Collagen (Type I)

BACKGROUND: Osteoporosis is highly prevalent among postmenopausal women and is characterized by a progressive 1-2% annual decline in bone mineral density (BMD). This deterioration contributes to more than 8.9 million fractures globally each year. The condition arises from an imbalance between bone formation and resorption. Emerging evidence suggests that probiotics may positively modulate bone metabolism through gut microbiota regulation, yet high-quality clinical data directly linking probiotic use to bone turnover markers remains limited. This meta-analysis investigates the effects of probiotic supplementation on bone formation and resorption markers in osteoporotic individuals. METHODS: A systematic review and meta-analysis were conducted on 15 randomized controlled trials (RCTs) involving 1,432 participants. The studies assessed various probiotic strains, dosages, and intervention periods ranging from 8 weeks to 12 months. Pooled effect sizes were calculated for key bone formation markers-procollagen type 1 N-terminal propeptide (P1NP) and osteocalcin-and resorption markers, including C-terminal telopeptide of type I collagen (CTX-I), N-terminal telopeptide (NTX), and tartrate-resistant acid phosphatase 5b (TRAP-5b). Subgroup and dose-response analyses were also performed. RESULTS: Probiotic supplementation significantly improved bone metabolism. Bone formation markers showed notable increases, including a significant rise in P1NP (MD = +8.4 μg/L; 95% CI: 3.1-13.7) and osteocalcin. Bone resorption markers, especially CTX-I, demonstrated significant reductions (SMD = -0.35; 95% CI: -0.52 to -0.18). Multi-strain probiotic formulations produced greater improvements in both bone formation and resorption compared with single-strain interventions. A clear dose-response trend was observed, with higher probiotic doses correlating with stronger increases in P1NP. Subgroup analyses showed that postmenopausal women experienced more pronounced benefits than mixed-gender groups. DISCUSSION: Probiotic supplementation is associated with enhanced bone formation and reduced bone resorption in individuals with osteoporosis. Multi-strain formulations and higher dosages yielded

PURPOSE: Gut microbiota has been implicated in bone health. However, the extent of the skeletal benefits of probiotic supplementation in humans remains unclear. A systematic review and meta-analysis was performed to appraise the efficacy of probiotic supplementation in improving bone health through a comprehensive qualitative and quantitative synthesis of the available randomized controlled trials. METHODS: The PubMed, Web of Science, and China National Knowledge Infrastructure databases were searched for RCTs reporting the effects of probiotic supplementation on bone mineral density (BMD), C-terminal telopeptide of type 1 collagen (CTX), or procollagen type 1 N-propeptide (P1NP). A random-effects model was used to generate the pooled weighted mean differences and 95% confidence intervals. RESULTS: Probiotic supplementation significantly increased lumbar spine aBMD (areal BMD) (+ 0.010; n = 16) and hip aBMD (+ 0.022 g/cm2; n = 9) but had no significant effect on femoral neck aBMD (n = 7), P1NP (n = 10), and CTX (n = 11). Moderate-to-high heterogeneity was present in all analyses, likely due to differences in participant characteristics and intervention characteristics. A tendency toward increased lumbar spine aBMD was observed across subgroups, although statistical significance was not always reached, while findings for other outcomes varied. Most trials included postmenopausal women, and restricting the analyses to this population yielded results consistent with the main analyses. The increase in lumbar spine aBMD remained significant regardless of trial exclusion, whereas the effect on hip aBMD became non-significant when key trials were omitted. CONCLUSION: Based on the evidence from the currently available RCTs, probiotic supplementation appears to lead to modest but statistically significant improvement in lumbar spine BMD and, to a lesser extent, hip BMD in postmenopausal women. © 2025. The Author(s), under exclusive licence to the International Osteoporosis Foundation and the Bone Health and Osteoporosis Foundation.

BACKGROUND: Diminished estrogen levels in women after menopause contribute to an elevated risk of decreased bone mineral density (BMD) and disturbed bone metabolism. Dietary supplements are extensively employed as substitutes for prescription drugs, serving as a significant approach to modulate bone metabolism and improve bone health. Nevertheless, a lack of robust evidence prevents clinicians and patients from making the best-informed choices at present. Accordingly, a network meta-analysis (NMA) was performed to provide a comprehensive comparison of the effects of different dietary supplements on bone turnover biomarkers among postmenopausal women. METHODS: PubMed, Embase, Cochrane Library, and Web of Science databases were retrieved from their inception to November 20, 2024. Randomized controlled trials (RCTs) assessing the strength of dietary supplements in women after menopause were adopted in this research. Primary outcome indicators encompassed C-terminal telopeptide of type I collagen (CTX), procollagen type I N-terminal propeptide (P1NP), osteocalcin (OC), bone alkaline phosphatase (BAP), alkaline phosphatase (ALP), and N-terminal telopeptide of type I collagen (NTX). Risk of bias assessment was performed for each enrolled trial utilizing the ROB 2.0. A Bayesian NMA was conducted utilizing the R software (V4.4.1). Publication bias was assessed utilizing Stata 15.1. RESULTS: Forty-three RCTs involving 5,184 postmenopausal women were adopted. Research findings revealed that CTX levels decreased most substantially with vitamin E supplementation (SUCRA: 82.37%). Combining vitamin D and vitamin K most effectively elevated P1NP (SUCRA: 100.00%) and OC (SUCRA: 97.05%) levels. The greatest increase in BAP levels (SUCRA: 95.50%) was observed with vitamin K supplementation. Calcium supplementation yielded the largest elevation in ALP levels (SUCRA: 96.68%). Furthermore, protein supplementation resulted in the most significant reduction in NTX levels (SUCRA: 81.20%). CONCLUSION: Dietary supplementation may serve as an important strategy for enhancing bone health in women after menopause by regulating bone metabolism. By promoting bone formation and inhibiting bone

