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A systematic review and meta-analysis of bone loss

in space travelers
1,2 1,2,3 ✉
Mariya Stavnichuk , Nicholas Mikolajewicz2,3, Tatsuya Corlett 2,3
, Martin Morris 4
and Svetlana V. Komarova

Bone loss in space travelers is a major challenge for long-duration space exploration. To quantify microgravity-induced bone loss in
humans, we performed a meta-analysis of studies systematically identified from searching Medline, Embase, Web of Science,
BIOSIS, NASA Technical reports, and HathiTrust, with the last update in November 2019. From 25 articles selected to minimize the
overlap between reported populations, we extracted post-flight bone density values for 148 individuals, and in-flight and post-
flight biochemical bone marker values for 124 individuals. A percentage difference in bone density relative to pre-flight was
positive in the skull, +2.2% [95% confidence interval: +1.1, +3.3]; neutral in the thorax/upper limbs, −0.7% [−1.3, −0.2]; and
negative in the lumbar spine/pelvis, −6.2 [−6.7, −5.6], and lower limbs, −5.4% [−6.0, −4.9]. In the lower limb region, the rate of
bone loss was −0.8% [−1.1, −0.5] per month. Bone resorption markers increased hyperbolically with a time to half-max of 11 days
[9, 13] and plateaued at 113% [108, 117] above pre-flight levels. Bone formation markers remained unchanged during the first
30 days and increased thereafter at 7% [5, 10] per month. Upon landing, resorption markers decreased to pre-flight levels at an
exponential rate that was faster after longer flights, while formation markers increased linearly at 84% [39, 129] per month for
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3–5 months post-flight. Microgravity-induced bone changes depend on the skeletal-site position relative to the gravitational vector.
Post-flight recovery depends on spaceflight duration and is limited to a short post-flight period during which bone formation
exceeds resorption.
npj Microgravity (2020)6:13 ; https://doi.org/10.1038/s41526-020-0103-2

INTRODUCTION Osteoblasts secrete bone specific alkaline phosphatase (BSAP) and

Since the mid-seventies, space travelers have been known to osteocalcin (OC), and produce a collagen type I-based organic
experience severe bone loss at a rate of 1–1.5% per month, which matrix, which is coupled with cleavage of C- and N-terminal
is only partially responsive to non-pharmacological counter- propeptides of collagen type I (PICP and PINP)12. Tissue-
measures1,2. Pharmacological treatments, such as anti-resorptive nonspecific alkaline phosphatase (AP) is also used as a bone
bisphosphonates, reduce bone loss in-flight, but may interfere formation marker12. During bone resorption, osteoclasts degrade
with the slow and often incomplete post-flight recovery2. Thus, organic matrix, releasing amino acids such as hydroxyproline (HP),
microgravity-induced bone loss is a significant and unresolved fragments of collagen type I, including C- and N-terminal
health risk for space travelers. telopeptides (CTX and NTX), as well as pyridinoline (PYD) and
Bones support body weight and transmit forces generated by deoxypyridinoline (DPD)12,13. The biochemical markers produced
muscles, adapting to endure mechanical loads3. The skeleton also by osteoblasts and osteoclasts are measured in the urine and
serves as a mineral reservoir4, accommodates hematopoietic serum to estimate bone turnover during spaceflight.
bone marrow5, and plays an active role in acid–base home- The science of space exploration is challenging and costly from
ostasis6. Since many of these functions are affected by micro- a technological and medical perspective. Small teams of
gravity, including reduced mechanical loading7, altered calcium individuals participate in missions of different duration in space-
homeostasis8, reduced hematopoiesis9, and altered metabo- craft that change dramatically with time. Thus, obtaining statistical
lism10, the relative contributions of different processes to bone power that is sufficient to discern biological effects from random
loss in space remain unresolved. Bone health is assessed using
variation is a prevalent challenge. Many studies have reported that
imaging radiography, a technique that over time has developed
humans lost bone during spaceflight1,2; however, it is difficult to
from projection radiography, through single photon absorptio-
metry (SPA), to dual X-ray absorptiometry (DXA) and quantitative find data related to (i) changes in different skeletal regions, (ii)
computed tomography (qCT) now widely used in a clinical temporal kinetics of bone loss, (iii) relationship between bone and
setting11. All these methods were used at some time to assess bone cell function, and (iv) degree of individual variability. With
bone health in space travelers, however, due to the absence of the objective to estimate these parameters, we used a meta-
radiographic equipment aboard spacecraft, all bone density analytic approach to combine systematically identified data
measurements were acquired on Earth, immediately before and reporting measurements of bone density or biochemical bone
after a spaceflight. markers in humans who have been to space according to the
Bone adaptation requires the actions of bone cells: bone- Fédération Aéronautique Internationale (FAI) definition. In the rest
forming osteoblasts and bone-destroying osteoclasts. Bone of the manuscript, we will use the term “astronaut” to define any
formation and resorption can be approximated from the person who traveled to space according to the FAI definition
biochemical by-products of osteoblast and osteoclast function. independent of their country of origin.

