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Glycosphingolipids (GSLs) are key constituents of membrane bilayers playing a role in structural integrity, cell signalling in microdomains, endosomes and lysosomes, and cell death pathways. Conversion of ceramide into GSLs is controlled by GCS (glucosylceramide synthase) and inhibitors of this enzyme for the treatment of lipid storage disorders and specific cancers. With a diverse range of functions attributed to GSLs, the ability of the GSC inhibitor, eliglustat, to reduce myeloma bone disease was investigated. In pre-clinical models of multiple myeloma, osteoclast-driven bone loss was reduced by eliglustat in a mechanistically separate manner to zoledronic acid, a bisphosphonate that prevents osteoclast-mediated bone destruction. Autophagic degradation of TNF receptor-associated factor 3 (TRAF3), a key step for osteoclast differentiation, was inhibited by eliglustat as evidenced by TRAF3 lysosomal and cytoplasmic accumulation. By altering GSL composition, eliglustat prevented lysosomal degradation whilst exogenous addition of missing GSLs rescued TRAF3 degradation to restore osteoclast formation in bone marrow cells from myeloma patients. This work highlights the clinical potential of eliglustat as a therapy for myeloma bone disease. Furthermore, using eliglustat as a lysosomal inhibitor in osteoclasts may widen its therapeutic uses to other bone disorders such as bone metastasis, osteoporosis and inflammatory bone loss.

BACKGROUND: Osteosarcoma has a complex pathogenesis and a poor prognosis. While advancements in medical technology have led to some improvements in the 5-year survival rate, substantial progress in its treatment has not yet been achieved. OBJECTIVE: To screen key molecular markers in osteosarcoma, analyze their relationship with osteosarcoma treatment drugs, and explore the potential disease mechanisms of osteosarcoma at the molecular level. METHODS: GSE99671 and GSE284259 (miRNA) datasets were obtained from the Gene Expression Omnibus database. Differential gene expression analysis and Weighted Gene Co-expression Network Analysis (WGCNA) on GSE99671 were performed. Functional enrichment analysis was conducted using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes separately for the differentially expressed genes and the module genes with the highest positive correlation to the disease. The intersection of these module genes and differentially expressed genes was taken as key genes. A Protein-Protein Interaction network was constructed, and correlation analysis on the key genes was performed using CytoScape software, and hub genes were identified. Hub genes were externally validated using the GSE28425 dataset and text validation was conducted. The drug sensitivity of hub genes was analyzed using the CellMiner database, with a threshold of absolute value of correlation coefficient |R| > 0.3 and P < 0.05. RESULTS AND CONCLUSION: (1) Differential gene expression analysis identified 529 differentially expressed genes, comprising 177 upregulated and 352 downregulated genes. WGCNA analysis yielded a total of 592 genes with the highest correlation to osteosarcoma. (2) Gene Ontology enrichment results indicated that the development of osteosarcoma may be associated with extracellular matrix, bone cell differentiation and development, human immune regulation, and collagen synthesis and degradation. Kyoto Encyclopedia of Genes and Genomes enrichment results showed the involvement of pathways such as PI3K-Akt signaling pathway, focal adhesion signaling pathway, and immune response in the onset of osteosarcoma. (3) The intersection analysis revealed a total of 59 key genes. Through Protein-Protein Interaction network analysis, 8 hub genes were selected, which were LUM, PLOD1, PLOD2, MMP14, COL11A1, THBS2, LEPRE1, and TGFB1, all of which were upregulated. (4) External validation revealed significantly downregulated miRNAs that regulate the hub genes, with hsa-miR-144-3p and hsa-miR-150-5p showing the most significant downregulation. Text validation results demonstrated that the expression of hub genes was consistent with previous research. (5) Drug sensitivity analysis indicated a negative correlation between the activity of methotrexate, 6-mercaptopurine, and pazopanib with the mRNA expression of PLOD1, PLOD2, and MMP14. Moreover, zoledronic acid and lapatinib showed a positive correlation with the mRNA expression of PLOD1, LUM, MMP14, PLOD2, and TGFB1. This suggests that zoledronic acid and lapatinib may be potential therapeutic drugs for osteosarcoma, but further validation is required through additional basic experiments and clinical studies. [ABSTRACT FROM AUTHOR]

In this study, hydroxyapatite (HAp) nanoparticles (NPs) were synthesized via hydrothermal synthesis method. The surfaces of HAp NPs were functionalized with (3-aminopropyl)triethoxysilane (APTES) and 2-chlorobenzoylthiourea (BT) to obtain HAp–APTES–BT NPs. The structural characterization of HAp submicron particles was made via FTIR and X-ray diffraction techniques. HAp–APTES and HAp–APTES–BT submicron particles were characterized via FTIR. The particle size of HAp submicron particles was determined to be 1281, 1484, and 1718 nm, and their zeta potentials were determined to be −3.38, −3.25, and −3.18. Zoledronic acid (ZA) was loaded onto the HAp–APTES–BT submicron particles under supercritical CO2 conditions (25 °C, 200 bar, 1 h). Drug release profiles of HAp–APTES–BT–ZA submicron particles were investigated in phosphate buffered saline solution (pH 7.4, 37 °C) for 72 h. The cytotoxic effects of HAp–APTES–BT–ZA submicron particles on Saos-2 cells were determined by 3-(4,5-dimethylthiazol-2-yl)-diphenyl tetrazolium bromide test. [ABSTRACT FROM AUTHOR]

Osteoporosis, a condition that primarily affects postmenopausal women and senior adults, presents a substantial public health dilemma despite its subtle manifestations. It is frequently dubbed the "silent disease of the twenty-first century." Osteoporosis is characterized by an imbalance in bone resorption and formation. The study was conducted over the course of one year in a 300-bed hospital, involving 150 patients. Individuals between the ages of 51 and 60 have an increased risk of developing osteoporosis and osteopenia, according to this study. In comparison with males, osteoporosis predominantly impacts women. Low bone mineral density among low-income populations as a result of inadequate nutrition, a high incidence of osteopenia and osteoporosis among postmenopausal women, and vitamin D deficiency among people living in cities are all contributory factors to the prevalence of osteoporosis in India. According to estimates, a considerable proportion of individuals in India suffer from osteoporosis and hip fractures at an earlier stage than in Western nations. We used the WHO's FRAX online instrument to ascertain the risk of fracture in this study. The management of this condition encompasses a wide range of aspects. For both men and women, pharmacological treatments such as denosumab, risedronate, alendronate, zoledronic acid, and bisphosphonates are among the treatment options for osteoporosis. In addition, nonpharmacological approaches to management are advised, including weight-bearing exercise, nicotine cessation, adequate calcium and vitamin D consumption, and fall prevention techniques. Individualized treatment options should be made based on risk-benefit analysis, patient preferences, fracture risk profile, and cost. The primary objective of this study is to provide a comprehensive examination of the existing diagnostic techniques, therapeutic approaches, and potential lifestyle modifications for osteoporosis. [ABSTRACT FROM AUTHOR]

