Alendronate as an effective countermeasure to disuse induced bone loss

Microgravity, similar to disuse immobilization on earth, causes rapid bone loss. This loss is believed to be an adaptive response to the reduced musculoskeletal forces in space and occurs gradually enough that changes occurring during short duration space flight are not a concern. Bone loss, however, will be a major impediment for long duration missions if effective countermeasures are not developed and implemented. Bed rest is used to simulate the reduced mechanical forces in humans and was used to test the hypothesis that oral alendronate would reduce the effects of long duration (17 weeks) inactivity on bone. Eight male subjects were given daily oral doses of alendronate during 17 weeks of horizontal bed rest and compared with 13 male control subjects not given the drug. Efficacy was evaluated based on measurements of bone markers, calcium balance and bone density performed before, during and after the bed rest. The results show that oral alendronate attenuates most of the characteristic changes in bone that are associated with long duration bed rest and presumably space flight.     

Use it or lose it--the hazards of bed rest and inactivity.

Professional experience and lay wisdom teach us the benefits of exercise and the hazards of idleness. Yet the myth persists that "bed rest is good for you" when ill or convalescing. Abundant scientific evidence in the past 50 years has demonstrated the specific damage done to each of the body''s organ systems by inactivity. Both aging and inactivity lead to strikingly similar kinds of deterioration. I summarize the data from military and veterans'' hospitals, rehabilitation experience, aerospace research, and gerontology and review the physiologic and metabolic changes of aging and inactivity, along with strategies to help prevent the iatrogenic complications of bed rest.     

New Onset of Constipation during Long-Term Physical Inactivity: A Proof-of-Concept Study on the Immobility-Induced Bowel Changes

Background

The pathophysiological mechanisms underlining constipation are incompletely understood, but prolonged bed rest is commonly considered a relevant determinant.

Aims

Our primary aim was to study the effect of long-term physical inactivity on determining a new onset of constipation. Secondary aim were the evaluation of changes in stool frequency, bowel function and symptoms induced by this prolonged physical inactivity.

Methods

Ten healthy men underwent a 7-day run-in followed by 35-day study of experimentally-controlled bed rest. The study was sponsored by the Italian Space Agency. The onset of constipation was evaluated according to Rome III criteria for functional constipation. Abdominal bloating, flatulence, pain and urgency were assessed by a 100mm Visual Analog Scales and bowel function by adjectival scales (Bristol Stool Form Scale, ease of passage of stool and sense of incomplete evacuation). Daily measurements of bowel movements was summarized on a weekly score. Pre and post bed rest Quality of Life (SF-36), general health (Goldberg’s General Health) and depression mood (Zung scale) questionnaires were administered.

Results

New onset of functional constipation fulfilling Rome III criteria was found in 60% (6/10) of participants (p=0.03). The score of flatulence significantly increased whilst the stool frequency significantly decreased during the week-by-week comparisons period (repeated-measures ANOVA, p=0.02 and p=0.001, respectively). Stool consistency and bowel symptoms were not influenced by prolonged physical inactivity. In addition, no significant changes were observed in general health, in mood state and in quality of life at the end of bed rest

Conclusions

Our results provide evidence that prolonged physical inactivity is relevant etiology in functional constipation in healthy individuals. The common clinical suggestion of early mobilization in bedridden patients is supported as well.     

Influence of repetitive Gz acceleration on structural and metabolic profile of m. vastus lateralis in monkeys exposed to 30 day bedrest

It was shown that changes in structural and metabolic indices of extensor muscles of the lower extremities were usually found in man after exposure to space flight or to bed rest. Similar changes were also observed in monkeys, space-flown on "Kosmos" biosatellites. Response to weightlessness and to restraint was found to be different in m. soleus and in m. vastus lateralis. Therefore, it is important to study structural and metabolic changes of m. vastus lateralis fibers under conditions of gravitational unloading in monkeys, who have motor apparatus similar to that of man, and are much more fruitful object of research. It is assumed that artificial gravity can serve as a countermeasure, aimed at diminishing effects of gravitational unloading. We have studied the effect of repeated gravity overloading, created by means of a centrifuge, on structural and metabolic indices of monkey m. vastus lateralis at the background of 30 day head down tilt bed rest (BR).     

