Treatment Of Postmenopausal Osteoporosis Research Articles

Morusin Inhibits RANKL-induced Osteoclastogenesis and Ovariectomized Osteoporosis.

Postmenopausal osteoporosis (PMOP) is a classic type of osteoporosis that has gradually become a significant health problem worldwide. There is an urgent need for a safe alternative therapeutic agent considering the poor therapeutic strategies currently available for this disease. The roots and bark of the Morus australis tree (Moraceae) are used to make a traditional Chinese medicine known as "Morusin", and accumulating evidence has demonstrated its multiple activities, such as anti-inflammatory and anti-tumor effects. In this study, we aim to explore the effect of Morusin on mouse osteoclasts and its mechanism. In this study, we explored the inhibitory effects of Morusin on murine osteoclasts in vitro and its mechanism, and the protective effect of Morusin on an ovariectomy (OVX)-induced osteoporosis model in vivo. The results showed that Morusin prevented OVX-induced bone loss and dramatically decreased RANKL-induced osteoclastogenesis. Morusin interfered with RANKL-activated NF- κB, MAPK, and PI3K/AKT signaling pathways. The expression of three master factors that control osteoclast differentiation, c-Fos, NFATc1, and c-Jun, was reduced by Morusin treatment. Collectively, in vitro results indicated that Morusin has a protective effect on OVX-induced bone loss in a mouse model. Our data provide encouraging evidence that Morusin may be an effective treatment for PMOP.

A practical approach for anabolic treatment of bone fragility with romosozumab.

Romosozumab, a fully humanized anti-sclerostin-antibody, is a bone-builder stimulating osteoblasts and inhibiting osteoclast by activation of the canonical Wnt-beta catenin signaling. This unique mechanism of action has the potential to address unmet needs in osteoporosis management. The multifaceted practical clinical issues related to romosozumab are discussed, especially focusing on the rationale of employing a sclerostin inhibitor to target bone fragility as first line or second line treatment in post-menopausal osteoporosis and in males at increased risk of fractures. Four randomized clinical trials with several post-hoc analyses and more than ten observational studies have consistently demonstrated that romosozumab is effective in rapidly increasing bone mineral density (BMD) and decreasing risk of vertebral, non-vertebral and hip fractures in post-menopausal women at very-high risk of fractures. In male osteoporosis, only data on BMD are available. Noteworthy, romosozumab was shown to be more effective and rapid than teriparatide in improving BMD, bone structure and strength at the hip, especially in women already treated with anti-resorptive drugs. Interestingly, even if romosozumab displays best results in treatment-naïve patients, its favourable effects on BMD were observed even in women previously treated with teriparatide or denosumab, although to a lesser extent. Based on the available evidence, romosozumab could be proposed as ideal drug in several clinical settings, such as non-fractured post-menopausal women at very-high risk of fractures, patients with recent hip fracture, patients non responder to bisphosphonates and short-term denosumab therapy.

Bone‐Targeting and Multishelled Oral Eldecalcitol Nanoparticles Improve Osteoporosis by Reconstruction of Osteogenic‐Osteoclastic Homeostasis

AbstractCurrent treatment of postmenopausal osteoporosis (PMOP) focuses on systemic administration of medication, neglecting to proactively modulate the local microenvironment of skeletal system for superior therapeutic performance. Eldecalcitol (ED‐71), a novel drug for treating osteoporosis, still requires research to overcome high‐frequency delivery and low‐utilization. Here, a bone‐targeting and multishelled nanoparticles are developed for step‐wise release of ED‐71. The nanoparticles are achieved by using the chitosan/alginate outer layer as protective barrier against gastric acid, pectin middle layer as adhesive agent that improved intestinal penetration, and ethylene diamine tetraacetic acid‐grafted mesoporous silica nanomaterials core as bone‐targeting nanocarriers. After oral administration, the ED‐71‐loaded nanoparticles (ME‐ED‐71@PCA) promotes osteogenic differentiation of bone marrow mesenchymal stem cells by reducing intracellular oxidative stress, and inhibits the osteoclast differentiation. ME‐ED‐71@PCA improves bone mass in ovariectomized‐mice by promoting osteogenesis and inhibiting osteoclastogenesis, and the efficacy is more pronounced than ED‐71 alone. ME‐ED‐71@PCA exhibits satisfactory therapeutic performance due to its step‐wise drug release and bone‐targeting compared to ED‐71 administration, providing a new approach to re‐establish bone metabolic homeostasis in PMOP.

