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Schematic illustration of circadian rhythm and commonly used terms. Midline-estimating statistic of rhythm (MESOR)
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There exists a marked circadian variation for several bone markers (BM), which is influenced by endogenous as well as exogenous factors including hormones, physical activity, and fasting. Consequently, was the aim of this review to provide an overview of the knowledge of the circadian variation of BM and which factors influence this rhythmicity. A...
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Citations
... Indeed, a marked circadian variation has been shown in some BTMs. Changes in CTx and OC expression with nighttime or early morning peaks have been highlighted [18,48,49]. On the contrary, BAP, P1NP, OPG, RANKL, and sclerostin did not appear to be significantly influenced by circadian rhythms [10,48]. ...
... Changes in CTx and OC expression with nighttime or early morning peaks have been highlighted [18,48,49]. On the contrary, BAP, P1NP, OPG, RANKL, and sclerostin did not appear to be significantly influenced by circadian rhythms [10,48]. Moreover, fasting has been shown to reduce CTx circadian variations, while it does not affect P1NP and OC expression [48]. ...
... On the contrary, BAP, P1NP, OPG, RANKL, and sclerostin did not appear to be significantly influenced by circadian rhythms [10,48]. Moreover, fasting has been shown to reduce CTx circadian variations, while it does not affect P1NP and OC expression [48]. Due to this recognized variability, the National Bone Health Alliance has suggested some tips to improve pre-analytical standardization of samples with the aim of improving the reliability and interpretation of data [50]. ...
Background: Fracture healing is a very complex and well-orchestrated regenerative process involving many cell types and molecular pathways. Despite the high efficiency of this process, unsatisfying healing outcomes, such as non-union, occur for approximately 5–10% of long bone fractures. Although there is an obvious need to identify markers to monitor the healing process and to predict a potential failure in callus formation to heal the fracture, circulating bone turnover markers’ (BTMs) utility as biomarkers in association with radiographic and clinical examination still lacks evidence so far. Methods: A systematic review on the association between BTMs changes and fracture healing in long bone non-union was performed following PRISMA guidelines. The research papers were identified via the PubMed, Cochrane, Cinahl, Web of Science, Scopus, and Embase databases. Studies in which the failure of fracture healing was associated with osteoporosis or genetic disorders were not included. Results: A total of 172 studies were collected and, given the inclusion criteria, 14 manuscripts were included in this review. Changes in circulating BTMs levels were detected during the healing process and across groups (healed vs. non-union patients and healthy vs. patients with non-union). However, we found high heterogeneity in patients’ characteristics (fracture site, gender, and age) and in sample scheduling, which made it impossible to perform a meta-analysis. Conclusions: Clinical findings and radiographic features remain the two important components of non-union diagnosis so far. We suggest improving blood sample standardization and clinical data collection in future research to lay the foundations for the effective use of BTMs as tools for diagnosing non-union.
... NE inhibits iPTH-induced Bmal1 expression in osteoblasts via βAR signaling Both plasma PTH and NE levels exhibit diurnal rhythms. 22,23 It has been reported that βAR signals in osteoblasts regulate bone anabolic metabolism via circadian clock genes. 18 Therefore, we further examined the expression of core clock genes (Bmal1, Clock, Per1, Per2, Cry1 and Cry2) (Fig. 5a-f) and found that NE significantly inhibited iPTH-induced Bmal1 expression, which was further reversed by propranolol intervention (Fig. 5a). ...
The autonomic nervous system plays a crucial role in regulating bone metabolism, with sympathetic activation stimulating bone resorption and inhibiting bone formation. We found that fractures lead to increased sympathetic tone, enhanced osteoclast resorption, decreased osteoblast formation, and thus hastened systemic bone loss in ovariectomized (OVX) mice. However, the combined administration of parathyroid hormone (PTH) and the β-receptor blocker propranolol dramatically promoted systemic bone formation and osteoporotic fracture healing in OVX mice. The effect of this treatment is superior to that of treatment with PTH or propranolol alone. In vitro, the sympathetic neurotransmitter norepinephrine (NE) suppressed PTH-induced osteoblast differentiation and mineralization, which was rescued by propranolol. Moreover, NE decreased the PTH-induced expression of Runx2 but enhanced the expression of Rankl and the effect of PTH-stimulated osteoblasts on osteoclastic differentiation, whereas these effects were reversed by propranolol. Furthermore, PTH increased the expression of the circadian clock gene Bmal1 , which was inhibited by NE-βAR signaling. Bmal1 knockdown blocked the rescue effect of propranolol on the NE-induced decrease in PTH-stimulated osteoblast differentiation. Taken together, these results suggest that propranolol enhances the anabolic effect of PTH in preventing systemic bone loss following osteoporotic fracture by blocking the negative effects of sympathetic signaling on PTH anabolism.
