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Investigations of the bone system and body composition in Mars-500 test-subjects (prior to and on completion of the experiment) involved dual-energy X-ray absorptiometry (DXA) using the HOLOGIC Delphy densitometer and the protocol performed to examine cosmonauts. Bone density of lumber vertebrae and femoral proximal epiphysis, and body composition were measured. Reliable changes in vertebral density found in 3 test-subjects displayed different trends from +2.6 to -2.4%. At the same time, the experiment decreased significantly mineral density of the femoral proximal epiphysis, including the neck, in all test-subjects. Four test-subjects had cranial mineralization increased by 5-9%, same as in some cosmonauts after space flight. All tests-subjects incurred adipose loss from 2 to 7 kg; one test-subject lost 20 kg, i.e. his adipose mass became three times less. Changes in lean mass (1-3 kg) typically were negative; as for changes in lean mass of extremities, they could be linked with adherence to one or another type of physical activity. Therefore, extended exposure to confinement may affect mineralization of some parts of the skeleton. Unlike real space missions and long-term bedrest studies conducted at the Institute of Biomedical Problems in the past, Mars-500 did not cause clinically significant mineral losses (osteoporosis, osteopenia), probably because of the absence of effects of microgravity.

Noninvasive technologies of bone investigations measure largely the main skeletal sites and are not quite suitable to have a look at the bone internal organization in situ. However, there are data obtained noninvasively in experiments on board the space biosatellites. The review is dedicated to analysis and comparison of the evidence for the bone organic and mineral matrix restructuring due to microgravity. These changes have presumably evolved in the course of the system reaction of bone tissue and the whole skeleton.

Systematically results and new analysis data on the investigation of human bone system in space flight, the orbital station Mir and International Space Station, are presented. The bone mineral density, bone mineral content, identified as bone mass and body composition using dual energy X-ray absorptiometry were measured. Theoretically, an expected bone mass loss in trabecular tissue of lower skeletal half may by described as a quickly developing but reversible osteopenia and considered as evidence of functional adaptation of bone tissue to the changing mechanical load. A hypothesis of main mechanisms of osteopenia in microgravity is presented. High individual variability of bone mass losses and stability of individual pattern of correlation between bone mass losses in different skeletal segments were found. It is not possible to identify the relationship between bone mass losses and duration of space missions. Therefore it is not a sufficient ground to calculate the probability of reaching the critical level of bone demineralization by prolonged space flight. The same relates to the probability of prognosis of bone quality changes. There is data about dual energy X-ray absorptiometry that is insufficient for this prognosis. The main direction of investigations is presented which might optimize the interplanetary mission from the point of view of skeletal mechanical functions preservation.

Analysis of the results of long-term investigations of bones in cosmonauts flown on the orbital station MIR and International space station (n = 80) was performed. Theoretically predicted (evolutionary predefined) change in mass of different skeleton bones was found to correlate (r = 0.904) with position relatively the Earth's gravity vector. Vector dependence of bone loss ensues from local specificity of expression of bone metabolism genes which reflects mechanic prehistory of skeleton structures in the evolution of Homo erectus. Genetic polymorphism is accountable for high individual variability of bone loss attested by the dependence of bone loss rate on polymorphism of certain bone metabolism markers. Parameters of one and the other orbital vehicle did not modulate individual-specific stability of the bone loss ratio in different segments of the skeleton. This fact is considered as a phenotype fingerprint of local metabolism in the form of a locus-unique spatial structure of distribution of noncollagenous proteins responsible for position regulation of endosteal metabolism. Drug treatment of osteoporosis (n = 107) evidences that recovery rate depends on bone location; the most likely reason is different effectiveness of local osteotrophic intervention into areas of bustling resorption.

Comparison of bone mineral density and fatty-acid blood content in 9 human subjects exposed to 370-d bed rest revealed correlation of the loss in femoral neck density with parameters of lipid exchange. On day-46 of BR, the absolute lipids content in erythrocyte membranes and blood serum decreased considerably (1.5-2 times) when compared with baseline data. At the end of the experiment, lipids content in serum, on the contrary, surpassed baseline values 2-3 times: however, it remained lowered in erythrocyte membranes of the control group till day-280 of BR. Arachidonic acid correlated with prostaglandins PGE2 and PGF2alpha involved in regulation of osteoclasts and osteoblasts activities. Correlation of decreases in femoral neck density and unsaturated fatty acids in blood serum and erythrocyte membranes varied with the human subjects.

