AbstractHuman spaceflight has been fascinating man for centuries, representing the intangible need to explore the unknown, challenge new frontiers, advance technology, and push scientific boundaries further. A key area of importance is cardiovascular deconditioning, that is, the collection of hemodynamic changes—from blood volume shift and reduction to altered cardiac function—induced by sustained presence in microgravity. A thorough grasp of the 0G adjustment point per se is important from a physiological viewpoint and fundamental for astronauts’ safety and physical capability on long spaceflights. However, hemodynamic details of cardiovascular deconditioning are incomplete, inconsistent, and poorly measured to date; thus a computational approach can be quite valuable. We present a validated 1D–0D multiscale model to study the cardiovascular response to long-term 0G spaceflight in comparison to the 1G supine reference condition. Cardiac work, oxygen consumption, and contractility indexes, as well as central mean and pulse pressures were reduced, augmenting the cardiac deconditioning scenario. Exercise tolerance of a spaceflight traveler was found to be comparable to an untrained person with a sedentary lifestyle. At the capillary–venous level significant waveform alterations were observed which can modify the regular perfusion and average nutrient supply at the cellular level. The present study suggests special attention should be paid to future long spaceflights which demand prompt physical capacity at the time of restoration of partial gravity (e.g., Moon/Mars landing). Since spaceflight deconditioning has features similar to accelerated aging understanding deconditioning mechanisms in microgravity are also relevant to the understanding of aging physiology on the Earth. 3205 npjmicrogr NPJ Microgravity NPJ Microgravity Nature Publishing Group PMC7529778 7529778 7529778 33083524 10.1038/s41526-020-00117-5 Cardiovascular deconditioning during long-term spaceflight through multiscale modeling Gallo Caterina 1 Ridolfi Luca 2 Scarsoglio Stefania 1 ✉ 1 Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Torino, Italy 2 Department of Environmental, Land and Infrastructure Engineering, Politecnico di Torino, Torino, Italy ✉ Corresponding author. We present a validated 1D–0D multiscale model to study the cardiovascular response to long-term 0G spaceflight in comparison to the 1G supine reference condition. Cardiac work, oxygen consumption, and contractility indexes, as well as central mean and pulse pressures were reduced, augmenting the cardiac deconditioning scenario. Exercise tolerance of a spaceflight traveler was found to be comparable to an untrained person with a sedentary lifestyle. At the capillary–venous level significant waveform alterations were observed which can modify the regular perfusion and average nutrient supply at the cellular level. The present study suggests special attention should be paid to future long spaceflights which demand prompt physical capacity at the time of restoration of partial gravity (e.g., Moon/Mars landing). Since spaceflight deconditioning has features similar to accelerated aging understanding deconditioning mechanisms in microgravity are also relevant to the understanding of aging physiology on the Earth. Subject terms: Biomedical engineering, Medical research status released display-pdf yes is-olf no is-manuscript no is-preprint no is-journal-matter no is-scanned no is-retracted no Received 2020 Jan 17; Accepted 2020 Aug 10; Collection date 2020. In view of future Moon or Mars missions, long-term cardiovascular deconditioning will need to be addressed to: (i) evaluate the efficacy of countermeasures and to optimize them in order to guarantee the astronauts’ safety; and (ii) establish risk thresholds, especially for physical activity after landing. Additionally, as space science is an extraordinary investment multiplier (9:1 return on investment by way of spin-offs from space technology), understanding space deconditioning can have impacts on other clinical conditions and on aging research 3 . The present study aims to computationally shed light on the cardiovascular knowledge gaps previously described, Despite the fact that hemodynamic changes are important and diversified the observed variations in the steady-state 0G spaceflight configuration are not dramatic per se. For instance, although E F reduction was not negligible (−10%), myocardial contractility reduction is considered clinically relevant when E F drops 20% or more, which has not been observed to date during any spaceflight 53 . After long-term spaceflight a 0G adaptation point imposed by a less demanding environment is indeed reached by the cardiovascular system. The scenario becomes potentially hazardous at the time of reentry on the Earth or partial gravity restoration (e.g., Moon/Mars landing). All these aspects, along with other spaceflight-induced effects such as muscular atrophy and bone demineralization, need to be properly addressed especially in long-term human space missions where prompt physical capability after partial or complete gravity restoration is required. The outcomes of the present study highlighted a wealth of cardiovascular information otherwise not yet available in vivo, showing how computational hemodynamics is particularly valuable in environmental conditions such as microgravity and spaceflight where even basic clinical measures are rarely available. Eventually, understanding the mechanisms of cardiovascular deconditioning during spaceflight will have a significant impact on the knowledge of aging physiology on the Earth 3 . Since deconditioning in spaceflight by gravity deprivation is strongly analogous to deconditioning on the Earth by gravity withdrawal, as in sedentary aging, long-term spaceflight physiology can offer precious hints for delaying or preventing modern lifestyle medical disorders related to increased longevity.

