BACKGROUND: Postmenopausal osteoporosis (PMOP) has been considered as a major causative factor for bone-joint pain and inducing pathologic fractures. Bu-Sui-Dan (BSD), a classic ancient herbal formula, has been shown to exhibit osteoprotective effects by promoting bone marrow development and bone growth. However, the exact mechanism of BSD are still unexplored.
OBJECTIVE: The study aimed to investigate the protective effect of BSD against osteoporotic injury, and to explore whether BSD regulated BMSCs\' osteogenic differentiation by targeting VGLL4, which in turn improved PMOP.
METHODS: The anti-osteoporotic effect of BSD was studied in ovariectomized (OVX) rats and bone marrow mesenchymal stem cells (BMSCs). Micro-CT imaging and HE staining were performed, and the levels of osteogenic protein RUNX2 and osteogenesis- related factor VGLL4 were determined. Co-immunoprecipitation (Co-IP) was further employed to delve into the effects of BSD on the interactions between TEAD4 and RUNX2. The key osteogenic factors 1ALP, COLl1A1, and Osterix expression were detected by RT-qPCR. Co-IP and proximity ligation assay (PLA) were employed to scrutinize the influence of BSD on TEAD4 and RUNX2 inter-binding. Moreover, VGLL4 knockdown in BMSCs was conducted to confirm the role of VGLL4 in the therapeutic mechanism of BSD.
RESULTS: BSD showed a dose-dependent protective effect against osteoporotic injury, as evidenced by improvement in bone volume, bone microarchitecture, and histomorphometry. Additionally, BSD treatment increased the levels of RUNX2 and its downstream target genes including ALP, COL1A1, and Osterix. Moreover, BSD upregulated VGLL4 expression and lessened TEAD4-RUNX2 interactions. In BMSCs experiment, BSD-containing serum could promote osteogenic differentiation of BMSCs, boosted the expression of osteogenesis-related factors and VGLL4 level. The knockdown of VGLL4 in BMSCs diminished the promotion effect of BSD in osteoblast differentiation, suggesting that VGLL4 play a vital role in the therapeutic effects exerted by BSD.
CONCLUSIONS: BSD ameliorated osteoporosis injury and promoted osteoblast differentiation through upregulation of VGLL4 levels, which in turn antagonized TEAD4-mediated RUNX2 transcriptional repression. Our study implied that BSD may be an osteoporosis therapeutic agent.

Postmenopausal osteoporosis (PMOP) is a metabolic disorder characterized by the loss of bone density, which increases the risk of developing complications such as fractures. A pivotal factor contributing to the onset of PMOP is the diminished osteogenic differentiation capacity of bone marrow mesenchymal stem cells (BMSCs). MicroRNAs (miRNAs) play a substantial role in this process; however, their specific impact on regulating BMSCs osteogenesis remains unclear. Studies have evidenced a reduced expression of miR-18a-5p in PMOP, and concomitantly, our observations indicate an augmented expression of miR-18a-5p during the osteogenic differentiation of BMSCs. This investigation seeks to elucidate the regulatory influence of miR-18a-5p on BMSC osteogenic differentiation and the underlying mechanisms. In vitro experiments demonstrated that the overexpression of miR-18a-5p facilitated the osteogenic differentiation of BMSCs, while the downregulation of miR-18a-5p yielded converse outcomes. Mechanistically, We employed bioinformatics techniques to screen out the target gene Notch2 of miR-18a-5p. Subsequently, dual-luciferase reporter gene assays and rescue experiments substantiated that miR-18a-5p promotes BMSC osteogenic differentiation by suppressing Notch2. Finally, miR-18a-5p was overexpressed via adenovirus injection into the femoral bone marrow cavity, with results demonstrating its capability to enhance osteogenic differentiation and alleviate PMOP symptoms. Our findings disclose that miR-18a-5p fosters osteogenic differentiation of BMSC by inhibiting Notch2, thereby offering novel targets and strategies for PMOP treatment.

