Allopurinol ameliorates high fructose diet induced hepatic steatosis in diabetic rats through modulation of lipid metabolism, inflammation, and ER stress pathway.

Excess fructose consumption contributes to development obesity, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD). Uric acid (UA), a metabolite of fructose metabolism, may have a direct role in development of NAFLD, with unclear mechanism. This study aimed to evaluate role of fructose and UA in NAFLD and explore mechanisms of allopurinol (Allo, a UA lowering medication) on NAFLD in Otsuka Long-Evans Tokushima Fatty (OLETF) rats fed a high fructose diet (HFrD), with Long-Evans Tokushima Otsuka (LETO) rats used as a control. There were six groups: LETO, LETO-Allo, OLETF, OLETF-Allo, OLETF-HFrD, and OLETF-HFrD-Allo. HFrD significantly increased body weight, epididymal fat weight, and serum concentrations of UA, cholesterol, triglyceride, HbA1c, hepatic enzymes, HOMA-IR, fasting insulin, and two hour-glucose after intraperitoneal glucose tolerance tests, as well as NAFLD activity score of liver, compared to the OLETF group. Allopurinol treatment significantly reduced hepatic steatosis, epididymal fat, serum UA, HOMA-IR, hepatic enzyme levels, and cholesterol in the OLETF-HFrD-Allo group. Additionally, allopurinol significantly downregulated expression of lipogenic genes, upregulated lipid oxidation genes, downregulated hepatic pro-inflammatory cytokine genes, and decreased ER-stress induced protein expression, in comparison with the OLETF-HFrD group. In conclusion, allopurinol ameliorates HFrD-induced hepatic steatosis through modulation of hepatic lipid metabolism, inflammation, and ER stress pathway. UA may have a direct role in development of fructose-induced hepatic steatosis, and allopurinol could be a candidate for prevention or treatment of NAFLD.

The association between lipoprotein (a) and carotid atherosclerosis in patients with type 2 diabetes without pre-existing cardiovascular disease: A cross-sectional study.

AIMS: Lipoprotein (a) [Lp(a)] has been considered a determinant of residual cardiovascular risk. We aimed to investigate associations between serum Lp(a) levels and carotid atherosclerosis. METHODS: This cross-sectional study included 662 type 2 diabetic patients without cardiovascular disease. The mean value of three right and left measurements was used to indentify increased carotid intima-media thickness (CIMT). A carotid plaque was defined as a focal wall thickening >50% of the surrounding IMT or its CIMT ≥1.5 mm. The presence of carotid atherosclerosis was defined as having CIMT ≥1.0 mm or carotid plaque. RESULTS: A total of 34.3% of patients had carotid atherosclerosis. The median Lp(a) level was significantly higher in subjects with carotid atherosclerosis (14.6 vs. 10.2 mg/dL, P < 0.001). The log-transformed Lp(a) level per 1-standard deviation increase was significantly associated with higher risk of the presence of carotid atherosclerosis (odds ratio [OR] 1.46; 95% confidence interval [CI] 1.16 - 1.84, P = 0.001) after adjusting other parameters. The log Lp(a) level was still significantly associated with the risk of carotid atherosclerosis in subjects with optimal low-density lipoprotein cholesterol (LDL-C) <100 mg/dL (OR 1.48; 95% CI 1.16 - 1.88, P = 0.001). Higher Lp(a) and LDL-C had an additive effect on the presence of carotid atherosclerosis. CONCLUSION: Elevated Lp(a) was significantly associated with the presence of carotid atherosclerosis in patients with type 2 diabetes, independent of conventional cardiometabolic risk factors.

Clinical Significance of Paraspinal Muscle Parameters as a prognostic factor for survival in Gastric Cancer Patients who underwent Curative Surgical Resection.

