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Human Reproduction Update 2010Every year 30% of individuals above age 65 fall, and falls are the principal cause of bone fractures. To reduce fracture incidence requires both prevention of falls and... (Review)
Review
BACKGROUND
Every year 30% of individuals above age 65 fall, and falls are the principal cause of bone fractures. To reduce fracture incidence requires both prevention of falls and maintenance of bone strength.
METHODS
PubMed searches were performed, for studies of the epidemiology of fractures, bone physiology, endocrine effects, osteoporosis measurement, genetics, prevention and effectiveness. Topic summaries were presented to the Workshop Group and omissions or disagreements were resolved by discussion.
RESULTS
Ageing reduces bone strength in post-menopausal women because estrogen deficiency causes accelerated bone resorption. Bone mineral density (BMD) decreased more than 2.5 standard deviation below the mean of healthy young adults defines osteoporosis, a condition associated with an increased risk of fractures. Risk factors such as age and previous fracture are combined with BMD for a more accurate prediction of fracture risk. The most widely used assessment tool is FRAX™ which combines clinical risk factors and femoral neck BMD. General preventive measures include physical exercise to reduce the risk of falling and vitamin D to facilitate calcium absorption. Pharmacological interventions consist mainly in the administration of inhibitors of bone resorption. Randomized controlled trials show treatment improves BMD, and may reduce the relative fracture risk by about 50% for vertebral, 20-25% for non-vertebral and up to 40% for hip fractures although the absolute risk reductions are much lower.
CONCLUSIONS
Although diagnosis of osteoporosis is an important step, the threshold for treatment to prevent fractures depends on additional clinical risk factors. None of the presently available treatment options provide complete fracture prevention.
Topics: Age Factors; Bone Density; Bone Resorption; Cost of Illness; Female; Fractures, Bone; Humans; Osteoporosis, Postmenopausal; Postmenopause; Prevalence; Risk Factors
PubMed: 20427370
DOI: 10.1093/humupd/dmq008 -
Research in Veterinary Science Apr 2019People with calcium oxalate (CaOx) urolithiasis and idiopathic hypercalciuria (IH) often have evidence of increased bone resorption, but bone turnover has not previously...
People with calcium oxalate (CaOx) urolithiasis and idiopathic hypercalciuria (IH) often have evidence of increased bone resorption, but bone turnover has not previously been investigated in dogs with these conditions. The aim of this study was to determine whether a marker of bone resorption, β-crosslaps, differs between dogs with CaOx urolithiasis and IH compared to controls. This retrospective, cross-sectional study used a canine specific ELISA to measure β-crosslaps concentrations in stored frozen serum samples from 20 dogs with CaOx urolithiasis and IH and 20 breed-, sex-, and age-matched stone-free controls (18 Miniature Schnauzers, 14 Bichons Frise, and 8 Shih Tzus). Dogs with CaOx urolithiasis and IH had lower β-crosslaps concentrations relative to controls (P = .0043), and β-crosslaps had a moderate negative correlation with urinary calcium-to-creatinine ratios (r = -0.44, P = .0044). Miniature Schnauzers had lower β-crosslaps concentrations than the other two breeds (P = .0035). The ELISA had acceptable intra-assay precision, but concentrations decreased when samples were repeatedly assayed over time. Assay recovery rates were also below acceptance criteria. In conclusion, Miniature Schnauzers, Bichons Frise, and Shih Tzus with CaOx urolithiasis and IH have evidence of decreased bone resorption compared to stone-free controls. This suggests that other causes of IH, such as intestinal hyperabsorption of calcium, underlie risk for CaOx urolithiasis in these breeds. Results should be confirmed in larger populations and with other β-crosslaps assays and additional biomarkers of bone turnover. The stability of canine serum β-crosslaps after freeze-thaw cycles and storage at various temperatures requires investigation.
