Propeptide Of Type Research Articles

Effects of anti-osteoporosis treatment in elderly patients with osteoporosis and lumbar discectomy and fusion.

The effect of anti-osteoporosis treatment in elderly patients with osteoporosis and lumbar discectomy and fusion (LIF) for lumbar degenerative diseases is not well known. This study aimed to evaluate the effect of perioperative anti-osteoporosis treatment in the patients with osteoporosis and LIF. From January to December 2022, patients were divided into three groups according to the inclusive criteria: the normal group (Group A), the osteopenia group (Group B) and the osteoporosis group (Group C). Quantitative computed tomography (QCT), height of the intervertebral space (HIS), segmental sagittal angle (SSA), visual analogue scale (VAS) score and Oswestry Disability Index (ODI) were compared between the groups at the follow-up time. The serum Ca2 + , osteocalcin (OC), propeptide of type I procollagen (PINP) C-terminal cross-linking telopeptide of type I collagen (β-CTX) and 25-OH vitamin D (25-OH VD) levels were compared between the groups at the time of follow-up. Interbody fusion was graded on the X-ray and CT images at the follow-up time. There were 165 patients in this study. There were significant differences in the mean age, mean score, HIS and SSA between the groups at the different follow-up times. There were significant differences in the concentrations of serum Ca2 + , OC, β-CTX, 25-OH VD and PINP at the sixth month after surgery between the groups. There were significant differences in the concentrations of serum Ca2 + , β-CTX and 25-OH VD between the pre-surgery and at six months after surgery in Group B and β-CTX and 25-OH VD in Group C. There was a significant difference in the degree of fusion between Group B and C (χ2= 5.6243, P< 0.05). In elderly patients with LIF and osteoporosis, anti-osteoporosis therapy could reduce bone resorption and thus facilitate fusion. Anti-osteoporosis medication tends to enhance radiological, functional, and fusion short-term outcomes.

The relationship and diagnostic efficacy of N-terminal propeptide type III collagen in pathological changes associated with non-alcoholic steatohepatitis.

This study delves into the role of N-terminal propeptide type III collagen (PIIINP) in the diagnosis and management of liver pathological changes associated with non-alcoholic steatohepatitis (NASH). We collected baseline information, pathological data, and serum PIIINP levels of 168 patients diagnosed with non-alcoholic fatty liver disease (NAFLD) via ultrasound imaging in our hospital. Based on the non-alcoholic fatty liver disease activity score (NAS), patients with different NAFLD patterns were divided into a Definite NASH group and a Not/borderline group. Differences in PIIINP levels and pathological features between the two groups were compared and analyzed. The diagnostic value of PIIINP for NASH was evaluated using the receiver operating characteristic (ROC) curve. Patients with NASH exhibited significantly higher values of homeostatic model assessment for insulin resistance (HOMA-IR), fibrosis biomarker fibrosis-4 (FIB-4), aminotransferase-to-platelet ratio index (APRI), and serum PIIINP levels than those classified as Not/borderline. A marked increase in the serum concentrations of PIIINP was observed with the severity of fatty degeneration, lobular inflammation, and hepatocellular ballooning. The AUC of PIIINP for diagnosing definite NASH was 0.766 (95% CI: 0.694, 0.839), APRI was 0.634 (95% CI: 0.549, 0.718), and FIB-4 was 0.621 (95% CI: 0.534, 0.708). The AUC of PIIINP for diagnosing definite NASH was significantly higher than that of APRI and FIB-4 (all p<0.05). Utilizing the predetermined threshold values for diagnostic parameters, the PIIINP measure demonstrated a sensitivity of 71.6% and a specificity of 73.6% in diagnosing definitive NASH when its value exceeded 7.72 ng/dL. This yielded a Youden index of 0.45. Similarly, when the APRI measure exceeded 0.21, it exhibited a sensitivity of 60.5% and a specificity of 63.2%, resulting in a Youden index of 0.24. Moreover, when the FIB-4 index surpassed 0.26, it showed a sensitivity of 46.9% and a specificity of 79.3%, culminating in a Youden index of 0.26. NASH patients in this study exhibited significantly elevated PIIINP serum levels, which were closely associated with hepatocyte pathological changes. PIIINP demonstrated superior competence in diagnosing NASH than APRI and FIB-4 and thus offers a viable alternative for the clinical diagnosis of NASH.

Effectiveness and Usefulness of Bone Turnover Marker in Osteoporosis Patients: A Multicenter Study in Korea

Background: This study aimed to investigate real-world data of C-terminal telopeptide (CTX), propeptide of type I collagen (P1NP), and osteocalcin through present multicenter clinical study, and retrospectively analyze the usefulness of bone turnover markers (BTMs) in Koreans. Methods: The study focused on pre- and post-menopausal patients diagnosed with osteoporosis and excluded patients without certain test results or with test intervals of over 1 year. The demographic data and 3 BTMs (CTX, P1NP, and osteocalcin) were collected. The patients were classified by demographic characteristics and the BTM concentrations were analyzed by the group. Results: Among women with no history of fractures, the levels of P1NP (N=2,100) were 43.544±36.902, CTX (N=1,855) were 0.373 ±0.927, and osteocalcin (N=219) were 10.81 ±20.631. Among men with no history of fractures, the levels of P1NP (N=221) were 48.498±52.892, CTX (N=201) were 0.370±0.351, and osteocalcin (N=15) were 7.868 ±10.674. Treatment with teriparatide increased the P1NP levels after 3 months in both men and women, with a 50% increase observed in women. Similarly, treatment with denosumab decreased the CTX levels after 3 months in both men and women, with a reduction of 50% observed in women. Conclusions: The results of this study can contribute to the accurate assessment of bone replacement status in Koreans. We also provide the P1NP level in the Korean population for future comparative studies with other populations.

