The human skeletal system in weightlessness: A review of research data,hypotheses, and the possibility of predicting the state in long-term (Interplanetary) missions

The long-term research of human skeletal system during spaceflight on the orbital station Mir and International Space Station (ISS) was summarized. The amount of bone mass and body composition was measured using a noninvasive method, dual-energy X-ray absorbtiometry (DXA) or osteodensitometry. Theoretically expected loss of bone mass in tubular structures of the lower part of the body during space flight with a duration of five to seven months is described by the phenomenon of fast-developing but reversible osteopenia and is considered a manifestation of functional adaptation of bone tissue to the changing mechanical load on the skeleton. A high individual variability of changes and stability of individual nature of the ratio of bone mass changes in different segments of the skeleton independently of the type of orbital station has been demonstrated. A strict dependence of bone mass changes on the flight duration cannot be established, and there are no grounds for calculating the probability of reaching the critical level of demineralization for the duration of flight increased to 1.5–2 years. There is even less probability to predict changes in bone structure (quality), which, together with the loss of bone mass, determine the risk of fracture. The data indicating that the DXA method is insufficient for such prognosis are presented. The main areas of research that would optimize the development of the project of interplanetary mission in terms of preservation of the mechanical function of the skeleton are considered.     

Plasma Copper and Bone Mineral Density in Osteopenia: An Indicator of Bone Mineral Density in Osteopenic Females

Copper concentrations in blood plasma have been determined in 25 osteopenic females using inductively coupled plasma–mass spectrometry. A high degree of correlations has been demonstrated between the copper concentrations in plasma and the bone mineral density of the lumbar spine as measured using dual energy X-ray absorptiometry and quantitative computerized tomography. Results clearly indicate the involvement of copper in bone health and osteopenia. It is further suggested that plasma copper might be useful as a cheap and simple method indicative of bone mineral density in osteopenic postmenopausal females.     

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.     

Physiological Factors Responsible for the Development of Osteopenia under Conditions of Mechanical Unloading

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 volume regulation, ion regulation, and the endocrine regulation of calcium homeostasis are the main mechanisms of osteopenia.     

Comparative analysis of changes in the skeleton of cosmonauts in long-term orbital flights and the possibilities of prediction for interplanetary missions

The results of long-term investigations of the bone system of humans during space flights (SFs) on board the Mir orbital station (OS) and international space station (ISS) using osteodensitometry are summarized. Comparative analysis of the results showed the absence of significant differences in changes in the bone mass (BM) in the crew members of both OSs. Theoretically, the expected bone mass losses in the trabecular bone structures of the lower part of the body in the process of a SF (five to seven months) are interpreted in some cases as quickly developing, but reversible, osteopenia and generally interpreted as the evidence of bone functional adaptation to altering mechanical loads on the skeleton. The high individual variability of changes and the stability of the individual character of the BM alteration ratio in different skeletal segments irrespective of the OS type are shown. Owing to the aforementioned individual features, it is not possible to establish a strict relationship between BM changes and the duration of space missions, and, therefore, there is no good reason for calculating the probability of achieving the critical demineralization level when the duration of an SF increases to 1.5–2 years. The probability of prediction of changes in the bone quality (structure) is still less, which, together with BM losses, determines the risk of fractures, and osteodensitometry for such an analysis is insufficient. The main directions of the studies, which could optimize the development of the interplanetary expedition project from the point of view of maintenance of the mechanical function of the skeleton, are considered.     

Mineral distribution in rat skeletons after exposure to a microgravity model

Exposure to space flight models induces changes in the distribution of bone mineral in the human skeleton that has the features of a gravitational gradient. Regional bone mineral measurements with dual energy x-ray absorptiometry (DEXA) in male adults exposed to head-down tilt bed rest for 30 days show non-significant decrements in the pelvis and legs with 10% increases in the head region. Horizontal bed rest for 17 weeks reveals losses of bone mineral ranging from 2.2 to 10.4% from the lumbar spine to the calcaneus and an increase of 3.4% in the skull. Investigation of this phenomena would be most definitively carried out in an animal model. One candidate is the flight simulation model in the rat which removes body weight from the hind limbs and induces a cephalad fluid shift by suspending the animal by the tail. Weanling rats exposed to this model showed bone mineral to be lower in the hind limbs and higher in the skull after 3 weeks. These findings are similar in older 200 g animals after 2 weeks tail suspension. The purpose of this study was to determine the effect of age on the distribution of skeletal mineral in this model.     