Densitometry of cosmonauts following long-duration missions shows reduction of bone mineral density (BMD). On the average, post-flight BMD remains within the normal range and the broad variability of individual BMD values sometimes is qualified as local osteopenia. Individual reactions are typed by similarity of amount and rate of BMD loss. At present, analysis of functionally significant polymorphism of bone metabolism genes is the most effective instrument for diagnostics of susceptibility to osteopenia and osteoporosis. The investigation was aimed to analyze polymorphism of genes of vitamin-D and (VDR) and calcitonin (CALCR) receptors, and of collagen-1 alpha-1-chain (Col1a-1) in candidate cosmonauts and cosmonauts returned from 5 to 7-mo. missions. According to the results of analysis, in the majority of cosmonauts rapid BMD loss correlated with TT genotype by VDR gene but not with genotypes Tt and tt and associated with carriage of incomplete s-allele in the Col1a1 gene. Yet, in several instances high BMD loss rates were personified with carriers of VDR gene alleles (homo- and heterozygote states--tt and Tt) and heterozygote by Col1a1 gene (Ss).

A summary of investigations results of human bone tissue changes in space flight on the orbital station (OS) Mir and international space station (ISS) using dual energy X-ray absorptiometry (DXA) is given. Results comparative analysis revealed an absence of significant differences in bone mass (BM) changes on the both OS. Theoretically expected BM loss was observed in bone trabecular structure of skeleton low part after space flight lasting 5-7 month. The BM losses are qualified in some cases as quicly developed but reversible osteopenia and generally interpreted as evidence of bone functional adaptation to the alterating mechanical loading. It was demonstrated the high individual variability BM loss amplitudes. Simultaneously was observed the individual pattern of BM loss distribution across different segments of skeleton after repetitive flights independently upon type of OS. In according with the above mentioned individual peculiarities it was impossible to establish the dependence of BM changes upon duration of space missions. Therefore we have not sufficiently data for calculation of probability to achive the critical demineralization level by the augmentation the space mission duration till 1.5-2 years. It is more less possibility of the bone quality changes prognosis, which in the aggregate with BM losses determines the bone fracture risk. It become clearly that DXA technology is unsuffitiently for this purpose. It is considered the main direction which may optimized the elaboration of the interplanetary project meaning the perfectly safe of skeleton mechanical function.

The results of long-standing investigations of the human bone system in the piloted Mir and International space station missions were reviewed. The noninvasive DXA technology was used to determine bone mass (BM) and body composition. Predictable BM losses in the lower body tubular bones during 5 to 7-mo. space missions are characteristic of rapid but recoverable osteopenia and viewed as functional adaptation to altering mechanic loading of the skeleton. These changes feature high individual variability. Interestingly, the extent of BM changes in different segments of the skeleton displays stability in individual crew members irrespective of space station design. No strong dependence of BM changes on flight duration has been established and, therefore, calculation of the probability of critical bone demineralization after 1.5 to 2 years in space flight is impractical. Still less is the possibility to predict impairment of the bone structure which, together with BM losses, preconditions the risk of fracture. The data presented witness DXA inadequacy for such prediction. Main areas of researches toward optimization of the exploration mission design and planning in the context of the skeleton mechanic function maintenance are considered.

The loss of bone mineral in NASA astronauts during spaceflight has been investigated throughout the more than 40 years of space travel. Consequently, it is a medical requirement at NASA Johnson Space Center (JSC) that changes in bone mass be monitored in crew members by measuring bone mineral density (BMD), with dual-energy X-ray absorptiometry (DXA) before and after flight, of astronauts who serve on long-duration missions (4-6 months). We evaluated this repository of medical data to track whether there is recovery of bone mineral that was lost during spaceflight. Our analysis was supplemented by BMD data from cosmonauts (by convention, a space traveler formally employed by the Russia Aviation and Space Agency or by the previous Soviet Union) who had also flown on long-duration missions. Data from a total of 45 individual crew members - a small number of whom flew on more than one mission - were used in this analysis. Changes in BMD (between 56 different sets of pre- and postflight measurements) were plotted as a function of time (days after landing). Plotted BMD changes were fitted to an exponential mathematical function that estimated: (i) BMD change on landing day (day 0) and (ii) the number of days after landing when 50% of the lost bone would be recovered ("50% recovery time") in the lumbar spine, trochanter, pelvis, femoral neck and calcaneus. In sum, averaged losses of bone mineral after long-duration spaceflight ranged between 2% and 9% across all sites with our recovery model predicting a 50% restoration of bone loss for all sites to be within 9 months.