Common metastasis sites for cervical cancer are the lungs, bones, liver, brain, ovaries, and lymph nodes, among other sites. Skin metastasis is very uncommon, and is only observed in approximately 1% of patients. The cancer spreads typically through lymphatic or blood vessels, but a definitive example of lymphatic spread has not been documented thoroughly in the existing literature. Cutaneous metastasis may be confused with cellulitis or a rash; hence, an immediate cutaneous biopsy of any suspicious lesions is recommended. There is no consensus regarding the treatment of this condition. Only one documented case has shown that a combination of paclitaxel, carboplatin, bevacizumab, and zoledronic acid can lead to a complete metabolic response. Our study, which used two cycles of albumin-bound paclitaxel, cisplatin, and bevacizumab, followed by four cycles of the same regimen plus terprelimab for metastases with CPS scores of Programmed death-ligand 1 (PD-L1) over 10, resulted in a stable complete response for over eight months. Our contribution may assist in formulating effective treatment guidelines for the cutaneous metastasis of squamous cervical carcinoma in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: This meta-analysis and systematic review compared denosumab (Dmab) and zoledronic acid (ZA) for managing bone metastases from advanced solid tumors and multiple myeloma, analyzing seven RCTs with 7441 patients. Both treatments had comparable outcomes for overall survival and disease progression. Dmab showed advantages in reducing skeletal-related events (SREs), delaying time to SREs, and reducing pathological fractures, particularly in breast cancer patients. It was also associated with fewer renal toxicities and acute phase reactions but increased risks of hypocalcemia and osteonecrosis of the jaw. Health-related quality of life improvements were observed with Dmab, alongside reduced analgesia use in some cancer types. Cost-effectiveness analyses revealed higher costs for Dmab, with marginal gains in quality-adjusted life years (QALYs). Notably, the cost-effectiveness of both agents is heavily influenced by healthcare system structures, drug pricing, and cancer type. While Dmab may benefit high-risk patients, ZA remains a cost-effective alternative in many settings. Background: Metastatic bone disease (MBD) presents significant challenges in patient management, leading to skeletal-related events (SREs), compromised health-related quality of life, and heightened pain experiences. Denosumab (Dmab) and zoledronic acid (ZA) are bone-modifying agents (BMAs) commonly employed to mitigate the sequelae of MBD. Previous meta-analyses have assessed primary outcomes such as overall survival, pathological fractures, radiation to bone, and the time to SREs within studies. However, a single comprehensive analysis comparing their efficacy across multiple primary and secondary outcomes, as well as cost-effectiveness in specific cancer types, has not yet been conducted. Methods: A literature search identified relevant randomized controlled trials (RCTs), and the primary outcomes included overall survival, pathologic fractures, radiation to bone, and the time to SREs within studies. Secondary outcomes included adverse events, pain, analgesia usage, quality of life, and cost. Results: Meta-analysis revealed that Dmab effectively reduced the need for bone-targeted radiation therapy and was superior to ZA in delaying the time to SREs, except in multiple myeloma. Dmab also reduced pathological fracture incidences in breast cancer patients by 39%. Conclusions: Our analysis suggests that while both agents similarly impact overall survival and disease progression, Dmab offers advantages in SRE reduction and improved HRQoL and pain outcomes with lower rates of opioid usage, albeit with higher risks of hypocalcemia and osteonecrosis in some subgroups. The consensus on cost-effectiveness is mixed and varies based on the cancer type and healthcare system, with some studies favoring Dmab's superior efficacy and safety, while others find ZA more cost-effective due to its lower cost. This study underscores the potential of Dmab as a preferred BMA for MBD management, especially for high-risk skeletal complications, while highlighting cancer-specific safety considerations. Further research is warranted to refine cancer-specific BMA use and optimize MBD management strategies. [ABSTRACT FROM AUTHOR]

Background and Objectives: Bone metastases in patients can cause significant quality-of-life declines due to skeletal-related events (SREs). SRE is defined as the occurrence of radiotherapy for bone pain, pathologic fracture, bone surgery, spinal cord compression, or hypercalcemia. Bone-modifying agents (BMAs), such as denosumab and zoledronic acid, are crucial in reducing the frequency and severity of SREs. The inhibition of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors has emerged as the standard treatment for hormone receptor-positive metastatic breast cancer, demonstrating significant improvements in survival outcomes. This study aims to compare the effectiveness of denosumab and zoledronic acid in preventing SRE in patients receiving CDK4/6 inhibitors with endocrine therapy. Materials and Methods: This retrospective study included 328 patients diagnosed with bone metastatic breast cancer receiving first-line CDK4/6 inhibitor therapy (palbociclib or ribociclib). Patients were assigned to receive either subcutaneous denosumab or intravenous zoledronic acid every 4 weeks. Time to the first skeletal-related event post bone-modifying agent initiation, SRE incidence, and the safety data were evaluated. The data were analyzed using independent samples t-tests, chi-square tests, and Kaplan–Meier methods for time-to-event data. Results: In the denosumab group, the median time to the first skeletal-related event was significantly longer than in the zoledronic acid group (44.55 months and 29.16 months, respectively). Denosumab treatment was associated with a statistically significant reduction in the risk of developing the first SRE after bone-modifying agent initiation compared to zoledronic acid (HR: 0.56, p = 0.001). Additionally, ECOG PS and the number of metastatic bone sites were identified as independent prognostic factors for time to the first SRE. The safety profile was consistent with previous studies reported in the literature. Conclusions: Our study demonstrated that when used with CDK4/6 inhibitors, denosumab is associated with a delay in SREs and a lower SRE incidence than zoledronic acid in patients with bone metastases. These findings support the efficacy of denosumab in preventing SREs and suggest that CDK4/6 inhibitors may have distinct effects on the bone microenvironment, particularly when combined with denosumab. [ABSTRACT FROM AUTHOR]

Objective This study aimed to analyze the influence of drug factors on the efficacy of bisphosphonate for chronic nonbacterial osteomyelitis to provide a reference for clinical treatment and promote clinical rational drug use by evaluation of effectiveness and safety of bisphosphonate treatment of chronic nonbacterial osteomyelitis. Methods Literature on the treatment of chronic nonbacterial osteomyelitis by using bisphosphonate was collected and analyzed from PubMed, Medline, Embase, Cochrane, ISI Web of Knowledge, CNKI, VIP, and Wanfang databases. Results A total of 489 cases were collected, with an average complete response rate of clinical presentation, laboratory tests and imaging findings of 80.37%, 80.56% and 79.22%, respectively. Except for opadronate, risedronate, ibandronate, pamidronate, alendronate, neidronate and zoledronate showed good efficacy, and the average complete response rates were 100%, 100%, 81.64%, 87.50%, 69.23% and 69.23%, respectively. The study found that in the pamidronate group, the average complete response rate of 0.5-1 mg/kg (maximum single dose≤60 mg) subgroup and the frequency of administration once every 3 months subgroup were better than other subgroups. Conclusion Bisphosphonate could be used to treat chronic nonbacterial osteomyelitis, which of efficacy were affected by different drug types, dose and frequency of administration. The optimal dose and frequency of administration of pamidronate were 0.5-1 mg/kg (maximum single dose≤60 mg) and once every 3 months, respectively. [ABSTRACT FROM AUTHOR]

