Osteoporosis, or rather the localised bone loss observed in patients with spinal cord injury, as well as during any type of immobilisation involves various processes and structures including the direct response of the musculoskeletal system to unloading, the central and peripheral nervous systems and their effects on bone cells and on the vascular system, the bone remodelling unit in its marrow compartment and a number of local factors controlling cell-cell cross-talk as well as calciotropic hormones. The authors present a detailed review of these different mechanisms which are all involved regardless of the type of immobilisation: pathological, environmental, or experimental. These factors are interconnected and put bone at the centre of the regulation of body homeostasis. A better knowledge of these mechanisms should promote the development of preventive therapies for the often neglected osteoporotic fractures that occur in patients with spinal cord injury.