C-terminal Cross-linking Telopeptide Of Type Research Articles

Prevalence and Risk Factors of Low Bone Mineral Density and Fractures of Young Thalassemia Patients

▪Background: Thalassemia is a common cause of anemia in Thailand. Blood transfusion and iron chelation lengthen life span of thalassemia patients. As a result, these patients are experiencing an emerging long-term complications including thalassemia-associated osteoporosis (TAO). However, prevalence of TAO and TAO-associated fractures in this population is uncertain.Objective: To investigate the prevalences of TAO and fractures among thalassemia patients and to identify clinical and laboratory factors that are associated with these conditions.Methods: Consecutive males (18-50 years) or premenopausal females with thalassemia who were followed up in the hematologic clinic at ChiangMai University from November 2017 to June 2018, were screened for TAO using the dual energy X-ray absorptiometry (DXA) for measuring bone mineral density (BMD) and vertebral fracture assessment (VFA). TAO was defined as low BMD (Z-score ≤ -2.0 SD) or presence of vertebral fractures from VFA. We collected clinical data and, determined laboratory investigation including fasting plasma glucose, serum testosterone or estradiol, thyroid function test, serum calcium, serum insulin like growth factor-1, serum C-terminal crosslinking telopeptide of type I collagen (CTX), serum procollagen type I N-terminal propeptide (P1NP), serum 25-hydroxy vitamin D (25-OHD), viral hepatitis B and C, and serum ferritin and non-transferrin-bound iron (NTBI; toxic form of iron). Outcomes were prevalence of TAO and fractures.Results: A total of 140 thalassemia patients were screened (89 transfusion-dependent thalassemia; TDT and 51 non-transfusion-dependent thalassemia; NTDT). Most patients received routine calcium (elemental calcium 600 mg/day) and vitamin D supplement (vitamin D2 20,000 IU/week). The prevalence of TAO was 75.7% (TDT 83.1%, NTDT 62.7%). The prevalence of vertebral fractures from VFA was 22.8% (TDT 24.7%, NTDT 19.6%). Among 106 patients with TAO, only 50 patients participated in this study (TDT 70%). Factors associated with lower mean BMD Z-score were current smoking, splenectomy history, vitamin D deficiency, diabetes mellitus, low IGF-1 level and serum NTBI above 2.2 uM. Fractures were common in patients with TDT than those with NTDT (51% vs. 20%, p=0.039). The prevalence of sub-optimal vitamin D level among Thai thalassemia patients was high at 50% even with vitamin D supplement. Factors associated with bone fractures were male sex (RR 1.66, 95%CI 1.02-2.70), hemoglobin level below 8 g/dl (RR 2.73, 95%CI 1.00-7.46), hypogonadism (RR 1.67, 95%CI 1.11-2.50), low IGF-1 level (RR 1.75, 95%CI 0.97-3.14) and serum NTBI above 1.5 uM (RR 6.14, 95%CI 0.96-39.47). Type of iron chelation, serum ferritin and the 2 bone turnover markers level (CTX and P1NP) were not associated with BMD or fractures.Conclusion: TAO is common among Thai thalassemia patients. We observed high prevalence of suboptimal vitamin D level in these patients. Male sex, high disease severity (low hemoglobin level and high serum NTBI) and secondary endocrinopathies may predict TAO and fractures. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The 24-hour serum profiles of bone markers in healthy older men and women.

The process of bone turnover displays variations over 24 h, with C-terminal cross-linked telopeptide of type 1 collagen (CTX) and osteocalcin exhibiting a nadir in the afternoon and a peak in the night. In contrast, N-terminal propeptide of type 1 procollagen (P1NP) did not display an apparent 24-hour rhythm. Other emerging novel biomarkers of bone, sclerostin and Dickkopf-related protein 1 (DKK1), are markers of osteocyte activity with limited data available regarding their 24-hour profiles. In this study, we aimed to extend available data on 24-hour profiles of CTX, osteocalcin, and P1NP and to assess the 24-hour profiles of sclerostin and DKK1 in healthy older men and women and to compare these between men and women. We measured these five bone markers in EDTA plasma collected every 4 h during 24 h in 37 healthy older men and women (range 52-76 years). Differences between time points were determined using repeated measures ANOVA and cosinor analyses were performed to determine circadian rhythmicity. The circadian rhythm of CTX was confirmed by the cosinor model, with women showing larger amplitude compared to men. Osteocalcin showed higher levels during nighttime compared to daytime in both men and women. For P1NP levels we observed a small but significant increase in the night in men. Sclerostin and DKK1 did not show a circadian rhythm, but sclerostin levels differed between time points. Because of the large intraindividual variation, DKK1 as measured in this study cannot be considered a reliable marker for diagnostic or research purposes. In conclusion, when measuring CTX, osteocalcin, P1NP, or sclerostin either in clinical practice or in a research setting, one should consider the 24-hour profiles of these bone markers.

