Cross-linked Carboxyterminal Telopeptide Of Type Research Articles

Bone mineral density in the various regions of the skeleton in women with subclinical hypothyroidism: the effect of biological factors, bone turnover markers and physical activity

Abstract Study aim: This cross-sectional study examined the relationship between biological factors, physical activity (PA), bone turnover markers (BTMs) and bone mineral density (BMD) in women with subclinical hypothyroidism (SCH) and healthy. Material and methods: The study included 135 women. Bone parameters were measured by the densitometry. Calcium, phosphorus, osteocalcin (OC), total alkaline phosphatase (ALP), bone-specific alkaline phosphatase (BALP), vitamin D and cross-linked carboxyterminal telopeptide of type I collagen (ICTP) were measured in blood serum. PA were evaluated by metabolic equivalent of task (MET). Results: Women with SCH had lower BMD in hip and lumbar spine, calcium, vitamin D and higher values of ICTP than the healthy group. In women with SCH, the affecting BMD in the femoral neck were ICTP (µg/l), (η² = 0.083), and also 25(OH)D (ng/ml), (η² = 0.080) and PA level (I/S), (η² = 0.115). BMD in the spine was affected by PA level (I/S), (η² = 0.173). The parameters affecting BMC in the femoral neck were 25(OH)D (ng/ml), (η² = 0.073). In all women sufficient levels of PA determined higher BMD. Conclusions: PA and BTMs significantly determine BMD levels. PA can be an important area of rehabilitation and physical therapy as an available measure to counteract BMD loss in postmenopausal healthy women and those with SCH.

Baseline serum levels of cross-linked carboxy-terminal telopeptide of type I collagen predict abatacept treatment response in methotrexate-naive, anticitrullinated protein antibody-positive patients with early rheumatoid arthritis

ObjectiveTo investigate correlations between biomarkers of bone remodelling and extracellular matrix turnover with baseline disease activity and treatment response in patients with early rheumatoid arthritis (RA).MethodsAssessing Very Early Rheumatoid arthritis...

Bone homeostasis disorders increased the mortality of sepsis patients: A preliminary retrospective cohort study.

Sepsis is a common clinical syndrome and nearly 20% of all deaths are related to sepsis. As an important part of the body, bone homeostasis disorders are closely related to inflammatory response, but the correlation between bone homeostasis and sepsis, sepsis shock was unknown. The objective of this study was to explore the relation of bone homeostasis on sepsis and sepsis shock. In this retrospective cohort study, patients were enrolled between April 2018 and May 2022 from Beijing Chaoyang hospital. Primary outcomes were serum indicators reflected bone homeostasis, such as cross-linked carboxy-terminal telopeptide of type I collagen (CTX-I), tartrate-resistant acid phosphatase 5b (TRACP-5b) and piezo-type mechanosensitive ion channel component 1 (PIEZO1). The data were analyzed retrospectively. among 88 evaluable patients, 45 were sepsis (19 were sepsis shock) and 43 were non-sepsis. There was no significant difference in age, gender, BMI, combination diseases, operation time, intraoperative blood loss, and hospital stay. Patients with sepsis or sepsis shock had higher serum CTX-I, TRACP-5b, PIEZO1 (p < 0.05). Spearman's rank correlation test showed that CTX-I, TRACP-5b, PIEZO1 and the three together (CTX-I + TRACP-5b + PIEZO1) had strong correlation with sepsis or sepsis shock (p < 0.05). The receiver operating characteristic curve (ROC) and precision-recall curve (PRC) showed that these indicators could predict the occurrence of sepsis or sepsis shock (p < 0.05). Besides, decision curve analysis (DCA) and interventions avoided curve (IAC) displayed a high net benefit of bone homeostasis disorders indicators on sepsis or sepsis shock. Kaplan-Meier survival curves revealed that sepsis or shock patients with high value indicators (>0.47227) had a higher mortality (p < 0.05). Bone homeostasis disorders could increase the mortality of sepsis and sepsis shock patients.

Ethanol alters the relationship between IGF-1 and bone turnover in male macaques.

