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At least 127 records · Page 7
All sourcesNASA NTRSDOE OSTI
NASA NTRS1992

Production of New Trabecular Bone in Osteopenic Ovariectomized Rats by Prostaglandin E2

Serum chemistry and bone morphometry of the proximal tibial metaphysis were performed in 3 month-old double fluorescent-labeled, female Sprague-Dawley rats subjected to bilateral ovariectomy or sham surgery for 4 months prior to treatment with 0, 0.3, 1,3, or 6 mg of prostaglandin E2 (PGE2)/kg/day subcutaneously for 30 days. The 4 month postovariectomized rats possessed an osteopenic proximal tibial metaphysis with 7% trabecular area compared with controls (19%). PGE2 treatment elevated osteocalcin levels and augmented proximal tibial metaphyseal bone area in ovariectomized and sham-operated rats. Osteopenic, ovariectomized rats treated with 6 mg (PGE2)/kg/day for 30 days restored bone area to levels of agematched sham-operated rats. Morphometric analyses showed increased woven and lamellar bone area, fluorescent-labeled perimeter (osteoblastic recruitment), mineral apposition rate (osteoblastic activity), bone formation rate (BFR/BV), and longitudinal bone growth. These dramatic bone changes were all significantly increased at the doseresponse manner. This study showed that in vivo PGE2 is a powerful activator of bone remodeling, it increases both bone resorption and bone formation, and produces an anabolic effect by shifting bone balance to the positive direction. Furthermore, PGE2-induced augmentation of metaphyseal bone area in ovariectomized rats was at least two times greater than in sham-operated rats.

Mori, S.↗
NASA NTRS1991

Long-term anabolic effects of prostaglandin-E2 on tibial diaphyseal bone in male rats

The effects of long-term prostaglandin E2 (PGE2) on tibial diaphyseal bone were studied in 7-month-old male Sprague-Dawley rats given daily subcutaneous injections of 0, 1, 3 and 6 mg PGE2/kg/day for 60, 120 and 180 days. The tibial shaft was measured by single photon absorptiometry and dynamic histomorphometric analyses were performed on double-fluorescent labeled undecalcified tibial diaphyseal bone samples. Exogenous PGE2 administration produced the following transient changes in a dose-response manner between zero and 60 days: (1) increased bone width and mineral density; (2) increased total tissue and total bone areas; (3) decreased marrow area; (4) increased periosteal and corticoendosteal lamellar bone formation; (5) activated corticoendosteal lamellar and woven trabecular bone formation; and (6) activated intracortical bone remodeling. A new steady-state of increased tibial diaphyseal bone mass and elevated bone activities were observed from day 60 onward. The elevated bone mass level attained after 60 days of PGE2 treatment was maintained at 120 and 180 days. These observations indicate that the powerful anabolic effects of PGE2 will increase both periosteal and corticoendosteal bone mass and sustain the transient increase in bone mass with continuous daily administration of PGE2.

Jee, Webster S. S.↗
NASA NTRS1976

Bone Formation Rate in Experimental Disuse Osteoporosis in Monkeys

Specific mechanisms underlying weightless and hypodynamic bone loss are obscure. A principal relationship which must be affected is the balance between bone formation and bone resorption rates. In order to better define the influence of those parameters on bone loss, and also to develop measurements in other species as a useful adjunct to human research, studies were undertaken with experimental monkeys. Tests were conducted with a total of 6 adult male monkeys, weighing 10-13 kg, and approximately 10-12 yrs. of age to evaluate specifically bone formation rate during the development of disuse osteoporosis and osteopenia. Three animals were restrained in a semi-recumbent position for six months; three animals served as normal caged controls. Food intake (Purina) was held relatively constant at 200g/day for each animal. Using a Norland Bone Mineral Analyzer, bone mineral losses of 3.5 to 6% were seen in the mid-shaft of the tibia and in the distal radius. Bone loss was confirmed radiographically, with observation of thinning of the proximal tibial cortex and trabeculae in the calcaneus. Bone formation rate was determined using standard Ca-47 kinetics under metabolic balance conditions. After six months of restraint, accretion was 7.2-13.2 mg Ca/kg/day, compared to 3.2-4.1 mg Ca/kg/day in caged controls and 3-8 mg Ca/kg/day in normal adult humans. Fecal and urine calcium was 25-40% higher in restrained animals than in controls. Dietary calcium absorption decreases during restraint, and calcium turnover increases, implying a rise in bone resorption rate concommitant with the observed rise in bone accretion rate. Further studies dealing specifically with bone resorption are underway to define this more fully.

