Calcium-fortified fresh milk ameliorates postmenopausal osteoporosis via regulation of bone metabolism and gut microbiota in ovariectomized rats

The aging of the global population has made postmenopausal osteoporosis prevention essential;however,pharmacological treatments are limited.Herein,we evaluate the effect of calcium-fortified fresh milk(FM)in ameliorating postmenopausal osteoporosis in a rat model established using bilateral ovariectomy.After 3 months of FM(containing vitamin D,and casein phosphopeptides,1000 mg Ca/100 g)or control milk(110 mg Ca/100 g milk)supplementation,bone changes were assessed using dual-energy X-ray absorptiometry,microcomputed tomography,and bone biomechanical testing.The results revealed that FM can regulate bone metabolism and gut microbiota composition,which act on bone metabolism through pathways associated with steroid hormone biosynthesis,relaxin signaling,serotonergic synapse,and unsaturated fatty acid biosynthesis.Furthermore,FM administration significantly increased bone mineral content and density in the lumbar spine and femur,as well as femoral compressive strength,while improving femoral trabecular bone parameters and microarchitecture.Mechanistically,we found that the effects may be due to increased levels of estrogen,bone formation marker osteocalcin,and procollagen typeⅠN-propeptide,and decreased expression of the bone resorption marker C-telopiptide and tartrate-resistant acid phosphatase 5b.Overall,the findings suggest that FM is a potential alternative therapeutic option for ameliorating postmenopausal osteoporosis.

Research trends in exercise therapy for the treatment of pain in postmenopausal osteoporosis over the past decade:A bibliometric analysis

BACKGROUND Postmenopausal osteoporosis(PMOP)is the most common form of primary osteoporosis among women,and the associated pain often drives patients to seek clinical intervention.Numerous studies have highlighted the unique clinical benefits of exercise therapy(ET)in alleviating PMOP-related pain.However,bibliometric analyses examining collaboration,development trends,and research frontiers in the field of ET for PMOP pain remain scarce.AIM To explore the research trends in ET for pain treatment in PMOP patients over the past decade.METHODS All scholarly works were meticulously sourced from the Science Citation Index-Expanded within the prominent Web of Science Core Collection.Utilizing the capabilities of CiteSpace 6.2.R5,we conducted a thorough analysis of publications,authors,frequently cited scholars,contributing nations,institutions,journals of significant citation,comprehensive references,and pivotal keywords.Additionally,our examination explored keyword cooccurrences,detailed timelines,and periods of heightened citation activity.This comprehensive search,from 2014 through 2023,was completed within a single day,on October 11,2023.RESULTS In total,2914 articles were ultimately included in the analysis.There was a rapid increase in annual publication output in 2015,followed by stable growth in subsequent years.Boninger,Michael L,is the most prolific author,whereas Ware JE has the most citations.The United States’global influence is significant,surpassing all other nations.The University of California System and Harvard University are the most influential academic institutions.J Bone Joint Surg Am is the most influential journal in this field.“Spinal cord injury”is the keyword that has garnered the most attention from researchers.The developmental pattern in this field is characterized by interdisciplinary fusion,with different disciplines converging to drive progress.CONCLUSION The academic development of the field of ET for pain in PMOP has matured and stabilized.Clinical management and rehabilitation strategies,along with the mechanisms underlying the relationship between ET and bone resorption analgesia,continue to be the current and future focal points of research in this field.

Postmenopausal Osteoporosis and Osteopenia Management with a Combination of Once-Monthly Oral Ibandronate and Cholecalciferol—A Systematic Review

Postmenopausal osteoporosis and osteopenia are chronic and uncurable conditions that invariably lead to an increased risk of vertebral, hip, and femoral neck fracture if left untreated. Clinical guidelines establish, in general, pharmacological combinations allied to lifestyle changes as the mainstay of their management, and also increasing bone marrow density, lowering fracture risk, and improving quality of life are their main therapeutic goals. The objective of this systematic review was to analyze the available data in the scientific medical literature regarding the role of the ibandronate and cholecalciferol combination in postmenopausal osteoporosis and osteopenia management. Based on our results, we concluded that the above combination is safe and feasible for the clinical control of both conditions.

