Accretion of bone mass and strength with parathyroid hormone prior to the onset of estrogen deficiency can provide temporary beneficial effects in skeletally mature rats.

Intermittent administration of parathyroid hormone (PTH) has been shown to be an anabolic agent for animal and human skeletons. In previous studies, PTH has been used concurrent with, or subsequent to, the onset of bone loss. However, it is entirely possible that PTH may be used as an anabolic agent in a situation where there is stable skeletal remodeling. Increasing bone mass at this time might confer long-lasting beneficial effects when bone loss begins, for example, subsequent to the loss of ovarian function. To test this hypothesis, we evaluated the effects of administering rat PTH(1-34) (80 microg/kg/day, subcutaneously [s.c.]) to 6-month-old rats for a 2-week period prior to ovariectomy, and followed the natural occurrence of bone loss over a 14-week period. To determine the effects of estrogen intervention on bone gained by PTH treatment, one group was repleted with 17beta-estradiol (10 microg/kg/day via s.c. implant). Serial measurements of bone mass in vivo at the distal femur were obtained at 2-week intervals using dual-energy X-ray absorptiometry, while histologic and mechanical strength data were obtained from excised proximal tibiae and distal femurs after sacrifice. Two weeks of PTH treatment resulted in an increase of bone mineral density (BMD), mechanical strength, and cancellous bone volume (CnBV/TV). Four weeks after PTH withdrawal, significant residual beneficial effects on BMD and strength, irrespective of ovarian status, were observed. However, 14 weeks after PTH withdrawal, although there were still residual effects on CnBV/TV in ovariectomized animals pretreated with PTH, the PTH effects on BMD and mechanical strength had been lost. Estradiol repletion during the rapid bone loss phase following ovariectomy prevented the reduction in BMD associated with either ovariectomy or PTH withdrawal. Our results suggest that: treatment of rats with PTH prior to ovariectomy produces an increase in BMD and strength, these beneficial effects extend for a period of at least three times the treatment duration, the BMD that is lost when PTH is discontinued equates to the amount accrued during the PTH treatment, estrogen replacement can be used to maintain the bone gained as a result of PTH treatment.

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.

Effect of cyclosporin A on bone mineral metabolism in experimental diabetes mellitus in the rat.

Cyclosporin A (CsA) is widely used in diabetic transplant patients and early type I diabetes mellitus. Diabetes produces a low-turnover osteopenia, and CsA conversely induces high-turnover osteopenia in rats. We investigated whether CsA would exacerbate diabetic osteopenia. Four groups of 10-week-old male Sprague-Dawley rats (n = 11/group) were studied: On day -6, groups A and C received saline and groups B and D received intravenous streptozotocin (55 mg/kg) to induce diabetes. From day 0, groups A and B received CsA vehicle and C and D received CsA (15 mg/kg) by daily gavage. Rats were bled on days -6, 0, 11, and 22 for serum bone gla protein (BGP), 1,25-(OH)2D, PTH, blood ionized Ca, and blood glucose determinations. Double tetracycline labeling was performed on days 9 and 20 for bone histomorphometry. After sacrifice on day 22, histomorphometric analysis was performed. Serum BGP, 1,25-(OH)2D, and PTH levels were significantly decreased in the diabetic alone (B) and diabetic plus CsA (D) groups and significantly increased in the CsA alone (group C). CsA alone (group C) induced cancellous bone loss by stimulated bone resorption. Cancellous bone loss in the diabetic alone rats (group B) was caused primarily by inhibited bone formation. No differences were found in cancellous bone mass, formation, or resorption parameters between diabetic alone (group B) and CsA-treated diabetic rats (group D). Neither CsA alone (group C) nor diabetic alone (group B) nor their combination affected cortical bone mass. CsA alone (group C) stimulated periosteal bone formation and endocortical bone resorption and inhibited endocortical formation, and diabetic alone (group B) inhibited both periosteal and endocortical bone formation. No parameters of tibial diaphyses in CsA-treated diabetic rats (group D) were different from diabetic alone. Thus the addition of CSA to the diabetic treated rats (group D) could not stimulate remodeling and appeared not to worsen significantly some of the alterations in bone formation and resorption. Possible explanations for this may be that CsA in vivo requires adequate levels of PTH, 1,25-(OH)2D, insulin, and perhaps growth factors to stimulate remodeling. The use of CsA in type I diabetic patients or in organ transplant recipients who remain diabetic after transplantation may in the short term not aggravate existing osteopenia based on these findings.

