Serum Bone Turnover Markers Research Articles

Self-reported Resistance Training Is Associated With Better HR-pQCT-derived Bone Microarchitecture in Vegan People.

A plant-based lifestyle is a global trend; lower bone mineral density and increased fracture risk in vegan people are reported. The primary objective was to assess trabecular and cortical bone microarchitecture in vegans and omnivores. Secondary objectives were to evaluate relationships between bone microarchitecture, nutrition parameters, and physical activity. This was an observational study at the Medical Department II, St. Vincent Hospital (tertiary referral center for gastrointestinal, metabolic, and bone diseases, and teaching hospital of the Medical University of Vienna), including 43 healthy nonobese female and male subjects on a plant-based diet for at least 5 years, and 45 healthy nonobese female and male subjects on an omnivore diet for at least 5 years. The main outcome measures were the parameters of trabecular and cortical bone microarchitecture (high-resolution peripheral quantitative computed tomography), serum markers of bone turnover, nutrient intake (nutrition protocol), and self-reported resistance training (physical activity questionnaires). In the vegan group, trabecular and cortical structure were altered compared with omnivores. Vegans not reporting resistance training had diminished bone microarchitecture compared with omnivores not reporting resistance training. In vegans and omnivores reporting resistance training, bone structure was similar. In both vegan subgroups (resistance training and not resistance training), a small number of correlations between nutrient intake and bone microarchitecture were observed without a conclusive pattern. Bone microarchitecture in vegans differed from matched omnivores but could not be explained solely by nutrient uptake. These differences were attenuated between the subgroups reporting resistance training. In addition to a well-planned diet, progressive resistance training on a regular basis should be part of the vegan lifestyle.

Filipino Children with High Usual Vitamin A Intakes and Exposure to Multiple Sources of Vitamin A Have Elevated Total Body Stores of Vitamin A But Do Not Show Clear Evidence of Vitamin A Toxicity

ABSTRACTBackgroundYoung children exposed to high-dose vitamin A supplements (VAS) and vitamin A (VA)–fortified foods may be at risk of high VA intake and high VA total body stores (TBS).ObjectivesTBS and estimated liver VA concentration were compared among children with adequate or high VA intake and different timing of exposure to VAS, and associations between estimated liver VA concentrations and biomarkers of VA toxicity were examined.MethodsChildren 12–18 mo of age (n = 123) were selected for 3 groups: 1) retinol intake >600 µg/d and VAS within the past mo, 2) retinol intake >600 µg/d and VAS in the past 3–6 mo, and 3) VA intake 200–500 µg retinol activity equivalents (RAE)/d and VAS in the past 3–6 mo. Dietary intake data were collected to measure VA intakes from complementary foods, breast milk, and low-dose, over-the-counter supplements. TBS were assessed by retinol isotope dilution, and VA toxicity biomarkers were measured. Main outcomes were compared by group.ResultsMean (95% CI) VA intakes excluding VAS were 1184 (942, 1426), 980 (772, 1187), and 627 (530, 724) µg RAE/d, in groups 1–3, respectively; mean VA intake was higher in groups 1 and 2 compared with group 3 (P < 0.05). Geometric mean (GM) (95% CI) TBS were 589 (525, 661), 493 (435, 559), and 466 (411, 528) µmol, respectively. GM TBS and GM liver VA concentrations were higher in group 1 compared with group 3 (liver VA concentration: 1.62 vs. 1.33 µmol/g; P < 0.05). Plasma retinyl ester and 4-oxo-retinoic acid concentrations and serum markers of bone turnover and liver damage did not indicate VA toxicity.ConclusionsIn this sample, most children had retinol intakes above the Tolerable Upper Intake Level (UL) and liver VA concentrations above the proposed cutoff for “hypervitaminosis A” (>1 µmol/g liver). There was no evidence of chronic VA toxicity, suggesting that the liver VA cutoff value should be re-evaluated. This trial was registered at www.clinicaltrials.gov as NCT03030339.

Baseline Testosterone Predicts Body Composition and Metabolic Response to Testosterone Therapy.