... M-CSF plays a role in the proliferation, differentiation, survival, and cytoskeletal rearrangement of osteoclast precursors, while RANKL is required for priming precursor cells. The balance between RANKL and another protein called osteoprotegerin (OPG) controls the differentiation and activation of osteoclasts [25]. The process of bone resorption involves the dissolution of the mineralized matrix, followed by the enzymatic degradation of the organic matrix. ...
... CTX and P1NP are the only ones with sufficient scientific documentation to attest to predictive value toward fracture risk, as demonstrated by two meta-analyses (Johansson et al. 2014;Tian et al. 2019). CTX and P1NP show marked circadian fluctuation, with significant diurnal variation in their levels (Diemar et al. 2022;Qvist et al. 2002). Since shift workers can experience circadian alterations and sleep disturbances that can result in reduced bone mass, this study evaluated CTX, P1NP and vitamin D levels in daytime and night shift workers. ...
... The increase in BTMs shown by night shift workers subtends a possible increase in the rate of bone turnover in these individuals. The circadian variability of both CTX and P1NP with a peak at night and in the early morning hours (Diemar et al. 2022), could highlight the sensitivity of the bone turn over process to circadian rhythm disruption. Consistent with our work, another recent study by Bukowska-Damska et al. (2020) showed elevated BTM values in night shift workers compared with daytime workers in a sample of 189 female blue-collar workers. ...
Night shift work is related to sleep disorders, disruption of circadian rhythm and low serum levels of vitamin D. It is known that all these conditions can adversely affect bone mass. The rate of bone turnover can be assessed through the measurement of molecules called bone turnover markers, including C-terminal telopeptide fragment of type I collagen (CTX) and procollagen type I N-terminal propeptide (P1NP). In this study, we evaluated the serum levels of CTX, P1NP and 25-Hydroxy Vitamin D in 82 male subjects (42 daytime workers and 40 night shift workers) to assess the possible risk of osteoporosis in male shift workers. Serum levels of CTX and P1NP were found to be higher in night shift workers than in daytime workers. No significant difference was found in vitamin D levels between night shift and daytime workers. The increased CTX and P1NP levels reveal a higher rate of bone turnover in night shift workers and thus a possible increased risk of osteoporosis in this category of workers compared with daytime workers. In view of this, our results highlight the importance of further studies investigating the bone health in male night shift workers.
... Examining the dynamic bone response to acute running exercise bouts is a logical approach to further investigate the effects of this exercise type on bone, which can be done by measuring changes in bone (re)modelling markers, measured in blood, before and after a running intervention. Almost all studies that have included these measurements, however, were not designed to directly answer this question and did not include a control (non-exercise) group, which makes it difficult to separate running-induced responses from circadian variation [14]. Furthermore, the results from the few studies that have included a running intervention and a control group are inconsistent. ...
... Studies were considered for inclusion if they included blood sample collections at baseline, before, during, and after prolonged, continuous treadmill running at an intensity of ≥ 65% VȮ 2max and with a duration of 60-120 min. In order to reduce variation due to circadian rhythms [14,22] and feeding [23][24][25], studies were only included if they were conducted in the morning with a baseline sample collected after an overnight fast and the rest of the samples collected in a fasted state or after consuming a non-caloric placebo. Studies were only included in this review if they involved a continuous treadmill running-based exercise bout to control for mechanical loading across studies. ...
... Together, these results suggest that the small decreases in circulating β-CTX-1 shown during and in the hours after running were caused by measurement error rather than as a result of the running intervention. These reductions in β-CTX-1 coincide with the circadian rhythm of this biomarker under fasting conditions [14], peaking in the early morning and declining in the later morning hours [51,52]. ...
Background
Circulating biomarkers of bone formation and resorption are widely used in exercise metabolism research, but their responses to exercise are not clear. This study aimed to quantify group responses and inter-individual variability of P1NP and β-CTX-1 after prolonged, continuous running (60–120 min at 65–75% V̇O2max) in young healthy adult males using individual participant data (IPD) meta-analysis.
Methods
The protocol was designed following PRISMA-IPD guidelines and was pre-registered on the Open Science Framework prior to implementation (https://osf.io/y69nd). Changes in P1NP and β-CTX-1 relative to baseline were measured during, immediately after, and in the hours and days following exercise. Typical hourly and daily variations were estimated from P1NP and β-CTX-1 changes relative to baseline in non-exercise (control) conditions. Group responses and inter-individual variability were quantified with estimates of the mean and standard deviation of the difference, and the proportion of participants exhibiting an increased response. Models were conducted within a Bayesian framework with random intercepts to account for systematic variation across studies.