Insulin-like growth factor 1 (IGF-1) influences bone turnover. Transient decreases in IGF-I levels and/or bioavailability may contribute to the detrimental effects of alcohol on bone. The goals of this non-human primate study were to i) evaluate the 20-h response of bone turnover markers to ethanol consumption and ii) assess how ethanol consumption influences the relationship between IGF-1 and these markers. Osteocalcin (bone formation), carboxyterminal cross-linking telopeptide of type 1 collagen (CTX, bone resorption), IGF-1, and IGF binding protein 1 (IGFBP-1) were measured in plasma from male rhesus macaques (N = 10, 8.4 ± 0.3 years) obtained at 12:00, 16:00, and 06:00 h during two phases: pre-ethanol (alcohol-naïve) and ethanol access. During the ethanol access phase, monkeys consumed 1.5 g/kg/day ethanol (4% w/v) beginning at 10:00 h. Osteocalcin and CTX were lower, and the ratio of osteocalcin to CTX was higher at each time point during ethanol access compared to the pre-ethanol phase. Pre-ethanol marker levels did not vary across time points, but markers varied during ethanol access. IGF-1 levels, but not IGFBP-1 levels, varied during the pre-ethanol phase. In contrast, IGF-1 levels were stable during ethanol access but IGFBP-1 levels varied. There were positive relationships between IGF-1 and turnover markers during the pre-ethanol phase, but not during ethanol access. In conclusion, chronic ethanol consumption reduces levels of bone turnover markers and blocks the normal positive relationship between IGF-1 and turnover markers and alters the normal relationship between IGF-1 and IGFBP-1. These findings support the hypothesis that chronic alcohol consumption leads to growth hormone/IGF-1 resistance.

A clinical trial of a unidirectional porous tricalcium phosphate filling for defects after resection of benign bone lesions: a prospective multicenter study.

Affinos (Kuraray, Japan) is a β-tricalcium phosphate bone substitute with a unidirectional porous structure. This study aimed to investigate its efficacy on the healing process after filling for bone defects. Fifty-six patients who met the inclusion criteria were divided into cohort 1 (n = 30), including bones other than phalanges and metacarpal/tarsal bones, and cohort 2 (n = 26), including phalanges and metacarpal/tarsal bones. Semi-quantified scores for material resorption and trabeculation through the defect were evaluated with radiographs after surgery. In some patients, levels of bone metabolic markers were assessed. The values of resorption and trabeculation increased steadily with time, and trabeculation progressed compared with resorption in both cohorts. In cohort 1, multiple regression analyses showed that the diaphyseal lesion, smaller defect volume, and increased resorption values at 3 months were associated with increased values of resorption 12 months after surgery (R2 = 0.66, p < 0.001). The trabeculation values at 2 months were positively related to the trabeculation values 12 months after surgery (R2 = 0.35, p = 0.002). In cohort 2, the increased resorption values at 2 months and smaller defect volume significantly correlated with the increased resorption values 12 months after surgery (R2 = 0.58, p < 0.001). The ratio from the baseline of pyridinoline cross-linked carboxyterminal telopeptide of type I collagen at 3 months was negatively associated with the trabeculation values 12 months after surgery (R = − 0.791, p = 0.004). Evaluation of radiographic images and bone metabolic markers in the early postoperative period may predict the healing status at 12 months postoperatively in the defects followed by Affinos filling.

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

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

Resveratrol Ameliorates High Altitude Hypoxia-Induced Osteoporosis by Suppressing the ROS/HIF Signaling Pathway.

Hypoxia at high-altitude leads to osteoporosis. Resveratrol (RES), as an antioxidant, has been reported to promote osteoblastogenesis and suppress osteoclastogenesis. However, the therapeutic effect of RES against osteoporosis induced by high-altitude hypoxia remains unclear. Thus, this study was intended to investigate the potential effects of RES on high-altitude hypoxia-induced osteoporosis both in vivo and in vitro. Male Wistar rats were given RES (400 mg/kg) once daily for nine weeks under hypoxia, while the control was allowed to grow under normoxia. Bone mineral density (BMD), the levels of bone metabolism-related markers, and the changes on a histological level were measured. Bone marrow-derived mesenchymal stem cells (BMSCs) and RAW264.7 were incubated with RES under hypoxia, with a control growing under normoxia, followed by the evaluation of proliferation and differentiation. The results showed that RES inhibited high-altitude hypoxia-induced reduction in BMD, enhanced alkaline phosphatase (ALP), osteocalcin (OCN), calcitonin (CT) and runt-related transcription factor 2 (RUNX2) levels, whereas it reduced cross-linked carboxy-terminal telopeptide of type I collagen (CTX-I) levels and tartrate-resistant acid phosphatase (TRAP) activity in vivo. In addition, RES attenuated histological deteriorations in the femurs. In vitro, RES promoted osteoblastogenesis and mineralization in hypoxia-exposed BMSCs, along with promotion in RUNX2, ALP, OCN and osteopontin (OPN) levels, and inhibited the proliferation and osteoclastogenesis of RAW264.7. The promotion effects of RES on osteoblastogenesis were accompanied by the down-regulation of reactive oxygen species (ROS) and hypoxia inducible factor-1α (HIF-1α) induced by hypoxia. These results demonstrate that RES can alleviate high-altitude hypoxia-induced osteoporosis via promoting osteoblastogenesis by suppressing the ROS/HIF-1α signaling pathway. Thus, we suggest that RES might be a potential treatment with minimal side effects to protect against high-altitude hypoxia-induced osteoporosis.

