Bisphosphonates as a Countermeasure to Space Flight Induced Bone Loss (Bisphosphonates) - 07.15.15

Overview | Description | Applications | Operations | Results | Publications | Imagery

ISS Science for Everyone

Science Objectives for Everyone
The purpose of the Bisphosphonates as a Countermeasure to Space Flight Induced Bone Loss study is to determine whether an antiresorptive agent, in conjunction with the routine in-flight exercise program, protects International Space Station (ISS) crew members from the regional decreases in bone mineral density documented on previous ISS missions.
Science Results for Everyone
ISS crew members exercise regularly to help reduce bone loss but still lose signifcant bone mass over a long mission.   A weekly pill may help. The Bisphosphonates as a Countermeasure to Space Flight Induced Bone Loss study tests biphosphonates, bone antiresorptive agents used to increase bone strength, in conjunction with routine in-flight exercise during long-term spaceflight. Bone measurements and comparisons of early model resistance exercise device or the advanced resistance exercise device (ARED) show that ARED and bisphosphonate together improve essentially all measures of bone physiology during spaceflight. Scientists conlude that exercise plus an antiresoptive drug may help prevent bone loss on long missions.

The following content was provided by Adrian D. LeBlanc, Ph.D., and is maintained in a database by the ISS Program Science Office.
Experiment Details

OpNom: Bisphosphonate

Principal Investigator(s)
Adrian D. LeBlanc, Ph.D., Universities Space Research Association, Houston, TX, United States
Toshio Matsumoto, Ph.D., M.D., University of Tokushima, Kuramoto, Japan

Co-Investigator(s)/Collaborator(s)
Joyce H. Keyak, Ph. D., University of California at Irvine, Irvine, CA, United States
Kenjiro Kohri, Ph.D., M.D., Nagoya University, Mizuho-ku, Japan
Toshitaka Nakamura, Ph.D., M.D., University of Occupational and Environmental Health, Kitakyushu, Japan
Hiroshi Ohshima, M.D., Ph.D., Japan Aerospace and Exploration Agency, Ibaraki, Japan
Linda C. Shackelford, M.D., Johnson Space Center, Houston, TX, United States
Harlan J. Evans, Ph.D., Wyle Laboratories, Houston, TX, United States
Jeffrey A. Jones, M.D., Baylor College of Medicine, Houston, TX, United States
Jay Shapiro, M.D., Kennedy Krieger Institute, Baltimore, MD, United States
Jean D. Sibonga, Ph.D., Johnson Space Center, Houston, TX, United States
Thomas F. Lang, Ph.D., University of California, San Francisco, CA, United States
Scott M. Smith, Ph.D., NASA, Houston, TX, United States
Elisabeth R. Spector, Wyle Laboratories, Houston, TX, United States

Developer(s)
NASA Johnson Space Center, Human Research Program, Houston, TX, United States

Sponsoring Space Agency
National Aeronautics and Space Administration (NASA)

Sponsoring Organization
Human Exploration and Operations Mission Directorate (HEOMD)

Research Benefits
Space Exploration

ISS Expedition Duration
October 2008 - Ongoing

Expeditions Assigned
18,19/20,21/22,23/24,25/26,27/28,29/30,31/32,33/34,35/36,37/38,39/40,41/42,43/44,45/46,47/48

Previous ISS Missions
Information Pending

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Experiment Description

Research Overview

  • The potential for loss of bone mass is one of the most important medical concerns for long-duration manned space flight with regional losses of 1 to 2 percent per month in spite of the fact that crew members exercise while in space. The resultant hypercalciuria (abnormally high calcium levels in urine) increases the risk of renal stone formation.
  • Bisphosphonates are a group of antiresorptive agents that block the breakdown of bone and are used to treat osteoporosis and and other disorders related to bone turnover. 
  • This study tests the effectiveness of alendronate, taken as a pill once per week before and during space flight.
  • If shown to be an effective countermeasure to space flight-induced bone loss, bisphosphonates or other antiresorptive agents could help prevent several bone-related problems for crew members on the International Space Station (ISS) and on future long-duration missions. These problems include loss of bone mineral mass and strength and the possibility of developing renal stones during or after space flight.

