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The most serious manifestations of osteoporosis are proximal femoral fractures, affecting over 250,000 elderly in the United States each year and 890,000 in the European Union in the year 2000 alone. The impact on public health and the resultant cost to the health care system highlight the urgency to identify those parameters significant to accurately predict bone quality and fracture risk at the proximal femur. Determinations of the proximal femur are employed to illustrate relevant applications of vQCT with the potential to be extrapolated to other skeletal sites and the research and development of novel biomaterials that could contribute to the restoration or improvement of bone function. We explain the underpinning of parameters for bone mass, BMD, and bone geometry, as well as the structural indices discriminated by vQCT. We further clarify the benefit of sub-regional analysis (trochanteric region separate from femoral neck region) and of compartmental analysis (cortical bone separate from trabecular bone). In order to gain insight into how these factors contribute to bone fragility, we show how vQCT information combined with finite element modeling (FEM) information, a structural analysis tool, allows for estimation of fracture load under various loading conditions including impact from a fall. We typify unique results obtained from studies on aging, drugs with bone impact, and spaceflight, which is difficult to reveal in vivo without vQCT. We show in vivo how aging results in heterogeneous effects in the trochanteric and femoral neck region and how the impact of long-term spaceflight differs between trabecular and cortical bone. We suggest future directions for vQCT, such as the improvement of accuracy and precision for longitudinal studies, the FEM analysis integration into individual patient evaluation for in vivo assessment of simulated fracture conditions, and the development of additional variables for enhancement of bone fragility evaluations. [ABSTRACT FROM AUTHOR]