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Experimental and Therapeutic Medicine Dec 2023Alendronate (ALN) is an anti-bone-resorptive drug with inflammatory side effects. ALN upregulates lipid A-induced interleukin (IL)-1α and IL-1β release by J774.1 cells...
Alendronate (ALN) is an anti-bone-resorptive drug with inflammatory side effects. ALN upregulates lipid A-induced interleukin (IL)-1α and IL-1β release by J774.1 cells via apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) activation. The present study examined whether ALN augmented lipid A-induced proinflammatory cytokine production using ASC-deficient mouse macrophage-like RAW264 cells. Pretreatment of RAW264 cells with ALN significantly augmented lipid A-induced IL-1β release, although ALN did not upregulate the expression of Toll-like receptor 4, myeloid differentiation factor 88 (MyD88) and caspase-11. Moreover, pretreatment of caspase-11-deficient RAW264.7 cells with ALN significantly augmented lipid A-induced IL-1β release. Notably, ALN upregulated the activation of FosB, c-Jun or JunD, but not c-Fos or NF-κB in RAW264 cells. Furthermore, pretreatment with the activator protein 1 (AP-1) inhibitor SR11302, but not the c-Fos inhibitor T-5224, before addition of ALN inhibited ALN-augmented IL-1β release by lipid A-treated RAW264 cells. SR11302 also reduced ALN-augmented lactate dehydrogenase release by the cells. These findings collectively suggested that ALN augmented lipid A-induced IL-1β release and cell membrane damage in ASC-deficient RAW264 cells via activation of AP-1, but not NF-κB.
PubMed: 38023354
DOI: 10.3892/etm.2023.12276 -
Cureus Oct 2023Primary hyperparathyroidism (PHPT) can be associated with osteoporosis (OP) and fractures. We present a case of a 49-year-old male referred to our osteoporosis...
Primary hyperparathyroidism (PHPT) can be associated with osteoporosis (OP) and fractures. We present a case of a 49-year-old male referred to our osteoporosis outpatient clinic due to a right femur osteoporotic fracture. At the age of 38, a right plantar nodular lesion was excised, and its histology was compatible with a deep dermis nodule formed by mononuclear and giant osteoclast-like cells. He has reported osteoporotic fractures since age 39 and renal colic episodes since age 45. His father had lipomas and renal colic episodes, and his paternal grandmother had lipomas. The laboratory evaluation was compatible with PHPT. A cervical ultrasound showed a 10mm single solid nodule in the left thyroid lobe, strongly hypoechogenic, with microcalcifications. Its cytology showed parathyroid tissue without atypia. Parathyroid scintigraphy had no uptake. A dual-energy X-ray absorptiometry scan showed a femoral neck Z-score of -4.3. He started alendronate/cholecalciferol (70mg/5600IU) weekly. He was submitted to a left hemithyroidectomy. Its histology showed an intrathyroidal parathyroid adenoma. Ectopic parathyroid adenomas are rare, of which 0.7%-6% are intrathyroidal. The excised foot lesion could be a brown tumour. Furthermore, calcium metabolism evaluation at that time might have allowed a PHPT diagnosis and its morbidity prevention. Osteoporotic fractures in young men must alert to secondary OP.
PubMed: 38021888
DOI: 10.7759/cureus.47461 -
Medicine Nov 2023Vertebroplasty (VP) effectively treats vertebral compression fractures (VCFs). However, the issue of secondary new VCFs (SNVCFs) after VP is yet to be addressed....