Enhanced oral bioavailability of levormeloxifene and raloxifene by nanoemulsion: simultaneous bioanalysis using liquid chromatography-tandem mass spectrometry.

Aim & objective: Levormeloxifene (L-ORM) and raloxifene (RAL) are selective estrogen receptor modulators used in the treatment of postmenopausal osteoporosis and breast cancer. Here, we developed and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous estimation of both drugs. Materials & methods: A quality-by-design (QbD) approach was used for the optimization of the nanoemulsion, and US FDA guidelines were followed for method validation. Results: Multiple reaction monitoring transitions were used for L-ORM (459.05→98.50), RAL (475.00→112.02) and internal standard (180.10→110.2). Analytes were resolved in a C18 column with 80:20 v/v% acetonitrile (ACN), 0.1% formic acid in triple-distilled water as a mobile phase. The developed method was linear over a concentration range of 1-600ng/ml. Pharmacokinetic results of free L-ORM-RAL and the L-ORM-RAL nanoemulsion showed Cmax of free L-ORM- 70.65±16.64, free RAL13.53±2.72, L-ORM nanoemulsion 65.07±14.0 and RAL-nanoemulsion 59.27±17.44ng/ml. Conclusion: Future findings will contribute to the treatment of postmenopausal osteoporosis and breast cancer using L-ORM and RAL.

Mijiao formula regulates NAT10-mediated Runx2 mRNA ac4C modification to promote bone marrow mesenchymal stem cell osteogenic differentiation and improve osteoporosis in ovariectomized rats

Ethnopharmacological relevanceThe Mijiao (MJ) formula, a traditional herbal remedy, incorporates antlers as its primary constituent. It can effectively treat osteoporosis (OP), anti-aging, enhance immune activity, and change depression-like behavior. In this study, we investigated that MJ formula is a comprehensive treatment strategy, and may provide a potential approach for the clinical treatment of postmenopausal osteoporosis. Aim of the studyThe purpose of this study was to determine whether MJ formula promoted osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and improved osteoporosis in ovariectomized rats by regulating the NAT10-mediated Runx2 mRNA ac4C modification. Materials and methodsFemale Sprague-Dawley (SD) rats were used to investigate the potential therapeutic effect of MJ formula on OP by creating an ovariectomized (OVX) rat model. The expression of osteogenic differentiation related proteins in BMSCs was detected in vivo, indicating their role in promoting bone formation. In addition, the potential mechanism of its bone protective effect was explored via in vitro experiments. ResultsOur study showed that MJ formula significantly mitigated bone mass loss in the OVX rat model, highlighting its potential as an OP therapeutic agent. We found that the possible mechanism of action was the ability of this formulation to stabilize Runx2 mRNA through NAT10-mediated ac4C acetylation, which promoted osteogenic differentiation of BMSCs and contributed to the enhancement of bone formation. ConclusionsMJ formula can treat estrogen deficiency OP by stabilizing Runx2 mRNA, promoting osteogenic differentiation and protecting bone mass. Conceivably, MJ formulation could be a safe and promising strategy for the treatment of osteoporosis.

Prediction of the Molecular Mechanism of Corni Fructus-Epimedii Folium- Rehmanniae Radix Praeparata in the Treatment of Postmenopausal Osteoporosis based on Network Pharmacology and Molecular Docking.

