RESUMO
OBJECTIVE: Bisphosphonates are prescribed to treat excessive bone resorption in patients with osteoporosis. However, its use is associated with potential adverse effects such as medication-related osteonecrosis of the jaw, prompting the introduction of the drug holiday concept in patients prior to dentoalveolar surgery. Furthermore, bisphosphonate discontinuation has been studied in vivo, in humans, and in animal models. However, it is not known whether this approach could affect bone cells in vitro. Therefore, the objective of this study was to investigate the potential effects of bisphosphonate discontinuation on pre-osteoblast and osteoblast activities in vitro. METHODOLOGY: Pre-osteoblasts (MC3T3) and osteoblasts were treated with bisphosphonate (alendronate) at concentrations of 1, 5, and 10 µM. Alendronate was then withdrawn at different time points. The negative control consisted of untreated cells (0 µM), while the positive control consisted of cells incubated with alendronate throughout the experiment. Cell viability, cell adhesion, cell cytoskeleton, mineralization, and gene expressions were investigated. RESULTS: Pre-osteoblasts and osteoblasts showed a decrease in cell viability after treatment with 5-10 µM alendronate for 4 days or longer. Two days of alendronate discontinuation significantly increased cell viability compared with the positive control. However, these levels did not reach those of the negative control. Bone nodule formation was reduced by alendronate. Discontinuation of alendronate regained bone nodule formation. Longer periods of discontinuation were more effective in restoring nodule formation than shorter periods. Addition of alendronate resulted in an increase in the percentage of dead cells, which, in turn, decreased when alendronate was discontinued. Alendronate affected the cell cytoskeleton by disassembling actin stress fibers. Cell adhesion and cell morphological parameters were also affected by alendronate. Discontinuation of alendronate restored cell adhesion and these parameters. Overall, the highest improvement after alendronate discontinuation was seen at 10 µM. However, alendronate treatment and discontinuation did not affect osteoblast gene expression. CONCLUSION: Discontinuation of alendronate helps to reverse the negative effects of the drug on cell viability, cell adhesion, and mineralization by restoring the cell cytoskeleton. Our data suggest the benefits of drug holiday and/or intermittent strategies for alendronate administration at the cellular level.
Assuntos
Alendronato , Conservadores da Densidade Óssea , Calcificação Fisiológica , Adesão Celular , Sobrevivência Celular , Citoesqueleto , Osteoblastos , Osteoblastos/efeitos dos fármacos , Alendronato/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Conservadores da Densidade Óssea/farmacologia , Citoesqueleto/efeitos dos fármacos , Animais , Adesão Celular/efeitos dos fármacos , Fatores de Tempo , Calcificação Fisiológica/efeitos dos fármacos , Camundongos , Expressão Gênica/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Análise de VariânciaRESUMO
Osteoclastic inhibition using antiresorptive bisphosphonates and osteogenic promotion using antisclerostin agents represent two distinct osteoporosis treatments in clinical practice, each individual treatment suffers from unsatisfactory therapeutic efficacy due to its indirect intervention in osteoclasis and promotion of osteogenesis simultaneously. Although this issue is anticipated to be resolved by drug synergism, a tempting carrier-free dual-medication nanoassembly remains elusive. Herein, we prepare such a nanoassembly made of antiresorptive alendronate (ALN) crystal and antisclerostin polyaptamer (Apt) via a nucleic acid-driven crystallization method. This nanoparticle can protect Apt from rapid nuclease degradation, avoid the high cytotoxicity of free ALN, and effectively concentrate in the cancellous bone by virtue of the bone-binding ability of DNA and ALN. More importantly, the acid microenvironment of cancellous bone triggers the disassociation of nanoparticles for sustained drug release, from which ALN inhibits the osteoclast-mediated bone resorption while Apt promotes osteogenic differentiation. Our work represents a pioneering demonstration of nucleic acid-driven crystallization of a bisphosphonate into a tempting carrier-free dual-medication nanoassembly. This inaugural advancement augments the antiosteoporosis efficacy through direct inhibition of osteoclasis and promotion of osteogenesis simultaneously and establishes a paradigm for profound understanding of the underlying synergistic antiosteoporosis mechanism of antiresorptive and antisclerostin components. It is envisioned that this study provides a highly generalizable strategy applicable to the tailoring of a diverse array of DNA-inorganic nanocomposites for targeted regulation of intricate pathological niches.
