Procollagen Type 1 N-terminal Propeptide Research Articles

#1235 Comparative effect on bone remodeling and inflammation biomarkers of citrate dialysate and bicarbonate dialysate in HDF-OL patients

Abstract Background and Aims Hemodialysis (HD) treatment increases the inflammatory state of chronic kidney disease (CKD), which is associated with dysregulation of mineral bone metabolism. Reduced inflammation and increased bone formation have been described in Hemodiafiltration (HDF) compared with conventional HD. On the other hand, HD and OL-HDF using citrate-enriched dialysate are known to be safe and anti-inflammatory. However, the effects of post-dilution OL-HDF with citrate dialysate compared to bicarbonate dialysate on biomarkers of bone formation and resorption have not been studied. We aimed to compare the effect of bone remodeling markers and inflammation of different dialysates (citrate vs bicarbonate) in post dilution OL- HDF treatment. Method A total of 33 patients on conventional HD with bicarbonate citrate were included. At month 1, 18 patients, who did not require individualized adjustment of the dialysate composition such as potassium, were changed to HD with citrate dialysate and 15 patients remained with bicarbonate dialysate. By the second month, however, all patients were on OL-HDF with no change in buffer dialysate. Pre-dialysis blood samples were taken in both treatment groups at baseline (prior to the initiation of citrate dialysate in 18 patients), and at the first, second and fifth months after the introduction of citrate. Measurements of mineral homeostasis (calcium, phosphate, magnesium, parathyroid hormone, intact parathyroid hormone), inflammation (interleukin-6, β2-microglobulin, C-reactive protein) and bone remodeling markers (carboxy-terminal crosslinked telopeptide of type 1 collagen (CTX), as a biomarker of bone resorption and procollagen type 1 N-terminal pro-peptide (P1NP), as a biomarker of bone formation) were performed. All samples were collected before a mid-week dialysis session. Mineral homeostasis measurements were also performed before and after HD at the first and second month of the switch to citrate dialysate. Normally distributed data were presented as mean (standard deviation, SD) and median (interquartile range). Intra-subjects comparisons were analyzed using paired sample t-test or Wilcoxon signed-rank test. Comparisons between groups were analyzed using Mann-Whitney U test. Statistical analyses were performed using the SPSS (version 15.0, Chicago, IL, USA). p-value < 0.05. Results Overall, 75.7% (n = 25) of the subjects were male, the median age was 69 years (SD: 12) and 39.3% suffered diabetes (n = 13). Patients on citrate and bicarbonate dialysates were comparable for age, sex, comorbidities, months on dialysis and anemia control. Baseline mineral, bone remodeling and inflammation markers before HD, were also comparable in both groups. Only patients on bicarbonate dialysate had higher β2-microglobulin levels at baseline. Changes in serum levels of mineral, bone remodeling and inflammatory biomarkers at 5 months compared to baseline for both groups are shown in Table 1. After 5 months of follow-up, a 22% trend-reduction (p = 0.08) in P1NP as bone formation biomarker was observed in patients on citrate dialysate compared to those on bicarbonate dialysate. In addition, the fold change observed in CTX as parameter of bone resorption was attenuated in the citrate dialysate group (11% vs 116% in the bicarbonate dialysate group, p < 0.001). β2-microglobulin levels decreased significantly in both groups at 5 months but It is explained by the known effect of OL-HDF treatment on the inflammatory state of dialysis patients. Conclusion In patients on OL-HDF treatment the use of the citrate as dialysate may provide a benefit in bone remodeling by reducing bone resorption and trend to balance the bone formation/resorption. However, our results are in line with previous studies, where caution should be adopted in patients with very high parathyroid hormone levels, as this may be enhanced by reduced mineral turnover.

#2034 CKD-MBD management: results from a national survey on bone turnover biomarkers practice and therapeutic strategies among Italian nephrologists

