Bone Resorption In Ovariectomized Rats Research Articles

Effects of Caffeic Acid and Its Derivatives on Bone: A Systematic Review.

PurposeCaffeic acid is a metabolite of hydroxycinnamate and phenylpropanoid, which are commonly synthesized by all plant species. It is present in various food sources that are known for their antioxidant properties. As an antioxidant, caffeic acid ameliorates reactive oxygen species, which have been reported to cause bone loss. Some studies have highlighted the effects of caffeic acid against bone resorption.MethodsA systematic review of the literature was conducted to identify relevant studies on the effects of caffeic acid on bone. A comprehensive search was conducted from July to November 2020 using PubMed, Scopus, Cochrane Library and Web of Science databases. Cellular, animal and human studies reporting the effects of caffeic acid, as a single compound, on bone cells or bone were considered.ResultsThe literature search found 226 articles on this topic, but only 24 articles met the inclusion criteria and were included in this review. The results showed that caffeic acid supplementation reduced osteoclastogenesis and bone resorption, possibly through its antioxidant potential and increased expression of osteoblast markers. However, some studies showed that caffeic acid did not affect bone resorption in ovariectomized rats and might impair bone mechanical properties in normal rats.ConclusionCaffeic acid potentially regulates the bone remodelling process by inhibiting osteoclastogenesis and bone resorption, as well as osteoblast apoptosis. Thus, it has medicinal values against bone diseases.

Cynomorium songaricum prevents bone resorption in ovariectomized rats through RANKL/RANK/TRAF6 mediated suppression of PI3K/AKT and NF-κB pathways

AimCynomorium songaricum Rupr., an edible and important Traditional Chinese medicine has long been used in folk for treatment of kidney deficiency, was chosen to estimate the antiosteoporotic activity and underlying molecular mechanism on rats induced by ovariectomy (OVX). Main methods9 of 45 rats were underwent bilateral laparotomy without removing the ovaries as sham group, remains were underwent bilateral ovariectomy and equally randomized into four groups: with vehicle (0.5% CMC-Na) as model group, estradiol valerate (1 mg/kg body weight/day) as positive control, with 100 and 300 mg/kg body weight/day of ethanol extracts of C. songaricum extract (CSE) as low and high dosage groups, respectively. Key findingsAfter 12 weeks of continues orally intervention, the decreases of bone mineral density, bone mineral content, tissue mineral content, as well as the increases of bone trabecular separation and bone resorption markers were significantly reversed by CSE in the OVX rats, and in particular, a contradictory phenomenon on calcium and phosphorus contents was observed and elucidated. Mechanistically, the expressions of tumor-necrosis factor receptor-associated factor 6 (TRAF 6), nuclear factor kappa B (RANK) and its ligand (RANKL), as well as the nuclear factor kappa B (NF-κB), phosphoinositide 3‑kinase (PI3K) and protein kinase B (AKT) levels were significantly down-regulated by CSE intervention, whereas the osteoprotegerin (OPG) was significantly up-regulated by CSE as compared to the control. SignificanceConcisely, C. songaricum exhibited potential therapeutic effect on bone metabolism of ovariectomized rats, and this effect was possibly exerted by RANKL/RANK/TRAF6 mediated down-regulation of NF-κB and PI3K/AKT pathways.

Bu-Shen-Tong-Luo decoction prevents bone loss via inhibition of bone resorption and enhancement of angiogenesis in ovariectomy-induced osteoporosis of rats

