PINP Levels Research Articles

A-112 Reference Intervals for Serum Concentrations of N-Terminal Propeptide of Type-I Procollagen (PINP) for Greek Adult Population

Abstract Background PINP is a sensitive indicator of the synthesis of type-I collagen. Serum PINP levels are affected by changes in bone metabolism and is a useful indicator of disease activity in Paget's disease, bone metastases of osteoblastic nature and in monitoring osteoporosis treatment. To interpret PINP, method and population specific reference intervals are needed. We aimed to determine reference intervals for serum concentrations of PINP for the Greek adult population. Methods We collected samples from 431 apparently healthy Greeks (140 men as well as 150 pre- and 139 post-menopausal women), who volunteered to participate in our study. Data on socio-demographic characteristics, medical histories and medications were collected and subjects with conditions or receiving medications that affecting bone metabolism were excluded. Dual-energy x-ray absorptiometry (DXA) used to measure bone mineral density (BMD) in all participants. All blood collections were performed in the morning after overnight fast. Measurements were performed by an automated chemiluminescent immunoassay on the Maglumi-X3 analyzer (Snibe, Shenzhen, China). This method measures the total-PINP in serum. The reference interval was defined as the central 95% range and determined according to CLSI guide C28-A3 using the MedCalc Software Results The table summarizes our results. DXA results revealed that 348 participants had normal BMD, 74 had osteopenia and 9 had osteoporosis which excluded from analysis. Since our data were not normally distributed (Shapiro-Wilk test) in any group and after the exclusion of outliers (Tukey test), we used the non-parametric method suggested by the CLSI guide in order to determine the reference intervals. Multiple regression analysis revealed that sex and menopausal status were factors affecting PINP values. Conclusions We provide reference intervals for the determination of PINP concentrations in serum for the Greek adult population using an automated immunoassay. Our data may aid to interpret bone turnover in the Greek adult population.

Effects of thunder-fire moxibustion on balance function and musculoskeletal metabolism in female patients of primary osteoporosis with low muscle mass

To observe the effects of thunder-fire moxibustion on the balance function and musculoskeletal metabolism in female patients of primary osteoporosis (POP) with low muscle mass. Sixty female patients of POP with low muscle mass were randomly divided into an observation group (30 cases, 5 cases dropped out) and a control group (30 cases, 2 cases dropped out). The patients in the control group were treated with oral administration of Caltrate D (1.5 g calcium carbonate + 125 IU vitamin D3), one tablet per day for 12 weeks. In addition to the control treatment, the patients in the observation group were treated with thunder-fire moxibustion at Mingmen (GV 4), Yaoyangguan (GV 3), bilateral Ganshu (BL 18), Shenshu (BL 23), and Dachangshu (BL 25), 30 min per acupoint, once every other day, three times a week, for 12 weeks. Balance function indexes (95% confidence ellipse area of the center of pressure [COP], total displacement, average speed), lumbar pain visual analogue scale (VAS), serum muscle metabolism factors (myostatin [MSTN], peroxisome proliferator-activated receptor γ coactivator-1α [PGC-1α]) and bone metabolism factors (aminoterminal propeptide typeⅠ procollagen [PINP], C-terminal telopeptide of typeⅠcollagen [CTX-Ⅰ]) were compared before and after treatment in both groups. Compared before treatment, the 95% confidence ellipse area of COP, total displacement, and average speed in the observation group were decreased after treatment (P<0.01), and the above indexes in the observation group were lower than those in the control group (P<0.05). Compared before treatment, the VAS scores in both groups were decreased after treatment (P<0.01), the score in the observation group was lower than that in the control group (P<0.01). Compared before treatment, the serum levels of MSTN, PINP and CTX-Ⅰ in the observation group were reduced after treatment (P<0.01), while the serum level of PGC-1α was increased (P<0.01). The control group showed a decrease in serum level of MSTN (P<0.05). The observation group had lower serum levels of MSTN and PINP (P<0.05) and higher serum level of PGC-1α (P<0.01) compared to the control group. The thunder-fire moxibustion can effectively relieve lumbar pain, improve balance function, and regulate musculoskeletal metabolism in female patients of POP with low muscle mass.

The role and mechanism of β-catenin-mediated skeletal muscle satellite cells in osteoporotic fractures by Jian-Pi-Bu-Shen formula.

