Procollagen Type I N-terminal Propeptide Research Articles

Once-weekly semaglutide versus placebo in adults with increased fracture risk: a randomised, double-blinded, two-centre, phase 2 trial

Previous studies have indicated that glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) may enhance bone formation and have neutral or beneficial effects on fracture risk. We evaluated the effect of the GLP-1RA semaglutide on the bone formation marker Procollagen type I N-terminal propeptide (PINP) in adults with increased fracture risk. This randomised, placebo-controlled, double-blinded, phase 2 clinical trial was conducted at two public hospitals in Denmark. We enrolled 64 men and women with increased fracture risk based on a T-score<-1.0at the total hip or lumbar spine and/or low-energy fracture within three years of recruitment. Participants were randomised (1:1) to receive once-weekly subcutaneous semaglutide 1.0mg or placebo. The primary outcome was changes in plasma (P)-PINP from baseline to week 52. Primary and safety outcomes were assessed and evaluated for all participants. This trial is complete and registered with ClinicalTrials.gov, NCT04702516. Between March 24 and December 8, 2021, 55 (86%) postmenopausal women and nine men with a mean age of 63 years (SD 5.5) and BMI of 27.5kg/m2 (SD 4.5) were enrolled. There was no effect on changes in P-PINP from baseline to week 52 between the two groups (estimated treatment difference (ETD) semaglutide versus placebo 3.8μg/L [95% CI-5.6 to 13.3]; p=0.418), and no difference in P-PINP levels between groups at week 52 (semaglutide 64.3μg/L versus placebo 62.3μg/L [95% CI-10.8 to 15.0]; p=0.749). The secondary outcomes showed higher plasma levels of bone resorption marker Collagen type I cross-linked C-terminal telopeptide (P-CTX) in the semaglutide group than in the placebo group (ETD 166.4ng/L [95% CI 25.5-307.3]; p=0.021). Compared to placebo, lumbar spine and total hip areal bone mineral densities (aBMD) were lower in the semaglutide groupafter 52 weeks ((ETD lumbar spine-0.018g/cm3 [95% CI-0.031 to-0.005]; p=0.007); ETD total hip-0.020g/cm2 ([95% CI-0.032 to-0.008]; p=0.001). Treatment differences in femoral neck aBMD were not observed ([95% CI [-0.017 to 0.006]; p=0.328). Further, body weight was lower in the semaglutide group than in the placebo group after 52 weeks (ETD-6.8kg [95% CI-8.8 to-4.7]; p<0.001). Thirty-one [97%] in the semaglutide group and 18 [56%] in the placebo group experienced at least one adverse event, including four serious events (two in each group). No episodes of hypoglycaemia or deaths were reported. In adults with increased fracture risk, semaglutide once weekly did not increase bone formation based on the bone formation marker P-PINP. The observed increase in bone resorption in the semaglutide group may be explained by the accompanying weight loss. Region of Southern Denmark, Novo Nordisk Foundation, and Gangsted Foundation. Novo Nordisk provided the investigational drug and placebo.

Icariin ameliorates osteoporosis by activating autophagy in ovariectomized rats.

Osteoporosis (OP) is a major problem that increases the mortality and disability rate worldwide. With an increase in the aging population, OP has become a major public threat to human health. Searching for effective and suitable targets for drug treatment in OP has become an urgent need. Osteoporosis is a metabolic bone disease characterized by reduced bone mass and density as well as micro-architectural deterioration. Icariin is a flavonoid extracted from plants of the genus Epimedium and has been shown to exert potential anti-OP activity. The present study was designed to observe the effect of icariin on OP and to clarify the underlying mechanisms in ovariectomized (OVX) rats. Hematoxylin and eosin (H&E) staining, von Kossa staining and micro-computed tomography (micro-CT) confirmed significant bone loss in the OVX group. Protein expression level was detected with western blot analysis. Icariin reversed a trend of increased bone turnover by reducing serum alkaline phosphatase (ALP), procollagen type I N-terminal propeptide (PINP), tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), and C-telopeptide of type I collagen (CTX-I). Furthermore, icariin decreased sequestosome 1 (p62) and increased microtubule-associated protein 1 light chain 3II/microtubule-associated protein 1 light chain 3I (LC3II/LC3I), autophagy-related protein 7 (Atg7), and Beclin 1 in the femur of OVX rats, improving the indicators of impaired autophagy in OP. Icariin reversed the significant upregulation of the serine/threonine protein kinase (Akt), mammalian target of rapamycin (mTOR) and unc-51-like autophagy activating kinase 1 (ULK1) at Ser757, and the downregulation of p-AMP-activated protein kinase (p-AMPK) and ULK1 phosphorylated at Ser555 in the OVX rats, suggesting that the mechanism of icariin action in OP treatment involves the activation and suppression of the AMPK/ULK1 and AKT/mTOR/ULK1 autophagy pathways, respectively.