The review deals with the analysis of osteodensitometry data from the cosmonauts flown on Russian space station MIR and the International space station and suppositions about involvement of different levels of metabolism regulation in bone loss triggered by insufficient mechanic loading in microgravity attendant by redistribution of body liquids. It is surmised that the initial reactions are associated with the biomechanical factor and recruitment of local mechanisms, i.e. osteocyte osteolysis and inhibition of osteoblast histogenesis. Regulation on the level of tissues and organs is responsible for destabilization of calcium homeostasis (low calcium absorption in the intestine and readsorption in the kidney). Changes in the hierarchy of ion and volume regulation may provoke osteoclast resorption which further increases osteopenia.

Hypothesized processes of changes found in spacecrew bones following 5 to 7 mo. orbital missions are reviewed. Selective osteopenia of trabecular bones in the lower skeleton is attributed to a greater weight loading at 1 g. Increased mineral content in the upper skeleton (dual energy X-ray adsoptiometry--DXA) and hypermineralization of the limbic spongious bone (computer tomography) appear to be secondary and reflect the body liquids redistribution headword including to the abdomen. The additional negative gradient of the lower skeleton mass during early readaptation (about 1.5 mo, after landing) can be explained by remodeling (resorption and bone formation) as a reaction to the "load return". Personal variability is probably a fingerprint of genetic determinism of bone mass and metabolic phenotype that may sometimes lead to an increased risk of fracture. The authors raise the discussion about practicality of the genetic osteopenia prediction for space flyers.

In the retrospective analysis of own experimental data and the literary overview of the slow-to-fast transformation of skeletal muscles (essentially postural and locomotor) in animals due to microgravity the authors scrutinize the muscle functional plasticity given heterodromous changes in the external mechanic field. Adaptation of the myofiber phenotype is ensured by polymorphism of muscle isoproteins and lability of the system providing energy for muscle contraction.

Results of multi-year bone observations in crewmembers of long-term (6 to 14 mos.) Salyut and Mir missions have been summarized. The theoretical expectation of bone losses (mineral bone density, MBD) was consistent only in the trabecular of the lower skeleton (lumbar spine, femur proximal epiphysis, pelvis). The upper skeleton bones (skull, cervical spine) demonstrated a clears-defined trend toward an increase in mineral content. There is a direct dependence of MBD losses on a skeleton bone position relative to the gravity vector and bone structure. Post-flight MBD did not, as a rule, deviate from the WHO-defined limits (T-criterion); in several instances MBD loss was qualified as local osteopenia. Shifts in MBD, same as MBD recovery rate, vary with subjects and, therefore, deny their dependence on flight duration. By and large, MBD shifts are interpreted as a functional adaptation of bone tissue to changing mechanic demands.

A summary of results of investigations by the author and a brief review of some literature data on human bone tissue deprived of mechanical loading (spaceflight, hypokinesia) is given. The direction and markedness of changes in bone mass--the bone mineral density and the bone mineral content--in different skeletal segments depend on their position relative to the gravity vector. A theoretically expected bone mass reduction was revealed in the trabecular structures of the bones of the lower part of the skeleton (local osteopenia). In the upper part of the skeleton, an increase in the bone mineral content is observed, which is considered as a secondary response and is due to redistribution of body fluids cephalad. The main cause of osteopenia is mechanical unloading. Arguments are presented that osteocyte osteolysis, delayed osteoblast histogenesis, and osteoclast resorption provoked by rearrangement in the hierarchy of the systems of fluid volume and ion regulation, and the endocrine control of calcium homeostasis are the main mechanisms of osteopenia.

