«Nutrients 2012, 4, 2047-2068; doi:10.3390/nu4122047 OPEN ACCESS nutrients ISSN 2072-6643 Review Space Flight Calcium: ...»
Nutrients 2012, 4, 2047-2068; doi:10.3390/nu4122047
Space Flight Calcium: Implications for Astronaut Health,
Spacecraft Operations, and Earth
Scott M. Smith 1,*, Torin McCoy 1, Daniel Gazda 2, Jennifer L. L. Morgan 3, Martina Heer 4,5
and Sara R. Zwart 6
Human Health and Performance Directorate, NASA Lyndon B. Johnson Space Center, Houston,
TX 77058, USA; E-Mail: firstname.lastname@example.org
Wyle Science, Technology & Engineering Group, Houston, TX 77058, USA;
E-Mail: email@example.com Oak Ridge Associated Universities/NASA Post-Doctoral Fellow, NASA Lyndon B. Johnson Space Center, Houston, TX 77058, USA; E-Mail: firstname.lastname@example.org Profil Institut fü Stoffwechselforschung GmbH, Hellersbergstrasse 9, 41460 Neuss, Germany;
r E-Mail: email@example.com University of Bonn, 53115 Bonn, Germany Division of Space Life Sciences, Universities Space Research Association, Houston, TX 77058, USA; E-Mail: firstname.lastname@example.org * Author to whom correspondence should be addressed; E-Mail: email@example.com;
Tel.: +1-(281)-483-7204; Fax: +1-(281)-483-2888.
Received: 11 October 2012; in revised form: 13 November 2012 / Accepted: 10 December 2012 / Published: 18 December 2012 Abstract: The space flight environment is known to induce bone loss and, subsequently, calcium loss. The longer the mission, generally the more bone and calcium are lost. This review provides a history of bone and calcium studies related to space flight and highlights issues related to calcium excretion that the space program must consider so that urine can be recycled. It also discusses a novel technique using natural stable isotopes of calcium that will be helpful in the future to determine calcium and bone balance during space flight.
Keywords: bed rest; bone; calcium; collagen crosslinks; dual-energy X-ray absorptiometry;
space flight Nutrients 2012, 4 2048
1. Introduction Bone and calcium metabolism have been a concern for space travelers, literally since before human space flight was a reality. A little more than a half century after the first human space flight, we have improved our understanding of the effects of space flight on calcium and bone, but we still have much to learn. We review here the current state of knowledge and describe ongoing studies, including application of the findings to space exploration and implications for the general population.
2. Bone Loss Space flight-induced bone and calcium loss have been documented for decades, and have been the subject of many reviews [1–5]. There have also been several evaluations of ground-based analogs, including the most common, bed rest [6,7]. Bed rest is a viable model of space flight-induced bone loss, producing metabolic changes and bone loss that are qualitatively similar to those brought on by space flight but have a smaller magnitude. Bone loss in bed rest is about half of that observed in space flight [8,9].
Documentation of negative calcium balance and increased calcium excretion during space flight first came from Gemini and Apollo missions of the 1960s and early 1970s [10,11], but bed rest studies documenting negative calcium balance go back even further, with initial documentation in the 1940s . Although urinary and fecal calcium excretion were shown clearly to increase on short-duration space flights (1–2 weeks of flight), not until the longer Skylab missions were flown (1973–1974) were actual changes in bone observed using densitometry [13,14].
In the 1990s the Russian space station Mir provided a platform for long-duration studies on changes in bone during space flight. Dual-energy X-ray absorptiometry (DXA) scans on astronauts and cosmonauts began to better characterize and quantify bone loss during space flight [2,15,16]. Although considerable site-to-site variability exists, along with crewmember-to-crewmember variability, in general, a 1.0%–1.5% loss of bone mineral density occurred per month of space flight . Bone biochemistry studies in the 1990s also expanded significantly, largely fueled by the identification of collagen crosslinks as markers that could be used to assess bone resorption, and development of immunoassays to measure these crosslinks along with markers of bone formation. Novel techniques are being developed to assess overall bone balance using stable isotopes of calcium. These techniques will be beneficial because they are noninvasive (only a urine sample is needed), might be possible to do during flight, and will give a picture of overall bone balance instead of resorption or formation alone. These techniques will be discussed in detail below.