Background: The quantitative and qualitative skeletal muscle parameters have been proposed to predict the outcome of patients with gastric cancer. However, the evidence for their association with long-term survival is still conflicting. This study aimed to investigate the effect of paraspinal muscle parameters on overall survival (OS) and disease-free survival (DFS) in patients with gastric cancer who underwent curative resection. Methods: Patients with stages I or II gastric cancer who underwent curative resection between October 2006 and June 2016 were identified from electrical medical records. Paraspinal muscle area and attenuation were measured at the level of the third lumbar vertebra using computerized tomography images. For the analysis of OS and DFS, proportional hazards model was used, incorporating demographic, pathologic, laboratory, and radiologic variables. Results: This study enrolled 296 patients (192 men and 104 women). In the multivariate proportional hazards model, total gastrectomy (hazard ratio [HR], 2.65; 95% Confidence interval [CI], 1.36-5.19; p = 0.0044), neutrophil-lymphocyte ratio (NLR) (HR, 1.27; 95% CI, 1.06-1.51; p = 0.0081), serum albumin level (HR, 0.16; 95% CI, 0.07-0.39; p < 0.0001), paraspinal muscle area adjusted for body surface area (PMABSA) (HR, 3.06; 95% CI, 1.65-5.67; p = 0.0004), and mean attenuation in paraspinal muscle (PMMA) (HR, 3.38; 95% CI, 1.75-6.53; p = 0.0003) were prognostic factors for OS. Similarly, total gastrectomy (HR, 2.11; 95% CI, 1.10-4.06; p = 0.0243), NLR (HR, 1.25; 95% CI, 1.06-1.48; p = 0.0071), serum albumin level (HR, 0.22; 95% CI, 0.10-0.51; p = 0.0035), PMABSA (HR, 2.42; 95% CI, 1.34-4.37; p = 0.0035), and PMMA (HR, 3.19; 95% CI, 1.71-5.93; p = 0.0003) were prognostic factors for DFS. Conclusions: The pretreatment paraspinal muscle parameters such as PMABSA and PMMA along with total gastrectomy, NLR, and serum albumin level could predict OS and DFS in patients with stages I or II gastric cancer who underwent curative surgical resection. Because PMABSA and PMMA are newly characterized parameters in gastric cancer, the relationship with the survival of these parameters requires further validation in further studies before they are subjected to clinical applications.

Incidence and mortality of subsequent vertebral fractures: analysis of claims data of the Korea National Health Insurance Service from 2007 to 2016.

BACKGROUND CONTEXT: Vertebral fracture is related to an increased risk for subsequent and recurrent osteoporotic fracture as well as increased mortality. However, no study has investigated the exact incidence and mortality of subsequent vertebral fractures. OBJECTIVE: The purpose of our study was to determine trends in the incidence and mortality of subsequent vertebral fractures after first-time vertebral fracture in Koreans older than 50 years using the national claims database. STUDY DESIGN: Retrospective cohort study. PATIENT SAMPLE: Data from the Korea National Health Insurance Service database from 2007 to 2016. OUTCOME MEASURES: The incidence of subsequent vertebral fracture during a 4-year follow-up period. The mortality and standardized mortality ratio (SMR) after subsequent vertebral fractures during the 1-year period after fracture were also determined. Analysis was restricted to patients older than 50 years. METHODS: The national claims data set was analyzed to find all new visits and revisits after 6 months from the last claim to a hospital or clinic for vertebral fractures and revisits in men and women aged 50 years or older between 2007 and 2016. The number of first-time vertebral fractures in 2012 was investigated to determine subsequent vertebral fractures. The incidence, mortality rates, and SMR of subsequent vertebral fractures were calculated. There were no sources of funding and no conflicts of interest associated with this study. RESULTS: During the 4-year follow-up period, the overall cumulative incidence of subsequent vertebral fractures were 27.53%. According to sex, the cumulative incidence of subsequent vertebral fractures was 20.09% in men and 29.98% in women. The cumulative mortality rate over the first year after subsequent vertebral fractures was 5%. The mortality rates over 1 year were 10.04% for men and 3.81% for women. The overall SMR at the 1-year follow-up after subsequent vertebral fractures was 10.58 (95% confidence interval: 9.29-12.05) in men and 3.88 (95% confidence interval: 3.5-4.3) in women. CONCLUSIONS: Our study showed that subsequent vertebral fractures were more common in women, with an incidence rate of 29.98% over 4 years. However, the mortality rate was higher in men, reaching 10.04% in 1 year. Subsequent vertebral fractures occurred in large numbers, and the mortality rates were relatively high. Thus, first vertebral fracture may be considered as an early warning of high risk for future subsequent vertebral fractures, especially in women.

Efficacy of risedronate with cholecalciferol on bone mineral density in Korean patients with osteoporosis.

