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Biomedical subjects

W S Jee

Publications and source records attributed to W S Jee.

At least 73 records · Page 4Linked to original sources
PubMed1995

Bone mineral metabolism in T lymphocyte-deficient and -replete strains of rat.

The immune and skeletal systems are known to interact. We have repeatedly shown that in contrast to in vitro data, the administration of T lymphocyte immunosuppressants, such as cyclosporin A, leads to an increase in bone resorption and a high turnover osteopenia. The purpose of this study was to characterize the bone metabolism of the T lymphocyte deficient Rowett athymic homozygous (rnu/rnu) nude rat. We wished to determine whether these rats share the bone abnormalities of cyclosporin A-treated rats. Eleven 10-week-old Sprague-Dawley rats and 12 similarly aged nude rats were studied over a 4-week period. Metaphyseal cancellous bone histomorphometry was similar in the two groups of rats and only differed with regard to percentage eroded perimeter (lower in nude rats, p = 0.0008) and longitudinal growth rate (49% lower in nude rats, p < 0.001). The nude rats had less body mass (p < 0.001) but nevertheless gained the same percentage of their body weight over the study period. The athymic rats had lower levels of serum, 1,25-dihydroxyvitamin D (p < 0.014) and serum osteocalcin(p < 0.009), and at the age of 14 weeks the nude rats had lower concentrations of serum creatinine (p = 0.001) and blood ionized calcium (p = 0.0002), yet serum PTH was similar throughout. RNA isolated from the contralateral tibias revealed that the nude group had lower steady-state levels of osteocalcin mRNA despite similar rates of bone formation. In its entirety, the data suggest that T cell deficiency per se is not necessarily associated with high turnover osteopenia.

Animals↗
PubMed1995

Partial maintenance of extra cancellous bone mass by antiresorptive agents after discontinuation of human parathyroid hormone (1-38) in right hindlimb immobilized rats.

The current study employs the immobilization (IM) rat model to induce osteopenia, parathyroid hormone (PTH) as the anabolic agent to restore bone mass, and 17 beta-estradiol, calcitonin, or risedronate as the maintenance agents to answer the following questions: How much cancellous bone loss occurs when PTH is withdrawn? Which antiresorptive or antiactivation agent maintains bone best? Ideally, what tissue-level histomorphometric conditions maintain added bone? Six-month-old female rats were treated with 200 micrograms PTH/day subcutaneously at 30 days post-IM for 75 days. Then PTH treatment was stopped and switched to a vehicle (no treatment), 10 micrograms calcitonin/kg/day, 10 micrograms 17 beta-estradiol/kg/day, or 5 micrograms risedronate twice weekly for another 15 days (early response) or 60 days (late response). The rats had their right hindlimb throughout the study. The current report deals only with the maintenance phase involving 92 animals. Bone histomorphometry was performed on the secondary spongiosa of the right proximal tibia metaphysis (PTM). Cessation of PTH treatment followed by vehicle administration for 15 days resulted in partial loss of trabecular bone area and thickness from stimulated bone resorption and the fall of all formation indices. By contrast, all three antiresorptive agents maintained the cancellous bone mass during the same period. However, after prolonged withdrawal of PTH for 60 days, we found that 17 beta-estradiol and calcitonin maintained the cancellous bone slightly better than no treatment, while risedronate partially protected it from the mechanostat-induced bone loss. The risedronate treatment retained 71% of the PTH-added bone while calcitonin retained 48%, estrogen 42%, and no treatment 32%. The favorable histomorphometry profile for maintenance was the sustained reduction in bone resorption and turnover and normal age-related bone balance. We concluded that 1) cessation of PTH treatment will result in the loss of two-thirds of the added bone in 60 days; 2) currently, risedronate at the dose level employed as a maintenance agent is far superior to 17 beta-estradiol or calcitonin because of its long retention in bone; however, a longer observation period might result in less difference; and 3) the ideal tissue-level histomorphometry continues depressing bone resorption and turnover and maintains a normal age-related bone balance. Furthermore, we found the "lose, restore plus add, and maintain (LRAM)" concept was successful in maintaining most of the PTH-induced extra bone by risedronate for 60 days. It was far superior to 17 beta-estradiol or calcitonin. Possibly the last two agents would be effective in maintaining a normal amount of bone but not in preserving an excessive amount of bone. Nevertheless, the current study further emphasizes that clinicians should consider using the LRM treatment strategy when they plan to treat osteoporosis with bone anabolic agents.

Animals↗
PubMed1995

Available animal models of osteopenia--small and large.

