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Bone Jul 2022Despite their ability to reduce fracture-risk and increase Bone Mineral Density (BMD) in osteoporotic women, bisphosphonates are reported to reduce formation of new...
Despite their ability to reduce fracture-risk and increase Bone Mineral Density (BMD) in osteoporotic women, bisphosphonates are reported to reduce formation of new bone. Reduced bone formation has been suggested to lead to accumulation of microfractures and contribute to rare side effects in cortical bone such as atypical femur fractures. However, most studies are limited to trabecular bone. In this study, the cortical bone remodeling in human iliac bone specimens of 65 non-treated and 24 alendronate-treated osteoporotic women was investigated using a new histomorphometric classification of intracortical pores. The study showed that only 12.4 ± 11% of the cortical pore area reflected quiescent pores/osteons in alendronate-treated patients versus 8.5 ± 5% in placebo, highlighting that new cortical remodeling events remain to be activated. The percent and size of eroded pores (events in resorption-reversal phase) remained unchanged, but their contribution to total pore area was 1.4-fold higher in alendronate versus placebo treated patients (66 ± 22% vs 48 ± 22%, p < 0.001). On the other hand, the mixed eroded-formative pores (events with mixed resorption-reversal-formation phases) was 2-fold lower in alendronate versus placebo treated patients (19 ± 14% vs 39 ± 23% of total pore area, p < 0.001), and formative pores (event in formation phase) was 2.2-fold lower in alendronate versus placebo treated patients (2.1 ± 2.4% vs 4.6 ± 3.6%, p < 0.01), and their contribution to total pore area was 2.4-fold lower (1.3 ± 2.1% vs 3.1 ± 4.4%, p < 0.05). Importantly, these differences between alendronate and placebo treated patients were significant in patients after 3 years of treatment, not after 2 years of treatment. Collectively, the results support that cortical remodeling events activated during alendronate treatment has a prolonged reversal-resorption phase with a delayed transition to formation, becoming increasingly evident after 3-years of treatment. A potential contributor to atypical femur fractures associated with long-term bisphosphonate treatment.
Topics: Alendronate; Bone Density; Bone Remodeling; Bone and Bones; Cortical Bone; Diphosphonates; Female; Humans
PubMed: 35413490
DOI: 10.1016/j.bone.2022.116419 -
Antimicrobial Agents and Chemotherapy Jan 2021New treatment strategies are required for cryptococcosis, a leading mycosis in HIV-AIDS patients. Following the identification of proteins differentially expressed in...
New treatment strategies are required for cryptococcosis, a leading mycosis in HIV-AIDS patients. Following the identification of proteins differentially expressed in response to fluconazole, we targeted farnesyl pryrophosphate synthetase (FPPS), an enzyme in the squalene biosynthesis pathway, using nitrogenous bisphosphonates. We hypothesized that these would disrupt squalene synthesis and thereby produce synergy with fluconazole, which acts on a downstream pathway that requires squalene. The susceptibilities of 39 clinical isolates from 6 different species of were assessed for bisphosphonates and fluconazole, used both independently and in combination. Effective fluconazole-bisphosphonate combinations were then assessed for fungicidal activity, efficacy against biofilms, and ability to resolve cryptococcosis in an invertebrate model. The nitrogenous bisphosphonates risedronate, alendronate, and zoledronate were antifungal against all strains tested. Zoledronate was the most effective (geometric mean MIC = 113.03 mg/liter; risedronate = 378.49 mg/liter; alendronate = 158.4 mg/liter) and was broadly synergistic when combined with fluconazole, with a fractional inhibitory concentration index (FICI) of ≤0.5 in 92% of isolates. Fluconazole and zoledronate in combination were fungicidal in a time-kill assay, inhibited biofilms, prevented the development of fluconazole resistance, and resolved infection in a nematode model. Supplementation with squalene eliminated bisphosphonate-mediated synergy, demonstrating that synergy was due to the inhibition of squalene biosynthesis. This study demonstrates the utility of targeting squalene synthesis for improving the efficacy of azole-based antifungal drugs and suggests bisphosphonates are promising lead compounds for further antifungal development.
