INTRODUCTION: Rheumatoid arthritis (RA) is associated with heightened cardiovascular disease and increased susceptibility to osteoporosis, with shared underlying mechanisms. This study aimed to investigate the association between vascular function and bone mineral density (BMD). METHODS: We conducted a cross-sectional study of 49 patients with RA at Tan Tock Seng Hospital, Singapore. Endothelial function was measured as reactive hyperaemia index (RHI)-endothelial peripheral arterial tonometry and aortic stiffness as carotid-femoral pulse wave velocity (cf-PWV) using SphygmoCor. Univariable and multivariable linear regression analyses were performed to evaluate the associations between BMD and vascular function. We used natural logarithm RHI (lnRHI) and cf-PWV as response variables, and each BMD as covariate, adjusting for body mass index, positive anti-cyclic citrullinated peptide, cumulative prednisolone dose, hydroxychloroquine use and Systematic COronary Risk Evaluation 2. RESULTS: We recruited 49 patients (mean age 61.08 ± 8.20 years), of whom 44 (89.80%) were women and 39 (81.25%) were Chinese. Significant associations were found between lnRHI and BMD at the lumbar spine (β = 0.4289, P = 0.037) and total hip (β = 0.7544, P = 0.014) in univariable analyses. Multivariable analyses confirmed these associations, showing that lower BMD at the lumbar spine (β = 0.7303, P = 0.001), femoral neck (β = 0.8694, P = 0.030) and total hip (β = 0.8909, P = 0.010) were significantly associated with worse lnRHI. No significant associations were found between BMD and cf-PWV. CONCLUSION Lower BMD is associated with endothelial dysfunction, but not aortic stiffness in patients with RA. Further longitudinal studies are needed to confirm these associations and understand the underlying mechanisms.
Humans ; Arthritis, Rheumatoid/complications* ; Female ; Male ; Bone Density ; Middle Aged ; Cross-Sectional Studies ; Vascular Stiffness ; Aged ; Singapore ; Pulse Wave Analysis ; Osteoporosis/complications* ; Endothelium, Vascular/physiopathology* ; Cardiovascular Diseases/complications* ; Carotid-Femoral Pulse Wave Velocity ; Hyperemia

This study aimed to explore the pharmacological mechanism of Yourenji Capsules(YRJ) in improving osteoporosis by combining network pharmacology and proteomics technologies. The SD rats were randomly divided into a blank control group and a 700 mg·kg~(-1) YRJ group. The rats were subjected to gavage administration with the corresponding drugs, and the blank serum, drug-containing serum, and YRJ samples were compared using ultra performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS/MS) to analyze the main components absorbed into blood. Network pharmacology analysis was conducted based on the YRJ components absorbed into blood to obtain related targets of the components and target genes involved in osteoporosis, and Venn diagrams were used to identify the intersection of drug action targets and disease targets. The STRING database was used for protein-protein interaction(PPI) network analysis of potential target proteins to construct a PPI network. Gene Ontology(GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment were performed using Enrichr to investigate the potential mechanism of action of YRJ. Ovariectomy(OVX) was performed to establish a rat model of osteoporosis, and the rats were divided into a sham group, a model group, and a 700 mg·kg~(-1) YRJ group. The rats were given the corresponding drugs by gavage. The femurs of the rats were subjected to label-free proteomics analysis to detect differentially expressed proteins, and GO functional enrichment and KEGG pathway enrichment analyses were performed on the differentially expressed proteins. With the help of network pharmacology and proteomics results, the mechanism by which YRJ improves osteoporosis was predicted. The analysis of the YRJ components absorbed into blood revealed 23 bioactive components of YRJ, and network pharmacology results indicated that key targets involved include tumor necrosis factor(TNF), tumor protein p53(TP53), protein kinase(AKT1), and matrix metalloproteinase 9(MMP9). These targets are mainly involved in osteoclast differentiation, estrogen signaling pathways, and nuclear factor-kappa B(NF-κB) signaling pathways. Additionally, the proteomics analysis highlighted important pathways such as peroxisome proliferator-activated receptor(PPAR) signaling pathways, mitogen-activated protein kinase(MAPK) signaling pathways, and β-alanine metabolism. The combined approaches of network pharmacology and proteomics have revealed that the mechanism by which YRJ improves osteoporosis may be closely related to the regulation of inflammation, osteoblast, and osteoclast metabolic pathways. The main pathways involved include the NF-κB signaling pathways, MAPK signaling pathways, and PPAR signaling pathways, among others.
