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Keywords:

  • DXA;
  • BIOCHEMICAL MARKERS OF BONE TURNOVER;
  • EXERCISE;
  • SEX DIFFERENCES;
  • RENAL STONE RISK

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References
  10. Supporting Information

Bone loss, a key concern for long-duration space travelers, is typically considered a female issue. The number of women who have flown long-duration space missions is now great enough to allow a quantitative comparison of changes in bone and renal stone risk by sex. Participants were 42 astronauts (33 men and 9 women) on long-duration missions to the International Space Station. Bone mineral density (by dual-energy X-ray absorptiometry) and biochemical markers of bone metabolism (from blood and urine samples) were evaluated before and after flight. Data were analyzed in two groups, based on available resistance exercise equipment. Missions were 49 to 215 days in duration, flown between 2000 and 2012. The bone density response to spaceflight was the same for men and women in both exercise groups. The bone mineral density response to flight was the same for men and women, and the typical decrease in bone mineral density (whole body and/or regional) after flight was not observed for either sex for those using an advanced resistive exercise device. Biochemical markers of bone formation and resorption responded similarly in male and female astronauts. The response of urinary supersaturation risk to spaceflight was not significantly different between men and women, although risks were typically increased after flight in both groups, and risks were greater in men than in women before and after flight. The responses of men and women to spaceflight with respect to these measures of bone health were not different. © 2014 American Society for Bone and Mineral Research.


Introduction

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References
  10. Supporting Information

In the 30 years since Sally Ride's inaugural spaceflight for American women, questions have been raised about sex differences in the responses to all aspects of spaceflight. Given that bone loss is one of the physiological concerns for astronauts, and sex differences occur in the incidence of bone diseases (eg, osteoporosis) on Earth, whether such differences exist in bone loss in space was an obvious area of inquiry and concern. Until recently, no study of sex differences in bone response to spaceflight has been possible.

Progress has recently been made in mitigating loss of bone mineral on long-duration space missions, either with exercise and nutrition[1] or with pharmaceuticals.[2] Heavy resistance exercise in well-nourished crews with adequate energy intakes and adequate vitamin D status has allowed maintenance of bone mineral density (BMD) after 4- to 6-month International Space Station (ISS) missions.[1] This came as a result of bone remodeling and not a simple suppression of bone resorption elevated by spaceflight.

Bone demineralization during spaceflight leads to an increased risk of forming kidney stones, starting in the first days of flight and continuing until after landing.[3-5] On 1- to 2-week Space Shuttle flights, as on Earth, urine biochemistry indicates that men have a greater risk for stone formation than women, but both have an increased supersaturation risk relative to before flight.[5, 6] However, the postflight increase for men puts them above the typical supersaturation threshold, whereas women show no greater risk than the general population.[6]

We tested the hypothesis that the rate of bone loss was not different between men and women during spaceflight for two different exercise protocols. We report here the first assessment of sex differences in bone and renal stone risks in response to spaceflight.

Materials and Methods

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References
  10. Supporting Information

The study was reviewed and approved by the NASA Johnson Space Center Institutional Review Board (IRB), and all protocols complied with the World Medical Association Declaration of Helsinki—Ethical Principles for Medical Research Involving Human Subjects. Written informed consent was obtained from crew members before they participated.

Participants

Data from 42 astronauts on ISS expeditions 1 to 32 (missions of 49 to 215 days' duration, flown between 2000 and 2012) were combined and analyzed in one of two data sets based on exercise equipment available during the participants' missions. Crew members who launched before November 14, 2008, had access to the interim resistive exercise device (iRED), and crew members who launched on or after November 14, 2008, had access to the advanced resistive exercise device (ARED). Data from some of these 42 crew members have been previously reported[1, 2, 7-10] but never with respect to the sex-specific effects. Subject demographics are shown in Supplemental Table S1.

Astronauts were excluded from this analysis if they were participating in an evaluation of bisphosphonates as a bone-loss countermeasure.[2] Participants in another study, in which potassium citrate was used to mitigate renal stone risk, were not excluded after findings with and without them were evaluated, and no differences in any overarching effects or conclusions were found. The means, SD, and statistical results presented include the 9 crew members supplemented with potassium citrate in the iRED group. When 3 men and 2 women each flew on two missions, each flight was treated as a unique event. All but one of the female astronauts were believed to have been premenopausal at the time of their mission; however, we do not have data pertaining to menstrual cycle regularity and/or surgical status for the others. Additionally, most female astronauts suppress menstrual cycles pharmacologically during flight.

