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NASA NTRS2007

Preliminary Assessment of Artificial Gravity Impacts to Deep-Space Vehicle Design

Even after more than thirty years of scientific investigation, serious concerns regarding human physiological effects of long-duration microgravity exposure remain. These include loss of bone mineral density, skeletal muscle atrophy, and orthostatic hypertension, among others. In particular, "Safe Passage: Astronaut Care for Exploration Missions," states "loss of bone density, which apparently occurs at a rate of 1% per month in microgravity, is relatively manageable on the short-duration missions of the space shuttle, but it becomes problematic on the ISS [International Space Station]. ...If this loss is not mitigated, interplanetary missions will be impossible." While extensive investigations into potential countermeasures are planned on the ISS, the delay in attaining full crew complement and onboard facilities, and the potential for extending crews tours of duty threaten the timely (< 20 years!) accumulation of sufficient data for countermeasures formulation. Indeed, there is no guarantee that even with the data, a practical or sufficiently robust set of countermeasures will be forthcoming. Providing an artificial gravity (AG) environment by crew centrifugation aboard deep-space human exploration vehicles, long a staple technique of science fiction, has received surprisingly limited engineering assessment. This is most likely due to a number of factors: the lack of definitive design requirements, especially acceptable artificial gravity levels and rotation rates, the perception of high vehicle mass and performance penalties, the incompatibility of resulting vehicle configurations with space propulsion options (i.e., aerocapture), the perception of complications associated with de-spun components such as antennae and photovoltaic arrays, and the expectation of effective crew micro-gravity countermeasures. These perception and concerns may have been overstated, or may be acceptable alternatives to countermeasures of limited efficacy. This study was undertaken as an initial step to try to understand the implications of and potential solutions to incorporating artificial gravity in the design of human deep-space exploration vehicles. Of prime interest will be the mass penalties incurred by incorporating AG, along with any mission performance degradation.

Joosten, B. Kent↗

NASA NTRS2016

Gene Expression and Structural Skeletal Responses to Long-Duration Simulated Microgravity in Rats

Spaceflight has deleterious effects on skeletal structure and function, specifically causingprofound loss in bone mass, density, and strength, as well as changes in expression levels of genes related to oxidative stress [Hyeon et al., Smith et al.]. It is known that bone resorption remains elevated after spaceflight and that bone density and strength fail to recover completely even years following spaceflight [Smith et al., Carpenter et al.]. However, our current understanding of the signaling pathways and molecular mechanisms that control bone loss and that link oxidative stress, bone resorption, and mechanical unloading of skeletal tissue is incomplete. Here, we aim to examine skeletal responses to simulated long-duration spaceflight on bone loss using the ground-based hindlimb unloading (HU) model in adult (9 months old) male rats. We hypothesized that simulated microgravity leads to the temporal regulation of oxidative-defense genes and pro-osteoclastogenic factors, showing progression and eventual plateau during long-term unloading, and that transient changes at early timepoints in these pathways precede skeletal adaptations to long-duration unloading. We will identify oxidativestress and bone resorption-related changes using global gene expression analysis (Affymetrix arrays) for both acute (within 14 days) and long-term timepoints (90 days). We will also use quantitative PCR to examine changes in expression of genes related to oxidative metabolism (e.g. Nrf2, SOD-1), bone turnover (resorption and formation markers, e.g. TRAP, osteocalcin respectively, SOST), and osteoclastogenesis (e.g. RANKL, OPG) at both early and late timepoints. We will then use detailed microarchitectural and structural analysis through microcomputed tomography to relate gene expression changes with structural changes in bone, expecting that plateaus in gene expression correlate with long-term changes in bone microarchitecture.

