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Objective: Biomarkers in osteoarthritis (OA) could serve as objective clinical indicators for various disease parameters, and act as surrogate endpoints in clinical trials for disease-modifying drugs. The aim of this systematic review was to produce a comprehensive list of candidate molecular biomarkers for knee OA after the 2013 ESCEO review and discern whether any have been studied in sufficient detail for use in clinical settings., Design: MEDLINE and Embase databases were searched between August 2013 and May 2018 using the keywords "knee osteoarthritis," "osteoarthritis," and "biomarker." Studies were screened by title, abstract, and full text. Human studies on knee OA that were published in the English language were included. Excluded were studies on genetic/imaging/cellular markers, studies on participants with secondary OA, and publications that were review/abstract-only. Study quality and bias were assessed. Statistically significant data regarding the relationship between a biomarker and a disease parameter were extracted., Results: A total of 80 studies were included in the final review and 89 statistically significant individual molecular biomarkers were identified. C-telopeptide of type II collagen (CTXII) was shown to predict progression of knee OA in urine and serum in multiple studies. Synovial fluid vascular endothelial growth factor concentration was reported by 2 studies to be predictive of knee OA progression., Conclusion: Despite the clear need for biomarkers of OA, the lack of coordination in current research has led to incompatible results. As such, there is yet to be a suitable biomarker to be used in a clinical setting.

Background: The pattern of change in maternal bone turnover throughout pregnancy is poorly characterized., Objectives: We investigated changes across pregnancy in a marker of maternal bone resorption, urinary C-terminal telopeptide of type I collagen (CTX), the influence of gestational vitamin D supplementation, and associations between CTX and maternal postnatal bone indices., Methods: MAVIDOS (the Maternal Vitamin D Osteoporosis Study) is a randomized, double-blind, placebo-controlled trial of 1000 IU cholecalciferol/d compared with placebo from 14 weeks of gestation to birth. Maternal second-void urinary α- and β-CTX were measured (ELISA) at 14 and 34 weeks of gestation; DXA was performed within 2 wk postpartum. The Mann-Whitney Rank Sum test, Spearman's rank correlation, and linear regression were used to compare median CTX values within and between groups from early to late pregnancy, and associations with maternal bone outcomes., Results: In total, 372 women had CTX and 25-hydroxyvitamin D [25(OH)D] measured in early and late pregnancy. CTX at 14 and 34 weeks of gestation were correlated in both placebo (r = 0.31) and cholecalciferol (r = 0.45) groups (P < 0.0001). Median CTX increased from 14 to 34 weeks of gestation in both groups (n = 372 total) [placebo (n = 188): from 223.6 to 449.7 μg/mmol creatinine; cholecalciferol (n = 184): from 222.3 to 419.3 μg/mmol creatinine; P = 0.03 for placebo compared with cholecalciferol difference in CTX at 34 weeks of gestation]. The conditional mean ± SD increase in CTX [z-score (SD)] from early to late pregnancy was greater in the placebo group (n = 188) than in the cholecalciferol group (n = 184) (placebo: 0.16 ± 0.92; cholecalciferol: -0.16 ± 1.06; P-difference < 0.01). Higher CTX at 34 weeks of gestation was associated, similarly in both groups, with lower maternal total hip and lumbar spine bone mineral content and bone mineral density (BMD) (e.g., lumbar spine BMD: β = -0.02 g · cm-2 · SD-1 increase in CTX; 95% CI: -0.027, -0.002 g · cm-2 · SD-1; P = 0.02, n = 283)., Conclusions: Maternal urinary CTX, a bone resorption marker, rises through pregnancy, although to a lesser degree with gestational cholecalciferol supplementation, and is inversely associated with maternal bone mass postpartum.This trial was registered at www.isrctn.com as ISRCTN 82927713 and eudract.ema.europa.eu as EudraCT 2007-001716-23., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Biochemical markers of bone turnover (BTMs), such as the bone alkaline phosphatase (bALP), procollagen type I N propeptide (PINP), serum cross-linked C-telopeptides of type I collagen (bCTx), and urinary cross-linked N-telopeptides of type I collagen (NTx), are used to manage therapy monitoring in osteoporotic patients. This systematic review analyzed the potential of these BMTs in predicting the clinical outcomes in terms of BMD, t-score, rate of fractures, and adverse events during the therapy setting in postmenopausal osteoporosis., Methods: All randomized clinical trials (RCTs) reporting data on biomarkers for postmenopausal osteoporosis were accessed. Only articles reporting quantitative data on the level of biomarkers at baseline and on the outcomes of interest at the last follow-up were eligible., Results: A total of 36,706 patients were retrieved. Greater values of bALP were associated with a greater rate of vertebral (P = 0.001) and non-vertebral fractures (P = 0.0001). Greater values of NTx at baseline were associated with a greater rate of adverse events at the last follow-up (P = 0.02). Greater values of CTx at baseline were associated with a greater rate of adverse events leading to discontinuation (P = 0.04), gastrointestinal adverse events (P = 0.0001), musculoskeletal adverse events (P = 0.04), and mortality (P = 0.04). Greater values of PINP at baseline were associated with greater rates of gastrointestinal adverse events (P = 0.02) at the last follow-up., Conclusion: The present analysis supports the adoption of BMTs during pharmacological therapy setting of patients suffering from osteoporosis., Level of Evidence: I, systematic review of RCTs.

Objective: To assess the effects of dextrose prolotherapy in patients with knee osteoarthritis on the levels of serum cartilage oligomeric proteinase and urinary C-terminal telopeptide of type II collagen, and on the Western Ontario McMaster Universities Index and numerical rating scale score for pain., Methods: A randomized controlled trial, in which participants were randomly allocated into 2 groups, receiving injections of either hyaluronic acid or dextrose prolotherapy. The hyaluronic acid group received 5 injections, 1 each on weeks 1, 2, 3, 4 and 5, and the dextrose prolotherapy group received 3 injections, 1 each on weeks 1, 5 and 9. Serum cartilage oligomeric proteinase, urinary C-terminal telopeptide of type II collagen, Western Ontario McMaster Universities Index score, and numerical rating scale score for pain were measured at baseline and 3 weeks after the last injection. Comparative analysis was conducted using Wilcoxon test within groups and analysis of covariance (ANCOVA) test between groups., Results: A total of 47 participants (21 allocated to hyaluronic acid, 26 allocated to dextrose prolotherapy) completed the protocol. Both interventions resulted in significant improvements in numerical rating scale scores for pain, total Western Ontario McMaster Universities Index scores, and its subscales score. However, the dextrose prolotherapy outperformed hyaluronic acid in numerical rating scale score for pain and level of urinary C-terminal telopeptide of type II collagen, with score changes differences of 0.93 (p = 0.042) and 0.34 (p = 0.048), respectively. No significant changes in level of serum cartilage oligomeric proteinase were found in either group., Conclusion: Dextrose prolotherapy is an alternative injection therapy for knee osteoarthritis, which was found to be associated with a significant reduction in urinary C-terminal telopeptide of type II collagen compared with hyaluronic acid injection. Neither injection method resulted in reduced serum cartilage oligomeric proteinase.

Objective: To examine the associations between bone turnover markers (BTMs) and bone mineral density (BMD) in older adults aged 60-85 years., Methods: A total of 1124 men (mean age, 69.1 years) and 1203 women (mean age, 70.7 years) from the National Health and Nutrition Examination Survey 1999-2002 were included in this cross-sectional analysis. Independent variables were serum bone-specific alkaline phosphatase (sBAP) and urinary N-telopeptide (uNTx), which are biomarkers of bone formation and resorption, respectively. Outcome variable was lumbar BMD. The associations of sBAP and uNTx levels with lumbar BMD was examined using multivariable linear regression models., Results: sBAP was negatively associated with lumbar BMD in each multivariable linear regression model, and this negative association was stable in both men and women men (men: β = -0.0028, 95% CI: -0.0046 to -0.0010; women: β = -0.0039, 95% CI: -0.0054 to -0.0023). On the other hand, uNTx was negatively associated with lumbar BMD after adjustment of relevant covariables (β = -0.0328, 95% CI: -0.0523 to -0.0133). However, in the subgroup analysis stratified by gender, this negative association remained only in older women (β = -0.0491, 95% CI: -0.0751 to -0.0231)., Conclusion: Our study suggested that elevated sBAP and uNTX levels correlated with decreased lumbar BMD, especially in older women. This finding indicated that maintaining BTMs at low levels may be beneficial to bone health for older adults.