Dietary intake during flight was determined using a food-frequency questionnaire, as previously reported.[11, 12]

Sample collection and biochemical analyses

Fasting blood samples and two 24-hour urine samples were collected 10 to 131 days (average 69 ± 24) before flight and again on landing day and 0 to 2 days after flight. Blood and urine samples were analyzed for indices of bone and calcium metabolism and vitamin D status, and have been previously described.[13-17] Full details are provided in Supplemental Methods.

Bone densitometry

As previously described,[11, 15, 18] areal BMD was determined once before (129 ± 90 days, range 31 to 454) and once after (12 ± 9 days, range 6 to 46 days) spaceflight by dual-energy X-ray absorptiometry (DXA) with a fan-beam densitometer (Hologic Discovery; Hologic, Inc., Waltham, MA, USA). Full details are provided in Supplemental Methods.

Statistical analysis

All statistical analyses were performed using Stata IC software (v 12.1, StataCorp, College Station, TX, USA) and setting 2-tailed α to reject the null hypothesis at 0.05. Continuous linear comparisons were made using duration of spaceflight and a preflight sample. All dependent variables were assessed multiple times, resulting in a longitudinal (repeated measures) experimental design. Full details are provided in Supplemental Methods.

Results

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References
  10. Supporting Information

The bone mineral density response to flight was the same for men and women, and the typical decrease in bone mineral density (whole-body and/or regional) after flight was not observed for either sex for those using the current exercise program (ie, ARED). Before spaceflight, total body and pelvis bone mineral densities were greater for men than women (Table 1). Early exercise protocols (iRED) failed to protect bone, with both men and women having lost total-body and pelvis bone mineral density. These losses were not observed in those using current exercise protocols (ie, ARED), in either whole-body or regional bone density determinations.

Table 1. Bone Mineral Density (g/cm2) Before and After Spaceflights of Different Durations
   Flight duration (days)Effect (p)
0 (Preflight)49 to150151 to 215SexDurationInteraction
  1. Individual flight durations and a repeated-measures design were used for statistical analysis. For the purpose of presentation in tables, the flight durations were grouped as above to provide a simpler view and to ensure anonymity of data, given that many flight durations had only 1 data point. ND = no data.

niREDWomen404   
  Men21516   
 AREDWomen532   
  Men1239   
Total body BMDiREDWomen1.16 ± 0.08ND1.11 ± 0.07<0.05<0.01 
  Men1.28 ± 0.111.17 ± 0.091.28 ± 0.08   
 AREDWomen1.12 ± 0.061.09 ± 0.071.12 ± 0.01<0.05  
  Men1.23 ± 0.101.17 ± 0.041.24 ± 0.09   
Pelvis BMDiREDWomen1.12 ± 0.09ND1.05 ± 0.10<0.05<0.01 
  Men1.24 ± 0.081.08 ± 0.091.18 ± 0.09   
 AREDWomen1.12 ± 0.131.05 ± 0.131.19 ± 0.01<0.01  
  Men1.29 ± 0.131.18 ± 0.041.26 ± 0.12   
Hip neck BMD (g)iREDWomen0.87 ± 0.10ND0.83 ± 0.10   
  Men0.89 ± 0.120.81 ± 0.130.83 ± 0.11   
 AREDWomen0.86 ± 0.120.85 ± 0.180.86 ± 0.04   
  Men0.88 ± 0.130.76 ± 0.050.89 ± 0.12   
Hip trochanter BMD (g)iREDWomen0.78 ± 0.10ND0.74 ± 0.12 <0.05 
  Men0.82 ± 0.100.73 ± 0.060.78 ± 0.10   
 AREDWomen0.74 ± 0.120.74 ± 0.160.71 ± 0.09   
  Men0.83 ± 0.120.74 ± 0.050.82 ± 0.11   
Total hip BMD (g)iREDWomen1.01 ± 0.12ND0.95 ± 0.13 <0.001 
  Men1.07 ± 0.100.97 ± 0.081.03 ± 0.10   
 AREDWomen0.96 ± 0.130.95 ± 0.180.92 ± 0.02   
  Men1.08 ± 0.130.96 ± 0.061.07 ± 0.10   
Total lumbar spine BMD (g)iREDWomen1.07 ± 0.11ND1.02 ± 0.10 <0.01 
  Men1.06 ± 0.100.99 ± 0.111.03 ± 0.09   
 AREDWomen1.07 ± 0.121.05 ± 0.171.08 ± 0.02   
  Men1.12 ± 0.101.05 ± 0.051.11 ± 0.08   