Influence of age on cyclosporin A-induced alterations in bone mineral metabolism in the rat in vivo.

Cyclosporin A (CsA) administered to actively growing young rats produces a high-turnover osteopenia. We investigated and compared the effect of CsA on the bone mineral metabolism in young rats with that of older rats, which have a lower rate of bone turnover. A group of 24 young (9 weeks) and 24 older (9 months) male Sprague-Dawley rats were orally administered 15 mg/kg of CsA or placebo daily for 24 days. Rats were weighed and serum assayed serially for bone gla protein (BGP), parathyroid hormone, ionized calcium, blood urea nitrogen, creatinine, and 1,25-dihydroxyvitamin D [1,25-(OH)2D]. After sacrifice, histomorphometric analysis was performed on undecalcified proximal tibial metaphysis with double-fluorescent labeling. Serum BGP levels were significantly elevated in both young and older rats administered CsA, and 1,25-(OH)2D levels were significantly elevated in CsA-treated young rats more than in older rats. Body weight was significantly reduced in CsA-treated older rats. There were mild but significant alterations in renal function in both groups receiving CsA. In the most comprehensive examination to date of the effects of CsA on bone histomorphometry, both young (-44%) and older rats (-20%) lost significant amounts of trabecular bone compared to their respective controls. Bone loss in young rats was mainly due to a reduced number of trabecular; older rats lost mainly trabecular thickness. Microanatomic nodal studies were consistent with these results. These data demonstrate that although cancellous bone loss induced by CsA is more marked in young rats, older rats with slower bone turnover are also at risk.

Rapamycin: a bone sparing immunosuppressant?

Immunosuppressant therpay is associated with osteoporosis both clinically, post-transplantation, and experimentally. In rats, cyclosporin A (CsA) and FK506 induce a state of high turnover rapid bone loss. After 14 days of administration in immunosuppressive doses, the more recently discovered immunosuppressant, rapamycin, resulted in no change of cancellous bone volume. A longer study over 28 days has now been carried out; contrasting the new drug with CsA and FK506. Sixty, 10-week-old Sprague-Dawley rats were randomly divided into five groups of 12 rats each. The first group served as an aging control. The remaining four groups received, by daily gavage, a combined vehicle placebo, CsA 15 mg/kg, FK506 5 mg/kg, and rapamycin 2.5 mg/kg, respectively. CsA- and FK506-treated rats, but not those treated with rapamycin, demonstrated high turnover osteoporosis with raised serum 1,25(OH)2D (p < 0.05) and elevated serum osteocalcin (p < 0.05). The trabecular bone area was decreased by 66% (p < 0.01) in the CsA group and 56% (p < 0.05) in the FK506-treated group compared with the control animals. The CsA- and the rapamycin-treated groups failed to gain weight and developed severe hyperglycemia (> 20 mmol/l, p < 0.001) by day 14 but which largely resolved by day 28. Unlike the groups treated with CsA and FK506, rapamycin-treated rats had no loss of trabecular bone volume but there was increased modeling and remodeling and a decreased longitudinal growth rate. Rapamycin may thus confer a distinct advantage over the established immunosuppressants in not reducing bone volume in the short term.(ABSTRACT TRUNCATED AT 250 WORDS)

Prostaglandin E2 administration prevents bone loss induced by orchidectomy in rats.

