Impact of Exercise-Induced Strains and Nutrition on Bone Mineral Density in Spaceflight and on the Ground

How Spaceflight/Unloading Impact BMD: Greater Bone Resorption

Of all the changes the human body incurs from spaceflight/unloading, bone loss is perhaps the most insidious. This is because unlike muscle atrophy, bone mineral density (BMD) losses in microgravity, which occur at slower rates than those for muscle, may never return to their preflight levels, even long after resumption of postflight ambulation. ^{51 , 60} While a recent review examined BMD in the non-weight-bearing skeleton, in-vitro animal and human bone cell physiology in microgravity, as well as molecular therapies to mitigate bone loss, the current literature review takes a different approach to focus on the impact of exercise-induced strains and nutrition on bone in spaceflight and ground-based models. ⁵⁷ Collectively referred to as “bone loss countermeasures” by the spaceflight community, the singular and combined effects of exercise and nutrition warrant continued inquiry to preserve skeletal health and integrity in astronauts and other disuse atrophy conditions. However, it is first important to understand the mechanisms and magnitude of BMD losses incurred from spaceflight and other disuse atrophy analogs.

As it relates to spaceflight, it is important to discuss mechanisms by which in-flight BMD losses occur, as such changes alter mechanotransduction and cellular physiology that increase bone resorption. Stem cells are precursors to bone cells that differentiate into the osteoblasts and osteoclasts vital to skeletal remodeling. Osteoclasts are derived and differentiate from stem cells via specific metabolic pathways. As part of bone remodeling on Earth, osteoclasts secrete acids that erode cortical and trabecular bone. ⁷⁸ As eroded bone sites reach critical depths, osteoclasts undergo apoptosis. Osteoclasts are responsive to pre- and anti-inflammatory cytokines that raise and lower bone resorption, respectively. ⁷⁸ In contrast, osteoblasts secrete bone-specific alkaline phosphatase, osteocalcin, and create a collagen type I-based matrix that raises BMD. ⁸⁰

Mechanotransduction is vital to bone remodeling, as it impacts osteoblast and osteoclast activity. It refers to conversion of mechanical stimuli into biochemical signals and is meditated by local fluid shear stresses and hydrostatic pressures. ^{38 , 55 , 79} On Earth, osteoblast and osteoclast activities are essentially equal, and produce only minor BMD changes over time. Yet cessation of gravity and normal mechanical loading elicit drastic mechanotransduction changes that evoke bone loss. Spaceflight impairs the ability of osteoclasts to sense mechanotransduction stimuli, with adverse consequences. ⁷⁸ Osteoclasts see their function increase in microgravity, as their differentiation, number, ability to resorb bone, and gene expression all rise in microgravity. ⁷⁸ In contrast, microgravity-induced mechanotransduction sees osteoblasts implode, and osteocytes undergo apoptosis, in as few as 3 d. ⁷⁸ These changes induce higher resorption during spaceflight.

Cessation of gravity and mechanical loading impacts cell remodeling pathways and subsequent osteoblast and osteoclast activity. Such pathways include transmembrane DNA nuclear factor kappaB (NF-_kB), sometimes called RANK. ^{6 , 82} NF-_kB activates genes that cause in-flight muscle and bone loss. NF-_kB rose ∼500% in microgravity and was elevated 14 d postflight. ^{6 , 94} NF-_kB is activated by the cytokine TNF-α ⁹⁴ . As RANK binds to its corresponding ligand (RANKL), differentiation begins and creates more osteoclasts and higher resorption. ^{29 , 82} BMD loss is abated by inhibition of RANKL. ⁴⁴ Osteoclasts also secrete sclerostin, which inhibits bone formation by reducing osteoblast differentiation. ^{82 , 88} Sclerostin also inhibits the protein Wnt and osteoblast differentiation, which limits their number and bone formation. ⁸⁸ Such changes in microgravity see bone loss rates rise 10-fold more than those who have osteoporosis on Earth. ⁸² In addition, a link exists between the neurovestibular and skeletal systems, as BMD losses in at least one disuse model (ageing) have a vestibular component. ⁸⁹ Neurovestibular changes in space may also contribute to in-flight BMD losses and are collectively part of a broad spectrum of perturbations known as space adaptation syndrome. ⁸⁹ Functional sensorimotor tests examined neurovestibular function aboard the International Space Station (ISS). ⁸⁹ With concurrent measurements of bone formation and resorption, a mechanistic link between in-flight neurovestibular impairments and BMD losses may be identified, but to date a direct cause and effect not been established.

