NOTE: End date changed to 9/30/2018 per PI (Ed., 9/10/18)

NOTE: Changed end date to 7/31/2016, although this is tentative, per PI saying work has not yet been completed (Ed., 4/29/16)

NOTE: Gap changes per IRP Rev E (Ed., 1/27/14)

NOTE: Title change per HRP and PI to "Feasibility Study: QCT Modality for Risk Surveillance of Bone - Effects of In-flight Countermeasures on Sub-regions of the Hip Bone"; previously "Occupational Risk Surveillance for Bone: Pilot Study - Effects of In-flight Countermeasures on Sub-regions of the Hip Bone" (Ed., 1/23/2013)

This pilot study proposes to use preflight and postflight QCT scanning of the hips in International Space Station (ISS) astronauts to evaluate the ability of in-flight countermeasures to prevent the occurrence of this clinical trigger. This study further hypothesizes that QCT scanning can distinguish the effects of different categories of in-flight countermeasures/activities on distinct sub-regions of the hip bone. For example, this pilot study will demonstrate that biochemically-based countermeasures (e.g., dietary manipulation of acidic to basic amino acid intake or bisphosphonates medication) will have a detectable prevention of BMD loss in hip trabecular compartment while biomechanically-based countermeasures (exercise regimens) will have detectable expansion of cortical bone apposition -- increasing both bone cross-sectional area and integral BMD as a consequence. These different effects on hip morphology will be subsequently translated to an effect on hip bone strength of the ISS astronaut. The combination of countermeasures that impact both compartments will more likely result in greater hip bone strength -- as estimated by analyzing QCT data by Finite Element Modeling (FEM) -- than of any singly applied countermeasure. This assertion will be approached in this pilot study by addressing the following Aims in each ISS astronaut:

1) Characterize the response of i) trabecular and cortical BMDs of the hip and ii) cross-sectional areas of cortical bone, trabecular bone, and integral bone, to countermeasures that are either based upon biochemistry or mechanical-loading -- with QCT measures. 2) Translate the QCT-measured changes in hip bone morphology (Aim 1) to hip bone fracture loads (aka, "hip bone strength") using FEM. 3) Characterize QCT-measured changes in hip bone morphology (Aim 1) following a 12-month postflight period on Earth and, in addition, translate these changes to the percentage recovery of preflight hip bone strength determined by FEM.

By addressing these aims this pilot study, using a research tool, will provide preliminary data that are critical for clinical issues related to fracture risk: Are in-flight countermeasures and postflight activities sufficient to protect against incidence of a clinical trigger for medical intervention? Do countermeasures protect against a decline in bone strength? Can hip bone strength be sufficiently recovered?

In addition, Trabecular Bone Score (TBS) analysis of DXA lumbar spine scans will be used to characterize bone microarchitecture of the lumbar spine and to determine if an effect of space flight can be detected in the retrospective ISS DXA data set. Like QCT, TBS may help fill a void with traditional DXA measurements, as it can differentiate between areas of bone that have the same areal BMD value but different 3-dimensional microsarchitecture in the trabecular bone compartment of the spine. This is achieved by retrospectively analyzing areal DXA scans and measuring the mean rate of variation of gray levels. Since QCT measurements in this study are being obtained only on the hip, TBS analyses will serve a similar purpose for the spine. In addition to the TBS analysis of ISS DXA scans, TBS analyses of retrospective precision study subjects will be used to determine measurement precision of this technique on a population similar to that of the astronauts.

Earth Benefits: This expanded assessment of skeletal integrity, being validated for space flight-induced bone loss in astronauts, would be relevant for the terrestrial, complicated patient (e.g., glucocorticoid-induced, alcohol-induced). Recently, FEM estimations of bone strength have been evaluated in population studies as predictors of incident hip fractures. These FE hip strengths are being evaluated for cut-points that would provide thresholds of acceptable bone health for active astronauts and aging retired astronauts. The development of these cut-points, as demonstrated for astronauts, would undergird the current discussions to use FE hip strength as a substitute for expensive and time-consuming prospective trials with fracture outcome -- the standard validation of hip fracture interventions.

