Bone loss and renal stone risk are longstanding concerns for astronauts. Bone resorption brought on by spaceflight elevates urinary calcium and the risk of renal stone formation. Loss of bone calcium ...leads to concerns about fracture risk and increased long-term risk of osteoporosis. Bone metabolism involves many factors and is interconnected with muscle metabolism and diet. We report here bone biochemistry and renal stone risk data from astronauts on 4- to 6-month International Space Station missions. All had access to a type of resistive exercise countermeasure hardware, either the Advanced Resistance Exercise Device (ARED) or the Interim Resistance Exercise Device (iRED). A subset of the ARED group also tested the bisphosphonate alendronate as a potential anti-resorptive countermeasure (Bis+ARED). While some of the basic bone marker data have been published, we provide here a more comprehensive evaluation of bone biochemistry with a larger group of astronauts. Regardless of exercise, the risk of renal stone formation increased during spaceflight. A key factor in this increase was urine volume, which was lower during flight in all groups at all time points. Thus, the easiest way to mitigate renal stone risk is to increase fluid consumption. ARED use increased bone formation without changing bone resorption, and mitigated a drop in parathyroid hormone in iRED astronauts. Sclerostin, an osteocyte-derived negative regulator of bone formation, increased 10-15% in both groups of astronauts who used the ARED (p<0.06). IGF-1, which regulates bone growth and formation, increased during flight in all 3 groups (p<0.001). Our results are consistent with the growing body of literature showing that the hyper-resorptive state of bone that is brought on by spaceflight can be countered pharmacologically or mitigated through an exercise-induced increase in bone formation, with nutritional support. Key questions remain about the effect of exercise-induced alterations in bone metabolism on bone strength and fracture risk.
Bed rest studies document that a lower dietary acid load is associated with lower bone resorption.
We tested the effect of dietary acid load on bone metabolism during spaceflight.
Controlled 4-d ...diets with a high or low animal protein–to-potassium (APro:K) ratio (High and Low diets, respectively) were given to 17 astronauts before and during spaceflight. Each astronaut had 1 High and 1 Low diet session before flight and 2 High and 2 Low sessions during flight, in addition to a 4-d session around flight day 30 (FD30), when crew members were to consume their typical in-flight intake. At the end of each session, blood and urine samples were collected. Calcium, total protein, energy, and sodium were maintained in each crew member's preflight and in-flight controlled diets.
Relative to preflight values, N-telopeptide (NTX) and urinary calcium were higher during flight, and bone-specific alkaline phosphatase (BSAP) was higher toward the end of flight. The High and Low diets did not affect NTX, BSAP, or urinary calcium. Dietary sulfur and age were significantly associated with changes in NTX. Dietary sodium and flight day were significantly associated with urinary calcium during flight. The net endogenous acid production (NEAP) estimated from the typical dietary intake at FD30 was associated with loss of bone mineral content in the lumbar spine after the mission. The results were compared with data from a 70-d bed rest study, in which control (but not exercising) subjects’ APro:K was associated with higher NTX during bed rest.
Long-term lowering of NEAP by increasing vegetable and fruit intake may protect against changes in loss of bone mineral content during spaceflight when adequate calcium is consumed, particularly if resistive exercise is not being performed. This trial was registered at clinicaltrials.gov as NCT01713634.
Bone loss is a current limitation for long-term space exploration. Bone markers, calcitropic hormones, and calcium kinetics of crew members on space missions of 4-6 months were evaluated. ...Spaceflight-induced bone loss was associated with increased bone resorption and decreased calcium absorption. INTRODUCTION: Bone loss is a significant concern for the health of astronauts on long-duration missions. Defining the time course and mechanism of these changes will aid in developing means to counteract these losses during space flight and will have relevance for other clinical situations that impair weight-bearing activity. MATERIALS AND METHODS: We report here results from two studies conducted during the Shuttle-Mir Science Program. Study 1 was an evaluation of bone and calcium biochemical markers of 13 subjects before and after long-duration (4-6 months) space missions. In study 2, stable calcium isotopes were used to evaluate calcium metabolism in six subjects before, during, and after flight. Relationships between measures of bone turnover, biochemical markers, and calcium kinetics were examined. RESULTS: Pre- and postflight study results confirmed that, after landing, bone resorption was increased, as indicated by increases in urinary calcium (p < 0.05) and collagen cross-links (N-telopeptide, pyridinoline, and deoxypyridinoline were all increased >55% above preflight levels, p < 0.001). Parathyroid hormone and vitamin D metabolites were unchanged at landing. Biochemical markers of bone formation were unchanged at landing, but 2-3 weeks later, both bone-specific alkaline phosphatase and osteocalcin were significantly (p < 0.01) increased above preflight levels. In studies conducted during flight, bone resorption markers were also significantly higher than before flight. The calcium kinetic data also validated that bone resorption was increased during flight compared with preflight values (668 +/- 130 versus 427 +/- 153 mg/day; p < 0.001) and clearly documented that true intestinal calcium absorption was significantly lower during flight compared with preflight values (233 +/- 87 versus 460 +/- 47 mg/day; p < 0.01). Weightlessness had a detrimental effect on the balance in bone turnover such that the daily difference in calcium retention during flight compared with preflight values approached 300 mg/day (-234 +/- 102 versus 63 +/- 75 mg/day; p < 0.01). CONCLUSIONS: These bone marker and calcium kinetic studies indicated that the bone loss that occurs during space flight is a consequence of increased bone resorption and decreased intestinal calcium absorption.