Assuntos
Alendronato , Cristalização , Osteoclastos , Osteogênese , Osteoporose , Alendronato/química , Alendronato/farmacologia , Osteogênese/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteoporose/tratamento farmacológico , Animais , Camundongos , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/química , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/farmacologia , Células RAW 264.7 , Humanos , Sinergismo FarmacológicoRESUMO
Introduction: Osteoporosis, characterized by dysregulation of osteoclastic bone resorption and osteoblastic bone formation, severely threatens human health during aging. However, there is still no good therapy for osteoporosis, so this direction requires our continuous attention, and there is an urgent need for new drugs to solve this problem. Methods: Traditional Chinese Medicine Salvia divinorum monomer pomolic acid (PA) could effectively inhibit osteoclastogenesis and ovariectomized osteoporosis. However, its poor solubility and lack of targeting severely limits its further application. A novel bone-targeting nanomedicine (PA@TLipo) has been developed to reconstruct the osteoporotic microenvironment by encapsulating pomolic acid in alendronate-functionalized liposomes. Through a series of operations such as synthesis, purification, encapsulation, and labeling, the PA@TLipo have been prepared. Moreover, the cytotoxicity, bone targeting and anti-osteoporosis effect was verified by cell and animal experiments. Results: In the aspect of targeting, the PA@TLipo can effectively aggregate on the bone tissue to reduce bone loss, and in terms of toxicity, PA@TLipo could increase the bone target ability in comparison to nontargeted liposome, thereby mitigating systemic cytotoxicity. Moreover, PA@TLipo inhibited osteoclast formation and bone resorption in vitro and reduced bone loss in ovariectomy-induced osteoporotic mice. Conclusion: In this study, a novel therapeutic agent was designed and constructed to treat osteoporosis, consisting of a liposome material as the drug pocket, PA as the anti-osteoporosis drug, and ALN as the bone-targeting molecule. And our study is the first to employ a bone-targeted delivery system to deliver PA for OVX-induced bone loss, providing an innovative solution for treating osteoporosis.
Assuntos
Alendronato , Lipossomos , Osteoporose , Animais , Lipossomos/química , Alendronato/química , Alendronato/farmacologia , Alendronato/administração & dosagem , Osteoporose/tratamento farmacológico , Feminino , Camundongos , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/química , Conservadores da Densidade Óssea/administração & dosagem , Osteoclastos/efeitos dos fármacos , Células RAW 264.7 , Humanos , Osso e Ossos/efeitos dos fármacos , Reabsorção Óssea/tratamento farmacológico , Homeostase/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , OvariectomiaRESUMO
BACKGROUND: Osteogenesis imperfecta (OI) is a genetic disorder of connective tissue caused by mutations associated with type I collagen, which results in defective extracellular matrix in temporomandibular joint (TMJ) cartilage and subchondral bone. TMJ is a fibrocartilaginous joint expressing type I collagen both in the cartilage and the subchondral bone. In the present study the effects of alendronate and altered loading of the TMJ was analyzed both in male and female OI mice. MATERIALS AND METHODS: Forty-eight, 10-weeks-old male and female OI mice were divided into 3 groups: (1) Control group: unloaded group, (2) Saline + Loaded: Saline was injected for 2 weeks and then TMJ of mice was loaded for 5 days, (3) alendronate + loaded: alendronate was injected for 2 weeks and then TMJ of mice was loaded for 5 days. Mice in all the groups were euthanized 24-h after the final loading. RESULTS: Alendronate pretreatment led to significant increase in bone volume and tissue density. Histomorphometrically, alendronate treatment led to increase in mineralization, cartilage thickness and proteoglycan distribution. Increased mineralization paralleled decreased osteoclastic activity. Our immunohistochemistry revealed decreased expression of matrix metallopeptidase 13 and ADAM metallopeptidase with thrombospondin type 1 motif 5. CONCLUSION: The findings of this research support that alendronate prevented the detrimental effects of loading on the extracellular matrix of the TMJ cartilage and subchondral bone.