Topics: Animals; Bone Resorption; Calcium Oxalate; Cross-Sectional Studies; Dog Diseases; Dogs; Female; Humans; Hypercalciuria; Male; Nephrolithiasis; Retrospective Studies
PubMed: 30641472
DOI: 10.1016/j.rvsc.2019.01.001 -
Cells Sep 2020Bone infections, also known as infectious osteomyelitis, are accompanied by significant inflammation, osteolysis, and necrosis. Osteoclasts (OCs) are the bone-resorbing... (Review)
Review
Bone infections, also known as infectious osteomyelitis, are accompanied by significant inflammation, osteolysis, and necrosis. Osteoclasts (OCs) are the bone-resorbing cells that work in concert with osteoblasts and osteocytes to properly maintain skeletal health and are well known to respond to inflammation by increasing their resorptive activity. OCs have typically been viewed merely as effectors of pathologic bone resorption, but recent evidence suggests they may play an active role in the progression of infections through direct effects on pathogens and via the immune system. This review discusses the host- and pathogen-derived factors involved in the in generation of OCs during infection, the crosstalk between OCs and immune cells, and the role of OC lineage cells in the growth and survival of pathogens, and highlights unanswered questions in the field.
Topics: Animals; Bacteria; Bone Resorption; Bone and Bones; Cell Lineage; Humans; Immunomodulation; Osteoclasts
PubMed: 32987689
DOI: 10.3390/cells9102157 -
Journal of Biomedical Science Oct 2015Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor expressed in many cell types, including osteoblasts, osteocytes, and osteoclasts. Nrf2 has... (Review)
Review
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor expressed in many cell types, including osteoblasts, osteocytes, and osteoclasts. Nrf2 has been considered a master regulator of cytoprotective genes against oxidative and chemical insults. The lack of Nrf2 can induce pathologies in multiple organs. Nrf2 deficiency promotes osteoclast differentiation and osteoclast activity, which leads to an increase in bone resorption. The role of Nrf2 in osteoblast differentiation and osteoblast activity is more complex. Nrf2 mediates anabolic effects within an ideal range. Nrf2 deletion suppresses load induced bone formation and delays fracture healing. Overall, Nrf2 plays an important role in the regulation of bone homeostasis in bone cells.
Topics: Animals; Bone Resorption; Cell Differentiation; Humans; NF-E2-Related Factor 2; Osteoclasts; Osteocytes
PubMed: 26511009
DOI: 10.1186/s12929-015-0212-5 -
International Journal of Molecular... Dec 2020Calcium (Ca) plays an important role in regulating the differentiation and function of osteoclasts. Calcium oscillations (Ca oscillations) are well-known phenomena in... (Review)
Review
Calcium (Ca) plays an important role in regulating the differentiation and function of osteoclasts. Calcium oscillations (Ca oscillations) are well-known phenomena in receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis and bone resorption via calcineurin. Many modifiers are involved in the fine-tuning of Ca oscillations in osteoclasts. In addition to macrophage colony-stimulating factors (M-CSF; CSF-1) and RANKL, costimulatory signaling by immunoreceptor tyrosine-based activation motif-harboring adaptors is important for Ca oscillation generation and osteoclast differentiation. DNAX-activating protein of 12 kD is always necessary for osteoclastogenesis. In contrast, Fc receptor gamma (FcRγ) works as a key controller of osteoclastogenesis especially in inflammatory situation. FcRγ has a cofactor in fine-tuning of Ca oscillations. Some calcium channels and transporters are also necessary for Ca oscillations. Transient receptor potential (TRP) channels are well-known environmental sensors, and TRP vanilloid channels play an important role in osteoclastogenesis. Lysosomes, mitochondria, and endoplasmic reticulum (ER) are typical organelles for intracellular Ca storage. Ryanodine receptor, inositol trisphosphate receptor, and sarco/endoplasmic reticulum Ca ATPase on the ER modulate Ca oscillations. Research on Ca oscillations in osteoclasts has still many problems. Surprisingly, there is no objective definition of Ca oscillations. Causality between Ca oscillations and osteoclast differentiation and/or function remains to be examined.