Abstract Background and Aims Advanced stages of chronic kidney disease (CKD) are constantly characterized by a mineral and bone disorders (MBD) syndrome concerning a complex systemic condition that includes laboratory abnormalities of bone and mineral metabolism involving calcium, phosphorus, parathyroid hormone (PTH), or vitamin D; abnormalities in bone turnover, mineralization, volume, or strength; extra-skeletal calcifications, such as vascular or other soft tissue. CKD-MBD syndrome determines relevant consequences in terms of fragility fractures, cardiovascular events and higher mortality. The nephrologist's awareness of CKD-MBD diagnostic and management tools and therapeutic strategies is key to improving CKD patients’ prognosis and outcomes. Method A new national survey (composed of 17 online questions) was conducted among Italian nephrologists to investigate the reference laboratory availability of bone turnover markers (BTMs), the clinical attitude on secondary hyperparathyroidism (sHPT) management, and the CKD-MBD therapeutic approach in different stages of CKD and dialysis patients. Results 89 Italian nephrologists participated in the survey. The reference laboratories largely fulfill the biomarkers request of ionized calcium (97.7%), phosphorus (100%), PTH (100%), alkaline phosphatase (ALP) (100%), magnesium (100%), 25-OH and 1,25-OH vitamin D levels (92.1%; 53.9%); while most of the hospital laboratories do not regularly support the availability of specific BTMs, both for diagnosis and monitoring the bone resorption and formation (Fig. 1)—such as bone ALP (75.3%), calcifediol (37.1%), calcitriol (40.5%), fibroblast growth factor-23 (FGF-23) (intact 9% and c-terminal 4.5%), vitamin K (33.7%), Klotho (6.75%, soluble 4.5%), osteocalcin (38.2%), matrix gla protein (10.1%), tartrate-resistant acid phosphatase 5b (TRAP-5b) (6.75%), cross-linked collagen type I peptide (CTX) (32.6%) and procollagen type 1 n-terminal propeptide (P1NP) (10.1%). The nephrologist's attitude to start management and treatment of sHPT is revealed to be mainly led by KDOQI (n = 42, 47%) and KDIGO (n = 39, 44%) guidelines considering their PTH cut-off values; in 53.9% of clinicians the measure of PTH levels is then performed every 3 months according to KDOQI guidelines. In relation to the definition of high turnover metabolic bone disease by BTMs, this metabolic pattern is identified in > 50% and 30-40% of patients with CKD 4-5D by 31.5% and 21.4% of nephrologists, respectively. 65% of clinicians currently considered ALP of equal importance as alterations of PTH as a predictor of fracture events. Other biomarkers, such as FGF-23, P1NP or TRAP-5b, emerge to not be still used in regular clinical practice. In patients diagnosed with CKD-MBD and skeletal fragility, 76.4% of nephrologists consider the AIFA (Italian Medicines Agency) note 79 to support osteoporosis treatment. The therapeutic strategies of CKD-MBD include the administration of vitamin D (e.g. cholecalciferol 27-37.1%, calcifediol 9-12.4%, calcitriol 42.7-55.1%) and its analogues (e.g. paricalcitol 23.6-52.8%) and the use of antiresorptive agents (e.g. alendronate 3.4%-23.6%, denosumab 22.5%-30.3%) with variable frequencies among different advanced CKD stages and for those patients on peritoneal or hemodialysis (Fig. 2). Conclusion Results present a suboptimal use of BTMs and a current heterogeneous therapeutic management of CKD-MBD syndrome and renal osteodystrophy in Italian clinical practice. The survey represents a starting point of work to further implement awareness of diagnostic and therapeutic issues of CKD-MBD.

Comparison of the pleiotropic effect of atorvastatin and rosuvastatin on postmenopausal changes in bone turnover: A randomized comparative study.

Statins are the first-line treatment for dyslipidemia, which is a major modifiable risk factor for atherosclerotic cardiovascular disease. Studies have shown that in addition to the beneficial lipid-lowering effect, statins also exhibit a number of pleiotropic effects that may find application in other diseases, including osteoporosis. This study aimed to assess the effect of statins on bone turnover, as measured by the concentration of bone turnover markers, and to compare the effect of atorvastatin as a lipophilic statin and rosuvastatin as a hydrophilic statin. This study included 34 postmenopausal women aged < 65 years with newly diagnosed dyslipidemia requiring statin therapy. Patients were randomly assigned to receive a statin drug. Statins were initiated at standard doses of 5 to 10 mg of rosuvastatin and 20 mg of atorvastatin. The levels of C-terminal telopeptide of type I collagen as a bone resorption marker and N-terminal propeptide of procollagen type I as a marker of bone formation, lipid concentrations and other biochemical parameters were assessed at baseline and after 6 and twelve months of treatment. There were no statistically significant differences between the levels of bone turnover markers before and 6 months after statin implementation (P > .05) - for all patients or subgroups according to statin use. Analysis of the results showed that after 12 months, there was a statistically significant decrease in N-terminal propeptide of procollagen type I concentration in all subjects (P = .004). By statin subgroup, a statistically significant decrease in N-terminal propeptide of procollagen type I was observed only in patients receiving rosuvastatin (P = .012) and not in those receiving atorvastatin (P = .25). Moreover, changes in bone turnover markers did not correlate with changes in lipid concentrations. These results may indicate the superiority of atorvastatin over rosuvastatin in inhibiting adverse changes in bone turnover in postmenopausal women. Confirmed by studies involving a larger population, the observed differences might find particular applications in clinical practice, and the choice of atorvastatin over rosuvastatin for women could be considered in the early postmenopausal period to reduce the risk of osteoporosis and subsequent osteoporotic fractures.

Effects of sodium-glucose cotransporter 2 inhibitors on bone metabolism in patients with type 2 diabetes mellitus: a systematic review and meta-analysis

BackgroundSodium glucose cotransporter 2 (SGLT2) inhibitors are widely used in type 2 diabetes mellitus (T2DM) therapy. The impact of SGLT2 inhibitors on bone metabolism has been widely taken into consideration. But there are controversial results in the study on the effect of SGLT2 inhibitors on bone metabolism in patients with T2DM. Therefore, we aimed to examine whether and to what extent SGLT2 inhibitors affect bone metabolism in patients with T2DM.MethodsA literature search of randomized controlled trials (RCTs) was conducted through PubMed, Web of Science, Embase, Cochrane databases, and Scopus from inception until 15 April 2023. Eligible RCTs compared the effects of SGLT2 inhibitors versus placebo on bone mineral density and bone metabolism in patients with T2DM. To evaluate the differences between groups, a meta-analysis was conducted using the random effects inverse-variance model by utilizing standardized mean differences (SMD).ResultsThrough screening, 25 articles were finally included, covering 22,828 patients. The results showed that, compared with placebo, SGLT2 inhibitors significantly increased parathyroid hormone (PTH, SMD = 0.13; 95%CI: 0.06, 0.20), and cross-linked C-terminal telopeptides of type I collagen (CTX, SMD = 0.11; 95%CI: 0.01, 0.21) in patients with T2DM, decreased serum alkaline phosphatase levels (ALP, SMD = -0.06; 95%CI: -0.10, -0.03), and had no significant effect on bone mineral density (BMD), procollagen type 1 N-terminal propeptide (P1NP), 25-hydroxy vitamin D, tartrate resistant acid phosphatase-5b (TRACP-5b) and osteocalcin.ConclusionsSGLT2 inhibitors may negatively affect bone metabolism by increasing serum PTH, CTX, and decreasing serum ALP. This conclusion needs to be verified by more studies due to the limited number and quality of included studies.Systematic review registrationPROSPERO, identifier CRD42023410701

