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BACKGROUND: Coronavirus disease 19 (COVID-19) is a viral infection mediated by coronavirus-2 that causes severe acute respiratory syndrome (SARS-CoV-2). The disease may affect biochemical parameters and electrolytes. C-terminal cross-linking telopeptide (CTX-I) is released during mature bone resorption and is a biomarker for predicting bone resorption. OBJECTIVES: As the pandemic progressed, understanding the effects of COVID-19 disease remained critical. Inflammatory responses triggered by the virus can result in a bone metabolism regulation imbalance. As such, this study aimed to analyze serum levels of CTX-I, calcium (CA), phosphorus (P), magnesium (Mg), C-reactive protein (CRP), and alkaline phosphatase (ALP) in COVID-19 patients to investigate the relationship between bone resorption and the disease. MATERIAL AND METHODS: The study included 56 individuals with COVID-19 (divided into mild, moderate and severe subgroups depending on disease severity) and 25 healthy adults as a control group. Serum CTX-I concentrations were measured with enzyme-linked immunosorbent assay (ELISA). In addition, CRP, Ca, Mg, P, and ALP levels were measured using an automated clinical chemistry analyzer. RESULTS: Serum CTX-I levels were significantly higher in COVID-19 patients than in the control group (p < 0.05). Furthermore, a positive weak relationship was detected between CRP and CTX-I (r = 0.303, p < 0.05). CONCLUSIONS: Increased serum CTX-I levels in the patient group caused COVID-19-driven bone degradation, though serum CTX-I levels did not differ according to disease severity.

Asunto(s)

Biomarcadores , Proteína C-Reactiva , COVID-19 , Colágeno Tipo I , Péptidos , Humanos , COVID-19/sangre , COVID-19/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Estudios de Casos y Controles , Biomarcadores/sangre , Estudios Prospectivos , Colágeno Tipo I/sangre , Adulto , Proteína C-Reactiva/análisis , Proteína C-Reactiva/metabolismo , Péptidos/sangre , Fosfatasa Alcalina/sangre , SARS-CoV-2 , Calcio/sangre , Resorción Ósea/sangre , Anciano , Índice de Severidad de la Enfermedad , Magnesio/sangre , Fósforo/sangre

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INTRODUCTION: We assessed whether collagen supplementation augments the effects of high-impact exercise on bone turnover and whether a higher exercise frequency results in a greater benefit for bone metabolism. METHODS: In this randomized, cross-over trial, 14 healthy males (age 24 ± 4 y, BMI 22.0 ± 2.1 kg/m2) performed 5-min of high-impact exercise once (JUMP+PLA and JUMP+COL) or twice daily (JUMP2+COL2) during a 3-day intervention period, separated by a 10-day wash out period. One hour before every exercise bout participants ingested 20 g hydrolysed collagen (JUMP+COL and JUMP2+COL2) or a placebo control (JUMP+PLA). Blood markers of bone formation (P1NP) and resorption (CTXI) were assessed in the fasted state before the ingestion of the initial test drinks and 24, 48, and 72 h thereafter. In JUMP+PLA and JUMP+COL, additional blood samples were collected in the postprandial state at 1, 2, 3, 4, 5 and 13 h after ingestion of the test drink. RESULTS: In the postprandial state, serum P1NP concentrations decreased marginally from 99 ± 37 to 93 ± 33 ng/mL in JUMP+COL, and from 97 ± 32 to 92 ± 31 ng/mL in JUMP+PLA, with P1NP levels having returned to baseline levels after 13 h (time-effect, P = 0.053). No differences in serum P1NP concentrations were observed between JUMP+PLA and JUMP+COL (time x treatment, P = 0.58). Serum CTX-I concentrations showed a ~ 50 % decline (time, P < 0.001) in the postprandial state in JUMP+COL (0.9 ± 0.3 to 0.4 ± 0.2 ng/mL) and JUMP+PLA (0.9 ± 0.3 to 0.4 ± 0.2 ng/mL), with no differences between treatments (time x treatment, P = 0.17). Fasted serum P1NP concentrations increased ~8 % by daily jumping exercise (time-effect, P < 0.01), with no differences between treatments (time x treatment, P = 0.71). Fasted serum CTX-I concentrations did not change over time (time-effect, P = 0.41) and did not differ between treatments (time x treatment, P = 0.58). CONCLUSIONS: Five minutes of high-impact exercise performed daily stimulates bone formation during a 3-day intervention period. This was indicated by an increase in fasted serum P1NP concentrations, rather than an acute increase in post-exercise serum P1NP concentrations. Collagen supplementation or an increase in exercise frequency does not further increase serum P1NP concentrations. The bone resorption marker CTX-I was not affected by daily short-duration high-impact exercise with or without concurrent collagen supplementation.