BACKGROUND: Although nutrition and exercise both influence bone metabolism, little is currently known about their interaction, or whether nutritional intervention can modulate the bone biomarker response to acute exercise. Improved understanding of the relationships between nutrition, exercise and bone metabolism may have substantial potential to inform nutritional interventions to protect the bone health of exercising individuals, and to elucidate mechanisms by which exercise and nutrition influence bone. OBJECTIVE: The aim was to synthesise available evidence related to the influence of nutrition on the response of the bone biomarkers procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX-1) to acute exercise, using a systematic review and meta-analytic approach. METHODS: Studies evaluating the influence of nutritional status or intervention on the bone biomarker response to an acute exercise bout were included and separated into four categories: (1) feeding status and energy availability, (2) macronutrients, (3) micronutrients and (4) other. Studies conducted on healthy human populations of any age or training status were included. Meta-analysis was conducted when data from at least five studies with independent datasets were available. In the case of insufficient data to warrant meta-analysis, results from individual studies were narratively synthesised and standardised mean effect sizes visually represented. RESULTS: Twenty-two articles were included. Of these, three investigated feeding status or energy availability, eight macronutrients, eight micronutrients (all calcium) and six other interventions including dairy products or collagen supplementation. Three studies had more than one intervention and were included in all relevant outcomes. The largest and most commonly reported effects were for the bone resorption marker CTX-1. Meta-analysis indicated that calcium intake, whether provided via supplements, diet or infusion, reduced exercise-induced increases in CTX-1 (effect size - 1.1; 95% credible interval [CrI] - 2.2 to - 0.05), with substantially larger effects observed in studies that delivered calcium via d

Vitamin D is a vital indicator of musculoskeletal health, as it plays an important role through the regulation of bone and mineral metabolism. This meta-analysis was performed to investigate the effects of vitamin D supplementation/fortification on bone turnover markers in women. All human randomised clinical trials reported changes in bone resorption markers (serum C-terminal telopeptide of type-I collagen (sCTX) and urinary type I collagen cross-linked N-telopeptide (uNTX)) or bone formation factors (osteocalcin (OC), bone alkaline phosphatase (BALP) and procollagen type-1 intact N-terminal propeptide (P1NP)) following vitamin D administration in women (aged ≥ 18 years) were considered. Mean differences (MD) and their respective 95 % CI were calculated based on fixed or random effects models according to the heterogeneity status. Subgroup analyses, meta-regression models, sensitivity analysis, risk of bias, publication bias and the quality of the included studies were also evaluated. We found that vitamin D supplementation had considerable effect on sCTX (MD: -0·038, n 22) and OC (MD: -0·610, n 24) with high heterogeneity and uNTX (MD: -8·188, n 6) without heterogeneity. Our results showed that age, sample size, dose, duration, baseline vitamin D level, study region and quality of studies might be sources of heterogeneity in this meta-analysis. Subgroup analysis also revealed significant reductions in P1NP level in dose less than 600 μg/d and larger study sample size (>100 participants). Moreover, no significant change was found in BALP level. Vitamin D supplementation/fortification significantly reduced bone resorption markers in women. However, results were inconsistent for bone formation markers.

AIM: The effects of vitamin D administration on bone turnover markers (BTMs) in adults are controversial. Thus, we carried out a meta-analysis of available randomised controlled trials (RCTs) to examine the impact of vitamin D supplementation on BTMs. METHODS: To identify relevant RCTs, we searched the PubMed/MEDLINE, Web of Science, Scopus, Cochrane Library and Embase databases for manuscripts published up to July 2022. The present study was conducted in agreement with the PRISMA guidelines. Weighed mean difference (WMD) and 95% confidence intervals (CI) were used to calculate the magnitude of the effect of the intervention. RESULTS: A total of 42 RCTs were included in the meta-analysis. The age of the participants enrolled in the RCTs ranged from 19.4 to 84 years. The pooled results depicted a decrease in deoxypyridinoline (DPD) concentrations (WMD: -1.58 nmol/mmol, 95% CI: -2.55, -.61, p = .001) following vitamin D supplementation. In addition, subgroup analyses demonstrated that vitamin D administration notably reduced procollagen type I N-terminal propeptide (PINP) levels in individuals aged >50 years and led to a pronounced decrease in alkaline phosphatase (ALP) values when the intervention lasted >12 weeks. No significant effect was observed on other BTMs, for example, collagen type 1 cross-linked C-telopeptide (CTX) and osteocalcin (OC) levels. CONCLUSION: Vitamin D administration decreases DPD, PINP and ALP levels, indicating a reduced bone turnover following the intervention. Other BTMs, for example, CTX or OC values, were not affected by vitamin D prescription. Vitamin D supplementation may exert a positive effect on some important BTMs. © 2023 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.

BACKGROUND: A high proportion of patients undergoing catheter ablation (CA) for atrial fibrillation (AF) experience recurrence of arrhythmia. This meta-analysis aims to identify pre-ablation serum biomarker(s) associated with arrhythmia recurrence to improve patient selection before CA. METHODS: A systematic approach following PRISMA reporting guidelines was utilised in libraries (Pubmed/Medline, Embase, Web of Science, Scopus) and supplemented by scanning through bibliographies of articles. Biomarker levels were compared using a random-effects model and presented as odds ratio (OR). Heterogeneity was examined by meta-regression and subgroup analysis. RESULTS: In total, 73 studies were identified after inclusion and exclusion criteria were applied. Nine out of 22 biomarkers showed association with recurrence of AF after CA. High levels of N-Terminal-pro-B-type-Natriuretic Peptide [OR (95% CI), 3.11 (1.80-5.36)], B-type Natriuretic Peptide [BNP, 2.91 (1.74-4.88)], high-sensitivity C-Reactive Protein [2.04 (1.28-3.23)], Carboxy-terminal telopeptide of collagen type I [1.89 (1.16-3.08)] and Interleukin-6 [1.83 (1.18-2.84)] were strongly associated with identifying patients with AF recurrence. Meta-regression highlighted that AF type had a significant impact on BNP levels (heterogeneity R2 = 55%). Subgroup analysis showed that high BNP levels were more strongly associated with AF recurrence in paroxysmal AF (PAF) cohorts compared to the addition of non-PAF patients. Egger's test ruled out the presence of publication bias from small-study effects. CONCLUSION: Ranking biomarkers based on the strength of association with outcome provides each biomarker relative capacity to predict AF recurrence. This will provide randomised controlled trials, a guide to choosing a priori tool for identifying patients likely to revert to AF, which are required to substantiate these findings. © 2021. Crown.

