Bone Loss in Long-Duration Spaceflight: Measurements and Countermeasures
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Thomas Lang, University of California San Francisco: "Bone Loss in Long-Duration Spaceflight: Measurements and Countermeasures." Presented at the 2013 International Space Station Research and Development Conference, http://www.astronautical.org/issrdc/2013.
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Bone Loss in Long-Duration Spaceflight: Measurements and Countermeasures
- 1. Thomas Lang, Radiology and Biomedical Imaging, UC San Francisco Space Station Research and Development Conference July 16,2013 BONE LOSS IN LONG-DURATION SPACEFLIGHT: MEASUREMENTS AND COUNTERMEASURES
- 2. ISS TOP DISCOVERIES IN MICROGRAVITY BONE LOSS: MEASUREMENTS AND COUNTERMEASURES • Thomas Lang, UC San Francisco, CT imaging studies • Joyce Keyak PhD, UC Irvine, Finite Element Modeling • Scott M Smith PhD, NASA JSC, Nutrition and Exercise Countermeasures • Adrian LeBlanc PhD, USRA, Exercise and Pharmacologic Countermeasures • Jean Sibonga PhD, NASA JSC, Bone and Mineral Laboratory • Peter Cavanagh PhD, U of Washington, Exercise and Musculoskeletal Biomechanics
- 3. MOTIVATION • Bone loss is a well-known medical consequence of long-duration spaceflight, anticipated long before the first space missions • Loss of bone mass is associated with loss of bone strength • Increased risk of fracture • In elderly men and women, each 10% decrease in bone mineral density results in a 2-3 fold increase in fracture risk • A mission related fracture would be a potentially life-threatening or mission-compromising event • Extensive bone loss during a mission may compromise long-term bone health in the decades after service is complete • Release of calcium from skeleton increases risk of renal stone development
- 4. EARLY STUDIES OF BONE LOSS IN SPACEFLIGHT Skylab (early 70’s): metabolic studies show loss of calcium and loss of bone from heel using early bone densitometry. Salyut missions showed loss of bone in heel MIR (1985-2001): first systematic study of bone loss using modern DXA technology. 19 cosmonauts measured pre- and post-flight at Star City. Key finding: Cosmonauts lost 1-1.5%/month bone density in hip and 1%/month from spine. Losses comparable to yearly post-menopausal women (LeBlanc et al J Musc Neur Int 2000) Head down bedrest studies: 90-day bedrest simulations of spaceflight showed bone loss similar to MIR. Bone loss was not reduced in subset of subjects who had a carefully controlled moderate exercise program (Leblanc J Bone and Min Res 1990), and was only reduced by an intense program of resistance exercise (Shackeford et al J App Phys 2004)
- 5. BONE LOSS AND COUNTERMEASURES: NASA SUPPORTED HUMAN STUDIES ON THE ISS • Studies of bone loss: • Previous studies had focused on bone mass. • New studies would move beyond bone mass to bone architecture, bone loading and strength • “Subregional assessment of bone loss in the axial skeleton in long- term spaceflight” (Thomas Lang) • “The Effect of Long-Duration Spaceflight on the Biomechanics of the Proximal Femur” (Thomas Lang) • “Foot Reaction Forces During Space Flight” (Peter Cavanagh) • Countermeasure prescriptions • Combination of exercise and nutrition (Scott M Smith, PhD) • Bisphosphonate as a countermeasure to bone loss (Adrian Leblanc)
- 6. DUAL-ENERGY X-RAY ABSORPTIOMETRY • Pros •Widely available •Inexpensive •Excellent reproducibility •Low x-ray exposure • Cons •2-D density (g/cm2) at various sites •Combines trabecular and cortical bone •Does not account for bone geometry •Does not evaluate bone strength per se
- 7. QCT: IMAGING TO QUANTIFY BONE ARCHITECTURE AND STRENGTH • Volumetric bone density of cortical and trabecular bone Equivalent concentration of CaHA in g/cm3 • Bone geometry Cross-sectional areas Tissue volumes Bone dimensions • Bone strength estimates Simple estimates of bending of compressive strength Finite element modeling (FEM) Joyce H. Keyak, PhD UC Irvine
- 8. SUBREGIONAL ASSESSMENT OF BONE LOSS IN THE AXIAL SKELETON IN LONG-TERM SPACEFLIGHT • 16 International Space Station Crewmembers with pre- flight, post-flight (within 3 weeks of landing) and one year measurements • Data gathered between 2001-2005 • DXA of spine and hip at JSC • Volumetric QCT of the proximal femur and spine performed at Methodist Hospital, Baylor College of Medicine
