Intact N-terminal Propeptide Research Articles

Bone turnover biomarkers reflect radiation-induced bone injuries in women with non-metastatic rectal cancer.

Preoperative radiotherapy (RT) for non-metastatic rectal cancer reduces local recurrence rates but can cause pelvic insufficiency fractures. Despite the high morbidity from RT-induced skeletal injuries, predictive and preventive measures are lacking. How these injuries are reflected by bone biomarkers are largely unknown. The aim was to assess longitudinal changes in bone biomarkers and their relation to RT-related bone injuries in women with rectal cancer. This longitudinal cohort study includes 47 women with non-metastatic rectal cancer treated with surgery ± preoperative RT with or without chemotherapy. Sclerostin, bioactive sclerostin, C-terminal telopeptide cross-links of collagen type I (CTX), bone-specific alkaline phosphatase (BALP), and type I procollagen intact N-terminal propeptide (PINP) were measured at baseline, after RT, and 1 yr postoperatively. Pelvic magnetic resonance imaging was used for detection of skeletal injury. Sixteen of 36 (44%) irradiated women had radiation-induced bone injuries and were compared to 11 women (RT-) and 20 women (RT+) without bone injuries. Serum CTX, BALP, and PINP increased during the first year after RT in women with radiation-induced bone injuries. The difference in mean change of CTX (p=.037) and BALP (p=.042) was conferred by longitudinal regression analyses adjusted for serum estradiol. Serum sclerostin and bioactive sclerostin remained stable over time. Taken together, bone markers may be of interest for future research on fracture prediction or preventive measures in women susceptible to radiation-induced bone injury. Due to few measure points, the full pattern cannot be captured regarding the relation over time between bone biomarkers and skeletal injury from irradiation.

Identification of novel risk factors for postoperative severe hypocalcemia in patients with primary hyperparathyroidism undergoing parathyroidectomy: a case control study

BackgroundPatients with primary hyperparathyroidism (PHPT) are at risk for severe hypocalcemia (SH) following parathyroidectomy (PTX), but limited data exist on the predictors of SH. We aimed to identify risk factors for early postoperative SH after PTX in patients with PHPT and to evaluate the predictive value of clinical parameters.MethodsA retrospective review of patients with PHPT who underwent PTX between January 2010 and December 2022 was performed. A total of 46 patients were included in the study, with 15 (32.6%) experiencing postoperative SH, 19 (41.3%) having calculi in the ureter or kidney, and 37 (80.4%) having osteoporosis. Patients were divided into SH and non-SH groups based on postoperative serum calcium levels. Preoperative biochemical indicators, bone turnover markers, and renal function parameters were analyzed and correlated with postoperative SH.ResultsStatistically significant (P < 0.05) differences were found in preoperative serum calcium (serum Ca), intact parathyroid hormone, serum phosphorus (serum P), serum Ca/P, percentage decrease of serum Ca, total procollagen type 1 intact N-terminal propeptide, osteocalcin (OC), and alkaline phosphatase levels between the two groups. Multivariate analysis showed that serum P (odds ratio [OR] = 0.989; 95% confidence interval [95% CI] = 0.981–0.996; P = 0.003), serum Ca (OR = 0.007; 95% CI = 0.001–0.415; P = 0.017), serum Ca/P (OR = 0.135; 95% CI = 0.019–0.947; P = 0.044) and OC levels (OR = 1.012; 95% CI = 1.001–1.024; P = 0.036) were predictors of early postoperative SH. The receiver operating characteristic curve analysis revealed that serum P (area under the curve [AUC] = 0.859, P < 0.001), serum Ca/P (AUC = 0.735, P = 0.010) and OC (AUC = 0.729, P = 0.013) had high sensitivity and specificity.ConclusionPreoperative serum P, serum Ca/P and osteocalcin levels may identify patients with PHPT at risk for early postoperative SH after PTX.

Limosilactobacillus reuteri 6475 and Prevention of Early Postmenopausal Bone Loss

