To What Extent does Research in Space Benefit Health of the Musculoskeletal System on Earth?

Introduction:

The value of space travel compared to the vast sums of money invested is often put under scrutiny. Original missions were backed by the idea of fulfilling human curiosity, however more recently the focus has shifted to how space exploration is able to benefit humanity as a whole. These benefits include a better understanding of: Earth’s current environment, the future of our plant, and benefits to health. As one of the key justifications of modern space travel it is one of NASAs principle areas of research and consequently it is expected that steps are being made toward improving health on Earth.

On Earth we experience 1-G of gravity; every part of our bodies is adapted to this. The International Space Station orbits around 250 miles above Earth. Here gravity is approximately 90% of that on Earth, however astronauts on the space station will not experience this strength of gravity as they are freefalling towards Earth; this results in that actual force of gravity experienced being closer to 0.001% of that on Earth (NASA 2001). This significant reduction in the strength of gravity is called microgravity. Since the first space flight this has presented multiple challenges to astronauts as, unlike the reduced air pressure and differing air composition which can be accurately controlled, scientists have not found any way of creating artificial gravity. However it also provides a unique environment in which the human body can be studied.

As technology has progressed humans have been able to spend increasing periods of time in space. Initial studies were carried out purely to ensure the safety of the astronauts on the mission. But projects such as Skylab and medical laboratories on the International Space Station have resulted in research with potential benefits to health on Earth.

Musculoskeletal impact:

Bone loss:

Bone is a dynamic tissue that is metabolically active, constantly broken down and rebuilt. It is able to repair itself and change shape and structure in response to external forces. The near absence of gravity during space flight disrupts the natural equilibrium experienced on Earth, resulting in the rate of break down being greater than the rate that new cells rebuild the bone. The bones can lose around 4g of calcium per month of exposure (Vasques. T. E and Pretorius. H, 1987, p.293). This can result in bone loss of 1-2%. Marked loss of bone is seen in the weight bearing bones: the legs, pelvis and lumbar vertebrae (Clément. G and Ment. C, 2011, p.182). These bones are designed to bear the majority of the body’s weight when upright and thus are most affected by gravity as they work against it. This is of particular concern to astronauts as it increases the fragility of the bone, greatly increasing the risk of bone fractures during extravehicular activities and on return to the 1-G environment of Earth, where they will often initially need assistance in walking. Bones also act as mineral reserves, 85% of phosphorous and 99% of calcium is stored in the bones (Moe. S, 2008, p.215) and their large surface area also provides a surface for mineral exchange.

Osteoclasts, derived from monocytes, circulate in the blood after their formation in the bone marrow. Whilst in the blood these monocytes differentiate into osteoclast precursors and remain this way until indirectly activated by parathyroid hormone (PTH). PTH causes osteoblasts to secrete cytokines and RANK Ligand (RANKL), which interacts with the cell surface receptor RANK- activating it and causing it to further differentiate to form multinucleated osteoclasts with a ruffled boarder that inserts into the bone matrix (Boyce. B, Yao. Z and Xing. L, 2009). They are attracted to sites on the surface of the bone destined for remodelling called Howship lacunae to which they tightly adhere. Once adhered, they secrete a large volume of acid, dissolving the mineral matrix, and enzymes through the ruffled boarder causing the hydrolysis of collagen and other organic molecules as well as dissolution of bone minerals particularly calcium (in decalcification) and phosphorus releasing them into the blood stream (Wheeless’ Textbook of Orthopaedics Online, 2012). This is the process of bone resorption and its overall effect is to reduce the mass of bone and increase the volume of certain minerals in the blood particularly calcium and phosphorus. There are various methods by which the levels of osteocytes may be reduced. One such way is via the inhibitor osteoprotegerin (OPG) which bonds with RANKL preventing it bonding to RANK and thus activating the osteoclasts precursor cells differentiation process.