Cardiac remodeling in patients with heart failure with mildly reduced ejection fraction and metabolic disorders: association with biomarkers and autonomic nervous system parameters

Aim. The high prevalence of obesity in a cohort of patients with heart failure and mildly reduced ejection fraction (HFmrEF) determines the relevance of clarifying the role of biomarkers and autonomic imbalance in myocardial remodeling, taking into account metabolic risk factors.Material and methods. We examined 19 men with postinfarction cardiosclerosis and class II HFmrEF (median age 62 years), overweight/class I-II obesity, type 2 diabetes in 53/47%, 48% of cases, respectively, who received therapy. The biomarker panel included N-terminal pro-brain natriuretic peptide (NT-proBNP), galectin-3, pro-collagen I C-terminal propeptide (PICP), N-terminal propeptide of procollagen type III (PIIINP), C-terminal telopeptide of type I collagen, matrix metalloproteinase-9 (MMP-9), tissue inhibitor of matrix proteinase-1 (TIMP-1), leptin and adiponectin. Heart rate variability (HRV) and turbulence were obtained using 24-hour Holter monitoring. We assessed the time and frequency domains of HRV (24 h) and 5 min recordings of wakefulness at rest, calculated TO (turbulence onset) and TS (turbulence slope).Results. Significant positive associations of leptin and TIMP-1 levels with left ventricular hypertrophy markers were confirmed. Positive correlations of peak e' with following HRV indicators were revealed: SDNN (r=0,68; p=0,02) and RMSSD (r=0,69; p=0,003). Lower TS values were associated with higher index parameters of left ventricular mass (p&lt;0,05 for all). Associations of biomarkers with autonomic nervous system (ANS) were observed: MMP-9 with RMSSD (r=0,54) and pNN50 (r=0,51); TIMP-1 with TO (r=0,46); PICP/PIIINP ratio with HFn (5 min) (r=-0,49); NT-proBNP/adiponectin ratio with SDNN (r=-0,49); leptin level with TS (r=-0,54) (p&lt;0,05 for all).Conclusion. In patients with HFmrEF of ischemic origin and additional metabolic risks, serum biomarkers of fibrosis, adipokines, and ANS parameters are associated mainly with markers of increased left ventricular filling pressure. The study results predetermine the further search for potential risk-stratification markers of unfavorable myocardial remodeling and prognosis in large samples of patients with metabolic deviations and HF with EF &gt;40% against the background of modern drug therapy.

Bone metabolism and inflammatory biomarkers in radiographic and non-radiographic axial spondyloarthritis patients: a comprehensive evaluation.

Axial spondyloarthritis (axSpA) is a heterogeneous disease that can be represented by radiographic axSpA (r-axSpA) and non-radiographic axSpA (nr-axSpA). This study aimed to evaluate the relationship between the markers of inflammation and bone turnover in r-axSpA patients and nr-axSpA patients. A cross-sectional study included 29 r-axSpA patients, 10 nr-axSpA patients, and 20 controls matched for age and sex. Plasma markers related to bone remodeling such as human procollagen type 1 N-terminal propeptide (P1NP), sclerostin, tartrate-resistant acid phosphatase 5b (TRACP5b), receptor activator of nuclear factor kappa B ligand (RANKL), and osteoprotegerin (OPG) were measured by an ELISA kit. A panel of 92 inflammatory molecules was analyzed by proximity extension assay. R-axSpA patients had decreased plasma levels of P1NP, a marker of bone formation, compared to controls. In addition, r-axSpA patients exhibited decreased plasma levels of sclerostin, an anti-anabolic bone hormone, which would not explain the co-existence of decreased plasma P1NP concentration; however, sclerostin levels could also be influenced by inflammatory processes. Plasma markers of osteoclast activity were similar in all groups. Regarding inflammation-related molecules, nr-axSpA patients showed increased levels of serum interleukin 13 (IL13) as compared with both r-axSpA patients and controls, which may participate in the prevention of inflammation. On the other hand, r-axSpA patients had higher levels of pro-inflammatory molecules compared to controls (i.e., IL6, Oncostatin M, and TNF receptor superfamily member 9). Correlation analysis showed that sclerostin was inversely associated with IL6 and Oncostatin M among others. Altogether, different inflammatory profiles may play a role in the development of the skeletal features in axSpA patients particularly related to decreased bone formation. The relationship between sclerostin and inflammation and the protective actions of IL13 could be of relevance in the axSpA pathology, which is a topic for further investigation.

