Effects of artificial gravity during bed rest on bone metabolism in humans.

We report results from a study designed to explore the utility of artificial gravity (AG) as a countermeasure to bone loss induced by microgravity simulation. After baseline testing, 15 male subjects underwent 21 days of 6 degrees head-down bed rest to simulate the deconditioning associated with spaceflight. Eight of the subjects underwent 1 h of centrifugation (AG; 1 G(z) at the heart, 2.5 G(z) at the feet) each day for 21 days, whereas seven of the subjects served as untreated controls (Con). Blood and urine were collected before, during, and after bed rest for bone marker determinations. Bone mineral density (BMD) and bone mineral content (BMC) were determined by dual-energy X-ray absorptiometry and peripheral quantitative computerized tomography before and after bed rest. Urinary excretion of bone resorption markers increased during bed rest, but the AG and Con groups did not differ significantly. The same was true for serum C-telopeptide. During bed rest, bone alkaline phosphatase (ALP) and total ALP tended to be lower in the AG group (P = 0.08, P = 0.09). Neither BMC nor BMD changed significantly from the pre-bed rest period in AG or Con groups, and the two groups were not significantly different. However, when AG and Con data were combined, there was a significant (P < 0.05) effect of time for whole body total BMC and total hip and trochanter BMD. These data failed to demonstrate efficacy of this AG prescription to prevent the changes in bone metabolism observed during 3 wk of bed rest.

Recovery of spaceflight-induced bone loss: bone mineral density after long-duration missions as fitted with an exponential function.

The loss of bone mineral in NASA astronauts during spaceflight has been investigated throughout the more than 40 years of space travel. Consequently, it is a medical requirement at NASA Johnson Space Center (JSC) that changes in bone mass be monitored in crew members by measuring bone mineral density (BMD), with dual-energy X-ray absorptiometry (DXA) before and after flight, of astronauts who serve on long-duration missions (4-6 months). We evaluated this repository of medical data to track whether there is recovery of bone mineral that was lost during spaceflight. Our analysis was supplemented by BMD data from cosmonauts (by convention, a space traveler formally employed by the Russia Aviation and Space Agency or by the previous Soviet Union) who had also flown on long-duration missions. Data from a total of 45 individual crew members - a small number of whom flew on more than one mission - were used in this analysis. Changes in BMD (between 56 different sets of pre- and postflight measurements) were plotted as a function of time (days after landing). Plotted BMD changes were fitted to an exponential mathematical function that estimated: (i) BMD change on landing day (day 0) and (ii) the number of days after landing when 50% of the lost bone would be recovered ("50% recovery time") in the lumbar spine, trochanter, pelvis, femoral neck and calcaneus. In sum, averaged losses of bone mineral after long-duration spaceflight ranged between 2% and 9% across all sites with our recovery model predicting a 50% restoration of bone loss for all sites to be within 9 months.

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.

Bone mineral loss and recovery after 17 weeks of bed rest.

The purpose of this work was to determine the rate and extent of bone loss and recovery from long-term disuse and in particular from disuse after exposure to weightlessness. For this purpose, bed rest is used to simulate the reduced stress and strain on the skeleton. This study reports on the bone loss and recovery after 17 weeks of continuous bed rest and 6 months of reambulation in six normal male volunteers. Bone regions measured were the lumbar spine, hip, tibia, forearm, calcaneus, total body, and segmental regions from the total-body scan. The total body, lumbar spine, femoral neck, trochanter, tibia, and calcaneus demonstrated significant loss, p less than 0.05. Expressed as the percentage change from baseline, these were 1.4, 3.9, 3.6, 4.6, 2.2, and 10.4, respectively. Although several areas showed positive slopes during reambulation, only the calcaneus was significant (p less than 0.05), with nearly 100% recovery. Segmental analysis of the total-body scans showed significant loss (p less than 0.05) in the lumbar spine, total spine, pelvis, trunk, and legs. During reambulation, the majority of the regions demonstrated positive slopes, although only the pelvis and trunk were significant (p less than 0.05). Potential redistribution of bone mineral was observed: during bed rest the bone mineral increased in the skull of all subjects. The change in total BMD and calcium from calcium balance were significantly (p less than 0.05) correlated, R = 0.88.