The impact of mammalian target of rapamycin inhibition on bone health in postmenopausal women with hormone receptor-positive advanced breast cancer receiving everolimus plus exemestane in the phase IIIb 4EVER trial

BackgroundBreast cancer and its treatments are associated with a detrimental effect on bone health. Here we report the results of an exploratory analysis assessing changes in levels of biomarkers of bone metabolism in patients enrolled in the phase IIIb 4EVER study. MethodsThe 4EVER trial investigated everolimus in combination with exemestane in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer. In this prespecified exploratory analysis, changes in biomarkers of bone turnover were assessed in patients from baseline to weeks 4, 12, and 24. The serum bone markers assessed were procollagen type 1 N-terminal propeptide (P1NP), C-terminal cross-linking telopeptide of type 1 collagen (CTX), osteocalcin, parathyroid hormone (PTH), and 25-hydroxyvitamin D (25-OH-vitamin D). On-treatment changes in bone markers over time were described per subgroup of interest and efficacy outcomes. ResultsBone marker data were available for 241 of 299 enrolled patients. At the final assessment, P1NP, osteocalcin, PTH, 25-OH-vitamin D (all P < 0.001), and CTX (P = 0.036) were significantly decreased from baseline values per the Wilcoxon signed-rank test. At the last assessment (24 weeks or earlier), levels of serum CTX and PTH were significantly lower (P = 0.009 and P = 0.034, respectively) among patients with vs. without prior antiresorptive treatment (ART). Serum CTX levels were significantly lower (P < 0.001), and 25-OH-vitamin D concentrations significantly higher (P = 0.029), at the last postbaseline assessment in patients receiving concomitant ART vs. those without ART. Changes from baseline in PTH and 25-OH-vitamin D concentrations to the final assessment were significantly smaller in patients with prior ART. Lower baseline serum concentrations of osteocalcin and PTH were associated with clinical response (partial vs. non-response) at 24 weeks. High serum levels of CTX and P1NP at baseline were risk factors for progression at 12 weeks. ConclusionsThese exploratory analyses support use of everolimus plus exemestane for the treatment of postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer, and add to the body of evidence suggesting a potentially favorable impact of everolimus on bone turnover. Trial registrationNCT01626222. Registered 22 June 2012, https://clinicaltrials.gov/ct2/show/NCT01626222.

C-Terminal Cross-Linked Telopeptides of Type II Collagen as Biomarker for Radiological Knee Osteoarthritis: A Meta-Analysis.

C-terminal cross-linked telopeptides of type II collagen (CTX-II) are one of the most frequently assessed markers for osteoarthritis (OA) diagnosis. The aim of this meta-analysis was to confirm the diagnostic value of urinary CTX-II in knee OA. PubMed, ScienceDirect, and EMBASE were searched for studies measured urinary CTX-II in patients with knee OA and in healthy controls. Urinary CTX-II levels were compared between knee OA patients and controls. Differences between groups were expressed as standardized mean differences (SMD) when individual outcomes were measured with different scales. Otherwise, outcomes were presented as mean differences (MD). Subgroup analyses were also conducted to compare efficiency of urinary CTX-II between Kellgren-Lawrence (KL) classification, genders, ethnicities, and study size. Thirteen studies involved a total of 2856 participants were included. Pooled SMD showed that urinary CTX-II levels were significantly elevated in knee OA group compared to controls (SMD 0.82; 95% CI 0.41-1.24; P < 0.0001). For KL 3 to 4 versus KL 2, higher urinary CTX-II levels were found in severe knee OA patients. Subgroup analyses revealed that urinary CTX-II performed better in females as compared with males and in European subjects as compared with Asian population. Also, study size did not influence the statistic results. This is the largest scale meta-analysis assessing the diagnostic performance of urinary CTX-II levels as biomarker for knee OA. According to our findings, urinary CTX-II levels have a potential to distinguish knee OA patients from healthy controls which can serve as biomarker for knee OA.

Membrane-Based Microwave-Mediated Electrochemical Immunoassay for the In Vitro, Highly Sensitive Detection of Osteoporosis-Related Biomarkers.