Abaloparatide Increases Lumbar Spine and Hip BMD in Japanese Patients With Osteoporosis: The Phase 3 ACTIVE-J Study.

ContextAbaloparatide reduced fracture risk in postmenopausal women with osteoporosis in the Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE). Its effect in Japanese patients remains unexamined.ObjectiveThis work aimed to determine the efficacy and safety of abaloparatide in increasing bone mineral density (BMD) in Japanese patients with osteoporosis at high fracture risk.MethodsThis was a randomized, double-blind, placebo-controlled study conducted in Japan. Postmenopausal women and men with osteoporosis with high fracture risk were given daily subcutaneous 80 µg abaloparatide or placebo for 78 weeks (18 months). The primary end point was percentage change in lumbar spine (LS) BMD from baseline at the last visit. Secondary end points included time-course changes in LS, total hip (TH), and femoral neck (FN) BMDs and bone turnover markers, and cumulative number of fractures.ResultsAbaloparatide increased LS, TH, and FN BMDs (mean [95% CI]) by 12.5% (10.3%-14.8%; P < .001), 4.3% (3.3%-5.3%), and 4.3% (2.9%-5.6%), respectively, vs placebo. Serum procollagen type I N-terminal propeptide increased rapidly to ~ 140% above baseline at 6 weeks and gradually decreased but was approximately 25% higher than baseline at 78 weeks. Serum carboxy-terminal cross-linking telopeptide of type I collagen gradually increased to 50% above baseline at 24 weeks and decreased gradually to the placebo-group level from 60 weeks. Four vertebrae of 3 participants in the placebo group, but none in the abaloparatide group, developed new vertebral fractures. The safety profile was similar to that in the ACTIVE study.ConclusionIn Japanese patients with postmenopausal and male osteoporosis with high fracture risk, abaloparatide for 78 weeks robustly increased LS, TH, and FN BMDs, suggesting a similar efficacy in Japanese patients vs the ACTIVE study population.

Bone Density, Geometry, and Mass by Peripheral Quantitative Computed Tomography and Bone Turnover Markers in Children with Diabetes Mellitus Type 1.

Background The type 1 diabetes mellitus (T1DM) is a chronic systemic autoimmune-mediated disease characterised by the insulin deficiency and hyperglycaemia. Its deleterious effect on bones concerns not only bone mass, density, and fracture risk but also may involve the linear growth of long bones. Studies on the lower leg in children with T1DM by pQCT have generated conflicting results, and most of the studies published so far focused only on a selected features of the bone. An additional information about growth, modelling, and remodelling processes can be gathered by the bone turnover marker measurement. The objective of the study was to evaluate bone mineral density, mass, and geometry using peripheral quantitative computed tomography as well as bone turnover markers in the patients with type 1 diabetes mellitus. Material and Methods. Bone mineral density, mass, and geometry on the lower leg using peripheral quantitative computed tomography and serum osteocalcin (OC) and carboxyterminal cross-linked telopeptide of type 1 collagen (CTx) were measured in 35 adolescents with T1DM (15 girls) aged 12.3-17.9 yrs. The results were compared to age- and sex-adjusted reference values for healthy controls. Results Both sexes reveal lower than zero Z-scores for lower leg 66% total cortical bone cross-sectional area to muscle cross-sectional area ratio (−0.97 ± 1.02, p = 0.002517 and −0.98 ± 1.40, p = 0.007050, respectively) while tibia 4% trabecular bone density Z-score was lowered in boys (−0.67 ± 1.20, p = 0.02259). In boys in Tanner stage 5 bone mass and dimensions were diminished in comparison to Tanner stages 3 and 4, while in girls, such a phenomenon was not observed. Similarly, bone formation and resorption were decreased in boys but not in girls. Consistently, bone turnover markers correlated positively with bone size, dimensions, and strength in boys only. Conclusions T1DM patients revealed a decreased ratio of cortical bone area/muscle area, reflecting disturbed adaptation of the cortical shaft to the muscle force. When analyzing bone mass and dimensions, boys in Tanner stage 5 diverged from “less-mature” individuals, which may suggest that bone development in these individuals was impaired, affecting all three: mass, size, and strength. Noted in boys, suppressed bone metabolism may result in impairment of bone strength because of inadequate repair of microdamage and accumulation of microfractures.