In this study, core drugs of clinical postmenopausal osteoporosis were retrieved using data mining, the drug molecular action target was predicted through network pharmacology, the key nodes of interaction were identified by combining postmenopausal osteoporosis-related targets, and the pharmacological mechanism of Traditional Chinese Medicine (TCM) against postmenopausal osteoporosis and other action mechanisms was explored. TCMISS V2.5 was used to collect TCM prescriptions of postmenopausal osteoporosis from databases, including Zhiwang, Wanfang, PubMed, etc., for selecting the highest confidence drugs. TCMSP and SwissTargetPrediction databases were selected to screen the main active ingredients of the highest confidence drugs and their targets. Relevant targets for postmenopausal osteoporosis were retrieved from GeneCards and GEO databases, PPI network diagrams construction and selection of core nodes in the network, GO and KEGG enrichment analysis, and molecular docking validation. Correlation analysis identified core drug pairs as 'Corni Fructus-Epimedii Folium- Rehmanniae Radix Praeparata' (SZY-YYH-SDH). After TCMSP co-screening and de-weighting, 36 major active ingredients and 305 potential targets were selected. PPI network graph was built from the 153 disease targets and 24 TCM disease intersection targets obtained. GO, KEGG enrichment results showed that the intersectional targets were enriched in the PI3K-Akt signalling pathway, etc. The target organs were mainly distributed in the thyroid, liver, CD33+_Myeloid, etc. Molecular docking results showed that the core active ingredients of the 'SZY-YYH-SDH' were able to bind to the pair core nodes and PTEN and EGFR. The results showed that 'SZY-YYH-SDH' can provide the basis for clinical application and treat postmenopausal osteoporosis through multi-component, multi-pathway, and multitarget effects.

Potential Role of Odanacatib in the Treatment of Postmenopausal Intervertebral Disc Degeneration

Odanacatib (ODN), a cathepsin K (CatK) inhibitor, is widely used for the treatment of postmenopausal osteoporosis. However, whether ODN is efficient in delaying intervertebral disc degeneration (IVDD) remaining unknown. We aimed to explore the effect of ODN in the postmenopausal IVDD using an ovariectomized (OVX) mouse model. We collected the disc tissues from female spinal fracture patients and analyzed the CatK expression in different estrogen levels. Besides, we injected ranged concentration of OND subcutaneously in the OVX mice and tested the disc height index (DHI), aggrecan positive area, collagen I, collagen II, inflammatory factors, and apoptosis-related gene expression comparing to control. The intervertebral disc degraded and the CatK gene expression decreased in the disc lacking of estrogen. OVX method increased the collagen I, MMP-3, MMP-13, caspase-3, and caspase-8 expression, but reduced DHI, and the content of aggrecan and collagen II, indicating an IVDD tendency. However, the ODN treatment could suppress MMP-3, MMP-13, caspase-3, and caspase-8 and protect the stability of extracellular matrix (ECM). ODN is a potential drug to delay the IVDD by suppressing apoptosis and ECM degradation.

Catgut embedding in acupoints combined with repetitive transcranial magnetic stimulation for the treatment of postmenopausal osteoporosis: study protocol for a randomized clinical trial.

To date, the clinical modulation for bone metabolism based on the neuro-bone mass regulation theory is still not popular. The stimulation of nerve systems to explore novel treatments for Postmenopausal osteoporosis (PMOP) is urgent and significant. Preliminary research results suggested that changes brain function and structure may play a crucial role in bone metabolism with PMOP. Thus, we set up a clinical trial to investigate the effect of the combination of repetitive transcranial magnetic stimulation (rTMS) and catgut embedding in acupoints (CEA) for PMOP and to elucidate the central mechanism of this neural stimulation in regulating bone metabolism. This trial is a prospective and randomized controlled trial. 96 PMOP participants will be randomized in a 1:1:1 ratio into a CEA group, an rTMS group, or a combined one. Participants will receive CEA, rTMS, or combined therapy for 3 months with 8 weeks of follow-up. The primary outcomes will be the changes in Bone Mineral Density scores, total efficiency of Chinese Medicine Symptoms before and after treatment. Secondary outcomes include the McGill Pain Questionnaire Short-Form, Osteoporosis Symptom Score, Mini-Mental State Examination, and Beck Depression Inventory-II. The leptin, leptin receptor, and norepinephrine levels of peripheral blood must be measured before and after treatment. Adverse events that occur during the trial will be recorded. CEA achieves brain-bone mass regulation through the bottom-up way of peripheral-central while rTMS achieves it through the top-down stimulation of central-peripheral. CEA combined with rTMS can stimulate the peripheral-central at the same time and promote peripheral bone mass formation. The combination of CEA and rTMS may play a coordinating, synergistic, and side-effect-reducing role, which is of great clinical significance in exploring better treatment options for PMOP.Clinical trial registration: https://www.chictr.org.cn/, identifier ChiCTR2300073863.