Highly sensitive and multiplexed in vitro detection of osteoporosis-related biochemical markers were carried out based on the membrane-based microwave-mediated electrochemical immunoassay (MMeEIA), where we can dramatically reduce the sample preparation time by shortening the incubation time of conjugation to obtain sensitive detection based on three dimensional conjugation of antibodies with target antigens in nylon membrane disk. C-terminal cross-linked telopeptide of type I collagen (CTx), Osteocalcin (OC), parathyroid hormone (PTH), and N-terminal propeptide of type I collagen (P1NP), which can be utilized to monitor the progress of osteoporosis, were quantified using their corresponding antibody immobilized in membranes. Coefficient of variations in this intra- and inter-assays were within 8.0% for all markers. When compared with data obtained from clinically used standard equipment (Roche modular E170), their coefficients of determination, R2 values, are mostly more than 0.9. They show that the results obtained from MMeEIA are in good agreement with that from the conventional clinical instruments.

Deletion of the Transcription Factor PGC-1α in Mice Negatively Regulates Bone Mass.

Peroxisome proliferator-activated receptor-gamma coactivator (PGC1α) is a transcription coactivator that interacts with a broad range of transcription factors involved in several biological responses. Here, we show that PGC1α plays a role in skeletal homeostasis since aged PGC1α-deficient mice (PGC1α-/-) display impaired bone structure. Micro-CT of the tibial mid-shaft showed a marked decrease of cortical thickness in PGC1α-/- (- 11.9%, p < 0.05) mice compared to wild-type littermate. Trabecular bone was also impaired in knock out mice which displayed lower trabecular thickness (Tb.Th) (- 5.9% vs PGC1α+/+, p < 0.05), whereas trabecular number (Tb.N) was higher than wild-type mice (+ 72% vs PGC1α+/+, p < 0.05), thus resulting in increased (+ 31.7% vs PGC1α+/+, p < 0.05) degree of anisotropy (DA), despite unchanged bone volume fraction (BV/TV). Notably, these impairments of cortical and trabecular bone led to a dramatic ~ 48.4% decrease in bending strength (p < 0.01). These changes in PGC1α-/- mice were paralleled by a significant increase in osteoclast number at the cortical bone surface and in serum level of the bone resorption marker, namely, C-terminal cross-linked telopeptides of type I collagen (CTX-I). We also found that in cortical bone, there was lower expression of mRNA codifying for the key bone-building protein Osteocalcin (Ocn). Interestingly, Collagen I mRNA expression was reduced in mesenchymal stem cells from bone marrow of PGC1α-/-, thus indicating that differentiation of osteoblast lineage is downregulated. Overall, results presented herein suggest that PGC1α may play a key role in bone metabolism.

Combination therapy of curcumin and alendronate modulates bone turnover markers and enhances bone mineral density in postmenopausal women with osteoporosis.

This study evaluated the effects of combination therapy of curcumin and alendronate on BMD and bone turnover markers in postmenopausal women with osteoporosis. In a randomized, double-blind trial study, 60 postmenopausal women were divided into three groups: control, alendronate, and alendronate + curcumin. Each group included 20 patients. Total body, total hip, lumbar spine and femoral neck BMDs were measured by dual-energy X-ray absorptiometry (DXA) at baseline and after 12 months of therapy. Bone turnover markers such as bone-specific alkaline phosphatase (BALP), osteocalcin and C-terminal cross-linking telopeptide of type I collagen (CTx) were measured at the outset and 6 months later. Patients in the control group suffered a significant decrease in BMD and increased bone turnover markers at the end of study. The group treated with only alendronate showed significantly decreased levels of BALP and CTx and increased levels of osteocalcin compared to the control group. The alendronate group also showed significant increases in the total body, total hip, lumbar spine and femoral neck BMDs at the end of study compared to the control group. In the curcumin + alendronate group, BALP and CTx levels decreased and osteocalcin levels increased significantly at the end of study compared to the control and alendronate groups. BMD indexes also increased in four areas significantly at the end of study compared to the control and alendronate groups. The combination of curcumin and alendronate has beneficial effects on BMD and bone turnover markers among postmenopausal women with osteoporosis. Arch Endocrinol Metab. 2018;62(4):438-45.

The level of vitamin D using the LC-MS/MS method and related factors in healthy Korean postmenopausal women.