Osteoblasts are the cells involved in the remodelling of bone; they produce osteoid, a mixture of bone collagen and other proteins, to replace the bone removed by the osteocytes. They are derived from the mesenchymal stem cells and are activated by PTH and certain hormones including oestrogen. They occupy the cavity left by the osteocytes and deposit osteoid, a substance with a high percentage composition of collagen. Minerals such as calcium and phosphorus then crystallise in this matrix trapping some of the osteoblasts, where they are then called osteocytes (AMGEN, 2012).

On Earth the balance of osteoblasts and osteoclasts results in the rate of bone removal and replacement being approximately equal. However osteoblasts are sensitive to load on the bones and so are more prevalent in areas of greater strain and thus this is where more osteoid is deposited. Where stress has been removed due to microgravity the production of osteoblast adjusts accordingly. Despite this variation the levels of osteocytes remain at the same level as at 1-G. The result of this is a net loss of bone mass and a build-up of calcium in the blood as it is released from the bones’ mineral matrix, thus leading to further complications such as the kidneys struggling to remove the calcium from the resorbed bone in the blood, increasing the likelihood of kidney stones (NASA, 2001).

Impact on Earth:

A key observation of the musculoskeletal system is that exposure to microgravity mimics the process of aging but over a much shorter time scale; the same mass of bone lost during one month of space flight can be equivalent to years of bone demineralisation on Earth. A particular aspect of this is the similarity in the bone loss experienced by astronauts and that of people suffering with osteoporosis. Osteoporosis affects around 3 million people in the UK; it heightens the risk of painful fractures to the wrists, hip and vertebrae (NHS, 2013), and with an aging population is effecting more people year on year. In many ways osteoporosis experienced on Earth is similar to the loss of calcium and mass in the bones of astronauts. Slight differences are recognised in osteoporosis on Earth as all bones are affected and often the first symptom is a fracture just above the wrist (Peters. M, 2013). However in space the noticeable changes are in the legs, hips and vertebrae, with negligible changes in mass elsewhere in the body. In

addition, many of the causes of osteoporosis on Earth are as a direct result of reduced oestrogen levels after menopause, whereas in space the role of hormones is insignificant.

Technological advances have been developed to detect and monitor both bone loss and strength. One such devise is the Scanning Confocal Acoustic Navigation system (SCAN)which produces high resolution images of bones which can be used to determine both strength (from structure) and mass (NSBRI, 2009). Currently the most common technology used to measure bone mineral density is Dual Energy X-Ray Absorptiometry (DXA). This technique involves passing X-Rays of two different densities through bone measuring the radiation per pixel detected on the other side. This can then be converted to an ‘areal density’ (in g/cm) this can then be used in combination with the number of pixels to calculate the BMD (bone mineral density) (Berger. A, 2002). However this technique is not completely precise as a lower BMD has a density similar to that of soft tissue and this means that distinction between the two tissues is not always clear. In addition, although DXA is able to give suitably accurate value for BMD is does not give an indication of the structure and therefore the quality of the bone, which is considered to be just as important in assessing the risk of fracture as bone mass (Qin. L, 2007 ). It produces an image of the bones with the denser areas being whiter and less dense a grey. SCAN is able to overcome these problems as it has been designed to have a high enough precision to distinguish between soft tissue and bone and to produce a detailed image showing the precise structure of the bone. This technology was initially created as a method of measure both bone mass and structure, smaller than technology currently use in order that it can be transported to orbiting research laboratories. It has since had application both conducting further research in order to better understand to effect of mechanical unloading on osteocytes in space and early identifying and diagnosis of osteoporosis on Earth. However this technology requires further development before it can be used on the hips and knee. A further technological advancement is in measuring bones’ fracture risk using bone bending stiffness, controlled by bone density. The Mechanical Response Tissue Analyser (MRTA) was design by NASA and like SCAN also measures both bone mineral density and structure, the advantage of it being that it is radiation free instead measuring the bones response to vibratory stimuli. However this technology can only be used on the ulna and tibia, this is still significant in the detection of osteoporosis as these are two of the most affected bones.