1
Department of Biomedical Engineering, McGill University, Montréal, Canada. 2Shriners Hospital for Children—Canada, Montréal, Canada. 3Faculty of Dentistry, McGill University,
Montréal, Canada. 4Schulich Library of Physical Sciences, Life Sciences and Engineering, McGill University, Montréal, Canada. ✉email: [email protected]

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 M. Stavnichuk et al.
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a b

IDENTIFICATION
10

Number of articles
8
Database search (5713) Other sources (7)
6
4
2
Records after duplicates removed (5066) 0
1970 1980 1990 2000 2010
Year of publication
SCREENING

Title/abstract screening (269) c Muscle function

Full-text screening (57) Calcium PTH
Fluid shift/balance
Metabolic
Cardiovascular
Duplicate populations (32)
Renal
INCLUSION

Hematological
Articles included in statistical analysis (25): Nervous/sensory
1. Bone density (11) Radiation/EVA
2. Biochemical marker (13) Genetic
3. Bone density and biochemical marker (1)

Fig. 1 Systematic review information flow and outcomes. a Prisma diagram. b Number of relevant articles by publication year.
c Physiological processes suggested to contribute to bone loss in space.
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RESULTS and lumbar vertebrae (region 3), and lower limbs (region 4) (Fig. 2
Publications on bone health in astronauts and Supplementary Table 1). Spaceflight resulted in significant
Article identification. The systematic search in Medline, Embase, bone gain in the skull region 2.2% [1.1, 3.3] and significant bone
Web of Science, and BIOSIS databases identified 5713 candidate loss in the thorax and upper limbs −1.4% [−2.1, −0.6], lumbar
articles related to bone health in humans who traveled to space spine/pelvis −6.2% [−6.7, −5.6], and lower limbs −4.9% [−5.6,
(Fig. 1a). Seven additional reports were found in the NASA −4.2]. The trends of bone density changes in each region were
technical report server database. After title/abstract screening, we consistent with changes in individual bones within each region
identified 269 articles relevant to bone health in astronauts (Fig. (Fig. 2 and Supplementary Table 2). Very short missions are likely
1a, b). Physiological factors identified as relevant to bone health in of insufficient duration to accurately detect changes in bone
astronauts included muscle function, calcium homeostasis, fluid density38. Therefore, we estimated bone density changes after
shift, metabolic, cardiovascular, and renal functions (Fig. 1c). After spaceflights longer than 28 days in region 2, where an updated
full-text screening, we identified 57 manuscripts which reported value was less different from baseline, −0.7% [−1.3, −0.2] and
numerical data on changes in bone-related outcomes during or region 4, where the new estimate indicated more severe bone loss
after spaceflight. −5.4% [−6.0, −4.9]. Coefficient of variation, which indicates
relative variability of the measure, was higher for regions 1 (26%)
Astronaut identification. To avoid duplicate datasets in the meta- and 2 (19%) compared to regions 3 (5%) and 4 (7%).
analysis, we attempted to identify astronauts in each study and
found a number of studies that reported the findings for the same Heterogeneity and bias. Statistical heterogeneity accounted for
astronauts. When two articles reported data for the overlapping >95% of the total variance in bone density data (Fig. 2). The meta-
astronaut populations, we included: (i) both studies if different analytic outcomes were not significantly influenced by study
outcomes were reported, (ii) the study reporting the more quality, year of publication, or any single dataset (Supplementary
complete dataset for overlapping reported outcomes, or (iii) the Fig. 1b, c). After ~20% of most heterogeneous studies were
study with a higher quality score for the same reported outcomes. removed, the homogenous datasets reported lower bone loss in
We could not ensure the absence of overlap between two studies, the upper limb and thorax region, but not in the lower limb region
therefore data for five astronauts may have been included twice in (Supplementary Fig. 1d, e). Funnel plot analysis suggested an
the analysis1,14. underreporting of positive bone density changes in region 2.
Temporal changes in bone density were examined using meta-
Articles included for meta-analysis. We selected 25 articles for regression and subgroup analysis for short (<100 days), inter-
meta-analysis, including 12 studies that reported bone density mediate (100–200 days), and long (>200 days) missions (Fig. 3). In
measures before and less than a week after a spaceflight1,14–23, region 2, meta-regression reported no relationship between bone
14 studies that contained data on biochemical bone markers24–36, density changes and mission duration, while subgroup analysis
and one study that reported both37. The final dataset contained demonstrated that highest bone loss was reported in short
data for ~189 astronauts (the number is approximate due to missions (Fig. 3a). In contrast, changes in lower limb bone density
remaining uncertainty in astronaut identification), with bone were strongly associated with mission duration by meta-
density measurements and biochemical bone markers available regression (p < 0.01) and subgroup analysis (Fig. 3b). Consistently,
for ~148 and ~124 astronauts, respectively. changes in individual heel bone density were also significantly
associated with mission duration (p < 0.01) (Fig. 3c). For both
regions 2 and 4, the rates of bone density change estimated from
Changes in bone density during spaceflight within-study regressions were higher and more variable compared
Skeletal site-specific changes in bone density. We examined to meta-analytic results (Fig. 3d). For the region 4, the rates of
changes in bone density in four skeletal regions: skull and neck bone loss were similar for all missions, missions longer than
(region 1), upper limbs and thoracic vertebrae (region 2), pelvis 30 days, and heel bone estimates (Fig. 3d). The most conservative

