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Project Title:  Space Radiation and Bone Loss: Lunar Outpost Mission Critical Scenarios and Countermeasures Reduce
Fiscal Year: FY 2012 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 10/01/2007  
End Date: 10/31/2011  
Task Last Updated: 06/05/2012 
Download report in PDF pdf
Principal Investigator/Affiliation:   Bateman, Ted A. Ph.D. / University of North Carolina at Chapel Hill 
Address:  152 MacNider Hall, CB 7575 
Dept of Biomedical Engineering 
Chapel Hill , NC 27599 
Email: bateman@unc.edu 
Phone: 720-810-3626  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of North Carolina at Chapel Hill 
Joint Agency:  
Comments: Previous affiliation was Clemson University; PI moved to UNC in fall 2010. 
Co-Investigator(s)
Affiliation: 
Nelson, Gregory  Loma Linda University 
Project Information: Grant/Contract No. NCC 9-58-BL01302 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2007 NSBRI-RFA-07-01 Human Health in Space 
Grant/Contract No.: NCC 9-58-BL01302 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees: 10 
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Osteo:Risk Of Early Onset Osteoporosis Due To Spaceflight (No longer used, July 2020)
Human Research Program Gaps: (1) Osteo04:We do not know the contribution of each risk factor on bone loss and recovery of bone strength, and which factors are the best targets for countermeasure application (IRP Rev E)
Task Description: Crews on exploratory missions will face complex radiation from cosmic and solar sources with components ranging from protons to iron. We have identified trabecular bone loss in mice after exposure to multiple radiation types with doses of 50 cGy and lower, suggesting space radiation can increase bone loss from reduced gravity during exploratory missions. We have identified that bone loss is rapid and initiated by an early activation of osteoclasts.

The impact of radiation on bone quality in reduced gravity is unknown, and must be studied to understand effects of space radiation on bone health. The long-term objective of the proposed research is the development of countermeasures to prevent bone loss during missions and thus reduce fracture risk.

To define the risks associated with space radiation-induced bone loss, the following aims were studied to examine the effects of modeled space radiation using scenarios applicable for Lunar Outpost missions:

Specific Aim 1: Examine the combined effects of a modeled solar particle event and unloading on bone, and subsequent recovery during reloading. Hypothesis: Proton radiation with unloading will induce a more severe bone loss than unloading alone.

Summary of Aim 1 Findings: • Mice that were exposed to a 1 Gy dose of protons and 28-days of hindlimb suspension experienced damage that was additive. Irradiation caused a 15% decline in trabecular bone mass in normally loaded mice and a 17% decline in skeletally unloaded mice. • A long-term suppression of bone formation inhibits recovery of bone mass.

Aim 1 Future Direction: The effects of mixed radiation, modeling solar particle events and cosmic radiation, needs to be modeled with fractionated exposure during skeletal disuse. It is important to understand if skeletal disuse modifies the threshold dose at which bone loss from radiation is observable. The degree to which animal models predict the human response to space radiation (astronauts) needs to be better understood by studying cancer patients receiving radiation therapy, particularly at the periphery of the radiation field where doses are lower.

Specific Aim 2: Examine the cellular and molecular mechanisms for initiating bone loss following exposure to several types of modeled space radiation, including acute proton exposure, low-dose-rate proton exposure, and mixed radiation types (proton and HZE). Understanding underlying molecular causes is critical to developing countermeasures for radiation-induced bone loss. Hypothesis: The initiating mechanism of bone loss is initiated by osteoclast activation caused by a radiation-induced inflammatory response.

Summary of Aim 2 Findings: • The acute response to 50 cGy dose of protons or heavy ions is the activation of osteoclastic bone resorption. • Serum markers for bone resorption increase 24 hours after exposure and osteoclast numbers and eroded surface are greater at 3-days. • Osteoclast activation is temporary, reducing to baseline levels approximately 10-days after irradiation. • We identified that this bone loss is preceded by death of bone marrow cells, followed by greater expression then levels of inflammatory cytokines IL-1, IL-6 and TNFalpha. • This osteoclast-mediated acute response is not mitigated by low-dose-rate exposure to protons. • Acute, osteoclast-mediated bone loss from 50 cGy proton exposure is approximately 50% that of a 2 Gy exposure. • The acute bone loss caused by heavy ions (oxygen, silicon, neon, iron) is approximately 30% - 50% greater than that caused by protons.

Aim 2 Future Direction: A more detailed description of acute relative biological effectiveness (RBE), both at the functional and cellular level, needs to be characterized. The association of acute marrow death and osteoclast activation needs to be studied at the causation level with cell culture models.

Specific Aim 3: Test the efficacy of three countermeasures for bone loss caused by proton exposure: 1) the bisphosphonate risedronate; 2) the RANKL blocking protein osteoprotegerin, and 3) an antioxidant agent, alpha-lipoic acid. Hypothesis: Potent inhibitors of bone resorption, both zoledronate and osteoprotegerin will prevent the bone loss caused by radiation. Antioxidants will address multiple radiation-induced problems; alpha-lipoic acid decreases osteoclast differentiation and activity.

Summary of Aim 3 Findings: • The osteoclast inhibiting bisphosphonate risedronate fully prevented bone loss from a 2 Gy whole body dose of X-rays • Because of intellectual property concerns with a patent application filing, the RANKL-inhibiting protein osteoprotegerin was not able to be tested. • As a substitute for OPG, two additional bisphosphonates, pamidronate and zoledronate, were tested. Zoledronate was more effective than pamidronate. • Neither of the antioxidant compounds alpha-lipoic acid nor n-acetal cystine (NAC) reduced bone loss from radiation exposure. • The IL-1 and TNFalpha blocking compounds, IL-1ra (Kineret) and TNFbp (Enbrel), were tested as potential countermeasures. Neither protein, independently or in combination, mitigated bone loss from radiation exposure.

Aim 3 Future Directions: As an antiresorptive agent that suppresses osteoclast activity through a different mechanism than bisphosphonates, osteoprotegerin should be studied as a countermeasure (intellectual property concerns are currently being addressed). The most effective dosing regimen for risedronate and zoledronate needs to be further refined. Additionally, a myostatin inhibitor should be studied as a countermeasure that may have positive effects on both bone and muscle. Finally, countermeasures should be tested in models that combine both skeletal challenges astronauts will be exposed to: microgravity and space radiation.

Research Impact/Earth Benefits: Pre- and Post-menopausal Women with Gynecological Tumors

Postmenopausal women receiving radiation therapy (RT) for pelvic tumors have a 65-200% increased risk of hip fracture compared to women receiving non-RT cancer treatment. It is generally accepted that RT damages local osteoblasts and vasculature resulting in a low turnover, gradual decline in bone mass. However, it has recently been observed in rodent models that ionizing radiation activates osteoclasts. To test the hypothesis that early osteoclastic resorption may cause a rapid loss of bone, changes in proximal femur strength, bone density, and mineral content were examined in women receiving RT for gynecological tumors. Eight women (age 36-71 years) with cervical (n=6), vaginal, or uterine cancer provided informed consent. CT scans were performed pre-RT and on the last day of RT (6 weeks later). Patients received 50.4 Gy over the course of 28 days. Total dose to the proximal femur was ~25.0 Gy. CT scans were used for finite element strength and volumetric quantitative CT (vQCT) analyses. Proximal femur strength was calculated for models representing a single-limb stance load (SL) and a fall load (FL) onto the posterolateral aspect of the greater trochanter. Volumetric bone mineral density (vBMD) and bone mineral content (BMC) were calculated via vQCT for trabecular (Tr), cortical (Co) and integral (Tr + Co) compartments of the proximal femur. Significance was determined by paired t-test. All patients lost proximal femur strength for both SL and FL conditions (-5%,-10% p<0.05). vBMD was reduced in both the Tr and integral (-17%,-6% p<0.01), but not the Co, compartments. BMC was reduced for all regions: Tr -24%, Co -14% and integral -16% (p <0.02). Co BMC decline is accompanied by a loss of Co, and integral volume (-14%,-10% p<0.05) indicating periosteal resorption and a thinning of the cortex. Linear regression analysis shows a greater loss of Tr BMC with decreasing age (p=0.03), but there was no correlation of age with BMD or strength changes. RT caused rapid decline of bone strength, density and mineral content in the proximal femur. Only an early activation of osteoclasts can account for this rate of loss (BMC decline >2%/wk). For context, the bone loss from 6-wks of RT is roughly equivalent to 3 years of bone loss in women due to menopause. Future studies will examine later time points to determine the degree of recovery. As more data are available, prophylactic treatment of radiation-induced bone loss with antiresorptives should be considered.