Asunto(s)

Remodelación Ósea , Colágeno Tipo I , Masculino , Humanos , Adulto Joven , Adulto , Estudios Cruzados , Biomarcadores/metabolismo , Colágeno , Procolágeno , Suplementos Dietéticos , Poliésteres/farmacología , Fragmentos de Péptidos

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BACKGROUND: Focal bone microcracks with osteoclast recruitment and bone lysis, may reduce fracture resistance in racehorses. As current imaging does not detect all horses at risk for fracture, the discovery of novel serum biomarkers of bone resorption or osteoclast activity could potentially address this unmet clinical need. The biology of equine osteoclasts on their natural substrate, equine bone, has never been studied in vitro and may permit identification of specific biomarkers of their activity. OBJECTIVES: (1) Establish osteoclast cultures on equine bone, (2) Measure biomarkers (tartrate resistant acid phosphatase isoform 5b [TRACP-5b] and C-terminal telopeptide of type I collagen [CTX-I]) in vitro and (3) Study the effects of inflammation. STUDY DESIGN: In vitro experiments. METHODS: Haematopoietic stem cells, from five equine sternal bone marrow aspirates, were differentiated into osteoclasts and cultured either alone or on equine bone slices, with or without a pro-inflammatory stimulus (IL-1ß or LPS). CTX-I and TRACP-5b were immunoassayed in the media. Osteoclast numbers and bone resorption area were assessed. RESULTS: TRACP-5b increased over time in osteoclast cultures without bone (p < 0.0001) and correlated with osteoclast number (r = 0.63, p < 0.001). CTX-I and TRACP-5b increased with time for cultures with bone (p = 0.002; p = 0.02 respectively), correlated with each other (r = 0.64, p < 0.002) and correlated with bone resorption (r = 0.85, p < 0.001; r = 0.82, p < 0.001 respectively). Inflammation had no measurable effects. MAIN LIMITATIONS: Specimen numbers limited. CONCLUSIONS: Equine osteoclasts were successfully cultured on equine bone slices and their bone resorption quantified. TRACP-5b was shown to be a biomarker of equine osteoclast number and bone resorption for the first time; CTX-I was also confirmed to be a biomarker of equine bone resorption in vitro. This robust equine specific in vitro assay will help the study of osteoclast biology.

Asunto(s)

Resorción Ósea , Fracturas Óseas , Enfermedades de los Caballos , Caballos , Animales , Osteoclastos , Fosfatasa Ácida Tartratorresistente/farmacología , Fosfatasa Ácida/farmacología , Isoenzimas/farmacología , Biomarcadores , Resorción Ósea/veterinaria , Fracturas Óseas/veterinaria , Inflamación/veterinaria , Enfermedades de los Caballos/diagnóstico

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PURPOSE OF REVIEW: To describe recent advances in the understanding of how gut-derived hormones regulate bone homeostasis in humans with emphasis on pathophysiological and therapeutic perspectives in diabetes. RECENT FINDINGS: The gut-derived incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is important for postprandial suppression of bone resorption. The other incretin hormone, glucagon-like peptide 1 (GLP-1), as well as the intestinotrophic glucagon-like peptide 2 (GLP-2) has been shown to suppress bone resorption in pharmacological concentrations, but the role of the endogenous hormones in bone homeostasis is uncertain. For ambiguous reasons, both patients with type 1 and type 2 diabetes have increased fracture risk. In diabetes, the suppressive effect of endogenous GIP on bone resorption seems preserved, while the effect of GLP-2 remains unexplored both pharmacologically and physiologically. GLP-1 receptor agonists, used for the treatment of type 2 diabetes and obesity, may reduce bone loss, but results are inconsistent. GIP is an important physiological suppressor of postprandial bone resorption, while GLP-1 and GLP-2 may also exert bone-preserving effects when used pharmacologically. A better understanding of the actions of these gut hormones on bone homeostasis in patients with diabetes may lead to new strategies for the prevention and treatment of skeletal frailty related to diabetes.

Asunto(s)

Resorción Ósea , Diabetes Mellitus Tipo 2 , Hormonas Gastrointestinales , Humanos , Incretinas/uso terapéutico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptido 1 Similar al Glucagón , Polipéptido Inhibidor Gástrico , Resorción Ósea/tratamiento farmacológico , Péptido 2 Similar al Glucagón

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Introduction: Sepsis is a common clinical syndrome and nearly 20% of all deaths are related to sepsis. As an important part of the body, bone homeostasis disorders are closely related to inflammatory response, but the correlation between bone homeostasis and sepsis, sepsis shock was unknown. The objective of this study was to explore the relation of bone homeostasis on sepsis and sepsis shock. Methods: In this retrospective cohort study, patients were enrolled between April 2018 and May 2022 from Beijing Chaoyang hospital. Primary outcomes were serum indicators reflected bone homeostasis, such as cross-linked carboxy-terminal telopeptide of type I collagen (CTX-I), tartrate-resistant acid phosphatase 5b (TRACP-5b) and piezo-type mechanosensitive ion channel component 1 (PIEZO1). Results: The data were analyzed retrospectively. among 88 evaluable patients, 45 were sepsis (19 were sepsis shock) and 43 were non-sepsis. There was no significant difference in age, gender, BMI, combination diseases, operation time, intraoperative blood loss, and hospital stay. Patients with sepsis or sepsis shock had higher serum CTX-I, TRACP-5b, PIEZO1 (p < 0.05). Spearman's rank correlation test showed that CTX-I, TRACP-5b, PIEZO1 and the three together (CTX-I + TRACP-5b + PIEZO1) had strong correlation with sepsis or sepsis shock (p < 0.05). The receiver operating characteristic curve (ROC) and precision-recall curve (PRC) showed that these indicators could predict the occurrence of sepsis or sepsis shock (p < 0.05). Besides, decision curve analysis (DCA) and interventions avoided curve (IAC) displayed a high net benefit of bone homeostasis disorders indicators on sepsis or sepsis shock. Kaplan-Meier survival curves revealed that sepsis or shock patients with high value indicators (>0.47227) had a higher mortality (p < 0.05). Conclusion: Bone homeostasis disorders could increase the mortality of sepsis and sepsis shock patients.