Exacerbating BMD losses, bone formation is suppressed within 4 d of spaceflight from altered osteoblast function that includes disrupted microtube organization, as well as smaller and fewer focal adhesions and their proteins, which promote greater resorption. ^{29 , 59 , 82} Yet before such adverse changes occur, osteoblasts secrete osteoprotegrin which blocks RANK from binding to RANKL to limit osteoclast differentiation. ⁸² However, RANKL:osteoprotegrin ratios rose after 15 d of spaceflight, which inevitably increases resorption. ⁸² Versus conditions on Earth, both spaceflight and bed rest, the latter a microgravity analog, see resorption rates rise up to 150%. ^{75 , 92} Resorption markers have been identified in the blood and urine. ^{60 , 64 , 89} When combined with reduced diuresis and urine acidification, kidney stone risk also rises in microgravity. ^{35 , 89} Yet to date, there were no reported kidney stone cases aboard U.S. spaceflights, which was attributed to proper preflight screening. ³¹ Yet urinary Ca⁺² oxalate crystal supersaturation raises the risk of in-flight kidney stones. ³¹ In-flight hydration, exercise, and nutritional countermeasures serve as the primary means to prevent urinary Ca⁺² supersaturation. ³¹ Regarding hydration, some imply in-flight fluid intake should increase from current values of 2.0–2.5 L · day⁻¹ to ∼3.2 L · day⁻¹ to lower Ca⁺² oxalate levels to those of preflight levels. ³¹   Fig. 1 below is a schematic which summarizes osteoblast and osteoclast activities in non-disuse and microgravity conditions.

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Degree of BMD Loss From Spaceflight/Unloading

Combined with altered mechanotransduction stimuli that increase osteoclast activity and bone resorption, cessation of mechanical loading by weight-bearing muscles and bones limits strain imparted to the skeleton and exacerbates BMD loss. ⁹² The magnitude of BMD loss in space varies by skeletal region and its degree of weight-bearing responsibility on Earth. ⁸⁰ Round-trip Mars missions are projected to last 3 yr. ⁵ With a nonlinear model to predict femoral BMD losses for a Mars mission, and actual data from astronauts after 132- and 228-d missions, it is projected between 62–100% of crewmembers will develop osteopenia, and 33% will be at risk for osteoporosis. ⁵ Unfortunately, the human skeleton is only partially responsive to current in-flight countermeasures, with greater BMD losses produced from missions of longer duration. ^{28 , 80}

Without countermeasures, in-flight BMD losses proceed at rates of 1–3% per month. ^{49 , 73 , 92} However, after 30 d of spaceflight, a meta-analysis showed BMD losses continue to proceed at rates of 0.1% per month for the upper limbs and thorax, yet persist at 0.8% per month for the lower limbs. ⁸⁰ Higher rates of loss occur to lower body load-bearing sites with large amounts of trabecular bone, such as the calcaneus, which was attributed to its higher remodeling rate. ^{80 , 89} While a 17-wk bed rest saw significant lumbar spine (−3.9%), femoral neck (−3.6%), and trochanter (−4.6%) BMD losses, higher deficits (−10.4%) were incurred by the calcaneus. ⁵²

Lower limb BMD losses correlate significantly to mission duration. ^{28 , 80} Other sites prone to BMD losses are the hip and spine, which are essential to weight-bearing and ambulation in terrestrial environments. ^{48 , 89} When trabecular bone of the hip and spine incurs limited weight-bearing and impact forces, higher resorption results. Postflight hip volumetric BMD (vBMD) values saw significant losses measured by quantitative computed tomography. ⁷⁶ Without countermeasures, trabecular hip vBMD declines 2.2–2.7% per month and was projected to decline 5.4% after 6 mo. ^{48 , 49 , 89} BMD losses, after 4.5–14.5 mo in space, were highest for the pelvis (−11%), lumbar vertebrae (−6%), and femoral neck (−8%). ³³ Vertebral BMD in cosmonauts saw significant losses after 5 (−3.2%) and 7 (−6.6%) mo of spaceflight. ⁶³

The magnitude of such BMD losses impedes restoration of normal skeletal health and function in crewmembers long after their return to Earth. Trabecular hip vBMD was not restored after 2 yr of postflight recovery in 40% of astronauts, which implies permanent bone microarchitecture changes and a higher fracture risk during weight-bearing and ambulation. ^{64 , 77} Postflight restoration of preflight lower body BMD values may require 3–4 yr of ambulation on Earth. ⁷⁸ In-flight hip and spine BMD losses may reach 10% annually without countermeasures. ⁵² Abating in-flight trabecular BMD hip and spine loss is an important NASA research emphasis. ⁶⁰