Animals ; Drugs, Chinese Herbal/administration & dosage* ; Osteoporosis/metabolism* ; Proteomics ; Rats ; Rats, Sprague-Dawley ; Network Pharmacology ; Female ; Protein Interaction Maps/drug effects* ; Capsules ; Humans ; Signal Transduction/drug effects*

Facing the requirements of promoting the healthy China initiative and improving people's health, the "bone health program" was proposed in 2024. In-depth development of a traditional Chinese medicine(TCM) prevention and control system is of strategic significance to the implementation of the "bone health program". Focusing on osteoporosis(OP), a representative disease affecting people's bone health, this paper concludes that accelerating the research on the prevention and control of OP by TCM is conducive to enhancing the knowledge and awareness of OP among the public, and it is beneficial to revealing the evolutionary pattern of OP and improving the understanding and management of this disease. Additionally, it can provide an overall framework for and strengthen the systematicity and completeness of the research on the prevention and treatment of OP by TCM. Meanwhile, it can help to explore new research paradigms and optimize the existing research model, so as to promote innovative breakthroughs in the prevention and treatment of bone health-related diseases by TCM. Under the overall layout of the "bone health program", importance should be attached to the early prevention and the innovation of very early diagnosis and intervention of OP. Emphasis should be put on the discovery of the target network of disease and treatment mechanism for revealing the core pathogenesis of OP and the therapeutic mechanism of TCM. In addition to local lesions of the bone and its clinical outcomes, attention should be paid to the development of multiple metabolic complications. The fusion of advanced interdisciplinary technologies should be promoted for OP and its complications, and thus a research and development system based on clinical application scenarios and driven by big data can be built. The measures above will facilitate the progress in the prevention and treatment of OP and other bone diseases by TCM and provide new momentum for enriching and deepening the research connotation of the "bone health program".
Osteoporosis/therapy* ; Humans ; Medicine, Chinese Traditional/methods* ; Drugs, Chinese Herbal/therapeutic use* ; China ; Bone and Bones/drug effects*

Recent studies have shown that an imbalance in iron metabolism can affect the composition and microstructural changes of bone, disrupting bone homeostasis and leading to osteoporosis(OP). The imbalance in iron metabolism, along with its induced local abnormal microenvironment and cellular iron death, has become a new focal point in OP research, drawing increasing attention from the academic community regarding the regulation of iron metabolism to prevent and manage OP. From the perspective of traditional Chinese medicine(TCM), iron metabolism imbalance has potential connections to TCM theories regarding internal organs, as well as treatments aimed at tonifying the kidney, strengthening the spleen, and activating blood circulation. Evidence is continually emerging that TCMs and effective components that tonify the kidney, strengthen the spleen, and activate blood circulation can prevent and manage OP by regulating iron metabolism. This article analyzes the relationship between iron and bone, as well as the effects of TCM formulations on improving iron metabolism and influencing bone metabolism, from the perspectives of iron metabolism mechanisms and TCM interventions, aiming to broaden existing clinical strategies for prevention and treatment and inject new momentum into the field of OP as it moves into a new era.