All scheduled testing sessions for the 10 original subjects and the 1-year mission subject were completed by March 2018. QCT scans were submitted to Dr. T. Lang at UCSF (University of California San Francisco) for analysis, including measures of cortical and trabecular BMD, as well as estimates of bone strength computed from Finite Element modeling of the QCT scans. The resulting data have been reduced and analyzed, and preliminary results from the n=10 group were presented at the NASA Human Research Program Investigators’ Workshop in Galveston, TX, (January 2018).

Final results from the n=10 group are now being written up in a manuscript to be submitted for publication in a peer-reviewed scientific journal. Data from the 1-year-mission subject are excluded from this manuscript due to the confounding effects of longer space flight duration, but may be written up as part of a larger, multidisciplinary, effort to document results from the 1-year mission.

There are two manuscript deliverables from the data generated by this study. i) “Supplemental Use of Quantitative Computed Tomography Hip Scans of Astronauts for Clinical Assessments at NASA” to be submitted to journal Aerospace Med Human Performance (Authors: J.D. Sibonga , E.R. Spector , B.E. Lewandowski , S.R. Zwart , S.M. Smith , T.F. Lang ) and ii) “The Utility of Hip Scans by Quantitative Computed Tomography (QCT) to Assess the Mitigation of Skeletal Changes during Spaceflights” to be submitted to journal Bone. (Authors: J.D. Sibonga , E.R. Spector , A.D. Leblanc , B. Lewandowski , M.E. Downs , L. Ploutz - Snyder , T. Lang).

NOTE: Changed end date to 7/31/2016, although this is tentative, per PI saying work has not yet been completed (Ed., 4/29/16)

NOTE: Gap changes per IRP Rev E (Ed., 1/27/14)

NOTE: Title change per HRP and PI to "Feasibility Study: QCT Modality for Risk Surveillance of Bone - Effects of In-flight Countermeasures on Sub-regions of the Hip Bone"; previously "Occupational Risk Surveillance for Bone: Pilot Study - Effects of In-flight Countermeasures on Sub-regions of the Hip Bone" (Ed., 1/23/2013)

This pilot study proposes to use preflight and postflight QCT scanning of the hips in ISS astronauts to evaluate the ability of in-flight countermeasures to prevent the occurrence of this clinical trigger. This study further hypothesizes that QCT scanning can distinguish the effects of different categories of in-flight countermeasures/activities on distinct sub-regions of the hip bone. For example, this pilot study will demonstrate that biochemically-based countermeasures (e.g., dietary manipulation of acidic to basic amino acid intake or bisphosphonates medication) will have a detectable prevention of BMD loss in hip trabecular compartment while biomechanically-based countermeasures (exercise regimens) will have detectable expansion of cortical bone apposition -- increasing both bone cross-sectional area and integral BMD as a consequence. These different effects on hip morphology will be subsequently translated to an effect on hip bone strength of the ISS astronaut. The combination of countermeasures that impact both compartments will more likely result in greater hip bone strength -- as estimated by analyzing QCT data by Finite Element Modeling (FEM) -- than of any singly applied countermeasure. This assertion will be approached in this pilot study by addressing the following Aims in each ISS astronaut:

1) Characterize the response of i) trabecular and cortical BMDs of the hip and ii) cross-sectional areas of cortical bone, trabecular bone, and integral bone, to countermeasures that are either based upon biochemistry or mechanical-loading -- with QCT measures. 2) Translate the QCT-measured changes in hip bone morphology (Aim 1) to hip bone fracture loads (aka, "hip bone strength") using FEM. 3) Characterize QCT-measured changes in hip bone morphology (Aim 1) following a 12-month postflight period on Earth and, in addition, translate these changes to the percentage recovery of preflight hip bone strength determined by FEM.

By addressing these aims this pilot study, using a research tool, will provide preliminary data that are critical for clinical issues related to fracture risk: Are in-flight countermeasures and postflight activities sufficient to protect against incidence of a clinical trigger for medical intervention? Do countermeasures protect against a decline in bone strength? Can hip bone strength be sufficiently recovered?