The objects of this study were to investigate whether prostaglandin E2 (PGE2) can prevent orchidectomy (ORX)-induced cancellous bone loss in growing male rats, and to determine the differential effects of PGE2 on sham-operated (sham) and ORX male rats. Fourteen-week-old Sprague-Dawley male rats were divided into groups of basal, vehicle-treated sham, PGE2-treated sham, vehicle-treated ORX, and PGE2-treated ORX rats for either 3 or 9 weeks. PGE2 was given at 6 mg/kg body weight daily by subcutaneous injection. Static and dynamic cancellous bone histomorphometry were performed on double-fluorescent labeled undecalcified proximal tibial metaphyseal sections. No effect was observed by ORX on body weight or longitudinal bone growth rate when compared with sham-operated controls. However, androgen deficiency caused significant increases in percent eroded perimeter, mineral apposition rate, and bone turnover (bone-volume-referent-bone formation rate), which resulted in a significant decrease in trabecular bone number, increase in trabecular separation, and a nonsignificant decrease in trabecular bone area by 3 weeks of ORX. After 9 weeks of ORX, trabecular bone area and number were significantly decreased, and trabecular separation, percent eroded perimeter, and the index of bone turnover (bone-volume-referent-bone formation rate) remained significantly increased while the index of bone formation (tissue-volume-referent-bone formation rate) was nonsignificantly decreased when compared with sham controls. When 6 mg PGE2/kg/day was given for 3 and 9 weeks, similar anabolic effects were observed in sham and ORX rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Temporal expression of the anabolic action of PTH in cancellous bone of ovariectomized rats.

When administered intermittently, parathyroid hormone (PTH) is a potent anabolic agent in both human and animal bone. To improve our understanding of this anabolic effect, we have examined the time course of PTH action in an established animal model of estrogen deficiency-induced bone loss: the ovariectomized rat. Animals were ovariectomized (Ovx) and allowed to lose bone for 6 weeks. A dose of 20 micrograms/kg/d of rat PTH (1-34) was administered s.c., 6 days each week for periods of 1, 2, 3, 4, 6 and 8 weeks. Animals were sacrificed for evaluation of skeletal histomorphometry of the proximal tibia and mechanical strength of the cancellous bone in the marrow cavity of the distal femur. Cancellous bone volume (Cn-BV/TV) increased gradually over 8 weeks of treatment (16.8 +/- 1.6 to 24.1 +/- 2.7%) as did the bone formation rate (0.308 +/- 0.054 to 1.659 +/- 0.293 microns3/micron2/d), as determined by an increase in both total mineralization surface (15.5 +/- 2.1 to 42.7 +/- 5.0%) and mineral apposition rate (1.88 +/- 0.20 to 3.55 +/- 0.39 microns/d). The largest increments in these variables reflecting bone formation occurred over the first week of treatment. This bone formation was accompanied by an increase in trabecular thickness (Tb.Th) (55.3 +/- 3.4 to 80.5 +/- 5.0 microns) without a corresponding increment in trabecular number (Tb.N) (3.65 +/- 0.17 to 3.55 +/- 0.26). Extensive tetracycline labels were visualized on the surface of trabecular rod-like and plate-like structures. A small transient, though not statistically significant, increase occurred in both eroded surface and urinary pyridinoline concentration immediately after the onset of PTH administration. Osteocalcin showed a small decrement in the first two weeks after PTH administration, but the levels were elevated when compared with the Ovx control in later weeks. Mechanical strength of the cancellous bone also increased significantly with PTH treatment (20.5 +/- 2.4 to 46.1 +/- 10.0 Newtons). Our results showed that: 1) intermittent PTH treatment of Ovx rats elicited an immediate increase of bone formation activity by the existing osteoblasts, 2) the increase of Cn-BV/TV after PTH administration resulted primarily from an increase in Tb.Th, and 3) improved mechanical strength after PTH treatment can be achieved by increases in Tb.Th without an increase in Tb.N.

On the mechanism of cancellous bone preservation in postmenopausal women with mild primary hyperparathyroidism.

