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JBMR Plus Mar 2024Hypoparathyroidism (HypoPT) is a rare disease, often inadequately controlled by conventional treatment. PARALLAX was a mandatory post-marketing trial assessing... (Clinical Trial)
Clinical Trial
UNLABELLED
Hypoparathyroidism (HypoPT) is a rare disease, often inadequately controlled by conventional treatment. PARALLAX was a mandatory post-marketing trial assessing pharmacokinetics and pharmacodynamics of different dosing regimens of recombinant human parathyroid hormone 1-84 (rhPTH[1-84]) for treating HypoPT. The present study (NCT03364738) was a phase 4, 1-yr open-label extension of PARALLAX. Patients received only 2 doses of rhPTH(1-84) in PARALLAX and were considered treatment-naive at the start of the current study. rhPTH(1-84) was initiated at 50 μg once daily, with doses adjusted based on albumin-corrected serum calcium levels. Albumin-corrected serum calcium (primary outcome measure), health-related quality of life (HRQoL), adverse events, and healthcare resource utilization (HCRU) were assessed. The mean age of the 22 patients included was 50.0 yr; 81.8% were women, and 90.9% were White. By the end of treatment (EOT), 95.5% of patients had albumin-corrected serum calcium values in the protocol-defined range of 1.88 mmol/L to the upper limit of normal. Serum phosphorus was within the healthy range, and albumin-corrected serum calcium-phosphorus product was below the upper healthy limit throughout, while mean 24-h urine calcium excretion decreased from baseline to EOT. Mean supplemental doses of calcium and active vitamin D were reduced from baseline to EOT (2402-855 mg/d and 0.8-0.2 μg/d, respectively). Mean serum bone turnover markers, bone-specific alkaline phosphatase, osteocalcin, procollagen type I N-terminal propeptide, and type I collagen C-telopeptide increased 2-5 fold from baseline to EOT. The HCRU, disease-related symptoms and impact on HRQoL improved numerically between baseline and EOT. Nine patients (40.9%) experienced treatment-related adverse events; no deaths were reported. Treatment with rhPTH(1-84) once daily for 1 yr improved HRQoL, maintained eucalcemia in 95% of patients, normalized serum phosphorus, and decreased urine calcium excretion. The effects observed on urine calcium and the safety profile are consistent with previous findings.
CLINICAL TRIAL IDENTIFIER
NCT03364738.
PubMed: 38741607
DOI: 10.1093/jbmrpl/ziad010 -
Analytical Methods : Advancing Methods... May 2024Despite the increasing efforts in improving bone health assessments, current diagnostics suffer from critical shortcomings. The present article therefore describes a...
Despite the increasing efforts in improving bone health assessments, current diagnostics suffer from critical shortcomings. The present article therefore describes a multiplex label-free immunosensor designed and validated for the assessment of two bone turnover markers (BTMs), namely beta isomerized C-terminal telopeptide of type I collagen (CTx) and Procollagen I Intact N-Terminal (PINP), the combination of which is needed to illustrate an accurate overview of bone health. The immunosensor was then tested outside and inside of a microsystem, with the aim of becoming compatible with a point of care system fabricated for automated assessment of these biomarkers later-on at patient side. Custom-made monoclonal antibodies were specifically designed for this purpose in order to guarantee the selectivity of the immunosensor. In the final platform, a finger prick blood sample is introduced into the microfluidic manifolds without any need for sample preparation step, making the tool suitable for near patient and outside of the central laboratory applications. The platform was exploited in 30 real blood samples with the results validated using electrochemiluminescence immunoassay. The results revealed the platform was capable of measuring the target analyte with high sensitivity and beyond the recommended clinical reference range for each biomarker (CTx: 104-1028 ng L and PINP: 16-96 μg L, correspondingly). They also showed the platform to have a limit of detection of 15 (ng L) and 0.66 (μg L), a limit of quantification of 49 (ng L) and 2.21 (μg L), and an inter- and intra-assay coefficient of variance of 5.39-6.97% and 6.81-5.37%, for CTx and PINP respectively, which is comparable with the gold standard. The main advantage of the platform over the state-of-the art was the capability of providing the results for two markers recommended for assessing bone health within 15 minutes and without the need for skilled personnel or costly infrastructure.