Objective: Considering the osteoarthritis (OA) model that integrates the biological, mechanical, and structural components of the disease, the present study aimed to investigate the association between urinary C-Telopeptide fragments of type II collagen (uCTX-II), knee joint moments, pain, and physical function in individuals with medial knee OA., Methods: Twenty-five subjects radiographically diagnosed with knee OA were recruited. Participants were evaluated through three-dimensional gait analysis, uCTX-II level, the WOMAC pain and physical function scores, and the 40m walk test. The association between these variables was investigated using Pearson's product-moment correlation, followed by a hierarchical linear regression, controlled by OA severity and body mass index (BMI)., Results: No relationship was found between uCTX-II level and knee moments. A significant correlation between uCTX-II level and pain, physical function, and the 40m walk test was found. The hierarchical linear regression controlling for OA severity and BMI showed that uCTX-II level explained 9% of the WOMAC pain score, 27% of the WOMAC physical function score, and 7% of the 40m walk test., Conclusion: Greater uCTX-II level is associated with higher pain and reduced physical function and 40m walk test performance in individuals with medial knee OA., (Copyright © 2020 Associação Brasileira de Pesquisa e Pós-Graduação em Fisioterapia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background & Aims: Nutrition is one of the most important environmental factors affecting the formation of osteopenia. The purpose of this study was to investigate the effects of dietary changes on bone formation and bone resorption markers of postmenopausal women with vertebral osteopenia., Methods: In this study, 108 women with postmenopausal vertebral osteopenia were included. Patients were observed for a month to identify their regular nutritional status. Before intervention, blood and urine samples were taken from all patients. Then, 2-day food consumption records were taken and the patients were divided into 4 groups. Different types of diets (opposite of their regular diets) were prepared for these groups (1: control, 2: reduced-carbohydrate, 3: reduced-protein, 4: reduced-sodium) and followed for 3 months. At the end of follow-ups, blood and urine samples were taken again and changes in osteocalcin (OC) and N-terminal telopeptide (NTX) levels were examined., Results: According to biochemical analysis, there was a significant decrease (p < 0,001) in OC levels in reduced protein group and an increase (p > 0,05) in reduced carbohydrate group. When NTX levels were assessed, a significant decrease (p < 0.001) in the reduced carbohydrate group and a significant increase in the reduced protein group (p < 0.05) were found., Conclusion: Our findings show that reduced carbohydrate diet protected whereas, reduced protein diet negatively affected bone health. Osteopenic individuals were thought to be able to improve bone health and their quality of life by early dietary intervention., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Breast cancer patients with bone metastases are usually managed with bone modifying agents, such as zoledronic acid and denosumab, and some bone turnover markers (BTMs) have been recognized as prognostic indicators in such patients. Although several studies have demonstrated the validity of BTMs as prognostic markers in patients treated with zoledronic acid, few studies have reported the utility of BTMs with denosumab treatment. In this study, we evaluated whether urinary N-telopeptide of type I collagen (u-NTX) can be a prognostic indicator in patients treated with denosumab., Methods: Thirty-six breast cancer patients newly diagnosed with bone metastases were evaluated retrospectively. Patients were treated with denosumab and anti-cancer drugs. u-NTX levels were measured 1 month before and after administration of denosumab, and the ratio of u-NTX levels before and after denosumab (change ratio) was assessed for its association with prognosis., Results: Levels of u-NTX decreased after denosumab administration in all patients except for one. The median value of the u-NTX change ratio was 0.766. Based on the change ratio, patients were divided into either a "high group" (n = 18) or a "low group" (n = 18). The low group showed significantly shorter overall survival (OS) compared with the high group (low group 15.0 months; high group 54.0 months; P = 0.012). Multivariate analysis indicated that the "low group" was an independent prognostic factor for OS (P = 0.028)., Conclusion: We demonstrated that the u-NTX change ratio in denosumab-treated breast cancer patients with bone metastases can be a prognostic marker.

Introduction: This study investigated the systemic response of serum bone alkaline phosphatase (SBAP) and urinary N-telopeptide (UNTX) to tobacco exposure and environmental tobacco smoke (ETS) and the possible effect modification (and variability) of this response by racial/ethnic origin. Methods: Data (n   =   5411) were obtained from the National Health and Nutrition Examination Survey, with data analysis done on adults aged ≥ 20   years. Outcome variables were SBAP and UNTX. Independent variable was tobacco exposure measured using serum cotinine levels and adjusted for covariates. Generalized linear models were used to explore associations. Results: A percentage increase in log transformed serum cotinine was associated with a 0.005 percentage increase in log transformed SBAP (CI: 0.002, 0.008) and 0.02 percentage increase in log transformed UNTX (CI: -0.01, 0.04) with interaction between cotinine and race/ethnicity ( p   =   0.01). Stratifying by race/ethnicity, tobacco exposure was associated with significant decreases in UNTX among non-Hispanic Whites - 0.008(-0.014, -0.002) and Mexican Americans -0.014 (-0.025, -0.002) only. Categories of serum cotinine were associated with a monotonic increase in SBAP ( p for trend <0.001) and monotonic non-linear decrease in UNTX ( p for trend   >   0.05). Conclusions: Tobacco and environmental tobacco exposure are associated with SBAP and increased bone formation. The response of UNTX to these exposures is modified by race/ethnicity with non-Hispanic Whites and Mexican-Americans less sensitive to the resorptive effects of tobacco exposure on bone.

Background: Cigarette smoking is a risk factor of osteoporosis and bone fracture. Tobacco smoke contains several polycyclic aromatic hydrocarbons. Thus, we hypothesized that environmental polycyclic aromatic hydrocarbon exposure is associated with bone loss and fracture risk. The present study examined the association between polycyclic aromatic hydrocarbon exposure and bone turnover in the general adult population., Methods: A total of 1408 eligible participants from the National Health and Nutrition Examination Survey (NHANES 2001-2006) were included in this cross-sectional analysis. The levels of urinary N-telopeptide and serum bone-specific alkaline phosphatase, which are biomarkers of bone resorption and formation, respectively, were assessed. Meanwhile, polycyclic aromatic hydrocarbon exposure was evaluated using the concentrations of urinary polycyclic aromatic hydrocarbon metabolites. The association between polycyclic aromatic hydrocarbon exposures and N-telopeptide, and bone-specific alkaline phosphatase levels was assessed using a multivariate linear regression model., Results: All polycyclic aromatic hydrocarbon metabolites except 3-phenanthrene were significantly associated with increased N-telopeptide levels (P < 0.05) after adjustment of relevant covariables. However, no significant relationship was observed between polycyclic aromatic hydrocarbon metabolites and bone-specific alkaline phosphatase levels. This relationship remained significant after the participants were assessed according to sex (P < 0.05). Additionally, all polycyclic aromatic hydrocarbon metabolites showed a positive association with N-telopeptide levels in participants aged <60 years (P < 0.05)., Conclusion: Polycyclic aromatic hydrocarbon exposure is associated with increased bone resorption among the general adult population in the United States. Further studies must assess the potential mechanisms associated with the adverse effects of polycyclic aromatic hydrocarbon exposure on bone loss.

People with sickle cell disease often report severe bone pain with repeated bouts of vaso-occlusive crises, but the extent of skeletal injury incurred during these painful episodes remain unclear. We sought to quantify bone degradation by comparing urinary concentrations of carboxyterminal cross-linked telopeptide of type I collagen (CTX-1), a well-described marker of bone resorption, in a prospective cohort of 52 adults with sickle cell disease enrolled in the Sickle Cell Pain Markers Study. We also questioned if changes in urinary CTX-1 concentrations correlated with changes in hemolysis and inflammatory markers measured both during and after resolution of a painful vaso-occlusive episode. Thirty-one of the 52 adults enrolled in the study had paired urine samples for CTX-1 analysis. Urinary CTX-1, corrected for urine creatinine, significantly decreased from a mean of 3.45 μg/mmol during vaso-occlusive crises to 2.62 μg/mmol at recovery (p = 0.01). Thus, increased bone loss appears to correlate with acute vaso-occlusive crises in sickle cell disease. Our finding that urinary CTX-1 can be used to probe bone degradation in sickle cell disease provides an important new tool for diagnosing and monitoring response to therapy for people with sickle cell-related bone loss., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We report a case of a 47-year-old woman with hypercalcemia 6 months after discontinuation of denosumab. She underwent right mastectomy for breast cancer and had received aromatase inhibitor and denosumab therapy for 5 years. Thirst, appetite loss, and bilateral ankle pain began few months after cessation of denosumab. She was admitted to the hospital for hypercalcemia and hyperthyroidism 6 months after the last dose of denosumab. Laboratory investigations revealed hypercalcemia, normophosphatemia, normal renal function, and elevated levels of fibroblast growth factor 23 (FGF-23). Serum tartrate-resistant acid phosphatase 5b and urine N-terminal cross-linked telopeptide of type I collagen were both elevated, and bone scintigraphy revealed increase of whole bone uptake. Radiological examinations showed no recurrence of breast cancer or tumors that secrete intact PTH or FGF-23. Hypercalcemia, which lasted for 1 month, was refractory to discontinuation of the aromatase inhibitor, normalization of thyroid hormone levels, saline hydration, and calcitonin administration, but was effectively treated with zoledronic acid. Abnormal uptake on bone scintigraphy and ankle pain both resolved a few months after treatment, and hypercalcemia has not recurred in the ensuing 2 years. In conclusion, we found elevated levels of circulating FGF-23 with hypercalcemia following the discontinuation of denosumab. FGF-23 might be a surrogate marker for massive bone resorption triggered by discontinuation of long-term denosumab treatment.

