Inhibition Of Bone Resorption Research Articles

Romosozumab for the treatment of osteoporosis - a systematic review.

Romosozumab, a new treatment of osteoporosis, is a monoclonal antibody that targets sclerostin and thereby exhibits a dual mechanism of action by stimulating bone formation and inhibiting bone resorption. This systematic review aims to assess the clinical efficacy and safety of romosozumab for treatment of primary and secondary osteoporosis. A comprehensive literature search was conducted in October 2023 across multiple databases including Embase, PubMed and Cochrane Library. Randomized controlled trials (RCTs) and observational studies evaluating the impact of romosozumab on BMD, bone turnover markers (BTM), fracture outcomes, and its safety profile were included. Data extraction and quality assessment were performed independently by two reviewers in accordance with PRISMA guidelines. A total of 36 articles met the inclusion criteria. Romosozumab significantly increased BMD at the lumbar spine, total hip, and femoral neck compared to placebo and active comparators in patients with primary osteoporosis. Sequential therapy with romosozumab followed by antiresorptives maintained or further increased BMD and reduced fracture risk. Romosozumab was generally well tolerated, however, an imbalance in cardiovascular adverse event was observed in one large clinical trial. Observational studies supported these findings. Specific subgroups of patients with secondary osteoporosis were assessed, demonstrating overall positive outcomes with romosozumab treatment. Romosozumab effectively increases BMD and reduces fracture risk, particularly when used as initial therapy in high fracture-risk patients. Sequential therapy with subsequent antiresorptive treatment optimizes long-term benefits. While generally well-tolerated, its cardiovascular safety profile requires further long-term studies to ensure its safety in clinical practice. Additional studies are needed to confirm efficacy and safety in patients with secondary osteoporosis.

Zhuangyao Jianshen Wan ameliorates senile osteoporosis in SAMP6 mice through Modulation of the GCN5L1-mediated PI3K/Akt/wnt signaling pathway

BackgroundSenile osteoporosis (SOP) is a systemic bone disease characterized by increased susceptibility to fractures. However, there is currently no effective treatment for SOP. The Zhuangyao Jianshen Wan (ZYJSW) pill is traditionally believed to possess kidney-nourishing and bone-strengthening effects, demonstrating efficacy in treating fractures. Despite this, its effectiveness and mechanism in SOP remain unclear. This study aims to investigate the therapeutic potential of ZYJSW in treating SOP in senescence accelerated mouse prone 6 (SAMP6, P6) mice, and elucidate the underlying mechanisms. MethodsFour-month-old SAMP6 mice were categorized into six groups: the model group (SAMP6), low, medium, and high-dose ZYJSW treatment groups, calcitriol treatment (positive control 1) group, and metformin treatment (positive control 2) group. Gastric administration was carried out for 15 weeks, and a normal control group comprising four-month-old Senescence-Accelerated Mouse Resistant 1 (SAMR1) mice. Changes in body weight, liver and kidney function, bone protective effects, and muscle quality were evaluated using various assays, including H&E staining, Goldner staining, bone tissue morphology analysis, Micro-CT imaging, and biomechanical testing. Qualitative analysis and quality control of ZYJSW were performed via LC-MS/MS analysis. To explore mechanisms, network pharmacology and proteomics were employed, and the identified proteins were validated by Western blotting. ResultsOral administration of ZYJSW to P6 mice exerted preventive efficacy against osteopenia, impaired bone microstructure, and poor bone and muscle quality. ZYJSW attenuated the imbalance in bone metabolism by promoting bone formation, as evidenced by the upregulation of key factors such as Runt-related transcription factor 2 (RUNX2), Bone Morphogenetic Protein (BMP2), Osteoprotegerin (OPG) and Osteocalcin (OCN), while simultaneously inhibiting bone resorption through the downregulation of TNF receptor associated factor 6 (TRAF6), Tartrate resistant acid phosphatase (TRAP), Receptor activator for nuclear factor-κB ligand (RANKL) and Cathepsin K (CTSK). Additionally, ZYJSW enhanced muscle structure and function by counteracting the elevation of Ubiquitin (Ub), Muscle RING-finger protein-1 (Murf-1), F-Box Protein 32 (FBOX32), and Myogenin (Myog). Network pharmacology predictions, proteomics analysis corroborated by published literature demonstrated the role of ZYJSW involving in safeguarding mitochondrial biogenesis. This was achieved by suppressing GCN5L1 expression, contributing to the heightened expression of TFAM, PGC-1α, and nuclear respiratory factor-1 (NRF-1) proteins. ZYJSW also positively modulated Wnt signaling pathways responsible for bone formation, due to regulating expressions of key components like β-catenin, GSK-3β, and LRP5. In addition, ZYJSW causes the downregulation of the PI3K/Akt pathway by inhibiting the phosphorylation of both PI3K and Akt. ConclusionsThe study highlights the significance of ZYJSW in preserving the health of both bone and muscle in P6 mice, potentially through the regulation of the GCN5L1-mediated PI3K/Akt/Wnt signaling pathway. The translational potential of this articleOur research provides evidence and a mechanistic rationale for ZYJSW as a candidate for SOP treatment, offering insights for further exploration and strategy development.

