Immobilisation or disuse is a condition known to be associated with a decrease in bone mass, osteopenia and in some people leading to osteoporosis with an increased risk of fractures. In this condition, previous histomorphometric and biochemical reports have shown an uncoupling between bone formation and resorption, but the exact sequence of the events resulting in bone loss is still not fully understood. In spinal cord injury for instance, the main finding soon after the onset is decreased osteoblastic activity associated with a dramatic increase in bone degradation. The overall consequence of these metabolic events is the development of a rapid and severe osteoporosis only observed in the paralysed part of the body associated with the loss of biomechanical strength and the biosynthesis of a structurally modified matrix which is unable to sustain normal mechanical stress. This situation dramatically increases the risk of fractures. The same uncoupling phenomenon has been described in healthy individuals who have been submitted to long duration bedrest and also in astronauts during spaceflight; but the timing, intensity and the metabolic subset may be different as these people do recover after cessation of the disuse period, which does not occur in paralysed patients. As new accurate and sensitive non-invasive techniques have become available recently to assess bone and connective tissue metabolism, more information is now available regarding bone loss in paralysed and/or immobilised individuals. These techniques should be definitely helpful in orientating new therapeutic trials with drugs and/or procedures intended to correct the musculoskeletal deleterious effects of disuse. This paper is therefore aimed at a review of bone metabolism in those with a severe spinal cord injury, or with a long duration of bedrest, or with loss of biomechanical function, or with actual or simulated spaceflight, in all instances using non-invasive techniques.