The creation of this technology holds further importance as radiation exposure is a known cause of bone loss. Radiation can cause the death of bone marrow cells and increase the number and activity of bone absorbing osteoclasts, contributing towards radiation induced osteoporosis. This is thought to be due to the increase in the cytokines and reactive oxygen species (ROS) produced by the bone marrow after exposure to radiation, which triggers osteoclast activation (Willey. J et al, 2011). This is significant to those with reduced bone mass as it is vital that further bone loss is avoided. Although the radiation used in DXA is fairly low dose this may cause marked bone losses in already weakened bones. This is particularly true for cancer patients whom suffer radiation induced osteoporosis as an effect of radiotherapy (Indiana University, 2012) and for whom it is vital that radiation exposure is kept to a minimum. The development is also significant to studies of bone loss and the treatments against it, as for the studies it is imperative that all factors other than those being tested are minimised, in order to obtain the most accurate results.

In order to maintain a healthy bone mass whilst in space astronauts must complete exercises on specialist machinery designed to put mechanical load on the bones. Astronauts on the ISS complete exercise for approximately two hours each day (although this may increase during periods when extra stress is likely

to be put on their bones such as before a spacewalk or before they return to Earth). A key piece of equipment that is used on space stations such as the ISS is the Combined Operational Load Bearing External Resistance Treadmill (T2). T2 is specially designed using high resistance bungee cords attached to a harness which places stress on the shoulders and hips. The resistance of the bungees can be adjusted in order that the load placed of the bone can be adjusted throughout the mission working up to 100% of the astronauts Earth weight and different loads can be placed on the bones of the astronauts depending on their weight (Canadian Space Agency, 2014). The variation can also allow experiments into the effect of differing loads on bone mass and experiments can be accurately calculate the effect of the length of time of exercise and bone mass as when not using the specialist equipment minimal stress is put onto the bones. Although this research provides useful information into the precise effects of exercise the range of exercises that can be completed are limited as an artificial load must be put on the body in order for it to have an effect on bone remodelling. This load cannot be distributed evenly across the body as gravity would be.

Additionally one method originally developed for and being tested in space, with the aim to reduce bone loss, is whole body vibration therapy. This method can be used in combination with exercise routines or by itself. Its aim is to duplicate the stresses put on bones by everyday life on Earth using slight vertical vibrations of around 90Hz; the astronaut is held on the plate by elastic straps allowing them to work on other tasks whilst they build up their bone mass. Each vibration puts a force on the bone equivalent to about one third the acceleration of gravity, it also causes the muscle around the bones to contract and relax dozens of times (National Osteoporosis Society, 2015). It is this acceleration and muscle contraction that exerts a force on the bone triggering bone remodelling; so far trials have shown that this technique can slow bone reduction by 61% (NASA, 2001).For many people on Earth this would be a more practical solution than exercising as the vast majority of osteoporosis suffers are over the age of 50 (U.S. National Library of Medicine). Intense exercise could put this demographic at an increased risk of bone fractures; they may also find it difficult to carry out the level of exercise required to maintain bone mass. Vibration therapy can be completed whilst carrying out other activities over a much shorter time period (ten to twenty minutes). Vibration therapy is now a common treatment for osteoporosis and has been particularly useful for those unable to participate in physical activity.

One of the key medications that has been tested as a treatment for bone loss are bisphosphates, these inhibit bone resorption by osteoclasts and so help to maintain bone mass preventing osteoporosis, or slowing the process of bone thinning and demineralisation (Barratt. M and Pool. S,2008). Astronauts have taken part in multiple clinical trials for these drugs, which (with evidence from bedrest studies) provided evidence for the effectiveness of these drugs. As bone loss is so much faster than experienced on Earth these studies can be completed over a shorter period of time and so the drug can be used by those on Earth with an increased risk of bone fracture more quickly.

Recent studies have suggested that the medication may be less potent in space than on Earth. This has been put down to the dramatically different environment in space and the need for special packaging and slightly different formulation required to ensure that they have a sufficient life span to last the duration of the experiments and that the conditions required for this are suitable for the limited space of a space station. Medications may have to be stored in chambers in which humidity and temperature can be accurately controlled, these containers also help to reduce the effects that increased radiation exposure and vibrations can have. The original medications often have to be altered slightly to prevent premature

degradation; even with these alterations medications in space tend to degrade faster than on the ground which can causes reduced potency and discoloration. There are also some more serious concerns relating to the by-products formed in this process (Livescience, 2011). This data has led to concerns that evidence of the effects of medications tested in space may not be consistent with the effect on Earth and therefore the data cannot be used as part of clinical trials. Despite this testing of drugs in space continues to give an insight into the general effect of the drugs and whether carrying out a longer term study on Earth is worthwhile.

