Mechanical stimuli are critical to the growth, maintenance, and repair of the skeleton. The adaptation of bone to mechanical forces has primarily been studied in cortical bone. As a result, the mechanisms of bone adaptation to mechanical forces are not well-understood in cancellous bone. Clinically, however, diseases such as osteoporosis primarily affect cancellous tissue and mechanical solutions could counteract cancellous bone loss. We previously developed an in vivo model in the rabbit to study cancellous functional adaptation by applying well-controlled mechanical loads to cancellous sites. In the rabbit, in vivo loading of the lateral aspect of the distal femoral condyle simulated the in vivo bone-implant environment and enhanced bone mass. Using animal-specific computational models and further in vivo experiments we demonstrate here that the number of loading cycles and loading duration modulate the cancellous response by increasing bone volume fraction and thickening trabeculae to reduce the strains experienced in the bone tissue with loading and stiffen the tissue in the loading direction.