Daily supplementation with the probiotic Limosilactobacillus reuteri ATCC PTA 6475 (L reuteri) vs placebo has previously been demonstrated to reduce bone loss in an estrogen deficiency mice model and older women, although the magnitude of the effect was small. We hypothesized that long-term treatment with L reuteri could result in clinically relevant skeletal benefits in postmenopausal osteoporosis. To evaluate whether daily supplementation with L reuteri vs placebo could reduce early postmenopausal bone loss and whether the effects remained or increased over time during 2 years of treatment. A double-blind, randomized, placebo-controlled clinical trial was conducted between December 4, 2019, and October 6, 2022, at a single center in Gothenburg, southwestern Sweden. Participants were recruited by online advertisements, and letters were sent to 10 062 women aged 50 to 60 years. Responding women (n = 752) underwent telephone screening, resulting in 292 women being invited to a screening visit. Of those who were screened, 239 women met all inclusion criteria and had no exclusion criteria. Capsules with L reuteri in 2 doses, 5 × 108 (low dose) or 5 × 109 (high dose) colony-forming units, taken twice daily or placebo were administered. All capsules also included cholecalciferol, 200 IU. The primary outcome was the relative change in tibia total volumetric bone mineral density (vBMD) over 2 years. Secondary outcomes included relative change in areal BMD of the lumbar spine and total hip, bone turnover markers C-terminal telopeptide cross-links of collagen type I and type I procollagen intact N-terminal propeptide, as well as tibia trabecular bone volume fraction and cortical vBMD. Both intention-to-treat and per-protocol analyses were conducted. A total of 239 postmenopausal women (median age, 55 [IQR, 53-56] years) were included. Tibia vBMD (primary outcome), hip and spine vBMD, and tibia cortical area and BMD decreased significantly in all groups, with no group-to-group differences (percent change tibia vBMD high dose vs placebo least-squares means, -0.08 [95 CI, -0.85 to 0.69] and low dose vs placebo least-squares means, -0.22 [95% CI, -0.99 to 0.55]). There were no significant treatment effects on any other predefined outcomes. A prespecified sensitivity analysis found a significant interaction between body mass index (BMI) and treatment effect at 2 years. No significant adverse effects were observed. In this randomized clinical trial of 239 early postmenopausal women, supplementation with L reuteri had no effect on bone loss or bone turnover over 2 years. The observed interaction between BMI and treatment effect warrants further investigation. ClinicalTrials.gov Identifier: NCT04169789.

Bone health in young adults with type 1 diabetes and progressive eGFR decline

BackgroundType 1 Diabetes (T1D) is associated with increased risk of fractures, worsened by presence of microvascular complications. This study’s objective is to determine the impact of progressive decline in estimated glomerular filtration rate (eGFR) on bone biomarkers and bone microarchitecture in youth with T1D.MethodsSlopes of eGFR were calculated using measures obtained at four timepoints from adolescence to young adulthood. Participants were identified as eGFR decliners if eGFR decreased ≥ 3ml/min/1.73m2/year. Bone health was assessed in young adulthood by high resolution peripheral quantitative computed tomography (HRpQCT Xtreme CTII) and bone biomarkers; osteocalcin, procollagen 1 intact n-terminal pro-peptide (P1NP), c-terminal telopeptide (CTX), and bone specific alkaline phosphatase. The relationship between diabetes duration, glycated hemoglobin, body mass index (BMI) and vitamin D level on bone biomarkers and microarchitecture was evaluated. Linear regression analysis was used for the statistical analysis in this study.ResultsNinety-nine study participants were studied with longitudinal evaluation of eGFR over 7.4 ± 1.0 years with mean age of 14.7 ± 1.7 years at baseline. Cross sectional evaluation of bone was performed at 21.3 ± 2.1 years. 44% participants had eGFR decline and showed 5% higher cortical porosity diameter than non-decliners (p = 0.035). Greater diabetes duration was associated with higher trabecular separation (p = 0.004) and lower trabecular number (p = 0.01). Higher level of 25 hydroxy-vitamin D was associated with lower trabecular separation (p = 0.01). Elevated glycated hemoglobin (p = 0.0008) and BMI (p = 0.009), were associated with lower markers of bone formation.ConclusionMild increase in cortical porosity diameter was found in youth with T1D and eGFR decline, however, overall measures of bone microarchitecture on HR-pQCT were similar between both groups and there were no statistically significant changes in bone biomarkers. Hence, skeletal impairments were limited in youth with different eGFR trajectories near peak bone mass. Longitudinal HR-pQCT studies are needed to further understand the impact of eGFR decline on bone microarchitecture. Optimal glycemic control, normal BMI and vitamin D status were supported by this study as important markers for good bone health.

Methionine as a regulator of bone remodeling with fasting.

Caloric restriction improves metabolic health but is often complicated by bone loss. We studied bone parameters in humans during a 10-day fast and identified candidate metabolic regulators of bone turnover. Pro-collagen 1 intact N-terminal pro-peptide (P1NP), a bone formation marker, decreased within 3 days of fasting. Whereas dual-energy x-ray absorptiometry measures of bone mineral density were unchanged after 10 days of fasting, high-resolution peripheral quantitative CT demonstrated remodeling of bone microarchitecture. Pathway analysis of longitudinal metabolomics data identified one-carbon metabolism as fasting dependent. In cultured osteoblasts, we tested the functional significance of one-carbon metabolites modulated by fasting, finding that methionine - which surged after 3 days of fasting - affected markers of osteoblast cell state in a concentration-dependent manner, in some instances exhibiting a U-shaped response with both low and high concentrations driving putative antibone responses. Administration of methionine to mice for 5 days recapitulated some fasting effects on bone, including a reduction in serum P1NP. In conclusion, a 10-day fast in humans led to remodeling of bone microarchitecture, potentially mediated by a surge in circulating methionine. These data support an emerging model that points to a window of optimal methionine exposure for bone health.