Menstrual Cycle Related Fluctuations in Circulating Markers of Bone Metabolism at Rest and in Response to Running in Eumenorrheic Females

This study examined potential fluctuations in bone metabolic markers across the menstrual cycle both at rest and after a 30-min bout of continuous running at 80% of V̇O2max. Resting and post-exercise (0, 30, 90min) sclerostin, parathyroid hormone (PTH), carboxy-terminal cross-linking telopeptide of type I collagen (β-CTXI), and procollagen type 1N propeptide (PINP) were assessed in 10 eumenorrheic women (age: 21 ± 3 y, BMI: 23.2 ± 3.0kg.m2) during the mid- to late-follicular (FP: day 8.0 ± 1.4) and mid-luteal (LP: day 22.0 ± 2.5) phases of the menstrual cycle. Ovulation was determined using ovulation kits and daily measurement of oral body temperature upon awakening. Menstrual cycle phase was subsequently confirmed by measurement of plasma estradiol and progesterone. On average, resting estradiol concentrations increased from 46.3 ± 8.9pg·mL-1 in the FP to 67.3 ± 23.4pg·mL-1 in the LP (p = 0.015), and resting progesterone increased from 4.12 ± 2.36ng·mL-1 in the FP to 11.86 ± 4.49ng·mL-1 in the LP (p < 0.001). At rest, there were no differences between menstrual cycle phases in sclerostin (FP: 260.1 ± 135.0pg·mL-1; LP: 303.5 ± 99.9pg·mL-1; p = 0.765), PTH (FP: 0.96 ± 0.64pmol·L-1; LP: 0.79 ± 0.44pmol·L-1; p = 0.568), β-CTXI (FP: 243.1 ± 158.0ng·L-1; LP: 202.4 ± 92.3ng·L-1; p = 0.198), and PINP (FP: 53.6 ± 8.9μg·L-1; LP: 66.2 ± 20.2μg·L-1; p = 0.093). Main effects for time (p < 0.05) were shown in sclerostin, PTH, β-CTXI and PINP, without phase or interaction effects. Sclerostin increased from pre- to immediately post-exercise (45%; p = 0.007), and so did PTH (43%; p = 0.011), both returning to resting concentrations 30min post-exercise. β-CTXI decreased from pre- to post-exercise (20%; p = 0.027) and was stillbelow its pre-exercise concentrations at 90min post-exercise (17%; p = 0.013). PINP increased immediately post-exercise (29%; p < 0.001), returning to resting concentrations at 30min post-exercise. These results demonstrate no effect of menstrual cycle phase on resting bone marker concentrations or on the bone metabolic marker response to intense exercise.

Predisposing factors for a second fragile hip fracture in a population of 1130 patients with hip fractures, treated at Oulu University Hospital in 2013–2016: a retrospective study

ObjectiveThe life-time risk of a second fragile hip fracture is 8.4%, but the risk factors that predispose to a second hip fracture remain unresolved. This study aimed to define risk factors that predisposed patients to a second hip fracture.MethodsFor this retrospective study, we retrieved clinical data on 1130 patients with fragile hip fractures (67.2% female, mean age: 79.3 years) that underwent surgery at the Oulu University Hospital in 2013–2016. These data included the fracture risk assessment score (measured with the FRAX tool), the bone-mass T-score, laboratory values, ambulatory capacity, and the time of death.ResultsIn this population, 12.4% of patients sustained a second hip fracture. The predisposing factors for a second hip fracture were: female (p = 0.016), a high FRAX score (p = 0.020), and low physical capacity (p < 0.001). The vitamin D level recommended for treating osteoporosis (i.e., vitamin D > 75 nmol/l) was observed in only 24% of patients, and 42% of patients had ionized calcium levels below the reference range. According to the level of the cross-linked carboxy-terminal telopeptide of type I collagen (ICTP), 37% of patients did not have high bone turnover. We found a positive correlation between age and ICTP (p = 0.001). The risk of death was higher after the second hip fracture (p = 0.005), but we found no difference in age between patients with first and second hip fractures (p = 0.11).ConclusionAfter a hip fracture, a second hip fracture is a well-known risk. Nevertheless, we found that only one-third of patients with a second hip fracture had used anti-osteoporosis medication at any time previously. These findings suggested that second hip fractures were most likely to occur in patients with osteopenic T-score values, in women more often than men, and in patients with high FRAX scores and low ambulatory capacity.