Topics: Antifungal Agents; Cryptococcosis; Cryptococcus; Cryptococcus neoformans; Diphosphonates; Fluconazole; Humans; Microbial Sensitivity Tests
PubMed: 33139289
DOI: 10.1128/AAC.01753-20 -
Journal of Nanobiotechnology Feb 2022Ovarian cancer is the most lethal gynecological cancer which is characterized by extensive peritoneal implantation metastasis and malignant ascites. Despite advances in...
BACKGROUND
Ovarian cancer is the most lethal gynecological cancer which is characterized by extensive peritoneal implantation metastasis and malignant ascites. Despite advances in diagnosis and treatment in recent years, the five-year survival rate is only 25-30%. Therefore, developing multifunctional nanomedicine with abilities of promoting apoptosis and inhibiting migration on tumor cells would be a promising strategy to improve the antitumor effect.
METHODS AND RESULTS
In this study, we developed a novel ACaT nanomedicine composed of alendronate, calcium ions and cyclin-dependent kinase 7 (CDK7) inhibitor THZ1. With the average size of 164 nm and zeta potential of 12.4 mV, the spherical ACaT nanoparticles were selectively internalized by tumor cells and effectively accumulated in the tumor site. Results of RNA-sequencing and in vitro experiments showed that ACaT promoted tumor cell apoptosis and inhibited tumor cell migration by arresting the cell cycle, increasing ROS and affecting calcium homeostasis. Weekly intraperitoneally administered of ACaT for 8 cycles significantly inhibited the growth of tumor and prolonged the survival of intraperitoneal xenograft mice.
CONCLUSION
In summary, this study presents a new self-assembly nanomedicine with favorable tumor targeting, antitumor activity and good biocompatibility, providing a novel therapeutic strategy for advanced ovarian cancer.
Topics: Animals; Apoptosis; Cell Line, Tumor; Humans; Mice; Nanomedicine; Ovarian Neoplasms; Protein Kinase Inhibitors; Xenograft Model Antitumor Assays
PubMed: 35193583
DOI: 10.1186/s12951-022-01300-4 -
BMC Chemistry Nov 2022Turkevich gold nanospheres are the original nanospheres that have been modified over time. Its combination with targeting medications such as alendronate, memantine, and...
Turkevich gold nanospheres are the original nanospheres that have been modified over time. Its combination with targeting medications such as alendronate, memantine, and tobramycin will provide additional benefits in targeting specific areas in the bone, brain, and microorganisms, respectively. Hence, The reactivity and stability of nanospheres with various drug concentrations (milli-,micro-, and nano-levels) have been studied. With alendronate, the absorbance spectra of nanospheres at [Formula: see text] 520 nm were always stable and no redshifts occurred. In contrast, the spectra with memantine and tobramycin were stable at the nano-level and redshifts occurred at the milli- and micro-levels. HRTEM and DLS revealed that the core diameter was relatively stable in all cases, whereas the hydrodynamic diameter and zeta potential varied with varying drug concentrations. Increasing concentration increased hydrodynamic diameter slightly with memantine (from 64.99 to 98.41 nm), dramatically with tobramycin (from 135.3 to 332.16 nm), and almost negligibly with alendronate (from 52.08 to 58.94 nm ). Zeta Potential, conversely, is reduced as concentration increases. Memantine had the greatest reduction in negativity, followed by tobramycin, but alendronate had a slight increase in negativity. Benefits from this research would be in targeted drug delivery, where stability and reactivity of gold nanospheres are critical.