Vertebroplasty (VP) effectively treats vertebral compression fractures (VCFs). However, the issue of secondary new VCFs (SNVCFs) after VP is yet to be addressed. Therefore, identification of risk factors for SNVCFs after VP may aid the development of strategies to minimize SNVCF risk. This study aimed to retrospectively evaluate risk factors for SNVCFs after VP, including those associated with the type of anti-osteoporotic treatment administered after VP. Data from 128 patients who underwent single-level VP were collected and reviewed. Patients were divided into 2 groups: those with (n = 28) and without (n = 100) SNVCF within 1 year of VP. We collected the following patient data: age, sex, site of compression fracture, medical history, bone mineral density (BMD), history of long-term steroid use, history of osteoporosis drug use, duration between fracture and VP, VP implementation method (unilateral or bilateral), cement usage in VP, cement leakage into the disc, compression ratio before VP, pre- and postoperative recovery ratio of the lowest vertebral body height, and kyphotic angle of fractured vertebrae. These data were analyzed to identify factors associated with SNVCFs after VP and to investigate the effects of the type of anti-osteoporotic treatment administered for SNVCFs. SNVCFs occurred in 28 patients (21.9%) within 1 year of VP. Logistic regression analysis identified BMD, cement leakage into the disc, and long-term steroid use to be significantly associated with the occurrence of SNVCFs. The group treated with zoledronate after VP had a significantly reduced SNVCF incidence compared with the group treated with calcium (P < .001). In addition, the zoledronate group had a lower SNVCF incidence compared with the groups treated with alendronate (P = .05), selective estrogen receptor modulators (P = .26), or risedronate (P = .22). This study showed that low BMD, presence of an intradiscal cement leak, and long-term steroid use were risk factors for developing SNVCFs following VP. Additionally, among osteoporosis treatments prescribed for VP, zoledronate may be the preferred choice to reduce the risk of SNVCFs.
Topics: Humans; Fractures, Compression; Retrospective Studies; Spinal Fractures; Osteoporotic Fractures; Zoledronic Acid; Osteoporosis; Vertebroplasty; Risk Factors; Bone Cements; Steroids; Treatment Outcome
PubMed: 38013362
DOI: 10.1097/MD.0000000000035042 -
Pharmaceutics Nov 2023Encapsulation of Doxorubicin (Dox), a potent cytotoxic agent and immunogenic cell death inducer, in pegylated (Stealth) liposomes, is well known to have major...
Encapsulation of Doxorubicin (Dox), a potent cytotoxic agent and immunogenic cell death inducer, in pegylated (Stealth) liposomes, is well known to have major pharmacologic advantages over treatment with free Dox. Reformulation of alendronate (Ald), a potent amino-bisphosphonate, by encapsulation in pegylated liposomes, results in significant immune modulatory effects through interaction with tumor-associated macrophages and activation of a subset of gamma-delta T lymphocytes. We present here recent findings of our research work with a formulation of Dox and Ald co-encapsulated in pegylated liposomes (PLAD) and discuss its pharmacological properties vis-à-vis free Dox and the current clinical formulation of pegylated liposomal Dox. PLAD is a robust formulation with high and reproducible remote loading of Dox and high stability in plasma. Results of biodistribution studies, imaging with radionuclide-labeled liposomes, and therapeutic studies as a single agent and in combination with immune checkpoint inhibitors or gamma-delta T lymphocytes suggest that PLAD is a unique product with distinct tumor microenvironmental interactions and distinct pharmacologic properties when compared with free Dox and the clinical formulation of pegylated liposomal Dox. These results underscore the potential added value of PLAD for chemo-immunotherapy of cancer and the relevance of the co-encapsulation approach in nanomedicine.
PubMed: 38004584
DOI: 10.3390/pharmaceutics15112606 -
Scientific Reports Nov 2023Osteoarthritis (OA) is a chronic degenerative joint disease characterized by pain and cartilage damage. Intra-articular (i.a) viscosupplementation with hyaluronic acid...
Osteoarthritis (OA) is a chronic degenerative joint disease characterized by pain and cartilage damage. Intra-articular (i.a) viscosupplementation with hyaluronic acid (HA) is frequently used for the management of OA. Preclinical studies have reported that bisphosphonates (BPs) may have a therapeutic potential to slow down or reverse the progression of OA. Among these, alendronate (ALN) has demonstrated chondroprotective effects in both in vitro and vivo experiments. This study evaluated the effects of a novel alendronate-hyaluronic acid (ALN-HA) conjugate on an OA in vivo model induced by medial meniscus destabilization (DMM). DMM surgery was performed on the knees of Sprague Dawley rats that received, after four weeks, one intra-articular (i.a.) injection of: (1) ALN-HA; (2) HA; (3) sodium chloride (NaCl). Sham-operated rats were used as control. Allodynia was assessed by Von Frey test. Joint degeneration was evaluated eight weeks after treatment by micro-computed tomography (micro-CT), histology, and immunohistochemistry. Collagen cross-linked C-telopeptides (CTX-I and CTX-II) serum levels were determined by ELISA. Paw withdrawal threshold increased in ALN-HA group when compared to rats treated with NaCl or HA. Micro-CT did not show differences between ALN-HA, HA and NaCl groups. ALN-HA injection produced significant improvements in articular cartilage degeneration showing an OARSI score lower than those of HA and NaCl, and reduced matrix metalloproteinase (MMP)-13, MMP-3, interleukin-6, vascular endothelial growth factor and Caspase-3 expression. CTX-I was reduced after ALN-HA treatment when compared to NaCl. Our results indicate that i.a. use of ALN after conjugation with HA limits OA development and progression in the rat DMM model, and may lead to the development of novel therapeutic strategies in OA management.
