Although high-resolution skeletal images are essential for accurate bone strength assessment, the current high-resolution imaging modalities have critical problems that remain to be solved such as high radiation doses, low signal-to-noise ratios, and long scan times. Resolution enhancement techniques, which have recently received much attention, have also been difficult to obtain acceptable image resolutions. Inspired by the self-optimizing capabilities of bone (i.e. reorienting the trabecula for maximum mechanical efficiency with minimum bone mass), this paper proposes a novel resolution enhancement method that can reconstruct a high-resolution skeletal image from a low-resolution image. In order to achieve this, the proposed method conducts mesh refinement for resolution upscaling and then performs topology optimization with a constraint for the bone mineral density deviation in order to preserve the subject-specific bone distribution data. The numerical results show that the proposed method successfully reconstructs the enhanced images of trabecular architecture in terms of structure similarity and apparent elastic modulus, thereby demonstrating the feasibility of the proposed method for skeletal image resolution enhancement. (C) 2016 Elsevier Ltd. All rights reserved.