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Annals of Pediatric Endocrinology &... Feb 2024Nonambulatory pediatric patients may have low bone mineral density (BMD) and increased risk of pathologic fractures. Though bisphosphonate therapy is the mainstream...
PURPOSE
Nonambulatory pediatric patients may have low bone mineral density (BMD) and increased risk of pathologic fractures. Though bisphosphonate therapy is the mainstream medical intervention in these children, clinical data regarding this treatment are limited. Therefore, this study aimed to evaluate the effectiveness and safety of bisphosphonate therapy in such children.
METHODS
We conducted a retrospective study of 21 nonambulatory children (Gross Motor Function Classification System level V) with BMD z-score ≤ -2.0 who were treated with intravenous pamidronate for at least 1 year. These patients received pamidronate every 4 months at a dose of 1.0 to 3.0 mg/kg for each cycle and had regular follow-ups for at least 1 year. The main outcome measures were changes in BMD, risk rate of fracture, biochemical data, and adverse events.
RESULTS
The average duration of pamidronate treatment was 2.0±0.9 years, and the mean cumulative dose of pamidronate according to body weight was 7.7±2.5 mg/kg/yr. After treatment, the mean lumbar spine bone mineral content, BMD, and height-for-age-z-score-adjusted BMD z-score (BMDhazZ) significantly improved. The relative risk of fracture after treatment was 0.21 (p=0.0032), suggesting that pamidronate treatment reduced fracture incidence significantly. The increase in the average dose per body weight in each cycle significantly increased the changes in BMDhazZ.
CONCLUSION
Pamidronate treatment improved the bone health of nonambulatory children with low bone density without any significant adverse events. Independent of cumulative dosage and duration of treatment, the effectiveness of pamidronate increased significantly with an increase in the average dose per body weight in subsequent cycles.
PubMed: 38461805
DOI: 10.6065/apem.2346028.014 -
Bone May 2024Osteogenesis imperfecta (OI) is a congenital disease comprising a heterogeneous group of inherited connective tissue disorders. The main treatment in children is...
INTRODUCTION
Osteogenesis imperfecta (OI) is a congenital disease comprising a heterogeneous group of inherited connective tissue disorders. The main treatment in children is bisphosphonate therapy. Previous animal studies have shown that bisphosphonates delay tooth eruption. The aim of this study is to determine whether patients with OI treated with pamidronate and/or zoledronic acid have a delayed eruption age compared to a control group of healthy children.
METHODS
An ambispective longitudinal cohort study evaluating the age of eruption of the first stage mixed dentition in a group of children with OI (n = 37) all treated with intravenous bisphosphonates compared with a group of healthy children (n = 89). Within the study group, the correlation (Pearson correlation test) between the type of medication administered (pamidronate and/or zoledronic acid) and the chronology of tooth eruption is established, as well as the relationship between the amount of cumulative dose received and tooth eruption.
RESULTS
The age of eruption of the study group was significantly delayed compared to the age of eruption of the control group for molars and lateral incisors (p < 0.05). Patients who received higher cumulative doses had a delayed eruption age compared to those with lower cumulative doses (p < 0.05). There is a high positive correlation between age of delayed tooth eruption and Zoledronic acid administration.
CONCLUSION
Patients with OI have a delayed eruption of the 1st stage mixed dentition compared to a control group of healthy children. This delayed eruption is directly related to the cumulative dose of bisphosphonates and the administration of zoledronic ac.
Topics: Child; Animals; Humans; Pamidronate; Zoledronic Acid; Osteogenesis Imperfecta; Tooth Eruption; Bone Density Conservation Agents; Longitudinal Studies; Diphosphonates; Bone Density
PubMed: 38458305
DOI: 10.1016/j.bone.2024.117069 -
Toxicology in Vitro : An International... May 2024Podocytes play a critical role in the formation and maintenance of the glomerular filtration barrier and injury to these cells can lead to a breakdown of the glomerular...
Podocytes play a critical role in the formation and maintenance of the glomerular filtration barrier and injury to these cells can lead to a breakdown of the glomerular barrier causing permanent damage leading to progressive chronic kidney disease. Matured podocytes have little proliferative potential, which makes them critical cells from a health perspective, but also challenging cells to maintain in vitro. Differentiating podocyte-like cells from induced pluripotent stem cells (iPSC) provides a novel and continuous source of cells. Here, we investigated the effect of a 24-h exposure to eight compounds, including the known glomerular toxins doxorubicin and pamidronate, on transcriptomic alterations in iPSC derived podocytes. Doxorubicin (50 nM), pamidronate (50 μM), sodium arsenite (10 μM), and cyclosporine A (15 μM) had a strong impact on the transcriptome, gentamicin (450 μg/ml), lead chloride (15 μM) and valproic acid (500 μM) had a mild impact and busulfan (50 μM) exhibited no impact. Gene alterations and pathways analysis provided mechanistic insight for example, doxorubicin exposure affected the p53 pathway and dedifferentiation, pamidronate activated several pathways including HIF1alpha and sodium arsenite up-regulated oxidative stress and metal responses. The results demonstrate the applicability of iPSC derived podocytes for toxicological and mechanistic investigations.
