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Aspirin Prevents Bone Loss in Ovariectomized Rats

Abstract

[Effect of cyclooxygenase-2 on bone loss in ovariectomized rats].

To investigate mechanism of cyclooxygenase-2 (COX-2) in bone loss in a postmenopausal osteoporosis (PMOP) rat mode with ovarietomy (OVX).
Forty female Sprague Dawley adult rats at age of 3 months were randomly divided into 4 groups, 10 in each group, including sham-operated (sham) group, OVX group, OVX treated with nilesteriol (OVX + E) group and OVX treated with aspirin (OVX + P) group. All rats in OVX, OVX + E and OVX + P groups underwent ovarietomy under abdominal anesthesia with 10% chloral hydrate. Rats in sham group were only taken with fat tissue with same weight under bilateral ovary. After surgery, penicillin was administered to prevent infection. At day 7 after surgery, agents were given by intragastric administration for 12 weeks. Nilestriol at 1.0 mg/kg was used in OVX + E group once a week, aspirin at 45 mg×kg⁻¹(×d⁻¹ was used in OVX + P group once a day. Saline with same volume was used in rats in sham and OVX groups. All agents were administered one time per day. Dose of agents were adjusted by weight per week. At end of study, bone mineral density (BMD) of right femurs and lumbar vertebrae 3-5 (L(3-5)) were measured. Morphology of bone was detected by hematoxylineosin, and expression of COX-2 was determined by immunohistochemistry staining.
(1) BMD:BMD of right femur and L(3-5) was (0.209 ± 0.010) g/cm² and (0.230 ± 0.012) g/cm² in sham group and (0.181 ± 0.008) g/cm² and (0.201 ± 0.016) g/cm² in OVX group, which reached statistical difference (P < 0.01). BMD of right femur and L(3-5) was (0.203 ± 0.009) g/cm² and (0.224 ± 0.028) g/cm² in OVX + E group and (0.200 ± 0.011) g/cm² and (0.204 ± 0.003) g/cm² in OVX + P group, which were all higher than those in OVX group (P < 0.01, P < 0.05). However, there was no statistical difference in BMD between OVX + E and OVX + P group (P > 0.05). (2) Morphology of bone:bone trabeculae became fewer and degenerated in OVX group. However, bone trabeculae were regular and dense in OVX + P group and OVX + E group, which were similar to those in sham group. (3) Expression of COX-2:cells with COX-2 positive and expression of COX-2 around bone trabeculae in OVX group were more than those in sham, OVX + E and OVX + P group.
COX-2 plays an important role in PMOP. Aspirin could prevent bone loss by decreasing COX-2 expression in OVX rats.

Guo Y, Zhang CY, Tian Y, DI JM…
Zhonghua Fu Chan Ke Za Zhi Jun 2012
PMID: 22932114

Review: NSAIDs Controversy

Abstract

Effect of non-steroidal anti-inflammatory drugs on bone turnover: an evidence-based review.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used for acute and chronic pain control and treatment of inflammation, osteoarthritis and rheumatoid arthritis. NSAIDs have been shown to inhibit bone healing in animal studies due to the inhibition of prostaglandin synthesis. However, little evidence exists regarding the effect of NSAID exposure on human bone metabolism. This systematic review summarizes the current literature of randomized controlled trials (RCTs) investigating NSAIDs with bone remodeling-related outcomes in humans. After performing computerized searches in the most widely indexed databases, study selection, data abstraction and risk of bias assessment were conducted in duplicate. The results were controversial regarding the association of NSAID with bone formation or resorption. Increased bone mineral density following NSAID exposure was reported by some studies. Based on the levels of biochemical markers, no effect was seen on bone formation, while some evidence was found for a decreased rate of bone resorption in NSAID patients. Trials investigating the effects of NSAID treatment on bone metabolism outcomes of human patients are limited. Further research is required to confirm or refute the findings of this systematic review.

Konstantinidis I, Papageorgiou SN, Kyrgidis A, Tzellos TG…
Rev Recent Clin Trials Mar 2013
PMID: 23016823

Vitamin D3 + K2 + Sr + Mg + DHA as Effective as Bisphosphonates in Women

Abstract

Combination of Micronutrients for Bone (COMB) Study: bone density after micronutrient intervention.

