This research focuses on the hierarchical structure of bone and associated mechanical properties at different scales to assess damage accumulation leading to premature failure, with or without instrumentation. In this work, an attempt was made to develop a framework of macro, micro, and nano damage accumulation models and implementing them to derive mechanical behavior of the bone. At macrolevel, retrospective evaluation of 313 subjects was conducted, and the damage of bone tissue was investigated with respect to subject demography including age, gender, race, body mass index (BMI), height and weight, and their role in initiating fracture. Experimental data utilized 28 human femoral bones implanted with cephalomedullary nails were used to develop damage prediction models. Investigation of three real life medical device failures identified the mechanical and clinical bases of bone failure. At the micro level, microdamage accumulation of the bone was investigated in 307 subjects and new effective morphological parameters at microscale were proposed. At the nano level, molecular dynamics simulation was performed to investigate the effect of interaction, orientation, and hydration on the atomic models of the bone composed of collagen helix and hydroxyapatite crystal. The results showed that bone density and maximum von Mises stress decreased drastically in elderly patients, implying fixation devices and implants used by the young cannot be used. The results also showed that the two-dimensional representation of the morphological parameters of the bone at microscale does not provide a realistic description of bone structure. Therefore, in this work, three-dimensional representations at microscale indicated that bone interconnectivity is higher in female patients than in male patients. Gender has a significant effect on microdamage distribution in the bone. More precautions should be taken into consideration for older female patients. Race should also be considered during modeling implants or suggesting therapeutic techniques. Caucasian subjects are more susceptible to bone fatigue failure than other races. The mechanical properties of bone are affected significantly by the orientation of the collagen fibril, which varies between ethnicities. Any change in the structure of the collagen-hydroxyapatite composite leads to variable bone diseases. There is significant difference in the ultimate tensile strength and toughness of the bone with respect to the orientation of the hydrated and un-hydrated collagen fibrils. Water content also influences the bone tissues’ elastic properties. The force in longitudinal direction (0°) provides more strength compared with the collagen fibril in the perpendicular direction (90°). Substituting Glycine with other amino acids affects the mechanical properties and strength of the collagen helix, collagenhydroxyapatite interface, and eventually affecting hydroxyapatite crystal. Appropriate models developed in each category showing experimental and computational relationships and their application in selecting implant materials.