Rael, Victoria E.↗

NASA NTRS2002

Core Research Program, Year 5

Dramatic losses of bone mineral density (BMD) and muscle strength are two of the best documented changes observed in humans after prolonged exposure to microgravity. Recovery of muscle upon return to a 1-G environment is well studied, however, far less is known about the rate and completeness of BMD recovery to pre-flight values. Using the mature tail-suspended adult rat model, this proposal will focus on the temporal course of recovery in tibial bone following a 28-d period of skeletal unloading. Through the study of bone density and muscle strength in the same animal, time-points during recovery from simulated microgravity will be identified when bone is at an elevated risk for fracture. These will occur due to the rapid recovery of muscle strength coupled with a slower recovery of bone, producing a significant mismatch in functional strength of these two tissues. Once the time-point of maximal mismatch is defined, various mechanical and pharmacological interventions will be tested at and around this time-point in attempt to minimize the functional difference of bone and muscle. The outcomes of this research will have high relevance for optimizing the rehabilitation of astronauts upon return to Earth, as well as upon landing on the Martian surface before assuming arduous physical tasks. Further. it will impact significantly on rehabilitation issues common to patients experiencing long periods of limb immobilization or bed rest.

Source record↗

NASA NTRS2002

Decreases in bone blood flow and bone material properties in aging Fischer-344 rats

The purpose of this study was to quantify precisely aging-induced changes in skeletal perfusion and bone mechanical properties in a small rodent model. Blood flow was measured in conscious juvenile (2 months old), adult (6 months old), and aged (24 months old) male Fischer-344 rats using radiolabeled microspheres. There were no significant differences in bone perfusion rate or vascular resistance between juvenile and adult rats. However, blood flow was lower in aged versus adult rats in the forelimb bones, scapulas, and femurs. To test for functional effects of this decline in blood flow, bone mineral density and mechanical properties were measured in rats from these two age groups. Bone mineral density and cross-sectional moment of inertia in femoral and tibial shafts and the femoral neck were significantly larger in the aged versus adult rats, resulting in increased (+14%-53%) breaking strength and stiffness. However, intrinsic material properties at midshaft of the long bones were 12% to 25% lower in the aged rats. Although these data are consistent with a potential link between decreased perfusion and focal alterations in bone remodeling activity related to clinically relevant bone loss, additional studies are required to establish the mechanisms for this putative relationship.

Non-NASA Center↗

NASA NTRS1999

Bone Loss in Space: Shuttle/MIR Experience and Bed Rest Countermeasure Program

Loss of bone mineral during space flight was documented in the 1970's Skylab missions. The USSR space program made similar observations in the 1980's. The Institute of Biomedical Problems in Moscow and NASA JSC in 1989 began to collect pre- and post-flight bone mineral density (BMD) using Hologic QDR 1000 DEXA scanners transferred from JSC to Moscow and Star City. DEXA whole body, hip, and lumbar spine scans were performed prior to and during the first week after return from 4- to 6-month missions (plus one 8-month mission and one 14- month mission) on the Mir space station. These data documented the extent and regional nature of bone loss during long duration space flight. Of the 18 cosmonauts participating in this study between 1990 and 1995, seven flew two missions. BMD scans prior to the second flight compared to the first mission preflight scans indicated that recovery was possibly delayed or incomplete. Because of these findings, NASA and IBMP initiated the study "Bone Mineral Loss and Recovery After Shuttle/Mir Flights" in 1995 to evaluate bone recovery during a 3-year post-flight period. All of the 14 participants thus far evaluated lost bone in at least one region of the spine and lower extremities during flight. Of the 14, only one to date has exhibited full return to baseline BNM values in all regions. The current study will continue until the last participant has reached full bone recovery in all regions, has reached a plateau, or until three years after the flight (2001 for the last mission of the program). Bone mineral density losses in space and difficulty in returning to baseline indicate a need for countermeasure development. In late 1996 NASA JSC and Baylor College of Medicine were approved to conduct two countermeasure studies during 17 weeks of bed rest. In 1997 the studies were begun in the bed rest facility established by NASA, Baylor College of Medicine, and The Methodist Hospital in Houston. To date, three bed rest controls, five resistive exercisers, and four subjects taking alendronate (a bisphoshonate that inhibits osteoclastic resorption of bone) have completed 17 weeks bed rest. In contrast to information currently available from space flight (n=28) and bed rest (n= 12) in which all individuals experienced bone loss in at least one region, one of four subjects taking alendronate and one of five subjects performing heavy resistive exercise at bed rest fully maintained bone density in all regions of the spine and lower extremities. Overall results of both countermeasures which will be presented are encouraging. The study will be completed by mid to late 2000 with 10 subjects in each of three groups.