Osteocyte-viability-based simulations of trabecular bone loss and recovery in disuse and reloading

Osteocyte apoptosis is known to trigger targeted bone resorption. In the present study, we developed an osteocyte-viability-based trabecular bone remodeling (OVBR) model. This novel remodeling model, combined with recent advanced simulation methods and analysis techniques, such as the element-by-element 3D finite element method and the ITS technique, was used to quantitatively study the dynamic evolution of bone mass and trabecular microstructure in response to various loading and unloading conditions. Different levels of unloading simulated the disuse condition of bed rest or microgravity in space. The amount of bone loss and microstructural deterioration correlated with the magnitude of unloading. The restoration of bone mass upon the reloading condition was achieved by thickening the remaining trabecular architecture, while the lost trabecular plates and rods could not be recovered by reloading. Compared to previous models, the predictions of bone resorption of the OVBR model are more consistent with physiological values reported from previous experiments. Whereas osteocytes suffer a lack of loading during disuse, they may suffer overloading during the reloading phase, which hampers recovery. The OVBR model is promising for quantitative studies of trabecular bone loss and microstructural deterioration of patients or astronauts during long-term bed rest or space flight and thereafter bone recovery.     

Body temperature and skin blood flow during a 14-day bed-rest in a head-down tilt position in humans

Exposure to microgravity or simulated microgravity is known to affect regulatory function in autonomic nervous system. With regard to thermoregulation, simulated microgravity impairs sweating and induces lower skin and higher internal temperatures during physical work. During supine rest after HDT bed rest, the internal temperatures were reported to be higher than those of pre-HDT bed rest in some studies but not in others. There is no report about the dynamic changes of skin blood flow during 14-day HDT bed rest. The process of HDT bed-rest deconditioning on the function of the thermoregulatory system is virtually unknown. The HDT induces an immediate cephalad fluid shift which would inhibit the sympathetic outflow through the arterial and cardiopulmonary baroreflexes, which may increase the skin blood flow. On the other hand, prolonged HDT bed rest induces dehydration, which will increase sympathetic outflow through cardiopulmonary baroreceptor modulation. Both sympathetic activation and dehydration itself will decrease skin blood flow. It seems probable that the general effect on skin blood flow may reverse along the HDT bed rest. However, the dynamic characters of skin blood flow and body temperature during the HDT bed rest have not been studied thoroughly. Therefore, the purpose of present study was to investigate the changes of skin blood flow and body temperature during 14 days HDT bed rest.     

Early and late renin and ANP modifications induced by bedrest

A number of studies have been devoted to better understand the cardiovascular adaptation to space flights. These studies included hemodynamic and hormonal studies, but few investigations of the rhythms exist in the literature. However, the importance of the modifications of rhythms in true or simulated weightlessness was underlined in some published works. Several factors are probably associated to modify the circadian rhythms. First, there is a reduction or an absence of gravity, an important environmental factor: second, space missions or bed rest simulations are conducted under confinement conditions which may influence many psychological functions. The resulting instability of the circadian state will affect other physiological systems, because circadian variations are a fundamental feature of many biological systems (sleep, endocrine and cardiovascular functions). The present study was undertaken to study the effect of as well as a continuous 28-day bed rest on the rhythms of circulating PRA and ANP, the modification of rhythmicity of systolic and diastolic blood pressure and heart rate during bed rest.     

Mechanical unloading impairs keratinocyte migration and angiogenesis during cutaneous wound healing.