Along with other investigations, patients presenting to an environmental health clinic with various chronic conditions were assessed for bone health status. Individuals with compromised bone strength were educated about skeletal health issues and provided with therapeutic options for potential amelioration of their bone health. Patients who declined pharmacotherapy or who previously experienced failure of drug treatment were offered other options including supplemental micronutrients identified in the medical literature as sometimes having a positive impact on bone mineral density (BMD). After 12 months of consecutive supplemental micronutrient therapy with a combination that included vitamin D(3), vitamin K(2), strontium, magnesium and docosahexaenoic acid (DHA), repeat bone densitometry was performed. The results were analyzed in a group of compliant patients and demonstrate improved BMD in patients classified with normal, osteopenic and osteoporotic bone density. According to the results, this combined micronutrient supplementation regimen appears to be at least as effective as bisphosphonates or strontium ranelate in raising BMD levels in hip, spine, and femoral neck sites. No fractures occurred in the group taking the micronutrient protocol. This micronutrient regimen also appears to show efficacy in individuals where bisphosphonate therapy was previously unsuccessful in maintaining or raising BMD. Prospective clinical trials are required to confirm efficacy.

Genuis SJ, Bouchard TP
J Environ Public Health 2012
PMID: 22291722 | Free Full Text

Prickly Pear Improves Bone Density in Women

Abstract

Intake of dehydrated nopal (Opuntia ficus indica) improves bone mineral density and calciuria in adult Mexican women.

The intake of dehydrated nopal (DN) at a high stage of maturity along with high calcium content could improve bone mineral density (BMD) and calciuria and thus prevent osteoporosis.
To evaluate the effect of calcium intake from a vegetable source (DN) on BMD and calciuria covering a 2-year period in menopausal and non-menopausal women with low bone mass (LBM).
The study was quasi-experimental, blinded, and randomized, and included 131 Mexican women aged 35-55. Urinary calcium/creatinine index (CCI) was determined; BMD was analyzed on lumbar spine and total hip regions. Four groups were studied: Control group (CG), women with normocalciuria and a minimum dose of DN; experimental group 1 (EG1), women with hypercalciuria and a minimum dose of DN; experimental group 2 (EG2), women with hypercalciuria, and a maximum dose of DN; and normal group (NG) for reference in BMD.
After the first semester of treatment, calciuria levels in women from both experimental groups returned to normal, remaining constant for the rest of the treatment. The percentage difference in BMD increased in the total hip region in the CG (pre 4.5% and post 2.1%) and EG2 (pre 1.8% and post 2.5%) groups significantly in comparison to NG and EG1, which exhibited a significant decrease in their BMD. BMD increased only for the lumbar region in the EG2 group (premenopausal).
The use of a vegetable calcium source such as nopal improves BMD in women with LBM in the total hip and lumbar spine regions principally in the premenopausal women, maintaining constant and normal calciuria levels.

Aguilera-Barreiro Mde L, Rivera-Márquez JA, Trujillo-Arriaga HM, Tamayo Y Orozco JA…
Food Nutr Res 2013
PMID: 23704856 | Free Full Text

Silymarin is a Beta Estrogen Agonist with Antiosteoporotic Effects in Ovariectomized Rats

Abstract

Silymarin is a selective estrogen receptor beta (ERbeta) agonist and has estrogenic effects in the metaphysis of the femur but no or antiestrogenic effects in the uterus of ovariectomized (ovx) rats.

Silymarin is a widely used standardized mixture of flavonolignans and its major component Silybinin binds to cytosolic estrogen receptors. Here, we demonstrate that this binding is exclusive to the estrogen receptor beta (ERbeta). Treatment of ovariectomized (ovx) rats with silymarin or estradiol (E2) may allow differentiation of biological effects mediated by the ERalpha or ERbeta. E2 inhibited serum LH, cholesterol, LDL and HDL concentrations in the blood and increased gene expression of IGF1, HbEGF and C3 in the uterus, while silymarin was totally ineffective or antagonistic in altering these parameters. Both, E2 and silymarin inhibited expression of uterine ERbeta gene. Hence, in the pituitary, liver (where the lipoproteins are synthesized) and uterus E2 acts primarily via the ERalpha. Exclusive estrogenic effects of silymarin were observed in the metaphysis of the femur (MF), on osteoblast parameters (gene expression of IGF1, TGFbeta1, osteoprotegerin, collagen-1alpha1, osteocalcin (OC)) and on the osteoclast activity marker tartrate resistant acid phosphatase (TRAP) gene expression of adult ovx rats. Our RT-PCR method detects ERbeta gene expression in all organs including developing bones but not in the MF of adult ovx rats. We conclude therefore, that the effects of silymarin in this part of the bone cannot be exerted via the ERalpha because it does not bind to this receptor subtype. Despite the failure to detect ERbeta mRNA in the MF of our animals the possibility exists that ERbeta protein is present and may mediate the effects of silymarin. Another possibility may be that the effect of silymarin and therefore possibly also of E2 in the MF may be mediated via other possibly not yet identified receptors or via an ERbeta splice variant which is not detected by our PCR-method.