Interleukin 10 (IL10) and IL15 Significantly Decreased in Chronic Myeloid Leukemia Patients Presenting with Tyrosine Kinase Inhibitor (TKI) Withdrawal Syndrome (TWS). Results from the Prospective, Explorative and Multicenter « Kiwis » Study Designed for TWS. Clinicaltrial.Gov ID: NCT03996096; Study Number: 18-206

Aims Treatment-free remission (TFR) has been included in practice guidelines as a new management goal for chronic myeloid leukemia (CML) patients, implying discontinuation of tyrosine kinase inhibitors (TKI). Paradoxically, TKI discontinuation gives rise to musculoskeletal pain and/or flushing, known as TKI withdrawal syndrome (TWS), in approximately 25% of patients with a reported median time of occurrence of 6 weeks. This syndrome is assumed to be caused by cytokine release, mast cell regrowth, or reactivation of an underlying inflammatory state. The KIWIS trial aimed at assessing these hypotheses by prospectively dosing biological markers before and after TKI discontinuation looking for any significant variation to be correlated to TWS. The secondary objectives were: description of the manifestations of TWS, assessment of TFR. Here, we will only focus on the primary objective. Methods The KIWIS study ( Clinicaltrial.govID: NCT03996096) was a multicenter prospective cohort of adult CML patients who had been treated with TKIs for at least 5 years, with a minimum of 2 years in deep molecular response (MR4.5). Patients with a history of inflammatory disease, those taking steroids, or those unable to complete the short form of the Brief Pain Inventory (BPI) were not included. BPI was used to assess pain severity and its impact on daily functioning. The arithmetic mean of the four severity items was used to score the severity of pain at different time points and identify patients with TWS. Blood samples were collected at baseline (M0), 1 month (M1), 2 months (M2), and 3 months (M3) post-discontinuation of TKI. We explored the following biomarkers: CRP, Rheumatoid Factor, tryptase, calcium, phosphate, Creatin Kinase, IL2, IL6, IL10, TGFβ, TNFα, IFNϒ, VEGF, PDGFβ, IL15, Crosslaps (CTX), Collagen pro-peptide type 1 (PINP1), and parathormone. Each patient served as their own control, and any variation of a biomarker by 20% from baseline was considered clinically significant. The BPI form was completed at the same time points as BCR-ABL follow-up: M0, M1, M2, M3, M4, M5, M6, M8, M10, and M12 following TKI withdrawal. The study was powered to include 50 patients. Results Out of the 50 patients, 16 (32%) developed TWS within the first 3 months, with a median onset time of 2 months. Patients' characteristics are displayed in table1. The baseline characteristics of patients in the TWS and non-TWS groups were similar. The duration of CML treatment was significantly longer in TWS patients compared to non-TWS patients (median: 9, Interquartile Range (IQR) [7-13] vs 7, IQR [6-8], p=0.039, respectively). No predictive factor for developing TWS were observed considering patients' characteristics and BPI scores at M0 in the univariate analysis. At M0, there were no significant differences between the two groups in terms of the concentration of each specific biomarker. In the TWS group, IL10, IL15, and IFNϒ levels decreased between inclusion and the M3 time point. For IL10, the median was 0.18 pg/ml (IQR: 0.12; 0.31) vs. 0.12 (IQR: 0.08-0.17), p=0.002; for IL15, 2.30 pg/ml (IQR: 1.77; 2.92) vs. 1.81 (IQR: 1.48; 2.25), p=0.026; and for IFNϒ, 5.92 pg/ml (IQR: 4.17; 12.49) vs. 4.24 pg/ml (IQR: 2.64; 7.99), p=0.036. In the non-TWS group, no significant differences were found. Changes in IL10 were positively correlated with changes in IL15 from M0 to M3 in all patients: r=0.42, p=0.009. No significant variations were observed in the two patient groups regarding the other biomarkers. Figure 1 exemplifies the evolution of IL10 (A: in TWS patients; B: in non-TWS patients) at M0 and M3. One patient missed the M3 time point sample. Conclusion This is the first study designed to prospectively investigate biomarkers associated with TWS. Our results suggest that TWS is not a cytokine-release-like syndrome but a distinct entity significantly associated with a decrease in IL10, IL15, and IFNϒ concentrations. It is worth noting that IL10 is an anti-inflammatory cytokine known to reduce pain; the role of IL15 and IFNϒ remains to be clarified. We hope that this study will pave the way for further investigations to fully understand the pathophysiology of TWS.

THU605 Impact Of Abnormal Circadian Cortisol Secretion On Bone Metabolism In Patients With Mild Autonomous Cortisol Secretion

