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Scientific Reports Sep 2023Nitrogen-containing bisphosphonates (NBPs), compounds that are widely used in the treatment of bone disorders, may cause side effects related to endothelial dysfunction....
Nitrogen-containing bisphosphonates (NBPs), compounds that are widely used in the treatment of bone disorders, may cause side effects related to endothelial dysfunction. The aim of our study was to investigate the effects of chronic 6-day exposure to two common bone-preserving drugs, alendronate and zoledronate, on endothelial function and oxidative metabolism of cultured human endothelial cells (EA.hy926). NBPs reduced cell viability, induced oxidative stress and a pro-inflammatory state and downregulated the prenylation-dependent ERK1/2 signaling pathway in endothelial cells. In addition, NBPs induced increased anaerobic respiration and slightly increased oxidative mitochondrial capacity, affecting mitochondrial turnover through reduced mitochondrial fission. Moreover, by blocking the mevalonate pathway, NBPs caused a significant decrease in the level of coenzyme Q10, thereby depriving endothelial cells of an important antioxidant and mitochondrial electron carrier. This resulted in increased formation of reactive oxygen species (ROS), upregulation of antioxidant enzymes, and impairment of mitochondrial respiratory function. A general decrease in mitochondrial respiration occurred with stronger reducing fuels (pyruvate and glutamate) in NBP-treated intact endothelial cells, and significantly reduced phosphorylating respiration was observed during the oxidation of succinate and especially malate in NBP-treated permeabilized endothelial cells. The observed changes in oxidative metabolism caused a decrease in ATP levels and an increase in oxygen levels in NBP-treated cells. Thus, NBPs modulate the energy metabolism of endothelial cells, leading to alterations in the cellular energy state, coenzyme Q10 redox balance, mitochondrial respiratory function, and mitochondrial turnover.
Topics: Humans; Diphosphonates; Alendronate; Zoledronic Acid; Endothelial Cells; Antioxidants
PubMed: 37758809
DOI: 10.1038/s41598-023-43377-3 -
Journal of Functional Biomaterials Sep 2023Hypertension and estrogen deficiency can affect bone metabolism and therefore increase the risk of osseointegration. Antihypertensive drugs such as losartan not only...
Hypertension and estrogen deficiency can affect bone metabolism and therefore increase the risk of osseointegration. Antihypertensive drugs such as losartan not only control blood pressure but also enhance bone healing. In addition, alendronate sodium is widely used to treat postmenopausal osteoporosis. Hence, we evaluated the effect of systemic antihypertensive and local alendronate coted on implants on osseointegration under hypertensive and estrogen-deficiency conditions. A total of 64 spontaneously hypertensive rats (SHRs) treated with losartan were randomly divided according to the estrogen-deficiency induction by ovariectomy (OVX) or not (SHAM), and whether the implant surface was coated with sodium alendronate (ALE) or not, resulting in four groups: SHR SHAM, SHR SHAM ALE, SHR OVX, and SHR OVX ALE. The removal torque, microcomputed tomography, and epifluorescence microscopy were the adopted analyses. The hypertensive and estrogen-deficiency animals presented a lower removal torque even when treated with alendronate on implant surface. The microcomputed tomography revealed a higher bone volume and bone-to-implant contact in the SHRs than the SHR OVX rats. Epifluorescence showed a decreased mineral apposition ratio in the SHR OVX ALE group. The data presented indicate that estrogen deficiency impairs osseointegration in hypertensive rats; in addition, alendronate coated on the implant surface does not fully reverse this impaired condition caused by estrogen deficiency.
PubMed: 37754885
DOI: 10.3390/jfb14090471 -
Frontiers in Immunology 2023Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure...
Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure HIV-1 infection include "shock and kill" strategies to disrupt latency using small molecules or latency-reversing agents (LRAs) to induce expression of HIV-1 enabling cytotoxic immune cells to eliminate infected cells. The modest success of current LRAs urges the field to identify novel drugs with increased clinical efficacy. Aminobisphosphonates (N-BPs) that include pamidronate, zoledronate, or alendronate, are the first-line treatment of bone-related diseases including osteoporosis and bone malignancies. Here, we show the use of N-BPs as a novel class of LRA: we found in assays using primary cells from ART-suppressed people living with HIV-1 that N-BPs induce HIV-1 from latency to levels that are comparable to the T cell activator phytohemagglutinin (PHA). RNA sequencing and mechanistic data suggested that reactivation may occur through activation of the activator protein 1 signaling pathway. Stored samples from a prior clinical trial aimed at analyzing the effect of alendronate on bone mineral density, provided further evidence of alendronate-mediated latency reversal and activation of immune effector cells. Decay of the reservoir measured by IPDA was however not detected. Our results demonstrate the novel use of N-BPs to reverse HIV-1 latency while inducing immune effector functions. This preliminary evidence merits further investigation in a controlled clinical setting possibly in combination with therapeutic vaccination.