Alendronate sodium induces G1 phase arrest and apoptosis in human umbilical vein endothelial cells by inhibiting ROS-mediated ERK1/2 signaling

Bisphosphonates are potent bone resorption inhibitors, among which alendronate sodium (ALN) is commonly prescribed for most osteoporosis patients, but long-term application of ALN can cause bisphosphonate-related osteonecrosis of jaw (BRONJ), the pathogenesis of which remains unclear. Previous studies have suggested that bisphosphonates cause jaw ischemia by affecting the biological behavior of vascular endothelial cells, leading to BRONJ. However, the impacts of ALN on vascular endothelial cells and its mechanism remain unclear. The purpose of this work is to assess the influence of ALN on human umbilical vein endothelial cells (HUVECs) and clarify the molecular pathways involved. We found that high concentration of ALN induced G1 phase arrest in HUVECs, demonstrated by downregulation of Cyclin D1 and Cyclin D3. Moreover, high concentration of ALN treatment showed pro-apoptotic effect on HUVECs, demonstrated by increased levels of the cleaved caspase-3, the cleaved PARP and Bax, along with decreased levels of anti-apoptotic protein Bcl-2. Further experiments showed that ERK1/2 phosphorylation was decreased. Additionally, ALN provoked the build-up of reactive oxygen species (ROS) in HUVECs, leading to ERK1/2 pathway suppression. N-acetyl-L-cysteine (NAC), a ROS scavenger, efficiently promoted the ERK1/2 phosphorylation and mitigated the G1 phase arrest and apoptosis triggered by ALN in HUVECs. PD0325901, an inhibitor of ERK1/2 that diminishes the ERK1/2 phosphorylation enhanced the ALN-induced G1 phase arrest and apoptosis in HUVECs. These findings show that ALN induces G1 phase arrest and apoptosis through ROS-mediated ERK1/2 pathway inhibition in HUVECs, providing novel insights into the pathogenic process, prevention and treatment of BRONJ in individuals receiving extended use of ALN.

Autophagy Regulator Rufy 4 Promotes Osteoclastic Bone Resorption by Orchestrating Cytoskeletal Organization via Its RUN Domain.

Rufy4, a protein belonging to the RUN and FYVE domain-containing protein family, participates in various cellular processes such as autophagy and intracellular trafficking. However, its role in osteoclast-mediated bone resorption remains uncertain. In this study, we investigated the expression and role of the Rufy4 gene in osteoclasts using small interfering RNA (siRNA) transfection and gene overexpression systems. Our findings revealed a significant increase in Rufy4 expression during osteoclast differentiation. Silencing Rufy4 enhanced osteoclast differentiation, intracellular cathepsin K levels, and formation of axial protrusive structures but suppressed bone resorption. Conversely, overexpressing wild-type Rufy4 in osteoclasts hindered differentiation while promoting podosome formation and bone resorption. Similarly, overexpression of a Rufy4 variant lacking the RUN domain mimics the effects of Rufy4 knockdown, significantly increasing intracellular cathepsin K levels, promoting osteoclastogenesis, and elongated axial protrusions formation, yet inhibiting bone resorption. These findings indicate that Rufy4 plays a critical role in osteoclast differentiation and bone resorption by regulating the cytoskeletal organization through its RUN domain. Our study provides new insights into the molecular mechanisms governing osteoclast activity and underscores Rufy4's potential as a novel therapeutic target for bone disorders characterized by excessive bone resorption.

