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Acta Pharmaceutica Sinica. B Feb 2024Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted drugs. It...
Boosting synergism of chemo- and immuno-therapies switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis by bisphosphonate coordination lipid nanogranules.
Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted drugs. It is critical to inspire new potential to remodel the value of this classical therapeutic strategy. Here, we fabricate bisphosphonate coordination lipid nanogranules (BC-LNPs) and load paclitaxel (PTX) to boost the chemo- and immuno-therapeutic synergism of cytotoxic drugs. Alendronate in BC-LNPs@PTX, a bisphosphonate to block mevalonate metabolism, works as both the structure and drug constituent in nanogranules, where alendronate coordinated with calcium ions to form the particle core. The synergy of alendronate enhances the efficacy of paclitaxel, suppresses tumor metastasis, and alters the cytotoxic mechanism. Differing from the paclitaxel-induced apoptosis, the involvement of alendronate inhibits the mevalonate metabolism, changes the mitochondrial morphology, disturbs the redox homeostasis, and causes the accumulation of mitochondrial ROS and lethal lipid peroxides (LPO). These factors finally trigger the ferroptosis of tumor cells, an immunogenic cell death mode, which remodels the suppressive tumor immune microenvironment and synergizes with immunotherapy. Therefore, by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis, BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.
PubMed: 38322346
DOI: 10.1016/j.apsb.2023.08.029 -
Beijing Da Xue Xue Bao. Yi Xue Ban =... Feb 2024To investigate the clinical application effect of double-layer soft tissue (DLST) suture closure technique in patients with mandible medication-related osteonecrosis of...
[Application of double-layer soft tissue suture closure technique in the surgical treatment of patients with mandible medication-related osteonecrosis of the jaw of early and medium stages].
OBJECTIVE
To investigate the clinical application effect of double-layer soft tissue (DLST) suture closure technique in patients with mandible medication-related osteonecrosis of the jaw (MRONJ) of early and medium stages resulted in application of anti-bone-resorptive drugs.
METHODS
Early to medium stage mandible MRONJ patients who underwent surgical treatment in the fourth ward of Peking University School and Hospital of Stomatology from October 2021 to September 2022 were included. Clinical information of the patients were collected, including primary disease, concomitant disease, medication regimen (drug type, duration of medication), MRONJ stage, clinical symptoms, imaging manifestations, etc. During surgery, after using marginal mandibulae resection to remove the necrotic bone, the wound was closed using DLST closure technique. Regular post-operative follow-up was performed to evaluate the therapeutic effect and complications of the DLST technique, the pain score and functional status of the patiens were evaluated.
RESULTS
This study totally included 13 patients, 12 women and 1 man, aged (66.69±13.14) years. Seven patients had osteoporosis, 2 had lung cancer, 3 had breast cancer and 1 had prostate cancer among their primary diseases; 7 had no concomitant diseases, 2 had diabetes mellitus, 2 had cardiovascular disease and 1 had dry syndrome. Intravenous zoledronic acid were used in 9 patients, the average duration was (37.7±20.0) months, and other drugs, such as letrozole tablets were taken in 7 patients at the same time; Denosumab injection was used in 3 patients for an average of (10.3±11.9) months; Alendronate sodium tablets were taken in 5 patients for an average of (55.20±27.20) months, and prednisone acetate tablets or acarbose tablets were taken to varying degrees in 2 patients. The average post-operative follow-up was 11.9 months (9 to 17 months), and all the 13 patients were cured without complications, such as pus overflow and so forth. The pre-operative score of Karnofsky performance status (KPS) in the patients was 68.46±14.05, and the post-operative score was 82.31±15.36, and the difference was statistically significant ( < 0.05). The pre-operative score of visual analogue scale (VAS) in the patients was 5.77±0.73 and the post-operative score was 0.38±0.51, and the difference had statistical significance ( < 0.001).
