1. Introduction

Musculoskeletal deterioration and its associated complications, i.e., disuse osteopenia and muscle atrophy, are significant threats for astronauts, which increase the risks of fractures during long-term space missions including staying in space station, lunar mission and during the trip to Mars. It has been over 40 years since the beginning of space exploration. Accumulated data have demonstrated that space flight, particularly in lone-term missions, has detrimental effects on bone and muscle. Results from shortterm space missions (2-12 weeks) indicated that space flight with microgravity alters calcium metabolism and bone mineral density (BMD) in several hundreds of men and women who have flown to space. As human space exploration now plan and prepare to extend the mission beyond the orbital, for example, manned missions to Mars through extended manned vehicle with 18 to 36 months of duration, one can imagine that the risks and the challenges to the musculoskeletal system will be tremendous. However, there is so little progress has been made in understanding the significance of the problem. There is almost a complete lack of on-board measurements for assessing longitudinal bone loss and muscle atrophy, as well as associated evaluations of countermeasurement outcomes. Relatively short-term flight data and ground-based human research may help to estimate the risks for the long-term space mission.

Development of new technologies will also lead to a better understanding of the barriers to long-term space exploration and to assist in the development of countermeasures to assure safe and productive missions. As defined by the National Research Council report entitled: A Strategy for Research in Space Biology and Medicine in the New Century (Osborn 1998) and the Vision for Space Exploration of the Human Research Program (HRP), there are several areas of fundamental scientific investigations that must be addressed to meet these goals. As an important recommendation, which echo those made by previous reports published by the National Research Council’s Space Studies Board (Dutton 1992; Smith 1991), the principal physiologic hurdle to man's extended presence in space is the osteopenia, musculoskeletal deterioration and fracture that parallel to reduced gravity, and by the NASA's Bioastronautics Roadmap and Human Research Program risk plans.

To review musculoskeletal changes as an effect in the short term space mission, Earthbased disuse osteoporosis results may help to predict the potential risks in the musculoskeletal system for the mission to Mars. Development of related technologies that has low mass, compact, highly reliable features will greatly impact the diagnosis and even therapeutics for bone loss and muscle atrophy during the long-duration space missions and even ground operations.

2. Microgravity Induced Bone Loss

Elucidation of microgravity-induced skeletal disorders will lead to a better understanding of barriers to long-term space exploration and assist in the development of countermeasures to assure safe and productive missions. Osteopenia is a disease characterized by the long-term loss of bone tissue, particularly in the weight-supporting skeleton (Riggs & Melton, III 1995; Riggs et al. 2006; Riggs 2009). On average, the magnitude and rate of the loss is staggering; astronauts lose bone mineral in the lower appendicular skeleton at a rate approaching 1.5%-2% per month (Lang 2006; LeBlanc et al. 2000b; LeBlanc et al. 2007). While osteopenia can affect the whole body, complications often occur predominantly at specific sites of the skeleton with great load bearing demands. The greatest BMD loss has been observed in the skeleton of the lower body, i.e., the pelvic bones (-11.99+1.22%) and the femoral neck (-8.17+1.24%), while there was no apparent decay found in the skull region (LeBlanc et al. 1996; LeBlanc et al. 2000b; LeBlanc et al. 2007) (see Figure 1).

Moreover, it is apparent that full recovery of bone mass may never occur (Goode 1999; Shackleford et al. 1999; LeBlanc et al. 2000b), potentiating skeletal complications in the astronaut's later life. Similar results were found in the bed rest studies (LeBlanc et al. 2000b; LeBlanc et al. 2007). In a -6 degrees head-down tilt of 7-day bed rest model for microgravity, it was observed that there was a decreased bone formation rate in the iliac crest. Thus, assuming in a 2.5~3-year return-trip to Mars, approximately half of an astronaut’s bone density may vanish, severely jeopardizing their health and well-being. The progressive adaptation of the human biological system for short and long-term space flight still remain largely unknown, i.e., current exercise countermeasure protocols can not sufficiently prevent bone loss (Grigoriev et al. 1998). One of the reasons is that it is extremely difficult in monitoring continuous adaptive decay of bone loss during a space flight. In order to understand these effects, we need a better description of human adaptation in space, and then with this information to create prevention and countermeasure strategies through new analysis and technology.