Osteoporosis is a metabolic bone disease. β-Catenin is associated with fractures. Jian-Pi-Bu-Shen (JPBS) can promote the healing of osteoporotic fractures (OPF). However, the mechanism of β-catenin-mediated skeletal muscle satellite cells (SMSCs) in OPF by the JPBS is unclear. SMSCs were isolated and divided into five groups. The results showed that the survival rate of SMSCs was significantly higher in the low, medium, and high dose JPBS-containing serum groups after 7 days of incubation. The ALP activity and the number of SMSCs mineralized in the JPBS-containing serum intervention group were elevated. Axin, GSK-3β, β-catenin siRNAs were constructed and transfected into cells. Transfection of siRNAs reduced Axin, GSK-3β, and β-catenin expressions, respectively. β-Catenin-siRNA reversed ALP activity, the number of SMSCs mineralized, and the expression of β-catenin, BMP2, Runx2, COL-I, SP7/Ostrix, Osteocalcin, and BMP-7. Transcriptomic results suggested that the TNF signaling pathway associated with OPF was enriched. SD rats were subjected to the construction of OPF model by removing the ovaries. JPBS decreased the levels of PINP, ALP, CTX, and NTX through β-catenin in OPF rats, while increasing Runx2, β-catenin expressions through β-catenin at the broken end of fractures. Moreover, JPBS decreased BMC, BMD, and BV/TV and improved pathological damage through β-catenin in OPF rats. JPBS decreased the expression of Axin, GSK-3β mRNA, and protein, but increased the expressions of β-catenin, Pax7, COL-II, COL-II, BMP2, and Runx2 through β-catenin in OPF rats. In conclusion, JPBS inhibits Axin/GSK-3β expression, activates the β-catenin signaling, and promotes the osteogenic differentiation of SMSCs.

Changes in serum bone turnover markers and bone mineral density Z-score in children with osteogenesis imperfecta after zoledronic acid treatment.

The study aimed to investigate the changes in the levels of serum bone turnover markers (BTMs) and bone mineral density (BMD) Z-score in pediatric patients with osteogenesis imperfecta (OI) after intravenous bisphosphonate therapy and their association with age and estimated glomerular filtration rate (eGFR). This retrospective study analyzed data from 10 pediatric OI patients treated with intravenous zoledronic acid for over 1 year. Patients' clinical data were collected. The levels of BTMs and BMD Z-score before and after zoledronic acid treatment were analyzed. Significant improvement in BMD Z-score was observed after 6 and 12 months of treatment compared to baseline (all p < 0.05). The N-terminal propeptide of type I procollagen (PINP) levels decreased over time (all p < 0.05), indicating that zoledronic acid treatment decreased bone turnover. The levels of beta-C-terminal telopeptide of type I collagen remained stable after treatment. No correlation was found between PINP level and age, eGFR, or BMD (all p > 0.05). Bisphosphonate treatment can improve BMD and decrease bone turnover (indicated by decreased levels of PINP) in pediatric OI patients. PINP may serve as an independent indicator for monitoring the efficacy of bisphosphonate treatment in pediatric OI patients, particularly in those under the age of 6, where standardized BMD Z-score criteria are lacking.

Early diagnostic value of ECT whole-body bone imaging combined with PINP and β-CTX for bone metastasis of lung cancer.

This research was aimed at investigating the early diagnostic value of emission computed tomograph (ECT) whole-body bone imaging combined with PINP and β-CTX for bone metastasis of lung cancer. Case data of 86 lung cancer patients were categorized into lung cancer with bone metastasis (LCWBM, 46 cases) and lung cancer without bone metastasis (LCWOBM, 40 cases) groups according to the presence or absence of bone metastasis. Patients' general information were collected. ECT whole-body bone imaging was used to detect bone metastases and the grading of the extent of disease (EOD) in both groups, and electrochemiluminescence was utilized to detect the serum levels of PINP and β-CTX. Spearman correlation analysis was employed to evaluate the correlation between EOD grading and PINP and β-CTX levels. Logistic univariate and multivariate regression was implemented to analyze the risk factors of bone metastasis of lung cancer. Receiver operating characteristic (ROC) curve was applied to analyze the diagnostic efficacy of the single test of ECT whole-body bone imaging, PINP, or β-CTX and the combination of the three tests. The differences in pathological type, clinical stage and EOD grading, the number of positive ECT cases, and the expression levels of PINP and β-CTX between the LCWBM and LCWOBM groups were statistically significant. In LCWBM patients with different EOD grading, the trends of the expression of PINP and β-CTX were grade 3 > grade 2 > grade 1 and grade 0. Further correlation analyses revealed that EOD grading showed a significant positive correlation with the PINP and β-CTX expression levels. Univariate logistic regression analysis demonstrated that adenocarcinoma, TNM stage IV, ECT positivity, and high expression of PINP and β-CTX were associated with bone metastasis of lung cancer, and multivariate logistic regression analysis indicated that ECT positivity, high expression of PINP and β-CTX were independent risk factors for bone metastasis of lung cancer. The area under the curve (AUC) of ECT, PINP, and β-CTX alone for the diagnosis of bone metastasis of lung cancer were 0.872, 0.888, and 0.874, respectively, and the AUC for the combined diagnosis of the three was 0.963, which was greater than that of any one of the individual indices, with a sensitivity of 86.96% and a specificity of 97.50% at a Youden index of 0.845. ECT whole-body bone imaging combined with PINP and β-CTX has high diagnostic value for bone metastasis of lung cancer.