Abstract Disclosure: J. Saini: None. R. Nathani: None. S. Singh: None. V. Fell: None. E. Atkinson: None. S. Achenbach: None. S. Khosla: None. I. Bancos: None. Background: Previous studies reported that both cortisol secretion and bone metabolism biomarkers follow a circadian pattern of secretion. Patients with mild autonomous cortisol secretion (MACS) demonstrate an increased risk of fractures. As most patients with MACS do not have increased cortisol production, we hypothesized that abnormal circadian cortisol secretion is associated with impaired bone metabolism. Objective: To compare the circadian secretory pattern of bone metabolism biomarkers in relation to cortisol circadian secretion in patients with MACS versus referent subjects. Methods: We conducted a pilot cross-sectional study of patients with MACS and referent subjects. MACS was diagnosed in patients with adrenal adenomas based on an abnormal 1 mg dexamethasone suppression test (cortisol &amp;gt;1.8 mcg/dL). Referent subjects with available abdominal imaging within 5 years and adrenal disorder were recruited from the community. Participants were admitted to the clinical research unit for blood sampling every 2 hours over 24h period. Measurements included total and free cortisol, calcium, parathyroid hormone (PTH), osteocalcin, amino-terminal propeptide type 1 collagen (PINP), and carboxy-terminal telopeptide of type 1 collagen (CTX). Subjects with disorders or medication affecting bone metabolism were excluded. Time periods of blood draw were categorized into the morning (6 to 12 hours), afternoon (14-18 hours) and night (20-2 hours). Delta (morning measurements/afternoon measurements) was calculated. Results: Subjects included 12 patients with MACS (median age 57, IQR 48-67, 83% women) and 10 referent subjects (median age 57, IQR 50-63, 80% women). The 24-hour area under the curve for total (10342 vs 9090 mcg/dL, p=0.468) and free cortisol (437 vs 329 mcg/dL, p=0.086) was no different between patients with MACS and referent subjects. However, the mean night total (6.7 vs 4.3 mcg/dL, p=0.056) and free cortisol (0.2 vs 0.1 mcg/dL, p=0.035) was higher in MACS vs referent subjects. The area under the curve for calcium, phosphorus, CTX, osteocalcin and PINP were similar between patients and referent subjects, however, the area under the curve for PTH was higher in patients vs referent subjects (mean 64179 vs 42602 pg/mL, p=0.021). Both delta total cortisol (mean 8.6 vs 5.5, p=0.01) and delta PTH (mean -1.5 vs 4.2, p=0.051) was higher in referent subjects vs patients with MACS. Conclusion: When compared to referent subjects, patients with MACS have similar 24-hour cortisol production but demonstrate an increase in night-time cortisol secretion and a blunting of diurnal cortisol (lower morning/afternoon cortisol). Patients with MACS have higher PTH production overall, as well as an abnormal diurnal PTH secretion. Noted abnormalities in PTH may contribute to the MACS-associated impairment in bone health. Presentation: Thursday, June 15, 2023

Effects of Bazedoxifene/Vitamin D Combination Therapy on Serum Vitamin D Levels and Bone Turnover Markers in Postmenopausal Women with Osteopenia: A Randomized Controlled Trial.

This study aimed to evaluate the effectiveness of bazedoxifene/vitamin D combination therapy in preventing osteoporosis in postmenopausal women with osteopenia. This was an open-label, multicenter randomized-controlled, phase 4 clinical trial. Women between ages of 55 and 70 years in 9 medical tertiary centers in Korea were enrolled and assigned into 2 groups: an experiment group and a control group. The experimental group received bazedoxifene 20 mg/vitamin D 800 IU tablets for 6 months, and the control group received calcium 100 mg/vitamin D 1,000 IU tablets for 6 months. A total of 142 patients (70 in the experimental group and 72 in the control group) were included. The least-square mean±standard error of change in propeptide of type I collagen after 3 months was -6.87±2.56% in the experimental group and 1.22±2.54% in the control group. After 6 months, it was -21.07±2.75% in the experimental group and 1.26±2.71% in the control group. The difference between the 2 groups was -22.33% (p<0.01). The change of C-terminal telopeptide was -12.55±4.05% in the experimental group and 11.02±4.03% in the control group after 3 months. It was -22.0±3.95% and 10.20±3.89, respectively, after 6 months. The difference between the 2 groups was -32.21% (p<0.01) after 6 months. There was no significant difference in adverse events between the 2 groups. The osteoporosis preventive effect and safety of administering bazedoxifene/vitamin D combination pill were confirmed in postmenopausal women who needed osteoporosis prevention.

Chinese Herbal Medicine 'Diwu' Suppresses Myeloma Bone Disease Via ERK/MAPK Signaling Pathway By Targeting CCL3