With the use of the methods of electron microscopy and autoradiography employing 3H-glycine the study was made of some morpho-functional cells-cells interactions (osteoblasts, osteocytes, macrophages, fibroblasts) in zones of adaptive remodeling of bone structures of the metaepiphyseal femoral bones of white rats which were during 28 days under experimental hypokinesia conditions, as well as of rats, flown on SLS-2 during 2 weeks. It is established that in zones of an increase of mineral matrix resorption some osteoblasts and osteocytes undergo destruction; a part of osteoblasts remains intact. The osteoclasts don't take part in destruction of osteoblasts and osteocytes. The utilization of the osteogenic cells detritus is accomplished by macrophages, coming to these zones. The resorption loci are filled not with the differentiating osteoblastic cells, as it is the case in the norm, but with fibroblasts and the bundles of collagen fibrils (fibrotic tissue) which do not undergo mineralization. Such changes are considered as one of the mechanisms of bone tissue response to a reduction of the supporting load.

GH and IGF-I have well recognized effects on bone elongation during development, but their importance for bone mineralization and structure during the growth phase are less well understood. Because children with GH deficiency are generally treated with GH, little detailed information exists in humans about the effects of long-term GH deficiency on bone development. The recently described syndrome of genetic GHRH receptor deficiency in Pakistan (dwarfism of Sindh) affords a unique opportunity to examine the question of GH deficiency on bone development because the affected patients have congenital, severe, isolated GH deficiency, which had never been treated because of societal reasons. We performed dual energy x-ray absorptiometry scans in four adult males (age, 23-30 yr) to address the question of bone mineralization. Areal bone mineral density (BMD) was low (mean Z scores: -3.3, -2.1, -3.7, and -1.7) in the lumbar spine, femoral neck, forearm, and total skeleton, respectively. This low areal BMD is in part caused by the small bone size in these dwarfed patients. When corrected for size, volumetric BMD (bone mineral apparent density) was normal to near normal (mean Z scores: -1.2, +0.8, and +0.8 for lumbar spine, femoral neck and total skeleton, respectively). We conclude that GH/IGF-I deficiency has relatively little impact on bone mineralization during the bone accretion phase. This is in marked contrast to their effect on bone elongation and overall bone size.

Main osteoporosis definitions and some results of bone tissue research in Russian astronauts, patients, and healthy subjects, using modern osteodensitometry, are presented. Bone mineral density (BMD) was regularly decreased at lower segments of skeleton. In the skull bone and some other sites of upper part of skeleton, a tendency was revealed for an increase of the bone mineral content (BMC). The mean value of bone loss was within the normal range and not correlated with duration of space flight; it revealed a high individual variability and in some cases was clinically qualified as local osteopenia. On the ground of analysis of own results and animal and bone cultural experiments data in microgravity conditions, the described changes seem to be reflecting a deceleration of bone formation as an adaptive response of bone tissue to the mechanical unloading. The response is realized mainly on the tissue level. It does not exclude bone resorption activity as a result of changes in hierarchy of water and electrolytes metabolism as reflected by body fluid redistribution in cranial direction. The results obtained broaden our notions on pathogenesis of some types of osteoporosis in clinic.

We examined the peculiarities of the structure of the blood-vascular bed and perivascular cells in zones of osteogenesis in the epiphyses and metaphises of femoral bones of rats, flown aboard the US laboratory SLS-2 for two weeks by electron microscopy and histochemistry. In zones of bone remodeling, there was a tendency for a reduction of sinusoid capillary specific volume. Endotheliocytes preserve the typical structure. In the population of perivascular cells, we discovered differentiating osteogenic cells that contained alkaline phosphomonoesterase as well as cells that don't contain this enzyme and differentiate into fibroblasts. The fibroblasts genesis in zones of adaptive remodeling of spongy bones leads to a further development of fibrous tissue that is not subject to mineralization., (c2003 COSPAR. Published by Elsevier Ltd. All rights reserved.)

The most typical changes for the bone under the space flight conditions and a long-term hypokinesia are the following: the decreasing in bone mass, the demineralization and a reducing of a mechanical strength. It can lead to osteopenia and osteoporosis development. Also it increases the risk of fractures of supporting bones. Osteopenies, caused by the microgravity, are partially connected with the increasing of a reduction of trabecular bones. [Cytological mechanisms of gravity-dependent reactions in a bone tissue remain in many respects not clear. The study purpose was the analysis of some ultrastructural changes in bone tissue cells of the monkeys (Macaca mulatta), staying during 2 weeks onboard the biosatellite "Bion-11".