Although it appears in Table 1 that those on the shorter-duration missions had more bone loss, this was not documented statistically and most likely is an artifact of the data presentation method. It is important to remember, as mentioned in “Statistical Analysis,” the data were analyzed using actual mission durations in a continuous linear model. However, we cannot present these data in that fashion, in part because of concerns about subject confidentiality, given that mission durations are often attributable to only one astronaut. Thus, data are presented in two ways, normalized to percentage change per month of spaceflight (Fig. 1, bone mineral density; Supplemental Fig. S1, bone mineral content [BMC]), and categorized into two groups, missions of longer or shorter duration than 150 days of spaceflight (Table 2 and Supplemental Table S2).

image

Figure 1. Bone mineral density data expressed as percentage change per month in women (gray bars) and men (black bars) for groups with different exercise hardware, interim resistance exercise device (iRED), and advanced resistance exercise device (ARED). Data are mean ± SD. iRED women n = 4, iRED men n = 21, ARED women n = 5, ARED men n = 12.

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Table 2. Markers of Bone and Calcium Metabolism Before and After Spaceflights of Different Durations
   Flight duration (days)Effect (p)
0 (Preflight)49 to 150151 to 215SexDurationInteraction
  1. a

    Log transformed.

  2. b

    One outlier removed.

  3. Individual flight durations and a repeated-measures design were used for statistical analysis. For the purpose of presentation in tables, the flight durations were grouped as above to provide a simpler view and to ensure anonymity of data, given that many flight durations had only 1 data point. ND = no data.

Blood analytes        
niREDWomen404   
  Men21516   
 AREDWomen532   
  Men1239   
25-hydroxyvitamin Da (nmol/L)iREDWomen92 ± 30ND76 ± 26   
  Men65 ± 1658 ± 2847 ± 17   
 AREDWomen89 ± 2382 ± 10113 ± 49  <0.05
  Men82 ± 2066 ± 1069 ± 12   
1,25-dihydroxyvitamin Da (pmol/L)iREDWomen140 ± 76ND187 ± 98   
  Men128 ± 54116 ± 33145 ± 57   
 AREDWomen130 ± 35166 ± 48238 ± 88 <0.001 
  Men135 ± 41177 ± 30185 ± 60   
Parathyroid hormonea,b (pg/mL)iREDWomen34 ± 13ND35 ± 24   
  Men39 ± 2334 ± 1339 ± 24   
 AREDWomen27 ± 1423 ± 445 ± 31   
  Men29 ± 829 ± 1131 ± 6   
Bone-specific alkaline phosphataseb (U/L)iREDWomen17 ± 4ND19 ± 3  <0.05
  Men22 ± 927 ± 531 ± 12   
 AREDWomen17 ± 522 ± 1031 ± 3<0.01<0.001 
  Men26 ± 737 ± 539 ± 7   

Some have hypothesized that it might be better to fly astronauts who have larger, denser bones before flight because they have a larger amount of bone to begin with and thus, in theory, would remain above the fracture risk threshold despite any losses. This implies, perhaps unintentionally, that men are better suited for spaceflight because they typically (and as observed here) start out with greater bone mineral content (Supplemental Table S2) and bone mineral density. Because the bone-loss effect of spaceflight on men and women is the same, we investigated this hypothesis further by combining all data (male, female, iRED, and ARED) and examined whether preflight BMC was correlated with percentage bone loss. We found that the percentage change in BMC after flight was inversely correlated with preflight BMC. As Fig. 2A shows, crew members with a greater initial BMC (mostly men) lost a larger percentage of bone during flight (p = 0.0179, r = 0.3638). When percentage BMC loss was normalized to months of flight duration (Fig. 2B), the correlation still suggested a trend (p = 0.0724, r = 0.2692) in this response. Therefore, crew members with greater BMC lose more bone (%) and lose it faster (%/flight duration), independent of sex and exercise. This goes against conventional wisdom, as outlined above, because crew members who started with more BMC end up losing more bone faster than crew members who started with less BMC.