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Immune checkpoint inhibitors (ICIs) has revolutionized the treatment of different advanced solid tumors, but most patients develop severe immune-related adverse events (irAEs). Although a bi-directional crosstalk between bone and immune systems is widely described, the effect of ICIs on the skeleton is poorly investigated. Here, we analyze the changes in plasma levels of type I collagen C-terminal telopeptide (CTX-I) and N-terminal propeptide of type I procollagen (PINP), reference makers of bone turnover, in patients treated with ICIs and their association with clinical outcome. A series of 44 patients affected by advanced non-small cell lung cancer or renal cell carcinoma, without bone metastases, and treated with ICIs as monotherapy were enrolled. CTX-I and PINP plasma levels were assessed at baseline and after 3 months of ICIs treatment by ELISA kits. A significant increase of CTX-I with a concomitant decreasing trend towards the reduction of PINP was observed after 3 months of treatment. Intriguingly, CTX-I increase was associated with poor prognosis in terms of treatment response and survival. These data suggest a direct relationship between ICIs treatment, increased osteoclast activity and potential fracture risk. Overall, this study reveals that ICIs may act as triggers for skeletal events, and if confirmed in larger prospective studies, it would identify a new class of skeletal-related irAEs.

RESUMEN

The aim of this study was to evaluate the effect of anti-tumor necrosis factor α (anti-TNF-α) therapy in combination with methotrexate on bone remodeling and osteoclastogenesis in female patients with RA. Serum levels of bone turnover markers (i.e., C- and N-terminal propeptides of type I procollagen (PICP and PINP), C- and N-terminal cross-linking telopeptides of type I collagen (CTX-I and NTX-I), and soluble receptor activator of nuclear factor κB ligand (sRANKL) and osteoprotegerin (OPG)) were determined by immunoassay at baseline and 15 months after initiation of treatment. Bone mineral density was measured by dual-energy x-ray absorptiometry. We found a significant decrease in serum PINP levels, a biomarker of bone formation, and higher levels of CTX-I and sRANKL indicative of increased bone resorption in RA patients prior to TNFαI treatment compared to the controls. Anti-TNF-α therapy was effective in improving bone metabolism in RA patients as reflected in a decrease in CTX-I (at least partially due to the RANKL/OPG reduction) and a concomitant increase in PINP levels. The bone metabolism changes were independent of the type of TNFαI used. PINP and CTX-I were found to be useful markers of bone metabolism, which may prove the effectiveness of TNF-α therapy earlier than the bone density assessment.

RESUMEN

OBJECTIVES: This study investigated the association of changes in cementum protein-1 (CEMP-1), dentine phosphoprotein (DPP), and c-terminal cross-linked telopeptide of type I collagen (CTX-I) levels in human gingival crevicular fluid (GCF) under constant load with external root resorption volume and amount of tooth movement. MATERIALS AND METHODS: In total, 11 healthy adult patients (mean age, 23.5 years [range, 18.3-37.7]; four men and seven women) were enrolled. GCF samples were obtained from premolars at T0, T1 (1 day), T2 (1 week), T3 (2 weeks), T4 (4 weeks), and T5 (8 weeks) under constant 100-gm buccal tipping force. Opposite premolars were used as controls. Teeth were extracted at T5, followed by quantification of external root resorption volume and histological analysis. RESULTS: In the test group, T5/T0 ratios of CEMP-1 and DPP levels, differential CEMP-1 levels between T5 and T0, and differential DPP levels between T2 and T0 correlated positively with root resorption volume (r = 0.734, 0.730, 0.627, and 0.612, respectively, all p < 0.05). CEMP-1 levels at T0 and T3 correlated negatively with root resorption volume (r = -0.603 and -0.706; all p < 0.05). CTX-I levels at T5 correlated positively with the amount of tooth movement (r = 0.848, p < 0.01). CONCLUSIONS: Alterations in CEMP-1 and DPP levels in human GCF at specific timepoints during orthodontic treatment may be associated with different degrees of external root resorption. CLINICAL RELEVANCE: This study demonstrates that changes in the levels of tissue-specific biomarkers in GCF may facilitate early detection of external root resorption during orthodontic tooth movement.