CONCLUSION
The double-layer soft tissue suture closure technique can achieve good clinical results in patients with MRONJ of the mandible using anti-bone-resorptive drugs alone, and can provide clinical treatment ideas for MRONJ patients with more complicated drug use.
Topics: Male; Humans; Female; Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density Conservation Agents; Zoledronic Acid; Mandible; Sutures; Diphosphonates
PubMed: 38318896
DOI: 10.19723/j.issn.1671-167X.2024.01.009 -
ACS Omega Jan 2024Titanium nanotube (TNT) arrays manufactured via electrochemical anodization have been widely used as local drug carriers due to their excellent biocompatibility and...
Titanium nanotube (TNT) arrays manufactured via electrochemical anodization have been widely used as local drug carriers due to their excellent biocompatibility and customizable nanotubular structures. However, the uncontrollable and abrupt drug release at the early stage decreases the drug release duration, leading to excessive drug concentration at the implantation site. In this study, a continuous drug delivery system based on TNTs was created. Initially, a basic ultrasound-assisted approach was utilized to deposit a polydopamine (PDA) coating onto TNTs to obtain PDA-modified TNTs. Next, TNTs-PDA were submerged in a calcium chloride solution to include Ca through Ca coordination between the PDA layer's catechol groups. Sodium alendronate (NaAL) was used as a model drug and loaded onto TNTs-PDA-Ca by immersing them in an NaAL solution. In the final step, NaAL was covalently attached to TNTs-PDA-Ca through coordination bonds with Ca. The samples underwent characterization through the use of various techniques, including field emission scanning electron microscopy, Fourier-transform infrared spectroscopy, X-ray diffraction patterning, X-ray photoelectron spectroscopy, and inductively coupled plasma emission spectrometry. The results indicated that the bioactivity of TNTs improved, and there was an enhancement in drug loading capacity and release performance due to modification with PDA and Ca. Furthermore, acidic conditions can cause significant drug release due to the cleavage of coordination bonds between the drug and Ca ions. Thus, the aforementioned drug delivery system represents a potentially promising approach for achieving sustained and controllable drug release.
PubMed: 38313478
DOI: 10.1021/acsomega.3c08772 -
Frontiers in Pharmacology 2024Several medications have been used for glucocorticoids-induced osteoporosis (GIO). However, the best therapeutic option for GIO is still controversial. A Bayesian...
Several medications have been used for glucocorticoids-induced osteoporosis (GIO). However, the best therapeutic option for GIO is still controversial. A Bayesian network meta-analysis was conducted to compare the efficacy and safety of denosumab, teriparatide and bisphosphonates for patients with GIO. Relevant randomized controlled trials published in PubMed, Embase, Cochrane Library and ClinicalTrials.gov up to August 2023 were searched. The following efficiency and safety outcomes were extracted for comparison: bone mineral density (BMD) percentage changes in lumbar spine, femur neck and total hip, and incidences of adverse events (AEs), serious adverse events (SAEs), vertebrae and non-vertebrae fracture. Bayesian random effects models were used for multiple treatment comparisons. 11 eligible RCTs involving 2,877 patients were identified. All the six medications including alendronate, risedronate, etidronate, zoledronate, teriparatide, and denosumab and were effective in increasing BMD. Teriparatide and denosumab were more effective in improving lumbar spine and femur neck BMD, and reducing vertebrae fracture. Alendronate and denosumab were more effective in improving total hip BMD. Alendronate and teriparatide had the lowest incidences of AEs and SAEs. Teriparatide denosumab and the bisphosphonates are all effective in improving BMD for GIO patients. Based on this network meta-analysis, teriparatide and denosumab have higher efficiency in improving lumbar spine and femur neck BMD, and reducing vertebrae fracture. 10.17605/OSF.IO/2G8YA, identifier CRD42023456305.