Animal models of osteopenia are reviewed. Endocrine excess or deficiency conditions include ovariectomy, orchidectomy, glucocorticoid excess and other endocrine states. Seasonal and reproductive cycles are usually transient and include pregnancy and lactation, egg-laying, antler formation and hibernation. Dietary conditions include calcium deficiencies, phosphate excess and vitamin C and D deficiencies. Mechanical usage effects include skeletal underloading models. Aging is also associated with osteopenia in many species.

Aging↗
PubMed1995

Droloxifene inhibits cortical bone turnover associated with estrogen deficiency in rats.

Droloxifene (DRO), an estrogen antagonist/agonist, has been shown to possess estrogen-like effects in inhibiting bone turnover leading to cancellous bone loss in ovariectomized (OVX) rats. The purpose of this study was to determine the effects of DRO on cortical bone turnover in OVX rats. Sprague-Dawley female rats at 5 months of age were sham-operated (sham, n = 8) and orally treated with vehicle, or OVX (n = 56) and orally treated with either vehicle, DRO at 0.1, 1, 5, or 10 mg/kg/day, or 17 alpha-ethynyl estradiol (EE) at 3 or 30 micrograms/kg/day for 4 weeks. Static and dynamic cortical bone histomorphometry was performed on double fluorescent labeled, undecalcified cross sections of tibial diaphyses (proximal to the tibiofibular junction). There were no significant differences in tibial diaphyseal cross sectional area, marrow cavity area, and cortical bone area between groups after 4 weeks of administration. Periosteal mineralizing surface, mineral apposition rate, and bone formation rate-surface referent and endocortical eroded surface increased significantly, while endocortical mineral apposition rate and bone formation rate-surface referent increased nonsignificantly in OVX controls compared to sham controls. Treatment with DRO at doses of 0.1 to 10 mg/kg/day dose-dependently attenuated the OVX-induced higher bone formation indices in both the periosteal and endocortical surfaces and higher bone resorption index in the endocortical surface. At the highest dose (10 mg/kg/day), DRO completely inhibited the increases in bone formation and resorption indices in OVX rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Adaptation of non-growing former epiphysis and metaphyseal trabecular bones to aging and immobilization in rat.

No data exit for distal tibia (DT), a bone site with growth plate closure at 3 months of age and with very low trabecular bone turnover rate. The purpose of this study was to characterize the response of DT to aging and immobilization (IM) in 6 to 16.5 month-old female rats. One hundred and forty six 6 month-old Sprague-Dawley rats were divided into aging controls and right hindlimb immobilization (RHLI) groups. The right hindlimb was immobilized against the abdomen with elastic bandages. Rats were sacrificed serially from 6 to 16.5 months old at intervals of 2 to 8 weeks. The histomorphometric study was performed on areas of former epiphyseal and metaphyseal trabecular bone of DT. No changes on bone mass or architecture were found in aging controls throughout the study. There was a decrease in bone mass of the former epiphysis after 3.5 months of IM due to resorption exceeding formation. Then it reverted to the aging control level at 4 months post IM. At the former metaphyseal site, significant bone loss (-19%) was observed as early as two weeks after IM. The peak bone loss (-54%) was reached at 1.5 months after IM and plateaued thereafter. The bone loss was mainly due to the reduction of trabecular thickness although trabecular number decreased significantly after 3.5 months IM. These results suggest that both former epiphysis and metaphyseal trabecular bones in DT can quickly adapt by losing bone to immobilization.

Adaptation, Physiological↗
PubMed1995

Remobilization partially restored the bone mass in a non-growing cancellous bone site following long term immobilization.

There is no report in the rat of the effects of remobilization (RM) in an adult bone site. The aim of this study was to determine whether complete recovery from IM-induced bone loss will occur in a non-growing bone site, the distal tibia. Seventy-five 6-month-old virgin Sprague-Dawley female rats were used in this study. Their hindlimbs were immobilized against the abdomen with bandages for 18 weeks, then remobilized for 2, 10 or 20 weeks. Distal tibial sections were analyzed in the former epiphysis, 0.3 mm proximal from the calcified cartilage, and in trabecular bone of the former metaphysis between 0.3 mm and 1.92 mm proximal to the former epiphysis. A significant bone loss occurred in both former epiphyseal and metaphyseal trabeculae at 18 weeks after IM. The lost bone was partially recovered at 10 weeks of RM, but the bone mass was still lower than in aging controls by the end of the study. The partial recovery was characterized by decreasing former epiphyseal bone porosity and thickening of former metaphyseal trabeculae with no effect on trabecular number. We concluded that both distal tibia regions only partially recovered, during 20 weeks of RM from the long time IM.