An Open-label Phase 2 Study of Eneboparatide, a Novel PTH Receptor 1 Agonist, in Hypoparathyroidism.

Hypoparathyroidism is a rare disorder characterized by a deficiency in PTH resulting in hypocalcemia, hyperphosphatemia, and hypercalciuria. Eneboparatide is an investigational peptide agonist of the PTH1 receptor for the treatment of chronic hypoparathyroidism (HP). To evaluate the efficacy, safety, and tolerability of eneboparatide in HP patients. Open-label, phase 2 study. Twenty-eight patients (21 women, 7 men), mean age (range): 58 years (28-72), with HP were enrolled into 2 consecutive cohorts (C1, n = 12 and C2, n = 16). Following an optimization period, daily subcutaneous injections of eneboparatide were administered for 3 months at a 20 µg/day (C1) or 10 µg/day (C2) starting dose. Conventional therapy was progressively removed, and eneboparatide could be titrated up to 60 µg (C1) or 80 µg (C2). Proportion of patients achieving independence from conventional therapy, albumin-adjusted serum calcium (ADsCa), 24-h urine calcium (uCa), serum bone turnover markers (serum carboxy-terminal telopeptide of type I collagen and procollagen 1 intact N-terminal propeptide), bone mineral density (BMD), and adverse events (AEs). After 3 months, ≥ 88% of patients achieved independence from conventional therapy while mean ADsCa was maintained within target range (7.8-9 mg/dL). Eneboparatide induced a rapid and sustained reduction of mean 24-hour uCa, even among patients with hypercalciuria. Bone turnover markers slightly increased, and BMD remained unchanged, consistent with progressive resumption of physiologic bone turnover. Eneboparatide was well tolerated with no serious AEs. Eneboparatide allowed independence from conventional therapy and maintenance of serum calcium within a target range while normalizing uCa excretion and producing a balanced resumption of bone turnover.

Demographic and disease-related factors impact bone turnover and vitamin D in children with hemato-oncological diseases.

Children with hemato-oncological diseases may have significant skeletal morbidity, not only during and after treatment but also at the time of diagnosis before cancer treatment. This study was designed to evaluate the vitamin D status and circulating bone metabolic markers and their determinants in children at the time of diagnostic evaluation for hemato-oncological disease. This cross-sectional study included 165 children (91 males, median age 6.9yr range 0.2-17.7yr). Of them, 76 patients were diagnosed with extracranial or intracranial solid tumors, 83 with leukemia, and 6 with bone marrow failure. Bone metabolism was assessed by measuring serum 25OHD, PTH, bone alkaline phosphatase, intact N-terminal propeptide of type I procollagen, and C-terminal cross-linked telopeptide of type I collagen. Vitamin D deficiency was found in 30.9% of children. Lower 25OHD levels were associated with older age, lack of vitamin D supplementation, season outside summer, and a country of parental origin located between latitudes -45° and 45°. Children diagnosed with leukemia had lower levels of markers of bone formation and bone resorption than those who had solid tumors or bone marrow failure. In conclusion, vitamin D deficiency was observed in one-third of children with newly diagnosed cancer. Bone turnover markers were decreased in children with leukemia, possibly because of the suppression of osteoblasts and osteoclasts by leukemic cells. The identification of patients with suboptimal vitamin D status and compromised bone remodeling at cancer diagnosis may aid in the development of supportive treatment to reduce the adverse effects of cancer and its treatment.

Loss of 24-hydroxylated catabolism increases calcitriol and fibroblast growth factor 23 and alters calcium and phosphate metabolism in fetal mice.