Changes in Collagen Type I C-Telopeptide and Procollagen Type I N-Terminal Propeptide During the Menopause Transition.

Collagen type I C-telopeptide (CTX) and procollagen type I N-terminal propeptide (PINP) are reference bone resorption and formation markers, respectively. To characterize CTX and PINP trajectories across the menopause transition (MT). This 18-year longitudinal analysis of a community-based cohort from the Study of Women's Health Across the Nation included 541 women (126 Black, 90 Chinese, 87 Japanese, 238 White) who transitioned from pre- to postmenopause. Multivariable mixed effects regression fit piecewise linear models of CTX or PINP relative to years from final menstrual period (FMP); covariates were race/ethnicity, body mass index (BMI), and age at FMP. In the referent participant (White, 52.46 years at FMP, BMI 27.12 kg/m2), CTX and PINP were stable until 3 years pre-FMP (premenopause). During the MT (3 years before to 3 years after the FMP), CTX and PINP increased 10.3% (P < .0001) and 7.5% (P < .0001) per year, respectively; MT-related gains totaled 61.9% for CTX and 45.2% for PINP. Starting 3 years post-FMP (postmenopause), CTX and PINP decreased 3.1% (P < .0001) and 2.9% (P < .0001) per year, respectively. Compared with the White participants, during the MT, Chinese participants had larger gains in CTX (P = .01), and Japanese women experienced greater increases in CTX (P < .0001) and PINP (P = .02). In postmenopause, CTX (P = .01) and PINP (P = .01) rose more in Japanese relative to White women. CTX and PINP are stable in premenopause, increase during the MT, and decrease in postmenopause. During the MT and postmenopause, bone turnover change rates vary by race/ethnicity.

Associations of Changes in Bone Turnover Markers with Change in Bone Mineral Density in Kidney Transplant Patients.

Bone loss after kidney transplantation is highly variable. We investigated whether changes in bone turnover markers associate with bone loss during the first post-transplant year. Bone mineral density (BMD) was measured at 0 and 12 months, with biointact parathyroid hormone, bone-specific alkaline phosphatase (BALP), intact procollagen type I N -terminal propeptide (PINP), and tartrate-resistant acid phosphatase isoform 5b (TRAP5b) measured at 0, 3, and 12 months post-transplant ( N =209). Paired transiliac bone biopsies were available in a subset ( n =49). Between-group differences were evaluated by Student's t test, Wilcoxon signed-rank test, or Pearson's chi-squared test. Changes in BMD varied from -22% to +17%/yr. Compared with patients with no change (±2.5%/yr), patients who gained BMD had higher levels of parathyroid hormone (236 versus 136 pg/ml), BALP (31.7 versus 18.8 μ g/L), and Intact PINP (121.9 versus 70.4 μ g/L) at time of transplantation; a greater decrease in BALP (-40% versus -21%) and Intact PINP (-43% versus -13%) by 3 months; and lower levels of Intact PINP (36.3 versus 60.0 μ g/L) at 12 months post-transplant. Patients who lost BMD had a less marked decrease, or even increase, in Intact PINP (+22% versus -13%) and TRAP5b (-27% versus -43%) at 3 months and higher Intact PINP (83.7 versus 60.0 μ g/L) and TRAP5b (3.89 versus 3.16 U/L) at 12 months compared with patients with no change. If none of the biomarkers decreased by the least significant change at 3 months, an almost two-fold (69% versus 36%) higher occurrence of bone loss was seen at 12 months post-transplant. Bone loss after kidney transplantation was highly variable. Resolution of high bone turnover, as reflected by decreasing bone turnover markers, associated with BMD gain, while increasing bone turnover markers associated with bone loss.

