It is clear that bone senses and responds to biomechanical stimuli towards the achievement and maintenance of a structurally appropriate skeletal structure. However, experimental results reflect a complex interaction between skeletal morphology and the mechanical environment, whereby any oversimplification (e.g., strain magnitude is the dominant determinant of bone mass) will camouflage the structural goals of the adaptive process and the biologic principles which control them. To the contrary, it is clear that, in addition to strain magnitude, bone tissue has the ability to differentiate between shear and normal strain, cycle number, loading frequency, and even fluid pressure and its gradients. The interdependent role of these mechanical signals were investigated through empiric and analytic models to provide support for the complex interactive mechanism of bone remodeling.

Bone’s ability to respond relatively high frequencies of mechanical stimuli is indicative as to how bone cells sense the signal for adaptation. This frequency sensitivity data extends beyond identifying the factor that stimulates bone formation. Data presented in Chapter 2 indicates that the most active inhibitor of bony ingrowth is the shear strain and stress generated at the bone-implant interface. While specific mechanical parameters, i.e., normal strains and strain gradients, may mildly encourage the bony ingrowth, shear actively inhibits it. To maximally stimulate bony ingrowth, implant design must promote specific stresses or strains and their gradients, while minimizing shear stress or strain at the bone-implant interface.

The ability of bone tissue to differentiate shear and normal strain conditions was evaluated by monitoring the adaptive response of axial and torsional loading conditions in a turkey ulna model (Chapter 3). Of three distinct regimens (disuse, axial and torsional loads), only disuse caused a significant change in gross areal properties as compared to controls (12% loss of bone), suggesting both axial and torsional loading conditions were suitable substitutes for functional signals normally responsible for bone homeostasis. However, the intracortical response was strongly dependent on the manner in which the bone was loaded. It appears that bone tissue can readily differentiate between distinct components of the strain environment, with strain per se necessary to retain coupled formation and resorption, shear strain achieving this goal by maintaining the status quo, while axial strain elevates intracortical turnover, but retains coupling.

The interdependent role of loading frequency, cycle number and intensity was investigated by quantifying the bone remodeling response to a relatively high frequency (30 Hz) loading regimen (Chapter 4). The applied strain distributions were correlated to site-specific surface modeling/remodeling and intracortical porosity under long duration loading, following disuse plus 18,000 of applied loading cycles with peak normal strain of 700 (is, and disuse plus 108,000 applied loading cycles induced at 100 μe. While new bone was found in the low cycle, high strain magnitude group, the sites correlated poorly with the distribution of induced strain. However, a strong correlation was observed between the preservation of bone mass and longitudinal normal strain (R=0.91) in the high cycle, low strain magnitude group. These results indicate that mechanical loading can hold anti-resorptive potential, even at levels less than 100 μe, should a sufficient number of strain cycles be applied. The data also support the interdependent role of loading frequency and cycle number, demonstrating the inhibition of bone resorption and intracortical turnover to be far more sensitive to high frequency, high cycle number loading than to an equal time dose of lower frequency (and thus low cycle number) loading, even though of much greater magnitude.

Considering the interdependent role of strain magnitude, shear and normal strain components, strain gradient and loading frequency, a likely candidate involved in the adaptive process may be the intracortical fluid pressure and resultant fluid flow which arises in the cortical bone matrix by the time-varying mechanical strain, which may serve as a critical signal to regulate cell activity. This hypothesis is supported by experiments described in Chapter 5, which evaluate whole bone fluid pressure and its gradient in a porous media model incorporated with in vivo streaming potential measurements. Based on the frequency dependent site specificity of the remodeling response (i.e., endosteal vs. periosteal), the most likely parameter which promotes surface new bone formation may be fluid pressure gradient and its corresponding fluid velocity, factors which are strongly mediated by loading frequency (Chapter 5 & 6). The mechanism of this fluid pressure gradient related remodeling response may be that osteocytic processes in the bone could serve as a mechanical signal receptors by ways of sensing the fluid flow induced by pressure gradients. Thus, perturbation of intracortical fluid flow, via alterations in functional activity, may provide a key influence in determining skeletal morphology. Finally, these results may improve our understanding of functional vertebrate morphology and etiologic processes in musculoskeletal diseases, and perhaps even provide insight into novel treatment regimens for the treatment of these diseases (i.e., osteoporosis), the acceleration of fracture repair, and the promotion of bony ingrowth.