We examined the histology and morphometry of biosamples (biopsies) of the iliac crest of monkeys, flown 14 days aboard the "Bion-11", using electron microscopy. We found, that some young osteocytes take part in the activation of collagen protein biosynthesis in the adaptive remodeling process of the bone tissue to microgravity conditions. Osteocyte lacunae filled with collagen fibrils; this correlates with fibrotic osteoblast reorganization in such zones. The osteolytic activity in mature osteocytes is intensified. As a result of osteocyte destruction, the quantity of empty osteocytic lacunae in the bone tissue increases., (c2002 COSPAR. Published by Elsevier Science Ltd. All rights reserved.)

Microgravity in space flight--situation of a maximum deficit of supporting loading on the skeleton and good model for finding-out of osteopenia and osteoporosis development laws, which are wide-spreading now and are "civilization diseases". Most typical for bones in conditions of a microgravitation by changes are: a decrease of intensity growth and osteoplastic processes, osteopenia and osteoporosis, decreasing of a mechanical strength and the risk of breaches arising (Oganov V.S., Schneider V. (1996)). Cytological mechanisms of gravity-dependent reactions in a bone tissue remain in many respects not-clear. By the purpose of our work was the analysis of some ultrastructural changes in bone tissue cells of the monkeys (Macaca mulatta), staying during two weeks onboard the biosatellite BION -11.

Mechanical stimulation of bone tissue determined by earth gravity is one of the main factors mediating the nature, rate and direction of functional adaptation of the bone system in the process of onto- and phylogenesis. Theoretically expected losses of bone mass under condition of mechanical load deficit under microgravity (osteopenia, osteoporosis) may become a factor that limits the duration of space flights. As a result of long-term studies some properties and regularities of change in human tissue after prolonged space flights (for 5-7 months) were established.

Iliac crest biopsies of Bion 11 monkeys were examined by electron microscopy. The flight samples contained a large number of inactive osteoblasts. Together with ultrastructural changes of the rough endoplasmic reticulum and the Golgi complex, the predominance of inactive osteoblasts pointed to a lower rate of specific syntheses. Some osteoblasts were transformed to fibroblast-like cells. It was found that osteogenesis declined, osteoid mineralization changed, and fibrotic zones developed.

Bone mineral density (BMD) of lumbar spine and tibia, as well as ultrasound propagation speed along the tibia, was measured in Bion 11 flight and control monkeys. The flight monkeys showed a delay in the growth-related (L-1) bone mass increase compared to the preflight period. Similar changes were detected in some control animals. The changes occurred primarily in metabolically active spongy bone, as shown by ultrasound data.

Results of the joint Russian/US studies of the effect of microgravity on bone tissues in 18 cosmonauts on return from 4.5- to 14.5-month long missions are presented. Dual-energy x-ray gamma-absorbtiometry (QDR-1000 W, Hologic, USA) was used to measure bone mineral density (BMD, g/cm2) and mineral content (BMC, g) in the whole body, the scalp including cervical vertebra, arms, ribs, sternal and lumbar regions of the spinal column, pelvis and legs. A clearly defined dependence of topography of changes upon the position of a skeletal segment in the gravity vector was established. The greatest BMD losses have been observed in the skeleton of the lower body, i.e. in pelvic bones (-11.99 +/- 1.22%), lumbar vertebra (-5.63 +/- 0.817%), and in proximal femur, particularly in the femoral neck (-8.17 +/- 1.24%). Bones of the upper skeleton were either unchanged (insignificant) or showed a positive trend. Overall changes in bone mass of the whole skeleton of male cosmonauts during the period of about 6 months on mission made up -1.41 +/- 0.406% and suggest the mean balance of calcium over flight equal to -227 +/- 62.8 mg/day. Reasoning is given to qualify these states of cosmonauts' bone tissues as local osteopenia. On the literature and results of authors' clinical evidence, discussed is availability of the densitometric data for predicting risk of trauma. A biological nature of the changes under observation is hypothesized.

Possible pathways of the origin and development of adaptive mechanisms in the living systems of various levels of organization are considered from the positions of biomechanics and bioenergetics. Main attention is paid to the specific feature of functional rearrangements in the living organisms during change of habitat, at the stage of their exit from water to land. The following problems of interaction between the living systems and gravity during evolution are discussed: cellular level of organization and transition to multicellularity, formation and improvement of the skeletal and skeletal-motor systems in plants and animals, and thermal homeostasis of the living organisms in the gravity field. We showed a leading role of gravity in organization of the morphofunctional status of the living organisms during their evolution.