Ethnopharmacological relevanceGathering three ancient formulas, traditional Chinese medicine Bu-Shen-Tong-Luo decoction (BSTLD) has been used to treat postmenopausal osteoporosis (PMO) at the Jiangsu Province Hospital of Chinese Medicine for decades. However, the effect of BSTLD on angiogenesis and bone resorption as well as its possible mechanism are still unknown. Aim of the studyThis study was aimed to evaluate the preventive effect of BSTLD on ovariectomy-induced bone loss and vasculature disorder, and to investigate the possible bone protection mechanism of BSTLD in inhibiting bone resorption by enhancing angiogenesis signaling in ovariectomy-induced osteoporosis of rats. Materials and methodsThe animal experiment was divided into five groups. Rats underwent either sham surgery with intact ovaries (SHAM, n = 10) or bilateral ovariectomy (OVX, n = 40). OVX rats were randomly divided into four groups and gavaged by water (vehicle, 12 mL/kg, n = 10), BSTLD (6 g/kg, n = 10), BSTLD (12 g/kg, n = 10) and 17β-estradiol (E2, 100 μg/kg, n = 10) daily for 12 weeks, respectively. The bone loss and microstructure of the distal femur were observed using micro-computed tomography (μCT). The biomechanical parameters of the femur were detected using three-point bending tests. The distribution of osteoclasts and endothelial cells were analyzed by immunohistochemistry. The mRNA and protein levels of angiogenesis-related hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF), as well as osteoclast activation-related signaling calcitonin receptor (CALCR), cathepsin K (CTSK), receptor activator of NF-κB ligand (RANKL), osteoprotegerin (OPG), and β-catenin were assayed by RT-PCR or Western blot. ResultsBSTLD protected trabecular bone mass density and trabecular bone microstructure from ovariectomy-induced osteoporosis in rats. BSTLD significantly reduced mRNA and protein levels of calcitonin receptor and CTSK in femoral metaphysis and inhibited bone resorption in ovariectomized rats. Furthermore, BSTLD stabilized HIF-1α activity and subsequently increased VEGF expression to enhance angiogenesis and modulated RANKL/OPG signaling in this animal model. ConclusionsThese results demonstrated that BSTLD reduced osteoclasts activation and bone resorption in ovariectomy-induced osteoporosis. Bone protection by BSTLD may be associated with its stimulation of HIF-1α/VEGF angiogenesis signaling and suppression of RANKL/OPG ratio. This study may provide evidence that BSTLD treats postmenopausal osteoporosis, especially with micro-circulation complication.

Synergistic Effects of Genistein and Zinc on Bone Metabolism and the Femoral Metaphyseal Histomorphology in the Ovariectomized Rats.

In this study, we evaluated the synergistic effects of genistein and zinc on bone metabolism, bone mineral density, and the femoral metaphyseal histomorphology in the ovariectomized rats. Sixty female Sprague-Dawley rats, aged 13weeks, were divided into sham-operated group (SHAM), ovariectomized group (OVX), genistein-treated group (OVX-Gen), zinc-treated group (OVX-Zn), genistein combined zinc-treated group (OVX-Gen-Zn), and 17β-estradiol-treated group (OVX-E) (n=10). Genistein, zinc, and 17β-estradiol injections were started immediately after OVX and continued for 10weeks. The OVX-Gen group was subcutaneous injections of genistein (5mg/kg once every day). The OVX-Zn group was given intragastric ZnSO4 (0.25mg/kg once every day) after bilateral ovariectomy. The OVX-Gen-Zn group was subcutaneous injections of genistein (5mg/kg), at the same time intragastric ZnSO4 (0.25mg/kg once every day). OVX-E group were intraperitoneally injected with 17β-estradiol (10μg/kg) once every other day. The results showed that genistein and zinc did not alter body weight in OVX rats. The soluble ZnSO4 had no effect to uterus weight loss. Genistein and zinc supplementation significantly increased the BMD of the femur and lumbar spine in OVX rats (P<0.05, vs. OVX control group). The BMD of the lumbar spine and femur in the OVX-Gen-Zn group is higher than that in the OVX-Gen and OVX-Zn groups (P<0.05), and there were no differences of BMD among the OVX-Gen-Zn, OVX-E, and SHAM groups (P>0.05). The femoral metaphyseal morphology and bone histomorphometric parameters revealed that the trabecular volume and thickness in the OVX-Gen-Zn and OVX-E groups were similar to that of SHAM group, and the OVX-Gen-Zn group had more trabecular volume than the OVX-Gen and OVX-Zn groups. Serum zinc was found to be significantly reduced in the OVX group when compared with SHAM. Serum zinc levels were enhanced in the OVX-Zn, OVX-Gen-Zn, and OVX-E groups and restored to normal levels. Serum calcium and serum phosphorus in the OVX-Gen-Zn group was greater than that in the OVX-Gen and OVX-Zn groups (P<0.05); the serum calcium, phosphorus, and ALP in the OVX-Gen-Zn group were similar to that of SHAM and OVX-E groups (P>0.05). The OVX group had higher osteocalcin, CTX, and RANKL than the SHAM group (P<0.01). They were lower in the OVX-Gen and OVX-Zn groups (P<0.05), and they were significantly lower in the OVX-Gen-Zn and OVX-E groups, than in the OVX group. There were no significant differences of osteocalcin, CTX, and RANKL among the OVX-Gen-Zn, OVX-E, and SHAM groups (P>0.05). OPG and OPG/RANKL ratios were significantly higher in the OVX-Gen and OVX-Zn groups than that in the OVX group (P<0.05). The OPG and OPG/RANKL ratio in the OVX-Gen-Zn group is higher than that in the OVX-Gen and OVX-Zn groups (P<0.05, vs. OVX-Gen group; P<0.01, vs. OVX-Zn group). The differences of the OPG and OPG/RANKL ratios between the OVX-Gen-Zn, OVX-E, and the SHAM groups were not significant (P>0.05). The results above indicate that the genistein and zinc have synergistic effects on both stimulation of bone formation and suppression of bone resorption in ovariectomized rats, thereby increasing bone mass.