image

Figure 2. Percentage change in total bone mineral content (BMC) for the whole flight (A) and percentage change normalized with flight duration (per month) (B) as a function of initial total BMC. Both figures indicate that the higher a person's preflight BMC, the more bone he or she loses, regardless of sex. iRED women n = 4, iRED men n = 21, ARED women n = 5, ARED men n = 12.

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Body composition responses to spaceflight were influenced by the exercise equipment available, but were not influenced by sex. As expected, body mass (Supplemental Table S3 and Supplemental Fig. S2) was greater for men than for women, with greater changes in iRED than ARED groups. In the iRED group, body composition (% lean, % fat) did not change (Supplemental Table S3 and Supplemental Fig. S2). Crew members exercising on the ARED had less body fat (mass and %) after flight and tended to have more lean tissue (mass and %). Thus, the current exercise protocol is literally bringing crew members home in better general physical shape than when they launched. Given decades of evidence for muscle atrophy and bone loss in astronauts, the changes observed with the current exercise regimen are very encouraging.

There was an interactive effect of sex and flight duration on the bone formation marker bone-specific alkaline phosphatase (BSAP) in crew members using the iRED. Specifically, BSAP was increased in male astronauts but not female astronauts in this group upon landing (Table 2). For astronauts using the ARED, BSAP increased with flight duration (p = 0.001) and was higher in men than women (p = 0.01). Osteocalcin, an index of bone turnover, was unaffected by sex and by spaceflight (Supplemental Table S4). Bone resorption, evaluated using urinary collagen crosslinks, responded similarly in male and female astronauts (Table 2 and Supplemental Table S4).

Although some differences between men and women existed in bone resorption markers (Table 2 and Supplemental Table S4), these differences were less or were not apparent when data were normalized to creatinine (an index of muscle mass) (Supplemental Table S5) or to preflight whole-body bone mass (data not presented).

The vitamin D intake of ARED crew members was observed to be greater than the vitamin D intake of iRED crew members (Supplemental Table S6). The serum 25-hydroxyvitamin D data reflect this increase (Table 2).

A common technique for assessing renal stone risk includes estimating supersaturation of stone-forming compounds in urine and provides an overview of the urine chemistry from a 24-hour urine collection.[17] With one exception (uric acid supersaturation), there was no significant difference between the response of men and women in estimated supersaturation risk after spaceflight, although supersaturation for other stone types was typically increased after flight in both groups and was greater in men than in women before and after flight (Table 3 and Supplemental Table S4). Most analytes were excreted in greater amounts by men than by women (Table 3 and Supplemental Table S4), and these differences tended to disappear when the data were normalized to creatinine (data not shown). Urinary calcium excretion was greater in men than women before flight, and there was little change after flight for either exercise group. Other markers related to stone formation risk were different between the two sexes in each exercise group and between the two sexes (Table 3 and Supplemental Table S4). Some of these differences are likely related to dietary intake differences between groups and to the changes in typical intake that occur soon after landing.

Table 3. Urinary Analytes and Calculated Renal Stone Supersaturation Risk Before and After Spaceflights of Different Durations
   Flight duration (days)Effect (p)
0 (Preflight)49 to 150151 to 215SexDurationInteraction
  1. a

    Square root transformed.

  2. b

    Log transformed.

  3. c

    One outlier removed.

  4. For all except struvite supersaturation data, a value of 2 is considered the average risk for the population, with values higher than that representing increased risk. For struvite supersaturation, values >75 are considered increased risk relative to the general population.17 Individual flight durations and a repeated-measures design were used for statistical analysis. For the purpose of presentation in tables, the flight durations were grouped as above to provide a simpler view and to ensure anonymity of data, given that many flight durations had only 1 data point. ND = no data.