Erxian decoction potentially prevents postmenopausal osteoporosis by modulating miR-335: a study based on bioinformatics analysis and preliminary clinical case validation

Background:miRNAs are closely related to bone metabolism.Studies have shown that Erxian decoction can improve bone metabolism,possibly achieving this regulatory effect through miRNA targets.Netinfer was used to predict the miRNA targets of Erxian decoction for the treatment of postmenopausal osteoporosis,and the results were validated by clinical trials.Methods:In this study,we identified possible targets of Erxian decoction in osteoporosis by means of network pharmacological analysis and bioinformatic prediction.Fifteen cases of postmenopausal osteoporosis with kidney Yin and Yang deficiency(In traditional Chinese medicine,kidney Yin nourishes and moistens the tissues of the internal organs of the body,while kidney Yang promotes and warms the tissues of the internal organs of the body.)were treated with Erxian decoction for four weeks,and serum bone metabolism indices(P1NP,osteocalcin,andβ-CTX)and miRNA-335-5p expression were measured before and after treatment.Results:The constructed miRNA postmenopausal osteoporosis related gene network of the effective compound of the Erxian decoction has 296 points and 981 edges.The 39 postmenopausal osteoporosis related genes regulated by miRNA-335-5p were enriched in ossification,while the signaling pathways were enriched in rheumatoid arthritis,the Toll signaling pathway,the HIF-1 signaling pathway,and the MAPK signaling pathway.After taking Erxian decoction,the expression of the serum bone formation index(P1NP,osteocalcin)and miRNA-335-5p gene expression levels increased significantly.The alterations in P1NP and osteocalcin were correlated with the changes in miRNA-335-5p.Conclusion:Circulating miRNA-335-5p may serve as an important target of Erxian decoction in the treatment of postmenopausal women.The effect of Erxian decoction on bone formation is significant,but the underlying mechanism requires further investigation.

Association of CA Repeat Polymorphism in Estrogen Receptor β Gene with Postmenopausal Osteoporosis in Chinese

Postmenopausal osteoporosis （PMO） is considered a polygenic disease. The estrogen receptor β （ESR2） gene is a candidate mediating the genetic influence on bone mass and the risk of osteoporosis. The aim of this study is to investigate the association of a cytosine-adenine （CA） repeat polymorphism in the fifth intron of the ESR2 gene with PMO in Chinese Han population. The CA repeat polymorphism was genotyped in a case-control study, involving 78 femoral neck PMO patients vs. 122 controls and 108 lumbar spine （L2-4） PMO patients vs. 92 controls. The （CA）n〈22 and （CA）n≥22 alleles were designated short （S） and long （L）, respectively. ESR2 genotype was categorically defined as SS （2 S alleles）, SL （having the mixed S and L alleles）, and LL （2 L alleles）. At both the femoral neck and the L2-4 region, LL genotype and L allele frequencies of the PMO group were significantly higher than those of the control group （P〈0.01）. The subjects with the SL, the LL, and the combined SL and LL genotype had a significant increased risk of PMO when compared with those with the SS genotype （P〈0.05）. After adjustments for age, years since menopause, menopausal age, and body mass index, logistic regression analysis showed that the subjects with the combined SL and LL genotype had increased risk of PMO when compared with those with the SS genotype both at the femoral neck （adjusted OR 4.923, 95% CI 1.986-12.203 , P=0.001） and the L2-4 （adjusted OR 2.267, 95% CI 1.121-4.598, P=0.023）. This extensive association study has identified the ESR2 CA repeat polymorphism to be independently associated with PMO at the femoral neck and the L2-4 in Chinese Han population. The data also suggested that the presence of the L allele may dominantly increase the risk of PMO at the two regions.

