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Long bone fractures are a concern in long-duration exploration missions (LDEM) where crew autonomy will exceed the current Low Earth Orbit paradigm. Current crew selection assumptions require extensive complete training and competency testing prior to flight for off-nominal situations. Analogue astronauts (n = 6) can be quickly trained to address a single fracture pattern and then competently perform the repair procedure. An easy-to-use external fixation (EZExFix) was employed to repair artificial tibial shaft fractures during an inhabited mission at the Mars Desert Research Station (Utah, USA). Bone repair safety zones were respected (23/24), participants achieved 79.2% repair success, and median completion time was 50.04 min. Just-in-time training in-mission was sufficient to become autonomous without pre-mission medical/surgical/mechanical education, regardless of learning conditions (p > 0.05). Similar techniques could be used in LDEM to increase astronauts' autonomy in traumatic injury treatment and lower skill competency requirements used in crew selection., (© 2023. Springer Nature Limited.)

Astronauts in microgravity experience multi-system deconditioning, impacting their inflight efficiency and inducing dysfunctions upon return to Earth gravity. To fill the sex gap of knowledge in the health impact of spaceflights, we simulate microgravity with a 5-day dry immersion in 18 healthy women (ClinicalTrials.gov Identifier: NCT05043974). Here we show that dry immersion rapidly induces a sedentarily-like metabolism shift mimicking the beginning of a metabolic syndrome with a drop in glucose tolerance, an increase in the atherogenic index of plasma, and an impaired lipid profile. Bone remodeling markers suggest a decreased bone formation coupled with an increased bone resorption. Fluid shifts and muscular unloading participate to a marked cardiovascular and sensorimotor deconditioning with decreased orthostatic tolerance, aerobic capacity, and postural balance. Collected datasets provide a comprehensive multi-systemic assessment of dry immersion effects in women and pave the way for future sex-based evaluations of countermeasures., (© 2023. Springer Nature Limited.)

Purpose of Review: Osteocytes are considered to be the cells responsible for mastering the remodeling process that follows the exposure to unloading conditions. Given the invasiveness of bone biopsies in humans, both rodents and in vitro culture systems are largely adopted as models for studies in space missions or in simulated microgravity conditions models on Earth., Recent Findings: After a brief recall of the main changes in bone mass and osteoclastic and osteoblastic activities in space-related models, this review focuses on the potential role of osteocytes in directing these changes. The role of the best-known signalling molecules is questioned, in particular in relation to osteocyte apoptosis. The mechanotransduction actors identified in spatial conditions and the problems related to fluid flow and shear stress changes, probably enhanced by the alteration in fluid flow and lack of convection during spaceflight, are recalled and discussed., (© 2021. The Author(s).)

Spaceflight-induced bone losses have been reliably reproduced in Hind-Limb-Unloading (HLU) rodent models. However, a considerable knowledge gap exists regarding the effects of low-dose radiation and microgravity together. Ten-week-old male C57BL/6J mice, randomly allocated to Control (CONT), Hind-Limb Unloading (HLU), and Hind-Limb Unloading plus Irradiation (HLUIR), were acclimatized at 28 °C, close to thermoneutral temperature, for 28 days prior to the 14-day HLU protocol. HLUIR mice received a 25 mGy dose of X-ray irradiation, simulating 14 days of exposure to the deep space radiation environment, on day 7 of the HLU protocol. Trabecular bone mass was similarly reduced in HLU and HLUIR mice when compared to CONT, with losses driven by osteoclastic bone resorption rather than changes to osteoblastic bone formation. Femoral cortical thickness was reduced only in the HLUIR mice (102 μm, 97.5-107) as compared to CONT (108.5 μm, 102.5-120.5). Bone surface area was also reduced only in the HLUIR group, with no difference between HLU and CONT. Cortical losses were driven by osteoclastic resorption on the posterior endosteal surface of the distal femoral diaphysis, with no increase in the numbers of dead osteocytes. In conclusion, we show that low-dose radiation exposure negatively influences bone physiology beyond that induced by microgravity alone.