The protective effect of lycopene intake on bone loss in ovariectomized rats.

Antioxidant lycopene supplementation has been shown to decrease oxidative stress and have beneficial effects on bone health. However, it remains unclear whether lycopene exerts its beneficial effect on bone metabolism through mitigation of oxidative stress in vivo. The aim of this study was to investigate whether lycopene intake protects against bone loss by reducing oxidative stress in ovariectomized rats. Female Sprague-Dawley 6-week-old rats were ovariectomized and randomly divided into four groups according to the lycopene content of their diet: 0, 50, 100, and 200ppm. The tibial bone mineral density (BMD) in the 50, 100, and 200ppm groups was significantly higher than that in the 0ppm group. Serum and urinary bone resorption marker levels were significantly lower in the 50, 100, and 200ppm groups than in the 0ppm group. There was no significant difference in systemic oxidative stress markers among all groups. However, systemic oxidative stress levels were inversely correlated with the tibial BMD. Our findings suggest that lycopene intake significantly inhibits bone loss by suppressing bone resorption in ovariectomized rats. Further studies are necessary to clarify the effect of lycopene on oxidative stress in local tissues such as bone tissue.

Hypergravity suppresses bone resorption in ovariectomized rats

The effects of gravity on bone metabolism are unclear, and little has been reported about the effects of hypergravity on the mature skeleton. Since low gravity has been shown to decrease bone volume, we hypothesized that hypergravity increases bone volume. To clarify this hypothesis, adult female rats were ovariectomized and exposed to hypergravity (2.9G) using a centrifugation system. The rats were killed 28days after the start of loading, and the distal femoral metaphysis of the rats was studied. Bone architecture was assessed by micro-computed tomography (micro-CT) and bone mineral density was measured using peripheral quantitative CT (pQCT). Hypergravity increased the trabecular bone volume of ovariectomized rats. Histomorphometric analyses revealed that hypergravity suppressed both bone formation and resorption and increased bone volume in ovariectomized rats.Further, the cell morphology, activity, proliferation, and differentiation of osteoclasts and osteoblasts exposed to hypergravity were evaluated in vitro. Hypergravity inhibited actin ring formation in mature osteoclasts, which suggested that the osteoclast activity was suppressed. However, hypergravity had no effect on osteoblasts. These results suggest that hypergravity can stimulate an increase in bone volume by suppressing bone resorption in ovariectomized rats.

D-003 does not possess oestrogenic potential in-vivo: findings of the uterotrophic assay

D-003 is a mixture of long-chain fatty acids purified from sugarcane wax that inhibits both cholesterol synthesis prior to mevalonate formation, and lipid peroxidation. D-003 has been shown to prevent bone loss and bone resorption in ovariectomized rats, and significantly improves bone resorption markers in postmenopausal women with reduced bone mineral density. As hormone-replacement therapy, D-003 displays cholesterol-lowering and anti-resorptive effects. We have studied its potential oestrogenic activity in-vivo using the uterotrophic assay. Rats were randomly distributed into five groups: a sham-operated group and four groups of ovariectomized rats, one treated with vehicle, one with D-003 (50 mg kg(-1)), one with oestradiol benzoate (30 microg kg(-1)) and one with D-003 (50 mg kg(-1)) plus oestradiol benzoate (30 microg kg(-1)). Treatments were administered for 14 days. Ovariectomy decreased the values of relative uterus weight, epithelium cell height and endometrial thickness compared with sham-operated rats, and these effects were all significantly reduced with oestradiol benzoate, but not with D-003. Concurrent administration of D-003 and oestradiol benzoate had statistically similar effects on all variables as oestradiol benzoate alone. In conclusions, D-003 orally given at 50 mg kg(-1), a dose that prevents bone loss and bone resorption in ovariectomized rats, did not display oestrogenic/anti-oestrogenic activity in-vivo, as assessed in the uterotrophic assay.