Topics: Humans; Biomarkers; Procollagen; Collagen Type I; Bone Remodeling; Peptide Fragments; Immunoassay; Peptides; Biosensing Techniques; Point-of-Care Systems
PubMed: 38738371
DOI: 10.1039/d4ay00207e -
EClinicalMedicine Jun 2024Previous studies have indicated that glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) may enhance bone formation and have neutral or beneficial effects on...
BACKGROUND
Previous studies have indicated that glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) may enhance bone formation and have neutral or beneficial effects on fracture risk. We evaluated the effect of the GLP-1RA semaglutide on the bone formation marker Procollagen type I N-terminal propeptide (PINP) in adults with increased fracture risk.
METHODS
This randomised, placebo-controlled, double-blinded, phase 2 clinical trial was conducted at two public hospitals in Denmark. We enrolled 64 men and women with increased fracture risk based on a T-score < -1.0 at the total hip or lumbar spine and/or low-energy fracture within three years of recruitment. Participants were randomised (1:1) to receive once-weekly subcutaneous semaglutide 1.0 mg or placebo. The primary outcome was changes in plasma (P)-PINP from baseline to week 52. Primary and safety outcomes were assessed and evaluated for all participants. This trial is complete and registered with ClinicalTrials.gov, NCT04702516.
FINDINGS
Between March 24 and December 8, 2021, 55 (86%) postmenopausal women and nine men with a mean age of 63 years (SD 5.5) and BMI of 27.5 kg/m (SD 4.5) were enrolled. There was no effect on changes in P-PINP from baseline to week 52 between the two groups (estimated treatment difference (ETD) semaglutide versus placebo 3.8 μg/L [95% CI -5.6 to 13.3]; p = 0.418), and no difference in P-PINP levels between groups at week 52 (semaglutide 64.3 μg/L versus placebo 62.3 μg/L [95% CI -10.8 to 15.0]; p = 0.749). The secondary outcomes showed higher plasma levels of bone resorption marker Collagen type I cross-linked C-terminal telopeptide (P-CTX) in the semaglutide group than in the placebo group (ETD 166.4 ng/L [95% CI 25.5-307.3]; p = 0.021). Compared to placebo, lumbar spine and total hip areal bone mineral densities (aBMD) were lower in the semaglutide group after 52 weeks ((ETD lumbar spine -0.018 g/cm [95% CI -0.031 to -0.005]; p = 0.007); ETD total hip -0.020 g/cm ([95% CI -0.032 to -0.008]; p = 0.001). Treatment differences in femoral neck aBMD were not observed ([95% CI [-0.017 to 0.006]; p = 0.328). Further, body weight was lower in the semaglutide group than in the placebo group after 52 weeks (ETD -6.8 kg [95% CI -8.8 to -4.7]; p < 0.001). Thirty-one [97%] in the semaglutide group and 18 [56%] in the placebo group experienced at least one adverse event, including four serious events (two in each group). No episodes of hypoglycaemia or deaths were reported.
INTERPRETATION
In adults with increased fracture risk, semaglutide once weekly did not increase bone formation based on the bone formation marker P-PINP. The observed increase in bone resorption in the semaglutide group may be explained by the accompanying weight loss.
FUNDING
Region of Southern Denmark, Novo Nordisk Foundation, and Gangsted Foundation. Novo Nordisk provided the investigational drug and placebo.
PubMed: 38737002
DOI: 10.1016/j.eclinm.2024.102624 -
Bone Reports Jun 2024Dairy foods are nutritional sources of calcium, phosphorus, protein, and other nutrients that improve bone health. However, the effects of dairy consumption on bone...
Dairy consumption, bone turnover biomarkers, and osteo sono assessment index in Japanese adults: A cross-sectional analysis of data from the Iwaki Health Promotion Project.
PURPOSE
Dairy foods are nutritional sources of calcium, phosphorus, protein, and other nutrients that improve bone health. However, the effects of dairy consumption on bone biomarkers in the Japanese population remain unclear. This study explored the association between dairy consumption and bone biomarkers in Japanese adults.
METHODS
This cross-sectional study was conducted as part of the Iwaki Health Promotion Project in Aomori, Japan. In total, 1063 adults were included in the analysis. Bone turnover marker levels were measured in local citizens during their annual medical checkups. The calcaneus osteo sono assessment index (OSI) was calculated using a quantitative ultrasound technique. The dietary intake of foods and nutrients was estimated using a food frequency questionnaire. Linear regression models were established using dairy consumption and bone biomarkers with adjustments. Statistic significance was considered by < 0.05.
