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Oncology Research 2024Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival. The treatment of bone metastases is challenging since many anticancer...
Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival. The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect. To improve the treatment efficacy, we developed Pluronic P123 (P123)-based polymeric micelles dually decorated with alendronate (ALN) and cancer-specific phage protein DMPGTVLP (DP-8) for targeted drug delivery to breast cancer bone metastases. Doxorubicin (DOX) was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity (3.44%). The DOX-loaded polymeric micelles were spherical, 123 nm in diameter on average, and exhibited a narrow size distribution. The experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release. The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated cells. Rapid binding of the micelles to hydroxyapatite (HA) microparticles indicated their high affinity for bone. P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model. experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic toxicity. In conclusion, our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.
Topics: Humans; Female; Micelles; Breast Neoplasms; Ligands; Quality of Life; Cell Line, Tumor; Doxorubicin; Polymers; Antineoplastic Agents; Drug Delivery Systems; Bone Neoplasms; Alendronate; Drug Carriers; Poloxalene
PubMed: 38560569
DOI: 10.32604/or.2023.044276 -
Journal of the Mechanical Behavior of... Jun 2024Glucocorticoid-induced osteoporosis (GIOP) changes the microarchitecture of bones and often leads to the reduction of bone-mineral density (BMD) and increased fracture...
Glucocorticoid-induced osteoporosis (GIOP) changes the microarchitecture of bones and often leads to the reduction of bone-mineral density (BMD) and increased fracture rates. Zebrafish has been used as an alternative model for GIOP, however, the interaction of GIOP, and its treatment, with zebrafish bone morphometrics and mechanical properties, remains a challenge. Thus, this study aimed to evaluate the effects of prednisolone and alendronate on the properties of zebrafish vertebrae. Adult 7-month-old zebrafish were distributed into four groups: control (CTRL), prednisolone-only (PN), alendronate-only (ALN), and the sequential use of both medicines (PN + ALN). Fish skeletons were scanned via micro-tomography (n = 3) to obtain vertebra morphometrics (e.g., BMD). Bone morphology was assessed using scanning electron microscopy (n = 4) and the biomechanical behaviour with nanoindentation technique (n = 3). The BMD decreased in PN (426.08 ± 18.58 mg/cm) and ALN (398.23 ± 10.20 mg/cm) groups compared to the CTRL (490.43 ± 41.96 mg/cm) (p < 0.001); however, administering the medicines in sequence recovered the values to healthy levels (495.43 ± 22.06 mg/cm) (p > 0.05). The bone layered structures remain preserved in all groups. The vertebrae of the groups that received ALN and PN + ALN, displayed higher modulus of elasticity (27.27 ± 1.59 GPa and 25.68 ± 2.07 GPa, respectively) than the CTRL (22.74 ± 1.60 GP) (p < 0.001). ALN alone increased the hardness of zebrafish vertebrae to the highest value among the treatments (1.32 ± 0.13 GPa) (p < 0.001). Conversely, PN + ALN (1.25 ± 0.11 GPa) showed unaltered hardness from the CTRL (1.18 ± 0.13 GPa), but significantly higher than the PN group (1.08 ± 0.12 GPa) (p < 0.001). ALN administered after GIOP development, rescued osteoporotic condition by recovering the BMD and bone hardness in zebrafish vertebrae.
Topics: Animals; Alendronate; Glucocorticoids; Zebrafish; Bone Density Conservation Agents; Osteoporosis; Spine; Bone Density; Prednisolone; Lumbar Vertebrae
PubMed: 38555661
DOI: 10.1016/j.jmbbm.2024.106521 -
Biomedicine & Pharmacotherapy =... May 2024Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. The aim of this study was to investigate the therapeutic potential of vitamin C,...
Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. The aim of this study was to investigate the therapeutic potential of vitamin C, glutamine, mesalazine, hydralazine, and alendronate as new drug candidates for the treatment of letrozole-induced PCOS in female Wistar rats. PCOS was induced in rats by intramuscular injection of estradiol valerate (2 mg/kg body weight for 28 days). The rats then received normal saline (PCOS group), letrozole (0.5 mg/kg), vitamin C (100 mg/kg), glutamine (1000 mg/kg), mesalazine (200 mg/kg), hydralazine (30 mg/kg), and alendronate (17.5 mg/kg). Serum testosterone, LH, FSH, estradiol and progesterone levels were determined by ELISA method. H&E staining was used for histological analysis in the ovarian tissues. The groups treated with hydralazine and alendronate, show a significant decrease in testosterone, LH hormone, cystic and atretic follicles, and a significant increase in the number of single layer, multilayer, antral, graafian follicles and the volume of corpus luteum as compared to the PCOS group. Hydrolazine and alendronate appear to be effective in restoring folliculogenesis and increasing ovulation in PCOS rat. So that the natural process of ovulation and the improvement of the histology of polycystic ovaries and its shift towards healthy and active ovaries were observed. This finding supports the potential beneficial effect of hydrolazine and alendronate on improving PCOS complication.
Topics: Animals; Female; Rats; Alendronate; Aromatase Inhibitors; Disease Models, Animal; Estradiol; Hydralazine; Letrozole; Luteinizing Hormone; Ovary; Polycystic Ovary Syndrome; Rats, Wistar; Testosterone
PubMed: 38552442
DOI: 10.1016/j.biopha.2024.116504 -
Advanced Healthcare Materials Mar 2024Magnesium phosphate bone cement (MPC) has gained widespread usage in orthopedic implantation due to its fast-setting and high initial strength benefits. However, the...
Magnesium phosphate bone cement (MPC) has gained widespread usage in orthopedic implantation due to its fast-setting and high initial strength benefits. However, the simultaneous attainment of drug-controlled release and osteogenic potential in MPC remains a significant challenge. Herein, a strategy to create a smart injectable cement system using nanocontainers and chondroitin sulfate is proposed. It employs nanocontainers containing alendronate-loaded mesoporous silica nanoparticles, which are surface-modified with polypyrrole to control drug release in response to near-infrared (NIR) stimulation. The alendronate-incorporated cement (ACMPC) exhibits improved compressive strength (70.6 ± 5.9 MPa), prolonged setting time (913 s), and exceptional injectability (96.5% of injection rate and 242 s of injection time). It also shows the capability to prevent degradation, thus preserving mechanical properties. Under NIR irradiation, the cement shows good antibacterial properties due to the combined impact of hyperthermia, reactive oxygen species, and alendronate. Furthermore, the ACMPC (NIR) group displays good biocompatibility and osteogenesis capabilities, which also lead to an increase in alkaline phosphatase activity, extracellular matrix mineralization, and the upregulation of osteogenic genes. This research has significant implications for developing multifunctional biomaterials and clinical applications.
PubMed: 38529833
DOI: 10.1002/adhm.202400207 -
Journal of Orthopaedic Surgery and... Mar 2024Patellofemoral osteoarthritis (PFJOA) is a subtype of knee OA, which is one of the main causes of anterior knee pain. The current study found an increased prevalence of...
Effects of alendronate on cartilage lesions and micro-architecture deterioration of subchondral bone in patellofemoral osteoarthritic ovariectomized rats with patella-baja.
BACKGROUND
Patellofemoral osteoarthritis (PFJOA) is a subtype of knee OA, which is one of the main causes of anterior knee pain. The current study found an increased prevalence of OA in postmenopausal women, called postmenopausal OA. Therefore, we designed the ovariectomized rat model of patella baja-induced PFJOA. Alendronate (ALN) inhibits osteoclast-mediated bone loss, and has been reported the favorable result of a potential intervention option of OA treatment. However, the potential effects of ALN treatment on PFJOA in the ovariectomized rat model are unknown and need further investigation prior to exploration in the clinical research setting. In this study, the effects of ALN on articular cartilage degradation and subchondral bone microstructure were assessed in the ovariectomized PFJOA rat model for 10 weeks.