Effects of weight lifting on bone mineral density in premenopausal women.

A group of 68 premenopausal women participated in a controlled 12 month exercise program. Two groups were matched according to age, body size (body mass index), and typical activity level. Data collection included bone mineral density (BMD) of the lumbar spine with dual-photon absorptiometry and of the os calcis with single-photon absorptiometry, lean body mass, urinary calcium/creatinine, and urinary gamma-carboxyglutamic acid (Gla). Subjects were given a daily 500 mg supplement of elemental calcium. There was no significant difference between groups in terms of diet, in urinary calcium/creatinine or Gla, or in lean body mass. The weight lifting group had a nonsignificant increase in mean lumbar BMD of 0.81% and the control group exhibited a nonsignificant decrease of 0.5%. However, a paired t-test revealed a significant change in the means in either group or as matched pairs. The relatively small change seen as a result of this modified Nautilus exercise program may prevent moderate weight lifting from being a practical answer for osteoporosis, even in a highly motivated population.

Cyclic therapy of osteoporosis with neutral phosphate and brief, high-dose pulses of etidronate.

We have designed a cyclic regimen for the treatment of osteoporosis based on the activate, depress, free, and repeat (ADFR) concept. Osteoclastic bone resorption is activated by 7 days of oral neutral phosphate and inhibited with a brief pulse (5 days) of etidronate disodium at a high dose (20 mg/kg body weight). Patients next take calcium supplements for 48 days before resuming phosphate to enter the next cycle. Osteoporotic women increased the bone mineral density of the lumbar spine at 6 months by 7.2 +/- 5.2% (mean +/- SD, N = 14) and at 12 months by 8.2 +/- 4.0% (N = 8). Control observations in regularly exercising postmenopausal women (N = 30) showed no significant change in spine mineral density after 20 months (0.5 +/- 3.2%), confirming the stability of the measurement technique. The two patients who responded poorly to the cyclic regimen each showed a blunted rise in serum PTH during oral phosphate administration, suggesting that the rise in PTH induced by oral phosphate may be an important component of this cyclic regimen. This preliminary study does not identify which component or components of the regimen are responsible for the increase in bone mass but provides positive encouragement for randomized studies designed to determine the optimum dosage, duration, and timing of each component of the regimen.

Zinc, copper, and nitrogen balances during bed rest and fluoride supplementation in healthy adult males.

The effects of bed rest and fluoride supplementation on zinc, copper, and nitrogen balances and Zn and Cu serum levels were measured in 15 healthy males. Subjects aged 19-54 y remained on a metabolic research ward for 10 wk. During weeks 1-5, subjects were ambulatory. During wks 6-10 they remained in continuous bed rest. During weeks 3-10 nine subjects received 10 or 20 mg F/d as sodium fluoride. Daily urine and weekly fecal composites were made and biweekly fasting blood samples were taken. Dietary intakes were 1.40 +/- 0.17 mg Cu/d (22.0 +/- 2.7 mumol Cu/d), 10.82 +/- 0.49 mg Zn/d (165.6 +/- 7.6 mumol Zn/d), and 14.27 +/- 0.23 g N/d (1019 +/- 16 mmol N/d). Bed rest increased urinary Zn and N excretions and fecal Zn excretions and decreased Zn balance (p less than 0.05) whereas Cu balance was unchanged. During bed rest, F supplementation increased Zn and N balances compared with untreated control subjects (p less than 0.05). These results are compatible with bone and muscle atrophy during bed rest and increased bone formation with F supplementation.

Nutrition and human physiological adaptations to space flight.

Space flight provides a model for the study of healthy individuals undergoing unique stresses. This review focuses on how physiological adaptations to weightlessness may affect nutrient and food requirements in space. These adaptations include reductions in body water and plasma volume, which affect the renal and cardiovascular systems and thereby fluid and electrolyte requirements. Changes in muscle mass and function may affect requirements for energy, protein and amino acids. Changes in bone mass lead to increased urinary calcium concentrations, which may increase the risk of forming renal stones. Space motion sickness may influence putative changes in gastro-intestinal-hepatic function; neurosensory alterations may affect smell and taste. Some or all of these effects may be ameliorated through the use of specially designed dietary countermeasures.

Zinc and copper balances in healthy adult males during and after 17 wk of bed rest.