Efficacy and Mechanism of Highly Active Umbilical Cord Mesenchymal Stem Cells in the Treatment of Osteoporosis in Rats.

A rat model of osteoporosis was induced with dexamethasone sodium phosphate. Highly active umbilical cord mesenchymal stem cells (HA-UCMSCs) and UCMSCs were isolated, cultured, identified, and infused intravenously once at a dose of 2.29 × 106 cells/kg. In the 4th week of treatment, bone mineral density (BMD) was evaluated via cross-micro-CT, tibial structure was observed via HE staining, osteogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs) was examined via alizarin red staining, and carboxy-terminal cross-linked telopeptide (CTX), nuclear factor-κβ ligand (RANKL), procollagen type 1 N-terminal propeptide (PINP) and osteoprotegerin (OPG) levels were investigated via enzyme-linked immunosorbent assays (ELISAs). BMMSCs were treated with 10-6 mol/L dexamethasone and cocultured with HA-UCMSCs and UCMSCs in transwells. The osteogenic and adipogenic differentiation of BMMSCs was subsequently examined through directional induction culture. The protein expression levels of WNT, β-catenin, RUNX2, IFN-γ and IL-17 in the bone tissue were measured via Western blotting. The BMD in the healthy group was higher than that in the model group. Both UCMSCs and HA-UCMSCs exhibited a fusiform morphology; swirling growth; high expression of CD73, CD90 and CD105; and low expression of CD34 and CD45 and could differentiate into adipocytes, osteoblasts and chondrocytes, while HA-UCMSCs were smaller in size; had a higher nuclear percentage; and higher differentiation efficiency. Compared with those in the model group, the BMD increased, the bone structure improved, the trabecular area, number, and perimeter increased, the osteogenic differentiation of BMMSCs increased, RANKL expression decreased, and PINP expression increased after UCMSC and HA-UCMSC treatment for 4 weeks. Furthermore, the BMD, trabecular area, number and perimeter, calcareous nodule counts, and OPG/RANKL ratio were higher in the HA-UCMSC treatment group than in the UCMSC treatment group. The osteogenic and adipogenic differentiation of dexamethasone-treated BMMSCs was enhanced after the coculture of UCMSCs and HA-UCMSCs, and the HA-UCMSC group exhibited better effects than the UCMSC coculture group. The protein expression of WNT, β-catenin, and runx2 was upregulated, and IFN-γ and IL-17 expression was downregulated after UCMSC and HA-UCMSC treatment. HA-UCMSCs have a stronger therapeutic effect on osteoporosis compared with that of UCMSCs. These effects include an improved bone structure, increased BMD, an increased number and perimeter of trabeculae, and enhanced osteogenic differentiation of BMMSCs via activation of the WNT/β-catenin pathway and inhibition of inflammation.</p>.

Effects of Exogenous GIP and GLP-2 on Bone Turnover in Individuals With Type 2 Diabetes.

Individuals with type 2 diabetes (T2D) have an increased risk of bone fractures despite normal or increased bone mineral density. The underlying causes are not well understood but may include disturbances in the gut-bone axis, in which both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are regulators of bone turnover. Thus, in healthy fasting participants, both exogenous GIP and GLP-2 acutely reduce bone resorption. The objective of this study was to investigate the acute effects of subcutaneously administered GIP and GLP-2 on bone turnover in individuals with T2D. We included 10 men with T2D. Participants met fasting in the morning on 3 separate test days and were injected subcutaneously with GIP, GLP-2, or placebo in a randomized crossover design. Blood samples were drawn at baseline and regularly after injections. Bone turnover was estimated by circulating levels of collagen type 1 C-terminal telopeptide (CTX), procollagen type 1 N-terminal propeptide (P1NP), sclerostin, and PTH. GIP and GLP-2 significantly reduced CTX to (mean ± SEM) 66 ± 7.8% and 74 ± 5.9% of baseline, respectively, compared with after placebo (P = .001). In addition, P1NP and sclerostin increased acutely after GIP whereas a decrease in P1NP was seen after GLP-2. PTH levels decreased to 67 ± 2.5% of baseline after GLP-2 and to only 86 ± 3.4% after GIP. Subcutaneous GIP and GLP-2 affect CTX and P1NP in individuals with T2D to the same extent as previously demonstrated in healthy individuals.

Alteration in the gut microbiome is associated with changes in bone metabolism after laparoscopic sleeve gastrectomy.