The state of bone tissue has been studied in 8 women subjected to a 120-day HDT. Four test subjects (Group A) performed physical exercises during the experiment. Mineral content (MC) in bone tissue and mineral density of the bones (MD) were determined with the help of dichromatic x-ray bone densitometer HOLOGIC QDR--100/W. The velocity of propagation of ultrasound in the shin bone was also determined. It is found that the hypokinesia-associated losses of bone mass in the lower segments of the skeleton of women were insignificant. In the control group (Group B, non-exercising subjects), there markedly increased MC in the bones of the upper body and there were the slight signs of hypomineralization of the segments of the lower body as well as the significant (in 2 test subjects) decrease of MC in the pelvic bones in the recovery period to the level lower than at the beginning of the experiment. In group A, the increase of MC in the upper skeleton was expressed to a lesser degree. At the recovery period the all changes were practically neutralized and there were no signs of bone mass loss. The velocity of ultrasound by the Day 90 of the experiment had the marked tendency for a decrease in group A persisting up to the end of experiment while in the group B its changes were oppositely directed. Within 2 months after the experiment in the majority of women the tendency for recovery of the initial state both by the absolute values of ultrasound velocity and by the profile of curves of their distribution over the anterior surface of the shinbone was noted. The results are discussed in comparison with findings obtained in the experiments with long-term hypokinesia in men and in the space missions.

The qualitative and quantitative histological and histochemical changes in the structure and macromolecular composition of lumbar intervertebral discs of rat during a 12.5-day space flight (Cosmos 1887 biosatellite) were determined using light and polarization microscopy. Semiquantitative histochemical, topo-optical reactions were measured and evaluated by retardation values of birefringence. (a) Lateral expansion and accumulation of the notochordal cells in the nucleus pulposus was observed in contrast with the vivarium control, where the chondroid cells dominated. (b) The cartilage and plate showed a swelling, which consisted mainly of hypertrophied cells sometimes with mild extracellular mineralization. (c) In the external zone of annulus fibrosus and cartilage end plate a mild decrease of orientation of collagen fibers was found. (d) A significant increase of orientation of hyase sensible glycosaminoglycans in the internal zone of annulus fibrosus and nucleus pulposus was observed. (e) In the external and internal zones of annulus fibrosus an increase of orientation of glycoproteids was revealed. The alterations of macromolecular components of intervertebral discs, cartilage end plates, and the osteoporotic changes of the lumbar vertebral bodies producing the looser structure of vertebral column after 12.5 day space flight suggest the necessity of the common evaluation of these structures, and may explain the heavy spinal pains of astronauts.

Bone system was examined in 112 liquidators; in 71 of these osseous tissue density was studied by osseous densitometer using bienergetic x-ray absorptiometry and in 45 x-ray examinations, analyses of biochemical and hormonal parameters were carried out. Spinal painful syndrome was detected in 61 to 82% of the examinees. For analysis of densitometric and x-ray parameters the liquidators were divided into 2 groups: group 1 included those who worked at the power plant in 1986 (55%) and group 2 were those who worked there in 1987-1989. Radiation doses in group 1 reliably surpassed those in group 2 (p < 0.001). Bone mineral density in the lumbar vertebrae was significantly lower in group 1 as against group 2 and lower in both groups vs. controls. More than 5% osseous mineral loss was revealed in 73% of group 1 liquidators and in 43% of group 2 ones. Analysis of spinal roentgenograms in 45 liquidators showed a high incidence of negligible and moderately expressed osteoporosis without compression fractures of vertebral bodies: osteopenia signs were found in 87% of group 1 examinees complaining of pain in the spine and in 73% of group 2 examinees; signs of osteochondrosis and spondylosis were detected in 40% of group 1 and in 47% of group 2 subjects. Hence, a higher incidence of osteopenia in liquidators, more manifest condition and its higher detection rate in subjects exposed to higher radiation doses indicate a certain contribution of radiation factor to the development of the osteopenia syndrome in liquidators.

In the Cosmos biosputnik 1514, 1667, 1887, 2044 and 1129 the rats 5, 7, 12,5, 15, 18,5 days were in weightlessness state. Due to the adaptation of the skeletal muscles' weightlessness the adaptation was different in various muscles, which depends on the time of participation in antigravitation, the composition of the fibers and from the biometrical characteristics. In different muscles, the changing of the metabolism and the structure of the muscles more than likely in connection with the changing of the myosin subordinate unit compositions. In our experiments we had studied, as to how the muscular atrophy changes, does it increase all the time, or does it balances out after reaching a certain stage.