PubMed: 36419078
DOI: 10.1186/s13065-022-00891-1 -
BioMed Research International 2019Periodontal bone regeneration relies on coupled and cooperative bone formation and resorption. Accordingly a novel strategy on concurrent use of platelet-rich fibrin... (Meta-Analysis)
Meta-Analysis Review
Periodontal bone regeneration relies on coupled and cooperative bone formation and resorption. Accordingly a novel strategy on concurrent use of platelet-rich fibrin (PRF) (anabolic agent) and 1% alendronate (ALN) (anticatabolic agent) was proposed recently in regenerative periodontal treatment. It was supposed to enhance bone formation and reduce bone resorption simultaneously. However, there is a lack of evidence-based studies to answer whether this concurrent application was superior to single application until now. Besides, concerns on ALN lead to some reservation on this synergistic way. ALN may impair new bone formation and necrotize jaws. Thus, in order to compare the clinical efficacy between PRF plus 1%ALN and PRF alone on periodontal bone regeneration, we performed present systematic review and meta-analysis. Because it is the prerequisite for measuring the combined efficacy of PRF plus 1%ALN, firstly we evaluated the effectiveness of 1%ALN. Our data indicated that adjunctive 1%ALN was effective in promoting periodontal bone repair. Further, PRF plus 1%ALN showed a greater capacity for periodontal regeneration than PRF alone with statistical significance. The findings of this study revealed the promising prospects on synergistic application of bone anabolic agents (PRF) and antiresorption medications (1%ALN) in regenerative periodontal treatment.
Topics: Alendronate; Bone Regeneration; Fibrin; Guided Tissue Regeneration, Periodontal; Humans; Osteogenesis; Platelet-Rich Fibrin
PubMed: 31531371
DOI: 10.1155/2019/9148183 -
Foods (Basel, Switzerland) Jul 2022This study aimed to evaluate the effects of enriched pumpkin on calcium status in ovariectomized rats. The study was conducted in sixty female Wistar rats, which were...
This study aimed to evaluate the effects of enriched pumpkin on calcium status in ovariectomized rats. The study was conducted in sixty female Wistar rats, which were divided into six groups: a group fed a standard diet (C) and five ovariectomized groups fed a standard diet (OVX_C) or a diet with calcium lactate (CaL), with calcium lactate-enriched pumpkin (P_CaL), with calcium lactate and alendronate (CaL_B), or with calcium lactate-enriched pumpkin with alendronate (P_CaL_B). After 12 weeks of the intervention, the rats were sacrificed, and their blood and tissues were collected. The calcium concentrations in serum and in tissues were measured using flame atomic absorption spectrometry (AAS). Serum concentrations of procollagen type-1 amino-terminal propeptide (PINP), parathyroid hormone PTH, estrogen (ES), and osteocalcin (OC) were determined with enzyme-linked immunosorbent assay (ELISA). It was found that enriched pumpkin increased the calcium level in the kidneys (194.13 ± 41.01 mg) compared to the C (87.88 ± 12.42 mg) and OVX_C (79.29 ± 7.66 mg) groups. The addition of alendronate increased the calcium level in the femurs (267.63 ± 23.63 mg) and more than six times in the kidneys (541.33 ± 62.91 mg) compared to the OVX_C group (234.53 ± 21.67 mg and 87.88 ± 12.42 mg, respectively). We found that the CaL, P_CaL, and CaL_B groups had significantly lower PINP serum concentrations (4.45 ± 0.82 ng/mL, 4.14 ± 0.69 ng/mL, and 3.77 ± 0.33 ng/mL) and higher PTH serum levels (3.39 ± 0.54 ng/dL, 3.38 ± 0.57 ng/dL, and 3.47 ± 0.28 ng/dL) than the OVX_C group (4.69 ± 0.82 ng/mL and 2.59 ± 0.45 ng/dL, respectively). In conclusion, pumpkin enriched with calcium lactate affects calcium status and normalizes PINP and PTH serum levels in ovariectomized rats. Diet with enriched pumpkin and alendronate increase calcium concentration in the femur. Enriched pumpkin causes calcium to accumulate in the kidneys of ovariectomized rats; alendronate significantly exacerbates this effect.
PubMed: 35885327
DOI: 10.3390/foods11142084 -
Osteoporosis International : a Journal... Jan 2023In this randomized, controlled trial, sequential therapy with once-weekly subcutaneous injection of teriparatide for 72 weeks, followed by alendronate for 48 weeks... (Randomized Controlled Trial)
Randomized Controlled Trial
Sequential therapy with once-weekly teriparatide injection followed by alendronate versus monotherapy with alendronate alone in patients at high risk of osteoporotic fracture: final results of the Japanese Osteoporosis Intervention Trial-05.