A Clinical Study of Yigu Capsule (益骨胶囊) in Treating Postmenopausal Osteoporosis

Objective: To observe the efficacy and safety of Yigu capsule (益骨胶囊, YGC), a Chinese herbal compound preparation, in treating postmenopausal osteoporosis (PMO) and to explore its possible mechanism. Methods: The clinical study was conducted in a prospective, randomized, double blinded method lasting for 6 months with placebo and positive control. Two hundred and ten PMO patients with confirmed diagnosis were assigned into the YGC group, the calciferol group and the placebo group. Besides being administered element calcium, they were treated with YGC, calciferol capsule and placebo capsule respectively. And such symptoms as newly found fracture and ostealgia, bone mineral density (BMD) of the 2nd-4th lumbar vertebrae (L_ 2-4 ) and upper femur, blood and urinary indexes for bone metabolism, sex hormone level and adverse reaction that occurred in patients were observed.Results: In the YGC group, the total effective rate was 95.50%, with no new occurrence of fractures, which was significantly better than that in the other two groups (P<0.05). Moreover, in the YGC group,the increase rate of BMD was 9.83% in L_ 2-4 , 4.09% in femoral neck, 4.60% in Wards triangle, 3.00% in greater trochanter, which was also better than that in the placebo group (P<0.05, P<0.01). As compared with the placebo group, levels in the YGC group of urinary oxyproline hydroxyproline/creatinine, urinary calcium/creatinine were significantly lower, serum and bone alkaline phosphatase, osteocalcin, estradiol and estradiol/testosterone were significantly higher, but no difference was shown in the comparison of testosterone level. In the observation period, no abnormality in blood or urine routine, liver or renal function was found. Only mild, transient gastro-intestinal response occurred in individual patients, but it did not affect the treatment. Conclusion: YGC could treat PMO effectively, as it could obviously increase the BMD of lumbar vertebrae and coxafemoral bone, elevate the alleviating rate of ostealgia and incessant motion time, yet causing no newly found compressive fracture of vertebrae, or and any related adverse reaction. YGC could not only promote the formation, but also inhibit the absorption of bone as well as increase the sex hormone level. Therefore, it is a pure Chinese herbal compound preparation worthy of further research and development.

Efficacy and Safety of Risedronate Sodium in Treatment of Postmenopausal Osteoporosis

Summary： To evaluate the efficacy and safety of risedronate sodium in treatment of postmenopausal osteoporosis, one-year randomized, double blind clinical trial was performed among 54 women with postmenopausal osteoporosis. The changes were compared in bone mineral density （BMD）, bone metabolism markers and adverse events after 12 months oral administration of risedronate sodium. BMD was measured by dual energy X-ray absorptionmetry （DEXA） and bone turnover marker was detected. The results showed that there was a significant increase in BMD of the lumbar spine （3.29 %±41.18 %, 4.51%±1.64 % respectively） after 6 and 12 months in the risedronate treatment group versus placebo control group （-0.62 %±0.24 %, 0.48 %±0. 18 % respectively）. Bone turnover was decreased to a stable nadir over 6 and 12 months for resorption markers [N-Telopeptide （NTx）, P〈0.05] and over 12 months for formation marker （ALP, P〈0.05; BGP, P〈0. 05）. The safety profile of risedronate sodium was similar to that of placebo. There were no trends toward increased frequency of any adverse experience except for gastrointestinal symptoms （7.1%）, rash （7.1%） and hematuria （3.6 %）, which were usually mild, transient, and resolved with continued treatment. It was concluded that risedronate was an efficacious and safe drug in treatment of postmenopausal osteoporosis.