First-in-human study of dosimetry, safety and efficacy for [177Lu]Lu-P15-073: a novel bisphosphonate-based radioligand therapy (RLT) agent for bone metastases.

Bisphosphonates are pivotal in managing bone tumors by inhibiting bone resorption. This study investigates the therapeutic potential of [177Lu]Lu-P15-073, a novel bisphosphonate, for radioligand therapy (RLT) in bone metastases. Ten patients (age 35 to 75) with confirmed bone metastases underwent therapy with a single dose of [177Lu]Lu-P15-073 (1,225 ± 84 MBq, or 33 ± 2 mCi). Prior to treatment, bone metastases were verified via [99mTc]Tc-MDP bone scans. Serial planar whole-body scans monitored biodistribution over a 14-day period. Dosimetry was assessed for major organs and tumor lesions, while safety was evaluated through blood biomarkers and pain scores. Serial planar whole-body scans demonstrated rapid and substantial accumulation of [177Lu]Lu-P15-073 in bone metastases, with minimal uptake in blood and other organs. The absorbed dose in the critical organ, red marrow, was measured at (0.034 ± 0.010 mSv/MBq), with a notably low normalized effective dose (0.013 ± 0.005 mSv/MBq) compared to other 177Lu-labeled bisphosphonates. Persistent high uptake in bone metastases was observed, resulting in elevated tumor doses (median 3.12Gy/GBq). Patients exhibited favorable tolerance to [177Lu]Lu-P15-073 therapy, with no new instances of side effects. Additionally, 87.5% (7/8) of patients experienced a significant reduction in pain scale (numerical rating scale, NRS, from 5.1 ± 2.3 to 3.0 ± 1.8). The tumor-background ratio (TBRmean) of [99mTc]Tc-MDP correlated significantly with [177Lu]Lu-P15-073 uptake (P < 0.01), indicating its potential for prediction of absorbed dose. This study demonstrates the safety, dosimetry, and efficacy of a single therapeutic dose of [177Lu]Lu-P15-073 in bone metastases. The treatment was well-tolerated with no severe adverse events. These findings suggest that [177Lu]Lu-P15-073 holds promise as a novel RLT agent for bone metastases.

Mapping RANKL- and OPG-expressing cells in bone tissue: the bone surface cells as activators of osteoclastogenesis and promoters of the denosumab rebound effect.

Denosumab is a monoclonal anti-RANKL antibody that inhibits bone resorption, increases bone mass, and reduces fracture risk. Denosumab discontinuation causes an extensive wave of rebound resorption, but the cellular mechanisms remain poorly characterized. We utilized in situ hybridization (ISH) as a direct approach to identify the cells that activate osteoclastogenesis through the RANKL/OPG pathway. ISH was performed across species, skeletal sites, and following recombinant OPG (OPG:Fc) and parathyroid hormone 1-34 (PTH) treatment of mice. OPG:Fc treatment in mice induced an increased expression of RANKL mRNA mainly in trabecular, but not endocortical bone surface cells. Additionally, a decreased expression of OPG mRNA was detected in bone surface cells and osteocytes of both compartments. A similar but more pronounced effect on RANKL and OPG expression was seen one hour after PTH treatment. These findings suggest that bone surface cells and osteocytes conjointly regulate the activation of osteoclastogenesis, and that OPG:Fc treatment induces a local accumulation of osteoclastogenic activation sites, ready to recruit and activate osteoclasts upon treatment discontinuation. Analysis of publicly available single-cell RNA sequencing (scRNAseq) data from murine bone marrow stromal cells revealed that Tnfsf11+ cells expressed high levels of Mmp13, Limch1, and Wif1, confirming their osteoprogenitor status. ISH confirmed co-expression of Mmp13 and Tnfsf11 in bone surface cells of both vehicle- and OPG:Fc-treated mice. Under physiological conditions of human/mouse bone, RANKL is expressed mainly by osteoprogenitors proximate to the osteoclasts, while OPG is expressed mainly by osteocytes and bone-forming osteoblasts.

Exploring the Impact of Catechins on Bone Metabolism: A Comprehensive Review of Current Research and Future Directions.