Shackelford, L. C.↗

NASA NTRS2004

Differential skeletal responses of hindlimb unloaded rats on a vitamin D-deficient diet to 1,25-dihydroxyvitamin D3 and its analog, seocalcitol (EB1089)

Conditions of disuse in bed rest patients, as well as microgravity experienced by astronauts are accompanied by reduced mechanical loading, reduced calcium absorption, and lower serum levels of 1,25(OH)2D3 (1,25-D), the active metabolite of vitamin D, all contributing to bone loss. To determine whether 1,25-D or a less calcemic analog, Seocalcitol or EB1089 (1 alpha,25-dihydroxy-22,24-diene-24,26,27-trihomovitamin D3) can alleviate bone loss in a rat hindlimb unloading model of disuse osteopenia, mature male rats originally on a vitamin D replete diet containing 1.01% calcium were transferred to a vitamin D-deficient diet containing 0.48% calcium and then tail suspended and treated for 28 days with vehicle, 0.05 microg/kg 1,25-D, or 0.05 microg/kg EB1089. The vitamin D-deficient diet caused a substantial decrease in bone mineral density (-8%), which may be compounded by hindlimb unloading (-10%). Exogenous 1,25-D not only prevented the bone loss but also increased the bone mineral density to greater than the baseline level (+7%). EB1089 was less effective in preventing bone loss. Analysis of site and cell-specific effects of 1,25-D and EB1089 revealed that 1,25-D was more active than EB1089 in the intestine, the site of calcium absorption, and in inducing osteoclastogenesis and bone resorption whereas EB1089 was more effective in inducing osteoblast differentiation. These studies suggest that elevating circulating 1,25-D levels presumably increasing calcium absorption can counteract bone loss induced by disuse or microgravity with its associated reductions in circulating 1,25-D and decreased calcium absorption.

Non-NASA Center↗

NASA NTRS1992

Lack of deleterious effect of slow-release sodium fluoride treatment on cortical bone histology and quality in osteoporotic patients

We evaluated the effects of intermittent slow-release sodium fluoride (SRNaF) and continuous calcium citrate therapy on cortical bone histology, reflection ultrasound velocity (material strength) and back-scattered electron image analysis (BEI) in 26 osteoporotic patients before and following therapy. All measurements were made on transiliac crest bone biopsies obtained before and following 2 years of therapy in each patient. For all 26 patients there were no significant changes in cortical bone histomorphometric parameters. In 15 patients in whom bone material quality was assessed by reflection ultrasound, there was no change in velocity (4000 +/- 227 SD to 4013 +/- 240 m/s). BEI disclosed no mineralization defects or the presence of woven bone. Mean atomic number (density) of bone increased slightly, but significantly (9.261 +/- 0.311 to 9.457 +/- 0.223, P = 0.031). While these changes are less marked than those observed for cancellous bone, they indicate that this form of therapy does not adversely affect cortical bone remodelling.

NASA Discipline Regulatory Physiology↗

NASA NTRS2004

Modeled Microgravity Disrupts Collagen I/Integrin Signaling During Osteoblastic Differentiation of Human Mesenchymal Stem Cells

Spaceflight leads to reduced bone mineral density in weight bearing bones that is primarily attributed to a reduction in bone formation. We have previously demonstrated severely reduced osteoblastogenesis of human mesenchymal stem cells (hMSC) following seven days culture in modeled microgravity. One potential mechanism for reduced osteoblastic differentiation is disruption of type I collagen-integrin interactions and reduced integrin signaling. Integrins are heterodimeric transmembrane receptors that bind extracellular matrix proteins and produce signals essential for proper cellular function, survival, and differentiation. Therefore, we investigated the effects of modeled microgravity on integrin expression and function in hMSC. We demonstrate that seven days of culture in modeled microgravity leads to reduced expression of the extracellular matrix protein, type I collagen (Col I). Conversely, modeled microgravity consistently increases Col I-specific alpha2 and beta1 integrin protein expression. Despite this increase in integrin sub-unit expression, autophosphorylation of adhesion-dependent kinases, focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2), is significantly reduced. Activation of Akt is unaffected by the reduction in FAK activation. However, reduced downstream signaling via the Ras-MAPK pathway is evidenced by a reduction in Ras and ERK activation. Taken together, our findings indicate that modeled microgravity decreases integrin/MAPK signaling, which likely contributes to the observed reduction in osteoblastogenesis.