Topics: Animals; Bone Resorption; Calcium; Calcium Channels; Calcium Signaling; Cell Differentiation; Humans; Osteoclasts; Osteogenesis
PubMed: 33375370
DOI: 10.3390/ijms22010180 -
Bone Jun 2013Glucocorticoids are used for the treatment of inflammatory and autoimmune diseases. While they are effective therapy, bone loss and incident fracture risk are high.... (Review)
Review
Glucocorticoids are used for the treatment of inflammatory and autoimmune diseases. While they are effective therapy, bone loss and incident fracture risk are high. While previous studies have found GC effects on both osteoclasts and osteoblasts, our work has focused on the effects of GCs on osteocytes. Osteocytes exposed to low dose GCs undergo autophagy while osteocytes exposed to high doses of GCs or for a prolonged period of time undergo apoptosis.
Topics: Animals; Autophagy; Bone Resorption; Glucocorticoids; Humans; Minerals; Osteocytes
PubMed: 23356984
DOI: 10.1016/j.bone.2013.01.034 -
The Journal of Biological Chemistry Dec 2023Osteoclasts are specialized cells responsible for bone resorption, a highly energy-demanding process. Focus on osteoclast metabolism could be a key for the treatment of...
Osteoclasts are specialized cells responsible for bone resorption, a highly energy-demanding process. Focus on osteoclast metabolism could be a key for the treatment of osteolytic diseases including osteoporosis. In this context, AMP-activated protein kinase α1 (AMPKα1), an energy sensor highly expressed in osteoclasts, participates in the metabolic reconfiguration during osteoclast differentiation and activation. This study aimed to elucidate the role of AMPKα1 during osteoclastogenesis in vitro and its impact in bone loss in vivo. Using LysMcre/0AMPK⍺1f/f animals and LysMcre/0 as control, we evaluated how AMPKα1 interferes with osteoclastogenesis and bone resorption activity in vitro. We found that AMPKα1 is highly expressed in the early stages of osteoclastogenesis. Genetic deletion of AMPKα1 leads to increased gene expression of osteoclast differentiation and fusion markers. In addition, LysMcre/0AMPK⍺1f/f mice had an increased number and size of differentiated osteoclast. Accordingly, AMPKα1 negatively regulates bone resorption in vitro, as evidenced by the area of bone resorption in LysMcre/0AMPK⍺1f/f osteoclasts. Our data further demonstrated that AMPKα1 regulates mitochondrial fusion and fission markers upregulating Mfn2 and downregulating DRP1 (dynamics-related protein 1) and that Ctskcre/0AMPK⍺1f/f osteoclasts lead to an increase in the number of mitochondria in AMPK⍺1-deficient osteoclast. In our in vivo study, femurs from Ctskcre/0AMPK⍺1f/f animals exhibited bone loss associated with the increased number of osteoclasts, and there was no difference between Sham and ovariectomized group. Our data suggest that AMPKα1 acts as a negative regulator of osteoclastogenesis, and the depletion of AMPKα1 in osteoclast leads to a bone loss state similar to that observed after ovariectomy.