#2708 Impact of dialysis modality on bone phenotype

Abstract Background and Aims Literature data suggest that low bone turnover is the prevailing bone phenotype in patients treated with peritoneal dialysis (PD) and point to high sclerostin as the central culprit. Lack of adequate controls, diagnostic heterogeneity, and a changing mineral metabolism landscape and armamentarium call for a cautious interpretation and confirmation in contemporary patients. Method Laboratory parameters of mineral metabolism (biointact parathyroid hormone (PTH), fibroblast growth factor 23 [FGF23] and sclerostin), bone turnover markers (bone alkaline phosphatase [BALP], intact procollagen type I N-terminal propeptide [PINP], tartrate-resistant acid phosphatase 5b [TRAP5b]) and bone mineral density (BMD) were assessed in 636 non-diabetic kidney transplant candidates of whom 447 were treated with hemodialysis (HD) and 189 with PD. A bone biopsy was performed in 204 patients (n = 134 HD; n = 70 PD), with bone sclerostin expression assessed in a subset (n = 52). Results Patients treated with PD had lower levels of PINP (79.6 vs 99.5 ug/L; p &amp;lt; 0.01) and BALP (20.2 vs 23.7 ug/L; p = 0.04) compared to those treated with HD. Histomorphometric parameters of bone formation were numerically lower in patients treated with PD, but significance was not reached. Bone mineralization was impaired in HD patients (osteoid width: 7.90 vs 6.75 µM; p = 0.01; osteoid maturation: 9 vs 6 days; p = 0.03), while frank osteomalacia was rare in both modalities (6.0%, both groups). BMD was higher in patients treated with PD compared to HD at skeletal sites rich in cortical bone (Z-score midshaft radius −0.4 ± 1.3 vs −0.9 ± 1.7; p = 0.04). PTH levels were comparable (150 vs 144 pg/mL, PD vs HD), while patients treated with PD showed higher serum phosphate (4.9 ± 1.3 vs 4.5 ± 1.6 mg/dl; p &amp;lt; 0.01) and FGF23 levels (3852 pg/ml vs 2361 pg/ml; p = 0.01). Circulating (1.82 ng/mL, both groups) and bone tissue expression (205 ± 126 vs 206 ± 112 positive osteocytes per mm2) of sclerostin did not differ between groups. Conclusion Patients treated with PD present a lower bone turnover, better mineralization, and higher cortical BMD than counterparts treated HD. Overall, differences are marginal and most probably clinically irrelevant. We speculate that inferior phosphate control may be in the causal pathway.

Neferine alleviates ovariectomy-induced osteoporosis by enhancing osteogenic differentiation of bone marrow mesenchymal stem cells via regulation of the p38MAPK pathway

ABSTRACT Objective Osteoporosis, a skeletal ailment marked by bone metabolism imbalance and disruption of bone microarchitecture, Neferine, a bisbenzylisoquinoline alkaloid with diverse pharmacological activities, has received limited attention in the context of osteoporosis treatment. Methods We employed a bilateral ovariectomy (OVX) rat model to induce osteoporosis and subsequently administered Neferine treatment for four weeks following successful model establishment. Throughout the modeling and treatment phases, we closely monitored rat body weights. We assessed alterations in bone tissue microstructure through micro-CT, HE staining, and safranin O-fast green staining. Levels of bone formation and resorption markers in serum were evaluated using ELISA assay. Western blot analysis was employed to determine the expression levels of p38MAPK, p-p38MAPK, and bone formation-related genes in bone tissue. We isolated and cultured OVX rat BMSCs (OVX-BMSCs) and induced osteogenic differentiation while simultaneously introducing Neferine and the p38MAPK inhibitor SB203580 for intervention. Results Neferine treatment effectively curbed the rapid weight gain in OVX rats, ameliorated bone loss, and decreased serum levels of TRAP, CTX-I, PINP, and BALP. Most notably, Neferine promoted the expression of bone formation-related factors in bone tissue of OVX rats, while concurrently activating the p38MAPK signaling pathway. In in vitro experiments, Neferine facilitated the expression of bone formation-related factors in OVX-BMSCs, increased the osteogenic differentiation potential of OVX-BMSCs, and activated the p38MAPK signaling pathway. Nevertheless, SB203580 partially reversed Neferine’s promotive effect. Conclusion Neferine can boost the osteoblastic differentiation of BMSCs and alleviate OVX-induced osteoporosis in rats by activating the p38MAPK signaling pathway.