Eldecalcitol protected osteocytes against ferroptosis of D-gal-induced senescent MLO-Y4 cells and ovariectomized mice

BackgroundActive vitamin D analog eldecalcitol is clinically applied in treatment of postmenopausal osteoporosis. This study aims to determine the role of eldecalcitol in the protection of osteocytes from senescence and the associated ferroptosis. MethodsThe MLO-Y4 osteocytes were exposed to D-gal inducing senescence. The ovariectomized (OVX) mice treated with D-gal using as an aging inducer were intraperitoneally injected with eldecalcitol. The multiplexed confocal imaging, fluorescence in situ hybridization and transmission electron microscopy were applied in assessing osteocytic properties. Immunochemical staining and immunoblotting were carried out to detect abundance and expression of molecules. ResultsThe ablation of vitamin D receptor led to a reduction in amounts of osteocytes, a loss of dendrites, an increase in mRNA expression of SASP factors and in protein expression of senescent factors, as well as changes in mRNA expression of ferroptosis-related genes (PTGS2 & RGS4). Eldecalcitol reversed senescent phenotypes of MLO-Y4 cells shown by improving cell morphology and density, decreasing β-gal-positive cell accumulation, and down-regulating protein expression (P16, P21 & P53). Eldecalcitol reduced intracellular ROS and MDA productions, elevated JC-1 aggregates, and up-regulated expression of Nrf2 and GPX4. Eldecalcitol exhibited osteopreserve effects in D-gal-induced aging OVX mice. The confocal imaging displayed its improvement on osteocytic network organization. Eldecalcitol decreased the numbers of senescent osteocytes at tibial diaphysis by SADS assay and attenuated mRNA expression of SASP factors as well as down-regulated protein expression of senescence-related factors and restored levels of ferroptotic biomarkers in osteocytes-enriched bone fraction. It reduced 4-HNE staining area, stimulated Nrf2-positive staining, and promoted nuclear translocation of Nrf2 in osteocytes of mice as well as inhibited and promoted protein expression of 4-HNE and Nrf2, respectively, in osteocytes-enriched bone fraction. ConclusionsThe present study revealed the ameliorative effects of eldecalcitol on senescence and the associated ferroptosis of osteocytes, contributing to its preservation against osteoporosis of D-gal-induced senescent ovariectomized mice.

Luteolin rescues postmenopausal osteoporosis elicited by OVX through alleviating osteoblast pyroptosis via activating PI3K-AKT signaling