In-Flight Pharmaceutical and Dietary Treatments to Abate BMD Losses

To address this issue and given their ability to reduce bone loss on Earth, pharmaceutical and dietary treatments were examined as countermeasures in microgravity and ground-based models. While dietary and pharmacological treatments given individually do little to prevent such losses, it was thought that by combining two or more with concurrent in-flight exercise, an additive effect on bone loss mitigation may occur. ^{44 , 82} Pharmaceuticals include bisphosphonates, which cause osteoclast apoptosis. ^{29 , 78} Bisphosphonates also limit in-flight urine Ca⁺² excretion to lower the risk of kidney stones, by as much as 30–125 mg · day⁻¹ as seen from 6-mo spaceflights. ³¹ Various combinations of bisphosphonate (alendronate at 70 mg · wk⁻¹) and resistive exercise treatments to abate bone loss were studied on the ISS. ⁷⁶ With data from three groups obtained before and after 6 mo of spaceflight, one group trained on the Interim Resistive Exercise Device, another on the advanced resistive exercise device (ARED), and a third combined ARED and bisphosphonate (70 mg · wk⁻¹) treatments. Each group incurred significant losses after 6 mo. Yet for cortical BMD, the ARED-bisphosphonate treatment had significantly smaller losses at the hip and lumbar spine, but not the femoral neck, than an ARED-only group. ⁷⁶ For trabecular bone, the ARED-bisphosphonate group had significantly better femoral neck BMD than the ARED-only treatment. ARED-bisphosphonate and ARED-only groups had similar hip and greater trochanter BMD values. A bisphosphonate-ARED treatment reduced resorption. ⁷⁶

Postflight bone loss at the femoral neck and hip persists despite in-flight ARED workouts. ⁵¹ While bisphosphonates limit bone loss, they cause numerous side-effects such as upper gastrointestinal disturbances, which occurred in two astronauts on the ISS. ^{43 , 44} Other side-effects include severe musculoskeletal pain, hypocalcemia, esophageal cancer, ocular inflammation, jaw osteonecrosis, atrial fibrillation, bone turnover suppression and, ironically, subtrochanteric femoral fractures. ⁴³ As it pertains to the latter, its occurrence is rare and was thought to result from long-term bisphosphonate use. ⁴³ Adequate vitamin D and Ca⁺² intakes are recommended, both on Earth and in microgravity, with bisphosphonate therapy. ^{43 , 76 , 89} Since the optimal dosage and duration of bisphosphonate administration exhibits considerable variability, in addition to the large and varied number of adverse side-effects, these drugs should be prescribed judiciously. ⁴³

Aside from bisphosphonates, other drugs were examined for their impact on bone. Statins were examined for their BMD effects, with positive outcomes at the total hip and lumbar spine, but not at the femoral neck or for vertebral fracture, in men. ² Yet statins had no positive outcomes on markers of bone formation or resorption. ² Their inability to elicit BMD gains in women, combined with their side-effects, suggests continued research on statins is needed before they can be used as an in-flight bone loss treatment. ² Other potential in-flight bone loss countermeasures include osteoanabolic and antisclerostin drugs. ^{68 , 71} Osteoanabolics improve bone formation, yet they have drawbacks that include limited compliance and many contraindications. ^{68 , 71} Compliance limitations include tissue-specific delivery of osteoanabolics at sufficient doses being difficult to achieve. ⁷¹ Another potential bone treatment is the antisclerostin drug romosozumab. It improves bone formation and suppresses resorption, which makes it a potent agent to combat BMD loss. ⁶⁸ However, its use is not without side-effects. Romosozumab (at 210-, 140-, and 70-mg injection dosages) is associated with a slight increase in the risk of osteoarthritis versus other comparator (alendronate, teriparatide, and placebo) agents examined in clinical trials. ⁶⁸

There was also a higher rate of cardiovascular events from romosozumab than with the bisphosphonate alendronate. ⁶⁸ The higher rate was attributed to a greater baseline risk, with fewer subjects on cardioprotective medication in groups treated with romosozumab. ⁶⁸ Nonetheless, romosozumab includes a warning that it may raise the risk of myocardial infarct, stroke, and cardiovascular death. ⁶⁸ Many osteoanabolic and antisclerostin trials did not include human subjects. ⁷¹ In addition, microgravity imposes unique changes to the human body that warrant concurrent drug administrations a higher risk than when the same treatment is given on Earth. The benefits of osteoanabolic and antisclerostin drugs warrant continued inquiry, but research on their safety for administration in microgravity remains a paramount concern.

Aside from various drugs, nutritional treatments were examined to abate bone loss. ⁸⁹ High kilocalorie, vitamin D, Ca⁺², and protein intakes were suggested as in-flight countermeasures to bone loss. ⁸⁹ Yet regarding the latter treatment, high-protein diets with large amounts of sulfur-rich amino acids lead to greater metabolic acidosis and bone resorption. ^{35 , 89} They may also cause hypercalciuria, which led some to also suggest intake of alkaline agents, like KHCO₃, to address this issue. ^{35 , 43} Several studies sought to address the problem of high-protein diets and greater bone resorption. ^{9 , 26 , 37} Two studies involved ambulatory subjects, ^{9 , 10} two others entailed bed rest, ^{26 , 37} while yet another collected data from crewmembers before and during spaceflight. ⁹⁵

