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International Journal of Molecular... Jun 2023Subchondral bone that has intense communication with the articular cartilage might be a potential target for pharmacological treatment in the early stages of...
Subchondral bone that has intense communication with the articular cartilage might be a potential target for pharmacological treatment in the early stages of osteoarthritis (OA). Considering the emerging data about the role of adipokines in the pathogenesis of OA, the administration of drugs that influence their level is also intriguing. Metformin and alendronate were administered in mice with collagenase-induced OA (CIOA) as a monotherapy and in combination. Safranin O staining was used for the assessment of changes in subchondral bone and articular cartilage. Before and after treatment, serum levels of visfatin and biomarkers of cartilage turnover (CTX-II, MMP-13, and COMP) were assessed. In the current study, the combined administration of alendronate and metformin in mice with CIOA led to the protection against cartilage and subchondral bone damage. In mice with CIOA, metformin led to a decrease in visfatin level. In addition, treatment with metformin, alendronate, or their combination lowered the level of cartilage biomarkers (CTX-II and COMP), while the level of MMP-13 was not influenced. In conclusion, personalized combination treatment in OA according to clinical phenotype, especially in the early stages of the disease, might lead to the identification of a successful disease-modifying therapeutic protocol in OA.
Topics: Mice; Animals; Alendronate; Metformin; Nicotinamide Phosphoribosyltransferase; Osteoarthritis; Cartilage, Articular; Biomarkers; Disease Models, Animal
PubMed: 37373251
DOI: 10.3390/ijms241210103 -
Clinical Interventions in Aging 2008Osteoporosis most commonly affects postmenopausal women, placing them at a significant risk of fractures. In particular, hip fractures are an important cause of... (Review)
Review
Osteoporosis most commonly affects postmenopausal women, placing them at a significant risk of fractures. In particular, hip fractures are an important cause of mortality and morbidity among postmenopausal women. Anti-resorptive therapies that produce greater decreases in bone turnover markers together with greater increases in bone mineral density (BMD) are associated with greater reductions in fracture risk, especially at sites primarily composed of cortical bone such as the hip. Thus, treatment with potent anti-resorptive drugs like alendronate is a strategy for preventing hip fractures in postmenopausal women with osteoporosis. The purpose of this paper is to discuss the efficacy of alendronate against hip fractures and the mechanism for this anti-fracture efficacy in postmenopausal women with osteoporosis. A meta-analysis of randomized controlled trials has shown that alendronate reduces the risk of hip fractures by 55% in postmenopausal women with osteoporosis. According to the analyses of the Fracture Intervention Trial, each 1 standard deviation reduction in a 1-year change in bone-specific alkaline phosphatase (BSAP) is associated with 39% fewer hip fractures in alendronate-treated postmenopausal women, and those with at least 30% reduction in BSAP have a 74% lower risk of hip fractures relative to those with less than 30%. Alendronate is effective in reducing the risk of hip fractures across a spectrum of ages. The mechanism for this anti-fracture efficacy has been clarified; alendronate strongly suppresses bone turnover and subsequently increases hip BMD, decreases cortical porosity, improves parameters of hip structure geometry (cortical thickness, cross-sectional area, section modulus, and buckling ratio), and produces more uniform mineralization (increases the mean degree of mineralization of bone) in cortical bone. A once-weekly regimen of alendronate administration provides better patient compliance and persistence with the treatment than the once-daily dosing regimen, leading to greater efficacy against hip fractures. Thus, the efficacy of alendronate against hip fractures has been confirmed in postmenopausal women with osteoporosis, especially with a once-weekly dosing regimen.
Topics: Alendronate; Bone Density Conservation Agents; Female; Hip Fractures; Humans; Osteoporosis, Postmenopausal; Postmenopause; Treatment Outcome
PubMed: 18982918
DOI: 10.2147/cia.s3177 -
Science Translational Medicine May 2020Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, are the most widely prescribed medications for diseases involving bone, with nearly 200 million...
Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, are the most widely prescribed medications for diseases involving bone, with nearly 200 million prescriptions written annually. Recently, widespread use of N-BPs has been challenged due to the risk of rare but traumatic side effects such as atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ). N-BPs bind to and inhibit farnesyl diphosphate synthase, resulting in defects in protein prenylation. Yet, it remains poorly understood what other cellular factors might allow N-BPs to exert their pharmacological effects. Here, we performed genome-wide studies in cells and patients to identify the poorly characterized gene, Loss of function results in selective resistance to N-BP-mediated loss of cell viability and the prevention of alendronate-mediated inhibition of prenylation. is required for alendronate inhibition of osteoclast function, and -deficient mice have impaired therapeutic responses to alendronate in both postmenopausal and senile (old age) osteoporosis models. Last, we performed exome sequencing on patients taking N-BPs that suffered ONJ or an AFF. is one of three genes that contain rare nonsynonymous coding variants in patients with ONJ or an AFF that is also differentially expressed in poor outcome groups of patients treated with N-BPs. We functionally validated this patient variation in as conferring cellular hypersensitivity to N-BPs. Our work adds key insight into the mechanistic action of N-BPs and the processes that might underlie differential responsiveness to N-BPs in people.