Several studies have demonstrated that cancellous bone mass and architecture are preserved in postmenopausal women with primary hyperparathyroidism (PHPT). To investigate the mechanism(s) that could account for this observation, we analyzed features of bone formation in 19 postmenopausal women with PHPT by bone histomorphometry. The results were compared with those from a comparable group of 34 healthy, postmenopausal women. Patients with PHPT were similar to control subjects in cancellous bone area as well as in trabecular width, separation, and number. However, in PHPT, elevations were observed in indexes of bone turnover, such as eroded surface, osteoid surface, mineralizing surface, bone formation rate at the tissue level, and activation frequency. At the level of the bone-remodeling unit, women with PHPT had significantly higher values for the wall width of trabecular bone packets (40.26 +/- 0.36 vs. 34.58 +/- 0.45 mm), the adjusted apposition rate (0.40 +/- 0.04 vs. 0.29 +/- 0.03 mm/day), and the active formation period (67.8 +/- 5.1 vs. 57.3 +/- 2.3 days). These findings are consistent with a stimulatory action of elevated PTH levels on the duration of the active bone formation phase in individual remodeling units and may account at least in part for the preservation of cancellous bone in postmenopausal women with mild PHPT.

Prednisolone alone, or in combination with estrogen or dietary calcium deficiency or immobilization, inhibits bone formation but does not induce bone loss in mature rats.

Glucocorticoid use has long been recognized as a risk factor for bone loss, resulting in an increased fracture incidence in humans. However, steroid-treated patients often present with other complications that predispose to bone loss, such as immobilization, and little is known about the interaction of these other risk factors for bone loss and glucocorticoids. In the present study, mature female rats were treated with prednisolone (Pred) or vehicle, in combination with ovariectomy (ovx), dietary calcium deficiency (LoCa), or right hind limb immobilization (IM). After 4 weeks of treatment, the rats were killed and the right tibia and tibiofibular junction were collected for quantitative histomorphometric analysis and the right femur was collected for bone mineral density (BMD) and mechanical strength determinations. As expected, ovx, LoCa, and IM decreased BMD in the distal femur and cancellous bone volume (CnBV/TV) in the proximal tibia. All Pred-treated groups responded with increases of BMD and CnBV/TV, when compared to their respective non-Pred treated groups. Mechanical strength testing of the cancellous bone of the distal femur reflected the changes in BMD and CnBV/TV. No differences in trabecular plate thickness were noted in any of the treatment groups. The Pred group showed a significant reduction in longitudinal growth rate, as well as bone formation rate (BFR/BS), in the proximal tibia when compared with their respective control groups, the latter indicated by a decrease in both mineralizing surface and mineral apposition rate. Most notably, osteoclast surface and urinary free pyridinoline, a bone resorption marker, increased significantly with each of the three risk factors. Pred treatment inhibited these increases but it did not exert significant reductions when used by itself. At the tibiofibular junction, there were no measurable changes in either total bone or cortical bone area. Endocortical BFR/BS were increased by ovx or LoCa but each was lowered by Pred treatment. Periosteal BFR/BS were increased by ovx and IM, and Pred exerted significant inhibition by itself and in combination with other risk factors. We conclude, therefore, that unlike the effects observed in humans treated with glucocorticoid, treatment of rats with prednisolone not only does not result in bone loss but may exert a protective effect on the skeleton through the inhibition of bone resorption.

Prostaglandin E2 restores cancellous bone to immobilized limb and adds bone to overloaded limb in right hindlimb immobilization rats.

The purpose of this study was to determine whether prostaglandin E2 (PGE2) can restore cancellous bone mass and architecture to osteopenic, continuously immobilized (IM), proximal tibial metaphysis (PTM) in female rats. The right hindlimb of three and one-half-month-old Sprague-Dawley female rats were immobilized by right hindlimb immobilization (RHLI) in which the right hindlimb was underloaded and the contralateral left limb was overloaded during ambulation. After 4 or 12 weeks of RHLI, the rats were treated with 3 or 6 mg PGE2/kg/day and RHLI for 8 or 16 weeks. Bone histomorphometry was performed on microradiographs of PTM. Immobilization (IM) induced a transient cancellous bone loss and decreased trabecular thickness, number and node density, and increased free end density that established a new steady state after 4 weeks of IM. Three or 6 mg PGE2/kg/d for 8 weeks beginning at 4 or 12 weeks of IM completely restored cancellous bone mass (+127% to +188%) and structure to the age-related control levels in spite of continuous IM. Another 8 weeks of treatment maintained bone mass and architecture at these levels. No differences in cancellous bone mass and architecture were found between the overloaded PTM or RHLI rats and the age-related controls. However, 3 and 6 mg/kg/d of PGE2 treatment started at 4 or 12 weeks for 8 weeks significantly increased cancellous bone mass in the overloaded PTM (+45 to +74% of untreated controls), and another 8 weeks of treatment maintained bone mass at these levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Greater bone formation induction occurred in aged than young cancellous bone sites.