The ambulatory studies induced metabolic acidosis with higher NaCl intakes. ^{9 , 10} Each ambulatory study entailed two 10-d interventions with a crossover. ^{9 , 10} Despite high NaCl intakes, KHCO₃ supplementation (90 mmol · d⁻¹) evoked a significant drop in glucocorticoid levels and reduced catabolism. ⁹ It was concluded that metabolic acidosis exacerbates bone loss. ¹⁰ The other ambulatory study had subjects supplement KHCO₃ (90 mmol · d⁻¹) for one 10-d intervention, while both 10-d periods entailed high NaCl diets. ⁹ Results showed KHCO₃ reduced bone resorption and improved buffer capacity. There was also a significant drop (−14%) in urinary glucocorticoids. Ca⁺² excretion and bone resorption significantly declined, by 12% and 8% respectively. ⁹ It was concluded that KHCO₃ limits acidosis, which in turn reduces protein and bone losses. ⁹

With a randomized crossover design, one bed rest study had subjects undergo two 21-d unloading periods either with, or without, KHCO₃ (90 mmol · d⁻¹) supplementation. ²⁶ Results showed KHCO₃ lowered urinary Ca⁺² excretion by neutralizing acids. ²⁶ However, it did not reduce bone resorption. ²⁶ To assess if high-protein diets elevate bone resorption, 16 women underwent 60 d of bed rest. ³⁷ Participants received one of two treatments with no crossover: controls ingested 1 g · kg⁻¹ of protein daily, while an experimental group consumed 1.45 g · kg⁻¹ of protein daily plus 0.72 g · d⁻¹ of branched chain amino acids. The high-protein group had a significant rise in C-telopeptide, a bone resorption marker linked to greater bone loss. ³⁷

A high-protein diet’s impact on bone was also assessed before and during spaceflight. ⁹⁵ With missions of 160 ± 20 d, 17 astronauts ingested 4-d diets with high, or low, protein to K⁺ ratios. ⁹⁵ In a randomized sequence, they consumed one high and one low 4-d diet preflight, and two high and two low 4-d diets in-flight. Ca⁺², total protein, energy, and Na⁺ were otherwise maintained with controlled diets. For both groups N-telopeptide (a bone resorption marker) and urinary Ca⁺² levels rose in microgravity, while bone-specific alkaline phosphatase (a bone formation marker) increased near the end of missions. Yet neither diet impacted expression of either bone marker or urinary Ca⁺² levels. It was concluded that low-acid diets may abate bone loss if: 1) an adequate level of Ca⁺² is provided and 2) in-flight resistive exercise is not performed. ⁹⁵

Perhaps a more direct nutritional strategy to abate bone loss is higher Ca⁺² intakes. ^{7 , 29 , 93} Yet Ca⁺² absorption in microgravity is impaired. ^{29 , 93} To address this problem and reduce bone loss, Ca⁺² and vitamin D supplementation, whereby the latter improves Ca⁺² homeostasis by absorbing more mineral from the bowel, are recommended. ²⁹ To limit negative Ca⁺² balances in microgravity, Ca⁺² and vitamin D supplementation were recommended at rates of 1000 mg · d⁻¹ and 800–1000 IU · d⁻¹, respectively, for missions up to a year in length. ²⁹ With in-flight Ca⁺² maintained at 1000 mg · d⁻¹, absorption was markedly reduced by Day 19 of spaceflight; there was also a sharp decline in plasma calcitrol unrelated to exogenous vitamin D and serum PTH levels. ⁸² Instead, plasma calcitrol losses were attributed to reduced synthesis in microgravity. ⁹³

Higher Ca⁺² dosages may offset its lower absorption in microgravity. ⁹³ To identify an ideal Ca⁺² dosage for spaceflight, two groups of men ingested either 1000 or 2000 mg · d⁻¹ of the mineral, with no crossover as bone markers were measured before, during, and after a 14-d bed rest. ⁷ Urinary Ca⁺² excretion and a bone resorption marker were higher during bed rest than before each ingested dose. Ca⁺² intakes of 2000 mg · d⁻¹, far greater than USRDA guidelines, did not stop resorption increases, and higher Ca⁺² intakes alone did not limit bone loss. It was concluded that higher Ca⁺² intakes are an adjunctive but important aid to limit BMD loss during unloading. ⁷