Assuntos
Alendronato , Conservadores da Densidade Óssea , Osteogênese Imperfeita , Articulação Temporomandibular , Animais , Alendronato/farmacologia , Alendronato/uso terapêutico , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/patologia , Camundongos , Masculino , Feminino , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/farmacologia , Articulação Temporomandibular/patologia , Articulação Temporomandibular/efeitos dos fármacos , Metaloproteinase 13 da Matriz/metabolismo , Proteína ADAMTS5 , Modelos Animais de Doenças , Densidade Óssea/efeitos dos fármacos , ProteoglicanasRESUMO
Osteoporotic bone defects are serious medical problems due to their sparse bone structure, difficulty in restoration and reconstruction, and high recurrence rates, which also result in heavy economic and social burdens. Herein, we developed a hierarchical hydrogel composed of alendronate sodium (AS)/Mg2+-loaded inverse opal methylpropenylated gelatin (GelMA) hydrogel microspheres (IOHM-AS-Mgs) within methylpropenylated poly(hyaluronic acid) (HAMA) for osteoporotic bone defect treatment. The IOHM-AS-Mgs displayed good cytocompatibility and cell adhesion and strongly stimulated osteogenesis at the transcriptomic and protein levels. When this treatment was applied to the osteoporotic bone defect area, HAMA was used to fix the microspheres. The results of the microcomputed tomography (micro-CT) and histological analyses indicated that the hierarchical hydrogel had the best therapeutic effect. Therefore, this hydrogel is a new candidate for osteoporotic bone defect treatment.
Assuntos
Alendronato , Gelatina , Ácido Hialurônico , Hidrogéis , Osteogênese , Osteoporose , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Gelatina/química , Animais , Hidrogéis/química , Osteoporose/tratamento farmacológico , Alendronato/farmacologia , Alendronato/química , Osteogênese/efeitos dos fármacos , Microesferas , Microtomografia por Raio-X , Regeneração Óssea/efeitos dos fármacos , Camundongos , HumanosRESUMO
Vascular calcification affects the prognosis of patients with renal failure. Bisphosphonates are regarded as candidate anti-calcifying drugs because of their inhibitory effects on both calcium-phosphate aggregation and bone resorption. However, calcification in well-known rodent models is dependent upon bone resorption accompanied by excessive bone turnover, making it difficult to estimate accurately the anti-calcifying potential of drugs. Therefore, models with low bone resorption are required to extrapolate anti-calcifying effects to humans. Three bisphosphonates (etidronate, alendronate, and FYB-931) were characterised for their inhibitory effects on bone resorption in vivo and calcium-phosphate aggregation estimated by calciprotein particle formation in vitro. Then, their effects were examined using two models inducing ectopic calcification: the site where lead acetate was subcutaneously injected into mice and the transplanted, aorta obtained from a donor rat. The inhibitory effects of bisphosphonates on bone resorption and calcium-phosphate aggregation were alendronate > FYB-931 > etidronate and FYB-931 > alendronate = etidronate, respectively. In the lead acetate-induced model, calcification was most potently suppressed by FYB-931, followed by alendronate and etidronate. In the aorta-transplanted model, only FYB-931 suppressed calcification at a high dose. In both the models, no correlation was observed between calcification and bone resorption marker, tartrate-resistant acid phosphatase (TRACP). Results from the lead acetate-induced model showed that inhibitory potency against calcium-phosphate aggregation contributed to calcification inhibition. The two calcification models, especially the lead acetate-induced model, may be ideal for the extrapolation of calcifying response to humans because of calcium-phosphate aggregation rather than bone resorption as its mechanism.
Assuntos
Reabsorção Óssea , Modelos Animais de Doenças , Compostos Organometálicos , Animais , Camundongos , Humanos , Compostos Organometálicos/farmacologia , Ratos , Difosfonatos/farmacologia , Masculino , Conservadores da Densidade Óssea/farmacologia , Alendronato/farmacologia , Calcinose/induzido quimicamente , Camundongos Endogâmicos C57BL , Calcificação Vascular/induzido quimicamenteRESUMO
Chronic myeloid leukemia is a hematological cancer, where disease relapse and drug resistance are caused by bone-hosted-residual leukemia cells. An innovative resolution is bone-homing and selective-active targeting of anticancer loaded-nanovectors. Herein, ivermectin (IVM) and methyl dihydrojasmonate (MDJ)-loaded nanostructured lipid carriers (IVM-NLC) were formulated then dually decorated by lactoferrin (Lf) and alendronate (Aln) to optimize (Aln/Lf/IVM-NLC) for active-targeting and bone-homing potential, respectively. Aln/Lf/IVM-NLC (1 mg) revealed nano-size (73.67 ± 0.06 nm), low-PDI (0.43 ± 0.06), sustained-release of IVM (62.75 % at 140-h) and MDJ (78.7 % at 48-h). Aln/Lf/IVM-NLC afforded substantial antileukemic-cytotoxicity on K562-cells (4.29-fold lower IC50), higher cellular uptake and nuclear fragmentation than IVM-NLC with acceptable cytocompatibility on oral-epithelial-cells (as normal cells). Aln/Lf/IVM-NLC effectively upregulated caspase-3 and BAX (4.53 and 15.9-fold higher than IVM-NLC, respectively). Bone homing studies verified higher hydroxyapatite affinity of Aln/Lf/IVM-NLC (1 mg; 22.88 ± 0.01 % at 3-h) and higher metaphyseal-binding (1.5-fold increase) than untargeted-NLC. Moreover, Aln/Lf/IVM-NLC-1 mg secured 1.35-fold higher in vivo bone localization than untargeted-NLC, with lower off-target distribution. Ex-vivo hemocompatibility and in-vivo biocompatibility of Aln/Lf/IVM-NLC (1 mg/mL) were established, with pronounced amelioration of hepatic and renal toxicity compared to higher Aln doses. The innovative Aln/Lf/IVM-NLC could serve as a promising nanovector for bone-homing, active-targeted leukemia therapy.