Topics: Alendronate; Animals; Bone and Bones; Diphosphonates; Humans; Mice; Nitrogen; Osteoclasts
PubMed: 32434850
DOI: 10.1126/scitranslmed.aav9166 -
Journal of Orthopaedic Surgery and... Sep 2022To observe the effect of enoxaparin sodium-polymethyl methacrylate (ES-PMMA) bone cement supplemented with alendronate (AN) on bone repair of bone defects in New Zealand...
BACKGROUND
To observe the effect of enoxaparin sodium-polymethyl methacrylate (ES-PMMA) bone cement supplemented with alendronate (AN) on bone repair of bone defects in New Zealand rabbits.
METHODS
Twenty-seven New Zealand rabbits were randomly divided into ES/AN, ES-PMMA and PMMA groups, with a total of 27 New Zealand rabbits. The drugs loaded in 40 g bone cement powder were as follows: ES/AN group 8000 AxaIU enoxaparin (ES) and 200 mg alendronate (AN), ES-PMMA group 8000 AxaIU enoxaparin (ES), PMMA group without drugs. A bone defect model with a length of 10 mm and a diameter of 5 mm was made from the left tibia of rabbits, and the prepared bone cement was placed in the tibia defect. At 4 weeks, 8 weeks and 12 weeks after the operation, 3 rabbits in each group were sacrificed, and left tibia samples were collected for histological scoring, HE staining and Masson staining. Bone mineral density and new bone volume were measured by imaging, and the related data were processed by one-way ANOVA and least significance difference (LSD) post hoc test.
RESULTS
(1) Bone mineral density (BMD, mg/mm3) around the bone defect: at the 4th week, BMD in the ES/AN group was higher than that in the PMMA group; at the 8th week, the BMD in the ES/AN group was significantly higher than that in the other two groups; and at the 12th week, the BMD in the ES/AN group was significantly higher than that in the other two groups. (2) New bone volume (BV, mm3): at the 4th week, BV in the ES/AN group was significantly higher than that in the other two groups, BV in the ES/AN group was significantly higher than that in the other two groups at the 8th and 12th weeks, and BV in the ES-PMMA group was higher than that in the PMMA group. (3) Histological score: at the 4th and 8th weeks, the histological score of the ES/AN group was higher than that of the PMMA group, and at the 12th week, the histological score of the ES/AN group was higher than that of the other two groups. (4) Cortical bone thickness (μm): at the 4th, 8th and 12th weeks, the cortical bone thickness in the ES/AN group was higher than that in the other two groups, and the cortical bone thickness in the ES-PMMA group was higher than that in the PMMA group. (5) The percentage of mature area of new bone in the ES/AN group was higher than that in the other two groups at the 4th week, and at the 8th and 12th weeks, the percentage of mature area of new bone in the ES/AN group and ES-PMMA group was significantly higher than that in the PMMA group.
CONCLUSION
(1) Enoxaparin sodium bone cement supplemented with alendronate was superior to enoxaparin sodium bone cement and PMMA bone cement in promoting bone repair of tibial bone defects in New Zealand rabbits. (2) Enoxaparin sodium bone cement is superior to PMMA bone cement in promoting bone repair, showing a certain osteogenic potential.
Topics: Animals; Rabbits; Alendronate; Bone Cements; Enoxaparin; Polymethyl Methacrylate; Powders
PubMed: 36175933
DOI: 10.1186/s13018-022-03330-y -
Bone Apr 2021Bisphosphonates are widely used anti-osteoporotic drugs targeting osteoclasts. They strongly inhibit bone resorption, but also strongly reduce bone formation. This...
Bisphosphonates are widely used anti-osteoporotic drugs targeting osteoclasts. They strongly inhibit bone resorption, but also strongly reduce bone formation. This reduced formation is commonly ascribed to the mechanism maintaining the resorption/formation balance during remodeling. The present study provides evidence for an additional mechanism where bisphosphonates actually impair the onset of bone formation after resorption. The evidence is based on morphometric parameters recently developed to assess the activities reversing resorption to formation. Herein, we compare these parameters in cancellous bone of alendronate- and placebo-treated postmenopausal osteoporotic patients. Alendronate increases the prevalence of eroded surfaces characterized by reversal cells/osteoprogenitors at low cell density and remote from active bone surfaces. This indicates deficient cell expansion on eroded surfaces - an event that is indispensable to start formation. Furthermore, alendronate decreases the coverage of these eroded surfaces by remodeling compartment canopies, a putative source of reversal cells/osteoprogenitors. Finally, alendronate strongly decreases the activation frequency of bone formation, and decreases more the formative compared to the eroded surfaces. All these parameters correlate with each other. These observations lead to a model where bisphosphonates hamper the osteoprogenitor recruitment required to initiate bone formation. This effect results in a larger eroded surface, thereby explaining the well-known paradox that bisphosphonates strongly inhibit bone resorption without strongly decreasing eroded surfaces. The possible mechanism for hampered osteoprogenitor recruitment is discussed: bisphosphonates may decrease the release of osteogenic factors by the osteoclasts, and/or bisphosphonates released by osteoclasts may act directly on neighboring osteoprogenitor cells as reported in preclinical studies.