OBJECTIVE: To explore the efficacy and safety of tibolone combined with zoledronic acid in the treatment of postmenopausal osteoporosis (PMO).
METHODS: We conducted a retrospective analysis of 121 PMO patients from March 2019 to July 2021. Patients were divided into two groups based on treatment regimen: an observation group (n=62) receiving zoledronic acid combined with tibolone and a control group (n=59) receiving tibolone monotherapy. We evaluated and compared therapeutic efficacy, bone mineral density, bone metabolism markers (osteocalcin, serum C-terminal telopeptide of type I collagen, and bone alkaline phosphatase), pain, knee joint function, incidence of fragility fractures, and adverse reactions. Logistic regression analysis was used to evaluate risk factors affecting treatment efficacy.
RESULTS: The observation group showed a significantly higher therapeutic effect (96.77%) compared to the control group (83.05%), and a lower incidence of fragility fractures (P=0.012). Before treatment, there were no significant differences in bone mineral density, bone metabolism markers, pain status, or knee function between the two groups (all P>0.05). However, after treatment, evaluations showed marked improvements in these parameters in both groups, with more significant enhancements observed in the observation group (all P<0.001). The incidence of adverse reactions did not significantly differ between the groups (20.97% vs 13.56%, P=0.282). Logistic regression analysis identified the use of tibolone combined with zoledronic acid as a protective factor for effective treatment.
CONCLUSIONS: Tibolone combined with zoledronic acid significantly increases bone mineral density, improves bone metabolism, and reduces pain in PMO patients, with a safety profile comparable to that of monotherapy. This regimen should be considered for clinical use in treating PMO.

The association between live microbe intake and osteoporosis in postmenopausal women remains unknown. The research findings indicated that an increased intake of live microbes through dietary sources was associated with a low prevalence of osteoporosis among postmenopausal women.
OBJECTIVE: To investigate the relationship between the consumption of live microbes in the diet and osteoporosis in postmenopausal women.
METHODS: A cross-sectional investigation using data obtained from the National Health and Nutrition Examination Survey was conducted. Participants were classified into three groups by using the dietary live microbe classification system developed by Sanders. Dual x-ray absorptiometry was used to measure body mineral density, and osteoporosis was diagnosed according to the World Health Organization criteria. We conducted a crude and adjusted multivariate logistic regression analysis, and utilized the restricted cubic splines model to assess the correlation between the consumption of live microbes in the diet and osteoporosis in postmenopausal women.
RESULTS: A total of 1378 women who had undergone menopause were enrolled in the study. After controlling for potential covariates, individuals with a high consumption of live microbes in their diet exhibited a notably low prevalence of osteoporosis in comparison to those with a low intake of dietary live microbes (odd ratio: 0.46, 95% confidence interval: 0.23, 0.93, P = 0.03). Subgroup analysis showed the stability of the results, and restricted cubic splines showed an approximate L-shape curve.
CONCLUSIONS: In this research, a higher consumption of live microbes in the diet was linked to a low prevalence of osteoporosis in postmenopausal women.

OBJECTIVE: This study aims to investigate the correlation between changes in bone mineral density (BMD) in postmenopausal women and circulating inflammatory markers.
METHODS: This retrospective study focused on postmenopausal women admitted to the orthopedic department of Suzhou Benq Medical Center from June 2022 to December 2023, following predetermined inclusion and exclusion criteria. We retrospectively collected data on initial blood routine test results and bone density measurements for all study subjects upon admission, including parameters such as white blood cell count (WBC), C-reactive protein, interleukin-6 (IL-6), and procalcitonin (PCT). Additionally, the systemic immune-inflammation index (SII) was calculated using neutrophil count, lymphocyte count, and platelet count. Statistical analyses using SPSS and GraphPad software were performed to assess the correlation between bone density and inflammatory markers.
RESULTS: Patients were classified into three groups based on BMD results, including 60 individuals in the osteoporosis (OP) group, 127 individuals in the osteopenia group, and 37 individuals in the Normal group, respectively. Principal component analysis analysis suggested that WBC, SII, and postmenopausal OP (PMOP) held significant feature values. Correlation analysis indicated a correlation between WBC (p = 0.021), IL-6 (p = 0.044), SII (p = 0.034), and PMOP. One-way ANOVA analysis revealed significant differences in IL-6 (p = 0.0179), SII (p = 0.0210), and PCT (p = 0.0200) among the three groups. Finally, ROC curve analysis demonstrated that SII (area under the curve = 0.716) has predictive value for PMOP.
CONCLUSIONS: This study identified a certain predictive value for PMOP through the assessment of inflammatory markers in peripheral blood using routine blood tests.