ABSTRACT
Introduction
Hypocalcemia is a known sequela of citrated blood product transfusion. Civilian data suggest hypocalcemia on hospital admission is associated with worse outcomes. Initial ...calcium levels in military casualties have not previously been analyzed. The objective of this retrospective review aimed to assess the initial calcium levels in military trauma casualties at different Forward Surgical Teams (FST) locations in Afghanistan and describe the effects of prehospital blood product administration on arrival calcium levels.
Materials and Methods
This is a retrospective cohort analysis of military casualties arriving from point of injury to one of two FSTs in Afghanistan from August 2018 to February 2019 split into four locations. The primary outcome was incidence of hypocalcemia (ionized calcium < 1.20 mmol/L).
Results
There were 101 patients included; 55 (54.5%) experienced hypocalcemia on arrival to the FST with a mean calcium of 1.16 mmol/L (95% confidence interval CI, 1.14 to 1.18). The predominant mechanism of injury consisted of blast patterns, 46 (45.5%), which conferred an increased risk of hypocalcemia compared to all other patterns of injury (odds ratio = 2.42, P = .042). Thirty-eight (37.6%) patients required blood product transfusion. Thirty-three (86.8%) of the patients requiring blood product transfusion were hypocalcemic on arrival. Mean initial calcium of patients receiving blood product was 1.13 mmol/L (95% CI, 1.08 to 1.18), which was significantly lower than those who did not require transfusion (P = .01). Eight (7.9%) of the patients received blood products before arrival, with 6/8 (75%) presenting with hypocalcemia.
Conclusions
Hypocalcemia develops rapidly in military casualties and is prevalent on admission even before transfusion of citrated blood products. Blast injuries may confer an increased risk of developing hypocalcemia. This data support earlier use of calcium supplementation during resuscitation.
Bone loss associated with disuse during bed rest (BR), an analog of space flight, can be attenuated by exercise. In previous studies, the efficacy of either aerobic or resistive exercise ...countermeasures has been examined separately. We hypothesized that a regimen of combined resistive and aerobic exercise during BR would prevent bone resorption and promote bone formation. After a 20-day ambulatory adaptation to controlled confinement and diet, 16 women participated in a 60-day, 6 degrees head-down-tilt BR and were assigned randomly to one of the two groups. Control subjects (CON, n=8) performed no countermeasure. Exercise subjects (EX, n=8) participated in an exercise program during BR, alternating between supine treadmill exercise within lower body negative pressure (3-4 d wk(-1)) and flywheel resistive exercise (2-3 d wk(-1)). By the last week of BR, excretion of helical peptide (CON, 79%+/-44 increase; EX, 64%+/-50, mean+/-SD) and N-terminal cross-linking telopeptide (CON, 51%+/-34; EX, 43%+/-56), markers of bone resorption, were greater than they were before BR in both groups (P<0.05). However, serum concentrations of the bone formation marker procollagen type I N propeptide were greater in EX than CON throughout and after bed rest (P<0.05), while concentrations of the bone formation marker bone alkaline phosphatase tended to be greater in EX than CON. Dual-energy X-ray absorptiometry results indicated that the exercise treatment significantly (P<0.05) attenuated loss of hip and leg bone mineral density in EX compared to CON. The combination of resistive and aerobic exercise did not prevent bone resorption but did promote bone formation, and helped mitigate the net bone loss associated with simulated microgravity.
The purpose of this study was to directly assess sex differences in bone loss, bone biochemistry, and renal stone risk in bed rest. Bed rest simulates some spaceflight effects on human physiology and ...can be used to address the potential existence of sex‐specific effects on bone metabolism and renal stone risk in space. We combined data from the control subjects in five head‐down‐tilt bed rest studies (combined n = 50 men, 24 women) of differing durations (14–90 days). All subjects were healthy volunteers. Mean age was 35 ± 9 years for women and 33 ± 8 years for men. The main outcome measures were bone density and biochemistry, and renal stone risk chemistry. Before bed rest began, men had higher bone mineral density and content (P < 0.001), and excreted more biomarkers of bone resorption and calcium per day than did women (P < 0.05). These differences remained during bed rest. A number of urine chemistry analytes increased (e.g., calcium) or decreased (e.g., sodium, citrate, and urine volume) significantly for men and women during bed rest. These changes may predispose men to higher stone risk. Men and women do not have substantially different responses to the skeletal unloading of bed rest.