Topics: Humans; HIV Infections; HIV-1; Virus Activation; Virus Latency; Alendronate; HIV Seropositivity
PubMed: 37744358
DOI: 10.3389/fimmu.2023.1219250 -
PloS One 2023Bone disease is highly prevalent in patients with chronic kidney disease (CKD), leading to an increased risk of bone fractures. This is due in part to metabolic...
Bone disease is highly prevalent in patients with chronic kidney disease (CKD), leading to an increased risk of bone fractures. This is due in part to metabolic acid-induced bone dissolution. Bisphosphonates (BPPs) are a potential treatment for inhibiting bone dissolution; however, there are limited studies observing the use of BPPs on acidotic patients. We aimed to determine efficacy of BPPs on maintaining bone health and pH regulation in acid-exposed mice. Using a diet-induced murine model of metabolic acidosis, we examined bone structure, composition, and mechanics as well as blood gases for three groups: control, acidosis, and acidosis + bisphosphonates (acidosis+BPP). Acidosis was induced for 14 days and alendronate was administered every 3 days for the acidosis+BPP group. The administration of BPP had little to no effect on bone structure, mechanics, and composition of the acidosis bones. However, administration of BPP did cause the mice to develop more severe acidosis than the acidosis only group. Overall, we discovered that BPPs may exacerbate acidosis symptoms by inhibiting the release of buffering ions from bone. Therefore, we propose that BPP administration should be carefully considered for those with CKD and that alkali supplementation could help minimize acidifying effects.
Topics: Animals; Mice; Alendronate; Ammonium Chloride; Diphosphonates; Acidosis; Osteolysis; Renal Insufficiency, Chronic
PubMed: 37713420
DOI: 10.1371/journal.pone.0291649 -
Journal of Comparative Effectiveness... Nov 2023To estimate the cost-effectiveness of treating postmenopausal osteoporosis (PMO) with weekly gastro-resistant risedronate 35 mg gastro-resistant tablets (RIS-GR),...
Cost-effectiveness of weekly gastro-resistant risedronate 35 mg, compared with weekly alendronate 70 mg tablets, in the treatment of postmenopausal osteoporosis in Spain.
To estimate the cost-effectiveness of treating postmenopausal osteoporosis (PMO) with weekly gastro-resistant risedronate 35 mg gastro-resistant tablets (RIS-GR), compared with weekly alendronate 70 mg tablets (ALN) in Spain. A probabilistic analysis (second-order Monte Carlo simulation) was performed with a time horizon of 5 years, from the perspective of the Spanish National Health System. The bone fracture probabilities were obtained from a cohort study of 3614 women from USA with PMO treated with RIS-GR (1807) or ALN (1807) (Thomasius, 2022). The pharmacological cost and the cost of fractures were obtained from Spanish sources (€ 2022). The utilities of patients with and without fracture (quality-adjusted life years [QALYs]) were obtained from the medical literature. Compared with ALN, treatment with RIS-GR can avoid 79 fractures (between 75 and 82) every 1000 patients treated, and 0.0119 QALYs would be gained (between 0.0098 and 0.0140) per patient. Additionally, GR-RIS would generate a cost saving per patient of €1994 (€1437-2904) with a probability of 99.7%. The scenario analyses confirmed the stability of the base case results. According to this study, RIS-GR would be the dominant treatment (lower costs with QALY gain) compared with ALN.
Topics: Humans; Female; Alendronate; Osteoporosis, Postmenopausal; Risedronic Acid; Bone Density Conservation Agents; Cost-Benefit Analysis; Cohort Studies; Spain; Etidronic Acid; Fractures, Bone; Quality-Adjusted Life Years
PubMed: 37712635
DOI: 10.57264/cer-2023-0115 -
Heliyon Sep 2023Bisphosphonates are known to induce a severe adverse effect known as medication-related osteonecrosis of the jaw (MRONJ). Previous studies have proven the impact of...