In addition, Trabecular Bone Score (TBS) analysis of DXA lumbar spine scans will be used to characterize bone microarchitecture of the lumbar spine and to determine if an effect of space flight can be detected in the retrospective ISS DXA data set. Like QCT, TBS may help fill a void with traditional DXA measurements, as it can differentiate between areas of bone that have the same areal BMD value but different 3-dimensional microsarchitecture in the trabecular bone compartment of the spine. This is achieved by retrospectively analyzing areal DXA scans and measuring the mean rate of variation of gray levels. Since QCT measurements in this study are being obtained only on the hip, TBS analyses will serve a similar purpose for the spine. In addition to the TBS analysis of ISS DXA scans, TBS analyses of retrospective precision study subjects will be used to determine measurement precision of this technique on a population similar to that of the astronauts.

Earth Benefits: This expanded assessment of skeletal integrity, being validated for spaceflight-induced bone loss in astronauts, would be relevant for the terrestrial, complicated patient (e.g., glucocorticoid-induced, alcohol-induced). Recently, FEM estimations of bone strength have been evaluated in population studies as predictors of incident hip fractures. These FE hip strengths are being evaluated for cut-points that would provide thresholds of acceptable bone health for active astronauts and aging retired astronauts. The development of these cut-points, as demonstrated for astronauts, would undergird the current discussions to use FE hip strength as a substitute for expensive and time-consuming prospective trials with fracture outcome -- the standard validation of hip fracture interventions.

The goal of this study is to demonstrate the surveillance value of QCT for assessing the clinical trigger for a possible intervention. To achieve this aim, the QCT data obtained to-date were reviewed in November 2013 in a closed-room session with the panel of clinical experts who first proposed the evidence-based clinical trigger at Bone Summit 2010. Bone Summit II was held at USRA and JSC on November 04 and 05, 2013. Charged with refining its recommendation, if required, the panel recommended that QCT testing continue, with an emphasis on obtaining data on at least 10 control subject crewmembers (currently, only 6 of the Hip QCT consented crewmembers fall into this category). A QCT recommendation, among others from this Bone Summit II was presented at a session entitled “To Mars and Beyond – How Will We Preserve the Musculoskeletal System in Long-Term Space Flights?” held during the 2014 American Society for Bone & Mineral Research [ASBMR] meeting, Houston, TX.

TBS analyses were completed for 51 ISS crewmembers’ pre and post flight DXA lumbar spine scans. These data were presented in a poster at the International Society for Clinical Densitometry’s 2014 annual meeting (Orlando, FL). A precision analysis of TBS data acquired from DXA scans (4.9% at 95% confidence level) was performed in a population similar to the astronaut corps. A retrospective TBS study was presented at the American Society of Bone and Mineral Research annual meeting (Houston, TX) to compare trends in BMD vs. TBS.

NOTE: Gap changes per IRP Rev E (Ed., 1/27/14)

NOTE: Title change per HRP and PI to "Feasibility Study: QCT Modality for Risk Surveillance of Bone - Effects of In-flight Countermeasures on Sub-regions of the Hip Bone"; previously "Occupational Risk Surveillance for Bone: Pilot Study - Effects of In-flight Countermeasures on Sub-regions of the Hip Bone" (Ed., 1/23/2013)

This pilot study proposes to use preflight and postflight QCT scanning of the hips in ISS astronauts to evaluate the ability of in-flight countermeasures to prevent the occurrence of this clinical trigger. This study further hypothesizes that QCT scanning can distinguish the effects of different categories of in-flight countermeasures/activities on distinct sub-regions of the hip bone. For example, this pilot study will demonstrate that biochemically-based countermeasures (e.g., dietary manipulation of acidic to basic amino acid intake or bisphosphonates medication) will have a detectable prevention of BMD loss in hip trabecular compartment while biomechanically-based countermeasures (exercise regimens) will have detectable expansion of cortical bone apposition -- increasing both bone cross-sectional area and integral BMD as a consequence. These different effects on hip morphology will be subsequently translated to an effect on hip bone strength of the ISS astronaut. The combination of countermeasures that impact both compartments will more likely result in greater hip bone strength -- as estimated by analyzing QCT data by Finite Element Modeling (FEM) -- than of any singly applied countermeasure. This assertion will be approached in this pilot study by addressing the following Aims in each ISS astronaut:

