The data Wortmannin presented support the validity of the assumption, in the C57BL/6 mouse unilateral tibia/fibula axial loading model [12], [27] and [29] at least, since they showed no difference in bone (re)modelling between the bones of appropriately matched mice in which no bones were loaded and those contra-lateral to bones which had received static or static plus dynamic loading. From this we draw the narrow inference that bones in the contra-lateral

limbs to those loaded at physiological levels sufficient to stimulate a vigorous osteogenic response can be used as non-loaded controls. We also draw the wider inference that functionally adaptive control of bone architecture is a local phenomenon within each bone that does not involve adjacent, regional or contra-lateral bones. The lack of uniformity in response in different regions of the loaded tibia suggests that the domain in which local strains influence (re)modelling is not only confined to the loaded bone but also is regional within it. While

we have no reason to believe that this inference does not have general applicability, prudence dictates that it should be verified in each experimental situation where it is employed. Our present experiment was not designed to establish the potential involvement of the nervous system in bones’ functionally adaptive response. In the earliest experiments using artificial loading, Hert et al. [34] showed that adaptation took

place in the tibia Natural Product Library molecular weight when the sciatic nerve had been sectioned. This accords with our experience [13]. Functional adaptation to loading has also been shown not to be affected by pharmacological blockade of the sympathetic nervous system [22]. These findings give us no reason to suggest that it is necessary to invoke nervous control in order to explain bones’ functionally adaptive control of bone (re)modelling. It was also not our intention to reproduce the experimental conditions in Sample et al.’s [30] study nor to explore experimentally the inconsistencies between Sodium butyrate their data and ours. There are a number of ways in which loading of one bone can have substantial effects on (re)modelling of adjacent and remote bones that are independent of normal, strain-related functionally adaptive (re)modelling. For example, new bone formation may be stimulated by the effects of trauma or interference with blood supply or be associated with the repair processes which any follow these events. We have no way of assessing whether these may have contributed to the responses reported by Sample et al. The animals they used were rapidly growing male Sprague–Dawley rats and young growing bone is more sensitive to such effects.