Favorable impact of PD1/PD-L1 antagonists on bone remodeling: an exploratory prospective clinical study and ex vivo validation

BackgroundSkeletal morbidity in patients with cancer has a major impact on the quality of life, and preserving bone health while improving outcomes is an important goal of modern antitumor treatment...

Oral daily PTH(1-34) tablets (EB613) in postmenopausal women with low BMD or osteoporosis: a randomized, placebo-controlled, 6-month, phase 2 study.

Anabolic treatment is indicated for high and very-high risk patients with osteoporosis, but acceptance is limited because current anabolic medications require subcutaneous injections. The purpose of this study was to assess the effects of a novel orally administered PTH tablet on serum markers of bone formation (PINP and osteocalcin), bone resorption (crosslinked C-telopeptide [CTX]), BMD, and safety in postmenopausal women with low BMD or osteoporosis. In this 6-mo, double-blind, placebo-controlled study, 161 patients were randomized to oral PTH tablets containing 0.5, 1.0, 1.5, or 2.5mg or placebo daily. Biochemical markers were assessed at 1, 2, 3, and 6mo and BMD of LS, TH, and FN was measured at 6mo. Biochemical marker changes were dose dependent with minimal or no effect at the 2 lowest doses. At the highest dose (2.5mg once daily), serum PINP and OC levels increased 30% within 1mo after oral PTH initiation (P< .0001), remained elevated through 3mo, and were back to baseline at 6mo. In contrast, serum CTX levels declined 16% and 21% below baseline at 3 and 6mo, respectively (both P≤ .02). At 6mo, 2.5mg tablets increased mean BMD vs placebo of the LS by 2.7%, TH by 1.8%, and FN by 2.8% (all P ≤ .01). There were no drug-related serious adverse events. The most common adverse events were headache, nausea, and dizziness. In contrast to subcutaneous PTH, the oral PTH tablet appears to increase BMD rapidly by the dual mechanism of stimulating formation and inhibiting bone resorption. This might be the first effective oral anabolic alternative to subcutaneous administration for the treatment of low BMD or osteoporosis.

Abstract 2920: In vitro assays for investigating the effects of cancer therapeutics on bone

Abstract Bone microenvironment is an important factor in regulating bone metastasis. When cancer cells home to bone they secrete factors that stimulate osteoclast activity leading to increased bone resorption. Stimulatory factors released from the resorbed bone matrix in turn promote proliferation of cancer cells and this process, referred as the vicious cycle, often leads to osteolytic lesions in bone when osteoclastic bone resorption exceeds osteoblastic bone formation. The vicious cycle observed in osteolytic disease occurs also in osteoblastic metastases, and in addition cancer cells produce osteoblast-stimulating factors. Cancers with bone metastases often include both osteolytic and osteoblastic lesions. Our aim was to establish in vitro cell culture models to study the effects of cancer therapeutics on osteoblast and osteoclast differentiation and activity. In the osteoclast differentiation assay, human osteoclast precursor cells (Lonza) were cultured on bovine bone slices for 7 days. Denosumab was added in the cultures at day 0, and tartrate-resistant acid phosphatase isoform 5b (TRACP 5b) activity was measured from the culture medium collected at day 7. Osteoclast activity was studied by allowing osteoclasts resorb bone after 7 days’ maturation period for additional 3 days in the presence of odanacatib. The amount of C-terminal cross-linked telopeptides of type I collagen (CTX-I) was measured in the culture medium collected at day 10 to quantitate osteoclast activity. Denosumab and odanacatib showed strong concentration dependent inhibition of osteoclast differentiation and activity, respectively. A mouse osteoblast progenitor cell line KS483 (Pharmatest Services) was used to study differentiation and activity of osteoblasts with test compounds bone morphogenetic protein 2 (BMP-2) and estradiol (E2). In the osteoblast differentiation assay, the activity of cellular alkaline phosphatase (ALP), a marker of osteoblast differentiation, was measured at day 8. In the osteoblast activity assay, the cells were cultured for 13 days. N-terminal propeptide of type I procollagen (PINP) secreted into the culture medium was determined at day 11 to indicate the effects on organic bone formation and calcium deposition was determined at the end of the study as a marker of inorganic bone formation. BMP-2 and E2 stimulated osteoblast differentiation and activity indicated by the increase in ALP activity, PINP and calcium levels. We conclude that these culture systems can be used for studying the effects of cancer therapeutics and identifying new potential compounds affecting the disease process of bone metastases with different mechanisms of action. Citation Format: Jenni H. Mäki-Jouppila, Mervi Ristola, Jukka Rissanen, Katja Fagerlund. In vitro assays for investigating the effects of cancer therapeutics on bone [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2920.