Adiponectin, an adipokine, regulates metabolic processes, including glucose flux, lipid breakdown, and insulin response, by activating adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2). We have previously shown that globular adiponectin (gAd), an endogenous form of adiponectin, has osteoanabolic and anti-catabolic effects in rodent models of postmenopausal osteopenia. Moreover, we reported the identification of a 13-mer peptide (ADP-1) from the collagen domain of adiponectin, which exhibited significant adiponectin-mimetic properties. Since the clinical development of gAd is constrained by its large size, here, we investigated the osteogenic property of ADP-1. ADP-1 induced osteoblast differentiation more potently than gAd. ADP-1 elicited osteoblast differentiation through two downstream pathways that involved the participation of adiponectin receptors. Firstly, it enhanced mitochondrial biogenesis and OxPhos, leading to osteoblast differentiation. Secondly, it activated the Akt-glycogen synthase kinase 3β-Wnt pathway, thereby increasing osteoblast differentiation. Additionally, ADP-1 suppressed the production of receptor-activator of nuclear kappa B ligand from osteoblasts, enabling it to act as a dual-action molecule (suppressing osteoclast function besides promoting osteoblast function). In osteopenic ovariectomized rats, ADP-1 increased bone mass and strength and improved trabecular integrity by stimulating bone formation and inhibiting bone resorption. Furthermore, by increasing ATP-producing intermediates within the tricarboxylic acid cycle in bones, ADP-1 likely fueled osteoblast function. Given its dual-action mechanism and high potency, ADP-1 offers a unique opportunity to address the unmet clinical need to reset the aberrant bone remodeling in osteoporosis to normalcy, potentially offering a disease-modifying impact.

UNASSIGNED: Given the bone sensitivity to mechanical stimulus, bone-loading exercises and applying the Pulsed Electromagnetic Fields (PEMF(s)) are recommended for promoting bone strength. In this context, these two interventions \'s effect on bone turnover markers (BTMs) in osteoporosis patients is yet to be clarified; consequently, an attempt is made in this study to compare the effect of these two interventions on bone turnover markers in women with Postmenopausal Osteoporosis (PMOP).
UNASSIGNED: This study is design as a randomized, single-center, three-arms, controlled trial. A total of 51 women with PMOP will be randomly assigned to three groups of 17, using opaque, sealed envelopes containing labels for A, B, and C groups. Group A) will receive bone-loading exercises, B) will follow the PEMF(s) and C) will be exposed to the combination of A and B. These three groups will require intervention for 24 sessions (2 sessions/week) next to their routine medical treatment (Alendronate+ Calcium+ Vitamin D). The primary outcome of this study is the serum biomarker of bone formation (bone-specific alkaline phosphatase, BSALP) and resorption (N-terminal telopeptide, NTX). The secondary outcomes consist of thoracic kyphosis angle, fear of falling, and quality of life. The outcomes are measured three times: at baseline, after 24 sessions of intervention, and at 12 weeks follow-up. A primary outcome will be measured and reported by a laboratory expert who is blinded to the participant grouping.
UNASSIGNED: The trial has the code of ethics for research (IR.TUMS.FNM.REC.1401.126) and the code of Iranian Registry of Clinical Trials (IRCT) (IRCT20221202056687N1). Study results are expected to be available by mid-2024.
UNASSIGNED: This trial will provide new practical knowledge on the bone-loading exercises and PEMFS(s)\'s effect on PMOP women. This knowledge is of the essence for physiotherapists, clinicians, other healthcare professionals, and policymakers in the healthcare system.