The effects of long-term bed rest on zinc and copper balances were measured in seven healthy men. Volunteers aged 22-54 y (mean +/- SD, 34 +/- 12 y), 168-185 cm in height (173 +/- 5 cm), and 64-86 kg in weight (74 +/- 9 kg) remained on a metabolic ward for 29 wk. Subjects were ambulatory during weeks 1-5, remained in continuous bed rest for weeks 6-22, and were reambulated during weeks 23-29. Copper and zinc were measured in weekly urine and fecal composites. Dietary intakes provided (mean +/- SD) 19.2 +/- 1.2 mumol Cu (1.22 +/- 0.08 mg), 211 +/- 11 mumol Zn (13.81 +/- 0.72 mg), 25.2 +/- 1.2 mmol Ca (1011 +/- 46 mg), 1086 +/- 46 mmol N (15.21 +/- 0.65 g), and 48.1 +/- 1.4 mmol K (1489 +/- 44 mg)/d. Bed rest increased fecal zinc excretion and decreased zinc balance, whereas copper balance was unchanged. Reambulation decreased fecal zinc excretion and increased both zinc and copper balances. These results suggest that during long-term bed rest or space flight, individuals will lose total body zinc and will retain more zinc and copper when they reambulate.

Procedures for receiving and opening packages containing radioactivity.

A concise set of procedures is presented to aid laboratory personnel in complying with Part 20.205 of Title 10, Chapter 1, of the Code of Federal Regulations, concerning the receipt and monitoring of radioactive materials. Because these regulations were written for a large and diverse community of licenses, they are difficult to implement on a day-to-day basis. The procedures presented here reduce the regulations to an operationally functional form.

A technique for measurement of xenon-133 air contamination.

A sensitive, inexpensive technique is described for measuring xenon-133 air contamination to levels below nonoccupational exposure limits. The method uses a column containing a measured amount of activated charcoal through which an air sample is passed. The relative effects of air flow rate, xenon concentration, air temperature, relative humidity, and characoal weight on the amount of trapped xenon are described.

Precision of regional bone mineral measurements obtained from total-body scans.

Newer bone densitometers using dual-photon absorptiometry (DPA) or dual energy x-ray absorptiometry (DEXA) are capable of measuring the total-body bone mineral; regional analysis of these scans would have significant utility if adequate precision were possible. This study investigated short term precision by weekly scanning (three to five times) normal subjects (total 48 scans) and long term precision by scanning a whole-body phantom 30 times over 15 mo. For the 30 phantom scans, a coefficient of variation (CV) of bone mineral content (BMC) and bone mineral density (BMD) was calculated for each region. Nonrandom changes were analyzed by plotting the phantom data with time and testing the slope of the fitted line for significance. Similarly for the subjects, a CV for each region and the mean value for all subjects was obtained. From this study we conclude (a) BMD is more precise than BMC, (b) long-term precision was poorer than short term, (c) long-term regional BMD precision (%) was: head, 3.2; arms, 2.8; legs, 1.6; ribs, 2.6; pelvis, 3.8; thoracic spine, 3.8; lumbar spine, 7.1; total spine, 2.4; trunk, 2.2; total body, 1.2.

Precision of dual photon absorptiometry measurements.

One of the important uses of bone absorptiometry is to examine the rate of bone mineral change in order to evaluate therapy and to identify individuals who need therapy. Generally, this involves comparing the difference between two scans obtained months to years apart. This study investigates the precision of dual photon absorptiometry using a human torso phantom, normal subjects, and abnormal patients. These studies showed that bone mineral calculated as g/cm2 was more precise than g/cm. Reanalysis of the same scan by the same individual produced an average error equivalent to that produced by scanning and analyzing the same subject on multiple occasions. Interobserver analysis error was essentially equal to the intraobserver error. In order to obtain maximum precision, care must be taken that the integrated area of a repeat scan is identical to the previous scan. Our findings indicate that to be confident (95%) of a real change between two scans a difference of at least 5.6% must be measured.

An improved tungsten-178/tantalum-178 generator system for high volume clinical applications.

