PURPOSE OF THE REVIEW: The purpose of this Review was to summarize the evidence on the associations among estrogen status, cellular senescence, the gut microbiome and osteoporosis. RECENT FINDINGS: Indicate that osteoporosis is a global public health problem that impacts individuals and society. In postmenopausal women, a decrease in estrogen levels is associated with a decrease in gut microbial diversity and richness, as well as increased permeability of the gut barrier, which allows for low-grade inflammation. The direct effects of estrogen status on the association between bone and the gut microbiome were observed in untreated and treated ovariectomized women. In addition to the direct effects of estrogens on bone remodeling, estrogen therapy could reduce the risk of postmenopausal osteoporosis by preventing increased gut epithelial permeability, bacterial translocation and inflammaging. However, in studies comparing the gut microbiota of older women, there were no changes at the phylum level, suggesting that age-related comorbidities may have a greater impact on changes in the gut microbiota than menopausal status does. Estrogens modify bone health not only by directly influencing bone remodeling, but also indirectly by influencing the gut microbiota, gut barrier function and the resulting changes in immune system reactivity.
- MeSH
- estrogeny * MeSH
- lidé MeSH
- osteoporóza MeSH
- postmenopauzální osteoporóza * MeSH
- remodelace kosti * MeSH
- stárnutí buněk MeSH
- střevní mikroflóra * MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Osteoporóza (OP) je systémové metabolické onemocnění charakterizované sníženým obsahem kostní hmoty a narušením mikroarchitektury kosti, což je příčinou zvýšené fragility kosti, a tím zvýšeného rizika zlomenin již při minimálním traumatu. Cílem léčby osteoporózy je restituce prořídlé kostní tkáně. Konečným a hlavním cílem je prevence zlomenin. Podle toho je možno také posuzovat účinnost léčby. Časnějším, nepřímým ukazatelem úspěšnosti léčby je zvýšení kostní denzity, nebo alespoň zpomalení jejího úbytku na fyziologickou hranici. Sklerostin je protein, který je u lidí kódován genem SOST. Sklerostin je produkován především osteocyty, má antianabolické účinky na novotvorbu kostí. Romosozumab je humanizovaná monoklonální protilátka IgG2 proti sklerostinu. Vývoj protilátky proti sklerostinu se jevil ideálním k ovlivnění novotvorby kosti právě pro téměř výhradní expresi genu SOST v kosti. Romosozumab se ukázal jako mimořádně účinný při zvyšování denzity kostního minerálu (BMD), modulaci markerů kostního obratu a redukci rizika fraktur. Při léčbě romosozumabem dochází k rychlému a účinnému snížení rizika zlomenin u postmenopauzálních žen s osteoporózou. Dvojí mechanizmus účinku činí z romosozumabu jedinečnou a účinnou možnost léčby osteoporózy, zejména v případech, v nichž je žádoucí rychlé navýšení denzity kostí. Významné snížení rizika zlomenin představuje podstatný klinický přínos.
Osteoporosis (OP) is a systemic metabolic disease characterized by reduced bone mass and disturbed bone microarchitecture, which causes increased bone fragility and thus increased risk of fractures even with minimal trauma. The goal of osteoporosis treatment is restitution of thinned bone tissue. The ultimate and main goal is fracture prevention. The effectiveness of treatment can also be judged accordingly. An early, indirect indicator of the success of treatment is an increase in bone density, or at least a slowing of bone loss to the physiological limit. Sclerostin is a protein that in humans is encoded by the SOST gene. Sclerostin is produced mainly by osteocytes and has antianabolic effects on bone formation. Romosozumab is a humanized IgG2 monoclonal antibody against sclerostin. The development of an antibody against sclerostin seemed ideal to affect bone formation precisely because of the almost exclusive expression of the SOST gene in bone. Romosozumab has proven to be extremely effective in increasing bone mineral density (BMD), modulating markers of bone turnover and reducing fracture risk. Treatment with romosozumab results in a rapid and effective reduction in fracture risk in postmenopausal women with osteoporosis. The dual mechanism of action makes romosozumab a unique and effective treatment option for osteoporosis, particularly in cases where rapid increases in bone density are desired. The significant reduction in fracture risk represents a substantial clinical benefit.