Gefitinib enhances healing of long bone fractures in rats via inhibition of the epidermal growth factor receptor signal pathway

Purpose: To investigate the influence of gefitinib on healing of long bone fractures in rats, and the involvement of epidermal growth factor receptor (EGFR) signal route in the process.&#x0D; Methods: A model of long bone fracture was established in 30 Sprague-Dawley (SD) rats which were allocated to control and study groups (n = 15/group). Rats in study group received gefitinib (100 mg/kg per day) via gavage, while control rats were given 0.55 % methylcellulose daily for 7 - 42 days. Fracture healing, maximum callus diameter, serum levels of bone markers and mRNA levels of bone turnover indices in the callus, were determined.&#x0D; Results: Following 1 week of therapy, fracture lines were clear in both groups, and callus was produced. On days 7, 14, 21, and 28, maximum callus diameter of study group was significantly higher than that of control group (p &lt; 0.05). However, there was no significant difference in the maximum callus diameter between the two groups after 42 days (p &gt; 0.05). On days 7, 14 and 21, there were significantly higher BALP and PINP levels, and TRACP-5b and CTX values in study group than in control (p &lt; 0.05). On days 7 and 14, study group COLa1 mRNA and osteocalcin (OC) mRNA was significantly raised, relative to control values. On days 7, 14 and 21, COL10 mRNA expression was significantly up-regulated in study group relative to controls (p &lt; 0.05). However, mRNA expression levels of COLa1, OC, COL10, and COL2A1 were similar in both groups at other time points.&#x0D; Conclusion: Gefitinib enhances the healing of long bone fractures and callus formation in rats, probably through inhibition of EGFR signaling pathway. Therefore, gefitinib is beneficial in bone formation in rats.

Correlation between the non-use of cooking oil fume extractors and bone mineral density in population aged 45 years and older in China: a cross-sectional study.

The correlation between the non-use of cooking oil fumes (COFs) extractors and bone mineral density (BMD) have not been clarified. Consequently, this study attempted to explore the impact of non-use COFs extractors on BMD in population aged 45 years and older based on a cross-sectional study. This study was a cross-sectional study within the framework of an ongoing prospective population-based cohort study in China. The multivariate linear regression models were used to evaluate the correlation between the non-use of fume extractors in family cooking and total lumbar spine (LS), femoral neck (FN), total hip BMD and levels of bone metabolism markers. A total of 3433 participants were included in the final analyses, of which 2607 (75.93%) participants used fume extractors. The results of models indicated that there were significant correlations of the non-use of fume extractors on total LS BMD (β = -0.024, 95% CI, -0.036, -0.012, p < 0.001), PINP (β = 4.363, 95% CI, 2.371, 6.356, p < 0.001) and ALP (β = 4.555, 95% CI, 2.593, 6.517, p < 0.001) levels. This study verified that the use of fume extractors is an efficacious measure to prevent LS bone loss. For the sake of public bone health, people should install a fume extractor in the kitchen and use it routinely when cooking.

Association between daily consumption of spicy food and bone mineral density in middle-aged and older adults: a cross-sectional study.

Background: Many studies have reported the effects of spicy food on human health, but no studies have been conducted on the impact of long-term spicy food consumption on bone mineral density (BMD). This study aimed to investigate the impact of daily consumption of spicy food on BMD in the population aged 50 years and older. Methods: This cross-sectional study was conducted from 2020 to 2022 in Jiangxi Province, China. This study investigated the differences in BMD between non-consumers and daily spicy food consumers in adults aged 50-85 years. A multiple linear regression model was used to investigate the association between spicy food consumption and BMD of the total lumbar spine (LS), femoral neck (FN), and total hip, as well as biochemical markers of bone metabolism (BMBM) levels. Results: The results showed that daily consumption of spicy food was negatively associated with total LS BMD (β = -0.013, P = 0.015). Subgroup analyses showed this negative association was more pronounced among smokers and drinkers compared to non-smokers (β: -0.006 vs. -0.042; P for interaction <0.05) and non-drinkers (β: -0.004 vs. -0.037; P for interaction <0.05). In addition, according to the daily frequency of spicy food consumption, the daily spicy food consumers were categorized into one meal per day, two meals per day, and three meals per day groups. Further analysis revealed that the negative association between spicy food and total LS BMD was progressively stronger as the frequency of daily consumption of spicy food increased (P for trend <0.05). For BMBM, daily consumption of spicy food was positively associated with serum PINP levels and negatively associated with serum Ca and serum Mg levels. Conclusions: Our study suggested that daily consumption of spicy food was associated with lower LS BMD in middle-aged and older Chinese adults, and this association was more pronounced in the smoking and drinking populations. The adverse effects of spicy food on LS BMD become progressively stronger with increasing frequency of daily consumption of spicy food. In addition, daily consumption of spicy food was associated with higher PINP levels and lower serum Ca and Mg levels.

ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi.

This study aims to investigate the impact of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) on vascular calcification in rats. The rationale behind studying ENPP1's role in vascular calcification lies in its potential to modulate calcification processes. Understanding this relationship can offer insights into novel therapeutic avenues for addressing vascular calcification-related disorders. In this experiment, vascular smooth muscle cell (VSMC) calcification was induced using β-glycerophosphoric acid. Subsequently, recombinant AAV9-carrying ENPP1 was introduced into VSMCs to achieve both in vitro and in vivo overexpression of ENPP1. The findings indicate that ENPP1 overexpression significantly reduces calcium and phosphorus content in the aorta (P < 0.05). Alizarin red and von Kossa staining reveal notable reductions in calcium salt deposits in VSMCs and aorta, respectively. Notably, the expression levels of BMP-2, PINP, OC, and BALP were substantially decreased in VSMCs (P < 0.05), underscoring ENPP1's role in impeding osteoblast-like transdifferentiation of VSMCs. Additionally, ENPP1 overexpression led to a significant increase in pyrophosphate (PPi) levels compared to control rats (P < 0.05). In conclusion, this study suggests that ENPP1 contributes to alleviating vascular calcification by elevating PPi levels and inhibiting the phenotypic transformation of VSMCs. These findings shed light on the potential therapeutic role of ENPP1 in mitigating vascular calcification-related complications.

The Effect of Two Years of Secukinumab Treatment on Bone Metabolism in Patients with Radiographic Axial Spondyloarthritis: Results from Daily Clinical Practice.

Our objective was to explore bone-related outcome and bone turnover markers (BTM) during 2 years of secukinumab treatment in patients with radiographic axial spondyloarthritis (r-axSpA) in daily clinical practice. Included were consecutive r-axSpA outpatients from the Groningen Leeuwarden axSpA (GLAS) cohort treated with secukinumab for 2 years. At baseline and 2 years, spinal radiographic damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; 0-72), cervical facet joint involvement according the "de Vlam" scoring method (0-15) and radiographic vertebral fractures (VF) using the "Genant" method (grade 0-3). At all visits, BTM reflecting collagen resorption (serum type I collagen C-telopeptide; sCTX), collagen formation (procollagen type 1 N-terminal peptide; PINP) and bone mineralization (bone-specific alkaline phosphatase; BALP) were measured and expressed in Z-scores to correct for the normal influence of age and gender. 17 r-axSpA patients were included; 53% male, mean age was 47±15 years, mean Ankylosing Spondylitis Disease Activity Score (ASDAS) 3.9±1.2, and 53% was biological naïve. The median 2-year progression rates were 1.1 for mSASSS and 0.5 for facet joints, which was less than the smallest detectable change. One traumatic VF (grade 3) occurred. Serum levels of sCTX and PINP remained stable during secukinumab treatment and BALP decreased significantly after 2 years, with median 0-2 year change in Z-scores of +0.1, -0.4, and -1.2, respectively. This explorative study of r-axSpA patients treated with secukinumab in daily clinical practice showed low radiographic spinal progression during 2 years of follow-up. Collagen resorption and formation markers remained stable, whereas mineralization marker BALP decreased significantly after 2 years. Our results are in line with the results of in vitro studies demonstrating that inhibition of IL17-A resulted in suppression of osteogenic differentiation with significant decrease in mineralization.