Association of Serum Dkk-1 Levels with β-catenin in Patients with Postmenopausal Osteoporosis

Wnt signaling plays an important role in the bone development and remodeling. The Wnt antagonist Dkk-1 is a potent inhibitor of bone formation. The aims of this study were firstly to compare the serum Dkk-1 levels in postmenopausal osteoporosis patients with age-matched healthy controls, and secondly, to assess the possible relationship between Dkk-1 and β-catenin, sclerostin, or bone turnover markers [CTX, PINP, N-MID-OT and 25（OH）D] in the setting of postmenopausal osteoporosis. A total of 350 patients with postmenopausal osteoporosis and 150 age-matched healthy controls were enrolled, and the serum levels of Dkk-1, β-catenin, sclerostin, OPG, and RANKL were detected by ELISA, and bone turnover markers [CTX, PINP, N-MID-OT and 25（OH）D] were measured by Roche electrochemiluminescence system in two groups. Serum Dkk-1 levels were significantly higher in postmenopausal osteoporosis group than in control group（P〈0.001）. Univariate analyses revealed that serum Dkk-1 levels were weakly negatively correlated to β-catenin（r=–0.161, P=0.003） and OPG（r=–0.106, P=0.047）, while multiple regression analysis showed a negative correlation between serum Dkk-1 levels with β-catenin（β=–0.165, P=0.009） and BMD（β=–0.139, P=0.027）, and a positive correlation between serum Dkk-1 levels and CTX（β=0.122, P=0.040） in postmenopausal osteoporosis group. No similar correlations ware observed in control group. The results provided evidence for the role of Dkk-1 in bone metabolism and demonstrated the link of Dkk-1 and Wnt/β-catenin in some ways.

Bisphosphonates Zoledronate and Alendronate for the Management of Postmenopausal Osteoporosis

Bisphosphonates are among the most frequently used antiresorptive drugs for the management of postmenopausal osteoporosis. We review here two of the commonly used bisphosphonates zoledronate and alendronate.

Curative Effect Analysis of Zoledronic Acid in the Treatment of Postmenopausal Osteoporosis with Different Bone Turnover Rates

Objective: To explore the clinical efficacy of Zoledronic Acid Injection in the treatment of postmenopausal osteoporosis with different bone turnover rates. Methods: A total of 63 patients diagnosed with postmenopausal osteoporosis were included in this study. Each patient was administrated 5 mg/100mL Zoledronic Acid (Aclasta) intravenously once and then given a one-year prescription of 600 mg/d oral Caltrate. The bone turnover parameters (PINP, β-cross, N-MID) were measured prior to the injection of Zoledronic Acid while the bone mineral density (BMD) and the pain scores of each patient were tested before treatment and after the one-year medication. On this basis, the patients were divided into several groups according to their bone turnover rates for intergroup comparison of treatment outcomes. Results: BMD results and pain scores of all participants were significantly improved at different levels after treatment. However, these improvements had no significant differences between the patients with high and low bone turnover rates. Conclusion: Zoledronic Acid Injection can relieve bone pain, enhance the quality of life and increase the BMD in patients with postmenopausal osteoporosis, regardless of the bone turnover status.

A candidate identification questionnaire for postmenopausal osteoporosis patients switched from daily or weekly bisphosphonate to once-monthly ibandronate: An open, prospective, multicenter study—BONCURE study

A candidate identification questionnaire (CIQ) was tested to determine its predictive value for patient-reported satisfaction in patients switched from once-weekly or once-daily treatment with a bisphosphonate to once-monthly dosing. This was a prospective, open-label, multicenter international study in patients with postmenopausal osteoporosis who had been receiving once-daily or once-weekly alendronate or risendronate for at least 3 months. Patients completed a CIQ, then commenced 150 mg monthly ibandronate for 6 months. Patients completed the Osteoporosis Patient Satisfaction Questionnaire (OPSAT-QTM) at baseline for 6 months. Scores were converted to composite satisfaction scores (CSS, scale 0-100). Totally 677 patients completed a CIQ, 645 were enrolled in the treatment phase and comprised the intent-to-treat (ITT) population, and 630 completed the study. In the ITT population, 68.1% patients answered “yes” to one or more CIQ questions. OPSAT-Q scores increased for the convenience, quality of life and overall satisfaction domains (p scores for the side effects domains were significant (p < 0.001) in the CIQ “yes” group, but not for the degree of bother (decrease in mean of 0.1 points, p = 0.50) or duration (no change, p = 0.84) of non-gastrointestinal side effects. Of 638 patients who completed the preference questionnaire, 93.0% of patients preferred the once-monthly dosing schedule and 563 patients (90.7%) found it more convenient. The most common adverse events were dyspepsia (1.9%), nausea (1.1%), and upper abdominal pain (0.9%). Patients are likely to prefer treatment with monthly ibandronate to a weekly or monthly bisphosphonate irrespective of their stated preference before switching treatment.