Animals↗
PubMed1995

Parathyroid hormone therapy accelerates recovery from immobilization-induced osteopenia.

Previous reports have shown that bone mass and architecture will partially recover by remobilization (RM) in immobilization (IM)-induced osteopenia. The aim of this study was to test whether PTH can accelerate the recovery during RM from the IM-induced osteopenia. Six-month-old Sprague-Dawley female rats were divided into aging and IM groups. The right hindlimb of rats was immobilized against the abdomen by elastic bandages for 18 weeks, then groups of rats were further IM or RM for 2, 10 and 20 weeks and given 30 or 80 micrograms hPTH (1-38)/kg/d s.c. Secondary spongiosa of proximal tibial metaphyses (PTM) were studied. Immobilization reduced the trabecular area, number and thickness at the first 18 weeks post IM, then plateaued. Ten weeks of RM restored 40% trabecular bone from IM controls due to thickening of the trabeculae. However, the trabecular area was still -14% and -13% lower than that of aging controls at 10 and 20 weeks. Two weeks of 30 micrograms PTH/kg/d in IM rats restored the bone to aging control levels, two weeks of 30 micrograms PTH/kg/d in RM rats and of 80 micrograms PTH/kg/d in both RM and IM rats added extra bone. Extending the treatment to 10 and 20 weeks, the same amount of total bone was added to both IM and RM rats. These findings indicate PTH is a powerful agent that can accelerate the recovery and add extra bone to osteopenic cancellous bone in both IM and RM rats.

Analysis of Variance↗
PubMed1995

Tomographic (pQCT) and biomechanical effects of hPTH(1-38) on chronically immobilized or overloaded rat femurs.

Six-month old rats chronically submitted to right hindlimb immobilization (IM) with mechanical overload (OL) of the left leg were treated 1 month later with 200 micrograms/kg/d of hPTH(1-38) for 15 or 75 days. Peripheral quantitative computed tomography (pQCT) scans and bending tests showed that hPTH increased cortical mass and volumetric BMD (vCtBMD) in both legs. However, elastic modulus of cortical bone and diaphyseal load-bearing capacity were improved only in OL bones. Improvement of diaphyseal strength was attributable to that of cortical bone quality, yet a stronger mechanostatic response of cortical modeling to bone material quality was also observed in treated OL bones. Data support hPTH(1-38) use for improving cortical bone mass and strength and point out a physical activity interaction with therapeutic results.

Analysis of Variance↗
PubMed1995

An in-vivo model for the rapid assessment of skeletal effects of anabolic agents.

We recently developed an in vivo model which can be used to rapidly assess the local skeletal effects of anabolic agents. In this model, 160 g Sprague-Dawley (SD) rats were used. A stainless steel cannula was inserted into the marrow cavity of the proximal tibia through the anterior-medial cortex 6 mm distal to the knee joint. The outer opening of the cannula was covered by skin. Agents with known anabolic skeletal effects or vehicle were injected daily for 10 days into the marrow region by a small needle passing through the cannula. Rats were also injected subcutaneously with a fluorescent bone marker to label the newly formed bone. Injection sites were fixed, embedded, and sectioned for histomorphometric analysis of trabecular bone. PTH and PGE2 stimulated a large amount of new trabecular bone formation in regions proximal and distal to the injection site as measured by histomorphometry. Control groups showed minimal bone formation, limited to formation of a thin layer of bony shell immediately surrounding the cannula. The profound anabolic skeletal effects of PTH and PGE2 seen in this Local Injection Model are similar to those seen in systemic injection (i.e. subcutaneous injection in intact or castrated male and female rats) previously reported. This Local Injection Model combines numerous advantages of in vivo models (systemic injection) and in vitro models when assessing agents with anabolic skeletal activities. Compared to conventional in vivo systemic injection models, this model enables detection of anabolic skeletal effects using very small quantities (in microgram) of test agents in a short treatment period (< 10 days).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Early effects of prostaglandin E2 on bone formation and resorption in different bone sites of rats.

