X-ray absorption spectroscopy is applied to investigate relationships between hierarchical organization of the skeleton and nanostructure of femoral bone in knee compartments and to understand the osteoarthritis (OA) related changes at the subcellular level. Our focus is on local electronic and atomic and molecular architectonics of the medial and lateral condyles of the femur resected during total knee arthroplasty in patients with medial compartmental knee OA. The element-specific and sitedependent peculiarities in spectral distributions of oscillator strength for core-to-valence transitions are revealed. The near Ca 2p andO1s edges x-ray absorption fine structure (Ca 2p andO1s NEXAFS) spectra of the saw cuts demonstrate substantial redistributions in intact and OA damaged areas on the proximal side, and on the proximal and distal sides of the samples. Examining the O1s NEXAFS spectra new chemical bonds are revealed on the proximal surface in the OA areas. Strong intra-atomic intershell Ca2+ 2p(3/2)(,1/2)(5) 3d(1) interaction specifies the great similarity of the Ca 2p NEXAFS spectra. Their analysis performed in combination with the x-ray photoelectron data has demonstrated the formation of non-apatite calcium in the OA areas of the samples. It is shown that NEXAFS spectroscopy is a powerful tool for deeper understanding relationship between hierarchical skeletal organization and nanostructure of native bone. Perspectives for development of novel methods for medical imaging and diagnosis of subchondral bone at the nanolevel are discussed.