Description
The purpose of this investigation is to determine whether bisphosphonates, in conjunction with the routine in-flight exercise program, protects International Space Station (ISS) crew members from the regional decreases in bone mineral density documented on previous ISS flights. Two dosing regimens were originally planned, an oral dose of 70 mg of alendronate taken weekly starting 3 weeks prior to flight and then throughout the flight and an intravenous (I.V.) dose of zoledronic acid, 4 mg, administered just once approximately 45 days before flight. However, only alendronate administration was actually tested. Control subjects, who participate in all pre-, in-, and post-flight tests, but do not ingest an antiresorptive agent, were added to control for the effects of improved exercise equipment aboard the ISS.

An interim review of the data for this study (04-E255/SMO 021) indicated that it was necessary to add a new control group whose results could be compared to those of crewmembers who have taken bisphosphonates. The original historical control group (14 crew members from early ISS flights) exercised using the Interim Resistive Exercise Device (IRED), while the bisphosphonate subject group (7 subjects, now complete) exercised on the newer Advanced Resistive Exercise Device (ARED). The new control group will help distinguish the relative effects of bisphosphonates versus the confounder of ARED. The control subjects will participate in essentially the same data collection protocol as the bisphosphonate group, but will not take the oral or i.v. bisphosphonate.

The primary measurement objective of this study is to obtain preflight and postflight Quantitative Computed Tomography (QCT) scans of the hip. The QCT scans provide volumetric bone density information of both cortical and trabecular (spongy) bone regions of the hip. This study aims to show that bisphosphonates significantly reduces bone mineral density loss and the increased risk of renal stone formation documented previously on untreated ISS crew members.

Secondary measurement objectives include: preflight and postflight Dual-energy X-Ray Absorptiometry (DXA) scans of the whole body, spine, hip, and heel; preflight and postflight scans of the tibia using peripheral Quantitative Computed Tomography (pQCT); preflight and postflight abdominal/retroperitoneal ultrasound scans; preflight and postflight blood draws to measure serum markers of bone metabolism, and preflight, in flight, and postflight urine collections to measure urinary markers of bone metabolism. Urine measurements are also used to look at the risk for developing renal stones before, during and after flight.

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Applications

Space Applications
The purpose of this investigation is to determine whether antiresorptive bisphosphonates, in conjunction with the routine in-flight exercise program, will protect ISS crew members from the regional decreases in bone mineral density and bone strength documented on previous ISS flights. If shown to be an effective countermeasure to space flight induced bone loss, bisphosphonates could prevent or ameliorate several potential bone-related problems identified in NASA's Critical Path Roadmap. If bisphosphonates improve the efficiency of in-flight exercise to maintain bone mass, then more crew time could be made available for other purposes.

Earth Applications
The benefits of this research are primarily for space travelers. Knowledge gained from this investigation may generate useful information applicable to patients on Earth with accelerated bone loss due to disuse (e.g., spinal cord injury patients or those with prolonged immobilization).

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Operations

Operational Requirements
This experiment requires the participation of long-duration crew members taking the drug compared with 10 control subjects. All subjects will complete DXA scans (Launch minus 45 days (L-45), Return plus 5 days (R+5), R+180, [not required for controls], and R+360), pQCT scans (L-45, R+5, R+180, [not required for controls], and R+360), high resolution QCT scans (L-45, R+5, R+360), ultrasound scans (L-180, R+30), 24-hr urine collections (L-45, R+0, early inflight, midflight, late inflight, R+30, R+360), and blood draws (L-45, R+0, R+30, and R+360). Alendronate subjects will complete an Alendronate Tolerance Test on L-180, and they will take Alendronate on L-17, L-10, and L-3.

Operational Protocols
While in flight, Alendronate subjects ingest one pill weekly. All subjects conduct three urine collection sessions (4 weeks, 12 weeks, and 24 weeks). Crew members also take a daily Vitamin D supplement for the duration of the mission.