Topics: Alendronate; Bone Remodeling; Bone Resorption; Diphosphonates; Humans; Osteoclasts; Osteogenesis
PubMed: 33465485
DOI: 10.1016/j.bone.2021.115850 -
Medicine Dec 2022Glucocorticoid-induced osteoporosis is the most common secondary cause of osteoporosis and the resulting fractures cause significant morbidity. Oral bisphosphonates are...
BACKGROUND
Glucocorticoid-induced osteoporosis is the most common secondary cause of osteoporosis and the resulting fractures cause significant morbidity. Oral bisphosphonates are currently regarded as first line options on the grounds of their low cost. However, teriparatide has been shown to be superior in its effects on bone mineral density and vertebral fracture risk in glucocorticoid-treated individuals with osteoporosis. We conducted a protocol for systematic review and meta-analysis to assess the effectiveness of alendronate and teriparatide in patients with glucocorticoid-induced osteoporosis.
METHODS
The study protocol has been registered on international prospective register of systematic review (PROSPERO registration number: CRD42022371561). The procedure of this protocol will be conducted according to the Preferred Reporting Item for Systematic Review and Meta-analysis Protocols guidance. PubMed, EMBASE, MEDLINE, the Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature Database, Wanfang Database, ClinicalTrials.gov trials registry, and Chinese Clinical Trial Registry will be searched from January 1980 to November 2022. Two authors will assess methodological quality of included studies separately by the Cochrane collaboration's risk of bias tool. We will apply RevMan 5.4 software for statistical analysis.
RESULTS
This study will provide a high-quality comprehensive evaluation of the efficacy and safety of alendronate and teriparatide for treating patients with glucocorticoid-induced osteoporosis.
CONCLUSION
The conclusion of our systematic review will provide evidence to judge whether teriparatide is an effective intervention for patients with glucocorticoid-induced osteoporosis.
Topics: Humans; Teriparatide; Alendronate; Glucocorticoids; Systematic Reviews as Topic; Meta-Analysis as Topic
PubMed: 36482548
DOI: 10.1097/MD.0000000000032090 -
Canadian Family Physician Medecin de... Mar 2001
Topics: Adult; Aged; Aged, 80 and over; Alendronate; Humans; Male; Middle Aged; Osteoporosis; Research Design; Sex Characteristics; Treatment Outcome
PubMed: 11281083
DOI: No ID Found -
European Journal of Cell Biology Dec 2023Alendronate (ALN) is a second-generation bisphosphonate widely used for osteoporosis and cancer-induced bone lesions. Many studies have confirmed a strong relationship...
Alendronate (ALN) is a second-generation bisphosphonate widely used for osteoporosis and cancer-induced bone lesions. Many studies have confirmed a strong relationship between osteonecrosis of the jaws (ONJ) development and oral bisphosphonates, especially ALN, although the molecular mechanisms underlying this pathology have not yet been elucidated. The reduction in bone turnover and vascularization usually observed in ONJ are the result of ALN action on different cell types harboured in oral microenvironment, such as osteoclasts, endothelial cells, and periodontal ligament stem cells (PDLSCs). In this perspective, the present study aims to investigate the effects of different ALN concentrations (2 μM, 5 μM, 10 μM, 25 μM, 50 μM) on the phenotype and functional properties of human PDLSCs (hPDLSCs). hPDLSCs showed a decrease in cell viability (MTT assay) only when treated with ALN concentration of 10 μM or larger for 48 h and 72 h. Cell cycle analysis revealed a moderate increase in proportion of S-phase cells after exposure to low ALN concentration (2-5 μM), an effect that was reverted after exposure to 10-50 μM ALN. Conversely, cell death was evidenced via Annexin V/PI assay at very high concentration of ALN (50 μM) after 4 days of treatment. In addition, we explored whether the effects of ALN on hPDLSCs growth and survival can be mediated by its ability to modulate oxidative stress. To this, we quantified the intracellular ROS amount and lipid peroxidation by using DCF probe and Bodipy staining, respectively. Flow cytometry analysis showed that ALN induced a dose-dependent reduction of intracellular oxidative stress and lipid peroxidation upon treatment with low concentrations at both 48 h and 72 h. Increased levels of oxidative stress was reported at 50 μM ALN and was also confirmed via TEM analysis. Despite the stability of the cellular immunophenotype, hPDLSCs showed impaired mobility after ALN exposure. Chronic exposure (7-14 days) to ALN in the range of 2-10 μM significantly decreased the expression of the differentiation-related factors ALP, RUNX2, COLI, and OPN as well as the osteogenic ability of hPDLSCs compared with untreated cells. Conversely, higher doses were found to be neutral. Our findings indicated that the effects of ALN on hPDLSCs behavior are dose-dependent and suggest a role for oxidative stress in ALN-induced cell death that may lead to novel therapeutic approaches for ONJ.