Background: The purpose of our study was to explore the effect of nitrogen-containing bisphosphonate (N-BP) on vascular calcification (VC) through animal experiments and a meta-analysis. Methods: In our animal experiments, Sprague-Dawley (SD) rats were randomly divided into a control group, a VC group, a low-dose zoledronic acid (ZOL) (20 µg/kg) group and a high-dose ZOL (100 µg/kg) group. The calcification of the aortic arch was observed by alizarin red staining. The calcium content of the aortic arch was measured. In our systematic review and meta-analysis, databases, including PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure (CNKI), and the Wanfang database, were searched from their inception to December 20, 2023. Eligible studies comparing N-BP versus no N-BP in the treatment of VC were included. Results: In our animal experiment, the red-stained calcification structure in the low-dose ZOL group was slightly reduced and the red-stained calcification structure in the high-dose ZOL group was significantly reduced compared with that in the VC. The calcium content in the low-dose ZOL group was slightly lower than that in the VC group, but the difference was not significant (P = 0.08). The calcium content in the high-dose ZOL group was significantly lower than that in the VC group (P < 0.0001). Our meta-analysis of human studies revealed that N-BP did not reduce the arterial calcification score (P = 0.46). Our meta-analysis of animal studies revealed that N-BP did not significantly reduce the arterial calcification score (P = 0.09), but N-BP reduced the arterial calcification area (P < 0.00001), arterial calcium content (P = 0.009) and PO4 content (P = 0.0001). Conclusions: Our animal experiment revealed that high-dose ZOL inhibited VC, but low-dose ZOL did not significantly inhibit VC. Our meta-analysis of human studies revealed that N-BP was not effective in the treatment of VC, but our meta-analysis of animal studies suggested a role of N-BP in inhibiting VC. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the safety, efficacy, and cost-effectiveness of combining Compound Kushen Injection (CKI) with zoledronic acid in the treatment of bone metastasis-induced cancer pain in malignant tumors. Methods: A comprehensive search of Chinese and English databases identified randomized controlled trials (RCTs) investigating CKI combined with zoledronic acid for bone metastases in malignancies. Methodological quality assessments were performed on all included studies, and a meta-analysis was conducted using RevMan 5.4.1 software. A cost-effectiveness analysis from the perspective of China's healthcare system employed a decision tree model to evaluate the short-term economic impact of the two treatment regimens. Sensitivity analyses assessed the robustness of the results. Results: Fourteen studies involving 1,269 patients were included in the meta-analysis. The results demonstrated that CKI combined with zoledronic acid was more effective than zoledronic acid alone in treating bone metastatic cancer pain (OR = 3.43, 95% CI: 2.51–4.67, P < 0.0001), with no significant difference in adverse reactions between the two groups. Incremental cost-effectiveness ratio (ICER) analysis revealed that the combination therapy incurred an additional cost of ¥18,863.16 for each unit of effect gained compared to zoledronic acid alone. Sensitivity analyses indicated stable results, showing that under the assumption of a willingness-to-pay threshold set at the average per capita disposable income in 2023, the combination of CKI and zoledronic acid was more cost-effective than zoledronic acid alone in treating bone metastatic cancer pain. Conclusion: Compared with zoledronic acid alone, the combination of CKI and zoledronic acid offers superior efficacy, high safety, and better cost-effectiveness in the treatment of bone metastasis-induced cancer pain in malignant tumors. [ABSTRACT FROM AUTHOR]

Summary: This study compared denosumab and zoledronic acid for treating osteoporosis in drug-naïve postmenopausal Korean women. Over 3 years, both drugs significantly increased bone mineral density. However, denosumab also improved fat-free mass, suggesting it may be a better initial treatment for osteoporosis with low muscle mass, assuming all other conditions remain constant. Background: Denosumab (DMAB) and zoledronic acid (ZOL), which are strong antiresorptive agents, are used to treat osteoporosis in postmenopause. Nonetheless, the data on their comparative efficacy in drug-naïve patients remain limited. Our research compared the therapeutic efficacy of DMAB and ZOL in drug-naïve postmenopausal Korean women with osteoporosis. Methods: In total, 120 women were enrolled and equally divided to the DMAB and ZOL groups. The bone density and biochemical parameters of the patients were monitored over 3 years. Furthermore, the changes in fat-free mass (FFM), which comprises muscle mass, were assessed by bioelectric impedance analysis. Baseline characteristics, including age, BMI, and the prevalence of fractures, were similar between the groups at the onset of the study. Serum 25(OH), calcium and, phosphorus levels and baseline bone mineral density (BMD) were also comparable between the groups. Results: Following 3 years of treatment, both groups exhibited a significant increase in BMD versus the baseline value. In particular, BMD increased by 9.7% and 5.1% at the lumber spine and total hip, respectively, in the DMAB group, versus increases of 7.1% and 4.4%, respectively, in the ZOL group. The increase in FFM was greater in the DMAB group. BMI-adjusted FFM decreased by 1.3% in the ZOL group, versus an increase of 3.6% in the DMAB group. Conclusions: Conclusively, both DMAB and ZOL are effective antiresorptive agents that improved BMD over 3 years in drug-naïve individuals. Moreover, DMAB might represent a more reliable initial option for patients with osteoporosis accompanied by low muscle mass. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives Materials and Methods Results Conclusions Bisphosphonate‐related osteonecrosis of the jaw (BRONJ) is a severe complication of bisphosphonate therapy, with unclear mechanisms. This study investigates the regulatory impact of zoledronic acid (ZOL) on osteoclasts and microRNA (miRNA) expression.Raw264.7 cells and bone marrow‐derived macrophages (BMMs) were used to assess ZOL's effects on proliferation and apoptosis. miRNA array analysis was performed during osteoclastogenesis with ZOL treatment. The role of miR‐483‐5p was examined using miR‐mimics and miR‐inhibitors. A rat BRONJ model was established for in vivo validation.A concentration of 2 μM ZOL, which did not affect cell proliferation or apoptosis, was used in subsequent experiments. ZOL altered the expression of 64 miRNAs (39 upregulated, 25 downregulated). miR‐483‐5p mimics alleviated ZOL‐induced inhibition of osteoclastogenesis, actin ring formation, bone resorption, and differentiation marker expression, whereas inhibitors enhanced these effects. In vivo, Ago‐miR‐483‐5p promoted wound healing in the BRONJ model, while Antago‐miR‐483‐5p impaired it.ZOL modulates osteoclast function in BRONJ through miR‐483‐5p inhibition. miR‐483‐5p may serve as a novel therapeutic target for BRONJ treatment, providing new insights into managing this complication. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study is to evaluate the concordance of results between the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON)–Pivotal Fracture Trial (PFT) and a nonrandomized database study designed to emulate the trial. Methods: HORIZON‐PFT evaluated the efficacy of zoledronic acid versus placebo in reducing the risk of hip fractures and found a 41% risk reduction over a three‐year treatment period (hazard ratio [HR] = 0.59; 95% confidence interval [95% CI] 0.42–0.83). Using two US claims databases from August 2007 to December 2020 or June 2021, we applied eligibility criteria from HORIZON‐PFT and identified women with osteoporosis who initiated zoledronic acid or raloxifene as a proxy for placebo. The study protocol was registered on ClinicalTrials.gov (NCT04736693) before inferential analyses. We compared HORIZON‐PFT and database study results using prespecified metrics. Results: Because of low adherence in clinical practice, on‐treatment follow‐up was truncated at 18 months in the database study. The hip fracture risk after 18 months was 9.3 in 1,000 in the trial and 8.3 in 1,000 in the database analysis. In the database study, zoledronic acid was associated with a 28% reduction in hip fractures risk compared with raloxifene (HR = 0.72; 95% CI 0.51–0.92). The attenuated effect of zoledronic acid in the database study may be explained by its shorter follow‐up, because the interpolated estimate of the effect in HORIZON‐PFT at 18 months was HRRCT (randomized controlled trial), 0.74, nearly identical to the observational estimate HRdatabase 0.72. Conclusion: Real‐world emulation of the HORIZON‐PFT found that zoledronic acid reduced hip fractures risk over an 18‐month follow‐up period. Limited adherence in clinical practice diminished the magnitude of its preventive effect and precluded long‐term estimation of effectiveness in this setting. [ABSTRACT FROM AUTHOR]