The main purposes of the study were (i) to evaluate serum vitamin D concentration in the forms of 25(OH)D2 , 25(OH)D3 and total 25(OH)D in Korean postmenopausal women using the LC-MS/MS method, which offers increased sensitivity and selectivity; (ii) to determine the relationship between the bone turnover marker, parathyroid hormone (PTH) and 25(OH)D3 , total 25(OH)D separately; and (iii) to determine the factors that may be associated with vitamin D deficiency using body composition analysis and laboratory blood tests. A total of 200 postmenopausal women were recruited from November 2012 to March 2014. To control for seasonal ultraviolet exposure time differences in serum 25(OH)D, laboratory tests were performed only from November to March when vitamin D is not synthesized. Independent relationships between 25(OH)D3 , total 25(OH)D and other variables were assessed by multiple regression analysis. The mean serum 25(OH)D2 , 25(OH)D3 and total 25(OH)D levels were 0.51 (±0.44) ng/mL, 14.23 (±7.05) ng/mL and 14.69 (±7.13) ng/mL, respectively. Both 25(OH)D3 and total 25(OH)D were positively correlated with erythrocyte sedimentation rate (ESR), Apo A-I and C-terminal cross-linked telopeptides of type I collagen in Korean postmenopausal women. Both serum 25(OH)D3 and total 25(OH)D were negatively correlated with alkaline phosphatase , PTH and percent body fat. However, osteocalcin showed a negative correlation (r = -0.451; P = 0.041) with only 25(OH)D3 and not with total 25(OH)D (r = -0.417; P = 0.064). Both 25(OH)D3 and total 25(OH)D were negatively correlated with PTH, a bone formation marker (alkaline phosphatase) and percent body fat. Both 25(OH)D3 and total 25(OH)D were positively correlated with a bone resorption marker (C-terminal cross-linked telopeptides of type I collagen), ESR and Apo A-I after multiple regression analysis.

Biochemical Markers of Bone Turnover and Risk of Incident Diabetes in Older Women: The Cardiovascular Health Study.

To investigate the relationship of osteocalcin (OC), a marker of bone formation, and C-terminal cross-linked telopeptide of type I collagen (CTX), a marker of bone resorption, with incident diabetes in older women. The analysis included 1,455 female participants from the population-based Cardiovascular Health Study (CHS) (mean [SD] age 74.6 [5.0] years). The cross-sectional association of serum total OC and CTX levels with insulin resistance (HOMA-IR) was examined using multiple linear regression. The longitudinal association of both markers with incident diabetes, defined by follow-up glucose measurements, medications, and ICD-9 codes, was examined using multivariable Cox proportional hazards models. OC and CTX were strongly correlated (r = 0.80). In cross-sectional analyses, significant or near-significant inverse associations with HOMA-IR were observed for continuous levels of OC (β = -0.12 per SD increment; P = 0.004) and CTX (β = -0.08 per SD; P = 0.051) after full adjustment for demographic, lifestyle, and clinical covariates. During a median follow-up of 11.5 years, 196 cases of incident diabetes occurred. After full adjustment, both biomarkers exhibited inverse associations with incident diabetes (OC: hazard ratio 0.85 per SD [95% CI 0.71-1.02; P = 0.075]; CTX: 0.82 per SD [0.69-0.98; P = 0.031]), associations that were comparable in magnitude and approached or achieved statistical significance. In late postmenopausal women, lower OC and CTX levels were associated with similarly increased risks of insulin resistance at baseline and incident diabetes over long-term follow-up. Further research to delineate the mechanisms linking abnormal bone homeostasis and energy metabolism could uncover new approaches for the prevention of these age-related disorders.

No association between the vitamin D pathway gene polymorphisms and bone biomarkers response to calcium and low dose calcitriol supplementation in postmenopausal Chinese women: a one-year prospective study

Introduction: The aim of the study was to explore the association between the vitamin D pathway gene variations and the bone biomarkers response to calcium and low dose calcitriol supplementation in postmenopausal Chinese women.Methods: A total of 110 healthy postmenopausal Chinese women (61.51 ± 6.93 years) were enrolled. The participants were supplemented with calcium (600 mg/d) and calcitriol (0.25 μg/d), for 1 year. Four biomarkers, serum levels of beta C-terminal cross-linked telopeptides of type I collagen (β-CTX), amino-terminal propeptide of type I collagen (P1NP), parathyroid hormone (PTH) and 25-hydroxyvitamin D [25(OH)D] were measured at baseline and 12-month follow-up. Multivariate regression models were established to explore the statistical association between the change rate of the four biomarkers and 15 key genes within the vitamin D metabolic pathway.Results: This exclusion process left 98 participants for analysis. Serum levels of P1NP, β-CTX and PTH were significantly decreased at the 12-month follow-up (all p < 0.05). Serum 25(OH)D level had no significant change (p > 0.05). No association was found between the vitamin D pathway gene polymorphisms and bone biomarkers response to calcium and low dose calcitriol supplementation.Conclusions: Genetic background of postmenopausal Chinese women might not influence supplemental response of the biomarkers to calcium and low dose calcitriol.