Asunto(s)

Resorción Radicular , Adulto , Diente Premolar , Biomarcadores/análisis , Femenino , Líquido del Surco Gingival/química , Humanos , Masculino , Técnicas de Movimiento Dental , Adulto Joven

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OBJECTIVES: This study explores changes in the bone homeostasis by testing the N-terminal collagen type I extension propeptide (PINP) marker for osteo-formation and the carboxy-terminal region of collagen type I (CTX-I) marker for osteo-resorption in patients taking tocilizumab for polymyalgia rheumatica (PMR). METHODS: Twenty patients were included in the prospective open-label TENOR study (Clinicaltrials.gov NCT01713842) and received three monthly tocilizumab infusions, followed by corticosteroids starting at week (W) 12. PINP and CTX-I were tested at inclusion (W0), after tocilizumab but before steroid initiation (W12), at the end of the protocol (W24) and were compared to healthy controls. Information regarding disease activity, bone mineral density using scanographic bone attenuation correlation (SBAC), inflammatory parameters and interleukin (IL)-6 levels were collected during the follow-up of the patients. RESULTS: PMR patients were characterised by a reduction in bone mineral density and a higher level of CTX-I relative to healthy controls matched in age and sex at baseline. PINP levels increased at W12 (P< 0.001, versus W0) following tocilizumab introduction and CTX-I levels decreased at W24 and after steroid initiation (P=0.001, versus W0). Such modifications explain the altered correlation observed between PINP and CTX-I at W0 (r=0.255 at W0 versus r=0.641 in healthy controls) and its correction after treatment (r=0.760 at W12 and r=0.767 at W24). Finally, greater changes in PINP were observed in patients whose circulating IL-6 levels decreased after tocilizumab therapy. CONCLUSIONS: Control of bone turnover, in part through the inhibition of the IL-6 axis, is observed during tocilizumab and subsequent steroid treatment of PMR.

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Polimialgia Reumática , Anticuerpos Monoclonales Humanizados/uso terapéutico , Biomarcadores , Densidad Ósea , Remodelación Ósea , Colágeno Tipo I , Humanos , Fragmentos de Péptidos , Polimialgia Reumática/diagnóstico por imagen , Polimialgia Reumática/tratamiento farmacológico , Estudios Prospectivos

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Type 2 diabetes (T2D) is characterized by increased fracture risk despite higher BMD and reduced bone turnover. BMD underestimates fracture risk in T2D, but the predictive role of bone turnover markers (BTMs) on fracture risk in T2D has not been explored. Thus, we sought to determine whether BTMs predict incident fractures in subjects with T2D. For this case-cohort study, we used data from the Health, Aging, and Body Composition (Health ABC) Study of well-functioning older adults, aged 70 to 79 years at baseline (April 1997-June 1998). The case-cohort sample consisted of (i) the cases, composed of all 223 participants who experienced incident fractures of the hip, clinical spine, or distal forearm within the first 9 years of study follow-up; and (ii) the subcohort of 508 randomly sampled participants from three strata at baseline (T2D, prediabetes, and normoglycemia) from the entire Health ABC cohort. A total of 690 subjects (223 cases, of whom 41 were in the subcohort) were included in analyses. BTMs (C-terminal telopeptide of type I collagen [CTX], osteocalcin [OC], and procollagen type 1 N-terminal propeptide [P1NP]) were measured in archived baseline serum. Cox regression with robust variance estimation was used to estimate the adjusted hazard ratio (HR) for fracture per 20% increase in BTMs. In nondiabetes (prediabetes plus normoglycemia), fracture risk was increased with higher CTX (HR 1.10; 95% confidence interval [CI], 1.01 to 1.20 for each 20% increase in CTX). Risk was not increased in T2D (HR 0.92; 95% CI, 0.81 to 1.04; p for interaction .045). Similarly, both OC and P1NP were associated with higher risk of fracture in nondiabetes, but not in T2D, with p for interaction of .078 and .109, respectively. In conclusion, BTMs did not predict incident fracture risk in T2D but were modestly associated with fracture risk in nondiabetes. © 2020 American Society for Bone and Mineral Research.

Asunto(s)

Remodelación Ósea , Diabetes Mellitus Tipo 2 , Fracturas Óseas/epidemiología , Anciano , Biomarcadores , Densidad Ósea , Estudios de Cohortes , Colágeno Tipo I , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Humanos , Fragmentos de Péptidos , Péptidos , Procolágeno

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It has been hypothesized that sweat loss during exercise causes a disruption in calcium homeostasis that activates bone resorption and over time leads to low bone mineral density. The purpose of this small pilot study was to determine whether dermal calcium loss from a bout of excessive sweating during light intensity physical activity triggers an increase in biomarkers of bone resorption. Biochemical markers related to bone homeostasis were measured before and after a 90 min Bikram hot yoga practice performed in a room heated to 105 °F with 40 % humidity. Participants were five females with a mean age of 47.4 ± 4.7 years. Nude body weight, serum total calcium (Ca2+), free ionized calcium, albumin, parathyroid hormone (PTH) and CTX-I were measured before and after a Bikram hot yoga practice. Mean estimated sweat loss was 1.54 ± 0.65 L, which elicited a 1.9 ± 0.9 % decrease in participant's body weight. Mean Ca2+ concentration in sweat was 2.9 ± 1.7 mg/dl and the estimated mean total calcium lost was 41.3 ± 16.4 mg. Serum ionized Ca2+ increased from 4.76 ± 0.29 mg/dl to 5.35 ± 0.36 mg/dl after the Bikram hot yoga practice (p = 0.0118). Serum PTH decreased from pre- 33.9 ± 3.3 pg/ml to post- 29.9 ± 2.1 pg/ml yoga practice (p = 0.0015) when adjusted for hemoconcentration (PTHADJ), implying a decrease in PTH secretion. We conclude that calcium loss in sweat during 90 min of Bikram hot yoga did not trigger an increase in PTH secretion and did not initiate bone resorption.