Space sojourns are challenging for life. The ability of the human body to adapt to these extreme conditions has been noted since the beginning of human space travel. Skeletal alterations that occur during spaceflight are now better understood owing to tools such as dual-energy X-ray densitometry and high-resolution peripheral quantitative CT, and murine models help researchers to understand cellular and matrix changes that occur in bone and that are difficult to measure in humans. However, questions remain with regard to bone adaptation and osteocyte fate, as well as to interactions of the skeleton with fluid shifts towards the head and with the vascular system. Further investigations into the relationships between the musculoskeletal system, energy metabolism and sensory motor acclimatisation are needed. In this regard, an integrated intervention is required that will address multiple systems simultaneously. Importantly, radiation and isolation-related stresses are gaining increased attention as the prospect of human exploration into deep space draws nearer. Although space is a unique environment, clear parallels exist between the effects of spaceflight, periods of immobilization and ageing, with possibly irreversible features. Space travel offers an opportunity to establish integrated deconditioning and ageing interventions that combine nutritional, physical and pharmaceutical strategies.

Risk for premature osteoporosis is a major health concern in astronauts and cosmonauts; the reversibility of the bone lost at the weight-bearing bone sites is not established, although it is suspected to take longer than the mission length. The bone three-dimensional structure and strength that could be uniquely affected by weightlessness is currently unknown. Our objective is to evaluate bone mass, microarchitecture, and strength of weight-bearing and non-weight-bearing bone in 13 cosmonauts before and for 12 months after a 4-month to 6-month sojourn in the International Space Station (ISS). Standard and advanced evaluations of trabecular and cortical parameters were performed using high-resolution peripheral quantitative computed tomography. In particular, cortical analyses involved determination of the largest common volume of each successive individual scan to improve the precision of cortical porosity and density measurements. Bone resorption and formation serum markers, and markers reflecting osteocyte activity or periosteal metabolism (sclerostin, periostin) were evaluated. At the tibia, in addition to decreased bone mineral densities at cortical and trabecular compartments, a 4% decrease in cortical thickness and a 15% increase in cortical porosity were observed at landing. Cortical size and density subsequently recovered and serum periostin changes were associated with cortical recovery during the year after landing. However, tibial cortical porosity or trabecular bone failed to recover, resulting in compromised strength. The radius, preserved at landing, unexpectedly developed postflight fragility, from 3 months post-landing onward, particularly in its cortical structure. Remodeling markers, uncoupled in favor of bone resorption at landing, returned to preflight values within 6 months, then declined farther to lower than preflight values. Our findings highlight the need for specific protective measures not only during, but also after spaceflight, because of continuing uncertainties regarding skeletal recovery long after landing. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

The weightless environment during spaceflight induces site-specific bone loss. The 30-day Bion-M1 mission offered a unique opportunity to characterize the skeletal changes after spaceflight and an 8-day recovery period in mature male C57/BL6 mice. In the femur metaphysis, spaceflight decreased the trabecular bone volume (-64% vs. Habitat Control), dramatically increased the bone resorption (+140% vs. Habitat Control) and induced marrow adiposity invasion. At the diaphysis, cortical thinning associated with periosteal resorption was observed. In the Flight animal group, the osteocyte lacunae displayed a reduced volume and a more spherical shape (synchrotron radiation analyses), and empty lacunae were highly increased (+344% vs. Habitat Control). Tissue-level mechanical cortical properties (i.e., hardness and modulus) were locally decreased by spaceflight, whereas the mineral characteristics and collagen maturity were unaffected. In the vertebrae, spaceflight decreased the overall bone volume and altered the modulus in the periphery of the trabecular struts. Despite normalized osteoclastic activity and an increased osteoblast number, bone recovery was not observed 8 days after landing. In conclusion, spaceflight induces osteocyte death, which may trigger bone resorption and result in bone mass and microstructural deterioration. Moreover, osteocyte cell death, lacunae mineralization and fatty marrow, which are hallmarks of ageing, may impede tissue maintenance and repair.