Dietary treatments also include omega-3 and isovaleric fatty acids (Ω-3FA, IVFA). ^{6 , 16 , 44} The Ω-3FA eicosapentanoic acid (EPA) inhibits NF-_KB and the ubiquitin proteolytic pathway that cause muscle and bone loss. ^{6 , 17} EPA (50 µM · d⁻¹) inhibited RANKL-induced differentiation and reduced NF-_KB to collectively limit osteoclast number and bone resorption. ⁹⁴ High EPA intakes correlated significantly with less N-telopeptide excretion during bed rest. ⁹⁴ It was concluded that EPA activates genes that suppress muscle and bone loss and may cause similar changes in microgravity. ⁹⁴ To take advantage of Ω-3FA, an antioxidant supplement was given during 60 d of bed rest to assess its impact on bone turnover. ⁴ Men (N = 20) adhered to a strict diet during bed rest and did not exercise. The supplement had 741 mg of polyphenols, 2.1 g of Ω-3FA, 168 mg of vitamin E, and 80 µg of Se. The supplement was ingested daily while protein intakes were kept constant. Energy consumption equaled 150% of subject’s basal metabolic rate plus an additional 10% of their total estimated energy cost. ⁴ While typical bed-rest-related changes occurred, the supplement did not impact serum Ca⁺², parathyroid hormone, or markers of bone resorption and formation. ⁴ Thus Ω-3FA, in addition to the other antioxidants within the supplement, was ineffective as a singular countermeasure to bone turnover during bed rest. ⁴

No in-flight guidelines for Ω-3FA exist, but 1.4–2.5 g · d⁻¹ is the range for suggested intake. ³ When administered concurrent to other treatments, Ω-3FA during long spaceflights may help abate bone loss. ^{6 , 44 , 50} High in-flight Ω-3FA intakes may suppress post-exercise inflammation. ⁶ Yet since inflammation is a normal feature of post-workout recovery, its mitigation by high Ω-3FA intakes may inhibit proper adaptations to in-flight exercise; thus, new Ω-3FA research is warranted. ⁶ IVFA, found in leucine-rich diets, limits osteoclast differentiation by suppressing specific genes. ¹⁶ IVFA also inhibits macrophage conversion to osteoclasts, which limit their number and bone resorption. ¹⁶ Given their promise, new EPA and IVFA research is warranted.

How Spaceflight/Unloading Impact BMD: Absence of Bone Strains

Spaceflight-induced BMD losses see an absence of bone strains preceding higher resorption. Insufficient strains, even when mechanical loading is provided by exercise, are a problem in microgravity. Strain refers to bone deformation, such as that produced by exercise, relative to its initial length or shape. ^{18 , 89} Three distinct strain features characterize mechanical loading stimuli: magnitude, rate, and frequency. ¹³ Magnitude denotes the absolute degree of distortion imparted by mechanical loading. ^{18 , 40 , 42} Frequency refers to how often strains are imparted, while rate is the change in magnitude per unit time. ^{18 , 40 , 91} Relationships among each strain feature are important, and specific mechanical loading stimuli must be consistently applied to best abate BMD loss in microgravity. ^{14 , 21} Yet most exercise modes and their hardware lack at least one bone strain feature. For instance, even among active adults, strain magnitudes for many activities are low. ¹³

Strains Produced by Exercise and Their Resultant Effects on Bone

In-flight strain restoration may best abate BMD loss in microgravity, since impact forces and mechanical loads generated by muscles are imparted to their skeletal attachment points to evoke subsequent remodeling. ^{13 , 42 , 91} Exercise-induced strains and their resultant remodeling were first examined in animal bones. ^{70 , 83 , 84} Results implied that once strain magnitudes exceeded osteogenic thresholds, strain rates and frequencies dictate the degree of osteogenesis. ^{40 , 41 , 81} In partial support of this finding, strains and their resultant adaptations were examined in rats assigned to one of five groups. ⁵⁸ Two groups were assigned to either a control or sham condition, while the others received peak tensile strains comparable to low- (450 µstrain), medium- (850 µstrain), or high-intensity (1250 µstrain) compressive loads 5 d · wk⁻¹ for 56 d. ⁵⁸ There were significantly better outcomes for the high-intensity versus the sham group. No significant differences occurred between the sham and control groups, or among the three strain groups. ⁵⁸

Given the strain application results and subsequent adaptations to animal bones, ^{18 , 40 , 81} research then examined if exercise improved BMD in humans. Yet results from those initial studies only saw modest changes. ^{62 , 65} They included interventions like whole-body vibration ^{25 , 72} or low-impact aerobic activity. ¹ Chronic walking did not abate bone loss in post-menopausal women. ¹⁵ This problem persists even in elite athletes from the sport of race walking, which was attributed to modest ground reaction (impact) forces and subsequent low strain magnitudes. ⁶⁵ Other athletes who exercise with low impact forces also incur lower BMD values. ²⁵ Exercise with high bone strain rates and frequencies, but low magnitudes, yield little ^{1 , 65 , 86} or no ¹⁵ BMD benefit.