Calcitriol circulates at low levels in normal human and rodent fetuses, in part due to increased 24-hydroxylation of calcitriol and 25-hydroxyvitamin D by 24-hydroxylase (CYP24A1). Inactivating mutations of CYP24A1 cause high postnatal levels of calcitriol and the human condition of infantile hypercalcemia type 1, but whether the fetus is disturbed by the loss of CYP24A1 is unknown. We hypothesized that loss of Cyp24a1 in fetal mice will cause high calcitriol, hypercalcemia, and increased placental calcium transport. The Cyp24a1+/- mice were mated to create pregnancies with wildtype, Cyp24a1+/-, and Cyp24a1 null fetuses. The null fetuses were hypercalcemic, modestly hypophosphatemic (compared to Cyp24a1+/- fetuses only), with 3.5-fold increased calcitriol, 4-fold increased fibroblast growth factor 23 (FGF23), and unchanged parathyroid hormone. The quantitative RT-PCR confirmed the absence of Cyp24a1 and 2-fold increases in S100g, sodium-calcium exchanger type 1, and calcium-sensing receptor in null placentas but not in fetal kidneys; these changes predicted an increase in placental calcium transport. However, placental 45Ca and 32P transport were unchanged in null fetuses. Fetal ash weight and mineral content, placental weight, crown-rump length, and skeletal morphology did not differ among the genotypes. Serum procollagen 1 intact N-terminal propeptide and bone expression of sclerostin and Blgap were reduced while calcitonin receptor was increased in nulls. In conclusion, loss of Cyp24a1 in fetal mice causes hypercalcemia, modest hypophosphatemia, and increased FGF23, but no alteration in skeletal development. Reduced incorporation of calcium into bone may contribute to the hypercalcemia without causing a detectable decrease in the skeletal mineral content. The results predict that human fetuses bearing homozygous or compound heterozygous inactivating mutations of CYP24A1 will also be hypercalcemic in utero but with normal skeletal development.

Effect of vitamin D supplementation or fortification on bone turnover markers in women: a systematic review and meta-analysis.

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.

Association of mineral and bone biomarkers with adverse cardiovascular outcomes and mortality in the German Chronic Kidney Disease (GCKD) cohort

Mineral and bone disorder (MBD) in chronic kidney disease (CKD) is tightly linked to cardiovascular disease (CVD). In this study, we aimed to compare the prognostic value of nine MBD biomarkers to determine those associated best with adverse cardiovascular (CV) outcomes and mortality. In 5 217 participants of the German CKD (GCKD) study enrolled with an estimated glomerular filtration rate (eGFR) between 30–60 mL·min−1 per 1.73 m2 or overt proteinuria, serum osteoprotegerin (OPG), C-terminal fibroblast growth factor-23 (FGF23), intact parathyroid hormone (iPTH), bone alkaline phosphatase (BAP), cross-linked C-telopeptide of type 1 collagen (CTX1), procollagen 1 intact N-terminal propeptide (P1NP), phosphate, calcium, and 25-OH vitamin D were measured at baseline. Participants with missing values among these parameters (n = 971) were excluded, leaving a total of 4 246 participants for analysis. During a median follow-up of 6.5 years, 387 non-CV deaths, 173 CV deaths, 645 nonfatal major adverse CV events (MACEs) and 368 hospitalizations for congestive heart failure (CHF) were observed. OPG and FGF23 were associated with all outcomes, with the highest hazard ratios (HRs) for OPG. In the final Cox regression model, adjusted for CV risk factors, including kidney function and all other investigated biomarkers, each standard deviation increase in OPG was associated with non-CV death (HR 1.76, 95% CI: 1.35–2.30), CV death (HR 2.18, 95% CI: 1.50–3.16), MACE (HR 1.38, 95% CI: 1.12–1.71) and hospitalization for CHF (HR 2.05, 95% CI: 1.56–2.69). Out of the nine biomarkers examined, stratification based on serum OPG best identified the CKD patients who were at the highest risk for any adverse CV outcome and mortality.

Acarbose diminishes postprandial suppression of bone resorption in patients with type 2 diabetes.

The alpha-glucosidase inhibitor acarbose is an antidiabetic drug delaying assimilation of carbohydrates and, thus, increasing the amount of carbohydrates in the distal parts of the intestines, which in turn increases circulating levels of the gut-derived incretin hormone glucagon-like peptide 1 (GLP-1). As GLP-1 may suppress bone resorption, acarbose has been proposed to potentiate meal-induced suppression of bone resorption. We investigated the effect of acarbose treatment on postprandial bone resorption in patients with type 2 diabetes and used the GLP-1 receptor antagonist exendin(9-39)NH2 to disclose contributory effect of acarbose-induced GLP-1 secretion. In a randomised, placebo-controlled, double-blind, crossover study, 15 participants with metformin-treated type 2 diabetes (2 women/13 men, age 71 (57-85years), BMI 29.7 (23.6-34.6kg/m2), HbA1c 48 (40-74mmol/mol)/6.5 (5.8-11.6%) (median and range)) were subjected to two 14-day treatment periods with acarbose and placebo, respectively, separated by a six-week wash-out period. At the end of each period, circulating bone formation and resorption markers were assessed during two randomised 4-h liquid mixed meal tests (MMT) with infusions of exendin(9-39)NH2 and saline, respectively. Glucagon-like peptide 2 (GLP-2) was also assessed. Compared to placebo, acarbose impaired the MMT-induced suppression of CTX as assessed by baseline-subtracted area under curve (P=0.0037) and nadir of CTX (P=0.0128). During acarbose treatment, exendin(9-39)NH2 infusion lowered nadir of CTX compared to saline (P=0.0344). Neither parathyroid hormone or the bone formation marker procollagen 1 intact N-terminal propeptide were affected by acarbose or GLP-1 receptor antagonism. Acarbose treatment induced a greater postprandial GLP-2 response than placebo treatment (P=0.0479) and exendin(9-39)NH2 infusion exacerbated this (P=0.0002). In patients with type 2 diabetes, treatment with acarbose reduced postprandial suppression of bone resorption. Acarbose-induced GLP-1 secretion may contribute to this phenomenon as the impairment was partially reversed by GLP-1 receptor antagonism. Also, acarbose-induced reductions in other factors reducing bone resorption, e.g. glucose-dependent insulinotropic polypeptide, may contribute.