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 M. Stavnichuk et al.
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Fig. 2 Spaceflight-related bone density changes in different skeletal regions. Forest plots of changes (Δ) in bone density (% of pre-flight) in
the skull, cervical vertebrae (region 1); upper limbs, thoracic vertebrae, ribs (region 2); pelvis, lumbar vertebrae (region 3); and lower limbs
(region 4) (left); and in individual bones (right). Circles/lines: effect sizes (marker sizes are proportional to number of astronauts) and 95% CI;
red diamonds/bands: overall effects ± 95% CI; blue diamonds/bands: overall effects ± 95% CI for data from missions longer than 28 days.
Dashed line: no change from pre-flight. N/d: not determined. Source papers are in mission order. Missions, their duration, number of missions/
aggregated missions (N), and sample sizes (n) are shown.

and precise estimates for the rate of bone loss were obtained for Different resorption and formation markers were pooled together
missions longer than 30 days, which were −0.1% [−0.2, 0.0] per for subsequent analysis.
month for upper limbs and thorax, and −0.8% [−1.1, −0.5] per
month for lower limbs. Coefficient of variation for the rate of bone In-flight changes in biochemical markers. In-flight, bone resorp-
loss in region 4 was similar for the aggregate (26%) and individual tion markers increased with a half-time to maximum of 11 [9, 13]
heel bone (23%) estimates. days to 113% [108, 117] above pre-flight levels (Fig. 4a, left). The
rate of increase for uDPD and uPYD was consistent with overall
Changes in biochemical bone markers during and after spaceflight estimates, while uNTX increased significantly faster with a half-
Agreement between biochemical markers. Pair-wise correlation time of 6 [5, 7] days (Fig. 4a, right). Bone formation markers
analysis for biochemical bone markers measured in serum (s) or demonstrated a weak positive association (R2 = 0.26, p < 0.001)
urine (u) demonstrated consistent changes for the markers of with time in-flight (Fig. 4b, left). The linear rate of formation
bone resorption uHP, uNTX, uDPD, and uCTX; and formation markers increase was 7% [5, 10] per month, which was consistent
sBSAP, sAP, and sP1CP, while uPYD and sOC correlated poorly with with estimates from single studies, and for individual markers
other biochemical markers (Supplementary Figs. 2 and 3). except for sPICP (Fig. 4b, right). Coefficients of variation were 9%

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 M. Stavnichuk et al.
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a Region 2 a b1uPYD

Δ resorption markers (%)

200
0 b1uDPD
150

Δ bone density (%)

Δ bone density (%)
5 b1uNTX
100
-1 b1inter
0 50 110 130 150
R = 0.74
2

b1inter= 113% (108,117) max Δ markers (%)

-2 -50
-5 b2inter = 11 days (9,13) b2
uPYD

R = 0.22
2
b2
uDPD

p = 0.57 -3 0 40 80 120 160

-10 b2
uNTX

Day of measurement b2
inter
0 100 200 0 100 200
Mission Duration (days) 5 10 15
b t1/2 Δ markers (days)

Δ formation markers (%)

b Region 4 150
10 0 100 b1sOC
b1sPICP
Δ bone density (%)

Δ bone density (%)