EFFECTS OF PROBIOTICS CONSUMPTION AND RESISTANCE EXERCISE ON BONE METABOLISM MARKERS IN PHYSICALLY INACTIVE YOUNG MALES

This study aims to investigate the effects of probiotics supplementation and resistance exercise on bone metabolism markers and parathyroid hormones in physically inactive young men. Fourty-one healthy participants completed the study. They were randomized into sedentary placebo control (C: n=10), probiotics (P: n=10), resistance exercise with placebo (E: n=12), and probiotics consumption with resistance exercise (PE: n=9) groups. Participants in the P and PE consumed multi-strain probiotics containing 3x1010 CFU of L. acidophilus BCMC® 12130, L. casei BCMC® 12313, L. lactis BCMC® 12451, B. bifidum BCMC® 02290, B. infantis BCMC® 02129 and B. longum BCMC® 02120 twice daily for 12 weeks. Participants in the E and PbE performed circuit training comprised of 10 resistance exercises 3 times/week. Body height and weight, blood pressure, resting heart rate and blood samples were collected at pre and post-tests. Blood samples were analysed for the concentration of bone formation markers [alkaline phosphatase (ALP) and osteocalcin (OC)], bone resorption marker [cross-linked carboxyterminal telopeptide of type 1 collagen (1CTP)] and parathyroid hormones (PTH). There were no significant differences (p&gt;0.05) in all measured parameters between groups and within each group (p&gt;0.05). Nevertheless, ALP and OC concentration exhibited increasing trends in PE group. There was a decreasing trend in PTH concentration in P and PE groups. As a conclusion, probiotics consumption with resistance exercise resulted in increased trends of bone formation markers and a small reduction in the bone resorption marker implying that this combination may elicit beneficial effects in improving bone formation in young physically inactive males.

Long-term effect of full-body pulsed electromagnetic field and exercise protocol in the treatment of men with osteopenia or osteoporosis: A randomized placebo-controlled trial

Background: Osteoporosis is the most prevalent metabolic disease affecting bones. Objective: To investigate the long-term effect of pulsed electromagnetic field (PEMF) combined with exercise protocol on bone mineral density (BMD) and bone markers in men with osteopenia or osteoporosis. Methods: Ninety-five males with osteopenia or osteoporosis (mean age, 51.26 ± 2.41 years; mean height, 176 ± 2.02 cm; mean weight, 83.08 ± 2.60 kg; mean body–mass index (BMI), 26.08 ± 1.09 kg/m2) participated in the study, and they were randomly assigned to one of three groups: Group 1 received a full-body PEMF and exercise protocol (PEMF +EX), Group 2 received a placebo full-body PEMF and exercise protocol (PPEMF +EX), and Group 3 received a full-body PEMF alone (PEMF). PEMF was applied for the whole body using a full-body mat three times per week for 12 weeks, with an exercise protocol that includes flexibility, aerobic exercise, strengthening, weight-bearing, and balance exercises followed by whole-body vibration (WBV) training. Outcome measures include BMD of total hip and lumbar spine and bone markers [serum osteocalcin (s-OC), Serum amino-terminal cross-linking telopeptide of type I collagen (s-NTX), Serum carboxy-terminal cross-linking telopeptide of type I collagen (s-CTX), Parathyroid hormones (PTH), Bone-specific Alkaline Phosphatase (BSAP), and 25-hydroxy vitamin D (Vit D)]. Results: The BMD of total hip and lumbar spine was significantly increased post-treatment in all groups, and more so in Group 1 and Group 2 than Group 3. There was a significant difference in bone markers in all groups, more so in Group 1 and Group 2 than in Group 3. Conclusion: PEMF combined with exercise protocol exerts a potent role for treating OP, is more effective than exercise and PEMF alone for increasing BMD and enhancing bone formation, and suppresses bone-resorption markers after 12-weeks of treatment with the impact lasting up to 6 months.

New reference intervals for endocrinological biomarkers in pediatric patients: what can we learn from the LIFE child study?

Abstract Objectives We established reference intervals for serum concentrations of hormones from healthy pediatric subjects and investigated their associations with gender, body mass index (BMI), puberty and oral contraceptives (oC). Methods We calculated reference intervals for the thyroid parameters thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), and calcitonin (Ct); the bone markers osteocalcin, procolagen type 1 N-propeptide, and carboxy-terminal cross-linking telopeptide of type 1 collagen; the calciotropic hormones 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone and the steroids cortisol, progesterone, 17-hydroxyprogesterone, androstenedione, testosterone, estradiol, dehydroepiandrosterone sulfate and aldosterone. Up to 10,002 blood serum samples from 3,229 healthy children and adolescents (age interval: 3 months to 20 years) were measured. To investigate the associations between the hormone levels with age, sex, weight status and the role of puberty-based changes, the measurement and BMI values were transformed into standard deviation scores. Results Most of the hormones depended on age- and gender. Puberty was linked to a, in part, temporary decrease in TSH, FT3 (for females), FT4, Ct, cortisol (for girls) and aldosterone (for boys) and peak in the bone marker and calciotropic hormones (excluding 25(OH)D) and nearly all remaining steroids. BMI had effects on the thyroid, bone, and calciotropic parameters, whereas oC led to increased cortisol, suppressed progesterone and estradiol values. Conclusions Age- and gender-specific reference intervals are essential for the interpretation of pediatric patients’ hormone measurements. Influencing factors as puberty, BMI, or oC should be taken into consideration for diagnosis and treatment monitoring.