Histamine Promotes Osteoclastogenesis through the Differential Expression of Histamine Receptors on Osteoclasts and Osteoblasts

In addition to the numerous roles of histamine in both the immune and nervous systems, previous studies have suggested that this bioamine might also be involved in bone metabolism. Following our observations of impaired bone resorption in ovariectomized rats after histamine receptor antagonist treatment, we focused in this study on osteoclasts and osteoclast precursors. We looked for a direct action of histamine on these cells using both in vivo and in vitro approaches. In vivo, we triggered a remodeling sequence in rat mandibular bone and treated the animals with either histamine or histamine receptor antagonists. Histamine was shown to increase the number of osteoclasts and osteoclast precursors whereas antagonists of histamine receptor-1 and -2 decreased both osteoclast recruitment and resorption. In vitro, spleen cells from histamine-deficient mice were treated with receptor activator for nuclear factor kappa B ligand and macrophage colony stimulating factor, giving rise to both reduced numbers of osteoclasts and decreased resorption on dentin slices. Histamine enhanced resorption in these cultures in a dose-dependent manner. In addition, we identified osteoclast precursors as a source of histamine. In contrast, histamine increased the receptor activator for nuclear factor kappa B ligand/osteoprotegerin ratio in primary osteoblasts that did not secrete histamine. We observed a differential expression of histamine receptor-1 and -2 mRNAs in both primary osteoclasts and osteoblasts, confirming their functional roles with selective antagonists. Thus, histamine acts directly on osteoclasts, osteoclast precursors, and osteoblasts, promoting osteoclastogenesis through autocrine/paracrine mechanisms.

Antiosteoporotic chemical constituents from Er-Xian Decoction, a traditional Chinese herbal formula

Aim of the study Er Xian Decoction (EXD), a traditional Chinese medicine formula, has long been used for the treatment of osteoporosis and menopausal syndrome in China. The present study was designed to investigate the antiosteoporotic constituents of EXD, and evaluate their antiosteoporotic effects in ovariectomized rats. Materials and methods Osteoblasts in neonatal calvaria cultures and osteoclasts derived from rat marrow cells were used to bioactivity-guided screen the active constituents. The proliferation of osteoblast was assayed by MTT methods. The activity of ALP and TRAP was measured by p- nitrophenyl sodium phosphate assay. The antiosteoporotic effects of icariin (1), anemarsaponin B II (8) and berberine (6) were verified by using OVX rats model. The bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry using the small animal scan mode. The undecalcified longitudinal proximal tibial metaphysical (PTM) sections were cut and stained for the bone histomorphometric analysis. Results Bioactivity-guided fractionation has led to the successful isolation of antiosteoporotic constituents, i.e., icariin (1), icariside I (2), baohuoside I (3), mangiferin (4), neomangiferin (5), berberine (6), anemarsaponin B (7), anemarsaponin BII (8), anemarsaponin C (9), anemarrhenasaponin I (10), rubiadin-1-methyl ether (11) and obaculactone (12) from EXD. Further study showed that icariin (1), anemarsaponin BII (8) and berberine (6) increased the BMD in ovariectomized rats, and icariin (1) not only increased the bone formation, but also inhibited bone resorption; anemarsaponin BII (8) mainly increased bone formation and berberine (6) only inhibited the bone resorption in ovariectomized rats. Conclusion Our findings demonstrate that multiple ingredients are responsible for antiosteoporotic activity in traditional Chinese medicine formula Er-Xian decoction.

Natural products as alternative treatments for metabolic bone disorders and for maintenance of bone health

Bone metabolism involves a complex balance between the deposition of matrix and mineralization and resorption. There is now good evidence that dietary components and herbal products can influence these processes, particularly by inhibiting bone resorption, thus having beneficial effects on the skeleton. For example, it has been reported that a number of common vegetables, including onion, garlic and parsley, can inhibit bone resorption in ovariectomized rats. Essential oils derived from sage, rosemary, thyme and other herbs inhibit osteoclast activity in vitro and in vitro and leading to an increase in bone mineral density. Soya, a rich source of isoflavones, has shown promising results and epidemiological evidence to support a use in maintaining bone health, and various traditional herbal formulae in Chinese and Ayurvedic medicine also have demonstrable effects in pharmacological models of osteoporosis. Recently, cannabinoids have been described as having positive effects on osteoblast differentiation, and the presence of cannabinoid receptors in bone tissue indicates a more complex role in bone metabolism than previously thought. The first part of this review briefly discusses normal bone metabolism and disorders caused by its disruption, with particular reference to osteoporosis and current pharmacological treatments. The effects of natural products on bone and connective tissue are then discussed, to include items of diet, herbal extracts and food supplements, with evidence for their efficacy outlined.