Milk contains a number of bone-beneficial nutrients. However, milk, due to the D-galactose content, might have unfavorable effects on bone health. A meta-analysis of randomized controlled trials (RCTs) was performed to clarify the effects of milk supplementation on bone mineral density (BMD), bone turnover markers [N-terminal telopeptide of type I collagen (NTx), C-terminal telopeptide of type 1 collagen (CTx), osteocalcin, bone alkaline phosphatase (BALP), and procollagen type 1 N-propeptide (P1NP)], and hormonal indices related to bone metabolism [parathyroid hormone (PTH), 25-hydroxyvitamin D [25(OH)D], and insulin-like growth factor 1 (IGF-1)] in adults. The PubMed and Web of Science databases were searched. A random-effects model was used to estimate the pooled effect sizes. A total of 20 RCTs were included. The trial duration ranged from 1 mo to 36 mo. Milk supplementation resulted in a small but significant increase in BMD at the hip (+0.004 g/cm2; n = 9 RCTs) and lumbar spine (+0.025 g/cm2; n = 7), but did not significantly affect whole-body BMD (n = 3) and femoral neck BMD (n = 7). Milk supplementation reduced the concentrations of P1NP (-5.20 ng/mL; n = 9), CTx (-0.16 ng/mL; n = 9), and NTx (-8.66 nmol bone collagen equivalents/mmol creatinine; n = 3). The concentrations of osteocalcin (n = 9) and BALP (n = 3) were not affected by milk supplementation. Reduced parathyroid hormone PTH (-1.01 pg/mL; n = 13) concentrations and increased IGF-1 (+1.79 nmol/l; n = 4) concentrations were observed with milk supplementation. 25(OH)D (+3.73 ng/mL; n = 11) concentrations were increased with vitamin-D fortified milk supplementation. The addition of milk to the diet may potentially increase the likelihood of preventing bone loss by restoring bone homeostasis through the modulation of the calcium-vitamin D-PTH axis, bone remodeling rate, and growth hormone/IGF-1 axis. © The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.

The current study presents a comprehensive systematic review and meta-analysis of randomized controlled trials (RCTs) on resveratrol and bone health biomarkers. PubMed, Scopus, and Web of Science (until September 2018) were searched to identify the potential RCTs with information on resveratrol supplementation and bone metabolism biomarkers. Mean differences (MD) were analyzed using a random-effects model. Pooling six RCTs (eight treatment arms with 264 subjects) together identified no significant reduction of serum Ca, osteocalcin, C-terminal telopeptide of type I collagen, and procollagen I N-terminal propeptide values after resveratrol supplementation over placebo treatment. However, a significant increase in serum alkaline phosphatase (ALP) (MD: 5.69 mg/mL, 95% CI: 3.58-7.80, I2 = 95.7%, P < 0.001) and bone alkaline phosphatase (BAP) (MD: 10.57 mmHg, 95% CI: 5.36-15.78, I2 = 99.2%, P < 0.001) values was observed after resveratrol treatment relative to placebo. The findings of this study indicate that resveratrol supplementation increased some key bone biomarkers, such as ALP and BAP. Further precise clinical trials of the effects of resveratrol supplementation on bone health should be conducted. © 2019 New York Academy of Sciences.

BACKGROUND: The aim is to evaluate via meta-analysis bone metabolism and bone mineral density (BMD) in morbidly obese patients before and after bariatric surgery. METHODS: We searched Medline, EMBASE, and the Cochrane Library for relevant studies published before January 2014. The following outcomes were evaluated: serum calcium, serum parathyroid hormone (PTH), serum 25-hydroxyvitamin D [25(OH)D], serum or urinary N-telopeptide (NTX), bone-specific alkaline phosphatase (BSAP), and bone mineral density (BMD). RESULTS: Ten studies, including 344 patients, met our inclusion criteria. Results showed a significant decrease in serum calcium (MD = -0.10, 95 %CI -0.14 to -0.07, P < 0.00001) and increase in serum PTH (MD = 12.41, 95 %CI 6.51 to 18.31, P < 0.00001) but no significant difference in serum 25(OH)D (MD = 1.35, 95 %CI -1.12 to 3.83, P = 0.28) following bariatric surgery. There were significant increases in serum or urinary NTX (MD = 18.49, 95 %CI 3.33 to 33.66, P = 0.02) and BSAP (MD = 7.47, 95 %CI 0.21 to 14.72, P = 0.04) but a significant decrease in BMD (MD = -0.08, 95 %CI -0.13 to -0.04, P < 0.00001) after bariatric surgery. CONCLUSION: BMD was significantly decreased, while bone turnover was elevated, and bone remodeling was accelerated following bariatric surgery. Basal bone metabolism should be evaluated preoperatively. To prevent secondary hyperparathyroidism and bone loss, calcium and vitamin D should be monitored closely and supplemented accordingly after the surgery.

BACKGROUND: Metabolic bariatric surgery (MBS) effectively reduces fat mass (FM), but how to best preserve muscle and bone mass after MBS is unknown. OBJECTIVE: This study aimed to evaluate the effect of aerobic, resistance and combined exercise regimens on body composition, bone mineral density (BMD) and physical function in adults following MBS. METHODS: Patients were randomized into aerobic, resistance, combined and control groups after undergoing MBS. Exercise groups completed a 26-week supervised program (three sessions per week) with progressively increasing intensity. The primary outcome was the change in fat-free mass (FFM) measured by dual-energy X-ray absorptiometry (DXA). Secondary outcomes included FM, hip, femoral neck and lumbar spine BMD, serum collagen type I C-telopeptide (CTX) and physical function (e.g., 6-min walk test and handgrip strength). Between-group differences were assessed using Bayesian analysis of covariance (ANCOVA) adjusted for age, sex, surgery type and baseline body mass index, with credible differences inferred when the 95% credible interval of the standardized effect size excluded zero. Associations between outcomes were assessed using Pearson correlation. RESULTS: Of 443 eligible candidates, 58 participants (aged 18-65 years, 70% women, BMI 41.7 ± 4.4 kg/m2) were randomized to aerobic (n = 15), resistance (n = 13), combined (n = 14) or control (n = 16) groups, and 91.3% were included in the analysis. The combined exercise group preserved more FFM (-5.1 ± 2.8 kg vs. -7.7 ± 2.8 kg; ES 0.60 [0.41, 0.77]) and reduced more FM (-11.9% ± 5.7% vs. -10.1% ± 4.9%, ES -0.64 [-0.85, -0.40]) than control. Aerobic training most attenuated total hip BMD loss (-0.037 ± 0.033 g/cm2, -3.3%) compared with control (-0.058 ± 0.021 g/cm2, -5.4%; ES 0.69 [0.42, 0.92]) and modestly attenuated femoral neck BMD loss (ES 0.30 [0.11, 0.48]), with no differences at the lumbar spine. The relative increase in serum CTX was smaller in the aerobic (157.8%; ES -0.44 [-0.65, -0.18]) and combined groups (161.8%; ES -0.42 [-0.63, -0.17]) compared with control (196.4%). Physical function improved modestly, with aerobic training showing a greater improvement in wa