We compared quantitatively vinculin-related adhesion parameters in osteoblastic cells submitted to opposite mechanical stresses, i.e., low deformation and frequency strain regimens (stretch condition) and microgravity exposure (relaxed condition). Cyclic deformation induced a biphasic response comprising new focal contacts formation followed by their clustering in ROS cells. Microgravity exposure induced a reduction in focal contact number and clustering in ROS cells. We previously demonstrated that 1% cyclic deformations at 0.05 Hz during a daily 10 min episode over 7 days stimulated ROS 17/2.8 growth as compared to static culture whereas relaxed ROS proliferated similarly to static culture (BC). To evaluate whether the proliferation (stretch) or the survival (relaxed) status of ROS cells influences focal contact organization, we inhibited ERKs proliferative-dependent pathway. Inhibition of proliferation by PD98059 was overcome although not fully restored by stretch. Furthermore stretch-induced clustering of vinculin-positive contacts still occurs in the presence of ERKs inhibitor, whereas the increase in focal contact number is abolished. In conclusion, we showed that focal contacts are mechanoeffectors and that hyper-mechanical stimulation could up regulate focal contacts size as compared to hypo-mechanical that down regulate clusterization., (c2003 COSPAR. Published by Elsevier Ltd. All rights reserved.)

Six days of microgravity (Bion10 mission) induced dramatic shape changes in ROS 17/2.8 osteoblasts (7). During the Foton 11 and 12 space flights, we studied the kinetics (0-4 days) of ROS 17/2.8 morphology and adhesion, the relationships between adhesion and cell cycle progression after 4 days in space, and osteoblastic growth and activity after 6 days in space. Quantitative analysis of high-resolution adhesion [focal adhesion area imaged by total interference reflection fluorescent microscopy (TIRFM)] and integrin-dependent adhesion (imaged on confocal microscope by vinculin and phosphotyrosine staining) as well as cell cycle phase classification [Ki-67 staining, S-G2, mitotic cells and G1 (postmitotic cells)] were performed using programs validated in parabolic flight and clinostat. We observed disorganization of the cytoskeleton associated with disassembling of vinculin spots and phosphorylated proteins within focal contacts with no major change in TIRFM adhesion after 2 and 4 days of microgravity. Postmitotic cells, alone, accounted for the differences observed in the whole population. They are characterized by immature peripheral contacts with complete loss of central spots and decreased spreading. Osteocalcin, P1CP and alkaline phosphatase, and proliferation were similar in flight cells and 1 g centrifuge and ground controls after 6 days. In conclusion, microgravity substantially affected osteoblastic integrin-mediated cell adhesion. ROS17/2.8 cells responded differently, whether or not they were cycling by reorganizing adhesion plaque topography or morphology. In ROS 17/2.8, this reorganization did not impair osteoblastic phenotype.

Space flight results in loss of bone mass, especially in weight-bearing bones, a condition that is suggested to be similar to disuse osteoporosis. As models to elucidate the underlying mechanism, bed rest studies were performed and bone metabolism in the rat both during space flight and during hindlimb unloading was investigated. The general picture is that bone formation is decreased partly as a result of reduced osteoblast function, whereas bone resorption is unaltered or increased. This deficit in bone mass can be replaced, but the time span for restoration exceeds the period of unloading. Changes in blood flow, systemic hormones, and locally produced factors are contributing in a yet undefined way to the response of osteoblastic cells to loading. The pathway by which loading and/or gravity are transduced into biochemical signals is still unknown. In vitro studies with osteoblastic cells show that their differentiation and cell morphology are altered during space flight. Elucidation of the involved signaling pathways has only recently been started. It is hoped that as the mechanisms by which bone responds to mechanical (un)loading are further understood, this insight will influence the treatment of other etiologies of osteoporosis.

Background: Microgravity induces bone loss by mechanism(s) that remain largely unknown., Methods: We measured biochemical markers related to bone remodeling in two cosmonauts before, during, and after 21- and 180-day space flights, respectively., Results: During both flights, type I procollagen propeptide and bone alkaline phosphatase decreased as early as 8 days after launch. Undercarboxylated osteocalcin percentage increased early and remained high during both flights. Vitamin K supplementation restored carboxylation of osteocalcin during the long-term flight. Urinary and serum C-telopeptide of type I collagen (CTX) increased as early as day 8 of the flights; the increase was greater in serum than in urine. Pyridinoline, free deoxypyridinoline, and N-telopeptide increased less than CTX during the short-term space flight. The circadian rhythm of bone resorption assessed by urine CTX and free deoxypyridinoline was not altered by microgravity., Conclusion: Vitamin K metabolism or action and bone remodeling may be altered in cosmonauts.

