Osteoporosis is the most common pathology affecting bone and is characterized by degradation of bone's structural integrity, leading to increased fracture risk. Fractures result from the compromised mechanical integrity of bone; thus, a deeper understanding of the governing factors in bone mechanics could provide insight to the pathology and treatment of osteolytic diseases like osteoporosis. Trabecular bone is the primary site of osteoporosis. As a mechanobiological tissue, degradation in trabecular structure can affect tissue mechanics, and impaired biological response to local mechanical signals can lead to structural deterioration. Both of these factors can contribute to the progression of osteoporosis. Therefore, this work aimed at understanding the interactions of mechanics and biology of these phases in relation to trabecular bone density and architecture. Trabecular bone structure and biology were found to have a significant effect on bone quality. The relationship between structure, biology, and solid phase mechanics in trabecular bone was studied using the ovariectomized ewe. Microdamage accumulation was quantified based on architecture and ovariectomy status. Degraded architecture predisposed bone to the new crack formation, and microdamage accumulation was exacerbated by ovariectomy. Fluid phase mechanics of trabecular bone was governed by the trabecular architecture. Computational fluid dynamics was used to model the relationship between trabecular architecture and permeability, which describes fluid flow resistance in porous materials. Predictive models were developed relating the anisotropic permeability to architectural parameters, which showed that permeability primarily depends on pore size, shape, and directionality. The mechanical environment of bone marrow was also found to have an effect on trabecular architecture. Knowledge of the structural-mechanical relationships in trabecular bone was used to guide work that applied loads to bone marrow in situ. Loading was associated with improvements in trabecular architecture, and the results suggested that shear stress plays a role in this response. This work contributes to a better understanding of the interactions between the structure, mechanics, and biology of trabecular bone in its mineralized and fluid phases. Critical factors in bone quality and fluid mechanics were described, and new tools were developed to further study, model, and develop treatments for osteoporosis.