The Collagen Synthesis Response to an Acute Bout of Resistance Exercise Is Greater when Ingesting 30 g Hydrolyzed Collagen Compared with 15 g and 0 g in Resistance-Trained Young Men

BackgroundResistance exercise (RE) stimulates collagen synthesis in skeletal muscle and tendon but there is limited and equivocal evidence regarding an effect of collagen supplementation and exercise on collagen synthesis. Furthermore, it is not known if a dose–response exists regarding the effect of hydrolyzed collagen (HC) ingestion and RE on collagen synthesis. ObjectiveTo determine the HC dose–response effect on collagen synthesis after high-intensity RE in resistance-trained young men. MethodsUsing a double-blind, randomized crossover design, 10 resistance-trained males (age: 26 ± 3 y; height: 1.77 ± 0.04 m; mass: 79.7 ± 7.0 kg) ingested 0 g, 15 g, or 30 g HC with 50 mg vitamin C 1 h before performing 4 sets’ barbell back squat RE at 10-repetition maximum load, after which they rested for 6 h. Blood samples were collected throughout each of the 3 interventions to analyze procollagen type Ⅰ N-terminal propeptide (PINP) and β-isomerized C-terminal telopeptide of type I collagen (β-CTX) concentration, and the concentration of 18 collagen amino acids. ResultsThe serum PINP concentration × time area under the curve (AUC) was greater for 30 g (267 ± 79 μg·L−1·h) than for 15 g (235 ± 70 μg·L−1·h, P = 0.013) and 0 g HC (219 ± 88 μg·L−1·h, P = 0.002) but there was no difference between 0 and 15 g HC (P = 0.225). The AUCs of glycine and proline were greater for 30 g than for 15 and 0 g HC (P < 0.05). Plasma β-CTX concentration decreased from −1 to +6 h (P < 0.05), with no differences between interventions. ConclusionsIngesting 30 g HC before high-intensity RE augments whole-body collagen synthesis more than 15 g and 0 g HC in resistance-trained young males.

Association of bone turnover markers and cognitive function in Chinese chronic schizophrenia patients with or without vitamin D insufficiency

BackgroundIncreasing evidence shows that bone turnover markers (BTMs) and vitamin D can affect human cognitive function. However, there are few studies that have investigated the association between BTMs and cognitive function in chronic schizophrenia patients. The aim of this study was to investigate the relationship between BTMs and cognitive function in chronic schizophrenia patients with or without vitamin D insufficiency (VDI).MethodsIn all, 118 chronic schizophrenia patients were enrolled in this cross-sectional study. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was applied to evaluate the cognitive function of the subjects. Blood analysis included bone turnover markers, vitamin D levels, and glycolipid levels.ResultsRelative to 72 vitamin D-sufficient (VDS) patients, 46 VDI patients had higher bone resorption markers levels and lower bone formation markers levels. Regression analysis showed that, in the total sample, CTX and language function exhibited independent positive correlation (p = 0.027, R2 change = 0.042), and in the VDS group, procollagen type I N-terminal propeptide (PINP) was independently negatively correlated with language function (p = 0.031, R2 change = 0.065), while the positive correlation between osteopontin (OPN) and delayed memory remained in the VDI group (p = 0.036, R2 change = 0.083).ConclusionOur study showed an association between the levels of BTMs and cognitive function among chronic schizophrenia patients. This correlation may have different mechanisms of action at different vitamin D levels.

Localization Of Procollagen Type I N-Terminal Propeptide in Bone Healing Treated by Local Application of Moringa Oliefera /Marine Collagen in Rats

Backgrounds: Bones healing is a complex multi steps process, Moringa Oliefera”s flavonoids and Marine collagen enhance minerals density of bones.Objectives: Differences in healing process in bones where evaluated in this study among bone defects that heal normally ( control group) and (experimental groups) using Marine collagen (MC), Moringa oleifera extract (MO) and combination of (MO &amp;MC). Material and Methods: in this study twenty albino rats, after anesthesia bone defects were created in both femurs by drilling. In ten rats, the right bone defects left to heal normally, and left MO added to the bone defects, in other ten rats MC added to the right bone defects, left defects treated with MO &amp; MC. Rats were scarified after 2 and 4 weeks. Immunohistochemical analysis of bone marrow stromal cells, osteocytes, osteoblasts and osteoclasts done using Procollagen type I N-terminal Propeptide (PINP). Results: Immunohistochemical result revealed stronger positive expression of PINP in bone defects treated with (MO&amp;MC) than that other groups Conclusions: Treatment of bone defects with MO and MC showed increase osteogenic capacity by increase the immunoreactivity of PINP.