Objective: To compare the progression of biochemical biomarkers of osteoarthritis (OA), knee pain, and function between nonobese patients (NON), obese patients without depression (OBESE), and obese patients with comorbid depression (O + D)., Design: Utilizing the FNIH OA Biomarkers Consortium dataset, we categorized knee OA patients into NON, OBESE, and O + D groups based on body mass index and Center for Epidemiological Studies-Depression (CES-D) scores. Subjective symptoms (Knee injury and Osteoarthritis Outcome Score Quality of Life subscale (KOOS QOL), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain and Physical Function scores, and the Short Form-12 (SF-12) Physical Component Score [PCS]) and objective measures of cartilage degradation and bone remodeling (urinary CTXII and CTXIα) were compared among groups at baseline and 2-year follow-up., Results: Of the 600 patients, 282 (47%) were NON, 285 (47.5%) OBESE, and 33 (5.5%) O + D. The O + D group had significantly worse pain and function both at baseline and 2-year follow-up ( P < 0.001 for all comparisons) as evidenced by self-reported measures on KOOS QOL, WOMAC Pain, WOMAC Physical Function, and SF-12 PCS. The O + D group also demonstrated significant increases in CTXII ( P = 0.01) and CTXIα ( P = 0.005), whereas the NON and OBESE groups did not., Conclusions: The combination of inferior knee pain, physical function, and significantly greater increases in biomarkers of cartilage degradation and bony remodelling suggest a more rapid progression for obese OA patients with comorbid depression. The link between systemic disease, inflammatory burden, and progressive cartilage degradation is in line with increasing concerns about a degenerative synovial environment in early osteoarthritic knees that progress to treatment failure with biologic restoration procedures.

We assessed whether a bone resorption marker, measured early in the menopause transition (MT), is associated with change in femoral neck size and strength during the MT. Higher levels of bone resorption were associated with slower increases in femoral neck size and faster decreases in femoral neck strength., Purpose: Composite indices of the femoral neck's ability to withstand compressive (compression strength index, CSI) and impact (impact strength index, ISI) forces integrate DXA-derived femoral neck width (FNW), bone mineral density (BMD), and body size. During the menopause transition (MT), FNW increases, and CSI and ISI decrease. This proof-of-concept study assessed whether a bone resorption marker, measured early in the MT, is associated with rates of change in FNW, CSI and ISI during the MT., Methods: We used previously collected bone resorption marker (urine collagen type I N-telopeptide [U-NTX]) and femoral neck strength data from 696 participants from the Study of Women's Health Across the Nation (SWAN), a longitudinal study of the MT in a multi-ethnic cohort of community-dwelling women., Results: Adjusted for MT stage (pre- vs. early perimenopause), age, body mass index (BMI), bone resorption marker collection time, and study site in multivariable linear regression, bone resorption in pre- and early perimenopause was not associated with transmenopausal decline rate in femoral neck BMD. However, each standard deviation (SD) increase in bone resorption level was associated with 0.2% per year slower increase in FNW (p = 0.03), and 0.3% per year faster declines in CSI (p = 0.02) and ISI (p = 0.01). When restricted to women in early perimenopause, the associations of bone resorption with change in FNW, CSI, and ISI were similar to those in the full sample., Conclusions: Measuring a bone resorption marker in pre- and early perimenopause may identify women who will experience the greatest loss in bone strength during the MT.

Background: Osteoporosis is a serious disease that causes bone fragility fractures and increases mortality. Bisphosphonates are the first-line drugs for osteoporosis. However, the gains in bone mineral density by use of bisphosphonates alone are limited., Case Presentation: We describe the clinical outcome of a Japanese woman with osteoporosis treated with bisphosphonates after multiple spinal fractures. After 3 years of treatment with the bisphosphonate alendronate, her lumbar bone mineral density and bilateral hip bone mineral density markedly increased by 61.9% and 32.5%, respectively., Conclusion: We considered that our patient's multiple fractures had caused a decrease in bone mineral density, which naturally improved with fracture healing to enhance the increase in bone mineral density with bisphosphonate treatment.

Background: Chronic kidney disease (CKD) is common in patients after heart transplantation (HTx). We assessed whether in HTx recipients the proteomic urinary classifier CKD273 or sequenced urinary peptides revealing the parental proteins correlated with the estimated glomerular filtration rate (eGFR)., Methods: In 368 HTx patients, we measured the urinary peptidome and analysed CKD273 and 48 urinary peptides with a detectable signal in >95% of participants. After 9.1 months (median), eGFR and the urinary biomarkers were reassessed., Results: In multivariable Bonferroni-corrected analyses of the baseline data, a 1-SD increase in CKD273 was associated with a 11.4 [95% confidence interval (CI) 7.25-15.5] mL/min/1.73 m2 lower eGFR and an odds ratio of 2.63 (1.56-4.46) for having eGFR <60 mL/min/1.73 m2. While relating eGFR category at follow-up to baseline urinary biomarkers, CKD273 had higher (P = 0.007) area under the curve (0.75; 95% CI 0.70-0.80) than 24-h proteinuria (0.64; 95% CI 0.58-0.69), but additional adjustment for baseline eGFR removed significance of both biomarkers. In partial least squares analysis, the strongest correlates of the multivariable-adjusted baseline eGFR were fragments of collagen I (positive) and the mucin-1 subunit α (inverse). Associations between the changes in eGFR and the urinary markers were inverse for CKD273 and mucin-1 and positive for urinary collagen I., Conclusions: With the exception of baseline eGFR, CKD273 was more closer associated with imminent renal dysfunction than 24-h proteinuria. Fragments of collagen I and mucin-1-respectively, positively and inversely associated with eGFR and change in eGFR-are single-peptide markers associated with renal dysfunction., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA.)

Endurance exercise can cause a decrease in serum ionized calcium (iCa) and increases in parathyroid hormone (PTH) and c-terminal telopeptide of type I collagen (CTX), which may be due to Ca loss in sweat., Purpose: This study aimed to determine whether exercise in a warm environment exaggerates the decrease in iCa and increases in PTH and CTX compared with a cool environment in older adults., Methods: Twelve women and men 61-78 yr old performed two identical 60-min treadmill bouts at ~75% of maximal heart rate under warm and cool conditions. Serum iCa, PTH, and CTX were measured every 15 min starting 15 min before and continuing for 60 min after exercise. Sweat Ca loss was estimated from sweat volume and sweat Ca concentration., Results: Sweat volume was low and variable; there were no differences in sweat volume or Ca concentration between conditions. iCa decreased after 15 min of exercise, and the change was similar in both conditions. Increases in PTH (warm: 16.4, 95% confidence interval [CI] = 6.2, 26.5 pg·mL; cool: 17.3, 95% CI = 8.1, 26.4 pg·mL) and CTX (warm: 0.08, 95% CI = 0.05, 0.11 ng·mL; cool: 0.08, 95% CI = 0.01, 0.16 ng·mL) from before to immediately after exercise were statistically significant and similar between conditions. Adjusting for plasma volume shifts did not change the results., Conclusion: The increases in PTH and CTX, despite the low sweat volume, suggest that dermal Ca loss is not a major factor in the decrease in iCa and increases in PTH and CTX observed during exercise in older adults.

Purpose : The correlation between serum levels of homocysteine and bone mineral density remains controversial. The aim of this study was to identify the potential factors associated with the levels of serum total homocysteine (S-Hcy) and urinary N-terminal telopeptide of type I collagen (U-NTX) in female osteoporotic patients. Materials and Methods : This cross-sectional study included 163 female osteoporotic patients, aged between 48 and 91 years, who had never been treated with anti-osteoporosis therapy. Background data including spine and hip bone mineral density, ongoing therapy for the metabolic disease, aortic calcification score as evaluated by lateral lumbar X-ray film, and recent fragility fracture history were obtained. S-Hcy, U-NTX levels, and creatinine clearance were measured. Results : Multiple linear regression analysis revealed a significant correlation between S-Hcy levels and aortic calcification score ( p = 0.022), creatinine clearance ( p = 0.004), and recent fracture history (within 1 year after fracture) ( p = 0.028); conversely, U-NTX levels correlated significantly with total hip bone mineral density ( p < 0.0001) and recent fracture history (p = 0.0007). Conclusions : S-Hcy levels had no correlation with bone mineral density, but were associated with the degree of aortic calcification, renal function, and fracture events. These confounding factors should be taken into consideration when the relationship between S-Hcy and bone mineral density is discussed.