PubMed: 38313307
DOI: 10.3389/fphar.2024.1336075 -
Bone Reports Mar 2024Bisphosphonates (BP) are anti-resorptive drugs that are widely used to prevent bone loss in osteoporosis. Since inhibition of bone resorption will cause a decrease in...
Bisphosphonates (BP) are anti-resorptive drugs that are widely used to prevent bone loss in osteoporosis. Since inhibition of bone resorption will cause a decrease in bone formation through a process called coupling, it is hypothesized that extended treatment protocols may impair bone healing. In this study, β-tri‑calcium-phosphate (βTCP) ceramics were inserted into critical-size long bone defects in estrogen-deficient mice under BP therapy. The study assessed the benefits of coating the ceramics with Bone Morphogenetic Protein-2 (BMP2) and an engineered BMP2 analogue (L51P) that inactivates BMP antagonists on the healing process, implant resorption, and bone formation. Female NMRI mice (11-12 weeks of age) were ovariectomized () or sham operated. Eight weeks later, after the manifestation of ovariectomy-induced osteoporotic bone changes, BP therapy with Alendronate (ALN) was commenced. After another five weeks, a femoral critical-size defect was generated, rigidly fixed, and βTCP-cylinders loaded with 0.25 μg or 2.5 μg BMP2, 2.5 μg L51P, and 0.25 μg BMP2/2.5 μg L51P, respectively, were inserted. Unloaded βTCP-cylinders were used as controls. Femora were collected six and twelve weeks post-implantation. Histological and micro-computer tomography (MicroCT) evaluation revealed that insertion of cylinders coated with 2.5 μg BMP2 accelerated fracture repair and induced significant bone formation compared to controls (unloaded cylinders or coated with 2.5 μg L51P, 0.25 μg BMP2) already six weeks post-implantation, independent of estrogen-deficiency and BP therapy. The simultaneous administration of BMP2 and L51P (0.25 μg BMP2/2.5 μg L51P) did not promote fracture healing six and twelve weeks post-implantation. Moreover, new bone formation within the critical-size defect was directly linked to the removal of the βTCP-implant in all experimental groups. No evidence was found that long-term therapy with ALN impaired the resorption of the implanted graft. However, osteoclast transcriptome signature was elevated in sham and animals upon treatment with BP, with transcript levels being higher at six weeks than at twelve weeks post-surgery. Furthermore, the transcriptome profile of the developing repair tissue confirmed an accelerated repair process in animals treated with 2.5 μg BMP2 implants. L51P did not increase the bioefficacy of BMP2 in the applied defect model. The present study provides evidence that continuous administration of BP does not inhibit implant resorption and does not alter the kinetics of the healing process of critical-size long bone defects. Furthermore, the BMP2 variant L51P did not enhance the bioefficacy of BMP2 when applied simultaneously to the femoral critical-size defect in sham and mice.
PubMed: 38304619
DOI: 10.1016/j.bonr.2024.101739 -
Aging Clinical and Experimental Research Jan 2024Osteoporotic-related fractures represent an increasing burden to patients, health care systems and society.
BACKGROUND
Osteoporotic-related fractures represent an increasing burden to patients, health care systems and society.
AIMS
This study estimated cost-effectiveness of sequential treatment with abaloparatide (ABL) followed by alendronate (ALN) compared to relevant alternative strategies in US men and women aged 50 to 80 years at very high fracture risk (bone mineral density T-score ≤ - 2.5 and a recent fracture).
METHODS
A lifetime Markov-based microsimulation model was used to estimate healthcare costs and quality-adjusted life years (QALYs). Comparators were sequential treatment with unbranded teriparatide (TPTD)/ALN, generic ALN monotherapy, and no treatment. Analyses were conducted based on initial fracture site (hip, vertebral, or any fracture) and treatment efficacy data (derived from clinical trials or a recent network meta-analysis).