Seidlová-Wuttke D, Becker T, Christoffel V, Jarry H…
J. Steroid Biochem. Mol. Biol. Aug 2003
PMID: 14568570

Silymarin has Antiosteoporotic and SERM Activity in Rats

Abstract

Evidences for antiosteoporotic and selective estrogen receptor modulator activity of silymarin compared with ethinylestradiol in ovariectomized rats.

Recently, growing multiple uses of silymarin (SIL) as a complementary and alternative medicine, for alcohol-induced liver disease, acute and chronic viral hepatitis, as well as some other nonhepatic indications have been reported. Therefore, more attention should be paid for the hormonal side effects of SIL. Since the available data on the possible estrogenic effects of SIL is rather rare, this study aimed to further elucidate the different estrogenic effects and antiosteoporotic activity of SIL in ovariectomized (OVX) rats. OVX rats were treated chronically (12 weeks) with ethinylestradiol (EE) or SIL. Uterine and body weight were measured in all animals. Biochemical markers of bone formation (total alkaline phosphatase (ALP), calcium, phosphorus and osteocalcin), endocrinological analysis (estradiol (E2), luteinizing hormone (LH), follicle stimulating hormone (FSH) and parathyroid hormone (PTH)) and serum total cholesterol and total lipids were estimated. Formalin fixed femora and uteri specimens were used for histopathological examination. In addition, the binding property of SIL to the two estrogen receptors (ER) subtypes was tested by molecular docking. EE (strong) and SIL (mild) stimulated uterine weight (increased uterus hyperplastic endometrial glands) but EE only prevented body weight gain following OVX. Treatment of OVX rats with both EE and SIL resulted in protection of trabecula thickness, decreased serum levels of ALP and increased serum levels of both calcium and phosphorus. In contrast to EE, SIL did not decrease OVX induced serum osteocalcin. EE not SIL decreased serum cholesterol, total lipids, LH and FSH and increased serum E2. Both EE and SIL increased serum PTH. The docking study revealed a high affinity of SIL towards ERbeta. In conclusion, findings derived in the present study presented an overview of SIL many estrogenic effects in OVX rats. SIL significantly prevents the bone loss in rats induced by OVX with mild proliferative effects in uterus. The observed effects may be due to additive beneficial effect of SIL on bone either due to direct interaction with ERbeta or increasing bone formation parameters including calcium, phosphorus, osteocalcin and PTH.

El-Shitany NA, Hegazy S, El-Desoky K
Phytomedicine Feb 2010
PMID: 19577454

Cowpeas Increase Bone Density in Ovariectomized Rats

Abstract

Effect of dietary legumes on bone-specific gene expression in ovariectomized rats.

In previous studies, we found that the consumption of legumes decreased bone turnover in ovariectomized rats. The purpose of the present study is to determine whether the protective effects on bone mineral density (BMD) and the microarchitecture of a diet containing legumes are comparable. In addition, we aim to determine their protective actions in bones by studying bone specific gene expression. Forty-two Sprague-Dawley rats are being divided into six groups during the 12 week study: 1) rats that underwent sham operations (Sham), 2) ovariectomized rats fed an AIN-93M diet (OVX), 3) ovariectomized rats fed an AIN-93M diet with soybeans (OVX-S), 4) ovariectomized rats fed an AIN-93M diet with mung beans (OVX-M), 5) ovariectomized rats fed an AIN-93M diet with cowpeas (OVX-C), and 6) ovariectomized rats fed an AIN-93M diet with azuki beans (OVX-A). Consumption of legumes significantly increased BMD of the spine and femur and bone volume of the femur compared to the OVX. Serum calcium and phosphate ratio, osteocalcin, expression of osteoprotegerin (OPG), and the receptor activator of nuclear factor κB ligand (RANKL) ratio increased significantly, while urinary excretion of calcium and deoxypyridinoline and expression of TNF-α and IL-6 were significantly reduced in OVX rats fed legumes, compared to OVX rats that were not fed legumes. This study demonstrates that consumption of legumes has a beneficial effect on bone through modulation of OPG and RANKL expression in ovariectomized rats and that legume consumption can help compensate for an estrogen-deficiency by preventing bone loss induced by ovarian hormone deficiency.