Signs of a Glucose- and Insulin-Independent Gut-Bone Axis and Aberrant Bone Homeostasis in Type 1 Diabetes.

Gut hormones seem to play an important role in postprandial bone turnover, which also may be affected by postprandial plasma glucose excursions and insulin secretion. To investigate the effect of an oral glucose tolerance test (OGTT) and an isoglycemic intravenous glucose infusion (IIGI) on bone resorption and formation markers in individuals with type 1 diabetes and healthy controls. This observational case-control study, conducted at the Center for Clinical Metabolic Research, Gentofte Hospital, Hellerup, Denmark, included 9 individuals with C-peptide negative type 1 diabetes and 8 healthy controls matched for gender, age, and body mass index. Subjects underwent an OGTT and a subsequent IIGI. We analyzed changes in bone resorption assessed by measurements of carboxy-terminal type I collagen crosslinks (CTX) and in bone formation as assessed by procollagen type I N-terminal propeptide (PINP) concentrations. Baseline CTX and PINP levels were similar in the 2 groups. Both groups exhibited significantly greater suppression of CTX during OGTT than IIGI. PINP levels were unaffected by OGTT and IIGI, respectively, in healthy controls. Participants with type 1 diabetes displayed impaired suppression of CTX-assessed bone resorption and inappropriate suppression of PINP-assessed bone formation during OGTT. Our data suggest the existence of a gut-bone axis reducing bone resorption in response to oral glucose independently of plasma glucose excursions and insulin secretion. Subjects with type 1 diabetes showed impaired suppression of bone resorption and reduced bone formation during OGTT, which may allude to the reduced bone mineral density and increased fracture risk characterizing these individuals.

Negative impact on bone homeostasis in postmenopausal women with non-metastatic breast cancer during cytotoxic chemotherapy.

The burden and mechanisms of endocrine therapy-related bone loss are well known, while there are limited data on chemotherapy-induced bone resorption. The study aimed to evaluate the effect of cytotoxic chemotherapy on bone homeostasis among postmenopausal women with non-metastatic breast cancer. Early and locally advanced postmenopausal non-metastatic breast cancer patients aged 45 to 65 planned for three cycles of anthracycline and four cycles of taxane chemotherapy administered along with dexamethasone (cumulative dose-256mg) as an antiemetic from June 2018 to December 2021 were included. Bone mineral density (BMD), bone turnover markers, calciotropic hormones, pro-inflammatory cytokines, oxidative stress, and total antioxidant levels (TAS) were measured. We recruited 109 patients, with early 34 (31.2%) and locally advanced breast cancer 75 (68.8%) with median age 53 (45-65) years. There was a significant decrease in the % BMD at the lumbar spine, neck of the femur, and total hip post-chemotherapy. There was a significant increase in serum C-terminal telopeptide of type I collagen (CTX) and procollagen type I N-terminal propeptide (PINP) levels post-chemotherapy. PINP/CTX ratio significantly decreased post-chemotherapy. Serum 25-OH vitamin D was significantly reduced with a compensatory increase in plasma iPTH levels. The change in CTX, PINP/CTX ratio, 25-OH vitamin D, iPTH, and oxidative stress index was more pronounced during anthracycline as taxane chemotherapy. There were no significant changes in pro-inflammatory cytokine levels. Chemotherapy and dexamethasone as antiemetic resulted in significant bone loss, as evidenced by bone turnover markers. Further studies are required to understand the mechanism of chemotherapy-induced bone loss and the need for bone-strengthening agents during chemotherapy.

Metabolic Syndrome in Aging Men as a Factor Affecting the Relationship between Mg, Ca, and P in Serum and Bone.