Life on Earth has evolved in the presence of a gravity constraint. Any change in the value of such a constraint has important physiological effects. Gravity reduction (microgravity) alters the performance of muscle, bone and, immune systems among others. Therefore, countermeasures to limit such deleterious effects of microgravity are needed considering future Lunar and Martian missions. Our study aims to demonstrate that the activation of mitochondrial Sirtuin 3 (SIRT3) can be exploited to reduce muscle damage and to maintain muscle differentiation following microgravity exposure. To this effect, we used a RCCS machine to simulate microgravity on ground on a muscle and cardiac cell line. During microgravity, cells were treated with a newly synthesized SIRT3 activator, called MC2791 and vitality, differentiation, ROS and, autophagy/mitophagy were measured. Our results indicate that SIRT3 activation reduces microgravity-induced cell death while maintaining the expression of muscle cell differentiation markers. In conclusion, our study demonstrates that SIRT3 activation could represent a targeted molecular strategy to reduce muscle tissue damage caused by microgravity.

The European Space Agency has recently announced to progress from low Earth orbit missions on the International Space Station to other mission scenarios such as exploration of the Moon or Mars. Therefore, the Moon is considered to be the next likely target for European human space explorations. Compared to microgravity (μg), only very little is known about the physiological effects of exposure to partial gravity (μg < partial gravity <1 g). However, previous research studies and experiences made during the Apollo missions comprise a valuable source of information that should be taken into account when planning human space explorations to reduced gravity environments. This systematic review summarizes the different effects of partial gravity (0.1-0.4 g) on the human musculoskeletal, cardiovascular and respiratory systems using data collected during the Apollo missions as well as outcomes from terrestrial models of reduced gravity with either 1 g or microgravity as a control. The evidence-based findings seek to facilitate decision making concerning the best medical and exercise support to maintain astronauts' health during future missions in partial gravity. The initial search generated 1,323 publication hits. Out of these 1,323 publications, 43 studies were included into the present analysis and relevant data were extracted. None of the 43 included studies investigated long-term effects. Studies investigating the immediate effects of partial gravity exposure reveal that cardiopulmonary parameters such as heart rate, oxygen consumption, metabolic rate, and cost of transport are reduced compared to 1 g, whereas stroke volume seems to increase with decreasing gravity levels. Biomechanical studies reveal that ground reaction forces, mechanical work, stance phase duration, stride frequency, duty factor and preferred walk-to-run transition speed are reduced compared to 1 g. Partial gravity exposure below 0.4 g seems to be insufficient to maintain musculoskeletal and cardiopulmonary properties in the long-term. To compensate for the anticipated lack of mechanical and metabolic stimuli some form of exercise countermeasure appears to be necessary in order to maintain reasonable astronauts' health, and thus ensure both sufficient work performance and mission safety.