RESULTS
From all analyses completed, sequential ABL/ALN demonstrated more QALYs for lower healthcare costs versus unbranded TPTD/ALN. No treatment was dominated (higher costs for less QALYs) versus ALN monotherapy. Sequential ABL/ALN resulted in favorable cost-effectiveness (at US threshold of $150,000/QALY) versus generic ALN monotherapy in men aged ≥ 50 years with any fracture type, women aged ≥ 65 years with any fracture type, and women aged ≥ 55 years having a hip or vertebral fracture.
DISCUSSION
Similar cost-effectiveness of sequential ABL/ALN versus unbranded TPTD/ALN, ALN monotherapy, and no treatment was observed in both US men and women at very high fracture risk, with a moderate improvement in cost-effectiveness in men versus women and in patients with a hip or vertebral fracture.
CONCLUSIONS
Sequential therapy with ABL/ALN was cost-effective in US men and women at very high risk of fractures.
Topics: Female; Humans; Male; Alendronate; Cost-Benefit Analysis; Osteoporotic Fractures; Parathyroid Hormone-Related Protein; Spinal Fractures; Middle Aged; Aged; Aged, 80 and over
PubMed: 38289413
DOI: 10.1007/s40520-023-02682-7 -
Frontiers in Immunology 2023Osteoporosis, one of the most common non-communicable human diseases worldwide, is one of the most prevalent disease of the adult skeleton. Glucocorticoid-induced...
INTRODUCTION
Osteoporosis, one of the most common non-communicable human diseases worldwide, is one of the most prevalent disease of the adult skeleton. Glucocorticoid-induced osteoporosis(GIOP) is the foremost form of secondary osteoporosis, extensively researched due to its prevalence.Probiotics constitute a primary bioactive component within numerous foods, offering promise as a potential biological intervention for preventing and treating osteoporosis. This study aimed to evaluate the beneficial effects of the probiotic on bone health and its underlying mechanisms in a rat model of glucocorticoid dexamethasone-induced osteoporosis, using the osteoporosis treatment drug alendronate as a reference.
METHODS
We examined the bone microstructure (Micro-CT and HE staining) and analyzed the gut microbiome and serum metabolome in rats.
RESULTS AND DISCUSSION
The results revealed that treatment significantly restored parameters of bone microstructure, with elevated bone density, increased number and thickness of trabeculae, and decreased Tb.Sp. Gut microbiota sequencing results showed that probiotic treatment increased gut microbial diversity and the ratio of Firmicutes to Bacteroidota decreased. Beneficial bacteria abundance was significantly increased (_NK4A136_group, , , , and _R_7_group), and harmful bacteria abundance was significantly decreased (). According to the results of serum metabolomics, significant changes in serum metabolites occurred in different groups. These differential metabolites were predominantly enriched within the pathways of Pentose and Glucuronate Interconversions, as well as Propanoate Metabolism. Furthermore, treatment of significantly increased serum levels of Pyrazine and gamma-Glutamylcysteine, which were associated with inhibition of osteoclast formation and promoting osteoblast formation. can protect rats from DEX-induced GIOP by mediating the "gut microbial-bone axis" promoting the production of beneficial bacteria and metabolites. Therefore is a potential candidate for the treatment of GIOP.
Topics: Adult; Humans; Animals; Rats; Gastrointestinal Microbiome; Glucocorticoids; Lactobacillus plantarum; Metabolome; Osteoporosis; Clostridiales
PubMed: 38264658
DOI: 10.3389/fimmu.2023.1285442 -
Antioxidants (Basel, Switzerland) Jan 2024The prolonged use of exogenous glucocorticoids, such as dexamethasone (Dex), is the most prevalent secondary cause of osteoporosis, known as glucocorticoid-induced...