Study Design: Prospective cohort study., Objective: To examine preoperative urinary cross-linked n-telopeptide (uNTx) and assess for association with fusion rates in patients undergoing single and multi-level anterior cervical decompression and fusion (ACDF)., Summary of Background Data: Although high rates of fusion have been reported for ACDF, the risk of pseudarthrosis remains substantial. An established marker of bone turnover, uNTx may prove useful as a predictor of fusion., Methods: Patients undergoing primary ACDF with allograft/plating technique from 2015 to 2017 by a single surgeon were consecutively enrolled and preoperative uNTx was collected. Patients undergoing revision, with creatinine >1.2, and with improperly-collected uNTx were excluded. Demographics, laboratory values, and fusion status were assessed at 6 months, 1 year, and 2 years postoperatively., Results: Of the 97 patients enrolled, 69 met inclusion criteria. Of included cases, 41%, 33%, 18%, and 8% underwent 1-, 2-, 3-, and 4-level ACDF, respectively. Overall, fusion rates were 37.3%, 70.9%, and 95.3% at 6 months, 1 year, and 2 years, respectively. uNTx was higher in the fusion group (31.1 vs. 22.2, P = 0.001) at 6 months and 1 year (30.0 vs. 21.0, P = 0.006), with no difference at 2 years. No differences were identified in the proportion of smokers, immunomodulatory agents, corpectomies, or fusion levels between groups. Multivariate regression analysis demonstrated that uNTx is an independent predictor of fusion (odds ratio, OR, 1.124, P = 0.003). Both groups experienced improvements in NDI and VAS neck pain at 6 months with no significant differences noted between groups. Of 16 patients with pseudarthrosis at 1 year, 2 underwent posterior cervical fusion for symptoms., Conclusion: Preoperative uNTx was greater in patients with successful ACDF fusion compared with patients with pseudarthrosis at 6 months and 1 year. A negative correlation was found between preoperative uNTx and motion on dynamic imaging. These results suggest that uNTx could serve to identify patients at risk for pseudarthrosis after ACDF., Level of Evidence: 3.

Calcium and nutrients are transferred from mothers to fetuses or infants during pregnancy or lactation, respectively, promoting metabolic changes in the mother, many uncharacterized. To evaluate these changes, we undertook two parallel studies. In one we analyzed fourteen clinical cases of vertebral fragility fractures, at or before three months after partum, in mothers who breastfed their infants. In the other, we enrolled 79 additional pregnant subjects, some who chose to breastfeed and others who did not, and analyzed changes in bone metabolic status starting between 34 and 36 weeks of gestation and ending one month after partum. In the larger group, bone-resorbing and bone-forming parameters such as serum TRACP5b and osteocalcin, respectively, significantly increased after partum. Among parameters that changed after partum, serum PTH and the bone-resorbing markers serum TRACP5b and urine NTX were significantly higher in mothers who only breastfed infants compared to mothers who fed infants formula or a mix of both. However, bone-forming parameters were comparable between breastfeeding and non-breast-feeding groups after partum, suggesting that elevated bone-resorption occurs only in the breastfeeding group. Radiographic analysis after partum demonstrated that no subject among the 79 analyzed showed vertebral fractures, even those who breastfed exclusively. Among fracture cases analyzed, subjects exhibited significantly lower bone mineral density than did non-fracture cases in breastfeeding-only subjects. We conclude that bone metabolic status significantly changes over the period between pregnancy and post-partum lactation, and that low bone mineral density seen in a small subset of breastfeeding-only cases likely causes post-partum vertebral fragility fractures.

This study compares serum and urine concentrations of relevant protein biomarkers among adult dogs with or without radiographic canine hip dysplasia (CHD). Adult (≥2 years of age), client-owned dogs (n = 74) radiographically categorized as having at least "good" hips (n = 49) or having "mild," "moderate," or "severe" hip dysplasia (n = 25) by the Orthopedic Foundation for Animals (OFA). Urine and serum samples were obtained from each dog at a single time-point and processed and analyzed for relevant protein biomarkers. Urinary concentrations of CTX-II (p < 0.001) and TIMP-1 (p = 0.002) were significantly lower in dogs with CHD compared to dogs with no CHD. ROC curve analyses were successful in establishing a panel of four biomarkers (urinary CTX-I and II, serum MMP-9, and serum PIICP) with high discriminatory capability for the presence or absence of hip dysplasia in adult dogs (AUC = 0.89). Urine and serum biomarkers can distinguish adult dogs with radiographic CHD from those with no CHD with a sensitivity of 0.95 and specificity of 0.77 using ROC analysis with AUC 0.89. Clinical Significance: This finding suggests that this simple, minimally invasive diagnostic technique has potential for discriminating dysplastic dogs from dogs with normal hips, with possible translational application to humans based on similar etiopathogenesis. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 9999:1-5, 2019., (© 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Background: Nausea and vomiting occur 50-90% during the first trimester of pregnancy. However, patients with hyperemesis gravidarum (HG) may be hospitalized at an incidence rate of 0.8-2% before the 20th week of gestational age. The symptoms generally start during the 5-6th gestational weeks, reaching the highest degree during the 9th week, and decline after the 16-20th weeks of gestation. Clinical findings are proportional to the severity of the disease and severe HG is characterized with dehydration, electrolyte imbalance, and nutritional deficiency as a result of vomiting., Methods: The study population consisted of two groups of pregnant volunteers at 5-12 weeks of gestation: a severe HG group and a control group. The HG severity was scored using the Pregnancy-Unique Quantification of Emesis (and nausea) (PUQE).The serum levels of the maternal Ca, parathyroid hormone (PTH), Na, K, blood urea nitrogen(BUN), creatinine, vitamin D(25OHD3), and the maternal urine NTx levels were compared between the groups., Results: In total, 40 volunteers were enrolled in this study: 20 healthy pregnant volunteers and 20 with severe HG. There were no statistically significant differences between the maternal characteristics. The first trimester weight loss of ≥5 kg was significantly higher in the severe HG group (p < 0.001), while the control group had a significantly higher sunlight exposure ratio than the severe HG group (p = 0.021). The urine NTx levels were significantly higher in the severe HG group (39.22 ± 11.68NTx/Cre) than in the control group(32.89 ± 8.33NTx/Cre) (p = 0.028).The serum Ca, PTH, Na, K, BUN, and creatinine levels were similar between the groups (p = 0.738, p = 0.886, p = 0.841, p = 0.957, p = 0.892, and p = 0.824, respectively). In the severe HG group, the serum 25OHD 3 levels were significantly lower than in the control group (p < 0.001)., Conclusions: The data from this study indicated that severe HG is associated with increased urine NTx levels. However, large-scale studies are required to understand the clinical significance of this finding, as well as the long-term consequences of elevated urine NTx levels and the underlying mechanisms., Trial Registration: NCT02862496 Date of registration: 21/07/2016.

Objectives: The aim of this study was to identify a marker for temporomandibular joint (TMJ) osteoarthritis (OA) diagnosis by comparing the concentrations of urinary pyridinoline (PYD), deoxypyridinoline (DPD), and C-terminal telopeptides type I collagen (CTX-I), and CTX-II of TMJ OA patients with those of a non-symptomatic group., Methods: PYD, DPD, CTX-I, and CTX-II concentrations in the urine of 36 non-symptomatic subjects and 31 TMJ OA subjects were analyzed., Results: The differences for only PYD and DPD were significant. In ROC analysis, PYD and DPD showed higher sensitivity and specificity than CTX-I and CTX-II. PYD and DPD concentrations in urine were significantly increased in TMJ OA patients and can therefore be used as a biomarker in the supplementary clinical diagnosis of TMJ OA., Discussion: The findings suggest that measurement of their concentration can be a supplementary method for clinical diagnosis of TMJ OA.

Objective: To examine changes in the bone and cardiovascular parameters and tolerability in middle-aged Japanese women taking equol supplement for a year., Design: This was a prospective observational study., Subjects and Setting: Participants were 74 women receiving outpatient care at Hamasite Medical Clinic, Minato-ku, Tokyo, from 2013 to 2015., Interventions: Participants received per oral equol-containing supplement, 10 mg/day., Outcome Measures: The primary outcome measures were percent changes in bone and cardiovascular parameters after 1 year supplementation with equol. The secondary measures included factors affecting the parameter changes and adverse effects associated with equol use for a year., Results: Reduction in arterial stiffness was observed after 12 months of equol supplement (1402.3 cm/s vs.1367.3 cm/s, p < 0.001). Significant reductions in respective parameters were observed in women with moderate and high risk for arteriosclerosis (median [95% confidence interval]: -3.2% [-5.79 to -0.74]; -12.65% [-18.52 to -4.28]; respectively); hypertriglyceridemia -45.53% [-70.24 to -5.58]; bone resorption risk (-15.15% [-23.71 to 1.56]; and bone fracture risk -26.68% [-76.43 to -5.99]. All 15 women with high baseline parathyroid hormone levels had achieved a median of 50% [-54.11 to -31.69] reduction from their baseline values. These associations were further confirmed in the results of multiple linear regression analysis. There were no reported adverse events or abnormal findings in the blood chemistry, Pap smear, mammography, and transvaginal ultrasound during periodic follow-ups., Conclusion: One year equol supplement was tolerable and induced improvement of certain bone and cardiovascular parameters, especially in higher risk groups. Further controlled studies are needed to explore long-term equol use for wellbeing of middle-aged women.