Cann, Christopher↗
NASA NTRS1999

Modeling Calcium Loss from Bones During Space Flight

Calcium loss from bones during space flight creates a risk for astronauts who travel into space, and may prohibit space flights to other planets. The problem of calcium loss during space flight has been studied using animal models, bed rest (as a ground-based model), and humans in-flight. In-flight studies have typically documented bone loss by comparing bone mass before and after flight. To identify changes in metabolism leading to bone loss, we have performed kinetic studies using stable isotopes of calcium. Oral (Ca-43) and intravenous (Ca-46) tracers were administered to subjects (n=3), three-times before flight, once in-flight (after 110 days), and three times post-flight (on landing day, and 9 days and 3 months after flight). Samples of blood, saliva, urine, and feces were collected for up to 5 days after isotope administration, and were analyzed for tracer enrichment. Tracer data in tissues were analyzed using a compartmental model for calcium metabolism and the WinSAAM software. The model was used to: account for carryover of tracer between studies, fit data for all studies using the minimal number of changes between studies, and calculate calcium absorption, excretion, bone calcium deposition and bone calcium resorption. Results showed that fractional absorption decreased by 50% during flight and that bone resorption and urinary excretion increased by 50%. Results were supported by changes in biochemical markers of bone metabolism. Inflight bone loss of approximately 250 mg Ca/d resulted from decreased calcium absorption combined with increased bone resorption and excretion. Further studies will assess the time course of these changes during flight, and the effectiveness of countermeasures to mitigate flight-induced bone loss. The overall goal is to enable human travel beyond low-Earth orbit, and to allow for better understanding and treatment of bone diseases on Earth.

Wastney, Meryl E.↗
NASA NTRS2009

Bisphosphonate as a Countermeasure to Space Flight-Induced Bone Loss

The purpose of this research is to determine whether anti-resorptive pharmaceuticals such as bisphosphonates, in conjunction with the routine in-flight exercise program, will protect ISS crewmembers from the regional decreases in bone mineral density and bone strength and the increased renal stone risk documented on previous long-duration space flights [1-3]. Losses averaged ~ 1 to 2 percent per month in such regions as the lumbar spine and hip. Although losses showed significant heterogeneity among individuals and between bones within a given subject, space flight-induced bone loss was a consistent finding. More than 90 percent of astronauts and cosmonauts on long-duration flights (average 171 days) aboard Mir and the ISS, had a minimum 5 percent loss in at least one skeletal site, 40 percent of them had a 10 percent or greater loss in at least one skeletal site, and 22 percent of the Mir cosmonauts experienced a 15 to 20 percent loss in at least one site. These losses occurred even though the crewmembers performed time-consuming in-flight exercise regimens. Moreover, a recent study of 16 ISS astronauts using quantitative computed tomography (QCT) demonstrated trabecular bone losses from the hip averaging 2.3 percent per month [4]. These losses were accompanied by significant losses in hip bone strength that may not be recovered quickly [5]. This rapid loss of bone mass results from a combination of increased and uncoupled remodeling, as demonstrated by increased resorption with little or no change in bone formation markers [6-7]. This elevated remodeling rate likely affects the cortical and trabecular architecture and may lead to irreversible changes. In addition to bone loss, the resulting hypercalciuria increases renal stone risk. Therefore, it is logical to attempt to attenuate this increased remodeling with anti-resorption drugs such as bisphosphonates. Success with alendronate was demonstrated in a bed rest study [8]. This work has been extended to space flight and two dosing regimens: 1) an oral dose of 70 mg of alendronate taken weekly during flight or 2) a single intravenous (IV) dose of 4 mg of zoledronic acid given several weeks before flight. Currently the study is focusing on the oral option because of NASA s safety concerns with the IV-administered drug. The protocol requests 10 male or female crewmembers on ISS flights of 90 days or longer. Controls are 16 previous ISS crewmembers with QCT scans of the hip performed by these same investigators. The primary outcome measure for this study is hip trabecular bone mineral density measured by QCT, but other measures of bone mass are performed including peripheral QCT (pQCT) and dual-energy x-ray absorptiometry. Serum and urinary bone markers and renal stone risk measured before, during, and after flight are included. Postflight data are currently being collected from 2 ISS crewmembers. Two additional crewmembers will return this spring after ~6-month missions. To date no untoward effects have been encountered.