Background： Multiple myeloma (MM) associated bone disease (MBD) is largely dependent on the bone marrow microenvironment (BME). The cross-talk between MM cells, bone marrow mesenchymal cells and myeloid progenitors affects the osteoclastogenesis. Traditional Chinese medicine 'Diwu' is effective for patients with arthritis and inflammation, also occasionally uses as one ingredient treating MM. But the effects of 'Diwu' in MBD are largely unknown. The aim of this study is to investigate the role and underlying mechanism of 'Diwu' in regulating BME and osteoclast differentiation. Methods： Myeloma cell lines RPMI-8226, NCI-H929, U266 and MM1 were treated with 'Diwu' extract. Killing effects was evaluated by the half inhibitory dose (IC50) value and proportion of apoptotic MM cells. RNA-seq was applied in 'Diwu' treated myeloma cells to identify MBD associated signaling pathways. RPMI-8226 was co-cultured with mesenchymal stromal cell (MSC) line HS5. Human monocyte cell line THP-1 was treated with CCL3 and M-CSF to form osteoclasts determined by tartrate-resistant acid phosphatase (TRACP) staining. Primary human MSCs were cultured into osteogenic or adipogenic differentiation, determined by alizarin red staining and oil red staining, respectively. RNAi technology was applied to knock down CCL3. The expression of osteoclast-specific genes TRACP and MAPK pathway-related genes was tested using quantitative real-time PCR. Phosphorylation and expression of MEK1, ERK, FOS were measured by Western Blot. The myeloma-bearing NOD/SCID mice were treated with intragastric 'Diwu'. Serum C-terminal telopeptide of type 1 collagen (CTXI) and propeptide of type I procollagen (PINP) was tested by ELISA. The tibia of mice was fixed and stained to analyze the differentiation and maturation of osteoblasts and osteoclasts. Micro-CT was used for bone destruction measurement. Results： 'Diwu' inhibited MM cells proliferation (IC50, 29.22-364.7μg/ml) in a dose-dependent manner and promoted apoptosis by upregulating protein expression of CASP3, BCL2. 'Diwu' decreased the secretion of chemokine (C-C motif) ligand 3 (CCL3) and receptor activator of nuclear factor-kappa B ligand (RANKL) in myeloma-MSC co-cultured system by diminishing the direct attachment and interaction of these two cells. The mRNA and protein levels of osteoclast-specific genes such as TRACP, and the phosphorylation and expression of MEK1, ERK, FOS in osteoclast were all reduced after 'Diwu' treatment. We observed improved osteogenic activation rather than lipid formation in hMSC differentiation. The level of TRACP isoform 5b (TRACP-5b) was significantly downregulated in mouse serum after 'Diwu' treatment for 14 days. Conclusions: Altogether, our results demonstrated that effective extract of Chinese herbal medicine 'Diwu' could simultaneously inhibit myeloma cells and suppress osteoclast formation, indicating an important role of 'Diwu' in regulating BM microenvironment. It is possible to translate 'Diwu' into clinical application as an oral agent for myeloma bone disease. Key words： 'Diwu'; Myeloma Bone Disease; Bone Marrow Microenvironment; CCL3; ERK/MAPK

Study on Risk Factors of Primary Non-traumatic OVCF in Chinese Elderly and a Novel Prediction Model.

Prevention of fragility fractures is one of the public health priorities worldwide, whilst the incidence of osteoporotic vertebral compression fractures (OVCF) continues to rise and lacks the corresponding accurate prediction model. This study aimed to screen potential causes and risk factors for primary non-traumatic osteoporotic vertebral compression fractures (NTOVCF) in the elderly by characterizing a patient population with NTOVCF and comparing it with a population of osteoporotic patients. Between January 2013 and January 2022, 208 elderly patients with unequivocal evidence of bone fragility manifested as painful NTOVCF were enrolled, and compared with 220 patients with osteoporosis and no fractures. The demographic data, bone turnover markers, blood routine, serum biochemical values, and radiological findings were investigated. Differences between the fracture and non-fracture groups were analyzed, and variables significant in univariate analysis and correlation analysis were included in the logistic analysis to build the risk prediction model for osteoporotic vertebral fractures. Univariate analysis using student's t-tests for continuous variables or a chi-squared test for categorical variables was conducted to identify risk factors. No significant differences were revealed regarding age, gender, BMI, smoking, alcohol consumption, blood glucose, propeptide of type I procollagen (P1NP), and N-terminal middle segment osteocalcin (N-MID) (P > 0.05). Parathyroid Hormone (PTH), 25(OH)D, serum albumin (ALB), hemoglobin (HB), bone mineral density (BMD), and cross-sectional area (CSA) of the paraspinal muscle in the fracture group were significantly lower than those in the control group; however, b-C-terminal telopeptide of type I collagen (β-CTX), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), non-prostatic acid phosphatase (NACP), and fatty degeneration ratio (FDR) were significantly higher than those in the control group (P < 0.05). Logistic regression analysis showed that ALB, HB, CSA, and BMD were negatively correlated with NTOVCF, while β-CTX, HDL-C, NACP, and FDR were positively correlated with NTOVCF. Decreased physical activity, anemia, hypoproteinemia, imbalances in bone metabolism, abnormal lipid metabolism, and degenerative and decreased muscle mass, were all risk factors for OVCF in the elderly, spontaneous fractures may be the consequence of cumulative declines in multiple physiological systems over the lifespan. Based on this risk model, timely detection of patients with high OVCF risk and implementation of targeted preventive measures is expected to improve the effect of fracture prevention.

Association of skin autofluorescence with low bone density/osteoporosis and osteoporotic fractures in type 2 diabetes mellitus.

BackgroundAdvanced glycation end products (AGEs) that abnormally accumulate in diabetic patients have been reported to damage bone health. We aimed to investigate the association between skin autofluorescence (SAF)‐AGEage (SAF − AGEs × age/100) and low bone density (LBD)/osteoporosis or major osteoporotic fractures (MOFs) in patients with type 2 diabetes mellitus (T2DM).MethodsThis study was nested in the prospective REACTION (Risk Evaluation of Cancers in Chinese Diabetic Individuals) study and included 1214 eligible participants. SAF was used to measure skin AGEs (SAF‐AGEs). Fracture events were determined by an in‐person clinical follow‐up. Binary logistic regression analysis, linear regression analysis, and a restricted cubic spline nested in logistic models were used to test outcomes.ResultsThe overall prevalence of LBD/osteoporosis in middle‐aged or elderly T2DM patients was 35.7% (n = 434), and the overall incidence of MOFs was 10.5% (n = 116). Logistic analysis showed a significantly positive relationship between quartiles of SAF‐AGEage and the risk of LBD/osteoporosis (odds ratio [OR] 2.02, 95% CI 1.34–3.03; OR 3.63, CI 2.44–5.39; and OR 6.51, CI 4.34–9.78) for the multivariate‐adjusted models, respectively. SAF‐AGEage was associated with MOFs with a multivariate‐adjusted OR of 1.02 (CI 0.52–2.02), 2.42 (CI 1.32–4.46), and 2.70 (CI 1.48–4.91), respectively. Stratified analyses showed that SAF‐AGEage was significantly associated with MOFs only in females, nonsmokers, nondrinkers, individuals with lower body mass index, and those without LBD/osteoporosis. Linear regression analyses showed that higher SAF‐AGEs were associated with a higher level of serum N‐terminal propeptide of type I procollagen (s‐PINP) and serum carboxy‐terminal cross‐linking peptide of type I collagen (s‐CTX), with a multivariate‐adjusted OR of 1.02 (CI 0.24–1.80) and 6.30 (CI 1.77–10.83), respectively.ConclusionsIn conclusion, SAF‐AGEage was positively associated with the prevalence of LBD/osteoporosis or MOFs in patients with T2DM. A positive association between SAF‐AGEs and the level of s‐PINP and s‐CTX was found.