Meyers, Valerie E.↗

NASA NTRS2024

Risk of Bone Fracture due to Spaceflight-induced Changes to Bone

The Human Research Program (HRP) is taking a biomechanical approach to assessing subsequent fracture risk in active astronauts as a consequence of spaceflight exposure. Triennial testing of active and retired astronauts continues as Space Medicine monitors for a premature diagnosis of primary osteoporosis, which is associated with age-related bone loss and skeletal fragility. This updated 2023 Fracture Evidence Report has expanded the description of skeletal changes to capture the full effects of spaceflight on bone: • Recent analysis of fractures from health records of the full astronaut cohort, suggests an increased incidence rate of hip and spine fractures in astronauts following longer spaceflight duration flights compared to incident rates found in shorter duration flights. • Routine preflight-to-postflight surveillance by DXA (dual-energy x-ray absorptiometry) does not provide the full detection of loss and recovery in the long-duration (LD) astronaut nor the full recovery of hip trabecular bone. • The inclusion of hip quantitative computed tomography (QCT) in flight studies delineates effects of spaceflight, of countermeasures, and of post-flight recovery on cortical and trabecular bone parameters—some of which are verified predictors of hip fracture in the aged. • QCT detects and compares the distinct countermeasure effects of the pharmaceutical alendronate and of resistive exercise (on the Advanced Resistive Exercise Device, ARED) in specific cortical and trabecular bone sub-regions during spaceflight. • A published comparison of QCT-determined loss rates of hip trabecular bone in LD astronauts compared to terrestrial cohorts suggest that accelerated loss rates in trabecular volumetric BMD (vBMD) during spaceflight might be analogous to skeletal effects of accelerated loss rates in females due to menopause, potentially leading to disruptions in trabecular microarchitecture. • A dataset of finite element (FE) estimates of hip bone strength in aging terrestrial cohorts (spanning astronaut age-range) provides comparative context for changes in the FE of hip bone strength in LD astronauts, including comparison (force unit of newton) to percentiles (50th, 75th, and 100th) of sex-matched aged humans with hip fractures. • Risk of fracture, due to the mechanical overloading of bones, is being updated with IMPACT, the next-generation tool suite for probabilistic risk assessment (PRA) for exploration missions being created by the Exploration and Medical Capability Element (ExMC) at NASA. IMPACT is currently in development and will not be included in this 2024 update. The risk for fracture necessitates understanding the relationship between applied loads to bone and the biomechanical competence of bone. The Risk for Early Onset Osteoporosis focuses on the weakened condition of bone (including development of new technologies, measurements of novel skeletal attributes, translation of multiple measures to an index of bone fragility, and interpretations of data used to reflect a weakened bone), while the Risk for Fracture assesses factors that influence the probability an astronaut would encounter applied loads exceeding the biomechanical competence of bones, resulting in fracture. This Evidence Report combines the research gaps and tasks associated with both risks.

Fracture↗

NASA NTRS2004

Techniques for deriving tissue structure from multiple projection dual-energy x-ray absorptiometry

Techniques for deriving bone properties from images generated by a dual-energy x-ray absorptiometry apparatus include receiving first image data having pixels indicating bone mineral density projected at a first angle of a plurality of projection angles. Second image data and third image data are also received. The second image data indicates bone mineral density projected at a different second angle. The third image data indicates bone mineral density projected at a third angle. The third angle is different from the first angle and the second angle. Principal moments of inertia for a bone in the subject are computed based on the first image data, the second image data and the third image data. The techniques allow high-precision, high-resolution dual-energy x-ray attenuation images to be used for computing principal moments of inertia and strength moduli of individual bones, plus risk of injury and changes in risk of injury to a patient.