Introduction: Ado-trastuzumab emtansine (T-DM1) is employed in the treatment of patients with HER2-positive breast cancer. The most common side effects are fatigue, diarrhoea, anaemia, transaminase elevation and drug-induced thrombocytopenia. This report describes a patient with metastatic breast cancer who developed drug-induced lupus due to T-DM1. Case Report: A 54-year-old woman was diagnosed with breast cancer in March 2018. She underwent modified radical mastectomy and axillary lymph node dissection (pT2N1aM0). Following supraclavicular lymph node metastasis in May 2018, she received 8 cycles of docetaxel, trastuzumab, and pertuzumab. In December 2020, the patient presented with axillary and intra-abdominal lymph node metastases, along with bone metastases observed on PET/CT scan. Treatment with T-DM1 and zoledronic acid was initiated. After 18 months on T-DM1, she developed drug-induced lupus. Her symptoms resolved with hydroxychloroquine treatment and discontinuation of T-DM1. Discussion: Drug-induced lupus is a clinical syndrome that shares similar features with systemic lupus erythematosus (SLE). The majority of patients present with symptoms such as arthralgia and myalgia. Hydralazine and procainamide are high-risk drugs for drug-induced lupus. Symptoms usually develop after months or years of use, but may also develop suddenly. Our patient also received TDM-1 treatment for 18 months. We present a case of TDM-1-associated drug-induced lupus in a patient with metastatic breast cancer. This is the first case of TDM-1-related drug-induced lupus reported in the literature. [ABSTRACT FROM AUTHOR]

Hormonal agents administered for metastatic castration-resistant prostate cancer (mCRPC) may lead to osteoporosis, skeletal events, reduced quality of life, and even reduced overall survival (OS). Bone-modifying agents may prevent those events but their effect on cancer-control outcomes remains uncertain. Relying on our institutional tertiary-care database, we explored the effect of bone-modifying agents (bisphosphonates such as zoledronic acid and denosumab) on OS and progression-free survival in patients with mCRPC with at least 1 bone metastasis using Kaplan-Meyer estimates and Cox regression models. Of 420 patients with mCRPC, 60% received bone-modifying agents who were younger (68 vs 69 years), with more systemic treatment lines for mCRPC (3 vs 2), and a higher proportion of initial de novo metastatic disease (72% vs 62%, all p ≤.04) than patients without bone-modifying agents. In progression-free survival analyses, no significant differences were observed between both groups. In OS analyses, significant median OS differences were observed in favor of patients with bone-modifying agents (58 vs 45 months; hazard ratio [HR]: 0.66), even after multivariable adjustment (HR: 0.37; both p ≤.01). In bone-modifying agent–stratified analyses, 57% received denosumab vs 43% bisphosphonates, with a significantly higher rate of Eastern Cooperative Oncology Group status of ≥2 in the bisphosphonates group. In progression-free and OS analyses, no significant differences were observed between bisphosphonates and denosumab patients, with numerically better results in progression-free survival analysis for denosumab after adjusting for covariates. The cumulative rate of osteonecrosis of the jaw at any treatment time was 12% in both groups and significantly decreased over time. Real-world data suggest a relatively low administration rate of bone-modifying agents in patients with osseous mCRPC. However, real-world data also suggest an OS benefit when bone-modifying agents are used, even after controlling for possible confounding patient and tumor characteristics. [ABSTRACT FROM AUTHOR]

Osteogenesis imperfecta (OI) is an uncommon bone disorder caused by mutations in type I collagen involved in bone matrix leading to increased fracture risk. There are several sub-categories within OI, with OI type I being the most common and mildest form. Women with OI considering pregnancy need to be aware of bone loss and fracture risk, particularly with lactation. We report the first case of a female with twin pregnancy and OI type I who presented with multiple vertebral fractures following delivery and postpartum lactation. Following endocrine review, she weaned breast-feeding but represented within weeks with further pain and magnetic resonance imaging (MRI) demonstrating new T12 and L1 fractures. Even after receiving intravenous zoledronic acid, she experienced further thoracic pain after lifting, and MRI demonstrated a further T7 fracture. Following modification of her treatment regimen to daily teriparatide injections for 12 months, repeat dual-energy X-ray absorptiometry scan showed a significant improvement in bone mineral density at the lumbar spine and left hip. Bone loss with lactation is an important consideration for women with OI considering pregnancy. Women with OI should be assessed by an endocrinologist prior to conception to optimize bone health and have an individualized plan to mitigate bone loss and fracture risk during pregnancy and the postpartum period. [ABSTRACT FROM AUTHOR]

Osteoporosis, a condition that primarily affects postmenopausal women and senior adults, presents a substantial public health dilemma despite its subtle manifestations. It is frequently dubbed the "silent disease of the twenty-first century." Osteoporosis is characterised by an imbalance in bone resorption and formation. The study was conducted over the course of one year in a 300-bed hospital, involving 150 patients. Individuals between the ages of 51 and 60 have an increased risk of developing osteoporosis and osteopenia, according to this study. In comparison with males, osteoporosis predominantly impacts women. Low bone mineral density among low-income populations as a result of inadequate nutrition, a high incidence of osteopenia and osteoporosis among postmenopausal women, and vitamin D deficiency among people living in cities are all contributory factors to the prevalence of osteoporosis in India. According to estimates, a considerable proportion of individuals in India suffer from osteoporosis and hip fractures at an earlier stage than in Western nations. We used the WHO's FRAX online instrument to ascertain the risk of fracture in this study. The management of this condition encompasses a wide range of aspects. For both men and women, pharmacological treatments such as denosumab, risedronate, alendronate, zoledronic acid, and bisphosphonates are among the treatment options for osteoporosis. In addition, nonpharmacological approaches to management are advised, including weight-bearing exercise, nicotine cessation, adequate calcium and vitamin D consumption, and fall prevention techniques. Individualised treatment options should be made based on risk-benefit analysis, patient preferences, fracture risk profile, and cost. The primary objective of this study is to provide a comprehensive examination of the existing diagnostic techniques, therapeutic approaches, and potential lifestyle modifications for osteoporosis.

Abstract Background Zoledronic acid (ZA) is widely used for the treatment of osteolytic bone metastases in malignancies and osteoporosis, but it has been associated with renal impairment. In this study, we investigated adverse events (AEs) related to renal and urinary system diseases associated with ZA using the U. S. FDA’s Adverse Event Reporting System. Methods We collected FAERS data from Q1 2004 to Q1 2024 and used the reporting odds ratio to detect AEs related to renal and urinary system diseases associated with ZA. Additionally, we applied multiple algorithms, including ROR, proportional reporting ratio, bayesian confidence propagation neural network, and multi-item gamma poisson shrinker, to quantify renal and urinary AEs under different indications. Results A total of 52,495 AE reports involving ZA as the primary suspect drug were identified. Among renal and urinary system diseases, 25 distinct AEs were recognized, with renal tubular necrosis being the most frequently reported. For different indications, renal tubular necrosis was the most reported AE in breast cancer and osteoporosis; nephrogenic diabetes insipidus was both the most frequent and strongest signal in lung cancer; proteinuria was most common in multiple myeloma, and polyuria in prostate cancer. Furthermore, most AEs occurred in patients who had been on ZA for more than 360 days, followed by those within the first 30 days of use. Conclusion Based on pharmacovigilance data from FAERS, different renal and urinary system AEs should be closely monitored and addressed according to the specific indications for which ZA is used.