Asunto(s)

Resorción Ósea/sangre , Calcio/sangre , Hormona Paratiroidea/sangre , Sudoración , Yoga , Adulto , Anciano , Femenino , Calor , Humanos , Persona de Mediana Edad , Proyectos Piloto , Sudor/química

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Hypocalcemia is a common finding in critically ill equine patients. Parathyroid hormone (PTH) helps to maintain calcium homeostasis in hypocalcemic patients by promoting renal calcium reabsorption and bone resorption. Increased serum PTH concentrations have been reported in critically ill people and animals, including horses and foals. It is unknown whether increased secretion of PTH is associated with markers of bone turnover in hospitalized foals. The goals of this study were to measure markers of bone resorption (C-terminal telopeptide of type I collagen [CTX-I]) and bone formation (osteocalcin [OCN]; alkaline phosphatase [ALP]) and to determine their association with PTH concentrations, disease severity, and mortality in hospitalized foals. This prospective, multicenter, cross-sectional study was conducted on 75 newborn foals ≤3 d old divided into hospitalized (n = 65; 41 septic; 24 sick nonseptic) and healthy (n = 10) groups. Blood samples were collected on admission to measure serum CTX-I, OCN, and PTH concentrations and ALP activity. Data were analyzed by nonparametric methods and univariate logistic regression. Serum CTX-I and PTH concentrations were significantly higher, whereas OCN concentrations were lower, in septic compared with healthy foals (P < 0.05). Serum ALP activity was not different between groups; however, it was lower in hospitalized and septic foals with low OCN concentrations (P < 0.05). In hospitalized foals, PTH concentrations were positively correlated with CTX-I concentrations and inversely associated with ALP activity (P < 0.05). High CTX-I and low OCN concentrations were associated with disease severity (P < 0.05). Hospitalized nonsurviving foals had significantly lower OCN concentrations compared with survivors (P < 0.05), but CTX-I concentrations were not associated with survival. Hospitalized foals with PTH concentrations >12.4 pmol/L were more likely to die (OR = 1.5; 95% CI = 1.1-4.16; P < 0.05). Elevated PTH and CTX-I together with reduced OCN concentrations and ALP activity in sick foals indicates that bone resorption is increased during critical illness, which may be a compensatory mechanism to correct hypocalcemia or reflect a response to systemic inflammation and metabolic imbalances. Bone resorption could negatively impact skeletal development in the growing foal. Low OCN and high PTH concentrations were predictors of nonsurvival in hospitalized foals.

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Fosfatasa Alcalina/sangre , Colágeno Tipo I/sangre , Enfermedades de los Caballos/sangre , Osteocalcina/sangre , Hormona Paratiroidea/sangre , Animales , Animales Recién Nacidos , Biomarcadores/sangre , Femenino , Caballos , Hospitales Veterinarios , Masculino , Sepsis/sangre , Sepsis/veterinaria

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Intermittent exercise might be an efficient means of exercise for improving bone strength and quality. The aim of our study was to examine the effect of intermittent running on bone turnover markers using altered exercise-to-rest intervals. Twelve males completed one control (no exercise), and three, 45-min intermittent protocols (5, 20, and 80 s intervals) matched for distance and speed. Fasted venous blood samples were collected at baseline, 1, 2 and 24 h post-exercise. Carboxyterminal crosslinked telopeptide (CTX-I) and procollagen type 1 amino-terminal propeptide (P1NP) were used as markers of bone resorption and formation. After adjustment for baseline, CTX-I concentration at 1 h was higher (very likely to most likely small) for 5 s (30.2%; ±90% confidence limits: 10%), 20 s (2.9.0%; ±10%) and 80 s (32.0%; ±10%) compared to control. The very likely small effect remained for 5 s at 2 h (30.2%; ±15%). The effect for 20 and 80 s was possibly trivial and possibly small/possibly trivial (∼14.5%; ±âˆ¼15%). Differences in P1NP concentrations were likely to very likely trivial (∼7.4%; ±âˆ¼7.6%). Circulating CTX-I concentration is affected acutely by intermittent running with short-interval (5 s) intermittent loading resulting in a prolonged attenuation in circadian rhythm of CTX-I up to 2 h that was not demonstrated as clearly by longer intervals despite matched internal and external training load.

