Bone Markers Research Articles

Osteogenic Effects of the Diospyros lotus L. Leaf Extract on MC3T3-E1 Pre-Osteoblasts and Ovariectomized Mice via BMP2/4 and TGF β Pathways.

Osteoporosis, a disease defined by the primary bone strength due to a low bone mineral density, is a bone disorder associated with increased mortality in the older adult population. Osteoporosis is mainly treated via hormone replacement therapy, bisphosphates, and anti-bone resorption agents. However, these agents exert severe side effects, necessitating the development of novel therapeutic agents. Many studies are focusing on osteogenic agents as they increase the bone density, which is essential for osteoporosis treatment. Here, we aimed to investigate the effects of Diospyros lotus L. leaf extract (DLE) and its components on osteoporosis in MC3T3-E1 pre-osteoblasts and ovariectomized mice and to elucidate the underlying related pathways. DLE enhanced the differentiation of MC3T3-E1 pre-osteoblasts, with a 1.5-fold elevation in ALP activity, and increased the levels of osteogenic molecules, RUNX family transcription factor 2, and osterix. This alteration resulted from the activation of bone morphogenic protein 2/4 (BMP2/4) and transformation of growth factor β (TGF β) pathways. In ovariectomized mice, DLE suppressed the decrease in bone mineral density by 50% and improved the expression of other bone markers, which was confirmed by the 3~40-fold increase in osteogenic proteins and mRNA expression levels in bone marrow cells. The three major compounds identified in DLE exhibited osteogenic and estrogenic activities with their aglycones, as previously reported. Among the major compounds, myricitrin alone was not as strong as whole DLE with all its constituents. The osteogenic activity of DLE was partially suppressed by the inhibitor of estrogen signaling, indicating that the estrogenic activity of DLE participated in its osteogenic activity. Overall, DLE suppresses osteoporosis by inducing osteoblast differentiation.

Surrogate markers in assessment of bisphosphonate effectiveness in osteoporosis treatment (bone mineral density, bone turnover markers)

A review of the literature which summarizes our knowledge on the use of surrogate markers of the osteoporosis treatment effectiveness when on bisphosphonate (BP) therapy. Bone mineral density (BMD) and markers of bone turnover, which have been shown to be associated with the clinical fracture end point, have been used as surrogate criteria for the effectiveness of treatment of osteoporosis in randomized controlled trials. When prescribing BP for the treatment of osteoporosis, BMD measurement every 12 months by dual-energy x-ray absorptiometry (DXA) is the well-described surrogate marker of BP efficacy. At the same time, stabilization of BMD is also a criterion for the treatment effectiveness since changes in BMD determined only 16% of the anti-fracture effectiveness of BP. Markers of bone remodeling can be used as surrogate markers after 3 (bone resorption) or 6 (bone formation) months from the start of BP therapy. A decrease of 30% or more is considered to be prognostically effective for both antifracture and BMD gain. There is a direct relationship between the degree of bone remodeling markers decrease and the antifracture effectiveness of BP therapy. The decrease in markers persists throughout the entire period of therapy and, accordingly, they can be used as surrogate markers of effectiveness and adherence to BP therapy throughout the entire treatment period. However, the presence of pathological fractures is a key clinical manifestation of osteoporosis and should be considered first in every decision making compared to any surrogate marker.Thus, when prescribing BP treatment, surrogate markers of changes in BMD and/or markers of bone remodeling can be used to monitor the effectiveness of treatment throughout the entire period of treatment and patients’ monitoring.

Effects of Erythropoietin-Promoted Fracture Healing on Bone Turnover Markers in Cats.

In orthopaedics, erythropoietin (EPO) is applied in the preoperative management of anaemic patients, but also as a stimulating factor to assist bone regeneration due to its angiogenic and osteoinductive potential. Since orthopaedists mainly rely on their clinical experience to assess bone healing, additional and more objective methods such as studying the dynamics of bone markers are needed. Therefore, the aim of this study was to investigate the plasma activity of bone-specific alkaline phosphatase (BALP), the N-terminal propeptide of type I collagen (PINP), the C-terminal telopeptide of type I collagen (CTX), and deoxypyridinoline (DPD) during the first 2 months of healing of comminuted fractures in cats, either non-stimulated or locally stimulated with recombinant human erythropoietin (rhEPO). The study included twelve cats of mixed breeds, aged 7.2 ± 4 months, weighing 2.11 ± 1.1 kg, with comminuted diaphyseal fractures of the femur. Surgical treatment with plate osteosynthesis was performed in all animals. The cats were randomly divided into two groups-a control (n = 6) and an EPO group (n = 6). The locally applied EPO leads to the increased activity of bone formation markers (BALP and PINP) during the second week after the osteosynthesis, preceding the peaks in the control group by two weeks. The studied bone resorption markers (DPD, CTX) varied insignificantly during the studied period. In conclusion, erythropoietin could serve as a promoter of bone healing in comminuted fractures in cats.

