Osteoporosis is a bone disease characterized by a low bone mass that may seriously lead to vertebral fractures. Nowadays, especially elderly people, are most vulnerable to this complication. Hence, it is essential to prevent and predict the high-risk of mechanical stress that causes bone fractures. In this paper, a new computational methodology is developed to prevent the increase in the risk of bone failure in osteoporotic cervical vertebra based on mechanical stress assessment. The cortical bone thickness and the trabecular bone density from computed tomography (CT) scan data are the main initial input parameters for the computation. The methodology is based on a combination of finite element (FE) modeling of the lower cervical spine and the design of experiment (DoE) technique to establish surface responses assessing mechanical stress in healthy and osteoporotic vertebrae. The results reveal that the mechanical stress applied to an osteoporotic cervical vertebra is higher by an average of 35% compared to a healthy vertebra, respecting the applied conditions. Based thereon, a safety factor ([Formula: see text]) is introduced to predict and indicate the state of osteoporosis in the vertebra. A safety factor [Formula: see text] is found to correspond to a healthy state, 1.85 [Formula: see text] 2.45 for an osteopenic state, 1 [Formula: see text] 1.85 for an osteoporotic state, and [Formula: see text] 1 to indicate a severe osteoporosis state. The developed computational methodology consists of an efficient tool for clinicians to prevent early the risk of osteoporosis and also for engineers to design safer prostheses minimizing both mechanical stress concentration and stress shielding.