RESULTS
In multivariate models, the tartrate-resistant acid phosphatase 5b and parathyroid hormone concentrations were inversely associated with dietary dairy consumption after adjusting for age and sex. The undercarboxylated osteocalcin, a procollagen type I N-terminal peptide to bone alkaline phosphatase ratio, and OSI were the directly associated with dairy consumption in multivariate models with adjustment.
CONCLUSIONS
Dairy consumption is partially associated with bone turnover biomarkers and OSI in adult Japanese participants. Habitual consumption of dairy foods may contribute to the nutritional supplementation for maintaining bone health, including turnover and structure.
CLINICAL TRIAL REGISTRY NUMBER AND WEBSITE WHERE IT WAS OBTAINED
The Japanese Clinical Trials Registry (UMIN000040459), https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000046175.
PubMed: 38736771
DOI: 10.1016/j.bonr.2024.101770 -
Plants (Basel, Switzerland) May 2024This present study investigated the anti-skin-aging properties of . Initially, phenolic compounds were isolated from a hot water extract of 's flower buds. Through...
This present study investigated the anti-skin-aging properties of . Initially, phenolic compounds were isolated from a hot water extract of 's flower buds. Through repeated chromatography (column chromatography, MPLC, and prep HPLC), we identified nine phenolic compounds (-), including a previously undescribed depside, rosarugoside D (). The chemical structure of 1 was elucidated via NMR, HR-MS, UV, and hydrolysis. Next, in order to identify bioactive compounds that are effective against TNF-α-induced NHDF cells, we measured intracellular ROS production in samples treated with each of the isolated compounds (-). All isolates reduced the level of ROS at a concentration of 10 μM. Particularly, two depsides-rosarugosides A and D ( and )-significantly inhibited ROS expression in TNF-α-induced NHDFs compared to the other phenolic compounds. Subsequently, the production of MMP-1 and procollagen type Ι α1 by these two depsides was examined. Remarkably, rosarugoside A () significantly decreased MMP-1 secretion at all concentrations. In contrast, rosarugoside D () regulated the expression of procollagen type Ι α1. These findings collectively suggest that extracts and their isolated compounds, rosarugosides A () and D (), hold significant potential for protecting against aging and skin damage. Overall, these findings suggest that extracts and their isolated compounds, rosarugosides A () and D (), have the potential to prevent and protect against aging and skin damage, although more specific quantitative analysis is needed.
PubMed: 38732481
DOI: 10.3390/plants13091266 -
Heart (British Cardiac Society) May 2024Heart failure (HF) is characterised by collagen deposition. Urinary proteomic profiling (UPP) followed by peptide sequencing identifies parental proteins, for over 70%...
OBJECTIVE
Heart failure (HF) is characterised by collagen deposition. Urinary proteomic profiling (UPP) followed by peptide sequencing identifies parental proteins, for over 70% derived from collagens. This study aimed to refine understanding of the antifibrotic action of spironolactone.
METHODS
In this substudy (n=290) to the Heart 'Omics' in Ageing Study trial, patients were randomised to usual therapy combined or not with spironolactone 25-50 mg/day and followed for 9 months. The analysis included 1498 sequenced urinary peptides detectable in ≥30% of patients and carboxyterminal propeptide of procollagen I (PICP) and PICP/carboxyterminal telopeptide of collagen I (CITP) as serum biomarkers of COL1A1 synthesis. After rank normalisation of biomarker distributions, between-group differences in their changes were assessed by multivariable-adjusted mixed model analysis of variance. Correlations between the changes in urinary peptides and in serum PICP and PICP/CITP were compared between groups using Fisher's Z transform.
RESULTS
Multivariable-adjusted between-group differences in the urinary peptides with error 1 rate correction were limited to 27 collagen fragments, of which 16 were upregulated (7 COL1A1 fragments) on spironolactone and 11 downregulated (4 COL1A1 fragments). Over 9 months of follow-up, spironolactone decreased serum PICP from 81 (IQR 66-95) to 75 (61-90) µg/L and PICP/CITP from 22 (17-28) to 18 (13-26), whereas no changes occurred in the control group, resulting in a difference (spironolactone minus control) expressed in standardised units of -0.321 (95% CI 0.0007). Spironolactone did not affect the correlations between changes in urinary COL1A1 fragments and in PICP or the PICP/CITP ratio.