Unlike whole-body vibration or low-impact aerobic activity, weight training offers higher mechanical loads for greater force exertion to presumably impart higher strain magnitudes. ^{39 , 62 , 92} Yet results from chronic (3–48 mo) weight training with heavy (70–90% 1RM) loads 2–5 d · wk⁻¹ only yielded small (+1–3%) BMD gains. ^{19 , 22 , 92} When a combined aerobic-strength training program was administered for 6 mo on the ISS, significant lower body BMD losses (∼−1.6%) persisted, regardless of whether crewmembers used a standard in-flight exercise prescription or one with a higher intensity. ²⁴ Strength training on flywheel-based hardware, concurrent to bisphosphonate therapy, only partially abated leg muscle and bone losses from a 90-d bed rest. ⁶⁹ Traditional weight training imparts strain magnitudes that exceed osteogenic thresholds, but, since repetitions occur slowly, low rates and frequencies limit its benefits. ^{19 , 23 , 92}

Since individual trabecular bone losses to the calcaneus, hip, and spine are among the highest incurred in microgravity, in-flight exercise to abate BMD loss was recommended for longer missions. ^{51 , 60} In-flight resistive exercise has the potential to restore mechanical loads and abate bone losses, with high volumes correlated to better skeletal preservation. ^{27 , 28} Yet mission duration, rather than exercise history or volume of in-flight physical activity, was identified as a more accurate bone loss predictor. ^{27 , 28} Better in-flight exercise prescriptions and hardware are needed to improve crewmember health, performance, and postflight recovery, particularly for longer missions. Current in-flight prescriptions generally see workouts occur 6 d · wk⁻¹, with 1.5 h and 1.0 h devoted to resistive and aerobic exercise, respectively. ⁵¹

Yet in-flight exercise hardware produces modest ground reaction forces that limit mechanical loads and bone strains. ⁸⁹ For instance, on the ISS, as treadmill speeds rose from 8.9 to 12.9 km · h⁻¹, there was only a slight increase in mechanical load stimuli. ³⁰ Mechanical loads from in-flight hardware were just 77% of Earth’s gravitational load for walking, 75% for running, and 65% for squats when each device was used at its maximal resistance setting, which shows ISS hardware does not impart sufficient mechanical loads as compared to when the same exercises are done on Earth. ³⁰ Higher intensities may impart greater strains to best protect against in-flight bone loss. ⁸⁹ Insufficient mechanical loads led to implementation of the ARED aboard the ISS. While it provided twice the absolute resistance of its predecessor, the interim resistive exercise device, it is not without its own drawbacks and will not be used on future manned spaceflights. ^{56 , 76} Similar issues may prevent use of the current in-flight treadmill on future long-term missions.

In-Flight Exercise and Subsequent Bone Changes

The treadmill is a common in-flight exercise mode. The most recent in-flight treadmill is the T2/COLBERT, which offers speeds of up to 20.4 km · h^{−1 67} . Vertical loads, meant to mimic the effects of gravity, are provided by a harness and bungee cords. ⁶⁷ Vertical loads are set to ∼50% of body mass for the first 1–2 wk of flight, and then gradually increased. ⁶⁷ Peak in-flight vertical loads approximate 70–80% of a crewmember’s body mass. ⁶⁷ In-flight training on the T2/COLBERT averaged 27 min per workout and entailed an average peak speed of 8 mi · hr⁻¹, or a mean power output of 117 watts. ⁷⁴ To prepare for a return to Earth, the final 3–4 wk of each crewmember’s ISS mission entail high training loads, with a focus on in-flight ARED and T2/COLBERT workouts, and the cessation of stationary cycle ergometry. ⁶⁷

To examine the merits of in-flight exercise, muscle and fat mass changes were assessed from six astronauts after 4–6 mo aboard the ISS. ³² They used the T2/COLBERT treadmill, along with an in-flight cycle ergometer and the ARED. Despite in-flight exercise, there was significant paraspinalis muscle atrophy (−9.0 ± 4.8%) and a significant gain in quadratus lumborum fat mass (7.3 ± 4.1%). ³² While higher intensities may have provided more benefit, the in-flight hardware did not address lumbar deconditioning in space. ³² A more comprehensive analysis revealed ∼600 min · wk⁻¹ of in-flight aerobic and resistive exercise during 178 ± 48 d in space did not fully protect against multisystem deconditioning in 46 astronauts. ⁷⁴ Deconditioning included significant hip and proximal femur BMD losses. With postflight BMD data collected 1 wk after their return to Earth, average percentage losses ranged from −0.5 to −9.0. ⁷⁵ With 95% confidence intervals also computed, the lower interval value for trabecular femoral neck BMD reached -14%. ⁷⁴ Since the BMD losses occurred despite ∼600 min · wk⁻¹ of T2/COLBERT and ARED workouts, a renewed focus to improve in-flight exercise countermeasures and hardware must occur to protect astronaut health and performance for long-term missions. ⁷⁴

In-flight exercise hardware was also devised by The Russian Space Agency to address the physical deconditioning incurred from space travel. ^{33 , 46 , 63} Among their more novel devices was the Penguin Suit, which included a series of bungee cords so lower body extensor muscles were kept lengthened when the suit was worn to limit their atrophy, and a Bracelet device comprised of multiple compression cuffs that sought to reduce the fluid shifts common to microgravity. ^{46 , 61} Outcomes from the use of these novel devices are unclear, due to limited amounts of published peer-reviewed material on their use as in-flight countermeasures. Yet in-flight BMD losses among cosmonauts at the lumbar vertebrae and femur were, on average, less while on the ISS versus MIR, presumably due to in-flight exercise hardware advances. ^{33 , 45 , 63} Given the benefits of better exercise hardware, further improvements in this area are vital to longer space missions.