3. Osteoporosis on Earth

Osteopenia and osteoporosis are reductions in bone mass or density that lead to deteriorated and fragile bones. Osteoporosis diminishes both the structure and strength of bone, each considered to be critical in defining the ability of the bone to resist fracture. It is the leading cause of bone fractures in postmenopausal women and in the elderly population for both men and women. About 13 to 18 percent of women aged 50 years and older and 3 to 6 percent of men aged 50 years and older have osteoporosis in the US alone (Melton, III et al. 2010; National Osteoporosis Foundation 2010).

Approximately 24 million people suffer from osteoporosis in the United States with an estimated direct annual cost of over $18 billion to national health programs. Aging is one of the primary factors to induce osteoporotic bone loss in both women and men (Riggs et al. 2000; Riggs et al. 2002), as well as disuse osteopenia (Bloomfield 2010). Using areal BMD assessed by dual energy x-ray absorptiometry (DXA), longitudinal studies with multiple populations over a 25-year period have revealed that loss of BMD is sensitive to aging in both women and men (see Figure 2). Both women and men lose BMD starting at around age 40, with women losing BMD more rapidly than men starting in their early 50s (Clarke & Khosla 2010). From age 50, women lose trabecular BMD rapidly in their vertebrae, pelvis, and ultradistal wrist, while men do not show an accelerated BMD during this time period. About 10 years after 50, women lose approximately 1.3%/year of BMD in cortical bone and 3.4%/year in trabecular bone. During the same period, men lose about 1.0%/year and 1.2%/year of BMD in cortical and trabecular bones, respectively (Figure 2). The rate of age-related bone loss is slower in the following decades after the 60s in both women and men. For example, from 60-70, women and men lose approximately 0.7%/year and 1.0%/per year in cortical and trabecular BMD, respectively. In an averaged age-related BMD trend, combined women’s and men’s cortical and trabecular bones’ data, a nonlinear BMD loss pattern was demonstrated (see Figure 3).

4. Microgravity Induced Bone Loss and Age-related BMD Reduction

From the pattern of age-related bone loss (Fig. 2), it is suggested that bone loss occurs more rapid in women than men, particularly in the trabecular bone regions, e.g., women lose approximately 33% more trabecular bone mineral than men at age of 70. However, it is observed that there are relatively similar rates of age-related cortical bone loss between men and women (Fig. 2). Based on the skeletal loss data in short-term space missions, significant BMD loss was observed among the astronauts population. Although the observation of bone loss occurred in both male and female astronauts, the physical condition of this group is among the healthiest in the population, e.g., controlled nutrition, active physical exercise, and closely medical monitor. If a combined agerelated BMD loss (i.e., averaging both cortical and trabecular bone loss in both men and women) is used, a phenomenological comparison may be applied between the aging population and astronauts in long term space missions, in which the age-related annual BMD loss rate may be similar to the monthly bone loss in space (Fig. 1, 3). This estimation may use age-related bone loss to predict the loss with spaceflight, which presumes that the astronauts (both male and female) will lose about the same amount of bone mass in one month as (combined female and male) aging Americans lose in one year. Based on this prediction, a power relation is proposed as %bone loss = 1985*(50+m) -0.771. It is estimated that long term space missions will significantly reduce bone density because of microgravity, in which it is predicted that a 30-month space mission would result in total of approximately 32% bone loss.