- 9. QCT IMAGING Image acquisitions Image Analyses Spine Hip
- 10. 3D FINITE ELEMENT MODELING Finite element model derived from QCT scan Map of material properties 3D finite element model of hip derived from CT scan JH Keyak Elastic modulus and strength derived for each QCT voxel parametrically from BMD Stance Fall Loading Conditions
- 11. Total Femur 39.000 40.000 41.000 42.000 43.000 44.000 45.000 46.000 47.000 48.000 PRE POST 12MONTH Visit Cort.Vol(cc) VQCT BONE LOSS RESULTS Minimum CSA 11.400 11.500 11.600 11.700 11.800 11.900 12.000 12.100 12.200 PRE POST 12MONTH Visit CSA(cm2) Total Femur 28.000 29.000 30.000 31.000 32.000 33.000 34.000 35.000 36.000 PRE POST 12MONTH Visit Int.BMC(g) Total Femur 0.110 0.115 0.120 0.125 0.130 0.135 0.140 0.145 0.150 PRE POST 12MONTH Visit Trab.vBMD(g/cc) Lang et al J Bone and Miner Research 2006 Cortical tissue volume Trabecular volumetric densityTotal Bone mass Femoral neck cross sectional area -16.5% -2.3%/mon +8 % p<0.001 v baseline -8% -1.3%/mon +8% -10.8% -1.6%/mon +8.1% +2.4% p<0.05 v baseline+1.0%
- 12. 40 50 60 70 80 90 Pre-Filght Post-Flight 1 Year Post-Flight 0 1000 2000 3000 4000 5000 HIP BONE STRENGTH: FALL LOADING IN MEN Astronauts Control Subjects Fracture Subjects HipBoneStrength(N) Age (years) Joyce H. Keyak PhD
- 13. LOW CORRELATIONS BETWEEN DXA CHANGES AND HIP BONE STRENGTH CHANGES. -6.0% -5.0% -4.0% -3.0% -2.0% -1.0% 0.0% 1.0% -2.0% -1.5% -1.0% -0.5% 0.0% Change in DXA Total Femur Areal BMD ChangeinFEStrength. Stance Fall Stance, R2=0.23 Fall, R2=0.05 Per Month Decrease in FE Strength vs. DXAAreal BMD Joyce Keyak PhD
- 14. BONE LOSS MEASUREMENTS DISCUSSION • Early ISS crews had experienced similar rates of bone loss to MIR crew • Trabecular and cortical bone compartments changed at different rates • Trab bone loss >> cortical bone loss • Recovery of bone mass comprises changes in bone structure • Increase in bone size • Impaired recovery of trabecular bone • Hip structure looks “older” • Hip bone strength loss higher than predicted by DXA • Some individuals lost over 30% of their hip strength over the course of a 6 month mission.
- 15. PROBLEMS WITH COUNTERMEASURES: EARLY ISS MISSIONS • Early crews used the interim resistive exercise device (iRED), a treadmill, and an exercise bicycle • For bone, crews carried out squats and deadlifts on the iRED • Treadmill running used tensioned loading devices to load subject on to treadmill with goal of 80% of body weight • The iRED had limited modes of usage, variable load over range of motion, and a maximum load capacity of 297 lbs • “Foot reaction forces in spaceflight” (PI: Peter Cavanagh) • 4 astronauts on mission wore leggings equipped with insole load measurement device to measure foot forces and estimate lower extremity loads • Foot forces in treadmill running were less than half those experienced on earth • In resistance exercise, loads on lower extremity ranged from 0.2-1.3 body weight • 30% of prescribed exercise time resulted in measureable loading • Early ISS crews consumed 70-80% of their energy requirements, resulting in 5-10% loss of body weight
- 16. ADVANCED RESISTANCE EXERCISE/NUTRITION Advanced Resistive Exercise Device (aRED) was launched to orbit in 2008 • 600 lb maximum load • Constant load across range of motion • Larger selection of motion Exercise/Nutrition Countermeasure Study Scott M Smith, PhD Vitamin D dose of 800 IU/day Food frequency questionaire (FFQ) was employed to record intake of basic dietary components: energy, protein, water, sodium, calcium, iron, and potassium. Five subjects exercising on aRED, and having optimized nutritional intake were compared to 12 iRED exercisers and MIR cosmonauts Bone density, body mass, lean mass, bone formation and resorption markers, and vitamin D levels were monitored