Moderate static magnetic field promotes fracture healing and regulates iron metabolism in mice

BackgroundFractures are the most common orthopedic diseases. It is known that static magnetic fields (SMFs) can contribute to the maintenance of bone health. However, the effect and mechanism of SMFs on fracture is still unclear. This study is aim to investigate the effect of moderate static magnetic fields (MMFs) on bone structure and metabolism during fracture healing.MethodsEight-week-old male C57BL/6J mice were subjected to a unilateral open transverse tibial fracture, and following treatment under geomagnetic field (GMF) or MMF. The micro-computed tomography (Micro-CT) and three-point bending were employed to evaluate the microarchitecture and mechanical properties. Endochondral ossification and bone remodeling were evaluated by bone histomorphometric and serum biochemical assay. In addition, the atomic absorption spectroscopy and ELISA were utilized to examine the influence of MMF exposure on iron metabolism in mice.ResultsMMF exposure increased bone mineral density (BMD), bone volume per tissue volume (BV/TV), mechanical properties, and proportion of mineralized bone matrix of the callus during fracture healing. MMF exposure reduced the proportion of cartilage in the callus area during fracture healing. Meanwhile, MMF exposure increased the number of osteoblasts in callus on the 14th day, and reduced the number of osteoclasts on the 28th day of fracture healing. Furthermore, MMF exposure increased PINP and OCN levels, and reduced the TRAP-5b and β-CTX levels in serum. It was also observed that MMF exposure reduced the iron content in the liver and callus, as well as serum ferritin levels while elevating the serum hepcidin concentration.ConclusionsMMF exposure could accelerate fracture healing via promote the endochondral ossification and bone formation while regulating systemic iron metabolism during fracture healing. This study suggests that MMF may have the potential to become a form of physical therapy for fractures.

Effects of empaglifozin on collagen biomarkers in patients with heart failure. Results from the EMPEROR trials

Abstract Background Extracellular matrix remodeling is one of the key pathways in progression of Heart Failure (HF). Clinical trials demonstrated that SGLT-2 inhibitors improved cardiovascular outcomes in HF patients, which may be partly explained by an effect on cardiac remodeling. Supporting data from preclinical studies suggested effects of SGLT-2 inhibitors on collagen synthesis and attenuation of fibrosis. However, the effect of SGLT-2 inhibitors on collagen turnover in HF patients is not fully elucidated. Purpose In patients of the EMPEROR-Preserved and EMPEROR-Reduced trials, across a wide spectrum of ejection fraction and renal function, the effect of empagliflozin on serum markers of collagen turnover was investigated. Methods 1084 patients (545 in empagliflozin and 539 in placebo) were included in the analysis. Biomarkers measured from serum samples at baseline, 12 and 52 weeks included PICP (a collagen type I formation marker; ELISA), PRO-C3 (a collagen type III formation marker; ECLIA), PINP (a collagen type I formation marker; ECLIA, Roche Diagnostics), PRO-C6 (a collagen type VI formation marker; ECLIA), C1M and C3M (markers of collagen type I and III degradation CLIA). A mixed model repeated measurements model (MMRM) was used to evaluate the treatment effects on the analysed biomarkers. Results Treatment with empagliflozin vs. placebo reduced PICP levels at week 12 and week 52, and reduced PRO-C3 at week 52. In contrast, no significant effect was observed on PINP, PRO-C6, C1M or C3M levels (Table 1). Conclusion Among patients with chronic HF, across a wide range of EF and of renal function, treatment with empagliflozin reduced the serum levels of PICP, a collagen type I formation marker, both at weeks 12 and 52 and PRO-C3, a collagen type III formation marker, at week 52. These results add support for an anti-fibrotic effect of empagliflozin and may help to explain the clinical effect of SGLT-2 inhibitors on cardiac remodeling.

Correlation between breast cancer and osteocalcin levels, and risk of hypertension in postmenopausal women: Implications for pharmacological intervention

Purpose: To investigate the correlation between breast cancer (BC), osteocalcin (OC) and hypertension risk in postmenopausal women.Methods: Two hundred patients with BC and 200 non–BC women who visited The First People's Hospital of Wenling Hospital, Wenling, China from June 2018 to March 2021 were included in the study. Fifty-three patients with hypertension and 157 non-hypertensive patients were included in the hypertension studies. The enrolled postmenopausal women were divided into control, BC, hypertensive and non–hypertensive groups and risk factors for hypertension were analyzed. Pearson's correlation coefficient was performed to correlate OC levels with clinical indices. The incidence of hypertension in each group was counted and its correlation with OC levels was determined using Chi–square test.Results: Age, BMI, OC, SBP, DBP, TC, TG, PTH and FPG levels were risk factors for the progression of hypertension in postmenopausal women (OR &gt; 1, p &lt; 0.05). Serum levels of OC in postmenopausal women had negative correlation with age, BMI, SBP, DBP, TC, TG, PTH, 25–(OH)D3 and FPG levels (r &lt; 0, p &lt; 0.05), but had positive correlation with HDL–C, CTX and PINP levels (r &gt; 0, p &lt; 0.05). With the elevation of OC levels, the incidence of hypertension showed a decreasing trend in postmenopausal women (p &lt; 0.05).Conclusion: Menopause is a risk factor for BC in women, while low OC levels are significantly related to elevated risk of hypertension in postmenopausal women. These findings suggest that armacological intervention to increase OC levels may have potential benefits in mitigating the risk of hypertension in postmenopausal women.