ContextMale hypogonadism adversely affects body composition, bone mineral density (BMD), and metabolic health. A previous report showed that pre-treatment testosterone (T) levels of <200 ng/dl is associated with greater improvement in spine BMD with T therapy. However, to date, there is no study that investigates whether baseline T levels also influence body composition and metabolic response to T therapy.ObjectiveThe aim of this study is to determine if there are differences in the changes in body composition, metabolic profile, and bone turnover markers, in addition to BMD, in response to T therapy in men with a baseline T level of <264 ng/dl compared to those with levels ≥264 ng/dl.MethodsThis is a secondary analysis of a single-arm, open-label clinical trial (NCT01378299) on pharmacogenetics of response to T therapy conducted between 2011 and 2016 involving 105 men (40–74 years old), with average morning T < 300 ng/dl, given intramuscular T cypionate 200 mg every 2 weeks for 18 months. Subjects were divided into those with baseline T levels of <264 ng/dl (N = 43) and those with ≥264 ng/dl (N = 57). T and estradiol (E2) were measured by liquid chromatography/mass spectrometry; serum bone turnover markers (C-telopeptide [CTX], osteocalcin, and sclerostin), adiponectin, and leptin were measured by enzyme-linked immunosorbent assay; glycated hemoglobin (HbA1c) was measured by high-performance liquid chromatography; and areal BMD and body composition was measured by dual-energy x-ray absorptiometry (DXA).ResultsMen with T < 264 ng/dl showed greater increases in total fat-free mass (FFM) at 18 months compared to those with T ≥ 264 ng/dl (4.2 ± 4.1 vs. 2.7 ± 3.8%; p = 0.047) and unadjusted appendicular FFM at 6 and 18 months (8.7 ± 11.5 vs. 4.4 ± 4.3%, 7.3 ± 11.6 vs. 2.4 ± 6.8%; p = 0.033 and p = 0.043, respectively). Men with T ≥ 264 ng/dl showed significant decreases in HbA1c at 12 months (−3.1 ± 9.2 vs. 3.2 ± 13.9%; p = 0.005), fasting glucose at 18 months (−4.2 ± 31.9 vs. 13.0 ± 57.3%; p = 0.040), LDL at 6 months (−6.4 ± 27.5 vs. 12.8 ± 44.1%; p = 0.034), and leptin at 18 months (−40.2 ± 35.1 vs. −27.6 ± 31.0%; p = 0.034) compared to those with T < 264 ng/dl. No significant differences in BMD and bone turnover markers were observed.ConclusionT therapy results in improvement in body composition irrespective of baseline T levels but T < 264 ng/dl is associated with greater improvement in FFM, whereas a T level of ≥264 ng/dl favors improvement in metabolic profile.

Calycosin prevents bone loss induced by hindlimb unloading

Bone loss induced by microgravity exposure seriously endangers the astronauts’ health, but its countermeasures still have certain limitations. The study aims to find potential protective drugs for the prevention of the microgravity-induced bone loss. Here, we utilized the network pharmacology approach to discover a natural compound calycosin by constructing the compound-target interaction network and analyzing the topological characteristics of the network. Furthermore, the hind limb unloading (HLU) rats’ model was conducted to investigate the potential effects of calycosin in the prevention of bone loss induced by microgravity. The results indicated that calycosin treatment group significantly increased the bone mineral density (BMD), ameliorated the microstructure of femoral trabecular bone, the thickness of cortical bone and the biomechanical properties of the bone in rats, compared that in the HLU group. The analysis of bone turnover markers in serum showed that both the bone formation markers and bone resorption markers decreased after calycosin treatment. Moreover, we found that bone remodeling-related cytokines in serum including IFN-γ, IL-6, IL-8, IL-12, IL-4, IL-10 and TNF-α were partly recovered after calycosin treatment compared with HLU group. In conclusion, calycosin partly recovered hind limb unloading-induced bone loss through the regulation of bone remodeling. These results provided the evidence that calycosin might play an important role in maintaining bone mass in HLU rats, indicating its promising application in the treatment of bone loss induced by microgravity.

Bone disturbances and progression of atherosclerosis in ApoE knockout mice.