Effect of Treadmill Exercise on Bone Mass in Female Rats

Increasing peak bone mass at skeletal maturity, minimizing bone loss during middle age and after menopause, and increasing bone mass and preventing falls in advanced age are important measures for preventing osteoporotic fractures in women. Exercise has generally been considered to have a positive influence on bone health. This paper reviews the effects of treadmill exercise on bone in young, adult, ovariectomized, and osteopenic female rats. Treadmill exercise increases cortical and cancellous bone mass of the tibia as a result of increased bone formation and decreased bone resorption in young and adult rats. The increase in lumbar bone mass seems to be more significant when long-term exercise is applied. Treadmill exercise prevents cancellous bone loss at the tibia as a result of suppressed bone resorption in ovariectomized rats, and increases bone mass of the tibia and mechanical strength of the femur, as a result of suppressed bone resorption and increased bone formation in osteopenic rats after ovariectomy. Treadmill exercise transiently decreases the serum calcium level as a result of accumulation of calcium in bone, resulting in an increase in serum 1,25-dihydroxyvitamin D(3) level and a decrease in serum parathyroid hormone level. We conclude that treadmill exercise may be useful to increase bone mass in young and adult rats, prevent bone loss in ovariectomized rats, and increase bone mass and bone strength in osteopenic rats, especially in the long bones at weight-bearing sites. Treadmill exercise may have a positive effect on the skeleton in young, and adult, ovariectomized, and osteopenic female rats.

Retracted: Effects of Vitamin K2 on Osteoporosis

1. Iwamoto J, Takeda T, Ichimura S. Combined treatment with vitamin K2 and bisphosphonate in postmenopausal women with osteoporosis. Yonsei Med J 2003; 44: 751-6. Available at: https://eymj.org/DOIx.php?id=10.3349/ymj.2019.60.1.115. It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript, the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

Reduction in bone formation and elevated bone resorption in ovariectomized rats with special reference to acute inflammation

Changes in bone modeling and remodeling in the tibia of growing rats within 30 days of ovariectomy (ovx) were evaluated by histomorphometric, mechanical, and biochemical means. Three days after ovx, suppressed bone formation was seen. This was shown by reduced osteoid volume, osteoblast surface, and bone formation rate in the secondary spongiosa, and a reduced longitudinal growth rate in the growth plate. In addition, the alkaline phosphatase and tartrate-resistant acid phosphatase activity in bone marrow supernatants was suppressed in conjunction with elevated serum sialic acid levels, indicating inflammation. Although estrogen deprivation itself may provoke the inflammatory process, the serum sialic acid level in the ovx group returned to the baseline level within 5 days after surgery, while that of estradiol in the ovx group remained consistently lower. This suggests that surgical stress, not estrogen deprivation, is the primary cause of the inflammatory response shortly after ovx. A significant difference ( p < 0.01) between the ovx and sham rats was seen in the osteoclast surface, which peaked on day 7 in the ovx rats. On day 14 postovariectomy, the bone formation rate peaked and remained constant until day 30. In the ovx rats, there was a sustained reduction in the serum albumin level until day 30. Estrogen deprivation may be the primary cause of these changes, because both surgical ovx and medical oophorectomy with gonadotropin-releasing hormone agonist (GnRHa) reduce the serum albumin level. In numerous studies dealing with changes after ovx in rats, we have observed: 1) a transient reduction in bone formation in relation to inflammatory changes evoked by ovx surgery, and 2) a sustained reduction in the serum albumin level for at least 30 days after ovx that is possibly due to estrogen deprivation.