Men and Women with Lung Cancer

The large degree of bone loss demonstrated in women with gynecological tumors receiving radiation therapy (RT) led to the development of a second, retrospective clinical trial to determine if this degree of loss occurred in patients receiving radiation therapy for other types of cancer and if men also experienced a loss of bone. vBMD loss was calculated 6-months after radiation therapy. Methods: A retrospective analysis of 25 lung cancer patients was performed. Change in volumetric bone mineral density (vBMD) was examined using pre- and 6 months post-RT thoracic CT scans. Ten women (mean age of 61 years) and 15 men (72 years) were studied. Patients typically received a total RT dose of ~66 Gy in 2.0 Gy/day fractions to the tumor. The trabecular bone of 6 vertebral bodies was contoured; the average CT density was calculated for pre- and post-RT contours. Results: The average loss of thoracic vertebra vBMD for each patient was -21% (p<0.001), with no difference in the degree of loss for women (-21%, p<0.001) and men (-21%, p<0.001). The degree of loss of vBMD (-21%) at the thoracic vertebra in both men and women receiving RT for lung cancer 6-months after RT is very similar to the degree of vBMD (-17%) and BMC loss (-24%) experienced by women with gynecological tumors only 6-weeks after therapy.

Task Progress & Bibliography Information FY2012 
Task Progress: The Executive Summary Statement outlines progress by Specific Aim. Task Progress is summarized here by HRP-IRP Risk and Gap:

• B3, MO5, N14, Acute7: The following therapies were tested: risedronate, pamidronate, zoledronate, alpha-lipoic acid, n-acetal cystine, Enbrel and Kineret. The FDA approved bisphosphonates risedronate, pamidronate and zoledronate where demonstrated to efficaciously prevent radiation-induced bone loss. Neither of the antioxidant compounds alpha-lipoic acid nor n-acetal cystine (NAC) reduced bone loss from radiation exposure.

• B11: Radiation causes an acute bone loss from osteoclast activation that persists due to long-term suppression of bone formation. Its effects are additive to the effects of skeletal disuse.

• Acute1: This osteoclast-mediated acute response is not mitigated by low-dose-rate exposure to protons. Acute, osteoclast-mediated bone loss from 50 cGy proton exposure is approximately 50% that of a 2 Gy exposure.

• Acute2: We have completed a clinical trial in women with gynecological tumors showing acute bone loss in 6-weeks after the first radiation therapy fraction. Bone loss declined in the lumbar vertebra as the distance from the target volume increased: bone loss was less with lower dose exposure. Studying cancer patients, particularly at the periphery of radiation exposure, may help predict bone loss in astronauts; for example low dose and dose rate exposure from an SPE.

• Acute3, Degen 7: Mice that were exposed to a 1 Gy dose of protons and 28-days of hindlimb suspension experienced damage that was additive. Irradiation caused a 15% decline in trabecular bone mass in normally loaded mice and a 17% decline in skeletally unloaded mice. A long-term suppression of bone formation inhibits recovery of bone mass.

• Degen1: This project initiated the development of animal models to study both the acute and degenerative effects of space radiation on bone tissue. Much more study is required to appropriately understand the effects of ionizing radiation skeletal tissue.

• Degen2: Radiation causes an acute bone loss from osteoclast activation that persists due to long-term suppression of bone formation. Its effects are additive to the effects of skeletal disuse. The acute response to 50 cGy dose of protons or heavy ions is the activation of osteoclastic bone resorption. Serum markers for bone resorption increase 24 hours after exposure and osteoclast numbers and eroded surface are greater at 3-days. Osteoclast activation is temporary, reducing to baseline levels approximately 10-days after irradiation. We identified that this bone loss is preceded by death of bone marrow cells, followed by greater expression then levels of inflammatory cytokines IL-1, IL-6 and TNFalpha.

• Degen3: There is virtually no latency period in the activation of osteoclastic bone resorption by exposure to doses of protons and heavy ions of doses as low as 50 cGy (and potentially lower).

Bibliography Type: Description: (Last Updated: 11/12/2020)  Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Lloyd SA, Simske SJ, Bogren LK, Olesiak SE, Bateman TA, Ferguson VL. "Effects of combined insulin-like growth factor 1 and macrophage colony-stimulating factor on the skeletal properties of mice." In Vivo. 2011 May-Jun;25(3):297-305. PMID: 21576402 , May-2011
Articles in Peer-reviewed Journals Willey JS, Lloyd SAJ, Nelson GA, Bateman TA. "Ionizing radiation and bone loss: space exploration and clinical therapy applications." Clinical Reviews in Bone and Mineral Metabolism. 2011 Mar;9(1):54-62. http://dx.doi.org/10.1007/s12018-011-9092-8 , Mar-2011
Articles in Peer-reviewed Journals Willey JS, Lloyd SA, Nelson GA, Bateman TA. "Space radiation and bone loss." Gravitational and Space Biology. 2011 Sep;25(1):14-21. PMID: 22826632; PMCID: PMC3401484 , Sep-2011
Articles in Peer-reviewed Journals Lloyd SA, Morony SE, Ferguson VL, Simske SJ, Stodieck LS, Warmington KS, Livingston EW, Lacey DL, Kostenuik PJ, Bateman TA. "Osteoprotegerin is an effective countermeasure for spaceflight-induced bone loss in mice." Bone. 2015 Dec;81:562-72. http://dx.doi.org/10.1016/j.bone.2015.08.021 ; PubMed PMID: 26318907 [Note originally reported in June 2012 as Epub 2015 Aug 28.] , Dec-2015
Articles in Peer-reviewed Journals Sullivan LK, Livingston EW, Lau AG, Rao-Dayton S, Bateman TA. "A mouse model for skeletal structure and function changes caused by radiation therapy and estrogen deficiency." Calcif Tissue Int. 2020 Feb;106(2):180-93. https://doi.org/10.1007/s00223-019-00617-x ; PMID: 31583426 , Feb-2020
Books/Book Chapters Willey JS, Lloyd SAJ, Bateman TA. "Radiation Therapy-Induced Osteoporosis." in "Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism" Ed. C. J. Rosen, J. E. Compston, J. B. Lian. Washington, D.C. : American Society for Bone and Mineral Research, 2009., Dec-2009
Significant Media Coverage Bateman T. "UNC media relations generated considerable media coverage associated with the STS-135 (last Space Shuttle flight) experiment with mice." Various media types, July 2011., Jul-2011
Project Title:  Space Radiation and Bone Loss: Lunar Outpost Mission Critical Scenarios and Countermeasures Reduce
Fiscal Year: FY 2011 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 10/01/2007  
End Date: 09/30/2011  
Task Last Updated: 01/11/2011 
Download report in PDF pdf
Principal Investigator/Affiliation:   Bateman, Ted A. Ph.D. / University of North Carolina at Chapel Hill 
Address:  152 MacNider Hall, CB 7575 
Dept of Biomedical Engineering 
Chapel Hill , NC 27599 
Email: bateman@unc.edu 
Phone: 720-810-3626  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of North Carolina at Chapel Hill 
Joint Agency:  
Comments: Previous affiliation was Clemson University; PI moved to UNC in fall 2010. 
Co-Investigator(s)
Affiliation: 
Nelson, Gregory  Loma Linda University 
Project Information: Grant/Contract No. NCC 9-58-BL01302 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2007 NSBRI-RFA-07-01 Human Health in Space 
Grant/Contract No.: NCC 9-58-BL01302 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Osteo:Risk Of Early Onset Osteoporosis Due To Spaceflight (No longer used, July 2020)
Human Research Program Gaps: (1) Osteo04:We do not know the contribution of each risk factor on bone loss and recovery of bone strength, and which factors are the best targets for countermeasure application (IRP Rev E)
Task Description: Crews on exploratory missions will face complex radiation from cosmic and solar sources with components ranging from protons to iron. We have identified trabecular bone loss in mice after exposure to multiple radiation types with doses ranging from 0.3 Gy to 2 Gy, suggesting space radiation may increase bone loss from reduced gravity during exploratory missions. The bone loss is rapid and initiated by an early activation of osteoclasts.