METHODS
Patella baja and estrogen withdrawal were induced by patellar ligament shortening (PLS) and bilateral ovariectmomy surgeries in 3-month-old female Sprague-Dawley rats, respectively. Rats were randomly divided into five groups (n = 8): Sham + V; OVX + V, Sham + PLS + V, OVX + PLS + V, OVX + PLS + ALN (ALN: 70 μg/kg/week). Radiography was performed to evaluate patellar height ratios, and the progression of PFJOA was assessed by macroscopic and microscopic analyses, immunohistochemistry and micro-computed tomography (micro-CT).
RESULTS
Our results found that the patella baja model prepared by PLS can successfully cause degeneration of articular cartilage and subchondral bone, resulting in changes of PFJOA. OVX caused a decrease in estrogen levels in rats, which aggravated the joint degeneration caused by PFJOA. Early application of ALN can delay the degenerative changes of articular cartilage and subchondral bone microstructure in castrated PFJOA rat to a certain extent, improve and maintain the micrometabolism and structural changes of cartilage and subchondral bone.
CONCLUSION
The early application of ALN can delay the destruction of articular cartilage and subchondral bone microstructure in castrated PFJOA rat to a certain extent.
Topics: Humans; Rats; Female; Animals; Infant; Alendronate; Rats, Sprague-Dawley; Patella; X-Ray Microtomography; Osteoarthritis, Knee; Cartilage, Articular; Bone Resorption; Disease Models, Animal; Estrogens
PubMed: 38528611
DOI: 10.1186/s13018-024-04677-0 -
JBMR Plus Apr 2024Bisphosphonates frequently provoke a cytokine-driven acute clinical response (ACR) characterized by fever, chills, arthralgias, and myalgias. More rarely, an association...
Bisphosphonates frequently provoke a cytokine-driven acute clinical response (ACR) characterized by fever, chills, arthralgias, and myalgias. More rarely, an association between aminobisphosphonates, such as alendronate and zoledronic acid, and rheumatologic and/or immune-mediated syndromes (RIMS) has been described. Herein we report 2 patients, one with a prior history of rheumatic disease and one without, who developed giant cell arteritis meeting the American College of Rheumatology 2022 criteria following zoledronic acid infusion. We subsequently review existing mechanistic and clinical literature supporting this link. The duration of symptoms and elevation of inflammatory markers may serve as indicators for differentiating between the more common ACR and less frequent but potentially morbid RIMS. Although the benefit of bisphosphonates will outweigh the risk of RIMS for most patients with high fracture risk, clinicians should be aware of this phenomenon to assist earlier diagnosis and treatment in affected individuals.
PubMed: 38523665
DOI: 10.1093/jbmrpl/ziae015 -
Archives of Osteoporosis Mar 2024This retrospective study compared the efficacy of anabolic agents (romosozumab and teriparatide) with that of alendronate in preventing subsequent vertebral body...
UNLABELLED
This retrospective study compared the efficacy of anabolic agents (romosozumab and teriparatide) with that of alendronate in preventing subsequent vertebral body fractures (SVBFs) after balloon kyphoplasty (BKP). All anabolic agents significantly reduced SVBFs. Romosozumab was most effective in increasing bone mineral density (BMD) and completely suppressed distant vertebral body fractures.
INTRODUCTION
To determine optimal anti-osteoporosis medications, we compared romosozumab and teriparatide to alendronate as a control from perioperative BKP to the 1st postoperative year for treatment and secondary fracture prevention in osteoporosis.
METHODS
A total of 603 patients who underwent initial BKP for osteoporotic vertebral fractures were evaluated and categorized into five groups based on drug administration: romosozumab (group R, 155 patients), twice-weekly teriparatide (group TW, 48), weekly teriparatide (group W, 151), daily teriparatide (group D, 138), and alendronate (control) (group C, 111). The 1-year incidence of SVBFs, BMD change rate, and probability of requiring BKP were compared among the groups.