Review of recommendations for bisphosphonate treatment interruption-discontinuation

Bisphosphonates are the main medications in the treatment of osteoporosis, which are effective in reducing the risk of fractures in patients with osteoporosis. It is known that after treatment with bisphosphonates, bone mineral density remains quite stable for a certain time, as well as markers of bone metabolism remain reduced, which, along with the side effects of long-term bisphosphonate therapy, determines the possibility of “Drug holidays”. At the same time, during a break in bisphosphonate treatment, the risk of fractures begins to increase, which is a reason to resume therapy.Currently, there is no uniform worldwide data of starting a “drug holidays” on bisphosphonates. The duration of the “drug holidays” also differs in clinical recommendations from different countries. When to conduct a risk assessment of fractures during a “drug holidays”? To answer these questions, we assessed existing clinical recommendations for treatment interruption/discontinuation of bisphosphonates. A literature search was conducted using the following resources: PubMed®, the Cochrane Library, websites of major international osteoporosis associations, and other targeted Internet searches. The main search terms were “Clinical Guideline of Osteoporosis”, “Bisphosphonates”, “Drug holidays in osteoporosis”, “Discontinuation of bisphosphonates”. Тhe search was carried out using articles in Russian and English published between January 1, 2016 and September 15, 2023. 17 clinical guidelines from different countries (Russian, American, European, Asian and Australian) were found and analyzed in which was information about the break in the treatment and withdrawal of bisphosphonates.The majority of clinical recommendations have the same opinion on the issue of starting “drug holidays”: with a moderate risk of fractures, you can take a break from treatment with tableted bisphosphonates after 5 years, after zoledronic acid — after 3 years of therapy. At high and very high risk of fractures, the duration of treatment is 10 and 6 years, respectively. The duration of “drug holidays” vary in the recommendations, but in most cases the decision-making is based not on the duration, but on the assessment of the risk of fractures with their regular reassessment, which includes previous and new low-energy fractures, the emergence of new risk factors, a decrease in BMD, the dynamics of bone markers, re-evalua­tion of FRAX®.

How Accurate Is Frameless Fiducial-Free Deep Brain Stimulation?

Frameless deep brain stimulation (DBS) offers advantages in terms of patient comfort and reduced operative time. However, the need for bony fiducial markers for localization remains a drawback due to the time-consuming and uncomfortable procedure. An alternative localization method involves the direct tracking of an intraoperative 3-dimensional scanner. This study aims to assess the accuracy of the NexFrame frameless DBS system in conjunction with the O-Arm (Medtronic Inc.), both with and without fiducial markers. The locations of 100 DBS leads were determined, with 50 cases using fiducial-free localization and 50 involving fiducial markers. The coordinates were compared with the expected intraoperative targets. Absolute errors in the X, Y, and Z coordinates (ΔX, ΔY, and ΔZ) were calculated, along with the vector error (Euclidean) (vector error ). The vector error averaged 1.61 ± 0.49 mm (right) and 1.52 ± 0.60 mm (left) for the group without fiducial bone markers and 1.66 ± 0.69 (right) and 1.44 ± 0.65 mm (left) for the other cohort (P = .76 right; P = .67 left). Absolute errors in the X, Y, and Z coordinates for the fiducial-free group were 0.88 ± 0.55, 0.79 ± 0.45, and 0.79 ± 0.57 mm (right) and 0.72 ± 0.37, 0.78 ± 0.56, and 0.77 ± 0.71 mm (left). For the group with fiducial markers, these errors were 0.87 ± 0.72, 0.92 ± 0.39, and 0.86 ± 0.50 mm (right) and 0.75 ± 0.33, 0.80 ± 0.51, and 0.73 ± 0.64 mm (left) with no statistically significant difference. Our analysis of the accuracy of NexFrame DBS, both with and without fiducial markers, using an intraoperative navigable cone-beam computed tomography, demonstrates that both techniques provide sufficient and equivalent 3-dimensional accuracy.

