Bisphosphonate Pretreatments Protect Cancellous Bone Density and Strength in Unloaded Adult Rats J.P. Elizondo1, J. M. Black, J. L. Kosniewski, J. E. Brezicha, S. E. Lenfest, S. A. Bloomfield, M. R. Allen, H. A. Hogan 1Texas A&M University, Dept. of Mechanical Engineering, College Station, TX LSMCE 2017, Indianapolis, IN October 7, 2017
NASA wants to go to mars by 2030s Bone loss is an issue
Cancellous Bone Loss in Space Bone adapts to loads placed on it No load on astronauts’ bones → rapid resorption Increased fracture risk Cancellous (“spongy”) is resorbed more than cortical[1] Normal ISS missions are about 6 mo. https://www.nasa.gov/centers/johnson/pdf/569954main_astronaut%20_FAQ.pdf Mission to Mars would be at least two to three years (6-months each way) http://www.mars-one.com/faq/mission-to-mars/how-long-does-it-take-to-travel-to-mars Buzz Aldrin suggested 10 years (Dunn, Marcia (27 August 2015). "Buzz Aldrin joins university, forming 'master plan' for Mars". AP News. Retrieved 30 August 2015.) [1]A. Leblanc, V. Schneider, L. Shackelford, S. West, V. Oganov, A. Bakulin, L. Voronin, Bone Mineral and Lean Tissue Loss After Long-Duration Spaceflight, J. of Musculoskeletal Neuronal Interaction, 1 (2000) 157-160. Image from https://depts.washington.edu/bonebio/ASBMRed/structure.html Human Femur Cross Section
BP incorporated in bone mineral Bisphosphonates Are most commonly administered osteoporosis drug Work by stopping resorption Have been used in astronauts[2] Affect bone for years after treatment Makes pretreatment a possibility X BP incorporated in bone mineral Nausea bad in space, some astronauts stopped taking ALN because of it Stay in human bone for ??? years [2]Leblanc, A., et al. "Bisphosphonates as a supplement to exercise to protect bone during long-duration spaceflight." Osteoporosis International 24.7 (2013): 2105-2114.
Rat Model for Microgravity Hindlimb unloading (HU) model Load removed from hindlimbs Analog for unloaded limbs of astronauts Hindlimb Unloaded Rat
Research Question Will bisphosphonate pretreatment protect from disuse-induced bone loss in the HU rat model?
Study Design Administered bisphosphonate pretreatment (4 weeks) Risedronate (RIS) and Alendronate (ALN) Put rats through HU protocol (4 weeks) Four groups: ambulatory control (AC), HU control, ALN+HU, RIS+HU Acclimation Drug Pretreat Unloading Recovery Euthanasia Day 0 Day 28 Day 56 Day 112 Get drugs from collaborators at Indiana Universtiy Clinical equivalent doses: ALN: 2.4ug/kg 3x/wk RIS: 1.2 ug/kg 3x/wk 6 mo old at day 0
Data Collection Ex Vivo peripheral quantitative computed tomography (pQCT) Reduced platen compression (RPC) mechanical testing Two cancellous-rich bone sites Proximal Tibia Metaphysis (PTM) Distal Femur Metaphysis (DFM) RPC Testing pQCT is basically an x-ray that computes BMD
pQCT Results HU
pQCT Results HU AC HUC RIS ALN
RPC Results HU
RPC Results HU
Conclusion Bisphosphonate pretreatment could be a viable alternative to concurrent treatment.
Acknowledgments All co-authors LSMCE organizers TAMUS LSAMP BTD (NSF Grant Award No. HRD-1612776) NASA Space Biology grant #NNX13AM43G NSBRI grant NCC9-58 (funded co-authors JEB and SEL)
Questions?
Supplemental pQCT Results HU
Supplemental pQCT Results HU
Supplemental RPC Results HU
Supplemental RPC Results HU
Alendronate in Human Astronauts Statistical Significance 1 = % change different from 0 2 = % change different from pre-ARED 3 = % change different from ARED Figure from Leblanc, A., et al. "Bisphosphonates as a supplement to exercise to protect bone during long-duration spaceflight." Osteoporosis International 24.7 (2013): 2105-2114.