1) Characterize the response of i) trabecular and cortical BMDs of the hip and ii) cross-sectional areas of cortical bone, trabecular bone and integral bone, to countermeasures that are either based upon biochemistry or mechanical-loading -- with QCT measures. 2) Translate the QCT-measured changes in hip bone morphology (Aim 1) to hip bone fracture loads (aka, "hip bone strength") using FEM. 3) Characterize QCT-measured changes in hip bone morphology (Aim 1) following a 12-month postflight period on earth and, in addition, translate these changes to the percentage recovery of preflight hip bone strength determined by FEM.

By addressing these aims this pilot study, using a research tool, will provide preliminary data that are critical for clinical issues related to fracture risk: Are in-flight countermeasures and postflight activities sufficient to protect against incidence of a clinical trigger for medical intervention? Do countermeasures protect against a decline in bone strength? Can hip bone strength be sufficiently recovered?

In addition, Trabecular Bone Score (TBS) analysis of DXA lumbar spine scans will be used to characterize bone microarchitecture of the lumbar spine and to determine if an effect of space flight can be detected in the retrospective ISS DXA data set. Like QCT, TBS may help fill a void with traditional DXA measurements, as it can differentiate between areas of bone that have the same areal BMD value but different 3-dimensional microsarchitecture in the trabecular bone compartment of the spine. This is achieved by retrospectively analyzing areal DXA scans and measuring the mean rate of variation of gray levels. Since QCT measurements in this study are being obtained only on the hip, TBS analyses will serve a similar purpose for the spine. In addition to the TBS analysis of ISS DXA scans, TBS analyses of retrospective precision study subjects will be used to determine measurement precision of this technique on a population similar to that of the astronauts.

QCT data obtained to date for the various studies were reviewed in a closed-room session with a panel of clinical experts invited to the second Bone Summit, held at USRA and JSC on November 04 and 05, 2013. The panel recommended that QCT testing continue, with an emphasis on obtaining data on at least 10 control subject crewmembers (currently, only 6 of the Hip QCT consented crewmembers fall into this category).

TBS analyses were completed for 51 ISS crewmembers’ pre and post flight DXA lumbar spine scans. These data were summarized in an abstract that has been submitted to the International Society for Clinical Densitometry’s 2014 annual meeting. Work is underway to complete TBS analyses of DXA precision study scans to determine reproducibility of the technique in a population similar to the astronaut corps.

NOTE: Title change per HRP and PI to "Feasibility Study: QCT Modality for Risk Surveillance of Bone - Effects of In-flight Countermeasures on Sub-regions of the Hip Bone"; previously "Occupational Risk Surveillance for Bone: Pilot Study - Effects of In-flight Countermeasures on Sub-regions of the Hip Bone" (Ed., 1/23/2013)

This pilot study proposes to use preflight and postflight QCT scanning of the hips in ISS astronauts to evaluate the ability of in-flight countermeasures to prevent the occurrence of this clinical trigger. This study further hypothesizes that QCT scanning can distinguish the effects of different categories of in-flight countermeasures/activities on distinct sub-regions of the hip bone. For example, this pilot study will demonstrate that biochemically-based countermeasures (e.g., dietary manipulation of acidic to basic amino acid intake or bisphosphonates medication) will have a detectable prevention of BMD loss in hip trabecular compartment while biomechanically-based countermeasures (exercise regimens) will have detectable expansion of cortical bone apposition -- increasing both bone cross-sectional area and integral BMD as a consequence. These different effects on hip morphology will be subsequently translated to an effect on hip bone strength of the ISS astronaut. The combination of countermeasures that impact both compartments will more likely result in greater hip bone strength -- as estimated by analyzing QCT data by Finite Element Modeling (FEM) -- than of any singly applied countermeasure. This assertion will be approached in this pilot study by addressing the following Aims in each ISS astronaut:

1) Characterize the response of i) trabecular and cortical BMDs of the hip and ii) cross-sectional areas of cortical bone, trabecular bone and integral bone, to countermeasures that are either based upon biochemistry or mechanical-loading – with QCT measures.