Introduction: Antiresorptive drugs are commonly used to treat cancer and bone metastases. These drugs can impose the risk of osteonecrosis of the jaw (ONJ). ONJ is a serious complication that can lead to significant morbidity and mortality. This study aimed to investigate the incidence and preventive measures utilization of ONJ among cancer patients treated with antiresorptive agent. Materials and Methods: This retrospective cohort study investigated 210 adult patients with cancer on either zoledronic acid (ZA) or denosumab at a tertiary cancer center. The primary endpoint was to determine the incidence rate of Osteonecrosis of the Jaw. Secondary endpoints were to determine the utilization rate of antiresorptive agent related ONJ preventive measures and the exposure duration of antiresorptive agents to the ONJ incidence. Results: Of 210 patients, 68 were on zoledronic acid (group 1) and 142 were maintained on denosumab (group 2). The median incidence rate of medication related ONJ (MRONJ) was 3.8 % (8 out of 210), with 4.4 % (3 out of 68) in the first group and 3.5 % (5 out of 142) in the second group. All ONJ cases were females with metastatic breast cancer to bone. The utilization rate of ONJ preventive measures was 5.2 %, including regular dental check-ups (3.3 %) and oral hygiene education (1.9 %). The median duration of exposure before ONJ was 1 year for zoledronic acid and 2 years for denosumab. Risk factors included female sex, diabetes mellitus, and hypertension. Duration of Denosumab exposure, but not ZA, was associated with incidence of ONJ. Conclusion: Higher incidence rate of ONJ among denosumab-treated group. The findings emphasize the importance of female sex, diabetes, and hypertension as significant risk factors. The use of preventive measures was found to be low, indicating a need for better education and awareness.

Abstract Objective To investigate the effects of zoledronic acid on muscle metabolism in mice with osteoporosis and sarcopenia and elucidate the possible underlying mechanism. Methods Twenty-four 8-week-old male C57BL/6J mice were randomly divided into four groups: non-suspension (N-SUS), suspension (SUS), suspension + zoledronic acid (ZA), and suspension + PTH(PTH) groups. Equal doses of saline, zoledronic acid, and PTH were administered subcutaneously. After 4 weeks, the mice were sacrificed, and body weight and muscle mass (gastrocnemius and soleus) were measured, the right tibia of mice was taken for micro-CT examination, and the muscle specimens were analyzed using HE staining, ATPase staining, western blotting, and real-time PCR. Results Compared with the N-SUS group, the bone mineral density (BMD), trabecular bone relative volume (BV/TV) and trabecular bone number (Tb.N) were significantly decreased in the SUS group (P

Abstract Medication-related osteonecrosis of the jaw is a rare but severe complication with challenging treatment protocols. Cold atmospheric plasma (CAP) has shown promising effects in wound healing, cell proliferation and viability. This study investigated the effect of CAP on osteoblasts in a culture medium containing bisphosphonates. Pilot study was designed to determine the optimal setting of CAP. MG-63 cells were exposed to zoledronic acid at a concentration of 10 micromolar for 72 h. Study groups with the best MTT assay results, were chosen for assessing OPG and RANKL genes by RT-PCR. Cell viability was significantly higher in groups 9 kV.1 mm.90 s, 10 kV.1 mm.60 s, and 12 kV.1 mm.60 s (P 0.05). OPG decreased in all test groups compared to BP (p 0.05). RANKL/OPG ratio in groups 9 kV.1 mm.90 s and 12 kV.1 mm.60 s significantly increased compared to BP (P

Background: Zoledronic acid (ZA) is widely used for the treatment of osteolytic bone metastases in malignancies and osteoporosis, but it has been associated with renal impairment. In this study, we investigated adverse events (AEs) related to renal and urinary system diseases associated with ZA using the U. S. FDA's Adverse Event Reporting System. Methods: We collected FAERS data from Q1 2004 to Q1 2024 and used the reporting odds ratio to detect AEs related to renal and urinary system diseases associated with ZA. Additionally, we applied multiple algorithms, including ROR, proportional reporting ratio, bayesian confidence propagation neural network, and multi-item gamma poisson shrinker, to quantify renal and urinary AEs under different indications. Results: A total of 52,495 AE reports involving ZA as the primary suspect drug were identified. Among renal and urinary system diseases, 25 distinct AEs were recognized, with renal tubular necrosis being the most frequently reported. For different indications, renal tubular necrosis was the most reported AE in breast cancer and osteoporosis; nephrogenic diabetes insipidus was both the most frequent and strongest signal in lung cancer; proteinuria was most common in multiple myeloma, and polyuria in prostate cancer. Furthermore, most AEs occurred in patients who had been on ZA for more than 360 days, followed by those within the first 30 days of use. Conclusion: Based on pharmacovigilance data from FAERS, different renal and urinary system AEs should be closely monitored and addressed according to the specific indications for which ZA is used. [ABSTRACT FROM AUTHOR]

The aim of the authors was to evaluate the periapical and endodontic conditions of patients with osteoporosis and compare them with those of age- and sex-matched controls. The association between bisphosphonate (BiP) use and periapical and endodontic status in patients with osteoporosis was also investigated. Panoramic radiographs of 711 patients with osteoporosis and 711 age- and sex-matched healthy patients were examined. The presence and number of root canal–filled teeth (RCFT), inadequate RCFT (iRCFT), and teeth with apical periodontitis (AP) were evaluated. BiP treatment history of patients with osteoporosis was also recorded. No significant difference was observed between the osteoporosis group and control group in terms of endodontic and periapical conditions. Results of bivariate logistic regression analysis showed a positive association between the number of teeth with AP and the number of iRCFT with AP and osteoporosis, and a negative association between the number of RCFT with AP and osteoporosis. Among the patients with osteoporosis, 37.5% used BiPs, specifically alendronate, ibandronate, zoledronate, and risedronate (34.3%, 24.9%, 10.6%, 7.2%, respectively). In addition, the results showed a negative association between BiP use and RCFT. As the number of teeth with AP and number of iRCFT with AP increased, patients were more likely to be in the osteoporosis group. These findings imply that periapical lesions may enlarge and become more detectable in patients with osteoporosis with lower bone density, and enhanced inflammatory response. Dentists can collaborate with health care professionals to manage the overall health of patients with osteoporosis to reduce the impact of osteoporosis on oral health and effectively treat dental problems, such as AP. [ABSTRACT FROM AUTHOR]

Introduction: Inflammatory factors leading to bone loss significantly increase the risk of tooth loosening or implantation failure. Zoledronic acid (ZOL) is a widely used medication for effectively inhibiting excessive bone destruction, but its effect on alleviating inflammatory bone loss remains to be elucidated. In this study, we investigated whether ZOL alleviates inflammatory bone resorption through immunomodulatory effect. Methods: The viability of the cells was evaluated by Cell Counting Kit 8 (CCK8) assay. Osteoclast (OC) differentiation and function were determined by tartrate‐resistant acid phosphatase (TRAP) staining and bone resorption pits assays, respectively. Autophagosomes and actin ring structures of OC were observed using transmission electron microscopy (TEM) and F‐actin ring staining, respectively. The microstructure in mice maxillary alveolar bone model was observed by micro computed tomography (Miro‐CT). Reverse transcription‐quantitative PCR (RT‐qPCR) to detect the mRNA expression of osteoclast‐related genes and Western blot (WB) analysis to evaluate the protein expression levels of autophagy‐related proteins and the NOD‐like receptor family pyrin domain‐containing protein 3 (NLRP3)‐related proteins in pre‐OCs. Results: The findings indicated that ZOL hindered lipopolysaccharide (LPS)‐mediated OC differentiation, formation, bone resorption activity and autophagosome levels. Furthermore, ZOL diminished the expression of genes associated with OC. And the expression of proteins ATG7, LC3II, Beclin1, NLRP3‐related proteins and tumor necrosis factor‐α (TNF‐α) protein were markedly decreased while P62 was increased, especially in the 1 μM ZOL group or MCC950 + ZOL group. Conclusions: ZOL has a certain immunomodulatory effect that exhibits anti‐inflammatory properties at lower concentrations, which can weaken LPS‐induced OCs differentiation and function, and NLRP3‐mediated autophagy pathway may participate in this process. [ABSTRACT FROM AUTHOR]

