Osteoporosis causes over 2 million skeletal fractures every year in people 50 years of age or older. Fractures predominantly happen at corticocancellous sites, such as the hip and spine. Due to lower accrual of bone mass during growth and rapid bone loss following menopause, 71% of these fractures occur in women. Mechanical loading, which stimulates bone formation, is a potential anabolic therapy for pathological bone loss. Determining the parameters of mechanical loading that stimulate osteogenesis in cancellous bone is critical for harnessing the therapeutic potential of mechanical stimuli. In this thesis, the effects of sex, aging, and estrogen deficiency on the adaptive response of cancellous bone were examined using in vivo tibial compression applied to mice.

The effect of sex on the cancellous adaptive response to tibial loading was investigated in growing mice. The magnitude of peak applied loads that corresponded to +1200 µε at the tibial mid-shaft was determined to be -11.5 N in both males and females from in vivo strain gauging. This peak load resulted in similar peak cancellous tissue strains of ~-2400 µε in females and ~-2100 µε. Following 2 weeks of tibial compression, male and female mice increased cancellous bone mass 73% in the proximal tibia, primarily through increased trabecular thickening (+75%). Tissue mineral density increased 18% and trabecular separation decreased 19% as well. As a result of adaptation, the proportion of the applied load carried by the cancellous compartment, rather than by the cortical shell, increased. In addition, the metaphyseal stiffness of the loaded limbs was greater than in control limbs. None of these loading-induced changes differed by sex.

Next, the effect of aging on the cancellous adaptive response was investigated in adult, osteopenic female mice, and this response was compared to that observed previously in growing mice. We applied the same peak compressive loads (-11.3 N) to one group of adult female mice (Load-Matched), which corresponded to +2200 µε mid-diaphyseal strains and peak cancellous tissue strains of -2257 µε. We applied the same peak mid-diaphyseal strains (+1200 µε) to a second group of adult female mice (Strain-Matched), engendered by -5.9 N peak applied load, which corresponded to peak cancellous tissue strains of -1112 µε. In the LM group, cancellous bone mass increased 49% through increased trabecular thickening (+64%), and cortical mass increased 41% through medullary contraction (-19%). These adaptive changes increased the metaphyseal stiffness of loaded limbs relative to control limbs (IMAX +88%, IMIN +54%). No adaptive response was observed in the SM group. The response in the cancellous compartment was reduced relative to that observed in growing mice. However, tibial loading recovered age-related loss to levels equivalent to control limbs of young animals, supporting the use of mechanical loading as a therapeutic intervention against osteoporotic fractures. In contrast, the response in the cortical compartment was enhanced relative to that in young mice. While both young and adult mice similarly increased IMAX and cortical area, adult mice underwent enhanced medullary contraction.

Finally, tibial compression was applied to osteopenic, estrogen-deficient adult female mice to demonstrate that mechanical loading can stimulate cancellous bone formation following estrogen withdrawal. Loading was applied immediately following ovariectomy (OVX) or sham (Sham) surgery and lasted 1, 2, and 6 weeks to characterize the adaptive response over time. Estrogen deficiency did not inhibit the adaptive response of cancellous bone in adult females. After 6 weeks of loading, cancellous bone mass increased similarly in Sham and OVX groups. Cancellous bone mass exhibited a bimodal change with loading due to the different effects of loading and estrogen deficiency, acting at different rates, on cancellous architecture. Loading primarily increased trabecular thickness while estrogen deficiency primarily increased separation. No differences in the control limbs between Sham and OVX groups were observed within the 6 week time period.

In summary, tibial compression elicited a robust anabolic response in cancellous bone, which increased mass in growing young male and female mice, and in osteopenic and estrogen deficient adult female mice. Cancellous mass occurred primarily through trabecular thickening and resulted in an overall stiffer tibia metaphysis. Tibial compression recovered age-related bone loss in osteopenic adult female mice to levels equivalent to the control limbs of young mice, even following estrogen withdrawal. These results demonstrate that mechanical loading can be targeted to corticocancellous sites to increase bone mass, improve structural integrity, and reduce risk for fracture. Additionally, these results demonstrate that mechanical loading can be implemented as a preventative measure, either in growing children, or pre- and peri-menopausal women, to increase peak bone mass and reduce risk of fracture.