5 50 b1
sBSAP
-2
0 b1
sAP
0
-5 -4 R2 = 0.26 b1intra
-50 b1
inter
b1inter = 7 (5,10)
-10 -6 -100 0 40 80 120 160 180
R = 0.39
2 -60 -40 -20 0 20
-15 p < 0.01 -8 Day of measurement rate (%/month)
-20
0 100 200 0 100 200 Fig. 4 Changes in biochemical bone markers during spaceflight. a
Mission Duration (days) The effect of flight duration on resorption markers (% pre-flight) was
c modeled using a sigmoidal function. Left: circles are study-level
Heel Bone d changes, marker sizes are proportional to number of astronauts,
15 Region 2 Region 4 black line/red band: mean fit/95% CI. Right: max levels (β1) and time
10 R2 = 0.24
Δ heel density (%)

to half-max (β2) with 95% CI for pooled (βinter) and individual (βuPYD,
p < 0.01 binter
5 βuDPD, βuNTX) markers. b The effect of flight duration on formation
0 binter > 30 days markers (% pre-flight) was assessed by meta-regression. Left: circles
-5 bindividual are study-level changes, marker sizes proportional to number of
-10 astronauts, black line, dark/light red bands: meta-regression with
bintra 95% confidence/prediction intervals, red lines: intra-study regres-
-15 -9 -7 -5 -3 -1 1 3
sions. Right: rates of change (β1) ± 95% CI for pooled (βinter, βintra)
-20 -9 -5 -1 3 -3 -2 -1 0 and individual (βsOC, βsPICP, βsBSAP, βsAP) markers.
-25
0 50 100 150 Δ bone density
Mission Duration (days) per month (%/month) individuals who participated in longer flights (Fig. 5b). In- and
post-flight changes in formation markers were fit with linear
Fig. 3 Changes in bone density as a function of mission duration. functions (Fig. 5c). While the complete in-flight formation marker
a–c Effect of space flight duration on changes in bone density (% of dataset suggested that bone formation increased in-flight (Fig.
pre-flight) in region 2 (upper body, a), region 4 (lower limbs, b), and 4b), mission-level datasets suggest that it remained unchanged or
heel bone of individual astronauts (c) was assessed by meta-
regression (left for (a–c)) and subgroup analysis (right for a, b). For slightly decreased in-flight (Fig. 5c). Upon return to Earth, bone
meta-regression, black solid line/red bands: inter-study (meta) formation markers increased linearly (Fig. 5c) with an overall rate
regression ± 95% confidence (dark red) and prediction (light red) of 2.8% [1.3, 4.3] per day or 84% [39, 129] per month (Fig. 5d). The
intervals; red lines: intra-study regressions. For subgroup analyses, reported rates of change were highly variable between studies,
mission-level changes were pooled by mission duration (<100, ranging from −12.0 to 213% per month. Only two studies
100–200, >200 days) and plotted as a function of average mission reported bone formation markers later than 30 days after landing.
duration. Horizontal error bars: range of mission durations within Caillot-Augusseau and colleagues reported that in one astronaut
subgroup; vertical error bars: pooled standard errors. Marker sizes from 1995 to 1997 Mir missions undercarboxylated osteocalcin
are proportional to number of astronauts. d Rate of bone loss for was still elevated 80 days post-flight26. Smith and colleagues
regions 2 (left) and 4 (right): slope coefficients β ± 95% CI for meta
regressions for all mission durations (βinter, black), missions longer reported that in 12 astronauts from Shuttle-Mir program bone
than 30 days (βinter > 30 days, blue), individual heel bone data formation markers returned to baseline by 150 days post-flight33.
(βindividual, green), and average intra-study regressions (βintra, red).
For region 2, βintra = −6 [−21, 9]. Potential mediators of spaceflight-related bone loss
We explored the availability of quantitative data for potential
for a half-time and 2% for maximal levels for bone resorption mediators of bone loss using the library of 269 papers selected for
markers, and 15% for formation markers. full-text screening. We identified studies that reported in-flight
changes in regulators of Ca2+ homeostasis16,25,27,33,34,37,39,
Post-flight changes in biochemical markers. The starting point for
stress37,39, and energy homeostasis40,41. Calcium regulating
post-flight recovery depends on how much biochemical markers
hormones, parathyroid hormone (PTH), 1,25-dihydroxyvitamin D,
changed in-flight, which in turn depends on flight duration. To
address this, we used a subset of studies reporting both in- and and calcitonin, were decreased by 11–23% early in spaceflight and
post-flight changes in biochemical markers, which were fit to gradually returned to pre-flight values thereafter (Fig. 6a). In-flight
piece-wise functions using the Monte-Carlo method (Fig. 5). In- changes in stress hormones, cortisol, epinephrine, and norepi-
flight changes in resorption markers were modeled with a nephrine were variable (Fig. 6b). Energy consumption decreased
sigmoidal function, and post-flight changes with an exponential in the first 30 days of spaceflight and slowly returned to baseline
function forced through the last in-flight value. Resorption by ~160 days, insulin levels decreased over 80 days in-flight, while
markers consistently decreased to pre-flight levels at an expo- growth hormone transiently increased early in-flight (Fig. 6c). The
nential rate (Fig. 5a), however, the rate of decay was faster in kinetics of changes in calcium regulating hormones and energy

