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Journal of Alzheimer's Disease : JAD 2024The amyloid-β (Aβ) enhances the number and activity of blood monocyte-derived osteoclasts (OCs). Individuals with osteoporosis (OP) face an increased risk of...
BACKGROUND
The amyloid-β (Aβ) 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 Aβ mediated by immune cells. Long-term anti-resorptive intervention with Alendronate inhibited OC activity in APP23 mice, leading to improvements in peripheral monocyte Aβ-degrading enzyme expression, Aβ-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.
Topics: Alzheimer Disease; Animals; Mice, Transgenic; Mice; Humans; Osteoclasts; Disease Progression; Alendronate; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Disease Models, Animal; Female; Male; Bone Density Conservation Agents
PubMed: 38701149
DOI: 10.3233/JAD-240096 -
Neurospine May 2024We investigated the clinical efficacy of anabolic agents compared with bisphosphonates (BPs) for the incidence of new osteoporotic vertebral fracture (OVF) and fracture...
Comparison of the Clinical Efficacy of Anabolic Agents and Bisphosphonates in the Patients With Osteoporotic Vertebral Fracture: Systematic Review and Meta-analysis of Randomized Controlled Trials.
OBJECTIVE
We investigated the clinical efficacy of anabolic agents compared with bisphosphonates (BPs) for the incidence of new osteoporotic vertebral fracture (OVF) and fracture healing of OVF in the patients with OVF via meta-analyses of randomized controlled trials (RCTs).
METHODS
Electronic databases, including PubMed, Embase, and Cochrane Library were searched for published RCTs till December 2022. The RCTs that recruited participants with osteoporosis at high-/very high-risk of fracture (a history of osteoporotic vertebral or hip fracture) or fresh OVF were included in this study. We assessed the risk of bias on every included RCTs, estimated relative risk (RR) for the incidence of new OVF and fracture healing of OVF, and overall certainty of evidence. Meta-analyses were performed by Cochrane review manager (RevMan) version 5.3. Cochrane risk of bias 2.0 and GRADEpro/GDT were applied for evaluating methodological quality and overall certainty of evidence, respectively.
RESULTS
Five hundred eighteen studies were screened, and finally 6 eligible RCTs were included in the analysis. In the patients with prevalent OVF, anabolic agents significantly reduced the incidence of new OVF (teriparatide and romosozumab vs alendronate and risedronate [RR = 0.57, 95% CI 0.45 - 0.71; p < 0.00001; high-certainty of evidence]; teriparatide vs risedronate [RR = 0.50, 95% CI 0.37 - 0.68; p < 0.0001; high-certainty of evidence]. However, there was no evidence of teriparatide compared to alendronate in fracture healing of OVF (RR = 1.23, 95% CI 0.95 - 1.60; p = 0.12; low-certainty of evidence).
CONCLUSION
In the patients with prevalent OVF, anabolic agents showed a significant superiority for preventing new OVF than BPs, with no significant evidence for promoting fracture healing of OVF. However, considering small number of RCTs in this study, additional studies with large-scale data are required to obtain more robust evidences.
PubMed: 38697911
DOI: 10.14245/ns.2347256.628 -
Microbiology Spectrum Jun 2024Candidiasis places a significant burden on human health and can range from common superficial vulvovaginal and oral infections to invasive diseases with high mortality....