Assuntos
Alendronato , Portadores de Fármacos , Ivermectina , Lactoferrina , Humanos , Animais , Portadores de Fármacos/química , Lactoferrina/química , Lactoferrina/farmacologia , Lactoferrina/administração & dosagem , Alendronato/química , Alendronato/farmacologia , Alendronato/administração & dosagem , Ivermectina/química , Ivermectina/análogos & derivados , Ivermectina/farmacologia , Ivermectina/administração & dosagem , Ivermectina/farmacocinética , Células K562 , Nanopartículas/química , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/administração & dosagem , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Lipídeos/química , Apoptose/efeitos dos fármacosRESUMO
Aminobisphosphonates (NBPs) are the first-choice medication for osteoporosis (OP); NBP treatment aims at increasing bone mineral density (BMD) by inhibiting the activity of farnesyl diphosphate synthase (FDPS) enzyme in osteoclasts. Despite its efficacy, inadequate response to the drug and side effects have been reported. The A allele of the rs2297480 (A > C) SNP, found in the regulatory region of the FDPS gene, is associated with reduced gene transcription. This study evaluates the FDPS variant rs2297480 (A > C) association with OP patients' response to alendronate sodium treatment. A total of 304 OP patients and 112 controls were enrolled; patients treated with alendronate sodium for two years were classified, according to BMD variations at specific regions (lumbar spine (L1-L4), femoral neck (FN) and total hip (TH), as responders (OP-R) (n = 20) and non-responders (OP-NR) (n = 40). We observed an association of CC genotype with treatment failure (p = 0.045), followed by a BMD decrease in the regions L1-L4 (CC = -2.21% ± 2.56; p = 0.026) and TH (CC = -2.06% ± 1.84; p = 0.015) after two years of alendronate sodium treatment. Relative expression of the FDPS gene was also evaluated in OP-R and OP-NR patients. Higher expression of the FDPS gene was also observed in OP-NR group (FC = 1.84 ± 0.77; p = 0.006) when compared to OP-R. In conclusion, the influence observed of FDPS expression and the rs2897480 variant on alendronate treatment highlights the importance of a genetic approach to improve the efficacy of treatment for primary osteoporosis.
Assuntos
Alendronato , Conservadores da Densidade Óssea , Densidade Óssea , Geraniltranstransferase , Osteoporose , Polimorfismo de Nucleotídeo Único , Falha de Tratamento , Humanos , Alendronato/uso terapêutico , Alendronato/farmacologia , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/genética , Feminino , Geraniltranstransferase/genética , Geraniltranstransferase/metabolismo , Masculino , Osteoporose/tratamento farmacológico , Osteoporose/genética , Idoso , Pessoa de Meia-Idade , Conservadores da Densidade Óssea/uso terapêutico , Genótipo , Alelos , Estudos de Casos e ControlesRESUMO
This Viewpoint discusses the ongoing lawsuit between plaintiffs who had been affected by atypical femoral fractures while receiving alendronate and the drug manufacturer.
