osteoprotegerin and Osteoporosis--Postmenopausal

This study aimed to assess the association between the T950C polymorphism and osteoporosis in postmenopausal Chinese women to further reduce the influence of different genetic backgrounds by meta-analysis and subgroup analysis.. Through November 2022, a systematic online investigation was performed with the aid of the Cochrane Library, EMBASE, PubMed, Web of Science and the Chinese National Knowledge Infrastructure to find case-control studies looking into the correlation between the osteoprotegerin gene (OPG) T950C polymorphism and postmenopausal osteoporosis susceptibility.. This study included 6 studies with a total of 1669 postmenopausal osteoporosis cases and 2992 controls. In the recessive model, postmenopausal women with the CC genotype (mutant homozygote at the T950C locus) had a lower risk of osteoporosis, indicating that the CC genotype of OPG T950C might show a preventive effect on osteoporosis after menopause. In a stratified analysis by geographic area, the population from South China had a significantly higher risk under the dominant model [CC + TC (heterozygote at the T950C locus) vs TT (wild-type homozygotes at the T950C locus): odds ratio = 1.34, 95% confidence interval = 1.17-1.54, P < .01], while the population from South China had a significantly lower risk under the recessive model (CC vs TC + TT: odds ratio = 0.79, 95% confidence interval = 0.69-0.95, P = .02).. Together, the OPG T950C polymorphism may be associated with osteoporosis risk in postmenopausal Chinese women, according to this meta-analysis. Because of the study's limitations, more large-scale research is needed to corroborate these findings.

Topics: East Asian People; Female; Genetic Predisposition to Disease; Humans; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Single Nucleotide; Postmenopause

Subjects with low bone mineral density and osteoporosis are more likely to suffer osteoporotic fractures during their lifetime. Polymorphisms in osteoprotegerin (OPG) gene are found to be associated with low bone mineral density and osteoporosis risk but their association with fracture risk is inconclusive. Here, we performed a meta-analysis to investigate the relationship between OPG polymorphisms with susceptibility to osteoporotic fractures.. Eligible studies investigating the association between common OPG polymorphisms (A164G, T245G, T950C, and G1181C) and risk of osteoporotic fracture were retrieved from PubMed, EMBASE, Web of Science, and the Cochrane Library. Odds ratio (OR) and the 95% confidence interval (CI) were calculated in the allelic, dominant, recessive, and homozygous model. Subgroup analyses of vertebral fractures, Caucasians, and postmenopausal women were also performed.. A total of 14 studies comprising 5459 fracture cases and 9860 non-fracture controls were included. A163G was associated with fracture risk in dominant (OR = 1.29, 95%CI 1.11-1.50), recessive (OR = 1.64, 95%CI 1.10-2.44), and homozygous model (OR = 1.73, 95%CI 1.16-2.59). T245G was significantly correlated with susceptibility to fractures in all genetic models. Subjects with CC genotype of T950C had a reduced risk of fracture compared to those with CT or TT genotypes (OR = 0.81, 95%CI 0.70-0.94, P = .004). Subgroup analysis showed that A163G and T245G but not T950C and G1181C were associated with vertebral fracture risk.. OPG A163G and T245G polymorphisms were risk factors of osteoporotic fractures while T950C had a protective role. These polymorphisms can be used as predictive markers of fractures.

Topics: Aged; Female; Humans; Middle Aged; Odds Ratio; Osteoporosis, Postmenopausal; Osteoporotic Fractures; Osteoprotegerin; Polymorphism, Genetic; Risk Factors

Osteoporosis is a common skeletal disorder in eldest people, especially in postmenopausal women. The osteoprotegerin (OPG) gene has been reported to be associated with the BMD and pathogenesis of osteoporosis. However, the results were inconsistent and inconclusive in previous studies.. A meta-analysis was performed to investigate the effect of four common OPG gene polymorphisms (A163G, G1181C, T245G, and T950C) on BMD in postmenopausal women.. A total of 23 eligible studies with 12,973 postmenopausal women were enrolled in present study. Individuals who with AA genotype of A163G were found to have slightly higher femoral hip (P = .03, SMD = 0.49, [95% CI] = [0.06, 0.91]) and total hip BMD (P = .002, SMD = -0.25, [95% CI] = [-0.42, -0.09]) than those with AG genotype. Subjects with GG genotype of G1181C was found to have lower BMD than those with CC or GC genotypes in lumbar spine (GG vs GC: P = .0002, SMD = -0.85, [95% CI] = [-1.29, -0.41]; GG vs CC: P = .02, SMD = -0.21, [-0.39, -0.03]) and total hip BMD (GG vs GC: P = .002, SMD = -0.25, [95% CI] = [-0.42, -0.09]; GG vs CC: P = .01, SMD = -0.15, [95% CI] = [-0.26, -0.03]). In addition, the subjects with GC genotype of G1181C was detected to have lower BMD than those with CC genotype in lumbar spine BMD (P < .05). Furthermore, individuals with TT genotype of T950C were shown to have significant lower lumbar spine BMD compared with those with genotype CC in Caucasian (P < .05). The lumbar spine BMD was lower for subjects with TC genotype of T950C than those with CC genotype in both Caucasian and Asian populations (P < .05). In contrast to A163G, G1181C, and T950G, no association was detected between T245G polymorphism and BMD (P > .05).. The present meta-analysis demonstrated the OPG A163G, G1181C, and T950G, but not T245G, might influence the BMD in postmenopausal women.

Topics: Bone Density; Female; Genetic Predisposition to Disease; Humans; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Single Nucleotide; Postmenopause

Osteoporosis has been reported to be at least partially developed in response to functional polymorphisms of the osteoprotegerin (OPG). However, conflicting results have been found. This meta-analysis aimed to provide an assessment of the relationship between the risk for developing osteoporosis and OPG T950C polymorphism in the Chinese population. Studies to be analyzed were identified with the literature search in PubMed, Embase, Web of Science, the Cochrane Library, and the Chinese National Knowledge Infrastructure during May 2017. Seven case-control studies that included a total of 1850 osteoporosis cases and 3074 controls were assessed in this meta-analysis. Overall, no significant associations could be detected between OPG T950C polymorphism and osteoporosis when all included studies were pooled into this meta-analysis. In a subgroup analyses, OPG T950C polymorphism was significantly associated with the osteoporosis risk in South China (CC+TC vs. TT: OR = 1.34, 95% CI = 1.17-1.54; CC vs. TC+TT: OR = 0.79, 95% CI = 0.69-0.95) and for studies that included postmenopausal osteoporosis (CC vs. TC+TT: OR = 0.78, 95% CI = 0.64-0.94) or hospital-based controls (CC vs. TC+TT: OR = 0.81, 95% CI = 0.68-0.96). In conclusion, the results of this meta-analysis suggest that OPG T950C polymorphism might be associated with an increased osteoporosis risk in the Chinese population.

Topics: Adult; Aged; Aged, 80 and over; Asian People; Case-Control Studies; China; Female; Genetic Predisposition to Disease; Genetic Variation; Hospitals; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Genetic; Risk Factors; Young Adult

In the beginning, that is from the 1960's, when a link between menopause and osteoporosis was first identified; estrogen treatment was the standard for preventing bone loss, however there was no fracture data, even though it was thought to be effective. This continued until the Women's Health Initiative (WHI) study in 2001 that published data on 6 years of treatment with hormone therapy that showed an increase in heart attacks and breast cancer. Even though the risks were small, 1 per 1500 users annually, patients were worried and there was a large drop off in estrogen use. In later analyses the WHI study showed that estrogen reduced fractures and actually prevented heart attacks in the 50-60 year age group. Estrogen alone appeared to be safer to use than estrogen+the progestin medroxyprogesterone acetate and actually reduced breast cancer. At the same time other drugs were being developed for bone that belong to the bisphosphonate group and the first generation of compounds showed moderate potency on bone resorption. The second and third generation compounds were much more potent and in a series of large trials were shown to reduce fractures. For the last 15 years the treatment of osteoporosis belonged to the bisphosphonate compounds, most of which reduce fracture rates by 50 percent. With the exception of gastrointestinal irritation the drugs are well tolerated and highly effective. The sophistication of the delivery systems now allow treatment that can be given daily, weekly, monthly and annually either orally or intravenously. Bone remodeling is a dynamic process that repairs microfractures and replaces old bone with new bone. In the last 10 years there has been a remarkable understanding of bone biology so that new therapies can be specifically designed on a biological basis. The realization that RANKL was the final cytokine involved in the resorption process and that marrow cells produced a natural antagonist called Osteoprotegerin (OPG) quickly led to two lines of therapy. First OPG was used as a therapy to block RANKL was initially successful but later antibodies against OPG developed and this line of treatment had to be discontinued. The next step was to develop a monoclonal antibody against RANKL and this proved to be highly effective in blocking bone resorption. It led to development of a drug Denosumab that successfully reduces fractures and is now one of the therapeutic options for osteoporosis treatment. On the anabolic side bone biology res

Topics: Aged; Aged, 80 and over; Alendronate; Antibodies, Monoclonal, Humanized; Bone Density; Bone Remodeling; Calcitonin; Denosumab; Diphosphonates; Estrogen Replacement Therapy; Female; Fractures, Bone; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Risk Factors; Selective Estrogen Receptor Modulators; Teriparatide

Whereas some studies have reported that the osteoprotegerin (OPG) gene is associated with osteoporosis risk in some studies, their results have proved inconclusive. We performed a meta-analysis of studies on the associations between OPG A163G and G1181C polymorphisms and the risk of osteoporosis.. A literature search in PubMed, Embase, Web of Science, Cochrane Library, and China Biological Medicine (CBM) databases was conducted to identify all eligible case-control studies published before August 15th, 2013. Pooled odds ratios with their corresponding 95% confidence intervals were used to evaluate the strength of the association under either a fixed- or random-effect model according to the heterogeneity test.. Ten case-control studies were included with a total of 1673 osteoporosis cases and 1554 healthy controls in this meta-analysis. For the OPG A163G polymorphism, the combined results showed that the G allele of the A163G polymorphism may be associated with an increased risk of osteoporosis. Stratified analyses showed that the magnitude of the effect was similar among the Caucasian and postmenopausal women subgroups. Unlike the A163G polymorphism, the meta-analysis results revealed that the C allele of the G1181C polymorphism may be associated with a decreased risk of osteoporosis, especially in the Asian and postmenopausal women subgroups. No publication bias was detected for either polymorphism.. Our findings showed that the G allele of the OPG A163G polymorphism may increase osteoporosis risk, whereas the C allele of the G1181C polymorphism may protect individuals from osteoporosis. Both of these effects were observed in postmenopausal women.

Topics: Adult; Aged; Case-Control Studies; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Middle Aged; Osteoporosis; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Single Nucleotide; Postmenopause; Risk Factors; Young Adult

An imbalance of the remodeling process for bone resorption leads to a loss of tissue with consequent microarchitectural damage, evident in conditions such as osteoporosis and related fragility fractures. Currently, pharmacological therapies are able to prevent or slow down bone resorption by inhibiting osteoclast activity. An innovative and targeted anti-resorptive approach is represented by the inhibition of RANK ligand (RANK-L), essential for the proliferation and activity of osteoclastic cells. The human monoclonal antibody against RANK-L (denosumab) has been approved for the treatment of osteoporosis. In clinical trials of patients with osteoporosis, inhibition of RANK-L has reduced bone loss and damage to the microarchitecture and was associated with an increase in mass and resistance at different skeletal sites, with most significant effects than those demonstrated by any other antiresorptive drugs. In addition, after 3 years of treatment, it showed a reduction in vertebral and non-vertebral fracture risk. Denosumab treatment also has not revealed any alteration in the physiological processes of fracture repair, showing no increase in the onset of complications 3 years after the fracture. The data show that denosumab offers an effective alternative therapeutic approach for the treatment of severe osteoporosis, with positive effects on BMD and reduction of fragility fractures risk. So, promising results in terms of therapeutic efficacy and reliability make desirable the wide clinical use of denosumab for the treatment of osteoporotic fractures in the near future.

Topics: Animals; Antibodies, Monoclonal, Humanized; Bone and Bones; Bone Density; Bone Density Conservation Agents; Bone Resorption; Cell Proliferation; Denosumab; Female; Fracture Healing; Fractures, Bone; Humans; Male; Mice; Osteoclasts; Osteoporosis; Osteoporosis, Postmenopausal; Osteoprotegerin; Postmenopause; Randomized Controlled Trials as Topic; RANK Ligand; Treatment Outcome

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bone and Bones; Denosumab; Homeostasis; Humans; Male; Mutation; Osteitis Deformans; Osteoclasts; Osteopetrosis; Osteoporosis; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand

Recent studies indicate that obesity is not a risk factor of osteoporosis. On the contrary, increased adipose tissue mass may have a protective effect against osteoporosis. This suggests that the positive influence of adipose tissue on bone tissue may be a consequence of the boost in load on the bone tissue, leading to increased bone anabolism. It may also be connected with changes frequently occurring in postmenopausal women in the formation of some osteotropic factors, mainly hormones such as estrogens, androgens, calciotropic hormones, somatotrophin axis hormones, leptin, and melatonin. The antiresorption effects of the above hormones on the bone are to a considerable extent executed through the RANKL/RANK/OPG system (receptor activator of nuclear factor-kB ligand/receptor activator of nuclear factor-kB/osteoprotegerin), the principal signaling pathway through which osteoblasts regulate the rate of the activated osteoclast pool. This effect may be achieved through a direct effect on the expressions OPG and/or RANKL in osteoblasts and marrow stroma cells and/or indirectly through cytokines, mainly interleukins (IL)-1 and -6, tumor necrosis factor-alpha(TNF-alpha), macrophage colony-stimulating factor (M-CSF), and tumor necrosis factor-beta (TNF-beta).

Topics: Female; Humans; Interleukin-1; Lymphotoxin-alpha; Macrophage Colony-Stimulating Factor; Menopause; Obesity; Osteoclasts; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Risk Factors; Tumor Necrosis Factor-alpha

The pathway of the receptor activator of the nuclear factor kappaB ligand (RANKL), RANK and osteoprotegerin (OPG) plays a central role in coupling bone formation and resorption during normal bone turnover and in a wide spectrum of diseases characterized by disturbed bone remodeling, increased bone resorption and bone destruction (osteoporosis, Paget's disease of bone, rheumatoid arthritis [RA], metastatic bone disease). Clinical trials indicate that denosumab, a RANKL-specific recombinant humanized monoclonal antibody, is effective in suppressing bone resorption, resulting in increase in bone mineral density (BMD) in post-menopausal women with low BMD, and has the potential to prevent progression of erosions in RA and of skeletal-related events in metastatic bone disease. The effects on fracture reduction in postmenopausal osteoporosis are awaited from the recently finished FREEDOM study. In clinical trials with denosumab, overall adverse events were similar to placebo or comparators, indicating a favorable safety profile in these diseases, which until now have been available up to 4 years, but data on long-term safety will be needed.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Arthritis, Rheumatoid; Bone Density; Bone Remodeling; Bone Resorption; Denosumab; Female; Fractures, Bone; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand

Receptor activator of nuclear factor-kB (RANK), its ligand (RANKL) and its decoy receptor osteoprotegerin (OPG) together play a key role in osteoclastogenesis. Alterations in the RANKL/ OPG ratio are central in the pathogenesis of bone loss, from osteoporosis in all its forms to malignancy-induced bone loss. This fact has led to the search for drugs capable of targeted RANKL inhibition in the management of skeletal disorders associated with bone loss. Promising preclinical data using OPG have paved the way for the development of the new agent denosumab, a high-affinity, high-specificity, fully human monoclonal antibody to RANKL, shown to be able to induce a dose-dependent, rapid, profound and sustained inhibition of bone resorption lasting for months after a single subcutaneous injection in healthy postmenopausal women, men and patients with multiple myeloma or metastatic breast cancer. Data from a phase II study in postmenopausal women with low bone mineral density (BMD) demonstrate that the sustained inhibition of bone resorption induced by three or six monthly subcutaneously administered denosumab was associated with significant increases in BMD for up to two years of treatment. Antifracture efficacy and long-term skeletal and extraskeletal safety of denosumab are being addressed in ongoing phase III trials. The potential of denosumab to prevent bone loss has also been demonstrated in malignancy-induced bone loss. Ongoing studies in rheumatoid arthritis are also promising.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bone Density; Bone Density Conservation Agents; Bone Diseases; Bone Remodeling; Denosumab; Female; Humans; Injections, Subcutaneous; Male; Neoplasms; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

The antiresorptive effect of a single 60-mg injection of the RANKL (receptor activator of NFkappaB ligand)-specific mAb, denosumab, substantially exceeds the effects of alendronic acid (70 mg weekly) yet increases in bone mass at the lumbar spine are identical for both agents. Important experimental and clinical observations illustrating some of the potential consequences of osteoclast deficiency and low-rate bone resorption for osteoblast function, bone mineralization, bone quality and related mechanical properties are summarized. This review also discusses whether the benefits for bone health can be improved when aggressively pushing the limits with novel antiresorptive medications.

Topics: Alendronate; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bone Density; Bone Density Conservation Agents; Bone Remodeling; Bone Resorption; Cell Count; Denosumab; Humans; Osteoclasts; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

The majority of current therapeutics for osteoporosis is targeting bone resorption by osteoclasts. Bisphosphonates, potent and specific inhibitors of bone resorption, are widely used for postmenopausal osteoporosis on the basis of large scale clinical trials which proved their ability to reduce fracture risk. Estrogen, which had been widely used in the US, lost its position of standard drug therapy for osteoporosis because of the recent evidence of increasing adverse events. On the other hand, the market share of selective estrogen-receptor modulators (SERMs), which utilize valuable functions of estrogen and have less adverse effects, has been climbing. Other novel therapeutic agents which aim at signal transduction of osteoclast differentiation and activation are promising as specific inhibitors of bone resorption.

Topics: Animals; Bone Density Conservation Agents; Bone Resorption; Cell Differentiation; Diphosphonates; Humans; Osteoclasts; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Selective Estrogen Receptor Modulators; Signal Transduction

Osteoporosis is a disorder in which loss of bone strength leads to fragility fractures. This review examines the fundamental pathogenetic mechanisms underlying this disorder, which include: (a) failure to achieve a skeleton of optimal strength during growth and development; (b) excessive bone resorption resulting in loss of bone mass and disruption of architecture; and (c) failure to replace lost bone due to defects in bone formation. Estrogen deficiency is known to play a critical role in the development of osteoporosis, while calcium and vitamin D deficiencies and secondary hyperparathyroidism also contribute. There are multiple mechanisms underlying the regulation of bone remodeling, and these involve not only the osteoblastic and osteoclastic cell lineages but also other marrow cells, in addition to the interaction of systemic hormones, local cytokines, growth factors, and transcription factors. Polymorphisms of a large number of genes have been associated with differences in bone mass and fragility. It is now possible to diagnose osteoporosis, assess fracture risk, and reduce that risk with antiresorptive or other available therapies. However, new and more effective approaches are likely to emerge from a better understanding of the regulators of bone cell function.

Topics: Animals; Bone and Bones; Bone Density; Bone Remodeling; Calcium; Cell Differentiation; Collagen; Estrogens; Fractures, Bone; Glycoproteins; Hematopoietic Stem Cells; Hormones; Humans; Leptin; Ligands; Mice; Models, Biological; Neurons; NF-kappa B; Nitric Oxide; Osteoblasts; Osteoporosis; Osteoporosis, Postmenopausal; Osteoprotegerin; Parathyroid Hormone; Prostaglandins; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Vitamin D; Vitamin D Deficiency

Growth hormone (GH) has a major role in the maintenance of bone mass in adults by regulating bone remodeling through a complex interaction of circulating GH, insulin-like growth factors (IGFs), IGF binding protein (IGFBPs), and locally produced IGFs and IGFBPs, acting in an autocrine and paracrine way. In vitro data has greatly increased our understanding of GH and IGFs effects and regulation in bone cells under controlled conditions, and especially the molecular pathways involved. However, the GH-and type I IGF-receptor are present in many tissues and various systemic factors may potentially regulate local expression of IGFs and IGFBPs in the intact organism. The use of genetically altered mice has changed this and had a major impact on defining the role of IGFs in skeletal homeostasis, and especially the role of systemic IGF-I in the development and maintenance of the adult skeleton. The focus of this review is to describe recent work on the effect of GH/IGF on remodeling in the adult skeleton emphasizing on data obtained in patient populations (i.e. acromegaly, GH deficiency, postmenopausal osteoporosis) and experimental models (i.e. animals with genetically altered expression of different GH and IGF family members) characterized by different systemic levels of these proteins. The role of IGF-I as a coupling agent between resorption and bone formation through effects on osteoprotegerin (OPG) and receptor activator of NFkappaB ligand (RANKL) are also discussed.

Topics: Animals; Bone and Bones; Carrier Proteins; Female; Glycoproteins; Growth Hormone; Humans; Membrane Glycoproteins; Mice; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Somatotropin; Receptors, Tumor Necrosis Factor; Somatomedins

Topics: Biomarkers; Bone Resorption; Carrier Proteins; Enzyme-Linked Immunosorbent Assay; Glycoproteins; Humans; Membrane Glycoproteins; Multiple Myeloma; Osteoclasts; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Solubility; Specimen Handling

The osteoprotegerin/RANKL/RANK system seems to be an essential signalling pathway by which osteoblasts control the pool size of active osteoclasts. According to the convergence hypothesis, numerous osteotropic hormones and cytokines act by increasing or decreasing the osteoprotegerin (OPG) or receptor activator of NF-kappa B ligand (RANKL) expression in osteoblasts. The role of OPG as the decoy receptor is to bind RANKL that prevents RANKL from activating its receptor RANK in osteoclast lineage cells. The effects are inhibition of osteoclasts differentiation and activation as well as induction of osteoclasts apoptosis. Estrogen and bisphosphonates stimulate the production of OPG that may, at least partly be responsible for their antirsorptive effect on bone. The results of reported experiments suggest that OPG could be a useful agent in therapy of excessive bone resorption diseases.

Topics: Aged; Bone Resorption; Female; Glycoproteins; Humans; Middle Aged; Osteoblasts; Osteoclasts; Osteoporosis, Postmenopausal; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Topics: Animals; Arthritis, Rheumatoid; Bone Diseases, Metabolic; Bone Neoplasms; Carrier Proteins; Cytokines; Female; Glycoproteins; Humans; Hyperparathyroidism; Ligands; Male; Membrane Glycoproteins; Mice; Mice, Knockout; Mice, Transgenic; Middle Aged; Osteitis Deformans; Osteoclasts; Osteoporosis; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Rats; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factor-alpha

In just 3 years, striking new advances have been made in understanding the molecular mechanisms that govern the crosstalk between osteoblasts/stromal cells and hemopoietic osteoclast precursor cells that leads to osteoclastogenesis. Led first by the discovery of osteoprotegerin (OPG), a naturally occurring protein with potent osteoclastogenesis inhibitory activity, rapid progress was made to the isolation of RANKL, a transmembrane ligand expressed on osteoblasts/stromal cells, that binds to RANK, a transmembrane receptor on hemopoietic osteoclast precursor cells. The interaction of RANK and RANKL initiates a signaling and gene expression cascade that results in differentiation and maturation of osteoclast precursor cells to active osteoclasts capable of resorbing bone. Osteoprotegerin acts as a decoy receptor; it binds to RANKL and blocks its interaction with RANK, thus inhibiting osteoclast development. Many of the calciotropic hormones and cytokines, including vitamin D3, parathyroid hormone, prostaglandin E2 and interleukin-11, appear to stimulate osteoclastogenesis through the dual action of inhibiting production of OPG and stimulating production of RANKL. Estrogen, on the other hand, appears to inhibit production of RANKL and RANKL-stimulated osteoclastogenesis. Recently, the results of the first clinical trial with OPG supported its potential as a therapeutic agent for osteoporosis. The new understanding provided by the RANK/RANKL/OPG paradigm for both differentiation and activation of osteoclasts has had tremendous impact on the field of bone biology and has opened new avenues for development of possible treatments of diseases characterized by excessive bone resorption.

Topics: Bone Resorption; Carrier Proteins; Female; Glycoproteins; Humans; Membrane Glycoproteins; Osteoclasts; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Under physiological conditions, maintenance of skeletal mass is the result of a tightly coupled process of bone formation and bone resorption. Disease states, osteoporosis included, arise when this delicate balance is disrupted such as in menopause, when estrogen levels decrease dramatically corresponding with the cessation of ovarian function. Current therapies for the treatment of osteoporosis, including estrogen replacement therapy, selective estrogen receptor modulators and bisphosphonates, are primarily based on blunting the resorption component of bone homeostasis. Although selective estrogen receptor modulators offer bone protection without the side effects of estrogen replacement therapy, there are some areas of improvement for the current generation of selective estrogen receptor modulators; particularly in reducing their antagonistic properties in the central nervous system that lead to vasomotor symptoms. There are few therapies that are focused on increasing bone formation, but they offer promising avenues in which to expand the repertoire of drugs to restore bone mass. Selective androgen receptor modulators, parathyroid hormone analogs, oxytocin analogs and statins, all with improved pharmacological properties in bone, are among the potential approaches to eliciting anabolic effects in the skeleton.

Topics: Androgens; Calcitriol; Combined Modality Therapy; Diphosphonates; Estrogen Receptor Modulators; Female; Glycoproteins; Hormone Replacement Therapy; Humans; Molecular Structure; Osteoporosis, Postmenopausal; Osteoprotegerin; Oxytocin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Osteoprotegerin ligand (OPGL, TNFS11) and its receptor RANK (TNFRS11A) are essential for the development and activation of osteoclasts and critical regulators of physiological bone remodeling and osteoporosis. Production of OPGL by activated T cells can directly regulate osteoclastogenesis and bone remodeling. This may explain why autoimmune diseases, cancers, leukemias, asthma and chronic viral infections such as hepatitis and HIV result in systemic and local bone loss. OPGL is also the pathogenetic factor that causes bone and cartilage destruction and clinical crippling in arthritis. Inhibition of OPGL binding to RANK via the natural decoy receptor osteoprotegerin (OPG) prevents bone loss in postmenopausal osteoporosis and cancer metastases and completely blocks crippling in a rat model of arthritis. Moreover, OPG expression is induced by estrogen which provides a molecular explanation of postmenopausal osteoporosis in women.

Topics: Animals; Arthritis; Bone Remodeling; Carrier Proteins; Dendritic Cells; Female; Glycoproteins; Humans; Lymph Nodes; Membrane Glycoproteins; Mice; Osteoporosis; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Rats; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; T-Lymphocytes

Pulsed electromagnetic fields (PEMFs) have been proven to enhance in vitro and in vivo osteogenesis with unknown mechanism. Aim of our study was to explore whether RANKL/OPG and Wnt/β-Catenin pathways could be involved in bone response to PEMFs in a setting of postmenopausal osteoporotic women. Forty-three women (mean age 62.8 ± 4.5 yr.) were randomized into two groups. The PEMFs group received PEMFs treatment (50 min treatment session/day, 6 treatment sessions/week, for a total of 25 times), by wearing a specific gilet applied to the trunk and connected to the electromagnetic device (Biosalus, by HSD Srl, Serravalle RSM), while women assigned to control group received sham PEMFs with the same device. BSAP as bone formation and CTX as bone resorption markers, RANKL, OPG, β-Catenin, DKK-1 and sclerostin were obtained at baseline, after 30 and 60 days. In PEMFs group, BSAP levels significantly increased after 30 and 60 days while CTX concentrations decreased at day 60. RANKL levels significantly decreased after 60 days. OPG was not significantly changed, but the RANKL/OPG ratio significantly decreased at day 30. DKK-1 levels decreased, while β-catenin concentrations increased after 30 and 60 days (P < 0.05). No significant changes of calcium, phosphorus, creatinine and sclerostin were detected. In the PEMFs group, at day 30, Δsclerostin was associated with ΔRANKL/OPG ratio (r = -0.5, P = 0.03) and ΔDKK-1 was associated with Δβ-Catenin (r = -0.47, P = 0.02). In women with postmenopausal osteoporosis, our data provide evidence of a PEMFs modulation of RANKL/OPG and Wnt/β-Catenin signaling pathways able to explain the metabolic effects of PEMFs on bone.

Topics: Adaptor Proteins, Signal Transducing; Biomarkers; Bone and Bones; Bone Morphogenetic Proteins; Bone Remodeling; Calcium; Creatinine; Electromagnetic Fields; Female; Genetic Markers; Humans; Intercellular Signaling Peptides and Proteins; Middle Aged; Models, Biological; Osteoporosis, Postmenopausal; Osteoprotegerin; Pilot Projects; RANK Ligand; Wnt Signaling Pathway

Although ferritin has been considered as a possible link between accelerated bone loss and atherosclerosis, the long-term impact of therapeutic agents widely used to treat osteoporosis, such as bisphosphonates, on ferritin levels has not been investigated. The present study investigated the effects of risedronate on serum ferritin levels in postmenopausal women with osteoporosis.. In an open-label, prospective, uncontrolled study, 68 postmenopausal women with osteoporosis were evaluated. Study participants received risedronate orally at a dose of 35 mg/week during a 6-month treatment period. Blood sampling for lipid profile, hemoglobin A1c, insulin, fibrinogen, C-reactive protein, osteoprotegerin, and ferritin was performed at baseline and after 6 months of treatment. Pulse-wave velocity and augmentation index at baseline were determined using SphygmoCor version 7.1 (AtCor Medical, Sydney, Australia).. Mean (SD) serum ferritin decreased significantly from 62.1 (44.8) to 46.7 (29.4) μg/dL (P < 0.0001) during the treatment period. On multiple linear regression analysis, the significant predictors of Δferritin were pulse-wave velocity (P = 0.04; effect size, 0.188), C-reactive protein (P = 0.021; effect size, 0.043), insulin (P = 0.011; effect size, 0.100), and high-density lipoprotein cholesterol (P = 0.046; effect size, 0.132) at baseline.. Risedronate treatment is associated with significantly decreased serum ferritin levels in postmenopausal women with osteoporosis and cardiovascular risk factors.

Topics: Aged; Bone Density Conservation Agents; C-Reactive Protein; Cardiovascular Diseases; Female; Ferritins; Fibrinogen; Glycated Hemoglobin; Humans; Insulin; Linear Models; Lipids; Lipoproteins, HDL; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Postmenopause; Prospective Studies; Pulse Wave Analysis; Research Design; Risedronic Acid; Risk Factors; Time Factors

Circulating osteoprogenitors and receptor activator of nuclear factor kappa-B ligand (RANKL) expression in immune cells have been implicated in the pathogenesis of osteoporosis and vascular calcification. The role played by statin therapy in the bone-vascular axis is unknown.. Twenty naïve postmenopausal osteoporotic hypercholesterolemic women were treated with Atorvastatin 40 mg/day for 3 months. Gene expression analysis was performed to assess modification in osteoprotegerin (OPG)/RANK/RANKL expression in isolated T cells and monocytes. A flow cytometry analysis was used to study changes in the levels of circulating osteoprogenitor cells.. After 3 months of treatment, Atorvastatin significantly reduced total cholesterol and LDL-C, without affecting HDL-C and triglycerides. Among circulating bone and phosphocalcium homeostasis markers, we found a significant increase in OPG levels (P < 0.01) and a modest reduction in osteocalcin (OCN) (P < 0.05). We also observed a significant reduction in RANKL expression in T cells (P < 0.05). No differences were found in the expression of RANK in T cells and RANKL and RANK in monocytes. OPG expression was low in both immune cell types and was not affected by the treatment. As for circulating osteoprogenitors, we found a significant reduction of CD34(+) BAP(+) (P < 0.05) and CD34(+) OCN(+) BAP(+) (P < 0.05) cells. In vitro studies showed that Atorvastatin reduced RANKL expression in activated human T-lymphoblastoid cells (Jurkat cell line).. Three-month Atorvastatin treatment leads to a reduction in circulating osteoprogenitor cells and RANKL expression in T cells, as well as increase in OPG serum levels. These data suggest that statins could have protective effects in the bone-vascular axis.

