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FASEB Journal : Official Publication of... Jul 2023Nonalcoholic steatohepatitis (NASH) has become a major concern that threatens human health worldwide. The underlying pathogenesis was crucial but remained poorly...
Nonalcoholic steatohepatitis (NASH) has become a major concern that threatens human health worldwide. The underlying pathogenesis was crucial but remained poorly understood. Here, we found that the expression of hepatic farnesyl diphosphate synthase (FDPS) was increased in mice and patients with NASH. Elevated FDPS levels were positively correlated with NASH severity. Overexpression of FDPS in mice provoked increased lipid accumulation, inflammation, and fibrosis, while hepatic FDPS deficiency protected mice from NASH progression. Importantly, pharmacological inhibition of FDPS with clinically used alendronate remarkably attenuated NASH-associated phenotypes in mice. Mechanistically, we demonstrated that FDPS increased its downstream product farnesyl pyrophosphate levels, which could function as an aryl hydrocarbon receptor (AHR) agonist to upregulate the expression of fatty acid translocase CD36, to accelerate the development of NASH. Collectively, these findings suggest that FDPS exacerbates NASH via AHR-CD36 axis and identify FDPS as a promising target for NASH therapy.
Topics: Animals; Humans; Mice; Alendronate; CD36 Antigens; Geranyltranstransferase; Non-alcoholic Fatty Liver Disease; Receptors, Aryl Hydrocarbon
PubMed: 37310396
DOI: 10.1096/fj.202300433RR -
BMC Musculoskeletal Disorders Sep 2023Bisphosphonate medications, including alendronate, ibandronate and risedronate administered orally and zoledronate, administered intravenously, are commonly prescribed...
BACKGROUND
Bisphosphonate medications, including alendronate, ibandronate and risedronate administered orally and zoledronate, administered intravenously, are commonly prescribed for the treatment of osteoporosis based on evidence that, correctly taken, bisphosphonates can improve bone strength and lead to a reduction in the risk of fragility fractures. However, it is currently unclear how decisions to select between bisphosphonate regimens, including intravenous regimen, are made in practice and how clinicians support patients with different treatments.
METHODS
This was an interpretivist qualitative study. 23 semi-structured telephone interviews were conducted with a sample of general practitioners (GPs), secondary care clinicians, specialist experts as well as those providing and leading novel treatments including participants from a community intravenous (IV) zoledronate service. Data analysis was undertaken through a process of iterative categorisation.
RESULTS
The results report clinicians varying experiences of making treatment choices, as well as wider aspects of osteoporosis care. Secondary care and specialist clinicians conveyed some confidence in making treatment choices including on selecting IV treatment. This was aided by access to diagnostic testing and medication expertise. In contrast GPs reported a number of challenges in prescribing bisphosphonate medications for osteoporosis and uncertainty about treatment choice. Results also highlight how administering IV zoledronate was seen as an opportunity to engage in broader care practices.
CONCLUSION
Approaches to making treatment decisions and supporting patients when prescribing bisphosphonates for osteoporosis vary in practice. This study points to the need to co-ordinate osteoporosis treatment and care across different care providers.
Topics: Humans; Female; Zoledronic Acid; Osteoporosis; Diphosphonates; Ibandronic Acid; Alendronate; Bone Density Conservation Agents; Osteoporosis, Postmenopausal
PubMed: 37770860
DOI: 10.1186/s12891-023-06865-1 -
Archives of Osteoporosis Mar 2024This retrospective study compared the efficacy of anabolic agents (romosozumab and teriparatide) with that of alendronate in preventing subsequent vertebral body...
UNLABELLED
This retrospective study compared the efficacy of anabolic agents (romosozumab and teriparatide) with that of alendronate in preventing subsequent vertebral body fractures (SVBFs) after balloon kyphoplasty (BKP). All anabolic agents significantly reduced SVBFs. Romosozumab was most effective in increasing bone mineral density (BMD) and completely suppressed distant vertebral body fractures.
INTRODUCTION
To determine optimal anti-osteoporosis medications, we compared romosozumab and teriparatide to alendronate as a control from perioperative BKP to the 1st postoperative year for treatment and secondary fracture prevention in osteoporosis.
