural integrity and gene expression controlling bone loss. A cohort of 29 TPF, operated 1–17 days post-injury, had biopsies from the fracture and an equivalent contralateral limb site, at surgery. Samples were assessed using micro-computed tomography and real-time RT-PCR analysis for the expression of genes known to be involved in bone remodeling and fracture healing. Significant decreases in the injured vs control side were observed for bone volume fraction (BV/TV, −13.5 ± 6.0%, p = 0.011), trabecular number (Tb.N, −10.5 ± 5.9%, p = 0.041) and trabecular thickness (Tb.Th, −4.6 ± 2.5%, p = 0.033). Changes in these parameters were more evident in patients operated 5–17 days post-injury, compared to those operated in the first 4 days post-injury. A significant negative association was found between Tb.Th (r = −0.54, p < 0.01) and BV/TV (r = −0.39, p < 0.05) in relation to time post-injury in the injured limb. Both BV/TV and Tb.Th were negatively associated with expression of key molecular markers of bone resorption, CTSK, ACP5, and the ratio of RANKL:OPG mRNA. These structure/gene expression relationships did not exist in the contralateral tibial plateau of these patients. This study demonstrated that there is a significant early time-dependent bone loss in the proximal tibia after TPF. This bone loss was significantly associated with altered expression of genes typically involved in the process of osteoclastic bone resorption but possibly also bone resorption by osteocytes. The mechanism of early bone loss in such fractures should be a subject of further investigation.