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Determination of Minimum, Efficacious Comparable Doses of Zoledronate and Osteoprotegerin: Maximizing Bone Mass and Turnover. S. Lloyd1, S.A. Hamilton2, C. Cheluvaraju2 and T.A. Bateman2 1Dept. of Pharmacology, U. of British Columbia, Vancouver, BC, Canada 2Dept. of Bioengineering, Clemson U., Clemson, SC.

   Bone loss is a major obstacle for the future of long duration spaceflight. In microgravity, skeletal unloading causes bone resorption, a decline in bone density, and an elevation in serum Ca2+. ISS studies reveal that the rate of bone loss is 1-1.5% per month and that recovery is incomplete up to a year post-flight (Lang et al., 2004). As mission lengths increase, this bone loss may lead to mission critical fractures. In order to prevent these effects, robust countermeasures must be developed. The use of two antiresorptive agents has been proposed: osteoprotegerin (OPG) and the bisphosphonate zoledronate (ZOL). Both are being investigated to find the minimum comparable dose to yield a maximal increase in bone mass and density, and the minimum dose required to prevent hypercalcemia. OPG may be preferable over ZOL because it is not incorporated into bone, so bone turnover is restored to preflight levels at a faster rate. MicroCT analysis of trabecular density and connectivity in the tibiae of treated female mice reveal that doses of 30 μg•kg-1 for ZOL and 100 μg•kg-1OPG have maximal response. Continuous administration of parathyroid hormone (PTH) is being utilized as a ground based model to simulate the elevated Ca+2 associated with spaceflight. However, murine PTH response was found to be markedly different than previous rat studies, where doses of 7.5 μg•kg-1PTH induced hypercalcemia. Analysis of blood Ca2+ revealed no significant (p>0.5) hypercalcemia up to 40 μg•kg-1 PTH; however, a dose of 80 μg•kg-1•day-1 was able to produce a stable and significant (p<0.05) hypercalcemia for 7 days. Future iterations of these studies will further narrow the range of ZOL and OPG and investigate their capacity to act prophylactically on PTH-treated mice to prevent hypercalcemia and maintain bone quality. The use of a malignancy hypercalcemia model is also being investigated as a viable alternative to PTH.

(Supported by Clemson University, BioServe Space Technologies (NASA NCC8-242) and the NSBRI through NASA NCC 9-58.)