Spector, Elisabeth↗
NASA NTRS2018

Prevention of Spaceflight-Induced Bone Loss: A Promising Dietary Countermeasure

Space radiation is one of the challenges for long-term spaceflight, especially for missions beyond low Earth Orbit. We have shown that a diet composed of 25% dried plum (DP) prevents radiation-induced bone loss. The DP diet fully protected the cancellous bone microarchitecture of mice exposed to ionizing radiation (gamma, proton, and HZE). In particular relevant to space radiation, we showed that the DP diet prevents bone loss due to 1Gy of sequential exposure of proton (1H, low linear energy transfer -LET-), and 1Gy of iron (56Fe, high-LET). In addition, total body exposure to 1Gy of HZE radiation (56Fe) impaired the osteoprogenitors in mice fed the control diet, as indicated by decreased osteoblast mineralization. In contrast, marrow stem cells from mice fed the DP did not exhibit these deficits. Based on these promising results supporting DP as a countermeasure to prevent space radiation induced-tissue damage, we conducted additional studies to combine radiation and simulated microgravity. We exposed skeletally mature male mice to simulated microgravity (using hindlimb unloading, HU) or total body irradiation (TBI, 2Gy 137Cs) or in combination (HU+TBI). We observed bone loss in the mice fed the control diet (CD) exposed to simulated spaceflight, as measured by cancellous bone microarchitecture parameters such as percent bone volume (BV/TV). In contrast, mice fed the DP diet did not exhibit similar bone loss with either treatments (HU or TBI) or combined (HU+TBI) as seen in most parameters. This was observed in both long bones (tibia) and axial bones (vertebrae). Furthermore, preliminary data shows that pre-feeding with the DP diet attenuates the HU-induced decrement in bone-forming osteoblasts colony counts and mineralization capacity of the osteoprogenitor cells. We also performed DP feeding at lower doses (5%, 10%) and found that these doses are less effective in preventing the radiation-induced bone loss. All our studies with the DP diet as a countermeasure were done with a period of pre-feeding ranging from 14 to 21 days before irradiation, and in order to test the capacity of the DP diet as a countermeasure provided after exposure to radiation, we exposed mice to 2Gy gamma radiation and then provided the DP diet 24 hours post-IR. Preliminary data indicates that DP mitigated the radiation-induced deficits in certain cancellous bone structural parameters. Finally, we showed that mice fed with the control diet (CD) increased oxidative damage in the serum after radiation exposure, whereas mice fed the DP diet do did not show such an increase. In summary, the DP diet is a promising countermeasure for spaceflight-induced tissue damage.

Schreurs, Ann-Sofie↗
NASA NTRS1995

Human parathyroid hormone-(1-38) restores cancellous bone to the immobilized, osteopenic proximal tibial metaphysis in rats