Insulin-Like Growth Factor-1 and Osteocalcin Are Correlated with Markers of Osteoporosis in Postmenopausal Women with Type-2 Diabetes

Objective: The study was conducted to evaluate the relation between insulin-like growth factor-1 and osteocalcin and markers of bone modulation (osteoprotegerin;OPG, receptor activator nuclear kappa B;RANK and RANK ligand;RANKL) in postmenopausal Type 2 diabetic women with and without osteoporosis. Methods: The study was conducted on 90 female divided into three groups (30 each). Group I included healthy postmenopausal women as a control, Group II included diabetic postmenopausal women without osteoporosis Group III included diabetic postmenopausal women with osteoporosis. Fasting blood samples were obtained for the determination of blood glucose, HbA1c, total and ionized calcium, OPG, RANK and RANKL. Also the levels of IGF-1 and osteocalcin were assessed. Results: In postmenopausal Type 2 diabetic women, the osteoporosis resulted in derangement in OPG/sRANKL system. The serum level of OPG was elevated while sRANKL declines in osteoporotic postmenopausal Type 2 diabetic women. IGF-1 level decreased in diabetic postmenopausal women but those women with osteoporosis showed a great decline by about 60%. IGF-1 level in osteoporotic diabetic postmenopausal women was correlated with BMD and most bone turnover markers (OPG, sRANKL, OPG/sRANKL). Osteocalcin declined significantly only in those women with osteoporosis not without osteoporosis. Conclusions: The circulating levels of OPG and sRANKL were not useful markers for bone status in postmenopausal women while the circulating levels of IGF-1 and osteocalcin might give useful information about bone status in postmenopausal diabetic women.

Correlation of serum total bilirubin content with bone metabolism and micro-inflammatory response in patients with postmenopausal osteoporosis

Objective:To study the correlation of serum total bilirubin (TBIL) content with bone metabolism and micro-inflammatory response in patients with postmenopausal osteoporosis. Methods: The patients diagnosed with postmenopausal osteoporosis by DEXA in Wuhan Zhongyuan Hospital between February 2015 and December 2017 were chosen as the OP group, the postmenopausal women who were proven to have normal bone mineral density by DEXA during the same period were chosen as control group, and the TBIL, bone metabolism markers, bone metabolism biochemical indexes and inflammation indexes were determined. Results: Serum TBIL, PINP, OPG, SOD, T-AOC and IL-10 levels as well as peripheral blood FOXP3 expression of OP group were significantly lower than those of control group whereas serum NTX, CTX, RANKL, AOPP, IL-17 and TNF-α levels as well as peripheral blood NOX1, FoxO3a, ROR-γt and NF-κB expression were significantly higher than those of control group;serum TBIL content of OP group was positively correlated with serum PINP, OPG, SOD, T-AOC and IL-10 levels as well as peripheral blood FOXP3 expression, and negatively correlated with serum NTX, CTX, RANKL, AOPP, IL-17 and TNF-α levels as well as peripheral blood NOX1, FoxO3a, ROR-γt and NF-κB expression.Conclusion: The decrease of serum TBIL in patients with postmenopausal osteoporosis can damage the bone metabolism and aggravate the micro-inflammatory response.