2) Translate the QCT-measured changes in hip bone morphology (Aim 1) to hip bone fracture loads (aka, “hip bone strength”) using FEM.

3) Characterize QCT-measured changes in hip bone morphology (Aim 1) following a 12-month postflight period on earth and, in addition, translate these changes to the percentage recovery of preflight hip bone strength determined by FEM.

By addressing these aims, this pilot study, using a research tool, will provide preliminary data that are critical for clinical issues related to fracture risk: Are in-flight countermeasures and postflight activities sufficient to protect against incidence of a clinical trigger for medical intervention? Do countermeasures protect against a decline in bone strength? Can hip bone strength be sufficiently recovered?

Earth Benefits: This improved assessment of skeletal integrity, being validated for spaceflight-induced bone loss in astronauts, would be relevant for the terrestrial, complicated patient (e.g., glucocorticoid-induced, alcohol-induced). Recently, FEM estimations of bone strength have been evaluated in population studies as predictors of incident hip fractures. These FE hip strengths are being evaluated for cut-points that would provide thresholds of acceptable bone health for active astronauts and aging retired astronauts. The development of these cut-points, as demonstrated for astronauts, would undergird the current discussions to use FE hip strength as a substitute for expensive and time-consuming prospective trials with fracture outcome – the standard validation of hip fracture interventions.

NOTE: Title change per HRP and PI to "Feasibility Study: QCT Modality for Risk Surveillance of Bone - Effects of In-flight Countermeasures on Sub-regions of the Hip Bone"; previously "Occupational Risk Surveillance for Bone: Pilot Study - Effects of In-flight Countermeasures on Sub-regions of the Hip Bone" (Ed., 1/23/2013)

This pilot study proposes to use preflight and postflight QCT scanning of the hips in ISS astronauts to evaluate the ability of in-flight countermeasures to prevent the occurrence of this clinical trigger. This study further hypothesizes that QCT scanning can distinguish the effects of different categories of in-flight countermeasures/activities on distinct sub-regions of the hip bone. For example, this pilot study will demonstrate that biochemically-based countermeasures (e.g., dietary manipulation of acidic to basic amino acid intake or bisphosphonates medication) will have a detectable prevention of BMD loss in hip trabecular compartment while biomechanically-based countermeasures (exercise regimens) will have detectable expansion of cortical bone apposition -- increasing both bone cross-sectional area and integral BMD as a consequence. These different effects on hip morphology will be subsequently translated to an effect on hip bone strength of the ISS astronaut. The combination of countermeasures that impact both compartments will more likely result in greater hip bone strength -- as estimated by analyzing QCT data by Finite Element Modeling (FEM) -- than of any singly applied countermeasure. This assertion will be approached in this pilot study by addressing the following Aims in each ISS astronaut:

1) Characterize the response of i) trabecular and cortical BMDs of the hip and ii) cross-sectional areas of cortical bone, trabecular bone and integral bone, to countermeasures that are either based upon biochemistry or mechanical-loading – with QCT measures.

2) Translate the QCT-measured changes in hip bone morphology (Aim 1) to hip bone fracture loads (aka, “hip bone strength”) using FEM.

3) Characterize QCT-measured changes in hip bone morphology (Aim 1) following a 12-month postflight period on earth and, in addition, translate these changes to the percentage recovery of preflight hip bone strength determined by FEM.

By addressing these aims, this pilot study, using a research tool, will provide preliminary data that are critical for clinical issues related to fracture risk: Are in-flight countermeasures and postflight activities sufficient to protect against incidence of a clinical trigger for medical intervention? Do countermeasures protect against a decline in bone strength? Can hip bone strength be sufficiently recovered?