The purpose of this study was to concomitantly determine oxidative DNAdamage and bone resorption following a rapid body mass reduction in association with energy restriction and exercise training, considering 17β-estradiol level, in female collegiate judokas. Eighteen nationally ranked university female judokas were enrolled as participants in this study. All participants continuously managed to reduce their body mass 8 days just before a competition. To detect cumulative effects of oxidative DNA damage and bone resorption, urinary samples were collected in the morning on three different days (Day 1= the beginning of body mass reduction; Day 4=mid-term of body mass reduction; Day 7=the day before the competition) for the later analysis of 8-hydroxy-2’- deoxyguanosine (8-OHdG) as well as cross-linked N-terminal telopeptides of Type I collagen (NTx). Urinary 8-OHdG and NTx levels were determined with high performance liquid chromatography and enzyme-linked immunosorbent assay, respectively. No significant alterations were observed in urinary 8-OHdG or NTx levels over a rapid body mass reduction period. The findings of the present study indicate that female judokas appear to have relatively less oxidative DNA damage determined by quantification of 8-OHdG and bone resorption over a rapid body mass reduction period, potentially due to the enhanced endogenous defense responses (training adaptation). These data can provide athletes and coaches with valuable information in considering an optimal body mass management program to avoid detrimental physiological and biological conditions.

Intra-articular corticosteroid injections (IACI) are commonly used interventions for pain relief in patients with knee osteoarthritis (OA). Biomarkers may be helpful in further elucidating how IACI exert their effect. The aim of this study is to look at the response of biomarkers of cartilage and bone metabolism after IACI in knee OA. Eighty subjects with symptomatic knee OA [45% male, mean age (SD) 64 (11) years] underwent routine knee joint injection with 40 mg triamcinolone acetonide and 4 ml 1% lignocaine. Knee pain (as pain subscale of WOMAC VAS) and biomarkers [C-telopeptides of type-II collagen (uCTX-II), and N-telopeptides of type-I collagen in urine; cartilage oligomeric matrix protein (COMP), hyaluronic acid, N-terminal propeptide of type-IIA collagen, and human cartilage glycoprotein-39 (YKL-40) in serum] were measured at baseline and 3 weeks after IACI. Radiographic severity of disease was evaluated using knee radiographs. Median uCTX-II, a cartilage degradation marker, was lower at 3 weeks post IACI compared with baseline: 306.3 and 349.9 ng/mmol, respectively (p < 0.01), which remained significant after Bonferroni correction. Apart from a weak trend of lower sCOMP post IACI (p = 0.089), other biomarkers showed no change after IACI. Both baseline uCTX-II values and the change in uCTX-II from baseline to 3 weeks post injection correlated with radiographic severity of joint space narrowing, but not osteophyte grade. No association between uCTX-II and pain was observed. This observational study suggests that IACI in knee OA may reduce cartilage degradation in the short term.

The aim of this study was to test the clinical efficacy of TissueGene-C (TG-C), a cell and gene therapeutic for osteoarthritis consisting of non-transformed and transduced chondrocytes (3:1) retrovirally transduced to overexpress transforming growth factor-β1. A total of 163 Kellgren-Lawrence grade 3 patients with knee osteoarthritis were randomly assigned to receive intra-articular TG-C or placebo. Primary efficacy measures included criteria for subjective assessment by International Knee Documentation Committee (IKDC) and pain severity by Visual Analog Scale (VAS) for 52 weeks. Secondary efficacy measures included IKDC and VAS at 26 and 39 weeks; pain, stiffness, and physical function by the Western Ontario and McMaster Universities Arthritis Index (WOMAC); and pain, symptoms, daily activities, function in sports and recreation, and quality of life by the Knee Injury and Osteoarthritis Outcome Score (KOOS), X-ray, magnetic resonance imaging, and soluble urine and blood biomarkers. TG-C was associated with statistically significant improvement over placebo in the total IKDC score and individual categories, and in the VAS score at 26, 39, and 52 weeks. WOMAC and KOOS scores also improved with TG-C over placebo. Patients treated with TG-C showed trends directed toward thicker cartilage and slower growing rates of subchondral bone surface area in the medial tibia, lateral tibia, lateral patella, and lateral patella femoral regions, although these were not statistically significant (p > 0.05). Serum C-terminal telopeptide of type I collagen (CTX-I) and urine CTX-II levels were lower over 1 year in TG-C than placebo-treated patients, with CTX-I level reaching statistical significance. These tendencies supported TG-C as holding great potential as a disease-modifying osteoarthritis drug. The most frequent adverse events in the TG-C group were peripheral edema (9%), arthralgia (8%), joint swelling (6%), and injection site pain (5%). TG-C was associated with statistically significant improvements in function and pain in patients with knee osteoarthritis. The unexpected adverse events were not observed.

This study investigated whether or not vitamin D and calcium supplementation affected bone metabolism and bone mineral density (BMD) over a period of four years of denosumab therapy in patients with primary osteoporosis. Patients were divided into a denosumab monotherapy group (22 cases) or a denosumab plus vitamin D and calcium supplementation group (combination group, 21 cases). We measured serum bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase (TRACP)-5b, urinary N-terminal telopeptide of type-I collagen (NTX), and BMD of the lumbar 1-4 vertebrae (L-BMD) and bilateral hips (H-BMD) at baseline and at 12, 24, 36, and 48 months of treatment. There were no significant differences in patient background. Serum BAP, TRACP-5b, and urinary NTX were significantly and comparably inhibited in both groups from 12 to 48 months versus baseline values. L-BMD was significantly increased at every time point in both groups, while H-BMD was significantly increased at every time point in the combination group only. There were significant differences between the groups for L-BMD at 24, 36, and 48 months ( P < 0.05) and for H-BMD at 12 months ( P < 0.05). Compared with denosumab monotherapy, combination therapy of denosumab plus vitamin D and calcium significantly increased H-BMD at 12 months and L-BMD from 24 to 48 months. These findings indicate that continuous vitamin D and calcium supplementation is important, especially for 12 months to improve H-BMD and from 24 to 48 months to improve L-BMD., Competing Interests: The authors declare no conflict of interest.

Background: Recently, methods for mimicking endogenous cortisol rhythms hereby potentially reducing the risk of systemic adverse effects of exogenous corticosteroids have been patented. Methods for sensitive detection of adverse effects on bone turnover of various doses, administration routes and regimens of exogenous corticosteroids have been patented. Urine cross-linked Ntelopeptides of Type I collagen (Ntx) have been established as a sensitive bone resorption marker and urine levels of Ntx have been found to exhibit a distinct diurnal rhythm., Objective: To assess whether the timing of administration of prednisolone affects the diurnal rhythm of Ntx in urine., Methods: Four girls and four boys aged 10.6 to 15.8 (mean 13.2) years with normal weight and height and pubertal stages I-IV were studied in an open randomized 2-periods cross-over trial, with a 1-day run in, and two 4-day periods of 5mg prednisolone in the morning and in the evening, respectively, separated by a 3-week washout period. At run in and on the last day of each treatment period, the first sample of urine was collected from 24.00 to 08.00h in the morning of the day of investigation. Thereafter, urine was collected in 4~hour intervals until 24.00 and in another 08.00h interval from 24.00 to 08.00h., Results: Compared to run in and morning prednisolone treatment urine Ntx levels were suppressed from 24.00 to 8.00h during treatment with prednisolone in the evening (P < 0.01 for both comparisons) and no statistically significant circadian rhythm was observed. During morning prednisolone treatment Ntx trough and peak levels occurred from 16.00 to 20.00 and 24.00 to 08.00h, respectively, and the Ntx levels were significantly reduced from 12.00 to 20.00h as compared to run in (P < 0.005) and prednisolone treatment in the evening (P < 0.01)., Conclusions: Depending on the time of administration, prednisolone interferes with diurnal rhythms in urine Ntx., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Currently, the only available evidence for the efficacy of once-weekly 17.5 mg risedronate in preventing vertebral fractures was obtained in a 48-week study in Japan. We performed a 156-week prospective, longitudinal, observational study to determine the efficacy of the 17.5 mg risedronate in preventing vertebral fractures. We included Japanese patients with established osteoporosis who were older than 50 years and had radiographically confirmed vertebral fractures. The primary endpoint was the incidence of vertebral fractures every 24 weeks, with the final interval spanning 36 weeks. We also calculated the change in bone mineral density of the lumbar spine (L 2-4 BMD) and urinary N-telopeptide of type I collagen (u-NTX), and assessed the incidence of adverse drug reactions and the drug adherence rate. Data from 241 patients were available for analysis of vertebral fracture prevention. The incidence rate of vertebral fractures decreased in a time-dependent manner (P = 0.0006; Poisson regression analysis). The risk ratio (fracture incidence per 100 person-years in the final 36 weeks versus that in the first 24 weeks) was 0.21 (95 % confidence interval 0.08-0.55). Compared to baseline values, L 2-4 BMD increased by 6.41 % at 156 weeks, while u-NTX decreased by 36 % at 24 weeks and was maintained thereafter (P < 0.0001). The incidence rate of adverse drug reactions was 9.18 %. Drug adherence rates assessed every 4 weeks were over 90 %. Our results indicate that 156 weeks of treatment with once-weekly 17.5 mg risedronate effectively reduced the risk of vertebral fracture in Japanese patients with established osteoporosis older than 50 years.