Plasma exosomal miR-30a-5p inhibits osteogenic differentiation of bone marrow mesenchymal stem cells from a chronic unpredictable mild stress-induced depression rat model

With rising society stress, depression-induced osteoporosis is increasing. However, the mechanism involved is unclear. In this study, we explored the effect of plasma exosomal miRNAs on bone marrow mesenchymal stem cell (BMSC) osteogenic differentiation in a chronic unpredictable mild stress (CUMS)-induced depression rat model. After 12 weeks of CUMS-induced depression, the pathological changes in the bone tissue and markers of osteogenic differentiation were tested by micro-computed tomography, hematoxylin-eosin staining, and quantitative real-time reverse transcription PCR (qRT-PCR). Plasma exosomes from rats were isolated and co-incubated with BMSCs for 14 d to detect the effect on osteogenic markers. Next-generation sequencing identified the miRNAs in the plasma exosomes, and the differential miRNAs were analyzed and verified by qRT-PCR. BMSCs were infected with lentivirus to upregulate miRNA-30a-5p and incubated in a medium that induced osteogenic differentiation for 14 d. The effect of miR-30a-5p on osteogenic differentiation was determined by qPCR and alizarin red staining. CUMS-induced depression rat model was established successfully, and exhibited reduced bone mass and damaged bone microstructure compared to that of the controls. The observed pathological changes suggested the occurrence of osteoporosis in the CUMS group, and the mRNA expression of osteogenic markers was also significantly reduced. Incubation of BMSCs with plasma exosomes from the CUMS group for 14 d resulted in a significant decrease in the expression of osteogenic markers. Twenty-five differentially expressed miRNAs in plasma exosomes were identified and upregulation of miR-30a-5p was observed to significantly inhibit the expression of osteogenic markers in BMSCs. Our findings contributed to a comprehensive understanding of the mechanism of osteoporosis caused by depression, and demonstrated the potential of miR-30a-5p as a novel biomarker or therapeutic target for the treatment of osteoporosis.

A radiographic and histological study to compare red (650 nm) versus near infrared (810 nm) diode lasers photobiomodulation for alveolar socket preservation

Previous findings indicated that the laser photobiomodulation is more effective than the control or placebo in preserving the alveolar socket. This study aimed to compare two different lasers regarding their effectiveness in aiding alveolar socket preservation. Twenty extraction sockets were selected then divided into two equal groups. Group A was exposed to 650 nm Diode laser, and Group B to 810 nm Diode laser following the same protocol and parameters after a standard alveolar socket preservation procedure with collagen plug. Radiographic analysis with cone beam computed tomography was done to compare the alveolar bone surface area immediately after extraction and three months post-operatively, while bone samples collected before implant drilling were histologically examined for newly formed bone evaluation and histomorphometric analysis in terms of percentage of new bone surface area, percentage of unmineralized bone and finally, immunohistochemical analysis of Osteocalcin reaction surface area as well as optical density. Radiographically, infrared (810 nm) Diode effect on alveolar bone surface area has significantly exceeded the red laser, while histologically, red (650 nm) Diode has demonstrated statistical significance regarding all parameters; newly formed bone surface area percentage, unmineralized bone area percentage and finally Osteocalcin bone marker reaction surface area percentage and optical density. Under the specified conditions and laser parameters, photobiomodulation using the 810 nm Diode got the upper hand radiographically, yet histologically, the red 650 nm Diode managed to dominate all histological parameters when both employed as an adjunct to alveolar socket preservation procedures.

Biochemical characteristics and clinical manifestation of normocalcemic primary hyperparathyroidism.