Topics: Aged; Atorvastatin; Biomarkers; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Jurkat Cells; Lipids; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Stem Cells; T-Lymphocytes; Time Factors; Treatment Outcome

Raloxifene is a selective estrogen receptor (ER) modulator (SERM) used for the treatment of osteoporosis. However, its efficacy and also its safety vary greatly among treated patients, and it might be influenced by the individuals' genetic background. As the receptor activator of the nuclear factor κB (RANK) ligand (RANKL)/RANK/osteoprotegerin (OPG) system is essential for osteoclastogensis and Wnt signaling pathway for osteoblastogenesis, we decided to evaluate the raloxifene treatment in regard to selected polymorphisms in key genes of these two main bone regulatory pathways.. Fifty-six osteoporotic postmenopausal women treated with raloxifene were genotyped for 11 polymorphisms located in six genes: -290C>T, -643C>T, and -693G>C in tumor necrosis factor receptor superfamily member 11 (TNFSF11), +34694C>T, +34901G>A, and +35966insdelC in tumor necrosis factor receptor superfamily member 11A (TNFRSF11A), K3N and 245T>G in tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), A1330V in LRP5, I1062V in LRP6, and -1397_-1396insGGA in SOST. For evaluation of treatment efficacy, bone mineral density (BMD) and biochemical markers of bone turnover were measured.. One-year change in total hip BMD was associated with +34901G>A in TNFRSF11A (p=0.040), whereas, for lumbar spine BMD, the association was shown for -1397_-1396insGGA in SOST (p=0.015). C-terminal crosslinking telopeptides of type I collagen (CTX) concentrations showed significant association with -643C>T single nucleotide polymorphism (SNP) in TNFSF11 (p=0.049) and +34694C>T in TNFRSF11A (p=0.022). No other association was found between 1-year change in BMDs or biochemical markers and the studied SNPs.. We have shown that, in postmenopausal osteoporotic women treated with raloxifene, the efficacy of raloxifene treatment might be influenced by +34901G>A in TNFRSF11A gene and -1397_-1396insGGA in the SOST gene as well as -643C>T in TNFSF11 gene and +34694C>T in TNFRSF11A gene. However, these findings need additional functional and clinical confirmation for potential pharmacogenetic use in the future.

Topics: Absorptiometry, Photon; Biomarkers; Bone Density; Female; Humans; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Single Nucleotide; Raloxifene Hydrochloride; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Selective Estrogen Receptor Modulators; Wnt Signaling Pathway

Although several studies have confirmed the bone-protective properties of dried plum, its exact mechanisms of action remain unclear. Recent research has shown that osteocytes may control bone formation via the production of sclerostin and bone resorption via the receptor activator of NF-κB ligand (RANKL) and its inhibitor osteoprotegerin (OPG). To investigate the mechanism of action of dried plum in reversing bone loss, we measured serum levels of RANKL, OPG and sclerostin in osteopenic postmenopausal women (n 160). Participants were randomly assigned to the treatment group of either 100 g dried plum/d or 75 g dried apple/d (comparative control) for 1 year. All participants received 500 mg Ca plus 400 IU (10 μg) vitamin D daily. Bone mineral densities (BMD) of the lumbar spine, forearm, hip and whole body were assessed at baseline and at the end of the study using dual-energy X-ray absorptiometry. Blood samples were collected at baseline and after 12 months to assess bone biomarkers. Dried plum significantly increased the BMD of the ulna and spine in comparison with the control group. In comparison with corresponding baseline values, dried plum increased the RANKL levels by only +1·99 v. +18·33% and increased the OPG levels by +4·87 v. - 2·15% in the control group. Serum sclerostin levels were reduced by - 1·12% in the dried plum group v. +3·78% in the control group. Although percentage changes did not reach statistical significance (P≤ 0·05), these preliminary data may indicate that the positive effects of dried plum on bone are in part due to the suppression of RANKL production, the promotion of OPG and the inhibition of sclerostin.

Topics: Adaptor Proteins, Signal Transducing; Biomarkers; Bone and Bones; Bone Density; Bone Density Conservation Agents; Bone Morphogenetic Proteins; Calcium, Dietary; California; Combined Modality Therapy; Dietary Supplements; Female; Food, Preserved; Fruit; Genetic Markers; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoporotic Fractures; Osteoprotegerin; Prunus; RANK Ligand; Risk; Severity of Illness Index; Vitamin D

Recent research results have confirmed the high significance of the OPG/RANK/RANKL system in the development of bone diseases.. The aim of the reported study was to assess gene expression levels of the OPG/RANK/RANKL system in peripheral blood mononuclear cells (PBMCs) after strontium ranelate (SR) and ibandronate administered to patients with postmenopausal osteoporosis.. A total of 89 postmenopausal women, aged 51 to 85 years, patients of the Outpatient Clinic of Osteoporosis of the Military Teaching Hospital in Lodz, were enrolled into the study. The patients were randomly assigned to different medical therapies: ibandronate and SR. Patients of the control group received only calcium and vitamin D₃ supplements. Patient visits were repeated after 3 and 6 months. Measurements of serum alkaline phosphatase concentrations and of RNA expression in PBMCs as well as of total serum calcium and phosphate levels and of their 24-hour urine excretion rates were carried out in material, collected at baseline and after 3 and 6 months of the therapy. Densitometry of the left hip and of the lumbar spine was done at the baseline visit and after 6 months.. The differences in gene expressions of RANKL and RANK were not significant during the study period and did not differ between the groups in a statistically significant manner. No OPG gene expression was observed in PBMCs of patients in any of the studied groups and at any time point. The tendency of correlation (P = .07) was observed between decreasing RANK gene expression and increasing bone mineral density in the patients treated with SR.. Both ibandronate and SR do not seem to cause any significant changes in gene expression levels of OPG/RANK/RANKL in PBMCs during the first 6 months of treatment.

Topics: Aged; Aged, 80 and over; Bone Density; Bone Density Conservation Agents; Calcium, Dietary; Cholecalciferol; Combined Modality Therapy; Dietary Supplements; Diphosphonates; Female; Gene Expression Regulation; Humans; Ibandronic Acid; Leukocytes, Mononuclear; Middle Aged; Organometallic Compounds; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; RNA, Messenger; Thiophenes

The aim of this study was to detect the influence of g.19124G>A genetic polymorphism in the osteoprotegerin (OPG) gene on bone mineral density (BMD) and osteoporosis in Chinese postmenopausal women.. A total of 403 primary osteoporosis subjects and 409 healthy controls were enrolled in this study. The BMD value of the femoral neck hip, lumbar spine (L(2-4)), and total hip was analyzed by Norland XR-46 dual energy X-ray absorptiometry. The polymerase chain reaction-restriction fragment length polymorphism method was utilized to investigate the genotype of g.19124G>A genetic polymorphism.. We found significant differences of the femoral neck hip, lumbar spine (L(2-4)), and total hip of BMD among different genotypes of g.19124G>A genetic polymorphism, individuals with the genotype GG had significantly higher BMD than those of genotype GA and AA (p<0.05).. These findings indicate that the g.19124G>A genetic polymorphism in the OPG gene is potentially related to BMD and osteoporosis in Chinese postmenopausal women, and the allele A could be associated with a lower BMD and an increased risk factor for osteoporosis.

Topics: Aged; Alleles; Asian People; Bone Density; China; Female; Genetic Predisposition to Disease; Genotype; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length

To evaluate whether bisphosphonates modulate vascular calcification by a modification in endothelial progenitor cells (EPCs) coexpressing osteoblastic surface markers and genes.. We performed a double-blind, randomized study of 20 healthy, early postmenopausal women (from February 1, 2008, through July 31, 2008) treated with placebo or risedronate sodium (35 mg/wk) for 4 months. Peripheral blood was collected at baseline and 4 months to determine serum inflammatory markers, osteoprotegerin, and receptor activator of nuclear factor-κB ligand levels and bone turnover markers. Peripheral blood mononuclear cells were stained for EPC surface markers (CD34, CD133, and vascular endothelial growth factor receptor/kinase insert domain receptor) and osteoblast markers (osteocalcin, alkaline phosphatase, and Stro-1).. Risedronate treatment resulted in a significant down-regulation of gene sets for osteoblast differentiation and proliferation in EPCs with a trend of decreasing EPCs coexpressing osteocalcin.. Our findings indicate that bisphosphonate treatment down-regulates the expression of osteogenic genes in EPCs and suggest a possible mechanism by which bisphosphonates may inhibit vascular calcification.

Topics: Biomarkers; Bone Density; Bone Density Conservation Agents; C-Reactive Protein; Calcium; Creatinine; Double-Blind Method; Down-Regulation; Endothelium; Enzyme-Linked Immunosorbent Assay; Etidronic Acid; Female; Flow Cytometry; Gene Expression Regulation; Humans; Interleukin-8; Middle Aged; Osteoblasts; Osteogenesis; Osteoporosis, Postmenopausal; Osteoprotegerin; Phosphorus; Placebos; RANK Ligand; Risedronic Acid; Stem Cells; Treatment Outcome; Vitamin D

To analyze the effects of nutritional intervention with a milk product enriched with soy isoflavones on quality of life and bone metabolism in postmenopausal Spanish women.. We performed a double-blind controlled randomized trial in ninety-nine postmenopausal women. Group S women (n=48) were randomized to consume milk product enriched with soy isoflavone (50 mg/day) while group C (n=51) consumed product control for 12 months. Parameters of quality of life (Cervantes scale), markers of bone metabolism and bone mass estimated by ultrasound of the calcaneus (QUS) were evaluated.. Overall, there was an improvement in the domains menopause (P=.015) and vasomotor symptoms (P<.001). S group emphasized the assessment of vasomotor symptoms (P=.001) and differed positively from group C in health (P=.019), sex (P=.021) and partner (P=.002). Serum levels TRAP (P<.001) and OPG (P=.007) decreased and concentrations of 25-OH-vitamin D increased (P<.001) without differences between groups. In the assessment of QUS, there was an increase in estimated bone mineral density in group S (P=.040), whereas in group C there were no significant differences.. Daily consumption of these milk products increases levels of 25-OH-vitamin D and decreases bone metabolism markers. Additional supplementation with soy isoflavones seems to improve quality of life and bone mass in Spanish postmenopausal women.

Topics: Acid Phosphatase; Aged; Animals; Bone and Bones; Bone Density; Dietary Supplements; Double-Blind Method; Female; Hot Flashes; Humans; Isoenzymes; Isoflavones; Middle Aged; Milk; Osteoporosis, Postmenopausal; Osteoprotegerin; Postmenopause; Quality of Life; Soy Milk; Spain; Tartrate-Resistant Acid Phosphatase; Vitamin D

Over the last few years, conclusive evidence of the involvement of the immune system in the regulation of bone metabolism has been identified. Consequently, one question that should be formulated concerns the possible effects of antiresorptive therapies on the immune system. Therefore, the purpose of the present work was to evaluate both the functionality of the immune system and bone turnover in women receiving antiresorptive therapies, such as hormone therapy (HT; n = 33) and raloxifene (RLX; n = 66), acting through estrogen receptors.. To that end, this study analyzed bone turnover markers in a population of postmenopausal women before and after beginning therapy and compared these with data of women not treated (NT; n = 102). In a subgroup of participants (NT = 33, RLX = 24, and HT = 26), we analyzed the effects of treatments on immune system parameters such as serum levels of interleukin (IL)-6, tumor necrosis factor α, and IL-1β; lymphocyte subpopulations; cell proliferation by peripheral blood mononuclear cells (PBMCs); in vitro production of IL-1β by PBMCs; and the expression of receptor activator of nuclear factor-κB ligand, transforming growth factor β, and IL-4 genes by PBMCs.. The results showed that bone resorption was inhibited strongly in women in the RLX and HT groups when compared with women in the NT group. Interestingly, the administration of RLX inhibited the production of the Wnt/β-catenin signaling pathway inhibitor Dickkopf Homolog-1 (P < 0.05) and tended to increase the levels of the osteoclastogenesis inhibitor osteoprotegerin at month 6 (P = 0.059). With regard to the immune system, the different treatments did not markedly perturb the parameters analyzed, with the exception of the increase in serum IL-1β detected in the HT group at month 6 (P < 0.05).. The main conclusions of the present work were that HT or RLX do not disturb the immune system and that both treatments have a similar antiresorptive power.

Topics: Bone Density Conservation Agents; Bone Remodeling; Cell Proliferation; Cells, Cultured; Female; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-1beta; Interleukin-4; Interleukin-6; Leukocytes, Mononuclear; Lymphocyte Subsets; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Raloxifene Hydrochloride; Receptor Activator of Nuclear Factor-kappa B; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

To evaluate the effect of risedronate treatment on osteoprotegerin (OPG), C-terminal cross-linking telopeptide of type 1 collagen (CTX), osteocalcin (OC), and deoxypyridinoline (DPD).. Eighty postmenopausal osteoporotic patients were randomized into two groups. In first group, patients received 35?mg of risedronate once a week and calcium with vitamin D per day. In second group, patients received only calcium with vitamin D per day. Bone turnover markers were measured at baseline, 1st, 3rd and 6th month.. OPG levels were significantly reduced at 1st and 6th month of treatment in both groups, but no statistically significant difference was detected between groups. In the group treated with risedronate, difference in CTX level was observed at 3rd month of treatment, while a difference in DPD and OC levels were observed at 6th month of treatment. The baseline OPG levels correlated with age, menopause duration, and CTX levels. There was no correlation between OPG levels and the levels of the other markers during treatment.. The present study showed that using risedronate in treatment of postmenopausal osteoporosis causes no specific changes in OPG levels; therefore, in contrast to some of the studies in the literature OPG may not be useful marker in monitoring of bisphosphonate.

Topics: Adult; Aged; Biomarkers; Bone and Bones; Bone Density; Bone Density Conservation Agents; Calcium; Etidronic Acid; Female; Femur; Follow-Up Studies; Humans; Lumbar Vertebrae; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Risedronic Acid; Vitamin D

There is much evidence suggesting that the decline in ovarian function after menopause is associated with spontaneous increases in proinflammatory cytokines. Treatment with risedronate is accompanied by significant changes in bone turnover and bone mineral density. The objective of this study was to determine the effects of risedronate treatment on the level of serum cytokines including receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin among postmenopausal women with osteoporosis. The study group consisted of 61 postmenopausal women with osteoporosis. Patients were randomly divided in two groups: In group 1 (n = 41) postmenopausal women received oral risedronate (35 mg/week), calcium (1,000 mg/day), and vitamin D (400 IU/day) for 12 months. In group 2 (control group; n = 20) patients received only oral calcium (1,000 mg/day) and vitamin D (400 IU/day). Bone mineral density (BMD) of lumbar spine (L1-L4) and proximal femur were determined using dual X-ray absorptiometry at baseline and after one year. Venous blood samples were obtained for determination of serum cytokines including interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), RANKL, osteoprotegerin, and markers of bone formation and resorption. Levels of serum cytokines were measured before therapy and after three and 6 months. Markers of bone metabolism were studied before therapy and after 6 months. In group 1 (risedronate plus calcium/vitamin D-treated patients), serum levels of RANKL and IL-1beta significantly decreased and the level of osteoprotegerin significantly increased after three and 6 months, but no significant difference was found in TNF-alpha level. In group 2, however, the level of serum cytokines did not change after three and 6 months. In cases of bone turnover, both markers of bone resorption and formation significantly decreased after 6 months in group 1. In conclusion risedronate could improve osteoporosis by increasing osteoprotegerin and reducing RANKL and IL-1beta.

Topics: Aged; Alkaline Phosphatase; Bone Density; Bone Density Conservation Agents; Calcium; Collagen Type I; Cytokines; Etidronic Acid; Female; Humans; Interleukin-1beta; Middle Aged; Osteocalcin; Osteoporosis, Postmenopausal; Osteoprotegerin; Peptides; RANK Ligand; Risedronic Acid; Tumor Necrosis Factor-alpha; Turkey; Vitamin D

Previous in vitro studies suggest that the anti-resorptive effect of raloxifene might be mediated by changes in several cytokines involved in the bone remodeling process. In this context, the osteoprotegerin (OPG)- receptor activator of NF kappa B ligand (RANKL) system is considered a key component in the osteoclastogenesis regulation. The aim of this study was to determine the effects of raloxifene treatment on serum concentrations of OPG, receptor RANKL and its relationship with biochemical markers of bone turnover and bone mineral density (BMD) in previously untreated women with post-menopausal osteoporosis. We selected 47 post-menopausal women (mean age 63+/-7 yr) with densitometric criteria of osteoporosis. We determined at baseline, 3, 6, and 12 months anthropometric parameters, biochemical markers of bone turnover, serum levels of 25(OH) D, serum levels of OPG and RANKL. BMD (dual-energy x-ray absorptiometry) in lumbar spine (LS) femoral neck and total hip was measured at baseline and 12 months after raloxifene (60 mg/day) treatment. Serum levels of OPG decreased in the 3rd and 6th month of treatment (p<0.001) and returned to basal levels in the 12th month. There was a significant decrease of RANKL levels and OPG/RANKL ratio after 1 yr of raloxifene treatment. In addition, BMD in LS increased significantly (2.5%) in the 12th month of treatment (p=0.031). Finally, the biochemical markers of bone turnover (total alkaline phosphatase, bone alkaline phosphatase, osteocalcin, tartrate-resistant acid phosphatase, urine cross-linked carboxi-terminal telopeptide of type I collagen) decreased significantly from the 3rd month of treatment. In conclusion, our results support the hypothesis that raloxifene may inhibit osteoclast activity, at least partly modulating the OPG-RANKL system.

Topics: Aged; Bone Density Conservation Agents; Calcium; Female; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Raloxifene Hydrochloride; RANK Ligand; Vitamin D

High bone turnover, with bone resorption exceeding bone formation, is a major mechanism of postmenopausal osteoporosis. Therefore, inhibition of bone resorption is a rational approach for the prevention of bone loss. The objective of the current study was to determine the short-term efficacy of once-weekly low-dose alendronate in the prevention of bone loss, via bone turnover markers, in early postmenopausal Korean women with moderate bone loss.. This study involved a 12-week, randomized, double-blind clinical trial that compared the effects of placebo with alendronate 20mg once weekly. All subjects received supplemental calcium 600 mg and vitamin D 400IU daily. We recruited 63 postmenopausal women (ranging from 50 to 65 years of age) with the lowest lumbar spine bone mineral density (BMD) at least 2.0 S.D. below the mean value for young healthy adults. BMD was measured at baseline and serum alkaline phosphatase (ALP), osteocalcin, C-terminal telopeptide of type I collagen (CTX), and osteoprotegerin (OPG) were measured at baseline and 12 weeks after treatment.. We randomly assigned 63 women to either placebo or alencronate 20 mg once a week for 3 months. Forty-nine women continued and completed all 3 months. After 3 months, bone resorption markers were significantly decreased in the alendronate group than in the placebo group: CTX -47.2% vs. 15% (p<0.01), ALP 1.6% vs. 25.9% (p=0.01), osteocalcin -29.2% vs. -13.6 (p=0.06). Women who received alendronate showed similar results to those who received placebo with regard to adverse events.. Once-weekly low-dose alendronate may be a cost-effective and safe method of suppressing bone turnover in early postmenopausal women with moderate bone loss.

Topics: Alendronate; Alkaline Phosphatase; Bone Density; Bone Density Conservation Agents; Collagen Type I; Double-Blind Method; Drug Administration Schedule; Female; Humans; Middle Aged; Osteocalcin; Osteoporosis, Postmenopausal; Osteoprotegerin; Peptides

This paper studies the effect of oral risedronate on osteoclast precursors, osteoclast formation, and cytokine production in 25 osteoporotic women. Risedronate is effective in reducing the number of osteoclast precursors, their formation, vitality, and activity and the level of RANKL and TNF-alpha in cultures.. Bisphosphonates inhibit bone resorption by acting against osteoclasts. Some in vitro studies suggest that they induce osteoclast apoptosis; others suggest that they exert an effect on the production of pro-osteoclastogenic cytokines. The effect of risedronate on osteoclastogenesis by peripheral blood mononuclear cells (PBMCs) in postmenopausal osteoporosis has not been previously studied. This paper examined the influence of risedronate on the formation of osteoclast precursors and cytokine production within the compass of osteoclastogenesis in osteoporosis.. This study was conducted on 38 osteoporotic women; 25 patients were treated with risedronate 5 mg/d, whereas 13 were treated with calcium 1 g/d and vitamin D 800 UI/d. The following parameters were assessed: changes in bone turnover, circulating osteoclast precursors, formation of osteoclasts in PBMC cultures, their activity and vitality, and variations in the production of pro-osteoclastogenic cytokines before and after therapy.. After 3 mo of risedronate, there was a significant reduction in the number and degree of differentiation of osteoclast precursors, osteoclast formation, vitality and activity, and in the level of RANKL and TNF in cultures and of TNF and osteoprotegerin (OPG) in serum, whereas in the group treated with calcium and vitamin D, there were no significant changes.. Our data show that risedronate is effective in lowering the number of circulating osteoclast precursors, their formation, vitality, and activity in cultures, and in reducing the level of pro-osteoclastogenic cytokines in culture supernatants and in serum.

Topics: Aged; Bone Density Conservation Agents; Calcium; Cell Survival; Cells, Cultured; Colony-Forming Units Assay; Etidronic Acid; Female; Humans; Middle Aged; Osteoclasts; Osteoporosis, Postmenopausal; Osteoprotegerin; Postmenopause; RANK Ligand; Risedronic Acid; Stem Cells; Time Factors; Tumor Necrosis Factor-alpha; Vitamin D

Risedronate and teriparatide have opposite actions on the osteoblast-osteoclast dipole and are expected to influence the RANK/RANKL/osteoprotegerin (OPG) system. We aimed to evaluate changes in serum OPG and RANKL after risedronate or teriparatide administration in postmenopausal osteoporotic women. Seventy-four postmenopausal Caucasian women (age 64.1+/-1.0 years) were studied. Women with osteopenia served as controls (group 1, n=30). Women with osteoporosis were randomly assigned to either risedronate 35 mg once weekly (group 2, n=21) or teriparatide 20 microg once daily (group 3, n=23) for six months. Blood samples for serum RANKL, OPG, N-terminal propeptide of type 1 collagen (P1NP), and C-terminal telopeptide of type 1 collagen (CTx) were obtained before treatment and three and six months after treatment. P1NP and CTx levels remained unchanged in group 1, decreased in group 2 (p<0.001), and increased in group 3 women (p<0.001) throughout the treatment. OPG levels remained unchanged while RANKL decreased gradually in all groups (p<0.001). There was no correlation between OPG or RANKL and P1NP or CTx. Our data suggest that neither antiresorptive nor osteoanabolic therapy causes specific alterations of serum OPG/RANKL levels; therefore, these cytokines cannot substitute for the established markers of bone turnover in the monitoring of response to osteoporosis treatment.

Topics: Aged; Biomarkers; Bone Density Conservation Agents; Calcium; Collagen Type I; Etidronic Acid; Female; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Risedronic Acid; Teriparatide

Osteoprotegerin (OPG) is a protein expressed by osteoblasts that, linking the receptor activator of nuclear factor kappaB (RANK) ligand (RANKL), produced by osteoblasts, blocks the process of osteoclastic differentiation and modulates osteoclastic apoptosis. Raloxifene (RAL) stimulates the production of OPG from osteoblasts, as demonstrated in vitro, carring out their antiresorption activity, at least in part, as means of the OPG/RANK/RANKL system. The aim of this study was to evaluate in vivo if the RAL treatment of postmenopausal women was associated to changes in serum OPG; moreover, to evaluate the serum changes of bone turnover modulators interleukin-6 (IL-6) and C-telopeptides of type-1 collagen (CrossLaps).. A prospective, randomized, placebo-controlled study was designed. A group of consecutive healthy postmenopausal women (n=40) referred to II Menopause Centre of the Department of Gynaecology of Second University of Naples for climacteric syndrome was enrolled and divided in two groups: (n=20) postmenopausal women received for 6 months oral raloxifene (60 mg/day) versus (n=20) postmenopausal women received placebo tablets.. Serum OPG levels in postmenopausal women after RAL treatment are statistically significant increased (P<0.001) versus baseline (P=0.007) versus placebo.. These in vivo data demonstrate that RAL could improve osteoporosis, also through an increase of OPG production by osteoblasts.

Topics: Bone Density; Collagen; Female; Humans; Interleukin-6; Middle Aged; Osteoblasts; Osteoporosis, Postmenopausal; Osteoprotegerin; Peptide Fragments; Prospective Studies; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators

To study the effects of Migu Tablet (MGT) on bone mineral density (BMD), serum levels of osteoprotegerin (OPG) and its ligand (OPGL), and bone metabolic markers in patients with postmenopausal osteoporosis (PMO).. BMD in 192 women of natural menopause, 48 to 65 years old, were determined. Among them, 160 women with PMO were randomized into 4 groups, 54 in the Migu Tablet group (MGTG), 53 in the Xianlin Gubao group (XLGBG) and 53 in the Leli Calcium group (LCG). And the other 32 women with BMD in normal range were set as the control group. Serum levels of OPG, OPGL, bone alkaline phosphates (sBAP), osteocalcin (sOC), cross-linked C-telopeptides of collagen type I (sCTx), and urine level of bone cross-linked N-telopeptides of collagen type I (uNTx) were measured before treatment and at the 12th and 24th week of treatment, with enzyme-linked immunosorbent assay (ELISA); BMD of orthophoric lumbar vertebrae, femoral neck, Ward's triangle and trochanter were determined by dual-energy X-ray absorptiometry at the same time as well.. After 24-week treatment, BMD was heightened to different degree, serum levels of OPG, sCTx, uNTx/Cr were significantly decreased and OPGL, sBAP, sOC were increased in the MGTG and XLGBG, while these indexes showed insignificant change in the LCG and the control group.. The effect of MGT in treating PMO were notable, just like that of XLGB, but single medication of calcium tablet cannot alleviate the disease and also incapable to prevent the loss of bone.

Topics: Bone Density; Drugs, Chinese Herbal; Female; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Phytotherapy; RANK Ligand; Tablets; Treatment Outcome

Malnutrition in elderly people contributes to osteoporosis and fracture. The aim of the study was to investigate the effects of nutritional improvement on bone metabolism in elderly community-dwelling women. A 12-month randomized controlled trial of 71 ambulant women aged > or =70 years with BMI < or =21 kg/m(2 )and osteoporosis at the hip was undertaken. They received either calcium (1 g) and vitamin D (800 units of cholecalciferol) only (group 1: n=35) or calcium/vitamin D and one or two cartons of a nutritional supplement drink which provided 300 Kcal, 12 g protein, 11.6 g fat and 36.8 g carbohydrate per carton (group 2: n=36). Body composition and bone mineral density (BMD) were assessed at baseline and 12 months. Biochemical markers of bone turnover were measured at baseline and at 1, 3, 6, 9 and 12 months. Group 2 gained significantly more weight [mean (SD) group 1: 0.15 (2.45), group 2:2.66 (2.8) kg P<0.001] and fat mass [group 1: -0.26 (1.8), group 2:1.9 (1.7) kg P<0.001]. BMD at the spine, femoral neck and total hip did not change significantly, although there was a positive trend at the total hip in group 2 [group 1: -0.5 (5.2), group 2:1.25 (3.3)%, P=0.13]. In a subgroup analysis, irrespective of their treatment group, there was a significant difference in changes in BMD at the lumbar spine and total hip in those who lost body weight (A) compared to those who had maintained or increased their weight (B), [mean (SD) % change in BMD lumbar spine; A: -1.64 (3.75), B: 0.96 (2.75) P=0.013, total hip A: -2.09 (6.0), B: 1.04 (3.3), P=0.05)] A significant reduction in serum CTX, a marker of bone resorption, was seen in group 2 [% decrease at 3 months, group 1: 1 (8.7), Group 2: 32 (5.8), P<0.01]. Serum osteoprotegerin (OPG) increased significantly in group 2 with a maximal increase (27%) observed at 6 ( P<0.01) and 9 months ( P<0.05). A small increase in bone-specific alkaline phosphatase was seen at 12 months in group 2 [% increase group 1:5 (5), group 2: 17 (6), P=0.05]. Serum osteocalcin increased at 12 months in group 2 ( P=0.01). Dietary improvement in elderly women with low BMI is associated with a reduction in bone resorption with a small but "net" positive effect on bone formation.

Topics: Aged; Alkaline Phosphatase; Anthropometry; Body Composition; Body Mass Index; Bone and Bones; Bone Density; Calcium; Collagen; Collagen Type I; Dietary Supplements; Female; Glycoproteins; Humans; Malnutrition; Osteoporosis, Postmenopausal; Osteoprotegerin; Peptides; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Vitamin D

Estrogen deficiency is the leading cause of postmenopausal osteoporosis(PMOP) and phytoestrogens soy isoflavones (SI) have been shown to improve PMOP. Equol (Eq), an in vivo metabolite of phytoestrogens soy isoflavones (SI), has a more stable structure and stronger biological activity than its parent compound and has the greatest estrogenic activity. However, there are few studies on the therapeutic effect of Eq on PMOP.. To explore the therapeutic effect and mechanisms of Eq on POMP.. Osteoblast-like cells ROS1728 were cultured with different doses of Eq, estradiol (E2), separately. The effect of Eq on the proliferation, apoptosis, cell cycle of osteoblasts were detected by CCK-8 and flow cytometry, and the expression of OPG/RANK/RANKL signaling pathway of osteoblasts was detected by Quantitative real-time PCR (qRT-PCR) and Western blot (WB), and RNA silencing technology were carried out to explore the receptors through which Eq plays a role. Then PMOP rat model was established and treated by Eq or E2 to further verification of the effect and mechanism of Eq on PMOP.. Eq promoted the proliferation and inhibited the apoptosis of osteoblasts and increased the proportion of osteoblasts in the S phase and G2/M phase in a dose-dependent manner. Mechanistically, Eq treatment upregulated the expression of OPG and OPG/RANKL ratio in osteoblasts and this regulatory effect was mainly mediated through the ERβ receptor. Furthermore, in vivo study, Eq improved microstructure and BMD of the femur of PMOP rat model, which imitated the osteoprotective effect of E2. Moreover, the Eq or E2 treatment increased serum levels of Ca, 1,25(OH)2D3, bone Gla-protein(BGP), and Type I procollagen (PC1), and reduced serum levels of phosphorus (P), parathyroid hormone(PTH), pyridinol (PYD), tartrate-resistant acid phosphatase (TRAP) and urinary level of deoxypyridinoline (DPD) in the treatment OVX group compared with the untreated OVX group. Meanwhile, Eq or E2 markedly induced the mRNA and protein expression of OPG and OPG/RANKL ratio.. Eq can combine with ERβ and exert a protective effect on PMOP by upregulating OPG/RANKL pathway.