A round-trip human mission to Mars is anticipated to last roughly three years. Spaceflight conditions are known to cause loss of bone mineral density (BMD) in astronauts, increasing bone fracture risk. There is an urgent need to understand BMD progression as a function of spaceflight time to minimize associated health implications and ensure mission success. Here we introduce a nonlinear mathematical model of BMD loss for candidate human missions to Mars: (i) Opposition class trajectory (400–600 days), and (ii) Conjunction class trajectory (1000–1200 days). Using femoral neck BMD data (N = 69) Spaceflight conditions are known to cause loss of bone mineral density (BMD) in astronauts, increasing bone fracture risk. There is an urgent need to understand BMD progression as a function of spaceflight time to minimize associated health implications and ensure mission success. Here we introduce a nonlinear mathematical model of BMD loss for candidate human missions to Mars: (i) Opposition class trajectory (400–600 days), and (ii) Conjunction class trajectory (1000–1200 days). Introduction A fracture occurs when a certain applied load exceeds the ultimate strength of the bone. A measurable, critical component for the bone strength is the areal bone mineral density (BMD) [ 1 ]. BMD loss is an established fracture risk factor due to bone weakening as measured in large epidemiological studies correlating BMD with the incidence of fragility fractures [ 2 – 4 ]. Current standards to monitor and maintain bone health in both NASA and ISS crewmembers are based in BMD measurements by dual-energy x-ray absorptiometry (DXA) [ 5 ]. In contrast, BMD recovery on Earth in the bones of various astronauts after spaceflights is well described by an exponential function [ 19 ]. Furthermore, there is terrestrial evidence that the loss of bone matrix and bone mineral due to conditions that result prolonged bed rest ( e . g . disuse medical conditions and/or spinal cord injury) eventually plateaus at 69.0% initial BMD, after a period of significant and progressive decline [ 18 , 20 , 21 ]. Thus, a non-linear, exponential decline of BMD in weight-bearing bones is a reasonable approach to model progressive bone loss in long-duration space missions. In this paper, we introduce for the first time a predictive mathematical model for the BMD loss defined by an exponential decrease in load bearing bones of the astronauts. By using this model, we predict BMD loss in the femoral neck for two potential missions to Mars. Methods Mathematical formulation There is terrestrial evidence that bone density is likely to plateau after a long period of loss in weight-bearing bones [ 18 , 20 , 21 ]. Further, there are no supporting data from astronauts available for time-frames relevant to interplanetary travel (all the candidate missions are in the order of years given current rocket capabilities). Therefore, we formulate that the change of areal BMD in weight-bearing bones at time t, BMD(t), during spaceflights as a one-phase exponential decay: B M D % ( t ) = ( C − P ) e − λ t + P BMD change is here expressed as percentage [%], λ corresponds to the BMD decay rate, and C to the areal bone mineral density right before launch: C = B M D % ( t = 0 ) = 0 % P corresponds to the plateau. The maximum total BMD loss has been previously estimated to be 69.0% relative to the astronauts’ pre-flight BMD [ 18 ], and obtained by combining data from different large studies in humans [ 23 , 24 ]. Table 1 includes all the data currently available in the literature (69 values in total, some expressed as mean ± SD, as indicated). Table 1 Percent loss in bone mineral density at femoral neck in astronauts (N = 69) after 132- to 228-day spaceflights. Time of spaceflight, t (days) Bone mineral density loss in femoral neck (%) Number of astronauts in the study (n) Reference 11 0 69 [ 32 , 33 ] 132 -1.3 1 [ 32 ] 132 -6.0 1 [ 32 ] 145 -4.5 1 [ 32 ] 150 ± 30 -9.4 ± 6.4 16 [ 33 ] 169 -3.5 1 [ 32 ] 169 -3.1 1 [ 32 ] 176 -11.4 1 [ 32 ] 176 -5.3 1 [ 32 ] 181 ± 47 -6.8 ± 1.1 46 [ 19 ] Once we calculated BMD loss by using the previous equation, we calculated the T-score for different ethnicities and sexes by using normative data from the National Health and The predictive model for the BMD loss in the femoral neck of the astronauts during a spaceflight of length ( BMD %( t )), based on the values listed in Table 2 , is the following: B M D % ( t ) = ( − 69 % ) e − 0.0006371 t + 69 % Table 2 Values of the parameters obtained for the mathematical model for the bone mineral density loss for long duration spaceflights. Parameter Value Decay rate, λ 6.371∙10 −4 (a.u.) Half life, t 1⁄2 1088 days Time constant, τ 1570 days Previous studies have calculated the duration of different strong candidate human missions to Mars [ 26 , 27 ]. This means that to keep the skeletal health of crewmembers after a spaceflight, the T-score should be maintained above the non-permissible outcome limit. Yet, for the majority of the cases included in this analysis, bone loss exceeds the non-permissible limit (T-score < -2). Previous studies using linear models to estimate the risk of fragility fractures in crewmembers showed low risk on missions <1 year in duration [ 28 ]. This study predicts that significant risks of fragility fractures in crewmembers arise from the long duration of a future mission to Mars. It is noteworthy to mention that this study can be also extended to other load-bearing bones apart from the femoral neck. Sibonga et al . demonstrated that spaceflight induced fracture risk increases not only in the femoral neck but in general [ 28 ]. In addition, we hope this non-linear model will also inspire future applications of a similar model to predict the bone mineral density loss of terrestrial patients under bed rest. In conclusion, we have presented a mathematical model for BMD loss in crewmembers that can be used to predict T-scores during long-duration spaceflights.

Space flight exposes astronauts to a unique environment characterized by microgravity, ionizing radiation, and other stressors that can profoundly affect the human body. Deep-space exploration-type missions to the Moon (NASA's Artemis and Gateway programs), Mars, and beyond will introduce prolonged exposure to health hazards, including but not limited to isolation and confinement, sleep disruption, and exposure to different types and quantities of particle radiation (i.e., high-energy and atomic number - HZE). There are also logistical implications of traveling farther from low Earth orbit (LEO), including limited access to medical help and supplies. Currently, the known effects of space travel on the cardiovascular system include dysrhythmias, altered vascular compliance, dysautonomia, and induction of a pro-inflammatory state. It is not known how these concerns, and other potentially unknown cardiovascular risks, will manifest during and/or after exploration-type missions. This manuscript comprehensively reviews the cardiovascular disease risks associated with deep space exploration. status released display-pdf yes is-olf no is-manuscript no is-preprint no is-journal-matter no is-scanned no is-retracted no Received 2025 Sep 15; Accepted 2026 Jun 9; Collection date 2026. Introduction The extraterrestrial environment harbors unique risk factors for human health, specifically cardiovascular health, including exposure to space radiation and microgravity, among other stressors, whose effects on human physiology and health remain largely unclear. However, with planned deep space missions and emerging interest in commercial spaceflight, the impact of various spaceflight stressors on short- and long-term health is increasingly important. Long-term post-career risks Months to decades after career ends Possible accelerated vascular stiffening, myocardial remodeling/fibrosis, atherosclerotic progression, CAC increase, and late radiation-associated cardiovascular