- Klíčová slova
- romosozumab,
- MeSH
- inhibitory kostní resorpce terapeutické užití MeSH
- klinické zkoušky jako téma MeSH
- kortikální kost účinky léků ultrastruktura MeSH
- kostní denzita účinky léků MeSH
- lidé MeSH
- monoklonální protilátky * terapeutické užití MeSH
- nežádoucí účinky léčiv MeSH
- osteoporotické fraktury prevence a kontrola MeSH
- osteoporóza * diagnóza farmakoterapie prevence a kontrola MeSH
- remodelace kosti účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- grafy a diagramy MeSH
- přehledy MeSH
Signální dráha receptoru pro epidermální růstový faktor (EGFR) se podílí na regulaci buněčných funkcí osteoklastů i osteoblastů. Útlum signalizace v této dráze aplikací inhibitorů tyrozinkinázy (EGFR-TKI) je využíván jako varianta protinádorové terapie u pacientů s nemalobuněčným karcinomem plic (NSCLC) s aktivačními mutacemi genu EGFR. Popisujeme případ pacientky s NSCLC léčené afacitinibem, u níž jsme pozorovali významnou supresi kostní remodelace doprovázenou vzestupem BMD, která byla dále potencována navazující aplikací denosumabu. Vliv inhibice EGFR-TKI na kostní metabolizmus není dostatečně prostudován. In vitro data ukazují, že inhibice EGFR vede k útlumu aktivity osteoblastů i osteoklastů. Další výzkum je žádoucí i s ohledem na významné přesahy do klinické praxe – kostní metastázy, nádorová postižení skeletu (SRE), osteonekróza čelisti (ONJ).
The EGFR signaling pathway is involved in the regulation of cellular functions of osteoclasts and osteoblasts. Suppression of signaling in this pathway by administration of EGFR-TKIs has been used as an option for anticancer therapy in NSCLC patients with activating mutations of the EGFR gene. We describe the case of an NSCLC patient treated with afacitinib in whom we observed a significant suppression of bone remodeling accompanied by an increase in BMD, which was further potentiated by downstream administration of denosumab. The effect of EGFR-TKI inhibition on bone metabolism has not been sufficiently studied. In vitro data show that EGFR inhibition leads to attenuation of osteoblast and osteoclast activity. Further research is also desirable in view of important overlaps into clinical practice (bone metastases, Skeletal-Related Events, OsteoNecrosis of the Jaw).
- MeSH
- afatinib * aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- denosumab aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- fatální výsledek MeSH
- geny erbB-1 účinky léků MeSH
- inhibitory kostní resorpce aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- inhibitory tyrosinkinasy aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- kostní denzita účinky léků MeSH
- lidé MeSH
- nemalobuněčný karcinom plic * komplikace terapie MeSH
- remodelace kosti * účinky léků MeSH
- senioři MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
INTRODUCTION: The Hueter-Volkmann law (HVL) of the response of growth plate to compression load is a basic concept in orthopaedics. However, little is known about the origin of HVL and its history. MATERIALS AND METHODS: A literature search was performed in original publications and historical sources. RESULTS: An analysis of all Volkmann ́s and Hueter ́s texts has shown that none of their publications was based on experiments, but on the data in the literature and their own clinical observations. They did not deal at all with the effect of pressure on the growth plate and mentioned this structure only marginally. The authors coined the opinion that increased pressure retards and decreased pressure accelerates bone growth. Julius Wolff criticized the HVL and concentrated all his arguments in the book "The law of bone remodeling". According to him, increased pressure leads to bone formation, decreased pressure to its resorption. The Wolff-Volkmann dispute was addressed in the German literature by a number of authors. Walther Müller in his monograph "The normal and pathological physiology of the bone" criticized Wolff for his concept of interstitial bone growth. In Müller ́s view, HVL applies to the growing bone and Wolff confuses growth with hypertrophy of the mature bone. CONCLUSION: The circumstances of the emergence of HVL are inaccurately and incompletely described in the current literature, as they are mostly taken from secondary sources. HVL, as it is presented today, is not the original formulation, but the result of a long historical evolution.