Park Y, Moon HJ, Paik DJ, Kim DY
Nutr Res Pract Jun 2013
PMID: 23766879 | Free Full Text

Maca Prevents Bone Loss in Ovariectomized Rats

Abstract

Effect of ethanol extract of Lepidium meyenii Walp. on osteoporosis in ovariectomized rat.

Maca (Lepidium meyenii Walp.) is a cruciferous plant from the Andes of Peru. The root of Maca is traditionally employed for its supposed properties in aphrodisiacs and improving fertility, it also has been widely used to help alleviate the symptoms of menopause. The purpose of this study was to evaluate the effect of ethanol extract of Maca on postmenopausal osteoporosis in ovariectomized rats. Female Sprague-Dawley rats were divided into four groups: Sham-operated and ovariectomized groups were fed with equivolume of distilled water, and the remaining ovariectomized groups were orally administrated with ethanol extract of Maca at 0.096 and 0.24 g/kg for 28 weeks. The findings derived from the basis of bone mineral density, biomechanical, biochemical and histopathological parameters indicated that higher dose of ethanol extract of Maca was effective in the prevention of estrogen deficient bone loss.

Zhang Y, Yu L, Ao M, Jin W
J Ethnopharmacol Apr 2006
PMID: 16466876

Babchi Increases Bone Density in Ovariectomized Rats

Abstract

Psoralea corylifolia extract ameliorates experimental osteoporosis in ovariectomized rats.

We evaluated the protective effect of Psoralea corylifolia L. (PCL) extract on the ovariectomized (OVX) rat model. The biochemical markers of bone turnover, calcium metabolism, and calcium balance were examined. PCL extract (25 mg or 50 mg/kg body weight/day) was orally administrated to OVX rats for 3 months. PCL extract did not alter weight gain or uterus weight in OVX rats. PCL extract significantly increased serum Ca (calcium) levels (p < 0.05, vs. OVX group) as well as decreased urinary Ca excretion (p < 0.05 vs. OVX group) in OVX rats. The upregulation of serum osteocalcin level by ovariectomy was suppressed by treatment with PCL extract in rats (p < 0.05, vs. OVX group). PCL extract increased bone mineral density at 50 mg/kg body weight/day in OVX rats (p < 0.05, vs. OVX group). Our results indicate that orally administrated PCL extract can decrease urinary calcium excretion and decrease serum osteocalcin in OVX rats, resulting in positive effects on bone mineral density as well as bone formation. In conclusion, our studies showed that PCL might be a potential candidate for treatment of postmenopausal osteoporosis.

Tsai MH, Huang GS, Hung YC, Bin L…
Am. J. Chin. Med. 2007
PMID: 17708633

Legumes, Especially Cowpeas, Improve Bone Markers in Rats

Abstract

Consumption of legumes improves certain bone markers in ovariectomized rats.

Soybeans are known to protect against osteoporosis, but other legumes frequently consumed in Asia have not been studied to learn if they have a similar protective effect. This study investigated the hypothesis that consumption of soybean, mung bean, cowpea, and adzuki bean has beneficial effects on bone biomarkers in ovariectomized rats. Female Sprague-Dawley rats were either sham operated (sham; n = 7) or surgically ovariectomized and then fed a regular AIN-93M diet (OVX; n = 7) or AIN-93M containing soybean (n = 7), mung bean (n = 7), cowpea (n = 7), or adzuki beans (n = 7) for 10 weeks. No bean consumption significantly altered the body, subcutaneous fat, or uterus weight; however, consumption significantly increased the serum calcium/phosphorous ratio and decreased urinary calcium excretion compared with those of the OVX group. Serum concentration of 17β-estradiol was significantly lower in the OVX group compared with that of the sham group and was lowest in the group fed OVX diet containing soybean. Serum osteocalcin concentration was significantly higher in all OVX rats given a diet with beans compared with the same diet without, but urinary deoxypyridinoline excretion was lowest in the group fed OVX diet containing cowpea. There were no significant differences in bone mineral density or bone mineral content of the right femur, tibia, or lumbar spine or in the trabecular bone volume of the tibia among the diet groups. In conclusion, the consumption of soybean, mung bean, cowpea, and adzuki bean in OVX rats improved osteocalcin, but only those fed cowpea showed decreased bone resorption biomarker, suggesting that cowpea may have the most protective effect on bone in OVX rats.

Lee SH, Jin N, Paik DJ, Kim DY…
Nutr Res May 2011
PMID: 21636018