Agreement of Parathyroid Hormone Status Measured by Intact and Biointact Parathyroid Hormone Assays among Chronic Kidney Disease Patients and Its Correlation with Bone Turnover Parameters.

This study aimed to determine the agreement between intact parathyroid hormone (iPTH) and biointact parathyroid hormone (bio-PTH) assays and to correlate them with bone markers. This cross-sectional study included 180 patients with chronic kidney disease (CKD) stages 3b, 4 and 5D. We measured their iPTH, bio-PTH, 25-hydroxyvitaminD (25(OH)D), C-terminal telopeptide collagen (CTX), procollagen 1 intact N-terminal propeptide (P1NP), calcium, phosphate and alkaline phosphatase (ALP). Higher iPTH than bio-PTH concentrations were seen in CKD stages 3b, 4 and 5D (58[62] versus 55[67] pg/mL, 94[85] versus 85[76] pg/mL and 378[481] versus 252[280] pg/mL, respectively). Both PTH assays showed good agreement among all the subjects, with an intraclass correlation coefficient of 0.832 (P-value < 0.001). The Passing-Bablok showed that the equation for the bio-PTH was PTH = 0.64 iPTH + 15.80, with r = 0.99. The Bland-Altman plots showed increased bias with an increasing PTH concentration. Both PTH assays showed a high positive correlation with CTX and P1NP, a moderate correlation with phosphate, a low correlation with ALP and calcium, and a negligible correlation with phosphate and 25(OH)D. The iPTH and bio-PTH assays were in agreement, but their bias increased with the PTH concentration. The unacceptable large bias indicates that the two assays cannot be used interchangeably. They had a variable correlation with the bone parameters.

Diabetes Mellitus Type 2 Patients with Abdominal Obesity Are Prone to Osteodysfunction: A Cross-Sectional Study.

The interaction between diabetes, obesity, and bone metabolism was drawing increasing public attention. However, the osteometabolic changes in diabetes mellitus type 2 (T2DM) patients with abdominal obesity have not been fully revealed. This study is aimed at investigating the association between abdominal obesity indices and bone turnover markers among T2DM participants. 4351 subjects were involved in the METAL study. Abdominal obesity indices included neck, waist, and hip circumference, visceral adiposity index (VAI), lipid accumulation product (LAP), waist-to-hip ratio (WHR), and Chinese visceral adiposity index (CVAI). They were applied to elucidate the nexus between β-C-terminal telopeptide (β-CTX), osteocalcin (OC), and intact N-terminal propeptide of type I collagen (P1NP). Abdominal obesity indices were strongly negatively associated with β-CTX and OC. Among males, five indices were negatively correlated with β-CTX (BMI, WC, LAP, WHR, and CVAI) and OC (BMI, NC, WC, WHR, and CVAI). There were no significant associations with P1NP. Among females, all eight indices were negatively associated with β-CTX. Seven indices were negatively related to OC (BMI, NC, WC, HC, LAP, WHR, and CVAI). The VAI was negatively correlated with P1NP. The present study demonstrated that in T2DM, abdominal obesity had an obviously negative correlation with bone metabolism. Abdominal obesity indices were significantly negatively associated with skeletal destruction (β-CTX) and formation (OC). In routine clinical practice, these easily obtained indices could be used as a preliminary screening method and relevant factors for osteodysfunction incidence risk at no additional cost and may be of particular value for postmenopausal women in T2DM populations.

Predictive biomarkers of ossification progression and bone metabolism dynamics in patients with cervical ossification of the posterior longitudinal ligament.