Topics: Humans; Podocytes; Induced Pluripotent Stem Cells; Transcriptome; Xenobiotics; Pamidronate; Doxorubicin; Gene Expression Profiling; Sodium Compounds; Arsenites
PubMed: 38447685
DOI: 10.1016/j.tiv.2024.105804 -
Physical Chemistry Chemical Physics :... Mar 2024Carbonic anhydrase IX (CA IX) is a subtype of the human carbonic anhydrase (CA) family and exhibits high expression in various solid tumors, rendering it a promising...
Carbonic anhydrase IX (CA IX) is a subtype of the human carbonic anhydrase (CA) family and exhibits high expression in various solid tumors, rendering it a promising target for tumor therapy. Currently, marketed carbonic anhydrase inhibitors (CAIs) are primarily composed of sulfonamides derivatives, which may have impeded their potential for further expansion. Therefore, we have developed a structure-based virtual screening approach to explore novel CAIs exhibiting distinctive structures and anti-tumor potential in the FDA database. experiments demonstrated that 3-pyridinemethanol (0.42 μM), procodazole (8.35 μM) and pamidronic acid (8.51 μM) exhibited inhibitory effects on CA IX activity. The binding stability and interaction mode between the CA IX and the hit compounds are further investigated through molecular dynamics simulations and binding free energy calculations. Furthermore, the ADME/Tox prediction results indicated that these compounds exhibited favorable pharmacological properties and minimal toxic side effects. Our study successfully applied computational strategies to discover three non-sulfonamide inhibitors of carbonic anhydrase IX (CA IX) that demonstrate inhibitory activity . These findings have significant implications for the development of CA IX inhibitors and anti-tumor drugs, contributing to their progress in the field.
Topics: Humans; Carbonic Anhydrase IX; Carbonic Anhydrase Inhibitors; Structure-Activity Relationship; Carbonic Anhydrases; Neoplasms; Sulfonamides; Sulfanilamide; Molecular Structure
PubMed: 38420672
DOI: 10.1039/d3cp05846h -
Annals of Geriatric Medicine and... Jun 2024Bisphosphonates are commonly used to treat osteoporosis. While renal toxicity is common with pamidronate and zoledronate, few ibandronate-related cases are reported. We...
Bisphosphonates are commonly used to treat osteoporosis. While renal toxicity is common with pamidronate and zoledronate, few ibandronate-related cases are reported. We describe a rare case of ibandronate-associated nephrotoxicity. An 88-year-old woman was admitted for edema. She had been receiving intravenous ibandronate treatment for postmenopausal osteoporosis and had no other diagnosed diseases. She was presented with proteinuria, hypoalbuminemia (1.9 g/dL), and an elevated serum creatinine level (1.8 mg/dL). Renal biopsy revealed podocyte disease, favoring a diagnosis of focal segmental glomerulosclerosis. She was treated with diuretics, tacrolimus, and fimasartan. Steroids were avoided due to severe osteoporosis. Three months later, the edema had subsided and the laboratory findings had improved (serum albumin 3.5 g/dL, serum creatinine 0.97 mg/dL). This case emphasizes the importance of careful monitoring of proteinuria and renal function during ibandronate treatment. In older adult patients, kidney biopsy and immunosuppressive treatment may be considered based on physical activity and underlying diseases.
PubMed: 38383148
DOI: 10.4235/agmr.23.0195 -
Frontiers in Endocrinology 2023Osteoporosis in childhood distinguishes itself from adulthood in four important ways: 1) challenges in distinguishing otherwise healthy children who have experienced... (Review)
Review
Osteoporosis in childhood distinguishes itself from adulthood in four important ways: 1) challenges in distinguishing otherwise healthy children who have experienced fractures due to non-accidental injury or misfortunate during sports and play from those with an underlying bone fragility condition; 2) a preponderance of monogenic "early onset" osteoporotic conditions that unveil themselves during the pediatric years; 3) the unique potential, in those with residual growth and transient bone health threats, to reclaim bone density, structure, and strength without bone-targeted therapy; and 4) the need to benchmark bone health metrics to constantly evolving "normal targets", given the changes in bone size, shape, and metabolism that take place from birth through late adolescence. On this background, the pediatric osteoporosis field has evolved considerably over the last few decades, giving rise to a deeper understanding of the discrete genes implicated in childhood-onset osteoporosis, the natural history of bone fragility in the chronic illness setting and associated risk factors, effective diagnostic and monitoring pathways in different disease contexts, the importance of timely identification of candidates for osteoporosis treatment, and the benefits of early (during growth) rather than late (post-epiphyseal fusion) treatment. While there has been considerable progress, a number of unmet needs remain, the most urgent of which is to move beyond the monotherapeutic anti-resorptive landscape to the study and application of anabolic agents that are anticipated to not only improve bone mineral density but also increase long bone cross-sectional diameter (periosteal circumference). The purpose of this review is to provide a practical guide to the diagnosis and management of osteoporosis in children presenting to the clinic with fragility fractures, one that serves as a step-by-step "how to" reference for clinicians in their routine clinical journey. The article also provides a sightline to the future, emphasizing the clinical scenarios with the most urgent need for an expanded toolbox of effective osteoporosis agents in childhood.