The gut microbiome is linked to osteoporosis. Previous clinical studies showed inconsistent results. This study aimed to characterize the gut microbiota feature and reveal its relation with diet in postmenopausal osteoporosis. Fifty-five postmenopausal women with osteoporosis (Op group) and forty-four age-matched postmenopausal women (normal bone mineral density, Con group) were included in this study. Fecal microbiota was collected and analyzed by shallow shotgun sequencing. Food frequency questionnaires were collected from both groups, and Spearman analysis was used to clarify its correlation with gut microbiota. A total of 2671 species from 29 phyla, 292 families, 152 orders, 80 classes were detected in the study. The two groups had no significant difference in the α and β diversity (p > 0.05). At the genus level, Anaerostipes was enriched in Op group (p < 0.05). At species level, Methanobrevibacter smithii, Bifidobacterium animalis, Rhodococcus defluvii, Lactobacillus plantarum, and Carnobacterium mobile were enriched in the Op group, while Bacillus luciferensis, Acetivibrio cellulolyticus, Citrobacter amalonaticus, and Bifidobacterium breve were differentially enriched in the Con group. Food frequency questionnaire showed that postmenopausal women with osteoporosis intaked more red meat, beer, white and red wine (p < 0.05), and the Con group had more yogurt, fruit, and tea consumption. Red meat consumption had a significant negative correlation with Streptosporangiales (p < 0.01) and Actinomadura (p < 0.05). Fruits intake negatively correlated with Nocardiaceae, Rhodococcus, and Rhodococcus defluvii (p < 0.05). More yogurt intake was consistently correlated with a greater abundance of Streptosporangiales. This study suggests that gut microbiota is significantly altered in the postmenopausal osteoporosis population at genus and species levels, and specific dietary intake might relate to these changes.

UNASSIGNED: Mesenchymal stem cells can develop into osteoblasts, making them a promising cell-based osteoporosis treatment. Despite their therapeutic potential, their molecular processes are little known. Bioinformatics and experimental analysis were used to determine the molecular processes of bone marrow mesenchymal stem cell (BMSC) therapy for postmenopausal osteoporosis (PMO).
UNASSIGNED: We used weighted gene co-expression network analysis (WGCNA) to isolate core gene sets from two GEO microarray datasets (GSE7158 and GSE56815). GeneCards found PMO-related genes. GO, KEGG, Lasso regression, and ROC curve analysis refined our candidate genes. Using the GSE105145 dataset, we evaluated KLF2 expression in BMSCs and examined the link between KLF2 and PIK3CA using Pearson correlation analysis. We created a protein-protein interaction network of essential genes involved in osteoblast differentiation and validated the functional roles of KLF2 and PIK3CA in BMSC osteoblast differentiation in vitro.
UNASSIGNED: We created 6 co-expression modules from 10 419 differentially expressed genes (DEGs). PIK3CA, the key gene in the PI3K-Akt pathway, was among 197 PMO-associated DEGs. KLF2 also induced PIK3CA transcription in PMO. BMSCs also expressed elevated KLF2. BMSC osteoblast differentiation involved the PI3K-Akt pathway. In vitro, KLF2 increased PIK3CA transcription and activated the PI3K-Akt pathway to differentiate BMSCs into osteoblasts.
UNASSIGNED: BMSCs release KLF2, which stimulates the PIK3CA-dependent PI3K-Akt pathway to treat PMO. Our findings illuminates the involvement of KLF2 and the PI3K-Akt pathway in BMSC osteoblast development, which may lead to better PMO treatments.

UNASSIGNED: Osteoporosis is a chronic systemic skeletal disorder characterized by compromised bone strength and an increased risk of fracture, with a high prevalence worldwide. It is associated with a negative quality of life and an increased morbidity and mortality. Postmenopausal women are more prone to develop osteoporosis, and many of them will suffer at least one fragility fracture along their lifetime.
UNASSIGNED: This review starts by summarizing the pathogenesis of postmenopausal osteoporosis (PMO), with focus on the estrogen deficiency-associated bone loss. It continues with the current PMO diagnostic and fracture risk prediction tools, and it finally addresses management of PMO. All the efficacy and safety profiles of the current and future osteoporosis medications are reviewed. Furthermore, strategies to optimize the long-term disease management are discussed. For this review, only publications in English language were selected. References were extracted from PubMed, Embase, and Medline.
UNASSIGNED: PMO disease management is far from being ideal. Educational and communication programs with the goal of improving disease knowledge and awareness, as well as reducing the health-care gap, should be implemented. In addition, most effective sequential prevention and treatment strategies should be initiated from the early menopause.