The efficacy of once-weekly risedronate with and without cholecalciferol in bone mineral density (BMD) in Korean patients with osteoporosis was compared. After 12 months, both spine and hip BMD increased significantly in both groups, but there was no significant difference between two groups. INTRODUCTION: This study investigated the efficacy and safety of once-weekly risedronate with and without cholecalciferol in BMD in Korean patients with osteoporosis. METHODS: This was a prospective, 12-month, randomized, open-labeled, actively controlled trial involving 41 hospitals. A total of 841 subjects with osteoporosis were randomized to once-weekly risedronate (35 mg) and cholecalciferol (5600 IU) in a single pill (RSD+, n = 642) or once-weekly risedronate (35 mg) alone (RSD, n = 199). BMD was measured via dual-energy X-ray absorptiometry at the lumbar spine and hip, and the serum levels of 25-hydroxy vitamin D (25(OH) D), parathyroid hormone (PTH), and alkaline phosphatase (ALP) were assayed at baseline and after 12 months of treatment. RESULTS: After 12 months, the lumbar spine, femoral neck, and total hip BMD increased significantly in both groups; there was no significant difference between two groups. Women in the RSD+ group exhibited significantly increased lumbar spine BMD, and subjects with previous fracture history in the RSD+ group had significantly increased total hip BMD compared with the RSD group. The serum 25(OH) D level increased significantly in the RSD+ group. The serum PTH level decreased in the RSD+ group but increased in the RSD group. The serum ALP level significantly decreased in both groups; there was no significant difference between two groups. CONCLUSIONS: A once-weekly pill containing risedronate and cholecalciferol had the equivalent antiresorptive efficacy on BMD compared with risedronate alone and improved 25(OH) D serum levels after 12 months of treatment without significant adverse events in Korean patients with osteoporosis.

Assessment of patient-reported outcomes (PROs): treatment satisfaction, medication adherence, and quality of life (QoL) and the associated factors in postmenopausal osteoporosis (PMO) patients in Korea.

Patient-reported outcomes (PROs) provide practical guides for treatment; however, studies that have evaluated PROs of women in Korea with postmenopausal osteoporosis (PMO) are lacking. This cross-sectional, multi-center (29 nationwide hospitals) study, performed from March 2013 to July 2014, aimed to assess PROs related to treatment satisfaction, medication adherence, and quality of life (QoL) in Korean PMO women using osteoporosis medication for prevention/treatment. Patient demographics, clinical characteristics, treatment patterns, PROs, and experience using medication were collected. The 14-item Treatment Satisfaction Questionnaire for Medication (TSQM) (score-range, 0-100; domains: effectiveness, side effects, convenience, global satisfaction), Osteoporosis-Specific Morisky Medication Adherence Scale (OS-MMAS) (score-range, 0-8), and EuroQol-5 dimensions questionnaire (index score range, - 0.22 to 1.0; EuroQol visual analog scale score range, 0-100) were used. To investigate factors associated with PROs, linear (treatment satisfaction/QoL) or logistic (medication adherence) regression analyses were conducted. A total of 1804 patients (age, 62 years) were investigated; 60.1% used bisphosphonate, with the majority (67.2%) using weekly medication, 27.8% used daily hormone replacement therapy, and 12.1% used daily selective estrogen receptor modulator. Several patients reported gastrointestinal (GI) events (31.6%) and dental visits due to problems (24.1%) while using medication. Factors associated with the highest OS-MMAS domain scores were convenience and global satisfaction. GI events were associated with non-adherence. TSQM scores for effectiveness, side effects, and GI risk factors were significantly associated with QoL. Our study elaborately assessed the factors associated with PROs of Korean PMO women. Based on our findings, appropriate treatment-related adjustments such as frequency/choice of medications and GI risk management may improve PROs.

Compound K attenuates glucose intolerance and hepatic steatosis through AMPK-dependent pathways in type 2 diabetic OLETF rats.