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 M. Stavnichuk et al.
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a 40 Arnaud 1995
b a 2+
Ca metabolism
0 Flight Duration (days) 10
-40 0 40 80 120 0

Δ Change (%)
Caillot 2000 PTH
80 0.8 R2=0.99 -10 Calcitonin
Δ resorption markers (% pre-flight)

40 y=0.0042(x)e0.114
0.6 -20 Vitamin D
0

tdecay
Smith 1998 0.4 -30
80
Skylab 2 -40
40 0.2 0 50 100 150 200
0 0 Day of measurement
160
120
Smith 1998 b Stress
Skylab 3
80 40
40
0.16

Δ Change (%)
0
0.12 R =0.67 Cortisol
2
160 Smith 1998 20
120 Skylab 4 Norepinephrine
80 0.08
tdecay

40 0
0.04 Epinephrine
0
150 Smith 2005 0 -20
y=0.0014x-0.013
100 -0.04
50 0 40 80 0 50 100 150 200
0 Flight Duration (days) Day of measurement
-50
0 100 200 c Energy
Time (days) 60
c d 40
Δ Change (%)

duration 20 Insulin
3000 1020 Arnaud 1995 hGH
2000 0 (days) [ref] 0
5.9 [30] Energy
1000 -20
consumption
Δ formation markers (% pre-flight)

0 9.5 [31]
-40
300 Caillot 2000 14 [25]
200 21 [26]
100
[24]
0 40 80 120 160
0 28
Day of measurement
-100 57 [37]
Collet 1997
79 [35] Fig. 6 Spaceflight-related changes in physiological factors poten-
800 tially contributing to bone health. Subgroup analyses of space-
120-180 [33]
400 flight-related changes (% pre-flight) in a regulators of calcium
120-180 [33] metabolism: PTH (n = 15–30 astronauts), calcitonin (n = 5–17), and
0
400 Smith 2005 124-199 [28] vitamin D (n = 12–27); b stress regulators: cortisol (n = 1–7),
300 124-196 [29] norepinephrine (n = 9) and epinephrine (n = 9); and c parameters
200 186 [27] related to energy metabolism: insulin (n = 3–6), growth hormone (n
100
195 [27] = 3–6), and energy consumption (n = 25–29). Data are means ± SEM
0 grouped by mission duration (<50, 50–100, 100–150, >150 days)
197 [27]
300 Grigoriev 1999
[27] with horizontal error bars indicating the range of mission durations
200 199
[27] within a subgroup.
100 208
2.8 (1.3, 4.3)
0
-100
0 100 200 0 5 consumption were alike to those of formation markers, while none
Time (days) rate (%/day) of the potential mediators behaved similar to resorption markers.
Fig. 5 Post-flight changes in biochemical bone markers. a, c
Changes in markers of resorption (a) and formation (c) (% of pre-
flight) were extracted from the studies that reported both in-flight Using meta-analysis to plan future space-flight studies
and post-flight measurements and fit to a piece-wise function: a
sigmoidal in-flight, exponential post-flight; c linear in-flight and We used meta-analytic variance estimates to calculate sample
post-flight. Black line/red band: mean fit/95% CI, studies are sizes required to detect expected spaceflight-related changes (%
arranged in order of mission duration (gray background). b The from pre-flight) in bone density, resorption markers, and forma-
effect of spaceflight duration on post-flight decay constant (τdecay) of tion markers with an 80% power at a 95% significance level. To
resorption markers was modeled using exponential function for all detect spaceflight-related change in bone density, 10–20 astro-
flight durations (top) or linear function for mission durations
<90 days (bottom). Black line/red band: mean fit/95% CI. d Forest
nauts and >2 months are required; to detect changes in resorption
plot of rates of post-flight changes in formation markers sorted by markers, 5–10 astronauts and 0.5–1 month are required; to detect
mission duration. Red circles: studies with in- and post-flight data, changes in formation markers, 10–20 astronauts and >4 months
black circles—studies with only post-flight data. Gray diamond/ are required. Appropriately powering investigation of specific
band: overall estimate ± 95% CI. countermeasures that target bone resorption or formation will
allow not only to draw rigorous conclusions, but also to identify
individuals particularly protected or prone to the microgravity-
induced bone loss.

