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Endocrinology and Metabolism (Seoul,... Apr 2022Denosumab, which has been approved for the treatment of osteoporosis since 2010, is a fully humanised monoclonal antibody against a cytokine, receptor activator of... (Review)
Review
Denosumab, which has been approved for the treatment of osteoporosis since 2010, is a fully humanised monoclonal antibody against a cytokine, receptor activator of nuclear factor kappa B ligand (RANKL), involved in bone resorption. Continued use of denosumab results in a potent and sustained decrease in bone turnover, an increase in bone mineral density (BMD), and a reduction in vertebral and hip fractures. The anti-resorptive effects of denosumab are reversible upon cessation, and this reversal is accompanied by a transient marked increase in bone turnover that is associated with bone loss, and of concern, an increased risk of multiple vertebral fractures. In this review, we outline the effects of denosumab withdrawal on bone turnover markers, BMD, histomorphometry, and fracture risk. We provide an update on recent clinical trials that sought to answer how clinicians can transition away from denosumab safely with follow-on therapy to mitigate bone loss and summarise the recommendations of various international guidelines.
Topics: Bone Density; Bone Remodeling; Denosumab; Female; Humans; Osteoporosis; Osteoporosis, Postmenopausal
PubMed: 35417954
DOI: 10.3803/EnM.2021.1369 -
Bone Oct 2020One of the key parameters for a successful treatment with any drug is the use of an optimal dose regimen. Bisphosphonates (BPs) have been in clinical use for over five...
One of the key parameters for a successful treatment with any drug is the use of an optimal dose regimen. Bisphosphonates (BPs) have been in clinical use for over five decades and during this period clinical pharmacokinetic (PK) and pharmacodynamic (PD) evaluations have been instrumental for the identification of optimal dose regimens in patients. Ideal clinical PK and PD studies help drug developers explain variability in responses and enable the identification of a dose regimen with an optimal effect. PK and PD studies of the unique and rather complex pharmacological properties of BPs also help determine to a significant extent ideal dosing for these drugs. Clinical PK and PD evaluations of BPs preferably use study designs and assays that enable the assessment of both short- (days) and long-term (years) presence and effect of these drugs in patients. BPs are mainly used for metabolic bone diseases because they inhibit osteoclast-mediated bone resorption and the best way to quantify their effects in humans is therefore by measuring biochemical markers of bone resorption in serum and urine. In these very same samples BP concentrations can also be measured. Short-term serum and urine data after both intravenous (IV) and oral administration enable the assessment of oral bioavailability as well as the amount of BP delivered to the skeleton. Longer-term data provide information on the anti-resorptive effect as well as the elimination of the BP from the skeleton. Using PK-PD models to mathematically link the anti-resorptive action of the BPs to the amount of BP at the skeleton provides a mechanism-based explanation of the pattern of bone resorption during treatment. These models have been used successfully during the clinical development of BPs. Newer versions of such models, which include systems pharmacology and disease progression models, are more comprehensive and include additional PD parameters such as BMD and fracture risk. Clinical PK and PD studies of BPs have been useful for the identification of optimal dose regimens for metabolic bone diseases. These analyses will also continue to be important for newer research directions, such as BP use in the delivery of other drugs to the bone to better treat bone metastases and bone infections, as well as the potential benefit of BPs at non-skeletal targets for the prevention and treatments of soft tissue cancers, various fibroses, and other cardiovascular and neurodegenerative diseases, and reduction in mortality and extension of lifespan.