The purpose of this study was to determine if human parathyroid hormone-(1-38) (hPTH(1-38)) can restore cancellous bone mass to the established osteopenic, immobilized proximal tibial metaphyses of female rats. The right hindlimbs of 6-month-old female Sprague-Dawley rats were immobilized by bandaging the right hindlimbs to the abdomen. After 30 days of right hindlimb immobilization, the rats were subcutaneously injected with 200 micrograms hPTH(1-38)/kg/day for 15 days (short-term treatment) or 75 days (longer-term treatment). Static bone histomorphometry was performed on the primary spongiosa, and both static and dynamic histomorphometry were performed on the secondary spongiosa of the right proximal tibial metaphyses. Immobilization for 30 days without treatment decreased trabecular bone area, number, and thickness in both primary and secondary spongiosa, and induced an increase in eroded perimeter and a decrease in tissue referent-bone formation rate in the secondary spongiosa. These changes reached a new steady state thereafter. Treatment with 200 micrograms hPTH(1-38)/kg/day for 15 days, beginning 30 days after immobilization, significantly increased trabecular bone area, thickness, and number in both primary and secondary spongiosa despite continuous immobilization when compared with controls. The short-term PTH treatment (15 days) significantly increased labeling perimeter, mineral apposition rate, and tissue referent-bone formation rate in the secondary spongiosa and stimulated longitudinal bone growth as compared with the controls. Longer PTH treatment (75 days) further increased trabecular bone area, thickness, and number as compared with controls and groups given short-term PTH treatment (15 days). The bone formation indices in the secondary spongiosa of the longer-term treated rats were lower than those of the short-term treated group, but they were still higher than those of controls. Our findings indicate that PTH treatment stimulates cancellous bone formation, and restores and adds extra cancellous bone to the established, disuse-osteopenic proximal tibial metaphysis of female rats with continuously immobilized right hindlimbs. These results suggest that PTH may be useful in treating disuse-induced osteoporosis in humans.

NASA Program Space Physiology and Countermeasures↗
NASA NTRS2004

Space flight and bone formation

Major physiological changes which occur during spaceflight include bone loss, muscle atrophy, cardiovascular and immune response alterations. When trying to determine the reason why bone loss occurs during spaceflight, one must remember that all these other changes in physiology and metabolism may also have impact on the skeletal system. For bone, however, the role of normal weight bearing is a major concern and we have found no adequate substitute for weight bearing which can prevent bone loss. During the study of this problem, we have learned a great deal about bone physiology and increased our knowledge about how normal bone is formed and maintained. Presently, we do not have adequate ground based models which can mimic the tissue loss that occurs in spaceflight but this condition closely resembles the bone loss seen with osteoporosis. Although a normal bone structure will respond to application of mechanical force and weight bearing by forming new bone, a weakened osteoporotic bone may have a tendency to fracture. The study of the skeletal system during weightless conditions will eventually produce preventative measures and form a basis for protecting the crew during long term space flight. The added benefit from these studies will be methods to treat bone loss conditions which occur here on earth.

Non-NASA Center↗
NASA NTRS2003

Triazolopyrimidine (trapidil), a platelet-derived growth factor antagonist, inhibits parathyroid bone disease in an animal model for chronic hyperparathyroidism

Parathyroid bone disease in humans is caused by chronic hyperparathyroidism (HPT). Continuous infusion of PTH into rats results in histological changes similar to parathyroid bone disease, including increased bone formation, focal bone resorption, and severe peritrabecular fibrosis, whereas pulsatile PTH increases bone formation without skeletal abnormalities. Using a cDNA microarray with over 5000 genes, we identified an association between increased platelet-derived growth factor-A (PDGF-A) signaling and PTH-induced bone disease in rats. Verification of PDGF-A overexpression was accomplished with a ribonuclease protection assay. Using immunohistochemistry, PDGF-A peptide was localized to mast cells in PTH-treated rats. We also report a novel strategy for prevention of parathyroid bone disease using triazolopyrimidine (trapidil). Trapidil, an inhibitor of PDGF signaling, did not have any effect on indexes of bone turnover in normal rats. However, dramatic reductions in marrow fibrosis and bone resorption, but not bone formation, were observed in PTH-treated rats given trapidil. Also, trapidil antagonized the PTH-induced increases in mRNA levels for PDGF-A. These results suggest that PDGF signaling is important for the detrimental skeletal effects of HPT, and drugs that target the cytokine or its receptor might be useful in reducing or preventing parathyroid bone disease.