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 M. Stavnichuk et al.
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DISCUSSION demonstrated that post-flight resorption markers quickly declined,
We systematically reviewed and quantitatively synthesized while formation markers increased linearly. Surprisingly, following
published literature on bone health in astronauts. Spaceflight- longer duration flights, resorption markers returned to baseline
related changes in bone density were skeletal-site-dependent, significantly faster than after shorter flights, while changes in
with bone gain reported in the skull and cervical vertebrae, no formation markers were minimally associated with flight duration.
change in the thorax and upper limbs, and progressive bone loss Nevertheless, based on previous studies26,32, the active recovery
in lumbar spines, pelvis, and lower limbs. Biochemical markers of phase, when bone resorption was suppressed and bone formation
bone resorption increased robustly within 11 [9,13] days to 113% was active, appears to be limited to 6 months post-flight, much
[108, 117] above pre-flight levels, while bone formation markers shorter than the time required for bone mass to return to pre-
increased slowly at a rate of 6% [5, 7] per month. Post-flight, flight values2.
resorption markers decreased exponentially at a rate that was Lack of mechanical loading has long been speculated to cause
faster after longer duration missions, while formation markers bone loss in microgravity. However, several lines of evidence
increased linearly at 84% [39, 129] per month. Changes in bone suggest that it is either not the sole factor, or that the effects of
resorption markers were the most consistent among individuals unloading do not comply with the Frost’s mechanostat theory48.
(coefficient of variation 2–9%), while individual variability was First, exercise regimes only partially protected against bone loss46.
higher for bone formation markers (coefficient of variation 15%) Second, bone gain was observed in the skull, which is
and for the rate of bone loss in lower limbs (coefficient of variation mechanically neutral. Finally, the mechanostat theory postulates
26%). Quantitative estimates of spaceflight-related changes in that unloading-induced bone loss is adaptive, implying that after
bone health provided by our study will inform future studies and strain is normalized by bone loss, the signal to induce bone
allow to generate novel hypotheses regarding the underlying resorption should diminish. However, we found no evidence of
mechanisms of observed effects. temporal adaptation of resorption markers. These data suggest a
contribution of additional mediators to bone loss in microgravity.
The meta-analytic estimate for the rate of bone loss of −0.8%
Over the 50 years of space travel, many factors, including altered
[−1.1, −0.5] per month in the lower limbs region is consistent with
calcium homeostasis8, stress49, altered metabolism50, and radia-
previous estimates of 1.0–1.5% decrease per month42. We have
tion51 have been suggested to contribute to bone loss in
found that bone is preserved in the upper skeleton and is lost in
astronauts. We suggest that the kinetics of microgravity-induced
the lower skeleton, thus corroborating the association between
changes in potential mediators can be used to implicate them in
bone density changes and skeletal site position relative to the
changes in bone resorption (factors that demonstrate fast switch
gravitational vector proposed by Oganov and colleagues19. These
to a new steady state) or bone formation (factors that change
data, as well as reported differences in trabecular and cortical
slowly with opposing trends during the initial and late stages of
bone1,42, suggest that local factors, such as mechanical environ- spaceflight). Preliminary estimates suggest that changes in
ment, or fluid redistribution43,44, are important determinants of regulators of calcium homeostasis and energy intake have similar
bone loss; or that bone cells sensitivity to systemic factors dynamic trends as formation markers, but none of the factors
depends on skeletal location and/or type45. These findings are also behaved similarly to resorption markers. Although no causative
important for the interpretation of biochemical bone markers data conclusions can be derived from these data, such analyses will
that reflect bone turnover in the entire skeleton, which has allow future studies to focus on more promising putative
opposing tendencies in different skeletal regions. mediators.
Bone loss in the lower limbs was progressive; however, long- The limitations related to the secondary analysis of published
duration missions reported less bone loss than intermediate data were inconsistent reporting and difficulty in unique
duration missions, suggesting that microgravity-induced bone loss identification of astronauts in recent publications. While this is
may diminish with time. Consistent with this notion, resorption commendable with respect to patient confidentiality and ethical
markers increased rapidly and plateaued after ~25 days in-flight, reporting of medical data52, we could not ensure that the data for
while formation markers increased slowly, yet continuously, so five astronauts were not included twice, and were limited in
that the ratio of resorption to formation appeared to gradually probing individual-level covariates. The limitations related to
reverse from favoring bone loss early in flight to favoring bone technical and biological factors included high variability in
formation later. However, this optimistic interpretation should be outcomes reported for short duration missions, and inconsistency
cautioned by the following considerations: (i) individual-level heel in some markers of bone turnover. To ensure the study validity, we
bone loss was proportional to flight durations; (ii) the highest conducted a comprehensive panel of diagnostic tests (single- and
individual bone loss was reported after an intermediate duration cumulative-study exclusion and funnel plot analyses) that
flight, likely overestimating bone loss in this subgroup; (iii) demonstrated that our estimates of bone loss in the lower limb
increase in bone formation markers was highly variable and region were robust. Since drastic changes in bone mass over
meta-analytic estimates differed from individual studies; (iv) 6–16 days missions are physiologically unfeasible53 and errors
longer duration missions included ISS flights that benefited from have been reported in early flight bone measurements23, we
advanced nutrition and exercise46. It is also of interest to consider believe that the estimates derived from flights longer than 30 days
whether consistent changes in bone resorption (coefficient of are more accurate.
variation 2–9%) are directly driven by microgravity, while more In summary, we have conducted a systematic quantitative
variable changes in bone formation (coefficient of variation 15%) review of bone health-related changes in astronauts who
are affected by individual’s covariates (i.e., age, physical activity, participated in the Gemini, Apollo, Soyuz, Skylab, Salyut, STS,
nutrition, etc.). More data from longer-duration spaceflights are Mir, and ISS missions. We demonstrate that microgravity-induced
required to test these hypotheses. changes in bone density depend on the position of the skeletal-
Although we limited our analyses to changes in bone density site relative to the gravitational vector, provide evidence that
measured immediately post-flight, several studies reported that bone loss may diminish during longer duration flights, and reveal
2–5 years are required to recover microgravity-induced bone that post-flight bone recovery depends on the duration of the
loss2,19,47, and that in some individuals the complete recovery was spaceflight but is limited by a relatively short phase during which
not achieved2. We used the studies that reported both in-flight bone formation exceeds resorption. Our study was limited by data
and post-flight changes in biochemical markers to account for the availability (~189 out of 565 astronauts), inconsistent reporting,
mission duration-dependent in-flight changes in bone markers. and incomplete information provided by certain studies—the
Consistent with study-level findings1,24,26,32,33,39, meta-analysis limitations reported by other systematic reviews of spaceflight-