Calciuma (mmol/d)iREDWomen3.7 ± 2.5ND4.1 ± 2.3   
  Men5.1 ± 2.14.4 ± 2.24.7 ± 2.2   
 AREDWomen3.0 ± 1.03.3 ± 1.83.9 ± 2.2<0.05  
  Men4.8 ± 1.66.7 ± 2.75.2 ± 2.7   
24-h volumeb,c (mL)iREDWomen2050 ± 648ND2203 ± 742   
  Men1860 ± 6931695 ± 10711629 ± 881   
 AREDWomen2570 ± 12711941 ± 13231772 ± 464   
  Men2311 ± 9212336 ± 3881594 ± 849   
N-telopeptideb,c (nmol/d)iREDWomen264 ± 88ND462 ± 185<0.01<0.001 
  Men445 ± 224577 ± 174653 ± 283   
 AREDWomen238 ± 41443 ± 221377 ± 170<0.01<0.01 
  Men455 ± 225609 ± 248781 ± 208   
C-telopeptidec (µg/d)iREDWomen1593 ± 677ND3489 ± 327 <0.01 
  Men2358 ± 11433418 ± 7583375 ± 1223   
 AREDWomen1242 ± 6552821 ± 15691371 ± 538  <0.05
  Men1939 ± 7694123 ± 15114154 ± 1,480   
Oxalatea,b,c (mg/d)iREDWomen26 ± 6ND49 ± 26  <0.01
  Men39 ± 1356 ± 3239 ± 18   
 AREDWomen37 ± 433 ± 1421 ± 6  <0.01
  Men36 ± 1142 ± 1038 ± 10   
Sodiuma (mmol/d)iREDWomen133 ± 53ND151 ± 87  <0.01
  Men164 ± 57134 ± 8297 ± 56   
 AREDWomen151 ± 3895 ± 3086 ± 62 <0.01 
  Men168 ± 60218 ± 9566 ± 33   
pHiREDWomen5.9 ± 0.3ND6.3 ± 0.4  <0.01
  Men6.0 ± 0.36.2 ± 0.55.7 ± 0.4   
 AREDWomen6.3 ± 0.36.0 ± 0.55.8 ± 0.5 <0.05 
  Men6.1 ± 0.46.5 ± 0.55.6 ± 0.3   
CaOx supersaturationb,ciREDWomen0.82 ± 0.57ND1.74 ± 1.71<0.01<0.05 
  Men1.71 ± 0.712.69 ± 2.052.79 ± 1.74   
 AREDWomen1.06 ± 0.952.39 ± 2.910.88 ± 0.17 <0.05 
  Men1.18 ± 0.651.79 ± 0.592.77 ± 1.49   
Brushite supersaturationbiREDWomen0.52 ± 0.34ND0.48 ± 0.40<0.01  
  Men1.43 ± 1.021.05 ± 1.220.86 ± 1.07   
 AREDWomen0.74 ± 0.541.12 ± 1.300.63 ± 0.88   
  Men1.38 ± 1.071.36 ± 0.460.88 ± 0.90   
Na urate supersaturationbiREDWomen2.02 ± 1.89ND1.27 ± 0.80   
  Men2.79 ± 2.152.04 ± 1.481.45 ± 1.31   
 AREDWomen1.65 ± 1.262.07 ± 2.470.62 ± 0.79 <0.05 
  Men2.15 ± 1.451.99 ± 0.631.20 ± 1.19   
Struvite supersaturationbiREDWomen0.98 ± 2.30ND0.44 ± 0.48   
  Men1.42 ± 3.142.24 ± 3.550.34 ± 0.40   
 AREDWomen1.16 ± 1.602.01 ± 4.360.40 ± 0.61   
  Men1.93 ± 3.691.59 ± 1.440.43 ± 0.81   
Uric acid supersaturationa,ciREDWomen1.81 ± 1.02ND0.74 ± 0.70  <0.01
  Men1.57 ± 0.911.63 ± 1.952.52 ± 1.84   
 AREDWomen0.63 ± 0.370.80 ± 0.561.17 ± 0.62   
  Men1.42 ± 0.880.74 ± 0.883.10 ± 2.14   

Discussion

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References
  10. Supporting Information

The response of bone to spaceflight was the same for men and women in both exercise groups. Men and women lost proportional amounts of bone under the early exercise protocol (iRED), but the current exercise protocol (ARED) protected against loss of bone mineral density in men and women equally. The ARED exercise group did not lose bone (in the whole body or specific regions), but they gained lean mass and lost fat mass during flight, whereas the iRED group lost bone and lean mass and gained fat mass.