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Biomarcadores/metabolismo , Remodelación Ósea , Colágeno Tipo I/metabolismo , Fragmentos de Péptidos/metabolismo , Péptidos/metabolismo , Procolágeno/metabolismo , Carrera , Adolescente , Adulto , Voluntarios Sanos , Humanos , Masculino , Adulto Joven

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BACKGROUND: We aimed to establish age- and gender-specific reference ranges for concentrations of the bone markers osteocalcin (OC), procollagen type 1 N-propeptides (PINP) and carboxy-terminal cross-linking telopeptide of type 1 collagen (CTX-I) as well as for the calciotropic hormones 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) in healthy infants, children and adolescents. In addition, the effect of age, gender, puberty and body mass index (BMI) on bone markers was investigated. METHODS: 2416 healthy subjects (5714 blood withdrawals), aged 3 months to 17 years, were included to estimate the age- and gender-dependence of reference ranges. Subsequently, measured values of the biomarkers were transformed to standard deviation scores (SDS) and their associations with age, gender and puberty were analyzed. Bone marker-SDS values of the reference cohort were compared with an obese cohort (n = 317 and 489 blood withdrawals) to analyze the effect of BMI. RESULTS: OC, PINP and CTX-I showed a distinct age- and gender-dependence with peak levels at 10 to 11 years (girls, Tanner 3) and 13 years (boys, Tanner 3-4). Children with obesity had significantly lower SDS levels for OC (-0.44), PINP (-0.27), CTX-I (-0.33), 25(OH)D (-0.43) and higher SDS levels for PTH (+0.44) than the reference cohort. CONCLUSIONS: OC, PINP and CTX-I vary with age, gender and pubertal stage. The body weight status has to be considered in the interpretation of pediatric OC, PINP, CTX-I, 25(OH)D and PTH levels. Consequences of childhood obesity on bone health should be carefully investigated in long-term studies.

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Remodelación Ósea , Hormona Paratiroidea , Adolescente , Biomarcadores , Niño , Colágeno Tipo I , Femenino , Humanos , Lactante , Masculino , Obesidad , Fragmentos de Péptidos , Procolágeno , Valores de Referencia , Vitamina D/análogos & derivados

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This study aimed to explore the improvement of hip replacement combined with alendronate sodium on the condition of patients with osteoporotic femoral neck fracture and factors affecting the efficacy of patients. In total, 140 patients with femoral neck fracture from July 2015 to October 2017 in the Affiliated Xuzhou Hospital of Jiangsu University were collected. Of these, 61 patients were treated with hip replacement as the control group and 79 patients were treated with alendronate sodium as the observation group on the basis of the control group. ELISA was used to detect levels of carboxy-terminal opeptide of type I collagen (CTX-I) and bone alkaline phosphatase (BALP) in serum of patients before and after treatment. Harris score was used to compare the clinical efficacy of patients after treatment. Changes in the expression of CTX-I and BALP before and after treatment were compared between the two groups, and the correlation between CTX-I and BALP levels and Harris score was analyzed. According to the clinical efficacy of patients, the two groups were divided into the significant effect group and poor effect group. Risk factors affecting the efficacy of patients were analyzed, and the ROC of subjects with risk factors was drawn. After treatment, the expression of BALP in serum increased significantly compared with that before treatment, and the expression of CTX-I decreased significantly. After treatment, the expression of BALP in serum in the observation group was significantly higher than that in the control group (P<0.05). Multivariate analysis revealed that age, time of operation, CTX-I after treatment and BALP after treatment were independent risk factors affecting the efficacy of patients. In conclusion, hip replacement combined with alendronate sodium can effectively improve the clinical efficacy of patients, and age, time of operation, CTX-I after treatment and BALP after treatment are found to be independent risk factors affecting the postoperative efficacy of patients.

RESUMEN

There is no agreement on the role of obesity as a protection or unfavorable factor on bone. In the present study, the association of body mass index (BMI) and waist circumference (WC) with osteocalcin, C-terminal telopeptide of type 1 collagen (CTX-I), highly sensitive C-reactive protein (hs-CRP), parathormon (PTH) and 25-hydroxyvitamin D (25(OH)D) in elderly people was investigated. This cross-sectional study was conducted on 178 elderly residents in Tehran, with a mean age of 67.04 (60-83). Serum osteocalcin, hs-CRP, 25(OH) D, PTH and urine CTX-I were measured for all participants. Waist circumference, weight and height were measured and BMI was calculated. Linear regression and Pearson correlation were performed to evaluate the relation of BMI and waist circumference with other variables. A significant inverse association was found between BMI with osteocalcin (ß = - 0.171, p = 0.027) after control for covariates. In addition, there were a significant relation of BMI and WC with hs-CRP (ß = 0.246, p = 0.002 and ß = 0.219, p = 0.006, respectively) and PTH (ß = 0.1169, p = 0.040 and ß = 0.200, p = 0.018), respectively. The present study did not show a significant relation of BMI and WC with urine CTX-I even after adjustment for potential confounders (ß = - 0.143, p = 0.065 and ß = - 0.104, p = 0.183, respectively). The present study has concluded that obesity is an undesirable factor for bone metabolism by reducing serum osteocalcin and by increasing hs-CRP and PTH which contribute to bone resorption.