We have determined the differences in the effects of continual prostaglandin E2 (PGE2) treatment in aged (non-growing) and young (growing) cancellous bone sites in 7-month-old Sprague-Dawley rats. The sites involved are the aged distal tibial metaphysis (DTM) with a closed epiphysis and the young proximal tibial metaphysis (PTM) with a slow growing, open epiphysis. The study involved rats treated with 0, 1, 3 or 6 mg PGE2/kg/d for 60, 120 and 180 days. Static and dynamic histomorphometry of percent trabecular area, and tissue-referent bone formation rate (BFR/TV) were determined in both DTM and PTM. In pretreatment controls, the secondary spongiosa of the two metaphyses contain the same amount of cancellous bone (11% in DTM vs. 13% in PTM), but markedly less bone formation in DTM (0.6%/y in DTM vs. 41.5%/y in PTM). After 60 days of 6 mg PGE2/kg/d treatment, %Tb.Ar was increased 607% in DTM and 199% in PTM, BFR/TV was increased to nearly 14 fold in DTM and only 5 fold in PTM. These results indicated the aged metaphysis of the DTM was much more responsive to PGE2 treatment than young, growing metaphysis of the PTM. The results of 120 and 180 days treatment did not significantly differ from 60 days treatment in both sites, indicating that the effect of continuous daily PGE2 treatment were in equilibrium after 60 days. We concluded that aged metaphysis was much more responsive to PGE2 treatment than young growing metaphysis.

Short-term immobilization-induced cancellous bone loss is limited to regions undergoing high turnover and/or modeling in mature rats.

Estrogen and calcium deficiencies increase both bone resorption and formation, whereas immobilization mainly decreases bone formation. How these functionally different risk factors for bone loss interact in cancellous bone undergoing modeling or remodeling activity is not well understood. Mature (6-month-old) female rats were subjected to sham operation (sham), ovariectomy (ovx), dietary calcium deficiency (LoCa, 0.1% Ca), and sciatic and femoral denervation (IM), ovx+IM, or LoCa+IM for 4 weeks. The primary spongiosa, the region of active modeling within 1 mm of the growth plate, in ovx, LoCa, and IM groups showed a decrease in cancellous bone volume, trabecular number, and connectivity when compared to sham controls. Groups combining two risk factors exhibited additive changes when compared with single risk factor groups. In the secondary spongiosa, an area with little modeling activity, ovx and LoCa groups, as expected, lost bone. In contrast with the primary spongiosa, IM alone did not induce bone loss in the secondary spongiosa, and the groups with a combination of IM and ovx or IM and LoCa showed a greater bone loss than either ovx or LoCa alone. Ovx and LoCa groups showed increases in both bone formation rate and eroded surface in the secondary spongiosa, while IM groups showed a decrease in bone formation rate. Combining IM with either ovx or LoCa resulted in increased eroded surface. The effects on cortical bone were assessed at the tibio-fibular junction. A trend toward decreased percentage of cortical bone area and an increase in marrow cavity area were observed in the combined deficiency groups only. These changes were the result of a statistically significant increase in endosteal eroded surface in IM+ovx and IM+LoCa groups. Our results demonstrate that immobilization-induced bone loss is restricted to the primary spongiosa where most modeling events occur. However, the inhibitory effect of IM on bone formation in the secondary spongiosa is unmasked in remodeling sites when a high turnover state is provided by either estrogen or dietary calcium deficiency. These results suggest that the presence of a risk factor, such as immobilization, which in the short-term causes inhibition of bone formation, does not predispose the skeleton to rapid cancellous bone loss except when accompanied by modeling or high turnover.