UNLABELLED
In this randomized, controlled trial, sequential therapy with once-weekly subcutaneous injection of teriparatide for 72 weeks, followed by alendronate for 48 weeks resulted in a significantly lower incidence of morphometric vertebral fracture than monotherapy with alendronate for 120 weeks in women with osteoporosis at high risk of fracture.
PURPOSE
To determine whether the anti-fracture efficacy of sequential therapy with teriparatide, followed by alendronate is superior to that of monotherapy with alendronate, a prospective, randomized, open-label, blinded-endpoint trial was performed.
METHODS
Japanese women aged at least 75 years were eligible for the study, if they had primary osteoporosis and if they were at high risk of fracture. Patients were randomly assigned (1:1) to receive the sequential therapy (once-weekly subcutaneous injection of teriparatide 56.5 μg for 72 weeks, followed by alendronate for 48 weeks) or monotherapy with alendronate for 120 weeks. The primary endpoint in the final analysis was the incidence of morphometric vertebral fracture during the 120-week follow-up period.
RESULTS
Between October 2014 and June 2020, 505 patients in the sequential therapy group and 506 in the monotherapy group were enrolled. Of these, 489 and 496, respectively, were included in the main analysis. The incidence of morphometric vertebral fracture during the 120-week follow-up period in the sequential therapy group (64 per 627.5 person-years, annual incidence rate 0.1020) was significantly lower than that in the monotherapy group (126 per 844.2 person-years, annual incidence rate 0.1492), with a rate ratio of 0.69 (95% confidence interval 0.54 to 0.88, P < 0.01). After 72 weeks, no patient had a severe adverse event that was considered related to the study drug.
CONCLUSION
Once-weekly injection of teriparatide, followed by alendronate resulted in a significantly lower incidence of morphometric vertebral fracture than alendronate monotherapy in women with osteoporosis who were at high risk of fracture. TRIAL REGISTRATION NUMBER, DATE OF REGISTRATION: jRCTs031180235 and UMIN000015573, March 12, 2019.
Topics: Humans; Female; Alendronate; Osteoporotic Fractures; Teriparatide; Bone Density Conservation Agents; Spinal Fractures; East Asian People; Prospective Studies; Osteoporosis; Bone Density; Osteoporosis, Postmenopausal
PubMed: 36239756
DOI: 10.1007/s00198-022-06570-0 -
International Journal of Women's Health 2022As one of the most potent osteoanabolic agents with a unique mechanism of action, romosozumab has high efficacy for osteoporosis treatment. It is a monoclonal antibody... (Review)
Review
As one of the most potent osteoanabolic agents with a unique mechanism of action, romosozumab has high efficacy for osteoporosis treatment. It is a monoclonal antibody against sclerostin, a natural inhibitor of the Wnt signaling pathway, and by inhibiting sclerostin, activation of Wnt signaling occurs with a cascade of changes ultimately leading to bone mineral density (BMD) gains. Romosozumab stimulates bone modeling and has a dual effect of activating bone formation while inhibiting bone resorption. With this unique mechanism of action, treatment with romosozumab leads to a rapid and significant gain in BMD; these gains are higher than seen with bisphosphonates, denosumab, or parathyroid hormone (PTH) analogs. The FRAME and ARCH studies represent two pivotal trials demonstrating the efficacy of romosozumab in treating osteoporosis. Treatment with romosozumab should be followed by an antiresorptive agent, as this approach has demonstrated maintenance of or greater increases in BMD and reduced fracture risk even after finishing romosozumab treatment. As an osteoanabolic agent, romosozumab has shown superiority to alendronate in reducing fracture risk, increasing bone density, and potentially more rapid fracture risk reduction. Recent data have suggested that romosozumab prior to antiresorptive therapy may be the ideal treatment sequence, especially in high-risk patients and patients at imminent risk of fracture. Carrying a black box warning, romosozumab should be avoided in patients who have had myocardial infarction or stroke in the past year. Further studies are needed to clarify the increased cardiovascular risk attributed to this drug. Romosozumab has expanded our osteoporosis armamentarium and has enabled novel approaches, including "treat to target." Future studies are needed to evaluate the optimal use sequence and to assess its safety, especially in patients with cardiovascular risk factors.