The in vivo effect of platelet-rich plasma (PRP) on supraspinatus tendon morphology and subacromial bursa cell gene expression in degenerative rotator cuff tears remains unclear. This randomized controlled trial evaluated the effect of preoperative leukocyte-poor PRP (LP-PRP) subacromial injection on supraspinatus tendon histology and subacromial bursa gene expression. Sixteen patients with full-thickness supraspinatus tears were randomized to receive an ultrasound-guided LP-PRP injection (n = 8) or no injection (n = 8) six weeks before arthroscopic repair. Tendon biopsies were assessed using the modified Movin score. Gene expression of collagen type I, II and III, metalloproteinase 3 and 13, and interleukin 1β and 6 genes from subacromial bursa cells was quantified using quantitative real-time PCR. The results of the two groups were compared to determine any statistically significant difference regarding all the examined parameters. The PRP group demonstrated a significantly lower total modified Movin score than controls (6.5 vs. 12.1, p = 0.002), with lower scores for fiber structure, fiber arrangement, nuclear rounding, inflammation and cell density (all p < 0.003), while angiogenesis did not differ (p = 0.149), indicating an architecture closer to that of normal tendon. No statistically significant differences in gene expression were observed (all p > 0.05), although collagen II and metalloproteinase 3 and 13 showed biologically relevant downregulation [fold change 0.23 (95%CI 0.05-1.09), 0.24 (95%CI 0.002-26.10), and 0.26 (95%CI 0.02-2.76), respectively]. The LP-PRP injection was associated with improved supraspinatus tendon histological characteristics and biologically relevant reductions in selected bursal genes, in the setting of supraspinatus tendon tear.

PURPOSE: To investigate whether experiencing ≥2 consecutive menstrual cycles of <36 days improved bone mineral density (BMD) and bone turnover markers in response to increased energy intake in young exercising women with oligo-amenorrhea. METHODS: The REFUEL study was a 12-month RCT designed to increase energy intake to improve menstrual function and bone health in exercising women with oligo-amenorrhea. Participants from the intervention group were considered recovered (REC; n = 14) if they experienced ≥2 consecutive menstrual cycles of <36 days, and non-recovered otherwise (non-REC; n = 11). DXA scans assessed body composition and BMD at baseline and at the last measurement time point (month 6, 9, or 12). Urinary estrone-1-glucuronide (E1G) and pregnanediol glucuronide were measured daily. Serum insulin-like growth factor-1 (IGF-1), carboxy-terminal telopeptide of type I collagen (CTx), procollagen type 1 N-terminal propeptide (P1NP), and osteocalcin were assessed at baseline and at the last measurement time point (month 3, 6, 9, or 12). Bone balance (BB) was calculated from P1NP, CTx, and osteocalcin ratios relative to a healthy reference population. Linear mixed models assessed changes over time. RESULTS: Significant group*time effects were observed for lumbar spine BMD (F(1,20.1) = 4.65, p = 0.043), BB calculated from P1NP and CTx (F(1,23) = 5.60, p = 0.027), E1G AUC (F(1,20.7) = 9.86, p = 0.005), and E1G mean (F(1,20.6) =11.84, p = 0.002), indicative of improvements in the REC group compared with non-REC. Significant group effects demonstrated higher IGF-1 in REC than non-REC (F(1,22.9) = 8.43, p = 0.009). CONCLUSION: These results indicate that a nutrition intervention can improve bone health when ≥2 consecutive menstrual cycles of <36 days are achieved.

BACKGROUND: Calcium hydroxyapatite (CaHA) is a well-established biostimulatory filler approved for hand rejuvenation. Recent approaches have explored dilution with polymicronutrient (PMN) solutions to enhance cellular metabolism and extracellular matrix (ECM) regeneration. AIMS: To evaluate the biological and clinical effects of CaHA diluted in a PMN solution (CaHA + PMN) compared with the conventional CaHA diluted in saline solution (CaHA + SS) for hand rejuvenation. METHODS: An in vitro study was conducted to assess fibroblast proliferation and gene expression of ECM components (COL1A1, COL3A1, and ELN) after exposure to CaHA diluted with PMN or SS. A prospective, split-hand, double-blind clinical trial (n = 22) compared both formulations regarding Hand Grading Scale (HGS), Global Aesthetic Improvement Scale (GAIS), skin hydration (corneometry), and dermal thickness (ultrasound imaging) at baseline, 15 and 90 days after treatment. RESULTS: In vitro, CaHA + PMN induced greater fibroblast proliferation and upregulated COL1A1 and ELN gene expression compared to CaHA + SS. Clinically, both treatments led to significant improvement from baseline in HGS (p < 0.001), skin hydration and dermal/hypodermal thickness, with no statistically significant differences between-group. Investigator-assessed GAIS and patient-reported satisfaction on a 5-point Likert scale also showed improvement in both groups. CONCLUSION: Both treatments demonstrated comparable clinical outcomes, suggesting that the strong biostimulating effect of CaHA may have overshadowed potential additive effects of PMN. Nonetheless, in vitro findings confirmed enhanced biological activity with CaHA + PMN, supporting its investigation as a complementary strategy in future studies. © 2026 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.