Topics: Bone Diseases, Metabolic; Bone Neoplasms; Bone Resorption; Diphosphonates; Humans; Osteoclasts
PubMed: 32599224
DOI: 10.1016/j.bone.2020.115501 -
Metabolism: Clinical and Experimental Aug 2019Burn injury results in a triad of inter-related adaptive responses: a systemic inflammatory response, a stress response, and a consequent hypermetabolic state which... (Review)
Review
Burn injury results in a triad of inter-related adaptive responses: a systemic inflammatory response, a stress response, and a consequent hypermetabolic state which supports the former two. Details of what precisely triggers these responses as well as the sequence of events leading up to these responses are not clear. We review the musculoskeletal effects of burn injury to determine the precise contributions of this system in the generation and sustenance of this post-burn triad as well as the possible effects of pharmacologic intervention in the musculoskeletal response to burns on the resulting hypermetabolism. Inflammation-associated bone resorption liberates calcium, which may either prolong or intensify the systemic inflammatory response. Phosphate and magnesium liberated from bone could contribute to sustaining the increased ATP turnover in skeletal muscle that accompanies burn hypermetabolism. Reduced bone formation resulting from both pro-inflammatory cytokines and elevated endogenous glucocorticoid production results in reduced bone mass and therefore reduced osteocalcin production, which may contribute to reduced glucose uptake by skeletal muscle. Moreover, bone resorption liberates muscle catabolic factors such as transforming growth factor β, which contribute to the muscle wasting of burn hypermetabolism. Pharmacologic intervention with anti-resorptive agents early in the process preserve bone and muscle mass post-burn and future research should address the consequences for the hypermetabolic triad duration and intensity accompanying burn injury.
Topics: Adenosine Triphosphate; Bone Resorption; Bone and Bones; Burns; Cytokines; Humans; Inflammation; Muscle, Skeletal
PubMed: 31181216
DOI: 10.1016/j.metabol.2019.06.001 -
Frontiers in Immunology 2019Bone is a highly dynamic organ that is continuously being remodeled by the reciprocal interactions between bone and immune cells. We have originally established an... (Review)
Review
Bone is a highly dynamic organ that is continuously being remodeled by the reciprocal interactions between bone and immune cells. We have originally established an advanced imaging system for visualizing the behavior of osteoclasts and their precursors in the bone marrow cavity using two-photon microscopy. Using this system, we found that the blood-enriched lipid mediator, sphingosine-1-phosphate, controlled the migratory behavior of osteoclast precursors. We also developed pH-sensing chemical fluorescent probes to detect localized acidification by bone-resorbing osteoclasts on the bone surface , and identified two distinct functional states of differentiated osteoclasts, "bone-resorptive" and "non-resorptive." Here, we summarize our studies on the dynamics and functions of bone and immune cells within the bone marrow. We further discuss how our intravital imaging techniques can be applied to evaluate the mechanisms of action of biological agents in inflammatory bone destruction. Our intravital imaging techniques would be beneficial for studying the cellular dynamics in arthritic inflammation and bone destruction and would also be useful for evaluating novel therapies in animal models of bone-destroying diseases.
Topics: Animals; Bone Resorption; Bone and Bones; Cell Communication; Lysophospholipids; Macrophages; Mice; Microscopy, Fluorescence, Multiphoton; Osteoblasts; Osteoclasts; Sphingosine; T-Lymphocytes
PubMed: 30972080
DOI: 10.3389/fimmu.2019.00596 -
Bioactive Materials Feb 2022Biomineralized collagen composite materials pose an intriguing alternative to current synthetic bone graft substitutes by offering a biomimetic composition that closely...
Biomineralized collagen composite materials pose an intriguing alternative to current synthetic bone graft substitutes by offering a biomimetic composition that closely resembles native bone. We hypothesize that this composite can undergo cellular resorption and remodeling similar to natural bone. We investigate the formation and activity of human osteoclasts cultured on biomineralized collagen and pure collagen membranes in comparison to cortical bone slices. Human monocytes/macrophages from peripheral blood differentiate into multinucleated, tartrate-resistant alkaline phosphatase (TRAP)-positive osteoclast-like cells on all substrates. These cells form clear actin rings on cortical bone, but not on biomineralized collagen or pure collagen membranes. Osteoclasts form resorption pits in cortical bone, resulting in higher calcium ion concentration in cell culture medium; however, osteoclast resorption of biomineralized collagen and collagen membranes does not measurably occur. Activity of osteoclast enzymes - TRAP, carbonic anhydrase II (CA-II), and cathepsin-K (CTS-K) - is similar on all substrates, despite phenotypic differences in actin ring formation and resorption. The mesh-like structure, relatively low stiffness, and lack of RGD-containing binding domains are likely the factors responsible for preventing formation of stable actin rings on and resorption of (biomineralized) collagen membranes. This insight helps to guide further research toward the optimized design of biomineralized collagen composites as a more biomimetic bone-graft substitute.