The aim of this study was to determine early effects of prostaglandin E2 (PGE2) on bone mass, formation and resorption in a growing cancellous bone site (the proximal tibial metaphysis, PTM), non-growing cancellous bone site (the distal tibial metaphysis, DTM), and cortical bone site (the tibial shaft, TX) with histomorphometric analysis. Six mg PGE2/kg/d was given s.c. to 6-month-old Sprague-Dawley female rats for 5, 10 or 16 days. Double fluorescent labels were given to 0, 10- and 16-day PGE2 treatment and 16-day control groups. Significant increase in bone mass was found after 16 days treatment in cancellous bone sites but not in the cortical bone site. Stimulated bone formation, indicated by the increase in osteoid perimeter, was observed as early as 5 days post-treatment in all 3 bone sites. Bone formation indices were increased after 10 days of treatment, however, there was no difference in selected bone formation indices between 10 and 16 days PGE2 treatments at all 3 bone sites. Significant increase in eroded surface and eroded surface covered with osteoid was observed in cancellous bone sites after 5 days, but decreased after 10 days of treatment. Although the eroded surface was not elevated in TX at the 5th day, the eroded surface covered with osteoid was increased on endocortical surface which indicated that PGE2 stimulated bone resorption on this surface prior to day 5. We concluded that PGE2 stimulated the bone formation and resorption as early as 5 days post-treatment. The levels of stimulated bone formation was TX > DTM > PTM.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Risedronate pretreatment does not hamper the anabolic effects of prostaglandin E2 in ovx rats.

Pretreatment of an anti-resorptive agent on the anabolic effects of prostaglandin E2 (PGE2) was studied on the proximal tibia and tibial shaft of ovariectomy (ovx) rats. Two days after ovx, rats were treated with either risedronate (Ris, 5 micrograms/kg twice weekly) or vehicle (V) for 60 days and then switched to 3 or 6 mg/kg/d PGE2 for 21 or 90 days. Bone area of both proximal tibial metaphysis (PTM) and tibial shaft (TX) were measured. Pretreatment with Ris increased the bone mass in PTM but not in TX of ovx rats. In the PTM, PGE2 produced the same percentage of new bone mass in both V- and Ris-pretreated ovx rats. The amount of new bone was almost the same after 3 weeks and 12 weeks of PGE2 treatment. There was no difference in the anabolic effects of 3 and 6 mg PGE2/kg/d in V-pretreated rats; however, the effects in Ris-pretreated groups were greater with 6 mg PGE2/kg/d than with 3 mg PGE2/kg/d. In TX, only the 6mg PGE2/kg/d administration added new bone on endocortical surfaces of both V- or Ris-pretreatment rats which leads to thickening the minimal cortical width, decreasing the marrow cavity and increasing total bone area. Both doses of PGE2 created new trabecular bone in the marrow cavity of tibial shaft in both vehicle- and Ris-pretreated ovx rats. These results suggest that Ris-pretreatment did not hamper the anabolic effects of PGE2 on either PTM or TX in ovx rats.

Aging↗
PubMed1995

Co-treatment of PGE2 and risedronate is better than PGE2 alone in the long-term treatment of ovariectomized-induced osteopenic rats.

We studied the effects of prostaglandin (PGE2) and risedronate (Ris) alone or in combination in 3.5-month-old intact and ovx-induced osteopenic rat skeletons to determine whether PGE2 plus Ris was more anabolic than PGE2 alone. Six mg PGE2/kg/d and 5 micrograms Ris/kg/2x/wk alone or in combination were given to sham-ovx and ovx rats for 30 or 90 days beginning 60 days post operation. Secondary spongiosa of proximal tibial metaphyses (PTM) was studied. Ovariectomy (ovx) induced dramatic bone loss. Ris increased bone mass in sham-ovx rats and prevented further bone loss in ovx rats. PGE2 treatment for 30 days added extra bone in sham-ovx rats and no further increase after 90 days treatment. Thirty days of PGE2 alone treatment restored the bone mass in ovx rats to the level of sham-ovx rats, but the restored bone was partially lost by 90 days of treatment. Co-treatment for 30 days produced the same amount of bone mass in both sham-ovx and ovx rats as PGE2 alone did. However, unlike the PGE2 alone treated, co-treatment animals continued to form more bone for 90 days. The difference in tissue-level histomorphometry between co-treatment and PGE2 alone was that the former depressed the bone resorption and turnover. These findings indicated that the long-term administration of PGE2 alone cannot maintain or continue to add bone mass in ovx rats but that co-treatment of a PGE2 with an anti-resorptive or activation agent can resist the influence of the mechanostat induced bone loss as well as continue to add bone.

Aging↗
PubMed1995

Intermittent treatment of prostaglandin E2 with risedronate is more anabolic than prostaglandin E2 alone in the proximal tibial metaphysis of ovariectomized rats.