UNLABELLED
Candidiasis places a significant burden on human health and can range from common superficial vulvovaginal and oral infections to invasive diseases with high mortality. The most common species implicated in human disease is , but other species like are emerging. The use of azole antifungals for treatment is limited by increasing rates of resistance. This study explores repositioning bisphosphonates, which are traditionally used for osteoporosis, as antifungal synergists that can improve and revitalize the use of azoles. Risedronate, alendronate, and zoledronate (ZOL) were tested against isolates from six different species of , and ZOL produced moderate antifungal activity and strong synergy with azoles like fluconazole (FLC), particularly in . FLC:ZOL combinations had increased fungicidal and antibiofilm activity compared to either drug alone, and the combination prevented the development of antifungal resistance. Mechanistic investigations demonstrated that the synergy was mediated by the depletion of squalene, resulting in the inhibition of ergosterol biosynthesis and a compromised membrane structure. In , synergy compromised the function of membrane-bound multidrug transporters and caused an accumulation of reactive oxygen species, which may account for its acute sensitivity to FLC:ZOL. The efficacy of FLC:ZOL was confirmed in a infection model, where combinations improved the survival of larvae infected with and to a greater extent than monotherapy with FLC or ZOL, and at reduced dosages. These findings demonstrate that bisphosphonates and azoles are a promising new combination therapy for the treatment of topical candidiasis.
IMPORTANCE
is a common and often very serious opportunistic fungal pathogen. Invasive candidiasis is a prevalent cause of nosocomial infections with a high mortality rate, and mucocutaneous infections significantly impact the quality of life of millions of patients a year. These infections pose substantial clinical challenges, particularly as the currently available antifungal treatment options are limited in efficacy and often toxic. Azoles are a mainstay of antifungal therapy and work by targeting the biosynthesis of ergosterol. However, there are rising rates of acquired azole resistance in various species, and some species are considered intrinsically resistant to most azoles. Our research demonstrates the promising therapeutic potential of synergistically enhancing azoles with non-toxic, FDA-approved bisphosphonates. Repurposing bisphosphonates as antifungal synergists can bypass much of the drug development pipeline and accelerate the translation of azole-bisphosphonate combination therapy.
Topics: Antifungal Agents; Drug Synergism; Microbial Sensitivity Tests; Azoles; Humans; Diphosphonates; Candida; Animals; Drug Resistance, Fungal; Candidiasis; Fluconazole; Biofilms; Candida glabrata; Candida albicans
PubMed: 38695556
DOI: 10.1128/spectrum.00121-24 -
Journal of Nanobiotechnology Apr 2024Osteoporosis is a highly prevalent metabolic disease characterized by low systemic bone mass and deterioration of bone microarchitecture, resulting in reduced bone...
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.
Topics: Animals; Alendronate; Thioctic Acid; Gold; Osteoporosis; Mice; Metal Nanoparticles; Female; Osteogenesis; Mice, Inbred C57BL; Bone Density Conservation Agents; Particle Size
PubMed: 38689294
DOI: 10.1186/s12951-024-02466-9 -
Antioxidants (Basel, Switzerland) Apr 2024Osteoporosis is a bone-debilitating disease, demonstrating a higher prevalence in post-menopausal women due to estrogen deprivation. One of the main mechanisms...
Osteoporosis is a bone-debilitating disease, demonstrating a higher prevalence in post-menopausal women due to estrogen deprivation. One of the main mechanisms underlying menopause-related bone loss is oxidative stress. -allylmercapto--acetylcysteine (ASSNAC) is a nuclear factor erythroid 2-related factor 2 (Nrf2) activator and cysteine supplier, previously shown to have anti-oxidation protective effects in cultured cells and animal models. Here, we studied the therapeutic potential of ASSNAC with and without Alendronate in ovariectomized (OVX) female mice. The experimental outcome included (i) femur and L3 lumbar vertebra morphometry via Micro-Computed Tomography (μCT); (ii) bone remodeling (formation vs. resorption); and (iii) oxidative stress markers in bone marrow (BM) cells. Four weeks after OVX, there was a significant bone loss that remained evident after 8 weeks, as demonstrated via µCT in the femur (cortical and trabecular bone compartments) and vertebra (trabecular bone). ASSNAC at a dose of 50 mg/Kg/day prevented bone loss after the four-week treatment but had no significant effect after 8 weeks, while ASSNAC at a dose of 20 mg/Kg/day significantly protected against bone loss after 8 weeks of treatment. Alendronate prevented ovariectomy-induced bone loss, and combining it with ASSNAC further augmented this effect. OVX mice demonstrated high serum levels of both C-terminal cross-linked telopeptides of type I collagen (CTX) (bone resorption) and procollagen I N-terminal propeptide (P1NP) (bone formation) after 2 weeks, and these returned to control levels after 8 weeks. Alendronate, ASSNAC and their combination decreased CTX and increased P1NP. Alendronate induced oxidative stress as reflected by decreased glutathione and increased malondialdehyde (MDA) levels, and combining it with ASSNAC partially attenuated these changes. These results portray the therapeutic potential of ASSNAC for the management of post-menopausal osteoporosis. Furthermore, ASSNAC ameliorates the Alendronate-associated oxidative stress, suggesting its potential to prevent Alendronate side effects as well as improve its bone-protective effect.