Topics: Humans; Adolescent; Child; Adult; Osteoporosis; Bone Density; Fractures, Bone; Bone Density Conservation Agents; Risk Factors
PubMed: 38374961
DOI: 10.3389/fendo.2023.1266986 -
Frontiers in Veterinary Science 2024Zoledronic acid (ZOL) is a third-generation bisphosphonate with a higher affinity for bone resorption areas than earlier bisphosphonates (i.e., pamidronate, PAM). In...
INTRODUCTION
Zoledronic acid (ZOL) is a third-generation bisphosphonate with a higher affinity for bone resorption areas than earlier bisphosphonates (i.e., pamidronate, PAM). In human medicine, ZOL provides improved bone pain relief and prolonged time to skeletal-related events compared to its older generational counterparts. Preclinical studies have investigated its role as an anti-neoplastic agent, both independently and synergistically, with radiation therapy (RT). ZOL and RT act synergistically in several neoplastic human cell lines: prostate, breast, osteosarcoma, and fibrosarcoma. However, the exact mechanism of ZOL's radiosensitization has not been fully elucidated.
METHODS
We investigated ZOL's ability to induce apoptosis in canine osteosarcoma cell lines treated with various doses of megavoltage external beam radiotherapy. Second, we evaluated cell cycle arrest in ZOL-treated cells to assess several neo-adjuvant time points. Finally, we treated 20 dogs with naturally occurring appendicular OS with 0.1 mg/kg ZOL IV 24 h before receiving 8 Gy of RT (once weekly fraction x 4 weeks).
RESULTS
We found that apoptosis was increased in all ZOL-treated cell lines compared to controls, and the combination of ZOL and RT resulted in dissimilar apoptosis between Abrams and D-17 and HMPOS cell lines. Cell cycle arrest (G2/M phase) was minimal and variable between cell lines but perhaps greatest at 48 h post-ZOL treatment. Only 10% of dogs treated with ZOL and RT developed pathologic fractures, compared to 44% of dogs historically treated with PAM and RT ( = 0.027).
DISCUSSION
ZOL and RT appear to be a well-tolerated combination treatment scheme for non-surgical candidates; future studies must elucidate the ideal timing of ZOL.
PubMed: 38362299
DOI: 10.3389/fvets.2024.1237084 -
Drug Development Research Feb 2024We conducted this paper to decipher the efficacy of the combined chemotherapy of zoledronic acid and pamidronate in treating bone metastases from nonsmall cell lung...
Combined chemotherapy of zoledronic acid and pamidronate in the treatment of bone metastases from nonsmall cell lung cancer and the effects on pain stress and bone metabolic indices.
OBJECTIVE
We conducted this paper to decipher the efficacy of the combined chemotherapy of zoledronic acid and pamidronate in treating bone metastases from nonsmall cell lung cancer (NSCLC) and the effects on pain stress and bone metabolic indices.
METHODS
Patients with bone metastases from NSCLC were allocated into Group A and Group B. Patients in the Group A were administrated with pamidronate combined chemotherapy and patients in the Group B were administrated with zoledronic acid combined chemotherapy. The efficacy, pain symptom scores, quality of life scores, serum inflammatory factor, serum bone metabolic indices, serum pain stress indicators, and the occurrence of adverse effects were compared in patients of the two groups.
RESULTS
The total effective rate of treatment was higher in the Group B than in the Group A. After treatment, reduced Numerical Rating Scale scores and elevated Karnofsky Performance Score score, reduced serum levels of N-terminal mid-fragment of osteocalcin, N-terminal propeptide of type I procollagen, bone-specific alkaline phosphatase, and type I collagen hydroxyl terminal peptide β special sequence, reduced serum levels of C-reactive protein, procalcitonin, tumor necrosis factor-α, and interleukin-6, as well as decreased levels of bradykinin, substance P, neuropeptide Y, and β-endorphin were found in the Group B versus the Group A. No notable difference was witnessed in the rate of adverse reactions between the Group A and the Group B.