- 17. J Bone and Miner Res 2012 Comparison of hip bone density changes in MIR crew, iRED users and aRED users In 5 aRED exercisers, data suggest lower rate of bone loss than MIR or iRED All groups showed increased rates of bone resorption aRED exercisers returned with higher lean mass and lower fat mass aRED users maintained higher energy intake, greater %required energy intake and higher intake of protein Across all subjects, inflight energy and protein intake were inversely correlated with bone loss in hip and pelvis
- 18. BISPHOSPHONATES AS A COUNTERMEASURE TO BONE LOSS Bisphosphonates, such as alendronate (FOSAMAXTM) have been used since the mid 90’s to treat osteoporosis, showing 30-50% reduction of fracture rates Bisphosphonates inhibit the action of osteoclasts that resorb bone and which show increased activity in disuse Alendronate attenuated bone loss in a earlier bedrest study (LeBlanc et al, J Bone and Miner Research 1999) NASA project to evaluate use of alendronate to reduce or prevent bone loss in ISS crew (PI: Adrian LeBlanc) Seven ISS crew members from NASA and JAXA took 70 mg alendronate/wk starting 3 weeks prior to launch and continuing through flight. All subjects exercised on aRED Subjects imaged with DXA and QCT pre and post-flight. QCT images analyzed with bone density and FEM software
- 19. LeBlanc et al Osteoporosis Internat 2013 Stance Strength (%) (SD) Fall Strength (%)(SD) Pre-aRED BIS+aRED
- 20. COUNTERMEASURE KEY POINTS • High intensity resistance exercise appears to reduce loss of bone density, although bone turnover is still elevated • Data support importance of fulfilling required energy and protein intake for reducing bone loss • Bisphosphonate study showed that even with aRED exercise, statistically significant hip bone loss occurs • Alendronate, combined with aRED, prevented bone loss at the hip, as documented by DXA, QCT and FEM. • Overall, data document that it is possible to prevent bone loss, mitigating changes in hip structure that may compromise bone health in later life
- 21. TRANSLATING FINDINGS TO MEDICAL OPERATIONS IN EXPLORATION ERA • Smaller spacecraft and different mission profiles imply logistical constraints • Optimal combination of drug and exercise to reduce drug dose and exercise dose • Emerging osteoporosis medications may offer reduced gastrointestinal side effects compared to bisphosponates • Combination of drugs and exercise to reduce loads and risk of injury • Develop state of the art bone health standards that incorporate new quantitative methods such as Finite Element Modeling (Jean Sibonga, PhD) • Finite Element Cut Point Task Group: Panel of leading clinicians are helping to develop new guidelines for using QCT and FEM data to assist flight physicians in assessment of astronaut skeletal health • Evidence –based recommendations recently published in key bone journal (Orwoll et al, J Bone and Miner Res 2013)
- 22. ACKNOWLEDGMENTS • Isra Saeed MD • John Kornak PhD • Ying Lu PhD • Alain Koyama • Alice Yu • Wenjun Li • Tadashi Kaneko • T. Matsumoto • H. Evans • L. Shackelford • E. Spector • R. Ploutz-Snyder • J. Jones • J. Shapiro • T. Nakamura • K. Kohri • H.Oshima • L. Ploutz-Snyder • M. Heer • S. Zwart Bone Loss Studies (QCT/FEM) NASA NNJ04HC7SA and NNJ04HF78G Countermeasure Studies NASA JSC Human Research Program
Notes de l'éditeur
- This talk is part of a Team Award for ISS-based research in bone loss and countermeasures. On behalf of my co-recipients Joyce Keyak, Scott Smith and Adrian Leblanc I am honored to present our progress in this area over the last 15 years. I would also like to recognize the valuable contributions of Jean Sibonga of NASA/JSC’s bone and mineral lab, and Peter Cavanagh at the University of Washington. I will be discussing their contributions to this research as well.
- Bone loss is one of the best-known complications of long-duration spaceflight, and was anticipated long before the first missions were undertaken in the 1970’s. Bone loss is a major health problem because it leads to reduced bone strength and eventually to bone fracture, one of the most widespread public health problems in our elderly population. Bone fracture would be a potentially mission limiting or even fatal problem during a mission, and uncontrolled bone loss, even if it doesn’t lead to a fracture in the short term could pose long term health issues for crew members decades after their mission.
