[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.

[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.

[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).

[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.

[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.

[Prevention of osteoporosis in rats by administration of xydiphone before and during hypokinesia]. / Profilaktika osteoporoza ksidifonom, vvodimym krysam do i vo vremia gipokinezii.

During 7 days prior to hypokinesia male Wistar rats were given 10 mg/kg xydiphone to ensure and additional bone pool. Then the rats were exposed to 32-day hypokinesia during which they were injected with 1 or 5 mg/kg xydiphone. Drug administration before hypokinesia prevented spongy bone losses in long bones, torso and pelvic bones. Xydiphone injections before and during hypokinesia not only prevented osteoporosis but also led to bone mass increase above the normal level. It is assumed that xydiphone stimulates the involvement of cells-precursors in the new bone formation. This method of osteoporosis prophylaxis can be recommended for space medicine application.

[Osteotropic effect of ksidifon administered subcutaneously to rats during immobilization]. / Osteotropnyi éffekt ksidifona pri podkozhnom vvedenii krysam vo vremia immobilizatsii.

The role of ksidifon in the prevention of immobilization-induced osteoporosis was investigated. Osteoporosis was produced by placing animals (Wistar male rats weighing 200-230 g) into small-size cages for 60 days. Every day the rats were injected subcutaneously with ksidifon (hydroxyethylidene bisphosphonic acid) at a dose of 1 or 5 mg/kg. It was found histomorphometrically that ksidifon in these doses inhibited losses of cancellous bone from tubular bones, trunk and pelvic bones. The ksidifon effect was closely correlated with the initial metabolic state of bones. The drug changed the balance of bone cells. The population of osteoblasts decreased greatly whereas that of osteoclasts either remained unchanged or increased slightly. It is concluded that ksidifon is an agent that can be used to prevent osteoporosis, provided that the physiological state of bone and the organism as a whole is taken into consideration.

[Changes in the physical condition, vestibular function and bone system in rats exposed to long-term rotation]. / Izmeneniia fizicheskogo sostoianiia, vestibuliarnoi funktsii i kostnoi sistemy u krys pri dlitel'nykh vrashcheniiakh.

The unrestrained rats were rotated for 21 and 30 days at 1.1 and 2.0 G. The exposure did not deteriorate their equilibrium function or physical condition, i. e. static and dynamic endurance. However, the exposure decreased the reactivity and sensitivity of the semicircular canals. Bone parameters-longitudinal and transverse bone growth, metaepiphysis morphometry-indicated that the rats developed an acute stress-reaction accompanied by an inhibited growth of limb bones during the first 7 days of rotation. By experimental day 30 the animals became adapted to the new environment.

[Effect of 24,25-dihydroxyvitamin D3 on precursor cells of osteogenesis in immobilized rats]. / Vliianie 24,25-dioksivitamina D3 na kletki-predshestvenniki osteogeneza krys v usloviiakh immobilizatsii.

The experiments were carried out on Wistar SPF rats that were immobilized for 35 days. By heterotopic marrow cell transplantation under the kidney capsule to the normal rats and by cloning these cells in vitro it was found that osteogenetic potentials were significantly inhibited and the amount of osteogenetic precursor cells was reduced. The addition of 24,25(OH)2D3 vitamin (at a dose of 1.25 micrograms per day) to the animal diet led to the normalization of the above parameters. It is assumed that immobilization-associated osteoporosis develops via, among other mechanisms, inhibition of histogenesis of stromal precursor cells. The beneficial role of vitamin D3 is actually the activation of histogenesis of these cells which results in the recovery of bone remodelling during immobilization.

[Comparison of the bone tissue reaction of rats to clinostatic and head-down tilt hypokinesia]. / Sopostavlenie reaktsii kostnoi tkani u krys pri klino- i antiortostaticheskoi gipokinezii.

Examination of spongy bones of rats exposed to clino- and antiorthostatic hypokinesia showed that changes in bone mass, bone cells and their precursors were similar in both cases. The bone resorption-bone formation process remained balanced. However, bone responses clino- and antiorthostatic hypokinesia exhibited certain differences. Clinostatic hypokinesia produced greater osteoporosis in the femoral bone, whereas bone losses in the humerus, sternum and pelvis were identical. Antiorthostatic hypokinesia led to osteoporosis that was identical in every bone examined. In addition, clino- and antiorthostatic hypokinesia caused different reactions of stromal precursor cells, the latter model producing a greater effect on them. It is concluded that immobilization-induced skeletal disorders are associated with a decreased rate of bone histogenesis which proceeds at a lower level rather than with the stress-reaction.

[Effect of diphosphonates on bone tissue of the rat during hypokinesia]. / Deistvie difosfonatov na kostnuiu tkan' krys pri gipokinezii.

