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Pharmacological Countermeasures for Bone Loss During Long-Duration Space Flight.  P.R. Cavanagh1,2, A.A. Licata2,3, and A.J. Rice1  Depts. of 1Biomedical Engineering, 2Orthopaedic Surgery, and 3Endocrinology, The Cleveland Clinic Foundation, Cleveland, OH.

   Bone loss in the lower extremities and lumbar spine is an established consequence of long duration human spaceflight.  Astronauts typically lose bone mass in the proximal femur at over 10 times the rate that occurs in postmenopausal women on Earth.  So far, pharmacological interventions have not been routinely used in space and countermeasure programs have depended solely upon exercise.  However, it is clear that the osteogenic stimulus has not been adequate to maintain bone mass, due to insufficient exercise load or duration.  Attention has therefore been focused on several of the pharmacological interventions that have been successful in preventing or attenuating osteoporosis on Earth.

   Anti-resorptives are the most common class of drugs used to treat osteoporosis in post-menopausal women, notably alendronate sodium (Fosamax — Merck), risedronate sodium (Actonel — P &G), zoledronate (Zometa — Novartis), and SERMs (Selective Estrogen Receptor Modulators) such as raloxifene (Evista — Lilly).  There has also been considerable recent interest in anabolic agents such as PTH and teriparatide (rhPTH [1-34]) (Forteo - Lilly).  Treatment with Vitamin D supplementation has also been used.  Recent studies of kindreds with abnormally high BMD have provided insight into the genetic regulation of bone mass.  This has led to potential therapeutic interventions based on the Wnt and BMP2 pathways.  Another target of interest is the RANK-L/osteoprotegerin (OPG) signalling pathway, which influences bone turnover by regulating osteoclast formation and maturation.  Trials using some of these therapies in space are being planned.  Among the factors to be considered are dose-response relationships, bone quality, post-use recovery, and combination therapies - all of which may have unique characteristics when the drugs are used in space compared to ground-based use.

   (Supported by National Space Biomedical Research Institute grants BL00401 and BL00402)