BACKGROUND/AIMS: Non-alcoholic fatty liver disease is associated with insulin resistance. Compound K (CK) is the final metabolite of panaxadiol ginsenosides that have been shown to exert antidiabetic effects. However, the molecular mechanism of the antidiabetic effects in the liver have not been elucidated; further, whether CK has beneficial effects in hepatosteatosis remains unclear. Therefore, we evaluated the effect of CK on hepatosteatosis as well as its mechanism in high-fat diet (HFD)-fed type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. METHODS: Twenty-four-week-old male OLETF rats were assigned to four groups: control (saline), CK 10 mg/kg, CK 25 mg/kg, or metformin 300 mg/kg (positive control); all treatments were administered orally for 12 weeks. RESULTS: Fasting glucose levels of the CK25 group were significantly lower than those of the control group during the 12 weeks. The results of the oral glucose tolerance test showed that both the glucose concentration after glucose loading and the fasting insulin levels of the CK25 group were significantly lower than those of the control. Hepatosteatosis was significantly improved by CK25. CK25 and metformin significantly increased the phosphorylation of hepatic adenosine monophosphate-activated protein kinase (AMPK). CK25 significantly inhibited the expression of sterol regulatory element-binding protein-1c and fatty acid synthase, while upregulating that of peroxisome proliferator-activated receptor-α and carnitine palmitoyltransferase-1. CONCLUSIONS: CK improved glucose intolerance and hepatosteatosis in HFD-fed OLETF rats through AMPK activation, which has dual mode of action that involves decreasing the synthesis of fatty acids and increasing fatty acid oxidation.

Effects of C-reactive protein on bone cells.

AIMS: Inflammatory processes are involved in bone remodeling. C-reactive protein (CRP) is an acute phase reactant that reflects different degrees of inflammation. Accumulating evidence suggests that CRP is an inflammatory marker and a direct cause of disease. Therefore, we examined the direct effects of CRP on bone cells. MAIN METHODS: We used RAW 264.7 cells to evaluate the direct effects of CRP on osteoclast differentiation. We carried out alkaline phosphatase (ALP) and bone nodule formation assays using MC3T3-E1 cells to evaluate osteoblast differentiation. Expression of osteoclast-specific and osteoblast-specific genes and effects on cell signaling pathways associated with cell differentiation were analyzed by reverse transcription polymerase chain reaction and Western blotting. KEY FINDINGS: CRP significantly and dose-dependently inhibited TRAP-positive multinucleated cell formation in RANKL-induced RAW 264.7 cell cultures. We observed suppression of p38, ERK and AKT mitogen-activated protein kinases induced by RANKL in Western blots after CRP treatment of RAW 264.7 cells. CRP also suppressed ALP activity and mineralization by Alizarin red S staining of MC3T3-E1 cell cultures. CRP suppressed osteoclast-specific and osteoblast-specific genes. Furthermore, CRP increased interferon beta (IFN-ß) mRNA expression and protein levels in RAW 264.7 and MC3T3-E1 cells, and these effects were suppressed by oxPAPC, an inhibitor of Toll-like receptor (TLR) signaling. SIGNIFICANCE: These data indicated that CRP may have a direct role on osteoclast and osteoblast differentiation via TLR signaling pathways.

Bisphenol A reduces differentiation and stimulates apoptosis of osteoclasts and osteoblasts.

AIMS: Bisphenol A (BPA), a major component of epoxy resins used in protective coatings, is a known endocrine-disrupting chemical. BPA has the ability of binding to estrogen receptors. In the current paper, we examine the direct effects of bisphenol A on in vitro osteoclast and osteoblast culture systems. MAIN METHODS: We evaluated the effects of BPA on osteoclast formation using bone marrow-derived macrophages and RAW 264.7 cells and on osteoblast differentiation using MC3T3-E1 cells. KEY FINDINGS: BPA significantly inhibited RANKL-induced, TRAP-positive multinucleated cell formation in bone marrow-derived macrophages and RAW 264.7 cell cultures in a dose-dependent manner (0.5 µM to 12.5 µM). We observed suppression of ERK, JNK, AKT, and p38 mitogen-activated protein kinases induced by RANKL in Western blotting after BPA treatment in RAW 264.7 cells. Furthermore, BPA suppressed Bcl-2 (anti-apoptotic) while stimulating Bax (pro-apoptotic) protein expression in RAW 264.7 cells. Bisphenol A also significantly suppressed ALP activities and bone nodule formation in MC3T3-E1 cell cultures. Specifically, the expression of Bcl-2 protein was decreased, and changes in expression of caspases 3, 8, and 9 were detected by BPA treatment in both cells. SIGNIFICANCE: We found that bisphenol A directly suppressed both osteoclastic and osteoblastic activities in vitro. Our data suggest that bisphenol A suppresses cell differentiation and survival.

Changes in Serum Osteocalcin are Not Associated with Changes in Glucose or Insulin for Osteoporotic Patients Treated with Bisphosphonate.