The impact of radiation on bone quality and fracture healing in reduced gravity is unknown, and must be studied to understand effects of space radiation on bone health. The long-term objective of the proposed research is the development of countermeasures to prevent bone loss during missions and thus reduce fracture risk.

To define the risks associated with space radiation-induced bone loss, the proposed aims will examine effects of modeled space radiation using scenarios applicable for Lunar Outpost missions:

Specific Aim 1: Examine the combined effects of a modeled solar particle event and unloading on bone, and subsequent recovery during reloading. Hypothesis: Proton radiation with unloading will induce a more severe bone loss than unloading alone.

Specific Aim 2: Examine the cellular and molecular mechanisms for initiating bone loss following exposure to several types of modeled space radiation, including acute proton exposure, low-dose-rate proton exposure, and mixed radiation types (proton and HZE). Understanding underlying molecular causes is critical to developing countermeasures for radiation-induced bone loss. Hypothesis: The initiating mechanism of bone loss is initiated by osteoclast activation caused by a radiation-induced inflammatory response.

Specific Aim 3: Test the efficacy of three countermeasures for bone loss caused by proton exposure: 1) the bisphosphonate risedronate; 2) the RANKL blocking protein osteoprotegerin, and 3) an antioxidant agent, alpha-lipoic acid. Hypothesis: Potent inhibitors of bone resorption, both zoledronate and osteoprotegerin will prevent the bone loss caused by radiation. Antioxidants will address multiple radiation-induced problems; alpha-lipoic acid decreases osteoclast differentiation and activity.

Research Impact/Earth Benefits: We have completed a clinical trial at the University of California - Irvine in collaboration with Drs. Keyak, Lang, and Carpenter. We show that women receiving radiation therapy for treatment of gynecological tumors lose bone mass at an extraordinary rate: during the six weeks of radiation therapy, on average women lose as much bone as a women will during the two years immediately after menopause. Dr. Bateman has also scored very well (7th percentile) on an NIH grant to study the preclinical aspects of bone loss in women with gynecological tumors receiving radiation therapy.

Study Summary:

Postmenopausal women receiving radiation therapy (RT) for pelvic tumors have a 65-200% increased risk of hip fracture compared to women receiving non-RT cancer treatment. It is generally accepted that RT damages local osteoblasts and vasculature resulting in a low turnover, gradual decline in bone mass. However, it has recently been observed in rodent models that ionizing radiation activates osteoclasts. To test the hypothesis that early osteoclastic resorption may cause a rapid loss of bone, changes in proximal femur strength, bone density, and mineral content were examined in women receiving RT for gynecological tumors.

Eight women (age 36-71 years) with cervical (n=6), vaginal, or uterine cancer provided informed consent. CT scans were performed pre-RT and on the last day of RT (6 weeks later). Patients received 50.4 Gy over the course of 28 days. Total dose to the proximal femur was ~25.0 Gy. CT scans were used for finite element strength and volumetric quantitative CT (vQCT) analyses. Proximal femur strength was calculated for models representing a single-limb stance load (SL) and a fall load (FL) onto the posterolateral aspect of the greater trochanter. Volumetric bone mineral density (vBMD) and bone mineral content (BMC) were calculated via vQCT for trabecular (Tr), cortical (Co) and integral (Tr + Co) compartments of the proximal femur. Significance was determined by paired t-test. All patients lost proximal femur strength for both SL and FL conditions (-5%,-10% p<0.05). vBMD was reduced in both the Tr and integral (-17%,-6% p<0.01), but not the Co, compartments. BMC was reduced for all regions: Tr -24%, Co -14% and integral -16% (p <0.02). Co BMC decline is accompanied by a loss of Co, and integral volume (-14%,-10% p<0.05) indicating periosteal resorption and a thinning of the cortex. Linear regression analysis shows a greater loss of Tr BMC with decreasing age (p=0.03), but there was no correlation of age with BMD or strength changes.

RT caused rapid decline of bone strength, density and mineral content in the proximal femur. Only an early activation of osteoclasts can account for this rate of loss (BMC decline >2%/wk). For context, the bone loss from 6-wks of RT is roughly equivalent to 3 years of bone loss in women due to menopause. Future studies will examine later time points to determine the degree of recovery. As more data are available, prophylactic treatment of radiation-induced bone loss with antiresorptives should be considered.

Task Progress & Bibliography Information FY2011 
Task Progress: Bisphosphonate Countermeasures: One of our accomplishments for the year include continuing with countermeasure development by improving bisphosphonate therapy. In early 2010 we published a paper (Willey et al., Bone 2009) showing that risedronate (a relatively high dose) effectively prevents bone loss from a 2 Gy whole body dose of X-rays. Because NASA is currently testing alendronate and zoledronate in astronauts on the International Space Station, we are testing these bisphosphonates for their ability to prevent space radiation-induced osteoporosis. We have tested a single dose of 5 ug/kg zoledronate to prevent bone loss from 2 Gy of X-rays. 5 ug/kg was chosen because it effectively prevents bone destruction in mice with breast and prostate cancer bone metastases. We also tested a single supra-clinical dose of 50 ug/kg. Compared to placebo treated control mice, 5 ug/kg did not effectively prevent bone loss, and 50 ug/kg prevented ~half of the bone loss. We are in the process of testing more frequent dosing (1-3 ug/kg/day).

Antioxidant Countermeasures: Oxidative stress after irradiation has been speculated to mediate radiation-induced bone loss, as some evidence points to the efficacy of a-lipoic acid. Antioxidants, including alipoic acid, have been effective in preventing bone loss in models of reduced-estrogen induced osteoporosis. We have tested the efficacy of high doses of two antioxidants in terms of preventing bone loss after irradiation (a-lipoic acid and ascorbic acid): Neither suppressed any functional bone loss.