5. Muscle Atrophy

Lower extremity muscle volume was also altered by disuse. Exposure to a 6-month space mission resulted in a decrease in muscle volume of 10% in the quadriceps, 19% in the gastrocnemius and soleus (LeBlanc et al. 2000a; LeBlanc et al. 2007; Ohshima 2010; Fitts et al. 2010; Trappe et al. 2009). Computed tomography measurements of the muscle cross sectional area (CSA) indicated a decrease of 10% in the gastrocnemius and 10-15% in the quadriceps after short-term missions (Narici et al. 2003). Similar results were concluded after spinal cord injury (SCI), where patients suffered significant 21%, 28% and 39% reductions in CSA at the quadriceps femoris, soleus and gastrocnemius muscles, respectively (Gorgey & Dudley 2007; Shah et al. 2006). In addition to the effects on whole muscle volume, muscle fiber characteristics were also altered due to inactivity (Roy et al. 2008; Zhong et al. 2005). There are two primary muscle fibers: slow (type I) fibers which play an important role in maintaining body posture while fast (type II) fibers that are responsive during physical activities. Under disuse conditions, all fiber types were decreased in size, by 16% for type I and by 23-36% for type II (Roy et al. 2008; Stewart et al. 2004; Zhong et al. 2005). The atrophied soleus muscles also underwent a shift from type I (-8% in fiber numbers) to type II fibers (Roy et al. 2008; Stewart et al. 2004).

Clinical muscle stimulations have been examined extensively in SCI patients to strengthen skeletal muscle and alleviate muscle atrophy with promising outcomes (Griffin et al. 2009; Lim & Tow 2007; Shields & Dudley-Javoroski 2007). A few physical training studies further investigated this electrical stimulation technique to determine its effect s on osteopenia. These studies showed mixed results with respect to bone density data (Dudley-Javoroski & Shields 2008; Griffin et al. 2009; Yang et al. 2009). Using dual energy X-ray absorptiometry, BeDell et al. found no change in BMD of the lumbar spine and femoral neck regions after functional electrical stimulation-induced cycling exercise, while Mohr et al. showed a 10% increase in BMD of the proximal tibia following 12 months of similar training (BeDell et al. 1996; Belanger et al. 2000). In a 24- week study of SCI patients in whom 25 Hz electrical stimulation was applied to the quadriceps muscles daily, Belanger and colleagues reported a 28% recovery of BMD in the distal femur and proximal tibia, along with increased muscle strength (Belanger et al. 2000). A number of reported animal studies also indicated that muscle stimulation can not only enhance muscle mass, but also bone mineral density (Swift et al. 2010). Both animal and human studies seem to strongly support that functional disuse can result in significant bone loss and muscle atrophy.

6. Noninvasive Osteoporosis Diagnosis

At present, osteoporotic bone loss is commonly assessed by measures of bone mineral density that reflects in vivo conditions of bone mass. Noninvasive measurements of BMD would be of value in predicting the risks of fracture, in assessing the severity of the disease, and in following responses to treatment. Several methods are available for the ground-based clinical measurement of bone mass, with the most commonly used methods being DXA and computed tomography (CT), and emerging technology like micro-CT. These modalities are capable to assess both bone density and structure properties of bone, e.g., trabecular orientation.

DXA is currently the gold standard technique being used because of its relative precision (~2%) and its whole body and/or multi-site imaging abilities (spine, hip, wrist and total skeleton). However, because the source and the detector cross the whole bone (including layers of cortex and trabeculae), current techniques are apparently insensitive for quantifying trabecular bone mass separately. That is, a certain percentage of bone mass must be lost before significant radiation attenuation occurs. In addition, DXA and CT, have limitations on X-ray ionizing radiation (70-140KVp, 10 mrem). There is a lack of precision due to surrounding soft tissue variations, and issues of non-repeatability due to patients' position. Another limitation of the X-ray based approaches may be a lack of the ability to assess bone’s integrity information on mechanical property which may be directly related to bone’s potentials to resist fracture. Due to these issues, the quality of bones (i.e., structure and strength properties), whether in normal or osteopenic, remains unknown (i.e. it is extremely difficult to monitor the strength and the conductivity in vivo). As a result, an improved diagnostic tool is needed to evaluate both the quantity and the quality of bone, which will help in the early detection and therefore the possible prevention and treatment for this disease.

7. Bone Quality and Fracture

If not only bone mineral density but also bone quality, e.g. stiffness and/or modulus, can be monitored or determined instantly during the space mission, then one can better understand the skeleton adaptation on a daily basis. In the case of osteopenia and/or osteoporosis, fractures can occur without a singular traumatic event. Such a database would provide detailed and progressive information of the skeletal modeling/remodeling response during the condition of microgravity, which would potentially direct treatment regimens to prevent or recover bone loss.

