Microsoft word - jsw hrp abstract.doc

The Bisphosphonate Risedronate Prevents Early Radiation-Induced Bone Loss at
Multiple Skeletal Locations
Willey, J.S.1, Livingston, E.W.1, Bowman, L.C.1, Robbins, M.E.2, Bourland, J.D.2, 1Department of Bioengineering, Clemson University, Clemson, SC 2Department of Radiation Oncology, Wake Forest University School of Medicine, Astronauts will be exposed to several skeletal challenges during long-duration missions. Space radiation, including protons from solar and cosmic sources, represents one such challenge. Several studies have recently identified skeletal atrophy in mouse models at 1 and 4 months after exposure to protons and X rays (modeling the effects of clinical exposure). Little attention has been given to increased osteoclast activity as a contributor to radiation-induced osteoporosis. Our aims were to: 1) identify if radiation induces early bone loss; 2) quantify changes in the osteoclast population, and 3) test an antiresorptive drug to mitigate the bone loss. For these experiments, moderate-dose X rays were chosen, as the RBE of X-rays and protons are similar and bone loss from a 1 Gy dose is similar (-13-15%) for both types. To test the first two aims, thirteen-week old C57BL/6 mice (n=6/group) received whole body radiation with 2 Gy X-rays (140 kVp). A 1 mm region of the proximal tibia distal to the growth plate was analyzed via microCT. Relative to non-irradiated controls, bone volume fraction (BV/TV; - 42%), trabecular connectivity (ConnD; -82%) and number (Tb.N; -24%) were lower 2 weeks after exposure (P < 0.05). Circulating TRAP5b was significantly elevated on Days 1 (+50%) and 3 (+14%). TRAP-stained sections at Day 3 had increased osteoclast number (+80%; P < 0.05) and surface (+210%; P < 0.001). For the 3rd aim, skeletally mature mice (twenty-week old; n=12/group) were irradiated (2 Gy) with or without injections of risedronate (0.1 mg/kg/wk). MicroCT analysis was performed at 3 sites: Proximal tibia; distal femoral metaphysis; and a region of the body of the 5th lumbar vertebra (L5). Bones were collected 1, 2, and 3 weeks after irradiation. Body mass was not affected by treatments. From animals only receiving radiation, significantly lower BV/TV relative to control was observed at all three skeletal sites and at all three time points. ConnD was significantly lower after irradiation at all time points in the proximal tibia; at Weeks 2 and 3 in the distal femur; and at Week 3 in L5. Tb.N in the distal femur was significantly lower than control at all time points, and was lower in L5 at Week 2 and Week 3. Structure model index (SMI) values indicated more rod-like trabeculae after radiation in L5 at all time points, but starting at Week 2 at the distal femur. Evidence of bone loss or deterioration was entirely absent at all time points in animals receiving both radiation and risedronate. This study demonstrated a rapid loss of trabecular bone after whole body radiation at several skeletal sites. Changes were preceded by an increase in osteoclast number. As risedronate prevented the atrophy, an increase in osteoclast activity likely contributed to the radiation-induced bone loss. Future studies need to 1) identify the mechanisms for this early osteoclast activation, and 2) test the effectiveness of risedronate as a countermeasure to prevent bone loss after exposure spaceflight-relevant radiation in combination with skeletal unloading.

Source: ftp://ftp.lpi.usra.edu/pub/outgoing/2009HRPWorkshop/BoneMuscleCountermeasures/1062Willey.pdf