Predisposition of Heredity: We have also performed an experiment comparing the response of 4 strains of mice to radiation-induced bone loss, with the goal of determining both improving our spaceflight model and determining if there is a hereditary/genotype predisposition to being radiation sensitive or in sensitive. We want to explore transitioning our model towards using a higher bone density strain of mouse. When combining radiation with another skeletal challenge, such as disuse, the low bone density C57BL/6 (B6) mice have very little bone remaining. BALBc mice do respond the same as B6 mice; the rate and degree of bone loss from irradiation are the same. We are in the process of analyzing data from two other strains: DBA mice are considered to be radiation resistant and C3H mice are less susceptible to disuse osteoporosis. We are potentially observing some preservation of bone moss in DBA and C3H mice, however more analysis is necessary.

Rotating wall vessel changes in osteoclast gene expression profile: We collaborated with Dr. Reddy at the Medical University of South Carolina on a project examining changes in gene expression profile in osteoclast cultures using the rotating wall vessel to model microgravity (Sambandam et al., J Cell Biochem 2010).

Bibliography Type: Description: (Last Updated: 11/12/2020)  Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Lawrence M, Willey J, Saynak M, Bateman T, Marks L. "Radiation Therapy Causes a Rapid Loss of Bone Mineral Density of Thoracic Vertebra in Women and Men Lung Cancer Patients." 2010 ASBMR Annual Meeting, Toronto, Canada, October 15-19, 2010.

J Bone Miner Res 2010;25 (Suppl 1). Available at http://www.asbmr.org/Meetings/AnnualMeeting/AbstractDetail.aspx?aid=b8337276-1e33-40fd-868d-020591d48589 Accessed January 11, 2011. , Oct-2010

Abstracts for Journals and Proceedings Lloyd S, Ferguson V, Simske S, Dunlap A, Livingston E, Bateman T. "Effects of Animal Enclosure Module Spaceflight Hardware on the Skeletal Properties of Ground Control Mice." 2010 ASBMR Annual Meeting, Toronto, Canada, October 15-19, 2010.

J Bone Miner Res 2010;25 (Suppl 1). Available at http://www.asbmr.org/Meetings/AnnualMeeting/AbstractDetail.aspx?aid=cfd9d910-f993-46b5-aca0-fb864b900ec2 Accessed January 11, 2011. , Oct-2010

Abstracts for Journals and Proceedings Bateman TA, Lang TL, Carpenter RD, Lawrence MV, Sehgal V, Ramsinghani NS, Kuo JV, Al-Ghazi M, Willey JS, Keyak JH. "Radiation Therapy Causes Rapid Loss of Proximal Femur Bone Strength and Density in Women with Gynecological Tumors." American Society for Radiation Oncology 52nd Annual Meeting, San Diego, CA, October 31-November 4, 2010.

International Journal of Radiation Oncology*Biology*Physics. 2010 Nov 1;78(3 Suppl):S597. http://dx.doi.org/10.1016/j.ijrobp.2010.07.1391 , Nov-2010

Abstracts for Journals and Proceedings Bateman TA, Lang TL, Carpenter RD, Lawrence MV, Sehgal V, Ramsinghani NS, Kuo JV, Al-Ghazi M, Willey JS, Keyak JH. "Radiation Therapy Causes Rapid Loss of Proximal Femur Bone Strength and Density in Women with Gynecological Tumors." 2010 ASBMR Annual Meeting, Toronto, Canada, October 15-19, 2010.

J Bone Miner Res 2010 25(Suppl 1). http://www.asbmr.org/Meetings/AnnualMeeting/AbstractDetail.aspx?aid=900fc549-8d96-4996-b24c-548993cb868c Accessed January 11, 2011. , Oct-2010

Articles in Peer-reviewed Journals Willey JS, Livingston EW, Robbins ME, Bourland JD, Tirado-Lee L, Smith-Sielicki H, Bateman TA. "Risedronate prevents early radiation-induced osteoporosis in mice at multiple skeletal locations." Bone. 2010 Jan;46(1):101-11. Epub 2009 Sep 9. PMID: 19747571 , Jan-2010
Project Title:  Space Radiation and Bone Loss: Lunar Outpost Mission Critical Scenarios and Countermeasures Reduce
Fiscal Year: FY 2010 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 10/01/2007  
End Date: 09/30/2011  
Task Last Updated: 09/15/2009 
Download report in PDF pdf
Principal Investigator/Affiliation:   Bateman, Ted A. Ph.D. / University of North Carolina at Chapel Hill 
Address:  152 MacNider Hall, CB 7575 
Dept of Biomedical Engineering 
Chapel Hill , NC 27599 
Email: bateman@unc.edu 
Phone: 720-810-3626  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of North Carolina at Chapel Hill 
Joint Agency:  
Comments: Previous affiliation was Clemson University; PI moved to UNC in fall 2010. 
Co-Investigator(s)
Affiliation: 
Nelson, Gregory  Loma Linda University 
Project Information: Grant/Contract No. NCC 9-58-BL01302 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2007 NSBRI-RFA-07-01 Human Health in Space 
Grant/Contract No.: NCC 9-58-BL01302 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Osteo:Risk Of Early Onset Osteoporosis Due To Spaceflight (No longer used, July 2020)
Human Research Program Gaps: (1) Osteo04:We do not know the contribution of each risk factor on bone loss and recovery of bone strength, and which factors are the best targets for countermeasure application (IRP Rev E)
Task Description: Crews on exploratory missions will face complex radiation from cosmic and solar sources with components ranging from protons to iron. We have identified trabecular bone loss in mice after exposure to multiple radiation types with doses ranging from 0.5 Gy to 2 Gy, suggesting space radiation may increase bone loss from reduced gravity during exploratory missions. The bone loss is rapid and initiated by an early activation of osteoclasts.

The impact of radiation on bone quality and fracture healing in reduced gravity is unknown, and must be studied to understand effects of space radiation on bone health. The long-term objective of the proposed research is the development of countermeasures to prevent bone loss during missions and thus reduce fracture risk.

To define the risks associated with space radiation-induced bone loss, the proposed aims will examine effects of modeled space radiation using scenarios applicable for Lunar Outpost missions:

Specific Aim 1: Examine the combined effects of a modeled solar particle event and unloading on bone, and subsequent recovery during reloading. Hypothesis: Proton radiation with unloading will induce a more severe bone loss than unloading alone.

Specific Aim 2: Examine the cellular and molecular mechanisms for initiating bone loss following exposure to several types of modeled space radiation, including acute proton exposure, low-dose-rate proton exposure, and mixed radiation types (proton and HZE). Understanding underlying molecular causes is critical to developing countermeasures for radiation-induced bone loss. Hypothesis: The initiating mechanism of bone loss is initiated by osteoclast activation caused by a radiation-induced inflammatory response.

Specific Aim 3: Test the efficacy of three countermeasures for bone loss caused by proton exposure: 1) the bisphosphonate risedronate; 2) the RANKL blocking protein osteoprotegerin, and 3) an antioxidant agent, alpha-lipoic acid. Hypothesis: Potent inhibitors of bone resorption, both zoledronate and osteoprotegerin will prevent the bone loss caused by radiation. Antioxidants will address multiple radiation-induced problems; alpha-lipoic acid decreases osteoclast differentiation and activity.

Research Impact/Earth Benefits: Bone atrophy and increased risk of bone fracture are consequences of exposure to radiation for cancer treatment. Osteopenia and osteoporosis have been characterized as pathological conditions following therapeutic irradiation. There is an increased incidence of spontaneous hip fractures demonstrated by patients receiving radiation to treat pelvic cancers. Postmenopausal women receiving radiotherapy to treat cervical, rectal and anal cancers have an increased hip fracture risk of 60-200% (Baxter et al., JAMA 2005). Morbidity and mortality statistics for hip fractures in this population are poor: nearly one in four will not survive a year after fracture and a significant majority of survivors will never return quality of life to pre-fracture abilities. As long-term survivorship increases with improved diagnosis and treatment, the morbidity and mortality associated with osteoporosis and hip fractures within this population is becoming a significant concern.