Normocalcemic primary hyperparathyroidism (nPHPT) is a condition characterized by persistently high levels of parathyroid hormone (PTH) and normal serum calcium levels in the absence of other causes for secondary hyperparathyroidism. The aim of the present study was to assess the clinical presentation and the biochemical characteristics in patients with nPHPT and to compare them with those in patients with hypercalcemic PHPT (hPHPT). The study included 316 patients (277 women and 39 men, average age 58.7 ± 12.1) diagnosed with PHPT. Total serum calcium, inorganic phosphates (PO4), PTH, urinary Ca (uCa), albumin, creatinine, 25(OH)D and bone markers (b-CTX and ALP) were examined in all of them. BMD of the lumbar spine (LS), distal third of the radius (DR), femoral neck (FN) and total proximal femur (TF) were measured by a dual-energy X-ray absorptiometry (DXA). The patients were divided into two groups according to albumin-corrected calcium (Ca) level - with hPHPT (Ca>2.62 mmol/L) and with nPHPT (Ca 2.12-2.62 mmol/l), without other causes for secondary hyperparathyroidism. The frequency of nPHPT was 15.2%. Normocalcemic patients had lower levels of PTH, higher PO4 and 25(OH)D, and smaller parathyroid adenomas. No significant difference in the frequency of osteoporosis, low-energy fractures, nephrolithiasis and gastrointestinal disorders was found between nPHPT and hPHPT. There was no difference in BMD between the two groups. The patients with nPHPT show a more favorable biochemical profile compared to those with hPHPT. Nevertheless, clinical manifestations and complications are similar, without a significant difference in the frequency of osteoporosis, nephrolithiasis, gastrointestinal disorders and low-energy fractures.

Oleanolic acid exerts bone anabolic effects via activation of osteoblastic 25-hydroxyvitamin D 1-alpha hydroxylase

Oleanolic acid (OA) is previously shown to exert bone protective effects in aged animals. However, its role in regulating osteoblastic vitamin D bioactivation, which is one of major causes of age-related bone loss, remains unclear. Our results revealed that treatment of OA significantly increased skeletal CYP27B1 expression and circulating 1,25(OH)2D3 in ovariectomized mice (p <0.01). Moreover, OA upregulated CYP27B1 protein expression and activity, as well as the vitamin D-responsive bone markers alkaline phosphatase (ALP) activity and osteopontin (OPN) protein expression, in human osteoblast-like MG-63 cells (p<0.05). CYP27B1 expression increased along with the osteoblastic differentiation of human bone marrow derived mesenchymal stem cells (hMSCs). CYP27B1 expression and cellular 1,25(OH)2D3 production were further potentiated by OA in cells at mature osteogenic stages. Notably, our study suggested that the osteogenic actions of OA were CYP27B1 dependent. In summary, the bone protective effects of OA were associated with the induction of CYP27B1 activity and expression in bone tissues and osteoblastic lineages. Hence, OA might be a potential approach for management of age-related bone loss.

Bone metabolism in children with normal weight and overweight/obesity in a northeastern region of Spain.

Bone mass progressively increases to peak during childhood and adolescence, which determines future bone health. Bone formation-resorption processes are assessed using bone markers. However, studies on the impact of obesity on bone turnover markers at this age are limited, and results are inconsistent. The objective of this study was to examine the potential impact of overweight/obesity on bone metabolism. A study was performed to compare parameters of bone metabolism in 45 girls and boys with normal weight (controls) and in a group of 612 girls and boys with overweight/obesity (cases) from the Exergames study (University of Zaragoza). Ages ranged from 8 to 12 years. Higher values of phosphorus and IGFBP-3 were observed in children with overweight/obesity, as compared to children with normal weight, (p=0.042) and (p=0.042), respectively. BAP, osteocalcin, magnesium, vitamin D and IGF-I concentrations were lower in the group with overweight/obesity, whereas calcium concentrations were higher in this group, although differences were not statistically significant. A negative correlation was found (r=-0.193) (p=0.049) between BAP and BMI. Although differences did not reach statistical significance, BAP and osteocalcin concentrations were lower in children with overweight/obesity. This added to the negative correlation found between BAP and MIC may demonstrate that overweight/obesity may negatively affect bone health already at a young age.

Evaluation of the trend of set-up errors during the treatment period using set-up margin in prostate radiotherapy