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Índice de Masa Corporal , Colágeno Tipo I/metabolismo , Osteocalcina/metabolismo , Péptidos/metabolismo , Circunferencia de la Cintura , Anciano , Biomarcadores/metabolismo , Huesos/metabolismo , Proteína C-Reactiva/metabolismo , Estudios Transversales , Femenino , Humanos , Irán , Masculino , Obesidad , Vitamina D/análogos & derivados , Vitamina D/metabolismo

RESUMEN

Measurements of bone markers (BMs) in peripheral blood or urine are a pivotal part of bone research within modern clinical medicine. In recent years the use of BMs increased substantially as they can be useful either to diagnose bone (related) disease and to follow its natural history, but also to monitor the effects of interventions. However, the use of BMs is still complicated mainly due to (pre)analytical variability of these substances, limited accessibility of assays, variable cut-off values in different countries and laboratories and heterogeneous results with regard to clinical implications of measuring BMs in several studies. This review will provide the clinician with a practical guide, based on current evidence, in which circumstances to test which bone markers for optimal diagnostic purposes, in order to improve patient care in different areas of bone diseases including Paget's disease, primary osteoporosis, tumor induced osteomalacia, hypophosphatemic rickets, van Buchem disease, chronic kidney disease, rheumatoid arthritis, neoplasma/multiple myeloma, type 2 diabetes mellitus and primary hyperparathyroidism. The clinician should consider fasting state, recent fractures, aging, menopausal status, concomitant liver and kidney disease when ordering and interpreting BM measurements as these factors might result in misleading BM concentrations. We found that BMs are clearly useful in the current diagnosis of tumor induced osteomalacia, van Buchem disease, Paget's disease and hypophosphatemic rickets. In addition, BMs are useful to monitor disease activity in chronic kidney disease, Paget's disease and are useful to monitor treatment adherence in osteoporosis.

Asunto(s)

Enfermedades Óseas/sangre , Enfermedades Óseas/orina , Remodelación Ósea/fisiología , Biomarcadores/sangre , Biomarcadores/orina , Enfermedades Óseas/diagnóstico , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/orina , Factor-23 de Crecimiento de Fibroblastos , Humanos , Osteítis Deformante/sangre , Osteítis Deformante/diagnóstico , Osteoporosis/sangre , Osteoporosis/diagnóstico , Osteoporosis/orina

RESUMEN

BACKGROUND: Cathepsin K is an attractive therapeutic target for diseases in which bone resorption is excessive such as osteoporosis and osteoarthritis (OA). The current paper characterized the pharmacological profile of the potent and selective cathepsin K inhibitor, MIV-711, in vitro and in cynomolgus monkeys, and assessed translation to human based on a single dose clinical study in man. METHODS: The potency and selectivity of MIV-711 were assessed in vitro using recombinant enzyme assays and differentiated human osteoclasts. MIV-711 was administered to healthy cynomolgus monkeys (3-30 µmol/kg, p.o.). Plasma levels of MIV-711 and the bone resorption biomarker CTX-I were measured after single dose experiments, and urine levels of CTX-I, NTX-I and CTX-II biomarkers were measured after repeat dose experiments. The safety, pharmacokinetics and pharmacodynamics (serum CTX-I) of MIV-711 were assessed in human healthy subjects after single ascending doses from 20 to 600 mg. RESULTS: MIV-711 was a potent inhibitor of human cathepsin K (Ki: 0.98 nmol/L) with > 1300-fold selectivity towards other human cathepsins. MIV-711 inhibited human osteoclast-mediated bone resorption with an IC50 value of 43 nmol/L. Single oral doses of MIV-711 to monkeys reduced plasma levels of CTX-I in a dose-dependent fashion by up to 57% at trough. The effect on CTX-I was linearly correlated to the plasma exposure of MIV-711, while the efficacy duration outlasted plasma exposure. Repeat oral dosing with MIV-711 also reduced urinary levels of the bone resorption biomarkers CTX-I (by 93%) and NTX-I (by 71%) and the cartilage degradation biomarker CTX-II (by 71%). MIV-711 was safe and well-tolerated when given as single ascending doses to healthy subjects. MIV-711 reduced serum CTX-I levels in a dose-dependent manner by up to 79% at trough. The relationship between MIV-711 exposure and effects on these biomarkers in humans was virtually identical when compared to the corresponding monkey data. CONCLUSIONS: MIV-711 is a potent and selective cathepsin K inhibitor with dose-dependent effects on biomarkers of bone and cartilage degradation in monkey and human. Taken together, MIV-711 shows promise for the treatment of bone and cartilage related disorders in humans, such as OA. Trial Registration EudraCT number 2011-003024-12, registered on June 22nd 2011.

Asunto(s)

Catepsina K/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/farmacología , Compuestos Orgánicos/farmacología , Administración Oral , Adulto , Animales , Biomarcadores/orina , Resorción Ósea/metabolismo , Resorción Ósea/patología , Inhibidores de Cisteína Proteinasa/administración & dosificación , Inhibidores de Cisteína Proteinasa/sangre , Inhibidores de Cisteína Proteinasa/farmacocinética , Femenino , Humanos , Macaca fascicularis , Masculino , Persona de Mediana Edad , Compuestos Orgánicos/administración & dosificación , Compuestos Orgánicos/sangre , Compuestos Orgánicos/farmacocinética , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Osteoclastos/patología , Adulto Joven