Background • Osteoporosis poses a significant health challenge characterized by reduced bone density and increased fracture risk. Percutaneous kyphoplasty, a common treatment, aims to stabilize vertebral fractures. However, adjunctive therapies like zoledronic acid remain underexplored in improving postoperative outcomes and bone health in these patients. Objective • This study aims to evaluate the efficacy of zoledronic acid combined with calcium carbonate and vitamin D3 in treating osteoporosis, providing valuable clinical insights. Methods • A cohort of sixty-six osteoporosis patients who underwent percutaneous kyphoplasty and received subsequent treatment at our hospital between March 2020 and March 2022 were selected. Thirty-three patients received calcium carbonate and vitamin D3 (control group), while the remaining thirty-three patients were treated with zoledronic acid alongside calcium carbonate and vitamin D3 (research group). Pre- and post-treatment assessments included bone mineral density measurements, bone metabolism and turnover marker evaluations, symptom improvement assessments using the Visual Analogue Scale (VAS) and the Oswestry Disability Index (ODI), monitoring of adverse reactions, and assessment of quality of life using the Core Quality of Life questionnaire (QOL-C30). A one-year follow-up was conducted to determine re-fracture incidence. Results • Post-treatment, the research group exhibited significantly lower VAS, ODI, tartrate-resistant acid phosphatase-5b, and osteocalcin levels compared to the control group, while bone alkaline phosphatase levels were higher (P < .05). There was no significant difference in adverse reaction incidence between the groups (P > .05), but the research group demonstrated higher QOL-C30 scores (P < .05). Follow-up analysis revealed no notable difference in re-fracture rates between the groups (P > .05). Conclusions • Zoledronic acid in combination with calcium carbonate and vitamin D3 effectively enhances bone health in osteoporosis patients, warranting its clinical recommendation. This regimen shows promise for improving patient outcomes in osteoporosis management. (Altern Ther Health Med. 2024;30(12):340-345). [ABSTRACT FROM AUTHOR]

Antiresorptive drugs are commonly used to treat cancer and bone metastases. These drugs can impose the risk of osteonecrosis of the jaw (ONJ). ONJ is a serious complication that can lead to significant morbidity and mortality. This study aimed to investigate the incidence and preventive measures utilization of ONJ among cancer patients treated with antiresorptive agent. This retrospective cohort study investigated 210 adult patients with cancer on either zoledronic acid (ZA) or denosumab at a tertiary cancer center. The primary endpoint was to determine the incidence rate of Osteonecrosis of the Jaw. Secondary endpoints were to determine the utilization rate of antiresorptive agent related ONJ preventive measures and the exposure duration of antiresorptive agents to the ONJ incidence. Of 210 patients, 68 were on zoledronic acid (group 1) and 142 were maintained on denosumab (group 2). The median incidence rate of medication related ONJ (MRONJ) was 3.8 % (8 out of 210), with 4.4 % (3 out of 68) in the first group and 3.5 % (5 out of 142) in the second group. All ONJ cases were females with metastatic breast cancer to bone. The utilization rate of ONJ preventive measures was 5.2 %, including regular dental check-ups (3.3 %) and oral hygiene education (1.9 %). The median duration of exposure before ONJ was 1 year for zoledronic acid and 2 years for denosumab. Risk factors included female sex, diabetes mellitus, and hypertension. Duration of Denosumab exposure, but not ZA, was associated with incidence of ONJ. Higher incidence rate of ONJ among denosumab-treated group. The findings emphasize the importance of female sex, diabetes, and hypertension as significant risk factors. The use of preventive measures was found to be low, indicating a need for better education and awareness. [ABSTRACT FROM AUTHOR]

Medication‐related osteonecrosis of the jaw (MRONJ) is a progressive condition that can cause significant bone loss and its diagnosis can be challenging. A 68‐year‐old man with a diagnosis of hepatocellular carcinoma, undergoing treatment with atezolizumab, bevacizumab and zoledronic acid, complained of spontaneous pain in the right lower second premolar. Oral examination revealed no dental changes and implants in the right jaw. A patient history and thorough clinical and radiographic examinations mimic endodontic disease. The implant crowns were removed, bleeding on probing, and peri‐implant pockets were observed. The main hypothesis was MRONJ Stage 2, and the surgical treatment was performed. The pain ceased and signs of MRONJ were not observed within 3 months. MRONJ should be considered as a hypothesis in the case of odontalgia and a patient's history of antiresorptive and antiangiogenic therapies. Furthermore, monitoring patients with dental implants in the mandible through detailed clinical and imaging evaluation is required. [ABSTRACT FROM AUTHOR]

Gluten-free bread (GFB) consisting of amaranth flour, tigernut (chufa tuber) flour, apple powder, carrot powder, and soy protein isolate can have osteoprotective effects. Glucocorticoid-induced osteoporosis (GIO) was chosen as a model of experimental osteoporosis. Experimental studies were carried out on white male Wistar rats (n = 150): Group 1 – healthy animals receiving standard diet (StD); Group 2 – GIO rats receiving StD; Group 3 – GIO animals receiving zoledronic acid (ZA) and StD; Group 4 – GIO rats receiving ZA and GFB; Group 5 – GIO animals receiving GFB. We evaluated the general condition of animals and carried out morphological and biochemical studies. Destructive changes in the spatial structure of the bone tissue in GIO, observed in Group 2, led to the inability of the bone to withstand the functional load. At the same time, isolated treatment with ZA had virtually no effect on the final morphological picture. Including GFB in the diet of experimental animals both alone and with ZA had a noticeable protective effect on conditions triggering GIO. [ABSTRACT FROM AUTHOR]

This study aimed to identify whether there is an ideal concentration for applying ozonized oil (OZ) in the post-exodontic alveoli of senescent rats treated with zoledronate (ZOL). Thirty-five female rats, aged 18 months, were divided into five groups: ZOL; ZOL+OZ500; ZOL+OZ600; ZOL+OZ700; and SAL. The groups treated with ZOL, and other concentrations of OZ received applications at a dose of 100 μg/kg, while the SAL group received saline. After three weeks of ZOL application, the animals underwent extraction of the lower first molar. Subsequently, local therapies were initiated: group ZOL+OZ500 at 500 mEq/kg; ZOL+Z600 at 600 mEq/kg; and ZOL+OZ700 at 700 mEq/kg at baseline, and on days 2 and 4 post-operation. Euthanasia was performed on day 28. The microtomographic parameter of bone volume and histometric data on the area of neoformed bone (NFBT) showed the highest values for the ZOL+OZ600 group (p < 0.05). All OZ groups had smaller areas of non-vital bone than the ZOL group (p < 0.05). The clinical appearance of the operated region showed the alveoli covered with soft tissue, particularly in the OZ groups. All the tested concentrations of OZ were able to prevent and modulate MRONJ. As it presents a greater amount of NFBT, the concentration of 600 mEq/kg seems to be ideal. [ABSTRACT FROM AUTHOR]