Background/Objectives: Degenerative musculoskeletal diseases represent a global health problem due to the progressive deterioration of affected individuals. As a bioactive compound, catechins have shown osteoprotective properties by stimulating osteoblastic cells and inhibiting bone resorption. Thus, this review aimed to address the mechanism of action of catechins on bone tissue. Methods: The search was applied to PubMed without limitations in date, language, or article type. Fifteen articles matched the topic and objective of this review. Results: EGCG (epigallocatechin gallate) and epicatechin demonstrated action on the osteogenic markers RANKL, TRAP, and NF-κβ and expression of BMPs and ALP, thus improving the bone microarchitecture. Studies on animals showed the action of EGCG in increasing calcium and osteoprotegerin levels, in addition to regulating the transcription factor NF-ATc1 associated with osteoclastogenesis. However, it did not show any effect on osteocalcin and RANK. Regarding human studies, EGCG reduced the risk of fracture in a dose-dependent manner. In periodontal tissue, EGCG reduced IL-6, TNF, and RANKL in vitro and in vivo. Human studies showed a reduction in periodontal pockets, gingival index, and clinical attachment level. The action of EGCG on membranes and hydrogels showed biocompatible and osteoinductive properties on the microenvironment of bone tissue by stimulating the expression of osteogenic growth factors and increasing osteocalcin and alkaline phosphate levels, thus promoting new bone formation. Conclusions: EGCG stimulates cytokines related to osteogenes, increasing bone mineral density, reducing osteoclastogenesis factors, and showing great potential as a therapeutic strategy for reducing the risk of bone fractures.

Bioinspired Glycopeptide Hydrogel Reestablishing Bone Homeostasis through Mediating Osteoclasts and Osteogenesis in Periodontitis Treatment.

Irreversible alveolar bone resorption is one of the important clinical manifestations of periodontitis, which is initiated by a plaque biofilm and exacerbated by the imbalance of osteoclast activity and osteogenesis, affecting a patient's masticatory function and resulting in a high recurrence rate of periodontitis. Herein, to reestablish bone homeostasis in periodontitis, a minocycline hydrochloride (MH)-loaded glycopeptide hydrogel (MH/GRWgel) is fabricated to mediate alveolar bone absorption through sequential antibacterial and RANKL-blocking activities. GRWgel shows an ECM-like fibrous and porous microstructure serving as a scaffold for cell proliferation and differentiation and holds the merits including injectability, self-healing properties, and good biocompatibility. After injection in situ, MH is released rapidly from the hydrogel in the early stage, demonstrating a potent antimicrobial effect to combat the biofilm in the deep periodontal pocket. Moreover, MH/GRWgel exhibits a high specific binding efficiency with RANKL to suppress osteoclast maturation by shielding the RANKL/RANK interaction and enhancing osteogenic differentiation, thereby synergistically regulating bone homeostasis. In the rat periodontitis model, MH/GRWgel significantly curtails periodontitis progression through antimicrobial activity, inhibition of alveolar bone resorption, and promotion of bone regeneration, which is superior to the treatment of a commercial gel. These findings suggest that MH/GRWgel with superiority in regulating bone homeostasis provides a promising therapeutic strategy for periodontitis.

Maltobionic acid protects against ovariectomy‐induced osteoporosis by suppressing bone resorption

AbstractBackgroundOsteoporosis is a debilitating disease characterized by decreased bone density. In this study, we evaluated the anti‐osteoporotic effect of maltobionic acid (MB), one of the components of honey, and calcium maltobionate (MBCa) on bone density and metabolism using a mouse model of osteoporosis. The underlying mechanisms of MB and MBCa action were also investigated.ResultsOvariectomized (OVX) mice were fed diet containing MB or MBCa for 80 days, and femoral bone mineral content and mineral density (BMD) were evaluated. As expected, OVX reduced BMD; however, the administration of MB and MBCa significantly prevented this decrease. Furthermore, MB and MBCa treatment significantly reduced the serum levels of tartrate‐resistant acid phosphatase 5b (TRACP‐5b), a bone resorption marker, and significantly increased the levels of serum calcitonin, compared to those in the OVX control group. In vitro, the relatively high‐dose levels of MB and MBCa inhibited osteoclast differentiation by decreasing the protein expression of nuclear factor of activated T‐cell cytoplasmic 1 (NFATc1), the master transcription factor of osteoclastogenesis.ConclusionOur results showed that osteoporotic mice treated with MB and MBCa had improved bone density and bone metabolism compared to the OVX controls. Moreover, it was hypothesized herein that the suppressive effect on osteoclast differentiation slightly contributed to these results concomitantly. These findings suggest that the intake of MB or MBCa may contribute to the maintenance of bone health, including the prevention of primary osteoporosis.