- Our ISS research took place against the background of previous studies of long-duration spaceflight. Astronats on Sklyalb for example had detailed metabolic studies of calcium balance, and this was shown to be negative in members of the crew that were studied. The signal work on bone loss in long-duration spacelfight was carried out by Leblanc and colleagues in the mid to late 90’s who used modern bone densotometers to study bone loss in the whole body, and in sites such as the hip and spine in 19 MIR cosmonauts. Their key finding was that cosmonauts lost an average of 1-1.5%/month of flight from their hips, which compared to yearly losses in postmenopausal women at rick for fractures. Parallel studies were done in bedreststuydes that simulated spaceflight. They found that bone loss could not be reduced by a carefully controlled exercise program and could only be brought into control by very heavy resistance exercise.
- I will talk about a subset of NASA supported ISS studies. Studies related to bone loss include two studies that I headed up, which focused on using imaging to study changes in bone architecture and strength, and a study led by Peter Cavangh to study loading of bone on the ISS. I will also talk about two successful projects to determine countermeasure prescriptions. One of them involves showing the feasibility of heavy onboard resistance exercise and carefully monitored nutirtion to reduce bone loss, and the other shows how adding an anti-resoprtive drug, alendronate, effectively prevents bone loss.
- We used QCT to evaulate 16 astonatus and cosmonauts who flew missions ranging 3.5 to 6.5 onths on the ISS. We imaged them pre-, post and one year after flight at the Methodist hospital at Baylor in downtown houston.We measured at the spine and hip with both QCT and DXA.
- Here we see QCT results. Because the hip shows the most important changes we focused on the hip. On the upper left you see the total hip bone mass from qCT. This is very tightly correlated with DXA. You can see that crew loseAbout an average of 1.6% per month, very similar to the MIR crew. You can also see that the loss is very nearly recovered after one year post mission. However, this pattern reflects very different things occuringint the cortical and trabecular bone. The trabecula bone loss at upper right is nearly 50% higher, and only one half of the loss is recovered one year later. If you look at cortical tissue volume on the lower, left, that is lost at a rate very similar to the bone mass loss, and is almost compltelety recovered. Hoever, although it is not shown here, the density of the cortical bone didn not increade. Finally, if you lookl at the loweer right, you see that a measure of bone size, the corsssecitonal area of the femoral neck, increases in the year after flight. The hip is growing bigger to most efficiently bear load in the context of lost trabecular bone and less dense corttical bone. This is the same pattern that occurs in aging. Using the same technique, you can see that elderly invidivuals, both men and owmen, show larger but much less dense bone than theur younger countermparts.
- Here we show Keyals work on hip bone strength loss. This is finite element modling of the hip under a sumulated fall laoding condition. At the left you see yellow points which represent the preflight values of the astronatus, blue, the postlfight and green measurements taken on six crew one year after. One the right you see FEM values form a group of eldrly men, who were imaged and then followed up for subsequent hip fractures. The red points are the strength values of men who did not farcture and the blude pint s are men who did.Looking at the difference between the mean pre-a dnpostflight values, shwon by the lines, it coresponds to the age-related loss of bone strength in the contol subjects between 70 and 90 years and the difference between fractures and controls. This clearly shows that if not recovred, this could pose long term health issues. The recovery data show that 4 out of 6 subjects did not revover their fall strength. This points to the importance of preventing these changes from happening.
- This is a nother of DrKeyals results. IT shows that changes in bone densityare not particularly good predictors of changes in bone strength, just as in the sense that the weight of a bridge is not necessarity the best predictorOf its failure laod. DXA changes is on the x asis and bone strenght in stance loading and fall loading on the y. If uyoui look at people who lost one percent per mornth of DXA bone density, the variation in rate of fall strength loss ranges from a small gain, to a 3% per month loss, with simialr results for stance strength.
- So to usmmaruze, we found that early ISS crews, expeditions 2-8 had simlar rates of hip and spine bone loss to MIR, and that changes in bone density and bone mass concealed different behaviro for coritcal and trabeuclar compartments. The recovery of bone was very interesting. The impaired recovery of volumetric bone density occurred with what we think is a compensatory increase in bone size. As aresult, the hip recovers its mass, but looks like an older bone, less dense but larger. The loss of hiop bone strength was over 50% larger than what was predicted by DXA, with some inviduals losing 30% of their strength over the course of a mission.