Resistive Exercise Hardware and Subsequent Bone Changes

The ARED is the most sophisticated form of in-flight resistance exercise hardware. It is also perhaps the longest used piece of in-flight resistive exercise hardware. With pressurized vacuum cylinders and large flywheels, the ARED attempts to simulate the physical sensation of lifting weights on Earth. ⁵⁶ The ARED’s large mass and physical footprint inevitably contribute to structural deformation, which is one reason it is not being considered for future long-term missions. ⁵⁶ In a study with ambulatory subjects, adaptations produced by ARED workouts were compared to those from free weights with no crossover. ⁵⁶ Outcomes measured included musculoskeletal- and performance-based variables. Both groups did workouts with the same exercises (squat, deadlift, calf raise) with identical set-repetition and rest-period protocols. Results included significant gains over time in both groups for many variables. Yet 16 wk of ARED workouts only produced small (+1.7%), but significant, areal BMD increases at the lumbar spine. ⁵⁶ ARED squat and deadlift exercise pictures from the ISS appear in Fig. 2 .

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ARED workouts on the ISS reduced BMD losses, yet it was not enough to address this problem alone. ^{44 , 76} The ARED, like other forms of resistive exercise, imparts high strain magnitudes to bone, but low strain rates and frequencies. ^{14 , 21} Mechanical-loading stimuli imparted to bone are most beneficial when each strain feature is high; this does not occur with most hardware and is a contributing factor to trabecular bone and BMD losses. ^{13 , 30} Yet one form of novel hardware, called an inertial exercise trainer (IET; Impulse Technologies, Knoxville TN), offers bones high strain magnitudes, rates, and frequencies yet does not require gravity to operate. ^{13 , 14 , 21} With a smaller mass and physical footprint than the ARED and the recently examined jump apparatus, ⁴⁷ the IET has the potential to serve as in-flight hardware aboard long-term manned space missions.

The IET has a polyurethane-coated 1.9-m guide rail onto which a 1-kg sled traverses as repetitions are performed. The sled connects to a high-tension low-stretch polymer cord interwoven among pulleys. With little frictional resistance, forces as low as ∼0.45 N initiate sled movement. Traditional exercise uses mass and the pull of gravity to offer resistance, but the start of each IET repetition imparts momentum. As the sled makes its way to the opposite end of the track, eccentric forces counter that momentum to complete each repetition. IET repetitions occur at high speeds and accelerations; when exercise entails fast movement rates, bone loss in disuse models may decline. ^{22 , 36 , 62} As the sled approaches the end of the guide rail, a new repetition propels it to the opposite direction. Upon directional changes, impact forces are imparted to bones at musculotendinous attachment sites to evoke high strain magnitudes. ^{8 , 14 , 23}

The IET’s design sees a person generate all forces and momentum in its operation. With 3.4 kg of added sled mass, the IET produced mean knee-extension peak force and Δforce/Δtime values of ∼900 N and 2250 N · sec⁻¹, respectively, as subjects averaged 2–2.5 repetitions per second. ¹⁴ Such values compare favorably to those for treadmill running. ⁸⁵ Successive IET repetitions use the stretch shortening cycle (SSC) to impart high strains. The SSC was vital to a 60-d bed rest to impart high strains. ³⁴ The IET substitutes high impact forces for heavy weights; combined with its fast repetitions, high strain magnitudes, rates, and frequencies are imparted to bones engaged in exercise. An IET image, with many of its components labeled, appears in Fig. 3 .

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Like the 16-wk ARED study with ambulatory subjects, a comparable investigation was done with the IET, which entailed 30 workouts done over a 10-wk period. ^{14 , 56} Subjects did IET workouts with their left leg, while their right served as an untreated control. ¹⁴ Workouts entailed three 60-s sets each of knee-extension, hip-extension, and calf-press exercises, separated by 90-s rests. Pre- and postintervention, subjects underwent strength tests (knee and ankle extensors of both legs), DXA scans (hip, knee, and ankles of both legs), and blood draws. In addition to left leg knee- and ankle-extensor strength gains, calcanei for that same leg saw a significant 33% BMD gain that was accompanied by a significant drop in bone resorption. ¹⁴ It was concluded that specific mechanical-loading stimuli must be applied to achieve osteogenesis, and that IET workouts imparted high strain magnitudes, rates, and frequencies. ¹⁴   Table I compares ambulatory training study outcomes and subsequent BMD results for several hardware modes.

Table I. Ambulatory Subject Training Studies and Subsequent Bone Mineral Density Results.