EFFECT OF ACUPUNCTURE ON SERUM INTERLUKIN-6 IN WOMEN WITH POSTMENOPAUSAL OSTEOPOROSIS

: To observe the effect of acupuncture on serum interlukin-6 (IL-6) level in women with post-menopausal osteoporosis. Methods: 59 cases of postmenopausal osteoporosis women were randomly divided into acupunctue group(n=32) and calcium D group(n = 27). In acupuncture group, Zusanli (ST 36), Sanyinjiao (SP 6), Shenshu (BL 23) and Pishu (BL 20) were punctured, 3 times every week, continuously for 6 months. In control group, patients were ordered to take Calcium D, one pill (containing 1500 mg calcium carbonate and VitD3) every morning, continuously for 6 months. Serum IL-6 was detected using radioimmunoassay. Results: After six months' treatment, the result showed that in acupuncture group serum IL-6 calcium level lowered while in control group serum IL-6 content increased. Statistical analysis indicates that there are no significant differences between two groups or between pre-treatment and post-treatment in every single group( P > 0.05). Conclusion: Although no statistical difference was found between two groups, acupuncture could decrease secretion of IL-6 in postmenopausal osteoporosis women to a certain degree, refrain the activity of osteoclast and improve the quality of bone.

Relationship between peroxiredoxins protein family levels and osteoporosis in postmenopausal woman

Objective:To observe the expression levels of the main molecules of peroxiredoxins (Prdxs) protein family (Prdx1, Prdx2, Prdx4 and Prdx6) in women with postmenopausal osteoporosis (PMOP), and to analyze their clinical diagnostic values.Methods: Patients diagnosed with PMOP in Hubei Provincial Hospital of Traditional Chinese Medicine and Wuhan Hospital of Traditional Chinese Medicine from May 2016 to March 2018 were included as the study group (72 cases), postmenopausal women with normal bone mineral density (BMD) in the same period were also collected as the control group (51 cases). Levels of Prdx1, Prdx2, Prdx4 and Prdx6 in plasma were determined by ELISA. mRNA levels of Prdx1, Prdx2, Prdx4 and Prdx6 in peripheral blood mononuclear cells (PBMC) were determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The correlations between Prdxs and clinical parameters were analyzed. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic values of Prdxs for PMOP.Results: Prdx1, Prdx4 and Prdx6 levels in the study group were significantly lower than those in the control group (P<0.05). The mRNA expression levels of Prdx1 and Prdx6 of PBMC in the study group were significantly lower than those in the control group (P<0.05). Several Prdxs protein levels (plasma) or mRNA levels (PBMC) in the study group were significantly correlated with lipid levels or inflammatory markers levels (P<0.05). The area under the curve (AUC) of plasma Prdx6 for diagnosing PMOP was 0.794 (95% CI =0.714-0.874). And the AUC of mRNA relative expression of Prdx6 in PBMC for diagnosing PMOP was 0.725 (95% CI =0.635-0.814).Conclusion: The decreased expression of Prdxs protein family (especially Prdx1 and Prdx6) is closely related to the incidence of PMOP, and the decreased Prdxs protein family may promote the occurrence of osteoporosis through the abnormal lipid metabolism pathway and the increased systemic inflammation pathway. The detections of Prdx6 levels in plasma and PBMC are of good diagnostic values for PMOP.

Network pharmacological study of Zuogui pill and Yougui pill for the treatment of postmenopausal osteoporosis

Background:Postmenopausal osteoporosis(PMO)is the most common primary osteoporosis in older women.This condition imposes a huge economic and medical burden on society.Aside from western medicine,traditional Chinese medicine is also widely used for the treatment of PMO,especially in Asian countries.Zuogui pill(ZGP)and Yougui pill(YGP)are classical formulas for the treatment of PMO with potent clinical effects.This study aimed to explore the potential active compounds,potential targets,and potential mechanisms of ZGP and YGP for the treatment of PMO.Methods:Compounds from ZGP and YGP were collected from three online databases,and these compounds were screened by oral bioavailability and drug-likeness.Their corresponding targets were determined from the Medicine Systems Pharmacology Database and Analysis platform.The corresponding targets for PMO were obtained from two disease databases.The target protein-protein interaction was identified through the STRING platforms and the core targets were ascertained by analyzing the protein-protein interaction network by using Cytoscape software.PMO-related genes were identified via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses to identify specific biological processes,cellular components,molecular functions and key signalling pathways of ZGP and YGP for PMO treatment.Results:A total of 68 compounds were screened from ZGP with 168 putative potential target genes,whereas 99 compounds were screened from YGP with 214 potential target genes associated with PMO.Most of the core components included quercetin and kaempferol,and most of the core targets were TP53,AKT1,MAPK1,JUN,TNF,HSP90AA1,APP,IL6,VEGFA,RELA,MAPK8,NR3C1,EGFR,CXCL8,ESR1,FOS and MAPK14.Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that ZGP and YGP treat PMO primarily via regulation of bone formation and resorption,anti-inflammatory immunity and hormonal regulation.Conclusion:Our data provided insights into the mechanisms,by which ZGP and YGP treat PMO.This study points out a direction for further research into ZGP and YGP monomers and pathways and offers a new clinical treatment option for non-traditional Chinese medicine clinicians in the treatment of PMO.