BackgroundRecently, osteoblast pyroptosis has been proposed as a potential pathogenic mechanism underlying osteoporosis, although this remains to be confirmed. Luteolin (Lut), a flavonoid phytochemical, plays a critical role in the anti-osteoporosis effects of many traditional Chinese medicine prescriptions. However, its protective impact on osteoblasts in postmenopausal osteoporosis (PMOP) has not been elucidated. PurposeThis research aimed to determine the effect of Lut in ameliorating PMOP by alleviating osteoblast pyroptosis and sustaining osteogenesis. Study designThis research was designed to investigate the novel mechanism of Lut in alleviating PMOP both in cell and animal models. MethodsOvariectomy-induced PMOP models were established in mice with/without daily gavaged of 10 or 20 mg/kg body weight Lut. The impact of Lut on bone microstructure, metabolism and oxidative stress was evaluated with 0.104 mg/kg body weight Estradiol Valerate Tablets daily gavaged as positive control. Network pharmacological analysis and molecular docking were employed to investigate the mechanisms of Lut in PMOP treatment. Subsequently, the impacts of Lut on the PI3K/AKT axis, oxidative stress, mitochondria, and osteoblast pyroptosis were assessed. In vitro, cultured MC3T3-E1(14) cells were exposed to H2O2 with/without Lut to examine its effects on the PI3K/AKT signaling pathway, osteogenic differentiation, mitochondrial function, and osteoblast pyroptosis. ResultsOur findings demonstrated that 20 mg/kg Lut, similar to the positive control drug, effectively reduced systemic bone loss and oxidative stress, and enhanced bone metabolism induced by ovariectomy. Network pharmacological analysis and molecular docking indicated that the PI3K/AKT axis was a potential target, with oxidative stress response and nuclear membrane function being key mechanisms. Consequently, the effects of Lut on the PI3K/AKT axis and pyroptosis were investigated. In vivo data revealed that the PI3K/AKT axis was deactivated following ovariectomy, and Lut restored the phosphorylation of key proteins, thereby reactivating the axis. Additionally, Lut alleviated osteoblast pyroptosis and mitochondrial abnormalities induced by ovariectomy. In vitro, Lut intervention mitigated the inhibition of the PI3K/AKT axis and osteogenesis, as well as H2O2-induced pyroptosis. Furthermore, Lut attenuated ROS accumulation and mitochondrial dysfunction. The effects of Lut, including osteogenesis restoration, anti-pyroptosis, and mitochondrial maintenance, were all reversed with LY294002 (a PI3K/AKT pathway inhibitor). ConclusionIn summary, Lut could improve mitochondrial dysfunction, alleviate GSDME-mediated pyroptosis and maintain osteogenesis via activating the PI3K/AKT axis, offering a new therapeutic strategy for PMOP.

Shengu granules ameliorate ovariectomy-induced osteoporosis by the gut-bone-immune axis.

Postmenopausal osteoporosis (PMOP) is a common chronic disease, and the loss of bone density and bone strength after menopause are its main symptoms. Effective treatments for PMOP are still uncertain, but Chinese medicine has some advantages in slowing down bone loss. Shengu granules are often used clinically to treat PMOP. It has been shown to be an effective prescription for the treatment of PMOP, and there is evidence that gut flora may play an important role. However, whether Shengu granules attenuate PMOP by modulating gut flora and related mechanisms remains unclear. In this study, we mainly examined the bone strength of the femur, the structure of the intestinal microbiota, SCFAs in the feces and the level of FOXP3 cells in the colon. To further learn about the inflammation response, the condition of the mucosa and the level of cytokines in the serum also included in the testing. In addition, to get the information of the protein expression, the protein expression of OPG and RANKL in the femur and the protein expression of ZO-1 and Occludin in the colon were taken into account. The osteoporosis was significantly improved in the SG group compared with the OVX group, and the diversity of intestinal flora, the secretion level of SCFAs and the expression level of FOXP3 were significantly increased compared with the OVX group. In terms of inflammatory indicators, the intestinal inflammation scores of the SG group was significantly lower than those in the OVX group. Additionally, the serum expression levels of IL-10 and TGF-β in the SG group were significantly increased compared with the OVX group, and the expression levels of IL-17 and TNF-α were significantly decreased compared with the OVX group. In terms of protein expression, the expression levels of ZO-1, Occluding and OPG were significantly increased in the SG group compared with the OVX group, and the expression level of RANKL was significantly decreased compared with the OVX group. Shengu granules treatment can improve the imbalance of intestinal flora, increase the secretion of SCFAs and the expression of FOXP3, which reduces the inflammatory response and repairs the intestinal barrier, as well as regulates the expression of OPG/RANKL signaling axis. Overall, Shengu granules ameliorate ovariectomy-induced osteoporosis by the gut-bone-immune axis.

Podocyte disease following treatment with intravenous ibandronate in an older patient.