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The Table I ARED and IET studies each used three similar exercises per workout. ^{14 , 56} The 33% calcaneal BMD gain from 10 wk of IET workouts is perhaps the highest rate of osteogenesis recorded. ¹⁴ The calcaneus has the most trabecular bone (>95%) of the human body and incurs among the largest BMD losses from spaceflight. ^{53 , 66 , 89} Since it is a weight-bearing bone, the calcaneus is responsive to mechanical-loading stimuli. ⁶⁶ Yet other bones examined in the IET study had no significant changes. ¹⁴ They include the hip, which is prone to bone loss in microgravity. ^{48 , 64 , 77} Since strain data were not obtained, it is unknown why osteogenesis was confined to the calcaneus, or if higher strains naturally occur at more distal bone sites. ¹⁴ IET workouts focused on the hip, spine, and calcaneus concurrent to bed rest may yield BMD changes that could one day aid future long-term spaceflights, yet such a study has yet to occur.

Proposed Future Directions

Reduced mechanical loading and higher osteoclast activity lead to in-flight BMD loss. ^{53 , 61 , 75} Other in-flight concerns, like higher radiation exposure, exacerbate bone loss. ⁸⁹ In-flight nutrition and exercise reduce BMD loss, though, to date, not to the extent needed for Mars missions. ^{13 , 64} High risks for osteopenia and osteoporosis are projected for Mars missions. ⁵ Male astronauts who fall laterally 1 m on Day 0 postflight are projected as 15% more likely to incur a hip fracture than if the same fall were to occur preflight. ⁵⁴ It declines to 6% more likely if the fall occurs 365 d postflight. ⁵⁴ Those percentages drop to 6% (postflight Day 0) and 2% (postflight Day 365) with improved in-flight exercise countermeasures and nutrition. Nutritional strategies, in addition to in-flight Ca⁺² and vitamin D supplements, may include diets rich in EPA and IVFA, and low in sulfur-rich proteins, to preserve BMD. ^{16 , 35 , 94} In-flight diets low in animal meats/proteins as well as salts and sugars, and rich in fruits, vegetables, dairy products, and water will keep kidney stone risk low, which is projected to rise with longer spaceflights. ³¹

A palpable void exists in the selection of future in-flight resistive exercise hardware. ⁷⁴ With the ARED absent on future missions, some advocate for flywheel-based devices, like that from the European Space Agency now aboard the ISS. Yet a prototype of that device, which imparted resistance with two flywheels that each had 23-cm radii, did not improve BMD values under ambulatory or simulated microgravity conditions. ^{11 , 12} For the ambulatory study, flywheel ergometry did not improve BMD, yet a group that trained exclusively on free-weight hardware had small yet significant BMD (+1.2%) gains. ¹¹ With unilateral limb suspension used to evoke unloading over a 40-d period, exercise on flywheel-based hardware only abated bone loss with concurrent intake (16 mg · d⁻¹) of the β₂-adrenergic agonist albuterol. ¹²

Since the ambulatory IET study yielded results that could lead to BMD-loss mitigation on future missions, a flight-ready version of the IET was created. ¹⁴ The flight-ready version has a frame onto which a movable platform is mounted. ²⁰ Linear and rotational resistance comes from concentric and eccentric forces that accelerate and decelerate a rotary assembly that serves as a movable platform. ²⁰ The assembly has a mass and volume of 17.4 kg and 790.5 cm³, respectively. The assembly pivots on a shaft to allow movement against half the frictional load of the ground-based IET. ²⁰ The flight-ready version has a 106-kg mass and a 114-ft³ area and appears in Fig. 4 . It requires a 12V DC 18-watt power supply and has a vibration/shock-cushioning system to limit in-flight perturbations. ²⁰ The flight-ready IET has a data collection module for analysis of exercise performance, and produces high impact forces during repetitions. ^{14 , 20} Like its ground-based predecessor, mechanical-loading stimuli from the flight-ready version may impart high strain magnitudes, rates, and frequencies. ^{14 , 20} These stimuli can be imparted with less mass, physical footprint, and power needs than the ARED or other in-flight exercise devices. ^{20 , 47 , 56}

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Before the flight-ready version of the IET is given consideration, it and the ground-based IET must undergo greater evaluation. Since the ambulatory IET study saw nonsignificant hip and spine changes, future research should focus on exercises that target skeletal sites unchanged in that investigation. ¹⁴ Given the ambulatory IET study’s gains to a primarily trabecular bone, ^{14 , 66} which incurs among the highest BMD losses in space, this hardware shows promise. ^{49 , 77 , 81} Persistent BMD gains to the calcaneus, but not other skeletal sites, in future IET studies imply higher relative strains are naturally imparted to distal bones. ¹⁴ If IET studies with microgravity analogs are successful, perhaps combined nutritional and exercise treatments, as described in this paper, could further abate BMD loss during long-term missions. If it does not, prudent in-flight concurrent intakes of bisphosphonates may best help address the problem of bone loss in space.