The purpose of this study was to quantify mechanical and architectural changes to knee joint periarticular subchondral cancellous bone in early stage experimental osteoarthritis (OA). Unilateral anterior cruciate ligament transection (ACLX) was performed on 10 dogs that were assigned randomly to two groups: 3 weeks or 12 weeks post-ACLX. Cylindrical bone cores excised from the medial condyle of the distal femur after death were scanned using high-resolution microcomputed tomography (μCT) and subsequently failed under unconstrained uniaxial compression. The apparent-level elastic modulus was less in the ACLX femur compared with the contralateral control, and the decrease was significant (−45%; p < 0.05) by 12-weeks post-ACLX. A finite element (FE) analysis based on μCT data simulated the uniaxial compression tests on a specimen-by-specimen basis to determine tissue modulus. No change in tissue modulus was detected, and a single tissue modulus of 5100 MPa (95% CI, ±600 MPa) explained the apparent-level modulus changes observed in the disease-related bone adaptation. The three-dimensional (3D) connectivity was evaluated from the original μCT data to quantify architectural alterations in contrast to tissue alterations. Significantly increased connectivity (through plate perforations) occurred as early as 3 weeks post-ACLX and was as high as 127% by 12 weeks post-ACLX in the distal femur. These measured changes indicated that architectural adaptation predominated over tissue modulus changes affecting apparent-level elastic modulus in the early stage of experimental OA and suggests that to maintain normal cancellous bone after a traumatic injury, early intervention should focus on preventing the substantial architectural alterations.