Accurate information on set-up error during radiotherapy is essential for determining the optimal number of treatments in hypofractionated radiotherapy for prostate cancer. This necessitates careful control by the radiotherapy staff to assess the patient's condition. This study aimed to develop an evaluation method of the temporal trends in a patient's specific prostate movement during treatment using image matching and margin values. This study included 65 patients who underwent prostate volumetric modulated arc therapy (mean treatment time, 87.2 s). Set-up errors were assessed using bone, inter-, and intra-fraction marker matching across 39 fractions. The set-up margin was determined by dividing the four periods into 39 fractions using Stroom's formula and correlation coefficient. The intra-fraction set-up error was biased in the anterior-superior (AS) direction during treatment. The temporal trend of set-up errors during radiotherapy slightly increased based on bone matching and inter-fraction marker matching, with a 1.6-mm difference in the set-up margin fractions 11 to 20. The correlation coefficient of the mean prostate movement during treatment significantly decreased in the superior-inferior direction, while remaining high in the left-right and anterior-posterior directions. Image matching contributed significantly to the improvement of set-up errors; however, careful attention is needed for prostate movement in the AS direction, particularly during short treatment times. Understanding the trend of set-up errors during the treatment period is essential in numerical information sharing on patient condition and evaluating the margins for tailored hypo-fractionated radiotherapy, considering the facility's image-guided radiation therapy technology.

The Effect of Clopidogrel and Ticagrelor on Human Adipose Mesenchymal Stem Cell Osteogenic Differentiation Potential: In Vitro Comparative Study.

Ticagrelor (TICA) and clopidogrel (CLP) are extensively used antiplatelet drugs that act by antagonizing the P2Y12 receptors that are found on platelets in addition to bone cells. Aim. The purpose of this study was to investigate the effect of clopidogrel and ticagrelor on stem cells osteogenic differentiation in vitro. Methods. Human adipose-derived mesenchymal stem cells (hAd-MSCs) were divided into (1) control group, (2) osteogenic group (osteo group), (3) clopidogrel group (CLP group), and (4) ticagrelor group (TICA group). The osteogenic differentiation potential was determined by mineralization nodule formation using Alizarin Red S staining, measuring ALP enzyme activity by alkaline phosphatase assay. Quantitative determination for osteogenic markers included osteocalcin (OC); runt-related transcription factor 2 (RUNX2) performed using western blot; osteoprotegerin (OPG) using enzyme-linked immunosorbent assay (ELISA) and inflammatory markers; and tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) measured using real-time polymerase chain reaction quantitative (RT-PCR) and ELISA. Results. In comparison to all study groups, the TICA group showed significant increase in the mineralized extracellular matrix, ALP enzyme activity, and bone markers expression as RUNX2 (P < 0.0001), OC, and OPG (P < 0.05). The expression of IL-6 and TNF-α was determined by RT-qPCR and ELISA techniques. TICA and CLP significantly decreased both markers compared to the control group. The TICA group showed statistically significant lower levels of both markers (P < 0.0001) than the CLP and control groups via the ELISA technique. Conclusion. TICA may possess a positive effect on hAd-MSCs osteogenic differentiation compared to CLP.

Computed tomography and three dimensional anatomical study of the liver in the chinchilla (Chinchilla lanigera).

Few instances of neoplastic formations in the liver of chinchillas have been found, even though the species is widely used in different scientific experiments. In the present article we investigate the anatomical features of the chinchilla's liver using CT and three dimension (3D) imaging. For the trials we used 12 (six males and six females) clinically healthy chinchillas all at 18 months of age. The animals were positioned in dorsal recumbency. We used Th8 to L2 vertebrae and the sternum as bone markers for the transverse CT study. The investigated anatomical landmarks for the CT coronal study were the vertebrae, costal arch, soft abdominal wall, diaphragm, stomach and the right kidney. 3D reconstructions were accomplished with a specific imaging software. On transverse and coronal CT images, the chinchilla's liver was composed of lobus hepatis sinister lateralis, 'middle lobe'-without proper Latin term in NAV 2017, lobus hepatis dexter and lobus caudatus. The 'middle lobe' was separated into the 'left middle lobe' and the 'right middle lobe'. Lobus hepatis dexter consisted of lobus hepatis dexter medialis and lobus hepatis dexter lateralis. There was an anatomical relation between the liver, fundus ventriculi and corpus ventriculi. Proc. caudatus was in close contact with the right kidney. Vesica fellea was elongated and ellipsoid. 3D reformatted images confirmed the results obtained by transverse and coronal CT studies. The CT density of the liver in HU was 195.6 ± 73.1. The CT and 3D reconstructed images were visualized at high resolution. This data could be used as a basis for further morphological and imaging studies.