NASA Discipline Cell Biology↗
NASA NTRS1997

Ectopic bone formation by marrow stromal osteoblast transplantation using poly(DL-lactic-co-glycolic acid) foams implanted into the rat mesentery

Porous biodegradable poly(DL-lactic-co-glycolic acid) foams were seeded with rat marrow stromal cells and implanted into the rat mesentery to investigate in vivo bone formation at an ectopic site. Cells were seeded at a density of 6.83 x 10(5) cells/cm2 onto polymer foams having pore sizes ranging from either 150 to 300 to 710 microns and cultured for 7 days in vitro prior to implantation. The polymer/cell constructs were harvested after 1, 7, 28, or 49 days in vivo and processed for histology and gel permeation chromatography. Visual observation of hematoxylin and eosin-stained sections and von Kossa-stained sections revealed the formation of mineralized bonelike tissue in the constructs within 7 days postimplantation. Ingrowth of vascular tissue was also found adjacent to the islands of bone, supplying the necessary metabolic requirements to the newly formed tissue. Mineralization and bone tissue formation were investigated by histomorphometry. The average penetration depth of mineralized tissue in the construct ranged from 190 +/- 50 microns for foams with 500-710-microns pores to 370 +/- 160 microns for foams with 150-300-microns pores after 49 days in vivo. The mineralized bone volume per surface area and total bone volume per surface area had maximal values of 0.28 +/- 0.21 mm (500-710-microns pore size, day 28) and 0.038 +/- 0.024 mm (150-300-microns, day 28), respectively. As much as 11% of the foam volume penetrated by bone tissue was filled with mineralized tissue. No significant trends over time were observed for any of the measured values (penetration depth, bone volume/surface area, or percent mineralized bone volume). These results suggest the feasibility of bone formation by osteoblast transplantation in an orthotopic site where not only bone formation from transplanted cells but also ingrowth from adjacent bone may occur.

NASA Discipline Developmental Biology↗
NASA NTRS1995

The molecular response of bone to growth hormone during skeletal unloading: regional differences

Hind limb elevation of the growing rat provides a good model for the skeletal changes that occur during space flight. In this model the bones of the forelimbs (normally loaded) are used as an internal control for the changes that occur in the unloaded bones of the hind limbs. Previous studies have shown that skeletal unloading of the hind limbs results in a transient reduction of bone formation in the tibia and femur, with no change in the humerus. This fall in bone formation is accompanied by a fall in serum osteocalcin (bone Gla protein, BGP) and bone BGP messenger RNA (mRNA) levels, but a rise in bone insulin-like growth factor-I (IGF-I) protein and mRNA levels and resistance to the skeletal growth-promoting actions of IGF-I. To determine whether skeletal unloading also induced resistance to GH, we evaluated the response of the femur and humerus of sham and hypophysectomized rats, control and hind limb elevated, to GH (two doses), measuring mRNA levels of IGF-I, BGP, rat bone alkaline phosphatase (RAP), and alpha 1(1)-procollagen (coll). Hypophysectomy (HPX) decreased the mRNA levels of IGF-I, BGP, and coll in the femur, but was either less effective or had the opposite effect in the humerus. GH at the higher dose (500 micrograms/day) restored these mRNA levels to or above the sham control values in the femur, but generally had little or no effect on the humerus. RAP mRNA levels were increased by HPX, especially in the femur. The lower dose of GH (50 micrograms/day) inhibited this rise in RAP, whereas the higher dose raised the mRNA levels and resulted in the appearance of additional transcripts not seen in controls. As for the other mRNAs, RAP mRNA in the humerus was less affected by HPX or GH than that in the femur. Hind limb elevation led to an increase in IGF-I, coll, and RAP mRNAs and a reduction in BGP mRNA in the femur and either had no effect or potentiated the response of these mRNAs to GH. We conclude that GH stimulates a number of markers of bone formation by raising their mRNA levels, and that skeletal unloading does not block this response, but the response varies substantially from bone to bone.

