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Biomedicine & Pharmacotherapy =... May 2024Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. The aim of this study was to investigate the therapeutic potential of vitamin C,...
Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. The aim of this study was to investigate the therapeutic potential of vitamin C, glutamine, mesalazine, hydralazine, and alendronate as new drug candidates for the treatment of letrozole-induced PCOS in female Wistar rats. PCOS was induced in rats by intramuscular injection of estradiol valerate (2 mg/kg body weight for 28 days). The rats then received normal saline (PCOS group), letrozole (0.5 mg/kg), vitamin C (100 mg/kg), glutamine (1000 mg/kg), mesalazine (200 mg/kg), hydralazine (30 mg/kg), and alendronate (17.5 mg/kg). Serum testosterone, LH, FSH, estradiol and progesterone levels were determined by ELISA method. H&E staining was used for histological analysis in the ovarian tissues. The groups treated with hydralazine and alendronate, show a significant decrease in testosterone, LH hormone, cystic and atretic follicles, and a significant increase in the number of single layer, multilayer, antral, graafian follicles and the volume of corpus luteum as compared to the PCOS group. Hydrolazine and alendronate appear to be effective in restoring folliculogenesis and increasing ovulation in PCOS rat. So that the natural process of ovulation and the improvement of the histology of polycystic ovaries and its shift towards healthy and active ovaries were observed. This finding supports the potential beneficial effect of hydrolazine and alendronate on improving PCOS complication.
Topics: Animals; Female; Rats; Alendronate; Aromatase Inhibitors; Disease Models, Animal; Estradiol; Hydralazine; Letrozole; Luteinizing Hormone; Ovary; Polycystic Ovary Syndrome; Rats, Wistar; Testosterone
PubMed: 38552442
DOI: 10.1016/j.biopha.2024.116504 -
Journal of Orthopaedic Surgery and... Mar 2024Patellofemoral osteoarthritis (PFJOA) is a subtype of knee OA, which is one of the main causes of anterior knee pain. The current study found an increased prevalence of...
Effects of alendronate on cartilage lesions and micro-architecture deterioration of subchondral bone in patellofemoral osteoarthritic ovariectomized rats with patella-baja.
BACKGROUND
Patellofemoral osteoarthritis (PFJOA) is a subtype of knee OA, which is one of the main causes of anterior knee pain. The current study found an increased prevalence of OA in postmenopausal women, called postmenopausal OA. Therefore, we designed the ovariectomized rat model of patella baja-induced PFJOA. Alendronate (ALN) inhibits osteoclast-mediated bone loss, and has been reported the favorable result of a potential intervention option of OA treatment. However, the potential effects of ALN treatment on PFJOA in the ovariectomized rat model are unknown and need further investigation prior to exploration in the clinical research setting. In this study, the effects of ALN on articular cartilage degradation and subchondral bone microstructure were assessed in the ovariectomized PFJOA rat model for 10 weeks.
METHODS
Patella baja and estrogen withdrawal were induced by patellar ligament shortening (PLS) and bilateral ovariectmomy surgeries in 3-month-old female Sprague-Dawley rats, respectively. Rats were randomly divided into five groups (n = 8): Sham + V; OVX + V, Sham + PLS + V, OVX + PLS + V, OVX + PLS + ALN (ALN: 70 μg/kg/week). Radiography was performed to evaluate patellar height ratios, and the progression of PFJOA was assessed by macroscopic and microscopic analyses, immunohistochemistry and micro-computed tomography (micro-CT).
RESULTS
Our results found that the patella baja model prepared by PLS can successfully cause degeneration of articular cartilage and subchondral bone, resulting in changes of PFJOA. OVX caused a decrease in estrogen levels in rats, which aggravated the joint degeneration caused by PFJOA. Early application of ALN can delay the degenerative changes of articular cartilage and subchondral bone microstructure in castrated PFJOA rat to a certain extent, improve and maintain the micrometabolism and structural changes of cartilage and subchondral bone.
CONCLUSION
The early application of ALN can delay the destruction of articular cartilage and subchondral bone microstructure in castrated PFJOA rat to a certain extent.
Topics: Humans; Rats; Female; Animals; Infant; Alendronate; Rats, Sprague-Dawley; Patella; X-Ray Microtomography; Osteoarthritis, Knee; Cartilage, Articular; Bone Resorption; Disease Models, Animal; Estrogens
PubMed: 38528611
DOI: 10.1186/s13018-024-04677-0 -
JBMR Plus Apr 2024Bisphosphonates frequently provoke a cytokine-driven acute clinical response (ACR) characterized by fever, chills, arthralgias, and myalgias. More rarely, an association...