The differential effect of modern intravenous iron on fibroblast growth factor 23 and phosphate in non-dialysis dependent CKD – the exploratory randomized controlled double-blind ExplorIRON-CKD study

BackgroundIntravenous iron is commonly used in patients with non-dialysis-dependent chronic kidney disease (CKD). Modern intravenous iron compounds (e.g. ferric derisomaltose (FDI), ferric carboxymaltose (FCM)) are increasingly utilized with similar efficacy. A differential effect in terms of hypophosphatemia has been noted following administration of FCM, which may be related to fibroblast growth factor 23 (FGF23). This study was designed to examine the comparative effects of FDI and FCM on FGF23, phosphate and other markers of bone turnover.MethodsThe single-center double-blind randomized controlled trial “Iron and Phosphaturia – ExplorIRON-CKD” primarily assessed the effects of FCM and FDI on intact FGF23 and phosphate, whilst also studying the impact on vitamin D, parathyroid hormone and phosphaturia. Bone markers including alkaline phosphatase, bone-specific alkaline phosphatase, procollagen type 1 N-terminal propeptide and carboxy-terminal collagen cross-linked telopeptide were monitored. Non-dialysis-dependent CKD patients (stage 3a-5) with iron deficiency with/without anemia (serum ferritin < 200 µg/L or transferrin saturation = 20% and serum ferritin 200-299 µg/L) were randomized to receive FDI or FCM in a 1:1 ratio. At baseline 1000 mg of intravenous iron was administered followed by 500-1000 mg at 1 month to achieve replenishment. Measurements were performed at baseline, 1–2 days following iron administration, 2 weeks, 1 month (second iron administration), 1–2 days following second administration, 2 months and 3 months following initial infusion.ResultsTwenty-six patients participated in the trial; 14 randomized to FDI and 12 to FCM. Intact FGF23 increased following administration of iron, and the increase was significantly higher with FCM compared to FDI (Baseline to 1–2 days following 1st administration: FDI: 3.0 (IQR: - 15.1 - 13.8) % vs. FCM: 146.1 (IQR: 108.1–203.1) %; p < 0.001 and Baseline to 1–2 days following 2nd administration: FDI: 3.2 (IQR: - 3.5 – 25.4) % vs. FCM: 235.1 (138.5–434.6) %; p = 0.001). Phosphate levels decreased in the FCM group, causing a significant difference versus FDI 2 weeks following administration of the first dose. A significantly greater decrease in 1,25 (OH)2 Vitamin D was noted with FCM. Several markers of bone turnover significantly changed following administration of FCM but not FDI.ConclusionsThe study suggests a differential effect on FGF23 following administration of FCM compared to FDI in non-dialysis-dependent CKD patients, similar to other patient groups. This may lead to changes consistent with hypovitaminosis D and alterations in bone turnover with potential clinical consequences. Further definitive studies are required to understand these differences of intravenous iron compounds.Trial registrationEuropean Union Drug Regulating Authorities Clinical Trials Database (EudraCT) number: 2019–004370-26 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004370-26/GB) (First date of trial registration: 03/12/2019).

Assessment of Biochemical Bone Turnover Markers in Polish Healthy Children and Adolescents.

Assessing bone turnover in paediatric populations is crucial for understanding the physiological changes occurring during skeletal development and identifying potential abnormalities. The objective of this study was to assess osteocalcin (OC), bone alkaline phosphatase (BALP), and C-terminal telopeptide of type I collagen (CTX-I) levels reflecting bone formation and resorption for age and sex in Polish healthy children and adolescents. A total of 355 healthy normal-weight children and adolescents (46.5% girls) aged 1-18 years old were recruited. Total body less head (TBLH) and spine L1-L4 were used in children to assess bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA). Bone marker concentrations were determined by immunoenzymatic methods. Bone marker levels in girls and boys started with higher values in the first year of life and subsequently decreased until reaching a nadir during the prepubertal period. The pubertal peak values of bone markers were reached at 11-13 years old in boys and at 9-11 years old in girls. After puberty, the adolescents showed a gradual decline in bone marker concentrations to the values observed in adults. We found positive correlations between OC level and TBLH-BMD (r = 0.329, p = 0.002), TBLH-BMD Z-score (r = 0.245, p = 0.023), and L1-L4 BMD (r = 0.280, p = 0.009) in the prepubertal group. We showed serum levels of bone turnover markers-BALP, OC, and CTX-I-in relation to age and sex in healthy Polish children and adolescents. The age intervals of these markers for girls and boys aged 1-18 years old may be clinically useful in the assessment of bone metabolism in individuals with skeletal disorders.

