[MINERAL BONE DENSITY AND BODY COMPOSITION IN PARTICIPANTS IN EXPERIMENT MARS-500].

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.

[Changes in bone structure according to the results of investigations on biosatellites of the "BION" series].

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.

[Mechanisms of human osteopenia and some peculiarities of bone metabolism in weightlessness conditions].

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.

[Characteristics of local human skeleton reactions to microgravity and drug treatment of osteoporosis in clinic].

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.

[Interrelation of dynamics of blood lipids and bone mineral density in humans during 370-day bed rest].

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.

[Analysis of polymorphism of bone metabolism genes and evaluation of the risk of osteopenia in cosmonauts].

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).

[Comparative analysis of cosmonauts skeleton changes after space flights on orbital station Mir and international space station and possibilities of prognosis for interplanetary missions].

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.

[Human bone system in microgravity: review of research data, hypotheses and predictability of musculoskeletal system state in extended (exploration) missions].

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.

Recovery of spaceflight-induced bone loss: bone mineral density after long-duration missions as fitted with an exponential function.

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.

[On possible mechanisms of osteopenia in humans in microgravity and situations imitating its effects].

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.

[Characteristics and patterns of the human bone reactions to microgravity].

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.

[Functional plasticity of mammalian skeletal muscles under microgravity].

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.

[Reactions of the human bone system in space flight: phenomenology].

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.

Bone status and fracture prevalence in Russian adults with childhood-onset growth hormone deficiency.

The consequences of lifelong untreated childhood-onset GH deficiency (COGHD) on adult bone and especially fracture prevalence are largely unknown due to the lack of data on long-term outcome of untreated patients. Therefore, we studied adult Russian patients (n = 66; 28 females and 38 males) with idiopathic GH-untreated COGHD. Patients had isolated GH deficiency (IGHD; n = 18, age 23 +/- 10 yr) or multiple pituitary hormone deficiency (MPHD) with open (OMPHD; n = 27, age 23 +/- 5 yr) or closed growth plates (CMPHD; n = 21, age 55 +/- 12 yr). Bone mineral content (BMC) and bone mineral density (BMD) values were compared with 821 normal Russian controls. Fracture prevalence was ascertained from medical history and compared with similar data from 333 normal controls. Height sd score was -4.6 (range, -1.8 to -8.1). This represents 82% of the height of normal Russian adults. BMC of the lumbar spine, femoral neck, and total body of patients with IGHD was 54, 71, and 59%, respectively, of that of age- and sex-matched controls (all P < 0 0.001). A similarly decreased BMC (42-69% of expected values) was found for all bone regions of patients with both OMPHD and CMPHD. Mean areal BMD measurements (g/cm(2)) varied (Z scores between -1.8 and -3.0), but the calculated true bone density (g/cm(3)) was normal in patients with IGHD or CMPHD and only slightly decreased (Z score, -0.8) in patients with OMPHD. Lifetime low-energy fracture prevalence was normal in patients with IGHD but substantially exceeded the expected prevalence in OMPHD (odds ratio of fracture = 3.0; 0.6 fractures per patient; P < 0.0001) or CMPHD patients (odds ratio for fracture = 7.4; 2.2 fractures per patient; P < 0.0001). In conclusion, IGHD and MPHD of childhood onset very substantially impair adult height and BMC. Although areal BMD is frankly decreased, volumetric bone density is unaffected, but nevertheless, the fracture prevalence in patients with MPHD is markedly increased. These observations demonstrate that not only volumetric density but also bone mass and shape are major determinants of bone strength.

Modern analysis of bone loss mechanisms in microgravity.

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.

Interactions of cells in zones of bone resorption under microgravity and hypokinesia.

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.

Bone demineralization mechanisms at level of free radicals and nanoscale subsystems of bone tissue.

Influence of simulated microgravity on characteristics of rat bones was investigated by electron paramagnetic resonance (EPR). For simulation of microgravity condition the hanging of animal by tail was used. The main measurements were performed for diaphysis of femoral bones. The quantity of native radicals Rn, localized in an organic matrix, and carbonate radicals CO2-, localized on a surface of bioapatite nanocrystals, were determined. The decrease of CO2- radical quantity in bones of experimental animals have shown, that due to simulation of microgravity the decrease of "collagen-nanocrystals" interaction takes place. It is shown that the EPR method open possibilities to receive the unique information about bone demineralization processes at level of free radicals and nanoscale subsystems of bone tissue.

[Study of skeleton gravitation physiology and problem of osteoporosis]. / Issledovaniia po gravitatsionnoi fiziologii skeleta i problema osteoporoza.

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.