CONCLUSION
Zoledronic acid combined with chemotherapy can effectively treat bone metastases of NSCLC and improve pain stress and bone metabolic status, which has value that can be promoted and applied in clinical treatment.
Topics: Humans; Zoledronic Acid; Carcinoma, Non-Small-Cell Lung; Pamidronate; Quality of Life; Lung Neoplasms; Bone Neoplasms
PubMed: 38349271
DOI: 10.1002/ddr.22147 -
Proceedings (Baylor University. Medical... 2024Approximately 70% of multiple myeloma patients develop pathologic fractures. Osteoclast inhibitors can provide reduction in vertebral fractures with an increased risk of...
BACKGROUND
Approximately 70% of multiple myeloma patients develop pathologic fractures. Osteoclast inhibitors can provide reduction in vertebral fractures with an increased risk of osteonecrosis of the jaw (ONJ). ONJ associated with currently used osteoclast inhibitors causes significant morbidity, often from delayed diagnosis and ineffective treatment.
METHODS
The TriNetX Diamond Network was used to create patient cohorts for each medication: alendronate, pamidronate, zoledronic acid, and denosumab. All patients had a diagnosis of multiple myeloma as identified by International Classification of Disease-10 (ICD-10) code C90.0. Pamidronate, zoledronic acid, and denosumab were each compared to alendronate for 5-year incidence of pathologic vertebral fracture (ICD-10 M48.50XA) and development of ONJ.
RESULTS
The 5-year risk of pathologic vertebral fracture was not statistically different between alendronate versus pamidronate, zoledronic acid, and denosumab. However, the 5-year risk of ONJ was significantly higher for both zoledronic acid and denosumab (relative risk 4.85 and 2.9, respectively).
CONCLUSION
This study shows that fracture reduction risk is comparable for all four treatments in multiple myeloma patients, but ONJ risk is lowest for alendronate and pamidronate. Overall, these data support the continued use of pamidronate and alendronate in multiple myeloma patients.
PubMed: 38343457
DOI: 10.1080/08998280.2023.2298667 -
Journal of Orthopaedic Science :... Feb 2024Periprosthetic bone loss following total hip arthroplasty (THA) threatens prosthesis stability. This systematic review and network meta-analysis aimed to compare the...
BACKGROUND
Periprosthetic bone loss following total hip arthroplasty (THA) threatens prosthesis stability. This systematic review and network meta-analysis aimed to compare the efficacy of anti-osteoporotic drugs for measures of hip function according to functional outcomes, periprosthetic femoral bone mineral density loss in each Gruen zone, and revision surgery after THA.
METHODS
The systematic search of six literature databases was conducted in December 2021 in accordance with PRISMA guidelines. Adult participants who underwent primary THA were included. A random-effects network meta-analysis was performed within a frequentist framework, and the confidence in the evidence for each outcome was evaluated using the CINeMA tool, which assessed the credibility of results from the network meta-analysis. We included 22 randomized controlled trials (1243 participants) comparing the efficacy and safety of bisphosphonates (including etidronate, clodronate, alendronate, risedronate, pamidronate, and zoledronate), denosumab, selective estrogen receptor modulator, teriparatide, calcium + vitamin D, calcium, and vitamin D. We defined the period for revision surgery as the final follow-up period.
RESULTS
Raloxifene, bisphosphonate, calcium + vitamin D, and denosumab for prosthetic hip function might have minimal differences when compared with placebos. The magnitude of the anti-osteoporotic drug effect on periprosthetic femoral bone loss varied across different Gruen zones. Bisphosphonate, denosumab, teriparatide might be more effective than placebo in Gruen zone 1 at 12 months after THA. Additionally, bisphosphonate might be more effective than placebo in Gruen zones 2, 5, 6, and 7 at 12 months after THA. Denosumab was efficacious in preventing bone loss in Gruen zones 6 and 7 at 12 months after THA. Teriparatide was likely to be efficacious in preventing bone loss in Gruen zone 7 at 12 months after THA. Raloxifene was slightly efficacious in preventing bone loss in Gruen zones 2 and 3 at 12 months after THA. Calcium was slightly efficacious in preventing bone loss in Gruen zone 5 at 12 months after THA. None of the studies reported revision surgery.
CONCLUSIONS
Bisphosphonate and denosumab may be effective anti-osteoporotic drugs for preventing periprosthetic proximal femoral bone loss due to stress shielding after THA, particularly in cementless proximal fixation stems, which are the most commonly used prostheses worldwide.
PubMed: 38342711
DOI: 10.1016/j.jos.2024.01.011