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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.

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 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.

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.

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.

To determine the effects of the relative inactivity and unloading on the strength of the tibias of monkeys, Macaca mulatta, we used a non-invasive test to measure bending stiffness, or EI (Nm2), a mechanical property. The technique was validated by comparisons of in vivo measurements with standard measures of EI in the same bones post-mortem (r2 = 0.95, P < 0.0001). Inter-test precision was 4.28+/-1.4%. Normative data in 24 monkeys, 3.0+/-0.7 years and 3.6+/-0.6 kg, revealed EI to be 16% higher in the right than left tibia (4.4+/-1.6 vs. 3.7+/-1.6 Nm2, P < 0.05). Five monkeys, restrained in chairs for 14 days, showed decreases in EI. There were no changes in EI in two chaired monkeys that lost weight during a 2-week space flight. The factors that account for both the decreases in bone mechanical properties after chair restraint at 1 g and lack of change after microgravity remain to be identified. Metabolic factors associated with body weight changes are suggested by our results.

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.

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.

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.

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.

Using invasive and noninvasive techniques, we studied bone changes in primates flown for 13 days on Cosmos-1887 and compared them with the data obtained from vivarium control animals and from the flown primates that were after flight exposed to a ground-based synchronous experiment in the biosatellite mockup. It was found that bone density in the diaphysis of the tibia decreased while its growth rate remained unchanged or diminished. Contact X-raying indicated a higher rate of endosteal resorption in the flown primates when compared with the controls. Histomorphometric measurements of iliac bioptates displayed signs of inhibited bone formation after flight. The above observations are discussed and compared with the results obtained in previous biosatellite flights and ground-based studies.

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

Seven male rats were exposed to 7 days of weightlessness in the Soviet mission COSMOS 1667 and compared with seven control rats by bone histomorphometric methods. In proximal tibial metaphysis, the trabecular bone volume was markedly reduced in flight animals. Trabeculae were decreased in number and thickness; this probably leads to alteration of bone mechanical properties. Formation activity (reflected by measurements of osteoid seams) was decreased at trabecular and endosteal levels. Resorption activity (estimated by count of osteoclast number and active resorption surfaces using a histoenzymologic method) remained unchanged. The imbalance between these cellular activities appears to be responsible for the loss of trabecular bone mass. In proximal femoral metaphysis, measurements were performed in an area located under the muscular insertions. The trabecular bone volume, despite a slight decrease in flight rats, was not significantly different from that of control rats. Furthermore, osteoclastic and osteoid parameters were unchanged. Differential responses between these two long bones need additional investigations. In thoracic and lumbar vertebrae no detectable change in bone mass and bone resorption parameters was found.

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