BACKGROUND: It is well known that there is a relationship between bone strength and the forces that are daily applied to the bone. However, bone is a highly heterogeneous material and it is still not clear how mechanical variables regulate the distribution of bone mass in a femur. METHODS: We studied the role of four mechanical variables, i.e. principal tensile/compressive stress, von Mises stress, and strain energy density (SED), in the regulation of bone mineral density (BMD) distribution in the human femur. The actual BMD in a femur was extracted from quantitative computed tomography (QCT) and used as a reference for comparison. A finite element model of the femur was constructed from the same set of QCT scans and then used in iterative simulations of femur remodeling under stance and walking loading. The finite element model was initially assigned a homogeneous BMD distribution. During the remodeling, femur BMD was locally modified according to one of the four mechanical variables. The simulations were stopped when BMD change in two consecutive iterations was adequately small. The four simulated BMD patterns were then compared with the actual BMD. RESULTS: It was found that the BMD pattern regulated by SED had the best similarity with the actual BMD. The medullary canal was successfully reproduced by simulated remodeling, indicating that in addition to its biological functions, the medullary canal has important biomechanical functions. CONCLUSIONS: Both the actual and simulated BMD distributions showed that the proximal femur has much lower BMD than the femur shaft, which may explain why hip fractures most often occur at the proximal femur.