Unfortunately, a skeleton at risk of fracture cannot simply be determined by the amount of bone (e.g., BMD) that exists; to a larger degree, the quality of the bone is just as important. While a formal definition of bone quality is somewhat elusive, at the very least it incorporates architectural, physical and biological factors that are critical to bone strength, such as bone morphology (i.e., trabecular connectivity, cross sectional geometry), properties of the tissue’s material (e.g., stiffness, strength), and its chemical composition and architecture (e.g., calcium concentration, collagen orientation, porosity, permeability). The ability to directly assess both bone density and quality (i.e., strength) would have great impact in predicting the risk of fracture.

8. Quantitative Ultrasound and Bone Quality Assessment

Recently, new methods in QUS have emerged with the potential to estimate cancellous bone modulus more directly. The primary advantage of ultrasonic techniques (UT) is that it is capable of measuring not only bone quantity, but also bone quality, i.e., estimation of the mechanical property of bone. Over the past 15 years, a number of research approaches have been developed to quantitate bone mass and structural stiffness using UT (Langton & Njeh 2008; Zheng et al. 2009). The advantages of QUS in comparison to X-ray-based technologies may be that it’s relatively simple and an inexpensive format that is non-invasive and free of ionizing radiation.

Research efforts have been made on bone quality assessments using image based QUS (Laugier et al. 2000; Qin et al. 2001; Qin et al. 2002). Preliminary results have shown that ultrasound imaging is capable to detect bone quality non-invasively through a developing scanning confocal acoustic navigation (SCAN) system (Qin et al. 2002; Qin et al. 2004; Qin et al. 2008; Xia Y. et al. 2005; Xia et al. 2007) (see Figure 4).

If QUS bone densitometry can be developed to provide “true” bone quality parameter-based diagnostic tools, i.e., directly related to bone’s structural and strength properties, and to target to multiple and critical skeletal sites such as hip and distal femur, QUS would have a greater impact on the diagnosis of bone diseases (e.g., osteoporosis) than currently available bone densitometry. The SCAN is intended to provide true images reflecting the bone’s structural and strength properties at a particular skeletal site of a peripheral limb and potentially in deep tissues like the great trachanter (Nicholson et al. 2001). The technology may further provide both density and strength assessments in the region of interests for the risks of fracture (Qin et al. 2002; Xia et al. 2005).

Most of the available systems measure the calcaneus using plane waves that utilize either water or gel coupling, e.g., Sahara (Hologic Inc., MA), QUS-2 (Metra Biosystems Inc., CA), Paris (Norland Inc., WI), and UBA 575 (Walker Sonix Inc., USA). At the beginning of the year, a bone scanning densitometry device for calcaneus ultrasound measurement was also made available using array plane ultrasound waves (GE-Lunar, Inc., USA). Using several available clinical devices, studies in vivo have shown the ability of QUS to discriminate patients with osteoporotic fractures from agematched controls (Njeh et al. 1997). It has been demonstrated that QUS predicts risks of future fracture generally as well as DXA (Bauer et al. 1997; Njeh et al. 1997). Table 1 has illustrated current quantitative ultrasound devices for calcaneus measurements.

9. Quantitative Ultrasound Parameters in Bone Measurement

Ultrasound may be applied to bone using a number of fundamental physical mechanisms: ultrasonic wave propagation velocity (UV) or speed of sound (SOS), energy attenuation (ATT), broadband ultrasound attenuation (BUA), and critical angle ultrasound parameters. Large perspective studies have confirmed that QUS measurements of BUA and UV can identify those individuals at risks of osteoporotic fracture as reliably as BMD (Langton & Njeh 2008; Zheng et al. 2009; Frost et al. 2001). It has been shown that both BUA and UV are decreased in individuals with risk factors for osteoporosis, i.e., primary hyperparathyroidism (Gomez et al. 1998), kidney disease (Wittich et al. 1998), and glucocorticoid use (Blanckaert et al. 1997). The proportion of women classified into each diagnostic category was similar for BMD and QUS. The strength of trabecular bone is an important parameter for bone quality. In vitro studies have correlated the UV with stiffness in trabecular bone samples (Xia et al. 2007). This indicates that ultrasound has the potential to be advantageous over the Xray based absorptiometry in assessing the quality of bone in addition to the quantity of bone. By determining the wave velocity through bone, the elastic modulus of bone specimens can be estimated.

