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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 -
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 -
Toxicology Feb 2024P-glycoprotein (Pgp) is a member of the ATP-binding cassette family of transporters that confers multidrug resistance to cancer cells and is actively involved in the...
P-glycoprotein (Pgp) is a member of the ATP-binding cassette family of transporters that confers multidrug resistance to cancer cells and is actively involved in the pharmacokinetics and toxicokinetics of a big variety of drugs. Extensive studies have provided insights into the binding of many compounds, but the precise mechanism of translocation across the membrane remains unknown; in this context, the major challenge has been to understand the basis for its polyspecificity. In this study, molecular dynamics (MD) simulations of human P-gp (hP-gp) in an explicit membrane-and-water environment were performed to investigate the dynamic behavior of the transporter in the presence of different compounds (active and inactive) in the binding pocket and ATP molecules within the nucleotide binding domains (NBDs). The complexes studied involve four compounds: cyclosporin A (CSA), amiodarone (AMI), pamidronate (APD), and valproic acid (VPA). While CSA and AMI are known to interact with P-gp, APD and VPA do not. The results highlighted how the presence of ATP notably contributed to increased flexibility of key residues in NBD1 of active systems, indicating potential conformational changes activating the translocation mechanism. MD simulations reveal how these domains adapt and respond to the presence of different substrates, as well as the influence of ATP binding on their flexibility. Furthermore, distinctive behavior was observed in the presence of active and inactive compounds, particularly in the arrangement of ATP between NBDs, supporting the proposed nucleotide sandwich dimer mechanism for ATP binding. This study provides comprehensive insights into P-gp behavior with various ligands and ATP, offering implications for drug development, toxicity assessment and demonstrating the validity of the results derived from the MD simulations.
Topics: Humans; Adenosine Triphosphate; ATP Binding Cassette Transporter, Subfamily B; Membrane Glycoproteins; Membrane Transport Proteins; Molecular Dynamics Simulation; Nucleotides; Protein Binding
PubMed: 38272384
DOI: 10.1016/j.tox.2024.153732 -
Proceedings (Baylor University. Medical... 2024Breast cancer is the most common cancer in women and most often metastasizes to the bone, resulting in skeletal-related events (SREs). Bone-modifying agents (BMAs)...
BACKGROUND
Breast cancer is the most common cancer in women and most often metastasizes to the bone, resulting in skeletal-related events (SREs). Bone-modifying agents (BMAs) including denosumab, a monoclonal antibody against the receptor activator of nuclear factor kappa-b ligand (RANKL), and pamidronate, a bisphosphonate, are used to prevent these adverse events.
METHODS
To analyze the efficacy of denosumab versus pamidronate, we used the TriNetX research platform and compared the outcomes of pathologic fracture, spinal cord compression, and overall 5-year survival rate between each pharmacotherapy.
RESULTS
There was no statistical difference for an increased risk in pathological fractures (2.7% vs. 2.8%, = 0.88), spinal cord compression (2.6% vs. 2.7%, = 0.88), or 5-year survival rate (45.5% vs. 52.4%, = 0.78) for the denosumab cohort versus the pamidronate cohort.
CONCLUSION
Since neither therapy showed an increased risk in the adverse effects measured in this study, factors such as patient preference, financial costs, and additional side effects of each medication should be taken into consideration when choosing a therapy for bone metastases in patients with breast cancer.
PubMed: 38174029
DOI: 10.1080/08998280.2023.2276623 -
CMAJ : Canadian Medical Association... Dec 2023
Topics: Humans; Pamidronate; Scleritis; Uveitis, Anterior; Diphosphonates
PubMed: 38110218
DOI: 10.1503/cmaj.230859 -
Materials (Basel, Switzerland) Nov 2023The near-infrared (NIR) fluorescence imaging modality has great potential for application in biomedical imaging research owing to its unique characteristics, such as low...