Epidemiological evidence supports a link between atherosclerosis and osteoporosis. These conditions might share common pathophysiological mechanisms, with inflammation being one of the hypotheses.Apolipoprotein E deficient mice (ApoE-/-) develop atherosclerotic lesions spontaneously, further aggravated by a high-fat diet. Their bone remodelling is also disturbed. We hypothesised that a proinflammatory state could be a common contributive factor for vessel and bone disturbances observed in this animal model. We evaluated vessels and bones of ApoE-/- and control C57BL/6 (B6) female mice fed a high-fat diet in five time-points (8, 16, 20, 24 and 28 weeks of age) and quantified the development of atherosclerotic lesions, analysed gene expression of inflammatory and bone remodelling proteins (IL-1β, IL-6, IL-17A, TNF, RANKL, and OPG), measured serum bone turnover markers (P1NP and CTX-I), performed bone (L3-L4 vertebras) histomorphometric analysis and evaluated biomechanical properties of bones. We compared the outcomes of B6 and ApoE-/- groups at each time-point and, within each group, over time. Atherosclerotic lesions developed as previously described for ApoE-/- mice, but no significant differences were found in bone histomorphometry or biomechanical properties between ApoE-/- and B6 mice. Also, gene expression (either in bones or aortas) and serum biomarkers were similar in both groups. When considering over time evaluations we found that bone histomorphometry changes were similar between ApoE-/- and B6 mice, but CTX-I/P1NP ratio was significantly increased (meaning higher resorption than bone formation) in ApoE-/- as compared to B6 mice. Our study suggests that inflammation is not the principal driver for atherosclerosis progression and bone disturbances in this animal model.

P885: PROSPECTIVE ASSESSMENT OF MYELOMA TUMOUR BURDEN AND BONE DISEASE USING DW-MRI AND EXPLORATORY BONE BIOMARKERS

Background: Key clinical priorities for multiple myeloma (MM) are to reduce tumour burden and complications, of which lytic bone disease is the major cause of morbidity. To guide treatment, there is a pressing need for biomarkers that can accurately quantify MM tumour burden and associated bone disease. To this end, Diffusion-Weighted Magnetic Resonance Imaging (DW-MRI) and bone turnover markers are promising radiological and serum metrics, respectively, although their clinical value in prospective assessment is unclear. Aims: LOOMIS was a single-centre observational cohort study that evaluated the relative merits of DW-MRI and bone turnover markers in prospectively assessing tumour burden and bone disease when added to standard clinical assessment, in patients with MM and monoclonal gammopathy of undetermined significance (MGUS). Methods: A total of 67 patients were enrolled (14 newly diagnosed MM, 12 relapsed MM, 15 smouldering MM, 14 MGUS and 12 healthy volunteers) between March 2018 and March 2020. At baseline (and 6-month follow-up for MM/MGUS), participants had a DW-MRI scan and serum measurements of established (P1NP, CTX-1, ALP) and exploratory (DKK1, sclerostin, RANKL:OPG ratio) bone turnover markers. MM/MGUS patients additionally had standard myeloma bloods and Dual-Energy X-ray Absorptiometry (DXA) at each visit, as correlates of tumour burden and bone loss. DW-MRI scans were double reported by expert Radiologists for Apparent Diffusion Coefficient (ADC) measurements of lytic bone lesion(s), and Myeloma Response Assessment and Diagnosis System (MY-RADS) Response Assessment Category (RAC) scoring. Patients were classified by International Myeloma Working Group (IMWG) response criteria as a clinical correlate of therapy response. Results: On assessment of baseline tumour burden, there was no correlation between single lesion DW-MRI ADC and serum paraprotein [p>0.05]; however, there was moderate positive correlation between serum DKK1 and serum paraprotein [r=0.39, p=0.04]. At follow-up, radiological MY-RADS RAC scoring correlated with conventional IMWG response criteria [p=0.015]; additionally, longitudinal relative change in serum DKK1 differed between IMWG-defined therapy responders (37% decrease) and non-responders (15% increase) [p<0.01]. On baseline assessment of bone loss, there was moderate positive correlation between serum sclerostin and DXA bone mineral density at femoral neck [r=0.40, p<0.01] and lumbar spine [r=0.54, p<0.001]. At follow-up, there was a moderate negative correlation between longitudinal % change in the RANKL:OPG ratio and % change in DXA bone mineral density at femoral neck [r= -0.45, p<0.01]. Summary/Conclusion: Our prospective trial validates DW-MRI-based MY-RADS RAC scoring as a qualitative radiological tool to assess therapy response. Whilst previous work has supported single lytic lesion ADC measurements as a correlate of tumour volume, we did not find this; small sample size and prior chemotherapy in our study may have limited our ability to detect this. In comparison, serum bone turnover markers such as DKK1 may provide a more global measure to quantify myeloma burden both at baseline diagnosis and longitudinally with therapy. Additionally, our data highlight serum sclerostin and RANKL:OPG ratio as potential biomarkers to assess and monitor bone loss. Overall, our study highlights emerging radiological and serum biomarkers of tumour burden and associated bone loss in MM and MGUS, which merit further exploration alongside uniformly treated cohorts, to better understand their clinical utility.