The diphosphonate effect on bones was studied in Wistar male rats weighing about 200 g. The rats were kept for 60 days in small-size cages where their motor activity was diminished. Every day the rats were given per os 0.3% solution of 1-hydroxy-ethylene-1,1-diphosphonate (HEDP) containing 9 mg/kg phosphorus. In the course of hypokinetic exposure the rats developed generalized osteoporosis. Histomorphometric measurements demonstrated that the drug did not prevent mineral losses from the tubular bones (humerus, femur). However, the drug led to a complete bone mass recovery in the pelvic and a partial recovery in the sternum. The drug also produced a preventive effect on the population of cells-precursors of osteogenesis the number of which decreases significantly during hypokinesia.

[Reactions of the adrenal cortex to immobilization stress in intact animals and against a background of hypokinesia]. / Ob osobennostiakh reaktsii kory nadpochechnikov na immobilizatsionnyi stress u intaktnykh zhivotnykh i na fone gipokinezii.

Morphological investigation of the rat adrenal cortex and corticosterone contents in the blood plasma demonstrated certain peculiarities in the adrenal reaction to the primary and repeated immobilization stress in intact animals and after hypokinesia. It has been stated that morphological manifestation to an acute stress reaction kinesia is less pronounced than at an analogous single effect. Investigation on corticosterone content in blood plasma revealed certain functional peculiarities in the adrenal cortex reactions in different variants of the experiments. Five hours after the beginning of the stress, corticosterone content was increased only at the initial immobilization, while at repeated stimulations during the same time it did not differ from the control. Changes in functional possibilities of the adrenal cortex in response to a repeated stimulation and in response to a new stimulation in animals previously adapted to another type of stress are discussed.

[Effect of 1,25-dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 on growth and remodeling of rat bones during hypokinesia (histomorphometric study)]. / Vliianie 1,25-dioksivitamina D3 i 24,25-dioksivitamina D3 na rost i remodelirovanie kostei krys pri gipokinezii (gistomorfologicheskoe issledovanie).

The tubular bones of the fore- and hindlimbs of rats immobilized for 5 weeks were examined morphometrically and histologically. The rats were regularly given per os 1,25(OH)2D3, 24,25(OH)2D3 or their combination. The uptake of 24,25(OH)2D3 at a dose of 1.25 micrograms or a combination of 1,25(OH)2D3 and 24,25(OH)2D3 at a dose of 0.03 + 0.25 micrograms led to the recovery of the linear and volume-weight rates of bone formation that changed during hypokinesia. However, these D3 metabolites did not restore the width of the epiphyseal growth plate, whereas the size of the primary and secondary spongiosa returned to normal or exceeded it in response to 24,25(OH)2D3 at a dose of 1.25 micrograms and 1,25(OH)2D3 at a dose of 0.15 micrograms, respectively (only these two doses were used); in other words, the D3 metabolites prevented osteoporosis which is typical of hypokinesia. It is assumed that hypokinesia may produce either disorders in D3 metabolism or changes in the sensitivity of bone cells to active D3 metabolites and other hormones that are directly or indirectly involved in osteogenesis regulation.

[Adrenal reactions of monkeys to antiorthostatic hypokinesia]. / Osobennosti reaktsii nadpochechnikov obez'ian v usloviiakh antiortostaticheskoi gipokinezii.

The following experiments were performed to study the morphology of the adrenals of male rhesus monkeys: six monkeys were exposed to clinostatic hypokinesia for 7 days and then to head-down tilt at -6 degrees for 12 days; two monkeys were exposed only to head-down tilt for 7 days and 5 monkeys were used as controls. The adrenals exhibited changes of three types: stress-reaction manifestations, activation of the glomerular area of the cortex, and synchronization of the medullary matter to noradrenaline production. All these changes reflect adaptive reactions of the animal body to head-down tilt.

[Reaction of osseous tissue and the osteoclast population in rats to biphosphonates and vitamin D3 under conditions of hypokinesia]. / Reaktsiia kostnoi tkani i populiatsii osteoklastov krys na bisfosfonaty i vitamin D3 v usloviiakh gipokinezii.

Oral administration of hydroxy-dimethyl aminopropylene biphosphonate (DMAP) at a dose of 0.5 mg/kg increased the volume density (mass) of trabecular bone in the tibial metaphysis of untreated rats and helped to maintain it at the normal level in hypokinetic rats. Oral administration of hydroxy-ethylidene biphosphonate (OEDP) at a dose of 20 mg/kg and vitamin 24,25(OH)2D3 at a dose of 1,25 micrograms did not induce any quantitative changes in bones of untreated or immobilized rats. The combined treatment with either biphosphonate and vitamin D3 exerted a similar effect as compared to that of biphosphonates used singly. During hypokinesia the total amount of osteoclasts declined. This effect was also seen in response to biphosphonates and vitamin D3. The two biphosphonates produced an opposite effect on the osteoclast population in untreated animals: it increased in response to OEDP and decreased in response to DMAP. In contrast to OEDP, low doses of DMAP can efficiently inhibit bone resorption upon various routes of its administration and can be viewed as a preventive and therapeutic drug in the case of osteoporosis.