The objective of this study was to evaluate the relationship between the prevalence of metabolic syndrome (MetS) and selected hormonal disorders and concentrations of magnesium (Mg), calcium (Ca), and phosphorus (P) in both blood serum and bone tissue. This study involved 152 men with and without MetS. In the blood of the patients we examined, we determined levels of: testosterone (TT), estradiol (E2), sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), insulin (I), osteocalcin (OC), and concentrations of markers of bone turnover. The concentration of Mg, Ca, and P was determined in the serum and bone tissue. In patients with MetS, the serum Ca concentration correlated with procollagen type I N-terminal propeptide (PINP) and parathyroid hormone (PTH). Among patients without MetS, the serum Ca concentration correlated with SHBG and OC, while Ca concentration in bone correlated with the lipid accumulation product (LAP) index and the body mass index (BMI). After analyzing the serum Mg concentration, positive correlations were observed with E2, PINP, and PTH in patients with MetS. In patients without MetS, the Mg concentration in bone positively correlated with the BMI and the LAP index. Our study findings suggest that increased Mg levels could have an impact on bone tissue metabolism. Elevated serum Mg levels may be associated with changes in sex hormone concentrations and alterations in bone turnover markers.

Impact of vitamin D supplementation on markers of bone turnover: Systematic review and meta-analysis of randomised controlled trials.

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. 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. 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. 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.

Comparison of the Effects of Metformin and Thiazolidinediones on Bone Metabolism: A Systematic Review and Meta-Analysis.

Studies have shown that people with diabetes have a high risk of osteoporosis and fractures. The effect of diabetic medications on bone disease cannot be ignored. This meta-analysis aimed to compare the effects of two types of glucose-lowering drugs, metformin and thiazolidinediones (TZD), on bone mineral density and bone metabolism in patients with diabetes mellitus. This systematic review and meta-analysis were prospectively registered on PROSPERO, and the registration number is CRD42022320884. Embase, PubMed, and Cochrane Library databases were searched to identify clinical trials comparing the effects of metformin and thiazolidinediones on bone metabolism in patients with diabetes. The literature was screened by inclusion and exclusion criteria. Two assessors independently assessed the quality of the identified studies and extracted relevant data. Seven studies involving 1656 patients were finally included. Our results showed that the metformin group had a 2.77% (SMD = 2.77, 95%CI [2.11, 3.43]; p < 0.00001) higher bone mineral density (BMD) than the thiazolidinedione group until 52 weeks; however, between 52 and 76 weeks, the metformin group had a 0.83% (SMD = -0.83, 95%CI: [-3.56, -0.45]; p = 0.01) lower BMD. The C-terminal telopeptide of type I collagen (CTX) and procollagen type I N-terminal propeptide (PINP) were decreased by 18.46% (MD = -18.46, 95%CI: [-27.98, -8.94], p = 0.0001) and 9.94% (MD = -9.94, 95%CI: [-16.92, -2.96], p = 0.005) in the metformin group compared with the TZD group.

Biomarkers for Prostate Cancer Bone Metastasis Detection and Prediction.

Prostate cancer (PCa) causes deaths worldwide, ranking second after lung cancer. Bone metastasis (BM) frequently results from advanced PCa, affecting approximately 90% of patients, and it also often results in severe skeletal-related events. Traditional diagnostic methods for bone metastases, such as tissue biopsies and imaging, have substantial drawbacks. This article summarizes the significance of biomarkers in PCa accompanied with BM, including (1) bone formation markers like osteopontin (OPN), pro-collagen type I C-terminal pro-peptide (PICP), osteoprotegerin (OPG), pro-collagen type I N-terminal pro-peptide (PINP), alkaline phosphatase (ALP), and osteocalcin (OC); (2) bone resorption markers, including C-telopeptide of type I collagen (CTx), N-telopeptide of type I collagen (NTx), bone sialoprotein (BSP), tartrate-resistant acid phosphatase (TRACP), deoxypyridinoline (D-PYD), pyridoxine (PYD), and C-terminal pyridinoline cross-linked telopeptide of type I collagen (ICTP); (3) prostate-specific antigen (PSA); (4) neuroendocrine markers, such as chromogranin A (CgA), neuron-specific enolase (NSE), and pro-gastrin releasing peptide (ProGRP); (5) liquid biopsy markers, such as circulating tumor cells (CTCs), microRNA (miRNA), circulating tumor DNA (ctDNA), and cell-free DNA (cfDNA) and exosomes. In summary, some of these markers are already in widespread clinical use, while others still require further laboratory or clinical studies to validate their value for clinical application.