PubMed: 34541399
DOI: 10.1016/j.bioactmat.2021.06.036 -
Frontiers in Immunology 2023Osteoclasts play a crucial role in bone resorption, and impairment of their differentiation can have significant implications for bone density, especially in individuals...
INTRODUCTION
Osteoclasts play a crucial role in bone resorption, and impairment of their differentiation can have significant implications for bone density, especially in individuals with HIV who may be at risk of altered bone health. The present study aimed to investigate the effects of HIV infection on osteoclast differentiation using primary human monocyte-derived macrophages as precursors. The study focused on assessing the impact of HIV infection on cellular adhesion, cathepsin K expression, resorptive activity, cytokine production, expression of co-receptors, and transcriptional regulation of key factors involved in osteoclastogenesis.
METHODS
Primary human monocyte-derived macrophages were utilized as precursors for osteoclast differentiation. These precursors were infected with HIV, and the effects of different inoculum sizes and kinetics of viral replication were analyzed. Subsequently, osteoclastogenesis was evaluated by measuring cellular adhesion, cathepsin K expression, and resorptive activity. Furthermore, cytokine production was assessed by monitoring the production of IL-1β, RANK-L, and osteoclasts. The expression levels of co-receptors CCR5, CD9, and CD81 were measured before and after infection with HIV. The transcriptional levels of key factors for osteoclastogenesis (RANK, NFATc1, and DC-STAMP) were examined following HIV infection.
RESULTS
Rapid, massive, and productive HIV infection severely impaired osteoclast differentiation, leading to compromised cellular adhesion, cathepsin K expression, and resorptive activity. HIV infection resulted in an earlier production of IL-1β concurrent with RANK-L, thereby suppressing osteoclast production. Infection with a high inoculum of HIV increased the expression of the co-receptor CCR5, as well as the tetraspanins CD9 and CD81, which correlated with deficient osteoclastogenesis. Massive HIV infection of osteoclast precursors affected the transcriptional levels of key factors involved in osteoclastogenesis, including RANK, NFATc1, and DC-STAMP.
CONCLUSIONS
The effects of HIV infection on osteoclast precursors were found to be dependent on the size of the inoculum and the kinetics of viral replication. These findings underscore the importance of understanding the underlying mechanisms to develop novel strategies for the prevention and treatment of bone disorders in individuals with HIV.
Topics: Humans; Osteoclasts; Cathepsin K; HIV-1; HIV Infections; NFATC Transcription Factors; Macrophages; Carrier Proteins; Cytokines
PubMed: 37404829
DOI: 10.3389/fimmu.2023.1206099 -
Dental Press Journal of Orthodontics 2017Root resorptions caused by orthodontic movement are not supported by consistent scientific evidence that correlate them with heredity, individual predisposition and...
Root resorptions caused by orthodontic movement are not supported by consistent scientific evidence that correlate them with heredity, individual predisposition and genetic or familial susceptibility. Current studies are undermined by methodological and interpretative errors, especially regarding the diagnosis and measurements of root resorption from orthopantomographs and cephalograms. Samples are heterogeneous insofar as they comprise different clinical operators, varied types of planning, and in insufficient number, in view of the prevalence of tooth resorptions in the population. Nearly all biological events are coded and managed through genes, but this does not mean tooth resorptions are inherited, which can be demonstrated in heredograms and other methods of family studies. In orthodontic root resorption, one cannot possibly determine percentages of how much would be due to heredity or genetics, environmental factors and unknown factors. There is no need to lay the blame of tooth resorptions on events taking place outside the orthodontic realm since in the vast majority of cases, resorptions are not iatrogenic. In orthodontic practice, when all teeth are analyzed and planned using periapical radiography or computerized tomography, and when considering all predictive factors, tooth resorptions are not iatrogenic in nature and should be considered as one of the clinical events inherent in the treatment applied.