BACKGROUND: Plasma concentrations of procollagen type-I C-terminal pro-peptide (PICP) and collagen type-I C-terminal telopeptide (CITP) may reflect collagen turnover and systemic fibrosis. We investigated the effect of pirfenidone, an anti-fibrotic agent, on PICP and CITP, and their association with myocardial fibrosis, using cardiovascular magnetic resonance to measure extracellular volume (ECV). METHODS: In the trial (Pirfenidone in Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction), PICP, CITP and PICP:CITP ratio were measured at baseline and follow-up in patients with ECV≥27% randomised (n=94) to pirfenidone or placebo, and at baseline only in patients who were not randomised because of ECV<27% (n=13). RESULTS: There was no association between baseline myocardial ECV and baseline log PICP, log CITP and log PICP:CITP ratio (p=0.19, p=0.13, p=0.60, respectively). Treatment with pirfenidone did not alter PICP, but reduced CITP and increased PICP:CITP ratio at 13 and 26 weeks (all p<0.05) but not at 52 weeks. After multivariable adjustment, there was a weak relationship between change in myocardial ECV and change in log PICP (R2 0.16, p=0.01) and log CITP (R2 0.12, p=0.04), but not log PICP:CITP ratio (p=0.56). CONCLUSIONS: In patients with stable heart failure with preserved ejection fraction, pirfenidone treatment had no sustained effect on plasma levels of PICP and CITP at 52 weeks. Changes in ECV during treatment with pirfenidone are associated with changes in plasma PICP and CITP, suggesting a weak association between changes in collagen volume/mass and plasma markers of collagen turnover. © Author(s) (or their employer(s)) 2026. Re-use permitted under CC BY. Published by BMJ Group.

Erratum in Int J Sport Nutr Exerc Metab. 2026 Jan 20;36(2):169. doi: 10.1123/ijsnem.2026-0006. The effects of Greek yogurt and whey protein supplementation on markers of bone turnover and inflammation were compared in university athletes over a competitive season. Participants (n = 32, 16 females) followed their habitual diets for an 8-week control period and were then randomly assigned to one of two trial arms: two servings per day of either 175 g of Greek yogurt (17 g protein) or isonitrogenous whey protein for a 16-week intervention period. Morning, fasting blood was collected at Weeks 0 (precontrol), 8 (postcontrol/preintervention), 16 (midintervention), and 24 (postintervention) and analyzed for osteocalcin, amino-terminal propeptide of Type I collagen, insulin-like growth factor 1, osteoprotegerin, C-telopeptides of Type I collagen, sclerostin, receptor activator of nuclear factor kappa-B ligand, tumor necrosis factor-alpha, interleukin 6, and interleukin 10. No main effects or interactions were found for markers of bone formation. In the Greek yogurt group, C-telopeptides of Type I collagen increased from pre- to postcontrol and returned to baseline concentrations postintervention while remaining stable throughout the study in whey protein (Time × Group interaction, p = .048). Receptor activator of nuclear factor kappa-B ligand increased from pre- to postcontrol (time effect, p = .014), returning to baseline by midintervention across groups. Males had higher sclerostin (sex effect, p = .021) and interleukin 10 (sex effect, p = .004) with no interactions. Interleukin 6 showed no main effects or interactions. Tumor necrosis factor-alpha increased pre- to postcontrol (time effect, p = .053) then decreased to baseline levels postintervention. Although protein supplementation, independent of source (wholefood or isolates), showed potential bone and inflammatory benefits during athletic training, it remains unclear whether these effects were solely attributable to the supplements.

Background: Impaired bone health is a recognized complication of type 1 diabetes. This study evaluated the effects of low-carbohydrate (LC) and Mediterranean (MED) diets on bone turnover markers in adolescents and young adults. Methods: In a 24-week randomized controlled trial, 40 individuals aged 12-21 years, with type 1 diabetes, were assigned to an LC or MED intervention (20 participants per group). C-terminal telopeptide (CTX) and procollagen type 1 N-terminal propeptide (P1NP) were measured at baseline and 24 weeks. Results: The groups had similar baselines. At 24 weeks, the between-group difference in delta glucose time in range was not statistically significant; median daily carbohydrate intake was 86 g (68-95) in LC and 130 g (102-173) in MED (p < 0.001). Comparing LC to MED, the median BMI z-score was lower (-0.1 [-0.3 to -0.1] vs. 0.0 [-0.1 to -0.1], p = 0.10), and calcium (p = 0.035) and magnesium intakes (p = 0.030) were lower. These associations did not remain statistically significant after false-discovery-rate correction. The median-adjusted alkaline phosphatase level decreased significantly in the LC group (p = 0.009). The median CTX changed following LC from 395 pg/mL (232-591) to 423 pg/mL (289-591) (p = 0.278); and following MED, from 357 pg/mL (244-782) to 296 pg/mL (227-661) (p = 0.245). P1NP changed in LC from 95 ng/mL (68-112) to 88 ng/mL (62-97) (p = 0.056) and in MED from 76 ng/mL (54-198) to 71 ng/mL (55-122) (p = 0.594). Conclusions: Exploratory analyses of bone turnover markers showed insignificant differences following LC and MED diets.

AIM: Plasma collagen 1a1 (Col-1a1), part of the α1 chain of collagen type-1, may be a marker of fibrosis in patients with heart failure (HF) and at increased risk of HF. We assessed associations amongst Col-1a1, NT-proBNP and echocardiographic parameters of cardiac structure and function and their relationship to prognosis in HFpEF. METHODS: We assessed 461 patients with HFpEF enrolled from the MEDIA-DHF cohort (mean age 74 [68, 80], 63 % women) and 516 those at risk of HF from the HOMAGE trial (mean age 73 [69, 79], 26 % women). Crude and adjusted linear regression models were used to evaluate the relationships amongst Col-1a1 (measured using proximity extension assay), NT-proBNP and echocardiographic measures. For the MEDIA-DHF study, the main outcome of interest was cardiovascular hospitalization and all-cause mortality. RESULTS: In both cohorts, patients with higher Col-1a1 levels were more likely to have poorer renal function, lower hemoglobin, higher NT-proBNP and lower prevalence of diabetes. In the MEDIA-DHF cohort, higher Col-1a1 was associated with higher NT-proBNP (β = 1.39; 95 %CI 1.08-1.80; p = 0.012), left atrial volume index (LAVi) (β = 4.57; 95 %CI 1.00-8.14; p = 0.013) and pulmonary artery systolic pressure (PAPs) (ß = 4.42; 95 %CI 1.47-7.37; p = 0.004). These results were corroborated in the HOMAGE trial: higher Col-1a1 was associated with higher NT-proBNP (ß = 0.20; 95 %CI 0.05-0.34; p = 0.009) and LAVi (ß = 2.32; 95 %CI 0.25-4.39; p = 0.028). Col-1a1 was not associated with the risk of the composite outcome in the MEDIA-DHF cohort. CONCLUSION: Col-1a1 was associated with NT-proBNP and LAVi in HFpEF as well as in patients at high risk of HF but not with outcomes in HFpEF. Further studies are needed to understand what role, if any, Col-1a1 has as a marker of fibrosis or prognosis in patients with HFpEF.