Charles, Jr., Harry K.↗

NASA NTRS2003

Hindlimb unloading has a greater effect on cortical compared with cancellous bone in mature female rats

This study was designed to determine the effects of 28 days of hindlimb unloading (HU) on the mature female rat skeleton. In vivo proximal tibia bone mineral density and geometry of HU and cage control (CC) rats were measured with peripheral quantitative computed tomography (pQCT) on days 0 and 28. Postmortem pQCT, histomorphometry, and mechanical testing were performed on tibiae and femora. After 28 days, HU animals had significantly higher daily food consumption (+39%) and lower serum estradiol levels (-49%, P = 0.079) compared with CC. Proximal tibia bone mineral content and cortical bone area significantly declined over 28 days in HU animals (-4.0 and 4.8%, respectively), whereas total and cancellous bone mineral densities were unchanged. HU animals had lower cortical bone formation rates and mineralizing surface at tibial midshaft, whereas differences in similar properties were not detected in cancellous bone of the distal femur. These results suggest that cortical bone, rather than cancellous bone, is more prominently affected by unloading in skeletally mature retired breeder female rats.

NASA Discipline Musculoskeletal↗

NASA NTRS2001

Ultrasonic wave propagation in trabecular bone predicted by the stratified model

The objective of this study was to investigate ultrasound propagation in trabecular bone by considering the wave reflection and transmission in a multilayered medium. The use of ultrasound to identify those at risk of osteoporosis is a promising diagnostic method providing a measure of bone mineral density (BMD). A stratified model was proposed to study the effect of transmission and reflection of ultrasound wave within the trabecular architecture on the relationship between ultrasound and BMD. The results demonstrated that ultrasound velocity in trabecular bone was highly correlated with the bone apparent density (r=0.97). Moreover, a consistent pattern of the frequency dependence of ultrasound attenuation coefficient has been observed between simulation using this model and experimental measurement of trabecular bone. The normalized broadband ultrasound attenuation (nBUA) derived from the simulation results revealed that nBUA was nonlinear with respect to trabecular porosity and BMD. The curve of the relationship between nBUA and BMD was parabolic in shape, and the peak magnitude of nBUA was observed at approximately 60% of bone porosity. These results agreed with the published experimental data and demonstrated that according to the stratified model, reflection and transmission were important factors in the ultrasonic propagation through the trabecular bone.

Non-NASA Center↗

NASA NTRS2017

Implementation and Integration of a Finite Element Model into the Bone Remodeling Model to Characterize Skeletal Loading

NASA's Digital Astronaut Project is developing a bone physiology model to predict changes in bone mineral density over the course of a space mission. The model intends to predict bone loss due to exposure in microgravity as well as predicting bone maintenance due to mechanical stimulus generated by exercise countermeasures. These predictions will be used to inform exercise device efficacy and to help design exercise protocols that will maintain bone mineral density during long exposures to microgravity during spaceflight. The mechanical stimulus and the stresses that are exhibited on the bone are important factors for bone remodeling. These stresses are dependent on the types of exercise that are performed and vary throughout the bone due to the geometry. A primary area of focus for bone health is the proximal femur. This location is critical in transmitting loads between the upper and lower body and have been known to be a critical failure point in older individuals with conditions like osteoporosis.

bone mineral content↗

NASA NTRS2002

Regional alterations of type I collagen in rat tibia induced by skeletal unloading

Skeletal unloading induces loss of mineral density in weight-bearing bones that leads to inferior bone mechanical strength. This appears to be caused by a failure of bone formation; however, its mechanisms still are not well understood. The objective of this study was to characterize collagen, the predominant matrix protein in bone, in various regions of tibia of rats that were subjected to skeletal unloading by 4 weeks tail suspension. Sixteen male Sprague-Dawley rats (4 months old) were divided into tail suspension and ambulatory controls (eight rats each). After the tail suspension, tibias from each animal were collected and divided into five regions and collagen was analyzed. The collagen cross-linking and the extent of lysine (Lys) hydroxylation in unloaded bones were significantly altered in proximal epiphysis, diaphysis, and, in particular, proximal metaphysis but not in distal regions. The pool of immature/nonmineralized collagen measured by its extractability with a chaotropic solvent was significantly increased in proximal metaphysis. These results suggest that skeletal unloading induced an accumulation of post-translationally altered nonmineralized collagen and that these changes are bone region specific. These alterations might be caused by impaired osteoblastic function/differentiation resulting in a mineralization defect.