Topics: Rats; Animals; Hyaluronic Acid; Alendronate; Menisci, Tibial; Sodium Chloride; X-Ray Microtomography; Vascular Endothelial Growth Factor A; Rats, Sprague-Dawley; Osteoarthritis; Injections, Intra-Articular; Cartilage, Articular; Disease Models, Animal
PubMed: 38001135
DOI: 10.1038/s41598-023-46965-5 -
World Journal of Clinical Cases Oct 2023Administering anti-osteoporotic agents to patients perioperatively is a widely accepted approach for improving bone fusion rates and reducing the risk of complications....
BACKGROUND
Administering anti-osteoporotic agents to patients perioperatively is a widely accepted approach for improving bone fusion rates and reducing the risk of complications. The best anti-osteoporotic agents for spinal fusion surgery remain unclear.
AIM
To investigate the efficacy and safety of different anti-osteoporotic agents in spinal fusion surgery network meta-analysis.
METHODS
Searches were conducted in four electronic databases (PubMed, EMBASE, Web of Science, the Cochrane Library and China National Knowledge Infrastructure (CNKI) from inception to November 2022. Any studies that compared anti-osteoporotic agents placebo for spinal fusion surgery were included in this network meta-analysis. Outcomes included fusion rate, Oswestry disability index (ODI), and adverse events. Network meta-analysis was performed by R software with the gemtc package.
RESULTS
In total, 13 randomized controlled trials were included in this network meta-analysis. Only teriparatide (OR 3.2, 95%CI: 1.4 to 7.8) was more effective than placebo in increasing the fusion rate. The surface under the cumulative ranking curve (SUCRA) of teriparatide combined with denosumab was the highest (SUCRA, 90.9%), followed by teriparatide (SUCRA, 74.0%), zoledronic acid (SUCRA, 43.7%), alendronate (SUCRA, 41.1%) and risedronate (SUCRA, 35.0%). Teriparatide (MD -15, 95%CI: -28 to -2.7) and teriparatide combined with denosumab (MD -20, 95%CI: -40 to -0.43) were more effective than placebo in decreasing the ODI. The SUCRA of teriparatide combined with denosumab was highest (SUCRA, 90.8%), followed by teriparatide (SUCRA, 74.5%), alendronate (SURCA, 52.7), risedronate (SURCA, 52.1%), zoledronic acid (SURCA, 24.2%) and placebo (SURCA, 5.6%) for ODI. The adverse events were not different between groups.
CONCLUSION
This network meta-analysis suggests that teriparatide combined with denosumab and teriparatide alone significantly increase the fusion rate and decrease the ODI without increasing adverse events. Based on current evidence, teriparatide combined with denosumab or teriparatide alone is recommended to increase the fusion rate and to reduce ODI in spinal fusion patients.
PubMed: 37969460
DOI: 10.12998/wjcc.v11.i30.7350 -
Archives of Endocrinology and Metabolism Nov 2023Bisphosphonates (BPs) are medications widely used in clinical practice to treat osteoporosis and reduce fragility fractures. Its beneficial effects on bone tissue have... (Review)
Review
Bisphosphonates (BPs) are medications widely used in clinical practice to treat osteoporosis and reduce fragility fractures. Its beneficial effects on bone tissue have been consolidated in the literature for the last decades. They have a high affinity for bone hydroxyapatite crystals, and most bisphosphonates remain on the bone surface for a long period of time. Benefits of long-term use of BPs: Large and important trials (Fracture Intervention Trial Long-term Extension and Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly-Pivotal Fracture Trial) with extended use of alendronate (up to 10 years) and zoledronate (up to 6 years) evidenced significant gain of bone mineral density (BMD) and vertebral fracture risk reduction. Risks of long-term use of BPs: The extended use of antiresorptive therapy has drawn attention to two extremely rare, although severe, adverse events. That is, atypical femoral fracture and medication-related osteonecrosis of the jaw are more common in patients with high cumulative doses and longer duration of therapy. BPs have demonstrated safety and effectiveness throughout the years and evidenced increased BMD and reduced fracture risks, resulting in reduced morbimortality, and improved quality of life. These benefits overweight the risks of rare adverse events.