Bisphosphonates frequently provoke a cytokine-driven acute clinical response (ACR) characterized by fever, chills, arthralgias, and myalgias. More rarely, an association between aminobisphosphonates, such as alendronate and zoledronic acid, and rheumatologic and/or immune-mediated syndromes (RIMS) has been described. Herein we report 2 patients, one with a prior history of rheumatic disease and one without, who developed giant cell arteritis meeting the American College of Rheumatology 2022 criteria following zoledronic acid infusion. We subsequently review existing mechanistic and clinical literature supporting this link. The duration of symptoms and elevation of inflammatory markers may serve as indicators for differentiating between the more common ACR and less frequent but potentially morbid RIMS. Although the benefit of bisphosphonates will outweigh the risk of RIMS for most patients with high fracture risk, clinicians should be aware of this phenomenon to assist earlier diagnosis and treatment in affected individuals.
PubMed: 38523665
DOI: 10.1093/jbmrpl/ziae015 -
Biological & Pharmaceutical Bulletin 2024Osteoporosis is caused by imbalance between osteogenesis and bone resorption, thus, osteogenic drugs and resorption inhibitors are used for treatment of osteoporosis....
Osteoporosis is caused by imbalance between osteogenesis and bone resorption, thus, osteogenic drugs and resorption inhibitors are used for treatment of osteoporosis. The present study examined the effects of (R)-4-(1-hydroxyethyl)-3-{4-[2-(tetrahydropyran-4-yloxy)ethoxy]phenoxy}benzamide (KY-273), a diphenyl ether derivative, on CDK8/19 activity, osteoblast differentiation and femoral bone using micro-computed tomography in female rats. KY-273 potently inhibited CDK8/19 activity, promoted osteoblast differentiation with an increase in alkaline phosphatase (ALP) activity, and gene expression of type I collagen, ALP and BMP-4 in mesenchymal stem cells (ST2 cells). In female rat femur, ovariectomy decreased metaphyseal trabecular bone volume (Tb.BV), mineral content (Tb.BMC), yet had no effect on metaphyseal and diaphyseal cortical bone volume (Ct.BV), mineral content (Ct.BMC) and strength parameters (BSPs). In ovaries-intact and ovariectomized rats, oral administration of KY-273 (10 mg/kg/d) for 6 weeks increased metaphyseal and diaphyseal Ct.BV, Ct.BMC, and BSPs without affecting medullary volume (Med.V), but did not affect Tb.BV and Tb.BMC. In ovariectomized rats, alendronate (3 mg/kg/d) caused marked restoration of Tb.BV, Tb.BMC and structural parameters after ovariectomy, and increased metaphyseal but not diaphyseal Ct.BV, Ct.BMC, and BSPs. In ovaries-intact and ovariectomized rats, by the last week, KY-273 increased bone formation rate/bone surface at the periosteal but not the endocortical side. These findings indicate that KY-273 causes osteogenesis in cortical bone at the periosteal side without reducing Med.V. In conclusion, KY-273 has cortical-bone-selective osteogenic effects by osteoblastogenesis via CDK8/19 inhibition in ovaries-intact and ovariectomized rats, and is an orally active drug candidate for bone diseases such as osteoporosis in monotherapy and combination therapy.
Topics: Humans; Rats; Female; Animals; Osteogenesis; Bone Density; Rats, Sprague-Dawley; X-Ray Microtomography; Osteoporosis; Ovariectomy; Mesenchymal Stem Cells; Minerals; Cyclin-Dependent Kinase 8
PubMed: 38508765
DOI: 10.1248/bpb.b23-00834 -
Immunology Letters Jun 2024Bacillus Calmette-Guérin (BCG) vaccination induces memory characteristics in innate immune cells and their progenitors, a process called trained immunity mediated by... (Randomized Controlled Trial)
Randomized Controlled Trial
Bacillus Calmette-Guérin (BCG) vaccination induces memory characteristics in innate immune cells and their progenitors, a process called trained immunity mediated by epigenetic and metabolic reprogramming. Cholesterol synthesis plays an amplifying role in trained immunity through mevalonate release. Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, can inhibit cholesterol synthesis. We explored their effects on trained immunity induced by BCG in a placebo-controlled clinical study (NL74082.091.20) in young, healthy individuals. Participants receiving single-dose oral alendronate on the day of BCG vaccination had more neutrophils and plasma cells one month after treatment. Alendronate led to reduced proinflammatory cytokine production by PBMCs stimulated with heterologous bacterial and viral stimuli one month later. Furthermore, the addition of alendronate transcriptionally suppressed multiple immune response pathways in PBMCs upon stimulation. Our findings indicate that N-BPs modulate the long-lasting effects of BCG vaccination on the cytokine production capacity of innate immune cells.