Progression of vertebral fractures in metastatic melanoma and non-small cell lung cancer patients given immune checkpoint inhibitors

IntroductionThe immune system mediates important effects on bone metabolism, but little has been done to understand immunotherapy’s role in this interaction. This study aims to describe and identify risk factors for the occurrence and/or exacerbation of vertebral fractures (vertebral fracture progression) during immune checkpoint inhibitors (ICIs). MethodsWe conducted an observational, retrospective, monocentric study. We collected data on melanoma and NSCLC patients, treated with first-line ICIs at the Medical Oncology Department ASST Spedali Civili of Brescia, between January 2015 and November 2021, and with a median follow-up of 20.1 (6–36) months. We collected data on patients, diseases, immune-related adverse events, and cortico-steroid therapy initiated on concomitant ICIs. ResultsWe identified 135 patients, 65 (48.2 %) with locally advanced/metastatic melanoma and 70 (51.8 %) with locally advanced/metastatic non-small cell lung cancer (NSCLC). Twenty-one (15.6 %) patients already had an asymptomatic vertebral fracture at baseline before starting ICIs in monotherapy. A total of ten patients, or 7.4 %, had a vertebra fracture progression defined as a new vertebral fracture or a worsening of a previous fracture. There was a strong relation between the steroid therapy and irAEs with vertebra fracture progression [OR (95 % CI) 8.1 (3.7–17.8) p-value < 0.001] in univariable analysis. However, only steroid therapy resulted to be an independent risk factor [8.260 (95 % CI 0.909–75.095); p-value 0.061] at the multivariable analysis. ConclusionConcurrent steroid therapy in patients receiving immunotherapy exposes them to a high risk of fractures due to skeletal fragility. The use of bone resorption inhibitors should be considered in these patients to prevent these adverse events.

EFFECTS OF USING HYDROXIAPATITE-GELATIN GEL AND ROSELLA EXTRACT TO PREVENT RELAPSE IN ORTHODONTIC TREATMENT

To correct malocclusion and malposition in dentistry using orthodontic treatment. Teeth that have moved through the bone with orthodontic devices tend to return to their original position or what is usually called relapse. Relapse is when the teeth return to their original position before orthodontic treatment was carried out. Relapse prevention can be achieved using mechanical devices but there are still some limitations. The use of scaffolds can be a solution in preventing tooth relapse because scaffolds can support cells to grow and develop into new bone in the damaged area. The scaffold components are hydroxyapatite, gelatin, and rosella flower extract which contains flavonoids to inhibit bone resorption. To find out whether these components are toxic or not before they are applied to the human body, a cytotoxicity test is carried out, which is a laboratory study. This research was carried out by incubating the hydroxyapatite scaffold, gelatin and rosella flower extract with osteoblast cells for 24 hours to see whether the rosella extract was toxic to osteoblast cells. Conclusion: This toxicity test shows that rosella flower extract as an ingredient in making scaffolds is not toxic to osteoblast cells.

The senolytic agent ABT263 ameliorates osteoporosis caused by active vitamin D insufficiency through selective clearance of senescent skeletal cells

