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Disuse Exacerbates Suppression of Bone Formation with Administration of Low-Dose Antiresorptive Drugs.  S.A.J. Lloyd and T.A. Bateman. Department of Bioengineering, Clemson University, Clemson, South Carolina.

 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. In a previous study, two antiresorptive drugs, the bisphosphonate zoledronic acid (ZOL) and the anti-RANKL protein osteoprotegerin (OPG), were investigated to find comparable, efficacious doses that yield a maximal increase in bone quality, while minimizing deleterious effects on bone turnover and mineralization. Following a series of five iterative trials in normally loaded female mice (C57BL/6J, 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). For this study, 72 mice were prophylactically administered ZOL, OPG, or PBS and assigned to loaded control (LC) or two-week HLS (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, it was noted that reductions in BFR brought about by HLS were exacerbated by antiresorptive treatment. These findings suggest that synergistic inhibition of osteoblasts may be occurring when antiresorptive treatments are provided during periods of disuse. This may have important implications for astronauts in microgravity, where bone formation is already suppressed. Development of refined antiresorptive dosing will tend to target countermeasures to the period of disuse, resulting in faster recovery and less adverse effects in the long term. Supported by a grant from NSBRI (NASA NCC9-58).