Osteoporosis/drug therapy* ; Humans ; Iron/metabolism* ; Drugs, Chinese Herbal/pharmacology* ; Animals ; Medicine, Chinese Traditional ; Bone and Bones/drug effects*

Osteoporosis(OP) is a senile bone disease characterized by an imbalance between bone remodeling and bone formation. Targeting pathogenesis of kidney deficiency, spleen deficiency, and blood stasis, Bushen Jianpi Huoxue Decoction has a significant effect on the treatment of OP by tonifying kidney, invigorating spleen, and activating blood circulation. MicroRNA(miRNA) and the anti-apoptotic protein B-cell lymphoma-2-like protein 1(BCL2L1) are closely related to bone cell metabolism. Therefore, in this study, the binding of miR-140-5p to BCL2L1 was detected by dual luciferase assay and polymerase chain reaction(PCR). After silencing or overexpressing miR-140-5p, the apoptosis, autophagy, and osteogenic function of human fetal osteoblast cell line 1.19(HFOB1.19) were observed by flow cytometry and Western blot. Bushen Jianpi Huoxue Decoction-containing serum was prepared by intragastric administration of Bushen Jianpi Huoxue Decoction in rats. Different concentrations of Bushen Jianpi Huoxue Decoction-containing serum were used to treat HFOB1.19 with or without miR-140-5p mimic. The expression of osteogenic proteins in each group was observed, and the role of miR-140-5p/BCL2L1 in apoptosis and autophagy of HFOB1.19 was studied, along with the effect of Bushen Jianpi Huoxue Decoction on these processes. As indicated by the dual luciferase assay, miR-140-5p bound to BCL2L1. Flow cytometry and Western blot showed that miR-140-5p promoted apoptosis and inhibited autophagy in HFOB1.19. After intervention with high, medium, and low doses of Bushen Jianpi Huoxue Decoction-medicated serum, compared with the miR-140-5p NC group, the expression of osteocalcin(OCN), osteopontin(OPN), Runt-related transcription factor 2(RUNX2), and transforming growth factor beta 1(TGF-β1) decreased in the miR-140-5p mimic group, while the expression of bone morphogenetic protein 2(BMP2) showed no significant difference under high-dose intervention. Therefore, miR-140-5p/BCL2L1 can promote apoptosis and inhibit autophagy in HFOB1.19. Bushen Jianpi Huoxue Decoction can affect the osteogenic effect of miR-140-5p through BMP2.
MicroRNAs/metabolism* ; Autophagy/drug effects* ; Apoptosis/drug effects* ; Humans ; Drugs, Chinese Herbal/administration & dosage* ; Animals ; Cell Line ; bcl-X Protein/metabolism* ; Osteoblasts/metabolism* ; Rats ; Osteoporosis/physiopathology* ; Male ; Rats, Sprague-Dawley ; Osteogenesis/drug effects*

Grounded in the theory of "all marrows dominated by brain", this study explored the therapeutic mechanism of Zuogui Pills in modulating the oxytocin(OXT)/oxytocin receptor(OXTR) feed-forward loop in the treatment of postmenopausal osteoporosis(PMOP). A PMOP rat model was established using ovariectomy, and 70 Sprague-Dawley female rats were randomly divided into the following groups: sham operation group, model group, estradiol group(17β-estradiol, 0.05 mg·kg~(-1)·d~(-1)), Zuogui Pills low, medium, and high dose groups(0.2, 0.4, 0.8 g·kg~(-1)·d~(-1), respectively), and an antagonist group(atosiban 0.9 mg·kg~(-1)·d~(-1) + 17β-estradiol 0.05 mg·kg~(-1)·d~(-1) + Zuogui Pills 0.4 g·kg~(-1)·d~(-1)). After 12 weeks of model establishment, treatment was administered by gavage once daily for another 12 weeks, followed by sample collection. Enzyme-linked immunosorbent assay(ELISA) was used to measure serum levels of estrogen(E_2), OXT, tartrate-resistant acid phosphatase(TRACP-5b), and bone alkaline phosphatase(BALP). Histopathological changes in the left distal femur were observed through hematoxylin and eosin(HE) staining. Micro-computed tomography(micro-CT) was used to analyze the microstructure of the right distal femur. Western blot was employed to detect the expression levels of OXTR, small GTP-binding protein Ras, Raf1 proto-oncogene(Raf1), mitogen-activated protein kinase kinase 1/2(MEK1/2), and extracellular signal-regulated kinase 1/2(ERK1/2), and their phosphorylated forms in tibial tissues. Compared with the model group, the Zuogui Pills medium and high dose groups showed significantly increased levels of E_2, OXT, and BALP, with a notable decrease in TRACP-5b levels. Morphologically, the trabeculae in the left distal femur were more tightly arranged. The fibrous structure in the right distal femur was significantly improved in the Zuogui Pills high dose group. Additionally, the expression of OXTR, Ras, p-Raf1, p-MEK1/2, and p-ERK1/2 proteins in tibial tissues was significantly increased. The therapeutic effect of the Zuogui Pills high dose group was partially inhibited when an OXTR antagonist was administered. These findings suggest that Zuogui Pills can regulate the OXT/OXTR feed-forward loop, activate the phosphorylation of the downstream Ras/Raf1/MEK/ERK signaling pathway, and ultimately improve bone mineral density, thereby exerting therapeutic effects in PMOP.