Biochemical markers of bone resorption in ovariectomized rats: therapeutic effects of vitamin D metabolites

Biochemical markers of bone resorption in ovariectomized rats: therapeutic effects of vitamin D metabolites

Persistent bone-sparing effect of interleukin-1 receptor antagonist: A hypothesis on the role of IL-1 in ovariectomy-induced bone loss

The recent finding that treatment with the interleukin-1 (IL-1) inhibitor, interleukin-1 receptor antagonist (IL-1ra) decreases bone loss and bone resorption in ovariectomized rats, strongly suggested that IL-1 mediates, at least in part, the effects of estrogen deficiency on bone resorption. Although in vitro studies have shown that IL-1 activates mature osteoclasts and stimulates osteoclastogenesis, the two main mechanisms by which estrogen deficiency stimulates bone resorption, it is still unclear whether IL-1 mediates both effects of estrogen deficiency in vivo. To investigate this matter, we have examined the changes in bone mineral density (BMD) which occur in ovariectomized rats after completion of 1 month of estrogen or IL-1ra treatment begun at the time of ovariectomy. Ovariectomy caused a marked decreased in BMD which was blocked by 17 beta estradiol and decreased by IL-1ra. Cessation of estrogen therapy was followed by a rapid induction of bone loss, indicating that estrogen blocks the activation and utilization of mature osteoclasts without depleting the bone microenvironment of osteoclast precursors and mature, inactive osteoclasts. In contrast, ovariectomized rats treated with IL-1ra maintained a stable bone density for the first 4 weeks after completion of the treatment. In these rats, bone loss resumed not earlier than 6 weeks after discontinuation of the IL-1ra treatment. Estrogen deficiency was necessary to unveil the bone-sparing effect of IL-1ra because in a control experiment in which rats were treated with IL-1ra for the 4 weeks before ovariectomy, BMD began to decrease immediately after ovariectomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Interleukin-1 receptor antagonist decreases bone loss and bone resorption in ovariectomized rats.

Interleukin-1 (IL-1), a cytokine produced by bone marrow cells and bone cells, has been implicated in the pathogenesis of postmenopausal osteoporosis because of its potent stimulatory effects on bone resorption in vitro and in vivo. To investigate whether IL-1 plays a direct causal role in post ovariectomy bone loss, 6-mo-old ovariectomized rats were treated with subcutaneous infusions of IL-1 receptor antagonist (IL-1ra), a specific competitor of IL-1, for 4 wk, beginning either at the time of surgery or 4 wk after ovariectomy. The bone density of the distal femur was measured non invasively by dual-energy X-ray absorptiometry. Bone turnover was assessed by bone histomorphometry and by measuring serum osteocalcin, a marker of bone formation, and the urinary excretion of pyridinoline cross-links, a marker of bone resorption. Ovariectomy caused a rapid increase in bone turnover and a marked decrease in bone density which were blocked by treatment with 17 beta estradiol. Ovariectomy also increased the production of IL-1 from cultured bone marrow cells. Ovariectomy induced-bone loss was significantly decreased by IL-1ra treatment started at the time of ovariectomy and completely blocked by IL-1ra treatment begun 4 wk after ovariectomy. In both studies IL-1ra also decreased bone resorption in a manner similar to estrogen, while it had no effect on bone formation. In contrast, treatment with IL-1ra had no effect on the bone density and the bone turnover of sham-operated rats, indicating that IL-1ra specifically blocked estrogen-dependent bone loss. In conclusion, these data indicate that IL-1, or mediators induced by IL-1, play an important causal role in the mechanism by which ovariectomy induces bone loss in rats, especially following the immediate post ovariectomy period.

Effect of naproxen on cancellous bone in ovariectomized rats

Nonsteroidal anti-inflammatory drugs (NSAIDs) affect bone metabolism in vitro and in vivo. They delay but do not alter the outcome of healing processes in bone. In some bone loss models, they block bone resorption and slow the rate of loss. We studied the effect of naproxen, a potent NSAID, on cancellous bone of the proximal tibial metaphysis of 6-month-old adult female ovariectomized rats. Animals were ovariectomized, divided into groups, and fed standard diets differing only in naproxen content for 42 days. The rats of the groups ate 2.0, 5.5, 12.7, and 32 mg naproxen per kg body weight per day, respectively. Serum levels of naproxen were determined. Bone volume, mineralizing surface, osteoblast activity, osteoclast surface, and bone resorption rate were determined by bone histomorphometric techniques. The rats' dose-related serum naproxen levels ranged from 4 to 28 micrograms/ml. Naproxen inhibited up to 70% of the bone loss occurring after ovariectomy at a serum level of 4 micrograms/ml. We deduced that naproxen blocked bone resorption in ovariectomized rats by slowing osteoclast activity at all doses. In contrast, naproxen slowed bone formation only at serum levels greater than 20 micrograms/ml in ovariectomized rats. These findings may have clinical relevance in helping to prevent postmenopausal bone loss in women.