npj Microgravity (2020) 13 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA
 M. Stavnichuk et al.
7
related health outcomes54,55. The analyses conducted in the multiple methods at a given time point for a group of astronauts were
current study are invaluable for the design of future spaceflight combined as unweighted means.
studies and identification of potential study challenges, as
demonstrated by our sample size calculations. Moreover, we Stratifying density measures by skeletal region. Bone density measures
demonstrated the feasibility of exploratory studies using prior were grouped into four skeletal regions: skull and neck (region 1), upper
literature to advance new concepts in understanding mechanisms limbs and thorax (region 2), lumbar vertebrae and pelvis (region 3), and
responsible for bone density changes observed in astronauts, lower limbs (region 4). Measurements for multiple bones in the same
which is imperative for a design of successful countermeasures. skeletal region for an individual or group of astronauts were pooled as
PNi
θi;j
unweighted means θi ¼ j¼1 Ni , where j is the measured bone, and Ni is
the number of bones measured in region i.
METHODS
This study was compliant with the Preferred Reporting Items for Systematic
Reviews and Meta-analysis (PRISMA) statement56. Pooling within-mission individuals and subpopulations. When outcomes
were reported for multiple individuals or subgroups of astronauts for a
given mission, Pmission-level means were obtained using sample-size
Information sources, search strategy, quality assessment ðni;j θi;j Þ
weighting θi ¼ P , where j is individual or subgroup within the
ni;j
A systematic search strategy that included the concepts of bones, bone
health, terms related to space travel, and the specific names of astronauts, mission i, and ni,j is 1 for individual astronauts or the number of astronauts
missions, and spacecraft was constructed by a medical librarian (MM) for per subgroup. Mission-level standard deviations SDi were computed in one
Ovid Medline (Supplementary Methods 1), translated to Embase (via Ovid), of three ways:
Web of Science, and BIOSIS Previews, and executed on November 21, 2017.
(1) Individual-level
rP data ffi were reported for multiple astronauts:
ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
An update was performed on Medline and Embase on November 1, 2019.
ðθi θi;j Þ
ni 2
NASA Technical report server and HathiTrust Digital Library were searched
SDi ¼ j¼1
ni 1 , where θi,j is the outcome for individual j in
for titles of missions and programs. Title/abstract screening was conducted
by two independent reviewers (S.V.K. and M.S.). Articles were included for mission i, and ni is the mission-level sample size.
full-text analysis if abstracts indicated reporting quantitative data for bone (2) Data s forffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
multiple subgroups of astronauts were reported:
P Ni
density or biochemical bone markers in humans during and/or after ððni;j 1ÞSD2i;j Þ
spaceflight. The eligible studies were scored for the reporting quality SDi ¼ P Ni
j¼1
, where SDi,j and ni,j are standard deviations
j¼1
ðni;j 1Þ
(Supplementary Methods 2).
and sample sizes, respectively, for subgroup j in mission i.
(3) Outcome was given for a single sP astronaut with no variance estimate:
ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
Data extraction N
ððni 1ÞSD2i Þ
Data extracted by M.S. and reviewed by T.C. included name and duration pooled estimate of SDp ¼ P
i¼1
N , where ni is the sample
i¼1
ðni 1Þ
of mission; number of astronauts; individual, mean or median percentage
changes in bone density or biochemical markers compared to pre-flight; size for mission i and N is the number of missions.
pre-flight, in-flight, or post-flight levels of biochemical markers; standard (4) For biochemical marker data, first the variation among different
deviations, standard errors of the mean, and/or interquartile ranges; day or markers reported per individual or group of astronauts at particular
range of days when measurements were performed. If the type of measure time point, SDm, was computed as in step (1). Then, the variation
of the dispersion was not stated, it was assumed to be a standard error, among astronauts SDa was computed as in step (2). The combined
qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
which ensures a conservative estimate. If a range of sample sizes was SDoverall reflected both variabilities: SDoverall ¼ SD2m þ SD2a .
reported, the smallest value was extracted. Data from graphs were
extracted using MetaLab57.
Heterogeneity and publication bias
  2  P 2
Study-level outcomes PN ^ ^FE ¼ Pi SEi 2θi , H2 ¼ Q ,
We used Q ¼ i¼1 SE2
i  θi  θFE , where θ
Outcomes for individuals or groups of astronauts who participated in the SE N1
i i
same mission were extracted or calculated as percentage from pre-flight where N is number of datasets, and I2 ¼ HH1
2
2  100% to assess
ðθx θpre Þ
θi ¼ θpre ´ 100% with standard deviations heterogeneity. Q comparison to a Chi-square distribution was used to
s ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
2 ffi test for homogeneity (pQ ≥ 0.05). Single- and cumulative-study exclusion
100% ´ SDpre
ð100%θx´ SDx Þ
2
θpre analysis assessed the impact of individual datasets on the overall outcome
SDi ¼ þ , where x is in- or post-flight data. When
npre nx and heterogeneity, as well as homogeneity threshold (TH)57. Publication