Effects of ultra-low dose hormone therapy on biochemical bone turnover markers in postmenopausal women: A randomized, placebo-controlled, double-blind trial.

ObjectiveEvaluate the effects of ultra-low-dose hormone therapy (Ultra-LD HT) with 17β-estradiol 0.5 mg and norethisterone acetate 0.1 mg (E2 0.5/NETA 0.1) versus placebo on bone turnover markers (BTM) in postmenopausal women.Study DesignA multicenter, double-blind, randomized, placebo-controlled study was performed with 107 participants who received one tablet daily of E2 0.5/NETA 0.1 or placebo for 24-weeks. Bone formation markers-N-terminal propeptide of type I procollagen (PINP) and Bone-specific alkaline phosphatase (BSAP), and bone resorption markers-C-telopeptide of type I collagen (CTX-I) and N-telopeptide crosslinked of type I collagen (NTX) were assessed before and at 12 and 24-weeks of treatment.ResultsWomen treated with E2 0.5/NETA 0.1 had a significant reduction in the PINP marker from baseline (58.49 ± 21.12 μg/L) to week 12 (48.31 ± 20.99 μg/L) and week 24 (39.16 ± 16.50 μg/L). Placebo group, the PINP marker did not differ significantly. The analysis of the BSAP indicated a significant increase in the placebo group (13.8 ± 5.09 μg/L and 16.29 ± 4.3 μg/L, at baseline and week 24, respectively), whereas in the treatment group the values did not change. The analysis of the NTX marker showed a significant reduction only in the treatment group (43.21 ± 15.26 nM/mM and 33.89 ± 14.9 nM/mM, at baseline and week 24, respectively). CTX-I had a significant decrease in the treatment group from baseline (0.3 ± 0.16 ng/L) to week 12 (0.21 ± 0.14 ng/L) and week 24 (0.21 ± 0.12 ng/L).ConclusionWomen receiving E2 0.5/NETA 0.1 experienced reductions in bone resorption and formation markers, an expected effect during the anti-resorptive therapy, suggesting a protective bone effect with the Ultra-LD HT.

Effect of Vitamin D Combined with Recombinant Human Growth Hormone in Children with Growth Hormone Deficiency.

Objective Growth hormone deficiency (GHD) refers to the complete or partial lack of pituitary growth hormone synthesis and secretion. This study is aimed at investigating the efficacy of vitamin D and recombinant human growth hormone (rhGH) in children with GHD. Methods A total of 100 children with GHD at our hospital were included between 1st January 2018 and 31st October 2020. The patients were divided into a study group (n = 70, received vitamin D combined with rhGH) and a control group (n = 30, received rhGH). The growth and development (bone age, growth rate, and height), bone metabolism (bone alkaline phosphatase (BAP), β-collagen degradation product (β-CTX), osteocalcin (OC), and amino-terminal propeptide type I procollagen (PINP)), insulin-like growth factor 1 (IGF-1), ghrelin, and adverse reactions in the two groups were measured before and 12 months after treatment. Results There were no significant differences in the bone age, growth rate, and height between the two groups before treatment. After 12 months of treatment, the bone age, growth rate, and height of the study group were significantly higher than those of the control group. After 12 months of treatment, the levels of serum BAP, PINP, and OC in the study group were significantly higher than those in the control group, while the levels of β-CTX in the study group were significantly lower than those in the control group. The serum IGF-1 level in the study group was significantly higher than that in the control group, while the ghrelin level in the study group was lower. There was no significant difference in the incidence of adverse reactions between the two groups. Conclusion Combined rhGH and vitamin D treatment can promote growth and development, improve bone metabolism, and regulate IGF-1 and ghrelin levels.

Total Flavonoids of Drynariae Rhizoma Improve Glucocorticoid-Induced Osteoporosis of Rats: UHPLC-MS-Based Qualitative Analysis, Network Pharmacology Strategy and Pharmacodynamic Validation.