37. Int J Cardiol. 2026 Mar 15;447:134109. doi: 10.1016/j.ijcard.2025.134109. Epub 2025 Dec 16. The association between collagen 1a1, NTproBNP and echocardiographic markers in patients with or at risk of HFpEF. Rastogi T(1), Kobayashi M(2), Ferreira JP(3), Lagrange J(4), Baudry G(1), Monzo L(1)

AIMS: LY06006, a biosimilar of denosumab, is a recombinant fully human monoclonal antibody targeting the receptor activator of nuclear factor κB ligand. LY06006 has completed Phase I and Phase III clinical studies. The objective of this study is to develop a pharmacokinetic (PK)/pharmacodynamic (PD) model of LY06006 in healthy male and osteoporotic female populations in China. METHODS: In total, 420 subjects were enrolled in this study, including 84 healthy male subjects from the Phase I study and 336 osteoporotic postmenopausal women from the Phase III study. A nonlinear mixed-effects model was used for model development. The free serum concentration of LY06006 was used for PK analysis, and Type 1 collagen C-terminal telopeptide was used for PD analysis. RESULTS: A two-compartment Michaelis-Menten approximate model was used to describe the PK profiles of LY06006. Body weight was a significant covariate for the volume of distribution of the central compartment (V1) and clearance. The estimated values of V1 in postmenopausal women with osteoporosis were 0.87×, those observed in healthy male subjects. The indirect effect model was used to describe PK/PD relationship. Subjects' height significantly influenced the baseline values of C-terminal telopeptide. CONCLUSION: A population PK/PD model was developed in Chinese healthy male subjects and postmenopausal osteoporotic women. A 60-mg dose of LY06006 achieves similar PD efficacy to denosumab. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry (https://www.chictr.org.cn/): ChiCTR2000039637, ChiCTR2000032882. © 2025 British Pharmacological Society.

THE AIM OF THE STUDY: To study in vivo the biological properties of simvastatin and pentoxifylline and their ability to potentiate the action of bone morphogenetic protein-2 (BMP-2) for bone tissue regeneration in conditions of simulated postmenopausal osteoporosis. MATERIALS AND METHODS: The study was performed on 60 female Wistar rats. To create conditions that provoke the development of osteoporosis, 30 rats underwent ovariectomy; 30 animals underwent false ovariectomy without removing the ovaries. After 8 weeks, changes in the levels of osteoporosis markers, osteocalcin (OCN) and type I collagen C-telopeptide (CTX-1), in blood serum were assessed in all animals by enzyme immunoassay. To assess the osteoinductive properties, all animals underwent subcutaneous implantation of drugs and their combinations with BMP-2. In each group, both with ovariectomy and in falsely operated animals, 5 subgroups of 6 animals each were formed: simvastatin (0.13 mg/ml) was implanted in group 1, pentoxifylline (0.14 mg/ml) in group 2, BMP-2 (100 mcg/ml) in group 3, simvastatin and BMP-2 (0.13 mg/ml and 100 mg/ml) in group 4, pentoxifylline and BMP-2 (0.14 mg/ml and 100 mcg/ml) in group 5. RESULTS: Simvastatin and pentoxifylline did not have osteoinductive properties. During BMP-2 implantation, the volume of newly formed bone tissue was 0.5±0.2% in the group of rats with ovariectomy and 2.8± 1.5% in falsely operated animals. In turn, implantation of simvastatin with BMP-2 caused the formation of bone tissue in the volume of 7.4±4.2% and 5.4±1.5%, and pentoxifylline - 0.01±0.001% and 2.1±1.5% in the groups of rats with ovariectomy and falsely operated animals, respectively. CONCLUSION: The results obtained demonstrate the possibilities of using well-known pharmacological substances to enhance the osteoinductive effect of BMP-2 and can be used to create new effective bone graft materials in dentistry and maxillofacial surgery. Publisher: ЦЕЛЬ ИССЛЕДОВАНИЯ: Изучить in vivo биологические свойства симвастатина и пентоксифиллина и их способность потенцировать действие костного морфогенетического белка-2 (BMP-2) для регенерации костной ткани в условиях моделируемого постменопаузального

Breast cancer liver metastasis (BCLM) is characterized by high incidence and poor prognosis, lacking effective therapeutic strategies. Recent evidence suggests that lipid metabolic reprogramming plays an important role in the initiation and development of BC metastasis. In clinical practice of traditional Chinese medicine, Citri Reticulatae Pericarpium-Reynoutria japonica Houtt. (CR) herb pair is used for the treatment of BCLM. In this study, we explored the active ingredients of CR herb pair and underlying mechanisms against BCLM. By RNA sequencing analysis, we showed that extracellular matrix protein 1 isoform a (ECM1a), a secreted multifunctional glycoprotein, was a vital link between liver-metastatic potential and fatty acid (FA)-biosynthesis program in triple-negative breast cancer (TNBC) cells. Through integrative screening approaches, nobiletin and polydatin were identified as the core active ingredients of the CR herb pair. As an ECM1a inhibitor, nobiletin+polydatin combination exerted superior synergistic inhibitory effects on TNBC cells and liver-metastatic xenograft models. We further revealed that nobiletin+polydatin combination impaired ECM1a-mediated tumor FA-biosynthesis program by downregulating PI3K/AKT/mTOR/SREBPs signaling. These results support nobiletin+polydatin combination as a novel and promising therapeutic option for BCLM and highlight the role of ECM1a as the targetable master regulator of lipid metabolism in BCLM. © 2025. The Author(s) under exclusive licence to The Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.