medians θ and interquartile ranges bi–ai were reported, we approximated bias was assessed by assuming that in the absence of bias study-level
i outcomes have a funnel shape distribution due to random sampling error.

ai þθ þbi  
θi ¼ 3 and SDi ¼ bηi ða
i
nÞ , where ηðnÞ ¼ 2E Zð3nþ1Þ=4Þ , and E(Z(n)) is the
i

58
value of order statistic of a random variable Z(n) . Mission-level standard Meta analysis
errors were computed as SEi ¼ p SDffiffiffii PN
ni , where ni is the mission sample size. ^N ¼ Pi¼1N ni θi , where θi and ni are the
We used sample size weighting: θ
i¼1
ni
Data preparation prior to meta-analysis outcomes and sample sizes for mission i, N is the number of datasets.
PN
To ensure statistical independence, the outcomes measured using c N ¼ i¼1 ððni; 1ÞSD2i Þ b
b N ¼ SD
pffiffiNffi ;
Standard deviation was SD PN ; standard error: SE
different methods, for different skeletal regions, or for subgroups of i¼1
ðni 1Þ N
astronauts in the same mission were pooled prior to meta-analysis as b N ¼ ± 1:96  SE
and 95% confidence intervals (CI) ¼ ± zð1α=2Þ  SE b N.
follows.

Different measurement methods. We assumed that any method used to Subgroup analysis
measure bone density provides different degrees of precision and accuracy
in assessment of the same quantity. We directly assessed that bone WhenPspecified, outcomes were grouped into P k bins, and binned means
^ Pnk;i θk;i
c ððnk;i 1ÞSD2 Þ
measurements obtained in the lower limb region using projection θk ¼ and standard deviations SDk ¼ P n 1 k;i were com-
radiography, SPA, DXA, and qCT were not significantly different (p = 0.57 nk;i ð k;i Þ
by ANOVA) (Supplementary Fig. 1a). We excluded two studies that used puted, where θk;i , nk,i, and SDk,i were the outcome, sample size, and
ultrasound to evaluate bone density in three astronauts24,59 because two standard deviation reported for study i belonging to bin k. The division for
ultrasound measurement techniques reported inconsistent data for the the subgroup analysis was performed to achieve approximately equal size
same individuals. Bone formation/resorption markers measured using group in each category.

Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2020) 13
 M. Stavnichuk et al.
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