This study aimed to establish biomarkers to predict the progression of ossification by examining ossification volume and bone metabolism dynamics in patients with ossification of the posterior longitudinal ligament (OPLL). We assessed OPLL progression using computed tomography-based three-dimensional (3D) image analysis and examined bone metabolism dynamics in 107 patients with OPLL (men, 72; women, 35; mean age, 63.6years). The volume of OPLL was calculated twice during the follow-up period, and OPLL progression was evaluated by the annual rate of ossification increase. Bone metabolism dynamics were assessed by routine blood tests and analysis of various serum biomarkers (including 25-hydroxyvitamin D, intact parathyroid hormone, fibroblast growth factor 23, intact N-terminal propeptide of type 1, tartrate-resistant acid phosphatase isoform 5b, sclerostin, and Dickkopf-1) and bone mineral density (BMD). Patients were classified into the progression (P) or non-progression (NP) group according to the annual rate of increase in previous 3D image analyses, and associated factors between these groups were compared. The P and NP groups consisted of 29 patients (23 men and 6 women) and 78 patients (49 men and 29 women), respectively. Univariate analysis revealed significant differences in terms of age, body mass index, serum phosphorus, serum sclerostin, and BMD. In multivariate analysis, age, serum phosphorus, and serum sclerostin were identified as independent factors associated with OPLL progression. Younger age, hypophosphatemia, and high serum sclerostin are risk factors for OPLL progression. Serum phosphorus and sclerostin could serve as important biomarkers for predicting ossification progression.

Early renal impairment affects hormonal regulators of calcium and bone metabolism and Wnt signalling and the response to vitamin D supplementation in healthy older adults

Bone and renal metabolism are regulated by common factors and there is extensive cross-talk between these organs (the ‘renal-bone-axis’). Ageing is associated with physiological changes including reduced bone mass, renal function and tissue sensitivity to regulatory hormones, impacting the renal-bone axis. We aimed to investigate the influence of estimated Glomerular Filtration Rate (eGFR) on plasma concentrations of vitamin D metabolites, Wnt signalling and bone metabolism in a dose ranging vitamin D3 RCT (12,000 IU, 24,000 IU, 48,000 IU/month for 1 year; n = 379, >70 y) with a baseline eGFR > 30 mL/min/1.73 m2. Participants were categorised on basis of eGFR (≥60 or mL/min/1.73 m2) based on 5 commonly used algorithms for eGFR. Differences between eGFR categories were tested with ANCOVA. Before supplementation commenced, a lower eGFR was associated with significantly higher concentrations of c-terminal and intact Fibroblast Growth Factor-23 (cFGF23; iFGF23), intact Parathyroid Hormone (iPTH) and Sclerostin (SOST) and lower Klotho, 1,25-dihydroxy Vitamin D (1,25(OH)2D) and Dickkopf-related Protein 1 (DKK1) concentrations. Differences between eGFR groups in 25-hydroxy Vitamin D (25(OH)D), 24,25-dihydroxy Vitamin D (24,25(OH)2D) and iPTH were only detected with eGFR based on Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Modification in Diet for Renal Disease (MDRD-4) algorithms. Differences in Bone Mineral Density and Content (BMD; BMC) and bone turnover markers were detected only with Cockcroft-Gault (CG). Pre- and post- supplementation comparisons showed differences in the response to supplementation by eGFR group. Plasma 25(OH)D, 24,25(OH)2D, 1,25(OH)2D and DKK1 increased and iPTH and C-terminal telopeptide (CTX) decreased in both groups. Plasma iFGF23, bone specific alkaline phosphatase (BAP) and Procollagen 1 intact N-terminal Propeptide (PINP) increased and phosphate decreased only in the group with eGFR ≥ 60 mL/min/1.73 m2. Findings were largely consistent across all eGFR algorithms. Post-supplementation, cFGF23, iFGF23, iPTH and SOST remained significantly higher in the lower eGFR group. Plasma 1,25(OH)2D and Klotho did no longer differ between eGFR groups. This was found for all eGFR algorithms, with the exception of iPTH and iFGF23, which were not significantly different with eGFR based on CG. Differences in BMD and BMC were detected with CKD-EPI-creatinine and MDRD-4 but not GC. This study showed that even a moderate decline in eGFR is associated with alterations in vitamin D metabolism, Wnt signalling and bone turnover markers. Renal function influenced the response to vitamin D supplementation. Supplementation increased Vitamin D metabolites in the group with moderate renal impairment to concentrations comparable to those found in the group with normal renal function. However, although CTX decreased, an increase in bone formation markers was not found in the group with eGFR 60 mL/min/1.73 m2. In conclusion, vitamin D supplementation had beneficial effects on markers of the renal-bone axis in older people with both normal and impaired renal function.

Effect of Zoledronic Acid in Hepatic Osteodystrophy: A Double-Blinded Placebo-Controlled Trial.