Background/ObjectiveActive vitamin D insufficiency accelerates the development of osteoporosis, with senescent bone cells and the senescence-associated secretory phenotype (SASP) playing crucial roles. This study aimed to investigate whether the senolytic agent ABT263 could correct osteoporosis caused by active vitamin D insufficiency by selectively clearing senescent cells. MethodsBone marrow mesenchymal stem cells (BM-MSCs) from young and aged mice were treated with ABT263 in vitro, and 1,25(OH)2D-insufficient (Cyp27b1+/−) mice were administered ABT263 in vivo. Cellular, molecular, imaging, and histopathological analyses were performed to compare treated cells and mice with control groups. ResultsABT263 induced apoptosis in senescent BM-MSCs by downregulating Bcl2 and upregulating Bax expression. It also induced apoptosis in senescent BM-MSCs from 1,25(OH)2D-insufficient mice. ABT263 administration corrected bone loss caused by 1,25(OH)2D insufficiency by increasing bone density, bone volume, trabecular number, trabecular thickness, and collagen synthesis. It also enhanced osteoblastic bone formation and reduced osteoclastic bone resorption in vivo. ABT263 treatment corrected the impaired osteogenic action of BM-MSCs by promoting their proliferation and osteogenic differentiation. Furthermore, it corrected oxidative stress and DNA damage caused by 1,25(OH)2D insufficiency by increasing SOD-2 and decreasing γ-H2A.X expression. Finally, ABT263 corrected bone cell senescence and SASP caused by 1,25(OH)2D insufficiency by reducing the expression of senescence and SASP-related genes and proteins. ConclusionABT263 can correct osteoporosis caused by active vitamin D insufficiency by selectively clearing senescent skeletal cells, reducing oxidative stress, DNA damage, and SASP, and promoting bone formation while inhibiting bone resorption. These findings provide new insights into the potential therapeutic application of senolytic agents in the treatment of osteoporosis associated with active vitamin D insufficiency. The translational potential of this articleThis study highlights the therapeutic potential of ABT263, a senolytic compound, in treating osteoporosis caused by active vitamin D insufficiency. By selectively eliminating senescent bone cells and their associated SASP, ABT263 intervention demonstrates the ability to restore bone homeostasis, prevent further bone loss, and promote bone formation. These findings contribute to the growing body of research supporting the use of senolytic therapies for the prevention and treatment of age-related bone disorders. The translational potential of this study lies in the development of novel therapeutic strategies targeting cellular senescence to combat osteoporosis, particularly in cases where vitamin D insufficiency is a contributing factor. Further clinical studies are warranted to validate the efficacy and safety of ABT263 and other senolytic agents in the treatment of osteoporosis in humans.

Europium-Doped 3D Dimensional Porous Calcium Phosphate Scaffolds as a Strategy for Facilitating the Comprehensive Regeneration of Bone Tissue: In Vitro and In Vivo.

In response to the challenges faced by clinicians treating bone defects caused by various factors, various bone repair materials have been investigated, but the efficiency of bone healing still needs to be improved due to the acting of scaffolds only in a single stage of bone tissue regeneration. We investigated the potential of a novel 3D scaffold to support different stages of bone tissue regeneration, including initial inflammation, proliferation, and remodeling. Eu (0, 0.5, 2, 3.5, 5, and 6.5%) was added to calcium polyphosphate to obtain 3D porous network-doped Eu calcium polyphosphate (EuCPP) scaffolds with ideal mechanical strength and pore size. Both in vitro and in vivo experiments proved that Eu3+ released from 5% EuCPP scaffolds could significantly promote the migration and proliferation of bone marrow stromal cells which effectively promote angiogenesis; 5% EuCPP could significantly upregulate the ratio of OPG/RANKL in MC3T3-E1 and promote the secretion of osteogenic-related growth factors (ALP and OPN) from MC3T3-E1, indicating the potential of the scaffold to inhibit bone resorption and promote bone formation. In conclusion, 5% EuCPP possesses the biological properties of pro-angiogenesis, anti-inflammation, pro-osteogenesis, and inhibiting bone resorption, which may provide a sustained positive effect throughout the process of bone tissue repair.

Inhibition of bone resorption by nanoparticle drug delivery system

Inhibition of bone resorption by nanoparticle drug delivery system

Metabolomic characterization of MC3T3-E1pre-osteoblast differentiation induced by ipriflavone-loaded mesoporous nanospheres