- MeSH
- dějiny 19. století MeSH
- dějiny 20. století MeSH
- lidé MeSH
- ortopedie * dějiny MeSH
- remodelace kosti fyziologie MeSH
- růstová ploténka * fyziologie MeSH
- vývoj kostí fyziologie MeSH
- Check Tag
- dějiny 19. století MeSH
- dějiny 20. století MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- historické články MeSH
- přehledy MeSH
Klinický význam osteoporózy spočívá v nárůstu výskytu nízkotraumatických zlomenin. Zlomeniny zvyšují morbiditu a mortalitu a vedou ke snížené kvalitě života a ztrátě autonomie. Léčba osteoporózy zahrnuje posouzení rizikových faktorů zlomenin, snížení ovlivnitelných rizikových faktorů prostřednictvím úpravy výživy a životního stylu a vedení farmakologické léčby u pacientů s vysokým rizikem zlomenin. Osteoporóza je chronické onemocnění, a proto potřebuje dlouhodobý plán léčby s individuálním přístupem k léčbě. Současné léky mají osteoanabolické účinky nebo a/nebo snižují kostní resorpci a dramaticky snižují výskyt zlomenin. U osob s vysokým rizikem zlomeniny je poměr přínosu oproti rizikům léčby příznivý až po dobu 10 let při léčbě aminobisfosfonáty nebo denosumabem. Léčba denosumabem ale nesmí být přerušena bez zahájení alternativní léčby, aby se zabránilo rychlé ztrátě BMD a zvýšení rizika zlomenin obratlů. U osob s velmi vysokým rizikem zlomeniny je třeba zvážit v 1. volbě osteoanabolickou léčbu teriparatidem nebo romosozumabem. Vzhledem k tomu, že délka léčby těmito léky je omezena na 12–24 měsíců, musí vždy navázat antiresorpční léky. Včasná diagnostika a léčba osteoporózy dramaticky snižuje výskyt zlomenin a umožní zachovat mobilitu, autonomii a kvalitu života
The clinical significance of osteoporosis lies in the low-trauma fractures that arise. Fractures lead to increased morbidity, excess mortality, decreased quality of life and loss of autonomy. Management of osteoporosis involves assessing risk factors for fracture, reducing modifiable risk factors through dietary and lifestyle changes, and the use of pharmacologic therapy for patients at significant risk of fractures. Osteoporosis is a chronic condition and therefore needs a long-term management plan with a personalized approach to treatment. Current medications build bone and/or decrease bone breakdown and reduce incident fractures. In individuals at high risk of fracture, the benefit versus risk profile is likely to be favourable for up to 10 years of treatment with bisphosphonates or denosumab. However, denosumab should not be stopped without considering alternative treatment in order to prevent rapid BMD loss and a potential rebound in vertebral fracture risk. In people at a very high risk of fracture, therapy with teriparatide or romosozumab should be considered in the first choice; however, since treatment duration with these drugs is restricted to 12-24 months, treatment should be continued with an antiresorptive drug. Early diagnosis and appropriate management of skeletal fragility can dramatically reduce fractures, and preserve mobility, autonomy, and quality of life.