Clinical utilization of the multiwire gamma camera (MWGC) requires low-energy radionuclides. The short-lived (9.3 min) tantalum-178 (178Ta) is ideally suited for the MWGC and can be produced from long-lived (21.7 day) tungsten-178 (178W) by a previously reported 178W/178Ta generator. This generator, however, is limited by sharp increase in breakthrough after elution of only 30-60 column-volumes. To optimize the 178W/178Ta generator for clinical use, varying eluant acid concentrations were evaluated. A reduced (from 0.1 to 0.03N) HCI concentration in the eluant, coupled with low operating temperatures (3 to 5 degrees C) allowed high (40 to 60%) 178Ta yield. Minimal 178W breakthrough (less than .01%) resulted, even after elution of more than 200 column-volumes. Each of six tested generators provided sterile, high activity (up to 100 mCi) 178Ta elutions for more than 30 days. Radiation dosimetry was estimated utilizing both human and animal biodistribution data. The whole body (critical organ) dose in adults and neonates were 1/20 (1/21) and 1/19 (1/50) respectively relative to that of technetium-99m (99mTc) as sodium pertechnetate. The optimized 178W/178Ta generator provides a commercially practical, safe source of low-energy radioisotope for the MWGC with substantial dosimetry advantages over 99mTc.

Validation of left ventricular volume measurements by radionuclide angiography.

A nongeometric, attenuation-corrected technique to quantitate left ventricular volumes using equilibrium radionuclide angiography was validated in vitro and in vivo. In vitro experiments were performed to derive a linear attenuation coefficient, which was then employed in the volume determinations using balloons in a water bath. Good in vitro correlation was found between radionuclide and actual volumes (r = 0.99, p less than 0.0001), over a wide range (5 to 400 ml). In vivo validation was done by comparing the nuclear technique to contrast angiography in 29 patients: Good correlations were found for end-diastolic volume (r = 0.98), end-systolic volume (r = 0.95), stroke volume (r = 0.96), and ejection fraction (r = 0.85). When the conventional linear attenuation coefficient was used, the radionuclide technique consistently overestimated volumes in vitro and in vivo. Although high intraobserver and interobserver correlation coefficients were found (r from 0.88 to 0.93), significant individual variability existed, particularly in the interobserver data. Our data provide unique validation of radionuclide volume determinations, using an experimentally determined attenuation coefficient, which results in improved accuracy.

A gamma camera for medical applications, using a multiwire proportional counter.

A multiwire proportional counter gamma camera, specifically designed for nuclear medicine applications, is portable and weighs less than 50 lb including shielding and collimator. The basic operating characteristics have been investigated with various radioactive sealed sources. The camera demonstrates a peak count rate of 850,000 cps, an intrinsic spatial resolution of 2.5 mm, and excellent image uniformity when used with x-ray sources in the range of 22-81 keV. Tests of the device with Ta-178--a very promising, short half-life (9.3 min), low-energy radionuclide--using 20 mCi injections provided images of quality comparable to those obtained from 15 mCi Tc-99m studies with conventional imaging devices. The camera used with Ta-178 offers particular promise in first-pass nuclear cardiology studies. Considerably improved study quality will likely result in this area because of the increased injectable dose levels offered by Ta-178 combined with the high-count rate capability and improved resolution.

Regional changes in muscle mass following 17 weeks of bed rest.

This work reports on the muscle loss and recovery after 17 wk of continuous bed rest and 8 wk of reambulation in eight normal male volunteers. Muscle changes were assessed by urinary levels of 3-methylhistidine (3-MeH), nitrogen balance, dual-photon absorptiometry (DPA), magnetic resonance imaging (MRI), and isokinetic muscle performance. The total body lean tissue loss during bed rest calculated from nitrogen balance was 3.9 +/- 2.1 (SD) kg (P < 0.05). Although the total loss is minimal, DPA scans showed that nearly all of the lean tissue loss occurred in the lower limbs. Similarly, MRI muscle volume measurements showed greater percent loss in the limbs relative to the back muscles. MRI, DPA, and nitrogen balance suggest that muscle atrophy continued throughout bed rest with rapid recovery after reambulation. Isokinetic muscle strength decreased significantly (P < 0.05) in the thigh and calf with no loss in the arms and with rapid recovery during reambulation. We conclude that there is great variability in the degree and location of muscle loss in bed rest and that the lower limb muscles are primarily affected.