Exploring the multicomponent synergy mechanism of Zuogui Wan(左归丸) on postmenopausal osteoporosis by a systems pharmacology strategy

OBJECTIVE: To explore the multi-component synergistic mechanism of Zuogui Wan(左归丸, ZGW) in treating postmenopausal osteoporosis(PMOP). METHODS: The main components and target genes of ZGW were screened via the Traditional Chinese Medicine Systems Pharmacology(TCMSP). In addition, the target gene sets of PMOP were derived from the Gene Cards and Online Mendelian Inheritance in Man databases. The search tool for recurring instances of neighbouring genes(STRING) 11.0 software was used to analyze the interaction among intersecting genes. Cytoscape 3.6.1 software and the Matthews correlation coefficient(MCC) algorithm were used to screen the core genes. Fifty Sprague-Dawley female rats were randomly divided into the sham-operated(Sham) group and the four ovariectomized(OVX) subgroups. Rats subjected to Sham or OVX were administered with the vehicle(OVX, 1 m L water/100 g weight), 17β-estradiol(E2, 50 μg·kg-1·d-1), and lyophilized powder of ZGW at a low dose of 2.3(ZGW-L) and high dose of 4.6(ZGW-H) g·kg-1·d-1 for three months. The bone density and bone strength were assessed using dual-energy X-ray and three-point bending tests, respectively. Furthermore, enzyme-linked immunosorbent assay, Hematoxylin-eosin staining, and western blot analysis were used to determine the potential pharmacological mechanisms of action of ZGW in PMOP. RESULTS: A total of 117 active compounds of ZGW were screened from the TCMSP. Furthermore, 108 intersecting genes of drugs and diseases were identified. Using STRING software and the MCC algorithm, ten core genes, including C-X-C chemokine living 8(CXCL8), C-C chemokine receptor type 2(CCR2), alpha-2a active receptor(ADRA2A), melatonin receptor type 1B(MTNR1B), and amyloid-beta A4 protein(APP), were identified. The anti-osteoporosis regulation network of ZGW was constructed using the Cytoscape software. The animal experiments demonstrated that ZGW groups significantly reduced the serum levels of β-C-terminal telopeptide of type I collagen(β-CTX) and increased serum levels of bone-specific alkaline phosphatase(BALP)(P < 0.05, P < 0.01). The OVX group exhibited a significant decrease in bone mineral density and bone strength compared with the Sham group(P < 0.01). Moreover, treatment with ZGW resulted in increased trabecular thickness, improved arrangement of trabecular structure, and reduced empty bone lacunae. Furthermore, treatment with ZGW significantly increased the protein expression of CXCL8, ADRA2A, and CCR2(P < 0.05, P < 0.01), and significantly decreased the protein expression of Runx2(P < 0.01). Furthermore, the ZGW and E2 groups demonstrated significantly increased BMD(P < 0.05, P < 0.01), improved bone strength(P < 0.05, P < 0.01), reduced expression of CXCL8, ADRA2A, and CCR2, and increased runt-related transcription factor 2 levels in bone tissue(P < 0.05, P < 0.01) compared with the OVX group. However, there were no significant differences in MTNR1B and APP expression among the groups. CONCLUSION: ZGW shows synergistic mechanisms in PMOP through multiple components, targets, and pathways.