BACKGROUND: Bisphosphonate is used in osteoporosis treatment to repress osteoclast activity, which then decreases levels of osteocalcin (OC). OC, a protein secreted by osteoblasts and released from the bone matrix during osteoclastic bone resorption, has been found to control blood glucose levels by increasing insulin production and sensitivity. The question addressed in this study is whether decreasing OC through bisphosphonate treatment will provoke a change in glucose homeostasis. METHODS: Eighty-four patients with osteoporosis were treated with once-weekly risedronate 35 mg and cholecalciferol 5,600 IU. We measured fasting plasma glucose (FPG), insulin, and undercarboxylated (Glu) and carboxylated (Gla) OC levels at baseline and after 16 weeks. To estimate insulin resistance (IR) and ß-cell function (B)%, homeostasis model assessment (HOMA)-IR and HOMA-B% were also calculated, respectively. RESULTS: The mean FPG level in total subjects increased significantly from 5.3 to 5.5 mmol/L, but no changes in blood glucose were noted in the 24 subjects with impaired fasting glucose. Glu and Gla OC levels declined significantly after treatment. No correlations were observed between changes in OC and changes in glucose, however. CONCLUSIONS: Bisphosphonate treatment for osteoporosis reduced OC, but this change was not associated with changes in glucose metabolism.

Validation of a new food frequency questionnaire for assessment of calcium and vitamin d intake in korean women.

BACKGROUND: Validated simple calcium questionnaires are available to assess the intake of calcium and vitamin D in western countries, but they are not appropriate for Koreans since dairy products are not the major source of calcium and vitamin D in Korea. Thus, the objective of the present study was to develop and validate a simple and easy food frequency questionnaire (FFQ) of calcium and vitamin D for Korean. METHODS: Two hundred and fifty-six women were asked to complete the validated FFQ used by the Korean National Health and Nutrition Examination Survey (KNHANES) and a newly developed FFQ, the Korean Calcium Assessment Tool (KCAT), which contain the 7 food groups with 24 categories of 45 food items that are consumed frequently by Koreans. RESULTS: Calcium intake was not significantly different between the two methods; Pearson's correlation coefficient of 0.98 indicated a positive correlation, and Cohen's kappa coefficient of 0.78 indicated the subjects were correctly classified. Bland-Altman plot also showed that the mean differences of the calcium intake as assessed by the two methods were in high agreement. However, the vitamin D intake assessed by KCAT was significantly higher than that assessed by the FFQ used in KNHANES. The vitamin D intakes as assessed by the two methods were positively correlated but the two methods were in moderate agreement. CONCLUSIONS: The results suggested that the newly developed KCAT was a valid tool for assessing the calcium intake in Korean women, but it might overestimate the vitamin D intake.

Serum bisphenol a concentration in postmenopausal women with osteoporosis.

OBJECTIVES: Bishphenol A (BPA) is a representative endocrine disruptor and is also known as a xenoestrogen. The objective of the present study is to investigate how many patients are exposed to BPA and to analyze the relationships between serum BPA concentration, bone mineral density (BMD) and biochemical bone markers in postmenopausal women with osteoporosis. METHODS: Total 51 patients were enrolled for measuring BPA and clinical variables including BMD and bone markers. The relationship between BPA and clinical variables were analyzed by the Pearson's correlation test and the Kruskal-Wallis test. Serum BPA concentration was measured by enzyme linked immunosorbent assay (ELISA). RESULTS: BPA was detected in all samples. The mean BPA concentration was 1.44 ± 0.52 ng/mL. There was no statistically significant correlation between BPA and clinical variables. CONCLUSION: There was no statistical significance between serum BPA concentration and clinical variables related to bone metabolism. To clarify the effect of BPA on bone metabolism, further large scaled and high risk group investigation may be needed.

Ghrelin suppresses tunicamycin- or thapsigargin-triggered endoplasmic reticulum stress-mediated apoptosis in primary cultured rat cortical neuronal cells.