- Klíčová slova
- romosozumab,
- MeSH
- bisfosfonáty aplikace a dávkování ekonomika klasifikace škodlivé účinky MeSH
- denosumab aplikace a dávkování ekonomika farmakologie škodlivé účinky MeSH
- fraktury kostí * etiologie prevence a kontrola MeSH
- humanizované monoklonální protilátky aplikace a dávkování ekonomika farmakologie škodlivé účinky MeSH
- inhibitory kostní resorpce aplikace a dávkování ekonomika klasifikace škodlivé účinky MeSH
- klinické rozhodování MeSH
- lidé MeSH
- osteoporóza * dietoterapie farmakoterapie komplikace terapie MeSH
- postmenopauzální osteoporóza farmakoterapie terapie MeSH
- remodelace kosti účinky léků MeSH
- riziko MeSH
- teriparatid aplikace a dávkování ekonomika farmakologie škodlivé účinky MeSH
- vápník metabolismus terapeutické užití MeSH
- vitamin D metabolismus terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Background: After injuries, infections, or tumor removal, endogenous healing depends on bone repair. Disorders of bone healing are difficult to treat in clinical settings. There are numerous induced methods for correcting bone abnormalities, such as the induced membrane technique, allogenic bone grafting, synthetic bone grafting, artificial joint replacement, and autologous bone grafting. However, the delivery of the bone graft and bone filling materials necessitates surgical implantation at the fracture site, which could cause edema, infection, and the development of heterotopic bone locally. Therefore, systemically administered osteogenic drugs will provide an excellent method for bone lesion healing. Aim of the study: to evaluate the systemic effect of metformin on bone healing after surgical induction of bony defect and to determine the amount of newly formed bone using histological, histomorphometric analysis, and the surface area measurement of newly formed bone. Also to study the safety of metformin administration at the administered dose for this purpose. Materials and methods: Twenty mature male New Zealand rabbits were separated into two groups, each including ten rabbits for the study. The same surgical procedure was performed on all rabbits. Two holes were made at the femur (3 mm in diameter and 3 mm in depth) and left empty. Metformin tablets were ground into a fine powder and the resultant powder was dissolved in 10ml of water to prepare a liquid dosage containing 50 mg /1ml of metformin. Metformin is administered orally to the rabbits through a feeding tube at a dose of 50 mg/kg body weight. Animals were euthanized at two-time intervals, 14 and 28 days. The femur was separated, sectioned preserved, and sent for histological analysis and histomor-phometry. Results: The results revealed that there is an increase in new bone formation and bone-forming cells in the metformin-treated group. Conclusion: Metformin increases bone healing by increasing the number of bone-forming cells and the surface area of newly formed bone tissues and causes less inflammatory response at the site of a bone lesion. So it possesses an osteogenic effect.
PURPOSE OF THE STUDY: The preclinical study aimed to compare the healing of segmental bone defects treated with biodegradable hyaluronic acid and tricalcium phosphate-based hydrogel with the established autologous spongioplasty. Another aim was to evaluate the hydrogel as a scaffold for osteoinductive growth factor of bone morphogenetic protein-2 (BMP-2) and stem cells. MATERIAL AND METHODS: The study was conducted in an in vivo animal model. A standardized rabbit model of a 15 mm long segmental bone defect of left radius was used. A total of 40 animals were divided into 5 groups of 8 individuals. In the KO- (negative control) group, the created defect was left to heal spontaneously. In the KO+ (positive control) group, the defect was filled with morselized bone autograft prepared from the resected segment. In the study group A, the defect was filled with hydrogel based on hyaluronic acid derivative and tricalcium phosphate. In the study group B, the defect was filled with hydrogel based on hyaluronic acid derivative, tricalcium phosphate and bone marrow aspirate. In the study group C, the defect was filled with hydrogel based on hyaluronic acid derivative, tricalcium phosphate, bone marrow aspirate and BMP-2. Healing was assessed using radiographs at 1, 6, and 12 weeks postoperatively and histology specimens were collected at 16 weeks postoperatively. RESULTS: Altogether 35 rabbits survived (KO- 7, KO+ 7, A 7, B 6, C 8) until the end of the study. As concerns the radiographic assessment, the best results were achieved by the groups KO+ and C, where new bone formation across the entire width of the bone defect was clearly seen at 6 and 12 weeks and the osteotomy line was completely healed too. At 12 weeks, complete bone remodelling was observed in all animals in the group KO+, whereas in the group C, bone remodelling was fully completed in 5 animals and partially completed in 3 animals. In terms of histological assessment, however, the best results were achieved by the group C, where the bone defect was completely remodelled into lamellar bone in 7 specimens, while in 1 specimen it healed with bony callus formation. In the group KO+, the defect was healed in 4 specimens by cartilaginous callus with loci of remodelling into bony callus, in 2 specimens the bony callus was predominant with cartilaginous callus areas, and only one defect was completely remodelled into lamellar bone. DISCUSSION: Compared to autografts that manifest osteogenic, osteoinductive and osteoconductive properties, the biodegradable hyaluronic acid and tricalcium phosphate-based hydrogel has osteoconductive properties only. Thus, it was also tested in our study as a scaffold for bone marrow cells and BMP-2 osteoinductive growth factor. Thanks to its semi-liquid properties, the biodegradable hyaluronic acid and tricalcium phosphate-based hydrogel is a promising material for use in 3D printing. CONCLUSIONS: The preclinical study in an in vivo animal model confirmed the beneficial effect of the biodegradable hyaluronic acid and tricalcium phosphate-based hydrogel on the healing of critical-size segmental bone defects. Better healing of these defects was also confirmed for filling composed of hydrogel and BMP-2 osteoinductive growth factor. The benefit of bone marrow aspirate mixed with hydrogel was not confirmed. KEY WORDS: bone defect, non-union, rabbit, hyaluronic acid, calcium phosphate, stem cells, BMP-2, scaffold, bone healing, spongioplasty.
