Meta-analysis of randomized controlled trials for the efficacy and safety of anti-interleukin-13 therapy with lebrikizumab in patients with uncontrolled asthma.

BACKGROUND: Several studies have evaluated the efficacy and safety of lebrikizumab treatment with uncontrolled asthma. However, most of these studies were small and conclusions were inconsistent. Furthermore, whether serum periostin can act as a good predictor of the response to lebrikizumab treatment is still not certain. METHOD: We conducted a systematic review and meta-analysis of randomized controlled trials to evaluate the efficacy and safety of lebrikizumab treatment with uncontrolled asthma. Trials were searched in PubMed, Embase, Web of Science and Cochrane. Outcome measures were the rate of asthma exacerbations, relative changes in the forced expiratory volume in the first second of expiration (FEV1) of predicted value (%) and incidence of adverse events. RESULT: Five trials were finally included. Compared with placebo lebrikizumab treatment significantly decreased the rate of exacerbations(risk ratio [RR] 0.66 [95% confidence interval {CI}, 0.54-0.80]; p < 0.0001; n = 2039) and increased FEV1% of predicted value (weighted mean difference [WMD] 5.46 [95% CI, 2.48-8.43]; p < 0.0003; n = 351). Patients with high levels of serum periostin had greater exacerbation rate reductions (RR 0.59 [95%CI, 0.50-0.70]; p < 0.00001; n = 1157) and FEV1 of predicted value improvement (WMD 7.18 [95% CI, 2.93-11.42]; p < 0.0009; n = 177) than patients with low periostin levels in exacerbation rate reductions (RR 0.73 [95% CI, 0.47-1.14]; p < 0.17; n = 882) and FEV1 of predicted value improvement (WMD3.79 [95% CI, 0.39-7.97]; p < 0.08; n = 174). There was no significant difference in the incidence of adverse events in patients with lebrikizumab compared to placebo (RR 1.03 [95% CI, 0.99-1.06]; p < 0.11; n = 2056). CONCLUSION: In patients with uncontrolled asthma, lebrikizumab treatment significantly decreased the rate of exacerbation and improved lung function, especially for patients with high periostin levels.

Alleviation of Glucocorticoid-Induced Osteoporosis in Rats by Ethanolic Reynoutria multiflora (Thunb.) Moldenke Extract.

Secondary osteoporosis is frequently due to the use of high-dose glucocorticoids (GCs). The existing strategy for managing glucocorticoid-induced osteoporosis (GIOP) is considered insufficient and remains in a state of ongoing evolution. Therefore, it is crucial to develop more precise and effective agents for the treatment of GIOP. The constituents of Reynoutria multiflora (Thunb.) Moldenke, specifically Polygonum multiflorum (PM) Thunb, have previously shown promise in mitigating osteopenia. This study aimed to investigate the therapeutic effects of an ethanolic PM extract (PMR30) against GIOP in male rats. Prednisone (6 mg/kg/day, GC) was continuously administered to rats to induce GIOP, and they were subjected to treatment with or without ethanolic PMR30 for a duration of 120 days. Serum was collected for biochemical marker analysis. Bone histomorphometric, histological, and TUNEL analyses were performed on tibia samples. The protein expressions of LC3, Agt5, and Beclin 1 in the femur underwent examination through western blotting. Prolonged and excessive GC treatment significantly impeded bone formation, concomitant with reduced bone mass and body weight. It also suppressed OCN and OPG/RANKL in serum, and decreased Beclin 1 and LC3 in bone. Simultaneously, there was an elevation in bone resorption markers and apoptosis. Treatments with both high dose and low dose of PMR30 alleviated GIOP, stimulated bone formation, and upregulated OCN and OPG/RANKL, while suppressing TRACP-5b, CTX-I, and apoptosis. The impact of PMR30 possibly involves the enhancement of autophagy proteins (LC3, Agt5, and Beclin 1) and the inhibition of apoptosis within the bone. PMR30 holds promise as a prospective therapeutic agent for preventing and treating GIOP.

Polygonum multiflorm alleviates glucocorticoid­induced osteoporosis and Wnt signaling pathway.