RESUMEN

BACKGROUND: MIV-711 is a highly potent and selective cathepsin K inhibitor. The current article summarizes the therapeutic effects of MIV-711 on joint pathology in rabbits subjected to anterior cruciate ligament transection (ACLT), and the prophylactic effects on joint pathology in dogs subjected to partial medial meniscectomy, two surgical models of osteoarthritis (OA). METHODS: Starting 1 week after surgery, rabbits were dosed daily via oral gavage with either MIV-711 or vehicle (n = 7/group) for 7 weeks. The four treatment groups were: (1) sham + vehicle; (2) ACLT + vehicle; (3) ACLT + MIV-711, 30 µmol/kg and (4) ACLT + MIV-711, 100 µmol/kg. Subchondral bone and articular cartilage structures were assessed by µCT, histomorphometry, and scoring. Dogs subjected to partial medial meniscectomy received either MIV-711 (30 µmol/kg) or vehicle (n = 15/group) via oral gavage once daily, starting 1 day before meniscectomy, for 28 days. Cartilage degradation was assessed at the macroscopic and microscopic levels. The exposures of MIV-711 were assessed in both studies and biomarkers reflecting bone resorption (HP-1 in rabbits, CTX-I in dogs) and cartilage degradation (CTX-II) were measured. RESULTS: In ACLT rabbits, MIV-711 decreased HP-1 levels by up to 72% (p < 0.001) and CTX-II levels by up to 74% (p < 0.001) compared to ACLT vehicle controls. ACLT surgery significantly reduced the total thickness of the subchondral bone plate and reduced trabecular bone volume in the femur and tibia. These effects were reversed by MIV-711. ACLT resulted in cartilage thickening, which was attenuated by MIV-711. MIV-711 did not affect osteophyte formation or Mankin scores. In dogs, MIV-711 reduced CTX-I and CTX-II levels by 86% (p < 0.001) and 80% (p < 0.001), respectively. Synovial CTX-II levels were reduced by 55-57% (p < 0.001) compared to baseline. MIV-711-treated animals had 25-37% lower macroscopic scores in the femur condyles and 13-33% lower macroscopic scores in the tibial plateaus. CONCLUSIONS: MIV-711 prevents subchondral bone loss and partially attenuates cartilage pathology in two animal models of OA. These beneficial effects of MIV-711 on joint pathology are observed in conjunction with decreases in bone and cartilage biomarkers that have been shown to be clinically attainable in human. The data support the further development of MIV-711 for the treatment of OA.

Asunto(s)

Lesiones del Ligamento Cruzado Anterior/tratamiento farmacológico , Catepsina K/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/uso terapéutico , Articulaciones/patología , Osteoartritis/tratamiento farmacológico , Animales , Ligamento Cruzado Anterior , Biomarcadores/sangre , Biomarcadores/orina , Resorción Ósea/patología , Cartílago Articular/diagnóstico por imagen , Cartílago Articular/efectos de los fármacos , Cartílago Articular/patología , Inhibidores de Cisteína Proteinasa/sangre , Inhibidores de Cisteína Proteinasa/farmacocinética , Inhibidores de Cisteína Proteinasa/farmacología , Modelos Animales de Enfermedad , Perros , Femenino , Articulaciones/diagnóstico por imagen , Articulaciones/efectos de los fármacos , Masculino , Compuestos Orgánicos , Osteoartritis/sangre , Osteoartritis/diagnóstico por imagen , Osteoartritis/patología , Análisis de Componente Principal , Conejos

RESUMEN

Paraben esters and their salts are widely used as preservatives in cosmetics, personal care products, pharmaceuticals, and foods. We and others have reported that parabens promote adipogenesis in vitro. Here, we investigated the effects of post-weaning exposure to parabens (methylparaben and butylparaben) on body weight, white adipose tissue mass, and obesity associated metabolic biomarkers in female obesity-prone C57BL/6J mice fed with a chow diet or a high fat diet. Methylparaben exposure by daily oral gavage (100 mg/kg/day) increased adiposity and serum leptin levels compared to the controls when fed the chow diet, but not the high fat diet. In contrast, butylparaben exposure did not induce such effects. Exposure to either paraben induced changes in gene expression related to adipocyte differentiation and lipogenesis in the white adipose tissue (WAT) and the liver, regardless of diet. Moreover, exposure to both parabens under the chow diet significantly decreased serum procollagen type 1 N-terminal propeptide (P1NP) but had no effects on C-terminal telopeptide of type I collagen (CTX-I) levels, suggesting that post-weaning exposure to paraben may negatively affect bone formation, but not bone resorption. Taken together, our results demonstrate that post-weaning exposure to paraben, methylparaben in particular, promotes adipogenesis but suppresses serum marker of bone formation in vivo. Our results add to the growing body of literature indicating potential negative health outcomes associated with paraben exposure. Further study of early life exposure to paraben on the development of fat and bone is warranted.

Asunto(s)

Adiposidad/efectos de los fármacos , Colágeno Tipo I/sangre , Parabenos/toxicidad , Fragmentos de Péptidos/sangre , Péptidos/sangre , Procolágeno/sangre , Animales , Biomarcadores/sangre , Peso Corporal/efectos de los fármacos , Remodelación Ósea , Conducta Alimentaria , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Osteogénesis , Conservadores Farmacéuticos/toxicidad , Distribución Aleatoria , Destete