PubMed: 36544862
DOI: 10.2147/IJWH.S315184 -
Nanomaterials (Basel, Switzerland) Feb 2023Different amounts of sodium-alendronate (ALN) were loaded into layered zirconium phosphates of alpha and gamma type (αZP and γZP) by means of topotactic exchange...
Different amounts of sodium-alendronate (ALN) were loaded into layered zirconium phosphates of alpha and gamma type (αZP and γZP) by means of topotactic exchange reactions of phosphate with ALN. In order to extend the exchange process to the less accessible interlayer regions, ALN solutions were contacted with colloidal dispersions of the layered solids previously exfoliated in single sheets by means of intercalation reaction of propylamine (for αZP) or acetone (for γZP). The ALN loading degree was determined by liquid P-nuclear magnetic resonance (NMR) and inductively coupled plasma (ICP), and it was reported as ALN/Zr molar ratios (Rs). The maximum R obtained for γZP was 0.34, while αZP was able to load a higher amount of ALN, reaching Rs equal to 1. The synthesized compounds were characterized by X-ray powder diffractometry, scanning electron microscopy (SEM), solid-state NMR, and infrared spectroscopy. The way the grafted organo-phosphonate groups were bonded to the layers of the host structure was suggested. The effect of ZP derivatives was assessed on cell proliferation, and the results showed that after 7 days of incubation, none of the samples showed a decrease in cell proliferation.
PubMed: 36839110
DOI: 10.3390/nano13040742 -
BioMed Research International 2020Osteonecrosis of the femoral head (ONFH) is a challenge for surgeons and is still without effective treatment method. This study is aimed at evaluating the combined...
Combined Pharmacotherapy with Alendronate and Desferoxamine Regulate the Bone Resorption and Bone Regeneration for Preventing Glucocorticoids-Induced Osteonecrosis of the Femoral Head.
BACKGROUND
Osteonecrosis of the femoral head (ONFH) is a challenge for surgeons and is still without effective treatment method. This study is aimed at evaluating the combined pharmacotherapy with alendronate and desferoxamine for preventing glucocorticoid-induced osteonecrosis of the femoral head (GIOFH) and evaluating the efficacy of the combined medicine in regulating the bone resorption and bone regeneration.
MATERIALS AND METHODS
Thirty-six rats were randomly assigned to three groups: group A received alendronate and desferoxamine ( = 12), group B received alendronate only ( = 12), and group C acted as the control group received placebo ( = 12). All rats induced the GIOFH using methylprednisolone combined with lipopolysaccharide. Eight weeks later, all rats were killed and their tissues were subjected to radiographic and histological analyses.
RESULTS
According to the results, alendronate administration improved the trabecular thickness and separation in micro-CT analysis but had no significant evidence in increasing the bone area and decreasing the ratio of osteocyte lacunae in histological analysis when compared with the control group. Meanwhile, the alendronate group had more OCs, but less OCN and VEGF levels along with decreased p-AKT, HIF-1, RANKL, and NFATc1 expressions than the control group. For comparison, alendronate combined with DFO further improved the bone volume, trabecular number, trabecular separation, and trabecular thickness with lower ratio of osteocyte lacunae and OC number, higher expression of OCN and VEGF and upregulated signal factors of HIF-1 and -catenin, and decreased RANKL and NFATc1.
CONCLUSION
Combined pharmacotherapy with alendronate and desferoxamine provide significant effects in regulating the bone resorption and bone regeneration for preventing GIOFN.
Topics: Alendronate; Animals; Bone Regeneration; Bone Resorption; Deferoxamine; Drug Therapy, Combination; Femur Head Necrosis; Glucocorticoids; Glycogen Synthase Kinase 3 beta; Male; NFATC Transcription Factors; Neovascularization, Physiologic; Osteogenesis; RANK Ligand; Rats, Wistar; Signal Transduction; Tartrate-Resistant Acid Phosphatase; X-Ray Microtomography; beta Catenin
PubMed: 33029500
DOI: 10.1155/2020/3120458