Laparoscopic sleeve gastrectomy (LSG), the most common bariatric surgical procedure, leads to durable weight loss and improves obesity-related comorbidities. However, it induces abnormalities in bone metabolism. One unexplored potential contributor is the gut microbiome, which influences bone metabolism and is altered after surgery. We characterized the relationship between the gut microbiome and skeletal health in severe obesity and after LSG. In a prospective cohort study, 23 adults with severe obesity underwent skeletal health assessment and stool collection preoperatively and 6mo after LSG. Gut microbial diversity and composition were characterized using 16S rRNA gene sequencing, and fecal concentrations of short-chain fatty acids (SCFA) were measured with LC-MS/MS. Spearman's correlations and PERMANOVA analyses were applied to assess relationships between the gut microbiome and bone health measures including serum bone turnover markers (C-terminal telopeptide of type 1 collagen [CTx] and procollagen type 1N-terminal propeptide [P1NP]), areal BMD, intestinal calcium absorption, and calciotropic hormones. Six months after LSG, CTx and P1NP increased (by median 188% and 61%, P< .01) and femoral neck BMD decreased (mean -3.3%, P< .01). Concurrently, there was a decrease in relative abundance of the phylum Firmicutes. Although there were no change in overall microbial diversity or fecal SCFA concentrations after LSG, those with greater within-subject change in gut community microbial composition (β-diversity) postoperatively had greater increases in P1NP level (ρ= 0.48, P= .02) and greater bone loss at the femoral neck (ρ= -0.43, P= .04). In addition, within-participant shifts in microbial richness/evenness (α-diversity) were associated with changes in IGF-1 levels (ρ= 0.56, P< .01). The lower the postoperative fecal butyrate concentration, the lower the IGF-1 level (ρ= 0.43, P= .04). Meanwhile, the larger the decrease in butyrate concentration, the higher the postoperative CTx (ρ= -0.43, P= .04). These findings suggest that LSG-induced gut microbiome alteration may influence skeletal outcomes postoperatively, and microbial influences on butyrate formation and IGF-1 are possible mechanisms.

Parathyroidectomy Improves Bone Density in Women With Primary Hyperparathyroidism and Preoperative Osteopenia.

Osteoporosis and/or bone fractures are indications of parathyroidectomy in primary hyperparathyroidism (PHPT), especially in women. However, the benefit of surgery in patients with osteopenia remains unclear. To evaluate bone mineral density (BMD) and bone remodeling biomarkers changes 1 year after parathyroidectomy in women with PHPT. In the prospective, monocentric, observational prospective cohort with primary hyperparathyroidism patients (CoHPT) cohort, women operated for sporadic PHPT since 2016 with ≥1 year follow-up were included. BMD (dual-X ray absorptiometry) and bone remodeling biomarkers [cross-linked C-telopeptide (CTX), procollagen type 1 N-terminal propeptide (P1NP), and bone-specific alkaline phosphatases] were assessed before and 1 year after parathyroidectomy. Referral center. A total of 177 women with PHPT (62.5 ± 13.3 years, 83.1% menopausal, 43.9% osteopenic, and 45.1% osteoporotic) were included. Parathyroidectomy. BMD change between before and 1 year after parathyroidectomy. Parathyroidectomy resulted in significant increase in BMD and decrease in serum bone remodeling biomarker concentrations. In the 72 patients with baseline osteopenia, mean BMD significantly increased at the lumbar spine [+0.05 g/cm2 (95% confidence interval [CI], 0.03-0.07)], the femoral neck [+0.02 g/cm2 (95% CI 0.00-0.04)], the total hip [+0.02 g/cm2 (95% CI 0.01-0.02)], and the forearm [+0.01 (95% CI 0.00-0.02)], comparable to osteoporotic patients. Among osteopenic patients, those with individual BMD gain (>0.03 g/cm2) at ≥1 site had higher preoperative serum CTX, P1NP, and urine calcium concentrations than those without improvement. Parathyroidectomy significantly improved BMD and remodeling biomarkers in women with osteopenia, thereby supporting the benefit of parathyroidectomy in these patients. Preoperative serum CTX and P1NP concentrations could be useful to predict expected BMD gain.

Real-world usage of Chronic Kidney Disease - Mineral Bone Disorder (CKD-MBD) biomarkers in nephrology practices.

Chronic kidney disease mineral bone disorder (CKD-MBD) is a condition characterized by alterations of calcium, phosphate, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF-23) metabolism that in turn promote bone disorders, vascular calcifications, and increase cardiovascular (CV) risk. Nephrologists' awareness of diagnostic, prognostic, and therapeutic tools to manage CKD-MBD plays a primary role in adequately preventing and managing this condition in clinical practice. A national survey (composed of 15 closed questions) was launched to inquire about the use of bone biomarkers in the management of CKD-MBD patients by nephrologists and to gain knowledge about the implementation of guideline recommendations in clinical practice. One hundred and six Italian nephrologists participated in the survey for an overall response rate of about 10%. Nephrologists indicated that the laboratories of their hospitals were able to satisfy request of ionized calcium levels, 105 (99.1%) of both PTH and alkaline phosphatase (ALP), 100 (94.3%) of 25(OH)D, and 61 (57.5%) of 1.25(OH)2D; while most laboratories did not support the requests of biomarkers such as FGF-23 (intact: 88.7% and c-terminal: 93.4%), Klotho (95.3%; soluble form: 97.2%), tartrate-resistant acid phosphatase 5b (TRAP-5b) (92.5%), C-terminal telopeptide (CTX) (71.7%), and pro-collagen type 1 N-terminal pro-peptide (P1NP) (88.7%). As interesting data regarding Italian nephrologists' behavior to start treatment of secondary hyperparathyroidism (sHPT), the majority of clinicians used KDOQI guidelines (n=55, 51.9%). In contrast, only 40 nephrologists (37.7%) relied on KDIGO guidelines, which recommended referring to values of PTH between two and nine times the upper limit of the normal range. Results point out a marked heterogeneity in the management of CKD-MBD by clinicians as well as a suboptimal implementation of guidelines in Italian clinical practice.