Although initially thought to improve an individual's ability to heal, mechanical unloading promoted by extended periods of bed rest has emerged as a contributing factor to delayed or aberrant tissue repair. Using a rat hindlimb unloading (HLU) model of hypogravity, we mimicked some aspects of physical inactivity by removing weight-bearing loads from the hindlimbs and producing a systemic cephalic fluid shift. This model simulates bed rest in that the animal undergoes physiological adaptations, resulting in a reduction in exercise capability, increased frequency of orthostatic intolerance, and a reduction in plasma volume. To investigate whether changes associated with prior prolonged bed rest correlate with impaired cutaneous wound healing, we examined wound closure, angiogenesis, and collagen content in day 2 to day 21 wounds from rats exposed to HLU 2 wk before excisional wounding. Wound closure was delayed in day 2 wounds from HLU rats compared with ambulatory controls. Although the levels of proangiogenic growth factors, fibroblast growth factor-2 (FGF-2), and vascular endothelial growth factor (VEGF) were similar between the two groups, wound vascularity was significantly reduced in day 7 wounds from HLU animals. To further examine this disparity, total collagen content was assessed but found to be similar between the two groups. Taken together, these results suggest that keratinocyte and endothelial cell function may be impaired during the wound healing process under periods of prolonged inactivity or bed rest.     

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.     

Effects of the renin-angiotensin-aldosterone system on the cardiovascular system during 20-days bed rest

Long term change of renin-angiotensin-aldosterone system (RAAS) induced by bed rest and its effects on cardiovascular system are still controversial. The purpose of this study was to obtain a general conclusion on these questions by analyzing our two 20-days horizontal bed rest experiments in past two years with 18 subjects. Plasma renin activity and aldosterone were consistently increased during the bed rest, but angiotensin II was increased only during the early days. Decrease in urinary sodium excretion and increase in urinary potassium excretion were observed during day 3-8 and day 7-12, respectively. Mean arterial pressure increased during day 3-8. Pulse pressure was returned to pre-bed rest level by day 10 after an initial decrease. All these results indicated an activated RAAS and its active effects on cardiovascular and overall fluid regulating systems during our horizontal bed rest studies. Direct effect of change in gravitational force on renal pressure-sensitive cells or effects related to physical inactivity may explain our results.     

Cardiac atrophy after bed rest and spaceflight.

Cardiac muscle adapts well to changes in loading conditions. For example, left ventricular (LV) hypertrophy may be induced physiologically (via exercise training) or pathologically (via hypertension or valvular heart disease). If hypertension is treated, LV hypertrophy regresses, suggesting a sensitivity to LV work. However, whether physical inactivity in nonathletic populations causes adaptive changes in LV mass or even frank atrophy is not clear. We exposed previously sedentary men to 6 (n = 5) and 12 (n = 3) wk of horizontal bed rest. LV and right ventricular (RV) mass and end-diastolic volume were measured using cine magnetic resonance imaging (MRI) at 2, 6, and 12 wk of bed rest; five healthy men were also studied before and after at least 6 wk of routine daily activities as controls. In addition, four astronauts were exposed to the complete elimination of hydrostatic gradients during a spaceflight of 10 days. During bed rest, LV mass decreased by 8.0 +/- 2.2% (P = 0.005) after 6 wk with an additional atrophy of 7.6 +/- 2.3% in the subjects who remained in bed for 12 wk; there was no change in LV mass for the control subjects (153.0 +/- 12.2 vs. 153.4 +/- 12.1 g, P = 0.81). Mean wall thickness decreased (4 +/- 2.5%, P = 0.01) after 6 wk of bed rest associated with the decrease in LV mass, suggesting a physiological remodeling with respect to altered load. LV end-diastolic volume decreased by 14 +/- 1.7% (P = 0.002) after 2 wk of bed rest and changed minimally thereafter. After 6 wk of bed rest, RV free wall mass decreased by 10 +/- 2.7% (P = 0.06) and RV end-diastolic volume by 16 +/- 7.9% (P = 0.06). After spaceflight, LV mass decreased by 12 +/- 6.9% (P = 0.07). In conclusion, cardiac atrophy occurs during prolonged (6 wk) horizontal bed rest and may also occur after short-term spaceflight. We suggest that cardiac atrophy is due to a physiological adaptation to reduced myocardial load and work in real or simulated microgravity and demonstrates the plasticity of cardiac muscle under different loading conditions.     