Background: Microgravity has been thought to induce osteoporosis because of reduced weight-bearing. However, up to now, few data have been available about its precise nature and timecourse., Methods: We measured bone mineral density (BMD) at the distal radius and tibia in 15 cosmonauts of the Russian MIR space station who sojourned in space either 1 (n=two), 2 (two), or 6 months (11). After recovery periods of similar duration to the space missions, BMD was measured for the 2-month and 6-month crews., Findings: Neither cancellous nor cortical bone of the radius was significantly changed at any of the timepoints. On the contrary, in the weight-bearing tibial site, cancellous BMD loss was already present after the first month and deteriorated with mission duration. In tibial cortices, bone loss was noted after a 2-month flight. In the 6-month group, cortical bone loss was less pronounced than that for cancellous bone. In some individuals, tibial deterioration was great. Actual BMD did not depend on preceding cumulative periods spent in space. During recovery, tibial bone loss persisted, suggesting that the time needed to recover is longer than the mission duration., Interpretation: In space, despite physical training, bone loss is an adaptive process that can become pathological after recovery on Earth. Striking interindividual variations in bone responses seem to suggest a need for adequate crew preselection. Targeted treatment or prevention strategies would be useful, not only for space purposes, but also for the increasing number of osteoporotic patients on Earth.

Spaceflight data obtained on bone cells, rodents, and humans are beginning to shed light on the importance of gravitational loading on the skeletal system. The space environment is a relevant model to explore the bone cell response to minimal strains. However, whether there is a direct effect of gravity on the cell rather than changes related to lack of convection forces in cell cultures performed in microgravity is unknown. In vitro studies carried out using osteoblastic cell cultures in space show changes in cell shape, suggesting that cell attachment structures as well as cytoskeleton reorganization might be involved. Valuable information is expected from in vitro models of an increase or decrease in mechanical stress in order to identify the different pathways of mechanoreception and mechanotransduction in the osteoblastic lineage. Results obtained from both humans and rodents after spaceflights indicated that bone mass changes are site specific rather than evenly distributed throughout the skeleton, thus emphasizing the need to perform measurements at different bone sites: weight- and non-weight-bearing bones, and cancellous and cortical envelopes. Bone mass measurements and biochemical parameters of bone remodeling are currently under evaluation in cosmonauts. Histomorphometric studies of bones from rats after space missions of various periods provided the time course of the cancellous bone cellular events: transient increase in resorption and sustained decrease in bone formation. The underlying bone loss occurred first in weight-bearing bones and later in less weight-bearing bones. During the postflight period, time required to recover the lost bone was greater than the mission length. Thus, the postflight period deserves more attention than it is currently receiving. On earth, the rat tail-suspension model is currently used to mimic spaceflight-induced bone loss. Data from the model confirmed the impairment of osteoblastic activity and showed an alteration in osteoblast recruitment with skeletal unloading. However, this model needs to be further validated.

This study reports the effects of a 14-day spaceflight followed by a 14-day reambulation period on bones of 56-day-old male rats compared with synchronous (S) and vivarium (V) control animals. Femur, tibia, and humerus bone mineral densities (BMD); bone calcium and phosphorus concentrations ([Ca2+] and [P]), measured by X-ray microanalysis (XRM), on tibia, vertebra, and calvaria; and histomorphometric data on proximal primary and secondary spongiosae (I and II SP, respectively) of the tibia and humerus were measured. After the flight in flown rats (compared with S), BMD was lower in the distal femur and remained similar to S in humerus and tibia, [Ca2+] and [P] were lower in tibia II SP and higher in calvaria, tibia I SP width and II SP bone volume were lower, resorption was markedly higher in tibia II SP, and no difference in formation parameters was observed. After reambulation, BMD was lower in long bones of both flight and S groups compared with V. Bone loss appeared in humeral II SP and worsened in tibial II SP in flown rats. Tibial formation parameters were higher in flown rats compared with V and S, indicating the onset of an active recovery. Tibial XRM [Ca2+] and [P] in flown rats remained below control levels.