Skeletal responses to space flight and the bed rest analog: a review

The potential for loss of bone mineral mass due to space flight was recognized by space scientists even before man's first venture into micro-gravity. Early life science studies in both the U.S. and Russian space programs attempted to measure the effects of reduced gravity on skeletal homeostasis, and these measurements have become more sophisticated with time. Bone-related measurements have typically included: bone mineral density measured by X-ray absorptiometry and more recently CT scanning; bonerelated hormones and other biochemical markers of bone turnover; and calcium excretion and balance. These measurements, conducted over the last 4 decades, have shed light on the nature of disuse bone loss and have provided preliminary information regarding bone recovery. Ground-based analog (bed rest) studies have provided information complementary to the space flight data and have allowed the testing of various countermeasures to bone loss. In spite of the wealth of knowledge obtained thus far, many questions remain regarding bone loss, bone recovery, and the factors affecting these skeletal processes. This paper will summarize the skeletal data obtained to date by the U.S. and Russian space programs and in ground-based disuse studies. In addition, related body composition data will be briefly discussed, as will possible countermeasures to space flight-induced bone loss.     

Decrease of bone mineral density and muscle and/or strength in the leg during 20 days horizontal bed rest

Ten individuals underwent 20 days of horizontal bed rest for this study of the influence of muscle mass and strength on bone mineral density. Muscle mass volume and cross sectional area were measured using magnetic resonance imaging and bone mineral density was determined by dual energy X-ray absorptiometry before and after bed rest. Measurements were made at various parts of the leg, including the knee. Gender differences were also determined. Results are presented and discussed.     

Cytogenetic characteristic of osteogenic cells in vitro as perspective predictors of osteopenia under microgravity

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.     

Study of skeleton gravitation physiology and problem of osteoporosis

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.     

The role of strain in the response of rapidly growing young male rat bones to parathyroid hormone

Human parathyroid hormone (hPTH 1-34) stimulates an anabolic response in human and animal skeletons; however, it is unclear if the effect is strain dependent. To determine if the anabolic response to hPTH (1-34) was dependent upon strain in rats we used 2 outbred strains (Sprague Dawley, Wistar), 2 inbred strains (Fischer 344, Wistar spontaneously hypertensive:SHR), and 2 mutant strains (Zucker obese, Zucker lean) of rats. Male rats, 5 weeks of age, from each strain were treated subcutaneously with 80 microg/kg body weight hPTH (1-34) or vehicle for 12 days. The response to PTH was similar in all strains whereby PTH exerted an anabolic effect on femoral bone mass and cancellous bone histology that was independent of strain differences. Histomorphometric indices of bone volume, mineralized surface and bone formation in lumbar vertebrae increased in all PTH-treated rats. Additionally, femur bone mineral content and bone mineral density measured by dual energy X-ray absorptiometry (DEXA), and ash weight increased in all PTH-treated rats. These increases occurred regardless of strain. In summary, PTH exerted comparable anabolic effects on bone mass, bone mineral density and bone formation in all rat models tested demonstrating that the skeletal responsiveness to PTH was not dependent upon strain.     