RESULTS
SVBF incidence was 3.9%, 6.5%, 8.3%, 6.0%, and 14.4% in groups R, D, TW, W, and C, respectively, with all other groups exhibiting significantly lower rates than group C. The groups that administered the anabolic agents had a notably lower incidence of distant fractures than group C. Compared with group C, group R showed significantly higher BMD change rates in lumbar vertebral bodies at 4, 8, and 12 months and group D at 12 months. Anabolic agent groups exhibited significantly higher improvement rates than group C after conservative treatment alone.
CONCLUSION
The anabolic agents were found to be more effective at reducing the incidence of SVBF (especially distant vertebral fractures) than alendronate. These agents decreased the rate of repeat BKP even after the occurrence of a fracture. Overall, the use of an anabolic agent for the treatment of osteoporosis after BKP is better than the use of alendronate, even when treatment is initiated in the perioperative stage.
Topics: Humans; Vertebral Body; Kyphoplasty; Teriparatide; Alendronate; Retrospective Studies; Anabolic Agents; Osteoporosis; Osteoporotic Fractures; Bone Density; Spinal Fractures; Fractures, Compression; Bone Density Conservation Agents
PubMed: 38512565
DOI: 10.1007/s11657-024-01374-7 -
Biological & Pharmaceutical Bulletin 2024Osteoporosis is caused by imbalance between osteogenesis and bone resorption, thus, osteogenic drugs and resorption inhibitors are used for treatment of osteoporosis....
Osteoporosis is caused by imbalance between osteogenesis and bone resorption, thus, osteogenic drugs and resorption inhibitors are used for treatment of osteoporosis. The present study examined the effects of (R)-4-(1-hydroxyethyl)-3-{4-[2-(tetrahydropyran-4-yloxy)ethoxy]phenoxy}benzamide (KY-273), a diphenyl ether derivative, on CDK8/19 activity, osteoblast differentiation and femoral bone using micro-computed tomography in female rats. KY-273 potently inhibited CDK8/19 activity, promoted osteoblast differentiation with an increase in alkaline phosphatase (ALP) activity, and gene expression of type I collagen, ALP and BMP-4 in mesenchymal stem cells (ST2 cells). In female rat femur, ovariectomy decreased metaphyseal trabecular bone volume (Tb.BV), mineral content (Tb.BMC), yet had no effect on metaphyseal and diaphyseal cortical bone volume (Ct.BV), mineral content (Ct.BMC) and strength parameters (BSPs). In ovaries-intact and ovariectomized rats, oral administration of KY-273 (10 mg/kg/d) for 6 weeks increased metaphyseal and diaphyseal Ct.BV, Ct.BMC, and BSPs without affecting medullary volume (Med.V), but did not affect Tb.BV and Tb.BMC. In ovariectomized rats, alendronate (3 mg/kg/d) caused marked restoration of Tb.BV, Tb.BMC and structural parameters after ovariectomy, and increased metaphyseal but not diaphyseal Ct.BV, Ct.BMC, and BSPs. In ovaries-intact and ovariectomized rats, by the last week, KY-273 increased bone formation rate/bone surface at the periosteal but not the endocortical side. These findings indicate that KY-273 causes osteogenesis in cortical bone at the periosteal side without reducing Med.V. In conclusion, KY-273 has cortical-bone-selective osteogenic effects by osteoblastogenesis via CDK8/19 inhibition in ovaries-intact and ovariectomized rats, and is an orally active drug candidate for bone diseases such as osteoporosis in monotherapy and combination therapy.