Topics: Animals; Equol; Estrogen Receptor beta; Female; Humans; Osteoblasts; Osteoporosis, Postmenopausal; Osteoprotegerin; Phytoestrogens; RANK Ligand; Rats

Topics: Alendronate; Animals; Anti-Inflammatory Agents; Antioxidants; Bone Density; Cell Line; Cell Proliferation; Cytokines; Disease Models, Animal; Female; Flavonols; Humans; Osteoporosis, Postmenopausal; Osteoprotegerin; Ovariectomy; Phytotherapy; RANK Ligand; Rats, Sprague-Dawley; Receptors, Calcitriol; Receptors, Estrogen

Epidemiology and pathogenesis of cardiovascular diseases (CVD) and osteoporosis are strikingly overlapping. This study presents matrix metalloproteinase-9 (MMP-9), as a simple molecular link more consistently associated with the pathophysiology of both osteoporosis and CVD risk factors. 40 adult female rats were randomly distributed into 4 groups [control sham-operated, untreated osteoporosis, carvedilol-treated osteoporosis and alendronate-treated osteoporosis]. After 8 weeks, blood samples were collected to estimate Lipid profile (Total cholesterol, HDL, Triglycerides), inflammatory markers (IL-6, TNF alpha, CRP and NO), and Bone turnover markers (BTM) (Alkaline phosphatase, osteocalcin and pyridinoline). The tibias were dissected to estimate MMP-9 and NF-kB gene expression, OPG, RANKL levels and for histological examination. Induction of osteoporosis resulted in a significant elevation in BTM, inflammatory markers and dyslipidemia. MMP-9 was significantly elevated and positively correlated with BTM, inflammation and dyslipidemia markers. Carvedilol and alendronate exerted a bone preservative role and attenuated dyslipidaemia and inflammation in accordance with their respective effect on MMP-9.

Topics: Alkaline Phosphatase; Amino Acids; Animals; Bone Remodeling; Cardiovascular Diseases; Cholesterol; Cortical Bone; Disease Models, Animal; Female; Gene Expression Regulation; Humans; Inflammation; Lipoproteins, HDL; Matrix Metalloproteinase 9; NF-kappa B; Osteocalcin; Osteoporosis, Postmenopausal; Osteoprotegerin; Ovariectomy; RANK Ligand; Rats; Risk Factors; Tibia; Triglycerides

Menopause is the leading cause of osteoporosis for elderly women due to imbalanced bone remodelling in the absence of oestrogen. The ability of tocotrienol in reversing established bone loss due to oestrogen deficiency remains unclear despite the plenitude of evidence showcasing its preventive effects. This study aimed to investigate the effects of self-emulsified annatto tocotrienol (SEAT) on bone histomorphometry and remodelling in ovariectomised rats. Female Sprague Dawley rats (n=36) were randomly assigned into baseline, sham, ovariectomised (OVX) control, OVX-treated with annatto tocotrienol (AT) (60 mg/kg), SEAT (60 mg/kg) and raloxifene (1 mg/kg). Daily treatment given through oral gavage was started two months after castration. The rats were euthanised after eight weeks of treatment. Blood was collected for bone biomarkers. Femur and lumbar bones were collected for histomorphometry and remodelling markers. The results showed that AT and SEAT improved osteoblast numbers and trabecular mineralisation rate (p<0.05 vs untreated OVX). AT also decreased skeletal sclerostin expression in OVX rats (p<0.05 vs untreated OVX). Similar effects were observed in the raloxifene-treated group. Only SEAT significantly increased bone formation rate and reduced RANKL/OPG ratio (p<0.05 vs untreated OVX). However, no changes in osteoclast-related parameters were observed among the groups (p>0.05). In conclusion, SEAT exerts potential skeletal anabolic properties by increasing bone formation, suppressing sclerostin expression and reducing RANKL/OPG ratio in rats with oestrogen deficiency.

Topics: Animals; Bixaceae; Bone and Bones; Bone Density; Bone Morphogenetic Proteins; Carotenoids; Disease Models, Animal; Emulsions; Estradiol; Female; Genetic Markers; Humans; Osteoporosis, Postmenopausal; Osteoprotegerin; Plant Extracts; RANK Ligand; Rats; Rats, Sprague-Dawley; Signal Transduction; Tocotrienols

The study was aimed to evaluate the potential of hydroalcoholic extract of Pinus roxburghii (PRE) stem bark in post-menopausal osteoporosis and its underlying mechanisms.. In silico docking of the markers was done using AutoDock version 4.2. for molecular targets: receptor activator of nuclear factor-κB (RANK), osteoprotegerin (OPG) and Cathepsin. Female Wistar rats of bodyweight 200-250 g were employed and surgical ovariectomy (OVX) was performed. PRE was administered at a dose of 100 and 200 mg/kg whereas standard drug, raloxifene given at 1 mg/kg orally for eight weeks.. PRE (20 and 40 µg/mL) significantly increased the cellular proliferation in osteoblastic UMR cell lines 11.58 and 15.09% respectively. Eight weeks after surgical removal of ovaries, a significant bone porosity was confirmed by modulation in bone breaking strength of tibia, lumber, and femur; bone mineral density (BMD), calcium, phosphorus, hydroxyproline levels in OVX group. Treatment with PRE 100 and 200 mg/kg significantly restored the bone loss. Real-time polymerase chain reaction (RT-PCR) analysis of molecular markers RANK, OPG and cathepsin and histology also confirmed the attenuation of bone loss. The quantification of quercetin, gallic acid, caffeic acid, catechin, tannic acid and ascorbic acid was done by high-performance liquid chromatography (HPLC) and high performance thin layer chromatography.. P. roxburghii produced anti-osteoporotic effect possibly due to estrogenic modulation, and improved bone remodeling.

Topics: Animals; Bone Density; Bone Density Conservation Agents; Bone Remodeling; Cathepsins; Cell Proliferation; Estrogens; Female; Humans; Osteoblasts; Osteoporosis, Postmenopausal; Osteoprotegerin; Pinus; Plant Extracts; Porosity; Raloxifene Hydrochloride; Rats; Receptor Activator of Nuclear Factor-kappa B; Treatment Outcome

E11/Podoplanin (Pdpn) is implicated in early osteocytogenesis and the formation of osteocyte dendrites. This dendritic network is critical for bone modelling/remodelling, through the production of receptor activator of nuclear factor κ B (RANK)-ligand (RANKL). Despite this, the role of Pdpn in the control of bone remodelling is yet to be established in vivo. Here we utilised bone-specific Pdpn conditional knockout mice (cKO) to examine the role of Pdpn in the bone loss associated with ovariectomy (OVX). MicroCT revealed that Pdpn deletion had no significant effect on OVX-induced changes in trabecular microarchitecture. Significant differences between genotypes were observed in the trabecular pattern factor (P<0.01) and structure model index (P<0.01). Phalloidin staining of F-actin revealed OVX to induce alterations in osteocyte morphology in both wild-type (WT) and cKO mice. Histological analysis revealed an expected significant increase in osteoclast number in WT mice (P<0.01, compared with sham). However, cKO mice were protected against such increases in osteoclast number. Consistent with this, serum levels of the bone resorption marker Ctx were significantly increased in WT mice following OVX (P<0.05), but were unmodified by OVX in cKO mice. Gene expression of the bone remodelling markers Rank, Rankl, Opg and Sost were unaffected by Pdpn deletion. Together, our data suggest that an intact osteocyte dendritic network is required for sustaining osteoclast formation and activity in the oestrogen-depleted state, through mechanisms potentially independent of RANKL expression. This work will enable a greater understanding of the role of osteocytes in bone loss induced by oestrogen deprivation.

Topics: Adaptor Proteins, Signal Transducing; Animals; Bone Remodeling; Collagen Type I; Disease Models, Animal; Female; Femur; Humans; Membrane Glycoproteins; Mice, Knockout; Osteoclasts; Osteogenesis; Osteoporosis, Postmenopausal; Osteoprotegerin; Ovariectomy; Peptides; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Osteoporosis is a degenerative disease that threatens bone health of the elderly (especially postmenopausal women). Since osteoporosis is important to prevent, the aim of this study was to investigate the regulation of desalted duck egg white peptides (DPs) on osteoporosis. In this study, the effects of DPs on bone formation were evaluated using MC3T3-E1 cells and ovariectomized (OVX) rats. DPs significantly enhanced the preosteoblasts proliferation, differentiation, and matrix mineralization via the upregulation of wnt3a expression, low-density lipoprotein receptor-related protein-5 (LRP-5), β-catenin, runt-related transcription factor 2 (Runx2), and osteoprotegerin (OPG) (P < 0.05). The intracellular calcium concentration was significantly elevated by DPs (P < 0.05), which is attributed to calcium influx and L-type calcium channels. Additionally, OVX rat model experiment indicated that DPs (600 mg/kg bw) had a superior effect against bone loss induced by estrogen deficiency, as it significantly declined bone turnover markers, and significantly increased biomechanical parameters (P < 0.05). Mineralized bone surfaces and bone microstructure were also obviously improved by DPs treatment. Immunohistochemical analysis showed that receptor activator of nuclear factor κ B (RANK) expression of tibia in DPs group was significantly reduced compared with the model group (P < 0.05). Our results demonstrated that DPs could enhance preosteoblasts differentiation and antiosteoporosis via wnt/β-catenin signal pathway and several key osteogenic transcription factors such as Runx2 and OPG. PRACTICAL APPLICATION: High-value utilization of salted duck egg white, a byproduct of food industry, is worthy of in-depth study. Desalted duck egg white peptides (DPs) were proved to promote bone formation, which suggests the potentials of DPs as cofactors in osteoporosis prevention.

Topics: Animals; beta Catenin; Bone and Bones; Calcium; Core Binding Factor Alpha 1 Subunit; Ducks; Egg White; Female; Humans; Low Density Lipoprotein Receptor-Related Protein-5; Mice; Osteogenesis; Osteoporosis, Postmenopausal; Osteoprotegerin; Peptides; Rats; Rats, Sprague-Dawley; Signal Transduction; Wnt3 Protein

Osteoporosis, a chronic disease that affects over 200 million people worldwide, presents a substantial medical and socioeconomic burden on the modern society. However, long-term intake of diets supplemented with different polyunsaturated fatty acids (PUFAs) can affect bone metabolism; thus, this study investigated the comparative effects of Antarctic krill oil (AKO, containing n-3 PUFAs) and arachidonic acid-rich oil (AAO, containing n-6 PUFAs) on bone resorption in a mice model of postmenopausal osteoporosis. Mice were orally administered with AKO (200 mg kg-1) or AAO (220 mg kg-1) once daily for 30 days, ovariectomized, followed by the continued administration of the respective samples for 90 days. Biomechanical and histomorphometric analyses revealed that AKO increased the bone mineral density (BMD) to enhance the biomechanical properties by increasing the mineral apposition rate and repairing the microstructure of the trabecular bone, whereas AAO had the opposite effect. The fatty acid analysis of the vertebra showed that AKO increased the n-3 PUFA (especially for DHA) content, thereby decreasing the ratio of n-6/n-3 PUFAs, which was negatively correlated with the BMD. However, AAO had the opposite effect due to high amounts of arachidonic acid. To explore the underlying mechanism responsible for these observations, we compared the classical bone resorption OPG/RANKL/NF-κB pathway mediated by PGE2/EP4. The ratio of n-6/n-3 PUFAs in the bone affected the production of PGE2, a factor regulating the OPG/RANKL pathway, thereby regulating osteoclastogenesis by stimulating the NF-κB pathway. The results of ELISA, qRT-PCR, and western blot demonstrated that AKO reduced the secretion of PGE2 and the expression of EP4, upregulating the ratio of OPG/RANKL in the bone, thereby decreasing TRAF6 expression to inhibit the activation of the NF-κB signaling pathway, and finally inhibiting the expression of nuclear transcription factors (c-fos and NFATc1) to prevent excessive osteoclastogenesis (TRACP, MMP-9, and Cath-K). Arachidonic acid is a precursor of PGE2 synthesis. AAO showed the opposite trend through the same pathway. Thus, AKO could significantly improve osteoporosis via the OPG/RANKL/NF-κB pathway mediated by PGE2/EP4 to inhibit osteoclastogenesis, whereas AAO aggravated osteoporosis via the same pathway. This is the first study to systematically compare the effects and mechanism of AKO and AAO in regulating bone resorption in osteoporotic mice to support r

Topics: Animals; Arachidonic Acid; Bone and Bones; Bone Density; Bone Resorption; Disease Models, Animal; Euphausiacea; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Female; Humans; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; NF-kappa B; Oils; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Signal Transduction; Tartrate-Resistant Acid Phosphatase; TNF Receptor-Associated Factor 6

Although drug therapies are available for postmenopausal osteoporosis, these drugs are not free of side effects and long-term adherence to them are low. A safe and effective nutritional approach to counter postmenopausal osteoporosis is an important research goal. We fed ovariectomized (OVX) Sprague-Dawley rats a diet supplemented with 1% or 2% green tomato extract (GTE). After 12 weeks, micro-computed tomography scans revealed that GTE supplementation effectively prevented distal femur bone loss. This prevention was due to improved bone formation and suppressed bone resorption as observed by the regulation of osteoblast and osteoclast activities. GTE supplementation also improved bone formation through Bmp2-Smad 1/5/8-Runx2 signaling, while bone resorption was regulated by the receptor activator of nuclear factor kappa-B (RANKL)/osteoprogeterin (OPG) pathway. These results suggest that GTE supplementation prevents severe postmenopausal bone loss by maintaining the regulation of bone homeostasis in OVX rats. GTE as a diet supplement might be a potential novel alternative for the prevention of postmenopausal osteoporosis.

Topics: Animals; Bone Density; Bone Morphogenetic Protein 2; Bone Resorption; Core Binding Factor Alpha 1 Subunit; Disease Models, Animal; Female; Humans; Osteogenesis; Osteoporosis, Postmenopausal; Osteoprotegerin; Ovariectomy; Phytotherapy; Plant Extracts; RANK Ligand; Rats; Rats, Sprague-Dawley; Signal Transduction; Smad Proteins, Receptor-Regulated; Solanum lycopersicum; Tomatine; Weight Gain

The purpose was to observe whether local administration Strontium (Sr) and Aspirin (Asp) can enhance the efficacy of β-Tricalcium phosphate(β-TCP) in the treatment of osteoporotic bone defect. The MC3T3-E1 cells were co-cultured with β-TCP, Sr/β-TCP, Asp-Sr/β-TCP scaffold and induced to osteogenesis, and the cell viability, mineralization ability were observed by MTT, Alizarin Red staining(ARS) and Western blotting(WB). Then this scaffolds were implanted into the femoral epiphysis bone defect model of ovariectomized(OVX) rats for 8 weeks. X-ray, Micro-CT, histology and Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis were used to observe the therapeutic effect and explore the possible mechanism. MTT, ARS results show that the cell mineralization and viability of Asp-Sr/β-TCP group is significantly higher than Control group, β-TCP group and Sr/β-TCP group. Protein expression show that the osteogenic protein expression such as ALP、OP、RUNX-2、OC and COL-1 of Asp-Sr/β-TCP group is significantly higher than Control group, β-TCP group and Sr/β-TCP group. X-ray images, Micro-CT and Histological analysis evaluation show that, group Asp-Sr/β-TCP presented the strongest effect on bone regeneration and bone mineralization, when compared with β-TCP group and Sr/β-TCP group. RT-qPCR analysis show that Asp-Sr/β-TCP, β-TCP group and Sr/β-TCP group showed increased BMP2, Smad1, OPG than the OVX group(p < 0.05), while Asp-Sr/β-TCP exhibited decreased TNF-α、IFN-γ and RANKL than the OVX group(p < 0.05). Our current study demonstrated that Asp-Sr/ β-TCP is a scheme for rapid repair of femoral condylar defects, and these effects may be achieved by inhibiting local inflammation and through BMP-2/Smad1 and OPG/RANKL signaling pathway.

Topics: 3T3 Cells; Animals; Anti-Inflammatory Agents; Aspirin; Bone Density; Bone Morphogenetic Protein 2; Bone Remodeling; Bone Substitutes; Calcium Phosphates; Disease Models, Animal; Female; Femur; Humans; Mice; Osteoblasts; Osteogenesis; Osteoporosis, Postmenopausal; Osteoprotegerin; Ovariectomy; RANK Ligand; Rats, Sprague-Dawley; Signal Transduction; Smad1 Protein; Strontium; Wound Healing

A decline of estrogen in menopause women is accompanied with increases in many pro-inflammatory cytokines and osteoporosis. Andrographolide (AP), from Andrographis paniculata, which has an anti-inflammatory activity, may have potential to alleviate osteoporosis during estrogen deficiency. Here we report the promoting effects of AP on the differentiation of mouse pre-osteoblastic (MC3T3-E1) cells by increasing the expression and activity of alkaline phosphatase (ALP), an osteoblastic gene-specific marker. AP also accelerated bone formation and increased bone structural gene production including collagen and osteocalcin. We demonstrate for the first time the promoting effect of AP on the differentiation of osteoblast involved with the OPG/RANKL signaling pathway. AP also protected bone loss in the estrogen-deficient (ovariectomized, OVX) rats after 12 weeks of treatment. It protected the loss of bone mineral density, bone microarchitecture, and improved bone turnover rate in OVX rats. This study provides an essential evidence for clinical applications and development of AP towards treating osteoporosis in post-menopausal women.

Topics: 3T3 Cells; Andrographis; Animals; Bone Density; Cell Differentiation; Disease Models, Animal; Diterpenes; Estrogens; Female; Humans; Mice; Osteoblasts; Osteogenesis; Osteoporosis, Postmenopausal; Osteoprotegerin; Ovariectomy; RANK Ligand; Rats; Rats, Sprague-Dawley

Topics: Animals; Biomarkers; Bone Density; Bone Remodeling; Cancellous Bone; Collagen Type I; Cortical Bone; Dietary Sugars; Disease Models, Animal; Drinking; Drinking Water; Female; Femur; Fructose; Humans; Mineral Waters; Osteoporosis, Postmenopausal; Osteoprotegerin; Ovariectomy; Peptides; RANK Ligand; Rats, Sprague-Dawley; X-Ray Microtomography

Topics: Animals; Aspirin; Bone Density; Cytokines; Female; Humans; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Rats; Rats, Sprague-Dawley; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction; Tomography, X-Ray Computed

MiR-21 is known to play a role in osteoclast proliferation and differentiation, but the role of serum miR-21 expression in osteoporosis remains unclear. Previous research found that serum miR-21 expression was positively correlated with bone mineral density in postmenopausal osteoporosis patients, but other factors involved in postmenopausal osteoporosis still unknown. This study aimed to determine the role of serum miR-21 expression, concentration of RANKL, OPG, TGF-β1, sclerostin and serum calcium, RANKL/OPG ratio, and physical activity on bone mineral density of spine in hypoestrogenic postmenopausal women with osteoporosis (PMOP) compared with no osteoporosis (PMNOP), with point of interest on the expression of serum miR-21.. this study was conducted by comparative cross-sectional design. The subjects were divided into 2 groups of PMOP and PMNOP. We used an absolute quantification real-time PCR method to determine serum miR-21 expressions level.. Median of serum miR-21 expression at the PMOP group was significantly higher compared to PMNOP group (p = 0.001). Serum miR-21 expression, RANKL, RANKL/OPG ratio, and physical activity were significantly correlated with BMD values in the PMOP group. Moderate physical activity was significantly negatively correlated with serum miR-21 expression. We also obtained a linear regression equation BMD = 1.373-0.085*Ln.miR-21-0.176*Log10.RANKL (R2 = 52.5%).. serum miR-21 expression in PMOP was higher compared with PMNOP. Serum miR-21 expression proved to have a negative effect on spinal BMD values in hypoestrogenic postmenopausal women with osteoporosis of 8.5%. Obtained equation of BMD = 1.373-0.085*Ln.miR-21-0.176*Log10.RANKL can explain the value of spinal BMD by 52.5%.

Topics: Bone Density; Calcium; Cross-Sectional Studies; Exercise; Female; Humans; MicroRNAs; Middle Aged; Multivariate Analysis; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Spine; Transforming Growth Factor beta1

The underlying mechanisms of vitamin D receptor (VDR) and osteoprotegerin (OPG) genetic variation associated with bone mineral density and osteoporosis remain uncertain. This study aimed to investigate the association of VDR and OPG gene polymorphism as well as gene-gene interaction and their haplotype combination with the risk of osteoporosis.. Polymerase chain reaction restriction fragment length polymorphism was carried out for single nucleotide polymorphism (SNP) detection. Generalized multifactor dimension reduction (GMDR) is used to identify the interaction. SHEsis software evaluated the haplotype and logistic regression was performed to assess the association between the SNPs within the VDR and OPG genes and osteoporosis.. The risk of osteoporosis in the VDR-rs2228570 polymorphism T-allele carriers was significantly higher than that in CC (CT/TT versus CC) individuals (adjusted odds ratio [OR] [95% confidence interval (CI)] = 1.76 [1.33-2.22]). The risk of osteoporosis was also higher in the G-allele carrier of the OPG-rs3102735 polymorphism than in individuals with the AA genotype (AG/GG vs. AA) (adjusted OR [95% CI] = 1.65 [1.27-2.14]). However, after adjusting for sex, age, and waist circumference covariates, no significant association of VDR-rs17879735 and OPG-rs2073618 with the osteoporosis risk was revealed. The GMDR method identified that gene-gene interactions were significant, but not for gene/AO interaction. Haplotypes were analyzed with SHEsis software. We did not detect a high-risk haplotype combination associated with osteoporosis.. Both VDR-rs2228570-T and OPG-rs3102735-G and their interactions are related to the increased risk of osteoporosis.

Topics: Aged; Aged, 80 and over; Asian People; China; Female; Gene Frequency; Gene-Environment Interaction; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Postmenopause; Receptors, Calcitriol

Osteoporosis is characterized by skeletal fragility and microarchitectural deterioration. The side effects of drugs to treat osteoporosis will negatively affect the health of patients. This study aimed to investigate the therapeutic effects of icariin combined with adipose-derived stem cells on osteoporosis in a postmenopausal osteoporosis model after ovariectomy in rats. After ovariectomy the rats were treated with icariin combined with adipose-derived stem cell transplantation. The levels of alkaline phosphatase, tartrate-resistant acid phosphatase, osteoprotegerin, and bone γ-carboxyglutamate protein in serum were determined by ELISA. The bone mineral density was measured by dual-energy X-ray absorptiometry. The mechanical properties were determined by a three-point bending test. The kidney functions were evaluated by an automatic analyzer and a diagnostic kit. Icariin combined with stem cells significantly reduced body weight gain caused by ovariectomy, significantly decreased alkaline phosphatase, tartrate-resistant acid phosphatase, and bone γ-carboxyglutamate protein content in serum, significantly increased osteoprotegerin content, significantly elevated bone mineral density of the lumbar spine, left femur, and right femur, and enhanced bone biomechanical properties of the femur, including maximum bending load, bending rigidity, and fracture energy, in osteoporotic rats. In addition, icariin combined with stem cells substantially decreased the damage to the liver and kidney in osteoporotic rats. Icariin combined with stem cells can not only ameliorate reduction of bone mass and disruption of the microarchitectural structure of bone tissue caused by osteoporosis in a rat model but can also have a beneficial effect on organ functions, such as those of the liver and kidney.

Topics: Absorptiometry, Photon; Adipose Tissue; Alkaline Phosphatase; Animals; Biomechanical Phenomena; Body Weight; Bone and Bones; Bone Density; Female; Femur; Flavonoids; Humans; Kidney; Liver; Osteocalcin; Osteoporosis, Postmenopausal; Osteoprotegerin; Rats, Sprague-Dawley; Stem Cell Transplantation; Stem Cells; Tartrate-Resistant Acid Phosphatase

Orthosiphon stamineus (OS) or Misai Kucing (Java tea) is a popular herbal supplement from Southeast Asia for various metabolic, age-related diseases. This study investigated the potential use of OS leaf extracts to ameliorate osteoporosis in ovariectomized rats.. Fifty-six female Sprague-Dawley rats were randomly allocated into eight groups (n = 7): SHAM (healthy sham control); OVX (ovarietomized) nontreated rats (negative control); OVX + Remifemin (100 mg/kg body weight), and 2% green tea extract (positive controls); OVX + OS 50% ethanolic and aqueous extracts, both at either 150 or 300 mg/kg. After 16 weeks, the rats' bones and blood were evaluated for osteoporosis indicators (protein and mRNA expressions), micro-computed tomography for bone histomorphometry, and three-point bending test for tibia mechanical strength.. The extracts dose-dependently and significantly (P < 0.05) improved bone strength and flexibility, bone mineral density, bone formation protein markers (P1NP), and bone histomorphometry. All extracts reduced the inflammation biomarker (interleukin-6). The extracts up-regulated osteoblastogenesis (bone morphogenetic protein-2) and collagen-1 synthesis (collagen type 1 alpha-1) mRNA expressions, and down-regulated bone resorption (TNFSF11 and nuclear factor-kappa B) mRNA expressions. Both the water and 50% ethanolic extract were effective. The effective dose is equivalent to 25 to 50 mg/kg extract for humans.. The extract showed bone-protective and antiosteoporotic effects (improving bone strength, flexibility, bone density, and bone morphometry) by reducing inflammation and the bone resorption biomarkers, while enhancing bone formation biomarkers and collagen synthesis.

Topics: Animals; Bone and Bones; Bone Density; Bone Morphogenetic Protein 2; Bone Resorption; Collagen Type I; Collagen Type I, alpha 1 Chain; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gene Expression; Humans; Inflammation; Interleukin-6; NF-kappa B; Orthosiphon; Osteoporosis, Postmenopausal; Osteoprotegerin; Ovariectomy; Peptide Fragments; Plant Extracts; Plant Leaves; Pliability; Procollagen; Random Allocation; RANK Ligand; Rats; Rats, Sprague-Dawley; Teas, Herbal; X-Ray Microtomography

The pathogenic mechanisms of postmenopausal osteoporosis (PMOP) development are complex and are related to multiple cellular signalling transduction pathways. The aim of this study was to compare the effects of electroacupuncture (EA) at GV4/GV6 versus BL20/BL23 on the bones in ovariectomised (OVX) rats to explore the pathways that mediate the effects of EA on bone.. Forty female Sprague-Dawley rats were allocated to one of four groups (n=10 rats each) that received sham surgery (Sham group), OVX surgery only (OVX group), OVX surgery plus EA at GV4/GV6 (GV group) and OVX surgery plus EA at BL20/BL23 (BL group). Bone turnover markers osteocalcin (OC) and tartrate-resistant acid phosphatase 5b (TRACP 5b) were measured in serum, and bone mineral density (BMD) of the lumbar vertebrae and histomorphology of the femur were evaluated. Moreover, the expression of osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) was detected by ELISA. The expression of lipoprotein receptor-related protein (LRP) 5, β-catenin, runt-related transcription factor (Runx) 2 involving Wnt/β-catenin signalling and p38, c-Jun N-terminal kinase (JNK) and extracellular regulated protein kinases 1/2 involving mitogen-activated protein kinase signalling were determined by Western blotting.. The two EA-treated groups demonstrated increased levels of OC and the BMD of lumbar vertebrae, decreased levels of TRACP 5b and improved bone microstructure in the femur, compared with the untreated OVX group (P<0.05). Histomorphology analysis showed that EA treatment significantly increased the values of the trabeculae (µm), trabecular area (%) and trabecular bone number (per mm) and reduced trabecular separation (mm), compared with the OVX group. In addition, the ratio of OPG to RANKL and LRP5, β-catenin and Runx2 expression were significantly upregulated, while the expression of phosphorylated (p)-p38 and p-JNK were downregulated in EA-treated groups compared with the OVX group.. EA attenuates PMOP and it appears that the mechanism involves the regulation of multiple targets and pathways.

Topics: Acupuncture Points; Animals; Bone Density; Core Binding Factor Alpha 1 Subunit; Electroacupuncture; Female; Humans; MAP Kinase Kinase 4; Osteocalcin; Osteoporosis, Postmenopausal; Osteoprotegerin; Ovariectomy; RANK Ligand; Rats; Rats, Sprague-Dawley; Signal Transduction; Tartrate-Resistant Acid Phosphatase

Osteoporosis and periodontal disease are linked by an altered receptor activator of nuclear factor κB ligand and osteoprotegerin ratio (RANKL/OPG), and medical treatment with bisphosphonate (BP) may help control these molecules. The effect of BP on clinical findings and gingival crevicular fluid (GCF) values of RANKL and OPG using enzyme-linked immunosorbent assays was evaluated in postmenopausal women; 13 patients with both chronic periodontitis and osteoporosis (group A), 12 systemically healthy patients with chronic periodontitis (group B), 12 periodontally healthy patients with osteoporosis (group C), and 10 systemically and periodontally healthy individuals (group D). Recordings were repeated at the end of months 1, 6, and 12 in groups A, B, and C. At the baseline, groups A and B exhibited the lowest OPG values (P < 0.05). After periodontal treatment, OPG values were markedly increased at the end of 6th month in group A and 12th month in group B (P < 0.008). There was no significant difference in GCF RANKL values among groups (P > 0.05) or during the observation period (P > 0.008). The use of BP may be effective in preventing periodontal breakdown by controlling the levels of these markers in osteoporosis as an adjunct to periodontal treatment.

Topics: Case-Control Studies; Chronic Periodontitis; Diphosphonates; Enzyme-Linked Immunosorbent Assay; Female; Gingival Crevicular Fluid; Humans; Male; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand

Postmenopausal osteoporosis (PO) has a strong genetic component. Presently, the published evidence on the association between the main single-nucleotide polymorphisms (SNPs) of the receptor activator of nuclear factor-kb ligand (RANKL), osteoprotegerin (OPG) and vitamin D receptor (VDR) and bone mass density (BMD) are scarce, mostly considering Italian population. This study sought to determine whether OPG (rs2073618), RANKL (rs9525641) and the VDR (rs2228570) SNPs were associated with BMD in a sample of 139 North-Italian postmenopausal women. The allelic distribution of rs9525641 in women with PO or osteopenia (OP + OPE group) differed from controls (p < 0.05), suggesting that this allele might confer a greater susceptibility to bone resorption. Concerning rs2228570, CC genotype was associated with OP + OPE women, with a worst total hip BMD. Notably, the combined genotype RANK (CT)-VDR (TT) was significantly associated to spine BMD (p < 0.05). In conclusion, this pilot study showed that rs9525641 and rs2228570 polymorphisms might contribute, separately or in combination, in determining BMD phenotype in selected postmenopausal populations.

Topics: Female; Genetic Predisposition to Disease; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Receptors, Calcitriol

Osteoprotegerin (OPG) is closely related to insulin resistance and bone remodeling. However, no studies have examined the role of OPG in postmenopausal women with coexistent impaired glucose and bone regulation. The present study investigated the relationship of OPG to glucose homeostasis and insulin resistance in postmenopausal osteoporotic women with different types of glucose tolerance.. In all, 114 postmenopausal osteoporotic women were divided into three groups according to glucose tolerance status: 51 with normal glucose tolerance (NGT, group 1), 31 with impaired glucose tolerance (IGT, group 2), and 32 with type 2 diabetes mellitus (DM, group 3). Study participants were evaluated for metabolic parameters, OPG, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), and bone mineral density parameters.. The OPG levels differed significantly across groups and increased from group 1 to group 3 in a continuous fashion (analysis of variance, P < 0.0001). In post-hoc analysis, OPG was significantly lower in osteoporotic women with NGT, than participants with IGT and DM (P < 0.05 and P < 0.0001, respectively). OPG was positively associated with HOMA-IR (P < 0.0001). No association between serum OPG levels and measures of BMD was observed. In a multiple regression analysis, OPG emerged as an independent predictor of HOMA-IR even after controlling for age, body mass index, and creatinine.. OPG is significantly higher in postmenopausal osteoporotic women with impaired glucose regulation (IGT and DM) than women with NGT. OPG was independently associated with insulin resistance assessed by HOMA-IR. Thus, measurement of OPG may potentially be considered as a prediabetic state screening in postmenopausal osteoporotic women.