Bisphosphonates are commonly used to treat osteoporosis. While renal toxicity is common with pamidronate and zoledronate, few ibandronate-related cases are reported. We describe a rare case of ibandronate-associated nephrotoxicity. An 88-year-old woman was admitted for edema. She had been receiving intravenous ibandronate treatment for postmenopausal osteoporosis and had no other diagnosed diseases. She was presented with proteinuria, hypoalbuminemia (1.9 g/dL), and an elevated serum creatinine level (1.8 mg/dL). Renal biopsy revealed podocyte disease, favoring a diagnosis of focal segmental glomerulosclerosis. She was treated with diuretics, tacrolimus, and fimasartan. Steroids were avoided due to severe osteoporosis. Three months later, the edema had subsided and the laboratory findings had improved (serum albumin 3.5 g/dL, serum creatinine 0.97 mg/dL). This case emphasizes the importance of careful monitoring of proteinuria and renal function during ibandronate treatment. In older adult patients, kidney biopsy and immunosuppressive treatment may be considered based on physical activity and underlying diseases.

Letter to the Editor from Mori and Mori: “Sequential Therapy for the Long-Term Treatment of Postmenopausal Osteoporosis”

Letter to the Editor from Mori and Mori: “Sequential Therapy for the Long-Term Treatment of Postmenopausal Osteoporosis”

Narrative Review of Traditional Chinese Medicine in the Treatment of Postmenopausal Osteoporosis.

An increasing percentage of people in China are suffering from osteoporosis, particularly postmenopausal osteoporosis (PMOP), as the country rapidly evolves into an aging culture. Patients with osteoporosis are inclined to endure fractures, as well as deformities and impairments, which drastically decrease people's quality of life. The benefits of traditional Chinese medicine (TCM) treatment have continued to become increasingly apparent as reports of adverse responses to Western medications increased. The main advantage of traditional Chinese medicine treatment is that pharmacological interactions may be employed to lessen adverse effects while increasing therapeutic efficacy. In addition, there are various exercise therapies created by medical doctors in the past generations, such as: Wuqinxi, Taijiquan, Baduanjin, Yijinjing, etc. Chinese medicine and exercise treatment for postmenopausal osteoporosis have garnered a lot of attention recently both domestically and internationally, and investigations demonstrate that these therapies have considerable therapeutic effects. The pathophysiology of postmenopausal osteoporosis, advancements of herbal therapy options, and exercise treatment options are all thoroughly addressed in this article.

Exosomal circFAM63Bsuppresses bone regeneration of postmenopausal osteoporosis via regulating miR-578/HMGA2 axis.

Postmenopausal osteoporosis (PMOP) affects hundreds of millions of elderly women worldwide. The imbalance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption is the key factor in the progression of PMOP. Recently, exosomal circular RNAshave been considered as critical regulators in physiological and pathological progress. However, their roles in PMOP still require further exploration. Herein, we identified that the expression of exosomal circFAM63B significantly increased in PMOP patients and is closely related to bone density. We further demonstrated that circFAM63B inhibits osteogenic differentiation of bone marrow stromal cells and bone formation in ovariectomy mice by using a combination of in vitro and in vivo experiment strategies. Mechanistically, circFAM63B promotes HMGA2 expression by inhibiting miR-578, thereby suppressing bone repair. Our study proved that exosomal circFAM63B suppresses the bone regeneration of PMOP by regulating the miR-578/HMGA2 axis, which may provide new insights into the pathogenesis and development of PMOP. Knocking down exosomal circFAM63B could be regarded as a new strategy for the treatment of PMOP.

