Translational vertebral motion during functional tasks manifests itself in dynamic loci for center of rotation (COR). A shift of COR affects moment arms of muscles and ligaments; consequently, muscle and joint forces are altered. Based on posture- and level-specific trends of COR migration revealed by in vivo dynamic radiography during functional activities, it was postulated that the instantaneous COR location for a particular joint is optimized in order to minimize the joint reaction forces. A musculoskeletal multi-body model was employed to investigate the hypotheses that (1) a posterior COR in upright standing and (2) an anterior COR in forward flexed posture leads to optimized lumbar joint loads. Moreover, it was hypothesized that (3) lower lumbar levels benefit from a more superiorly located COR. The COR in the model was varied from its initial position in posterior-anterior and inferior-superior direction up to ±6 mm in steps of 2 mm. Movement from upright standing to 45° forward bending and backwards was simulated for all configurations. Joint reaction forces were computed at levels L2L3 to L5S1. Results clearly confirmed hypotheses (1) and (2) and provided evidence for the validity of hypothesis (3), hence offering a biomechanical rationale behind the migration paths of CORs observed during functional flexion/extension movement. Average sensitivity of joint force magnitudes to an anterior shift of COR was +6 N/mm in upright and -21 N/mm in 30° forward flexed posture, while sensitivity to a superior shift in upright standing was +7 N/mm and -8N/mm in 30° flexion. The relation between COR loci and joint loading in upright and flexed postures could be mainly attributed to altered muscle moment arms and consequences on muscle exertion. These findings are considered relevant for the interpretation of COR migration data, the development of numerical models, and could have an implication on clinical diagnosis and treatment or the development of spinal implants.