Results
P1NP levels increased during and immediately after running, when the proportion of response was close to 100% (75% CrI: 99 to 100%). P1NP levels returned to baseline levels within 1 h and over the next 4 days, showing comparable mean and standard deviation of the difference with typical hourly (0.1 ± 7.6 ng·mL⁻¹) and daily (− 0.4 ± 5.7 ng·mL⁻¹) variation values. β-CTX-1 levels decreased during and up to 4 h after running with distributions comparable to typical hourly variation (− 0.13 ± 0.11 ng·mL⁻¹). There was no evidence of changes in β-CTX-1 levels during the 4 days after the running bout, when distributions were also similar between the running data and typical daily variation (− 0.03 ± 0.10 ng·mL⁻¹).
Conclusion
Transient increases in P1NP were likely biological artefacts (e.g., connective tissue leakage) and not reflective of bone formation. Comparable small decreases in β-CTX-1 identified in both control and running data, suggested that these changes were due to the markers’ circadian rhythm and not the running intervention. Hence, prolonged continuous treadmill running did not elicit bone responses, as determined by P1NP and β-CTX-1, in this population.
... The circadian rhythm [26] is the first factor to be considered, as it will determine whether early morning sample collection is required. CTX is significantly influenced by circadian rhythm, with peak values occurring between 1:30 and 4:30 a.m., and minimum values occurring between 11 a.m. and 3 p.m. [2]. ...
... Therefore, it is recommended to draw blood between 8 and 10 a.m. Less significant circadian variability has been observed in PINP and bone alkaline phosphatase [26]. ...
Bone markers are a group of substances released into circulation during bone formation and/or resorption. These substances can be measured in blood and urine to obtain information about metabolic bone disorders. This review provides an insight into factors influencing bone marker variability and describes different approaches to minimize variability and interpret results appropriately. Variability in bone marker concentrations results from biological and analytical variability across assays. Other influencing factors include gender, age, physical exercise, circadian rhythm, and diet. The multiplicity of influencing factors hinders the establishment of accurate reference values. Gaining a deep understanding of bone marker variability is the first step to ascertain their clinical usefulness. Bone marker variability can be minimized by controlling as many variables as it is possible and through the standardization of patient preparation and sample collection and handling.
... El ritmo circadiano [26] es el primer factor a tener en cuenta y el que va a determinar que pueda ser necesario recoger la muestra a primera hora de la mañana. El CTX tiene un sustancial ritmo circadiano, observándose que el pico máximo se observa entre las 1:30 y las 4:30 de la madrugada, mientras que el mínimo se observa entre las 11 y las 15 horas (2). ...
... Por ello, se recomienda realizar la extracción de sangre entre las 8 y las 10 de la mañana. En cambio, el ritmo circadiano de PINP y fosfatasa alcalina ósea es de menor amplitud [26]. ...
Resumen
Los biomarcadores óseos son un conjunto de sustancias que son liberadas a la circulación sanguínea durante el proceso de formación y/o resorción ósea y que podemos medir en sangre y orina para obtener información sobre los trastornos metabólicos del hueso. La revisión traza una perspectiva sobre los factores que influyen en la variabilidad de los biomarcadores óseos y describe los aspectos a considerar para reducirla al máximo e interpretar los resultados de manera adecuada. La variabilidad que podemos observar en la concentración de los biomarcadores óseos engloba diversos aspectos que abarcan desde su variabilidad biológica y la variabilidad de los ensayos empleados en su medida hasta la variabilidad derivada de la influencia de numerosos factores, entre los cuales el sexo, la edad, el ejercicio, su ritmo circadiano o la dieta. Todo ello se refleja en la dificultad de establecer valores de referencia precisos. El conocimiento de esta variabilidad es el primer desafío que debe afrontar su empleo en la práctica clínica. Es necesario minimizar la variabilidad de los biomarcadores óseos controlando el máximo de variables que sea posible, así como estandarizando la preparación del paciente antes de la toma de las muestras, así como su obtención y manejo.
... For e.g., it was demonstrated that OPG is one of the key biologically active substances that determine the relationship between metabolic syndrome and cardiovascular risk [65][66][67]. Clinical studies established that OPG may also be a risk factor for progressive atherosclerotic cardiovascular disease [84,[97][98][99]. ...