Multilevel categoric factorial design for optimization of raloxifene hydrochloride solid dispersion in PVP K30 by hot-melt extrusion technology

Raloxifene Hydrochloride (RLH) is a selective estrogen receptor modulator (SERM) used for the treatment and prevention of postmenopausal osteoporosis. This Active Pharmaceutical Ingredient (API) belongs to class II biopharmaceutics classification system (BCS) hence it is characterized by solubility-limited bioavailability. The goal of this study is to develop solid dispersion with improved dissolution properties, and enhanced bioavailability via hot-melt extrusion technology. The solid dispersions were made by blending RLH with polyvinylpyrrolidone and polyethylene oxide as polymeric carriers. Design of experiment (DOE) was employed to systematically assess the impact of the formulation variables and their interaction on the drug release profile. The HME conditions were optimized at 165 °C and 150 rpm, ensuring efficient processing. Our findings revealed that Tween 80 and Cremophor RH 40, at a 10 % w/w concentration, served as effective plasticizers for PVP K30. The formulation featuring the highest proportion of PVP K30 (80 % w/w) and Tween 80 as a surfactant exhibited remarkable enhancement of drug release, with over 80 % of the drug dissolving within 30 min and about 100 % within 60 min. The drug has transformed from the crystalline into the amorphous state as confirmed by Differential Scanning Calorimetry (DSC) and Powder X-Ray Diffraction (PXRD), The lead formulation met the USP acceptance criteria for content uniformity, and exhibited a substantial increase in solubility compared to the pure drug across various media.

The Mechanism of Action and Experimental Verification of Narenmandula in the Treatment of Postmenopausal Osteoporosis.

Narenmandula is a classic ancient remedy in Inner Mongolia, historically used for gastrointestinal diseases. In recent decades, Inner Mongolia Medical University found that it has a significant effect in promoting fracture healing and increasing bone density, and has been used to treat postmenopausal osteoporosis (PMOP), but its mechanism is unclear. Identify the mechanism of action of Narenmandula for PMOP treatment. Network pharmacology, molecular docking and ovarian departing rat models were used to verify the relevant mechanism of Narenmandula in the treatment of PMOP. We confirmed that NRMDL prescription can improve OVX-induced bone loss, improve trabecular density, and relieve osteoporosis. Upon screening of network pharmacology, we obtained 238 overlapping genes of Narenmandula and PMOP, and analyzed AKT, IL1B, and IL6 as key genes by network topology. Among the 1143 target genes that interact with PMOP, 107 NRMDL active compounds correspond to 345 target genes and 238 overlapping genes. Network topology analysis showed the top 8 active ingredients, such as quercetin and kaempferol, and the top 20 key genes, such as AKT, IL1B, IL6, INS, JUN, STAT3, TNF, TP53, etc. Enrichment analysis revealed involvement of PI3K-Akt, HIF-1, FoxO, MAPK, and TNF signaling pathways. In addition, we found the most important active compounds bind tightly to core proteins, which were verified by molecular docking analysis. The AKT-related pathway had good binding energy, and the pathway was verified by cell and animal experiments. The potential mechanism and efficacy of Narenmandula against PMOP may be related to the PI3K-AKT pathway.

Τhe story of sclerostin inhibition: the past, the present, and the future.

Sclerostin inhibits osteoblast activity by hampering activation of the canonical Wnt signaling pathway and simultaneously stimulates osteoclastogenesis through upregulation of the receptor activator of NFκB ligand (RANKL). Thus, antibodies against sclerostin (Scl-Abs), besides promoting bone formation, suppress bone resorption and dissociate bone formation from resorption. This dual action results in remarkable increases of bone mineral density which are of a greater magnitude compared to the other antiosteoporotic treatments and are accompanied by decreases of fracture risk at all skeletal sites. The anabolic effect subsides after the first few months of treatment and a predominantly antiresorptive effect remains after this period, limiting its use to 12months. Furthermore, these effects are largely reversible upon discontinuation; therefore, subsequent treatment with antiresorptives is indicated to maintain or further increase the bone gains achieved. Romosozumab is currently the only Scl-Ab approved for the treatment of severe postmenopausal osteoporosis. Indications for use in other populations, such as males, premenopausal women, and patients with glucocorticoid-induced osteoporosis, are pending. Additionally, the efficacy of Scl-Abs in other bone diseases, such as osteogenesis imperfecta, hypophosphatasia, X-linked hypophosphatemia, and bone loss associated with malignancies, is under thorough investigation. Cardiovascular safety concerns currently exclude patients at high cardiovascular risk from this treatment.