It is known that long­term excessive administration of glucocorticoid (GC) results in osteoporosis. The present study aimed to evaluate the protective effects of Polygonum multiflorm (PM) on the bone tissue of rats with GC­induced osteoporosis (GIO). A total of 90 6­month­old female Sprague Dawley rats (weight range, 190­210 g) were randomly divided into nine groups: Control (normal saline); prednisone (GC; 6 mg·kg­1·d­1; Model); GC plus PMR30 (the 30% ethanol eluent fraction of PM) (H) (400 mg·kg­1·d­1); GC plus PMR30 (M) (200 mg·kg­1·d­1); GC plus PMR30 (L) (100 mg·kg­1·d­1); GC plus PMRF (fat­soluble fraction of PM) (H) (400 mg·kg­1·d­1); GC plus PMRF (M) (200 mg·kg­1·d­1); GC plus PMRF (L) (100 mg·kg­1·d­1); GC plus calcitriol (CAL; 0.045 µg·kg­1·d­1; positive). Rats were administered intragastrically with prednisone and/or the aforementioned extracts for 120 days, and weighed once/week. The serum was collected for detection of biochemical markers. The left tibia was used for bone histomorphometry analysis. The right tibia was prepared for hematoxylin and eosin staining. The left femur was used to analyze the protein expression of dickkopf­1 (DKK1), WNT inhibitory factor 1 (WIF1) and secreted frizzled related protein 4 using western blotting. Long­term excessive treatment of prednisone inhibited the bone formation rate accompanied with a decrease in bone mass, growth plate, body weight, and the level of bone­specific alkaline phosphatase and hydroxyl­terminal propeptide of type I procollagen in the serum. Furthermore, a simultaneously increase in the level of tartrate resistant acid phosphatase­5b and cross­linked carboxy­terminal telopeptide of type I collagen in the serum, in addition to DKK1, and WIF1 protein expression, was observed. PMR30 (M and L) and PMRF (H) groups were able to reduce the negative effects of GC on the bones. PMR30 (M and L) and PMRF (H) dose demonstrated a protective effect of PM on bone tissue in GIO rats. The mechanism underlying the preventive effect of PM for the treatment of GIO may be associated with direct upregulation of the canonical Wnt/ß­catenin signaling pathway.

Preventive effects of Polygonum multiflorum on glucocorticoid-induced osteoporosis in rats.

In Traditional Chinese Medicine, Polygonum multiflorum (PM) is known for its anti-aging properties. A previous study by our group showed that extracts of PM were able to prevent and treat bone loss in vivo, and the active components emodin and 2,3,5,4,-tetrahydroxystilbene-2-O-ß-glucoside (TSG) promoted the osteogenic differentiation of mesenchymal stem cells in vitro. The aim of the present study was to investigate the preventive effects of PM on glucocorticoid-induced osteoporosis (GIO) in rats. A crude extract of PM was prepared with 75% ethanol, purified and enriched using a D-101 macroresin column and elution with 30% ethanol, and the material obtained was assessed by high-performance liquid chromatography. Male or female Sprague Dawley rats (n=180) were randomly divided into nine groups: Control, prednisone, prednisone plus calcitriol (CAL), prednisone plus 30% ethanolic eluate of PM [high (H), medium (M) and low (L) dose] and prednisone plus crude extract of PM (H, M and L dose). Prednisone was orally administered to the osteoporosis model rats for 21 weeks, alongside which they received PM extracts. The weight of the viscera, anterior tibial muscle and other tissues was recorded at the end of the experiment. The femur and lumbar vertebra were collected for the measurement of three-dimensional microarchitecture by micro-computed tomography scanning, assessment of biomechanical properties and determination of bone mineral density (BMD). In the 30% ethanolic eluate of the PM extract, the content of TSG and combined anthraquinone was 9.20 and 0.15%, respectively, and that in the crude extract of PM was 2.23 and 0.03%, respectively. Over 6 weeks, the weight of the rats the in prednisone group decreased (P<0.05), while the weight of rats treated with M and H doses of 30% ethanolic eluate was increased compared with that in the prednisone group (P<0.05). Rats exposed to prednisone exhibited a deteriorated bone microarchitecture, low BMD, decreased bone volume/total volume and poor biomechanical properties. Furthermore, the weight of the adrenal gland and the anterior tibial muscle was decreased. 30% ethanolic eluate of PM at M and L doses and crude extract of PM at the H dose counteracted the alterations of skeletal and other characteristics induced by prednisone in rats, as did CAL. In conclusion, extracts of PM exerted a protective effect on bone tissue in GIO rats.

Tetrahydroxystilbene glucoside isolated from Polygonum multiflorum Thunb. demonstrates osteoblast differentiation promoting activity.