This study reports on the metabolic changes accompanying the differentiation of MC3T3-E1 osteoprogenitor cells induced by mesoporous bioactive glass nanospheres (nMBG) loaded with ipriflavone (nMBG-IP). Ipriflavone (IP) is a synthetic isoflavone known for inhibiting bone resorption, maintaining bone density, and preventing osteoporosis. Delivering IP intracellularly is a promising strategy to modulate bone remodeling at significantly lower doses compared to free drug administration. Our results demonstrate that nMBG are efficiently internalized by pre-osteoblasts and, when loaded with IP, induce their differentiation. This differentiation process is accompanied by pronounced metabolic alterations, as monitored by NMR analysis of medium supernatants and cell extracts (exo- and endo-metabolomics, respectively). The main effects include an early-stage intensification of glycolysis and changes in several metabolic pathways, such as nucleobase metabolism, osmoregulatory and antioxidant pathways, and lipid metabolism. Notably, the metabolic impacts of nMBG-IP and free IP were very similar, whereas nMBG alone induced only mild changes in the intracellular metabolic profile without affecting the cells' consumption/secretion patterns or lipid composition. This finding indicates that the observed effects are primarily related to IP-induced differentiation and that nMBG nanospheres serve as convenient carriers with both efficient internalization and minimal metabolic impact. Furthermore, the observed link between pre-osteoblast differentiation and metabolism underscores the potential of utilizing metabolites and metabolic reprogramming as strategies to modulate the osteogenic process, for instance, in the context of osteoporosis and other bone diseases.

Efficacy of a single 5mg zoledronic acid infusion in preventing bone loss and fracture in postmenopausal women with breast cancer.

Chemotherapy-induced bone loss (CTIBL) is common among breast cancer patients, requiring comprehensive assessment and intervention. Zoledronic acid, a strong inhibitor of bone resorption, is effective in CTIBL management, though information on dosing and intervals, particularly the efficacy of the 5mg annual dose for osteoporosis in breast cancer patients, is limited. In this 12-month prospective observational study, 85 breast cancer patients were divided into three groups: 17 received no treatment, 17 received tamoxifen, and 51 received anastrozole or letrozole (AI). Post-surgery, patients were administered a single 5mg dose of zoledronic acid and monitored over 12months for changes in bone mineral density (BMD), fracture rates, and biochemical markers. Initially, the AI group was the oldest, averaging 59.1 ± 8.7years. At baseline, no significant differences in variables, except age, were observed. After 12months, BMD increased in all groups following a single zoledronic acid dose, with the smallest increase in the AI group at the lumbar spine: no treatment (2.4% ± 6.1%), tamoxifen (2.6% ± 3.4%), AI (0.6% ± 14.5%) (p = 0.778). CTx and P1NP levels were consistently suppressed up to 12months post-treatment, with smaller reductions in the AI group. There were no significant differences in fracture or bone metastasis rates among groups. A single infusion of 5mg zoledronic acid was effective in increasing bone density in breast cancer patients. However, AI-treated patients showed less improvement in vertebral bone mineral density and biochemical markers. Further long-term studies with larger cohorts are needed.

Local Application of a New Chalconic Derivative (Chalcone T4) Reduces Inflammation and Oxidative Stress in a Periodontitis Model in Rats.

Chalcones are phenolic compounds with biological properties. This study had the aim to evaluate the effects of topical administration of a new synthetic chalcone, Chalcone T4, in an animal model of periodontitis induced by ligature. Forty rats were distributed in the following experimental groups: negative control (without periodontitis and topical application of distilled water), positive control (periodontitis and topical application of distilled water), chalcone I and II (periodontitis and topical application of 0.6 mg/mL and 1.8 mg/mL, respectively). Chalcone or distilled water was administered into the gingival sulcus of the first molars daily for 10 days, starting with the ligature installation. The following outcomes were evaluated: alveolar bone loss (µCT and methylene blue dye staining), quantification of osteoclasts (histomorphometry), cell infiltrate and collagen content (stereometry), gene expression of mediators (Nfact11, Tnf-α, Mmp-13, iNos, Sod and Nrf2) by (RT-qPCR); expression of BCL-2 and Caspase-1 (immunohistochemistry). Chalcone T4 inhibited bone resorption and prevented collagen matrix degradation. Reduction in the expression of inflammatory markers (Nfact11, Tnf-α, Mmp-13, and Caspase-1), attenuation of oxidative stress (iNOS reduction, and increase in Sod), and pro-apoptotic effect of the compound (BCL-2 reduction), were associated its effects on periodontal tissues. Topical application of Chalcone T4 prevented bone resorption and inflammation, demonstrating potential in the adjunctive treatment of periodontitis.