Objectives: The influence of glucocorticoid therapy on bone resorption in dogs using a urine N-telopeptide assay was investigated., Materials and Methods: Thirty-one dogs receiving oral glucocorticoids and 31 age-matched healthy control dogs were enrolled. Urine N-telopeptide concentration was measured using a commercially available immunoassay and results were expressed as a ratio against urinary creatinine concentration. Dogs receiving glucocorticoids were divided into three subgroups based on daily glucocorticoid dose and three subgroups based on treatment duration. Urine N-telopeptide concentration was then compared between groups., Results: Urine N-telopeptide concentration was significantly higher in dogs receiving glucocorticoids compared to the control group., Clinical Significance: This preliminary study demonstrates significant increase in urine N-telopeptide concentration in dogs receiving glucocorticoid therapy compared to control dogs. Further studies are needed to assess whether this increase in urine N-telopeptide concentration correlates with decreases in bone mineral density as has been identified in humans., (© 2017 British Small Animal Veterinary Association.)

Introduction: Little is known about the efficacy of osteoporosis medication in patients with low levels of walking state, namely, influence by immobilization levels. We retrospectively compared the efficacy of the daily teriparatide therapy in patients with low and high levels of walking state to detect possible immobilization-related differences., Methods: We analyzed 661 patients treated with 20 μg/day of teriparatide for 24 months. We measured the changes in the bone mineral density (BMD) of the lumbar spine (LS) and of the femoral neck (FN), the changes in serum procollagen type I N-terminal propeptide (PINP) levels and urinary N-telopeptide (uNTX) excretion. To compare the results of BMD and bone turnover marker, the patients were divided into two subgroups, low levels of walking state and high levels of walking state., Results: Compared with baseline, in the low levels of walking state subgroup, the percent LS BMD and FN BMD increased significantly by 12.8 ± 8.9% and 5.0 ± 13.8% at 24 months, respectively (p < 0.01 vs baseline for LS and FN, respectively); the mean absolute LS BMD and FN BMD change was 0.101 ± 0.067 g/cm 2 and 0.017 ± 0.063 g/cm 2 at 24 months, respectively. In the high levels of walking state subgroup, the percent LS BMD and FN BMD increased significantly by 13.4 ± 9.5% and 3.1 ± 7.8% at 24 months, respectively; the mean absolute LS BMD and FN BMD change was 0.104 ± 0.068 g/cm 2 and 0.017 ± 0.042 g/cm 2 at 24 months, respectively. The increases in percent and absolute BMD in LS and FN, and the changes in PINP and uNTX were similar between the subgroups., Conclusions: The efficacy of the daily teriparatide treatment is similar between low levels of walking state patients and high levels of walking state patients and was not influenced by immobilization levels.

Few data exist on bone turnover in South Asian women and it is not well elucidated as to whether Western dwelling South Asian women have different bone resorption levels to that of women from European ethnic backgrounds. This study assessed bone resorption levels in UK dwelling South Asian and Caucasian women as well as evaluating whether seasonal variation in 25-hydroxyvitamin D [25(OH)D] is associated with bone resorption in either ethnic group. Data for seasonal measures of urinary N-telopeptide of collagen (uNTX) and serum 25(OH)D were analysed from n=373 women (four groups; South Asian postmenopausal n=44, South Asian premenopausal n=50, Caucasian postmenopausal n=144, Caucasian premenopausal n=135) (mean (±SD) age 48 (14) years; age range 18-79years) who participated in the longitudinal D-FINES (Diet, Food Intake, Nutrition and Exposure to the Sun in Southern England) cohort study (2006-2007). A mixed between-within subjects ANOVA (n=192) showed a between subjects effect of the four groups (P<0.001) on uNTX concentration, but no significant main effect of season (P=0.163). Bonferroni adjusted Post hoc tests (P≤0.008) suggested that there was no significant difference between the postmenopausal Asian and premenopausal Asian groups. Season specific age-matched-pairs analyses showed that in winter (P=0.04) and spring (P=0.007), premenopausal Asian women had a 16 to 20nmolBCE/mmol Cr higher uNTX than premenopausal Caucasian women. The (amplitude/mesor) ratio (i.e. seasonal change) for 25(OH)D was predictive of uNTX, with estimate (SD)=0.213 (0.015) and 95% CI (0.182, 0.245; P<0.001) in a non-linear mixed model (n=154). This showed that individuals with a higher seasonal change in 25(OH)D, adjusted for overall 25(OH)D concentration, showed increased levels of uNTX. Although the effect size was smaller than for the amplitude/mesor ratio, the mesor for 25(OH)D concentration was also predictive of uNTX, with estimate (SD)=-0.035 (0.004), and 95% CI (-0.043, -0.028; P<0.001). This study demonstrates higher levels of uNTX in premenopausal South Asian women than would be expected for their age, being greater than same-age Caucasian women, and similar to postmenopausal Asian women. This highlights potentially higher than expected bone resorption levels in premenopausal South Asian women which, if not offset by concurrent increased bone formation, may have future clinical and public health implications which warrant further investigation. Individuals with a larger seasonal change in 25(OH)D concentration showed an increased bone resorption, an association which was larger than that of the 25(OH)D yearly average, suggesting it may be as important clinically to ensure a stable and steady 25(OH)D concentration, as well as one that is high enough to be optimal for bone health., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The correlation of in vitro inhibition of cathepsin K (CatK) activity and in vivo suppression of collagen I biomarkers was examined with three selective CatK inhibitors to explore the potential translatability from animal species to human. These inhibitors exhibited good in vitro potencies toward recombinant CatK enzymes across species, with IC 50 values ranging from 0.20 to 6.1 nM. In vivo studies were conducted in animal species following multiple-day dosing of the CatK inhibitors to achieve steady-state plasma drug concentration-time profiles. Measurement of urinary bone resorption biomarkers (cross-linked N-terminal telopeptide and helical peptide of type I collagen) revealed drug concentration-dependent suppression of biomarkers, with EC 50 values estimated to be 12 to 160 nM. Marked improvement in the correlation between in vitro and in vivo CatK activities was observed with the application of unbound (free) fraction in plasma, consistent with the conditions stipulated by the free-drug hypothesis. These results indicate that the in vitro-in vivo translation of CatK inhibition observed in animal species can translate to humans when the unbound fraction of the inhibitor is considered. Interestingly, residual levels of urinary bone resorption marker were detected as the suppression reached saturation (at an average of 82% inhibition), an apparent phenomenon observed regardless of the species, biomarker, or compound examined. Since cathepsin enzymes other than CatK were reported to catalyze cleavage of collagen I, it is hypothesized that CatK-mediated degradation of collagen I in bone represents ~82% of overall collagen I turnover in the body.

The aim of the study was to investigate the efficacy of pre-emptive, early, and delayed pulsed electromagnetic field (PEMF) treatment on cartilage and subchondral trabecular bone in knee osteoarthritis (OA) rats induced by low-dose monosodium iodoacetate (MIA). Seventy-five 12-week-old male Sprague-Dawley rats were assigned to five groups: OA (n = 30), pre-emptive PEMF (n = 10), early PEMF (n = 10), delayed PEMF (n = 10), and control (n = 15). Osteoarthritis was induced by injecting 0.2 mg MIA in rat's right knee joint. Control rats received a single sterile saline injection in the right knee. Male rats received pre-emptive (n = 10, day 0-end of week 4), early (n = 10, end of week 4-end of week 8), or delayed (n = 10, end of week 8-end of week 12) PEMF treatment (75 Hz, 1.6 mT). After 4, 8, and 12 weeks, rats were sacrificed at each time point and right knees were harvested. After sacrifice, micro-computed tomography, histology, and biomarker analyses were performed. We found pre-emptive PEMF treatment preserved subchondral trabecular bone microarchitecture and prevented subchondral bone loss in MIA-induced OA rat model. Early and delayed PEMF treatment maintained subchondral trabeculae. PEMF treatment increased bone and cartilage formation, and decreased bone and cartilage resorption. Pre-emptive and early PEMF treatment had moderate effects on cartilage degradation. Time point of treatment initiation is crucial for treating OA. PEMF might become a potential biophysical treatment modality for osteoarthritis. Bioelectromagnetics. 38:227-238, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: Renal fibrogenesis is associated with increased ECM remodeling and release of collagen fragments in urine in progressive renal disease. We investigated the diagnostic value of urinary collagen degradation products in a proteinuria-driven fibrosis rat model with and without anti-fibrotic S1P-receptor modulator FTY720 treatment., Methods: Proteinuria was induced in male Wistar rats by Adriamycin (ADR) injection (n = 16). Healthy rats served as controls (n = 12). Six weeks post-injection, all underwent renal biopsy, and FTY720-treatment started in ADR-rats (n = 8) and controls (n = 6). Others remained untreated. Rats were sacrificed after 12 weeks. Collagen type I (C1M) and III (C3M) degradation fragments were measured in blood and urine using ELISA. Kidneys were stained for various inflammatory and fibrotic markers., Results: Six weeks post-injection proteinuria increased (versus controls, P < 0.001) and although no accumulation of interstitial renal collagen type III (iColl3) was observed at this time, urinary C3M (uC3M) and C1M (uC1M) were significantly increased (both P < 0.001). At 12 weeks, uC3M (P < 0.001) and uC1M (P < 0.01) further increased in ADR-rats versus controls, just as fibronectin, PDGF-β receptor, hyaluronan (all P < 0.01), iColl3, PAS, myofibroblasts, macrophages and T-cells (all P < 0.05). FTY720-treatment reduced accumulation of immune cells, α-SMA+ myofibroblasts and PAS-score, but not iColl3 and uC3M. Correlation analyses indicated that uC3M and uC1M reflected and predicted tubulointerstitial fibrogenesis., Conclusions: These data displayed urinary collagen breakdown products as sensitive early markers of interstitial fibrosis, preceding histological fibrotic changes, which might replace the invasive renal biopsy procedure to assess fibrosis. Anti-fibrotic FTY720 intervention reduced some fibrotic markers without affecting collagen type III metabolism.