BackgroundGlucocorticoid-induced osteoporosis (GIOP) is a common form of secondary osteoporosis caused by the protracted or a large dosage of glucocorticoids (GCs). Total flavonoids of Drynariae rhizoma (TFDR) have been widely used in treating postmenopausal osteoporosis (POP). However, their therapeutic effects and potential mechanism against GIOP have not been fully elucidated.MethodsUltra-high-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC-ESIQ-TOF-MS) experiments were performed for qualitative analysis. We performed hematoxylin-eosin (HE) staining and microcomputed tomography (micro-CT) analysis to detect the changes in bone microstructure. The changes in biochemical parameters in the serum samples were determined by performing an enzyme-linked immunosorbent assay (ELISA). The prediction results of network pharmacology were verified via quantitative real-time polymerase chain reaction (qRT-PCR) to elucidate the potential mechanism of TFDR against GIOP.ResultsA total of 191 ingredients were identified in vitro and 48 ingredients in vivo. In the in-vivo experiment, the levels of the serum total cholesterol (TC), the serum triglyceride (TG), Leptin (LEP), osteocalcin (OC), osteoprotegerin (OPG), bone morphogenetic protein-2 (BMP-2), propeptide of type I procollagen (PINP), tartrate-resistant acid phosphatase (TRACP) and type-I collagen carboxy-terminal peptide (CTX-1) in the TFDR group significantly changed compared with those in the GIOP group. Moreover, the TFDR group showed an improvement in bone mineral density and bone microstructure. Based on the results of network pharmacology analysis, 67 core targets were selected to construct the network and perform PPI analysis as well as biological enrichment analysis. Five of the targets with high “degree value” had differential gene expression between groups using qRT-PCR.ConclusionTFDR, which may play a crucial role between adipose metabolism and bone metabolism, may be a novel remedy for the prevention and clinical treatment of GIOP.

Higher Levels of Plasma Hyaluronic Acid and N-terminal Propeptide of Type III Procollagen Are Associated With Lower Kidney Function in Children With Non-alcoholic Fatty Liver Disease.

ObjectiveHyaluronic acid (HA) and N-terminal propeptide of type III procollagen (PIIINP) are two non-invasive biomarkers of liver fibrosis in non-alcoholic fatty liver disease (NAFLD). We examined the relationships of plasma levels of HA and PIIINP with kidney function in children with NAFLD.MethodsPlasma HA and PIIINP levels were measured using two commercially available enzyme-linked immunosorbent assay kits in a cohort of 106 Caucasian overweight or obese children with biopsy-proven NAFLD. Glomerular filtration rate (eGFR) was estimated using the Bedside Schwartz equation. Genotyping for the patatin-like phospholipase domain-containing protein-3 (PNPLA3) rs738409 variant was performed using an allelic discrimination assay.ResultsChildren with fibrosis F2 had significantly higher plasma PIIINP and HA levels than those with F0 or F1 fibrosis. Liver fibrosis was positively associated with plasma HA and PIIINP, as well as with the presence of the risk allele G of PNPLA3 rs738409 variant, and negatively with eGFR. Moreover, eGFR showed significant inverse associations with HA and PIIINP levels, as well as the presence of G of PNPLA3 rs738409, and liver fibrosis stage. Notably, our multivariable regression models showed that higher plasma PIIINP (standardized beta coefficient: −0.206, P = 0.011) and HA levels (standardized beta coefficient: −0.531, P < 0.0001) were associated with lower eGFR values, even after adjustment for age, sex, systolic blood pressure, PNPLA3 rs738409 genotype, and any stage of liver fibrosis.ConclusionsHigher levels of HA and PIIINP were associated with lower eGFR values in Caucasian children with biopsy-proven NAFLD, independently of PNPLA3 rs738409 genotype and other potential confounding factors.

Dietary-Lifestyle Patterns Associated with Bone Turnover Markers, and Bone Mineral Density in Adult Male Distance Amateur Runners-A Cross-Sectional Study.

Background: Excessive mileage can be detrimental to bone mineral density among long-distance runners. The negative effects of mileage could be alleviated by appropriate nutrition. The purpose of this study was to analyse the dietary-lifestyle patterns in relation to bone mineral density and bone turnover markers among amateur marathoners. Methods: A total of 53 amateur male distance runners were divided into two clusters by k-means cluster analysis. Bone mineral density was measured by dual X-ray absorptiometry (DXA). Blood was drawn to analyse bone resorption marker C-terminal telopeptide (cTX) and bone formation marker amino-terminal propeptide of type I collagen (PINP). Food frequency intake and lifestyle information were measured by multicomponent questionnaire KomPAN®. Yearly average mileage per month was taken from each participant. Results: There were two distinguished clusters: Less-healthy-more-active-low-Z-score (LessHA) (n = 33) and More-healthy-less-active-high-Z-score (MoreHLA) (n = 20). LessHA had a lower frequency intake of pro-healthy food groups, a lower number of meals during a typical day, and a higher mileage training than the group of athletes who followed the MoreHLA. Athletes following the LessHA pattern also had a lower Z-score in the lumbar spine and femoral bone and a lower PINP. Conclusion: The current study suggests that pro-healthy dietary patterns and lower mileage may favour higher bone mineral density in male amateur marathoners.

BMP1 is not required for lung fibrosis in mice

Bone morphogenetic protein 1 (BMP1) belongs to the astacin/BMP1/tolloid-like family of zinc metalloproteinases, which play a fundamental role in the development and formation of extracellular matrix (ECM). BMP1 mediates the cleavage of carboxyl terminal (C-term) propeptides from procollagens, a crucial step in fibrillar collagen fiber formation. Blocking BMP1 by small molecule or antibody inhibitors has been linked to anti-fibrotic activity in the preclinical models of skin, kidney and liver fibrosis. Therefore, we reason that BMP1 may be important for the pathogenesis of lung fibrosis and BMP1 could be a potential therapeutic target for progressive fibrotic disease such as idiopathic pulmonary fibrosis (IPF). Here, we observed the increased expression of BMP1 in both human IPF lungs and mouse fibrotic lungs induced by bleomycin. Furthermore, we developed an inducible Bmp1 conditional knockout (cKO) mouse strain. We found that Bmp1 deletion does not protect mice from lung fibrosis triggered by bleomycin. Moreover, we found no significant impact of BMP1 deficiency upon C-term propeptide of type I procollagen (CICP) production in the fibrotic mouse lungs. Based on these results, we propose that BMP1 is not required for lung fibrosis in mice and BMP1 may not be considered a candidate therapeutic target for IPF.