Mechanisms of disuse muscle atrophy: role of oxidative stress

Prolonged periods of skeletal muscle inactivity lead to a loss of muscle protein and strength. Advances in cell biology have progressed our understanding of those factors that contribute to muscle atrophy. To this end, abundant evidence implicates oxidative stress as a potential regulator of proteolytic pathways leading to muscle atrophy during periods of prolonged disuse. This review will address the role of reactive oxygen species and oxidative stress as potential contributors to the process of disuse-mediated muscle atrophy. The first section of this article will discuss our current understanding of muscle proteases, sources of reactive oxygen in muscle fibers, and the evidence linking oxidative stress to disuse muscle atrophy. The second section of this review will highlight gaps in our knowledge relative to the specific role of oxidative stress in the regulation of disuse muscle atrophy. By discussing unresolved issues and suggesting topics for future research, it is hoped that this review will serve as a stimulus for the expansion of knowledge in this exciting field.     

Physical inactivity as the culprit of metabolic inflexibility: evidence from bed-rest studies

Although it is no longer debatable that sedentary behaviors are an actual cause of many metabolic diseases, the physiology of physical inactivity has been poorly investigated for this purpose. Along with microgravity, the physiological adaptations to spaceflights require metabolic adaptations to physical inactivity, and that is exceedingly well-simulated during the ground-based microgravity bed-rest analogs. Bed rest thus represents a unique model to investigate the mechanisms by which physical inactivity leads to the development of current societal chronic diseases. For decades, however, clinicians and physiologists working in space research have worked separately without taking full awareness of potential strong mutual questioning. This review summarizes the data collected over the last 60 years on metabolic adaptations to bed rest in healthy subjects. Our aim is to provide evidence that supports the hypothesis that physical inactivity per se is one of the primary causes in the development of metabolic inflexibility. This evidence will focus on four main tenants of metabolic inflexiblity: 1) insulin resistance, 2) impaired lipid trafficking and hyperlipidemia, 3) a shift in substrate use toward glucose, and 4) a shift in muscle fiber type and ectopic fat storage. Altogether, this hypothesis places sedentary behaviors upstream on the list of factors involved in metabolic inflexibility, which is considered to be a primary impairment in several metabolic disorders such as obesity, insulin resistance, and type 2 diabetes mellitus.     

Effects of Head-Down Bed Rest on the Executive Functions and Emotional Response

Prolonged bed rest may cause changes in the autonomic nervous system that are related to cognition and emotion. This study adopted an emotional flanker task to evaluate the effect of 45 days -6° head-down bed rest (HDBR) on executive functioning in 16 healthy young men at each of six time points: the second-to-last day before the bed rest period, the eleventh, twentieth, thirty-second and fortieth day during the bed rest period, and the eighth day after the bed rest period. In addition, self-report inventories (Beck Anxiety Inventory, BAI; Beck Depression Inventory, BDI; Positive Affect and Negative Affect Scale, PANAS) were conducted to record emotional changes, and the participants’ galvanic skin response (GSR), heart rate (HR) and heart rate variability (HRV) were assessed as measures of physiological activity. The results showed that the participants’ reaction time on the flanker task increased significantly relative to their responses on the second-to-last day before the period of bed rest, their galvanic skin response weakened and their degrees of positive affect declined during the bed rest period. Our results provide some evidence for a detrimental effect of prolonged bed rest on executive functioning and positive affect. Whether this stems from a lack of aerobic physical activity and/or the effect of HDBR itself remains to be determined.     