Assuntos
Alendronato , Conservadores da Densidade Óssea , Rotulagem de Medicamentos , Fraturas Ósseas , Fraturas do Quadril , Humanos , Fraturas Ósseas/induzido quimicamente , Fraturas Ósseas/prevenção & controle , Estados Unidos , United States Food and Drug Administration/legislação & jurisprudência , United States Food and Drug Administration/normas , Alendronato/efeitos adversos , Alendronato/farmacologia , Alendronato/uso terapêutico , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Fraturas do Quadril/induzido quimicamente , Fraturas do Quadril/fisiopatologia , Remodelação Óssea/efeitos dos fármacos , Fraturas Espontâneas/induzido quimicamente , Fraturas Espontâneas/fisiopatologia , Aprovação de Drogas/legislação & jurisprudência , Rotulagem de Medicamentos/legislação & jurisprudência , Rotulagem de Medicamentos/normasRESUMO
The aim of this systematic review was to answer the following question: "Does alendronate, a nitrogen-containing bisphosphonate, improve or impair alveolar socket healing after tooth extraction in animal models"? To this end, a systematic review of the literature was carried out in PubMed, Scopus, LILACS, Web of Science, as well as in the gray literature up to May 2023. Preclinical studies that evaluated alveolar healing after tooth extraction and the intake of sodium alendronate compared with placebo were included. Two investigators were responsible for screening the articles independently, extracting the data, and assessing their quality through the SYRCLE's RoB tool for randomized trials in animal studies. The study selection process, study characteristics, risk of bias in studies, impact of alendronate on bone healing, and certainty of evidence were described in text and table formats. Methodological differences among the studies were restricted to the synthesis methods. The synthesis of qualitative results followed the Synthesis Without Meta-analysis (SWiM) reporting guideline. From the 19 included studies, five were considered to have low risk, three were of unclear risk, and eleven presented a high risk of bias. The studies were considered heterogeneous regarding alendronate posology, including its dosage and route of administration. Furthermore, a variety of animal species, different age ranges, diverse teeth extracted, and exposure or not to ovariectomy contributed to the lack of parity of the selected studies. Our results indicated that alendronate monotherapy negatively affects the early phase of wound healing after tooth extraction in preclinical studies, suggesting that the bone resorption process after tooth extraction in animals treated with alendronate might impair the bone healing process of the extraction socket. In conclusion, alendronate administration restrains bone resorption, thereby delaying alveolar socket healing . Future studies should be conducted to validate these findings and to better understand the effects of alendronate therapy on oral tissues.
Assuntos
Alendronato , Conservadores da Densidade Óssea , Extração Dentária , Alvéolo Dental , Cicatrização , Alendronato/farmacologia , Alendronato/uso terapêutico , Extração Dentária/efeitos adversos , Animais , Cicatrização/efeitos dos fármacos , Alvéolo Dental/efeitos dos fármacos , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêuticoRESUMO
Background: The amyloid-ß (Aß) enhances the number and activity of blood monocyte-derived osteoclasts (OCs). Individuals with osteoporosis (OP) face an increased risk of developing dementia or Alzheimer's disease (AD). Despite this association, the contribution of bone-resorbing OCs to the progression of AD pathology remains unclear. Objective: Our objective was to investigate the potential impacts of OCs on the development of AD pathology. Methods: We conducted targeted analysis of publicly available whole blood transcriptomes from patients with AD to characterize the blood molecular signatures and pathways associated with hyperactive OCs. In addition, we used APP23 transgenic (APP23 TG) AD mouse model to assess the effects of OCs pharmacological blockade on AD pathology and behavior. Results: Patients with AD exhibited increased osteoclastogenesis signature in their blood cells, which appears to be positively correlated with dysfunction of peripheral clearance of Aß mediated by immune cells. Long-term anti-resorptive intervention with Alendronate inhibited OC activity in APP23 mice, leading to improvements in peripheral monocyte Aß-degrading enzyme expression, Aß-deposition, and memory decline. Conclusions: Our findings suggest that OCs have a disease-promoting role in the development and progression of AD, possibly linked to their modulation of peripheral immunity. These findings guide future research to further elucidate the connection between OP and AD pathogenesis, highlighting the potential benefits of preventing OP in alleviating cognitive burden.
Assuntos
Doença de Alzheimer , Progressão da Doença , Camundongos Transgênicos , Osteoclastos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Camundongos , Humanos , Osteoclastos/metabolismo , Alendronato/farmacologia , Alendronato/uso terapêutico , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Modelos Animais de Doenças , Feminino , Masculino , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêuticoRESUMO
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 in vitro 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. In vivo 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.