Topics: Aged; Bone Density; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin Resistance; Osteoporosis, Postmenopausal; Osteoprotegerin

Osteoporosis is one of the most common bone diseases, and radix of Pueraria lobata (Willd.) Ohwi possesses an obvious therapeutical effect on postmenopausal osteoporosis.. This study investigates the anti-osteoporotic activity of the puerarin 6"-O-xyloside (PXY) on ovariectomized mice and its related mechanism.. Osteoporotic mice model was established by ovariectomy (OVX). A total of 50 mice were divided into five groups (n = 10): sham, OVX group, PXY treatment groups (20, 40, and 60 mg/kg/d, i.p.). After 12 weeks' treatment, body weights were recorded. Then, mice were sacrificed, and serum samples were collected to determine the blood calcium, blood phosphorus, alkaline phosphatase (ALP), and osteoprotegerin (OPG) concentrations and uterine index was assayed. The thigh-bones of mice were collected to evaluate histopathological changes. In the in vitro experiment, the effect of PXY on osteoblasts' proliferation was evaluated and western blotting was performed to determine expressions of OPG and the receptor activators of NF-κB ligand (RANKL), as well as the ratio of OPG/RANKL.. PXY (40 and 60 mg/kg/d, i.p.) obviously decreased body weights and increased uterine index of OVX (p < 0.05), and improved osteoporotic syndromes of OVX mice; PXY also significantly increased the concentrations of blood calcium, blood phosphorus, ALP, and OPG of OVX mice (p < 0.05); moreover, PXY obviously up-regulated the ratio of OPG/RANKL (p < 0.05).. Our results demonstrated that the puerarin 6"-O-xyloside possesses significant anti-osteoporotic activity on ovariectomy mice.

Topics: Alkaline Phosphatase; Animals; Biomarkers; Bone and Bones; Bone Density Conservation Agents; Bone Remodeling; Calcium; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Glycosides; Humans; Isoflavones; Mice, Inbred ICR; Osteoblasts; Osteoporosis, Postmenopausal; Osteoprotegerin; Ovariectomy; Phosphorus; RANK Ligand; Time Factors

The aim of the study was to explore the association between OPG, RANKL, and RANK gene variations and the bone mineral density (BMD) response to alendronate therapy in postmenopausal Chinese women with osteoporosis or osteopenia.. In the present study, 40 single-nucleotide polymorphisms (SNPs) in the OPG, RANKL, and RANK genes were genotyped in 501 postmenopausal Chinese women with osteoporosis or osteopenia who were given alendronate (70 mg weekly) orally for 1 year. The BMD at the lumbar spine 1-4 (L1-L4), femoral neck, and total hip was measured.. A total of 442 patients completed 1 year of alendronate therapy. The rs7239261 SNP of the RANK gene was significantly associated with baseline L1-L4 BMD (P=0.0004) after correction for age and BMI. Participants with the SNP A allele (C/A and A/A) had a higher BMD than those with the C/C genotype (C/A vs. C/C, P=0.001; A/A vs. C/C, P=0.025). Haplotypes AG of rs7239261-rs12969154, GG of rs3826619-rs11877530, and CACG of rs1805034-rs8083511-rs17069895-rs7231887 in the RANK gene were genetic protective factors toward a higher baseline L1-L4 BMD. No association was observed between any SNP or haplotype of the OPG, RANKL, and RANK genes and the response of BMD to alendronate therapy.. The RANK gene might contribute to genetic variability in L1-L4 BMD in postmenopausal Chinese women with osteoporosis or osteopenia. No evidence of an association between any SNP or haplotype of the OPG, RANKL, and RANK genes and the response of BMD to alendronate therapy was found in postmenopausal Chinese women with osteoporosis or osteopenia.

Topics: Alendronate; Bone Density; Bone Diseases, Metabolic; China; Female; Femur Neck; Humans; Lumbar Vertebrae; Osteoporosis, Postmenopausal; Osteoprotegerin; Pelvic Bones; Polymorphism, Single Nucleotide; Postmenopause; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Treatment Outcome

In this study, we aimed to explore the association between polymorphisms in the period (PER) gene and bone response to hormone therapy (HT) in postmenopausal Korean women.. The PER1 c.2284C > G, c.2247C > T, PER2 c.3731G > A, PER3 c.2592G > A, c.3083T > C polymorphisms, and PER3 54bp variable number of tandem repeats (VNTR) were analyzed in 509 postmenopausal Korean women who received HT. Bone mineral density (BMD) at the lumbar spine and femoral neck before and after 1 year of HT and serum levels of osteoprotegerin (OPG), soluble receptor activator of the nuclear factor-κB ligand (sRANKL) and bone turnover markers were measured after 6 months of HT.. The PER1 c.2884 C > G polymorphism and PER3 54bp VNTR were associated with annual percent changes in BMD of the femoral neck after 1 year of HT (p < 0.05). Changes in BMD at the femoral neck in the non-CC genotype of the PER1 c.2884C > G polymorphism and in the 4-repeat homozygote of PER3 54bp VNTR were significantly lower than those in CC genotype and non-4-repeat homozygote, respectively. The PER1 c.2884C > G polymorphism was associated with the non-response (>3% BMD loss/year after HT) of HT. The non-CC genotype of the PER1 c.2884C > G polymorphism showed a 1.92-times higher risk of non-response at the lumbar spine and/or femoral neck (p = 0.01) compared with the CC genotype. No significant changes in bone markers after 6 months of HT were noted according to the PER1 c.2884C > G polymorphism.. The PER1 c.2884C > G polymorphism may be associated with risk of non-response to HT in postmenopausal Korean women.

Topics: Bone Density; Estrogen Replacement Therapy; Estrogens, Conjugated (USP); Female; Femur Neck; Genotype; Humans; Lumbar Vertebrae; Medroxyprogesterone; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Period Circadian Proteins; Polymorphism, Genetic; Postmenopause; RANK Ligand; Republic of Korea

Postmenopausal osteoporosis (PO) is a major public health issue which affects a large fraction of elderly women. Emerging in vitro evidence suggests a central role of oxidative stress (OxS) in postmenopausal osteoporosis (PO) development. Contrariwise, the human studies on this topic are still scarce and inconclusive. In the attempt to address this issue, we sought to determine if OxS, as assessed by 8-hydroxy-2-deoxyguanosine (8-OHdG), may influence the level of receptor activator of nuclear factor-κb ligand (RANKL)/osteoprotegerin (OPG) ratio (a central regulator of bone metabolism) in a sample (n = 124), including postmenopausal women with osteoporosis, osteopenia and normal bone mass density (BMD). The most striking result that emerged in our study was the independent and positive (beta = 0.449, p = 0.004, and R(2) = 0.185) association between the OxS marker and RANKL/OPG ratio which was found in osteopenic but not in the other 2 sample groups. If confirmed by longitudinal studies, our findings would suggest that OxS is implicated in the derangement of bone homeostasis which precedes PO development. In line with these considerations, antioxidant treatment of postmenopausal women with moderately low BMD might contribute to preventing PO and related complications.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Bone Density; Deoxyguanosine; Female; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand

This study investigated the effects of combined ovariectomy with dexamethasone treatment on rat lumbar vertebrae in comparison with osteoporosis induced via ovariectomy or dexamethasone alone, and analysis of the associated molecular mechanism.. Sixty-two female Sprague-Dawley rats (3 months' old) were randomly divided into five treatment groups: an untreated baseline (BL) group; those receiving a sham operation (SHAM); those receiving a dexamethasone injection alone (DEXA); those undergoing bilateral ovariectomy (OVX); and those subjected to both ovariectomy and dexamethasone injection (OVX-DEXA). Animals in the BL group were euthanized at the beginning of the experiment, whereas animals in the remaining groups were euthanized at the end of the first month (M1), second month (M2), or third month (M3). Bone mineral density, bone microarchitecture, biomechanical properties of vertebrae, and serum levels of estrogen, amino-terminal propeptide of type I collagen (PINP), and β-C-telopeptide of type I collagen (β-CTX) were measured. In addition, we examined biglycan, runt-related transcription factor 2 (RUNX2), osteoprotegerin (OPG), lipoprotein receptor-related protein-5 (LRP-5), cathepsin K (CTSK), and sclerostin mRNA expression.. Bone mineral content and bone mineral density were markedly lower in the OVX-DEXA group compared with the OVX group at all time points examined. The relative bone surface (BS/TV, mm(-1), relative bone volume (BV/TV,%), and trabecular number (Tb.N, 1/mm) were markedly lower in the OVX-DEXA group compared with the remaining groups, whereas trabecular separation (Tb.Sp, mm) was markedly higher in the OVX-DEXA group compared with the remaining groups at M2 or M3. The OVX-DEXA group showed lower compressive strength and lower stiffness compared with the other groups at M2 and M3. Compressive displacement and energy absorption capacity were also markedly lower in the OVX-DEXA group compared with the OVX group at M3. Estradiol levels were markedly lower in the OVX-DEXA group compared with the other groups. Biglycan, runt-related transcription factor 2, osteoprotegerin, and lipoprotein receptor-related protein-5 were down-regulated in the DEXA, OVX, and OVX-DEXA groups compared with the BL and SHAM groups, whereas cathepsin K and sclerostin were up-regulated in the OVX-DEXA group compared with the DEXA and OVX groups.. Ovariectomy combined with dexamethasone induced more serious osteoporosis in the rat lumbar spine than either ovariectomy or dexamethasone alone. The combined effect may be due to a combination of suppressed bone formation and increased bone resorption related to an estradiol deficit.

Topics: Animals; Biglycan; Biomarkers; Biomechanical Phenomena; Bone Density; Bone Morphogenetic Proteins; Cathepsin K; Core Binding Factor Alpha 1 Subunit; Dexamethasone; Estradiol; Female; Genetic Markers; Glucocorticoids; Humans; Low Density Lipoprotein Receptor-Related Protein-5; Lumbar Vertebrae; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Osteoprotegerin; Ovariectomy; Rats; Rats, Sprague-Dawley; RNA, Messenger

The study aimed to investigate cellular expression of IL-17 by CD4+ T-cells in osteoporotic postmenopausal women.. We enrolled 25 postmenopausal women with osteoporosis (PostMO) and 25 postmenopausal women with normal bone mineral density measurements (PostM) to examine the production of IL-17, tumor necrosis factor α (TNFα) and receptor activator of nuclear factor x03BA;-B ligand (RANKL) by CD4+ T-cells and IL-17, RORx03B3;t, TNFα and RANKL mRNA levels in CD4+ T-cells. Circulating concentrations of IL-17 along with IL-6, TNFα, RANKL and osteoprotegerin (OPG) were also determined.. Osteoporotic postmenopausal women had higher serum concentrations of IL-17 (3.7 ± 1.3 vs. 2.5 ± 1.1 ng/ml, p = 0.042), IL-6 (158 ± 56 vs. 105 ± 39 pg/ml, p = 0.044), TNFα (138 ± 41 vs. 74 ± 11 pg/ml, p < 0.001) and OPG (1.7 ± 0.4 vs. 1.3 ± 0.4 ng/ml, p = 0.039) than healthy controls. The IL-17-producing CD4+ T-cells were higher in the PostMO group than in the PostM group (7.1 ± 2.4 vs. 4.9 ± 1.4%, p = 0.0015). Additionally, osteoporotic postmenopausal women had greater mRNA levels of IL-17 (3.5 ± 2.9 vs. 1.2 ± 1.0%, p = 0.019) and RORx03B3;t (5.7 ± 2.5 vs. 2.2 ± 1.0%, p < 0.001) in CD4+ T-cells than in healthy controls.. Our findings implied that the upregulated production of IL-17 may play an important role in regulating bone loss in osteoporotic postmenopausal women.

Topics: Aged; Asian People; Bone Density; CD4-Positive T-Lymphocytes; Cytokines; Female; Humans; Interleukin-17; Middle Aged; Nuclear Receptor Subfamily 1, Group F, Member 3; Osteoporosis, Postmenopausal; Osteoprotegerin; Postmenopause; RANK Ligand; Tumor Necrosis Factor-alpha; Up-Regulation

The aim of this study was to evaluate quantitative changes in OPG and RANKL proteins after treatment with strontium ranelate (SR) and ibandronate in patients with postmenopausal osteoporosis.. A total of 89 women with postmenopausal osteoporosis (PO), aged 51-85 years, patients of the Outpatient Clinic of Osteoporosis of the Military Teaching Hospital in Lodz, were enrolled in the study. The patients were randomly assigned to different therapies: ibandronate and (SR). Patients of the control group received only calcium and vitamin D3 supplements. The patients' visits were repeated after three and six months. Measurements of beta-CTX (C-terminal Telopeptide of type 1 collagen), osteocalcin, RANKL, osteoprotegerin (OPG), alkaline phosphatase concentrations in serum, as well as of total 24-hour calcium and phosphate levels in serum and urine, were carried out in material collected at baseline and after three and six months of therapy. Left hip and lumbar spine densitometry was done twice (at baseline visit and after six months).. In all three groups there were no significant differences noted in the concentrations of OPG and RANKL serum protein levels during the study period. Both negative and positive correlations or tendencies of correlations were found between OPG serum concentrations and BMD changes in the SR group.. Both ibandronate and SR do not seem to cause any significant changes in OPG and RANKL protein serum levels during the first six months of treatment. OPG may play a role in osteoclast activity suppression in the course of treatment with ibandronate in patients with PO. OPG may play an important role in the mechanism of SR therapy and may be viewed as a potentially valuable parameter for monitoring and predicting the course of treatment with SR in PO.

Topics: Aged; Aged, 80 and over; Alkaline Phosphatase; Bone Remodeling; Diphosphonates; Drug Therapy, Combination; Female; Humans; Ibandronic Acid; Middle Aged; Osteocalcin; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Thiophenes

Periapical bone loss is one of the prominent pathological and clinical features of periapical periodontitis. Previous studies have demonstrated that follicle‑stimulating hormone (FSH) could directly affect skeletal remodelling by stimulating the formation and the function of osteoclasts in vitro and in vivo. However, the effect of FSH on periapical bone loss remained to be fully elucidated. In the current study, a rat model was established in order to verify the effect of FSH in experimental periapical lesions. It was identified that FSH aggravated the bone loss of periapical lesions. In addition, RANKL‑, TRAP‑, TNF‑α‑ and IL‑1β‑positive cells were increased significantly in FSH‑treated groups, which indicated that the function of FSH in bone loss may be mediated through the increasing activity of osteoclasts and the increased secretion of inflammatory cytokines. The results of the current study suggested that FSH, independent of oestrogen, may aggravate periapical bone loss by FSH receptors, which may serve an important role in the immune and inflammatory response of the host to root canal and periradicular infection during menopause.

Topics: Animals; Female; Follicle Stimulating Hormone; Humans; Interleukin-1beta; Osteoclasts; Osteoporosis, Postmenopausal; Osteoprotegerin; Ovariectomy; Periapical Periodontitis; Periapical Tissue; RANK Ligand; Rats; Rats, Sprague-Dawley; Receptors, FSH; Tumor Necrosis Factor-alpha

Osteoprotegerin (OPG) and receptor activator of nuclear factor-kappa B ligand (RANKL) have been revealed in the pathogenesis of primary osteoporosis and other metabolic bone diseases. This study was designed to assess the effect of 17-β estradiol (E2) treatment and angiotensin converting enzyme inhibitor (ACEI), captopril, on osteoporosis induced by ovariectomy in rats and discussing the role of OPG/RANKL ratio in their action. Thirty two adult female rats were divided into four equal groups. Group I: control group, Group II: ovariectomized (OVX) non treated group, Group III: OVX rats treated with E2, Group IV: OVX rats treated with captopril. OVX rats showed a significant decrease in serum Ca2+ and OPG levels with significant increase in serum RANKL, osteocalcin, alkaline phosphatase activity and urinary hydroxyproline levels. Treatment with captopril as well as E2 led to a significant improvement in bone markers levels with a significant increase in OPG/RANKL ratio. Image analysis technique revealed that there was a significant improvement in cortical bone thickness (CBT) and mean trabecular bone density (TBD) in OVX rats treated with either E2 or ACEI. So, we can conclude that the protective effect of E2 and ACEI on osteoporosis may be mediated by influencing OPG/RANKL signaling.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Calcification, Physiologic; Captopril; Estradiol; Estrogens; Female; Femur; Humans; Osteoporosis, Postmenopausal; Osteoprotegerin; Ovariectomy; RANK Ligand; Rats; Treatment Outcome

Association between 22 single nucleotide polymorphisms (SNPs) in the TNFSF11, TNFRSF11A, and TNFRSF11B genes in the RANKL/RANK/OPG pathway with bone mineral density (BMD) in 881 post-menopausal women. Our results suggest that TNFSF11 and TNFRSF11A, but not TNFRSF11B, genetic polymorphisms influence BMD mainly in the femoral neck in post-menopausal Chinese women.. The aim of this study was to assess the relationship of polymorphisms in the TNFSF11, TNFRSF11A, and TNFRSF11B genes in the RANKL/RANK/OPG pathway with bone mineral density (BMD) in a cohort of Chinese post-menopausal women.. A cross-sectional study was conducted in 881 post-menopausal women aged 50-89 years. All participants underwent lumbar spinal (LS) and femoral neck (FN) BMD evaluation by dual-energy X-ray absorptiometry. Twenty-two TNFSF11, TNFRSF11A, and TNFRSF11B SNPs were genotyped. We tested whether a single SNP or a haplotype was associated with BMD variations.. Two SNPs in the TNFSF11 gene (rs2277439 and rs2324851) and one in the TNFRSF11A gene (rs7239261) were found to be significantly associated with FN BMD (p = 0.014, 0.013, and 0.047, respectively). Haplotype TGACGT of TNFSF11 rs9525641-rs2277439-rs2324851-rs2875459-rs2200287-rs9533166 was a genetic risk factor toward a lower FN BMD (beta = -0.1473; p = 0.01126). In contrary, haplotype TAGCGT of TNFSF11 rs9525641-rs2277439-rs2324851-rs2875459-rs2200287-rs9533166 was genetic protective factor for LS BMD (beta = 0.3923; p = 0.04917).. Our findings suggest that TNFSF11 and TNFRSF11A, but not TNFRSF11B, genetic polymorphisms influence BMD mainly in the femoral neck in post-menopausal Chinese women. This contributes to the understanding of the role of genetic variation in this pathway in determining bone health.

Topics: Absorptiometry, Photon; Aged; Aged, 80 and over; Bone Density; Cross-Sectional Studies; Female; Femur Neck; Genetic Predisposition to Disease; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Single Nucleotide; Postmenopause; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction

Osteoporosis is a common disease that is characterized by low bone mineral density (BMD), deterioration in bone microarchitecture, and increased fracture risk. Due to its important role in bone biology, the TNFRSF11B gene, coding for OPG, has been considered as a candidate gene for osteoporosis. In this study, single nucleotide polymorphisms (SNPs) A163G, T245G, and G1181C (rs3102735, rs3134069, and rs2073618, respectively) within the TNFRSF11B gene were studied for association with BMD and fracture incidence in a cohort of 327 postmenopausal Slovak women. Genomic DNA was extracted and purified from peripheral blood leukocytes by the commercial kit JetQuick (Genomed GmbH, Germany) using a standard protocol. Genotyping was performed using the Custom TaqMan® SNP Genotyping Assays. The lumbar L1-L4 spine BMD (g/cm(2)) and T-score in the subgroup of Slovak postmenopausal women with osteoporotic fractures were significantly lower than those in the subgroup of women without fracture (p = 0.0025; p = 0.0009). We identified the T245G (rs3134069) polymorphism in the TNFRSF11B gene associated with osteoporotic fractures (vertebral fractures: p = 0.0320; non-vertebral fractures: p = 0.0005; all fractures: 0.0000). The polymorphism T245G (rs3134069) in the TNFRSF11B gene could be used together with other genetic markers to identify individuals at high risk of osteoporotic fractures. The results from the present study provided more evidence to reveal the role of TNFRSF11B gene polymorphisms in BMD and the risk of osteoporotic fractures.

Topics: Adult; Aged; Aged, 80 and over; Bone Density; Fractures, Bone; Gene Frequency; Genetic Association Studies; Genotype; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Single Nucleotide; Postmenopause; Slovakia

The aim of the study was to evaluate the frequency of gene polymorphisms OPG -163A/G, -950T/C and 1181G/C, assessing their relations with the clinical parameters of osseous turnover and the degree of postmenopausal osteoporosis.. The study included 800 women of postmenopausal (505) and reproductive (295) age from Poland. The postmenopausal group included women with osteoporosis and osteopenia, as well as healthy individuals. All the women of reproductive age were healthy. The frequency of the tested gene polymorphisms was evaluated within the group where BMD (bone mineral density) was marked and also in the control group.. The frequencies of the polymorphisms of OPG genotypes in the women were characteristic of the population.. OPG -950T/C polymorphism has been associated with body weight and birth weight. OPG 1181G/C and OPG -163A/G polymorphisms have been associated not only with body weight and birth weight, but also with reduced bone density and an increased risk of postmenopausal osteoporosis.. Evaluation of the polymorphism -950T/C of the OPG gene showed that the CC genotype may appear as an increased risk factor for the faster loss of bone mass and the onset of osteoporosis in Polish postmenopausal women. This polymorphism may be a genetic marker that is responsible for the development of osteoporosis. The homozygous genotypes of polymorphisms 1181G/C and -163A/G of the OPG gene may play a role in increased risks of osteoporosis and may be linked to the birth weights of women.

Topics: Adult; Bone Density; Female; Genetic Predisposition to Disease; Genotype; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Genetic; Postmenopause; Premenopause

To determine the serum level of cytokines in women with coronary heart disease (CHD) concurrent with osteoporosis (OP) and in those with isolated CHD; to assess a relationship of the levels of cytokines, osteoprotegerin (OPG), and transforming growth factor-β (TGF-β) to the ten-year absolute risk of osteoporotic fractures, the presence of fractures in the history, and that of CHD; and to establish the role of elevated cytokine levels in the development of future fractures.. A cross-sectional cohort study included 98 women (mean age, 71.2?8.6 years) with CHD. Forty-eight patients had CHD concurrent with severe OP. The Fracture Risk Assessment Tool (FRAX) was applied to estimate a ten-year absolute risk for fractures in all the patients. The serum levels of OPG, TGF-β, interleukin (IL)-1β, IL-4, IL-6, IL-8, and IL-10, and tumor necrosis factor-a (TNF-α) were measured by enzyme immunoassay.. The women with comorbidity were found to have higher levels of OPG, TGF-β, IL-6, IL-8, IL-10, and TNF-α than those with isolated CHID. There was a direct correlation between fractures, CHID, and IL-10 and TNF-α levels and an inverse relationship between fractures, CHD, and IL-8; between CHD and OPG levels. Conclusion. The women with comorbidity were noted to have elevated levels of proinflammatory cytokines and OPG; a correlation was between cytokine levels and fractures and CHD. Increased OPG and IL-6 levels are independent predictors of fractures.. Цель исследования. Определить содержание цитокинов в сыворотке крови у женщин с сочетанием ишемической болезни сердца (ИБС) и остеопороза (ОП) и женщин с изолированной ИБС; оценить взаимосвязь уровней цитокинов, остеопротегерина (OPG), трансформирующего β-фактора роста (ТФР-β), с показателем абсолютного 10-летнего риска остеопоротических переломов, наличием переломов в анамнезе, наличием ИБС; установить роль повышенных уровней цитокинов в развитии будущих переломов. Материалы и методы. В одномоментном когортном исследовании приняли участие 98 женщин ИБС, средний возраст 71,2±8,6 года. У 48 пациенток имелось сочетание ИБС и тяжелого ОП. Всем пациенткам оценивали абсолютный 10-летний риск переломов по FRAX, определяли уровень OPG, ТФР-β, интерлейкинов-1β, 4, 6, 8, 10, α-фактора некроза опухоли (α-ФНО) в сыворотке крови методом иммуноферментного анализа. Результаты. Выявлено, что у женщин, имеющих сочетанную патологию, уровень OPG, ТФР-β, ИЛ-6, ИЛ-8, ИЛ-10 и α-ФНО, выше чем у женщин с изолированной ИБС. Установлена прямая корреляция между наличием переломов, ИБС и уровнем ИЛ-10 и α-ФНО, а также обратная связь между наличием переломов, ИБС и ИЛ-8; наличием ИБС и уровнем OPG. Заключение. У женщин с сочетанной патологией отмечено повышение уровня провоспалительных цитокинов и OPG, установлена корреляция между уровнем некоторых цитокинов и наличием переломов и ИБС. Повышение уровней OPG и ИЛ-6 являются независимыми предикторами переломов.

Topics: Aged; Bone Density; Cohort Studies; Coronary Disease; Female; Humans; Interleukins; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Russia; Severity of Illness Index; Statistics as Topic; Transforming Growth Factors; Tumor Necrosis Factor-alpha

The Receptor activator of nuclear factor-kappa B ligand (RANKL)/RANK/Osteoprotegerine (OPG) system has been proposed as essential for osteoclast biology and identified as key part in regulating the physiology and pathology of the skeletal system. The study of the RANKL/RANK/OPG system has increased the understanding of the mechanisms involved in the bone remodeling process, especially in postmenopausal osteoporosis and periodontal disease. Bisphosphonates have become the mainstay of the treatment and prevention of post-menopausal osteoporosis. They inhibit the formation and dissolution of calcium phosphate crystals in bone and also osteoclasts, thus reducing bone turnover.Current investigations relate osteoporosis with the appearance and progression of periodontal disease. Although the etiology of both is different, the bone loss present in both shares several characteristics. Thus, therapy used for osteoporosis can be considered of value in the treatment of periodontal disease. The aim of this study was to evaluate the levels of RANKL, OPG and their relationship in gingival crevicular fluid (GCF) in patients with periodontal disease and postmenopausal osteoporosis/ osteopenia in relation to consumption of bisphosphonates. We studied 66 periodontal active sites obtained from 17 post- menopausal women patients aged between 45-70 years old with osteoporosis/osteopenia and periodontal disease. GCF samples were collected using sterile filter paper strips. To determine the concentration of RANKL and OPG, a commercial ELISA assay was used. The values of RANKL, OPG and their ratio (RANKL/ OPG) were compared with Mann-Whitney U Test. The values of RANKL, OPG and their ratio obtained in patients with osteoporosis/osteopenia and periodontal disease with or without bisphosphonates treatment showed no differences. Bisphosphonates do not alter the concentration of RANKL and OPG and their ratio in the GCF of patients with osteoporosis/ osteopenia and periodontal disease, probably because these cytokines may not be the main target of bisphosphonates to inhibit bone resorption in periodontal disease.. El sistema: Receptor activador del factor nuclear kappa-B ligando (RANKL)/RANK/Osteoprotegerina (OPG) ha sido propuestos como esencial para la biología osteoclástica, ya que ha sido identificado como participante clave en la regulación fisiológica y patológica del sistema óseo. El estudio del sistema RANKL-RANK-OPG ha facilitado la comprensión de los mecanismos intervinientes en el proceso de remodela- ción ósea, especialmente en la osteoporosis post-menopáusica y la enfermedad periodontal. Los bisfosfonatos se han convertido en el pilar principal del tratamiento y prevención de la osteoporosis post-menopáusica. Ellos inhiben la formación y disolución de los cristales de fosfato de calcio en el hueso y también inhiben a los osteoclastos reduciendo el recambio óseo. Actualmente, varios trabajos de investigación asocian la osteoporosis con el inicio y la progresión de la enfermedad periodontal. Aunque la etiología de ambas es diferente, la pérdida de masa ósea comparte varias características y la terapéutica utilizada para la osteoporosis puede ser considera de valor para el tratamiento de la enfermedad periodontal. El objetivo de este estudio fue evaluar el efecto del consumo de bifosfonatos en fluido crevicular (FC) sobre los niveles de RANKL, OPG y la relación RANKL/OPG en pacientes post-menopáusicas con enfermedad periodontal y osteoporosis/ osteopenia. Se estudiaron 66 sitios periodontalmente activos obtenidos de pacientes mujeres post-menopáusicas con edades entre 45-70 años de edad con enfermedad periodontal y osteoporosis/ osteopenia. La toma del FC se realizó mediante tiras de papel de filtro estériles. Para determinar la concentración de RANKL y OPG se utilizó el ensayo de ELISA comercial siguiendo las instrucciones del fabricante. Los valores obtenidos de las citoquinas y su relación fueron comparados con el Test U de Mann-Whitney. No se observaron diferencias en las concentraciones de RANKL y OPG encontradas, ni en su relación, en pacientes con enfermedad periodontal y osteoporosis/osteopenia con y sin tratamiento de bifosfonatos. Esto sugiere que probablemente estas citoquinas no serian el blanco principal de los bifosfonatos para inhibir la resorción ósea en la enfermedad periodontal.

Topics: Diphosphonates; Female; Gingival Crevicular Fluid; Humans; Osteoporosis, Postmenopausal; Osteoprotegerin; Periodontal Diseases

Resveratrol (Res), a polyphenol that is abundant in many medicinal plants and is a selective oestrogen receptor modulator, exhibits multiple biological activities. In the present study, we determined whether Res prevents oestrogen deficiency-induced osteopenia and whether Res administration decreases pathological changes in the endometrium and lumen of the uterus compared with oestradiol replacement therapy (ERT). A total of sixty 3-4-month-old female Wistar rats were randomly divided into a sham-operated group (Sham) and five ovariectomy (OVX) subgroups, i.e. OVX rats as a control group (OVX); OVX rats receiving oestradiol valerate (ERT, 0·8 mg/kg); and OVX rats receiving Res 20, 40 and 80 mg/kg. Daily oral administration was initiated at week 2 after OVX for 12 weeks. A dose-response difference was observed in the effects of Res on bone mineral density (BMD) and trabecular microarchitecture. Only at the highest dose, bone loss was almost equivalent to that observed in the ERT group. The dose-response effects of Res on the biochemical parameters (alkaline phosphatase, IL-6, TNF-α and transforming growth factor-β1 concentrations in the serum as well as urinary Ca and P excretion) and the expressions of receptor activator of nuclear factor κB ligand (RANKL) and the RANKL:osteoprotegerin protein ratio in the femur were also observed. Furthermore, the thickening of the endometrium and the infiltration of lymphocytes were prevented in all the three Res-treated groups compared with the ERT group. In conclusion, Res treatment not only improves BMD and trabecular microarchitecture but also does not affect the uterus and Res might be a potential remedy for the treatment of postmenopausal osteoporosis.