Resistance exercise as a countermeasure to disuse-induced bone loss.

During spaceflight, skeletal unloading results in loss of bone mineral density (BMD). This occurs primarily in the spine and lower body regions. This loss of skeletal mass could prove hazardous to astronauts on flights of long duration. In this study, intense resistance exercise was used to test whether a training regimen would prevent the loss of BMD that accompanies disuse. Nine subjects (5 men, 4 women) participated in a supine maximal resistance exercise training program during 17 wk of horizontal bed rest. These subjects were compared with 18 control subjects (13 men, 5 women) who followed the same bed rest protocol without exercise. Determination of treatment effect was based on measures of BMD, bone metabolism markers, and calcium balance obtained before, during, and after bed rest. Exercisers and controls had significantly (P < 0.05) different means, represented by the respective following percent changes: lumbar spine BMD, +3% vs. -1%; total hip BMD, +1% vs. -3%; calcaneus BMD, +1% vs. -9%; pelvis BMD, -0.5% vs. -3%; total body BMD, 0% vs. -1%; bone-specific alkaline phosphatase, +64% vs. 0%; alkaline phosphatase, +31% vs. +5%; osteocalcin, +43% vs. +10%; 1,25 dihydroxyvitamin D, +12% vs. -15%; parathyroid hormone intact molecule, +18% vs. -25%; and serum and ionized calcium, -1% vs. +1%. The difference in net calcium balance was also significant (+21 mg/day vs. -199 mg/day, exercise vs. control). The gastrocnemius and soleus muscle volumes decreased significantly in the exercise group, but the loss was significantly less than observed in the control group. The results indicate that resistance exercise had a positive treatment effect and thus might be useful as a countermeasure to prevent the deleterious skeletal changes associated with long-duration spaceflight.

Feasibility study: in vivo neutron activation for regional measurement of calcium using californium 252.

The feasibility of using a collimated 252Cf neutron source to measure regional changes in skeletal calcium was tested because in vivo regional activation of diseased bone should offer advantages over the more widely reported total-body calcium measuring techniques. Regional activation allows examination of discrete regions where the greatest changes in calcium content occur. Additionally, a simpler radiation facility is required for regional studies. Using a 5.5-mug 252Cf source, thermal neutron flux and absorbed dose were measured in a tissue-equivalent phantom. Detection efficiency of 49Ca gamma rays for conditions simulating regional activation were measured using a 29-cm-diameter X 10-cm-thickness sodium iodide detector. These in vitro measurements indicate that a collimated 252Cf source can be used for regional neutron activation of the lower spine and legs. Preliminary calculations indicate that a 1-3-mg source provides adequate count rates for statistical accuracy with a bone marrow dosage acceptable for human patients and normal subjects.

Changes in intervertebral disc cross-sectional area with bed rest and space flight.

STUDY DESIGN: We measured the cross-sectional area of the intervertebral discs of normal volunteers after an overnight rest; before, during, and after 5 or 17 weeks of bed rest; and before and after 8 days of weightlessness. OBJECTIVES: This study sought to determine the degree of expansion of the lumbar discs resulting from bed rest and space flight. SUMMARY OF BACKGROUND DATA: Weightlessness and bed rest, an analog for weightlessness, reduce the mechanical loading on the musculoskeletal system. When unloaded, intervertebral discs will expand, increasing the nutritional diffusion distance and altering the mechanical properties of the spine. METHODS: Magnetic resonance imaging was used to measure the cross-sectional area and transverse relaxation time (T2) of the intervertebral discs. RESULTS: Overnight or longer bed rest causes expansion of the disc area, which reaches an equilibrium value of about 22% (range 10-40%) above baseline within 4 days. Increases in disc area were associated with modest increases in disc T2. During bed rest, disc height increased approximately 1 mm, about one-half of previous estimates based on body height measurements. After 5 weeks of bed rest, disc area returned to baseline within a few days of ambulation, whereas after 17 weeks, disc area remained above baseline 6 weeks after reambulation. After 8 days of weightlessness, T2, disc area, and lumbar length were not significantly different from baseline values 24 hours after landing. CONCLUSIONS: Significant adaptive changes in the intervertebral discs can be expected during weightlessness. These changes, which are rapidly reversible after short-duration flights, may be an important factor during and after long-duration missions.