Assuntos
Antineoplásicos , Neoplasias Ósseas , Neoplasias da Mama , Poloxaleno , Humanos , Feminino , Micelas , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Ligantes , Qualidade de Vida , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Polímeros/química , Polímeros/uso terapêutico , Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos , Neoplasias Ósseas/tratamento farmacológico , Alendronato/farmacologia , Alendronato/química , Alendronato/uso terapêutico , Portadores de Fármacos/química , Portadores de Fármacos/uso terapêuticoRESUMO
Osteoporosis is a highly prevalent metabolic disease characterized by low systemic bone mass and deterioration of bone microarchitecture, resulting in reduced bone strength and increased fracture risk. Current treatment options for osteoporosis are limited by factors such as efficacy, cost, availability, side effects, and acceptability to patients. Gold nanoparticles show promise as an emerging osteoporosis therapy due to their osteogenic effects and ability to allow therapeutic delivery but have inherent constraints, such as low specificity and the potential for heavy metal accumulation in the body. This study reports the synthesis of ultrasmall gold particles almost reaching the Ångstrom (Ång) dimension. The antioxidant alpha-lipoic acid (LA) is used as a dispersant and stabilizer to coat Ångstrom-scale gold particles (AuÅPs). Alendronate (AL), an amino-bisphosphonate commonly used in drug therapy for osteoporosis, is conjugated through LA to the surface of AuÅPs, allowing targeted delivery to bone and enhancing antiresorptive therapeutic effects. In this study, alendronate-loaded Ångstrom-scale gold particles (AuÅPs-AL) were used for the first time to promote osteogenesis and alleviate bone loss through regulation of the WNT signaling pathway, as shown through in vitro tests. The in vivo therapeutic effects of AuÅPs-AL were demonstrated in an established osteoporosis mouse model. The results of Micro-computed Tomography, histology, and tartrate-resistant acid phosphatase staining indicated that AuÅPs-AL significantly improved bone density and prevented bone loss, with no evidence of nanoparticle-associated toxicity. These findings suggest the possible future application of AuÅPs-AL in osteoporosis therapy and point to the potential of developing new approaches for treating metabolic bone diseases using Ångstrom-scale gold particles.
Assuntos
Alendronato , Ouro , Nanopartículas Metálicas , Osteoporose , Ácido Tióctico , Animais , Alendronato/química , Alendronato/farmacologia , Ácido Tióctico/química , Ácido Tióctico/farmacologia , Ouro/química , Osteoporose/tratamento farmacológico , Camundongos , Nanopartículas Metálicas/química , Feminino , Osteogênese/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Conservadores da Densidade Óssea/química , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Tamanho da PartículaRESUMO
OBJECTIVES: Toll-like receptors (TLRs) recognize whole cells or components of microorganisms. Alendronate (ALN) is an anti-bone-resorptive drug that has inflammatory side effects. The aim in this study was to examine whether ALN augments TLR2 ligand-induced proinflammatory cytokine production using mouse macrophage-like RAW264.7 cells transfected with murine apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) gene (hereafter, referred to as "RAW-ASC cells"). METHODS: RAW-ASC cells were pretreated with or without ALN and then incubated with or without TLR2 ligands. The levels of secreted mouse IL-1α, IL-1ß, IL-6, and tumor necrosis factor-α (TNF-α) in culture supernatants and the activation of activator protein-1 (AP-1) or nuclear factor-κB (NF-κB) were measured using enzyme-linked immunosorbent assay (ELISA). The expressions of myeloid differentiation factor 88 (MyD88), caspase-11, nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), ASC, NF-κB p65, and actin were analyzed via Western blotting. TLR2 expression was analyzed using flow cytometry. RESULTS: ALN substantially upregulated the Pam3CSK4-induced release of IL-1α, IL-1ß, IL-6, and TNF-α and MyD88 expression in RAW-ASC cells. ST-2825, a MyD88 inhibitor, inhibited the ALN-augmented release of these cytokines. Pretreatment with ALN augmented Pam3CSK4-induced NF-κB activation in RAW-ASC cells and upregulated AP-1 activation. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S protein and ALN synergically upregulated the release of IL-1α, IL-1ß, IL-6 and TNF-α in RAW-ASC cells. CONCLUSIONS: Our findings suggest that ALN augments TLR2 ligand-induced proinflammatory cytokine production via the upregulation of MyD88 expression, and this augmentation is accompanied by the activation of NF-κB and AP-1 in RAW-ASC cells.