Effects of prostaglandin E2 and F2 alpha on the skeleton of osteopenic ovariectomized rats.

This article contains the histomorphometric evaluation of the effects of prostaglandin F2 alpha (PGF2 alpha) on cancellous bone from the lumbar vertebra and cortical bone from the tibial shaft of ovariectomized, osteopenic rats. These effects were then compared with those of prostaglandin E2 (PGE2). Three-month-old rats were either ovariectomized (ovx) or sham-ovx. Then, either PGF2 alpha or PGE2 in doses of 1 and 3 mg/kg/day was given subcutaneously for 21 days at 150 days post ovx. Histomorphometric analysis was performed separately on both the primary and secondary spongiosae of the fourth lumbar vertebral bodies (LVB) and on tibial shafts. The ovx rats exhibited osteopenia in both primary (-23% to -37%) and secondary (-20%) spongiosae of the LVB, but not in the tibial shafts at 150 and 171 days post ovx. In the LVB, PGE2 in doses of 1 or 3 mg/kg/day for 21 days restored trabecular bone volume to the levels of sham-ovx controls in the primary spongiosa. However, in the secondary spongiosa, the treatments only thickened the trabeculae. The effects of the PGF2 alpha treatment were similar to those of the PGE2 in both the primary and the secondary spongiosae. While both PGF2 alpha and PGE2 treatments stimulated bone formation in the LVB as indicated by the increases in labeled perimeter, tissue and bone area-based bone formation rates, PGE2 is about 10 times more potent than PGF2 alpha in these effects. The PGE2 treatment also elevated activation frequency in the LVB, while the PGF2 alpha treatment did not. The treatments differed in that PGE2 at these dose levels did not alter the eroded surface in the LVB while PGF2 alpha decreased it significantly. Thus, the increase of the ratio of labeled to eroded perimeter in the LVB in PGF2 alpha-treated animals was much more than that in PGE2-treated animals. In the tibial shafts, PGE2 in doses of 1 and 3 mg/kg/day produced new marrow trabeculae in 2 of 6 and 3 of 6 of the ovx rats. However, no new trabecula was found in PGF2 alpha-treated tibial shafts. Higher doses of PGE2 also increased periosteal labeled perimeter, MAR, and BFR/BS, while PGF2 alpha did not produce any significant change in these parameters. Both PGE2 and PGF2 alpha in doses of 1 and 3 mg/kg/day increased the labeled perimeter, MAR and BFR/BS and decreased the eroded perimeter in the endocortical surface. We concluded that both PGF2 alpha and PGE2 in doses of 1 and 3 mg/kg/day for 21 days exhibited anabolic bone effects. The effects were mostly confined to an increase in trabecular volume in the primary spongiosa of the LVB and in the endocortical surface of tibial shafts. The tissue level mechanism behind this appears to be that PGE2 and PGF2 alpha can both stimulate osteoblast recruitment and activity. Overall, we found PGE2 to be more potent than PGF2 alpha at the same dose level at the endocortical surface. Furthermore, new marrow trabecular bone formed only after PGE2 treatment. PGF2 alpha differed from PGE2 by significantly reducing the trabecular eroded surface in ovx rats.

Prostaglandin E2 increases bone strength in intact rats and in ovariectomized rats with established osteopenia.