OBJECTIVES
Bisphosphonates are known to induce a severe adverse effect known as medication-related osteonecrosis of the jaw (MRONJ). Previous studies have proven the impact of bisphosphonates on microperfusion; therefore, this study aimed to investigate alendronate-induced microcirculatory reactions in the calvarial periosteum of rats.
STUDY DESIGN
Bone chambers were implanted into 48 Lewis rats. Microhemodynamics, inflammatory parameters, functional capillary density and defect healing were examined after alendronate treatment for two and six weeks using repetitive intravital fluorescence microscopy for two weeks.
RESULTS
Microhemodynamics remained unchanged. In alendronate-treated rats, inflammation was slightly increased, functional capillary density was significantly reduced (day 10: controls 100.45 ± 5.38 cm/cm, two weeks alendronate treatment 44.77 ± 3.55 cm/cm, six weeks alendronate treatment 27.54 ± 2.23 cm/cm) and defect healing was decelerated. The changes in functional capillary density and defect healing were dose-dependent.
CONCLUSION
The bisphosphonate alendronate has a significant negative impact on periosteal microperfusion in vivo. This could be a promising target for the treatment of MRONJ.
PubMed: 37681156
DOI: 10.1016/j.heliyon.2023.e19468 -
Cureus Aug 2023Osteoporosis affects a significant number of postmenopausal women in the United States. Screening is performed using clinical assessments and bone mineral density scans... (Review)
Review
Osteoporosis affects a significant number of postmenopausal women in the United States. Screening is performed using clinical assessments and bone mineral density scans via dual x-ray absorptiometry. Oral therapy is indicated to prevent pathologic fractures in those deemed at increased risk following screening. Bisphosphonates including alendronate, ibandronate, and risedronate are currently first-line oral therapeutics in fracture prevention following the diagnosis of osteoporosis. Hormonal therapies include estrogen-containing therapies, selective estrogen receptor modulators, and other compounds that mimic the effects of estrogen such as tibolone. Lifestyle modifications such as supplementation and physical activity may also contribute to the prevention of osteoporosis and are used as adjuncts to therapy following diagnosis. These therapeutics are limited primarily by their adverse effects. Treatment regimens should be tailored based on significant risk factors demonstrated by patients, adverse effects, and clinical response to treatment. The most severe risk factors relevant to pharmacological selection involve hormone replacement therapies, where concern for venous thrombosis, coronary artery disease, breast, and uterine cancer exist. Bisphosphonates are most commonly associated with gastrointestinal discomfort which may be mitigated with proper administration. Although adverse effects exist, these medications have proven to be efficacious in the prevention of vertebral and non-vertebral fractures in post-menopausal women. Fracture risk should be weighed against the risk of adverse events associated with each of the regimens, with clinical judgment dictating the treatment approach centered around patient goals and experiences.
PubMed: 37664395
DOI: 10.7759/cureus.42870 -
Heliyon Aug 2023Inorganic pyrophosphate (PPi) is the endogenous inhibitor for vascular calcification (VC). The present study was to investigate the effects of adenosine disodium...
Inorganic pyrophosphate (PPi) is the endogenous inhibitor for vascular calcification (VC). The present study was to investigate the effects of adenosine disodium triphosphate (ADTP) and alendronate sodium (AL), two exogenous PPi sources, on the atheromatous calcification (AC) in Apolipoprotein E knockout (ApoE KO) mice. ApoE KO mice were randomly divided into five groups: ApoE KO group, ApoE KO + ADTP (Low) group, ApoE KO + ADTP (High) group, ApoE KO + AL (Low) group and ApoE KO + AL (High) group. The mice in ApoE KO + ADTP (Low) group and ApoE KO + ADTP (High) group were intraperitoneally injected with ADTP with dose of 0.5 and 1.0 mg/kg/day for 2 months respectively. The mice in ApoE KO + AL (Low) group and ApoE KO + AL (High) group were intraperitoneally injected with AL with dose of 0.6 and 1.2 mg/kg/day for 2 months respectively. The age matched C57 mice were used as control group. All ApoE KO and C57 mice were fed with normal chow throughout the experiment. The calcification was evaluated using von Kossa method. The contents of PPi, triglyceride (TG), total cholesterol (TC), high density lipoprotein (HDL) and low density lipoprotein (LDL), tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), interferon-γ (IFN-γ) and interleukin-10 (IL-10) as well as the activity of alkaline phosphatase (ALP) in serum were measured. The results showed that compared with C57 mice, ApoE KO mice developed severe AC accompanied with high levels of TC, TG, LDL, IL-6, TNF-α and IFN-γ in serum and with low levels of PPi and IL-10 in serum. Both ADTP and AL dose-dependently reduced the AC in ApoE KO mice compared with that of ApoE mice, without affecting the contents of lipid profiles. In addition, ADTP and AL increased the contents of PPi and IL-10 while decreased the contents of TNF-α, IL-6 and IFN-γ in serum of ApoE KO mice, having no affection on ALP activity. The results suggested that ADTP and AL reduced AC in ApoE KO mice by increasing the PPi level and regulating the inflammation.