The near-infrared (NIR) fluorescence imaging modality has great potential for application in biomedical imaging research owing to its unique characteristics, such as low tissue autofluorescence and noninvasive visualization with high spatial resolution. Although a variety of NIR fluorophores are continuously reported, the commercially available NIR fluorophores are still limited, owing to complex synthetic processes and poor physicochemical properties. To address this issue, a small molecular NIR fluorophore (SMF800) was designed and developed in the present work to improve in vivo target-specific fluorescence imaging. After conjugation with pamidronate (PAM) and bovine serum albumin (BSA), the SMF800 conjugates exhibited successful in vivo targeting in bone and tumor tissues with low background uptake, respectively. The improved in vivo performance of the SMF800 conjugate demonstrated that the small molecular NIR fluorophore SMF800 can be widely used in a much broader range of imaging applications. The structure of SMF800, which was developed by considering two important physicochemical properties, water solubility and conjugatability, is first introduced. Therefore, this work suggests a simple and rational approach to design small, hydrophilic, and conjugatable NIR fluorophores for targeted bioimaging.
PubMed: 38005156
DOI: 10.3390/ma16227227 -
Nature Aging Nov 2023The stem cell theory of aging dictates that a decline in the number and/or function of stem cells causes tissue degeneration and aging; however, it still lacks...
The stem cell theory of aging dictates that a decline in the number and/or function of stem cells causes tissue degeneration and aging; however, it still lacks unequivocal experimental support. Here, using lineage tracing and single-cell transcriptomics, we identify a population of CD133 bone marrow-derived endothelial-like cells (ELCs) as potential endothelial progenitor cells, which contribute to tubular structures in vitro and neovascularization in vivo. We demonstrate that supplementation with wild-type and young ELCs respectively restores neovascularization and extends lifespan in progeric and naturally aged mice. Mechanistically, we identify an upregulation of farnesyl diphosphate synthase (FDPS) in aged CD133 ELCs-a key enzyme in isoprenoid biosynthesis. Overexpression of FDPS compromises the neovascularization capacity of CD133 ELCs, whereas FDPS inhibition by pamidronate enhances neovascularization, improves health measures and extends lifespan in aged mice. These findings highlight stem cell-based strategies for the treatment of progeria and age-related pathologies.
Topics: Mice; Animals; Endothelial Progenitor Cells; Longevity; Neovascularization, Pathologic; Stem Cells
PubMed: 37946040
DOI: 10.1038/s43587-023-00512-z -
Pharmaceuticals (Basel, Switzerland) Oct 2023We report a 4-year-old with Gorham-Stout disease (GSD) who was treated with a combination of bisphosphonate, sirolimus, and atenolol. A previously healthy 4-year-old...
We report a 4-year-old with Gorham-Stout disease (GSD) who was treated with a combination of bisphosphonate, sirolimus, and atenolol. A previously healthy 4-year-old girl presented with back pain after falling on her back 2 months prior. Thoracolumbar spine X-ray revealed diffuse compression spinal fractures in T9-L2. Magnetic resonance imaging (MRI) confirmed multiple compression fractures at T9-L5 and revealed a paraspinal mass along the T1-L1 level. Based on clinical, radiological, and histopathological findings, Gorham-Stout disease was diagnosed. Treatment with sirolimus (0.5 mg twice daily, 1.6 mg/m) was initiated and intravenous bisphosphonate (pamidronate, 1 mg/kg for 3 days, total 3 mg/kg every 4 months) was added for back pain; she had immediate improvement in back pain. After 9 months with this treatment, she had a mild increase in paraspinal lymphangiomatosis and aggravation in T9-L5 compression fractures; atenolol was administered. The patient underwent 11 months of combination treatment with bisphosphonate, sirolimus, and atenolol, and MRI showed mild degree of reduction in the paraspinal lesions at L1-L5. The patient is currently in stable condition with no back pain or side effects. The triple combination treatment with bisphosphonate, sirolimus, and atenolol may be helpful in stabilizing the disease course of GSD.
PubMed: 37895975
DOI: 10.3390/ph16101504