This loss of bone mass following radiotherapy has been hypothesized to occur as a result of damage to bone-forming osteoblasts and the bone vasculature itself. While previous studies typically observed atrophy as a late effect, loss of volumetric bone mineral content has been reported in cervical cancer patients five weeks post treatment and described as a low-turnover type of osteoporosis. An inhibition of osteoblasts and osteoblast progenitors from radiation exposure has been further described both in vitro and in vivo, and we have reported a long-term reduction of bone mass in irradiated mice. Despite evidence that bone loss can occur soon after irradiation, a putative increase in osteoclast activity has received little attention as a potential contributor to radiation-induced osteoporosis.

To date, pharmacological interventions to prevent bone loss caused by radiation therapy have not been employed. In fact, no animal model currently exists to identify causal mechanisms and to properly develop such therapies. Our work through the last year has identified a rapid activation of osteoclasts after radiation exposure that is prevented by treatment with risedronate.

The following aims supported by NSBRI have direct clinical relevance.

Specific Aim 2a: Radiation exposure results in an early activation of osteoclasts leading to rapid bone loss (Willey et al., Radiation Res, 2008).

Specific Aim 3: Risedronate prevents radiation-induced bone loss (Willey et al., Bone, in press).

Clinical Trials: Radiation therapy (RT) to treat cervical and lung cancers cause a decline in proximal femur strength and thoracic lumbar vertebra bone mineral density, respectively.

Procter and Gamble Pharmaceuticals awarded us an unrestricted grant to study bone loss in cervical cancer patients (PI Dr. Joyce Keyak University of California at Irvine). A finite element model of the proximal femur was developed from CT imaging taken on the last day of RT (6 weeks after starting RT) and compared to the pretreatment planning CT scan. FEA tests the strength of the femur when single-leg stance and falling loads are applied. Of the four patients studied to date, there is a significant decline in single leg stance load (p = 0.04) and a trend towards a decline in fall load (p = 0.11).

Dr. Larry Marks (Chair, Dept. of Radiation Oncology, UNC Chapel Hill) has thoracic CT scans from approximately 100 lung cancer patients before and six months after RT. The goal of the original prospective study was to examine the development of lung fibrosis. The body of 6 thoracic vertebrae from 15 of these patients have been analyzed. On average, the patients lost -21% vBMD in these six vertebrae. For women, there is a significant correlation with the degree of vBMD decline and age, with greater loss occurring with increasing age (p = 0.03). A similar trend was observed among men (p = 0.07).

Task Progress & Bibliography Information FY2010 
Task Progress: Crews on exploratory missions will face complex radiation from cosmic and solar sources with components ranging from protons to iron. We have identified trabecular bone loss in mice after exposure to multiple radiation types with doses ranging from 0.5 Gy to 2 Gy, suggesting space radiation may increase bone loss from reduced gravity during exploratory missions. The bone loss is rapid and initiated by an early activation of bone resorbing cells.

The impact of radiation on bone quality in reduced gravity is unknown, and must be studied to understand effects of space radiation on bone health. The long-term objective of the proposed research is the development of countermeasures to prevent bone loss during missions and thus reduce fracture risk.

The second year of this project was very productive, with progress made on all three Aims.

Specific Aim 1: Bone loss from exposure to a 1 Gy whole-body dose of protons and skeletal loading is additive. Manuscript in preparation.

Specific Aim 2b: Exposure to a dose of <50 cGy radiation of mixed type results in both cortical and trabecular bone loss. Paper published July 2008.

Specific Aim 2c: Bone loss from exposure to ionizing radiation is a local response and is preceded by greater expression on proinflammatory cytokines.

Specific Aim 3a: Risedronate prevents radiation-induced bone loss. Publication in press for the journal Bone.

Specific Aim 3b: Ongoing tests of IL-1 receptor antagonist, TNF binding protein and ascorbic acid (vitamin C) as countermeasures to block local 1) radiation mediated inflammation, and 2) reactive oxygen species created by ionizing radiation and resulting cell death.

Bibliography Type: Description: (Last Updated: 11/12/2020)  Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Allen DL, Bandstra ER, Harrison BC, Thorng S, Stodieck LS, Kostenuik PJ, Morony S, Lacey DL, Hammond TG, Leinwand LL, Argraves WS, Bateman TA, Barth JL. "Effects of spaceflight on murine skeletal muscle gene expression." J Appl Physiol. 2009 Feb;106(2):582-95. PubMed PMID: 19074574 , Feb-2009
Articles in Peer-reviewed Journals Bandstra ER, Thompson RW, Nelson GA, Willey JS, Judex S, Cairns MA, Benton ER, Vazquez ME, Carson JA, Bateman TA. "Musculoskeletal changes in mice from 20-50 cGy of simulated galactic cosmic rays." Radiation Research, 2009 Jul;172(1):21-9. PubMed PMID: 19580504 , Jul-2009
Articles in Peer-reviewed Journals Lloyd SA, Yuan YY, Simske SJ, Riffle SE, Ferguson VL, Bateman TA. "Administration of high-dose macrophage colony-stimulating factor increases bone turnover and trabecular volume fraction." J Bone Miner Metab. 2009 Sep;27(5):546-54. Epub 2009 Mar 27. PubMed PMID: 19326045 , Sep-2009
Articles in Peer-reviewed Journals Lloyd SA, J, Bandstra ER, Travis ND, Nelson GA, Bourland JD, Pecaut MJ, Gridley DS, Willey JS, Bateman TA. "Spaceflight-relevant types of ionizing radiation and cortical bone: Potential LET effect?" Advances in Space Research. 2008 Dec 15;42(12):1889-97. PMID: 19122806 , http://dx.doi.org/10.1016/j.asr.2008.08.006 , Dec-2008
Articles in Peer-reviewed Journals Willey JS, Livingston EW, Robbins ME, Bourland JD, Tirado-Lee L, Smith-Sielicki H, Bateman TA. "Risedronate prevents early radiation-induced osteoporosis in mice at multiple skeletal locations." Bone. 2009 Sep 8. [Epub ahead of print] PubMed PMID: 19747571 , Sep-2009
Awards Lemus M. "Exceptional Research Opportunities Program from the Howard Hughes Medical Institute, Summer 2009." May-2009
Awards Tirado L. "Travel Award from Society for Advancement of Chicanos and Native Americans in Science (SACNAS) for the International Polar Year: Global Change in Our Communities Conference, Salt Lake City, Utah, October 09-12, 2008." Oct-2008
Patents N/A. Application submitted. Patent Application, February 2008. Feb-2008 Bateman TA, Willey JS. "Use of antiresorptive compounds to prevent radiation-induced activation of osteoclasts and resulting bone loss."
Project Title:  Space Radiation and Bone Loss: Lunar Outpost Mission Critical Scenarios and Countermeasures Reduce
Fiscal Year: FY 2009 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 10/01/2007  
End Date: 09/30/2011  
Task Last Updated: 11/05/2008 
Download report in PDF pdf
Principal Investigator/Affiliation:   Bateman, Ted A. Ph.D. / University of North Carolina at Chapel Hill 
Address:  152 MacNider Hall, CB 7575 
Dept of Biomedical Engineering 
Chapel Hill , NC 27599 
Email: bateman@unc.edu 
Phone: 720-810-3626  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of North Carolina at Chapel Hill 
Joint Agency:  
Comments: Previous affiliation was Clemson University; PI moved to UNC in fall 2010. 
Co-Investigator(s)
Affiliation: 
Nelson, Gregory  Loma Linda University 
Project Information: Grant/Contract No. NCC 9-58-BL01302 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2007 NSBRI-RFA-07-01 Human Health in Space 
Grant/Contract No.: NCC 9-58-BL01302 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Osteo:Risk Of Early Onset Osteoporosis Due To Spaceflight (No longer used, July 2020)
Human Research Program Gaps: (1) Osteo04:We do not know the contribution of each risk factor on bone loss and recovery of bone strength, and which factors are the best targets for countermeasure application (IRP Rev E)
Task Description: Crews on exploratory missions will face complex radiation from cosmic and solar sources with components ranging from protons to iron. We have identified trabecular bone loss in mice after exposure to multiple radiation types with doses ranging from 0.5 Gy to 2 Gy, suggesting space radiation may increase bone loss from reduced gravity during exploratory missions. The bone loss is rapid and initiated by an early activation of osteoclasts.