Non-NASA Center↗

NASA NTRS2001

Alterations of collagen matrix in weight-bearing bones during skeletal unloading

Skeletal unloading induces loss of bone mineral density in weight-bearing bones. The objectives of this study were to characterize the post-translational modifications of collagen of weight-bearing bones subjected to hindlimb unloading for 8 weeks. In unloaded bones, tibiae and femurs, while the overall amino acid composition was essentially identical in the unloaded and control tibiae and femurs, the collagen cross-link profile showed significant differences. Two major reducible cross-links (analyzed as dihydroxylysinonorleucine and hydroxylysinonorleucine) were increased in the unloaded bones. In addition, the ratios of the former to the latter as well as pyridinoline to deoxypyridinoline were significantly decreased in the unloaded bones indicating a difference in the extent of lysine hydroxylation at the cross-linking sites between these two groups. These results indicate that upon skeletal unloading the relative pool of newly synthesized collagen is increased and it is post-translationally altered. The alteration could be associated with impaired osteoblastic differentiation induced by skeletal unloading that results in a mineralization defect.

Non-NASA Center↗

NASA NTRS2004

Variations in Urine Calcium Isotope: Composition Reflect Changes in Bone Mineral Balance in Humans

Changes in bone mineral balance cause rapid and systematic changes in the calcium isotope composition of human urine. Urine from subjects in a 17 week bed rest study was analyzed for calcium isotopic composition. Comparison of isotopic data with measurements of bone mineral density and metabolic markers of bone metabolism indicates the calcium isotope composition of urine reflects changes in bone mineral balance. Urine calcium isotope composition probably is affected by both bone metabolism and renal processes. Calcium isotope. analysis of urine and other tissues may provide information on bone mineral balance that is in important respects better than that available from other techniques, and illustrates the usefulness of applying geochemical techniques to biomedical problems.

Skulan, Joseph↗

NASA NTRS2015

Directed Research in Bone Discipline: Refining Previous Research Observations for Space Medicine

Dual-energy X-ray absorptiometry bone mass density, as a sole index, is an insufficient surrogate for fracture; Clinical Practice Guidelines using bone mass density (both World Health Organization and FRAX) are not specific for complicated subjects such as young, healthy persons following prolonged exposure to skeletal unloading (i.e. an attribute of spaceflight); Research data suggest that spaceflight induces changes to astronaut bones that could be profound, possibly irreversible and unlike age-related bone loss on Earth.; There is a need to objectively assess factors across human physiology that are also influenced by spaceflight (e.g., muscle) that contribute to fracture risk. Some of these objective assessments may require innovative technologies, analyses and modeling.; Astronauts are also exposed to novel situations that may overload their bones highlighting a need integrate biomechanics of physical activities into risk assessments.; As we accumulate data, which reflects the biomechanical competence of bone under specific mechanically-loaded scenarios (even activities of daily living), BONE expects Bone Fracture Module to be more sensitive and/or have less uncertainty in its assessments of fracture probability.; Fracture probability drives the requirement for countermeasures. Level of evidence will unlikely be obtained; hence, the Bone Research and Clinical Advisory Panel (like a Data Safety Monitoring Board) will provide the recommendations.

Sibonga, Jean D.↗

NASA NTRS2007

Bone Research at NASA: Career Pathway to the Space Program

This viewgraph document is comprised of two presentations about Bone Research at NASA. The first document has slides that show the percent of bone loss from specific bones as demonstrated from research of the Mir cosmonauts, and the required preflight and postflight BMD measurements for long duration flights. The second presentation entitled "Recovery of Spaceflight-induced Bone Loss: Bone Mineral Density after Long-duration Missions as Fitted with an Exponential Function" reviews the recovery of Bone Mineral Density (BMD) after long duration missions. Between 1990 and 2004, 56 missions were flown with 45 crewmembers for an average of 181 days +/- 47 days. For each of these flights the change in BMD was calculated after the flight. The BMD changes were plotted against the number of days for bone recovery after the landing. The plots for the bones that were measured are shown.

Sibonga, Jean D.↗