This study is designed to test how intermittent application of prostaglandin E2 (PGE2) and risedronate (Ris) alone or in combination acts on the cancellous bone mass in estrogen-deficient rats. Sprague-Dawley rats were ovariectomized (ovx) or sham-ovx'd at 6 months of age. PGE2 (6mg/kg/d), Ris (5 micrograms/kg/twice a week) or PGE2 plus Ris were given for 60 days to ovx rats immediately after operation and followed by 60 days without treatment. The drugs were then reapplied for another 60 days. Static histomorphometry was performed on the secondary spongiosa of proximal tibial metaphysis (PTM). Sixty days of ovx lost trabecular bone and number, Ris prevented ovx-induced bone loss. PGE2 added 48% extra cancellous bone, but the new bone was completely lost after 60 days of withdrawal. Another 60 days of PGE2 treatment only partially restored the trabecular bone, the bone mass was still -42% lower than that of sham-ovx controls. Co-treatment of PGE2 with Ris added the same amount of bone as PGE2 alone after the first 60 days treatment period, but differed from PGE2 alone in that the new bone lost less during the 60 days withdrawal period. Re-application of co-treatment for another 60 days added more extra bone. We concluded that intermittent co-treatment with anabolic and anti-resorptive agents is more effective than anabolic agent alone in long-term therapy of cancellous bone in estrogen-deficient rats.

Analysis of Variance↗
PubMed1995

Intermittent treatments of prostaglandin E2 plus risedronate and prostaglandin E2 alone are equally anabolic on tibial shaft of ovariectomized rats.

Effects of intermittent administration of prostaglandin E2 (PGE2), risedronate (Ris) and their combination on bone mass were studied on the cortical bone of tibial shafts of ovariectomized (ovx) rats. Six month old ovx rats were treated immediately after operation with subcutaneous injections of 6 mg PGE2/kg/d, 5 micrograms Ris/kg/2x/wk or their combination for 60 days each of an on/off/on cycle. PGE2 alone and in combination with Ris added the same amount of new bone in the first 60 days on period. During the 60 days off period, newly added endocortical and marrow trabecular bone disappeared in PGE2 alone treatment groups. In co-treatment group, the marrow trabeculae were only partly lost. There was no difference in total bone area between co-treatment and PGE2 alone groups after another 60 days on treatment. Our findings indicate that co-treatment was better in the maintenance of newly added endocortical and marrow trabecular bone during the off period; however, it formed less bone than PGE2 alone during the second treatment period, and ended up with the same amount of bone with both treatments.

Animals↗
PubMed1995

Maintenance therapy for added bone mass or how to keep the profit after withdrawal of therapy of osteopenia.

Since continuous therapy for osteoporosis can be expensive and may have detrimental effects, there is a need to develop a strategy to maintain bone mass after withdrawal of treatment. The bone maintained by estrogen and calcitonin therapies and exercise, but the added bone induced by anabolic agents disappears upon cessation of treatment. To avoid this pitfall, the concepts of activation, restore and maintain (ARM) or loss, restore and maintain (LRM), the on/off administration of combined anabolic agent with an antiresorptive or antiactivation agent, and cyclical treatment of the two regimes have been employed successfully in "keeping the profit" (maintaining bone) in preclinical studies. The data for the disappearance of bone upon cessation of certain osteopenic treatments, its mechanism of loss and the development of maintenance concept and subsequent preclinical studies indicate that there was no need for costly continuous therapy in the treatment strategy for osteoporosis.

Animals↗
PubMed1995

Effects of on/off anabolic hPTH and remodeling inhibitors on metaphyseal bone of immobilized rat femurs. Tomographical (pQCT) description and correlation with histomorphometric changes in tibial cancellous bone.

An anabolic effect of hPTH(1-38) (s.c. doses of 200 micrograms/kg/d during 75 days) on trabecular and cortical bone mass is tomographically described in the metaphyseal region of immobilized rat femurs using pQCT technology, in agreement with previous histomorphometrical studies of the proximal tibial metaphyses. Correlations between pQCT and histomorphometrical data showed that this effect derived from a stimulation of endosteal and trabecular bone modeling that induced a transference from trabecular to cortical bone mass. Loss of effects after withdrawal, resulting from a stimulation of bone remodeling, could be total or partially prevented by subsequent s.c. injections of risedronate (5 micrograms/kg/2/wk), 17-B-estradiol (10 micrograms/kg/d) or calcitonin (10 micrograms/kg/d) given during 60 days, in this order of effectiveness. The preventive potency was proportionally related to the reduction induced in histomorphometric indices of bone resorption.

Animals↗