Clinical observation of concentrated growth factor (CGF) combined with iliac cancellous bone and composite bone material graft on postoperative osteogenesis and inflammation in the repair of extensive mandibular defects

PurposeTo evaluate the effects of concentrated growth factor (CGF), combined with a mixture of iliac cancellous and composite bone materials, on the repair of extensive mandibular defects. Patients and MethodsThis clinical trial involved patients with mandibular defects caused by large cystic lesions. The test group comprised 16 patients who underwent CGF combined with iliac cancellous bone and composite bone materials to repair extensive mandibular defects, whereas the control group comprised eight patients who underwent vascularised free fibula grafts for mandibular segmental defects. Postoperative exudatum was collected from patients on the 1st, 2nd, 3rd, and 4th days postoperatively, and osteogenic factor, including alkaline phosphatase (ALP), osteocalcin (BGP), and procollagen type I N-terminal propeptide (PINP), and inflammatory cytokines were performed. Additionally, regular cone beam computed tomography (CBCT) scans were conducted before and after surgery. ResultsOn postoperative days 1–4, the expression levels of ALP, BGP, and PINP were higher in the test group, while those of IL-1α, IL-1β, IL-6, IL-8, and TNF-α, which were identified as co-differentially expressing inflammatory cytokines, were all down-regulated in the exudatum of the test group. Regular CBCT radiological scans revealed a significant osteogenic effect in the test group. ConclusionThe use of CGF combined with iliac cancellous bone and composite bone materials to repair extensive mandibular jaw defects facilitates bone formation and reductions in inflammation in the defect area in the short term, which deserves further research in clinical practice.

A standardized extract of Coleus forskohlii root protects rats from ovariectomy-induced loss of bone mass and strength, and impaired bone material by osteogenic and anti-resorptive mechanisms.

In obese humans, Coleus forskohlii root extract (CF) protects against weight gain owing to the presence of forskolin, an adenylate cyclase (AC) activator. As AC increases intracellular cyclic adenosine monophosphate (cAMP) levels in osteoblasts that has an osteogenic effect, we thus tested the skeletal effects of a standardized CF (CFE) in rats. Concentrations of forskolin and isoforskolin were measured in CFE by HPLC. CFE and forskolin (the most abundant compound present in CFE) were studied for their osteogenic efficacy in vitro by alkaline phosphatase (ALP), cAMP and cyclic guanosine monophosphate (cGMP) assays. Femur osteotomy model was used to determine the osteogenic dose of CFE. In growing rats, CFE was tested for its osteogenic effect in intact bone. In adult ovariectomized (OVX) rats, we assessed the effect of CFE on bone mass, strength and material. The effect of forskolin was assessed in vivo by measuring the expression of osteogenic genes in the calvarium of rat pups. Forskolin content in CFE was 20.969%. CFE increased osteoblast differentiation and intracellular cAMP and cGMP levels in rat calvarial osteoblasts. At 25 mg/kg (half of human equivalent dose), CFE significantly enhanced calcein deposition at the osteotomy site. In growing rats, CFE promoted modeling-directed bone formation. In OVX rats, CFE maintained bone mass and microarchitecture to the level of sham-operated rats. Moreover, surface-referent bone formation in CFE treated rats was significantly increased over the OVX group and was comparable with the sham group. CFE also increased the pro-collagen type-I N-terminal propeptide: cross-linked C-telopeptide of type-I collagen (PINP : CTX-1) ratio over the OVX rats, and maintained it to the sham level. CFE treatment decreased the OVX-induced increases in the carbonate-to-phosphate, and carbonate-to-amide-I ratios. CFE also prevented the OVX-mediated decrease in mineral crystallinity. Nanoindentation parameters, including modulus and hardness, were decreased by OVX but CFE maintained these to the sham levels. Forskolin stimulated ALP, cAMP and cGMP in vitro and upregulated osteogenic genes in vivo. CFE, likely due to the presence of forskolin displayed a bone-conserving effect via osteogenic and anti-resorptive mechanisms resulting in the maintenance of bone mass, microarchitecture, material, and strength.