As we enter a phase of space exploration that will involve long-duration flights, there is a need to use ground-based models to study the long-term effects of countermeasures to prevent the loss of bone mineral in microgravity. Mineral balances, hormone levels, and bone density were measured for 360 days in nine bed rest subjects treated with an exercise program used by cosmonauts. Four of these subjects received the bisphosphonate, ethane-1-hydroxy-1-disphosphonate, 900 mg daily, a drug known to inhibit bone resorption. Compared to a 120 day control period, the bisphosphonate combined with exercise reduced negative calcium balances by 50% for the first 120 days, 80% for the second 120 days, and 69% during the third 120 days. Exercise alone had no effect until the second 120 day period, when calcium balance improved 52%. Negative phosphorus balances were not affected by either treatment. Magnesium balances were negative during the first 120 days and returned to nearly normal during the last 240 days in both groups. The combined exercise and bisphosphonate treatment prevented increases in serum ionized calcium and decreases in plasma calcitonin during the first 120 days, as well as trends toward decreases in the mineral density of the femoral neck. These results suggest that bisphosphonates can be efficiently used together with exercise to reduce calcium loss and prevent some of the changes in mineral metabolism during long-term simulated microgravity.

A technique of quantitative digital roentgenography (QDR) being a current modification of dual photon absorptiometry (DPA) was used to measure bone mineral density (BMD) in the crewmembers of the 6-9th expeditions onboard Mir orbital station after space missions of 132 to 176 days in duration. Total mineral losses were, on average, 0.4% of a preflight level, and in the most test subjects the postflight BMD of the skull, ribs and arms increased and that of lumbar vertebrae, pelvis and legs decreased. The most marked local postflight mineral losses occurred in the proximal femur bone (the femoral neck and the greater trochanter--up to 14%). The observed changes did not depend on flight duration. These findings are being compared to the results of similar studies conducted during the 120-day (NASA) and 370-day (IBMP) hypokinesia experiments. The possibility of existing the general mechanism of modifying mineral status of the skeleton due to different situation related deficiency of musculoskeletal load.

The influence of spaceflight on the distribution of succinate dehydrogenase (SDH) activity throughout the cross section of fibers in the soleus was studied in five male rats and in five rats maintained under ground-based simulated flight conditions (control). The flight (COSMOS 1887) was 12.5 days in duration, and the animals were killed approximately 2 days after return to 1 G. Fibers were classified as slow-twitch oxidative or fast-twitch oxidative-glycolytic in histochemically prepared tissue sections. The distribution of SDH activity throughout the cross section of 20-30 fibers (each type) was determined using quantitative histochemical and computer-assisted image analysis techniques. In all the fibers, the distribution of SDH activity was significantly higher in the subsarcolemmal than in intermyofibrillar region. After spaceflight the entire regional distribution of SDH activity was significantly altered in the slow-twitch oxidative fibers. The fast-twitch oxidative-glycolytic fibers of the spaceflight muscles exhibited a significantly lower SDH activity only in their subsarcolemmal region. These data suggest that when determining the influence of spaceflight on muscle fiber oxidative metabolism enzymes, it is important to consider the location of the enzyme throughout the cross section of a fiber. Furthermore the functional properties of the soleus that depend on the metabolic support of mitochondria in the subsarcolemmal region may be primarily affected by exposure to microgravity.