Background: Giant cell reparative granulomas are nonneoplastic, benign lesions that can expand and dissolve bone. Fibrous dysplasia is a benign condition in which normal bone tissue is replaced by abnormally proliferating immature reticular bone and fibrous tissue. The combination of giant cell reparative granuloma and fibrous dysplasia is extremely rare and can pose diagnostic and therapeutic challenges because of the complexity of clinical presentation. Case Presentation: We here present a patient who had a combination of fibrous dysplasia of bone and a giant cell reparative granuloma. An elderly male was admitted to the hospital with a blood‐streaked nasal discharge, blurry vision in his right eye, and an enlarged mass under the chin. A CT scan revealed that the lesion had infiltrated the head and face extensively, including the right maxillary sinus, sieve sinus, and the right nasal cavity, contraindicating surgery. The patient received a total dose of 30 Gy of 6 MV x‐ray radiotherapy delivered through helical tomotherapy over 15 sessions, with a single dose of 2 Gy being administered five times a week. Concurrently, The dose is 4 mg of zoledronic acid administered intravenously once every 21 days. After treatment, the patient's nasal congestion was significantly relieved, the vision of the right eye improved, and the mandibular lesion was significantly reduced. Conclusions: Treatment with radiotherapy combined with zoledronic acid for our patient's inoperable osteolytic giant cell reparative granuloma adjacent to vital nerves and blood vessels was extremely effective and safe. This case report provides a reference for the management of this rare combination. [ABSTRACT FROM AUTHOR]

Background: Osteogenesis imperfecta (OI) is a rare genetic disorder affecting mainly type I collagen, which leads to bone fragility and deformities. OI patients also present craniofacial abnormalities such as macrocephaly and malocclusion. Recently, craniofacial dysmorphism was highlighted in the osteogenesis imperfecta mouse (oim), a validated model of the most severe form of OI. This study explores the impact of zoledronic acid (ZA), commonly administered to OI patients to increase bone mass and mechanical strength, on oim craniofacial structure. Methods: Fifteen oim received a single intravenous ZA injection (100 µg/kg) at 5 weeks (ZA group), while fifteen remained untreated (control). Before euthanasia at 14 weeks, in vivo computed tomography provided craniometric data. Post-euthanasia, heads underwent peripheral Quantitative Computed Tomography (pQCT); coronal decalcified sections through temporomandibular joints were analyzed (n = 6/mouse) after Masson's trichrome staining (3 sections) or under polarized light to study collagen birefringence (3 sections). Results: In vivo craniometry highlighted the positive effect on vertical growth in ZA oim models as compared to untreated ones, with significant increases in mandibular length and incisor height and without any change in transversal dimensions. The pQCT scans showed the significantly higher total mineral density and cortical mineral density of the mandibular ramus in the ZA than the untreated group. Via microscopic analysis, the cranial vault was thicker and the collagen birefringence was higher in the ZA group than in the untreated group, but differences were not significant. Conclusion: To conclude, ZA had some beneficial effects on craniofacial vertical height and ramus density and, to a lower extent, on vault thickness, while transversal dimensions did not seem to be influenced by ZA intake. These data emphasize the need to consider the whole skeleton when treating OI patients. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of zoledronic acid on muscle metabolism in mice with osteoporosis and sarcopenia and elucidate the possible underlying mechanism. Methods: Twenty-four 8-week-old male C57BL/6J mice were randomly divided into four groups: non-suspension (N-SUS), suspension (SUS), suspension + zoledronic acid (ZA), and suspension + PTH(PTH) groups. Equal doses of saline, zoledronic acid, and PTH were administered subcutaneously. After 4 weeks, the mice were sacrificed, and body weight and muscle mass (gastrocnemius and soleus) were measured, the right tibia of mice was taken for micro-CT examination, and the muscle specimens were analyzed using HE staining, ATPase staining, western blotting, and real-time PCR. Results: Compared with the N-SUS group, the bone mineral density (BMD), trabecular bone relative volume (BV/TV) and trabecular bone number (Tb.N) were significantly decreased in the SUS group (P < 0.01), the trabecular bone separation(Tb.Sp)was significantly increased (P < 0.01), which was reversed in ZA and PTH group (P < 0.01).Compared to the SUS group, the body and muscle weights of the ZA and PTH groups were significantly increased. Compared to the SUS group, the muscle structure was less damaged, the proportion of type I muscle fibers was increased, and the protein expression of β-catenin and AKT were upregulated in the ZA and PTH groups(P < 0.05). In addition, the mRNA expression levels of Wnt3a, Wnt16, Myf5, and PI3K were significantly increased (P < 0.05), where as those of Myogenic Differentiation Antigen(MyoD)and Myogenin (MyoG) were significantly decreased (P < 0.05). No significant differences were observed between the ZA and PTH groups. Conclusions: Zoledronic acid can reduce muscle loss and damage by upregulating the mRNA expression of Wnt and PI3K and the protein expression of β-catenin and AKT.Our results provide a novel basis for the development of drugs for the treatment of osteoporosis combined with sarcopenia. [ABSTRACT FROM AUTHOR]

This study assessed the effectiveness of the local use of green propolis-loaded lipid nanoparticles (GPlnp) as an adjuvant therapy to scaling and root planing (SRP) to manage experimental periodontitis (EP) in ovariectomized rats treated with zoledronate. Ten weeks before the experiment, 48 female rats were ovariectomized. On day 0, a ligature was installed in the lower first molar to induce EP. From day 0 to day 42, half of the rats were treated with vehicle (VEH), while the other half were treated with 100μg/Kg of zoledronate (ZOL). On day 14, the rats were allocated into the following groups: VEH-NLT, VEH-SRP, VEH-SRP-GPlnp, ZOL-NLT, ZOL-SRP, and ZOL-SRP-GPlnp. VEH-NLT and ZOL-NLT received no local treatment. VEH-SRP and ZOL-SRP received SRP and irrigation with physiological saline solution. VEH-SRP-GPlnp and ZOL-SRP-GPlnp received SRP and irrigation with GPlnp. A single SRP session was carried out, and four irrigation sessions were conducted (on days 14, 16, 18, and 20). On day 42, all animals were euthanized. The hemimandibles were processed for histological, histometric (percentage of total bone tissue (PTBT) and non-vital bone tissue (PNVBT)) and immunohistochemical (TNFα, IL-1β, and TRAP) analysis. VEH-SRP-GPlnp showed better tissue repair, higher PTBT, and lower immunolabeling for TNFα and IL-1β compared to the groups treated with VEH. ZOL-SRP-GPlnp showed a favorable tissue repair, with lower PNVBT, less local inflammation, and lower immunolabeling for TNFα and IL-1β compared to the groups treated with ZOL. Irrigation with GPlnp proved to be effective as an adjuvant therapy to SRP in treating EP in ovariectomized rats treated with zoledronate. [ABSTRACT FROM AUTHOR]