Reduced Circulating Levels of miR-491-5p and miR-485-3p Are Associated with the Occurrence of Vertebral Fractures in Postmenopausal Women with Osteoporosis.

Objective Postmenopausal women experiences osteoporotic structural damage and bone fragility resulting from reduced bone formation and increased bone resorption. Osteoporosis frequently affects the vertebral column and causes compression fractures. This study aims to characterize roles of miRNAs in osteoporosis and subsequent incidence risk of vertebral fractures for postmenopausal women. Methods. Differentially expressed miRNAs between osteoporotic patients with vertebral fractures and osteoporotic patients without fracture were identified. This retrospective study included 78 osteoporotic patients with vertebral fractures and 82 osteoporotic patients without vertebral fractures. The plasma levels of bone metabolic markers, 25-hydroxyvitamin D (25-(OH)VitD), propeptide of type I procollagen (PINP), and β-Carboxyl terminal peptide (β-CTx), were detected using the patented electro-chemiluminescence (ECLIA) method. The expression levels of miR-491-5p and miR-485-3p were determined by qRT-PCR. Pearson correlation analysis was carried out to assess the relationship between miR-491-5p, miR-485-3p, and bone metabolic markers. Receiver operating characteristic (ROC) curves and the area under the ROC curve (AUC) were used to evaluate the performance of miR-491-5p and miR-485-3p in diagnosing the occurrence of vertebral fractures in osteoporotic patients.Results: The plasma levels of PINP and β-CTx were elevated but the plasma level of 25-(OH)VitD was declined in osteoporotic patients with vertebral fractures when comparable to those without (< 0.05). The plasma expression levels of miR-491-5p and miR-485-3p were declined osteoporotic patients with vertebral fractures when comparable to those without (< 0.001). Pearson correlation analysis revealed that the relative expression level of miR-491-5p was negatively correlated with the level of 25-(OH)VitD (r = -0.518, < 0.001) but positively correlated with the levels of PINP (r = 0.547, < 0.001) and β-CTx (r = 0.380, < 0.001). We also observed a negative correlation between the relative expression level of miR-485-3p and 25-(OH)VitD (r = -0.388, < 0.001), a positive correlation between miR-485-3p and PINP (r = 0.422,< 0.001). ROC curves for prediction of vertebral fracture following osteoporosis in postmenopausal women by miR-491-5p expression yielded 0.866 AUC and by miR-485-3p expression produced 0.848 AUC. Conclusion The data suggest that downregulated expressions of miR-491-5p and miR-485-3p may be involved in the occurrence of vertebral fractures in postmenopausal women with osteoporosis.

Left ventricular function is related with amphiregulin and fibrosis markers in cirrhotic cardiomyopathy.

The relationship between left ventricle (LV), extracellular matrix remodeling and fibrosis-linked amphiregulin (ARG) in cirrhotic cardiomyopathy (CCM) is unknown. The aim of the study was to investigate the associations between markers of extracellular matrix remodeling and ARG in cirrhosis and their association with indicators of ventricular remodeling and LV functional parameters. In hepatitis C virus (HCV) patients with cirrhosis, who underwent echocardiography, the presence of left ventricular diastolic dysfunction (LVDD) was determined by having gradable diastolic dysfunction in accordance with modified 2020 Cirrhotic Cardiomyopathy Consortium criteria. A total of 87 cirrhotic patients were consecutively analyzed. Based on detailed echocardiographic assessment - 35 HCV patients with cirrhosis had normal left ventricular diastolic function (non-CCM group), whereas 52 patients had LVDD (CCM group). ARG was measured by enzyme-linked immunosorbent assay. The ARG levels were significantly increased in the CCM group compared to the non-CCM group (P<0.001). ARG levels in all HCV patients were independently associated to the presence of CCM, and showed significant correlations with LVDD. The close relationship between ARG levels and the direct serum marker of fibrosis, and selected markers of extracellular matrix (i.e. transforming growth factor-beta1 (TGF-β1), and carboxyterminal propeptide of type I collagen (PICP), amino-terminal propeptide of type III procollagen (PIIINP), tissue inhibitor of matrix proteinase-1 (TIMP-1), respectively), ventricular remodeling (i.e. N-terminal pro B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin-T (hs-TnT)), and LV functional parameters suggest an active role in the myocardial injury. Using ROC analysis, the best marker for the diagnosis of CCM was NT-proBNP with AUROC = 0.796. The area under the curve of ARG (AUROC = 0.709) for predicting CCM was greater than this for PICP (AUROC = 0.662) and similar to this hs-TnT (AUROC = 0.753). The simultaneous monitoring of serum ARG and markers of extracellular matrix and ventricular remodeling can be helpful for the alterations in myocardial function control in HCV patients with cirrhosis.

Declining serum bone turnover markers are associated with the short-term positive change of lumbar spine bone mineral density in postmenopausal women.