Topics: Animals; Antioxidants; Biomarkers; Bone Density; Bone Density Conservation Agents; Dietary Supplements; Disease Models, Animal; Endometrial Hyperplasia; Endometrium; Estrogen Replacement Therapy; Female; Femur; Humans; Osteoporosis, Postmenopausal; Osteoprotegerin; Phytoestrogens; Random Allocation; RANK Ligand; Rats; Rats, Wistar; Resveratrol; Stilbenes; Time Factors

Postmenopausal osteoporosis is one of the most common disorders in women after menopause, which is linked to an estrogen deficiency and characterized by an excessive loss of trabecular bone. Rubus coreanus and Astragalus membranaceus have been used for their various pharmacological properties in Asia as a traditional medicine. The present study evaluated the anti-osteoporotic effects of the optimal combination of Rubus coreanus and Astragalus membranaceus in 7:3 mixture (RAM) in ovariectomized (OVX) mice by investigating bone biomechanical properties and the serum levels of TNF-α, osteocalcin, RANKL, OPG, and RANK-RANKL signal-related osteoclast differentiation markers.. A total of 36 mature female outbred ICR (Institute of cancer research) strain mice (7 weeks) were divided into 6 groups with 7 mice in each group as follows: (1) Sham-operated control mice (Sham) received daily oral phosphate-buffered-saline (PBS) of equal volumes through gavage. (2) OVX mice received a daily oral gavage of PBS (OVX). (3) OVX mice were treated daily with 50mg/kgb.w./day of RAM (4) with 100mg/kgb.w./day of RAM or (5) with 200mg/kgb.w./day of RAM via oral gavage. (6) OVX mice received i.p. injections of 17β-estradiol (E2) (0.1mg/kgb.w./day) three times per week for 12 weeks.. Micro-CT images showed that oral administration of RAM to OVX mice prevented tibial bone loss, preserved trabecular bone microarchitecture, and improved bone biomechanical properties. RAM administration also showed recovery effects on the levels of TNF-α, OPG and RANKL concentration in OVX-states. Additionally, we found that the mechanism by which RAM elicited anti-osteoporotic effects was by down-regulating the expression of TRAF6 and NFATc1 in RANKL-RANK pathway, a route of osteoclast differentiation, followed by reducing the production of osteoclast differentiation factors, calcitonin receptors and cathepsin K.. Our research strongly suggests that RAM can be clinically used in the prevention and treatment of postmenopausal osteoporosis.

Topics: Animals; Astragalus propinquus; Cathepsin K; Drug Therapy, Combination; Female; Fruit; Humans; Mice; Mice, Inbred ICR; NFATC Transcription Factors; Osteocalcin; Osteoporosis, Postmenopausal; Osteoprotegerin; Ovariectomy; Phytotherapy; Plant Extracts; Plant Roots; Radiography; RANK Ligand; Receptors, Calcitonin; Rosaceae; Tibia; TNF Receptor-Associated Factor 6; Tumor Necrosis Factor-alpha

The role of proinflammatory IL-17 cytokine was studied in postmenopausal bone loss between 31 osteopenic and 41 osteoporotic women. The effect of serum IL-17A, soluble receptor activator of NF-κB (sRANK) ligand, and osteoprotegerin (OPG) levels on lumbar bone mineral densities was measured. The results demonstrated an increased IL-17A-mediated sRANK ligand elevation in postmenopausal osteoporotic bone loss.. IL-17 proinflammatory cytokine is a new inducer of bone loss. Postmenopausal osteoporosis represents a cross talk between estrogen deprivation and increased immune reactivity. The role of IL-17 was studied in the bone loss of postmenopausal osteoporosis.. Serum IL-17A, sRANK ligand, and OPG levels were investigated on bone mineral densities (BMDs) in the total lumbar (L1-L4) region in 18 pre- and 72 postmenopausal women. IL-17A, sRANK ligand, OPG levels, and BMDs were measured with enzyme-linked immunosorbent assay (ELISA) and dual-energy X-ray absorptiometry (DXA).. Increased serum IL-17A, sRANK ligand, and OPG levels were demonstrated in postmenopausal osteoporotic women compared to osteopenic women (3.65 ± 0.61 vs 3.31 ± 0.43 ng/ml for IL-17A, P < 0.007; 2.88 ± 0.84 vs 2.49 ± 0.61 ng/ml for sRANK ligand, P < 0.027; and 1.43 ± 0.07 vs 1.39 ± 0.07 ng/ml for OPG, P < 0.038). In postmenopausal women, IL-17A levels correlated inversely with total lumbar BMDs (P < 0.008, r = -0.279) and positively with sRANK ligand levels (P < 0.0001, r = 0.387) or the ratio of sRANK ligand and OPG (P < 0.013, r = 0.261), but did not with OPG levels alone.. Increased IL-17A levels are involved in postmenopausal osteoporosis, playing a role in the bone-resorpting processes.

Topics: Aged; Aged, 80 and over; Bone Density; Bone Diseases, Metabolic; Female; Humans; Interleukin-17; Lumbar Vertebrae; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Premenopause; RANK Ligand

Gene candidate and genome-wide association studies have revealed tens of loci of susceptibility for osteoporosis. Some limitations such as sample size, use of confounding variables, and control for multiple testing and for population stratification, however, represent common problems in these studies that make replication in independent cohorts desirable and even necessary. The main objective of the present study is to replicate previous data on three functional polymorphisms in a cohort of Spanish women. To that end, we performed an association study of three functional polymorphisms previously associated with bone phenotypes in the LRP5, TNFRSF11B, and FGFBP1 genes with low bone mineral density (BMD) in a cohort of 721 Spanish women, most of them postmenopausal. We detected a strong significant association, even when correcting for multiple comparisons, for polymorphism rs312009 in the LRP5 gene with low BMD at the lumbar-spine site. These were women with the CC genotype, which showed the worst bone parameters. Moreover, these women had a higher risk of osteoporosis (adjusted odds ratio 2.82, P = 0.001) than women with the TT/TC genotype. This association seems to be caused because the rs312009 single nucleotide polymorphism (SNP) is located at a binding site for the transcription factor RUNX2 at the 5' region of the LRP5 gene, and the T allele seems to be a better transcriber than the C allele. Regarding the other two SNPs, only the rs4876869 SNP in the TNFRSF11B gene showed a suggestive trend for both skeletal sites. These results underscore the significance of the LRP5 gene in bone metabolism and emphasize the significance of the replication of previous results in independent cohorts.

Topics: Alleles; Bone Density; Carrier Proteins; Female; Genotype; Humans; Intercellular Signaling Peptides and Proteins; Low Density Lipoprotein Receptor-Related Protein-5; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Single Nucleotide; Spain

Osteoporosis is a common multifactorial disease in postmenopausal women. This study aimed to investigate the association of the g.27563G>A osteoprotegerin (OPG) genetic polymorphism with bone mineral density (BMD) and osteoporosis. A case-control study was carried out with 435 osteoporosis postmenopausal women cases and 442 age-matched healthy controls. The BMD at the femoral neck hip, lumbar spine (L₂₋₄), and total hip were assessed by Norland XR-46 dual-energy X-ray absorptiometry. The genotypes of the g.27563G>A genetic polymorphism were detected by created restriction site-polymerase chain reaction and verified by DNA sequencing methods. We detected that the g.27563G>A genetic polymorphism was a non-synonymous mutation that resulted in an arginine (Arg) to glutamine (Gln) amino acid replacement (p.Arg333Gln). Significant differences were found in the BMD of the femoral neck hip, lumbar spine (L₂₋₄), and total hip among different genotypes of the g.27563G>A genetic polymorphism. Subjects with the genotype GG had significantly higher BMD values than those with genotypes GA and AA (P < 0.05). Our data indicated that the A allele of the g.27563G>A genetic polymorphism in OPG could be associated with lower BMD values in the Chinese postmenopausal women evaluated, and that it might be an increased risk factor for osteoporosis.

Topics: Aged; Alleles; Asian People; Bone Density; Case-Control Studies; China; Female; Femur Neck; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Single Nucleotide

In the present study, we aimed to investigate the association between genetic polymorphisms in period (PER) genes and bone mineral density (BMD) in postmenopausal Korean women.. The PER1 c.2247C> T and c.2884C> G polymorphisms; the PER2 c.661G> A and c.3731G> A polymorphisms; the PER3 c.2592G> A, c.3029C> T, c.3035C> T, and c.3083T> C polymorphisms, and the 54 bp variable number tandem repeats polymorphism were analyzed in 551 postmenopausal Korean women. Serum leptin, soluble leptin receptor, osteoprotegerin, soluble receptor activator of the nuclear factor-κB ligand, and bone markers including bone alkaline phosphatase and carboxy-terminal telopeptide of type I collagen were measured, and the lumbar spine and femoral neck BMDs were also determined.. The PER2 c.661G> A, PER3 c.3029C> T and c.3035C> T polymorphisms were not observed. The PER2 and PER3 polymorphisms evaluated were not related to BMD, whereas associations of the c.2247C> T and c.2884C> G polymorphisms in PER1 with the lumbar spine BMD were observed both singly and in combination. The CC haplotype homozygotes showed significantly lower lumbar spine BMD than participants with other genotypes. Additionally, 2.01-fold higher odds for osteoporosis of the lumbar spine were found in the CC haplotype homozygotes compared to women not carrying the haplotype CC allele. No significant differences in bone markers were detected according to the PER1 haplotype genotype.. Our results suggest that both the PER1 c.2247C> T and c.2884C> G polymorphisms may be genetic factors affecting the lumbar spine BMD in postmenopausal Korean women.

Topics: Aged; Alkaline Phosphatase; Asian People; Bone Density; Collagen Type I; Female; Femur Neck; Genotype; Haplotypes; Humans; Leptin; Lumbar Vertebrae; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Peptides; Period Circadian Proteins; Polymorphism, Genetic; Postmenopause; Receptors, Leptin

The objective of this study is to evaluate the relationship between the g.27450A>T genetic variant of osteoprotegerin (OPG) gene and osteoporosis in Chinese postmenopausal women. A total of 886 subjects were enrolled in this study. The femoral neck hip, lumbar spine (L2-4), and total hip bone mineral density (BMD) were detected by dual-energy X-ray absorptiometry (DEXA). The genotyping of the g.27450A>T genetic variant of OPG gene was investigated by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing methods. Significant differences in the femoral neck hip, lumbar spine (L2-4), and total hip BMD among different genotypes were found, and the subjects with AA genotype were significantly higher than those of AT and TT genotypes (P<0.05). The allele-A could be a decreased risk factor for osteoporosis. Results from this study support that the g.27450A>T genetic variant of OPG gene has potential relationship with BMD and osteoporosis in Chinese postmenopausal women.

Topics: Alleles; Asian People; Bone Density; Female; Femur Neck; Gene Frequency; Genetic Predisposition to Disease; Genotype; Hip; Humans; Lumbar Vertebrae; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Restriction Fragment Length

To investigate diet and nutrition-related factors associated with bone loss in a group of postmenopausal (PM) women. Nutritional intake, inflammatory markers and body composition (weight, body mass index, fat/lean mass) were analysed for associations with bone mineral density (BMD).. A cross sectional study examining correlations between BMD (Duel-energy X ray absorptiometry; (DXA) and dietary intake (3-day diaries), body composition and plasma bone and inflammatory markers: C-terminal telopeptide of type I collagen (CTX) and procollagen type I N propeptide (P1NP), C- reactive protein (CRP), interleukin 6 and 10 (IL-6, IL-10), tumour necrosis factor (TNF) and osteoprotegerin (OPG).. Community dwelling women from the Auckland, Hawke's Bay and Manawatu regions in New Zealand.. 142 healthy, PM women aged 50-70 years.. OPG (per kilogram fat mass) was increased in women with osteoporosis (p<0.001) compared to groups classified with normal BMD and osteopenia. Protein, vitamin B12, zinc, potassium and dairy intake were all positively correlated with higher BMD while dairy and potassium intakes also inversely correlated with CTX. Body composition (weight, BMI and fat/lean mass) had strong positive associations with BMD. Multiple regression analysis showed body weight, potassium and dairy intake were predictors of increased BMD in PM women and explained 39% (r2=0.39, p< 0.003) of variance.. BMD was negatively correlated with OPG and positively with weight, dairy and potassium intake. This study highlights the importance of maintaining adequate body weight and emphasising dairy and potassium predominantly sourced from fruit/vegetables to reduce bone loss at midlife.

Topics: Absorptiometry, Photon; Aged; Body Composition; Body Mass Index; Body Weight; Bone Density; Bone Diseases, Metabolic; C-Reactive Protein; Collagen Type I; Cross-Sectional Studies; Cytokines; Dairy Products; Diet; Dietary Proteins; Female; Health; Humans; Inflammation; Interleukin-10; Interleukin-6; Middle Aged; New Zealand; Osteoporosis, Postmenopausal; Osteoprotegerin; Peptide Fragments; Peptides; Postmenopause; Potassium; Procollagen; Tumor Necrosis Factor-alpha; Vitamin B 12; Zinc

Previous studies suggest that the osteoprotegerin gene (OPG) plays an important role in the development of osteoporosis. This study aims to investigate the potential association between OPG genetic polymorphisms and bone mineral density (BMD) and osteoporosis in postmenopausal women. 938 Chinese postmenopausal women were enrolled. The lumbar spine (L(2-4)) BMD, neck BMD, and total hip BMD were measured by dual energy X-ray absorptiometry (DEXA). The genotypes of OPG genetic polymorphisms were evaluated by the created restriction site-polymerase chain reaction (CRS-PCR), PCR-restriction fragment length polymorphism (PCR-RFLP), and DNA sequencing methods. Our data indicated that subjects with genotype TT of the g.26395T>C genetic polymorphism showed a significantly higher adjusted value of BMD when compared with those of genotypes TC and CC. Subjects with genotype AA of the g.27649A>G genetic polymorphism showed a significantly higher adjusted value of BMD than those of genotypes AG and GG. These findings suggest that the OPG genetic polymorphisms may affect BMD and osteoporosis in Chinese postmenopausal women.

Topics: Aged; Bone Density; China; DNA Mutational Analysis; Female; Genetic Predisposition to Disease; Genotype; Hip; Humans; Lumbar Vertebrae; Middle Aged; Neck; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Genetic; Radiography

It has been forecasted that the rabbiteye blueberry could inhibit osteoporosis. However, the inhibition and prevention of osteoporosis via rabbiteye blueberry are still elusive. This study was aim to evaluate the anti-osteoporosis effects of rabbiteye blueberry in ovariectomized rats.. Thirty rats were randomly divided into three groups of ten rats each as follows: sham-operated group (SG), ovariectomized model control group (OMG), and ovariectomized rabbiteye blueberry treatment group (OBG). The blood mineral levels, the alkaline phosphatase (ALP) activity, and osteoprotegerin (OPG) level were determined. The expression analyses of type I collagen, integrin-β1, and focal adhesion kinase (FAK) were performed. Besides, the bone mineral density (BMD) and bone histomorphometry (BH) were measured.. The ALP activity in SG and OBG was significantly lower than that in OMG. For the OPG level, the significant increase of OPG level in OBG was indicated compared with the other groups. The mRNA expression levels of type I collagen, integrin-β1, and FAK in OMG were significantly lower than those in other groups. The BMD in OMG were all significantly lower than those in SG and OBG. For BH, blueberry significantly improved the trabecular bone volume fraction, trabecular thickness, mean trabecular bone number, and bone formation rate, and decreased the trabecular separation, the percent of bone resorption perimeter, and mean osteoclast number in OBG compared with OMG.. The rabbiteye blueberries had an effective inhibition in bone resorption, bone loss, and reduction of bone strength of ovariectomized rats and could improve the BMD, osteogenic activity, and trabecular bone structure.

Topics: Alkaline Phosphatase; Animals; Blueberry Plants; Bone Density; Disease Models, Animal; Female; Humans; Osteoporosis, Postmenopausal; Osteoprotegerin; Ovariectomy; Rats, Sprague-Dawley

Primary osteoporosis is a common health problem in postmenopausal women. This study aimed to detect the association of the g.19074G>A genetic variant in the osteoprotegerin gene (OPG) with bone mineral density (BMD) and primary osteoporosis. The created restriction site-polymerase chain reaction method was used to investigate the g.19074G>A genetic variant. The BMD of the femoral neck hip, lumbar spine (L2-4), and total hip were assessed by dual-energy X-ray absorptiometry (DEXA) in 856 unrelated Chinese postmenopausal women. We found significant differences in the BMDs of the femoral neck hip, lumbar spine (L2-4), and total hip among different genotypes; individuals with the GG genotype had significantly higher BMDs than those with the GA and AA genotypes (P < 0.05). Our results indicated that the A allele was an increased risk factor for primary osteoporosis and the g.19074G>A genetic variant of the OPG gene was associated with BMD and primary osteoporosis in Chinese postmenopausal women.

Topics: Absorptiometry, Photon; Aged; Alleles; Asian People; Binding Sites; Bone Density; China; Deoxyribonucleases, Type II Site-Specific; DNA Mutational Analysis; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Linkage Disequilibrium; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Risk Factors

The aim of this study was to evaluate effect of diosgenin (DG) on rats that had osteoporosis-like features induced by ovariectomy (OVX). Seventy-two six-month-old female Wistar rats were subjected to either ovariectomy (n = 60) or Sham operation (SHAM group, n = 12). Beginning at one week post-ovariectomy, the OVX rats were treated with vehicle (OVX group, n = 12), estradiol valerate (EV group, n = 12), or DG at three doses (DG-L, -M, -H group, n = 12, respectively). After a 12-week treatment, administration of EV or DG-H inhibited OVX-induced weight gain, and administration of EV or DG-H or DG-M had a significantly uterotrophic effect. Bone mineral density (BMD) and indices of bone histomorphometry of tibia were measured. Levels of protein and mRNA expression of osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL) in tibia were evaluated by immunohistochemistry and in situ hybridization. Our results show that DG at a high dose (DG-H) had a significant anti-osteoporotic effect compared to OVX control. DG-H treatment down-regulated expression of RANKL and up-regulated expression of OPG significantly in tibia from OVX rats compared to control, and thus lowered the RANKL/OPG ratio. This suggests that the anti-osteoporotic effect of DG might be associated with modulating the RANKL/OPG ratio and DG had potential to be developed as alternative therapeutic agents of osteoporosis induced by postmenopause.

Topics: Animals; Body Weight; Bone Density; Bone Density Conservation Agents; Diosgenin; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Estradiol; Estrogen Replacement Therapy; Female; Gene Expression Regulation; Humans; Organ Size; Osteoporosis, Postmenopausal; Osteoprotegerin; Ovariectomy; RANK Ligand; Rats; Rats, Wistar; Tibia; Uterus

Bone remodelling is a vital process which enables bone to repair, renew and optimize itself. Disorders in the bone remodelling process are inevitably manifested in bone-related diseases, such as hypothyroidism, primary hyperparathyroidism and osteoporosis. In our previous work, a predator-prey based mathematical model was developed to simulate bone remodelling cycles under normal and two pathological conditions, hypothyroidism and primary hyperparathyroidism, for trabecular bone at a fixed point. However, the biochemical meanings of the model parameters were not fully explored. This article first extends the previous work by proposing relationships between the model parameters and biochemical factors involved in the bone remodelling process and by examining whether those relationships do predict the behaviours observed in vivo. The model is then applied to the simulation and investigation of bone remodelling of postmenopausal osteoporosis. The proposed connections are supported by good agreement between the model simulations and published experimental observations for the normal condition and all three pathological variations in bone remodelling.

Topics: Animals; Biological Clocks; Bone and Bones; Bone Remodeling; Computer Simulation; Female; Humans; Middle Aged; Models, Biological; Oscillometry; Osteoporosis, Postmenopausal; Osteoprotegerin; Predatory Behavior; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction

Several studies report that the OPG is an important candidate gene in the pathogenesis of osteoporosis. This study aimed to detect the potential association of OPG gene polymorphisms with osteoporosis in postmenopausal women. We recruited 928 subjects containing 463 with primary postmenopausal osteoporosis and 465 healthy volunteers as controls. The BMD of neck hip, lumbar spine (L(2-4)), and total hip were assessed by dual-energy X-ray absorptiometry (DEXA). Through the created restriction site-polymerase chain reaction (CRS-PCR), PCR-restriction fragment length polymorphism (PCR-RFLP), and DNA sequencing methods, the g.18873C>T and g.27522G>A have been investigated. As for g.18873C>T, our data indicated that subjects with CC genotype have significantly higher BMD value than those of CT and TT genotypes (all P values < 0.05). As for g.27522G>A, the BMD values of subjects with GG genotype were significantly higher than those of GA and AA genotypes (all P values < 0.05). Our findings suggest that the OPG g.18873C>T and g.27522G>A genetic polymorphisms are associated with the decreased risk for osteoporosis in Chinese postmenopausal women.

Topics: Aged; Aged, 80 and over; Alleles; Asian People; Bone Density; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Single Nucleotide

Previous evidence supports that the osteoprotegerin (OPG) gene is one of the most important candidate genes for influencing the pathogenesis of osteoporosis. The objective of this study was to investigate the relationship between OPG gene polymorphisms and osteoporosis in Chinese postmenopausal women. A total of 764 subjects were included in this study. The bone mineral density (BMD) in the lumbar spine (L2-4), neck hip and total hip was determined by dual-energy X-ray absorptiometry (DEXA). The g.19190C>A and g.25602A>G SNPs were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), created restriction site PCR (CRS-PCR) and DNA sequencing methods. As for g.19190C>A, our data suggested that the BMD value of lumbar spine (L2-4), neck hip and total hip for subjects with CC genotype was significantly higher than that of CA and AA genotypes (P<0.05). No significant difference was detected between the association of g.25602A>G genotypes with spine BMD and neck hip BMD, while total hip BMD almost reached the significant level (P=0.063). These findings provide more evidence that the SNPs in OPG gene could affect BMD and osteoporosis, and the allele-A of g.19190C>A and allele-G of g.25602A>G genetic variants are associated with increased risk for osteoporosis in Chinese postmenopausal women.

Topics: Absorptiometry, Photon; Aged; Aged, 80 and over; Bone Density; Case-Control Studies; China; DNA Mutational Analysis; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Genetic

Labisia Pumila var. alata (LPva) has shown potential as an alternative to estrogen replacement therapy (ERT) in prevention of estrogen-deficient osteoporosis. In earlier studies using postmenopausal model, LPva was able to reverse the ovariectomy-induced changes in biochemical markers, bone calcium, bone histomorphometric parameters and biomechanical strength. The mechanism behind these protective effects is unclear but LPva may have regulated factors that regulate bone remodeling. The aim of this study is to determine the bone-protective mechanism of LPva by measuring the expressions of several factors involved in bone formative and resorptive activities namely Osteoprotegerin (OPG), Receptor Activator of Nuclear Factor kappa-B Ligand (RANKL), Macrophage-Colony Stimulating Factor (MCSF) and Bone Morphogenetic Protein-2 (BMP-2).. Thirty-two female Wistar rats were randomly divided into four groups: Sham-operated (Sham), ovariectomized control (OVXC), ovariectomized with Labisia pumila var. alata (LPva) and ovariectomized with ERT (Premarin) (ERT). The LPva and ERT were administered via daily oral gavages at doses of 17.5 mg/kg and 64.5 μg/kg, respectively. Following two months of treatment, the rats were euthanized and the gene expressions of BMP-2, OPG, RANKL and MCSF in the femoral bones were measured using a branch - DNA technique.. The RANKL gene expression was increased while the OPG and BMP-2 gene expressions were reduced in the OVXC group compared to the SHAM group. There were no significant changes in the MCSF gene expressions among the groups. Treatment with either LPva or ERT was able to prevent these ovariectomy-induced changes in the gene expressions in ovariectomized rats with similar efficacy.. LPva may protect bone against estrogen deficiency-induced changes by regulating the RANKL, OPG and BMP-2 gene expressions.

Topics: Analysis of Variance; Animals; Bone Morphogenetic Protein 2; Disease Models, Animal; Female; Gene Expression; Humans; Macrophage Colony-Stimulating Factor; Osteoporosis, Postmenopausal; Osteoprotegerin; Ovariectomy; Plant Extracts; Primulaceae; RANK Ligand; Rats; Rats, Wistar

Osteoporosis is an important and common complex health problem, particularly in postmenopausal women. It is characterized by a reduction in bone mineral density (BMD) and a deterioration of bone microarchitecture with a consequent increase of fracture risk. The osteoprotegerin (OPG) gene is considered to play an important role in the pathogenesis of osteoporosis. We analyzed SNPs of the OPG gene and associations between these polymorphisms and BMD in 399 Chinese postmenopausal women. BMD was quantified at the lumbar spine (L2-4), femoral neck, and total hip. The g.2264T>C and g.27676A>C SNPs were detected by PCR-RFLP and DNA sequencing methods. A significant association with spine BMD was found for g.27676A>C. The spine BMD value for subjects with genotype AA was significantly higher than those with genotypes GA and AA. No significant association was detected between any of the SNP marker genotypes and the other traits. We conclude that g.27676A>C in the OPG gene affects spine BMD and that the C allele is associated with increased risk for osteoporosis in Chinese postmenopausal women.

Topics: Aged; Aged, 80 and over; Bone Density; China; Female; Genetic Association Studies; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Single Nucleotide

The objective of this study was to evaluate the association of single nucleotide polymorphisms (SNPs) of osteoprotegerin gene (OPG) with bone mineral density (BMD) and osteoporosis. A total of 338 Chinese postmenopausal women with primary osteoporosis and 367 healthy controls were enrolled. The lumbar spine (L₂₋₄), total hip and femoral neck hip of BMD were assessed by dual-energy X-ray absorptiometry (DEXA). OPG genetic variants were genotyped through polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), created restriction site-PCR (CRS-PCR) and DNA sequencing methods. In this study, the g.18861A>G and g.25548C>T SNPs were detected and our data suggested that the significant differences of spine BMD, femoral neck hip BMD and total hip BMD were found among different g.18861A>G genotype, subjects with the AA genotype were significantly higher than those of AG and GG genotypes (p < 0.05). The g.25548C>T variant was not significantly associated with spine BMD, femoral neck hip BMD and total hip BMD (p > 0.05), while almost reached at the significant level in total hip BMD (p = 0.061). These findings suggeste that OPG gene variants are related to BMD and osteoporosis in Chinese postmenopausal women.

Topics: Absorptiometry, Photon; Aged; Alleles; Bone and Bones; Bone Density; Case-Control Studies; China; Female; Femur Neck; Gene Frequency; Genetic Association Studies; Hip Joint; Hospitals, Urban; Humans; Lumbar Vertebrae; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Single Nucleotide; Risk Factors; Urban Health

To observe the effect of treadmill exercise on the mRNA expression of osteoprotegerin, RANKL and RUNX2 in bone tissue of ovariectomized rat,and to investigate the mechanism of treadmill exercise for the preventing and treating postmenopausal osteoporosis.. Thirty healthy adult SD rats which average weight was (270 +/- 10) g were randomly divided into 3 groups: sham-operation group, ovariectomized group and treadmill exercise group. Each group had 10 rats. After anesthesia, ovariectomized group and treadmill exercise treated group were operated by bilateral ovarian resection, sham group by sham operation. Sham-operation group and ovarian rats were normal breed. Rats in the exercise group were treated by running on treadmill for animal at 1 week after the operation. Running speed was 18 meters per minutes lasting 45 minutes in one day, and worked six days per week for 11 weeks. All rats were killed after 12 weeks. After decalcification, left femur head was made to paraffin slice and observed by inverted phase contrast microscope for histological examination. Total RNA were extracted from the right femur heads and the mRNA expression of OPG,RANKL and RUNX2 were examined by real time PCR.. The femur heads of ovariectomized group showed thin trabecular bone and less bone cells, meanwhile trabecular bone of exercise group looked thicker in histological examination. The mRNA expression of OPG (0.131 +/- 0.080), RANKL (8.013 +/- 3.550) and RUNX2 (3.245 +/- 5.090) was seen in the ovariectomized group. Meanwhile different results were found as the mRNA expression of OPG (0.566 +/- 0.260), RANKL (5.232 +/- 3.670) and RUNX2 (2.753 +/- 3.680) in the group of treadmill exercise. In compared with ovariectomized group, the mRNA expression of OPG in treadmill exercise increased and the result had statistical significance,whereas mRNA expression of RNAKL and RUNX2 decreased but the results had no statistical significance.. The effect of exercise treating postmenopausal osteoporosis is tightly correlated with the up-regulation of expression of OPG. This provides a new train of thought of postmenopausal osteoporosis treatment for the future study.

Topics: Adult; Animals; Bone Density; Core Binding Factor Alpha 1 Subunit; Exercise Test; Exercise Therapy; Female; Femur; Humans; Osteoporosis, Postmenopausal; Osteoprotegerin; Ovariectomy; RANK Ligand; Rats; Rats, Sprague-Dawley

To investigate the effects of genetic and non-genetic factors on bone mineral densities (BMDs) and osteoporotic fractures. This was a cross-sectional study to investigate the relationships between 18 SNPs and non-genetic factors with BMDs and osteoporotic fractures in 1012 Chinese Han women. Five SNPs in genes GPR177, CTNNB1, MEF2C, SOX6, and TNFRSF11B were associated with L1-4 or total hip BMDs. rs11898505 in SPTBN1 gene was associated with osteoporotic fractures. Subjects carrying the largest number of risk alleles (highest 10 %) not only had lower BMD values as compared to those carrying the least number of risk alleles (lowest 10 %), they also had a higher risk of fracture [P = 0.002, OR = 2.252, 95 %CI (1.136, 4.463)]. Results from multivariate stepwise regression analysis revealed that age [P < 0.001, OR = 1.038, 95 % CI (1.018, 1.058)], number of falls in a year [P < 0.001, OR = 2.347, 95 % CI (1.459, 3.774)], the G risk allele in rs11898505 [P = 0.023, OR = 1.559, 95 % CI (1.062, 2.290)], and the L1-4 BMD [P = 0.017, OR = 0.286, 95 % CI (0.102, 0.798)] were associated with the occurrence of osteoporotic fractures. Genetic (rs11898505) and non-genetic factors (age, number of falls in a year and L1-4 BMD) could work in concert to contribute to the risk of osteoporotic fractures.

Topics: Accidental Falls; Adult; Aged; Aging; Asian People; Bone Density; China; Cohort Studies; Cross-Sectional Studies; Female; Genetic Association Studies; Hip Joint; Humans; Lumbar Vertebrae; MADS Domain Proteins; MEF2 Transcription Factors; Middle Aged; Myogenic Regulatory Factors; Osteoporosis, Postmenopausal; Osteoporotic Fractures; Osteoprotegerin; Polymorphism, Single Nucleotide; Radiography; Spectrin; Young Adult

Osteoprotegerin gene (OPG) is an important candidate gene of osteoporosis. The objective of this study was to evaluate the association between OPG gene polymorphisms and bone mineral density (BMD). A total of 336 Chinese postmenopausal women were included in this study. OPG gene polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), created restriction site-PCR (CRS-PCR) and DNA sequencing methods. BMD was evaluated at the lumbar spine (L(2-4)), total hip and femoral neck. Two single-nucleotide polymorphisms (SNPs) (g.21775C>T and g.23367T>C) were identified and the association analysis showed significant difference of spine BMD among different g.23367T>C genotype, subjects with the genotype TT was significantly higher than those of genotype TC and CC. Such a significant difference was not observed at the neck hip BMD and total hip BMD. The g.21775C>T polymorphism was not significantly associated with spine BMD, total hip BMD and neck hip BMD in the studied subjects. These findings suggested that OPG gene polymorphisms were associated with BMD in Chinese postmenopausal women. Results from this study will be helpful in further studies to determine the role of OPG gene in osteoporosis.