Non-NASA Center↗
NASA NTRS2014

Role of Oxidative Damage in Radiation-Induced Bone Loss

During prolonged spaceflight, astronauts are exposed to both microgravity and space radiation, and are at risk for increased skeletal fragility due to bone loss. Evidence from rodent experiments demonstrates that both microgravity and ionizing radiation can cause bone loss due to increased bone-resorbing osteoclasts and decreased bone-forming osteoblasts, although the underlying molecular mechanisms for these changes are not fully understood. We hypothesized that excess reactive oxidative species (ROS), produced by conditions that simulate spaceflight, alter the tight balance between osteoclast and osteoblast activities, leading to accelerated skeletal remodeling and culminating in bone loss. To test this, we used the MCAT mouse model; these transgenic mice over-express the human catalase gene targeted to mitochondria, the major organelle contributing free radicals. Catalase is an anti-oxidant that converts reactive species, hydrogen peroxide into water and oxygen. This animal model was selected as it displays extended lifespan, reduced cardiovascular disease and reduced central nervous system radio-sensitivity, consistent with elevated anti-oxidant activity conferred by the transgene. We reasoned that mice overexpressing catalase in mitochondria of osteoblast and osteoclast lineage cells would be protected from the bone loss caused by simulated spaceflight. Over-expression of human catalase localized to mitochondria caused various skeletal phenotypic changes compared to WT mice; this includes greater bone length, decreased cortical bone area and moment of inertia, and indications of altered microarchitecture. These findings indicate mitochondrial ROS are important for normal bone-remodeling and skeletal integrity. Catalase over-expression did not fully protect skeletal tissue from structural decrements caused by simulated spaceflight; however there was significant protection in terms of cellular oxidative damage (MDA levels) to the skeletal tissue. Furthermore, we used an array of countermeasures (Antioxidant diets and injections) to prevent the radiation-induced bone loss, although these did not prevent bone loss, analysis is ongoing to determine if these countermeasure protected radiation-induced damage to other tissues.

oxidative damage↗
NASA NTRS1985

Evidence that Resorption of Bone by Rat Peritoneal Macrophages Occurs in an Acidic Environment

Skeletal loss in space, like any form of osteoporosis, reflects a relative imbalance of the activities of cells resorbing (degrading) or forming bone. Consequently, prevention of weightlessness induced bone loss may theoretically be accomplished by (1) stimulating bone formation or (2) inhibiting bone resorption. This approach, however, requires fundamental understanding of the mechanisms by which cells form or degrade bone, information not yet at hand. An issue central to bone resorption is the pH at which resorption takes place. The pH dependent spectral shift of a fluorescent dye (fluorescein isothiocyanate) conjugated to bone matrix was used to determine the pH at the resorptive cell bone matrix interface. Devitalized rat bone was used as the substrate, and rat peritoneal macrophages were used as the bone resorbing cells. The results suggest that bone resorption is the result of generation of an acidic microenvironment at the cell matrix junction.

Blair, H. C.↗
NASA NTRS1995

Characterization of microgravity effects on bone structure and strength using fractal analysis

The effect of micro-gravity on the musculoskeletal system has been well studied. Significant changes in bone and muscle have been shown after long term space flight. Similar changes have been demonstrated due to bed rest. Bone demineralization is particularly profound in weight bearing bones. Much of the current techniques to monitor bone condition use bone mass measurements. However, bone mass measurements are not reliable to distinguish Osteoporotic and Normal subjects. It has been shown that the overlap between normals and osteoporosis is found for all of the bone mass measurement technologies: single and dual photon absorptiometry, quantitative computed tomography and direct measurement of bone area/volume on biopsy as well as radiogrammetry. A similar discordance is noted in the fact that it has not been regularly possible to find the expected correlation between severity of osteoporosis and degree of bone loss. Structural parameters such as trabecular connectivity have been proposed as features for assessing bone conditions. In this report, we use fractal analysis to characterize bone structure. We show that the fractal dimension computed with MRI images and X-Ray images of the patella are the same. Preliminary experimental results show that the fractal dimension computed from MRI images of vertebrae of human subjects before bedrest is higher than during bedrest.