It is thought that in response to mechanical stress the body releases a biochemical signal that triggers the process of bone remodelling. By determining how the body translates the forces into signals it may reveal how aging processes, immobilisation and inactivity affect bone formation and remodelling and subsequent structure. This would allow for a more precise understanding of the how changes to exercise, hormones, diets and medications that are tested are affecting the bones on a molecular level, opposed to trialling multiple methods of bone mass maintenance and determining which works best through experimental evidence (NASA, 2004). There is currently an operation on the ISS exploring osteocytes and mechano-transduction called Osteo-4. Osteo-4’s mission report sets out its objectives as to ‘study gene expression in osteocytes under microgravity conditions and analysis of gene expression patterns under microgravity conditions [to provide an insight] into mechano-transduction pathways and mineral ion regulation’. It also states that the ‘results derived from these proposed studies could have significant implications for therapy of bone disorders related to disuse or immobilisation’ (NASA, 2015).It is likely that the results of this study will contribute towards a better understanding of the mechanisms behind bone loss due to mechanical unloading and in turn improve diagnosis and treatment. The progress made in space medicine is due to the almost gravity free environment in which technology and treatments can be tested. On Earth the closest means of replicating this environment is through bed rest studies which remove much of the stress placed on bones. However the bones still experience low magnitude but high frequency vibrations not present in microgravity. Both bed rest studies and research in microgravity display similar patterns, but bone demineralisation in bed rest studies take place over a much longer time period, this can be as much as tenfold (Lang. T, 2013) and so the complete process of bone demineralisation can often not be studied . The high frequency vibrations may be great enough to stimulate some bone growth; this can render research into mechanical responses void as multiple forces are acting on the bone (Clément. G and Ment. C, 2011,p 209). Also research into the effects of exercise cannot be measured using bed rest studies - as soon as the person gets up from the bed they are working against gravity. This means that studies must be carried out although studies of people who suffer osteoporosis (or other conditions for which bones lose mass) can take a very long time and as many osteoporosis suffers are elderly they may not be able to complete the study socomplete data may not be collected. This data is often less reliable as there are more uncontrolled variables, reducing their effectiveness in assessing the reliability of the methods.

Recently there has been particular interest in this area due to the creation of a potential cure of paralysis giving people the possibility of mobility provided that their bone and muscle mass is great enough to support them after years of reduced stress due to reduced load. Being able to increase bone mass and improve bone structure may also have applications for other conditions which lead to loss of bone such as cerebral palsy, rheumatoid arthritis and cystic fibrosis and in response to certain medications and treatments: it is for this reason that this research continues to be funded.

Muscle loss:

As astronauts work in a weightless environment very little muscle contraction is needed to support their bodies or move around, when this takes place over a long period of time muscles lose their strength and deteriorate through muscular atrophy. Much like the effect that microgravity has on bones, the greatest atrophy takes place on the weight baring muscles -the postural muscles; an example of skeletal muscles that make up around 40% of the body’s total weight. Skeletal muscles are composed of fibres that are around 50µm in diameter, each fibre is comprised of hundreds of myofibrils (consisting of myosin and actin allowing the muscle to contract) as well as mitochondria for adenosine triphosphate (ATP) production and internal membranes to regulate ion content. Each muscle fibre is supplied by a motor nerve which allows it to contract in response to an action potential (Clément. G and Ment. C, 2011, p.185). There are two main types of fibre. Type I or oxidative fibres which are associated with low long duration forces and Type II or glycolytic fibres which produce more powerful shorter duration forces sprinters (Clément. G and Ment. C, 2011 p.186). Even a short mission can cause an astronaut to loss 10-20% of their muscle mass, and a longer mission can lead to up to 50% atrophy (The Fundamentals of Space Medicine, 2011, p.181). These losses are not dissimilar to the loses seen in the elderly or immobile at a result of reduced physical activity.