Topics: Animals; Female; Mice; Bone Resorption; Cell Differentiation; Mice, Inbred C57BL; Osteoclasts; Osteogenesis; Osteoporosis; RANK Ligand
PubMed: 37871745
DOI: 10.1016/j.jbc.2023.105379 -
International Journal of Molecular... May 2022Osteoclasts, which resorb the bone, and osteoblasts, which form the bone, are the key cells regulating bone homeostasis. Osteoporosis and other metabolic bone diseases... (Review)
Review
Osteoclasts, which resorb the bone, and osteoblasts, which form the bone, are the key cells regulating bone homeostasis. Osteoporosis and other metabolic bone diseases occur when osteoclast-mediated bone resorption is increased and bone formation by osteoblasts is decreased. Analyses of tyrosine kinase Src-knockout mice revealed that Src is essential for bone resorption by osteoclasts and suppresses bone formation by osteoblasts. Src-knockout mice exhibit osteopetrosis. Therefore, Src is a potential target for osteoporosis therapy. However, Src is ubiquitously expressed in many tissues and is involved in various biological processes, such as cell proliferation, growth, and migration. Thus, it is challenging to develop effective osteoporosis therapies targeting Src. To solve this problem, it is necessary to understand the molecular mechanism of Src function in the bone. Src expression and catalytic activity are maintained at high levels in osteoclasts. The high activity of Src is essential for the attachment of osteoclasts to the bone matrix and to resorb the bone by regulating actin-related molecules. Src also inhibits the activity of Runx2, a master regulator of osteoblast differentiation, suppressing bone formation in osteoblasts. In this paper, we introduce the molecular mechanisms of Src in osteoclasts and osteoblasts to explore its potential for bone metabolic disease therapy.
Topics: Animals; Bone Resorption; Homeostasis; Mice; Osteoclasts; Osteoporosis; Protein-Tyrosine Kinases
PubMed: 35628319
DOI: 10.3390/ijms23105508 -
Journal of Musculoskeletal & Neuronal... Sep 2018Bone erosions develop early in the course of rheumatoid arthritis (RA) and deteriorate progressively, causing joint damage and resulting in impaired functional capacity... (Review)
Review
Bone erosions develop early in the course of rheumatoid arthritis (RA) and deteriorate progressively, causing joint damage and resulting in impaired functional capacity of patients. During the last years, considerable number of studies has increased our understanding of the pathogenetic mechanisms mediating the development of bone erosions in RA. Increased production of RANKL and other cytokines, dysregulation of innate immune mechanisms, autoantibodies specific to RA and alterations of microRNA expression stimulate differentiation and function of osteoclasts, which are responsible for the development of bone erosions. Besides, increased levels of cytokines, overproduction of antagonists of the canonical Wnt signaling pathway and deficient production of bone morphogenetic proteins result in impaired osteoblast differentiation and function, undermining the capacity of bone erosions to repair. Disease-modifying antirheumatic drugs, synthetic or biological, currently used in the treatment of RA, can halt the progression of bone erosions and may even lead to partial repair, although complete repair is unattainable. Targeting pathogenetic mechanisms participating in the erosive process may add to the therapeutic effect of DMARDs and help in the prevention or repair of bone erosions. However, more studies are still needed to confirm whether such therapeutic strategies are effective.
Topics: Arthritis, Rheumatoid; Bone Resorption; Cytokines; Disease Progression; Humans; Osteogenesis
PubMed: 30179207
DOI: No ID Found -
Cells Aug 2019Arthritis is inflammation of the joints accompanied by osteochondral destruction. It can take many forms, including osteoarthritis, rheumatoid arthritis, and psoriatic... (Review)
Review
Arthritis is inflammation of the joints accompanied by osteochondral destruction. It can take many forms, including osteoarthritis, rheumatoid arthritis, and psoriatic arthritis. These diseases share one commonality-osteochondral destruction based on inflammation. The background includes a close interaction between osseous tissues and immune cells through various inflammatory cytokines. However, the tissues and cytokines that play major roles are different in each disease, and as a result, the mechanism of osteochondral destruction also differs. In recent years, there have been many findings regarding not only extracellular signaling pathways but also intracellular signaling pathways. In particular, we anticipate that the intracellular signals of osteoclasts, which play a central role in bone destruction, will become novel therapeutic targets. In this review, we have summarized the pathology of arthritis and the latest findings on the mechanism of osteochondral destruction, as well as present and future therapeutic strategies for these targets.
Topics: Arthritis; Bone Resorption; Bone and Bones; Cartilage; Cytokines; Humans; Inflammation; Osteoclasts; Signal Transduction
PubMed: 31382539
DOI: 10.3390/cells8080818