Animals ; Rats, Sprague-Dawley ; Rats ; Female ; Drugs, Chinese Herbal/administration & dosage* ; Oxytocin/genetics* ; Receptors, Oxytocin/genetics* ; Humans ; Osteoporosis, Postmenopausal/genetics* ; Bone and Bones/drug effects* ; Brain/drug effects* ; Bone Marrow/drug effects*

Osteoporosis(OP) is a metabolic bone disorder characterized by reduced bone mass and degenerative bone tissue. Osteoporotic pain(OPP) is its most common clinical symptom, significantly affecting the quality of life of patients. With the limitations of modern medical treatments and the intensification of aging, it is imperative to explore more cost-effective interventions for OPP. This paper, based on databases such as China National Knowledge Infrastructure(CNKI), VIP, Wanfang, BioMed, and Web of Science, uncovered the connection between the pathogenesis of OPP in traditional Chinese medicine(TCM) and modern medical mechanisms and retrospectively summarized the basic and clinical research methods and evidence of TCM prescriptions in the treatment of OP and related pain diseases. Studies have shown that TCM prescriptions, focusing on treatments such as nourishing the kidney, strengthening the spleen, and activating blood circulation to remove blood stasis, can significantly improve pain symptoms, increase bone mineral density(BMD), and adjust bone metabolic indicators such as C-terminal telopeptide of type Ⅰ collagen(CTX), serum bone Gla-protein(S-BGP), and alkaline phosphatase(ALP). The mechanisms of action of TCM prescriptions in treating OP and improving OPP symptoms were related to signaling pathways such as Wnt/β-catenin, nuclear factor kappa-B(NF-κB), mitogen-activated protein kinase(MAPK), phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt), and the osteoprotegerin(OPG)/receptor activator of NF-κB(RANK)/receptor activator of NF-κB ligand(RANKL) axis. Further strengthening the accumulation and analysis of clinical data, rigorously designing and conducting randomized controlled trials of TCM treatments for OPP with large sample sizes, standardizing outcome measures in basic and clinical research by using methods such as the core outcome set(COS), and incorporating mass spectrometry and omics approaches to uncover more potential active components and mechanisms may contribute to a deeper exploration of the advantages and essence of TCM prescriptions in the treatment of OPP.