METHODS
A total of 603 patients who underwent initial BKP for osteoporotic vertebral fractures were evaluated and categorized into five groups based on drug administration: romosozumab (group R, 155 patients), twice-weekly teriparatide (group TW, 48), weekly teriparatide (group W, 151), daily teriparatide (group D, 138), and alendronate (control) (group C, 111). The 1-year incidence of SVBFs, BMD change rate, and probability of requiring BKP were compared among the groups.
RESULTS
SVBF incidence was 3.9%, 6.5%, 8.3%, 6.0%, and 14.4% in groups R, D, TW, W, and C, respectively, with all other groups exhibiting significantly lower rates than group C. The groups that administered the anabolic agents had a notably lower incidence of distant fractures than group C. Compared with group C, group R showed significantly higher BMD change rates in lumbar vertebral bodies at 4, 8, and 12 months and group D at 12 months. Anabolic agent groups exhibited significantly higher improvement rates than group C after conservative treatment alone.
CONCLUSION
The anabolic agents were found to be more effective at reducing the incidence of SVBF (especially distant vertebral fractures) than alendronate. These agents decreased the rate of repeat BKP even after the occurrence of a fracture. Overall, the use of an anabolic agent for the treatment of osteoporosis after BKP is better than the use of alendronate, even when treatment is initiated in the perioperative stage.
Topics: Humans; Vertebral Body; Kyphoplasty; Teriparatide; Alendronate; Retrospective Studies; Anabolic Agents; Osteoporosis; Osteoporotic Fractures; Bone Density; Spinal Fractures; Fractures, Compression; Bone Density Conservation Agents
PubMed: 38512565
DOI: 10.1007/s11657-024-01374-7 -
Toxicology and Applied Pharmacology Oct 2023Alendronate, a nitrogen-containing bisphosphonate, has reported long-term clinical success in the management of distinct bone-related conditions, particularly in the...
Alendronate, a nitrogen-containing bisphosphonate, has reported long-term clinical success in the management of distinct bone-related conditions, particularly in the modulation of post-menopausal osteoporosis. Nonetheless, whether the inhibitory activity over osteoclastic cells' functionality is widely acknowledged, contradictory evidence arises from the assessment of alendronate activity over osteoblastic populations. This may be of particular relevance in situations in which bone formation exceeds bone resorption, with further emphasis on embryonic development, since alendronate can cross the placental barrier and alendronate-based therapies are being extended into women of reproductive age. Accordingly, the present study aims to assess the effects of alendronate, at distinct concentrations (1.5EM to 1.5EM) on bone tissue development, within a translational animal model - the embryonic chicken development model. Embryos, at the beginning of osteogenesis (day 7) were exposed to different alendronate concentrations for 4 days. Embryos were following characterized for skeletal development by histomorphometric analysis upon histochemical staining, microtomographic analysis, and gene expression assessment of genes related to osteoclastogenic/osteoclastic and osteoblastogenic/osteogenic differentiation, as well as to the immuno-inflammatory activation. The findings revealed that exposure to alendronate had a dose-dependent impact on skeletal growth and mineralization. This effect was evidenced by diminished bone volume and reduced bone surface parameters, with the 1.5EM concentration leading to a remarkable reduction of over 50%. Additionally, a decreased osteoclastogenic/osteoclastic gene expression was verified, associated with a diminished osteoblastogenic/osteogenic program - within the 30-50% range for 1.5E-7 M, supporting the diminished bone formation process. An increased inflammatory activation may contribute, at least in part, to the attained outcomes. Overall present findings suggest a negative influence of alendronate on the embryonic bone development process in a dose-dependent manner, highlighting the potential risk of alendronate use during embryonic development.
Topics: Female; Pregnancy; Animals; Chick Embryo; Alendronate; Osteogenesis; Chickens; Placenta; Embryonic Development
PubMed: 37652309
DOI: 10.1016/j.taap.2023.116673 -
Bone Dec 2023Fluoroquinolone antibiotics are known to induce serious tendinopathies and ligament disorders (TPLDs) on rare occasion, but it is less well-appreciated whether such...