Evaluation of Bone Turnover in Patients With Type 1 Diabetes Mellitus

Background: The purpose of the study was to assess the effect of changes in male and female’s body with type 1 diabetes mellitus (T1DM) on the state of the bone mineral density and the metabolic rate, and to determinate the direction of changes in serum markers of bone remodeling and bone mineral density in both sexes due to this disease. Methods: Bone mineral density (with dual-energy X-ray absorptiometry (DXA)) and serum bone remodeling markers (alkaline phosphatase (ALP), procollagen type 1 intact N-terminal propeptide (P1NP) and C-terminal cross-linking telopeptide of type I collagen (b-CTx)) were measured in 57 female and 41 male with T1DM (n = 98) and in a group control, consisting of 43 female and 39 male (n = 82). Results: Analysis of the obtained results showed lower values in all the surveyed areas of patients with diabetes, in comparison with the control group. It was found that the studied bone formation markers (ALP, P1NP) behave differently. While the P1NP level is significantly reduced in female with T1DM vs. control group patients (P 0.05). B-CTx showed a significant negative correlation with the T-score of lumbar spine (r = -0.431, P = 0.000). Conclusions: Based on the results of studying the T-score it was found that in male and female with diabetes, in comparison with the control group, the bone density in the vertebrae was reduced. In men with T1DM changes in the T-score in the spine were found less intense than those in female. J Endocrinol Metab. 2018;8(1):2-5 doi: https://doi.org/10.14740/jem483w

Electroacupuncture ameliorates subchondral bone deterioration and inhibits cartilage degeneration in ovariectomised rats.

To investigate the effects of electroacupuncture (EA) on subchondral bone mass and cartilage degeneration in an experimental animal model of osteoarthritis (OA) induced by ovariectomy (OVX). Ninety 3-month-old female Sprague-Dawley rats were randomly divided into the following three groups (n = 30 each): sham operation without treatment (control group); OVX without treatment (OVX group);, and ovariectomy with EA treatment (EA group). Rats in the EA group received EA treatment from the day of OVX. Ten rats in each group were randomly killed at 4, 8 and 12 weeks after operation. EA reduced urine C-terminal cross-linking telopeptide of type I collagen from 4 weeks after OVX, reduced C-terminal cross-linking telopeptide of type II collagen and body weight from 8 weeks after OVX, and increased serum 17β-oestradiol from 4 weeks after OVX compared with the OVX group (all p<0.01). In the EA group, trabecular bone volume ratio, trabecular thickness and trabecular number increased, and trabecular separation were reduced at each time point compared with the OVX group (p<0.05, p<0.01, respectively). In the EA group, osteoprotegerin (OPG) expression was increased and receptor activator of nuclear factor kappa-B ligand (RANKL) expression was reduced at each time point compared with the OVX group (p<0.05, p<0.01, respectively). Mankin scores and mRNA expression of matrix metalloproteinase-13 (MMP-13) were lower in EA versus OVX groups at 12 weeks after OVX (both p<0.01). The results suggest that EA inhibits subchondral bone loss by regulating RANK/RANKL/OPG signalling and protects articular cartilage by inhibiting MMP-13 in OVX rats.

Evaluation of gingival crevicular fluid and peri-implant sulcus fluid levels of periostin: A preliminary report.

Periostin is a protein present in alveolar bone and periodontal ligament whose function is related to response to external forces. The aims of this study are to detect levels of periostin in peri-implant sulcular fluid (PISF) and gingival crevicular fluid (GCF) and to evaluate the relationship between periostin, pyridinoline cross-linked carboxyterminal telopeptide of Type I collagen (ICTP), and C-terminal cross-linked telopeptide of Type I collagen (CTX) levels and clinical inflammatory symptoms and duration of functional loading. The study population comprised nine women and four men with mean age 43.23 ± 12.48. Twenty "bone-level designed" dental implants (DIs) placed in molar or premolar sites, without any signs of peri-implant bone loss and with a restoration in function for at least 12 months, were included in the study with 20 contralateral natural teeth (NT) as controls. Clinical parameters and restoration dates of the implants were recorded. PISF, GCF, ICTP, CTX, and periostin levels were evaluated using enzyme-linked immunosorbent assay. ICTP, CTX, and periostin levels were similar between DI and NT groups. There were no statistically significant differences between PISF and GCF values. When implants were grouped as healthy (gingival index [GI]=0) and inflamed (GI≥0), ICTP levels and PISF volume were lower in healthy implants compared with the inflamed group. Both periostin and CTX levels were negatively correlated with functioning time, suggesting less bone remodeling around DIs at later stages of functioning. Findings of this study suggest collagen breakdown products may be used as markers to evaluate peri-implant metabolism.