Objective: Equol, an active metabolite possessing estrogen-like activity, is produced by the action of intestinal flora on soy isoflavones. There is an increasing evidence regarding its efficacy in the relief of menopausal symptoms, suppression of decreased bone mineral density, and lipid profile improvement. Only those with equol-producing capacity, however, seem to benefit. Thus, we examined the relationship between equol producer status and parameters associated with lifestyle-related diseases in women from their 20s to 80s., Methods: This cross-sectional study was conducted among 743 women (21-89 y; average age: 52.5 ± 11.8 y) who have undergone health screening at Tokyo Midtown Medical Center and given consent to participate in the study. The relationship between equol producer status and metabolic parameters was assessed., Results: In our study, 236 women (32%) were equol producers. Equol producers had significantly lower triglycerides and higher high-density lipoprotein cholesterol levels compared with nonproducers. Equol-producing women in their 50s showed significantly lower body fat level, visceral fat area, triglyceride levels, pulse wave velocity, uric acid levels, and high sensitivity C-reactive protein levels. In addition, women in their 60s showed significantly higher levels of high-density lipoprotein cholesterol. In multivariate logistic regression, for women in their 50s, equol production was significantly associated with lower arterial stiffness and uric acid levels, and a high ratio of eicosapentaenoic acid to arachidonic acid, whereas it was significantly associated with lower urinary N-telopeptides in their 60s., Conclusions: Equol producer status was associated with favorable metabolic parameters, in women in the early phase postmenopause, with the transitional periods noted with declining intrinsic estrogen levels.

Background/aims: Osteoporosis is found to have high prevalence after gastrectomy and therefore, it is important to prevent this condition by means of effective medication, such as alendronate sodium hydrate., Methods: A total number of 48 gastric cancer patients diagnosed with osteoporosis after R0 gastrectomy was registered in this study between December 2013 and August 2014. Twenty-three patients received intravenous (i.v.) alendronate sodium hydrate and 25 patients received the drug in an oral jelly form. Serological and urinary examinations related to bone metabolism and bone mineral density (BMD) were performed periodically and the results obtained from the 2 groups were compared., Results: BMD increased, serum levels of bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase-5b, and the urine level of urine N-terminal telopeptide decreased with time in both groups. However, the serum Ca level did not change. Two-way analysis of variance revealed no significant differences in these factors between the 2 groups., Conclusion: It is essential to prevent both forms of osteoporosis by using alendronate sodium hydrate after gastrectomy for gastric cancer. A prospective, randomized, controlled trial in many patients following long duration should be conducted to clarify the benefits of i.v. alendronate sodium hydrate., (© 2017 S. Karger AG, Basel.)

A previously established mechanism-based disease systems model for osteoporosis that is based on a mathematically reduced version of a model describing the interactions between osteoclast (bone removing) and osteoblast (bone forming) cells in bone remodeling has been applied to clinical data from women (n = 1,379) receiving different doses and treatment regimens of alendronate, placebo, and washout. The changes in the biomarkers, plasma bone-specific alkaline phosphatase activity (BSAP), urinary N-telopeptide (NTX), lumbar spine bone mineral density (BMD), and total hip BMD, were linked to the underlying mechanistic core of the model. The final model gave an accurate description of all four biomarkers for the different treatments. Simulations were used to visualize the dynamics of the underlying network and the natural disease progression upon alendronate treatment and discontinuation. These results complement the previous applications of this mechanism-based disease systems model to data from various treatments for osteoporosis., (© 2016 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Markers of bone metabolism, such as N-telopeptide of type I collagen (NTX), have been demonstrated to be prognostic in previous trials of breast cancer (BC) patients with bone metastases (BMs). In the present study, we tested the survival effect of the NTX response to zoledronic acid (ZA) at 3 and 12 months in a contemporaneous cohort of BC patients with BMs and evaluated the influence of extraskeletal metastatic disease on NTX variation., Patients and Methods: The present study was a prospective cohort study of consecutive BC patients diagnosed and treated at a single center. Patients presenting with de novo radiological evidence of BMs who started monthly intravenous ZA were included. Urinary NTX was measured at baseline and 1, 3, 6, 9, and 12 months after ZA introduction., Results: Overall, 71 patients were enrolled, 32 with BMs and 39 with BMs plus extraskeletal metastases. The proportion of patients with elevated NTX at baseline and 3 and 12 months was 49.3%, 26.6%, and 34.2%, respectively. The variables associated with survival included age at diagnosis, tumor estrogen receptor status, and NTX at 3 and 12 months. Multivariate analysis showed that, in addition to age at diagnosis, only the 3-month NTX level was significantly associated with survival. Patients with BMs plus extraskeletal metastases had an erratic NTX variation pattern, unrelated to survival., Conclusion: In the present contemporaneous cohort of BC patients with BMs, the NTX response at 3 months was strongly associated with survival. Furthermore, an early response to ZA was strongly associated with long-term NTX control. Finally, patients with BMs plus extraskeletal metastases had an erratic NTX variation., Implications for Practice: The present study showed that when accommodating recent therapy innovations and longer patient survival, the N-telopeptide (NTX) variation at 3 months is strongly associated with survival. In this setting, in addition to a few other clinicopathological features, NTX is a powerful prognostic marker. Moreover, early NTX correction associates with persistently normal NTX. This might identify a subgroup of patients with a good prognosis who are eligible for premature zoledronic acid (ZA) de-escalation. Finally, patients with bone plus extraskeletal metastases showed an erratic variation of NTX, raising concerns that a single ZA regimen might not fit all patients. Future trials should test its effect according to the presence of extraskeletal involvement., Competing Interests: of potential conflicts of interest may be found at the end of this article., (©AlphaMed Press.)

The urinary cross-linked N-terminal telopeptide of type I collagen (uNTx) levels in infantile osteogenesis imperfecta (OI) have not been well studied. Here we investigated the levels of uNTx in infants with OI and healthy infants. We collected spot urine samples from 30 infants with OI (male/female, 14/16; Sillence classification, I/II/III/IV: 15/3/6/6; age, 5.2±4.4 months) and 120 healthy infants (male/female, 75/45; age, 5.1±4.1 months) for the measurement of uNTx levels. The uNTx levels of the OI infants were significantly lower than those of the healthy infants (mean±SD, 1,363.7±530.1 vs. 2,622.2±1,202.6 nmol BCE/mmol Cr; p＜0.001). The uNTx levels of the infants with type I OI were significantly lower than those of the age-matched healthy infants, although an overlap was observed between the 2 groups. Among the 1-month-old infants, the uNTx levels of the infants with types I, III or IV OI were significantly lower than those of the healthy infants, without overlap (1,622.5±235.8 vs. 3,781.0±1,027.1 nmol BCE/mmol Cr; p＜0.001). These results indicate that uNTx levels are significantly lower in infants with OI than in healthy infants, and they suggest that uNTx might be useful as a reference for diagnosing OI.