The impact of radiation on bone quality and fracture healing in reduced gravity is unknown, and must be studied to understand effects of space radiation on bone health. The long-term objective of the proposed research is the development of countermeasures to prevent bone loss during missions and thus reduce fracture risk.

To define the risks associated with space radiation-induced bone loss, the proposed aims will examine effects of modeled space radiation using scenarios applicable for Lunar Outpost missions:

Specific Aim 1: Examine the combined effects of a modeled solar particle event and unloading on bone, and subsequent recovery during reloading. Hypothesis: Proton radiation with unloading will induce a more severe bone loss than unloading alone.

Specific Aim 2: Examine the cellular and molecular mechanisms for initiating bone loss following exposure to several types of modeled space radiation, including acute proton exposure, low-dose-rate proton exposure, and mixed radiation types (proton and HZE). Understanding underlying molecular causes is critical to developing countermeasures for radiation-induced bone loss. Hypothesis: The initiating mechanism of bone loss is initiated by osteoclast activation caused by a radiation-induced inflammatory response.

Specific Aim 3: Test the efficacy of three countermeasures for bone loss caused by proton exposure: 1) the bisphosphonate risedronate; 2) the RANKL blocking protein osteoprotegerin, and 3) an antioxidant agent, alpha-lipoic acid. Hypothesis: Potent inhibitors of bone resorption, both zoledronate and osteoprotegerin will prevent the bone loss caused by radiation. Antioxidants will address multiple radiation-induced problems; alpha-lipoic acid decreases osteoclast differentiation and activity.

Research Impact/Earth Benefits: Bone atrophy and increased risk of bone fracture are consequences of exposure to radiation for cancer treatment. Osteopenia and osteoporosis have been characterized as pathological conditions following therapeutic irradiation. There is an increased incidence of spontaneous hip fractures demonstrated by patients receiving radiation to treat pelvic cancers, with incidents generally being documented one to five years after therapy. Postmenopausal women receiving radiotherapy to treat cervical, rectal and anal cancers have an increased hip fracture risk of 60-200% (Baxter et al., JAMA 2005). Morbidity and mortality statistics for hip fractures in this population are poor: nearly one in four will not survive a year after fracture and a significant majority of survivors will never return quality of life to pre-fracture abilities. As long-term survivorship increases with improved diagnosis and treatment, the morbidity and mortality associated with osteoporosis and hip fractures within this population is becoming a significant concern.

This loss of bone mass following radiotherapy has been hypothesized to occur as a result of damage to bone-forming osteoblasts and the bone vasculature itself. While previous studies typically observed atrophy as a late effect, loss of volumetric bone mineral content has been reported in cervical cancer patients five weeks post treatment and described as a low-turnover type of osteoporosis. An inhibition of osteoblasts and osteoblast progenitors from radiation exposure has been further described both in vitro and in vivo, and we have reported a long-term reduction of bone mass in irradiated mice. Despite evidence that bone loss can occur soon after irradiation, a putative increase in osteoclast activity has received little attention as a potential contributor to radiation-induced osteoporosis.

The effect of radiation on the number and activity of osteoclasts is varied in published reports, from observed decreases in osteoclast numbers, to stable numbers, to a qualitative description of an increase in the osteoclast population. A better understanding of the effects of radiation on osteoclasts needs to be addressed in order to reduce or prevent the subsequent bone atrophy and fracture risk.

To date, pharmacological interventions to prevent bone loss caused by radiation therapy have not been employed. In fact, no animal model currently exists to identify causal mechanisms and to properly develop such therapies. Our work through the last year has identified a rapid activation of osteoclasts after radiation exposure that is prevented by treatment with risedronate.

The following aims supported by NSBRI have direct clinical relevance.

Specific Aim 2a: Radiation exposure results in an early activation of osteoclasts leading to rapid bone loss.

Female C57BL/6 mice were exposed to a 2 Gy whole-body dose of x-rays, or not irradiated. A serum marker for osteoclast activity (TRAP5b) was significantly increased 1 and 3 days after exposure (50% and 14%, respectively). Histological examination of bones collect from mice 3 days after exposure revealed a significant increase osteoclast number and surface. There were no changes in serum osteocalcin (a marker for osteoblast activity) or osteoblast surface.

Specific Aim 3: Risedronate prevents radiation-induced bone loss.

Twenty-week-old female C57BL/6 mice were exposed to a 2 Gy whole-body dose of x-rays, or not irradiated. Groups (3 groups) included non-irradiated controls administered a placebo injection, irradiated mice administered a placebo injection, and irradiated mice treated with risedronate (30 ug/kg every other day. Within these three groups mice were humanely euthanized at 1, 2, and 3 weeks after exposure. There was significant bone loss of trabecular bone at three skeletal sites (proximal tibia, distal femur, and 5th lumbar spine) at 1 weeks after exposure. Risedronate prevented this bone loss entirely.

Task Progress & Bibliography Information FY2009 
Task Progress: Crews on exploratory missions will face complex radiation from cosmic and solar sources with components ranging from protons to iron. We have identified trabecular bone loss in mice after exposure to multiple radiation types with doses ranging from 0.5 Gy to 2 Gy, suggesting space radiation may increase bone loss from reduced gravity during exploratory missions. The bone loss is rapid and initiated by an early activation of bone resorbing cells.

The impact of radiation on bone quality in reduced gravity is unknown, and must be studied to understand effects of space radiation on bone health. The long-term objective of the proposed research is the development of countermeasures to prevent bone loss during missions and thus reduce fracture risk.

The first year of this project was very productive, with progress made on all three Aims.

Aim 1: Bone loss from exposure to a 1 Gy whole-body dose of protons and skeletal loading is additive.

Mice were exposed to a 1 Gy dose or protons and hindlimb suspended, a model for skeletal unloading, for a duration of 4-weeks (mimicking long-term spaceflight). Despite a profound bone loss from unloading, mice exposed to both unloading and protons had significantly more bone loss than unloaded mice not exposed to radiation.

Aim 2a: Radiation exposure results in an early activation of osteoclasts leading to rapid bone loss.

Mice were exposed to a 2 Gy dose of x-rays, or not irradiated. A serum marker for osteoclast activity (TRAP5b) was significantly increased 1 and 3 days after exposure. Histological examination of bones collect from mice 3 days after exposure revealed a significant increase osteoclast number and surface. There were no changes in serum osteocalcin (a marker for bone formation) or osteoblast surface.