Topics: Absorptiometry, Photon; Aged; Asian People; Bone Density; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Postmenopause

The objective of this study is to investigate the relationship between soluble components of the interleukin 6 (IL-6) system mediating and modifying IL-6 trans-signaling and the RANKL-RANK-osteoprotegerin system in postmenopausal women with rheumatoid arthritis (RA). The following parameters were investigated in 126 postmenopausal women with RA: IL-6, soluble IL-6-receptor (sIL-6R), soluble glycoprotein 130 (sgp130), sRANKL, osteoprotegerin (OPG), osteocalcin, erythrocyte sedimentation rate and C-reactive protein in sera, pyridinolin and desoxypyridinolin crosslinks in the morning urine. Bone mineral density (BMD) was measured by dual X-ray absorptiometry at the lumbar spine (BMD-LS) and at the femoral neck (BMD-FN). Predictors of RANKL/OPG ratio and BMD were evaluated by multiple linear regression analysis. The following determinants of the RANKL/OPG ratio were identified: sIL-6R/sgp130 ratio and daily glucocorticoid (GC) dose as positive determinants in the whole group (R (2) = 0.56; P = 0.001), sIL-6R/sgp130 ratio as the exclusive positive determinant in patients with GC therapy (R (2) = 0.48; P = 0.001) and sgp130 as negative determinant in patients without GC (R (2) = 0.42; P = 0.031). Sgp130 was highly significantly positively correlated with OPG in the whole group (P < 0.001) as well as in patients with (n = 70; P < 0.05) and without GC therapy (n = 56; P < 0.01). sIL-6R was the main negative predictor of BMD-LS (R (2) = 0.41; P = 0.019). High sIL-6R/sgp130 ratio and/or low sgp130 are associated with a high sRANKL/OPG ratio in sera of postmenopausal women with RA indicating the critical significance of IL-6 trans-signaling for an increase in the RANKL/OPG ratio and of bone resorption. Inhibition of IL-6 trans-signaling may be an effective bone-protecting principle in postmenopausal women with RA.

Topics: Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Biomarkers; Bone Density; Cytokine Receptor gp130; Female; Glucocorticoids; Humans; Interleukin-6; Linear Models; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Postmenopause; Predictive Value of Tests; RANK Ligand; Receptors, Interleukin-6; Risk Factors; Signal Transduction

Adiponectin, a fat derived cytokine, is a potential independent contributor to bone mineral density (BMD); however, its action on bone metabolism in humans is still unclear.. The aim of this study was to investigate the relationship of adiponectin with bone mass indices and bone metabolic markers in middle-aged post-menopausal women without diabetes.. A random sample consisted of 81 post-menopausal women (age range 45-61 yr, osteopenic/osteoporotic no.=43) was studied. Lumbar-spine BMD (BMD(L2-L4)) and total-body bone mineral content (TBBMC) were measured with dual X-ray absorptiometry. Plasma levels of total and high-molecular weight (HMW) adiponectin, osteoprotegerin (OPG), soluble receptor activator of nuclear factor-κB ligand (sRANKL) and IGF-I were determined.. No association was observed between total or HMW adiponectin and BMD(L2-L4) or TBBMC. On the contrary, adiponectin levels were positively associated with OPG levels (partial r=0.276, p=0.015) and negatively with IGF-I (partial r=-0.438, p<0.001), in multiple regression models after adjustment for potential confounders. HMW adiponectin showed a negative association with IGF-I (partial r=-0.266, p=0.049) in the multiple regression models but not with OPG, TBBMC or BMD(L2-L4).. Although we failed to show statistically significant association between circulating adiponectin levels and indices of bone mass in women during the postmenopausal period, we showed significant associations with OPG and IGF-I levels, suggesting an anabolic role of adiponectin, which may contribute in the understanding of the interplay between adipose tissue-derived hormones and bone metabolism.

Topics: Absorptiometry, Photon; Adiponectin; Biomarkers; Bone and Bones; Bone Remodeling; Female; Humans; Insulin-Like Growth Factor I; Lumbar Vertebrae; Middle Aged; Molecular Weight; Osteoporosis, Postmenopausal; Osteoprotegerin; Postmenopause; RANK Ligand

Osteoporosis is a complex health disease characterized by low bone mineral density (BMD), which is determined by an interaction of genetics with metabolic and environmental factors. The tumor necrosis factor receptor superfamily, member 11b (TNFRSF11B) gene, has been investigated in relation to BMD. Three polymorphisms in/nearby TNFRSF11B have been associated with BMD variations in some populations. The aim of this study was to investigate the possible association among three SNPs of TNFRSF11B and their haplotypes with the presence of BMD variations in postmenopausal Mexican Mestizo women.. One thousand unrelated postmenopausal women of Mexican-Mestizo ethnic origin, who attended the outpatient clinic for routine, general medical evaluation, were invited and 750 women accepted to participate in the study. A structured questionnaire for risk factors was applied and BMD was measured in total hip and lumbar spine by dual-energy X-ray absorptiometry. DNA was obtained from blood leukocytes. Three single-nucleotide polymorphisms in TNFRSF11B gene were studied: rs4355801, rs2073618, and rs6993813. Real-time PCR allelic discrimination was used for genotyping. Deviations from Hardy-Weinberg equilibrium were tested. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r(2), and haplotype analysis was conducted.. Of the subjects, 31% had osteoporosis, 45.1% had osteopenia, and 23.9% had normal BMD. Genotype and allele distributions showed no significant differences; however, A-G-T haplotype was associated with variations in femoral neck BMD (P=0.022).. In our study population, analysis of the haplotypes of TNFRSF11B is a better genetic marker for variations in BMD.

Topics: Absorptiometry, Photon; Aged; Alleles; Bone Density; Bone Diseases, Metabolic; Female; Femur; Genetic Markers; Haplotypes; Humans; Leukocytes; Linkage Disequilibrium; Mexico; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Single Nucleotide; Postmenopause; Prevalence; Reference Values; Risk Factors; Surveys and Questionnaires

Osteoporosis (OP) is an age-related disease associated with increased production of reactive oxygen species (ROS) and a reduction in antioxidant defense system, such as low activity of glutathione S-transferase (GST) family. The enzyme activity of the member of GSTs, GSTP1, depends on gene polymorphisms such as: Ala114Val and Ile105Val. The aim of this study was to evaluate the association between genetic polymorphisms of the GSTP1 gene and BMD variation and biochemical bone remodeling markers in 523 Slovenian pre- and post-menopausal women.. Observational pilot study in a representative cohort of Slovenian patients with adjustment for potential confounders (age, height, weight, years since menopause, smoking status and glucocorticoid use) using univariate one-way and two-way analyses.. Ala114Val and Ile105Val polymorphisms genotypes of GSTP1 gene, bone mineral density (BMD) values of total hip (_th), femoral neck (_fn) and lumbar spine (_ls), plasma osteocalcin (OC), serum bone alkaline phosphatase (BALP), free soluble RANKL and serum osteoprotegerin (sOPG) concentrations were determined.. Our results show that the Ala114Val heterozygotes are (borderline) significantly associated with higher concentrations of pOC (p=0.052) and decreased BMD_fn values (p=0.053) and the same trend is shown for BMD_th and BMD_ls values in osteopenic postmenopausal women. Furthermore, significantly higher concentrations of pOC were determined among Val allele carriers of Ile105Val gene polymorphism (p=0.037) and in carriers with the absent 114Ala-105Ile haplotype combination, again in osteopenic post-menopausal women. In addition, in pre-menopausal women the significant associations between sOPG and Ala114Val genotypes subgroups and between sBALP and Ile105Val genotypes subgroups, alone or in combination with Ala114Val, were determined (0.032, 0.026 and 0.008, respectively).. Since significant associations existed in Ala114Val genotype and 114Ala-105Ile haplotype subgroups, these variations can be useful for determining low BMD and high pOC risk in postmenopausal women.

Topics: Adult; Aged; Biomarkers; Bone Density; Bone Diseases, Metabolic; Bone Remodeling; Female; Genotype; Glutathione S-Transferase pi; Haplotypes; Heterozygote; Humans; Menopause; Middle Aged; Osteocalcin; Osteoporosis, Postmenopausal; Osteoprotegerin; Pilot Projects; Polymorphism, Genetic; Postmenopause; Premenopause; Slovenia

To evaluate the protective effects of strontium fructose 1,6-diphosphate (FDP-Sr), a novel strontium salt that combined fructose 1,6-diphosphate (FDP) with strontium, on bone in an ovariectomy-induced model of bone loss.. Eighty female Sprague-Dawley rats were ovariectomized (OVX) or sham-operated. Three months later, the rats were assigned to six groups (10 for each): sham-operated, OVX control, OVX+FDP-Sr (110, 220, or 440 mg/kg), or OVX+strontium ranelate (SR, 180 mg/kg). Drugs were administered orally for 3 months. When the treatment was terminated, the following parameters were assessed: bone mineral density (BMD), the biomechanical properties of the femur and lumbar vertebrae, trabecular histomorphology, serum phosphorus, calcium, bone-specific alkaline phosphatase (B-ALP), tartrate-resistant acid phosphatase 5b (TRACP5b), N-telopeptide of type I collagen (NTx) and a series of markers for oxidative stress. Receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) levels in serum were measured using ELISA and their gene expression levels in the bone were measured using R-T PCR.. Treatment with FDP-Sr (220 or 440 mg/kg) or SR (180 mg/kg) significantly increased the BMD and improved the bone microarchitecture and bone strength in OVX rats. The treatments also decreased in the levels of H(2)O(2) and MDA, restored the CAT level in serum and bone marrow, increased the serum B-ALP and decreased NTx and TRACP 5b in OVX rats. Treatment with FDP-Sr decreased the RANKL level, and increased the OPG level in serum in a dose-dependent manner. It also significantly down-regulated the RANKL expression and up-regulated OPG expression in bone marrow.. FDP-Sr may be an effectve treatment for postmenopausal osteoporosis that acts, in part, via a decrease in osteoclastogenesis through the OPG\\RANKL\\RANK pathway.

Topics: Animals; Bone and Bones; Bone Density; Female; Fructosediphosphates; Humans; Immunologic Factors; Insulin-Like Growth Factor I; Osteoporosis, Postmenopausal; Osteoprotegerin; Oxidative Stress; RANK Ligand; Rats; Rats, Sprague-Dawley; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction

The aim of this study was to explore the association between polymorphisms in Wnt antagonist genes and bone response to hormone therapy (HT) in postmenopausal Korean women.. A prospective study was conducted with 303 postmenopausal women receiving sequential estrogen plus progestogen therapy in a university hospital. The dickkopf (Dkk) 1 c.318A>G, Dkk2 c.437G>A, Dkk3 c.1003A>G, secreted frizzled-related protein (sFRP) 1 rs3242C>T, rs16890444C>T, sFRP3 c.970C>G, sFRP4 c.958C>A, c.1019G>A, and sFRP5 c.20G>C polymorphisms were analyzed, and bone mineral density (BMD) at the lumbar spine and femoral neck (FN) was measured before and after 1 year of sequential estrogen plus progestogen therapy.. The percentage changes in BMD of the FN after 1 year of HT were found to be significantly (P < 0.05) different according to the haplotype genotype composed of the sFRP4 c.958C>A and c.1019G>A polymorphisms after adjustment for baseline BMD. The percentage change in BMD at the FN after 1 year of HT was significantly higher in the AA/AG haplotype genotype than in the AG/CG (P < 0.01) or CG/CG (P < 0.05) haplotype genotype. However, any single and combined polymorphisms measured were not related with nonresponsiveness to HT when a nonresponder was defined as a woman who had lost more than 3% of BMD per year after HT.. The haplotype genotypes of sFRP4 c.958C>A and c.1019G>A polymorphisms are genetic factors that affect changes in BMD of the FN after HT in postmenopausal Korean women.

Topics: Bone Density; Estrogen Replacement Therapy; Female; Femur Neck; Genotype; Glycoproteins; Haplotypes; Humans; Intercellular Signaling Peptides and Proteins; Intracellular Signaling Peptides and Proteins; Korea; Lumbar Vertebrae; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Genetic; Postmenopause; Progestins; Prospective Studies; Proto-Oncogene Proteins; Wnt Proteins

Osteoporosis is a common complex and polygenic disease in postmenopausal women, which is characterized by a decrease in bone mineral density (BMD). The osteoprotegerin (OPG) is an important candidate gene in the pathogenesis of osteoporosis. The aim of this study was to investigate the association between single-nucleotide polymorphisms (SNPs) in the OPG gene and BMD.. OPG gene polymorphisms and BMD were analyzed in 352 Chinese postmenopausal women. BMD was quantified at the lumbar spine (L2-4), femoral neck, and total hip.. Through polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing methods, an allelic variant corresponding to the G→A mutations at position 23276 in exon 3 of the OPG gene could be detected. The association between g.23276 G>A polymorphisms and BMD was analyzed, and a significant association was found between g.23276 G>A and spine BMD. The mean of genotype GG was significantly higher than those of genotype GA and AA. There was no significant difference in neck hip BMD and total hip BMD among different genotypes.. These findings suggested that g.23276 G>A genotypes in the OPG gene were associated with spine BMD in Chinese postmenopausal women. The A-allele was associated with lower BMD and an increased risk for osteoporosis.

Topics: Bone Density; Female; Genetic Predisposition to Disease; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Single Nucleotide; Postmenopause

Osteoporosis and periodontal disease are chronic diseases, in the pathogenesis of which plasma osteoprotogerin (OPG) and RANKL are important. The study aimed to investigate the relationship between periodontal disease and plasma cytokines, vitamin D and bone mineral density in postmenopausal women with and without osteoporosis.. One hundred and eighty-five postmenopausal women with osteoporosis and 185 age- and sex-matched control subjects were recruited. Periodontal disease was subdivided into active or past periodontal disease. Osteoprotegerin, RANKL, 25-hydroxyvitamin D₃ (25OHD), biochemical markers of bone turnover (serum C-terminal telopeptide, CTX), anthropometry and bone mineral density were measured.. A significantly higher proportion of the women with osteoporosis had active or past periodontal disease or both compared with control subjects (87.6 vs. 37.8%, p < 0.001). Plasma 25OHD was significantly lower (p < 0.001) and RANKL and OPG significantly higher in the women with osteoporosis than in control subjects (p < 0.0001). RANKL, OPG and CTX were significantly higher in women with active periodontal disease than in those without (p < 0.001), as were OPG and CTX in past periodontal disease (p < 0.001). In active and past periodontal disease, 25OHD was significantly lower (p < 0.001). Multiple logistic regression analysis showed that periodontal disease was best predicted by RANKL, 25OHD, C-terminal telopeptide and weight, r² = 10.4%.. Periodontal disease is more common in women with osteoporosis and is associated with lower vitamin D and higher concentrations of RANKL and OPG. Raised cytokines may provide the underlying mechanism that links these two conditions.

Topics: Aged; Bone Density; Bone Remodeling; Calcifediol; Case-Control Studies; Collagen Type I; Cytokines; Female; Humans; Logistic Models; Lumbar Vertebrae; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Peptides; Periodontal Diseases; RANK Ligand; Surveys and Questionnaires

The osteoprotegerin/RANKL system modulates bone remodelling. Alendronate and raloxifene are anti-resorptive drugs effective in osteoporotic disease. They reduce fracture risk, the activity of bone remodelling and increase bone mineral density. It is not known if they can exert a direct effect in osteoblasts via the osteoprotegerin/RANKL system. Our objective was to assess the effects of alendronate and raloxifene among osteoprotegerin production (ELISA), as well as osteoprotegerin and RANKL expression (RT-PCR), in primary cultures of human osteoblasts (hOB). We compared 17 osteoporotic patients with 16 patients affected by osteoarthritis in basal conditions and after incubation with alendronate (10(-6) M), raloxifene (10(-7) M) or 17-β estradiol (10(-7) M) for 24 h. The statistical analysis was determined by ANOVA. Osteoprotegerin protein secretion in hOB cultures was higher in patients with osteoporosis than osteoarthritis. Osteoprotegerin secretion levels remained unchanged after each treatment. The osteoporotic group was more sensitive to treatment. Both raloxifene (34%) and estradiol (37%) increased osteoprotegerin mRNA expression, and alendronate (118%) and raloxifene (61%) increased the mRNA expression of RANKL. The RANKL/osteoprotegerin mRNA ratio was higher in osteoporotic than osteoarthritic patients. In the osteoporotic group, the RANKL/osteoprotegerin mRNA ratio was significantly increased after treatment with alendronate (112%) and after treatment with raloxifene (60%). These results indicate a direct action of alendronate and raloxifene on hOB cultures from osteoporotic patients, and the cited drugs are able to modulate the osteoprotegerin/RANKL system.

Topics: Aged; Aged, 80 and over; Alendronate; Bone Density Conservation Agents; Bone Remodeling; Cells, Cultured; Estradiol; Female; Humans; Male; Middle Aged; Osteoarthritis; Osteoblasts; Osteoporosis, Postmenopausal; Osteoprotegerin; Raloxifene Hydrochloride; RANK Ligand; RNA, Messenger

Osteoprotegerin (OPG) and receptor activator of nuclear factor κ B ligand (RANKL) play a critical role in the regulation of bone turnover, but the relative importance of these two cytokines in the pathogenesis of postmenopausal osteoporosis is controversial.. To investigate the relationship between circulating levels of OPG, RANKL, bone turnover and bone mineral density (BMD) in postmenopausal women.. A cross-sectional study of 185 women with osteoporosis and 185 age- and sex-matched control subjects was undertaken. Measurements were made of plasma OPG, RANKL, interleukin-6 (IL-6), sex steroids, calciotropic hormones, biochemical markers of bone turnover, BMD and anthropometry. Health questionnaires were administered.. Plasma RANKL was significantly higher (p<0.0001) in women with osteoporosis (0.66±0.67 pmol/l) than in control subjects (0.37±0.38 pmol/l), as was plasma OPG (18.70±9.70 pmol/l in women with osteoporosis, 10.44±5.85 pmol/l in control subjects; p<0.0001). OPG/RANKL ratio was higher in women with osteoporosis (51.3) than in control subjects (36.6). The women with osteoporosis also had significantly higher biochemical markers of bone turnover, IL-6 and parathyroid hormone and lower 25-hydroxyvitamin D and oestradiol than the control subjects. Multiple regression analysis showed that lumbar spine and femoral neck BMD in postmenopausal women were best predicted by OPG and RANKL, giving an R(2) value of 15.5% and 14.9%, respectively.. This study indicates that the circulating levels of OPG and RANKL are inversely related to BMD and contribute to the development of osteoporosis in postmenopausal women.

Topics: Absorptiometry, Photon; Aged; Anthropometry; Biomarkers; Bone Density; Bone Remodeling; Case-Control Studies; Cross-Sectional Studies; Female; Femur Neck; Humans; Lumbar Vertebrae; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand

Alendronate (AL) is commonly used for the prevention and treatment of osteoporotic fractures. Little is known about the effects of AL administration on osteoclast differentiation from human marrow progenitor cells. We used marrow discarded during orthopedic surgery to test the hypothesis that cultures of bone marrow-derived stem cells (BMCs) from subjects receiving AL (+AL) may differ from control subjects with respect to in vitro osteoclast differentiation and regulatory factors. The number of osteoclasts generated in BMC cultures from control subjects was 4.7-fold greater than that from +AL subjects (P = 0.015). RANKL expression in +AL BMCs was 57% of that in controls (P = 0.001), and OPG expression in +AL BMCs was greater than in controls (153%, P = 0.01). The mean RANKL/OPG ratio in BMCs was 0.65 ± 0.35 for +AL specimens and 1.28 ± 0.53 for controls (P = 0.031). In addition, we assessed the direct effect of AL on expression of RANKL and OPG in marrow stromal cells isolated from nine control women. Treatment with AL downregulated RANKL expression and upregulated OPG expression, with an average 50% decrease in RANKL/OPG ratio at 10(-7) M (P = 0.004). These results show that osteoclast differentiation is dysregulated in marrow isolated from +AL subjects. Furthermore, AL may inhibit human osteoclastogenesis by affecting the key regulatory genes in marrow cells.

Topics: Aged, 80 and over; Alendronate; Bone Marrow Cells; Case-Control Studies; Cell Differentiation; Diphosphonates; Female; Gene Expression Regulation; Humans; Orthopedics; Osteoclasts; Osteoporosis; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Stem Cells

Osteoprotegerin (OPG) inhibits osteoclast function by acting as a decoy receptor for receptor activator of nuclear factor-κB ligand (RANKL), thus being an important candidate gene for osteoporosis. Three recent genome-wide association studies also identified the TNFRSF11B gene, coding for OPG, as playing a key role in bone mineral density (BMD) regulation. As variations in the TNFRSF11B gene could alter the susceptibility to osteoporosis, the aim of study was to investigate association of two TNFRSF11B gene polymorphisms with BMD and serum OPG concentration in postmenopausal women.. 478 postmenopausal women were genotyped for the presence of TNFRSF11B gene polymorphisms 245T > G (rs3134069) and 1181G > C (rs2073618). BMDs and serum OPG concentrations were measured.. Two common haplotypes GT and CT occurred in 41.2% and 52.4% of subjects. In osteoporotic postmenopausal women, lumbar spine BMD was associated with polymorphisms 245T > G and 1181G > C, as well as with CT haplotype (p values 0.013, 0.006 and 0.006, respectively). Additionally, femoral neck BMD showed the association with 245T > G (p = 0.047). No other statistically significant associations with BMD were found for the studied SNPs and haplotypes. No association with serum OPG concentration was shown in any of the studied groups.. Our results suggest that, in postmenopausal osteoporosis, polymorphisms 245T > G and 1181G > C, as well as haplotype CT in TNFRSF11B gene influence BMD.

Topics: Adult; Aged; Aged, 80 and over; Bone Density; Female; Femur Neck; Genotype; Haplotypes; Humans; Lumbar Vertebrae; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Single Nucleotide

The aim of this study was to explore the association between Wnt signaling pathway gene polymorphisms and response to hormone therapy (HT) as related to bone mineral density (BMD) in postmenopausal Korean women.. The BMD and serum levels of osteoprotegerin, the soluble receptor activator of the nuclear factor κB ligand, and bone turnover markers were measured in 308 postmenopausal women receiving sequential estrogen + progestogen therapy. Results were analyzed according to the low-density lipoprotein receptor--related protein (LRP5) 5 c.266A > G, c.3893C > T, frizzled receptor 6 gene c.1033A > C, axin II c.148C > T, adenomatous polyposis coli c.5645T > A, and T-cell factor 1 c.766G > A polymorphisms.. The rates of 1-year changes in BMD and changes at 6 months in osteoprotegerin, soluble receptor activator of the nuclear factor κB ligand, and bone turnover markers after HT did not differ significantly between all single and haplotype genotypes of the genes studied. When a nonresponder was defined as a woman who had lost more than 3% of BMD per year after HT, women with T allele of the LRP5 c.3893C > T polymorphism showed a significantly higher risk of nonresponse at both the lumbar spine and femoral neck than did women with C allele. The risk of nonresponse at the lumbar spine was significantly higher in women with G allele of the LRP5 c.266A > G polymorphism than that in women with A allele, and the c.266G/c.3893T (GT) haplotype allele showed a similar trend.. The LRP5 c.266A > G and c.3893C > T polymorphisms may be associated with risk of nonresponse to HT in postmenopausal Korean women.

Topics: Biomarkers; Bone Density; Drug Resistance; Drug Therapy, Combination; Estrogen Replacement Therapy; Estrogens; Female; Humans; LDL-Receptor Related Proteins; Low Density Lipoprotein Receptor-Related Protein-5; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Genetic; Progestins; Signal Transduction; Wnt Proteins

Polymorphisms within the TNFRSF11B gene have been studied and associated with osteoporosis and fracture risk. Osteoprotegerin (OPG), the product of this gene, is a key negative regulator of osteoclastogenesis and is secreted by osteoblasts/stromal cells. A previous study in Maltese postmenopausal women showed positive association of low bone mineral density (BMD) with a polymorphism found within the promoter region of this gene (C950T). In this study, direct DNA sequencing revealed 12 variants with polymorphisms C950T, G1181C and rs4876869 observed to be in strong linkage disequilibrium. The constructed haplotype T-G-T was found to increase the risk for a low BMD, while C-G-T and C-C-C have a protective role; thus, we investigated the functional role of both C950T and rs4876869 in vitro. The promoter region, including the C950T alleles, was amplified by PCR, cloned into pGL3 enhancer vector and transfected into HeLa, COS-7 and RAW264.7 cell lines. After incubation, luciferase activity was measured. The T/C (rs4876869) change was tested for its possible effect on pre-mRNA splicing, using an exon-trapping vector. A statistical significant difference in gene expression was observed between the alleles for T950C, with the T allele showing a lower luciferase expression in all cell lines (P<0.01). For rs4876869, exon skipping was observed for the C allele, while only one transcript harbouring the whole exon was observed for the T allele. Our findings suggest that the T-G-T haplotype might be increasing the risk for osteoporosis due to lower quantities of the full OPG transcript being expressed resulting in a higher bone resorption.

Topics: Adult; Aged; Base Sequence; Bone Density; Female; Gene Expression Regulation; Genes, Reporter; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Single Nucleotide; Postmenopause; Risk; RNA Precursors; RNA Splicing; RNA, Messenger

Prevalence of osteoporosis, a systemic disease characterized by an impairment of bone mass, will continue to increase due to an ageing population and result in greater risks of fractures with disastrous medical and socioeconomic consequences. A better understanding of the regulation pathway of bone remodeling has led to the identification of new therapeutic targets. Denosumab, a monoclonal antibody against Receptor Activator of Nuclear factor κB-ligand (key molecule in osteoclastogenesis) is a fast-working, reversible antiresorptive treatment. A subcutaneous injection is required twice a year, a significant advantage over bisphosphonates whose efficiency is limited by an inadequate long-term compliance. The only anabolic agent currently available, Teriparatide (parathyroid hormone residues 1-34), administered daily via subcutaneous injection, stimulates both sides of bone remodeling in favour of bone formation. Anti-sclerostin antibodies neutralize an inhibitor of Wnt pathway, the master switch for osteoblastic differentiation, and meet the challenge of pioneering an anabolic drug that does not increase bone resorption. If the tolerance of these promising treatments is good in clinical trials of short duration, their implication in signaling pathways affecting various tissues means that one has to keep a very close watch on their long-term potential risks. Finally, the endocrinologists must be aware that the local regulating factors of bone remodeling recently identified (sclerostin, osteoprotegerin) seem to be the key mediators of hormones with bone tropism.

Topics: Adaptor Proteins, Signal Transducing; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bone Density Conservation Agents; Bone Morphogenetic Proteins; Bone Remodeling; Clinical Trials as Topic; Denosumab; Diphosphonates; Female; Genetic Markers; Humans; Male; Mice; NF-kappa B; Osteoporosis; Osteoporosis, Postmenopausal; Osteoprotegerin; Patient Compliance; RANK Ligand; Rats; Teriparatide; Treatment Outcome; Wnt Signaling Pathway

RANKL and its decoy receptor osteoprotegerin (OPG) is a mediator system involved in bone resorption and may be responsible for the homeostatic mechanism of normal bone remodeling. The serum levels of both OPG and soluble RANKL (sRANKL), the level of RANKL in primary cultures of osteoblasts, and the bone level of Zn(2+) were measured in six women with postmenopausal osteoporosis and three women without osteoporosis (control group). As compared to control cases, patients with less than 15 years of estrogenic deprivation (cohort 1, n=3) presented increased levels of OPG (109.82%, p<0.002), sRANKL (229.13%, p<0.001) and RANKL OBL (272.35%, p<0.001), and decreased levels of Zn(2+) (67.81%, p<0.001), whereas patients with more than 15 years of estrogenic deprivation (cohort 2, n=3) showed decreased levels of OPG (70.44%, p<0.003), and Zn(2+) (61.41%, p<0.001), and increased levels of sRANKL (181.69%, p<0.002) and RANKL OBL (201.1%, p<0.002). The significantly increased levels of sRANKL and RANKL OBL in postmenopausal osteoporosis demonstrate osteoclastogenesis activation. According to the length of the estrogenic deprivation period, postmenopausal women with osteoporosis presented either increased (cohort 1) or decreased (cohort 2) OPG levels demonstrating osteoblast activation and osteoblast apoptosis stimulation, respectively. The bone levels of Zn(2+) were significantly decreased showing limited proliferation and differentiation of the osteoblasts.

Topics: Aged; Biomarkers; Bone Remodeling; Case-Control Studies; Cell Proliferation; Cells, Cultured; Female; Humans; Ions; Mesenchymal Stem Cells; Middle Aged; Models, Biological; Osteoblasts; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Zinc

Osteoprotegerin (OPG) and receptor activator of nuclear factor kappaB ligand (RANKL) are bone turnover modulators expressed by osteoblasts. The aim of this study was to assess the relationship between the circulating OPG/RANKL system, age and bone mass, in fertile age and postmenopausal women.. In this cross-sectional observational study on 48 patients (fertile age, n = 22; postmenopause, n = 26), we investigated the correlation between serum OPG and RANKL, age and bone mineral density (BMD). Serum concentrations of OPG and RANKL were determined by enzyme-linked immunosorbent assay (ELISA); estimate BMD evaluation was performed with heel quantitative ultrasonometry (QUS).. Serum OPG significantly increased (p = 0.003) and serum RANKL significantly decreased (p = 0.002), in the postmenopausal group compared to fertile age women. A significant correlation of serum OPG with age (r(s) = 0.39, p = 0.047) and BMD (r(s) = 0.45, p = 0.023) in postmenopausal women, and between RANKL and BMD (r(s) = 0.48, p = 0.024) in fertile age was found.. These data demonstrate in vivo that the OPG/RANKL system is significantly associated with menopausal status and could play a role in postmenopausal osteoporosis.

Topics: Adult; Age Factors; Biomarkers; Bone Density; Cross-Sectional Studies; Female; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Receptor Activator of Nuclear Factor-kappa B

Osteoprotegerin plays a key role in bone remodelling. We studied the association between 24 polymorphisms and haplotypes on the OPG gene and bone mineral density and fractures. After multiple-testing correction, one SNP and two block-haplotypes were significantly associated with FN BMD. Two other block-haplotypes were associated with fracture.. Osteoprotegerin (OPG) plays a key role in bone remodelling. Here we studied the association between polymorphisms and haplotypes on the OPG gene and bone mineral density (BMD) and fractures.. Twenty-four single nucleotide polymorphisms (SNPs) were selected to cover six haplotypic blocks and were genotyped in 964 postmenopausal Spanish women. Haplotypes were established with HaploStats. Association was analysed by GLM (for BMD) and logistic regression (for fractures) both at single SNP and haplotype levels.. Upon adjustment for multiple testing (p < 0.0073), one of the SNPs (SNP #17, rs1032129) remained significantly associated with FN BMD (p = 0.001). Four block-haplotypes stood multiple-testing correction. Two remained associated with FN BMD and two with fracture. The association of block-4 haplotype "AC" (of SNPs #18 and #17) with FN BMD (p = 0.0002) was stronger than that of SNP#17 alone and was the best result overall. A global assessment of the results indicated that all the alleles and haplotypes with a protective effect, at p < 0.05, belonged to a frequent long-range haplotype.. In conclusion, these results provide a detailed picture of the involvement of common variants and haplotypes of the OPG gene in bone phenotypes.

Topics: Age Factors; Aged; Bone Density; Female; Genetic Association Studies; Genotype; Haplotypes; Humans; Linkage Disequilibrium; Middle Aged; Osteoporosis, Postmenopausal; Osteoporotic Fractures; Osteoprotegerin; Polymorphism, Single Nucleotide; Prospective Studies

Osteoporosis is characterized by low bone mass, microarchitectural deterioration of bone tissue leading to increased bone fragility, and a resulting susceptibility to fractures. Distinctive environmental bone marrow conditions appear to support the development and maintenance of the unbalance between bone resorption and bone formation; these complex bone marrow circumstances would be reflected in the fluid surrounding bone marrow cells. The content of regulatory molecules in the extracellular fluid from the human bone marrow is practically unknown. Since the content of cytokines such as adiponectin, leptin, osteoprogeterin (OPG), soluble receptor activator of nuclear factor kappaB ligand (s-RANKL), tumor necrosis factor alpha, and interleukin 6 (IL-6) may elicit conditions promoting or sustaining osteoporosis, in this work we compared the concentrations of the above-mentioned cytokines and also the level of the soluble receptors for both IL-6 and leptin in the extracellular fluid from the bone marrow of nonosteoporotic and osteoporotic human donors. A supernatant fluid (bone marrow supernatant fluid [BMSF]) was obtained after spinning the aspirated bone marrow samples; donors were classified as nonosteoporotic or osteoporotic after dual-energy X-ray absorptiometry (DXA) measuring. Specific commercially available kits were used for all measurements. The cytokines' concentration in BMSF showed differently among nonosteoporotic and osteoporotic women; this last group was characterized by higher content of proinflammatory and adipogenic cytokines. Also, osteoporotic BMSF differentiated by decreased leptin bioavailability, suggesting that insufficient leptin action may distinguish the osteoporotic bone marrow.