PubMed: 38671921
DOI: 10.3390/antiox13040474 -
Phytomedicine : International Journal... Jul 2024Postmenopausal osteoporosis (PMOP) is a systemic bone disease characterized by low bone mass and microstructural damage. Morinda Officinalis (MO) contains various...
BACKGROUND
Postmenopausal osteoporosis (PMOP) is a systemic bone disease characterized by low bone mass and microstructural damage. Morinda Officinalis (MO) contains various components with anti-PMOP activities. Morinda Officinalis-derived extracellular vesicle-like particles (MOEVLPs) are new active components isolated from MO, and no relevant studies have investigated their anti-osteoporosis effect and mechanism.
PURPOSE
To investigate the alleviating effect of MOEVLPs on PMOP and the underlying mechanism.
METHODS
Differential centrifugation and ultracentrifugation were used to isolate MOEVLPs from MO. Transmission electron microscopy (TEM), flow nano analyzer, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), agarose gel electrophoresis, and thin-layer chromatography were employed to characterize MOEVLPs. PMOP mouse models were utilized to examine the anti-PMOP effect of MOEVLPs. H&E and immunohistochemical staining were used for drug safety and osteogenic effect assessment. Mouse embryo osteoblast precursor cells (MC3T3-E1) were used in vitro experiments. CCK-8 kit, alizarin red staining, proteomic, bioinformatic analyses, and western blot were used to explore the mechanism of MOEVLPs.
RESULTS
In this study, MOEVLPs from MO were successfully isolated and characterized. Animal experiments demonstrated that MOEVLPs exhibited specific femur targeting, were non-toxic to the heart, liver, spleen, lung, kidney, and aorta, and possessed anti-PMOP properties. The ability of MOEVLPs to strengthen bone formation was better than that of alendronate. In vitro experiments, results revealed that MOEVLPs did not significantly enhance osteogenic differentiation in MC3T3-E1 cells. Instead, MOEVLPs promoted the proliferation of MC3T3-E1 cells. Proteomic and bioinformatic analyses suggested that the proliferative effect of MOEVLPs was closely associated with the mitogen-activated protein kinase (MAPK) signaling pathway, particularly the altered expression of cAMP response element-binding protein (CREB) and ribosomal S6 kinase 1 (RSK1). Western blot results further confirmed these findings.
CONCLUSION
Our studies successfully isolated high-quality MOEVLPs and demonstrated that MOEVLPs can alleviate PMOP by promoting osteoblast proliferation through the MAPK pathway. MOEVLPs have the potential to become a novel and natural anti-PMOP drug.