Plasma serotonin precursors and metabolite are correlated with bone mineral density and bone turnover markers in patients with postmenopausal osteoporosis.

Serotonin (5-HT) precursors regulate bone remodeling. This study aims to investigate the correlation of plasma 5-HT precursors and metabolite with bone mineral density (BMD) and bone turnover markers in postmenopausal osteoporosis (PMOP) patients. The age, body mass index (BMI), and years since menopause (YSM) were documented for 348 postmenopausal women in normal/osteopenia/osteoporosis (OP) groups, with lumbar spine and femoral neck BMD measured. Serum bone turnover markers (PINP/β-CTX) and plasma 5-HT, 5-HT precursors (Trp/5-HTP) and metabolite (5-HIAA) were measured by ELISA. OP patients were allocated to high/low expression groups following ROC analysis of 5-HT/Trp/5-HTP/5-HIAA. The relationship of plasma 5-HT/Trp/5-HTP/5-HIAA, BMD, and bone turnover markers with PMOP was analyzed using logistic regression analysis. The correlation of plasma 5-HT/Trp/5-HTP/5-HIAA with BMD and bone turnover markers was analyzed using Pearson's correlation analysis, followed by logistic regression analysis of the relationship between plasma 5-HT/Trp/5-HTP/5-HIAA and BMD, bone turnover markers and PMOP. BMI, YSM, BMD and PINP, and β-CTX levels differed among groups. Levels of plasma 5-HT precursors/metabolite were increased in OP patients. Individuals with high 5-HT precursors/metabolite levels had low BMD and high PINP/β-CTX levels. The 5-HT precursors/metabolite negatively-correlated with BMD and positively-correlated with PINP/β-CTX. BMI, YSM, BMD, and PINP/β-CTX/Trp/5-HTP/5-HT related to PMOP and were independent risk factors for OP. Plasma 5-HT precursors and metabolite negatively-correlate with BMD and positively-correlate with PINP/β-CTX in PMOP patients. Peripheral 5-HT precursors and metabolite level may be a new direction of treatment of PMOP and bone metabolism-related disorders.

Jiangu granules ameliorate postmenopausal osteoporosis via rectifying bone homeostasis imbalance: A network pharmacology analysis based on multi-omics validation.

Postmenopausal osteoporosis (PMOP) is a series of reactions to bone homeostasis dysregulation mediated by estrogen deficiency in elderly women. Jiangu granules, a traditional Chinese medicine formula, has been proven as an effective treatment approach for PMOP, which still needs more research iin its complex regulatory mechanisms. Our study aimed to identify the putative targets and regulatory mechanisms of Jiangu granules in PMOP treating. We utilized the NHANES database to compare the clinical information of normal population and PMOP patients. Associated with transcriptomics and proteomic data, we identified the PMOP-related genes, and further studied them with bioinformatic methods including and prognosis model. Network pharmacology was applied for confirming the action targets of Jiangu granules in PMOP. We verified the safety and effectiveness in PMOP treatments of Jiangu granules, and also demonstrated our hypothesis in rats. We discovered that the PMOP patients had higher monocytes than the normal women. Moreover, the transcriptomics and proteomic analysis suggested that the dysregulation of PMOP-related genes expression was associated with monocytes, and the Notch pathway were the critical targets representing bone homeostasis imbalance highly involved in the occurrence of PMOP. We also ascertained network pharmacology results further revealing that Jiangu granules might treat PMOP via recovering the bone homeostasis imbalance identified above. In vivo experiments, we confirmed the high efficacy which mainly resulted from function in mitigating the imbalance in bone homeostasis by recovering the normal expression of PMOP-related genes associated with monocytes, Notch, and steroid pathway in the rat models. Our finding underscored the clinical potential of Jiangu granules in treating PMOP, and enriched the comprehension of the related pathogenic and therapeutic mechanisms.