Early flight experiments with animals pointed to a decrease in bone formation as the metabolic key to bone loss, whereas human studies (both space flight and bed rest) clearly pointed to an increase in bone resorption, with bone formation being either unchanged or slightly decreased [17–22]. Further research documented that the discrepancy between the animal and human data was not caused by a problem with the animal model itself, but rather by an issue with the age of the animals used in those early flight studies. In young rats, bone formation is suppressed during space flight. In mature rats, bone resorption predominates and little change is seen in bone formation , as evidenced in hindlimb-suspension studies. These differences in mechanism of bone metabolism must be considered Nutrients 2012, 4 2049 when interpreting results from space flight studies. Young animals are commonly used in research, and provide an added benefit for space flight studies in that more animals may be flown in the limited space available for animal research on these missions. Although any model has limitations, and these need to be carefully accounted for, animal studies do provide the ability to do more extensive research on mechanisms of bone loss.
In 2000, the first crews took up residence on the International Space Station (ISS), marking the beginning of what many hope will be a permanent human presence off the planet. One of the novel aspects of the ISS was the inclusion of resistance exercise equipment. Details of these efforts will be described below, but although initial evaluations were disappointing , possibly because of altered kinematics , recent evidence illustrates the potential of proper nutrition and exercise regimens to prevent whole-body and regional loss of bone mineral density  during extended space flight.
3. Calcium Isotopes and Relevance for Bone Turnover
Analytical techniques to assess bone health, bone loss, and bone metabolism continue to evolve with technology. Although densitometry techniques (such as DXA and quantitative computerized tomography) provide valuable assessment of specific bones, these techniques detect only relatively large changes in bone, and it takes several months for changes of this magnitude to occur. Studying calcium requires either intensive balance studies or tracer kinetic studies. Bone biochemical markers can provide more rapid assessments of changes in bone formation or resorption, but assessing the relative association of these two factors has not been possible to date, and thus it is difficult to assess net changes in bone calcium content.
A new technique to rapidly detect and quantitatively predict changes in bone mineral balance (the ratio of bone formation to resorption) has recently been validated in a bed rest model .
Changes in bone mineral balance as a result of bed rest can be detected by measuring the ratios of stable calcium isotopes in urine from individuals who have not received any stable isotope tracers .
This calcium isotope biomarker is based on natural, biologically induced variations. These variations are a result of the 6 naturally occurring calcium isotopes (40Ca, 42Ca, 43Ca, 44Ca, 46Ca, and 48Ca) reacting at different rates depending on their mass . In general, isotopic selectivity can occur in all elements with multiple stable isotopes, and has been measured in light elements such as hydrogen, oxygen, carbon, and nitrogen for many decades. These variations arise because the vibrational frequencies of any chemical bonds are a function of the masses of the constituent nuclides. As a result, more energy is required to break bonds formed from heavy isotopes than for the same bond with a lighter isotope. In chemical reactions that do attain equilibrium (which are rare in biology), heavier isotopes are preferentially concentrated in the strongest chemical bonding environments. In chemical reactions that do not attain equilibrium (e.g., kinetic reactions), the bonds incorporating lighter isotopes usually react more quickly than those incorporating heavier isotopes. Kinetic processes like diffusion, evaporation, and precipitation, preferentially select lighter isotopes because they move faster than heavy isotopes [30,31]. In soft tissue (e.g., blood, urine), variations in the calcium isotope composition exist because bone formation depletes soft tissue of lighter calcium isotopes most likely as a result of isotope selectivity during osteoblast-induced calcium precipitation. Bone resorption releases that isotopically light calcium back into soft tissue. Therefore, when bone is being resorbed, as Nutrients 2012, 4 2050 is the case during bed rest, the urinary calcium isotope abundance shifts toward lighter values (i.e., −δ44/42Ca; more 42Ca and less 44Ca relative to baseline). Applying this technique to a bed rest study, it was shown that the calcium isotope ratio shifted in a direction consistent with bone loss after just 7 days of bed rest, long before detectable changes in bone density occur. Consistent with this interpretation, the calcium isotope variation accompanied changes observed in N-telopeptide, while bone-specific alkaline phosphatase, a bone-formation biomarker, was unchanged (Figure 1) .