Polygonum multiflorum Thunb. is a traditional Chinese medicinal herb that has been widely used to treat age-associated diseases. Tetrahydroxystilbene glucoside (TSG), also known as 2,3,5,4-tetrahydroxystilbene-2-O-ß-D-glucoside, is a major component of this herb. The present study was designed to investigate the osteogenic differentiation promoting activity of TSG in rat mesenchymal stem cells (MSCs) and in zebrafish. Preliminary experiments using MTT assay and ALP methods indicate that the high potential activity for promoting osteogenic differentiation was observed when 50% ethanol eluate was used. Further isolation and purification of TSG from the 50% ethanol eluate was performed by bioassay-guided fractionation, and its structure was confirmed using nuclear magnetic resonance and mass spectrometry analyses. In addition, the relative content of TSG with the highest potential activity in the promotion of osteogenic differentiation was identified as 14.34% by reversed-phase high performance liquid chromatography. Subsequently, the osteogenic differentiation promoting abilities of TSG in MSCs were examined. The results demonstrated that TSG promoted the alkaline phosphatase activity at concentrations of 1.56-25 µg/ml, while it increased the content of osteocalcin 7 days after treatment with 6.25-25 µg/ml in MSCs. Furthermore, experiments in zebrafish indicated that different concentrations of TSG (3.12-12.5 µg/ml) protected against further bone loss induced by 10 µmol/l dexamethasone (Dex), simulating an osteoporosis (OP) model. TSG treatment (12.5 µg/ml) in Dex-induced zebrafish significantly increased the area of nodules by 50.14% compared with the untreated model group. In conclusion, TSG, as a major component of P. multiflorum Thunb. exhibited an osteogenic promoting activity in MSCs and in zebrafish. The results provided scientific evidence to support the potential use of TSG for protecting the bone in degenerative diseases, such as OP.

Upper gastrointestinal safety and tolerability of oral alendronate: A meta-analysis.

Osteoporosis (OP), which is a common bone disease associated with reduced bone mineral density and disordered bone microstructure, may result in an increased risk of bone fracture. The present study aimed to investigate the frequency of alendronate (Aln)-associated upper gastrointestinal tract adverse events (GIAEs) in postmenopausal women with OP. The following databases were searched in order to identify relevant studies: Medline (using PubMed as the search engine), Embase, the Web of Science and the Cochrane Central Register of Controlled Trials (up to December 2014). Studies were selected for inclusion if they were randomized, double-blind, placebo-controlled trials, which had investigated the safety of Aln versus a placebo for the treatment of postmenopausal women with OP. The primary outcomes of the included studies were total adverse events (AEs) and upper GIAEs, whereas individual upper GIAEs were considered as secondary outcomes. The general characteristics and outcomes of each study were abstracted by two independent researchers, and Review Manager 5.3 software was used for data syntheses and the meta-analysis. A total of nine studies, including 15,192 randomized patients, met the inclusion criteria and contributed to some or all of the meta-analysis outcomes. The Mantel-Haenszel method was used to calculate risk ratios, and their 95% confidence intervals (CI) were determined using either the fixed or random effects model, depending on the level of heterogeneity. The relative risk (95% CI) of AEs associated with Aln treatment, as compared with the placebo group, was 1.01 (0.97-1.06), and the relative risk (95% CI) of discontinued Aln treatment due to AEs was 1.04 (0.91-1.19). In addition, the relative risk (95% CI) of upper GIAEs was 1.02 (0.99-1.06), and the relative risk (95% CI) of discontinued Aln treatment due to upper GIAEs was 1.23 (0.97-56). In addition, these results remained robust to sensitivity analyses. The results of the present study suggested that Aln has a good GI tract tolerability, and that daily treatment with 10 mg Aln sodium does not increase the risk of GIAEs in postmenopausal women with OP.

Meta-analysis of long-term vitamin D supplementation on overall mortality.

INTRODUCTION: It has been suggested that vitamin D is effective to prevent mortality. However, there is no consistent conclusion that the effects of vitamin D supplementation on all-cause mortality are associated with duration of treatment. We conducted a meta-analysis regarding this issue in an effort to provide a more robust answer. METHODS: A comprehensive search in a number of databases, including MEDLINE, Embase and The Cochrane Central Register of Controlled Trials, was conducted for collecting randomized controlled trials (RCTs) on vitamin D supplementation preventing mortality. Two investigators independently screened the literature according to the inclusive and exclusive criteria and the relative data were extracted. Data analysis was performed by using Review Manager 5.0 software. RESULTS: Data from forty-two RCT s were included. Vitamin D therapy significantly decreased all-cause mortality with a duration of follow-up longer than 3 years with a RR (95% CI) of 0.94 (0.90-0.98). No benefit was seen in a shorter follow-up periods with a RR (95% CI) of 1.04 (0.97-1.12). Results remain robust after sensitivity analysis. The following subgroups of long-term follow-up had significantly fewer deaths: female only, participants with a mean age younger than 80, daily dose of 800 IU or less, participants with vitamin D insufficiency (baseline 25-hydroxyvitamin D level less than 50 nmol/L) and cholecalciferol therapy. In addition, the combination of vitamin D and calcium significantly reduced mortality and vitamin D alone also had a trend to decrease mortality in a longer time follow up. CONCLUSIONS: The data suggest that supplementation of vitamin D is effective in preventing overall mortality in a long-term treatment, whereas it is not significantly effective in a treatment duration shorter than 3 years. Future studies are needed to identify the efficacy of vitamin D on specific mortality, such as cancer and cardiovascular disease mortality in a long-term treatment duration.