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Results/More Information

High bone loss for astronauts during long-duration spaceflight has been a persistent problem and a major concern in spite of rigorous exercise countermeasures onboard the International Space Station (ISS). Excessive calcium from dissolved bone also contributes to the formation of possibly debilitating kidney stones in space. This study investigates the effectiveness of bisphosphonate drugs coupled with exercises on the Advance Resistive Exercise Device (ARED) in preventing loss of bone mass in long-term ISS crewmembers. The latest data from 7 astronauts who took Fosamax ®, a bisphosphonate drug, and worked out on ARED are compared to previous data from 18 astronauts who exercised using an early model resistance exercise device, called the interim resistance exercise device (IRED), and to 11 other astronauts who exercised with ARED only. Pre- and post-flight bone scans, ultrasound, and bone marker results show reduction in bone loss from multiple skeletal sites and maintained hip strength. These findings indicate that the ARED exercises significantly lessen bone loss compared with the older device although post-flight decreases in the femur neck and hip remained. The combination of the ARED and bisphosphonate reduced the typical decline in bone physiology during spaceflight including: bone mineral density of the spine, hip, and pelvis, losses in trabecular and cortical bone mass in the hip, bone strength of the hip, elevated levels of bone resorption markers, and urinary excretion of calcium. Overall these results suggest that the ARED device improved bone balance compared with the pre-ARED group and analysis shows maintained Bone Mineral Density (BMD) in the group that received bisphosphonate treatment plus ARED. Researchers conclude that the combination of exercise plus an antiresoptive drug such as Fosamax ® may be useful for protecting bone health during long-duration spaceflight.

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Results Publications

    LeBlanc AD, Matsumoto T, Jones JA, Shapiro J, Lang TF, Shackelford LC, Smith SM, Evans HJ, Spector ER, Ploutz-Snyder RJ, Sibonga JD, Keyak JH, Nakamura T, Kohri K, Ohshima H.  Bisphosphonates as a supplement to exercise to protect bone during long-duration spaceflight. Osteoporosis International. 2013 July; 24(7): 2105-2114. DOI: 10.1007/s00198-012-2243-z. PMID: 23334732.

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Ground Based Results Publications

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ISS Patents

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Related Publications

    Shapiro J, Beck TJ, Mustapha B, Ruff CB, Ballard P, Brintzenhofescoz K, Caminis J.  Zoledronic Acid Counteracts Bone Loss in the Spinal Cord Injury Model of Microgravity. Journal of Bone and Mineral Research. 2004; 19: S445.

    LeBlanc AD, Schneider VS, Shackelford LC, West S, Oganov VS, Bakulin AV, Voronin L.  Bone Mineral and lean tissue loss after long duration spaceflight. Journal of Musculoskeletal and Neuronal Interactions. 2000; 1(2): 157-160.

    Bone HG, Hosking D, Devogelaer J, Tucci JR, Emkey RD, Tonino RP, Rodriguez-Portales JA, Downs RW, Gupta J, Santora AC, Liberman UA.  Alendronate Phase III Osteoporosis Treatment Study Group. Ten years' experience with alendronate for osteoporosis in postmenopausal women. New England Journal of Medicine. 2004; 350(12): 1189-1199.

    LeBlanc AD, Driscoll TB, Shackelford LC, Evans HJ, Rianon NJ, Smith SM, Feeback DL, Lai D.  Alendronate as an Effective Countermeasure to Disuse Induced Bone Loss. Journal of Musculoskeletal and Neuronal Interactions. 2002; 2(4): 335-343.

    Watanabe Y, Ohshima H, Mizuno K, Sekiguchi C, Fukunaga M, Kohri K, Rittweger J, Felsenberg D, Matsumoto T, Nakamura T.  Intravenous pamidronate prevents femoral bone loss and renal stone formation during 90-day bed rest. Journal of Bone and Mineral Research. 2004; 19(11): 1771-1778.

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Related Websites

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Imagery

image One mm thick sections through the mid frontal plane of the hip, showing regions of evaluation in white superimposed on a false color image of the Quantitative Computed Tomography (QCT) data. The left hand image shows the cortical region of the femoral neck and the right hand image shows the trabecular bone regions. Courtesy image of NASA.
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