Fluoroquinolone antibiotics are known to induce serious tendinopathies and ligament disorders (TPLDs) on rare occasion, but it is less well-appreciated whether such adverse reactions result from the use of bisphosphonates (BPs). In this study, we assessed the correlation between TPLDs and the use of BPs via U.S. FDA Adverse Event Reporting System (FAERS) database. Bayesian and nonproportional analyses were applied to data retrieved from the FAERS database from the first quarter of 2004 to the third quarter of 2022. A total of 3202 reported cases of TPLDs were associated with five BPs (alendronate, pamidronate, ibandronate, risedronate, zoledronate), with statistically significant reporting odds ratio (ROR), proportional reporting ratio (PRR), and information component (IC). Alendronate showed the highest association with tendinopathies and ligament disorders (ROR = 16.30, PRR = 15.47, IC = 3.88), while zoledronate had the lowest association (ROR = 2.13, PRR = 2.12, IC = 1.08), which was consistent with the results of top 10 preferred terms (PTs) under the narrow standardized MedDRA queries (SMQs) sorted by frequency of reports. Excluding zoledronate, over half of patients who reported BP-related TPLDs were hospitalized, either briefly or extendedly. This was especially true for alendronate, which showed the highest rate of hospitalization (83.25 %), however, the mortality rate reported by those taking alendronate were significantly lower than those of zoledronate and pamidronate. In addition, the clinical characteristics of BP-related TPLDs was analyzed. It is more common to reported in middle-aged and elderly females, the highest proportion was in 50-69 years old. Except for osteoporosis, osteopenia, and osteoporosis prophylaxis, cancer bone metastasis was also the indication of some BPs. The most often reported concomitant/prior medicines were calcium supplements, another BPs, antitumor agents, and nonsteroidal anti-inflammatory drugs. In conclusion, we provide a comprehensive overview of the correlation and clinical characteristics, and prognosis of BP-related TPLDs deserving continued surveillance and appropriate management.
PubMed: 37739298
DOI: 10.1016/j.bone.2023.116919 -
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 -
Advanced Healthcare Materials Mar 2024Chemotherapy remains the primary treatment method for osteosarcoma after surgery. However, the lack of selectivity of chemotherapy for osteosarcoma leads to...
Chemotherapy remains the primary treatment method for osteosarcoma after surgery. However, the lack of selectivity of chemotherapy for osteosarcoma leads to unpredictable therapeutic effects, undesirable side effects, and drug resistance. A platinum(IV) (Pt ) prodrug amphiphile (ALN-Pt -Lipo) covalently bound to alendronate (ALN) and a lipid tail is designed to overcome these limitations. ALN-Pt -Lipo can self-assemble into Pt lipid nanoparticles (APt ) for osteosarcoma targeting chemotherapy and bone destruction inhibition. It is demonstrated that APt achieved an eightfold increase in the eradication of osteosarcoma cells compared to cisplatin and threefold selective inhibition of osteosarcoma cells over breast cancer cells via APt in vitro. After intravenous injection, APt effectively accumulates at the osteosarcoma site in vivo, resulting in significantly suppressed primary osteosarcoma growth, and alleviation of bone destruction. Therefore, APt delivers a promising solution for enhanced chemotherapy targeting and bone destruction inhibition in osteosarcoma.
Topics: Humans; Prodrugs; Antineoplastic Agents; Alendronate; Cisplatin; Osteosarcoma; Nanoparticles; Bone Neoplasms; Cell Line, Tumor
PubMed: 37988194
DOI: 10.1002/adhm.202302746 -
International Journal of Biological... Dec 2023A novel co-hybrid nano-apatite (n-HA) by introducing lignin derivatives (LDs) and alendronate (ALE) was designed to reinforce poly(lactide-co-glycolide) (PLGA). The...
A novel co-hybrid nano-apatite (n-HA) by introducing lignin derivatives (LDs) and alendronate (ALE) was designed to reinforce poly(lactide-co-glycolide) (PLGA). The effect of different addition methods and contents of LDs, lignin derivatives sorts of lignosulfonate (LS), alkali lignin (AL) and carboxymethyl lignin (CML), and the addition order of ALE on the dispersion of hybrid n-HA, and reinforce effective for PLGA were investigated by FTIR, XRD, TEM, TGA, XPS, N adsorption/desorption, zeta potential, dispersion experiments, universal testing machine, SEM, DSC and POM. The results showed that the addition order could regulate the growth of n-HA crystal planes by binding with Ca, and co-hybrid HA by LDs and ALE possessed better dispersion owing to the synergistic effect. Moreover, 10 wt% LS-ALE-n-HA displayed the best reinforce effect, and the tensile strength of composite was 24.43 % higher than that of PLGA, even 15 wt% LS-ALE-n-HA was added, it still exhibited reinforce effect for PLGA. In vitro soaking in simulated body fluid (SBF) results indicated that LS-ALE-n-HA delayed tensile strength reduce of PLGA and promoted bone-like apatite deposition. The cell proliferation results demonstrated that the hybrid n-HA by the introduction of ALE endowed PLGA with better cell adhesion and proliferation.