The bone mineral density and the biochemical parameters exploring bone cell activities were analyzed in two cosmonauts who spent 1 and 6 months, respectively, in the Russian MIR station. Measurements were performed before the flight, after the flight, and after a recovery period. At the end of the first month, peripheral QCT measurements indicated a slight decrease of trabecular bone mass in the distal tibial metaphysis. However, after 6 months of spaceflight, a more marked loss of trabecular and cortical bones was observed in the tibia, and was still significant after 6 month recovery in the trabecular compartment, whereas a decrease was no longer observed in the cortical envelope. No change was observed in either compartment of the distal radius at any time. Ultrasound BUA of the calcaneus was greatly reduced by the first month, followed by a more dramatic decrease after month 6. Ultrasound SOS detected no change. Parameters reflecting bone formation activity appeared to be depressed after both missions. In contrast, no dramatic change in resorption parameters was observed, except for a trend toward an increase in pyridinoline. In conclusion, the lower weight-bearing bones appeared more sensitive than the upper ones in terms of spaceflight-induced bone loss. This probably explained the absence of marked systemic biochemical data changes. This study further suggests that recovery in the tibial trabecular compartment 6 months after landing was not completed after a 6 month mission.

There is a large body of evidence that microgravity- or immobilization-induced bone loss is mainly related to osteoblastic cell impairment. Osteoblasts are sensitive to increased mechanical stress and could therefore be responsible for unloading-induced bone changes. However, the nature of osteoblast involvement remains unclear. The effects of the space environment on cells have been studied extensively, but little information about anchorage-dependent cell cultures of the 25 different cell types flown in space has been published. We studied the effects of long-term weightlessness on the cell shape of cultured osteoblasts during the Russian Bion 10 space-flight. This experiment required the development of special automatic culture devices (the plunger-box culture system) finalized with the constructors. Multiple feasibility experiments were performed to allow osteoblast culture for 6 days in microgravity. The study revealed plunger-box biocompatibility; optimization of ROS 17/2.8 (mammalian adherent cells) culture under closed conditions (without gas exchange); and transport of viable cells for 5 days. During the 6 days of microgravity, the growth curves of ground controls and cells in space were roughly similar. Alkaline phosphatase activity was enhanced twofold in microgravity. ROS 17/2.8 cell morphology began to change significantly after 4 days of microgravity; they became rounder and covered with microvilli. At the end of the flight, the cells exhibited mixed morphological types, piling cells, stellar shape, and spread out cells, resembling ground controls or 1g flight controls (centrifuge). We demonstrated that ROS 17/2.8 cells were viable during a 6 day automatic culture in space and were sensitive to space related conditions. They adapted their structure and function to this environment, characterized by loss of mechanical stimuli.

The influence of 14 days of spaceflight on cancellous bone of male Wistar rats was assessed by histomorphometric analysis. In proximal tibia, no difference was found between flight, synchronous, vivarium, and basal groups for epiphyseal bone volume or trabecular arrangement. In metaphysis, primary spongiosa width was reduced in flight rats, suggesting an alteration in bone longitudinal growth. In flight rats, secondary spongiosa evidenced a trend toward decreased bone mass, trabecular number and thickness, and osteoid surfaces, whereas there was a tendency toward increased osteoclast number compared with vivarium control but not with synchronous rats. In femoral fossa trochanteri, an area facing deep muscular insertions, no changes in bone volume or structure were noted among the different groups. However, a reduction of osteoid surfaces was seen in flight and synchronous groups compared with the other groups. Resorption activity was increased in flight rats compared with control rats. In thoracic vertebral body, osteoblastic surfaces decreased similarly in flight and synchronous rats. In lumbar vertebral body, decreased osteoblastic surfaces and increased osteoclastic parameters were observed in flight and synchronous rats. The more striking effects of spaceflight were the decrease in tibial primary spongiosa width and the increase in resorption activity of the femoral fossa trochanteri. In all other sites, cellular alterations appeared similar in flight and synchronous rats, suggesting a role for physiological stress. The time course of events would depend on initial growth and turnover rates of bone, its weight-bearing function on earth, and the presence of muscular insertions.