Non-invasive assessment of failure torque in rat bones with simulated lytic lesions using computed tomography based structural rigidity analysis

This study applies CT-based structural rigidity analysis (CTRA) to assess failure torque of rat femurs with simulated lytic defects at different locations (proximal and distal femur) and diameters (25% and 50% of the cross-section at the site), and compared the results to those obtained from mechanical testing. Moreover, it aims to compare the correlation coefficients between CTRA-based failure torque and DXA-based aBMD versus actual failure torque. Twenty rats were randomly assigned to four equal groups of different simulated lesions based on size and location. Femurs from each animal underwent micro-computed tomography to assess three-dimensional micro-structural data, torsional rigidity using structural rigidity analysis and dual energy X-ray absorptiometry to assess bone mineral density. Following imaging, all specimens were subjected to torsion. Failure torque predicted from CT-derived structural rigidity measurements was better correlated with mechanically derived failure torque [R(2)=0.85] than was aBMD from DXA [R(2)=0.32]. In summary, the results of this study suggest that computed tomography based structural rigidity analysis can be used to accurately and quantitatively measure the mechanical failure torque of bones with osteolytic lesions in an experimental rat model. Structural rigidity analysis can provide more accurate predictions on maximal torque to mechanical failure than dual energy X-ray absorptiometry based on bone mineral density.     

Changes in bone mineral density and microarchitecture in cosmonauts after a six-month space flight

The effect of microgravity on the bone tissue of cosmonauts has been studied after a six-month space flight. The volumetric bone mineral density (VBMD) and the bone structural characteristics of distal segments in the radius and tibia have been studied by means of peripheral quantitative computed tomography (pQCT). The changes in VBMD were found to correlate with the position of the bone relative to the vector of gravity. In the radius, reversible hypermineralization, together with thickening of the compact bone were recorded. In the tibia, reversible osteopenia was characterized by significant losses in both compact and trabecular bones. Irrespective of the position relative to the vector of gravity, there was a trend towards microarchitectural deterioration, such as a decrease in the trabecula number and increase in the bone tissue heterogeneity. Postflight dynamics of structural parameters showed an integrative character with nonlinear time dependence.     

Mechanisms of gravity-dependent changes in the bone tissue

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".     

Relationships between bone mass and micro-architecture at the mandible and iliac bone in edentulous subjects: a dual X-ray absorptiometry, computerised tomography and microcomputed tomography study

doi: 10.1111/j.1741‐2358.2011.00527.x Relationships between bone mass and micro‐architecture at the mandible and iliac bone in edentulous subjects: a dual X‐ray absorptiometry, computerised tomography and microcomputed tomography study Objectives: To compare bone volume, bone mineral density, cortical thickness and bone micro‐architecture in a series of paired mandibular and iliac bone samples analysed by various imagery techniques to see whether relationships exist between the various techniques and between mandibular and iliac bone. Materials and methods: Bone samples from the mandible and ilium were harvested in 20 cadavers and analysed by dual energy X‐ray absorptiometry (DXA), computerised tomography (CT) on a conventional hospital machine and microCT. Results: Significant correlations were found between Hounsfield density obtained by CT, and bone mass determined by microCT but not with DXA values. Cortical thickness measurements were well correlated between CT and microCT. No relationships were found between mandibular and iliac bone, when considering mineral density, cortical thickness, bone volume or micro‐architecture. Conclusion: In clinical practice, CT remains the most appropriate routine means for bone qualitative and quantitative evaluation at the mandible. In this ex vivo study, these results confirm that mandibular bone status does not reflect the axial skeletal one and assist in the placement of implants with dental prostheses in old or osteoporotic patients.     

X-ray densitometric characteristics of bone mineral density in patients with impaired biliation

Dual-energy X-ray absorptiometry was used to examine 20 patients with obstructive jaundice, who had undergone external biliary drainage in the first surgical stage. A clinical comparison group comprised 34 patients without hepatobiliary diseases. Bone mineral density was measured in the lumbar spine, proximal femur, and ultradistal antibrachium. Impaired biliation was found to result in bone loss in the early-stage of the disease, which was more marked in the spongy bone. This allows the ultradistal antibrachium to be identified as a main observation area for dual-energy X-ray absorptiometry to make an early diagnosis of mineralization disorders. The integrated T index (Tint) calculated on the basis of the X-ray densitometry of a few skeletal portions may be used to obtain generalized information on bone mineral density.     