Spaceflight (flight) and tail suspension-hindlimb unloading (unloaded) produced significant decreases in fiber cross-sectional areas of the adductor longus (AL), a slow-twitch antigravity muscle. However, the mean wet weight of the flight AL muscles was near normal, whereas that of the suspension unloaded AL muscles was significantly reduced. Interstitial edema within the flight AL, but not in the unloaded AL, appeared to account for this apparent disagreement. In both experimental conditions, the slow-twitch oxidative fibers atrophied more than the fast-twitch oxidative-glycolytic and fast-twitch glycolytic fibers. Immunostaining showed that slow-twitch oxidative fibers expressed fast myosin, producing hybrid fibers containing slow and fast myosin isoforms. Two-dimensional gel electrophoresis of flight AL muscles revealed increased content of fast myosin light chains and decreased amounts of slow myosin light chains and fatty acid-binding protein. In the flight AL, absolute mitochondrial content decreased, but the relatively greater breakdown of myofibrillar proteins maintained mitochondrial concentration near normal in the central intermyofibrillar regions of fibers. Subsarcolemmal mitochondria were preferentially lost and reduced below normal concentration. Elevated fiber immunostaining for ubiquitin conjugates was suggestive of ubiquitin-mediated breakdown of myofibrillar proteins. On return to weight bearing for 8-11 h, the weakened atrophic muscles exhibited eccentric contraction-like lesions (hyperextension of sarcomeres with A-band filaments pulled apart and fragmented), tearing of the supporting connective tissue, and thrombosis of the microcirculation. Segmental necrosis of muscle fibers, denervation of neuromuscular junctions, and extravasation of red blood cells were minimal. Lymphocyte antibody markers did not indicate a significant immune reaction. The flight AL exhibited threefold more eccentric-like lesions than the unloaded AL; the high reentry G forces experienced by the flight animals, but not the unloaded group, possibly accounted for this difference. Muscle atrophy appears to increase the susceptibility to form eccentric contraction-like lesions after reloading; this may reflect weakening of the myofibrils and extracellular matrix. Microcirculation was also compromised by spaceflight, such that there was increased formation of thrombi in the post-capillary venules and capillaries. This blockage led to edema by 8-11 h after resumption of weight bearing by the COSMOS 2044 rats. The present findings indicate that defective microcirculation most likely accounted for the extensive tissue necrosis and microhemorrhages observed for COSMOS 1887 rats killed 2 days after landing.

Contractile properties of skeletal muscles of rats were investigated using glycerinated muscle preparations that were obtained from Cosmos-1887 animals flown for 13 days (plus 2 days on the ground) and from rats that remained hypokinetic for 13 days on the ground. In the flow rats, the absolute mass of postural muscles remained unchanged while their relative mass increased; this may be attributed to their enhanced hydration which developed during the first 2 days after landing. Strength losses of the postural muscles were less significant than after previous flights. Comparison of the Cosmos-1887 and hypokinesia control data has shown that even 2-day exposure to 1 G after 13-day flight can modify drastically flight-induced changes.

The informative value of diagnosis of osteoporosis in 53 patients with Itsenko-Cushing disease was assessed by visual estimation of radiograms of the axial skeleton, standard x-ray densitometry of the phalanges of the thumbs and single-photon absorptiometry of the distal parts of antebrachial bones. Diagnosis of osteoporosis and its evaluation over time were shown to be accurate in combination of visual assessment of radiograms of the axial skeleton with standard x-ray densitometry of the peripheral parts of the skeleton. Single-photon absorptiometry revealed no decrease in the level of the osseous mineral in the forearm of patients with endogenous hypercorticoidism. In the majority of female patients this indicator even exceeded the normal age value. Possible causes of this phenomenon are under discussion.

The results of studying the bone tissue of cosmonauts after the flights (4-8 month) have been compared to the data of investigating the healthy individuals during head-down tilt (HDT, 370 days). Noninvasive methods (computer tomography, gammaphoton absorptiometry) revealed a decrease in the vertebral spongy mineral density or a increase of this parameter by a similar magnitude versus the individual preflight values in some cosmonauts. During studies of clinical cases of osteoporosis it was shown that the vertebral mineral density ratios and presence or absence of vertebral compression fractures in different age groups are nonequal.

The results of several years of laboratory studies concerning the space flight influence on the skeletal muscles of white rats are presented, comprising change and adaptation factors, and a comparison of the effects of 5- versus 18-22 days' space flights.

By computer tomography, mineral density of lumbar vertebrae and their segments as well as back muscle (++ilio-costal, extensor and ++inter-spinal) density and mass were measured in four Salyut-7 crewmembers before and after extended flights (of 5 and 7 months in duration). These findings are in good agreement with the results of prolonged bed rest studies in which trabecular bone of vertebral bodies was investigated: mineral density diminished only in some (approximately 10%) of the test subjects. At the same time mineral density loss was seen in the vertebral elements where muscles were attached. Also, muscle mass was reduced. It is emphasized that the level of changes was not correlated with flight time. Further investigations in this area are discussed.