Ghrelin functions as a neuroprotective agent and rescues neurons from various insults. However, the molecular mechanisms underlying ghrelin neuroprotection remains to be elucidated. An accumulation of unfolded proteins in the endoplasmic reticulum (ER) leads to ER stress and then induces ER stress-mediated cell death. Here, we report that acylated ghrelin inhibited tunicamycin- or thapsigargin-triggered ER stress-induced apoptotic cell death in primary rat cortical neurons. An analysis using a specific inhibitor of phosphatidylinositol-3-kinase (PI3K), LY294002, showed that ghrelin prevented apoptosis via the activation of PI3K signaling pathway. Ghrelin suppressed tunicamycin- or thapsigargin-induced upregulation and nuclear translocation of C/EBP homologous protein (CHOP). Ghrelin also inhibited tunicamycin or thapsigargin induction of PRK-like ER kinase (PERK), eukaryotic translation initiation factor-2α (eIF2α) and activating transcription factor (ATF) 4. Exposure of cells to tunicamycin or thapsigargin resulted in nuclear translocation of forkhead box protein O1 (Foxo1), which was reduced by pretreatment with ghrelin. The protective effect of ghrelin was accompanied by an increased phosphorylation of Akt and glycogen synthase kinase (GSK)-3ß. Furthermore, ghrelin phosphorylated and inactivated pro-apoptotic BAD and Foxo1. In addition, phospho-Akt was translocated to the nucleus in response to ghrelin and PI3K inhibition by LY294002 prevented ghrelin-induced effect on phospho-Akt localization. Our study suggests that suppression of CHOP activation via the inhibition of PERK/eIF2α/ATF4 pathway and prevention of Foxo1 activation and nuclear translocation may contribute to ghrelin-mediated neuroprotection during ER stress responses. Our data also suggest that PI3K/Akt-mediated inactivation of GSK-3ß, BAD and Foxo1 may be associated with the anti-apoptotic effect of ghrelin.

Efficacy of risedronate with cholecalciferol on 25-hydroxyvitamin D level and bone turnover in Korean patients with osteoporosis.

BACKGROUND: We performed a randomized, double-blind, prospective, 16-week clinical trial to evaluate the efficacy and safety of risedronate with and without cholecalciferol on 25-hydroxyvitamin D [25(OH)D] levels and bone markers in Korean patients with osteoporosis. METHODS: We randomly assigned 164 adults with osteoporosis to one of two treatment groups: weekly risedronate 35 mg and cholecalciferol 5600 IU combined in a single pill (RSD+) or weekly risedronate 35 mg alone (RSD). We measured serum levels of 25(OH)D, parathyroid hormone (PTH), and bone markers and performed muscle function tests, at baseline and after 16 weeks of treatment. RESULTS: After 16 weeks of treatment, mean serum 25(OH)D increased significantly from 39·8 to 70·8 nmol/l in the RSD+ group and declined significantly from 40·5 to 35 nmol/l in the RSD group. Although both treatment groups had significant increases in serum PTH over baseline during the study, the RSD group had a significantly larger increase than the RSD+ group (13·6 vs 4·8 ng/l; P = 0·0005). In both groups, serum bone-specific alkaline phosphatase (BSAP) and C-terminal telopeptide (CTX) declined rapidly; there were no significant differences between groups. There was also no significant difference between groups in lower-extremity function tests. The overall incidence of clinical adverse events was not significantly different between groups. CONCLUSION: In patients with osteoporosis, a once-weekly pill of risedronate and cholecalciferol provided equivalent antiresorptive efficacy to risedronate alone in terms of bone turnover and improved 25(OH)D level over a 16-week treatment period without significant adverse events.

Comparison of monthly ibandronate versus weekly risedronate in preference, convenience, and bone turnover markers in Korean postmenopausal osteoporotic women.

Patient preferences, convenience, and bone turnover markers were evaluated for the monthly ibandronate over the weekly risedronate regimen in Korean postmenopausal osteoporotic women. This was a 6-month, prospective, randomized, open-label, multicenter study with a two-period and two-sequence crossover treatment design. After a 30-day screening period, eligible participants with postmenopausal osteoporosis were randomized to receive either monthly oral ibandronate 150 mg for 3 months followed by weekly oral risedronate 35 mg for 12 weeks (sequence A) or the same regimen in reverse order (sequence B). Patient preference and convenience were evaluated by questionnaire. The changes in serum C-telopeptide after 3 months of treatment were analyzed. A total of 365 patients were enrolled in this study (sequence A 182, sequence B 183). Of patients expressing a preference (83.4%), 74.8% preferred the monthly ibandronate regimen over the weekly regimen (25.2%). More women stated that the monthly ibandronate regimen was more convenient (84.2%) than the weekly regimen (15.8%). There was no significant difference in the change in bone turnover marker between the two treatments. The two regimens were similarly tolerable. There were fewer adverse events in the monthly ibandronate group compared to the weekly risedronate group in terms of gastrointestinal side effects (nausea and abdominal distension). This study revealed a strong preference and convenience for monthly ibandronate over weekly risedronate in Korean postmenopausal osteoporotic women. There was no significant difference in change of bone turnover marker and safety profile between the two regimens.