Topics: Animals; Extracellular Vesicles; Morinda; Mice; MAP Kinase Signaling System; Female; Osteoporosis, Postmenopausal; Osteoblasts; Osteogenesis; Humans; Disease Models, Animal
PubMed: 38663117
DOI: 10.1016/j.phymed.2024.155628 -
The Journal of Oral Implantology Jun 2024A systematic review was designed to investigate the effect of treatment with oral bisphosphonate (BP) on osseointegration of dental implants and the incidence of... (Meta-Analysis)
Meta-Analysis Review
A systematic review was designed to investigate the effect of treatment with oral bisphosphonate (BP) on osseointegration of dental implants and the incidence of BP-related osteonecrosis of the jaw (BRONJ) in postmenopausal women. Multiple electronic databases, including MEDLINE (PubMed), EMBASE, and SCOPUS, were searched to find all eligible articles published since 1990. All titles and abstracts retrieved by searching information sources were evaluated independently by 2 authors against the eligibility criteria. The number of cases ranged from 11 to 235, and the number of controls ranged from 14 to 343. Alendronate was used in all other studies. Risedronate was used in 6 studies, while ibandronate was used in 4 studies. The number of implants in cases ranged from 25 to 1267, while in controls, the number of implants ranged from 28 to 1450. The time between the placement of implant and the follow-up visit ranged from 4-6 months to 8 years. The results show that out of 2582 placed implants, 50 (1.94%) failed in BP-treated patients. This is while out of 4050 placed implants, 188 (4.6%) failed in the non-BP group. The results from the meta-analysis demonstrated that BP therapy is significantly associated with increased implant failure rates (RR = 1.73 [95% CI, 1.03-2.83], P = .04). Overall, the qualitative assessment of this review suggests that oral treatment with BPs in postmenopausal women does not increase the rate of dental implant failure. Thus, further studies with larger sample sizes should compare BP and non-BP groups in regard to dental implants.
Topics: Humans; Female; Diphosphonates; Dental Implants; Bone Density Conservation Agents; Dental Restoration Failure; Postmenopause; Bisphosphonate-Associated Osteonecrosis of the Jaw; Osseointegration; Administration, Oral
PubMed: 38660740
DOI: 10.1563/aaid-joi-D-23-00069 -
Therapeutic Advances in Musculoskeletal... 2024Subjects with a fragility fracture have an increased risk of a new fracture and should receive effective strategies to prevent new events. The medium-term to long-term...
BACKGROUND
Subjects with a fragility fracture have an increased risk of a new fracture and should receive effective strategies to prevent new events. The medium-term to long-term strategy should be scheduled by considering the mechanisms of action in therapy and the estimated fracture risk.
OBJECTIVE
A systematic review was conducted to evaluate the sequential strategy in patients with or at risk of a fragility fracture in the context of the development of the Italian Guidelines.
DESIGN
Systematic review and meta-analysis.
DATA SOURCES AND METHODS
PubMed, Embase, and the Cochrane Library were investigated up to February 2021 to update the search of a recent systematic review. Randomized clinical trials (RCTs) that analyzed the sequential therapy of antiresorptive, anabolic treatment, or placebo in patients with or at risk of a fragility fracture were eligible. Three authors independently extracted data and appraised the risk of bias in the included studies. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Effect sizes were pooled in a meta-analysis using fixed-effects models. The primary outcome was the risk of refracture, while the secondary outcome was the bone mineral density (BMD) change.
RESULTS
In all, 17 RCTs, ranging from low to high quality, met our inclusion criteria. A significantly reduced risk of fracture was detected at (i) 12 or 24 months after the switch from romosozumab to denosumab placebo to denosumab; (ii) 30 months from teriparatide to bisphosphonates placebo to bisphosphonates; and (iii) 12 months from romosozumab to alendronate the only alendronate therapy (specifically for vertebral fractures). In general, at 2 years after the switch from anabolic to antiresorptive drugs, a weighted BMD was increased at the lumbar spine, total hip, and femoral neck site.
CONCLUSION
The Task Force formulated recommendations on sequential therapy, which is the first treatment with anabolic drugs or 'bone builders' in patients with very high or imminent risk of fracture.
PubMed: 38654732
DOI: 10.1177/1759720X241234584 -
Science Advances Apr 2024Osteoarthritis (OA) treatment is limited by the lack of effective nonsurgical interventions to slow disease progression. Here, we examined the contributions of the...