Simple Summary: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype, has poor prognosis, and lacks targeted therapies. Schlafen12 (SLFN12) is a protein linked to survival in TNBC. SLFN12 influences the expressions of important cancer genes and other SLFN family members, but it is unclear how these genes change following chemotherapy. This study indicates that SLFN12 overexpressing TNBC cells with chemotherapy agents resulted in the differential expressions of eight cancer genes. Further, when TNBC cells were treated with chemotherapy and hairpin adenovirus to knock down SLFN12, IFN-α2 treatment was able to increase SLFN family mRNA expression and decrease cell viability. Together, these results indicate the importance of examining SLFN family interactions with gene profiles in an effort to produce a targeted treatment approach for TNBC patients. Background/Objectives: Schlafen12 (SLFN12) is an intermediate human Schlafen protein shown to correlate with survivability in triple-negative breast cancer (TNBC). SLFN12 causes differential expressions of significant cancer genes, but how they change in response to chemotherapy remains unknown. Our aim is to identify the effect of chemotherapy on genes that improve TNBC outcomes and other SLFN family members following SLFN12 knockout or overexpression. Methods: We overexpressed SLFN12 using a lentiviral vector and knocked out SLFN12 (AdvShSLFN12) using a hairpin adenovirus in MDA-MB-231 TNBC cells. Cells were treated with camptothecin, paclitaxel, zoledronic acid, or carboplatin to evaluate the SLFN12 signature cancer genes associated with improved TNBC outcomes using qPCR. Additionally, cells were treated alone and in combination with AdvShSLFN12, IFN-α2 (known SLFN12 stimulator), carboplatin, and paclitaxel. After treatment, the viable cell numbers were analyzed utilizing a colorimetric crystal violet assay for cell viability. Results: The SLFN family and SLFN12 cancer signature gene mRNA expressions were analyzed by RT-qPCR. Treating SLFN12-overexpressing TNBC cells with chemotherapy agents resulted in the differential expressions of eight cancer-related genes. Notably, GJB3 was downregulated following treatment with each chemotherapeutic drug. Inducing SLFN12 with IFN-α2 resulted in decreased cell viability and increased SLFN12 mRNA levels following treatment with paclitaxel or carboplatin. Conclusions: These results suggest that SLFN12 overexpression significantly affects the expressions of genes driving phenotypic changes in response to chemotherapy and influences additional SLFN family members following IFN-α2 treatment. This may contribute to improving the survival of patients with SLFN12 overexpression. Additionally, patient SLFN12 levels can be used as a factor when pursuing personalized chemotherapy treatments. [ABSTRACT FROM AUTHOR]

Medication-related osteonecrosis of the jaw is a rare but severe complication with challenging treatment protocols. Cold atmospheric plasma (CAP) has shown promising effects in wound healing, cell proliferation and viability. This study investigated the effect of CAP on osteoblasts in a culture medium containing bisphosphonates. Pilot study was designed to determine the optimal setting of CAP. MG-63 cells were exposed to zoledronic acid at a concentration of 10 micromolar for 72 h. Study groups with the best MTT assay results, were chosen for assessing OPG and RANKL genes by RT-PCR. Cell viability was significantly higher in groups 9 kV.1 mm.90 s, 10 kV.1 mm.60 s, and 12 kV.1 mm.60 s (P < 0.05). Expression of RANKL in these groups was significantly lower than the positive control group (medium culture without zoledronic and plasma treatment) and higher than the BP group (culture with zoledronic without plasma treatment), except for the 12 kV.1 mm.60 s group, which did not differ significantly from the positive control group (P > 0.05). OPG decreased in all test groups compared to BP (p < 0.05), except for the 12 kV.1 mm.60 s group, which did not significantly differ from BP (P > 0.05). RANKL/OPG ratio in groups 9 kV.1 mm.90 s and 12 kV.1 mm.60 s significantly increased compared to BP (P < 0.05).CAP treatment may enhance the viability of osteoblasts exposed to bisphosphonates, increase their activity levels, enhance osteoclast activity, and improve bone turnover rates. [ABSTRACT FROM AUTHOR]

Background: Osteonecrosis of the jaw (ONJ) stands as a severe complication linked to the use of bisphosphonates, particularly zoledronic acid, which is widely prescribed for managing conditions like osteoporosis and bone metastasis. This study is geared towards the development and validation of a clinical prediction model for ONJ in patients undergoing zoledronic acid treatment. Methods: We harnessed data from the FDA Adverse Event Reporting System (FAERS) as our training dataset, while the Canada Vigilance Adverse Reaction (CVAR) database served as the testing dataset. The study encompassed patients treated with zoledronic acid and subsequently diagnosed with ONJ. We analysed a range of predictive factors, including breast cancer, bone metastasis, osteoporosis, vitamin D and calcium levels, comorbidities, the number of concomitant medications, dosage, age, weight, and gender. Logistic regression and nomogram analysis were the chosen methodologies for constructing the predictive model. To evaluate the model's performance, we utilized receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). Results: The study encompassed a total of 2,126 patients in the training cohort, 911 patients in the internal test cohort from the FAERS database, and 121 patients in the external test cohort from the CVAR database. Notable predictors for ONJ included bone metastasis (OR: 1.65, 95% CI: 1.22–2.24), osteoporosis (OR: 0.33, 95% CI: 0.21–0.52), the number of concomitant medications (OR: 1.07, 95% CI: 1.05–1.09), and the dosage of zoledronic acid (OR: 1.24, 95% CI: 1.10–1.39). The nomogram exhibited robust discriminatory power, evidenced by an area under the curve (AUC) of 0.77 in the training cohort, 0.76 in the internal test cohort, and 0.90 in the external test cohort. Calibration plots demonstrated a strong alignment between observed and predicted probabilities. Furthermore, DCA highlighted the prediction model's significant net benefit across various threshold probabilities. Conclusion: By leveraging data from both the FAERS and Canadian databases, this study has successfully developed and validated a clinical prediction model for ONJ in patients receiving zoledronic acid. This model stands as a valuable tool for clinicians, enabling them to pinpoint high-risk patients and make evidence-based treatment decisions to minimize the risk of ONJ. [ABSTRACT FROM AUTHOR]

Accelerated sub-lesional bone loss is common in the first 2–3 years after traumatic spinal cord injury (TSCI), particularly in the distal femur and proximal tibia. Few studies have explored efficacy of antiresorptives for acute bone loss prevention post-TSCI, with limited data for knee bone mineral density (BMD) or beyond two years follow-up. An open-label non-randomized study was performed at Royal North Shore Hospital and Royal Rehab Centre, Sydney between 2018 and 2023. An 'acute interventional cohort' (n = 11) with TSCI (duration ≤ 12-weeks) received a single infusion of 4 mg zoledronic acid (ZOL) at baseline. A 'chronic non-interventional cohort' (n = 9) with TSCI (duration 1–5-years) did not receive ZOL. All participants underwent baseline and 6-monthly blood tests (including CTx and P1NP) and 12-monthly DXA BMD scans (including distal femur and proximal tibia). Participants were predominantly Caucasian and male (mean age 38.4 years). At baseline, the 'acute' cohort had higher serum CTx, P1NP and sclerostin concentrations, while the 'chronic' cohort had lower left hip and knee BMD. Majority with acute TSCI experienced an acute phase reaction after ZOL (9/11; 82%). In the acute cohort, left hip BMD fell by mean ~ 15% by 48 months. Left distal femoral and proximal tibial BMD declined by mean ~ 6–13% at 12 months and ~ 20–23% at 48 months, with a tendency towards greater BMD loss in motor-complete TSCI. A single early ZOL infusion in acute TSCI could not attenuate rapidly declining hip and knee BMD. Prospective controlled studies are required to establish the optimal strategy for preventing early bone loss after acute TSCI. [ABSTRACT FROM AUTHOR]

Intravenous zoledronic acid is an established and generally well tolerated form of antiresorptive therapy for osteoporosis. Although mild arthralgias are a well-documented manifestation of the acute phase response to intravenous bisphosphonates, more severe musculoskeletal reactions manifesting as debilitating pain and joint effusions have been rarely documented in the current literature. In this case report, we discuss the case of a 55-year-old woman who developed severe painful bilateral knee effusions within 1 week of her first zoledronic acid infusion for osteoporosis. Prescribing physicians and patients should be made aware of this uncommon but important adverse effect to zoledronic acid. [ABSTRACT FROM AUTHOR]