Sequential treatment of teriparatide and alendronate versus alendronate alone for elevation of bone mineral density and prevention of refracture after percutaneous vertebroplasty in osteoporosis: a prospective study

BackgroundPercutaneous vertebroplasty was the most common strategy for osteoporotic vertebral compression fracture. However, refracture after vertebroplasty also occurred and bone mineral density (BMD) was one of the main factors associated with refracture after percutaneous vertebroplasty.AimsTo investigate the efficacy of a short-sequential treatment of teriparatide followed by alendronate on prevention of refracture after percutaneous vertebroplasty in osteoporotic patients, and compare it with the therapy of alendronate alone.MethodsFrom January 2018 to January 2020, we recruited 165 female osteoporosis patients after percutaneous vertebroplasty who were assigned into sequential treatment of teriparatide followed by alendronate group (TPTD + ALN group) and alendronate alone group (ALN group). The vertebral fracture occurred during this process was also recorded in both the groups. A total of 105 participants completed the 1-year follow-up. Furthermore, BMD and serum procollagen type I N-terminal propeptide (PINP) and C-terminal cross-linking telopeptide of type I collagen (CTX) were compared between the two groups during 1-year follow-up.ResultsThe 105 patients were finally included, with 59 in ALN group and 46 in TPTD + ALN group. During 1-year follow-up, the vertebral refracture rate in TPTD + ALN group was much lower than that in ALN group (2.2% vs. 13.6%, p < 0.05). At 12 months, the BMDs at lumbar in TPTD + ALN group were significantly elevated when compared to the ALN group (0.65 ± 0.10 vs. 0.57 ± 0.07, p < 0.001).Discussion and conclusionA short-sequential administration of teriparatide followed by alendronate was more effective in elevating the BMD and decreasing the refracture rate at 12-month follow-up, compared to the counterpart with alendronate alone.

Роль сывороточных маркеров в оценке состояния рубца на матке

Objective. To analyze the levels of serum fibrosis markers, procollagen type I N-terminal propeptide (PINP) and procollagen type III N-terminal propeptide (PIIINP), in relation to birth outcomes in patients with uterine scar after one previous cesarean section (CS). Patients and methods. This prospective study included 76 women with uterine scar after one previous CS. All patients had their PINP and PIIINP levels determined upon admission. Depending on birth outcomes, patients were divided into two groups: the study group consisted of 36 women who had spontaneous vaginal delivery without complications, and the comparison group was represented by 40 women who underwent unplanned cesarean delivery due to the development of complications. Results. Patients with successful birth outcomes in the presence of uterine scar had significantly lower levels of serum fibrosis markers: PINP reached 46.1 ng/mL and PIIINP – 2.6 μg/L, while in the comparison group, these values were 64.1 ng/mL and 4.2 μg/L, respectively. Such peculiarity of values may be associated with elevated expression of type I and III collagens. This mechanism provoked rapid fibrosis development, which was clinically manifested by uterine scar rupture during labor. Conclusion. Serum markers of fibrosis (PINP and PIIINP) are promising indicators for their further study as part of the problem of uterine scar assessment, but more observations are needed. For the conclusive evidence of their informativeness, it is important to perform immunohistochemical analysis of scar tissue samples with quantitative estimation of type I and III collagens and to compare these findings with peripheral blood values. Key words: uterine scar, connective tissue disorder, fibrosis, collagen, procollagen type I N-terminal propeptide, procollagen type III N-terminal propeptide

Utility of bone turnover markers in metabolic bone diseases

Bone turnover markers (BTMs) are biochemical indicators that provide information about the rate of bone remodeling, which involves the continuous process of bone formation and bone resorption. BTMs are measured in blood or urine samples and are used in the diagnosis, monitoring, and management of various metabolic bone diseases. They aid in the diagnosis of metabolic bone diseases by providing information about the bone turnover status. Abnormal levels of BTMs can indicate increased bone resorption or decreased bone formation, which are characteristic of certain conditions such as osteoporosis, osteomalacia, or Paget's disease. BTMs can provide insights into the severity of metabolic bone diseases. For example, in osteoporosis, elevated levels of bone resorption markers such as C-terminal telopeptide of type I collagen (CTX) or tartrate-resistant acid phosphatase 5b (TRACP-5b) indicate increased bone breakdown and higher fracture risk. Similarly, low levels of bone formation markers like procollagen type I N-terminal propeptide (PINP) or osteocalcin can indicate reduced bone formation and decreased bone strength. BTMs are valuable tools for assessing the response to treatment in metabolic bone diseases. Changes in BTM levels over time can indicate the effectiveness of interventions such as pharmacotherapy, lifestyle modifications, or surgical interventions. Decreased levels of bone resorption markers or increased levels of bone formation markers suggest a positive response to treatment, whereas persistent abnormal BTM levels may indicate the need for treatment adjustment.It's important to note that BTMs should be interpreted in conjunction with other clinical factors and imaging studies. They provide valuable information about bone turnover dynamics but should not be relied upon as standalone diagnostic or prognostic tools.