The prolonged use of exogenous glucocorticoids, such as dexamethasone (Dex), is the most prevalent secondary cause of osteoporosis, known as glucocorticoid-induced osteoporosis (GIO). The current study examined the preventative and synergistic effect of aqueous chicory extract (ACE) and ethanolic purslane extract (EPE) on GIO compared with Alendronate (ALN). The phytochemical contents, elemental analysis, antioxidant scavenging activity, and ACE and EPE combination index were evaluated. Rats were randomly divided into control, ACE, EPE, and ACE/EPE MIX groups (100 mg/kg orally), Dex group (received 1.5 mg Dex/kg, Sc), and four treated groups received ACE, EPE, ACE/EPE MIX, and ALN with Dex. The bone mineral density and content, bone index, growth, turnover, and oxidative stress were measured. The molecular analysis of RANK/RANKL/OPG and Nrf2/HO-1 pathways were also evaluated. Dex causes osteoporosis by increasing oxidative stress, decreasing antioxidant markers, reducing bone growth markers (OPG and OCN), and increasing bone turnover and resorption markers (NFATc1, RANKL, ACP, ALP, IL-6, and TNF-α). In contrast, ACE, EPE, and ACE/EPE MIX showed a prophylactic effect against Dex-induced osteoporosis by modulating the measured parameters and the histopathological architecture. In conclusion, ACE/EPE MIX exerts a powerful synergistic effect against GIO by a mode of action different from ALN.
PubMed: 38247490
DOI: 10.3390/antiox13010066 -
Experimental Biology and Medicine... Dec 2023With the aging population and the popularity of implant prostheses, an increasing number of postmenopausal osteoporosis (PMOP) patients require implant restorations;...
With the aging population and the popularity of implant prostheses, an increasing number of postmenopausal osteoporosis (PMOP) patients require implant restorations; however, poor bone condition affects the long-term stability of implant prostheses. This study aimed to investigate the therapeutic effect of quercetin (QR) compared with alendronate (ALN), the primary treatment for PMOP, on mandibular osteoporosis (OP) induced by ovariectomy (OVX) in female rats. Adult female rats were treated with QR (50 mg/kg/day), ALN (6.25 mg/kg/week) by gavage for 8 weeks, chloroquine (CQ, 10 mg/kg/twice a week), and cytokine release inhibitory drug 3 (MCC950, 10 mg/kg/three times a week) by intraperitoneal injection for 8 weeks after bilateral OVX. Blood samples were collected prior to euthanasia; the mandibles were harvested and subjected to micro-computed tomography (micro-CT) and pathological analysis. QR administration controlled weight gain and significantly improved the bone microstructure in OVX rats, increasing bone mass, and bone mineral density (BMD), reducing bone trabecular spacing, and decreasing osteoclast numbers. Western blotting, real-time quantitative PCR (RT-qPCR), and serum markers confirmed that QR inhibited interleukin- 1β (IL-1β) and interleukin-18 (IL-18) on the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) protein 3 (NLRP3) pathway thereby inhibiting osteoclast differentiation, immunofluorescence and western blotting also confirmed that QR inhibited autophagy in OVX rats and suppressed the number of tartrate-resistant acid phosphatase (TRAP)-stained positive osteoclasts. The findings suggest that QR may protect the bone structure and prevent bone loss in osteoporotic rats by inhibiting the NLRP3 pathway and autophagy in osteoclasts with comparable effects to ALN, thus QR may have the potential to be a promising alternative supplement for the preventive and therapeutic treatment of PMOP.
Topics: Animals; Female; Rats; Alendronate; Autophagy; Bone Density; Bone Density Conservation Agents; NLR Family, Pyrin Domain-Containing 3 Protein; Osteoporosis; Osteoporosis, Postmenopausal; Ovariectomy; Quercetin; X-Ray Microtomography
PubMed: 38240215
DOI: 10.1177/15353702231211977 -
BioMed Research International 2023[This retracts the article DOI: 10.1155/2022/1213278.].
[This retracts the article DOI: 10.1155/2022/1213278.].
PubMed: 38188785
DOI: 10.1155/2023/9817304