Development of a prediction model for future risk of radiographic hip osteoarthritis

To develop and validate a prognostic model for incident radiologic hip osteoarthritis (HOA) and determine the value of previously identified predictive factors. We first validated previously reported predictive factors for HOA by performing univariate and multivariate analyses for all predictors in three large prospective cohorts (total sample size of 4548 with 653 incident cases). The prognostic model was developed in 2327 individuals followed for 10 years from the Rotterdam Study-I (RS-I) cohort. External validation of the model was tested on discrimination in two other cohorts: RS-II (n=1435) and the Cohort Hip and Cohort Knee (CHECK) study (n=786). From the total number of 28 previously reported predictive factors, we were able to replicate 13 factors, while 15 factors were not significantly predictive in a meta-analysis of the three cohorts. The basic model including the demographic, questionnaire, and clinical examination variables (area under the receiver-operating characteristic curve (AUC)=0.67) or genetic markers (AUC=0.55) or urinary C-terminal cross-linked telopeptide of type II collagen (uCTX-II) levels (AUC=0.67) alone were poor predictors of HOA in all cohorts. Imaging factors showed the highest predictive value for the development of HOA (AUC=0.74). Addition of imaging variables to the basic model led to substantial improvement in the discriminative ability of the model (AUC=0.78) compared with uCTX-II (AUC=0.74) or genetic markers (AUC=0.68). Applying external validation, similar results were observed in the RS-II and the CHECK cohort. The developed prediction model included demographic, a limited number of questionnaire, and imaging risk factors seems promising for prediction of HOA.

Bone Turnover Status: Classification Model and Clinical Implications.

Aim: To develop a practical model for classification bone turnover status and evaluate its clinical usefulness.Methods: Our classification of bone turnover status is based on internationally recommended biomarkers of both bone formation (N-terminal propeptide of type1 procollagen, P1NP) and bone resorption (beta C-terminal cross-linked telopeptide of type I collagen, bCTX), using the cutoffs proposed as therapeutic targets. The relationships between turnover subtypes and clinical characteristic were assessed in1223 hospitalised orthogeriatric patients (846 women, 377 men; mean age 78.1±9.50 years): 451(36.9%) subjects with hip fracture (HF), 396(32.4%) with other non-vertebral (non-HF) fractures (HF) and 376 (30.7%) patients without fractures.Resalts: Six subtypes of bone turnover status were identified: 1 - normal turnover (P1NP>32 μg/L, bCTX≤0.250 μg/L and P1NP/bCTX>100.0[(median value]); 2- low bone formation (P1NP ≤32 μg/L), normal bone resorption (bCTX≤0.250 μg/L) and P1NP/bCTX>100.0 (subtype2A) or P1NP/bCTX<100.0 (subtype 2B); 3- low bone formation, high bone resorption (bCTX>0.250 μg/L) and P1NP/bCTX<100.0; 4- high bone turnover (both markers elevated ) and P1NP/bCTX>100.0 (subtype 4A) or P1NP/bCTX<100.0 (subtype 4B). Compared to subtypes 1 and 2A, subtype 2B was strongly associated with nonvertebral fractures (odds ratio [OR] 2.0), especially HF (OR 3.2), age>75 years and hyperparathyroidism. Hypoalbuminaemia and not using osteoporotic therapy were two independent indicators common for subtypes 3, 4A and 4B; these three subtypes were associated with in-hospital mortality. Subtype 3 was associated with fractures (OR 1.7, for HF OR 2.4), age>75 years, chronic heart failure (CHF), anaemia, and history of malignancy, and predicted post-operative myocardial injury, high inflammatory response and length of hospital stay (LOS) above10 days. Subtype 4A was associated with chronic kidney disease (CKD), anaemia, history of malignancy and walking aids use and predicted LOS>20 days, but was not discriminative for fractures. Subtype 4B was associated with fractures (OR 2.1, for HF OR 2.5), age>75 years, CKD and indicated risks of myocardial injury, high inflammatory response and LOS>10 days.Conclusions: We proposed a classification model of bone turnover status and demonstrated that in orthogeriatric patients altered subtypes are closely related to presence of nonvertebral fractures, comorbidities and poorer in-hospital outcomes. However, further research is needed to establish optimal cut points of various biomarkers and improve the classification model.