Topics: Humans; Rats; Female; Animals; Osteogenesis; Bone Density; Rats, Sprague-Dawley; X-Ray Microtomography; Osteoporosis; Ovariectomy; Mesenchymal Stem Cells; Minerals; Cyclin-Dependent Kinase 8
PubMed: 38508765
DOI: 10.1248/bpb.b23-00834 -
Immunology Letters Jun 2024Bacillus Calmette-Guérin (BCG) vaccination induces memory characteristics in innate immune cells and their progenitors, a process called trained immunity mediated by... (Randomized Controlled Trial)
Randomized Controlled Trial
Bacillus Calmette-Guérin (BCG) vaccination induces memory characteristics in innate immune cells and their progenitors, a process called trained immunity mediated by epigenetic and metabolic reprogramming. Cholesterol synthesis plays an amplifying role in trained immunity through mevalonate release. Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, can inhibit cholesterol synthesis. We explored their effects on trained immunity induced by BCG in a placebo-controlled clinical study (NL74082.091.20) in young, healthy individuals. Participants receiving single-dose oral alendronate on the day of BCG vaccination had more neutrophils and plasma cells one month after treatment. Alendronate led to reduced proinflammatory cytokine production by PBMCs stimulated with heterologous bacterial and viral stimuli one month later. Furthermore, the addition of alendronate transcriptionally suppressed multiple immune response pathways in PBMCs upon stimulation. Our findings indicate that N-BPs modulate the long-lasting effects of BCG vaccination on the cytokine production capacity of innate immune cells.
Topics: Humans; BCG Vaccine; Cytokines; Alendronate; Male; Adult; Female; Young Adult; Vaccination; Leukocytes, Mononuclear; Immunity, Innate; Healthy Volunteers; Immunologic Memory
PubMed: 38479480
DOI: 10.1016/j.imlet.2024.106851 -
Journal of Bone and Mineral Research :... May 2024Romosozumab treatment in women with postmenopausal osteoporosis increases bone formation while decreasing bone resorption, resulting in large BMD gains to reduce... (Randomized Controlled Trial)
Randomized Controlled Trial
Romosozumab treatment in women with postmenopausal osteoporosis increases bone formation while decreasing bone resorption, resulting in large BMD gains to reduce fracture risk within 1 yr. DXA-based 3D modeling of the hip was used to assess estimated changes in cortical and trabecular bone parameters and map the distribution of 3D changes in bone parameters over time in patients from 2 randomized controlled clinical trials: FRAME (romosozumab vs placebo followed by denosumab) and ARCH (romosozumab vs alendronate followed by alendronate). For each study, data from a subset of ~200 women per treatment group who had TH DXA scans at baseline and months 12 and 24 and had provided consent for future research were analyzed post hoc. 3D-SHAPER software v2.11 (3D-SHAPER Medical) was used to generate patient-specific 3D models from TH DXA scans. Percentage changes from baseline to months 12 and 24 in areal BMD (aBMD), integral volumetric BMD (vBMD), cortical thickness, cortical vBMD, cortical surface BMD (sBMD), and trabecular vBMD were evaluated. Data from 377 women from FRAME (placebo, 190; romosozumab, 187) and 368 women from ARCH (alendronate, 185; romosozumab, 183) with evaluable 3D assessments at baseline and months 12 and 24 were analyzed. At month 12, treatment with romosozumab vs placebo in FRAME and romosozumab vs alendronate in ARCH resulted in greater increases in aBMD, integral vBMD, cortical thickness, cortical vBMD, cortical sBMD, and trabecular vBMD (P < .05 for all). At month 24, cumulative gains in all parameters were greater in the romosozumab-to-denosumab vs placebo-to-denosumab sequence and romosozumab-to-alendronate vs alendronate-to-alendronate sequence (P < .05 for all). 3D-SHAPER analysis provides a novel technique for estimating changes in cortical and trabecular parameters from standard hip DXA images. These data add to the accumulating evidence that romosozumab improves hip bone density and structure, thereby contributing to the antifracture efficacy of the drug.
Topics: Humans; Alendronate; Female; Denosumab; Absorptiometry, Photon; Bone Density; Aged; Antibodies, Monoclonal; Imaging, Three-Dimensional; Middle Aged; Hip
PubMed: 38477808
DOI: 10.1093/jbmr/zjae028