disease; however, persistent LEO-related vascular impairment has not been clearly demonstrated, and the epidemiology is mixed. Based on longitudinal follow-up studies, event-rate studies, CAC surveillance, and radiation-risk modeling, the strongest uncertainty is for deep-space exposure. Limited musculoskeletal activity at or near zero-gravity during exploration-type space missions results in progressive alterations in the cardiovascular system, including up to a 12 ± 6.9% loss of left ventricular (LV) mass 16 , which reduces cardiac function. Also, there is substantial evidence on the effects of microgravity on cardiovascular physiology. Yet the combined effects of space radiation, reduced gravity, and other unique health risks remain understudied, and the degenerative risks to the cardiovascular system associated with long-duration space missions remain uncertain. Overall, there is limited evidence suggesting that the spaceflight environment increases the risk of life-threatening arrhythmias 42 ; however, several possible mechanisms by which important electrophysiologic changes could occur have been proposed, including the effect of long-term microgravity exposure on elevated In deep space, the increased prevalence of HZE ions and secondary neutrons leads to a higher ionization density (LET), which generally correlates with a higher RBE for late-term cardiovascular and stochastic outcomes compared to the proton-dominant environment of LEO. In LEO, such as on the ISS, the Van Allen Belt (Earth’s protective geomagnetic field) provides shielding from GCRs and solar particle events (SPEs); however, there is still exposure to high-LET IR with dose rates ~100 times higher than those on the ground 64 . By using metrics such as the Risk of Exposure-Induced Death (REID) and accounting for uncertainty quantification, these models allow mission planners to evaluate the probability that an astronaut will exceed Permissible Exposure Limits (PELs) during long-duration lunar or Martian transits 24 . As the NASA Human Research Program (HRP) evolves, these frameworks are increasingly incorporating non-cancer hazards - specifically radiation-induced CVD by integration of the Astro-CHARM clinical tool into NASA’s radiation risk models, which seeks to quantify global cardiovascular risk in middle-aged astronaut populations 92 . 97 , NASA can better estimate the REID for deep-space missions, ensuring that cardiovascular protection is prioritized alongside cancer prevention. While the studies discussed here demonstrate both acute and long-term effects of HZE IR exposure on CVD risk, they are limited by several factors, including limited frequency of IR exposure (single versus fractionated), doses, and energies, which may not reflect the space environment. Without exercise countermeasures, these effects would be far more severe—rapid deconditioning would accelerate bone loss, muscle wasting, and reductions in CO and vascular tone, significantly increasing the risk of orthostatic intolerance, arrhythmias, and impaired performance during mission-critical tasks such as planetary landing or extravehicular activity. Exercise, therefore, remains a cornerstone for maintaining muscle and bone mass, preserving aerobic capacity, supporting vascular function, and sustaining cardiac performance, all of which are critical for reducing CVD risk during long-duration exploration missions. Insights into risks of multi-year Mars missions To date, human spaceflight research has largely been limited to short-duration missions (<30 days) and current ISS expeditions (~6–12 months). Extrapolating findings from these missions to multi-year expeditions to Mars raises unique challenges that extend beyond radiation exposure. Mars-class missions will expose astronauts to an integrated set of hazards, including radiation, altered gravity, isolation, and distance from Earth, which interact with genetic predispositions and chronic deconditioning to shape long-term outcomes 24 .