Topics: Absorptiometry, Photon; Adipocytes; Adipose Tissue; Aged; Biomarkers; Bone Marrow; Bone Resorption; Cytokines; Female; Humans; Inflammation; Osteoblasts; Osteoporosis, Postmenopausal; Osteoprotegerin; Postmenopause

Osteoprotegerin (OPG) is a potent inhibitor of osteoclasts and plays an important role in bone metabolism. Relatively high serum levels of OPG have been observed in postmenopausal women with osteoporosis compared with age-matched controls. No data, however, are available on the relationship between low bone density and serum OPG levels in postmenopausal hemodialysis (HD) patients.. The enrolled subjects included 28 postmenopausal HD patients and 28 age-matched postmenopausal women with normal renal function as controls. Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry (DEXA) in both hips. Low BMD was defined as femoral neck T-score <-2.5. Serum OPG levels were measured using a commercial enzyme-linked immunosorbent assay (ELISA) kit.. Eight of the age-matched postmenopausal controls (28.6%) and 12 of the postmenopausal HD patients (42.9%) had low BMD. There was no statistically significant difference in low BMD between postmenopausal HD patients and age-matched postmenopausal patients (p = 0.263). The serum OPG level was significantly higher in the postmenopausal HD group (p < 0.001). Increased serum OPG (p = 0.017) and decreased serum albumin (p = 0.021) were significantly correlated with low BMD in postmenopausal HD patients. Univariate linear regression analysis showed that serum albumin (r = -0.455, p = 0.015) was negatively correlated, whereas age (r = 0.423, p = 0.025) and the length of time since menopause (r = 0.397, p = 0.036) were positively correlated with the serum OPG level in postmenopausal HD patients. Multivariate forward stepwise linear regression analysis showed that serum OPG (adjusted R(2) = 0.262, p = 0.003) was an independent predictor of low BMD in postmenopausal HD patients and explained 26.2% of the variance.. Serum OPG is associated with low BMD in postmenopausal HD patients.

Topics: Aged; Biomarkers; Bone Density; Case-Control Studies; Female; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Pilot Projects; Regression Analysis; Renal Dialysis; Serum Albumin

Atherosclerosis and osteoporosis appear to be epidemiologically correlated. Most (but not all) animal and clinical studies suggest that osteoprotegerin (OPG) may represent a possible molecular link between bone loss and vascular calcification. The aim of this study was to investigate the association of OPG with bone mineral density (BMD) and vascular plaques, in order to contribute to a better understanding of the link between atherosclerosis and osteoporosis. The study population consisted of 100 consecutive postmenopausal women referred for routine osteoporosis screening. BMD was evaluated by dual-energy X-ray absorptiometry. Presence of carotid or femoral plaques was examined by ultrasonography. OPG was measured by enzyme immunoassay. Seventy-two subjects had low bone mass and were categorized as osteopenic (32) or osteoporotic (40). Fifty-two subjects had one or more atherosclerotic plaques at carotid or femoral level. Both lumbar spine and femoral BMD were associated with the number of plaques (r=-0.5370; p<0.0001, and r=-0.4423; p=0.0012, respectively), however only spine BMD remained significantly associated with the number of plaques after adjustment. OPG serum values showed a significant association with age (r(2)=0.057; p=0.042). The association between OPG and the number of plaques was significant only in patients with concomitant involvement of carotid and femoral districts (r(2)=0.758; p<0.0001).

Topics: Aged; Aged, 80 and over; Arteries; Atherosclerosis; Bone Density; Carotid Arteries; Female; Femoral Artery; Femur; Humans; Incidence; Lumbar Vertebrae; Osteoporosis, Postmenopausal; Osteoprotegerin; Plaque, Atherosclerotic

Osteoprotegerin (OPG) appears to represent the molecular link between bone resorption and vascular calcification, and may help to explain the high prevalence of atherosclerosis and osteoporosis in postmenopausal women. We investigated a possible association between serum OPG levels and arterial stiffness in postmenopausal women with osteoporosis. 70 postmenopausal women with osteoporosis and cardiovascular risk factors but without coronary artery disease were evaluated for metabolic, inflammatory parameters and serum OPG levels. Pulse wave velocity (PWV) and augmentation index (AIx) were performed as a simple noninvasive recording of the two artery sites pressure waveform using SphygmoCor (version 7.1, AtCor Medical, Sydney, Australia). Serum OPG levels were significantly, positively associated with AIx (r=0.39, p=0.003) and with PWV (r=0.81, p<0.0001). No association between OPG levels and hemodynamic variables or measures of glucose metabolism was observed. Among inflammatory markers, OPG was significantly, positively associated with fibrinogen (r=0.323, p=0.015). In a multiple linear regression analysis, OPG was independent predictor of PWV (standardized beta=0.75, p<0.0001) and AIx (standardized beta=0.41, p=0.01). Serum OPG is potentially an independent predictor of early vascular adverse changes in osteoporotic postmenopausal women.

Topics: Aged; Aorta; Atherosclerosis; Biomarkers; Blood Glucose; Carotid Arteries; Elasticity; Female; Humans; Inflammation Mediators; Linear Models; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Predictive Value of Tests; Pulsatile Flow; Radial Artery; Risk Assessment; Risk Factors

1alpha,25-dihydroxyvitamin D(3) upregulates tumour necrosis factor superfamily member 11 (TNFSF11) that codes for the receptor activator of nuclear factor kappaB ligand (RANKL), and downregulates osteoprotegerin (OPG) expression. We have analyzed the individual effects of polymorphisms in the vitamin D receptor gene (VDR), OPG and TNFSF11, and searched for interactions between them. Six hundred and forty one subjects were evaluated: 239 osteoporotic and 228 non-osteoporotic post-menopausal, 57 pre-menopausal women and 117 elderly men. The subjects were genotyped for BsmI, FokI and Cdx2 in VDR, K3N in OPG and -290C>T, -643C>T and -693G>C in TNFSF11 gene. Bone mineral density (BMD) and biochemical markers were measured. In the osteoporotic women, femoral neck BMD (BMD-fn) showed associations with BsmI(VDR) and Cdx2(VDR) (P=0.015 and 0.047 respectively), and lumbar spine BMD (BMD-ls) with K3N(OPG) and -290C>T(TNFSF11) (P=0.021 and 0.017). No association with BMD was found in the non-osteoporotic women. In the pre-menopausal women, the Cdx2(VDR) polymorphism was associated with BMD-fn and total hip BMD (P=0.011 and 0.011). In elderly men, FokI(VDR) was associated with BMD-fn and BMD-ls (P=0.040 and 0.036). Interestingly, the -290C>T(TNFSF11)-K3N(OPG) combination was associated with BMD-th (P=0.041) in the osteoporotic women. In the non-osteoporotic women, the combination K3N(OPG)-Cdx2(VDR) was associated with BMD-ls, BMD-th and BMD-fn (P=0.032, 0.049 and 0.022), and the combination -290C>T(TNFSF11)-K3N(OPG) with BMD-fn (P=0.029). For the first time, the presence of gene-gene interactions between VDR, OPG and TNFSF11 genes was studied. Our results strongly suggest further confirmation of their combined influence on larger cohorts.

Topics: Adult; Aged; Bone Density; Female; Genotype; Humans; Male; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Genetic; Postmenopause; Premenopause; Receptors, Calcitriol; Tumor Necrosis Factor-alpha

There is increasing evidence suggesting that adiponectin plays a role in the regulation of bone metabolism.. This was a cross-sectional study of 34 post-menopausal women with and 37 without osteoporosis. All subjects had body mass index (BMI), bone mineral density (BMD), total-, high molecular weight (HMW)-adiponectin and their ratio, osteoprotegerin (OPG), a marker of bone resorption (betaCTX) and formation (P1NP) measured.. We observed a positive correlation between BMI and BMD (r=0.44, p<0.001). When normalised for BMI, total-, HMW-adiponectin concentrations and HMW/total-adiponectin ratio were significantly lower in obese compared to lean subjects but there was no difference between those with or without osteoporosis. There were significant negative correlations between HMW/total-adiponectin ratio and BMI (r=-0.27, p=0.030) and with OPG (r=-0.44, p<0.001).. Our data suggests that there is no significant difference in the circulating concentration of fasting early morning total- or HMW-adiponectin in post-menopausal women with or without osteoporosis. The correlation between HMW/total-adiponectin ratio and OPG may indicate that adiponectin could influence bone metabolism by altering osteoblast production of OPG thereby affecting osteoclasts mediated bone resorption.

Topics: Adiponectin; Aged; Aged, 80 and over; Analysis of Variance; Biomarkers; Body Mass Index; Bone and Bones; Bone Density; Collagen Type I; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Middle Aged; Molecular Weight; Osteoporosis, Postmenopausal; Osteoprotegerin; Peptide Fragments; Peptides; Postmenopause; Procollagen

Osteoprotegerin (OPG) plays a crucial role in the control of bone resorption through competitive inhibition of receptor activator of nuclear factor kappaB ligand (RANKL). This process leads to inhibition of osteoclasts differentiation and activity. The aim of the following study was to evaluate the distribution of genotypes of -163A>G and 1181G>C polymorphisms in OPG gene and analyze their relationship with bone mineral density (BMD) and other parameters of bone turnover in population of Polish postmenopausal women.. The study included 310 postmenopausal Caucasian women (54.48+/-8.53 years); 139 women with osteoporosis, 107 with osteopenia and 64 healthy women. Genetic analysis was performed by PCR/RFLP reaction. BMD value was measured by dual energy X-ray absorptiometry (DXA).. For -163A>G polymorphism the higher frequency of heterozygotes AG (26.6 vs. 18.7%, ns) and slight overrepresentation of mutated G allel (14.1 vs. 10.9%, ns) in the osteoporosis group was observed. The frequency of recessive CC homozygotes and C alleles of 1187G>C polymorphism did not differ among the investigated groups. The distribution of particular haplotypes of -163A>G and 1181G>C polymorphisms in all subgroups was similar. Correlation between values of investigated parameters of bone turnover and frequency of genotypes of investigated polymorphisms has not been observed.. The overrepresentation of heterozygous AG genotype and mutated G allele of -163A>G polymorphism of OPG gene in the group of women with osteoporosis might suggest the significance of this variant in the development of osteoporosis. A more extensive analysis of genetic variants of RANKL/RANK/OPG signal pathways, joint with an investigation of modulated influence of estrogens, TNF-alpha or several interleukin influencing the development of osteoporosis is necessary.

Topics: Absorptiometry, Photon; Adult; Bone Density; Female; Genetic Predisposition to Disease; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; RANK Ligand

While the role of osteoclasts in bone loss has been well investigated, the involvement of osteoblast-lineage cells has not been completely elucidated. Several genes contribute to normal osteoblastic differentiation from mesenchymal stem cells (MSCs), but an understanding of their role in the pathogenesis of osteoporosis is still lacking. The present study was undertaken to evaluate a possible alteration of osteogenic gene expression as a mechanism contributing to bone loss.. We studied the osteogenic differentiation process in MSCs obtained from the peripheral blood of 31 patients with osteoporosis and 20 normal donors. The cells were evaluated by colony-forming unit-fibroblastic assay and cultured in osteogenic medium to analyze the transcription factors runt-related transcription factor 2 (RUNX-2) and Sp7 and the bone-related genes COL1A1, SPARC, and SPP1 after 3, 8, and 15 days of differentiation. In addition, to determine possible differences between the 2 groups in terms of osteoclastic and osteoblastic activation, we quantified the osteoprotegerin (OPG) and RANKL levels in the supernatants of osteoblastic culture.. Circulating MSCs were increased in osteoporosis patients compared with normal donors. In contrast, gene expression analysis revealed down-regulation of RUNX2, Sp7, COL1A1, SPARC, and SPP1 in patients with osteoporosis, associated with a lower OPG:RANKL ratio.. These results suggest that an alteration of osteoblastic differentiation may contribute to the pathogenesis of osteoporosis. The noninvasive approach used in the present study could be proposed as a useful tool for studying mesenchymal involvement in bone diseases.

Topics: Aged; Bone Resorption; Case-Control Studies; Cell Differentiation; Cells, Cultured; Collagen Type I; Collagen Type I, alpha 1 Chain; Core Binding Factor Alpha 1 Subunit; Female; Humans; Mesenchymal Stem Cells; Middle Aged; Osteoblasts; Osteogenesis; Osteonectin; Osteopontin; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Sp7 Transcription Factor; Transcription Factors

In the estrogen-regulated RANK ligand (RANKL)/RANK/osteoprotegerin (OPG) pathway, estrogen deficiency favors osteoclast maturation, leading to increased bone resorption compared with bone formation. Treatment of low bone mineral density (BMD) should be based on fracture risk, assessed using the WHO Fracture Risk Algorithm (FRAX(R)). Criteria for treatment are 10-year overall fracture risk ≥ 20% or 10-year hip fracture risk ≥ 3%. Vitamin D supplementation at levels higher than those traditionally recommended may be appropriate for healthy menopausal women. Multiple strategies are needed to effectively manage osteoporosis in postmenopausal women.

Topics: Absorptiometry, Photon; Accidental Falls; Aged; Algorithms; Biomarkers; Bone Density; Bone Density Conservation Agents; Calcium; Congresses as Topic; Diphosphonates; Drug Interactions; Drug Therapy, Combination; Estrogen Replacement Therapy; Female; Food-Drug Interactions; Hip Fractures; Humans; Life Style; Mass Screening; Middle Aged; Osteoporosis, Postmenopausal; Osteoporotic Fractures; Osteoprotegerin; Practice Guidelines as Topic; RANK Ligand; Risk Assessment; Risk Factors; Treatment Outcome; Vitamin D

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biomarkers; Bone Density Conservation Agents; Denosumab; Female; Humans; Neoplasms; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Spinal Fractures

To investigate whether the polymorphism of osteoprotegerin (OPG) gene is associated with the change of BMD (bone mineral density) after alendronate therapy in postmenopausal women with osteoporosis and determine the correlation between genotypes and therapeutic effect.. Eighty postmenopausal osteoporotic patients were recruited with an average age of (64.2 +/- 7.7) years old. Every patient took oral alendronate (Fosamax) 70 mg weekly and Caltrate 600 mg daily for 12 months. At pre- and post-treatment, BMD was measured at lumbar spine 2 - 4 and hip sites. PCR-RFLP was performed for three polymorphisms at the promoter site of OPG gene (A163G, T245G and T950C).. One-year therapy was accomplished in 67 patients. Patients with G allele (genotype AG and GG) of site A163G, the baseline BMD of vertebral L2-4, inter-troche and total hip were lower than genotype AA [(0.732 +/- 0.113) g/cm(2) vs (0.819 +/- 0.157) g/cm(2), (0.775 +/- 0.101) g/cm(2) vs (0.843 +/- 0.124) g/cm(2) and (0.667 +/- 0.105) g/cm(2) vs (0.725 +/- 0.091) g/cm(2)]. Patients with G allele (genotype TG and GG) of site T245G, baseline BMD of vertebral L2-4, inter-troche and total hip were lower than genotype TT [(0.723 +/- 0.111) g/cm(2) vs (0.819 +/- 0.155) g/cm(2), (0.776 +/- 0.102) g/cm(2) vs (0.840 +/- 0.124) g/cm(2) and (0.670 +/- 0.109) g/cm(2) vs (0.721 +/- 0.091) g/cm(2)]. After one-year therapy, at site A163G, the percentage of BMD change at inter-troche was higher in genotype AA than in genotypes AG and GG [2.50 (3.47)% vs 0.88% (3.47%)%, P = 0.014]. While at site T245G, the percentage of BMD change at inter-troche and total hip were higher in genotype TT than in genotype TG and GG 2.50% (3.47%) vs 0.61% (3.31%), P = 0.011; 2.72% (2.68%) vs 0.89 (3.01%), P = 0.046].. The G allele of sites A163G and T245G may be the risk allele of postmenopausal osteoporosis. Furthermore, patients with genotypes AA (A163G) and (T245G) show a better therapeutic effect to alendronate.

Topics: Aged; Alendronate; Alleles; Bone Density; Female; Genotype; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Genetic

Arterial calcification leading to increased arterial stiffness, a powerful risk factor for cardiovascular disease, may underlie the association of osteoporosis with cardiovascular disease in postmenopausal women. Osteoprotegerin (OPG), an indirect inhibitor of osteoclastogenesis, may be involved in arterial calcification. We examined relationships between calcification of subclinical atherosclerotic plaque and arterial stiffness with bone mineral density (BMD) and OPG in a group of 54 postmenopausal women referred for routine osteoporosis screening by dual-energy X-ray absorptiometric scanning of the lumbar spine and hip. Presence of calcified and noncalcified plaque in carotid and femoral arteries was examined using ultrasonography. Pulse wave velocity (PWV), a measure of arterial stiffness, was determined by sequential tonometry over the carotid and femoral region. Fifty-nine percent of osteoporotic women had calcified (echogenic) plaque at one or more sites compared with 42% and 20% for women with osteopenia and normal BMD, respectively (P = 0.04). There was a significant negative correlation between PWV and hip BMD (r = -0.35, P = 0.01), which remained significant when age, mean arterial pressure, and serum lipids were taken into account (P = 0.05). No significant relationships were observed between serum concentrations of OPG and lumbar spine or total hip BMD or with the number of arterial sites with calcified or noncalcified plaque. However, there was a strong correlation between OPG and PWV (r = 0.44, P = 0.001), which remained significant when adjusted for age (P = 0.01). These findings suggest that decreased BMD is associated with arterial calcification and stiffening and raise the possibility that OPG is a marker of arterial stiffening, independent of any association with BMD.

Topics: Adult; Aged; Aged, 80 and over; Atherosclerosis; Biomarkers; Bone Density; Calcinosis; Carotid Arteries; Female; Hip Joint; Humans; Lumbar Vertebrae; Mass Screening; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Radiography; Ultrasonography

Osteoporosis has been associated with cardiovascular disease. We found increased augmentation index, a measure of wave reflections and arterial stiffness, and central pressures in osteoporotic postmenopausal women. They also showed a higher estimated aortic pulse wave velocity, indicating a stiffer aorta. These changes may increase cardiovascular risk in postmenopausal osteoporosis.. Evidence suggests a link between osteoporosis and cardiovascular disease. We investigated whether augmentation index (AIx), a measure of pulse wave reflections and arterial stiffness, is increased and related to the osteoprotegerin (OPG)/receptor activator of nuclear factor-kappa B ligand (RANKL) system in postmenopausal osteoporosis.. AIx and central aortic haemodynamics were assessed using pulse wave analysis in 182 cardiovascular disease-free osteoporotic postmenopausal women and in 160 controls. Statistical analysis was performed by unpaired t test, Mann-Whitney test, Spearman's correlation coefficient, and multivariate linear regression analysis.. AIx (37.2 +/- 7.0 vs. 29.6 +/- 9.2 %, P < 0.0001) and central aortic systolic (117.5 +/- 12.1 vs. 111.4 +/- 12.2 mmHg, P < 0.0001) and pulse (40.5 +/- 10.3 vs. 36.4 +/- 8.1 mmHg, P = 0.0007) pressures were significantly higher in osteoporotic patients than in controls. The estimated aortic pulse wave velocity (PWV) was also significantly higher in the osteoporotic group. In multivariate analysis for osteoporotic patients, femoral neck and lumbar spine bone mineral density T scores were independent negative predictors of AIx (P < 0.0001). AIx was not correlated with serum levels of OPG and RANKL.. Osteoporotic postmenopausal women show increased AIx and central aortic pressures, and a higher estimated aortic PWV, indicating a stiffer aorta. Such alterations may increase cardiovascular risk in postmenopausal osteoporosis.

Topics: Aorta; Blood Flow Velocity; Blood Pressure; Bone Density; Case-Control Studies; Female; Femur Neck; Humans; Italy; Lumbar Vertebrae; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Pulsatile Flow; RANK Ligand; Vascular Resistance

Serum IGF-I level was negatively correlated with OPG and OPG/RANKL ratio, but positively correlated with RANKL. Serum OPG level in the highest quintile of IGF-I was significantly lower than that in the lowest. We conclude that the effect of IGF-I on bone remodeling may be mediated by the OPG/RANKL system.. Insulin-like growth factor I (IGF-I) is an important factor in coupling bone remodeling, activating both formation and resorption. Compared with the many studies on the role of IGF-I in bone formation, the information regarding its effects on bone resorption is limited and conflicting. The balance of the two peptides produced by osteoblasts, osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand (RANKL), is critical for the bone resorption process. Our study was designed to analyze the relationships of serum concentrations of IGF-I with OPG, RANKL, OPG/RANKL ratio as well as BMDs in healthy Chinese women.. BMDs at lumbar spine and proximal femur in 504 pre- and postmenopausal women were measured by DXA. Serum levels of IGF-I, OPG and RANKL were also measured. Pearson's correlation and partial correlation analysis, ANOVA, covariance analysis and stepwise multiple regression analysis were used as appropriate.. Age was negatively correlated with serum levels of IGF-I (r = -0.702, p < 0.001). IGF-I was negatively correlated with OPG and OPG/RANKL ratio, but positively correlated with RANKL. The relationship between IGF-I and BMDs disappeared after adjustment for age. In postmenopausal women, IGF-I was lower in women with osteoporosis than in those with normal BMD (p = 0.056), but no differences were found among OPG, RANKL and OPG/RANKL ratio. Serum levels of OPG in the highest quintile of IGF-I were significantly lower than those in the lowest quintile of IGF-I, while no difference was found in RANKL. In the multiple regression analysis model, serum levels of IGF-I were the main determinants of the bone mass in Chinese women.. In conclusion, the relationship between decreasing IGF-I and BMDs in healthy Chinese women influenced by age, whereas the effect of IGF-I on bone remodeling (bone resorption) may be mediated by the OPG/RANKL system.

Topics: Adult; Aging; Bone Density; Bone Diseases, Metabolic; Female; Femur; Humans; Insulin-Like Growth Factor I; Lumbar Vertebrae; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Postmenopause; RANK Ligand

The mechanisms regulating the anabolic response of the skeleton to intermittent exogenous parathyroid hormone (PTH) administration are not fully elucidated. The aim of this prospective study was to evaluate the acute effect (up to 1 month) of teriparatide (TPTD; human recombinant PTH 1-34) on serum levels of osteoprotegerin (OPG) and receptor activator for nuclear factor-kappaB ligand (RANKL) in women with established osteoporosis.. Twenty-three postmenopausal Caucasian women with established osteoporosis (mean age 66.7+/-1.6 years) received daily injections of 20 microg TPTD for 12 months.. Serum samples for total calcium (Ca), phosphate, alkaline phosphatase, N-terminal propeptide of type I collagen, intact PTH (iPTH), OPG, and RANKL were obtained at baseline, 1 h, 1 day, and 1 month after initiation of therapy. Lumbar spine bone mineral density (BMD) was measured before and 12 months after TPTD treatment.. Serum total Ca increased and iPTH gradually decreased with TPTD treatment. Serum OPG levels remained unchanged, while RANKL increased gradually during the study (P<0.001). There was no correlation between OPG or RANKL and BMD changes or iPTH levels.. TPTD therapy in women with postmenopausal osteoporosis results in acute increase in serum RANKL levels but does not affect serum OPG. These changes may reflect an increase in the number of active osteoblasts with therapy and might be responsible for the acceleration of bone turnover rate that characterizes TPTD.

Topics: Aged; Alkaline Phosphatase; Bone and Bones; Bone Density Conservation Agents; Calcium; Female; Humans; Osteoporosis, Postmenopausal; Osteoprotegerin; Phosphorus; Prospective Studies; RANK Ligand; Teriparatide

The aim of this study was to elucidate the detail profiles of circulating osteoprotegerin (OPG) and soluble receptor activator of nuclear factor kappaB ligand (sRANKL) in post-menopausal women.. Eighty Japanese post-menopausal women were enrolled in this cross-sectional study. Circulating OPG and free fraction of sRANKL (free sRANKL), PTH, calcium and phosphorus, age, years since menopause, body mass index, bone mineral density of the vertebral bodies (LBMD) and bone turnover markers were determined in each subject.. In rank order correlation analysis, serum OPG concentrations had a significant positive correlation with age (r=0.291, p=0.024) and a marginal significant negative correlation with LBMD (r=-0.247, p=0.062). However they did not have correlations with LBMD or other parameters after adjustment for age. Serum free sRANKL concentrations had a significant positive correlation with age (r=0.332, p=0.010) and a significant negative correlation with LBMD (r=-0.608, p<0.001). This correlation with LBMD persisted after adjustment for age. In a multiple regression analysis with a stepwise model, the main determinants of LBMD were age and serum free sRANKL (p=0.015 and p=0.006, respectively).. We found the increase in circulating OPG and sRANKL with age and a robust negative correlation between circulating free sRANKL and LBMD after adjustment for age. The increase in circulating free sRANKL may reflect directly or indirectly the conditions coexistent with bone loss in post-menopausal women.

Topics: Alkaline Phosphatase; Bone Density; Calcium; Collagen Type I; Female; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Parathyroid Hormone; Peptides; Phosphorus; Postmenopause; RANK Ligand; Solubility

Topics: Calcinosis; Coronary Disease; Estrogen Replacement Therapy; Estrogens; Female; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin

We investigated the association of the G/A polymorphism at Val80 of the cytochrome P450 family 19 (CYP19) gene, the A163G polymorphism of the osteoprotegerin (OPG) gene with bone mineral density (BMD) in 200 randomly selected postmenopausal women in Chongqing. Single nucleotide polymorphisms were detected by polymerase chain reac-tion-restriction fragment length polymorphism (PCR-RFLP). BMD of the proximal femur and lumbar spine (L2-4) was measured by NORLAND XR-46 dual-energy X-ray absorptiometer (DEXA). The frequencies of genotypes in these women were as follows: GG (19.5), GA (44.5%), AA (36.0%) for the Val80 polymorphism in CYP19; and AA (13.0%), AG (42.0%), GG (45.0%) for the A163G polymorphism in OPG. The distribution of genotype frequency was in Hardy-Weinberg equilibrium (P0.05). ANCOVA and multiple stepwise regression analysis showed the Val80 polymor-phism in the third exon of the CYP19 gene was not associated with the BMD in postmenopausal women (P0.05). Except for the trochanter region, BMD at the femoral neck, Ward's triangle, and L2-4 was lower in subjects with AG/GG/AG+GG genotypes than those with the AA genotype for the A163G polymorphism and A163G genotypes were associated with BMD at these skeletal regions in postmenopausal women (P0.05). A163G polymorphism resides in the promoter region of the OPG gene and its genotype distribution is significantly different among different ethnic groups. Our results indicate that the AA genotype might have some beneficial effect on BMD and the variant G allele might reduce BMD in postmenopausal women.

Topics: Adult; Aged; Amino Acid Substitution; Aromatase; Asian People; Bone Density; Female; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Point Mutation; Polymorphism, Genetic; Valine; Women's Health

A number of polymorphisms in various genes have been identified and associated with bone mineral density (BMD) and with an increased risk of osteoporosis.. In this study, three single nucleotide polymorphisms (SNPs) within the TNFRSF11B gene were studied for association with an increased risk of osteoporosis in postmenopausal Maltese women (n=126).. Analysis was performed by PCR restriction fragment length polymorphism (RFLP) while BMD at the lumbar spine, femoral neck, Ward's triangle and trochanter was measured by DEXA.. No significant association was observed between genotypes and BMD for all polymorphisms studied within this gene. Homozygotes CC (T(950)-C) were observed to have the highest BMD at all anatomical sites although statistical significance was not reached when comparing the three genotypes. A statistical significant difference was observed in the distribution of genotype frequencies for this polymorphism between normal individuals and those that were either osteopenic or osteoporotic at one or both anatomical sites, with the TT genotype associated more frequently with low BMD. The T(950)-C and G(1181)-C polymorphisms were in strong linkage disequilibrium with each other but not with the A(163)-G polymorphism further upstream in the OPG promoter. Statistical significance was reached when constructing haplotypes, where the A-T-G haplotype was found to be more frequent in individuals with low BMD.. These results indicate the possible role of TNFRSF11B gene variants in postmenopausal bone loss in women in Malta.

Topics: Absorptiometry, Photon; Aged; Analysis of Variance; Biomarkers; Bone Remodeling; Female; Glycoproteins; Haplotypes; Humans; Malta; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Single Nucleotide; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Risk Factors; Statistics, Nonparametric

Topics: Animals; Bone Diseases; Bone Resorption; Carrier Proteins; Disease Models, Animal; Female; Glycoproteins; Humans; Membrane Glycoproteins; Osteoclasts; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

The possible relationships between biochemical measurements and both densitometric and radiographic indexes of skeletal fragility were evaluated in 65 postmenopausal women with monoclonal gammopathy of undetermined significance (MGUS). There was a significantly higher prevalence of vertebral fractures in the MGUS group compared with a control population (P < or = 0.001). The MGUS patients were then grouped according to the presence or absence of at least one mild vertebral fracture. Patients with fractures (Fx, n=34) were older (62.8 +/- 6.1 years), with long-standing disease (8.8 +/- 7.1 years) when compared with those without fractures (NFx, n=31; 59.7 +/- 5.0 years, P < or = 0.05 and 5.8 +/- 4.1 years, P < or = 0.05). The receptor activator of nuclear factor kappa-B ligand/osteoprotegerin ratio was higher in Fx compared with NFx (0.092 +/- 0.018 vs. 0.082 +/- 0.020; P < or = 0.05). Lumbar spine (0.811 +/- 0.14 vs. 0.956 +/- 0.12 g/cm2), femoral neck (0.660 +/- 0.09 vs. 0.747 +/- 0.10 g/cm2) and total bone mineral density (BMD) (0.788 +/- 0.11 vs. 0.884 +/- 0.11 g/cm2) were lower (all P < or = 0.001) in FxMGUS compared with Nfx patients. Receiver operating characteristic curves identified lumbar BMD as the variable that best predicted vertebral fractures (area under the curve 0.817; 95% confidence interval, 0.713-0.921). This study provides an indication for the measurement of BMD in MGUS patients, as a means of predicting vertebral fractures, especially in those that are asymptomatic. Patients with prevalent fractures should undergo pharmacological treatment to prevent further fractures.