Assuntos
Alendronato , Citocinas , Fator 88 de Diferenciação Mieloide , Receptor 2 Toll-Like , Regulação para Cima , Animais , Alendronato/farmacologia , Camundongos , Receptor 2 Toll-Like/metabolismo , Receptor 2 Toll-Like/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Regulação para Cima/efeitos dos fármacos , Citocinas/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/imunologia , Células RAW 264.7 , Ensaio de Imunoadsorção Enzimática , Ligantes , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Sinergismo FarmacológicoRESUMO
Osteoarthritis (OA) treatment is limited by the lack of effective nonsurgical interventions to slow disease progression. Here, we examined the contributions of the subchondral bone properties to OA development. We used parathyroid hormone (PTH) to modulate bone mass before OA initiation and alendronate (ALN) to inhibit bone remodeling during OA progression. We examined the spatiotemporal progression of joint damage by combining histopathological and transcriptomic analyses across joint tissues. The additive effect of PTH pretreatment before OA initiation and ALN treatment during OA progression most effectively attenuated load-induced OA pathology. Individually, PTH directly improved cartilage health and slowed the development of cartilage damage, whereas ALN primarily attenuated subchondral bone changes associated with OA progression. Joint damage reflected early transcriptomic changes. With both treatments, the structural changes were associated with early modulation of immunoregulation and immunoresponse pathways that may contribute to disease mechanisms. Overall, our results demonstrate the potential of subchondral bone-modifying therapies to slow the progression of OA.
Assuntos
Cartilagem Articular , Osteoartrite , Hormônio Paratireóideo , Animais , Camundongos , Alendronato/farmacologia , Alendronato/uso terapêutico , Osso e Ossos , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Osteoartrite/patologia , Hormônio Paratireóideo/farmacologia , Hormônio Paratireóideo/uso terapêutico , Remodelação Óssea/efeitos dos fármacos , Suporte de CargaRESUMO
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.
Assuntos
Reabsorção Óssea , Cartilagem Articular , Osteoartrite do Joelho , Humanos , Ratos , Feminino , Animais , Lactente , Alendronato/farmacologia , Ratos Sprague-Dawley , Patela/diagnóstico por imagem , Microtomografia por Raio-X , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/tratamento farmacológico , Osteoartrite do Joelho/metabolismo , Cartilagem Articular/metabolismo , Reabsorção Óssea/tratamento farmacológico , Modelos Animais de Doenças , EstrogêniosRESUMO
The antitumoral activity of hydroxymethylene bisphosphonates (HMBP) such as alendronate or zoledronate is hampered by their exceptional bone-binding properties and their short plasmatic half-life which preclude their accumulation in non-skeletal tumors. In this context, the use of lipophilic prodrugs represents a simple and straightforward strategy to enhance the biodistribution of bisphosphonates in these tissues. We describe in this article the synthesis of light-responsive prodrugs of HMBP alendronate. These prodrugs include lipophilic photo-removable nitroveratryl groups which partially mask the highly polar alendronate HMBP scaffold. Photo-responsive prodrugs of alendronate are stable in physiological conditions and display reduced toxicity compared to alendronate against MDA-MB-231 cancer cells. However, the antiproliferative effect of these prodrugs is efficiently restored after cleavage of their nitroveratryl groups upon exposure to UV light. In addition, substitution of alendronate with such photo-responsive substituents drastically reduces its bone-binding properties, thereby potentially improving its biodistribution in soft tissues after i.v. administration. The development of such lipophilic photo-responsive prodrugs is a promising approach to fully exploit the anticancer effect of HMBPs on non-skeletal tumors.
Assuntos
Neoplasias , Pró-Fármacos , Humanos , Alendronato/farmacologia , Alendronato/química , Pró-Fármacos/farmacologia , Distribuição Tecidual , Difosfonatos/farmacologia , Difosfonatos/químicaRESUMO
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 (2â¯mg/kg body weight for 28 days). The rats then received normal saline (PCOS group), letrozole (0.5â¯mg/kg), vitamin C (100â¯mg/kg), glutamine (1000â¯mg/kg), mesalazine (200â¯mg/kg), hydralazine (30â¯mg/kg), and alendronate (17.5â¯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.