Topics: Humans; BCG Vaccine; Cytokines; Alendronate; Male; Adult; Female; Young Adult; Vaccination; Leukocytes, Mononuclear; Immunity, Innate; Healthy Volunteers; Immunologic Memory
PubMed: 38479480
DOI: 10.1016/j.imlet.2024.106851 -
European Journal of Medicinal Chemistry Apr 2024The antitumoral activity of hydroxymethylene bisphosphonates (HMBP) such as alendronate or zoledronate is hampered by their exceptional bone-binding properties and their...
The antitumoral activity of hydroxymethylene bisphosphonates (HMBP) such as alendronate or zoledronate is hampered by their exceptional bone-binding properties and their short plasmatic half-life which preclude their accumulation in non-skeletal tumors. In this context, the use of lipophilic prodrugs represents a simple and straightforward strategy to enhance the biodistribution of bisphosphonates in these tissues. We describe in this article the synthesis of light-responsive prodrugs of HMBP alendronate. These prodrugs include lipophilic photo-removable nitroveratryl groups which partially mask the highly polar alendronate HMBP scaffold. Photo-responsive prodrugs of alendronate are stable in physiological conditions and display reduced toxicity compared to alendronate against MDA-MB-231 cancer cells. However, the antiproliferative effect of these prodrugs is efficiently restored after cleavage of their nitroveratryl groups upon exposure to UV light. In addition, substitution of alendronate with such photo-responsive substituents drastically reduces its bone-binding properties, thereby potentially improving its biodistribution in soft tissues after i.v. administration. The development of such lipophilic photo-responsive prodrugs is a promising approach to fully exploit the anticancer effect of HMBPs on non-skeletal tumors.
Topics: Humans; Alendronate; Prodrugs; Tissue Distribution; Diphosphonates; Neoplasms
PubMed: 38460269
DOI: 10.1016/j.ejmech.2024.116307 -
BMC Pediatrics Mar 2024Fanconi-Bickel syndrome is characterized by hepatorenal disease caused by anomalous glycogen storage. It occurs due to variants in the SLC2A2 gene. We present a male...
BACKGROUND
Fanconi-Bickel syndrome is characterized by hepatorenal disease caused by anomalous glycogen storage. It occurs due to variants in the SLC2A2 gene. We present a male patient of 2 years 7 months old, with failure to thrive, hepatomegaly, metabolic acidosis, hypophosphatemia, hypokalemia, hyperlactatemia.
RESULTS
Exome sequencing identified the homozygous pathogenic variant NM_000340.2(SLC2A2):c.1093 C > T (p.Arg365Ter), related with Fanconi-Bickel syndrome. He received treatment with bicarbonate, amlodipine, sodium citrate and citric acid solution, enalapril, alendronate and zolendronate, and nutritional management with uncooked cornstarch, resulting in an improvement of one standard deviation in weight and height.
CONCLUSIONS
The importance of knowing the etiology in rare genetic disease is essential, not only to determine individual and familial recurrence risk, but also to establish the treatment and prognosis; in this sense, access to a new genomic technology in low- and middle-income countries is essential to shorten the diagnostic odyssey.
Topics: Humans; Male; Fanconi Syndrome; High-Throughput Nucleotide Sequencing; Homozygote; Prognosis; Child, Preschool
PubMed: 38454379
DOI: 10.1186/s12887-024-04641-1 -
Radiology Case Reports May 2024Paget's disease of bone is a disorder of osteoclasts which hampers the physiological process of bone remodeling. It is the most common metabolic orthopedic disease in...
