Systematic study of bones' responses to loading requires simple non-invasive models in appropriate experimental animals where the applied load is controllable and the changes in bone quantifiable. Herein, we validate a model for applying axial loads, non-invasively to murine tibiae. This allows the effects of mechanical loading in both cancellous and cortical bone to be determined within a single bone in which genetic, neuronal and functional influences can also be readily manipulated. Using female C57Bl/J6 mice, peak strains at the tibial mid-shaft were measured during walking (<300 micro epsilon tension) and jumping (<600 micro epsilon compression) with single longitudinally oriented strain gauges attached to the bone's lateral and medial surfaces. Identically positioned gauges were also used to determine, for calibration, the strains engendered by external applied compressive tibial loading between the flexed knee and ankle ex vivo. Applied loads between 5 and 13 N produced strains of 1150-2000 micro epsilon on the lateral surface, and in vivo repetitions of these loads on alternate days for 2 weeks produced significant load magnitude-related increases in cortical bone formation that were similar in mice at 8, 12 and 20 weeks of age. Micro-CT scans showed that loading significantly increases trabecular bone volume in 8 week old mice, but modifies trabecular organization with decreases in trabecular bone volume in 12 and 20 week old mice. This model for loading the tibia has several advantages over other approaches, including scope to study the effects of loading in cancellous as well as cortical bone, against a background of either disuse or of treatment with osteotropic agents within a single bone in normal, mutant and transgenic mice.