Acharya, Raj S.↗
NASA NTRS1992

Prostaglandin E2 Prevents Disuse-Induced Cortical Bone Loss

The object of this study was to determine whether prostaglandin E2 (PGE2) can prevent disuse (underloaded)-induced cortical bone loss as well as add extra bone to underloaded bones. Thirteen-month-old retired female Sprague-Dawley breeders served as controls or were subjected to simultaneous right hindlimb immobilization by bandaging and daily subcutaneous doses of 0, 1, 3, or 6 mg PGE2/kg/d for two and six weeks. Histomorphometric analyses were performed on double-fluorescent labeled undecalcified tibial shaft sections (proximal to the tibiofibular junction). Disuse-induced cortical bone loss occurred by enlarging the marrow cavity and increasing intracortical porosity. PGE2 treatment of disuse shafts further increased intracortical porosity above that in disuse alone controls. This bone loss was counteracted by enhancement of periosteal and corticoendosteal bone formation. Stimulation of periosteal and corticoendosteal bone formation slightly enlarged the total tissue (cross-sectional) area and inhibited marrow cavity enlargement. These PGE2-induced activities netted the same percentage of cortical bone with a different distribution than the beginning and age related controls. These findings indicate the PGE2-induced increase in bone formation compensated for the disuse and PGE2-induced bone loss, and thus prevented immobilization induced bone loss.

Jee, Webster S. S.↗
NASA NTRS1994

Effects of Prostaglandin E2 and Risedronate Administration on Cancellous Bone in Older Female Rats

The effects of Prostaglandin E2 (PGE2) and Risedronate (Ris) both separately and in combination (PGE2 + Ris) were studied on the intact aged female rat skeleton to determine whether the combination of PGE2 with an antiresorptive agent is more effective anabolically than PGE2 alone. Nine month-old Sprague-Dawley rats were injected subcutaneously either with vehicle, 6 mg PGE2/kg per day, 1 or 5 microgram Ris/kg twice a week, or 6 mg PGE2/kg per day plus 1 or 5 microgram Ris/kg twice a week (PGE2 + 1 Ris or PGE2 + 5 Ris) for 60 days. After the treatment, we determined the longitudinal bone growth rate, the qualitative appearance of the primary spongiosa (PS), and the static and dynamic bone histomorphometry of the secondary spongiosa (SS) of the proximal tibial metaphysis (PTM) by examining undecalcified longitudinal sections after double fluorescent labeling. The relative effects of these treatments on longitudinal bone growth were ranked as follows: PGE2 + 5 Ris greater than PGE2 + 1 Ris = basal greater than PGE2 greater than 1 microgram Ris = 5 microgram Ris = aging. The density of the PS was ranked as follows: PGE2 + 5 Ris greater than PGE2 + 1 Ris = PGE2 = 5 microgram Ris = 1 microgram Ris greater than basal = aging. The increase in density of the PS was the result of stimulated longitudinal growth and the action of bisphosphonate. Bone mass in the SS was ranked as follows: PGE2 + 5 Ris = PGE2 + 1 Ris = PGE2 greater than 5 microgram Ris = 1 microgram Ris = aging = basal. However, PGE2 alone and its cotreatment with Ris accumulated bone by different tissue mechanisms. PGE2 alone created new bone by increasing activation frequency 8.3-fold and the formation to resorption ratio 1.3-fold from the controls. The combination of PGE2 and Ris depressed activation frequency (-54% to -74%), and bone formation rate (tissue-based -31%, and bone-based -42%) and eroded surface (-79% to -81%), so as to increase the formation to resorption ratio (three- to four-fold) over PGE2 alone. The increased ratio was due primarily to a greater decrease in eroded perimeter than in labeled perimeter. The major finding of this study is that the combination of PGE2 and a bisphosphonate (Ris) is more anabolic than PGE2 or Ris alone when endochondral ossification is active, but PGE2 + Ris is no more anabolic than PGE2 alone in old bone without endochondral ossification. However, the tissue mechanisms by which PGE2 alone and PGE2 + Ris treatments accumulated bone differed in that the latter allowed the same bone mass to accumulate with lower levels of cell recruitment and activity.