Paget's disease of bone is a disorder of osteoclasts which hampers the physiological process of bone remodeling. It is the most common metabolic orthopedic disease in the Caucasian populace; we report the diagnosis of Paget's disease of bone in a South-Asian male in his early 50s with a history of gastrointestinal symptoms, weight loss and back pain. An alkaline phosphatase level of 1104 IU/L was noted. A 3-phase bone scan showed noncontiguous heterogenous nuclear uptake. After exhaustive evaluation, the patient was diagnosed with Paget's disease of bone. Despite the disease activity being mitigated by alendronate and monitored by ALP levels within normal range per protocol, the patient had compression fractures of the vertebrae requiring early reinitiation of oral bisphosphonates. This raised doubts about the efficacy of metabolic marker-based management in Paget's disease of bone.
PubMed: 38434784
DOI: 10.1016/j.radcr.2024.01.037 -
Journal of Feline Medicine and Surgery Feb 2024Cats with ionized hypercalcemia that were fed diets with either more than 200 mg calcium per 100 kilocalories (kcal), a calcium:phosphorus (Ca:P) ratio greater than...
CASE SERIES SUMMARY
Cats with ionized hypercalcemia that were fed diets with either more than 200 mg calcium per 100 kilocalories (kcal), a calcium:phosphorus (Ca:P) ratio greater than 1.4:1 or both, based on diet history, were included in this case series. Ionized hypercalcemia was documented at least twice in all cats before enrollment. Cats were referred for evaluation of ionized hypercalcemia (n = 5) or were incidentally found to have ionized hypercalcemia (n = 5). After medical workups, cats were diagnosed with either idiopathic hypercalcemia (IHC; n = 7) or chronic kidney disease (n = 3). Cats receiving medications to treat IHC (eg, alendronate, corticosteroids) were excluded. Nutritional recommendations were made to transition the cats to diets with less thn 200 mg calcium per 100 kcal and a Ca:P ratio less than 1.4:1. Ionized calcium (iCa) concentrations were rechecked in all cats, with a median recheck time of 9 weeks (range 3-20). Of the 10 cats, nine (90%) had a decrease in iCa. Of the 10 cats, six (60%) became normocalcemic after the diet change, three (30%) had a partial response and one (10%) did not respond. Of the four cats that did not achieve normocalcemia with a change in diet, two (50%) received chia seeds (1-2 g per day), and at the next recheck, both cats' iCa concentrations had normalized. Three cats had a long-term follow-up. Ionized normocalcemia was maintained for at least two consecutive follow-up visits over a median follow-up period of 33 weeks (range 12-34).
RELEVANCE AND NOVEL INFORMATION
Dietary calcium concentrations and the dietary Ca:P ratio appear to be important variables in considering nutritional approaches for hypercalcemic cats.
Topics: Cats; Animals; Hypercalcemia; Calcium; Renal Insufficiency, Chronic; Alendronate; Cat Diseases
PubMed: 38415620
DOI: 10.1177/1098612X241229811 -
Orthopedic Research and Reviews 2024While osteoporosis increases the risk of fragility fractures, bisphosphonate has been proven to increase bone strength and reduce the risk of vertebral and non-vertebral...
BACKGROUND
While osteoporosis increases the risk of fragility fractures, bisphosphonate has been proven to increase bone strength and reduce the risk of vertebral and non-vertebral fractures. In addition to its efficacy, substituting the brand with generic medication is a strategy to optimize healthcare expenditures. This study aimed to evaluate the efficacy of generic alendronate treatment and assess potential adverse events in patients with osteoporosis.
MATERIALS AND METHODS
A retrospective review was conducted on 120 patients who met the indications for osteoporosis treatment, received weekly generic alendronate (70 mg) for >1 year, and underwent evaluation through standard axial dual-energy X-ray absorptiometry (DXA). The outcomes of this study were the percent change in bone mineral density (BMD) at the lumbar spine, femoral neck, and total hip after one year of treatment. The major adverse events occurring during medication that led to the discontinuation of drug administration were documented.
RESULTS
Most patients were female (96.7%) with an average age of 69.0 ± 9.3 years. The percent change in BMD increased at all sites after one year of generic alendronate treatment (lumbar spine: 5.6 ± 13.7, -value <0.001; femoral neck: 2.3 ± 8.3, -value = 0.023; total hip: 2.1 ± 6.2, -value = 0.003), with over 85% of patients experiencing increased or stable BMD. Three patients discontinued the medication due to adverse effects: two had dyspepsia, and one had persistent myalgia.
CONCLUSION
Generic alendronate may be considered an effective antiresorptive agent for osteoporosis treatment with a low incidence of adverse effects.
PubMed: 38410814
DOI: 10.2147/ORR.S445202