Modern markers for evaluating bone disease in multiple myeloma (Review).

Multiple myeloma (MM) is a bone marrow neoplasia with increasing incidence compared to previous years. Although new therapeutic molecules have been introduced, it remains an incurable disease with severe repercussions to patients. For many patients, bone disease represents a severe problem often causing pain, pathological bone fractures, and spinal cord compression, which affects the quality of life. This article analyzes the main markers of bone destruction in MM as well as risk factors for severe bone damage. Bone complications have a negative impact on the quality of life of patients with MM, along with other associated complications (renal failure, hypogammaglobulinemia, osteolytic bone disease, hypercalcemia, anemia). The markers of bone destruction described in this article include: interleukin (IL)-6, tumor necrosis factor (TNF)-α, receptor activator of nuclear factor kappa-Β ligand (RANKL), osteoprotegerin (OPG), amino- and carboxy-terminal cross-linking telopeptide of type I collagen (NTX, CTX), human bone sialoprotein (BSP) and dickkopf-1 secreted glycoprotein (DKK1). The future practical applicability of this literature review would be the large-scale determination of markers of bone destruction that correlate with the negative evolution to complications of bone disease or the implications that these markers have in regards to treatment.

Long-term effect of full-body pulsed electromagnetic field and exercise protocol in the treatment of men with osteopenia or osteoporosis: A randomized placebo-controlled trial

Background: Osteoporosis is the most prevalent metabolic disease affecting bones. Objective: To investigate the long-term effect of pulsed electromagnetic field (PEMF) combined with exercise protocol on bone mineral density (BMD) and bone markers in men with osteopenia or osteoporosis. Methods: Ninety-five males with osteopenia or osteoporosis (mean age, 51.26 ± 2.41 years; mean height, 176 ± 2.02 cm; mean weight, 83.08 ± 2.60 kg; mean body–mass index (BMI), 26.08 ± 1.09 kg/m2) participated in the study, and they were randomly assigned to one of three groups: Group 1 received a full-body PEMF and exercise protocol (PEMF +EX), Group 2 received a placebo full-body PEMF and exercise protocol (PPEMF +EX), and Group 3 received a full-body PEMF alone (PEMF). PEMF was applied for the whole body using a full-body mat three times per week for 12 weeks, with an exercise protocol that includes flexibility, aerobic exercise, strengthening, weight-bearing, and balance exercises followed by whole-body vibration (WBV) training. Outcome measures include BMD of total hip and lumbar spine and bone markers [serum osteocalcin (s-OC), Serum amino-terminal cross-linking telopeptide of type I collagen (s-NTX), Serum carboxy-terminal cross-linking telopeptide of type I collagen (s-CTX), Parathyroid hormones (PTH), Bone-specific Alkaline Phosphatase (BSAP), and 25-hydroxy vitamin D (Vit D)]. Results: The BMD of total hip and lumbar spine was significantly increased post-treatment in all groups, and more so in Group 1 and Group 2 than Group 3. There was a significant difference in bone markers in all groups, more so in Group 1 and Group 2 than in Group 3. Conclusion: PEMF combined with exercise protocol exerts a potent role for treating OP, is more effective than exercise and PEMF alone for increasing BMD and enhancing bone formation, and suppresses bone-resorption markers after 12-weeks of treatment with the impact lasting up to 6 months.