Lin, B. Y.↗
NASA NTRS1999

Bone Loss in Space: Shuttle/MIR Experience and Bed Rest Countermeasure Program

Loss of bone mineral during space flight was documented in the 1970's Skylab missions. The USSR space program made similar observations in the 1980's. The Institute of Biomedical Problems in Moscow and NASA JSC in 1989 began to collect pre- and post-flight bone mineral density (BMD) using Hologic QDR 1000 DEXA scanners transferred from JSC to Moscow and Star City. DEXA whole body, hip, and lumbar spine scans were performed prior to and during the first week after return from 4- to 6-month missions (plus one 8-month mission and one 14- month mission) on the Mir space station. These data documented the extent and regional nature of bone loss during long duration space flight. Of the 18 cosmonauts participating in this study between 1990 and 1995, seven flew two missions. BMD scans prior to the second flight compared to the first mission preflight scans indicated that recovery was possibly delayed or incomplete. Because of these findings, NASA and IBMP initiated the study "Bone Mineral Loss and Recovery After Shuttle/Mir Flights" in 1995 to evaluate bone recovery during a 3-year post-flight period. All of the 14 participants thus far evaluated lost bone in at least one region of the spine and lower extremities during flight. Of the 14, only one to date has exhibited full return to baseline BNM values in all regions. The current study will continue until the last participant has reached full bone recovery in all regions, has reached a plateau, or until three years after the flight (2001 for the last mission of the program). Bone mineral density losses in space and difficulty in returning to baseline indicate a need for countermeasure development. In late 1996 NASA JSC and Baylor College of Medicine were approved to conduct two countermeasure studies during 17 weeks of bed rest. In 1997 the studies were begun in the bed rest facility established by NASA, Baylor College of Medicine, and The Methodist Hospital in Houston. To date, three bed rest controls, five resistive exercisers, and four subjects taking alendronate (a bisphoshonate that inhibits osteoclastic resorption of bone) have completed 17 weeks bed rest. In contrast to information currently available from space flight (n=28) and bed rest (n= 12) in which all individuals experienced bone loss in at least one region, one of four subjects taking alendronate and one of five subjects performing heavy resistive exercise at bed rest fully maintained bone density in all regions of the spine and lower extremities. Overall results of both countermeasures which will be presented are encouraging. The study will be completed by mid to late 2000 with 10 subjects in each of three groups.

Shackelford, L. C.↗
NASA NTRS2002

Is Animal Age a Factor In the Response of Bone to Spaceflight?

The rodent bone response to spaceflight may be influenced by a multitude of actors including flight duration, strain, and housing. Review of bone formation rates during spaceflight suggests that age may also play a role in the response. Weanling rats show fewer bone changes than older rats. To determine if the long bones of weanling rats were insensitive to weight-bearing, a hindlimb unloading experiment was conducted simultaneously with a 9d shuttle flight in 34d old group-housed male rats. All animals were injected with bone markers 7d and 1d before flight and euthanized at landing, 24hr, and 72hr following recovery. If no differences in body weight, bone length, or bone formation at the tibiofibular junction were noted at the different time points, data were combined for each group. No significant differences in body weight were found at any time period among the groups. The humerus, tibia, and femur elongated significantly during the flight period with no difference in lengths between groups at the end of the flight period. The group-housed flight rats showed no change in cortical bone formation rate compared to preflight values, flight controls, or vivarium controls. However, the hindlimb unloading group showed a significant 30% decrease in bone formation rate compared to all other groups. Individually-housed 38d old animals flown for 14d showed approx. 10% suppression of cortical growth. We speculate that the mechanical threshold required for cross-sectional bone growth is reached in group-house weanling rats during spaceflight, perhaps, through physical interactions, and that the weanling animals are sensitive to loading. However, the threshold is not fully reached in either singly-housed flight or hindlimb unloaded weanling rats. Older singly-housed flight animals appear to show equal or greater bone changes compared to hindlimb unloaded rats. We conclude that age, flight duration, strain, and housing have important roles in rodent skeletal responses to spaceflight.

Morey-Holton, E. R.↗