CONCLUSIONS
Spironolactone decreased serum markers of collagen synthesis and predominantly downregulated urinary collagen-derived peptides, but upregulated others. The interpretation of these opposite UPP trends might be due to shrinking the body-wide pool of collagens, explaining downregulation, while some degree of collagen synthesis must be maintained to sustain vital organ functions, explaining upregulation. Combining urinary and serum fibrosis markers opens new avenues for the understanding of the action of antifibrotic drugs.
TRIAL REGISTRATION NUMBER
NCT02556450.
PubMed: 38729636
DOI: 10.1136/heartjnl-2023-323796 -
Cancer Genetics Jun 2024Although lncRNAs are recognized to contribute to the development of oral squamous-cell carcinoma (OSCC), their exact function in invasion and cell migration is not...
Although lncRNAs are recognized to contribute to the development of oral squamous-cell carcinoma (OSCC), their exact function in invasion and cell migration is not clear. In this research, we explored the molecular and cellular mechanisms of FOXD2-AS1 in OSCC. Prognostic and bioinformatics analyses were used to test for the differential expression of FOXD2-AS1-PLOD1. Following FOXD2-AS1 suppression or overexpression, changes in cell viability were measured using the CCK-8 test; changes in cell migration and invasion abilities were measured using the migration and the Transwell assay. The expression of associated genes and proteins was found using Western blot and RT-qPCR. Analysis of luciferase reporter genes was done to look for regulatory connections between various molecules. The FOXD2-AS1-PLOD1 pair, which was highly expressed in OSCC, was analyzed and experimentally verified to be closely related to the prognosis of OSCC, and a nomogram model and correction curve were constructed. The inhibition of FOXD2-AS1 resulted in the reduction of cell activity, migration, invasion ability and changes in genes related to invasion and migration. In vivo validation showed that inhibition of FOXD2-AS1 expression slowed tumor growth, and related proteins changed accordingly. The experiments verified that FOXD2-AS1 negatively regulated miR-185-5 p and that miR-185-5 p negatively regulated PLOD1. In addition, it was found that the expression of PLOD1, p-Akt and p-mTOR proteins in OSCC cells was reduced by the inhibition of FOXD2-AS1, and FOXD2-AS1 and PLOD1 were closely related to the Akt/mTOR pathway. Increased expression of FOXD2-AS1 promotes OSCC growth, invasion and migration, which is important in part by targeting miR-185-5 p/PLOD1/Akt/mTOR pathway activity.
Topics: Humans; MicroRNAs; RNA, Long Noncoding; TOR Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Cell Movement; Mouth Neoplasms; Cell Proliferation; Neoplasm Invasiveness; Mice; Animals; Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; Cell Line, Tumor; Signal Transduction; Gene Expression Regulation, Neoplastic; Female; Squamous Cell Carcinoma of Head and Neck; Male; Prognosis; Carcinoma, Squamous Cell; Mice, Nude
PubMed: 38729078
DOI: 10.1016/j.cancergen.2024.05.001 -
Medicine May 2024Statins are the first-line treatment for dyslipidemia, which is a major modifiable risk factor for atherosclerotic cardiovascular disease. Studies have shown that in... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
BACKGROUND
Statins are the first-line treatment for dyslipidemia, which is a major modifiable risk factor for atherosclerotic cardiovascular disease. Studies have shown that in addition to the beneficial lipid-lowering effect, statins also exhibit a number of pleiotropic effects that may find application in other diseases, including osteoporosis. This study aimed to assess the effect of statins on bone turnover, as measured by the concentration of bone turnover markers, and to compare the effect of atorvastatin as a lipophilic statin and rosuvastatin as a hydrophilic statin.
METHODS
This study included 34 postmenopausal women aged < 65 years with newly diagnosed dyslipidemia requiring statin therapy. Patients were randomly assigned to receive a statin drug. Statins were initiated at standard doses of 5 to 10 mg of rosuvastatin and 20 mg of atorvastatin. The levels of C-terminal telopeptide of type I collagen as a bone resorption marker and N-terminal propeptide of procollagen type I as a marker of bone formation, lipid concentrations and other biochemical parameters were assessed at baseline and after 6 and twelve months of treatment.