Bone Health of Hemophilia Ａ Patients Using Emicizumab

Background: Hemophilia patients have been observed to exhibit a higher prevalence of osteoporosis compared to age-matched general population. However, the underlying mechanism responsible for this association remains poorly understood. One hypothesis proposes that factor VIII itself may possess additional physiological functions that contribute to bone health. Conversely, alternative viewpoints suggest that overall coagulation function or thrombin generation may play a pivotal role in maintaining optimal bone health. The introduction of emicizumab, a bispecific antibody that mimics the coagulation function of factor VIII but possesses a structurally distinct composition, presents an opportunity to shed light on this matter. Therefore, the primary objective of this study is to explore and compare the bone health status of hemophilia patients, distinguishing between those utilizing emicizumab and those who are emicizumab-naïve. Method: From June 2019 to June 2023, at the hemophilia center of National Taiwan University Hospital, additional examinations to assess the patients' bone health were performed with routine annual joint health evaluations for patients with hemophilia A (PwHA) and B (PwHB). This included the use of dual-energy X-ray absorptiometry scan (DEXA) to measure the bone mineral density (BMD) of the lumbar spine, hip, and femur. Furthermore, the serum levels of procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide (CTX) were measured as reference markers for bone formation and bone resorption, respectively. The Kruskal-Wallis test was utilized to statistically evaluate the observations among the three groups. Results: The study population was divided into three distinct groups based on their hemophilia subtype and treatment: PwHA who had been utilizing emicizumab for more than one year (n=8), PwHA individuals receiving regular factor VIII treatment (n=16), and PwHB (n=10). The analysis of the collected data, as presented in the accompanying table, revealed that the three groups exhibited similar characteristics in terms of age, annual bleeding rate, and joint conditions. Moreover, no statistically significant differences were detected in the measurements of bone mineral densities (BMDs) and biomarkers. However, it is worth noting that there appeared to be a potential trend toward higher levels of P1NP in the PwHB group.In the case of PwHA patients using emicizumab, we examined the longitudinal changes in T-score of BMD over time. Notably, three PwHA patients with baseline T-scores below zero demonstrated improvements in their T-scores after one year of emicizumab treatment. Conclusion: The results of this study indicate a lack of significant disparities in bone health between individuals utilizing emicizumab and those who are not. Furthermore, our findings suggest that emicizumab usage does not lead to a decline in bone health over the observed period.

Utility and Limitations of TALLYHO/JngJ as a Model for Type 2 Diabetes-Induced Bone Disease.

Type 2 diabetes mellitus (T2DM) increases risk of fractures due to bone microstructural and material deficits, though the mechanisms remain unclear. Preclinical models mimicking diabetic bone disease are required to further understand its pathogenesis. The TALLYHO/JngJ (TH) mouse is a polygenic model recapitulating adolescent-onset T2DM in humans. Due to incomplete penetrance of the phenotype ~25% of male TH mice never develop hyperglycemia, providing a strain-matched nondiabetic control. We performed a comprehensive characterization of the metabolic and skeletal phenotype of diabetic TH mice and compared them to either their nondiabetic TH controls or the recommended SWR/J controls to evaluate their suitability to study diabetic bone disease in humans. Compared to both controls, male TH mice with T2DM exhibited higher blood glucose levels, weight along with impaired glucose tolerance and insulin sensitivity. TH mice with/without T2DM displayed higher cortical bone parameters and lower trabecular bone parameters in the femurs and vertebrae compared to SWR/J. The mechanical properties remained unchanged for all three groups except for a low-energy failure in TH mice with T2DM only compared to SWR/J. Histomorphometry analyses only revealed higher number of osteoclasts and osteocytes for SWR/J compared to both groups of TH. Bone turnover markers procollagen type 1 N-terminal propeptide (P1NP) and tartrate-resistant acid phosphatase (TRAP) were low for both groups of TH mice compared to SWR/J. Silver nitrate staining of the femurs revealed low number of osteocyte lacunar and dendrites in TH mice with T2DM. Three-dimensional assessment showed reduced lacunar parameters in trabecular and cortical bone. Notably, osteocyte morphology changed in TH mice with T2DM compared to SWR/J. In summary, our study highlights the utility of the TH mouse to study T2DM, but not necessarily T2DM-induced bone disease, as there were no differences in bone strength and bone cell parameters between diabetic and non-diabetic TH mice. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Deteriorated bone microarchitecture caused by sympathetic overstimulation in pheochromocytoma and paraganglioma.

Despite the potentially destructive effect of sympathetic activity on bone metabolism, its impact on bone microarchitecture, a key determinant of bone quality, has not been thoroughly investigated. This study aims to evaluate the impact of sympathetic activity on bone microarchitecture and bone strength in patients with pheochromocytoma and paraganglioma (PPGL). A cross-sectional study was conducted in 38 PPGL patients (15 males and 23 females). Bone turnover markers serum procollagen type 1 N-terminal propeptide (P1NP) and β-carboxy-terminal crosslinked telopeptide of type 1 collagen (β-CTX) were measured. 24-h urinary adrenaline (24hUE) and 24-h urinary norepinephrine levels (24hUNE) were measured to indicate sympathetic activity. High-resolution peripheral quantitative computed tomography (HR-pQCT) was conducted to evaluate bone microarchitecture in PPGL patients and 76 age-, sex-matched healthy controls (30 males and 46 females). Areal bone mineral density (aBMD) was measured by dual-energy X-ray absorptiometry (DXA) simultaneously. PPGL patients had a higher level of β-CTX. HR-pQCT assessment revealed that PPGL patients had notably thinner and more sparse trabecular bone (decreased trabecular number and thickness with increased trabecular separation), significantly decreased volume BMD (vBMD), and bone strength at both the radius and tibia compared with healthy controls. The deterioration of Tt.vBMD, Tb.Sp, and Tb.1/N.SD was more pronounced in postmenopausal patients compared with the premenopausal subjects. Moreover, subjects in the highest 24hUNE quartile (Q4) showed markedly lower Tb.N and higher Tb.Sp and Tb.1/N.SD at the tibia than those in the lowest quartile (Q1). Age-related bone loss was also exacerbated in PPGL patients to a certain extent. PPGL patients had significantly deteriorated bone microarchitecture and strength, especially in the trabecular bone, with an increased bone resorption rate. Our findings provide clinical evidence that sympathetic overstimulation may serve as a secondary cause of osteoporosis, especially in subjects with increased sympathetic activity.