The effects of A. senticosus supplementation on serum lipid profiles, biomarkers of oxidative stress, and lymphocyte DNA damage in postmenopausal women.

This study examined the effects of Acanthopanax senticosus supplementation on serum lipid profiles, biomarkers of oxidative stress, and lymphocyte DNA damage in postmenopausal women. Forty postmenopausal women, ages 40-65, were randomly divided into two groups: (1) control group (calcium) and (2) treatment group (calcium plus A. senticosus). Both groups were treated for 6 months. Blood samples were obtained before and after supplementation at 6 months. The following blood parameters were measured: serum total cholesterol, triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), serum malondialdehyde (MDA), ccdd protein-carbonyl (PC) levels, the degree of lymphocyte DNA damage by comet assay, total ferric reducing antioxidant power (FRAP), uric acid, and total bilirubin in serum. The treatment group had significant decreases (p<0.001) in serum LDL (127.54+/-29.79mg/dL vs 110.33+/-22.26mg/dL) and the LDL/HDL ratio (2.40+/-0.65 vs 2.11+/-0.58) after A. senticosus supplementation. Serum MDA concentrations decreased by 2.2% in the control group and by 12.61% in the treatment group after 6 months of intervention; however, the reductions were not significant in either group. Protein-carbonyl levels and lymphocyte DNA damage decreased significantly (p<0.001 and p<0.05, respectively) after 6 months of A. senticosus supplementation. These results suggest that A. senticosus supplementation may have beneficial effects against oxidative stress and improve serum lipid profiles without subsequent side effects.

Annexin II stimulates RANKL expression through MAPK.

UNLABELLED: We report that AX-II, in addition to inducing GM-CSF expression, also increases membrane-bound RANKL synthesis by marrow stromal cells and does so through a previously unreported MAPK-dependent pathway. Thus, both GM-CSF and RANKL are required for AX-II stimulation of OCL formation. INTRODUCTION: Annexin II (AX-II) is an autocrine/paracrine factor secreted by osteoclasts (OCLs) that stimulates human OCL formation and bone resorption in vitro by inducing bone marrow stromal cells and activated CD4+ T cells to produce granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF in turn increases OCL precursor proliferation and further enhances OCL formation. However, the induction of GM-CSF by AX-II cannot fully explain its effects on OCL formation. In this study, we tested the capacity of AX-II to induce the expression of RANKL and the corresponding signaling pathways AX-II employs in human marrow stromal cells to induce RANKL. We also showed that both GM-CSF and RANKL are required for OCL formation induced by AX-II. MATERIALS AND METHODS: Real-time RT-PCR and Western blot analysis were used to detect RANKL and osteoprotegerin (OPG) mRNA and protein expression in unfractionated human bone marrow mononuclear cells stimulated with AX-II. Soluble RANKL in the conditioned medium was analyzed by ELISA. Activation of the MAPK pathway by AX-II was tested by Western blot. The effects of OPG and anti-GM-CSF on AX-II-induced OCL formation were also examined. RESULTS AND CONCLUSION: In addition to upregulating GM-CSF mRNA, AX-II increased RANKL mRNA expression dose-dependently in unfractionated human bone marrow mononuclear cells and modestly increased soluble RANKL in unfractionated human bone marrow mononuclear cell conditioned medium. However, AX-II markedly increased membrane-bound RANKL on human bone marrow stromal cells. Treatment of marrow stromal cells with AX-II activated MAP-kinase (ERKs) and PD 98059 abolished the effect but did not block the increase in GM-CSF. Interestingly, OPG, a natural decoy receptor for RANKL, or anti-GM-CSF partially inhibited OCL formation by AX-II in human bone marrow cells, and the combination of OPG and anti-GM-CSF completely blocked AX-II-induced OCL formation. These data show that AX-II stimulates both the proliferation and differentiation of OCL precursors through production of GM-CSF and RANKL respectively.