Mars is the fourth planet from the Sun. It is also known as the "Red Planet", for its orange-red appearance. Mars is a desert-like rocky planet with a tenuous atmosphere that is primarily carbon dioxide (CO2). At the average surface level the atmospheric pressure is a few thousandths of Earth's, atmospheric temperature ranges from −153 to 20 °C (−243 to 68 °F), and cosmic radiation is high. Mars r Mars is the fourth planet from the Sun. It is also known as the "Red Planet", for its orange-red appearance. Mars is a desert-like rocky planet with a tenuous atmosphere that is primarily carbon dioxide (CO2). At the average surface level the atmospheric pressure is a few thousandths of Earth's, atmospheric temperature ranges from −153 to 20 °C (−243 to 68 °F), and cosmic radiation is high. Mars retains some water, in the ground as well as thinly in the atmosphere, forming cirrus clouds, fog, frost, larger polar regions of permafrost and ice caps (with seasonal CO2 snow), but no bodies of liquid surface water. Its surface gravity is roughly a third of Earth's or double that of the Moon. Its mean diameter, 6,779 km (4,212 mi), is about half the Earth's, or… Mars lost its magnetosphere 4 billion years ago, possibly because of numerous asteroid strikes, so the solar wind interacts directly with the Martian ionosphere, lowering the atmospheric density by stripping away atoms from the outer layer. Both Mars Global Surveyor and Mars Express have detected ionized atmospheric particles trailing off into space behind Mars, and this atmospheric loss is being studied by the MAVEN orbiter. Compared to Earth, the atmosphere of Mars is quite rarefied. Atmospheric pressure on the surface today ranges from a low of 30 Pa (0.0044 psi) on Olympus Mons to over 1,155 Pa (0.1675 psi) in Hellas Planitia, with a mean pressure at the surface level of 600 Pa (0.087 psi). The highest atmospheric density on Mars is equal to that found 35 kilometres (22 mi) above Earth's surface. The resulting mean surface pressure is only 0.6% of Earth's 101.3 kPa (14.69 psi). The scale height of the atmosphere is about 10.8 kilometres (6.7 mi), which is higher than Earth's 6 kilometres (3.7 mi), because the surface gravity of Mars is only about 38% of Earth's. The atmosphere of Mars consists of about 96% carbon dioxide, 1.93% argon and 1.89% nitrogen along with traces of oxygen and water. The atmosphere is quite dusty, containing particulates about 1.5 μm in diameter which give the Martian sky a tawny color when seen from the surface. It may take on a pink hue due to iron oxide particles suspended in it.

Long-term exposure causes multiple health problems, one of the most significant being loss of bone and muscle mass. Over time these deconditioning effects The effects of spaceflight on the human body are complex and largely harmful over both short and long term. Significant adverse effects of long-term weightlessness include muscle atrophy and deterioration of the skeleton (spaceflight osteopenia). Other significant effects include a slowing of cardiovascular system functions, decreased production of red blood cells (space anemia), balance disorders F… The effects of spaceflight on the human body are complex and largely harmful over both short and long term. Significant adverse effects of long-term weightlessness include muscle atrophy and deterioration of the skeleton (spaceflight osteopenia). Other significant effects include a slowing of cardiovascular system functions, decreased production of red blood cells (space anemia), balance disorders, eyesight disorders and changes in the immune system. Additional symptoms include fluid redistribution (causing the "moon-face" appearance typical in pictures of astronauts experiencing weightlessness), loss of body mass, nasal congestion, sleep disturbance, and excess flatulence. A 2024 assessment noted that "well-known problems include bone loss, heightened cancer risk, vision impairment, weakened immune systems, and mental health issues... [y]et what's going on at a molecular level hasn't always been clear", arousing concerns especially vis a vis private and commercial spaceflight now occurring without any scientific or medical research being conducted among those populations regarding effects. Overall, NASA refers to the various deleterious effects of spaceflight on the human body by the acronym RIDGE (i.e., "space radiation, isolation and confinement, distance from Earth, gravity fields, and hostile and closed environments"). However, beyond the limited protection of Earth's magnetosphere, interplanetary human missions are much more vulnerable. Lawrence Townsend of the University of Tennessee and others have studied the most powerful solar flare ever recorded. Radiation doses astronauts would receive from a flare of this magnitude could cause acute radiation sickness and possibly even death. There is scientific concern that extended spaceflight might slow down the body's ability to protect itself against diseases. Radiation can penetrate living tissue and cause both short and long-term damage to the bone marrow stem cells which create the blood and immune systems. Long-term exposure causes multiple health problems, one of the most significant being loss of bone and muscle mass. Over