Topics: Durapatite; Polylactic Acid-Polyglycolic Acid Copolymer; Alendronate; Polyglycolic Acid; Polyglactin 910; Lignin; Lactic Acid
PubMed: 37696379
DOI: 10.1016/j.ijbiomac.2023.126785 -
Frontiers in Medicine 2023Osteoporosis is a silent chronic obstructive pulmonary disease (COPD) comorbidity that is often under-detected. We aimed to study the prevalence and potential predictors...
BACKGROUND
Osteoporosis is a silent chronic obstructive pulmonary disease (COPD) comorbidity that is often under-detected. We aimed to study the prevalence and potential predictors of osteoporosis in COPD. Dynamic changes in bone mass density (BMD) and treatment efficacy of bisphosphonate were also assessed.
METHODS
This prospective cohort study included COPD patients between January 2017 and January 2019. Demographics data, spirometric parameters, and C-reactive protein (CRP) were collected. Bone mineral density (BMD) at the lumbar spine (L2-4) and both femoral necks were measured after enrollment and the 12-month follow-up. Participants were categorized into three groups per the baseline BMD T-score: normal (≥ - 1.0), osteopenia (between -1.0 and - 2.5), and osteoporosis (≤ - 2.5). In the osteoporosis group, alendronate 70 mg/week with vitamin D and calcium was prescribed.
RESULTS
In total, 108 COPD patients were enrolled. The prevalence of osteoporosis and osteopenia were 31.5 and 32.4%, respectively. Advanced age, lower body mass index (BMI), history of exacerbation in the previous year, and high CRP levels were significant predictors of osteoporosis. After 12 months, 35.3% in the osteoporosis group reported new vertebral and femoral fractures, compared to none in the non-osteoporosis group ( < 0.001). In the normal BMD and osteopenia groups showed a further decline in BMD after 12-month. Conversely, the osteoporosis group showed a statistically significant improvement in BMD after anti-resorptive treatment ( < 0.001).
CONCLUSION
The prevalence of osteoporosis was high in Thai COPD patients. Advanced age, lower BMI, history of exacerbation, and high CRP levels were potential predictors. A rapid decline in BMD was observed in COPD patients without treatment.
PubMed: 37614952
DOI: 10.3389/fmed.2023.1214277 -
Advanced Healthcare Materials Oct 2023Restoring bone homeostasis is the key to the treatment of osteoporosis. How to increase osteogenic ability or inhibit osteoclast activity has always been a topic of...
Restoring bone homeostasis is the key to the treatment of osteoporosis. How to increase osteogenic ability or inhibit osteoclast activity has always been a topic of great concern. In recent years, short peptides with biological activity have received great attention in bone repair. However, the application of short peptides is still limited due to the lack of a stable and targeted delivery system. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles modified by alendronate (AL) to transport osteogenic peptides (OGP) (AL-PLGA@P NPs) are designed. Benefiting from the high affinity of AL for hydroxyapatite, AL-PLGA@P NPs have the ability to target bone. In this delivery system, OGP that promotes osteogenesis synergizes with AL, which inhibits osteoclasts, to regulate bone homeostasis, which gives them more advantages in the treatment of osteoporosis. The data shows that nanoparticles can selectively deliver peptides to the bone surface without systemic toxicity. Moreover, nanoparticles can upregulate osteogenesis-related factors (ALP, Runx-2, and BMP2) and downregulate osteoclast-related factors (TRAP and CTSK) in vitro. With AL-PLGA@P NPs, bone microarchitecture and bone mass are improved in ovariectomized osteoporosis rats. Therefore, this study proposes a novel osteoporosis-based drug system that effectively improves bone density.
PubMed: 37562069
DOI: 10.1002/adhm.202300560