Inhibition of cathepsin-K and matrix metalloproteinase by photodynamic therapy

ObjectivesThe objective of this study was to determine the effects of antimicrobial photodynamic therapy (aPDT) with indocyanine green (ICG) and toluidine blue (TB) on protease activity (matrix-bound cathepsin K and matrix metalloproteinase (MMP) and dentin bond strength. MethodsCaries-free human third molars were assigned to five groups: 1—control group, 2—application of ICG with activation using an 810 nm diode (aPDT), 3—application of ICG, 4—application of TB with activation using a 660 nm diode (aPDT), and 5—application of TB. For the enzymatic investigation, dentin beams were incubated for either 3 days or 3 weeks. Aliquots of the incubation media were analyzed by ELISA for CTX (C-terminal cross-linked telopeptide of type I Collagen) and ICTP (cross-linked carboxy-terminal telopeptide of type I collagen). For microtensile bond strength testing (μTBS), composite resins were layered onto the tooth surface; the samples were then subjected to μTBS. Kruskall–Wallis and Mann–Whitney U tests were applied for statistical analysis of CTX and ICTP, one way-ANOVA and Tukey’s test were applied for statistical analysis of μTBS. ResultsPretreating the dentin matrices with aPDT decreased the endogenous protease activity. ICG with laser activation resulted in the highest μTBS. Therefore, aPDT should be considered as a treatment method because it can reduce MMP-mediated dentin degradation and increase the μTBS. SignificanceInhibiting endogenous protease activity improves the stability of the dentin–adhesive bond and the durability of the bond strength.

Between-subject and within-subject variability in measures of biochemical markers of bone turnover in cynomolgus and rhesus macaques

Development of optimal bone mass during early adulthood is determined by the balance between bone formation and resorption. The utility of minimally invasive biomarkers for monitoring bone turnover balance in maturing non-human primates has received limited attention. This study evaluated the biological variation of osteocalcin (a marker of bone formation), carboxyterminal cross-linking telopeptide of type 1 collagen (CTX, a marker of bone resorption), and the ratio of osteocalcin to CTX (reflecting bone turnover balance), in 136 rhesus and cynomolgus macaques aged 3.8–11.6 years. In a subsample of the animals (n = 28), blood samples were collected at monthly intervals over 4 months. Between-subject analysis revealed that there were no sex or species differences for CTX. Osteocalcin and the ratio of osteocalcin to CTX were higher in males than in females, and in rhesus macaques than in cynomolgus macaques. There were no changes in osteocalcin, CTX, or the ratio of osteocalcin to CTX across 4 months for any of the groups. In contrast, there was considerable within-subject variation in osteocalcin and CTX concentrations. However, differences in values exhibited no discernible pattern, suggesting that within-subject variation can be reduced by averaging repeat measurements. In summary, the data provide reference values for male and female rhesus and cynomolgus macaques and support the utility of osteocalcin and CTX as biomarkers to monitor bone turnover at the population level.

Long-term effect of full-body pulsed electromagnetic field and exercise protocol in the treatment of men with osteopenia or osteoporosis: A randomized placebo-controlled trial

Background: Osteoporosis is the most prevalent metabolic disease affecting bones. Objective: To investigate the long-term effect of pulsed electromagnetic field (PEMF) combined with exercise protocol on bone mineral density (BMD) and bone markers in men with osteopenia or osteoporosis. Methods: Ninety-five males with osteopenia or osteoporosis (mean age, 51.26 ± 2.41 years; mean height, 176 ± 2.02 cm; mean weight, 83.08 ± 2.60 kg; mean body–mass index (BMI), 26.08 ± 1.09 kg/m 2) participated in the study, and they were randomly assigned to one of three groups: Group 1 received a full-body PEMF and exercise protocol (PEMF +EX), Group 2 received a placebo full-body PEMF and exercise protocol (PPEMF +EX), and Group 3 received a full-body PEMF alone (PEMF). PEMF was applied for the whole body using a full-body mat three times per week for 12 weeks, with an exercise protocol that includes flexibility, aerobic exercise, strengthening, weight-bearing, and balance exercises followed by whole-body vibration (WBV) training. Outcome measures include BMD of total hip and lumbar spine and bone markers [serum osteocalcin (s-OC), Serum amino-terminal cross-linking telopeptide of type I collagen (s-NTX), Serum carboxy-terminal cross-linking telopeptide of type I collagen (s-CTX), Parathyroid hormones (PTH), Bone-specific Alkaline Phosphatase (BSAP), and 25-hydroxy vitamin D (Vit D)]. Results: The BMD of total hip and lumbar spine was significantly increased post-treatment in all groups, and more so in Group 1 and Group 2 than Group 3. There was a significant difference in bone markers in all groups, more so in Group 1 and Group 2 than in Group 3. Conclusion: PEMF combined with exercise protocol exerts a potent role for treating OP, is more effective than exercise and PEMF alone for increasing BMD and enhancing bone formation, and suppresses bone-resorption markers after 12-weeks of treatment with the impact lasting up to 6 months.