- MeSH
- fosforečnany vápenaté * farmakologie MeSH
- hydrogely farmakologie MeSH
- kostní morfogenetický protein 2 * MeSH
- králíci MeSH
- kyselina hyaluronová * farmakologie MeSH
- modely nemocí na zvířatech MeSH
- radius chirurgie zranění MeSH
- regenerace kostí účinky léků MeSH
- tkáňové podpůrné struktury * MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- zvířata MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- MeSH
- bisfosfonátová osteonekróza čelistí patofyziologie MeSH
- bisfosfonáty aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- denosumab aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- lidé MeSH
- mnohočetný myelom * farmakoterapie komplikace MeSH
- nežádoucí účinky léčiv MeSH
- osteolýza * chemicky indukované MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- směrnice pro lékařskou praxi MeSH
- MeSH
- buňky pojivové tkáně MeSH
- chrupavka MeSH
- fraktury kostí MeSH
- fraktury růstové ploténky MeSH
- hojení fraktur MeSH
- kosti a kostní tkáň * anatomie a histologie fyziologie krevní zásobení metabolismus MeSH
- kostra anatomie a histologie MeSH
- lidé MeSH
- osteogeneze MeSH
- pojivová tkáň MeSH
- remodelace kosti fyziologie MeSH
- růstová ploténka fyziologie růst a vývoj MeSH
- vývoj kostí MeSH
- Check Tag
- lidé MeSH
Bone turnover markers (BTMs) are released during the bone remodelling cycle and are measurable in blood or urine, reflecting bone remodelling rate. They have been useful in elucidating the pharmacodynamics and effectiveness of osteoporosis medication in clinical trials and are increasingly used in routine clinical management of osteoporosis, especially for monitoring therapy, in addition to their use in other metabolic bone disease such as Paget's disease of bone and osteomalacia. Serum β isomerised C-terminal telopeptide of type I collagen and pro-collagen I N-terminal propeptide have been designated as reference BTMs for use in osteoporosis. In addition, bone-specific isoenzyme of alkaline phosphatase (B-ALP) secreted by osteoblasts and tartrate-resistant acid phosphatase 5b (TRACP-5b) secreted by osteoclasts are also found to be specific markers of bone formation and resorption, respectively. The concentrations of the latter enzymes in blood measured by immunoassay provide reliable measures of bone turnover even in the presence of renal failure. B-ALP is recommended for use in the assessment of renal bone disease of chronic kidney disease, and TRACP-5b shows promise as a marker of bone resorption in that condition. BTMs in blood do not suffer from biological variation to the same extent as the older BTMs that were measured in urine. Appropriate patient preparation and sample handling are important in obtaining accurate measures of BTMs for clinical use. Reference change values and treatment targets have been determined for the reference BTMs for their use in monitoring osteoporosis treatment. Further ongoing studies will enhance their clinical applications.