Aim 2b: Exposure to a dose of <50 cGy radiation of mixed type results in both cortical and trabecular bone loss.

Bones were collected from a study in which mouse brains were exposed to collimated iron radiation. These conditions resulted in exposure to a complex mixtures of charged particles transmitted by the collimator. Measured radiation doses of uncollimated secondary particles were 0.47 Gy at the proximal humerus. The proximal humerus of irradiated mice had lower trabecular bone volume fraction, lower trabecular thickness, greater cortical porosity, and lower polar moment of inertia.

Aim 3: Risedronate prevents radiation-induced bone loss.

Mice were exposed to a 2 Gy dose of x-rays, or not irradiated. Groups (3) included non-irradiated controls administered a placebo injection, irradiated mice administered a placebo injection, and irradiated mice treated with risedronate (30 ug/kg every other day). Within these three groups mice were humanely euthanized at 1, 2, and 3 weeks after exposure. There was significant bone loss of trabecular bone at three skeletal sites (proximal tibia, distal femur, and 5th lumbar spine) 1 week after exposure. Risedronate prevented this bone loss entirely.

Bibliography Type: Description: (Last Updated: 11/12/2020)  Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Bowman LS, Livingston EW, Willey JS, Robbins ME, Bourland JD, Bateman TA. "Radiation-induced bone loss: description of dose, time course, age, strain and sex variables." American Society for Bone and Mineral Research 30th Annual Meeting, Montreal, Canada, Sept. 12-16, 2008.

American Society for Bone and Mineral Research, Abstract Book, September 2008. , Sep-2008

Abstracts for Journals and Proceedings Willey JS, Livingston EW, Bowman LC, Robbins ME, Bourland JD, Bateman TA. "Risedronate prevents early radiation-induced bone loss at multiple skeletal sites." American Society for Bone and Mineral Research 30th Annual Meeting, Montreal, Canada, Sept. 12-16, 2008.

American Society for Bone and Mineral Research, Abstract Book, September 2008. , Sep-2008

Abstracts for Journals and Proceedings Bandstra ER, Riffle SE, Lloyd SA, Willey JS, Nelson GA, Pecaut MJ, Bateman TA. "Combined effect of irradiation and unloading on murine bone." American Society for Bone and Mineral Research 30th Annual Meeting, Montreal, Canada, Sept. 12-16, 2008.

American Society for Bone and Mineral Research, Abstract Book, September 2008. , Sep-2008

Abstracts for Journals and Proceedings Willey JW, Livingston EW, Bowman LC, Robbins ME, Bourland JD, Bateman TA. "The antiresorptive agent risedronate prevents early radiation-induced bone loss." 2008 Radiation Research Society 54th Annual Meeting, Boston, MA, Sept 20-24, 2008.

Radiation Research Society, Abstract Book, September 2008. , Sep-2008

Abstracts for Journals and Proceedings Willey JS, Gridley DS, Pecaut MJ, Norrdin RW, Bateman TA. "An acute 7 gray dose of gamma-radiation induces a profound and rapid loss of trabecular bone in mice." American Society for Bone and Mineral Research 29th Annual Meeting, Honolulu, HI, Sept. 16-19, 2007.

American Society for Bone and Mineral Research 29th Annual Meeting, Honolulu, HI, Sept. 16-19, 2007. Abstract Book, September 2007. , Sep-2007

Abstracts for Journals and Proceedings Lloyd SA, Bateman TA. "Disuse exacerbates suppression of bone formation with administration of low-dose antiresorptive drugs." American Society for Gravitational and Space Biology 23rd Annual Meeting, Moffett Field, CA, October 25-28, 2007.

Gravitational and Space Biology 2007 Oct;21(1):18. , Oct-2008

Abstracts for Journals and Proceedings Bandstra ER, Pecaut MJ, Anderson ER, Willey JS, De Carlo F, Stock SR, Gridley DS, Nelson GA, Bateman TA. "Bone loss following proton irradiation." American Society for Gravitational and Space Biology 23rd Annual Meeting, Moffett Field, CA, October 25-28, 2007.

Gravitational and Space Biology 2007 Oct;21(1):16. , Oct-2007

Abstracts for Journals and Proceedings Livingston EW, Bateman TA. "Long-term effects of heavy ion radiation on bone loss in mice." American Society for Gravitational and Space Biology 23rd Annual Meeting, Moffett Field, CA, October 25-28, 2007.

Gravitational and Space Biology 2007 Oct;21(1):18. , Oct-2007

Abstracts for Journals and Proceedings Smith LC, Bateman TA. "Effect of low-energy x-rays on trabecular bone loss in mice." American Society for Gravitational and Space Biology 23rd Annual Meeting, Moffett Field, CA, October 25-28, 2007.

Gravitational and Space Biology 2007 Oct;21(1):9. , Oct-2007

Abstracts for Journals and Proceedings Tirado L, Willey JS, Bateman TA. "Effect of low dose ionizing radiation on bone metabolism in rats." American Society for Gravitational and Space Biology 23rd Annual Meeting, Moffett Field, CA, October 25-28, 2007.

Gravitational and Space Biology 2007 Oct;21(1):13. , Oct-2007

Abstracts for Journals and Proceedings Riffle S, Yuan YY Bateman TA. "Macrophage colony stimulating factor produces increased trabecular bone density and turnover, characteristic of an anabolic agent." American Society for Gravitational and Space Biology 23rd Annual Meeting, Moffett Field, CA, October 25-28, 2007.

Gravitational and Space Biology 2007 Oct;21(1):13. , Oct-2007

Abstracts for Journals and Proceedings Anderson ER, Willey JS, Nagatoni J, Bateman TA. "Examining the early response of osteoclasts to ionizing radiation." American Society for Gravitational and Space Biology 23rd Annual Meeting, Moffett Field, CA, October 25-28, 2007.