Using histomorphometric analysis, we compared the effects of 7 d spaceflight (Biocosmos 1667) and 7 d tail-suspension in tibiae of 12-13 weeks old male Wistar rats. The skeletal alterations induced by both true and simulated weightlessness in the proximal tibial metaphysis consisted of an inhibition of longitudinal growth as indicated by the reduction of the primary spongiosa thickness. In both primary and secondary spongiosae, the loss of trabecular bone was more extensive in flight rats than in suspended rats. Impairment in cancellous and endocortical osteoid surfaces occurred in microgravity and 1-G conditions but with greater magnitude in the spongy space in flight rats. In suspended rats, the cancellous mineralization rate was decreased, suggesting an alteration of the formation activity. Bone resorption remained unchanged in flight rats whereas a twofold increase occurred in simulated conditions. These data support the hypothesis that mechanisms of bone loss in space are not entirely identical to those of tail-suspension model on Earth. New experiments allowing comparison between actual spaceflight and spaceflight simulations must be developed in order to explore common alterations and to understand differential mechanisms in the bone system.

Five pregnant female growing rats have been orbited for five days aboard the Cosmos 1514 soviet biological satellite. They were compared to five female rats kept in vivarium and five female conditioned rats in synchronised way. Histomorphometric studies were performed in order to investigate: 1. The early effects of weightlessness on the bone mass in loading (tibiae and femur) and unloading bones (thoracic and lumbar vertebrae). 2. The changes of osteoblastic and osteoclastic activities. A short exposure does not induce changes in the bone mass and the inner structure of loading and unloading bones. These results fit in well with human data available in the literature: they show that weightlessness doesn't change bone mass in the early phase of a spaceflight. However extrapolation of animal results to men is discussed. In unloading bones (vertebrae) osteoblastic activity was not measurable. Osteoclasts detected by histoenzymologic method don't change as far as their number per mm3 of trabecular bone is concerned. However the number per mm2 of trabecular area increases. It seems likely that an increase of the osteoclastic population occurs in trabecular bone. In loading bones, formation activity (appreciated by the measurement of osteoid seam thickness) and total osteoclastic resorption surfaces were not modified. These results are different from those of longer flights.

During the 51 G franco-american mission in weightlessness, calcium metabolism and hormonal regulation were analyzed in two astronauts (a male, a female) before (30,7 and 4 days) and after (0,2 and 5 days) the 7-day spaceflight. Calcium, phosphate, alkaline phosphatase, GLA protein, 25 hydro-vitamin D, 1-25 dihydroxyvitamin D, parathyroid hormone, 24 h urinary calcium, total, dialysable and nondialysable hydroxyproline and glycosaminoglycans (GAG) were measured in blood and urine. Only urinary parameters are increased after space flight. Blood parameters, in particular hormone measurements, are unchanged. The data indicate stimulation of resorptive activity which could result in bone matrix atrophy and demineralisation. On the contrary, no bone formation impairment is noted since alkaline phosphatase and GLA protein are unchanged. These changes are not dependent on hormonal variations. They could only reflect the mechanical bone adaptation to weightlessness.

Five pregnant growing rats were orbited for 5 days aboard the Soviet COSMOS 1514 biologic satellite. The bone effects of weightlessness were studied and compared to those of five pregnant rats kept in vivarium and five pregnant conditioned rats. Bone histomorphometric studies were performed to investigate the early effects of weightlessness in loaded (tibia-femur) and unloaded (thoracic and lumbar vertebrae) bones. A short exposure to weightlessness does not induce any change in bone mass and inner structure in either type of bone. In unloaded bones, the number of osteoclasts per square millimeter of the trabecular surface significantly increased when measured after histochemical demonstration of tartrate-resistant acid phosphatase. It is likely that a stimulation of bone resorption activity occurs in the trabeculae of unloaded bones during the early phase of a spaceflight. In tibia, osteoid seam thickness and total osteoclastic resorption surfaces at the endosteal level were not modified.