Non-alcoholic fatty liver disease (NAFLD) is reaching epidemic proportions worldwide. Moreover, the prevalence of this liver disease is expected to increase rapidly in the near future, aligning with the rise in obesity and the aging of the population. The pathogenesis of NAFLD is considered to be complex and to include the interaction between genetic, metabolic, inflammatory, and environmental factors. It is now well documented that NAFLD is linked to the other conditions common to insulin resistance, such as abnormal lipid levels, metabolic syndrome, and type 2 diabetes mellitus. Additionally, it is considered that the insulin resistance may be one of the main mechanisms determining the disturbances in both bone tissue metabolism and skeletal muscles quality and functions in patients with NAFLD. To date, the association between NAFLD and osteoporosis has been described in several studies, though it worth noting that most of them included postmenopausal women or elderly patients and originated from Asia. However, taking into account the health and economic burdens of NAFLD, and the increasing prevalence of obesity in children and adolescents worldwide, further investigation of the relationship between osteopenia, osteoporosis and sarcopenia in NAFLD, including in young and middle-aged patients, is of great importance. In addition, this will help to justify active screening and surveillance of osteopenia and osteoporosis in patients with NAFLD. In this review, we will discuss various pathophysiological mechanisms and possible biologically active molecules that may interplay between NAFLD and bone tissue metabolism.
... VC in patients with CKD is associated with several traditional and nontraditional risk factors of CVD, including mineral metabolism disorders, for which serum sclerostin is a marker [5,6]. Indeed, sclerostin is a key osteocyte-derived soluble inhibitor of the Wnt signaling pathway and an indicator of bone formation that can suppress osteoblast differentiation and proliferation and promote osteoblast apoptosis [7,8]. Serum or circulating sclerostin is significantly increased among uremic patients and might promote CKD progression [9,10]. ...
Vascular calcification (VC) is recognized as a predictor of all-cause and CVD mortality in chronic kidney disease (CKD). VC in CKD is possibly associated with serum sclerostin. The study systematically investigated the role of serum sclerostin in VC in CKD. Following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols, a systematic search was performed of the PubMed, Cochrane Library, and EMBASE databases from inception to 11 November 2022, to identify relevant eligible studies. The data were retrieved, analyzed, and summarized. The hazard ratios (HRs) and odds ratios (ORs) with their corresponding confidence intervals (CIs) were derived and pooled. Thirteen reports (3125 patients) met the inclusion criteria and were included. Sclerostin was associated with the presence of VC (pooled OR = 2.75, 95%CI = 1.81–4.19, p < 0.01) and all-cause mortality (pooled HR = 1.22, 95%CI = 1.19–1.25, p < 0.01) among patients with CKD, but with a decreased risk of cardiovascular events (HR = 0.98, 95%CI = 0.97–1.00, p = 0.02). This meta-analysis suggests that serum sclerostin is associated with VC and all-cause mortality among patients with CKD.
... Additionally, levels of sCOMP remain stable both within minutes (interday) and 1-2 days post-exertion (intraday), demonstrating both strong interday and intraday reliability [87]. Nonetheless, sCOMP levels fluctuate following circadian rhythmicity patterns, like CTX-II [88], so it is recommended that sampling is always performed at the same time of the day (best in the morning), and in patients that follow a stable dietary regime [88]. Furthermore, sCOMP appears to be better for the detection of knee OA, while CTX-II seems more specific for the detection of hip OA [36]. ...
... Additionally, levels of sCOMP remain stable both within minutes (interday) and 1-2 days post-exertion (intraday), demonstrating both strong interday and intraday reliability [87]. Nonetheless, sCOMP levels fluctuate following circadian rhythmicity patterns, like CTX-II [88], so it is recommended that sampling is always performed at the same time of the day (best in the morning), and in patients that follow a stable dietary regime [88]. Furthermore, sCOMP appears to be better for the detection of knee OA, while CTX-II seems more specific for the detection of hip OA [36]. ...
Physiological aging triggers a cascade of negative effects on the human body and the human joint is only one of the several compartments affected by this irreversible and natural process. Osteoarthritis and cartilage degeneration can cause pain and disability; therefore, identifying the molecular processes underlying these phenomena and the biomarkers produced during physical activity is of critical importance. In the present review, the main goal was to identify and discuss the articular cartilage biomarkers analyzed in studies in which physical or sports activities were adopted and eventually to propose a standard operating procedure for the assessment. Articles collected from Pubmed, Web of Science, and Scopus were scrutinized to detect reliable cartilage biomarkers. The principal articular cartilage biomarkers detected in these studies were cartilage oligomeric matrix protein, matrix metalloproteinases, interleukins, and carboxy-terminal telopeptide. The articular cartilage biomarkers identified in this scoping review may aid in a better comprehension of where research on the topic is heading and offer a viable instrument for streamlining investigations on cartilage biomarker discovery.