It is well documented that prostaglandin E2 (PGE2) has the ability to stimulate bone formation, improve bone structure, and increase bone mass in intact or osteopenic rat models. However, the effects of PGE2 on the mechanical properties of bone have not been investigated previously. The purpose of our study was to determine the effects of PGE2 on the mechanical strength of bones in rapidly growing, adult, and ovariectomized rat models. In study I, PGE2 at 3 mg/kg per day, or vehicle, was given by daily subcutaneous injections for 30 days to rapidly growing (3-month-old) intact male rats. Compared with controls, PGE2 significantly increased initial maximal load and stiffness of cancellous bone at the distal femoral metaphysis (DFM) as determined by an indentation test. As determined by a compression test, rats treated with PGE2 showed a significant increase in maximal load, and a nonsignificant increase in stiffness in the fifth lumbar vertebral body (L5) when compared with controls. In study II, PGE2 at 3 mg/kg per day, or vehicle, was given by daily subcutaneous injection for 30 days to mature (10-month-old) intact male rats. PGE2 treatment significantly increased initial maximal load and stiffness of the DFM and L5. PGE2 induced a significant increase in maximal load, but not stiffness, in the femoral neck (FN), as determined by a cantilever compression test. There was an increase in maximal load in a three-point bending test at the femoral shaft (FS) although the increase did not achieve statistical significance. No change in stiffness in the FS was found after PGE2 treatment. In study III, 3-month-old female rats were sham-operated or ovariectomized (ovx) for 30 days. Thereafter, PGE, at 1 or 3 mg/kg, or vehicle, were given by daily subcutaneous injection to these rats for 30 days. After 30 and 60 days, ovx induced a significant decrease in initial maximal load and stiffness of cancellous bone at the DFM as compared with sham controls. In ovx rats with established osteopenia, PGE2 at 1 mg/kg per day nonsignificantly increased the initial maximal load and stiffness, whereas, at 3 mg/kg per day, PGE2 completely restored the initial maximal load and stiffness of DFM to sham control levels. Similarly, maximal load and stiffness of L5 decreased significantly in ovx rats compared with sham controls at 30 days postsurgery. PGE2 at 1 mg/kg per day partially restored the maximal load, whereas, at 3 mg/kg per day, it completely restored the maximal load and stiffness of L5 in the established osteopenia, ovx rats. At the FS, PGE2 at 3 mg/kg per day nonsignificantly increased maximal load (+11%) and significantly increased stiffness (+25%) compared with ovx controls. Neither ovx nor PGE2 treatment caused a significant change in the maximal load and stiffness of the FN in this study. These results reveal that PGE2 significantly increased the mechanical strength at various skeletal sites in rapidly growing and mature male rats, although the increase in femoral shafts was not statistically different. Furthermore, PGE2 completely restored mechanical strength to the cancellous bone in ovx rats with established osteopenia.

The deleterious effects of long-term cyclosporine A, cyclosporine G, and FK506 on bone mineral metabolism in vivo.

Administration of cyclosporine A to male and female rats accelerates bone remodeling and causes bone loss, among other side-effects. The newer immunosuppressant drugs, FK506 and CsG, have been synthesized to counteract the toxic effects of CsA, yet maintain clinical efficacy. We investigated the in vivo effects of long-term administration of these drugs on bone mineral metabolism in the rat. Five groups of Sprague-Dawley rats, 15 per group, were allocated to receive by daily gavage for a period of 28 days: (1) Cs-vehicle; (2) CsA 15 mg/kg b.w.; (3) CsG 15 mg/kg b.w.; (4) FK506 vehicle; (5) FK506 5 mg/kg b.w. Blood was sampled on days 0, 14, and 28 for measurement of ionized calcium (Ca2+), parathyroid hormone (PTH), 1,25-(OH)2-vitamin D, and bone gla protein (BGP). Tibiae were removed on day 28 after double calcein labeling for histomorphometric analysis. Immunosuppressant groups were compared with the respective vehicle groups. Neither CsA or CsG affected the levels of Ca2+ or PTH, whereas by day 28 FK506 caused a decrease in Ca2+ and a corresponding rise in PTH (P < 0.05). The 1,25-(OH)2-vitamin D and BGP levels in both the CsA and CsG groups were increased on days 14 and 28 (P < 0.05), while FK506 had no effect on these serum levels. Tibial bone histomorphometry revealed that all 3 immunosuppressants increased measures of bone formation and bone resorption, accompanied by a significant reduction in percent trabecular area, most marked with FK506. This report demonstrates that all three immunosuppressants have adverse effects on bone--most deleterious with FK506.

A convenient method of measuring the thermal conductivity of biological tissue.