Topics: Absorptiometry, Photon; Aged; Biomarkers; Bone Density; Bone Remodeling; Carrier Proteins; Female; Femur Neck; Glycoproteins; Hip; Humans; Linear Models; Lumbar Vertebrae; Membrane Glycoproteins; Middle Aged; Monoclonal Gammopathy of Undetermined Significance; Neck; Osteoporosis, Postmenopausal; Osteoprotegerin; Prevalence; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; ROC Curve; Sensitivity and Specificity; Spinal Fractures

We recently identified gamma-glutamyltransferase (GGT) as a novel bone-resorbing factor. The present study was undertaken to determine whether GGT is a marker of bone resorption in two genetic models of hyper- and hypo-function of osteoclasts, as well as in postmenopausal women with accelerated bone resorption, using type I collagen N-telopeptide (NTX) and deoxypyridinoline (DPD) as established biochemical markers. Urinary excretion of GGT, corrected for creatinine, was found to be increased in osteoprotegerin (OPG)-deficient osteoporotic mice as well as in patients with postmenopausal osteoporosis (67-83 years of age); in both cases the urinary level decreased after treatment of patients or mice with alendronate, a selective inhibitor of bone resorption, concomitantly with a reduction in DPD and NTX. Conversely, in osteopetrotic op/op mice, urinary GGT increased in parallel with DPD after induction of osteoclasts with M-CSF injection. Constant infusion of parathyroid hormone (PTH) also increased urinary GGT along with DPD. In a survey of 551 postmenopausal women (50-89 years of age) at their regular health checkup, urinary GGT excretion exhibited a high correlation with DPD (rho = 0.49, p < 0.0001). The calculated sensitivity and specificity for diagnosing elevated bone resorption, as determined by a DPD value higher than 7.6 nM/mM Cr, were 61% and 92%, respectively, when a cut-off value of 40 IU/g Cr was assigned for urinary GGT. Since GGT activity can be measured inexpensively in large numbers in a very short time, the measurement of urinary level may provide a convenient and useful method for mass screening to identify those with increased bone turnover and hence at increased risk for bone fracture.

Topics: Aged; Aged, 80 and over; Alendronate; Amino Acids; Animals; Biomarkers; Bone Density Conservation Agents; Bone Resorption; Collagen Type I; Female; gamma-Glutamyltransferase; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Osteoporosis, Postmenopausal; Osteoprotegerin; Peptides

Regulation of osteoclastic activity is critical for understanding bone loss associated with the postmenopausal period. In vitro and animal studies have revealed the role of OPG as a decoy receptor that neutralizes the effect of RANKL on the differentiation and activation of osteoclasts. However, the role of the OPG-RANKL system in postmenopausal osteoporosis is controversial. Thus, the aim of this study was to investigate the relationship among circulating levels of OPG, RANKL, bone turnover markers (BTM), bone mineral density (BMD) and vertebral fractures in postmenopausal women. We determined anthropometric parameters, circulating OPG and RANKL, BTM, estradiol, BMD by dual X-ray absorptiometry at the lumbar spine (LS) and femoral neck (FN), and pre-existing vertebral fractures in 206 ambulatory postmenopausal women of a mean age of 62 years (SD 7). Circulating OPG was significantly related to age (r =0.158; P =0.023), years since menopause (r =0.167; P =0.016) and BMD (LS Z-score: r =0.240; P =0.001, FN Z-score: r =0.156; P =0.025). Over half of the women had undetectable RANKL (n =113; 54.9%). There were no significant differences in clinical variables, BTM or BMD among women with detectable vs. undetectable RANKL. OPG was found to be independently associated with osteoporosis (OR: 2.9, 1.4-5.9) and prevalent vertebral fractures (OR: 2.5, 1.2-5.4). We conclude that serum OPG levels are independently associated with bone mass and prevalent vertebral fractures in postmenopausal women.

Topics: Absorptiometry, Photon; Acid Phosphatase; Aged; Alkaline Phosphatase; Biomarkers; Bone Density; Carrier Proteins; Estradiol; Female; Femur Neck; Glycoproteins; Humans; Isoenzymes; Lumbar Vertebrae; Membrane Glycoproteins; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Prospective Studies; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Spinal Fractures; Tartrate-Resistant Acid Phosphatase

The objective was to identify single nucleotide polymorphisms (SNPs) in exons of the osteoprotegerin gene and to analyze the relationship between the SNPs and bone mineral density in postmenopausal women. We used polymerase chain reaction (PCR) and direct sequencing methods to identify SNPs and genotypes in 205 postmenopausal women. BMD at the lumbar spine (L2-4) and femoral neck (FN) were measured by dual-energy X-ray absorptiometry (DEXA). Serum osteocalcin (OC), osteoprotegerin (OPG), receptor activator of nuclear factor kappaB ligand (RANKL) and urinary N-telopeptide of type I collagen (NTx) were also measured. In exon 1 of the OPG gene, we found the Lys3Asn SNP. In 205 postmenopausal women, the Asn-allele frequency was 26.0%, and the distribution of Lys3Asn genotypes was Lys-Lys 56.6%, Lys-Asn 34.6% and Asn-Asn 8.8%, respectively. BMD at the lumbar spine (L2-4) of the Asn-Asn genotype was significantly higher (9.5-12.6%) than Lys-Asn and Lys-Lys genotypes (P=0.012), with evidence for an allele dose effect (P=0.008). Results remained similar after adjustment for age and body mass index. The Lys3Asn polymorphism of the OPG gene alone accounted for 7.7% of the variance of the L2-4 BMD in a multiple regression model. Logistic regression analysis revealed that the OPG genotype Lys-Lys had a 2.7 times (95% CI: 0.83-9.11) greater risk for osteopenia/osteoporosis than the Asn-Asn genotype. The Lys3Asn polymorphism in the OPG gene is associated with L2-4 BMD in postmenopausal women. The Lys-allele is associated with lower BMD and an increased risk for osteoporosis.

Topics: Absorptiometry, Photon; Aged; Bone Density; Bone Diseases, Metabolic; Carrier Proteins; Collagen; Collagen Type I; Exons; Female; Femur Neck; Gene Frequency; Genotype; Glycoproteins; Humans; Lumbar Vertebrae; Membrane Glycoproteins; Middle Aged; Osteocalcin; Osteoporosis, Postmenopausal; Osteoprotegerin; Peptides; Polymorphism, Single Nucleotide; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

We evaluated the association of different genotypes in C161-->T substitution in exon 6 of peroxisome proliferator-activated receptor-gamma (PPARgamma) gene with bone turnover markers, bone mineral density (BMD), and serum osteoprotegerin (OPG) in female subjects to reveal the role of PPARgamma in bone.. In 263 healthy Korean women (mean age 52 years), anthropometric measurements were taken along with measurements of lumbar spine and femoral neck BMD, bone turnover markers, such as alkaline phosphatase, serum calcium, phosphorus, 24-hour urine calcium, phosphorus excretion, and urine deoxypyridinoline. Serum follicular stimulating hormone levels were measured and serum OPG levels were measured with the enzyme-linked immunosorbent assay method. Polymerase chain reaction-restriction fragment length polymorphism was performed.. Allele frequencies were 0.804 for the C allele and 0.196 for the T allele. There were no differences in mean age, body mass index, BMD, and bone turnover markers among different genotypes, and the subjects with T alleles had significantly lower serum OPG levels. There were no differences in the prevalence of metabolic bone diseases according to the genotypes. When analyzed according to the menopausal status, only postmenopausal subjects with T alleles showed significantly lower serum OPG levels.. The frequencies of C161-->T substitution in exon 6 of the PPARgamma gene in Korean females were similar to other races and women with T alleles showed significantly lower serum OPG levels and it was especially noted for postmenopausal subjects, which supports the possible concurrent association of PPARgamma and OPG with estrogen status in female subjects.

Topics: Alleles; Analysis of Variance; Anthropometry; Base Sequence; Bone and Bones; Bone Density; Cohort Studies; Female; Gene Frequency; Genotype; Glycoproteins; Humans; Korea; Middle Aged; Molecular Sequence Data; Mutation; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymerase Chain Reaction; Polymorphism, Genetic; PPAR gamma; Probability; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Reference Values; Risk Assessment; Sensitivity and Specificity; Statistics, Nonparametric

Osteoprotegerin (OPG) is a recently discovered member of the tumour necrosis factor receptor superfamily. It plays a crucial role in the control of bone resorption and its gene could therefore be a good candidate gene for osteoporosis. The aim of our work was to find polymorphisms in the OPG gene and to investigate their possible contribution to the genetic susceptibility to osteoporosis by testing for their association with bone mineral density (BMD).. The whole OPG gene coding region was screened for the presence of polymorphisms in a group of 60 osteoporotic women by single-strand conformation polymorphism analysis (SSCP) approach. Association of the discovered polymorphisms with bone mineral density was investigated in 136 Slovenian postmenopausal women.. We detected eight OPG gene polymorphisms that were confirmed by direct DNA sequencing, deletion 4752_4753delCT and nucleotide substitutions 1181G>C, 1217C>T, 1284G>A, 4501C>T, 6893A>G, 6950A>C and 8738T>A. Nucleotide substitutions 1284G>A and 8738T>A have not been previously described. Polymorphisms 4752_4753delCT, 6893A>G and 6950A>C were in complete linkage and the same was true for 1217C>T and 4501C>T. The association with BMD was found only for polymorphism 1181G>C. Subjects with genotype 1181GG had significantly lower lumbar spine BMD than subjects displaying 1181GC.. By our approach we detected eight polymorphisms in the OPG gene. According to our analysis polymorphism 1181G>C is associated with BMD and could therefore be considered as an element of genetic susceptibility to osteoporosis.

Topics: Aged; Bone Density; DNA; Female; Genetic Predisposition to Disease; Genotype; Glycoproteins; Heteroduplex Analysis; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Polymorphism, Single-Stranded Conformational; Postmenopause; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

To evaluate the effects of genetic polymorphisms of OPG, RANK, and ESR1, which regulate osteoclastogenesis, on bone mineral density (BMD), a cross-sectional study was conducted in 650 Korean postmenopausal women. BMDs of the distal radius and the calcaneus were measured by dual energy X-ray absorptiometry (DXA). Genetic polymorphisms of OPG 163 A > G, 1181 G > C; RANK 421 C > T, 575 T > C; and ESR1 1335 C > T, 2142 G > A were determined by matrix-assisted laser desorption/ionization-time of flight (MALDI-ToF) mass spectrometry. The differences between the BMDs of the genotypes of OPG, RANK, and ESR1 were analyzed by multiple linear regression model adjusted for age and body mass index. Women with the OPG 1181 CC genotype had higher BMDs at the distal radius (7%) and calcaneus (10%) than those with the GG genotype; and these differences were statistically significant (P = 0.001 and P = 0.007, respectively). A significant association was also observed between RANK 575 T > C and calcaneus BMD (P for trend = 0.017). No significant association was observed between BMDs and the polymorphisms of ESR1. The association between OPG 1181 G > C and BMD was profound in subjects with the RANK 575 TT or ESR1 2142 GG genotypes; women with OPG 1181 CC had higher BMDs at the distal radius (11%) and calcaneus (11%) than those with OPG 1181 GG only in women with RANK 575 TT genotype (P = 0.002 and P = 0.021, respectively). These results suggest that OPG genetic polymorphisms, especially with the RANK 575 TT or ESR1 2142 GG genotypes, are related to low BMD in postmenopausal Korean women.

Topics: Adult; Aged; Bone Density; Carrier Proteins; Cross-Sectional Studies; Estrogen Receptor alpha; Female; Glycoproteins; Humans; Korea; Membrane Glycoproteins; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Single Nucleotide; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

An isopropanolic extract (iCR) from the rhizomes of Cimicifuga racemosa (black cohosh) is used an alternative in the treatment of menopausal symptoms, and animal studies suggest positive skeletal effects. iCR stimulated osteoblastic OPG protein secretion by 3- to 5-fold as early as 12 h without affecting RANKL expression. The iCR effect, abrogated by the pure estrogen receptor antagonist ICI 182,780, also enhanced ALP activity (4-fold) and osteocalcin expression (3-fold), possibly contributing to the skeletal effects of black cohosh.. Despite its positive effects on the skeleton, estrogen replacement therapy is no longer recommended as first-line therapy for the prevention and treatment of postmenopausal osteoporosis because it increases cardiovascular, thromboembolic, and breast cancer risk. Recently, herbal therapeutics such as an isopropanolic extract (iCR) from the rhizomes of Cimicifuga (=Actaea) racemosa (black cohosh) are gaining interest as an alternative in the treatment of menopausal symptoms. Whereas animal studies in rats suggest positive skeletal effects, the mechanism of its actions on bone cells remain unclear. RANKL is essential for osteoclast formation and activation, while osteoprotegerin (OPG) neutralizes RANKL.. In this study, we assessed the effects of iCR on OPG and RANKL mRNA steady-state levels by semiquantitative RT-PCR and on protein production by an ELISA system in human osteoblasts (hOBs).. Under serum-free conditions, treatment with iCR increased OPG mRNA levels and protein secretion of hOBs by 2- to 3-fold in a dose-dependent manner, with a maximum effect at a 10(6)-fold dilution of iCR (p < 0.001) after 24-48 h. Time-course experiments indicated a stimulatory effect of iCR on osteoblastic OPG protein secretion by 3- to 5-fold (p < 0.001) as early as 12 h, whereas RANKL expression was very low and was not found to be modulated by iCR. Of note, the stimulatory effect of iCR on OPG production was abrogated by the pure estrogen receptor antagonist ICI 182,780. Moreover, iCR enhanced two osteoblastic differentiation markers, bone-specific alkaline phosphatase activity and osteocalcin expression, by up to 4- and 3-fold, respectively (p < 0.001).. Our data suggest that iCR enhances differentiation and increases the OPG-to-RANKL ratio of normal human osteoblasts. These effects may contribute to the positive skeletal effects of black cohosh.

Topics: 2-Propanol; Adult; Alkaline Phosphatase; Carrier Proteins; Cell Differentiation; Cells, Cultured; Cimicifuga; Dexamethasone; Dose-Response Relationship, Drug; Enzyme Activation; Estradiol; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Fulvestrant; Gene Expression; Glycoproteins; Humans; Male; Membrane Glycoproteins; Menopause; Osteoblasts; Osteocalcin; Osteoporosis, Postmenopausal; Osteoprotegerin; Plant Extracts; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Progesterone; Receptors, Tumor Necrosis Factor; RNA, Messenger

Osteoprotegerin (OPG), a secreted member of the tumor necrosis factor receptor family, is a potent inhibitor of osteoclast activation and differentiation. In animal models OPG prevents bone loss, and in humans bone resorption can be reduced by injections of OPG. OPG may also play a role in cardiovascular disease since mice lacking the OPG gene display arterial calcification. In a screening effort of the OPG gene, we recently discovered a single nucleotide polymorphism in the promoter region of OPG (T950C), and reported an association with vascular morphology and function in 59 healthy individuals. Due to the pronounced effect of OPG on bone turnover, the present study was conducted to investigate whether OPG polymorphisms are also associated with bone mineral density or with fracture. The relationship between single nucleotide polymorphisms in the promoter region of OPG (T950C) and the first intron (C1217T), and bone mineral density, measured by DXA in the hip or spine or ultrasound of the heel, was investigated in the Malmö OPRA-study of 1044 women, all 75 years old. The possible relation to fracture incidence was also analyzed. Among the 858 and 864 individuals respectively, genotyped, no significant associations between the investigated single nucleotide polymorphisms and bone mineral density measurements (T950C P = 0.50-0.64, C1217T P = 0.51-1.00), quantitative ultrasound measurements of the calcaneus, or fractures (T950C P = 0.61-0.66, C1217T P = 0.14-0.33) were found. Thus, our results show that polymorphisms in the OPG gene, one of which has previously been found to be associated with cardiovascular morphology and function, are not associated with bone mineral density in elderly Swedish women.

Topics: Aged; Bone Density; Calcaneus; Cohort Studies; Female; Fractures, Spontaneous; Glycoproteins; Humans; Incidence; Introns; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Sweden; Ultrasonography

To investigate the effect of promoter region polymorphism of osteoprotegerin (OPG) gene on bone mineral density (BMD) and markers of bone turnover in postmenopausal women.. The OPG genotype were determined by PCR-RFLP in 259 postmenopausal women of Han race in Shanghai area, and BMD at lumbar-spine, femoral neck, trochanter and Ward's triangle etc., were measured by dual-energy X-ray absorptiometry (DEXA). Some markers of bone turnover were also detected.. Hardy-Weinberg equilibrium was evident for OPG polymorphism. The frequency of the genotype is as following: TT59%, TC28%, CC13%. Postmenopausal women were divided into two groups. Women aged less than 65 years old were in group I, and aged 65 years old and over were in group II. In group I the BMD at femur neck area was 0.64 g/cm(2) +/- 0.11 g/cm(2), 0.67 g/cm(2) +/- 0.11 g/cm(2), 0.68 g/cm(2) +/- 0.14 g/cm(2) of TT, TC, CC genotypes respectively, among which a significant difference was observed (P < 0.05 by ANOVA), and the significant difference also presented after adjusted by age and BMI, but not found the significant difference in other markers. In group II, significant link was not observed between OPG polymorphism and BMD with markers of bone turnover.. OPG polymorphism may have an effect on the BMD of postmenopausal women aged less than 65. It is possibly that the role of OPG gene mainly on the obtaining of peak BMD in women.

Topics: Absorptiometry, Photon; Aged; Bone Density; Cross-Sectional Studies; Female; Gene Frequency; Genotype; Glycoproteins; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Genetic; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Serum GH and IGF-I levels decline with increasing age, whereas osteoprotegerin (OPG) increases. IGFs as well as OPG are present in bone matrix and mediate the effects of many upstream hormones (e.g. estrogen). To evaluate whether changes in these proteins may to some extent explain the decrease in bone mass in postmenopausal or senile osteoporosis, we measured bone contents of IGF-I, IGF-II, IGF binding protein (IGFBP)-3, IGFBP-5, and OPG in combined extracts obtained after EDTA and guanidine hydrochloride extraction in 60 postmenopausal women aged 47-74 (mean, 63) yr with a previous distal forearm fracture and a hip or spine Z-score less than 0. We found age-related increases in IGFBP-3 (r = 0.35; P < 0.01), IGFBP-5 (r = 0.59; P < 0.001), and OPG (r = 0.36; P < 0.01) in cortical bone, significantly inversely correlated with femoral neck and lumbar spine BMD. A correlation between age and OPG was also detected in trabecular bone (r = 0.27; P < 0.05). A pronounced age-related decrease in cortical calcium contents (r = -0.60; P < 0.001), positively correlated with femoral neck and lumbar spine BMD, was also found. No age-related changes were detected for IGF-I or IGF-II. The present study demonstrates age-related changes in cortical bone contents of IGFBPs, calcium, and OPG, possibly related to the pathophysiology of postmenopausal osteoporosis. As for OPG, our findings probably represent compensatory responses to increased osteoclastic resorption.

Topics: Age Factors; Aged; Bone and Bones; Bone Density; Calcium; Cross-Sectional Studies; Female; Glycoproteins; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Protein 5; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Topics: Bone Remodeling; Bone Resorption; Carrier Proteins; Female; Glycoproteins; Humans; Membrane Glycoproteins; Middle Aged; Mutation; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Studies in rodents have implicated various cytokines as paracrine mediators of increased osteoclastogenesis during estrogen deficiency, but increases in RANKL, the final effector of osteoclastogenesis, have not been demonstrated. Thus, we isolated bone marrow mononuclear cells expressing RANKL on their surfaces by two-color flow cytometry using FITC-conjugated osteoprotegerin-Fc (OPG-Fc-FITC) as a probe. The cells were characterized as preosteoblastic marrow stromal cells (MSCs), T lymphocytes, or B lymphocytes by using Ab's against bone alkaline phosphatase (BAP), CD3, and CD20, respectively, in 12 premenopausal women (Group A), 12 early postmenopausal women (Group B), and 12 age-matched, estrogen-treated postmenopausal women (Group C). Fluorescence intensity of OPG-Fc-FITC, an index of the surface concentration of RANKL per cell, was increased in Group B over Groups A and C by two- to threefold for MSCs, T cells, B cells, and total RANKL-expressing cells. Moreover, in the merged groups, RANKL expression per cell correlated directly with the bone resorption markers, serum C-terminal telopeptide of type I collagen and urine N-telopeptide of type I collagen, in all three cell types and inversely with serum 17beta-estradiol for total RANKL-expressing cells. The data suggest that upregulation of RANKL on bone marrow cells is an important determinant of increased bone resorption induced by estrogen deficiency.

Topics: Adult; Apoptosis Regulatory Proteins; Bone Resorption; Carrier Proteins; Female; Flow Cytometry; Glycoproteins; Humans; Membrane Glycoproteins; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha

Pre-clinical data have shown that osteoprotegerin (OPG) inhibits osteoclast function and therefore plays an important role in bone remodelling. This study aimed to evaluate the clinical value of serum OPG. Do higher OPG serum levels reflect decreased bone resorption and perhaps higher bone mass in women? Serum OPG levels were measured in 177 healthy women (aged 17-85 years) and in 48 untreated patients (mean age 71 +/- 5) with established osteoporosis, and related to age, bone mass, markers of bone turnover and, in the case of patients with osteoporosis, to pre-existing vertebral fractures. In healthy women OPG levels showed a positive correlation with age (r = 0.25, p < 0.001) but not to bone mass or markers of bone turnover. In women with osteoporosis, however, there was a strong relationship between serum OPG and markers of bone turnover (serum c-terminal crosslinked telopeptides of thpe I collagen (sCTX): r = +0.82, p < 0.0001; osteocalcin (OC): r = +0.69, p < 0.0001), with patients who had higher levels of bone-turnover markers showing higher serum levels of OPG. After adjustment for bone mass and bone markers, patients with pre-existing vertebral fractures had significantly lower serum OPG levels than patients without fractures (57 +/- 8 vs. 97 +/- 10 pg/ml, [mean +/- SE], p < 0.01). The age-dependent increase of OPG as an antiresorptive factor may reflect an insufficient paracrine mechanism of bone cells to compensate for bone loss in older age. In patients with osteoporosis, however, OPG correlated strongly with markers of bone turnover; this may point toward a higher level of RANKL/OPG expression in these patients. Finally, low OPG serum levels seem to be associated with vertebral fractures. We hypothesise that low OPG levels in preset conditions of bone turnover may indicate a higher risk of fracture in patients with osteoporosis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Bone Density; Bone Diseases, Metabolic; Bone Resorption; Female; Fractures, Spontaneous; Glycoproteins; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Reference Values; Spinal Fractures

Type I osteoporosis occurs within 20 years after menopause and is associated with excessive cancellous bone loss and fractures of the vertebrae and distal radius. We have suggested that it may be caused by estrogen deficiency plus some additional factor predisposing to excessive bone loss. One such factor might be a greater degree of sex steroid deficiency, a possibility that could not be previously excluded because assays of sufficient sensitivity have only recently become available. Thus, we studied 36 women with vertebral fractures due to typical high turnover type I postmenopausal osteoporosis and 36 normal postmenopausal women using new ultrasensitive assays with detection limits of 1 pg/ml for estradiol, 5 pg/ml for estrone and 5 ng/dl for testosterone to test if type I osteoporosis results from enhanced responsiveness of bone to estrogen deficiency. Mean levels of serum sex steroids were identical in both groups, but bone turnover was increased by up to 55% in the women with type I osteoporosis. Moreover, compared with controls, the osteoporotic women had a 51% higher ( P<0.01) serum osteoprotegerin level, which was likely a compensatory response to the increased bone turnover. In the osteoporotic women, 1-year treatment with transdermal estrogen in 14 women reduced total deoxypyridinoline, an index of bone resorption, by 58% as compared with placebo treatment in 17 women ( P<0.001). Thus, as compared to controls, postmenopausal osteoporotic women had comparable sex steroid levels but higher bone turnover levels that were responsive to estrogen therapy. This is consistent with the hypothesis that the greater bone loss in type I osteoporosis is the result of impaired responsiveness of bone to low postmenopausal levels of sex steroids.

Topics: Aged; Bone Resorption; Estradiol; Estrone; Female; Glycoproteins; Gonadal Steroid Hormones; Humans; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Spinal Fractures; Testosterone

Osteoporosis (OP) is a systemic metabolic lesion of the skeleton involving a reduced osseous tissue weight and an impaired microarchitectonics, which worsens the bone strength and contributes to a higher risk of bone fractures. An essential spread of OP and of osteoporotic fractures among populations in various countries, including Russia, a high-severity outcome, and big economic expenses related with treatment and rehabilitation are indicative of a high social OP significance. OP is a multi-factor pathology provoked by impaired processes in osseous remodeling with a higher resorption of osseous tissue and a reduced osteogenesis. A study of molecular mechanisms of intercellular interaction in OP resulted in discovering new elements in the family of tumor necrosis factor (TNF) and their ligands and receptors (RANKL-RANK-OPG), which are of primary importance in osteoclastogenesis and which are molecular mediators in many regulatory effects. The key drugs applicable to prevention and treatment of OP are also described in the article. The current methods of OP prevention and treatment improve the bone quality and reduce the incidence rate of fracture in an essential share of patients.

Topics: Adult; Age Factors; Aged; Bone Density; Diphosphonates; Female; Glycoproteins; Hip Fractures; Humans; Male; Middle Aged; Moscow; Multicenter Studies as Topic; Osteoporosis; Osteoporosis, Postmenopausal; Osteoprotegerin; Placebos; Prospective Studies; Randomized Controlled Trials as Topic; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Risk Factors; Russia; Sex Factors; Spinal Fractures; United States

Osteoprotegerin (OPG) is a recently identified citokine with an important role in bone remodeling, that acts as a decoy receptor for RANKL; OPG was shown to be an important inhibitor of osteoclast differentiation and activation. Leptin influences bone metabolism by acting on differentiated osteoblasts, having an anabolic effect on bone. The relationship between circulating OPG levels and osteoporosis in postmenopausal women is controversial. Thus, one of the aims of our study was to investigate the relationships between OPG levels and biochemical markers of bone turnover and bone density in women with and without osteoporosis. We have investigated 135 postmenopausal women, including a group with osteoporosis (n=76, mean age 59+/-8 years) and a group with severe osteoporosis (n=31, mean age 64+/-8 years), using healthy postmenopausal women (n=28, mean age 48+/-9 years) as controls. The serum concentrations of OPG were determinated by ELISA. Serum estradiol was measured by Enzyme Immunoassay (EIA). The markers of bone formation and resorption were measured by standard methods. Leptin was measured by ELISA. Bone mineral density at lumbar spine and femoral neck was measured by dual energy x-ray absorptiometry (DEXA). There was a significant positive association between serum OPG levels and age (r=0.27; p<0.001), both in the postmenopausal women as a whole and in the cohort with osteoporosis. Circulating OPG levels were significantly higher in both osteoporotic groups (p<0.005 and p<0.01, respectively) than in the control group. There were no significant associations between serum OPG levels and bone density, bone markers and serum estradiol. Serum leptin levels were significantly associated with age (r=0.18, p<0.03), estradiol (r=0.2, p<0.05) and BMD (r=0.25, p<0.008); there was no significant relationship between leptin and bone turnover markers. We conclude that serum OPG levels increase with age, both in healthy and osteoporotic postmenopausal women. This could represent a possible protective mechanism against bone loss. Serum leptin levels also increase with age and are positively associated with estradiol and BMD and not significantly associated with bone turnover markers.

Topics: Adult; Bone Density; Bone Resorption; Estradiol; Female; Glycoproteins; Humans; Leptin; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Leptin; Receptors, Tumor Necrosis Factor

Osteoprotegerin (OPG), a secreted glycoprotein and a member of the tumor necrosis factor receptor superfamily, is considered to play an important role in the regulation of bone resorption by modifying osteoclast differentiation. Overexpression of OPG in mice has been reported to result in osteopetrosis, whereas targeted disruption of OPG in mice has been associated with osteoporosis. Accordingly, OPG could be a strong candidate gene for susceptibility to human osteoporosis. Here, we analyzed whether OPG is involved in the etiology of osteoporosis using both linkage and association analyses. We recruited 164 sib pairs in Gunma prefecture, which is located in the central part of Honshu (mainland Japan), for a linkage study, and 394 postmenopausal women in Akita prefecture, which is in the northern part of Honshu, for an association study. We identified two microsatellite polymorphisms in the linkage study, and six single-nucleotide polymorphisms (SNPs) in the OPG region for the association study. Although, no evidence of significant linkage between OPG and osteoporosis was found, a possible association of one SNP, located in the promoter region of the gene, was identified. A haplotype analysis with the six SNPs revealed that four major haplotypes account for 71% of the alleles in the Japanese population.

Topics: Base Sequence; Bone Density; Female; Genetic Linkage; Glycoproteins; Haplotypes; Humans; Molecular Sequence Data; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Osteoprotegerin (OPG) is a recently discovered member of the TNF receptor superfamily that acts as an important paracrine regulator of bone remodeling. OPG knockout mice develop severe osteoporosis, whereas administration of OPG can prevent ovariectomy-induced bone loss. These findings implicate a role for OPG in the development of osteoporosis. In the present study, we screened the OPG gene promoter for sequence variations and examined their association with bone mineral density (BMD) in 103 osteoporotic postmenopausal women. Single-strand conformation polymorphism analysis followed by DNA sequencing revealed a presence of four nucleotide substitutions: 209 G-->A, 245 T-->G, 889 C-->T, and 950 T-->C. The frequencies of genotypes were as follows: GG (89.3%), GA (10.7%) for 209 G-->A polymorphism; TT (89.3%), TG (10.7%) for 245 T-->G polymorphism; and TT (25.2%), TC (53.4%), CC (21.4%) for 950 T-->C polymorphism. Substitution 889 C-->T was found in only two patients. Statistically significant association of genotypes with BMD at the lumbar spine (P = 0.005) was observed for 209 G-->A and 245 T-->G polymorphisms. Haplotype GATG was associated with lower BMD as compared with GGTT haplotype. Our results suggest that 209 G-->A and 245 T-->G polymorphisms in the OPG gene promoter may contribute to the genetic regulation of BMD.

Topics: Aged; Base Sequence; Body Constitution; Bone Density; DNA Primers; Female; Genetic Variation; Glycoproteins; Humans; Osteoporosis, Postmenopausal; Osteoprotegerin; Polymorphism, Single-Stranded Conformational; Promoter Regions, Genetic; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Osteoprotegerin (OPG)/osteoclastogenesis inhibitory factor (OCIF) is a soluble member of the tumor necrosis factor receptor family of proteins and plays an important role in the negative regulation of osteoclastic bone resorption. Whether OPG/OCIF circulates in human blood and how its level changes under pathological conditions is not known. To address these issues, a panel of monoclonal antibodies was generated against recombinant OPG/OCIF and screened for reactivity with solid-phase monomeric and homodimeric forms of the recombinant protein. Antibodies that showed high affinity for both forms of OPG/OCIF and those that selectively recognized the homodimer were identified, enabling development of two types of sensitive enzyme-linked immunosorbent assay (ELISA): one that detects both forms of OPG/OCIF equally and one specific for the homodimer. Characterization of circulating OPG/OCIF with these ELISAs revealed that the protein exists in human serum mainly in the monomeric form. The serum concentration of OPG/OCIF increased with age in both healthy Japanese men and women, and was significantly higher in postmenopausal women with osteoporosis than in age-matched controls. Within the osteoporotic group, serum OPG/OCIF concentrations were higher in patients with low bone mass. Serum OPG/OCIF concentrations were also significantly increased in those postmenopausal women with a high rate of bone turnover, as determined by increased serum bone-specific alkaline phosphatase and urinary excretion of pyridinoline and deoxypyridinoline. The results suggested that circulating OPG/OCIF levels are regulated by an age-related factor(s) and that the increased serum concentration may reflect a compensative response to enhanced osteoclastic bone resorption and the resultant bone loss rather than a cause of osteoporosis.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antibodies, Monoclonal; Antibody Specificity; Bone Density; Bone Diseases, Metabolic; Case-Control Studies; Dimerization; Enzyme-Linked Immunosorbent Assay; Female; Glycoproteins; Humans; Male; Mice; Middle Aged; Osteoporosis, Postmenopausal; Osteoprotegerin; Protein Conformation; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Recombinant Proteins