A two-pronged approach to inhibit ferroptosis of MSCs caused by the iron overload in postmenopausal osteoporosis and promote osseointegration of titanium implant

Postmenopausal osteoporosis(PMOP)is a prevalent condition among elderly women.After menopause,women exhibit decreased iron excretion,which is prone to osteoporosis.To design a specific titanium implant for PMOP,we first analyze miRNAs and DNA characteristics of postmenopausal patients with and without osteoporosis.The results indicate that iron overload disrupts iron homeostasis in the pathogenesis of PMOP.Further experiments confirm that iron overload can cause lipid peroxidation and ferroptosis of MSCs,thus breaking bone homeostasis.Based on the findings above,we have designed a novel Ti implant coated with nanospheres of caffeic acid(CA)and deferoxamine(DFO).CA can bind on the Ti surface through the two adjacent phenolic hydroxyls and polymerize into polycaffeic acid(PCA)dimer,as well as the PCA nanospheres with the repetitive 1,4-benzodioxan units.DFO was grafted with PCA through borate ester bonds.The experimental results showed that modified Ti can inhibit the ferroptosis of MSCs in the pathological environment of PMOP and promote osseointegration in two main ways.Firstly,DFO was released under high oxidative stress,chelating with excess iron and decreasing the labile iron pool in MSCs.Meanwhile,CA and DFO activated the KEAP1/NRF2/HMOX1 pathway in MSCs and reduced the level of intracellular lipid peroxidation.So,the ferroptosis of MSCs is inhibited by promoting the SLC7A11/GSH/GPX4 pathway.Furthermore,the remained CA coating on the Ti surface could reduce the extracellular oxidative stress and glutathione level.This study offers a novel inspiration for the specific design of Ti implants in the treatment of PMOP.

The Present State and Perspective in Treatment of Primary Osteoporosis by Acupuncture and Moxibustion

Primary osteoporosis, a commonly encountered metabolic bone disease in the postmenopausal women and the aged people, can be classified by modern medicine into postmenopausal osteoporosis (Type I) and senile osteoporosis (Type II). The disease seriously affects health and quality of life of the people as it often cause ostealgia, fracture and the secondary symptoms or diseases. Presently, the pharmacotherapy (including both Chinese herbal drugs and western drugs) remains the first among all other therapeutic methods which are mainly adopted in treatment of the disease at home and abroad. Studies related have been curried out quite early and systematically, and considerable progress has been made, but limit of the pharmacotherapy has also been found. Certain non-drug treatments (such as dietetic therapy, physical exercise, acupuncture and moxibustion, and qigong, especially acupuncture and moxibustion therapy, although with a late start, have been proved effective with satisfactory results. The following is a summary of all the contributions concerned.……

Repurpose dasatinib and quercetin:Targeting senescent cells ameliorates postmenopausal osteoporosis and rejuvenates bone regeneration

Clinical therapies developed for estrogen-deficiency-driven postmenopausal osteoporosis(PMO)and related diseases,such as bone degeneration,show multiple adverse effects nowadays.Targeting senescent cells(SnCs)and the consequent senescence-associated secretory phenotype(SASP)with a combination of dasatinib and quercetin(DQ)is a recently developed novel therapy for multiple age-related diseases.Herein,we found that estrogen deficiency induced-bone loss was attributed to a pro-inflammatory microenvironment with SASP secretions and accelerated SnC accumulation,especially senescent mesenchymal stem cells(MSCs)characterized by exhaustion and dysfunction in middle aged rats.Systematically targeting SnCs with DQ strikingly ameliorated PMO and restored MSC function.Local administration of DQ and bone morphogenetic protein 2(BMP2)in combination promoted osteogenic differentiation of MSCs and rejuvenated osteoporotic bone regeneration.Our results repurposed DQ as an attractive therapy for treating PMO and related diseases.