Literature on the treatment of pre-transplant hepatic osteodystrophy (HOD) is limited. The general treatment measures and their timing are currently adopted from the literature on postmenopausal osteoporosis. Therefore, we conducted this randomized study to investigate the effect of zoledronic acid (ZA) on HOD. We randomized 36 male patients with cirrhosis (Child-Pugh class A and B) into 19 to the ZA arm and 17 to the placebo arm, respectively. Patients in the ZA arm received a single infusion of 4 mg ZA dissolved in 100 mL of normal saline at baseline, while patients in the placebo arm received a similar infusion of normal saline at baseline. The primary outcome of the study was the change in lumbar spine bone mineral density (LS-BMD) at 12 months. Of 36 patients, 28 completed the study (15 in the ZA arm and 13 in the placebo arm). The mean increase in LS-BMD (g/cm2) in the ZA and placebo arms was 5.11% (3.50) and 0.72% (4.63) [P = 0.008], respectively. The trabecular bone score (TBS) did not improve significantly in either arm. The incidence of vertebral fractures (VFs) was similar in both arms. There was a significant decrease in plasma beta-C-terminal telopeptide (β-CTX) levels in the ZA arm compared to the placebo arm, while the change in plasma levels of procollagen 1 intact N-terminal propeptide (P1NP) was similar in both arms. Six patients (31.6%) in the ZA arm experienced adverse reactions such as fever and myalgia. ZA improved LS-BMD in male patients with HOD by decreasing bone resorption. However, it may not improve trabecular microarchitecture or prevent morphometric VFs in this population.

A novel approach for fibrous dysplasia assessment using combined planar and quantitative SPECT/CT analysis of Tc-99m-diphosphonate bone scan in correlation with biological bone turnover markers of disease activity.

To investigate the emerging role of Tc-99m-labeled diphosphonate (Tc-99m-DPD) uptake quantification by SPECT/CT in fibrous dysplasia (FD) bone lesions and its correlation with biological bone turnover markers (BTMs) of disease activity. Seven patients (49 ± 16 years) with a confirmed diagnosis of FD were included in this retrospective study. Bone scans with Tc-99m-DPD and quantitative SPECT/CT (xSPECT/CT) were performed. SUVmax (maximum standard unit value) and SUVmean (mean standard unit value) were measured in all FD bone lesions. The skeletal burden score (SBS) was assessed on planar scintigraphy and multiplied by mean SUV max and SUVmean to generate two new parameters, SBS_SUVmax and SBS_SUVmean, respectively. Planar and xSPECT/CT quantitative measures were correlated with biological BTMs of disease activity, including fibroblast growth factor 23 (FGF-23), alkaline phosphatase (ALP), procollagen 1 intact N-terminal propeptide (P1NP) and C-terminal telopeptide (CTX), as well as scoliosis angle measured on radiographs. Statistical significance was evaluated with Spearman's correlations. A total of 76 FD bone lesions were analyzed, showing an average SUVmax and SUVmean (g/mL) of 13 ± 7.3 and 8 ± 4.5, respectively. SBS, SBS_SUVmax and SBS_SUVmean values were 30.8 ± 25.6, 358 ± 267 and 220.1 ± 164.5, respectively. Mean measured values of FGF-23 (pg/mL), ALP (U/L), P1NP (μg/L) and CTX (pg/mL) were 98.4 (22-175), 283.5 (46-735), 283.1 (31-1,161) and 494 (360-609), respectively. Mean scoliosis angle was 15.7 (7-22) degrees. We found a very strong positive correlation between planar-derived SBS and CTX (r = 0.96, p = 0.010), but no significant correlation between SUVmax or SUVmean and biological BTMs. SBS_SUVmax showed a strong to very strong positive correlation with CTX (ρ = 0.99, p = 0.002), FGF-23 (ρ = 0.91, p = 0.010), ALP (ρ = 0.82, p = 0.020), and P1NP (ρ = 0.78, p = 0.039), respectively. This study showed that biological BTMs are significantly correlated with diphosphonate uptake on bone scan, quantified by a new parameter combining information from both planar and quantitative SPECT/CT. Further analysis of bone scan quantitative SPECT/CT data in a larger patient population might help better characterize the skeletal disease burden in FD, and guide treatment and follow-up.

The Evaluation of Xiaozeng Qianggu Tablets for Treating Postmenopausal Osteoporosis via up-Regulated Autophagy.