Assuntos
Alendronato , Inibidores da Aromatase , Hidralazina , Síndrome do Ovário Policístico , Animais , Feminino , Ratos , Alendronato/farmacologia , Inibidores da Aromatase/farmacologia , Modelos Animais de Doenças , Estradiol/sangue , Hidralazina/farmacologia , Hidralazina/uso terapêutico , Letrozol , Hormônio Luteinizante/sangue , Ovário/efeitos dos fármacos , Ovário/patologia , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/patologia , Ratos Wistar , Testosterona/sangueRESUMO
Bone histomorphometric endpoints in transilial biopsies may be associated with an increased risk of atypical femoral fracture (AFF) in patients with osteoporosis who take antiresorptives, including bisphosphonates (BPs). One way to test this hypothesis is to evaluate bone histomorphometric endpoints in age-, gender-, and treatment time-matched patients who either had AFF or did not have AFF. In this study, we performed transiliac bone biopsies in 52 White postmenopausal women with (n = 20) and without (n = 32) AFFs, all of whom had been treated for osteoporosis continuously with alendronate for 4-17 yr. Despite the matched range of treatment duration (4-17 yr), AFF patients received alendronate for significantly longer time (10.7 yr) than non-AFF patients (8.0 yr) (P = .014). Bone histomorphometric endpoints reflecting microstructure and turnover were assessed in cancellous, intracortical, and endocortical envelopes from transilial biopsy specimens obtained from BP-treated patients 3-6 mo after AFF and from non-AFF patients with similar age-, gender-, and range of BP treatment duration. However, in both cancellous and intracortical envelopes, AFF patients had significantly lower wall thickness (W.Th) and higher osteoclast surface (Oc.S/BS) than non-AFF patients. In addition, AFF patients had significantly higher eroded surface (ES/BS) only in the intracortical envelope. None of the dynamic variables related to bone formation and turnover differed significantly between the groups. In conclusion, in the ilium of BP-treated patients with osteoporosis, AFF patients have lower thickness of superficial bone (lower W.Th) of the cancellous and cortical envelopes than non-AFF patients. AFF and non-AFF patients have a similar bone turnover rate in the ilium. Furthermore, in this population, as in previous work, AFF is more likely to occur in BP-treated patients with longer treatment duration.
Bisphosphonates (BPs) are widely used to prevent osteoporotic fracture and treat osteoporosis. However, prolonged use of BPs may increase the risk of atypical femoral fracture (AFF), and their pathogenesis remains unclear. This study compared the bone histomorphometric findings in cancellous and cortical bones between White osteoporotic women with (n = 20) and without AFF (n = 32), who had received BP treatment for a matched duration of 417 yr. The BP-treated patients with AFF had significantly lower wall thickness (W.Th) in both cancellous and cortical bones compared to BP-treated patients without AFF. There were no significant differences in bone formation, turnover, or mineral apposition rate between BP-treated AFF and non-AFF patients. In conclusion, our study results suggest that AFF risk is increased in BP-treated patients with smaller young and healthy superficial bone areas (indicated by lower W.Th). Surprisingly, we also discovered that patients with and without AFF have similar bone turnover rates, which contradicts previous beliefs. Our findings provide valuable insights into the potential factors contributing to AFF in BP-treated patients.
Assuntos
Fraturas do Fêmur , Humanos , Feminino , Fraturas do Fêmur/patologia , Fraturas do Fêmur/diagnóstico por imagem , Fraturas do Fêmur/induzido quimicamente , Idoso , Pós-Menopausa , Pessoa de Meia-Idade , Difosfonatos/efeitos adversos , Alendronato/efeitos adversos , Alendronato/farmacologia , Alendronato/uso terapêutico , BrancosRESUMO
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.
Osteoporosis is a chronic condition in which bones become weak and are more likely to break (fracture) with minimal force such as tripping or falling. A fracture, especially in the elderly, is a serious condition that affects daily activities and quality of life. Romosozumab, an approved medication for patients with osteoporosis, increases bone mass and bone strength thereby reducing fracture risk. In this study, 3D reproductions of patients' hip bones were generated from standard images of a bone density test with DXA from women in the FRAME clinical trial where they received romosozumab or placebo for 12 mo followed by 12 mo of denosumab or the ARCH clinical trial where they received romosozumab or alendronate for 12 mo, followed by 12 mo of alendronate. We found that patients treated with romosozumab for the first 12 mo had significantly greater increases in bone strength compared with those who received placebo or alendronate. After 24 mo, total gains in bone strength measurements were greater in patients treated with romosozumab first. Our study shows that DXA-based 3D modelling provides a novel technique for examining changes in bone strength and supports the use of romosozumab to improve hip bone strength and reduce fracture risk.