There are numerous animal and human models to study the effects upon the skeleton of eliminating mechanical usage by immobilization (IM). Care must be taken in employing the various models. They all have the same pattern of bone loss, but they respond slightly differently in the location and the amount of bone loss, depending upon the degree of unloading. Experimental immobilization studies involving local disuse-induced bone loss models can lose up a baseline level of 60% of their trabecular bone mass. This baseline level suggests a physiological threshold where basal hormonal and cellular activity determined by genetics is reached in the absence of mechanical stimuli. During the transient, immediate, or acute phase of immobilization, remodeling-dependent bone loss occurs in bone adjacent to marrow and from an increase in bone resorption and a decrease in formation. At steady state, or chronic phase, bone mass has plateaued at baseline with cellular activities back to normal levels. Further lowering of immobilization-induced bone loss from immobilization baseline levels can occur with nonmechanical factors like estrogen deficiency. A reasonable working model of immobilization-induced bone loss uses Frost's mechanostat theory and skeletal adaptation to mechanical usage highway to show the IM-induced bone loss, the mechanical usage feedback from the overloaded osteopenic bone and the modification of the IM-induced baseline response with non-mechanical agents. Lastly, an investigator should employ the combination of IM plus OVX model for evaluating agents in the prevention and healing of osteoporosis because it combines the skeletal response of estrogen deficiency in postmenopausal osteoporosis and age-related bone loss due to decreased physical activity.