These findings are consistent with previously published results for subsets of these groups,[1, 10] and moreover, the varying responses of both men and women support earlier conclusions that early exercise protocols (with iRED) were insufficient to protect bone[10] and that the current ISS exercise program (with ARED) is making significant strides toward improving the bone health of astronauts, regardless of sex, during spaceflight.[1] It is worth noting that this is the third study reporting DXA data from ISS crews that had access to the ARED (although sex was not addressed in other articles). We report here data from 6 more crew members than the second article[2] and 9 more than the first.[1] Furthermore, we replicated statistical analyses here with the subset of crew members from the second study[2] and found no difference in results or conclusions.

The responses of biochemical markers of bone metabolism were similar in men and women. Bone formation, as assessed by BSAP, is typically unchanged during flight,[14, 20] with a recently documented exception being astronauts performing heavy resistance exercise during flight.[1] A rapid increase occurs postflight as the body begins to readapt to 1g.[11] Similar to previous spaceflight studies,[1, 11, 14, 20-24] bone resorption was increased after spaceflight, regardless of exercise type.

Vitamin D is an important hormone for bone and calcium metabolism, and vitamin D deficiency is of concern for astronauts because their food sources of vitamin D are limited and they lack ultraviolet light exposure in the shielded spacecraft.[1] As a result, vitamin D supplements have been provided to all ISS crews. In 2007, the provision doubled from 400 IU/d to 800 IU/d, starting around the time the ARED was deployed on ISS (in 2008). It is noteworthy that in these individuals, with no exposure to ultraviolet light and a food system with limited vitamin D sources, intake of 700 to 800 IU vitamin D/d maintains circulating vitamin D levels above Institute of Medicine recommendations for bone health and close to what many consider to be “optimal” levels (eg, 75 to 80 nmol/L, 30 to 32 ng/mL).[25]

Spaceflight is associated with an increased risk of renal stone formation, largely because of the increased calcium excretion secondary to bone loss.[3, 26, 27] The effects of spaceflight on renal stone risk documented here are consistent with earlier publications, where sex comparisons were not possible.[26, 27] We document here, however, that the response to spaceflight is the same in men and women. For sodium urate stones, the average supersaturation risk for astronauts before flight exceeded that for the general population, for both men and women. The risk of forming calcium oxalate stones increased after flight for both men and women in both the iRED and ARED groups. These data highlight the criticality of increased fluid consumption even after flight.

In summary, this study provides the first detailed analysis of sex differences in bone and renal stone effects of spaceflight. The data document that, although on Earth sex differences exist in bone mineral density and content and in renal stone risk, the effects of spaceflight seem to be nondiscriminatory in this regard. Furthermore, the data reported here document the relative success of the current spaceflight exercise regimen. Although work remains to be done, to answer further questions, the progress noted here and in recent reports is extremely encouraging.

Acknowledgments

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References
  10. Supporting Information

We thank the astronauts for their time and willingness to participate in this study. We thank the staff of the NASA Johnson Space Center Nutritional Biochemistry Laboratory for their assistance in processing and analyzing the samples and in all aspects of carrying out this project. We thank the NASA JSC Immunology/Biochemical Analysis Lab for assistance with the renal stone profile analyses. We thank Jane Krauhs for editorial assistance.

This project was funded by the NASA Human Research Program and by a grant from the German Federal Ministry for Economics and Technology/DLR Forschung unter Weltraumbedingungen (50WB0931) to MH.

Authors' roles: Study design: SS, SZ, MH, EH, LS, and JM. Study conduct: SS and SZ. Data collection: JM, EH, and SZ. Data analysis: SZ and JM. Data interpretation: SS, SZ, MH, EH, LS, and JM. Drafting manuscript: SS and JM. Revising manuscript content: SS, SZ, MH, EH, LS, and JM. Approving final version of manuscript: SS, SZ, MH, EH, LS, and JM. SS takes responsibility for the integrity of the data and the accuracy of the data analysis.

References

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References
  10. Supporting Information
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Supporting Information

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References
  10. Supporting Information

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