Human exposure to reduced weightbearing results in bone loss. The rate of bone loss during microgravity exposure is similar to that of a post-menopausal women. In fact, the maintenance of bone mass is intimately dependent on exercise. Therefore, exercise associated mechanical loads to bone tissue are an important countermeasure to prevent disuse-induced bone loss. However, the types of exercise modalities required to prevent such bone loss are unclear. Moreover, how mechanical loading to bone translates into molecular osteogenic signals in bone cells is unknown. Radiation exposure is another potent inducer of bone loss, namely observed on Earth in the clinical setting following radiotherapy procedures. It is expected that long duration space missions outside the protection of Earth’s magnetosphere will result in significant galactic cosmic radiation exposure. However, the magnitude of bone loss resulting from this galactic cosmic radiation exposure is unclear. Moreover, it is unknown if radiation exposure will exacerbate disuse-induced bone loss. Therefore, a series of experiments were designed to determine: 1) Will simulated galactic cosmic radiation exacerbate reduced weightbearing-induced bone loss? 2) Will pharmacological activation of the putative mechanosensing Wnt pathway enhance exercise-induced bone mass gain? To address these questions the experimental study series employed two animal models of reduced weightbearing, hindlimb unloading and partial weightbearing. These model test-beds enabled the evaluation of two novel countermeasures (simulated resistance exercise and glycogen synthase kinase-3 (GSK-3) therapeutic) and simulated exposure to space radiation environments. To test the impact of simulated space radiation (28Si) one study of the series was conducted at Brookhaven National Laboratory. To quantify the impact of the abovementioned countermeasures and space radiation on bone, mechanical testing, peripheral quantitative computed tomography, micro-computed tomography, histomorphometry, and immunohistochemistry served as primary outcome measures. The primary findings are: 1) Low-dose high-LET radiation negativity impacts maintenance of bone mass by lowering bone formation and increasing bone resorption. This impaired bone formation response is in part due to sclerostin induced suppression of Wnt signaling. 2) Combining GSK-3 inhibition with high intensity exercise mitigates cancellous bone loss and restores cortical periosteal growth during disuse.