The Effect of BMI, Age, Gender, and Pubertal Stage on Bone Turnover Markers in Chinese Children and Adolescents

ObjectivesTo ascertain the associations of serum bone turnover markers (BTMs) levels with body mass index (BMI) in Chinese children and adolescents, and whether the influence of BMI, age, pubertal stage on BTMs varied by gender.MethodsA total of 500 students (180 controls and 320 children and adolescents with overweight/obesity) aged 9–14 years were randomly selected from the Chinese National Survey on Students Constitution and Health Cohort. Serum levels of BTMs, including bone formation marker bone alkaline phosphatase (BAP), collagen type 1 C-terminal propeptide (CICP), and bone resorption markers C-terminal telopeptide of type-I collagen (CTX) were determined by commercial enzyme-linked immunosorbent assay kits. The associations among BMI, age, gender, pubertal stage, and BTMs were analyzed.ResultsSerum levels of CICP and CTX in overweight/obese children and adolescents were lower than those in controls (p<0.05). Moreover, after subgroup analysis stratified by gender, the decreased serum CICP and CTX levels in overweight/obese children and adolescents were observed only in boys (p<0.05). After adjustment of age and pubertal stage, there was a negative correlation between serum BAP and BMI in both boys and girls (p<0.05). However, the correlations between serum CICP, CTX levels, and BMI were significant in boys but not in girls. Serum BAP and CICP levels were independently correlated with BMI, age, gender, and pubertal stage, while CTX levels were independently correlated with BMI, age, and gender (p<0.05). BAP, CICP, and CTX levels showed a clear age, gender, and pubertal stage dependence with significantly higher values in boys (p<0.05).ConclusionsOur findings support the associations between serum BTMs levels and BMI in Chinese children and adolescents, and suggest age, gender, and pubertal stage differences in this relationship that warrant future studies.

Bone Turnover Marker (BTM) Changes after Denosumab in Giant Cell Tumors of Bone (GCTB): A Phase II Trial Correlative Study.

Simple SummaryGiant cell tumors of bone (GCTB) are a histologically benign, yet often aggressive, skeletal tumor. Surgery is the only potentially curative treatment option, but may be associated with severe morbidity and loss of function. Denosumab, a monoclonal antibody directed to RANK ligand, is approved for GCTB treatment. Here we report the results of a phase II correlative study on sBTMs (carboxytermnal-crosslinked-telopeptide of type I collagen (s-CTX), alkaline phosphatase (ALP), bone-alkaline phosphatase (bALP), parathyroid hormone (sPTH), and osteocalcin (OCN) in GCTB patients treated with denosumab. The main finding of the present research is that the use of denosumab in patients with GCTB induces the bALP/ALP/OCN and s-CTX reduction, with a concomitant increase in sPTH. High baseline s-CTX identifies a group of patients at higher risk of progression of the disease. Stratification of the GCTB patients based on s-CTX might guide type of surgery and follow-up.Background: Giant cell tumors of bone (GCTB) are osteolytic tumors. Denosumab, a RANK-L inhibitor, is approved for GCTB. Data on serum bone turnover marker (sBTM) changes are lacking. We present a phase II correlative study on sBTMs in GCTB patients treated with denosumab. Methods: All GCTB patients receiving denosumab within a multicentre, open-label, phase 2 study were enrolled. Serum levels of carboxyterminal-crosslinked-telopeptide of type I collagen (s-CTX), alkaline phosphatase (ALP), bone-alkaline phosphatase (bALP), parathyroid hormone (sPTH), and osteocalcin (OCN) were prospectively assessed (baseline, T0, 3 months, T1, 6 months, T2). The primary endpoint was assessment of sBTM changes after denosumab; the secondary endpoints were disease-free survival (DFS) and sBTM correlation. Results: In 54 cases, sBTMs decreased during denosumab treatment except for sPTH. With a median follow-up of 59 months, 3-year DFS was 65% (%CI 52–79), with a significantly worse outcome for patients with high (≥500 UI/mL) s-CTX at baseline, as compared to low s-CTX (<500 UI/mL) (3-year DFS for high CTX 45% (95%CI 23–67) vs. 75% (95%CI 59–91) for low s-CTX. Higher median ALP and s-CTX were found for patients with tumor size ≥ 5 cm (p = 0.0512; p = 0.0589). Conclusion: Denosumab induces ALP/OCN and s-CTX reduction. High baseline s-CTX identifies a group of patients at higher risk of progression of the disease.