Sex differences in the effects of repeated ketamine infusions on bone markers in patients with unipolar and bipolar depression

BackgroundPatients with depression, especially women, are associated with low bone mineral density (BMD). Traditional antidepressants are associated with negative effects on BMD. Few studies have examined the effect of ketamine on BMD, and it remains unclear whether there are sex differences in the effects of ketamine on BMD in patients with depression.MethodsA total of 102 patients with unipolar and bipolar depression were administered six infusions of intravenous ketamine over a 12-day period. Plasma levels of eight bone markers were examined at baseline, 24 h after the sixth infusion and again 2 weeks (Days 13 and 26).ResultsLinear mixed models showed all bone markers had significant time main effect (all p < 0.05). Compared with baseline, the whole sample showed increased levels of leptin and osteoprotegerin at Days 13 and 26, as well as Dickkopf-related protein 1 at Day 13, and decreased levels of osteocalcin, sclerostin, osteopontin, parathyroid hormone and fibroblast growth factor 23 at Days 13 and 26 (all p < 0.05). Females had a higher level of leptin at Days 13 and 26, and lower levels of osteocalcin and sclerostin at Day 13 than males (all p < 0.05). Increases of leptin were associated with depressive symptom improvements at Day 13 and Day 26 in females (both p < 0.05). In males, higher baseline osteocalcin levels were associated with greater depressive symptom improvement at Day 26 (β = 0.414, p = 0.009).ConclusionsOur results suggest that repeated ketamine infusions may be associated with modulation of bone markers in patients with depression and present sex differences. Baseline osteocalcin level may be served as a predictor for the antidepressant effects of ketamine in males.Trial registration Data were derived from an open label clinical trial, which was registered at Chinese Clinical Trial Registry (ChiCTR-OOC-17012239). Registered 26 May 2017. http://www.chictr.org.cn

Prevalence of Morphometric Vertebral Fractures After Bariatric Surgery and Its Relationship with Bone Mineral Density and Bone Markers.

Bariatric surgery (BS) can lead to bone loss and an increased fracture risk. To determine the morphometric vertebral fracture (MVF) prevalence, and its relationship with bone mineral density (BMD), and biomarker's turnover after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), we analyzed post-surgery X-rays of the spine in 80 patients (88% female, 51% RYGB, age 41.2 [6.8] years) from 117 participants' retrospective cohort (1-2 years, >2 and <5 years, and >5 years). We still analyzed body composition and BMD by dual-energy X-ray absorptiometry and bone parameters. MVF prevalence was 17.5% (14/80), with no statistical difference between groups (p = 0.210). RYGB group had a higher prevalence of secondary hyperparathyroidism (SHPT) (PTH ≥ 65 pg/ml; 18.4% vs 7.8%, respectively, p = 0.04), PTH (61.3 vs 49.5 pg/ml, p = 0.001), CTX (0.766 [0.29] ng/ml vs 0.453 [0.30] ng/ml, p = 0.037), and AP (101.3 [62.4] U/L vs 123.9 [60.9] U/L, p = 0.027) than the SG group. Up to 5 years postoperatively, RYGB had a lower total (1.200 [0.087] vs 1.236 [0.100] g/cm2, p = 0.02), femoral neck (1.034 [0.110] vs 1.267 [0.105], p = 0.005), and total femur BMD (1.256 [0.155] vs 1.323 [0.167], p = 0.002) than SG group. We found no statistically significant difference between the MFV (+) and MVF (-) groups regarding age, sex, BMI, surgery time, BMD, or bone and metabolic parameters, including leptin. We found a high prevalence of MVF after BS with no differences between RYGB and SG.

The Phenotype of Mesenchymal Stromal Cell and Articular Chondrocyte Cocultures on Highly Porous Bilayer Poly-L-Lactic Acid Scaffolds Produced by Thermally Induced Phase Separation and Supplemented with Hydroxyapatite.