Humans ; Osteoporosis/genetics* ; Drugs, Chinese Herbal/administration & dosage* ; Retrospective Studies ; Bone Density/drug effects* ; Medicine, Chinese Traditional ; Pain/metabolism* ; Animals

This study applied the grading of recommendations assessment, development and evaluation(GRADE) system and the integrated evidence chain-based effectiveness evaluation of traditional Chinese medicine(Eff-iEC) to evaluate the evidence for 12 commonly used Chinese patent medicines for the treatment of osteoporosis, which are frequently recommended in guidelines or expert consensuses. The results showed that Xianling Gubao Capsules/Tablets were rated as C(low-level evidence) according to the GRADE system, and as BA~+B~+(intermediate evidence) according to the Eff-iEC system. Jintiange Capsules were rated as C(low-level evidence) by the GRADE system, and as AA~+B(high-level evidence) by the Eff-iEC system. Gushukang Granules/Capsules were rated as C(low-level evidence) by GRADE system, and as BA~+B~+(intermediate evidence) by Eff-iEC system. Zuogui Pills were rated as C(low-level evidence) by GRADE system, and as AA~(++)B~+(high-level evidence) by Eff-iEC system. Qianggu Capsules were rated as D(extremely low-level evidence) by GRADE system, and as AA~+B~+(high-level evidence) by Eff-iEC system. Zhuanggu Zhitong Capsules were rated as D(extremely low-level evidence) by GRADE system, and as BA~+B(intermediate evidence) by Eff-iEC system. Jingui Shenqi Pills were rated as D(extremely low-level evidence) by GRADE system, and as AA~+B(high-level evidence) by Eff-iEC system. Quanduzhong Capsules were rated as D(extremely low-level evidence) by GRADE system, and as AD~+B~+(low-level evidence) by Eff-iEC system. Epimedium Total Flavones Capsules were rated as D(extremely low-level evidence) by GRADE system, and as AAB~+(high-level evidence) by Eff-iEC system. Yougui Pills were rated as D(extremely low-level evidence) by GRADE system, and as AA~(++)B~(+ )(high-level evidence) by Eff-iEC system. Qigu Capsules were rated as D(extremely low-level evidence) by GRADE system, and as BB~+B(intermediate evidence) by Eff-iEC system. Liuwei Dihuang Pills were rated as C(low-level evidence) by GRADE system, and as AA~(++)B~+(high-level evidence) by Eff-iEC system. Overall, the Eff-iEC system provides a more comprehensive assessment of the effectiveness evidence for traditional Chinese medicine(TCM) than the GRADE system. However, it still has certain limitations that hinder its wider promotion and application. In terms of clinical evidence evaluation, both the Eff-iEC and GRADE systems reflect that the current clinical research quality on Chinese patent medicines for the treatment of osteoporosis is generally low. High-quality clinical trials are still needed in the future to further validate clinical efficacy.
Drugs, Chinese Herbal/therapeutic use* ; Osteoporosis/drug therapy* ; Humans ; Nonprescription Drugs/therapeutic use* ; Evidence-Based Medicine ; Medicine, Chinese Traditional

Glucocorticoid-induced osteoporosis(GIOP) is a serious metabolic bone disease caused by long-term application of glucocorticoids(GCs). Traditional Chinese medicine(TCM) has unique advantages in improving bone microstructure and antagonizing hormone toxicity. This paper systematically reviews the theoretical research, clinical application, and basic research progress of TCM intervention in GIOP. In terms of theoretical research, the theory of "kidney governing bone and generating marrow" indicates that the kidney is closely related to bone development, revealing that core pathogenesis of GIOP is Yin-Yang disharmony, which can be discussed using the theories of "Yin fire", "ministerial fire", and "Yang pathogen damaging Yin". Thus, regulating Yin and Yang is the basic principle to treat GIOP. In terms of clinical application, effective empirical prescriptions(such as Bushen Zhuanggu Decoction, Bushen Jiangu Decoction, and Zibu Ganshen Formula) and Chinese patent medicines(Gushukang Capsules, Hugu Capsules, Xianling Gubao Capsules, etc.) can effectively increase bone mineral density(BMD) and improve calcium and phosphorus metabolism. The combination of traditional Chinese and western medicine can reduce the risk of fracture and play an anti-GIOP role. In terms of basic research, it has been clarified that active ingredients of TCM(such as fraxetin, ginsenoside Rg_1, and salidroside) reduce bone loss and promote bone formation by inhibiting oxidative stress, ferroptosis, and other pathways, effectively improving bone homeostasis. Additionally, classical prescriptions(Modified Yiguan Decoction, Modified Qing'e Pills, Zuogui Pills, etc.) and Chinese patent medicines(Gushukang Granules, Lurong Jiangu Dropping Pills, Gubao Capsules, etc.) can improve bone marrow microcirculation, promote osteoblast differentiation, and inhibit bone cell apoptosis through multiple pathways, multiple targets, and multiple mechanisms. Through the above three aspects, the TCM research status on GIOP is elucidated in the expectation of providing reference for its diagnosis and treatment using traditional Chinese and western medicine treatment programs.