Bone mineral density, osteopenia, and osteoporosis in the rhesus macaques of Cayo Santiago

This cross-sectional study investigates metabolic bone disease and the relationship between age and bone mineral density (BMD) in males and females of a large, well-documented skeletal population of free-ranging rhesus monkeys (Macaca mulatta), from the Caribbean Primate Research Center Museum collection from Cayo Santiago, Puerto Rico. The sample consists of 254 individuals aged 1.0-20+ years. The data consist of measurements of bone mineral content and bone mineral density, obtained from dual-energy X-ray absorptiometry (DEXA), of the last lumbar vertebra from each monkey. The pattern of BMD differs between male and female rhesus macaques. Females exhibit an initial increase in BMD with age, with peak bone density occurring around age 9.5 years, and remaining constant until 17.2 years, after which there is a steady decline in BMD. Males acquire bone mass at a faster rate, and attain a higher peak BMD at an earlier age than do females, at around 7 years of age, and BMD remains relatively constant between ages 7-18.5 years. After age 7 there is no apparent effect of age on BMD in the males of this sample; males older than 18.5 years were excluded due to the presence of vertebral osteophytosis, which interferes with DEXA. The combined frequency of osteopenia and osteoporosis in this population is 12.4%. BMD values of monkeys with vertebral wedge fractures are generally higher than those of virtually all of the nonfractured osteopenic/osteoporotic individuals, thus supporting the view that BMD as measured by DEXA is a useful but imperfect predictor of fracture risk, and that low BMD may not always precede fractures in vertebral bones. Other factors such as bone quality (i.e., trabecular connectivity) should also be considered. The skeletal integrity of a vertebra may be compromised by the loss of key trabeculae, resulting in structural failure, but the spine may still show a BMD value within normal limits, or within the range of osteopenia.     

Bone Mineral Density and Molecular Genetic Markers of Bone Remodeling in Blood of Cosmonauts after Long-term Missions on Board the International Space Station

The results of the investigation of the bone system of 24 Russian cosmonauts after long-term (124–199 days) missions on board the International space station (ISS) are presented. Functional adaptation of the bone system involves some complex changes in the metabolic activity of osteoblasts and osteoclasts, such as alterations of the serum concentrations of osteocalcin, tartrate-resistant acid phosphatase (TRAP), osteoprotegerin, and the activator ligand of the receptor of nuclear factor kappa-B (RANKL); in addition, in peripheral blood leucocytes, there are changes in the expression of genes regulating the development of skeletal system and bone mineral metabolism. Significant variability in the mineral density of femoral neck and molecular genetic markers studied after long-term space flights indicates individual variability of the balance of the processes of bone remodeling, bone formation and resorption. Significant bone mass losses in the femoral bone of cosmonauts are associated with more pronounced changes in the markers of metabolic activity of osteoclasts.     

Bone loss: Quantitative imaging techniques for assessing bone mass in rheumatoid arthritis

Osteoporosis is associated with low bone mass and microarchitectural deterioration of bone tissue with clinical manifestation of low trauma fractures. Rheumatoid arthritis (RA) is a risk factor due to generalized and articular bone loss. This minireview presents past and current bone mass measurement techniques in RA. These techniques include: plain radiographs, absorptiometry, quantitative computed tomography (QCT) and ultrasound. The most widely used technique is dual x-ray absorptiometry (DXA). RA patients have lower bone mass as compared with normals and substantial bone loss may occur early after the onset of disease. Measurement of bone mineral density (BMD) at the hand using either DXA or ultrasound maybe a useful tool in the management of RA patients.     

Bone loss. Quantitative imaging techniques for assessing bone mass in rheumatoid arthritis

Osteoporosis is associated with low bone mass and microarchitectural deterioration of bone tissue with clinical manifestation of low trauma fractures. Rheumatoid arthritis (RA) is a risk factor due to generalized and articular bone loss. This minireview presents past and current bone mass measurement techniques in RA. These techniques include: plain radiographs, absorptiometry, quantitative computed tomography (QCT) and ultrasound. The most widely used technique is dual x-ray absorptiometry (DXA). RA patients have lower bone mass as compared with normals and substantial bone loss may occur early after the onset of disease. Measurement of bone mineral density (BMD) at the hand using either DXA or ultrasound maybe a useful tool in the management of RA patients.