Effects of Bisphosphonates Treatments in Osteopenic Older Women: A Systematic Review and Meta-Analysis

Aims: To review the effects of bisphosphonates on bone density, fractures, and bone markers in osteopenic older women. Methods: Relevant articles published before February 2022 were searched in PubMed, EMBASE, and the Cochrane Library. All randomized controlled trials that reported incident fractures, bone mineral density (BMD), bone markers, or adverse events with bisphosphonates in osteopenic older women were included. The quality of included studies was assessed using the Cochrane Risk of Bias tool. The risk ratios (RRs) for fractures, net percent change in bone mineral density and differences in bone markers were calculated using a meta-analysis. Results: A total of 11 studies were included in our meta-analysis. Bisphosphonates significantly increased the percent changes in the lumbar spine BMD (WMD, 5.60; 95% CI, 4.16–7.03; I 2 = 93.6%), hip BMD (WMD, 4.80; 95% CI, 2.93 to 6.66; I 2 = 97.1%), total body BMD (WMD, 3.24; 95% CI, 2.12–4.35; I 2 = 90.9%), femoral neck BMD (WMD, 4.02; 95% CI, 1.70–6.35; I 2 = 91.8%) and trochanter BMD (WMD, 5.22; 95% CI, 3.51–6.93; I 2 = 83.6%) when compared to placebo. Zoledronate was associated with a great treatment effect on fragility fracture (RR, 0.63; 95% CI, 0.50–0.79), clinical vertebral fracture (RR, 0.41; 95% CI, 0.22–0.76), and radiographic vertebral fracture (RR, 0.60; 95% CI, 0.27–1.35) compared to placebo. Meanwhile, alendronate was also associated with beneficial effects on fragility fracture (RR, 0.40; 95% CI, 0.15–1.07), clinical vertebral fracture (RR, 0.46; 95% CI, 0.17–1.24), and radiographic vertebral fracture (RR, 0.64; 95% CI, 0.38–1.09). In addition, the use of bisphosphonates reduced the concentration of procollagen type I N-terminal propeptide (PINP) and C-terminal telopeptide of type I collagen (CTX) over placebo by 15.79 (95% CI, −18.92 to −12.66; I 2 = 28.4%), −0.23 (95% CI, −0.35 to −0.10; I 2 = 91.3%), respectively. Although there was insufficient evidence to determine their safety, these bisphosphonates may have an effect on cancer, cardiac events, and mortality in osteopenic older women. Conclusion: All bisphosphonates examined were associated with beneficial effects on fractures, BMD, and bone markers in women with osteopenia. Further randomized controlled trials are necessary to clarify the safety of bisphosphonates in women with osteopenia.

Relationships of Serum Bone Turnover Markers With Metabolic Syndrome Components and Carotid Atherosclerosis in Patients With Type 2 Diabetes Mellitus

ObjectiveThis study aimed to investigate the association of serum bone turnover markers (BTMs) with metabolic syndrome components and carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM).MethodsWe performed a cross-sectional based study in T2DM populations. Serum BTMs including N-terminal osteocalcin (N-MID), β-cross-linked C-telopeptide of type I collagen (β-CTX), and procollagen type I N-terminal propeptide (PINP) were measured by immunoassay method. Carotid artery intima-media thickness and carotid artery plaque (CAP) were measured by B-mode ultrasound.ResultsThe serum N-MID, PINP, and β-CTX levels significantly lower in the CAP group compared with the non-CAP group. N-MID and PINP levels were inversely associated with fasting blood glucose, HOMA-IR, CRP, eGFR, and triglycerides (all P < 0.05), whereas β-CTX levels were negatively associated with triglycerides (P < 0.05). After multiple adjustment, the odds ratios (ORs) were substantially higher for CAP with decreased N-MID level (OR = 0.958; 95% CI = 0.926–0.991; P = 0.013). However, serum levels of PINP and β-CTX were not associated with the presence of CAP. Multivariate logistic regression analysis further revealed that serum N-MID, PINP, and β-CTX levels were significantly associated with hypertriglyceridemia, whereas serum N-MID and β-CTX levels were associated with overweight/obesity risk.ConclusionsThese findings indicated that serum N-MID level was an independent risk factor for carotid atherosclerosis, whereas BTM levels were associated with other metabolic syndrome components in a T2DM population.