In contrast, the loading regimens we use in the tibia/fibula as well as ulna to assess strain-related adaptation (less than 2000 microstrain; 40 cycles at 10 Hz with 10-s intervals between each cycle [a total of 400 s]) [12], PLX-4720 in vitro [13], [27] and [29] are designed to produce a realistic physiological stimulus capable of stimulating a measurable osteogenic

response while avoiding collateral stimulation associated with trauma and interference with blood supply both within the bone and around the loading cups. We select to use “three-dimensional” high-resolution (5 μm) μCT rather than “two-dimensional” fluorescent histomorphometry as our main tool to quantify functional adaptation in order to be able to analyze precisely comparative sites of the small mouse loaded and contra-lateral non-loaded bones. In our present study, when we employed the same histomorphometric analysis as Sample et al. [30], it revealed no substantial differences from the μCT data and thus confirmed the absence of any differences in (re)modelling between non-loaded bones regardless of whether they were contra-lateral to bones which had been loaded or to those which had not. Our inference that strain-related functional adaptation in bone is a local phenomenon that does not extend to other bones or involve systemic or nervous intervention is limited to strains

within the physiological range. Strains higher than this, or those repeated far more often, or perhaps with faster strain rates may well induce damage in the bone tissue not and/or damage-related changes in the bone cells. In this situation, it is quite possible VE-821 price that the responses to these events

may spread beyond the bones actually loaded and incorporate systemic involvement and/or involvement of the nervous system. Indeed, Sample et al. [30] observed no or less systemic and contra-lateral (re)modelling responses when they employed lower strains (760 and 2000 microstrains). The immediate experimental implication of this is that it would be prudent in any study that relies on use of contra-lateral non-loaded bones as controls to establish the level of loading-related stimulation that does not exceed the level necessary to stimulate local, strain-related functional adaptation. More intensive strain regimens may engender effects that extend beyond the local confines of the loaded bones. The wider implication may be that there is a distinction between the mechanisms involved in strain-related functional adaptation, the (re)modelling of which leads to adaptive changes in bone architecture presumably to regulate functional strains and the trauma-related (re)modelling which involves wider responses. In the present study, a static load of 2.0 N did not affect cortical bone of the right loaded tibiae/fibulae or their longitudinal lengths.