Dental Panoramic Radiographic Indices as a Predictor of Osteoporosis in Postmenopausal Saudi Women.

BackgroundMany oral presentations of osteoporosis-a bone metabolic disease-were recorded. Thus, we aimed to assess panoramic radiomorphometric indices with bone mineral density (BMD) values among Saudi postmenopausal women and its importance in the prediction of osteoporosis.MethodsA total of 431 Saudi women were enrolled in this study. Panoramic radiographs were obtained at the time of BMD measurement. Subjects were fatherly classified into; normal BMD, osteopenia, and osteoporosis groups. Serum follicle-stimulating hormone, luteinizing hormone (LH), estradiol (E2), 25-hydroxy-vitamin D (25[OH]D) and intact-parathyroid hormone were measured. Moreover, serum creatinine, calcium, and phosphate, together with serum osteocalcin (s-OC), procollagen type I N-terminal propeptide (s-PINP) and cross-linked C-terminal telopeptide of type 1 collagen (s-CTX) were measured. Receiver-operator curve (ROC) curve analysis for use of mandibular cortical width (MCW), panoramic mandibular index (PMI), and maxillary-mandibular ratio (M/M ratio) to differentiate women with osteoporosis or osteopenia from normal subjects was calculated. Cut off values of 4.6 at T score <−1 and 4.1 at T score ≤−2.5 were used.ResultsBody mass index is significantly low in the osteoporotic group. There is no significant difference in serum levels of LH, E2, calcium, phosphate, and 25(OH)D between the studied groups. Moreover, s-OC, C-terminal propeptide of procollagen type I, s-PINP, s-CTX, and urinary-CTX are significantly higher in osteoporosis than normal and osteopenia groups. ROC curve analysis revealed that MCW and PMI showed significant data while M/M ratio is non-significant.ConclusionsIt could be concluded that MCW as an important panoramic radiographic parameter can be used for prediction and diagnosis of osteoporosis in postmenopausal Saudi women with low BMD.

The Glucagon-Like Peptide-1 Receptor Agonist Exendin-4 Inhibits Lipopolysaccharide-Induced Osteoclast Formation and Bone Resorption via Inhibition of TNF-α Expression in Macrophages.

Glucagon-like peptide-1 (GLP-1) receptor agonists are an effective treatment approach for type 2 diabetes. Recently, anti-inflammatory effects of GLP-1 receptor agonists have also been reported. Lipopolysaccharide (LPS) induces inflammation and osteoclast formation. In this study, we investigated the effect of exendin-4, a widely used GLP-1 receptor agonist, in LPS-induced osteoclast formation and bone resorption. LPS with or without exendin-4 was administered on mouse calvariae by daily subcutaneous injection. The number of osteoclasts, the ratio of bone resorption pits, and the level of C-terminal cross-linked telopeptide of type I collagen (CTX) were significantly lower in LPS- and exendin-4-coadministered mice than in mice administered with LPS alone. RANKL and TNF-α mRNA expression levels were lower in the exendin-4- and LPS-coadministered group than in the LPS-administered group. Our in vitro results showed no direct effects of exendin-4 on RANKL-induced osteoclast formation, TNF-α-induced osteoclast formation, or LPS-induced RANKL expression in stromal cells. Conversely, TNF-α mRNA expression was inhibited in the exendin-4- and LPS-cotreated macrophages compared with cells treated with LPS alone. These results indicate that the GLP-1 receptor agonist exendin-4 may inhibit LPS-induced osteoclast formation and bone resorption by inhibiting LPS-induced TNF-α production in macrophages.

Changes of Circulating MicroRNAs in Response to Treatment With Teriparatide or Denosumab in Postmenopausal Osteoporosis.

Expression of microRNAs (miRs) related to bone metabolism in the serum may be affected by antiosteoporotic treatment. To investigate the effect of two antiosteoporotic agents with opposite effects on bone metabolism on miR expression profile in the serum. Observational, open label, nonrandomized clinical trial. The outpatient clinics for Metabolic Bone Diseases of 424 General Military Hospital, Thessaloniki, Greece. Postmenopausal women with low bone mass were treated with either teriparatide (TPTD; n = 30) or denosumab (n = 30) for 12 months. Changes in the serum expression of selected miRs linked to bone metabolism at 3 and 12 months of treatment. Secondary measurements: associations of measured miRs with changes in bone mineral density (BMD) at 12 months and the bone turnover markers (BTMs) C-terminal cross-linking telopeptide of type I collagen and procollagen type I N-terminal propeptide at 3 and 12 months. We found significantly decreased relative expression of miR-33-3p at 3 months (P = 0.03) and of miR-133a at 12 months (P = 0.042) of TPTD treatment. BMD values at 12 months of TPTD treatment were significantly and inversely correlated with miR-124-3p expression at 3 months (P = 0.008). Relative expression of miR-24-3p and miR-27a was correlated with changes in BTMs during TPTD treatment and of miR-21-5p, miR-23a-3p, miR-26a-5p, miR-27a, miR-222-5p, and miR-335-5p with changes in BTMs during denosumab treatment. Circulating miRs are differentially affected by treatment with TPTD and denosumab. TPTD affects the relative expression of miRs related to the expression of RUNX-2 (miR-33) and DKK-1 gene (miR-133).