Structural and functional state of bone in patients with arteriovenous malformations of the lower extremities

Background. Disruption of regional blood flow in patients with arteriovenous malformations (AVMs) of the lower extremities changes the conditions of bone tissue functioning. The purpose was to study the structural and functional state of bone tissue and its metabolism in patients with AVMs of the lower extremities using dual-energy X-ray absorptiometry and the markers of bone turnover. Materials and methods. Fifteen patients with AVMs had been examined. The clinical class of chronic venous disease (CVD) was evaluated according to CEAP; patients were divided into 2 subgroups: the first one was with CVD C1-C3 and the second one was with CVD C4-C6. Bone mineral density (BMD) was studied based on the X-ray absorptiometry. The level of bone metabolism markers, such as procollagen type 1 N-terminal propeptide (P1NP), C-terminal cross-linking telopeptide of type 1 collagen (β-CTx) and osteocalcin, 25-hydroxyvitamin D (25(ОН)D) and parathyroid hormone were studied. Results. Disturbances of the bone tissue indices of the affected limb were found in 70 % of the patients. Also, the statistically significant difference in BMD of the affected limb compared to the healthy limb was established (р = 0.005). A multidirectional level of P1NP was detected; β-CTx exceeded norm in 80 % of the patients; osteocalcin exceeded norm in 33 % of the cases. In 67 % of the patients, a decrease in serum level of 25(OH)D was noted. Increase of the β-CTx level in the first subgroup and its decrease in the second one was associated with stabilization of the AVMs course and age-related changes in the hormonal background of the patients. Conclusions. Disturbances in the structural state of bone tissue of the affected limb were found in 70 % of the patients; statistically significant difference between the BMD of the affected and healthy limb obviously caused by the influence of regional hemodynamic disturbances. Various deviations of the metabolism markers were found, which indicates the need to develop a system of drug therapy.

OR23-05 Log-term Efficacy And Safety Of Transcon PTH In Adults With Hypoparathyroidism: 52-week Results From The Open-label Extension Of The Phase 3 Pathway Trial

OR23-05 Log-term Efficacy And Safety Of Transcon PTH In Adults With Hypoparathyroidism: 52-week Results From The Open-label Extension Of The Phase 3 Pathway Trial

The relationship between length of denosumab treatment for postmenopausal osteoporosis and serum TRAcP5b measured six months after the last injection.

In women with postmenopausal osteoporosis the aetiology of the observed inverse relationship between duration of denosumab (Dmab) therapy and bone loss after its discontinuation is currently unknown. In studies in mice inhibition of RANKL is associated with an increase in osteomorphs and osteoclast precursors that recycle into osteoclasts and may accumulate with time. We hypothesized that longer inhibition of RANKL by Dmab will be followed by the synchronous formation of a larger number of osteoclasts after stopping treatment. To test this hypothesis, we measured serum TRAcP5b, a marker of osteoclast numbers, in postmenopausal women treated with Dmab for different periods of time up to 10years. TRAcP5b, C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP) were measured at 6.0months ± 15days after last Dmab injection in 59 women who had received Dmab for 4.0 ± 2.3years (range 1-10years). Of these, 38 were treatment naïve (group 1) and 21 had received other treatments prior Dmab (group 2). Duration of Dmab treatment was not related to serum TRAcP5b values or to TRAcP5b/CTX ratio either in the whole cohort or in each of the two groups separately. In contrast, serum TRAcP5b values were significantly correlated with serum CTX values (rs = 0.619; p < 0.001), but not with serum P1NP values or BMD at all skeletal sites. Our observations indicate that serum TRAcP5b, measured at 6months after a Dmab injection, is not a useful early marker for time-dependent increased accumulation of osteoclasts in humans and for identification of patients at risk for a higher rebound increase in bone resorption.

Correlation analysis and clinical significance of Musculoskeletal Ultrasound semi-quantitative grading with bone salt metabolism, Rheumatoid factor and Erythrocyte Sedimentation rate in patients with Rheumatoid Arthritis.