The causes of muscular atrophy are similar to those of loss of bone mass where there is an imbalance between osteoblast and osteoclast number and activity. The body constantly uses amino acids to build the protein from which muscle is made and when in orbital gravity there is an imbalance - protein synthesis decreases whilst protein degradation increases; after four months in space protein synthesis may decrease by as much as 15% (Stationminuet, 2009).

Several methods have been devised to measure muscular atrophy these include muscle dynamometers which are traditionally used to measure hand strength. However these have been adapted to measure the torque of many joints, most relevant for its application in space medicine and the knee and hip. A further method is to measure the urinary output of nitrogen. Amino acids are the subunits from which proteins are made, as protein degradation increases more amino acids are broken down and as nitrogen is a key component of the amino acids its concentration in urine can be measured to estimate the rate at which protein degradation is taking place. One of the most useful methods of analysing muscle is by muscle biopsy. Small samples of muscle are taken which can then be studied under a microscope to analyse structure and on which tests can be carried out. This technique has shown promise in understanding cell signalling pathways associated with nerve muscle connections in microgravity (ESA, 2015).

Implications on Earth:

Several physics countermeasures are used on board the ISS in order to counteract these effects. The most studied of these is the Advanced Resistive Exercise Device (ARED) this is used to mimic free-weight exercises under gravity. This consists of piston-driven vacuum cylinders, which the astronauts must do work against in order to maintain muscle strength and volume. The load of the device can be adjusted from 0N to around 2670N equivalent to about 600lb on Earth (NASA Education, 2012). The device

allows astronauts to perform a number of exercises including dead lift, squats, heel raises, bench press, bicep curls and tricep extension. This allows a wide range of muscles to be exercised and helps to ensure that the astronauts maintain muscle strength throughout their bodies (NASA, 2015). Although beneficial to astronauts the ARED has little relevance to improving muscular atrophy on Earth as much of its role is to simulate Earth’s gravity: the same effect can be achieved on Earth using simple weights. A further issue with the use of exercise to treat muscular atrophy on Earth is that many of those of suffer from muscular atrophy are elderly and thus unable to carry out intensive physical exercise required.

A further physical countermeasure used by astronauts is the Penguin suit this was one of the first countermeasures used to prevent muscle deterioration by the Russian during the space race. It uses elastic bands and pulleys which are woven into the fabric in order to create a force against which the body can work. These suits were worn for long periods of time whilst in orbit in order to produce a constant force on the body (Encyclopaedia Astronautica Online, 2011). Although now not commonly worn by astronauts these suits have been slightly modified and found use in treatment of children with physical disabilities resulting from cerebral palsy and other neurological conditions originating from damage to the brain or spinal cord (Wikipedia, 2015). These suits known as Adeli suits use the basic design of the penguin suit with pulleys and elastic integrated into their design. Its designers claim that the suit allows the body to be held in proper physical alignment during physical exercise whilst providing a force for the body to work against helping to build up muscle without restricting movement. Research so far has showed that the suit has therapeutic effects on the movement and coordination of children with cerebral palsy along with the normal reflex pathways in the central nervous system. However as yet there is insufficient evidence for it to be generally recognised as an effective treatment (Turner. A.E, 2007).

One of the key aims of studying the muscles in space is to better understand the process of muscular atrophy. Muscle biopsies have shown suggested that the reason for the decline of protein synthesis, particularly in contractile tissues, is due to a decrease of gene expression and translation of messenger RNA into protein (Piantdosi. C.A, 2003). It is thought that hormonal and biochemical changes may contribute towards the increased muscle degradation, however further research must be completed in this area in order for a conclusion to be made.

