Safe and effective countermeasures to spaceflight-induced osteoporosis are required to mitigate the potential for mission-critical fractures and ensure long-term bone health in astronauts. Two antiresorptive drugs, the bisphosphonate zoledronic acid (ZOL) and the anti-RANKL protein osteoprotegerin (OPG), were investigated to find the minimum, comparable doses that yield a maximal increase in bone quality, while minimizing deleterious effects on turnover and mineralization. Through a series of five trials in normally loaded female mice (n=56/trial), analysis of trabecular volume fraction and connectivity using microcomputed tomography (microCT), along with biomechanical testing, quantitative histomorphometry, and compositional analysis, was used to select 45 µg/kg ZOL and 500 µg/kg OPG as doses that satisfy these criteria. These doses were then examined for their ability to mitigate bone loss following short-term unloading through hindlimb suspension (HLS). 72 mice were prophylactically administered ZOL, OPG, or PBS and assigned to loaded control (LC) or two-week HLS groups (n=12 for each of 6 groups). Both antiresorptives were able to preserve trabecular microarchitecture and femoral elastic and maximum force in HLS mice (+30-40% ZOL/OPG vs. PBS). In HLS mice, antiresorptive dosing reduced resorption perimeter at the femoral endocortical surface by 30% versus PBS. In LC mice, antiresorptives produced no change in bone formation rate (BFR); however, reductions in BFR brought about by HLS were exacerbated by antiresorptive treatment, suggesting synergistic inhibition of osteoblasts during disuse. Refined antiresorptive dosing will tend to target countermeasures to the period of disuse, resulting in faster recovery and less adverse effects for astronauts.