Objective Postmenopausal osteoporosis (PMOP) is a common age-associated disease in the life course. Clinically, Xiaozeng Qianggu Tablets (XQT) have a potent therapeutic effect on the PMOP. However, the bioactive components and the mechanism of XQT underlying the PMOP treatment were unclear and it should be explored to discover the scientific connotation in traditional medical practice. Methods The components in XQT were identified by UPLC-Q-TOF/MS. The animal model of PMOP was established by surgical ovariectomy in the female Sprague-Dawley rats. After treatment of XQT, the therapeutic effect was assessed by the determination of bone metabolism biomarkers in serum and histopathological examination. The effect of XQT on the autophagy and bone micro-situation were tested using western blot, RT-qPCR, and transmission electron microscope. Results There were 27 compounds identified in XQT, including catalpol, monotropein, verbascoside, cryptochlorogenic acid, 5,7-dihydroxychromone 7-rutinoside, biorobin, and so on. The bone metabolism markers (alkaline phosphatase, bone alkaline phosphatase, procollagen type I intact N-terminal propeptide, cross-linked carboxy-terminal telopeptide of type I collagen, and tartrate-resistant acid phosphatase) were significantly increased in the PMOP rats and reversed by XQT administration. Moreover, the width of bone trabeculae and the ratio of the area of calcium deposition to bone trabeculae were also improved after treating the middle dose of XQT. Meanwhile, the bone micro-structure was improved by XQT. The mRNA and protein expression of unc-51 like kinase 1, beclin-1, and microtubule-associated protein 1B-light chain 3 in PMOP rats were down-regulated and up-regulated by XQT administration. Conclusions The compounds in XQT, including catalpol, monotropein, verbascoside cryptochlorogenic acid, and so on, were valuable for further pharmacy evaluation. The pathological changes and bone micro-structure were improved by XQT, and the down-regulated autophagy level was also restored, which suggested a potent effect of XQT on treating PMOP, corresponding to its clinic use.

Lipocalin-2 is associated with FGF23 in WNT1 and PLS3 osteoporosis.

BackgroundThe pathogenic mechanisms of early-onset osteoporosis caused by WNT1 and PLS3 mutations are incompletely understood and diagnostic biomarkers of these disorders are limited. Recently, lipocalin-2 has been recognized as an osteokine involved in bone development and homeostasis. However, the role of lipocalin-2 in WNT1 and PLS3 osteoporosis is unknown.ObjectiveWe aimed to investigate if plasma lipocalin-2 could be utilized as a biomarker for WNT1 and PLS3 osteoporosis and to evaluate the association between lipocalin-2 and other parameters of bone metabolism.MethodsWe measured plasma lipocalin-2 in 17 WNT1 and 14 PLS3 mutation-positive patients and compared them to those of 34 mutation-negative (MN) healthy subjects. We investigated possible associations between lipocalin-2 and several bone biomarkers including collagen type I cross-linked C-telopeptide (CTX), alkaline phosphatase (ALP), type I procollagen intact N-terminal propeptide (PINP), intact and C-terminal fibroblast growth factor 23 (FGF23), dickkopf-1 (DKK1) and sclerostin as well as parameters of iron metabolism (iron, transferrin, transferrin saturation, soluble transferrin receptor and ferritin).ResultsWe found no differences in plasma lipocalin-2 levels in WNT1 or PLS3 patients compared with MN subjects. However, lipocalin-2 was associated with C-terminal FGF23 in WNT1 patients (r=0.62; p=0.008) and PLS3 patients (r=0.63, p=0.017), and with intact FGF23 in PLS3 patients (r=0.80; p<0.001). In addition, lipocalin-2 correlated with serum transferrin in WNT1 patients (r=0.72; p=0.001).ConclusionWe conclude that plasma lipocalin-2 is not altered in WNT1 or PLS3 mutation-positive subjects but is associated with FGF23 in abnormal WNT1 or PLS3 signaling and with iron status in abnormal WNT1 signaling.

Association of nesfatin-1 levels and bone remodeling markers in patients with rheumatoid arthritis

Aim. To evaluate the association of nesfatin-1 (NF-1) levels and bone remodeling markers in patients with rheumatoid arthritis (RA).Materials and methods. 110 patients (105 women and 5 men) with RA, classified by ACR/EULAR 2010 criteria were enrolled in our study. All patients undergone complete clinical and laboratory examination. NF-1 serum levels were determined using a commercial test-systems (RayBio® Nesfatin Enzyme Immunoassay [EIA] Kit). Statistical analysis was performed using a software package Statistica 12.0. The results were considered statistically significant at p &lt; 0.050.Results. Significant positive correlation was determined between serum NF-1 levels and Intact N-Terminal Propeptide of Type 1 Procollagen (P1NP) levels (r = 0.218; p = 0.022). Serum NF-1 levels were not associated with bone mineral density in lumbar spine and femur. Serum NF-1 levels didn't correlate with body composition indices and Beta-CrossLaps levels. Patients with osteoporosis (n = 53) and osteoporotic fractures (n = 25) had statistically significant higher levels of NF-1 (Z = –2.060; p = 0.040 и Z = –2.370; p = 0.017 respectively). However, serum NF-1 levels didn’t correlate with cumulative dose of glucocorticoids (ρ = 0.090; p = 0.368) and the duration of glucocorticoids intake (ρ = 0.070; p = 0.462).Conclusions. In our study, we determined the significant positive correlation between NF-1 and P1NP levels, supposingly due to NF-1 possible effect on the osteoblasts differentiation and function. Patients with osteoporosis and osteoporotic fractures had higher median blood serum levels of NF-1.