Bilayer scaffolds could provide a suitable topology for osteochondral defect repair mimicking cartilage and subchondral bone architecture. Hence, they could facilitate the chondro- and osteogenic lineage commitment of multipotent mesenchymal stromal cells (MSCs) with hydroxyapatite, the major inorganic component of bone, stimulating osteogenesis. Highly porous poly-L-lactic acid (PLLA) scaffolds with two layers of different pore sizes (100 and 250 µm) and hydroxyapatite (HA) supplementation were established by thermally induced phase separation (TIPS) to study growth and osteogenesis of human (h) MSCs. The topology of the scaffold prepared via TIPS was characterized using scanning electron microscopy (SEM), a microCT scan, pycnometry and gravimetric analysis. HMSCs and porcine articular chondrocytes (pACs) were seeded on the PLLA scaffolds without/with 5% HA for 1 and 7 days, and the cell attachment, survival, morphology, proliferation and gene expression of cartilage- and bone-related markers as well as sulfated glycosaminoglycan (sGAG) synthesis were monitored. All scaffold variants were cytocompatible, and hMSCs survived for the whole culture period. Cross-sections revealed living cells that also colonized inner scaffold areas, producing an extracellular matrix (ECM) containing sGAGs. The gene expression of cartilage and bone markers could be detected. HA represents a cytocompatible supplement in PLLA composite scaffolds intended for osteochondral defects.

ACCURACY OF A FRAMELESS OPTICAL STEREOTACTIC NEURONAVIGATION SYSTEM FOR BRAIN BIOPSY IN CATS: A CADAVERIC STUDY

Image-guided stereotactic techniques can display the locations of surgical instruments and biopsy targets in real time, allowing minimally invasive brain biopsies with reduced risk. This study aimed to assess the accuracy of an optical frameless neuronavigation system in feline cadavers and describe potential influencing factors. Phantom lesions were created in different brain regions and depths in 15 feline cadavers. After installing eight fiducial markers in the frontal bone and zygomatic arches, magnetic resonance imaging (MRI) was performed, and the images were imported into the neuronavigation system. Following patient and instrument registration, diluted gadolinium was injected into the phantom lesion (target), guided by the neuronavigation system. The coordinates of the target and contrast points were determined on repeated MRI scans and the distance between them was defined as the targeting error. The time from target selection to the completion of gadolinium injection was recorded as the required time. The targeting error and required time were compared between the initial 30% and final 30% of the collected data to assess the influence of operator experience. Among 76 lesions, the mean targeting error was [Formula: see text][Formula: see text]mm (95% confidence interval 2.76–3.15[Formula: see text]mm). Lesion location, lesion depth, and operator experience did not affect the accuracy; however, operator experience reduced the required time. This frameless optical neuronavigation system is potentially feasible for feline brain biopsy. The demonstrated accuracy substantiates its clinical utility for feline brain lesions [Formula: see text][Formula: see text]mm, and is comparable to that of other neuronavigation systems described in dogs.

Hormonal contraceptive use is associated with altered bone structural and metabolic responses to military training in women: An observational cohort study

Military training increases tibial density and size. Female sex hormones may influence the adaption of bone to loading, but it is unknown if women using different hormonal contraceptives adapt similarly to military training. One hundred and sixteen women (57 women not using hormonal contraceptives [non-users], 38 combined oral contraceptive pill [COCP] users, 21 depot medroxyprogesterone acetate [DMPA] users) completed this study. Tibial volumetric bone mineral density (vBMD) and geometry were measured by peripheral quantitative computed tomography (4 %, 14 %, 38 %, and 66 % sites) at the start (week 1) and end (week 14) of British Army basic training. Circulating markers of bone and calcium metabolism were measured at weeks 1, 2, 4, 6, 10, and 14. Training increased trabecular vBMD at the 4 % site, periosteal perimeter at the 14 % and 66 % sites, and total area, cortical area, cortical thickness, and bone strength at all sites (0.1 to 1.6 %, p ≤ 0.009), with no differences between hormonal contraceptive groups (p ≥ 0.127). Trabecular vBMD increased at the 14 % site in non-users (0.8 %, p = 0.005), but not in COCP or DMPA users (p ≥ 0.205). Periosteal perimeter increased at the 38 % site in COCP (0.4 %, p < 0.001) and DMPA (0.5 %, p < 0.001) users, but not in non-users (p = 0.058). Training had no effect on periosteal perimeter at the 4 % site or cortical vBMD or endosteal perimeter at any site (p ≥ 0.168). βCTX decreased and PINP increased during training with no difference between hormonal contraceptive groups. Training increased iPTH in non-users, but not COCP or DMPA users. Hormonal contraceptives may exert site-specific effects on the mechanobiology of bone, with higher endogenous oestradiol promoting trabecularisation and inhibiting periosteal expansion in non-users compared with hormonal contraceptive users.