The effects of icariin on wound healing of extraction sites with administration of zoledronic and dexamethasone: A rat model study.

This study was intended to investigate the effects of icariin on the healing of tooth extraction sites under the systemic administration of zoledronic and dexamethasone. Thirty female rats underwent bilateral ovariectomy and were randomly assigned to 5 groups: SS group received a weekly injection of saline, while ZD, ZD + LICA, ZD + MICA, and ZD + HICA groups received zoledronic with dexamethasone for 8 weeks. One week later, mandibular first molars were extracted in all groups. Then, 30, 60, and 120 mg/kg icariin were intragastrically given to ZD + LICA, ZD + MICA, and ZD + HICA groups daily for 10 weeks, while saline was given to SS group and ZD group. Blood samples and mandibles were harvested for examinations after 10 weeks. Significantly smaller wound area was noted in SS and ZD + HICA groups, but the incidence of bisphosphonate-related osteonecrosis of the jaws (BRONJ) was not significantly different. Groups injected with zoledronic and dexamethasone had higher C-terminal cross-linked telopeptide of type 1 collagen (CTX-1), tartrate-resistant acid phosphatase 5b (TRACP 5b), and the number of osteoclast cells, with less vascular endothelial growth factor (VEGF) and osteocalcin (OCN). In contrast, CTX-1, TRACP 5b, and the number of osteoclast cells declined after using icariin and promoted VEGF and OCN were noted and the effects were in a dosage-dependent manner. Concurrent use of zoledronic and dexamethasone inhibits the expression of VEGF, OCN, and wound healing and increases the number of osteoclast cells, serum CTX-1, and TRACP-5b after discontinuation for 10 weeks. Icariin weakens those effects in a dose-dependent manner but does not influence the onset of BRONJ.

Low bone turnover in premenopausal women with type 2 diabetes mellitus as an early process of diabetes-associated bone alterations: a cross-sectional study

BackgroundIndividuals with Diabetes Mellitus (DM) are at increased risk for fracture due to the decrease in bone strength and quality. Serum procollagen type I intact N-terminal (P1NP) and serum C-terminal cross-linking telopeptide of type I collagen (CTX) as markers of bone formation and resorption, respectively, have been reported to be decreased in T2DM. It remains unclear whether diabetes-associated alterations in the bone turnover of T2DM individuals are related to the longer duration of the disease or may occur earlier. Furthermore, previous studies on BTMs in T2DM individuals have mostly been done in postmenopausal women with T2DM, which might have masked the DM-induced alterations of bone turnover with concurrent estrogen deficiency. This study aims to assess the levels of serum P1NP and CTX as markers of bone turnover in premenopausal women with and without T2DM.MethodsThis cross-sectional study involves 41 premenopausal women with T2DM, and 40 premenopausal women without DM. Sampling was done consecutively. P1NP and CTX measurement was done using the electrochemi-luminescence immunoassay (ECLIA) method. Other data collected include levels of HbA1C, ALT, creatinine, eGFR and lipid profile.ResultsMedian (interquartile range) P1NP in T2DM is 29.9 ng/ml (24.7–41.8 ng/ml), while in non-DM is 37.3 ng/ml, (30.8–47.3 ng/ml; p = 0.007). Median (interquartile range) CTX in T2DM is 0.161 ng/ml (0.106–0.227 ng/ml), while in non-DM is 0.202 ng/ml (0.166–0.271 ng/ml; p = 0.0035). Levels of P1NP and CTX in the T2DM group did not correlate with the duration of disease, age, BMI or the levels of HbA1C.ConclusionsPremenopausal women with T2DM indeed have lower bone turnover when compared with non-DM controls. This significantly lower bone turnover process starts relatively early in the premenopausal age, independent of the duration of DM. Gaining understanding of the early pathophysiology of altered bone turnover may be key in developing preventive strategies for diabetoporosis.