Evaluation of Functional Components of Lactobacillus plantarum AR495 on Ovariectomy-Induced Osteoporosis in Mice And RAW264.7 Cells

Osteoporosis is a disease characterized by abnormal bone metabolism, where bone resorption outpaces bone formation. In this study, we investigated the key functional components of Lactobacillus plantarum AR495 in mitigating ovariectomy (OVX)-induced osteoporosis in mice. The results indicated that both Lactobacillus plantarum AR495 and its fermentation broth significantly reduced urinary calcium and deoxypyridinoline (DPD) levels in the mice. These interventions inhibited bone resorption and improved trabecular bone architecture by modulating the nuclear factor κB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) signaling pathway. Additionally, the L. plantarum AR495 and fermentation broth groups inhibited the RANKL/TRAF-6 and TLR4/MYD88 pathways, leading to enhanced bone metabolism, improved intestinal barrier function, and reduced intestinal inflammation. In vitro experiments revealed that AR495 fermentation supernatant fractions larger than 100 kDa and those between 50–100 kDa significantly decreased the activity of the osteoclast marker TRAP, regulated the expression of the TLR4/MYD88 pathway, and inhibited osteoclast formation, thereby alleviating the OVX-induced osteoporosis phenotype. These findings suggest that these components may be primary functional elements of L. plantarum AR495 in the treatment of osteoporosis.

Etelcalcetide ameliorates bone loss in chronic kidney disease-mineral and bone disorder by activation of IRF7 and necroptosis pathways

Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a multifaceted clinical syndrome characterized by mineral imbalances, abnormalities in bone metabolism, chronic inflammation and vascular calcification. Etelcalcetide, a second-generation intravenous calcimimetic agent, has been approved for treating high-turnover renal osteodystrophy, effectively targeting the pathophysiological mechanisms underlying this condition. We investigate the impacts of etelcalcetide on osteoclast (OC) differentiation and functionality in CKD-MBD via three critical mechanisms: inflammation initiated by interferon regulatory factor 7 (IRF7), receptor-interacting protein (RIP)-mediated necroptosis and apoptosis-induced cell death. The low-dose (CKD + L) or high-dose (CKD + H) of etelcalcetide groups significantly improved biochemical markers compared to the CKD control mice. Additionally, etelcalcetide-treated CKD mice significantly improved cortical and trabecular bone parameters. In an in vitro study, etelcalcetide was observed to bolster the IRF7-mediated IFNβ response in OC differentiation. Furthermore, it stimulated RIP-mediated necroptosis via RIP and MLKL activation, inhibiting bone resorption. Moreover, the drug increased levels of caspases 3 and 9, inducing cell death in OCs. These findings suggest that etelcalcetide regulates bone metabolism and reduces skeletal issues in CKD-MBD. Etelcalcetide likely enhances bone parameters in CKD-MBD mice by regulating IRF7 pathways and inhibiting OC differentiation. It also improves bone health and promotes RIP-mediated necroptosis and apoptosis pathways within OCs.

Single-cell Transcriptomic Analysis Identifies Senescent Osteocytes that Trigger Bone Destruction in Breast Cancer Metastasis.

Breast cancer bone metastases increase fracture risk and are a major cause of morbidity and mortality among women. Upon colonization by tumor cells, the bone microenvironment undergoes profound reprogramming to support cancer progression, which disrupts the balance between osteoclasts and osteoblasts and leads to bone lesions. A deeper understanding of the processes mediating this reprogramming could help develop interventions for treating patients with bone metastases. Here, we demonstrated that osteocytes in established breast cancer bone metastasis develop premature senescence and a distinctive senescence-associated secretory phenotype (SASP) that favors bone destruction. Single-cell RNA sequencing identified osteocytes from mice with breast cancer bone metastasis enriched in senescence, SASP markers, and pro-osteoclastogenic genes. Multiplex in situ hybridization and AI-assisted analysis depicted osteocytes with senescence-associated satellite distension, telomere dysfunction, and p16Ink4a expression in mice and patients with breast cancer bone metastasis. Breast cancer cells promoted osteocyte senescence and enhanced their osteoclastogenic potential in in vitro and ex vivo organ cultures. Clearance of senescent cells with senolytics suppressed bone resorption and preserved bone mass in mice with breast cancer bone metastasis. These results demonstrate that osteocytes undergo pathological reprogramming by breast cancer cells and identify osteocyte senescence as an initiating event triggering lytic bone disease in breast cancer metastases.