10. Clinical Application & Therapeutic Effects of Ultrasound

Low-intensity pulsed ultrasound (LIPUS) is a form of mechanical energy that is transmitted through and into biological tissues as an acoustic pressure wave and has been widely used in medicine as a non-invasive therapeutic tool that has shown an accelerated rate of healing of fresh fractures (Favaro-Pipi et al. 2010; Qin et al. 2006). Substantial basic science data demonstrated that ultrasound has a strong positive influence on each of the three key stages of the healing process (inflammation, repair, and remodeling) because it enhances angiogenic, chondrogenic, and osteogenic activities. The mechanism of ultrasound therapy for fracture healing may be related to the differential energy absorption of ultrasound that gives rise to acoustic streaming. Its resultant fluid flow as a mechanotransduction signal (Qin et al. 2003; Cowin 2002; Cowin & Cardoso 2010) and induced gradients of mechanical strain are recognized as strong determinants of bone-modeling. It has been confirmed by clinical evidence that ultrasound has a role in the treatments of delayed unions and nonunions. The efficacy of LIPUS stimulation in acceleration of the normal fracture repair process was even observed when performed with a diagnostic sonographic device (Heybeli et al. 2002). However, the effectiveness of localized LIPUS with optimized intensity has been not fully investigated. Therapeutic ultrasound and some operative ultrasound use intensities as high as 1- 30 W/cm², which may cause considerable heating in living tissues. The use of ultrasound as a surgical instrument involves even higher levels of intensity (5 to 300 W/cm²), and sharp bursts of energy are used to fragment calculi, to initiate the healing of nonunions, to ablate diseased tissues such as cataracts, and even to remove methylmethacrylate cement during revision of prosthetic joints (Wells 2001). The intensity level used for imaging, which is five orders of magnitude below that used for surgery, is regarded as non-thermal and nondestructive. Current therapeutic ultrasound uses plane waves and exposes the energy to a broad range of tissues. The radical changes of density inherent in a healing callus may result in a significant lose in the amounts of energy in the pathway of the ultrasound. A localized and targeted/guided exposure of LIPUS may overcome these limitations and dramatically increase the efficiency of the treatment. A proposed combined diagnostic and therapeutic QUS with focal scan model can overcome these.

Thus, a non-invasive assessment of trabecular bone strength and density is extremely important in predicting the risks of fracture in space and ground operations. QUS has emerged with the potential to directly detect trabecular bone strength. To overcome the current hurdles such as soft tissue and cortical shell interference, improving the “quality” of QUS and the application of the technology for future clinical usages, the development of image based ultrasound technology will concentrate on several main areas: (1) increasing the resolution, sensitivity, and accuracy in diagnosing longitudinal bone loss to predict the risk of fracture and evaluate treatment effects; (2) predicting local trabecular bulk stiffness and the microstructure of bone, and generating a physical relationship between ultrasound parameters and bone quality; and (3) providing targeted treatment for stress fracture and traumatic fracture using ultrasound. An integrated diagnostic and therapeutic ultrasound system may ultimately provide noninvasive, non-radiation, portable and low weight modality for longitudinal bone loss in extended space mission.

11. Summary

Based on the results of musculoskeletal loss in a 6-month stay on the international space station, it is clear that musculoskeletal tissues will face accelerated decay under a microgravity environment. A trip to Mars and possibly back to Earth, can take between 18-30 months in space, and will have significant impacts on bone and muscle. It is important that the prediction of such a loss may be implemented with age-related human osteoporotic bone mineral density loss, which in turn may provide understanding of the rate and the pattern of bone loss in an extended microgravity environment. The development of suitable technologies, like low weight and noninvasive ultrasound, may impact both diagnosis and countermeasure treatment in future long duration space missions.

Acknowledgments: This work is kindly supported by the National Space Biomedical Research Institute through NASA contract NCC 9-58, the National Institute of Health (R01 AR52379 and R01AR49286), and the US Army Medical Research and Materiel Command. The author wishes to thank Maria Pritz and Minyi Hu for their excellent technical assistance on this manuscript.