Objective:While serum bone turnover markers (BTMs) and bone mineral density (BMD) have been confirmed as useable risk assessment tools for postmenopausal osteoporosis, the associations between BTMs and BMD changes are still ambiguous. The aim of this study was to explore the underlying associations between BTMs and BMD changes in postmenopausal women.Methods:Between January 2015 and October 2020, 135 postmenopausal women were retrospectively enrolled. They were divided into two groups according to lumbar spine (LS) 1-4 BMD change (1 y T-score minus baseline T-score, Group 1 [n = 36] < 0 and Group 2 [n = 99] ≥ 0). The changes of BTMs (N-terminal middle segment osteocalcin [N-MID], propeptide of type I procollagen [P1NP], and β-C-terminal telopeptide of type I collagen [β-CTX]) and their associations with LS 1-4 BMD change were analyzed. The biochemical indices and clinical parameters related with LS 1-4 BMD change were also evaluated.Results:The 1 year N-MID, P1NP, β-CTX and Phosphorus in Group 2 were lower than those in Group 1 (P < 0.05), their changes within 1 year were significantly negatively correlated with LS 1-4 BMD change (R2 = –0.200, P < 0.001; R2 = –0.230, P < 0.001; R2 = –0.186, P < 0.001; R2 = –0.044, P = 0.015; respectively). Except for the Phosphorus change (area under the curve [AUC] = 0.623), the changes of N-MID, P1NP, and β-CTX and their 1 year levels had similar AUC to diagnose the short-term LS 1-4 BMD change (AUC > 0.7 for all, with the AUC of 1 y P1NP being the largest at 0.803). Binary logistic regression analysis showed that the physical activity and drug intervention were the determinant factors for the LS 1-4 BMD change (odds ratio = 6.856, 95% confidence interval: 2.058-22.839, P = 0.002; odds ratio = 5.114, 95% confidence interval: 1.551-16.864, P = 0.007; respectively).Conclusions:Declining N-MID, P1NP, β-CTX, and Phosphorus are associated with the short-term increase of LS 1-4 BMD within 1 year. Physical activity and drug intervention are factors significantly influencing the change of LS 1-4 BMD in postmenopausal women.

Development of a Chemiluminescence Assay for Total N-Terminal Propeptide of Type I Collagen and Its Evaluation in Lung Transplantation.

Serum P1NP, one of the important biomarkers for bone turnover, is commonly used for the prediction of bone fracture and the prognosis of osteoporosis after therapy. We developed a P1NP chemiluminescence assay and evaluated changes in bone metabolism markers in lung transplant patients. The screened 2 P1NP antibodies with constructed antigens and α-1 chain antigens expressed by the Corynebacterium glutamate expression system were applied into assay development. The assay performance was evaluated to examine the reliability. A normal Q-Q plot was used to establish male reference interval. Changes of bone metabolism markers before and after lung transplantation in 19 patients were evaluated. The linear factor R of P1NP reagent was greater than 0.99. The limit of detection was 3.32 ng/ml. The precision of the three batches of P1NP reagents was lower than 8%. Method comparison with Roche P1NP reagent showed that the correlation coefficient R2 was 0.91. In the monitoring of bone mass in a short time, bone metabolism markers can better indicate the change of bone mass, while the traditional bone mineral density detection is lagging behind the bone metabolism markers. P1NP and β-CrossLap to bone mass change in patients after lung transplantation, and P1NP and β-CrossLap are very good clinical markers for bone mass monitoring.

Ethnic characteristics of bone remodeling in female patients with type 2 diabetes mellitus

Background: Structural and metabolic disorders of bone tissue in women with T2DM have no clinical manifestations, but they are accompanied by the risk of fractures.Aim: To study the parameters of bone metabolism, BMD and microarchitectonics in female patients with T2DM in the Buryat population.Materials and methods: The observational single-center one-stage controlled study included 73 women with T2DM, which were divided into 2 groups depending on the functional state of the ovaries (reproductive and postmenopausal periods). In each group, subgroups of the Buryat and Russian populations were identified. The first group included 34 patients with T2DM of the reproductive period: 16 from the Buryat population and 18 from the Russian population. The second group consisted of 39 postmenopausal patients with T2DM: 17 from the Buryat population and 22 from the Russian population. The study of BMD in the lumbar spine (L1-L4), femoral neck (Neck), in the proximal femur (Total hip), trabecular bone score (TBS), serum osteocalcin (OC), N-terminal propeptide type 1 procollagen was carried out (P1NP), vitamin D 25 (OH), blood plasma type I collagen C-terminal telopeptide (β-Cross laps) and ionized calcium (iCa).Results: In female patients with T2DM of the reproductive age of the Buryat population, an increase in both markers of osteosynthesis P1NP (p=0.035), OC (p=0.047), and bone resorption β-Cross laps (p=0.040) was found relative to the similar group of the Russian population. In women with T2DM in the postmenopausal period of the Buryat population, there was also an increase in P1NP (p = 0.016), OC (p = 0.048), β-Cross laps (p = 0.020) compared with the group of postmenopausal women in the Russian population. Structural disorders, characterized by a decrease in TBS, were detected only in the postmenopausal period in female patients of the Buryat population compared to women in the Russian population (p = 0.029).Comparative analysis among women with T2DM of the Buryat population, depending on the functional state of the ovaries, showed that activation of bone remodeling with an increase in P1NP (p = 0.019), OC (p = 0.004) and β-Cross laps (p = 0.004) is characteristic of postmenopausal women accompanied by a decrease in BMD Neck (p = 0.006), BMD Total hip (p = 0.003), BMD L1-L4 (p = 0.049) and TBS (p = 0.020) relative to female patients with T2DM in the reproductive period.Conclusion: In women with T2DM in the Buryat population, both in the reproductive and postmenopausal periods, an increase in bone remodeling markers and BMD stability was found when compared with the corresponding groups of patients in the Russian population. The postmenopausal period was characterized by an additional decrease in TBS in patients with T2DM in the Buryat population relative to women in the Russian population.