Topics: Humans; Periodontal Ligament; Alendronate; Diphosphonates; Endothelial Cells; Cell Differentiation; Stem Cells; Cells, Cultured; Cell Proliferation
PubMed: 37604089
DOI: 10.1016/j.ejcb.2023.151354 -
BioMed Research International 2022Diabetes is a chronic disease caused by defective insulin secretion in the body, resulting in metabolic abnormalities with persistent blood glucose elevation.... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Diabetes is a chronic disease caused by defective insulin secretion in the body, resulting in metabolic abnormalities with persistent blood glucose elevation. Osteoporosis is the most common diabetes complication. The aim of this study was to perform a meta-analysis of the effects of alendronate combined with atorvastatin compared with alendronate alone in the treatment of osteoporosis in diabetes mellitus.
METHODS
Two researchers independently used PubMed, ScienceDirect, Cochrane Library, Wanfang Data, CNKI, and VIP databases to search for all relevant studies that met the inclusion criteria and used RevMan 5.3 and STATA 16.0 for data analysis.
RESULTS
Fourteen studies that met the inclusion criteria were selected, including 1456 patients. Among the data extracted in this meta-analysis, bone mineral density (BMD) was the primary outcome measurement, while total effective rate, VAS, osteoprotegerin (OPG), bone Gla protein (BGP), bone alkaline phosphatase (BAP), blood P and Ca, and adverse effects were secondary outcome measurements. Our results showed that alendronate combined with atorvastatin is more effective than alendronate alone, with higher BMD, OPG, BGP, and BAP, more significant pain relief, and fewer adverse events.
CONCLUSION
The results of this meta-analysis indicate that alendronate combined with atorvastatin is a better treatment for osteoporosis in diabetes mellitus, showing more effective and higher BMD and fewer adverse events than alendronate alone.
Topics: Alendronate; Alkaline Phosphatase; Atorvastatin; Bone Density; Bone Density Conservation Agents; Diabetes Mellitus; Female; Humans; Osteocalcin; Osteoporosis; Osteoporosis, Postmenopausal
PubMed: 35178452
DOI: 10.1155/2022/6747469 -
Advanced Science (Weinheim,... May 2023Ovarian cancer is the most lethal gynecological malignancy. Most patients are diagnosed at an advanced stage with widespread peritoneal dissemination and ascites....
Ovarian cancer is the most lethal gynecological malignancy. Most patients are diagnosed at an advanced stage with widespread peritoneal dissemination and ascites. Bispecific T-cell engagers (BiTEs) have demonstrated impressive antitumor efficacy in hematological malignancies, but the clinical potency is limited by their short half-life, inconvenient continuous intravenous infusion, and severe toxicity at relevant therapeutic levels in solid tumors. To address these critical issues, the design and engineering of alendronate calcium (CaALN) based gene-delivery system is reported to express therapeutic level of BiTE (HER2×CD3) for efficient ovarian cancer immunotherapy. Controllable construction of CaALN nanosphere and nanoneedle is achieved by the simple and green coordination reactions that the distinct nanoneedle-like alendronate calcium (CaALN-N) with a high aspect ratio enabled efficient gene delivery to the peritoneum without system in vivo toxicity. Especially, CaALN-N induced apoptosis of SKOV3-luc cell via down-regulation of HER2 signaling pathway and synergized with HER2×CD3 to generate high antitumor response. In vivo administration of CaALN-N/minicircle DNA encoding HER2×CD3 (MC-HER2×CD3) produces sustained therapeutic levels of BiTE and suppresses tumor growth in a human ovarian cancer xenograft model. Collectively, the engineered alendronate calcium nanoneedle represents a bifunctional gene delivery platform for the efficient and synergistic treatment of ovarian cancer.
Topics: Female; Humans; Alendronate; Calcium; Cell Line, Tumor; Ovarian Neoplasms; T-Lymphocytes; Animals
PubMed: 36932888
DOI: 10.1002/advs.202204654