- Thesedisapponitngreuslts took place in the context of acounteremasure environment on ISS that had a lot of problems in the early years. There were three exercise devices, a reistance machine called iRED, a treadmill and an exercise bike. The iREDhd a limted load capacitym and limited modes of usage. It had reliability issues, and was not operative all of the time. Some of these issues were highlighted in an experiemnt led by Peter Cavanagh. They equirped 4 crew members with insole load measurement sensors and processing devices to measure foot forces and estiamte lower extremity loads. In this subset of cew, theu found that foot forces in exeprces treadmill were less than half those on earth, and the forces in resistianceexericse were not adquate, much less than two body weights. Only a thord of the exercise time alloted was actually sepndt generating detectable loads. In additon to exercise issues, there were nutritional isses. Crews were not getting their energy requirements and were losing 5-10% of their wieght as a result.
- In 2008, a new more powergul exercise device, the aRED, was launced and installed on the ISS. This device allowed 600lb load (>3x body wieght for most crew), a constant load over range of motion, and a larger selection of exercisemodels. The efficacy of the aRED in combination with improved nutirtionagiant bone loss was studied by Scott Smith and Colleagues. They evaluated pre and postfguht DXA of 5 subjects who had 800 IU or vitamin D per day. Nitrotional intake was carefully montiroed and measurements were moade of bone density, body mass, lean mass and chemical measures of bone formation, resoprtion and vitamin D.
- The study was piblsiehd in 2012 in the journal of bone miner res. The plot on the right shows a trend towrds lower rate of bone loss in the aRED subjects (right hand column) compared to iRED and MIR subjects. The ARED subjects had postlfight BMD which was not statistically signiicantly smaller than preflight. Interestingly these encorougaging density results occurred even though the bone resoprtion markers were increased in this group along with the other subjects. This group of 5 subjects had some psoitive effects, including presenrvation of energy and protein blance. This is very important, as an aluysis in the paper showed a correlation bweteen bone loss in the pelvis and proetin and energy intake.
- Another project evaluated whether adding alendronate to the aRED exercise regimen could prevent or reduce bone loss. Alendronate is a bisphosphnoate, a type of drug that is very widely used clinically to treat osteoporosis with significant success since the mid-90’s resulting in 30%-50% reduction in fracture rate. This class of drug acts on osteoclasts, the bone resorbing cells, blocking htem from attaching or lmiliting their funciton. In a Previous study, alendronate had been shown to blcok bone loss in the hip and soine in a bedrest model. The current project called for an evailation of its ability to prevent bone loss in ISS crew, all of whom exercised on the aRED. They were imaged pre and postflight with DXA, QCT and FEM. They took 70 mg/day starting 3 weeks prior to flight and conitneuing through the mission
- Here are the reuslts, published this year in Osteoprosis International. From left to right you see results for DXA of the femoral neck, trochanter, total femur pelvis and spine. Triangles are crew who took the drug supplement, squares were 7 ared exercisers, and open diamonds were ired exercisers from the early study by Lang et al. The signal result is that treated crew prserved their DXA measures with changes at or very close to zero for all measures of bone density. The ired measures showed losses ranging 5-7% over the course of their mission, and the ared exercisers showed significant losses that were intermediate between the two. QCT data were avilable for trabecular and cortical bone for the same regions of the hip, and these showed that the drug treatment prevented significant bone loss. Represented in color are the results for finite element modeling which show that the alendroantetrated subjects had non significant bone strength loss.
- Thus, while pre-a nd post flight BMD measures provided evidence that exercise could reduce the rate of bone loss, a relatively small amount of bone loss by DXA still occurs, consistnte with the increased level of bone resoprtion observed in the aRED study, which also showed the importance of fulfilling nutritional requirements in terms of energy and protein intake. Adding biisphonate showed succcess in stopping bone loss by mutiple measures. Together, thiseedata indicate that it is possible to prevent the alterations in hip structure that can predispose towards froacture in later life.
- At this point, it is worth considering scenarious for translating these findings to mdeical operations in the expolration era, where there will be new constraints on crew time, logistics and spacecraft characteristics that mightlimit the time available for exericse and the complexity and size of the devices. One question is the extent to which the countermeasures can be combined to develop an optimal pairing on drug treatment and exercise. Can the combination be used to reduce the dose of drug and the loads and time involved in exercise? Another aspect of this is the development of bone health standards for crew that incorporate state of the art methos such as FEM. Here I would like to point to the importance of Jean Sibonga in leading this effort, in which a panel of leading clinicians, many of whom were pioneers in the employment of DXA and other measures to come up with standrafds for osteoporosis diangosisis and treatment to develop guidelines for DXA, QCT and FEM in the astronaut populations. Their set of evidence based recommendations were recently pbihsiehd un the journal of bone and mienral research. So all in all, there has been tremendous progress, but the wold of detail is just beginning.