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.
Topics: Animals; Mice; Alendronate; Bone and Bones; Cartilage, Articular; Osteoarthritis; Parathyroid Hormone; Bone Remodeling; Weight-Bearing
PubMed: 38640238
DOI: 10.1126/sciadv.adk8402 -
Health Technology Assessment... Apr 2024Bisphosphonates are a class of medication commonly used to treat osteoporosis. Alendronate is recommended as the first-line treatment; however, long-term adherence (both...
BACKGROUND
Bisphosphonates are a class of medication commonly used to treat osteoporosis. Alendronate is recommended as the first-line treatment; however, long-term adherence (both treatment compliance and persistence) is poor. Alternative bisphosphonates are available, which can be given intravenously and have been shown to improve long-term adherence. However, the most clinically effective and cost-effective alternative bisphosphonate regimen remains unclear. What is the most cost-effective bisphosphonate in clinical trials may not be the most cost-effective or acceptable to patients in everyday clinical practice.
OBJECTIVES
1. Explore patient, clinician and stakeholder views, experiences and preferences of alendronate compared to alternative bisphosphonates. 2. Update and refine the 2016 systematic review and cost-effectiveness analysis of bisphosphonates, and estimate the value of further research into their benefits. 3. Undertake stakeholder/consensus engagement to identify important research questions and further rank research priorities.
METHODS
The study was conducted in two stages, stages 1A and 1B in parallel, followed by stage 2: • Stage 1A - we elicited patient and healthcare experiences to understand their preferences of bisphosphonates for the treatment of osteoporosis. This was undertaken by performing a systematic review and framework synthesis of qualitative studies, followed by semistructured qualitative interviews with participants. • Stage 1B - we updated and expanded the existing Health Technology Assessment systematic review and clinical and cost-effectiveness model, incorporating a more comprehensive review of treatment efficacy, safety, side effects, compliance and long-term persistence. • Stage 2 - we identified and ranked further research questions that need to be answered about the effectiveness and acceptability of bisphosphonates.
RESULTS
Patients and healthcare professionals identified a number of challenges in adhering to bisphosphonate medication, balancing the potential for long-term risk reduction against the work involved in adhering to oral alendronate. Intravenous zoledronate treatment was generally more acceptable, with such regimens perceived to be more straightforward to engage in, although a portion of patients taking alendronate were satisfied with their current treatment. Intravenous zoledronate was found to be the most effective, with higher adherence rates compared to the other bisphosphonates, for reducing the risk of fragility fracture. However, oral bisphosphonates are more cost-effective than intravenous zoledronate due to the high cost of zoledronate administration in hospital. The importance of including patients and healthcare professionals when setting research priorities is recognised. Important areas for research were related to patient factors influencing treatment selection and effectiveness, how to optimise long-term care and the cost-effectiveness of delivering zoledronate in an alternative, non-hospital setting.
CONCLUSIONS
Intravenous zoledronate treatment was generally more acceptable to patients and found to be the most effective bisphosphonate and with greater adherence; however, the cost-effectiveness relative to oral alendronate is limited by its higher zoledronate hospital administration costs.
FUTURE WORK
Further research is needed to support people to make decisions influencing treatment selection, effectiveness and optimal long-term care, together with the clinical and cost-effectiveness of intravenous zoledronate administered in a non-hospital (community) setting.
LIMITATIONS
Lack of clarity and limitations in the many studies included in the systematic review may have under-interpreted some of the findings relating to effects of bisphosphonates.
TRIAL REGISTRATION
This trial is registered as ISRCTN10491361.
FUNDING
This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR127550) and is published in full in ; Vol. 28, No. 21. See the NIHR Funding and Awards website for further award information.
Topics: Humans; Diphosphonates; Alendronate; Zoledronic Acid; Osteoporotic Fractures; Osteoporosis
PubMed: 38634483
DOI: 10.3310/WYPF0472