Gravitational and Space Biology 2007 Oct;21(1):4. , Oct-2007

Articles in Peer-reviewed Journals Yuan YY, Kostenuik PJ, Ominsky MS, Morony S, Adamu S, Simionescu DT, Basalyga DM, Asuncion FJ, Bateman TA. "Skeletal deterioration induced by RANKL infusion: a model for high-turnover bone disease." Osteoporos Int. 2008 May;19(5):625-35. PMID: 18038244 , May-2008
Articles in Peer-reviewed Journals Allen DL, Bandstra ER, Harrison BC, Thorng S, Stodieck LS, Kosteniuk PJ, Morony S, Lacey DL, Hammond TG, Leinwand LL, Argraves WS, Bateman TA, Barth JL. "Effects of spaceflight on murine skeletal muscle gene expression." J Appl Physiol. Submitted, 2008. , Sep-2008
Articles in Peer-reviewed Journals Bandstra ER, Pecaut MJ, Anderson ER, Willey JS, De Carlo F, Stock SR, Gridley DS, Nelson GA, Levine HG, Bateman TA. "Long-term dose response of trabecular bone in mice to proton radiation." Radiat Res. 2008 Jun;169(6):607-14. PMID: 18494551 , Jun-2008
Articles in Peer-reviewed Journals Bandstra ER, Thompson RW, Nelson GA, Judex S, Cairns MA, Benton ER, Willey JS, Vazquez ME, Carson JA, Bateman TA. "Bone and muscle changes in skeletally mature mice in response to modeled galactic cosmic rays." Radiat Res. Submitted, 2008. , Sep-2008
Articles in Peer-reviewed Journals Gridley DS, Obenaus A, Bateman TA, Pecaut MJ. "Long-term changes in rat hematopoietic and other physiological systems after high-energy iron ion irradiation." Int J Radiat Biol. 2008 Jul;84(7):549-59. PMID: 18661371 , Jul-2008
Articles in Peer-reviewed Journals Lloyd SA, Travis ND, Lu T, Bateman TA. "Development of a low-dose anti-resorptive drug regimen reveals synergistic suppression of bone formation when coupled with disuse." J Appl Physiol. 2008 Mar;104(3):729-38. PMID: 18174391 , Mar-2008
Articles in Peer-reviewed Journals Lloyd SA, Yuan YY, Kostenuik PJ, Ominsky MS, Lau AG, Morony S, Stolina M, Asuncion FJ, Bateman TA. "Soluble RANKL induces high bone turnover and decreases bone volume, density, and strength in mice." Calcif Tissue Int. 2008 May;82(5):361-72. PMID: 18465074 , May-2008
Articles in Peer-reviewed Journals Lloyd SA, Yuan YY, Simske SJ, Riffle SE, Ferguson VL, Bateman TA. "Administration of high-dose macrophage colony-stimulating factor increases bone turnover and trabecular volume fraction." J Bone Miner Metab. Submitted, 2008. , Sep-2008
Articles in Peer-reviewed Journals Willey JS, Grilly LG, Howard SH, Pecaut MJ, Obenaus A, Gridley DS, Nelson GA, Bateman TA. "Bone architectural and structural properties after 56Fe26+ radiation-induced changes in body mass." Radiat Res. 2008 Aug;170(2):201-7. PMID: 18666808 , Aug-2008
Articles in Peer-reviewed Journals Willey JS, Lloyd SA, Robbins ME, Bourland JD, Smith-Sielicki H, Bowman LC, Norrdin RW, Bateman TA. "Early increase in osteoclast number in mice following whole-body irradiation with 2 Gy X-rays." Radiat Res. 2008 Sep;170(3):388-92. PMID: 18763868 , Sep-2008
Awards Riffle S. "2008 ACC Undergraduate Research Conference (one of ten Clemson representatives), Florida State University, Tallahassee, Florida, April 19, 2008." Apr-2008
Awards Tirado L. "2008 ACC Undergraduate Research Conference (one of ten Clemson representatives), Florida State University, Tallahassee, Florida, April 19, 2008." Apr-2008
Awards Tirado L. "Travel Award from Society for Advancement of Chicanos and Native Americans in Science (SACNAS) for the International Polar Year: Global Change in Our Communities, July 2008." Jul-2008
Awards Lemus M. "Undergraduate Research Fellowship from the South Carolina Space Grant Consortium, April 2008." Apr-2008
Awards Bateman TA. "Thora W. Halstead Young Investigator's Award, American Society for Gravitational and Space Biology (ASGSB), October 2007." Oct-2007
Awards Anderson E. "Best Undergraduate Research Presentation and Travel Awards from the American Society for Gravitational and Space Biology, October 2007." Oct-2007
Awards Willey J. "Post-doctoral Fellowship from the National Space Biomedical Research Institute, October 2007." Oct-2007
Awards Bowman L. "Graduate Student Research Program Fellowship from the South Carolina Space Grant Consortium, April 2008." Apr-2008
Books/Book Chapters Bateman TA, Bandstra ER, Willey JS, Lloyd SA, Yuan YY, Bourne J. "How animal models inform the debate." in "Bone loss during spaceflight : etiology, countermeasures, and implications for bone health on Earth." Ed. P.R. Cavanagh, A.J. Rice. Cleveland : Cleveland Clinic Press, c2007. p. 189-199., Dec-2007
Papers from Meeting Proceedings Bandstra ER, Judex S, Vazquez ME, Bateman TA. "Murine bone loss following local irradiation." 29th Annual Meeting of the American Society for Bone and Mineral Research, Honolulu, HI, September 16-19, 2007.

29th Annual Meeting of the American Society for Bone and Mineral Research, Abstract Book, September 2007. , Sep-2007

Project Title:  Space Radiation and Bone Loss: Lunar Outpost Mission Critical Scenarios and Countermeasures Reduce
Fiscal Year: FY 2008 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 10/01/2007  
End Date: 09/30/2011  
Task Last Updated: 11/29/2007 
Download report in PDF pdf
Principal Investigator/Affiliation:   Bateman, Ted A. Ph.D. / University of North Carolina at Chapel Hill 
Address:  152 MacNider Hall, CB 7575 
Dept of Biomedical Engineering 
Chapel Hill , NC 27599 
Email: bateman@unc.edu 
Phone: 720-810-3626  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of North Carolina at Chapel Hill 
Joint Agency:  
Comments: Previous affiliation was Clemson University; PI moved to UNC in fall 2010. 
Co-Investigator(s)
Affiliation: 
Jones, Jeffrey  NASA JSC 
Midura, Ronald  The Cleveland Clinic Foundation 
Nelson, Gregory  Loma Linda University 
Project Information: Grant/Contract No. NCC 9-58-BL01302 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2007 NSBRI-RFA-07-01 Human Health in Space 
Grant/Contract No.: NCC 9-58-BL01302 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:  
No. of PhD Candidates:  
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) HHC:Human Health Countermeasures
Human Research Program Risks: (1) Osteo:Risk Of Early Onset Osteoporosis Due To Spaceflight (No longer used, July 2020)
Human Research Program Gaps: (1) Osteo04:We do not know the contribution of each risk factor on bone loss and recovery of bone strength, and which factors are the best targets for countermeasure application (IRP Rev E)
Task Description: Crews on exploratory missions will face complex radiation from cosmic and solar sources with components ranging from protons to iron. We have identified trabecular bone loss in mice after exposure to a 2 Gy dose of multiple radiation types, suggesting space radiation may increase bone loss from reduced gravity during exploratory missions. An increase in serum markers of bone resorption in rats three days post-exposure to 2 Gy indicates bone loss may be rapid.

The impact of radiation on bone quality and fracture healing in reduced gravity is unknown and must be studied to understand effects of space radiation on bone health. The long-term objective of this project is the development of countermeasures to prevent bone loss during missions and thus reduce fracture risk.

To define the risks associated with space radiation-induced bone loss, the following aims will examine effects of modeled space radiation using scenarios applicable for Lunar Outpost missions:

1. Examine combined effects of a modeled solar particle event and unloading on bone, and subsequent recovery during reloading. Hypothesis: Proton radiation with unloading will induce a more severe bone loss than unloading alone.

2. Examine initiation of osteoclast activation and subsequent bone loss following exposure to several types of modeled space radiation, including acute proton exposure, low-dose-rate proton exposure and mixed radiation types (proton and HZE). Understanding underlying molecular causes is critical to developing countermeasures for radiation-induced bone loss. Hypothesis: The initiating mechanism of bone loss is radiation-induced inflammation, increasing RANKL production due to damaged marrow, causing early osteoclast activation.

3. Test the efficacy of three countermeasures for bone loss caused by proton exposure: a) The bisphosphonate zoledronate; b) The RANKL blocking protein osteoprotegerin; and c) An antioxidant agent, -lipoic acid. Hypothesis: Potent inhibitors of bone resorption, both zoledronate and osteoprotegerin will prevent the bone loss caused by radiation. Antioxidants will address multiple radiation-induced problems; -lipoic acid decreases osteoclast differentiation and activity.

Research Impact/Earth Benefits: 0

Task Progress & Bibliography Information FY2008 
Task Progress: New project for FY2008.

Bibliography Type: Description: (Last Updated: 11/12/2020)  Show Cumulative Bibliography Listing
 
 None in FY 2008