To determine the correlation and clinical significance of musculoskeletal ultrasound semi-quantitative grading with bone salt metabolism, rheumatoid factor and erythrocyte sedimentation rate (ESR) in patients with rheumatoid arthritis. This is a clinical comparative study. A total of 240 patients with rheumatoid arthritis admitted to Baoding NO.1 Central Hospital were selected according to the DAS28 score of rheumatoid arthritis, and were divided into four groups, with 60 cases in each group from May 2020 to May 2022. The differences and correlation of musculoskeletal ultrasound semi-quantitative grading, bone metabolism indicators, erythrocyte sedimentation rate and rheumatoid factor among the four groups were statistically analyzed. The scores of bone erosion, synovial hyperplasia, joint effusion and intrasynovial blood flow in Group-H were significantly higher than those in Group-R, L and M, with statistically significant differences(p=0.00). The procollagen Type-1 N-terminal propeptide(P1NP), bone-specific alkaline phosphatase(BALP) and osteoprotegerin(OPG) in Group-H were significantly lower than those in Group-R, L and M, with statistically significant differences(p=0.00); The tartrate-resistant acid phosphatase(TRAC) in Group-H was significantly higher than that in Group-R, L and M, with a statistically significant difference(p=0.00). The levels of RF and ESR in Group-H were significantly higher than those in Group-R, L and M, with statistically significant differences(p=0.00). Musculoskeletal ultrasound semi-quantitative grading is correlated with the level of bone salt metabolism, rheumatoid factor and ESR in patients with rheumatoid arthritis. It can be combined with laboratory examination to objectively judge the severity of the course of rheumatoid arthritis.

Procollagen type 1 N-terminal propeptide is associated with adverse outcome in acute chest pain of suspected coronary origin.

Extracellular matrix (ECM) is an integral player in the pathophysiology of a variety of cardiac diseases. Cardiac ECM is composed mainly of collagen, of which type 1 is the most abundant with procollagen type 1 N-terminal Propeptide (P1NP) as a formation marker. P1NP is associated with mortality in the general population, however, its role in myocardial infarction (MI) is still uncertain, and P1NP has not been investigated in acute chest pain. The objective of the current study was to assess the role of P1NP in undifferentiated acute chest pain of suspected coronary origin. 813 patients from the Risk in Acute Coronary Syndromes study were included. This was a single-center study investigating biomarkers in consecutively enrolled patients with acute chest pain of suspected coronary origin, with a follow-up for up to 7 years. Outcome measures were a composite endpoint of all-cause death, new MI or stroke, as well as its individual components at 1, 2, and 7 years, and cardiac death at 1 and 2 years. In multivariable Cox regression analysis, quartiles of P1NP were significantly associated with the composite endpoint at 1 year of follow-up with a hazard ratio for Q4 of 1.82 (95% CI, 1.12-2.98). There was no other significant association with outcomes at any time points. P1NP was found to be an independent biomarker significantly associated with adverse clinical outcome at one year in patients admitted to hospital for acute chest pain of suspected coronary origin. This is the first report in the literature on the prognostic value of P1NP in this clinical setting. NCT00521976.

Free and bioavailable 25-hydroxyvitamin D thresholds for bone metabolism and their associations with metabolic syndrome in Chinese women of childbearing age.

The free hormone hypothesis suggests that free and bioavailable 25-hydroxyvitamin D [25(OH)D] may better reflect vitamin D bioactivity. This study aimed to determine the free and bioavailable 25(OH)D characteristics, estimate their thresholds based on parathyroid hormone (PTH) and bone turnover markers (BTMs), assess their associations with the risk of metabolic syndrome (MetS), and evaluate their potential advantages. A cross-sectional study was conducted using a nationally representative database (n = 1,505, female, 18-45 years). Serum total 25(OH)D, vitamin D-binding protein, albumin, PTH, and BTMs [osteocalcin, β-CrossLaps of type 1 collagen containing cross-linked C-telopeptide (β-CTX), and procollagen type 1 N-terminal propeptide (P1NP)] were measured. Free 25(OH)D and bioavailable 25(OH)D were calculated. The threshold associations of 25(OH)D with PTH and BTMs were analyzed. The relationship between 25(OH)D and MetS risk was examined. An intervention study was then performed in 39 women (18-47 years) to assess the associations of increasing 25(OH)D with PTH and BTMs after vitamin D supplementation. In the cross-sectional study, the three forms of 25(OH)D were found to have similar distribution characteristics. Free and bioavailable 25(OH)D correlated well with total 25(OH)D. Significant total 25(OH)D cutoffs were observed for PTH (14.19 ng/mL and 18.03 ng/mL), osteocalcin (15.14 ng/mL), β-CTX (14.79 ng/mL), and P1NP (15.08 ng/mL). Free and bioavailable 25(OH)D cutoffs were only found for P1NP (3.47 pg/mL and 1.66 ng/mL, respectively). A total 25(OH)D of <15.14 ng/mL was marginally associated with a higher risk of reduced high-density lipoprotein cholesterol (HDL-C) [odd ratios (OR) = 1.371 (0.991-1.899)]. The ORs of higher versus lower free and bioavailable 25(OH)D levels for reduced HDL-C were 0.770 (0.621-0.956) and 0.772 (0.622-0.958), respectively. The results of the intervention study indicated that PTH and BTMs responded more sensitively to total 25(OH)D than to free or bioavailable 25(OH)D. Free and bioavailable 25(OH)D only had a threshold effect on P1NP. The active 25(OH)D thresholds could be used for risk assessment of reduced HDL-C. However, no superiority of free or bioavailable 25(OH)D was found based on the response of PTH and BTMs to changes in 25(OH)D in Chinese women of childbearing age following vitamin D supplementation. http://www.chictr.org.cn, ChiCTR2200058290.