We examined response to bone mineral density (BMD) gains in the MOVER study following treatment with intravenous (IV) ibandronate 1 mg/month, and investigated the characteristics of a non-responder group. At 1 year, responder rates for patients with BMD increases >0 % were similar with IV ibandronate 0.5 or 1 mg/month and oral risedronate 2.5 mg/day. However, after 3 years, responder rates with BMD increases ≥3 % were highest with ibandronate 1 mg at all bone sites (>80 % at the lumbar spine [L2-L4] and >50 % at all femur sites, which was significantly higher than with risedronate). Non-responders were defined by BMD increases ≤3 % at L2-L4 or ≤0 % at total hip, and ≤50 % reduction in creatinine-corrected urinary collagen type 1 cross-linked C-telopeptide (uCTX) from baseline to 1 year. There were a small number of non-responders in the ibandronate 1 mg group: 3.3 % (10/299) with ≤0 % total hip BMD increase and ≤50 % uCTX reduction from baseline. These non-responders had lower 25-hydroxyvitamin D (25[OH]D) levels than responders, but no differences in kidney function, L2-L4 BMD or bone turnover marker baseline values. Throughout the study, non-responders failed to show any increases in BMD. Our analysis demonstrates significantly higher responder rates with IV ibandronate 1 mg/month than with risedronate at 3 years. A small number of non-responders in the ibandronate group had lower 25(OH)D baseline levels than responders, suggesting that 25(OH)D levels could be a useful indicator of BMD response to therapy.

The purpose of this study was to assess the ability of urinary N-telopeptide (U-NTX) to gauge rate of bone loss across and after the menopause transition (MT). U-NTX measurement was measured in early postmenopause in 604 participants from the Study of Women's Health Across the Nation (SWAN). We examined the association between U-NTX and annualized rates of decline in lumbar spine and femoral neck bone mineral density (BMD) across the MT (1 year before the final menstrual period [FMP] to time of U-NTX measurement), after the MT (from time of U-NTX measurement to 2 to 4 years later), and over the combined period (from 1 year before FMP to 2 to 4 years after U-NTX measurement). Adjusted for covariates in multivariable linear regression, every standard deviation (SD) increase in U-NTX was associated with 0.6% and 0.4% per year faster declines in lumbar spine and femoral neck BMD across the MT; and 0.3% (lumbar spine) and 0.2% (femoral neck) per year faster declines over the combined period (across and after the MT) (all p < 0.01). Each SD increase in U-NTX was also associated with 44% and 50% greater risk of fast bone loss in the lumbar spine (defined as BMD decline in the fastest 16% of the distribution) across the MT (p < 0.001, c-statistic = 0.80) and over the combined period (across and after the MT) (p = 0.001, c-statistic = 0.80), respectively. U-NTX measured in early postmenopause is most strongly associated with rates of bone loss across the MT, and may aid early identification of women who have experienced fast bone loss during this critical period. © 2016 American Society for Bone and Mineral Research., (© 2016 American Society for Bone and Mineral Research.)

Fingolimod is a sphingosine-1-phosphate receptor agonist used to inhibit the inflammatory activity of multiple sclerosis (MS), and has been shown to suppress osteoporosis in mouse models. In this study, levels of bone turnover markers were quantified in serum and urine samples from MS patients treated with fingolimod. Compared with untreated MS patients and healthy controls, fingolimod-treated MS patients had a significantly lower level of the bone resorption marker type I collagen cross-linked N-telopeptide in urine. This finding was prominent in female but was not seen in male subjects. Our results suggest that fingolimod may have a beneficial effect on bone mass loss in female MS patients., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Unlabelled: Some patients with osteoporosis do not respond to teriparatide treatment. Prior bisphosphonate use, lower bone turnover marker (BTMs) concentrations, and lower early increases in BTMs were significantly associated with a blunted lumbar spine (LS) bone mineral density (BMD) response to daily treatment with teriparatide, although the impact was limited., Introduction: Some osteoporosis patients do not respond to teriparatide treatment. To better understand the factors underlying treatment nonresponses, we compared nonresponders' and responders' characteristics., Methods: We retrospectively analyzed 354 male and female patients with osteoporosis who were administered teriparatide (20 μg/day) for 24 months. The patients were categorized as responders (≥3 % lumber spine (LS) bone mineral density (BMD) increase) or nonresponders (<3 % LS BMD increase), and the groups were compared., Results: The univariate analyses determined that prior bisphosphonate use, a lower baseline procollagen type I N-terminal propeptide (PINP) concentration and a lower urinary N-telopeptide of type I collagen (uNTX) concentration at baseline were significantly associated with teriparatide nonresponses, but these factors were not significant following multivariate analysis. Diminished early increases in the bone turnover markers (BTMs) were also related to nonresponses after teriparatide treatment began. In the nonresponders, the mean (standard deviation (SD)) absolute LS and femoral neck (FN) BMD changes were -0.002 g/cm(2) (0.032) and -0.010 g/cm(2) (0.045), respectively. In the responders, the mean (SD) absolute LS and FN BMD changes were 0.118 g/cm(2) (0.056) and 0.021 g/cm(2) (0.046), respectively. The serum PINP and uNTX levels increased rapidly in both groups, but the responders showed higher early absolute serum PINP and uNTX increases., Conclusions: The factors associated with nonresponses were prior bisphosphonate use, lower baseline BTM levels, and lower early increases in the BTMs after starting teriparatide treatment, but the impact of these factors on achieving a ≥3 % LS BMD increase at 24 months was limited.

Objectives: Bone mineral density (BMD) loss is a major chronic complication in HIV patients. We performed a prospective study to determine the time course of BMD changes and to find prognostic factors of BMD loss in HIV patients on combination antiretroviral therapy (cART)., Patients and Methods: Subjects were 54 male Japanese HIV patients who had been on cART ≥1 year with no therapeutic agents for osteoporosis. Patients were observed for ≥1 year (median 3.1 years) and underwent annual BMD analyses using dual energy X-ray absorptiometry. Changes in BMD at lumbar spine and femoral neck were calculated for each person-year of all the patients. Clinical factors were also collected simultaneously with BMD examinations to determine prognostic factors for BMD loss., Results: In total, 173 person-years in 54 patients were observed. One third (19, 35.2%) and slightly over half (30, 55.6%) patients showed BMD decreases at lumbar spine and femoral neck, respectively. However, the median BMD changes at lumbar spine and femoral neck were 0.0% and -0.52% per year, respectively. Monovariant and mixed model analyses determined that decreased serum bone specific alkaline phosphatase (BAP, p = 0.0047) and increased urinary N-terminal telopeptide (uNTx, p = 0.0011) were prognostic factors for BMD loss at lumbar spine and femoral neck, respectively., Conclusions: BMD at both lumbar spine and femoral neck changed little on average in HIV patients on cART. Decreased serum BAP or increased uNTx may be helpful to predict progressive BMD loss in the following year and to select patients for BMD follow-up or initiation of anti-osteoporosis treatment., (Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Aims: Urine proteome analysis (UPA) has already provided accurate discriminatory patterns of urinary peptides for renal disease, coronary artery disease, and asymptomatic LV diastolic dysfunction. UPA has now been used to characterize a discriminatory peptide biomarker pattern and establish a diagnostic classifier for heart failure patients with reduced ejection fraction (HFrEF) in the presence of chronic kidney disease (CKD)., Methods and Results: We analysed the urine proteome profiles obtained by capillary electrophoresis online coupled to micro-TOF (time of flight) mass spectrometry of 126 individuals, 59 HFrEF patients and 67 controls matched for age, sex, and renal function. In total, 107 significant discriminatory peptides were identified and used to establish a support vector machine-based classifier that was successfully applied to a test set of 25 HFrEF patients and 33 controls, achieving 84% sensitivity and 91% specificity. The majority of sequenced peptides were fragments of collagen type I and III., Conclusion: UPA was able to identify a set of HFrEF-specific urinary peptide biomarkers on a background of CKD that were successfully utilized to establish a syndrome's classifier., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)

Background: The underlying mechanisms for increased osteopenia and fracture rates in patients with diabetes are not well understood, but may relate to chronic systemic inflammation. We assessed the effect of treating periodontal disease (POD), a cause of chronic inflammation, on inflammatory and bone turnover markers in patients with diabetes., Materials and Methods: Using an investigator-administered questionnaire, we screened a cross-section of patients presenting for routine outpatient diabetes care. We recruited 22 subjects with POD. Inflammatory and bone turnover markers were measured at baseline and 3 months following POD treatment (scaling, root planing and subantimicrobial dose doxycycline)., Results: There were nonsignificant reductions in high-sensitivity C-reactive protein (6.34-5.52mg/L, P = 0.626) and tumor necrosis factor-alpha (10.37-10.01pg/mL, P = 0.617). There were nonsignificant increases in urinary C-terminal telopeptide (85.50-90.23pg/mL, P = 0.684) and bone-specific alkaline phosphatase (7.45-8.79pg/mL, P = 0.074). Patients with >90% adherence with doxycycline were 6.4 times more likely to experience reduction in tumor necrosis factor-alpha (P = 0.021) and 2.8 times more likely to experience reductions in high-sensitivity C-reactive protein (P = 0.133)., Conclusions: Treatment of POD in patients with diabetes resulted in nonsignificant lowering of inflammatory markers and nonsignificant increase in bone turnover markers. However, adherence to doxycycline therapy resulted in better treatment effects., (Copyright © 2016 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)