Topics: Humans; Root Resorption
PubMed: 28902245
DOI: 10.1590/2177-6709.22.4.022-027.oin -
Journal of International Oral Health :... Dec 2013Invasive cervical resorption is a relatively uncommon form of external root resorption exhibiting no external signs. The resorptive condition is often detected by... (Review)
Review
Invasive cervical resorption is a relatively uncommon form of external root resorption exhibiting no external signs. The resorptive condition is often detected by routine radiographic examination. The clinical features vary from a small defect at the gingival margin to a pink coronal discoloration of the tooth crown resulting in ultimate cavitation of the overlying enamel which is painless unless pulpal or periodontal infection supervenes. Radiographic features of lesions vary from well-delineated to irregularly bordered mottled radiolucencies, and these can be confused with dental caries. A characteristic radiopaque line generally separates the image of the lesion from that of the root canal, because the pulp remains protected by a thin layer of predentin until late in the process. Histopathologically, the lesions contain fibrovascular tissue with resorbing clastic cells adjacent to the dentin surface. More advanced lesions display fibro-osseous characteristics with deposition of ectopic bonelike calcifications both within the resorbing tissue and directly on the dentin surface. How to cite this article: Kandalgaonkar SD, Gharat LA, Tupsakhare SD, Gabhane MH. Invasive Cervical Resorption: A Review. J Int Oral Health 2013;5(6):124-30 .
PubMed: 24453457
DOI: No ID Found -
Frontiers in Cell and Developmental... 2021Cystic fibrosis (CF)-related bone disease has emerged as a significant comorbidity of CF and is characterized by decreased bone formation and increased bone resorption.... (Review)
Review
Cystic fibrosis (CF)-related bone disease has emerged as a significant comorbidity of CF and is characterized by decreased bone formation and increased bone resorption. Both osteoblast and osteoclast differentiations are impacted by cystic fibrosis transmembrane conductance regulator (CFTR) mutations. The defect of CFTR chloride channel or the loss of CFTRs ability to interact with other proteins affect several signaling pathways involved in stem cell differentiation and the commitment of these cells toward bone lineages. Specifically, TGF-, nuclear factor-kappa B (NF-B), PI3K/AKT, and MAPK/ERK signaling are disturbed by CFTR mutations, thus perturbing stem cell differentiation. High inflammation in patients changes myeloid lineage secretion, affecting both myeloid and mesenchymal differentiation. In osteoblast, Wnt signaling is impacted, resulting in consequences for both bone formation and resorption. Finally, CFTR could also have a direct role in osteoclasts resorptive function. In this review, we summarize the existing literature on the role of CFTR mutations on the commitment of induced pluripotent stem cells to bone cells.
PubMed: 34026749
DOI: 10.3389/fcell.2021.611921 -
Journal of Conservative Dentistry : JCD Jan 2013Resorption is a pathologic process that often eludes the clinician with its varied etiologic factors and diverse clinical presentations. The key cells involved in tooth...
Resorption is a pathologic process that often eludes the clinician with its varied etiologic factors and diverse clinical presentations. The key cells involved in tooth resorption are odontoclasts which are multinucleated cells that produce resorption lacunae. Resorption can be classified as internal and external resorption. Internal resorption has been described as a rare occurrence as compared to external resorption. This article describes the pathogenesis of tooth resorption and various forms of internal resorption along with some clinical cases. Early diagnosis is the key factor in the successful management of resorptive lesions.
PubMed: 23349568
DOI: 10.4103/0972-0707.105290