time these deconditioning effects can impair astronauts' performance, increase their risk of injury, reduce their aerobic capacity, and slow down their cardiovascular system. As the human body consists mostly of fluids, gravity tends to force them into the lower half of the body, and our bodies have many systems to balance this situation. When released from the pull of gravity, these systems continue to work, causing a general redistribution of fluids into the upper half of the body. This is the cause of the round-faced 'puffiness' seen in astronauts, and may contribute to observations of altered speech motor control in astronauts. Redistributing fluids around the body itself causes balance disorders, distorted vision, and a loss of taste and smell. A 2006 Space Shuttle experiment found that Salmonella typhimurium, a bacterium that can cause food poisoning, became more virulent when cultivated in space. It is related to motion sickness, and arises as the vestibular system adapts to weightlessness. Symptoms of SAS include nausea and vomiting, vertigo, headaches, lethargy, and overall malaise. The first case of SAS was reported by cosmonaut Gherman Titov in 1961. Since then, roughly 45% of all people who have flown in space have suffered from this condition. ==== Bone and muscle deterioration ==== A major effect of long-term weightlessness involves the loss of bone and muscle mass. In a weightless environment, astronauts put almost no weight on the back muscles or leg muscles used for standing up. Those muscles then start to weaken and eventually get smaller. This results in a loss of bone tissue approximately 1.5% per month especially from the lower vertebrae, hip, and femur. Due to microgravity and the decreased load on the bones, there is a rapid increase in bone loss, from 3% cortical bone loss per decade to about 1% every month the body is exposed to microgravity, for an otherwise healthy adult. The rapid change in bone density is dramatic, making bones frail and resulting in symptoms that resemble those of osteoporosis. On Earth, the bones are constantly being shed and regenerated through a well-balanced system which involves signaling of osteoblasts and osteoclasts. A study demonstrated that in healthy mice, osteoclasts appearance increased by 197%, accompanied by a down-regulation of osteoblasts and growth factors that are known to help with the formation of new bone, after only sixteen days of exposure to microgravity. Elevated blood calcium levels from the lost bone result in dangerous calcification of soft tissues and potential kidney stone formation. It is still unknown whether bone recovers completely. Unlike people with osteoporosis, astronauts eventually regain their bone density. After a 3–4 month trip into space, it takes about 2–3 years to regain lost bone density. New techniques are being developed to help astronauts recover faster. The majority of current data comes from missions of short duration and so some of the long-term physiological effects of living in space are still unknown. A round trip to Mars with current technology is estimated to involve at least 18 months in transit alone. Knowing how the human body reacts to such time periods in space is a vital part of the preparation for such journeys.

to microgravity by resetting to a new equilibrium state within a relatively short time. Upon return to a gravitational field from space, the same rapid effects may be seen in reverse [ 8 ]. Many of these immediate indispositions can interfere with crewmember critical operational procedures associated with entering orbit or returning to Earth. The lack of readiness in managing certain situations due to adaptation disturbances can represent a risk for mission success, and it is necessary to find effective and rapid countermeasures, both pharmacological and otherwise. Other physiological systems manifest weightlessness effects on a longer term (weeks to months). For short-duration missions, these changes may be minor or even undetectable. On longer flights, the effects can become more pronounced. The recovery of astronauts from these symptoms depends on the time of exposure to stress factors related to the space environment; the longer they stay, the longer the recovering time [ 8 , 9 ]. Among long-term effects on human physiology, we find muscle atrophy, bone demineralization and, therefore, alteration in calcium balance, immune function dysregulation, endocrine disorders, such as insulin resistance [ 10 , 11 ], and cardiovascular deconditioning that leads to orthostatic intolerance [ 12 ]. Currently, these physiological changes present major obstacles to long-term space missions. Therefore, it is fundamental to develop countermeasures aimed at preventing or slowing down the progression of these complications. This review discusses alteration of human physiological parameters related to bone metabolism due to long-term weightlessness exposure and examines the effectiveness of both pharmacological and non-pharmacological countermeasures. 2. Bone Loss and Osteoporosis Reduction in bone density related to microgravity is due to an imbalance of bone remodeling induced by changes in bone cells. Studies of ground-based simulated microgravity showed that morphology and funct