Metabolic disruptions induced by reduced ambulatory activity in free-living humans

Physical inactivity likely plays a role in the development of insulin resistance and obesity; however, direct evidence is minimal and mechanisms of action remain unknown. Studying metabolic outcomes that occur after transitioning from higher to lower levels of physical activity is the best tool to answer these questions. Previous studies have successfully used more extreme models of inactivity, including bed rest, or the cessation of exercise in highly trained endurance athletes, to provide novel findings. However, these models do not accurately reflect the type of inactivity experienced by a large majority of the population. Recent studies have used a more applicable model in which active (～10,000 steps/day), healthy young controls are asked to transition to an inactive lifestyle (～1,500 steps/day) for a 14-day period. The transition to inactivity resulted in reduced insulin sensitivity and increased central adiposity. This review will discuss the outcomes of these studies, their implications for the cause/effect relationship between central adiposity and insulin resistance, and provide rationale for why inactivity induces these factors. In addition, the experimental challenges of directly linking acute responses to inactivity to chronic disease will also be discussed.     

Immobilization and bone structure in humans

Long-term immobilization is known to result in substantial bone loss. The present review examined the existing evidence for deterioration of bone structure during long-term disuse in humans. Paralysis due to spinal cord injury, long-term exposure to microgravity in space or tightly restricted mobility during bed rest provide reasonable models to assess the influence of immobilization on bone structure. Expectedly, the duration of immobilisation was the major determinant of bone loss, but irrespective of whether the skeletal unloading was due to irrecoverable paralysis, long-term spaceflight or bed rest, the mean pattern of structural deterioration of bone, mainly manifest as substantial cortical thinning and trabecular bone loss, was quite similar. However, skeletal responses to disuse can be highly variable between individuals. Apparently the relative decline in individual’s bone loading in relation to loading prior to immobilization accounts for inter-individual variation.     

Simulated microgravity [bed rest] has little influence on taste,odor or trigeminal sensitivity

Anecdotal evidence suggests that astronauts' perceptions of foods in space flight may differ from their perceptions of the same foods on Earth. Fluid shifts toward the head experienced in space may alter the astronauts' sensitivity to odors and tastes, producing altered perceptions. Our objective was to determine whether head-down bed rest, which produces similar fluid shifts, would produce changes in sensitivity to taste, odor or trigeminal sensations. Six subjects were tested three times prior to bed rest, three times during bed rest and two times after bed rest to determine their threshold sensitivity to the odors isoamylbutyrate and menthone, the tastants sucrose, sodium chloride, citric acid, quinine and monosodium glutamate, and to capsaicin. Thresholds were measured using a modified staircase procedure. Self-reported congestion was also recorded at each test time. Thresholds for monosodium glutamate where slightly higher during bed rest. None of the other thresholds were altered by bed rest.     

Exercise-induced pyruvate dehydrogenase activation is not affected by 7 days of bed rest

To test the hypothesis that physical inactivity impairs the exercise-induced modulation of pyruvate dehydrogenase (PDH), six healthy normally physically active male subjects completed 7 days of bed rest. Before and immediately after the bed rest, the subjects completed an oral glucose tolerance test (OGTT) and a one-legged knee extensor exercise bout [45 min at 60% maximal load (W(max))] with muscle biopsies obtained from vastus lateralis before, immediately after exercise, and at 3 h of recovery. Blood samples were taken from the femoral vein and artery before and after 40 min of exercise. Glucose intake elicited a larger (P ≤ 0.05) insulin response after bed rest than before, indicating glucose intolerance. There were no differences in lactate release/uptake across the exercising muscle before and after bed rest, but glucose uptake after 40 min of exercise was larger (P ≤ 0.05) before bed rest than after. Muscle glycogen content tended to be higher (0.05< P ≤ 0.10) after bed rest than before, but muscle glycogen breakdown in response to exercise was similar before and after bed rest. PDH-E1α protein content did not change in response to bed rest or in response to the exercise intervention. Exercise increased (P ≤ 0.05) the activity of PDH in the active form (PDHa) and induced (P ≤ 0.05) dephosphorylation of PDH-E1α on Ser2?3, Ser2?? and Ser3??, with no difference before and after bed rest. In conclusion, although 7 days of bed rest induced whole body glucose intolerance, exercise-induced PDH regulation in skeletal muscle was not changed. This suggests that exercise-induced PDH regulation in skeletal muscle is maintained in glucose-intolerant (e.g., insulin resistant) individuals.