Figure 1. Variations in bone biochemical markers N-telopeptide (NTX, top panel) and bone-specific alkaline phosphatase (BSAP, middle panel), along with calcium isotopes (bottom panel), during and after bed rest (days 0 to 40).
Percent changes were calculated as the difference between the measured value at each time point and the average of the pre-bed rest values (baseline, days to left of day 0) for that individual. All values are mean ± SD. The calcium isotopes shift in a direction consistent with bone loss after just 7 days of bed rest and track the signal observed in NTX while BSAP remains unchanged.
Note: This figure is adapted with permission from , Copyright © 2012 National Academy of Sciences. Data are from 12 subjects.
Nutrients 2012, 4 2051 As the relationship between calcium isotopes and bone mineral balance is well established based on the isotope selectivity principles described above and preliminary work measuring the offset between soft tissue and bone [32,33], this relationship can be used to quantitatively translate the changes in the calcium isotope ratio in urine to changes in bone mineral density using a simple model (Figure 2) .
Using this model it was estimated that subjects lost 0.25% ± 0.07% (1 SD) of their bone mass from day 7 to day 30 of bed rest . This rate of loss extrapolates to a loss of 1.36% ± 0.38% of skeletal mass over 119 days, which is equivalent, within error, to bone loss rates determined by DXA scans in long-term (119-day) bed rest studies .
Figure 2. Schematic of model pools and fluxes used to quantify bone loss.
Fdiet is the flux of calcium absorbed from diet, Fbone and Fresorp are the bone formation and resorption fluxes, and Furine and Fbile are the net excretion fluxes of calcium through urine and bile respectively. 44/42Casoft and δ44/42Cabone are the Ca isotopic compositions of the soft tissue and bone pools, δ44/42Cadiet and δ44/42Caurine are the isotopic compositions of the fluxes of Ca absorbed from diet and excreted in urine, and ε44/42Cabone, ε44/42Caurine, and ε44/42Cabile are the isotopic variations associated with forming bone, urine, and bile, respectively, from the soft tissue pool. Note: This figure is adapted with permission from , Copyright © 2012 National Academy of Sciences.
A preliminary study examined the calcium isotope shift in bed rest subjects undergoing three different treatments (untreated bed rest, the bisphosphonate alendronate, and intense resistance exercise) [35,36]. In this study there were significant differences in isotope response: the control group’s calcium isotope composition shifted in a direction consistent with bone resorption, while the alendronate and resistance exercise groups’ calcium isotope composition shifted in a manner suggesting maintained and slightly increased bone formation, respectively .
Given the rapid signal observed using calcium isotope measurements and the potential to quantitatively assess bone loss, this technique is ideally suited for space flight studies in which changes Nutrients 2012, 4 2052 in bone formation and resorption are not only being altered by space flight itself but are being manipulated by various countermeasures.
4. Dietary Calcium When bone loss is considered, calcium intake is an obvious initial concern. Skylab crews consumed an average of 894 ± 142 (SD) mg calcium/day  while participating in carefully planned and executed metabolic balance studies over the entire course of their missions (28, 59, and 84 days) [14,37].
Based on reviews of available information, a decision was made requiring that the ISS food system shall provide 1000–1200 mg calcium per day , similar to Earth-based recommendations. Proximate analysis of the foods provided in the ―standard‖ menu revealed that calcium content of the ISS menu averages 1020 ±109 mg calcium/day .
Although the crews self-select meals while they are on board the ISS, dietary intake estimates using a food frequency questionnaire designed for space flight documented actual intakes of calcium during flight that were in the same range as in the ―standard‖ menu, 1068 ± 384 mg calcium/day in one report , and 912 ± 229 and 1025 ± 309 mg calcium/day in another . Thus, intakes typically are close to or meeting planned calcium intake during flight, which is similar to the Earth-based recommended intake.
5. Calcium Absorption, Metabolism, and Excretion