RESULTS
There were no statistically significant differences between the levels of bone turnover markers before and 6 months after statin implementation (P > .05) - for all patients or subgroups according to statin use. Analysis of the results showed that after 12 months, there was a statistically significant decrease in N-terminal propeptide of procollagen type I concentration in all subjects (P = .004). By statin subgroup, a statistically significant decrease in N-terminal propeptide of procollagen type I was observed only in patients receiving rosuvastatin (P = .012) and not in those receiving atorvastatin (P = .25). Moreover, changes in bone turnover markers did not correlate with changes in lipid concentrations.
CONCLUSIONS
These results may indicate the superiority of atorvastatin over rosuvastatin in inhibiting adverse changes in bone turnover in postmenopausal women. Confirmed by studies involving a larger population, the observed differences might find particular applications in clinical practice, and the choice of atorvastatin over rosuvastatin for women could be considered in the early postmenopausal period to reduce the risk of osteoporosis and subsequent osteoporotic fractures.
Topics: Humans; Rosuvastatin Calcium; Female; Atorvastatin; Middle Aged; Bone Remodeling; Postmenopause; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Biomarkers; Collagen Type I; Osteoporosis, Postmenopausal; Dyslipidemias
PubMed: 38728464
DOI: 10.1097/MD.0000000000038122 -
Journal of Investigative Medicine : the... Jun 2024The study aimed to investigate the changes in the levels of serum bone turnover markers (BTMs) and bone mineral density (BMD) Z-score in pediatric patients with...
The study aimed to investigate the changes in the levels of serum bone turnover markers (BTMs) and bone mineral density (BMD) Z-score in pediatric patients with osteogenesis imperfecta (OI) after intravenous bisphosphonate therapy and their association with age and estimated glomerular filtration rate (eGFR). This retrospective study analyzed data from 10 pediatric OI patients treated with intravenous zoledronic acid for over 1 year. Patients' clinical data were collected. The levels of BTMs and BMD Z-score before and after zoledronic acid treatment were analyzed. Significant improvement in BMD Z-score was observed after 6 and 12 months of treatment compared to baseline (all p < 0.05). The N-terminal propeptide of type I procollagen (PINP) levels decreased over time (all p < 0.05), indicating that zoledronic acid treatment decreased bone turnover. The levels of beta-C-terminal telopeptide of type I collagen remained stable after treatment. No correlation was found between PINP level and age, eGFR, or BMD (all p > 0.05). Bisphosphonate treatment can improve BMD and decrease bone turnover (indicated by decreased levels of PINP) in pediatric OI patients. PINP may serve as an independent indicator for monitoring the efficacy of bisphosphonate treatment in pediatric OI patients, particularly in those under the age of 6, where standardized BMD Z-score criteria are lacking.
PubMed: 38715223
DOI: 10.1177/10815589241254047 -
Nature Communications May 2024Immunotherapy with chimeric antigen receptor T cells for pediatric solid and brain tumors is constrained by available targetable antigens. Cancer-specific exons present...
Immunotherapy with chimeric antigen receptor T cells for pediatric solid and brain tumors is constrained by available targetable antigens. Cancer-specific exons present a promising reservoir of targets; however, these have not been explored and validated systematically in a pan-cancer fashion. To identify cancer specific exon targets, here we analyze 1532 RNA-seq datasets from 16 types of pediatric solid and brain tumors for comparison with normal tissues using a newly developed workflow. We find 2933 exons in 157 genes encoding proteins of the surfaceome or matrisome with high cancer specificity either at the gene (n = 148) or the alternatively spliced isoform (n = 9) level. Expression of selected alternatively spliced targets, including the EDB domain of fibronectin 1, and gene targets, such as COL11A1, are validated in pediatric patient derived xenograft tumors. We generate T cells expressing chimeric antigen receptors specific for the EDB domain or COL11A1 and demonstrate that these have antitumor activity. The full target list, explorable via an interactive web portal ( https://cseminer.stjude.org/ ), provides a rich resource for developing immunotherapy of pediatric solid and brain tumors using gene or AS targets with high expression specificity in cancer.
Topics: Humans; Brain Neoplasms; Animals; Exons; Child; Receptors, Chimeric Antigen; Mice; Immunotherapy; Alternative Splicing; Fibronectins; Xenograft Model Antitumor Assays; Gene Expression Regulation, Neoplastic; RNA-Seq; T-Lymphocytes; Cell Line, Tumor; Immunotherapy, Adoptive
PubMed: 38702309
DOI: 10.1038/s41467-024-47649-y