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We report here that bed rest‐induced bone loss, bone biochemistry, and renal stone risk in humans does not depend on sex. These data are a compilation and analysis of original data from our multiple (published) studies; none of those were adequately powered to assess sex differences. Thus, the resulting findings provide an important new look at the data.
The impact of microgravity on the human body is a significant concern for space travelers. We report here initial results from a pilot study designed to explore the utility of artificial gravity (AG) ...as a countermeasure to the effects of microgravity, specifically to bone loss. After an initial phase of adaptation and testing, 8 male subjects underwent 21 days of 6° head‐down bed rest to simulate the deconditioning associated with space flight. Six of the subjects underwent 1 h of centrifugation (AG, 1 gz at the heart, 2.5 gz at the feet) each day for 21 days, while 2 of the subjects served as untreated controls (CN). Blood and urine were collected before, during, and after bed rest for bone marker determinations. Comparing the last week of bed rest to before bed rest, urinary excretion of the bone resorption marker n‐telopeptide increased 95 ± 59% (mean ± SD) in CN but only 32 ± 26% in the AG group. Similar results were found for another resorption marker, helical peptide (increased 57 ± 0% and 35 ± 13% in CN and AG respectively). Bone‐specific alkaline phosphatase did not change during bed rest. The study will continue with additional subjects and measures, including calcium tracer kinetic studies. These initial data demonstrate the potential effectiveness of short‐radius, intermittent AG as a countermeasure to the bone deconditioning that occurs during bed rest.
Supported by the NASA AG‐Bed Rest Project (IMAG Pilot Study, PIs: WH Paloski and LR Young).
This review will highlight evidence from crew members flown on space missions >90 days to suggest that the adaptations of the skeletal system to mechanical unloading may predispose crew members to an ...accelerated onset of osteoporosis after return to Earth. By definition, osteoporosis is a skeletal disorder--characterized by low bone mineral density (BMD) and structural deterioration--that reduces the ability of bones to resist fracture under the loading of normal daily activities. 'Involutional' or age-related osteoporosis is readily recognized as a syndrome afflicting the elderly population because of the insipid and asymptomatic nature of bone loss that does not typically manifest as fractures until after age ~60. It is not the thesis of this review to suggest that spaceflight-induced bone loss is similar to bone loss induced by metabolic bone disease; rather this review draws parallels between the rapid and earlier loss in females that occurs with menopause and the rapid bone loss in middle-aged crew members that occurs with spaceflight unloading and how the cumulative effects of spaceflight and ageing could be detrimental, particularly if skeletal effects are totally or partially irreversible. In brief, this report will provide detailed evidence that long-duration crew members, exposed to the weightlessness of space for the typical long-duration (4--6 months) mission on Mir or the International Space Station, (1) display bone resorption that is aggressive, that targets normally weight-bearing skeletal sites, that is uncoupled to bone formation, and that results in areal BMD deficits that can range between 6 and 20% of preflight BMD; (2) display compartment-specific declines in volumetric BMD in the proximal femur (a skeletal site of clinical interest) that significantly reduces its compressive and bending strength and may account for the loss in hip bone strength (i.e., force to failure); (3) recover BMD over a post-flight time period that exceeds spaceflight exposure but for which the restoration of whole bone strength remains an open issue and may involve structural alteration; and (4) display risk factors for bone loss--such as the negative calcium balance and down-regulated calcium-regulating hormones in response to bone atrophy--that can be compounded by the constraints of conducting mission operations (inability to provide essential nutrients and vitamins). The full characterization of the skeletal response to mechanical unloading in space is not complete. In particular, countermeasures used to date have been inadequate, and it is not yet known whether more appropriate countermeasures can prevent the changes in bone that have been found in previous flights. Knowledge gaps related to the effects of prolonged (>=6 months) space exposure and to partial gravity environments are substantial, and longitudinal measurements on crew members after spaceflight are required to assess the full impact on skeletal recovery.
This minireview provides an overview of known and potential gender differences in physiological responses to spaceflight. The paper covers cardiovascular and exercise physiology, barophysiology and ...decompression sickness, renal stone risk, immunology, neurovestibular and sensorimotor function, nutrition, pharmacotherapeutics, and reproduction. Potential health and functional impacts associated with the various physiological changes during spaceflight are discussed, and areas needing additional research are highlighted. Historically, studies of physiological responses to microgravity have not been aimed at examining gender-specific differences in the astronaut population. Insufficient data exist in most of the discipline areas at this time to draw valid conclusions about gender-specific differences in astronauts, in part due to the small ratio of women to men. The only astronaut health issue for which a large enough data set exists to allow valid conclusions to be drawn about gender differences is orthostatic intolerance following shuttle missions, in which women have a significantly higher incidence of presyncope during stand tests than do men. The most common observation across disciplines is that individual differences in physiological responses within genders are usually as large as, or larger than, differences between genders. Individual characteristics usually outweigh gender differences per se.
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