Topics: Humans; Female; Diphosphonates; Bone Density Conservation Agents; Quality of Life; Osteoporosis; Alendronate; Zoledronic Acid; Fractures, Bone; Osteoporosis, Postmenopausal
PubMed: 37948565
DOI: 10.20945/2359-4292-2022-0334 -
Pharmacogenomics and Personalized... 2023The aim of this study was to explore the association between polymorphisms and the response to alendronate treatment in postmenopausal Chinese women with low bone...
PURPOSE
The aim of this study was to explore the association between polymorphisms and the response to alendronate treatment in postmenopausal Chinese women with low bone mineral density.
PATIENTS AND METHODS
In this study, 460 postmenopausal women from Shanghai were included. All of them were treated with weekly oral alendronate 70 mg, daily calcium 600 mg and vitamin D 125 IU for a year. Four tag single nucleotide polymorphisms (SNPs) in gene were genotyped. Bone mineral densities of lumbar spine (L1-L4), femoral neck and total hip were measured at baseline and after 12 months of treatment, respectively.
RESULTS
After 1-year of treatment, there was no significant differences in BMI between baseline and follow-up. After alendronate treatment, the BMD of L1-4, femoral neck and total hip all increased significantly (all < 0.001), with average increases of 4.33 ± 6.42%, 1.85 ± 4.20%, and 2.36 ± 3.79%, respectively. There was no significant difference in BMD at L1-L4, the femoral neck and total hip between different genotype groups at baseline (>0.05). After 1-year treatment with alendronate, rs12746973 and rs10847 were associated with the % change of BMD at L1-L4 (=0.038) and % change of BMD at femoral neck (=0.038), respectively. Furthermore, rs10847 was associated with BMD response at femoral neck (=0.013). However, the associations were not significant after Bonferroni correction.
CONCLUSION
We concluded that the common variations of gene were potentially associated with the therapeutic response to alendronate treatment in Chinese women with low bone mineral density. However, further validation is needed.
PubMed: 37920752
DOI: 10.2147/PGPM.S425357 -
RSC Advances Oct 2023The computational analysis of drug release from metal-organic frameworks (MOFs), specifically UiO-66, is the primary focus of this research. MOFs are recognized as...
The computational analysis of drug release from metal-organic frameworks (MOFs), specifically UiO-66, is the primary focus of this research. MOFs are recognized as nanocarriers due to their crystalline structure, porosity, and potential for added functionalities. The research examines the release patterns of three drugs: temozolomide, alendronate, and 5-fluorouracil, assessing various factors such as the drugs' distance from the UiO-66 centers, the interaction of drug functional groups with Zr metal ions, and the drug density throughout the nanocarrier. Findings reveal that 5-fluorouracil is located furthest from the UiO-66 center and exhibits the highest positive energy compared to the other drugs. Alendronate's density is observed to shift to the carrier surface, while 5-fluorouracil's density significantly decreases within the system. The drug density diminishes as the distance from the UiO-66 center of mass increases, suggesting a stronger positive interaction between the drugs and the nanocarrier. Moreover, Monte Carlo calculations were employed to load drugs onto the UiO-66 surface, leading to a substantial release of 5-fluorouracil from UiO-66. Quantum and Monte Carlo adsorption localization calculations were also conducted to gather data on the compounds' energy and geometry. This research underscores the potential of MOFs as nanocarriers for drug delivery and highlights the crucial role of temperature in regulating drug release from UiO-66. It provides insights into the complex dynamics of drug release and the factors influencing it, thereby emphasizing the promise of UiO-66 as a viable candidate for drug delivery. This work contributes to our understanding of UiO-66's role and sets the stage for improved performance optimization in the cancer treatment.
PubMed: 37920197
DOI: 10.1039/d3ra05587f