MiR-210 improves postmenopausal osteoporosis in ovariectomized rats through activating VEGF/Notch signaling pathway

BackgroundTo explore the effect and mechanism of action of miR-210 on postmenopausal osteoporosis (PMPO) in ovariectomized rats in vivo.MethodsAn ovariectomized (OVX) rat model was established by ovariectomy. Tail vein injection was performed to overexpress and knock down miR-210 in OVX rats, followed by the collection of blood and femoral tissues from each group of rats. And quantitative real-time polymerase chain reaction (qRT-PCR) was applied to assess the expression level of miR-210 in femoral tissues of each group. Micro computed tomography (Micro CT) was adopted to scan the microstructure of the femoral trabecula in each group to obtain relevant data like bone mineral density (BMD), bone mineral content (BMC), trabecular bone volume fraction (BV/TV), trabecular thickness (Tb.Th), bone surface-to-volume ratio (BS/BV), and trabecular separation (Tb.Sp). ELISA was used for determining the level of bone alkaline phosphatase (BALP), amino-terminal propeptide of type I procollagen (PINP), osteocalcin (OCN), and C-terminal telopeptide of type I collagen (CTX-1) in serum; and Western blot for the protein level of Runt-related transcription factor 2 (Runx2), osteopontin (OPN), and collagen type I alpha 1 (COL1A1) in femoral tissues.ResultsMiR-210 expression was significantly decreased in femoral tissues of OVX rats. Overexpression of miR-210 could obviously increase BMD, BMC, BV/TV and Tb.Th, whereas significantly decrease BS/BV and Tb.Sp in femurs of OVX rats. Moreover, miR-210 also downregulated BALP and CTX-1 level, upregulated PINP and OCN level in the serum of OVX rats promoted the expression of osteogenesis-related markers (Runx2, OPN and COL1A1) in the femur of OVX rats. Additionally, further pathway analysis revealed that high expression of miR-210 activated the vascular endothelial growth factor (VEGF)/Notch1 signaling pathway in the femur of OVX rats.ConclusionHigh expression of miR-210 may improve the micromorphology of bone tissue and modulate bone formation and resorption in OVX rats by activating the VEGF/Notch1 signaling pathway, thereby alleviating osteoporosis. Consequently, miR-210 can serve as a biomarker for the diagnosis and treatment of osteoporosis in postmenopausal rats.

Lactobacillus rhamnosus GG ameliorates osteoporosis in ovariectomized rats by regulating the Th17/Treg balance and gut microbiota structure

ABSTRACT Background With increasing knowledge about the gut – bone axis, more studies for treatments based on the regulation of postmenopausal osteoporosis by gut microbes are being conducted. Based on our previous work, this study was conducted to further investigate the therapeutic effects of Lactobacillus rhamnosus GG (LGG) on ovariectomized (OVX) model rats and the immunological and microecological mechanisms involved. Results We found a protective effect of LGG treatment in OVX rats through changes in bone microarchitecture, bone biomechanics, and CTX-I, PINP, Ca, and RANKL expression levels. LGG was more advantageous in promoting osteogenesis, which may be responsible for the alleviation of osteoporosis. Th17 cells were imbalanced with Treg cells in mediastinal lymph nodes and bone marrow, with RORγt and FOXP3 expression following a similar trend. TNF-α and IL-17 expression in colon and bone marrow increased, while TGF-β and IL-10 expression decreased; however, LGG treatment modulated these changes and improved the Th17/Treg balance significantly. Regarding the intestinal barrier, we found that LGG treatment ameliorated estrogen deficiency-induced inflammation and mucosal damage and increased the expression of GLP-2 R and tight junction proteins. Importantly, 16S rRNA sequencing showed a significant increase in the Firmicutes/Bacteroidetes ratio during estrogen deficiency. Dominant intestinal flora showed significant differences in composition; LGG treatment regulated the various genera that were imbalanced in OVX, along with modifying those that did not change significantly in other groups with respect to the intestinal barrier, inflammation development, and bile acid metabolism. Conclusions Overall, LGG ameliorated estrogen deficiency-induced osteoporosis by regulating the gut microbiome and intestinal barrier and stimulating Th17/Treg balance in gut and bone.