Phase 2 Study of Carfilzomib and Bone Metabolism in Patients with Relapsed Multiple Myeloma

Background: Carfilzomib is an epoxyketone proteasome inhibitor (PI) that binds selectively and irreversibly to the constitutive proteasome and immunoproteasome. In addition to its direct cytotoxicity, PIs possess bone anabolic effect, by facilitating osteoblast differentiation, which in turn, inhibits multiple myeloma (MM) growth. However, the relative contribution of carfilzomib on direct tumor killing and bone formation has been difficult to discern when it is used in combination with other agents such as steroids, chemotherapeutics, or immunomodulatory agents (iMiDs); most of which increase bone loss.Objective: We explored the effect of single agent carfilzomib on bone metabolism and disease response in patients with relapsed MM.Methods: We conducted a phase II study of single-agent carfilzomib at 56 mg/m2 day 1, 2, 8, 9, 15, 16 of a 28 day cycle in patients with relapsed MM. Serum markers of bone resorption including carboxyterminal cross-linked telopeptide of type I collagen (ICTP) and tartrate resistant acid phosphatase 5b (TRACP 5b) and bone formation markers including N-terminal type 1 procollagen (P1NP) and osteocalcin (OC) were analyzed at baseline and 6 months after therapy, and compared using paired t-tests. Imaging using 18F-NaF PET-CT scans to monitor bone response and 8F-FDG PET-CT to measure localized tumor burden were done at baseline and 6 months post treatment. For each patient, the three sites with the highest baseline SUVs and an iliac crest (representing an uninvolved site) were selected for quantitative comparisons using paired t-test.Results: Ten patient were accrued. Average age was 70.1 +/- 6.79 (mean +/- SD) years. Median prior lines of therapy was 2. 9 were evaluable for response. Overall response rate was 77.8%: VGPR (1/9: 11%), partial response (6/9: 67%), stable disease (2/9: 22%). Median PFS was 11.5 months. Overall survival was 21.9 months. Common treatment adverse events (AE) were comparable to previous reports including diarrhea (40%), fever (40%), dyspnea (30%) and fatigue (30%). Grade 3/4 AEs, occurring in 10% each included neutropenia, thrombocytopenia, dyspnea, fatigue, vomiting, ataxia, heart failure and pulmonary edema.Serum ICTP and TRACP were elevated at baseline in 80% of subjects; means (+/- SD) of serum ICTP (14.4 +/- 3.1 ug/L) and TRACP (8.2 +/- 4.2 U/L), respectively. Both markers declined significantly after therapy (means +/- SD of serum ICTP 8.4 +/- 3.1 ug/L and TRACP (5.2 +/- 4.2 U/L); p<0.01), suggesting osteoclast suppression. Serum PINP and OC varied among subjects; 5 patients with low levels and 4 normal levels and 1 with elevated level: mean (+/- SD) of PINP 25 +/- 23 ug/L and OC (18 +/- 12 ug/L). Neither post treatment mean PINP nor OC differed significantly from baseline overall (p=0.16). However, all subjects who achieve PR or better had a more than 25% increase in PINP and OC, suggesting increased new bone formation.8F-FDG and 18F-NaF were positive in all subjects. Number of active sites and SUVs vary largely among subjects. 18F-NaF images mirrored the 8F-FDG signals, appearing as rings around the tumor sites, suggesting a bone reaction to the localized tumors. 6 of 9 subjects had post treatment PET/CTs for paired comparison. Post treatment 8F-FDG SUV of representative sites decreased significantly, while 18F-NaF SUVs varied; 58% of lesions had a decline in SUV, while 32% were unchanged and 10% were brighter, suggesting heterogeneous bone response. 18F-NaF SUVs of iliac sites decreased post treatment, suggesting a lower bone turnover overall. CT scans showed increased sclerosis at the rim of lytic lesions without significant change in lesion size, at this early time point.Conclusion: Carfilzomib at 56 mg/m2 dosing strongly inhibits bone resorption and demonstrates bone anabolic effects, in addition to cytotoxicity, in relapsed MM. Single agent use allows bone response analysis without the confounding effects of other anti-MM agents used in combination therapy. Response rates and side effects are favorable to prior reports. Serum markers of bone remodeling are useful for an assessment of overall bone metabolism while the 18F-NaF PET/CT allows assessment of both local and systemic changes but lacks specificity. Studies of osteoblast differentiation from subject's bone marrow stromal cells pre and post treatment are ongoing. Whether carfilzomib can heal bone lesions requires longer follow up. DisclosuresSuvannasankha:Celgene: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding; Janssen Pharmaceuticals: Research Funding. Abonour:Celgene: Other: Steering committee, Research Funding; Prothena: Research Funding; Takeda: Other: Steering committee, Research Funding. Roodman:PharmaMar: Research Funding.