Some argue the research can be complete on Earth via laboratory based animal studies, the most common of which are studies on rats suspended by their tails to reduce force on their hind limbs simulating weightlessness; this experiment can be taken further by immobilising the rats to minimise work done by the muscles when curving their backs to groom themselves. These models have been validated by taking rats into space to prove the similar effect on muscle volume and structure. This research has been used to produce a timeline of structural and functional changes to skeletal muscle, which have been quantified (Chowdhury. P et al, 2013). Although this provides useful information into understanding the process of muscular atrophy, and data from these studies are used as estimates for designing equipment for space, there are several aspects of these experiments that are difficult to control and different from Earth. Suspension causes rats emotional stress which in turn often results in reduced food consumption (Morey–Holten E.R and Golbus R.K, 2002). It is important that these rats eat a similar amount to the control rats as calorie intake directly affects the ability of muscles to maintain their mass. If this aspect cannot be controlled the studies are not valid and thus cannot be used to study the changes. A further reason that the model does not give a completely accurate representation of the effect of microgravity on muscle mass comes from differences between rat and human muscle structure. A particular difference is the relative

proportions and fibres type I and II and their plasticity in response to changes of environment. Also in the hind limbs of rats the hamstring muscles have the greatest volume, they are twice as massive as the quadriceps, whereas in humans this trend is reversed (Harvard.edu, 2010). This means that the data cannot be used to analyse the overall strength loss as the different muscles contribute to the torque, it is only relevant for use in muscle biopsy.

Conclusion:

Space is a unique environment and is the only place which the musculoskeletal system can be studied without gravity having any influence. As a consequence scientists have been able to evaluate the exact effects of potential countermeasures and study the mechanisms causing musculoskeletal deterioration to gain a better understanding of how they work and what goes wrong to result in the conditions seen on Earth.

So far space medicine has contributed towards important developments in the understanding and treatment of osteoporosis and muscular atrophy. SCANS is currently the most accurate means of diagnosing osteoporosis and assessing the risk of bone fracture. Vibration therapy and the penguin suit, both originally designed to combat microgravity in space, have been successful in treating conditions of the musculoskeletal system on Earth. However the lack of gravity experienced by astronauts means that the conditions under which the experiences take place are dramatically different from those on Earth. This means that not all of the evidence collected in space can be directly applied to Earth. Also as yet the conditions of space are not fully understood so it can be difficult to identify exactly which body systems microgravity effects and how these changes occur.

It must be considered that space medicine is a relatively new area. Much of the research carried out so far has been to benefit the health of astronauts in order that their health and the success of the mission is not compromised as the duration of space missions increases. This focus is now, more than ever, changing using this environment to benefit both humans on Earth and in space. The advancements made since the first space flight in 1961have brought technology to the point where there are currently astronauts on the International Space Station half way through their one year mission. This year-long project has been set up with the aim of validating countermeasures to weightlessness, isolation and radiation which have applications for both future long duration space flight and medical applications on Earth (NASA, 2015). One of the unique aspects of this mission is the twins study. Scott Kelly set off on the mission whilst his identical twin Mark Kelly has remained on Earth. As the twins have the same DNA geneticists are able to look for genetic markers and change in gene expression, which are thought to cause some of the problems experienced in space such as muscular atrophy. The twins telomeres will also be studied. Telomeres are found on the ends of strands of DNA and shorten with age; this research will show the effect of space travel on the aging process and may provide further data on what causes the telomeres to shorten (Space.com, 2015). This research could have a dramatic impact on our understanding of the aging process and help to understand and treat many degenerative conditions. Research goes beyond the musculoskeletal system. Space medicine extends over many areas including: immunology, microbiology, cardiology, ophthalmology and technology which all have the potential to contribute to improved health on Earth.

Overall the benefit of studying the musculoskeletal system in microgravity has had minimal impact to health on Earth due the relatively same amount of research that has been carried out so far and

environmental differences such as radiation exposure that make evaluating countermeasure more difficult. However the research that has been carried out so far has provided useful information which in turn has enabled longer duration space missions to be carried out. It is these longer duration missions such as the one year missions that are likely to provide medical information that will be beneficial to health on Earth. This is particularly true for understanding the mechanisms of bone loss and muscular atrophy which can be studied much more easily in the complete absence of gravity. Research such as this which leads to a better understanding is very likely to lead to improved countermeasures being developed on Earth- therefore indirectly leading to improved health on Earth.

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