The basic principle of the thermal conductivity probe is described. Thin probes were developed based on this principle, with a reproducibility of 5.3% and relative error less than 6.0%. Each measurement can be completed in 90 s and the temperature increase can be controlled within 2 degrees C. Using the probes, the thermal conductivities of pig fat, meat, liver, kidney and live and dead snake head were measured and it was found that water content plays an important role in influencing the magnitude of the thermal conductivity of biological tissues. The probe can be used over a temperature range from -40 to 150 degrees C.

[Numerical study of the effects (correction of efects) of size of inlets and outlets of ventilation system in experimental space station cabin].

OBJECTIVE: To make the status of flow and heat transfer fit the requirement of comfortable condition in the experimental cabin and ventilation and cooling in the apparatus cabin of the space station. METHOD: In present numerical simulation, a model approximate the practice at condition of the ventilation pipeline and influence of inlet and outlet was used, so that there is no need of supposing the distribution of outlets. In microgravity condition, the influence of the size of inlets and outlets on the flow field in the experimental space station cabin was studied. According to different function zones in the experimental space station cabin, the region at evenness parameter was put forward. RESULT: The taper inlet and crescent outlet had the best integrated performance. CONCLUSION: The use of variational section was recommended in designing and building of ventilation project in space station cabin.

[Analysis of mass optimization of manned spacecraft ECLSS thermo-hydraulic network].

OBJECTIVE: To reduce the weight of manned spacecraft Environment Control and Life Support System (ECLSS). METHOD: Based on network analysis theory, the flow and thermo-hydraulic network composed of gas and liquid loops in manned spacecraft ECLSS was explored to reduce the weight of ECLSS. The physical models and mathematical models of flow, heat transfer and weight calculation in the network were established. The thermodynamic parameters and weight of the network were calculated on the bases of energy balance, heat transfer relation and the component weight relation. And influencing factors on the system weight were discussed. RESULT: (1) There is an optimal pipe diameter in the system and the diameter is influenced by flow rate to a large extent; (2) The weight can be reduced by raising inlet temperature properly; (3) The best heat exchange layout makes the weight lightest. CONCLUSION: The obtained results are of importance for reducing launching weight of manned spacecraft.

[Optimization analysis of ventilation and dehumidification in manned spacecraft].

OBJECTIVE: To achieve the optimized design of system operational parameters and system components in air ventilation and dehumidification of manned spacecraft. METHOD: Mathematical-physical model of air ventilation and dehumidification system was established. Through the design of optimal operational parameters for system performance, heat and moisture in the cabin of manned spacecraft could be removed effectively, dewing could be prevented, and the comfort demand of the astronauts could be met. Equivalent mass of the system in different operational parameters and system components was analyzed by calculation. RESULT: The dew point temperature and the comfortability depended on the temperature and humidity of the influx, ventilation rate, and evaporation of moisture in the cabin. There were two ways to control the operational parameters of air ventilation and dehumidification system. The method based on controlling temperature didn't use recuperative heat exchangers in the loop, and the system structure for the design was simple, but it didn't meet the requirement of dissipating moisture in some conditions. The other method was based on controlling the moisture, and it could steadily keep the dew point temperature in the cabin and control the occurrence of dew. But the system structure of this design was relatively complex. CONCLUSION: Mass and power consumption of the system could be reduced by selecting appropriate parameters and adopting the measures of optimization.

[Mass optimization of thermal network model of coupled dual-loop thermal control system in spacecraft].

OBJECTIVE: To deal with the mass optimization of thermal control system as well as environmental control and life support system (ECLSS) of manned spacecraft. METHOD: The thermo-hydraulic network composed of coupled liquid dual-loop and gas loops was studied. Physical and mathematical models were established and used for flow, heat transfer and mass calculation in the network. The influences of various operational and structural parameters on the mass were analyzed. RESULT: There were optimal pipe diameters for internal loop and external loop; there existed an upper limit of flow rate in the internal loop and lower limit in the external loop; there were also optimal flow rates in the loops and optimal exit temperature of the radiator. CONCLUSION: Reasonable design of these parameters were very important for reducing the system mass.