PubMed: 37654451
DOI: 10.1016/j.heliyon.2023.e19214 -
Journal of Pharmacy & Bioallied Sciences Jul 2023Class II mandibular furcation defect is a periodontal condition characterized by a cul-de-sac lesion, a definite parallel constituent with only a portion of alveolar...
Class II mandibular furcation defect is a periodontal condition characterized by a cul-de-sac lesion, a definite parallel constituent with only a portion of alveolar bone remaining intact. There may be involvement of vertical bone loss. Local drug deliveries such as Boric acid, alendronate gel, and other drugs exhibited anti-inflammatory, antibacterial & osteoblastic differentiation activity. The present systematic review compares the drugs based on their outcomes and pharmacological action. To analzse & compare various forms of local drug delivery systems on a class II furcation. A search was conducted using PubMed, Google scholar, science direct, and Pub Med central using MeSH terms - local drug delivery in periodontics, boric acid in the management of class II mandibular furcation, simvastatin in the treatment of furcation. A total of 560 articles were screened; 58 out of 560 were full-text articles accessed for eligibility, and five articles were included in the systematic review. PRISMA guidelines were used for reporting this review. In addition, five randomized controlled trials were enclosed and used in this systematic review. The various local drugs used in treating class II mandibular furcation defects are effective in the prevention of bleeding on probing, bone resorption, gingival bleeding index and increase in the bone fill, and microbial deposit removal. The managing of class II mandibular furcation defect with the drugs mentioned in this review can be effective by reducing several clinical parameters such as bleeding on probing, gingival indices, osteoblastic differentiation, bone fill, etc., Considering the results of the studies, it can be concluded that it can be used as a therapeutic therapy against class II furcation defects with positive outcomes.
PubMed: 37654351
DOI: 10.4103/jpbs.jpbs_572_22 -
Journal of Pharmacy & Bioallied Sciences Jul 2023The chief aim in managing periodontal diseases is the elimination of causative factors that may vary from pathogens to physical parameters. In the current systematic...
INTRODUCTION
The chief aim in managing periodontal diseases is the elimination of causative factors that may vary from pathogens to physical parameters. In the current systematic review, the effectiveness of "" as a supplement to ")" in the management of periodontitis is calibrated from the previous studies.
MATERIALS AND METHODS
An extensive online search in the various databanks of EMBASE, Medline, Pubmed, and Scopus was conducted. The keywords searched were "Probing depth (PD)" which was the main endpoint, and variations in " (CAL)" and/or " (BD) fill" were the secondary variants that were searched for in the current study. The data collected were tabulated and compared using the means and the standard deviations. Using the random effect method the mean variations and the confidence intervals (95%) of the parameters were assessed.
RESULTS
Eight studies were finalized. Alendronate was utilized as a supplement to SRP in seven studies, four of which employed topical administration and three of which used oral alendronate. A substantial grade of heterogeneity for Probing depth ( < 0.0001), Clinical Attachment Level ( = 0.007), and Bone Defect fill ( < 0.0001) was observed amongst groups when comparing the properties of adjunctive BT to SRP alone. In comparison to SRP alone, SRP with bisphosphonate treatment significantly reduced PD ( = 0.002), increased CAL ( = 0.008), and filled BD ( < 0.001).
CONCLUSIONS
Although BT as an adjunct appears to be successful in treating periodontitis, its practical applicability is questionable due to the possibility of developing jaw osteonecrosis and the short-range follow-up of the research.
PubMed: 37654331
DOI: 10.4103/jpbs.jpbs_504_22