Facial aging is a multifactorial process involving changes in bone, fat compartments, ligaments, muscles, and skin. Collagen biostimulators, including synthetic agents and autologous platelet concentrates, have gained attention for facial rejuvenation. Injectable platelet-rich fibrin (i-PRF), a second-generation autologous concentrate, has shown promising regenerative properties due to its natural composition and growth factors. Cosmetic peptides, such as palmitoyl pentapeptide-4 (Matrixyl) and Tetrapeptide-21 (GEKG), are also studied for their ability to stimulate collagen synthesis and remodel the extracellular matrix. This in vitro study examined the potential synergistic effects of i-PRF combined with Matrixyl or GEKG on human dermal fibroblast viability, proliferation, and ECM-related gene expression. Fibroblasts were cultured under six conditions: control, i-PRF alone, Matrixyl alone, GEKG alone, i-PRF + Matrixyl, and i-PRF + GEKG. Viability and proliferation were assessed via MTT, crystal violet, and RealTime-Glo™ assays. Gene expression of COL1A1, FN1, and HAS1 was measured using RT-qPCR. The combinations, especially i-PRF + GEKG, led to increased cell viability and upregulated ECM-related genes at 72 h. These effects were stronger than the individual treatments, suggesting synergistic effects, especially with GEKG. These findings highlight the clinical potential of combining autologous platelet concentrates with bioactive peptides for dermal regeneration. Further preclinical and clinical studies are warranted.

Background: The restoration of collagen and elastin in human dermal fibroblasts plays a crucial role in anti-aging and skin rejuvenation therapies. Numerous studies have examined the effects of various antioxidants on skin health, but there is limited research comparing their combined effects on collagen and elastin synthesis in human dermal fibroblasts. Objective: The objective of this study was to evaluate the individual and combined effects of N-acetylcysteine (NAC), Coenzyme Q10 (CoQ10), Niacinamide (NIAC), Gamma Cyclodextrin (GAMMA), Retinol (RET), Epigallocatechin Gallate (EGCG), and Ellagic Acid (ELA) on collagen type I and elastin synthesis in human dermal fibroblasts (HDFs). Methods: Human dermal fibroblasts were treated with individual and combined antioxidants. The expression of collagen type I and elastin was measured using mRNA analysis, immunofluorescence staining, and matrix protein assays. The study focused on the effects of EGCG in combination with other antioxidants like RET, CoQ10, and NAC to identify synergistic effects. Results: The combination of EGCG + RET and EGCG + CoQ10 showed the most significant increase in both elastin and collagen type I synthesis, surpassing the effects of individual antioxidants. EGCG demonstrated the highest fold change in elastin mRNA expression, while the combination treatments notably enhanced the extracellular matrix restoration in HDFs. Conclusion: The combination of EGCG with CoQ10, Retinol, or NAC presents a promising strategy for enhancing skin elasticity and firmness by promoting both elastin and collagen synthesis. These findings suggest that antioxidant combinations can be developed for effective anti-aging skincare formulations.

Idiopathic pulmonary fibrosis (IPF) remains an intractably fatal disorder, despite the recent advent of anti-fibrotic medication. Successful treatment of IPF, like many chronic diseases, may benefit from the concurrent use of multiple agents that exhibit synergistic benefit. In this light, phosphodiesterase type 5 inhibitors (PDE5-Is), have been studied in IPF primarily for their established pulmonary vascular effects. However, recent data suggest certain PDE5-Is, particularly vardenafil, may also reduce transforming growth factor beta 1 (TGF-β1) activation and extracellular matrix (ECM) accumulation, making them a potential target for therapy for IPF. We evaluated fibroblast TGF-β1-driven extracellular matrix (ECM) generation and signaling as well as epithelial mesenchymal transformation (EMT) with pretreatment using the PDE5-I vardenafil. In addition, combinations of vardenafil and nintedanib were evaluated for synergistic suppression of EMC using a fibronectin enzyme-linked immunosorbent assay (ELISA). Finally, the effects of vardenafil on fibrosis were investigated in a bleomycin mouse model. Our findings demonstrate that vardenafil suppresses ECM generation alone and also exhibits significant synergistic suppression of ECM in combination with nintedanib in vitro. Interestingly, vardenafil was shown to improve fibrosis markers and increase survival in bleomycin-treated mice. Vardenafil may represent a potential treatment for IPF alone or in combination with nintedanib. However, additional studies will be required.

A dysregulation of the wound healing process can lead to the development of various intractable ulcers or excessive scar formation. Therefore it is essential to identify novel pharmacological strategies to promote wound healing and restore the mechanical integrity of injured tissue. The goal of the present study was to formulate a nano-complex containing melittin (MEL) and diclofenac (DCL) with the aim to evaluate their synergism and preclinical efficacy in an in vivo model of acute wound. After its preparation and characterization, the therapeutic potential of the combined nano-complexes was evaluated. MEL-DCL nano-complexes exhibited better regenerated epithelium, keratinization, epidermal proliferation, and granulation tissue formation, which in turn showed better wound healing activity compared to MEL, DCL, or positive control. The nano-complexes also showed significantly enhanced antioxidant activity. Treatment of wounded skin with MEL-DCL nano-complexes showed significant reduction of interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) pro-inflammatory markers that was paralleled by a substantial increase in mRNA expression levels of collagen, type I, alpha 1 (Col1A1) and collagen, type IV, alpha 1 (Col4A1), and hydroxyproline content as compared to individual drugs. Additionally, MEL-DCL nano-complexes were able to significantly increase hypoxia-inducible factor 1-alpha (HIF-1α) and transforming growth factor beta 1 (TGF-β1) proteins expression compared to single drugs or negative control group. SB431542, a selective inhibitor of type-1 TGF-β receptor, significantly prevented in our in vitro assay the wound healing process induced by the MEL-DCL nano-complexes, suggesting a key role of TGF-β1 in the wound closure. In conclusion, the nano-complex of MEL-DCL represents a novel pharmacological tool that can be topically applied to improve wound healing.