Osteoporosis/physiopathology* ; Humans ; Glucocorticoids/adverse effects* ; Drugs, Chinese Herbal/administration & dosage* ; Animals ; Medicine, Chinese Traditional ; Bone Density/drug effects*

This study investigates the therapeutic effect and underlying mechanism of Compound Ziyin Granules(CZYG) on postmenopausal osteoporosis(PMOP) induced by bilateral ovariectomy in rats. Six-month-old female SD rats were randomly divided into sham-operated(sham) group, ovariectomy(OVX) model group, high-, medium-, and low-dose CZYG groups, and alendronate sodium(AS) group. After 30 days of model establishment, treatment was administered by gavage once daily for 8 weeks, followed by sample collection. Enzyme-linked immunosorbent assay(ELISA) was used to measure serum levels of calcium ions, alkaline phosphatase(AKP), estrogen(E_2), osteoprotegerin(OPG), osteocalcin(BGP), tartrate-resistant acid phosphatase(TRAP), and type Ⅰ procollagen N-terminal propeptide(PINP). Hematoxylin-eosin(HE) staining was used to observe the histopathological changes in the femurs of rats, while micro-computed tomography(micro-CT) was used to analyze the microstructure of the distal femur. Western blot analysis was performed to measure the expression levels of bone metabolism-related proteins, including wingless-type MMTV integration site family member 2(Wnt2), β-catenin, low-density lipoprotein receptor-related protein 5(LRP5), glycogen synthase kinase-3β(GSK-3β). The mRNA expression levels of Wnt2, β-catenin, LRP5, GSK-3β, p-GSK-3β were determined by quantitative real-time PCR(qRT-PCR). Thirty days after bilateral ovariectomy, compared to the sham group, the OVX group showed significant increases in body weight and significant decreases in uterine coefficient. After 8 weeks of treatment, compared to the OVX group, CZYG(medium and high doses) and AS reduced body weight, with high-dose CZYG and AS significantly increasing the uterine coefficient. Serum levels of AKP and TRAP were significantly elevated, while levels of calcium, E_2, BGP, and OPG were significantly decreased in the OVX group. Compared to the OVX group, CZYG and AS significantly reduced serum levels of AKP and TRAP, while high-dose CZYG and AS notably increased the levels of E_2, BGP, OPG, and PINP. Micro-CT and HE staining results indicated that CZYG(medium and high doses) and AS significantly increased bone tissue volume, trabecular number, bone mineral density, and improved the microstructure of the femur. Compared to the OVX group, high-dose CZYG and AS significantly upregulated the protein and mRNA expression levels of Wnt2, β-catenin, and LRP5, and downregulated the phosphorylation level of p-GSK-3β. These results suggest that CZYG can improve PMOP by promoting estrogen secretion, improving bone metabolism indicators, increasing trabecular number and bone mineral density. Its mechanism may be related to the regulation of the Wnt/β-catenin signaling pathway.
Animals ; Female ; Rats, Sprague-Dawley ; Osteoporosis, Postmenopausal/genetics* ; Rats ; Wnt Signaling Pathway/drug effects* ; Humans ; Drugs, Chinese Herbal/administration & dosage* ; beta Catenin/genetics* ; Osteoprotegerin/metabolism* ; Ovariectomy ; Calcium/blood* ; Bone Density/drug effects*