INTRODUCTION: We report on the in vitro and ex vivo effects of chiral (R)-10-hydroxystearic acid (10-HSA) compared with other mono-hydroxystearic acid regioisomers and stearic acid (SA) together with its benefit when combined with retinol. METHODS: Following treatment with hydroxystearic acids peroxisomal proliferator-activated receptor alpha (PPARα) activity was determined in a luciferase reporter gene assay, collagen type I was assessed in primary human dermal fibroblasts by immunohistochemistry, modification of the intracellular fibroblast collagen proteome was studied by mass-spectrometry-based proteomics and collagen type III was assessed by immunohistochemistry on human ex vivo skin. RESULTS: 10-HSA was the most effective PPARα agonist (15.7× induction; p < 0.001), followed by 9-HSA (10.1× induction) and then 12-HSA (4.9× induction) with 17-HSA (1.7× induction) being similar to the effects of stearic acid (1.8× induction). Collagen type I levels were increased in primary human fibroblasts by 2.12× and 1.56× for 10-HSA and 9-HSA, respectively, in vitro with the10-HSA being significant (p < 0.05), whereas 12-HSA and SA had no statistical effect over the untreated control. 10-HSA and 12-HSA modified the intracellular fibroblast collagen proteome slightly with significant increases in collagen alpha-1 (VI) and alpha-3 (VI) proteins but only 10-HSA increased levels of collagen alpha-2 (V), alpha-1 (III), alpha-1 (I) and alpha-2 (I) (all p < 0.05) with the increases being significantly different between 10-HSA and 12-HSA for collagen alpha-1 (I), collagen-3 (VI) and collagen alpha-2 (I) (p < 0.01). Collagen type III in ex vivo skin was increased +47% (p < 0.05) by 0.05% (1.7 mM) retinol, +70% (p < 0.01) by 0.01% (0.33 mM) 10-HSA and the combination increased levels by +240% (p < 0.01 for either ingredient). CONCLUSION: Chiral (R)-10-HSA has been shown to be superior to 9, 12 and 17-HSA as a PPARα agonist. Moreover, 10-HSA stimulated collagen synthesis in monolayer fibroblast culture as assessed by proteomics and immunohistochemically. Furthermore, we also show the synergistic effects of 10-HSA with retinol on collagen III synthesis in skin explants. These result

The additive effects of prostaglandin (PG)-EP2 agonists on a PG-FP agonist toward adipogenesis in two- or three-dimension (2D or 3D) cultures of 3T3-L1 cells was examined by lipid staining, the mRNA expression of adipogenesis related genes, and extracellular matrixes (ECMs) including collagen molecules (Col) -1, -4 and -6, and fibronectin (Fn), and the sizes and physical properties of 3D sphenoids, as measured by a micro-squeezer. The results indicate that adipogenesis induced 1) an enlargement in the sizes of 3D sphenoids, 2) a substantial enhancement in lipid staining, the expression of the PParγ, Ap2 and Leptin genes, and 3) a significant decrease in the stiffness of the 3D sphenoids. These effects were inhibited by bimatoprost acid (BIM-A), but 4) adipogenesis induced significant down-regulation of Col1 and Fn, and the significant up-regulation of the Col4 and Col6 genes were unchanged by BIM-A. On the addition of an EP2 agonist, such as omidenepag (OMD) or butaprost (Buta), to BIM-A, 1) the sizes of the 3D sphenoids were further decreased, 2) lipid staining was decreased (2D; OMD, 3D; Buta) 3) the stiffness of the 3D sphenoids was increased by Buta, 4) the expression of PParγ was up-regulated (2D; Buta) or unchanged (3D), the expression of Ap2 was down-regulated (2D; OMD) or up-regulated (3D; Buta), and the expression of Leptin was increased (2D), 5) the expression of all four (OMD) or all except Col4 (buta) in 2D, and Col1and Col4 (OMD) in 3D were up-regulated. These collective findings indicate that the addition of an EP2 agonist, OMD or Buta significantly modulated the BIM-A induced suppression of adipogenesis as well as physical properties of 2D and 3D cultured 3T3-L1 cells in different manners.

Corneal wound healing depends on extracellular matrix (ECM) and topographical cues that modulate migration and proliferation of regenerating cells. In our study, silk films with either flat or nanotopography patterned parallel ridge widths of 2000, 1000, 800 nm surfaces were combined with ECMs which include collagen type I (collagen I), fibronectin, laminin, and Poly-D-Lysine to accelerate corneal wound healing. Silk films with 800 nm ridge width provided better cell spreading and wound recovery than other size topographies. Coating 800 nm patterned silk films with collagen I proves to optimally further increased mouse and rabbit corneal epithelial cells growth and wound recovery. This enhanced cellular response correlated with redistribution and increase in size and total amount of focal adhesion. Transcriptomics and signaling pathway analysis suggested that silk topography regulates cell behaviors via actin nucleation ARP-WASP complex pathway, which regulate filopodia formation. This mechanism was further explored and inhibition of Cdc42, a key protein in this pathway, delayed wound healing and decreased the length, density, and alignment of filopodia. Inhibition of Cdc42 in vivo resulted in delayed re-epithelization of injured corneas. We conclude that silk film nanotopography in combination with collagen I constitutes a better substrate for corneal wound repair than either nanotopography or ECM alone.

Asthma is a chronic obstructive lung disorder involving hyperresponsive lung tissue. This study evaluated the protective effects of riparin II against asthma and determined the synergistic effects of riparin II with ephedrine in treatment of asthma. Asthma was induced by intraperitoneal injection of Al(OH)3 (100 mg) with ovalbumin 1 mg/kg and subsequent exposure to 2% ovalbumin aerosol for 1 week. All animals were treated with riparin II 50 mg/kg and ephedrine 25 mg/kg alone and in combination for the duration of the study. Interleukin levels were assessed in the serum and bronchoalveolar lavage fluid (BALF) of asthmatic rats, while inflammatory cell infiltration was determined in the lungs. Airway remodelling was determined by assessing the lung tissue expression levels of transforming growth factor beta 1 (TGF-β1), Smad, and collagen I in asthmatic rats. There were lower levels of cytokines in the serum and BALF in riparin II-treated rats than in negative control rats. Moreover, inflammatory cell and IgE levels were reduced while interferon level was enhanced in the lungs of riparin II-treated rats, compared to negative control rats. These data reveal that treatment with riparin II ameliorates the altered expression of TGF-β1, Smad, and collagen I in lung tissue of asthmatic rats. In conclusion, riparin II treatment alone and in combination with ephedrine ameliorated the hyperresponsiveness of lung tissue due to reductions in airway remodelling and inflammation in asthmatic rats.