1378-P: Chronic Sleep Deprivation Impaired Bone Formation in Growing Rats and Downregulated PI3K/AKT Signaling in Bone Tissues

Background: Sleep deprivation (SD) , recognized as a public health epidemic, impaired glucose metabolism, yet little is known about the association between sleep and bone health. Methods: Twenty 5-week-old male Wistar rats and randomly divided into the CSD and normal control (NC) groups after one-week acclimatization. After a 6-week intervention of sleep deprivation, the distal femurs of both groups were harvested for micro-computed tomography scans and histological analysis. Meanwhile, the femur tissues were measured the mRNA and protein expression via RNA sequencing and immunohistochemical analysis. Serum bone turnover markers were evaluated at 0, 2, 4, and 6 weeks. Result: CSD impaired the bone growth, showing an imbalance of bone turnover status, dysphasia in the metaphysis growth plate, and deterioration of bone microarchitecture. Further, CSD suppressed bone formation, showing that the expression of osteogenesis-related proteins (col1α1 and osteocalcin) and mRNA (igf1, bglap, runx2, col1α1, pth1r) are down-regulated. Differentially expressed genes were detected, and functional enrichment analyses revealed that the PI3K/AKT pathway was significantly down-regulated in the CSD group. While Diabetic cardiomyopathy, Oxidative phosphorylation, and Neurodegenerative disease-related pathways were up-regulated. Conclusion: These results suggest that CSD can significantly impaired bone health, and it may exert these effects in part by suppressing bone formation and osteoblast differentiation, and inactivating the PI3K/AKT signaling pathway. Disclosure X.Duan: None. L.Guo: None. Funding National Natural Science Foundation of China (Grant No. 81670763 and 81471050)

Total n-6 Polyunsaturated Fatty Acid and Linoleic Acid Dietary Intakes Are Associated With Lower Serum Osteocalcin Among Postmenopausal Women

ObjectivesOur research group has recently shown that plasma linoleic acid (LA), an essential n-6 polyunsaturated fatty acid (PUFA), was inversely associated with whole body bone mineral density (BMD) Z-score in a general US adult population. We aimed to determine whether dietary LA, arachidonic acid (AA) or total n-6 intake are likewise associated with serum bone turnover markers (BTMs) and BMD at sites prone to fracture, including total hip, lumbar spine, and femoral neck, among postmenopausal women without osteoporosis. MethodsThis was a cross-sectional study of healthy women (N = 34; 50–65 years) with onset of menopause < 5 years. Fasting serum samples were obtained, and BMD indexes were measured by dual X-ray absorptiometry (DXA) in the same visit. BMD values were converted to T-scores. Three-day food records were collected, and calorie-adjusted nutrient intakes calculated using Nutrition Data System for Research software. Serum concentrations of osteocalcin (OC, a bone formation biomarker) and C-terminal telopeptides of Type I collagen (CTX, a bone resorption biomarker) were measured by ELISA. Relationships between LA and each BMD T-score and serum BTM were assessed using linear regression adjusting for age, race, and body mass index. ResultsTotal n-6 PUFA and LA intakes were not significantly associated with any BMD T-scores. AA intake was positively associated with lumbar spine BMD T-score [β = 10.4, (95% CI: 0.3, 20.5), P < 0.04]. For serum BTMs, total n-6 PUFA and LA intakes were inversely associated with serum osteocalcin [β = –6.8, 95% CI: (–13.2, –0.5) and β = –6.8, 95% CI: (–13.1, –0.5) respectively, both P < 0.05] but not significantly associated with serum CTX. AA intake was not significantly associated with either BTM. ConclusionsDietary intake of total n-6 PUFAs and LA were inversely associated serum OC, while AA intake was positively associated with lumbar spine BMD. Cellular mechanistic and intervention studies in clinical populations are needed to confirm effects of total n-6 PUFA, LA, and AA intake on bone formation and BMD over time. Funding SourcesNational Institutes of Health, John and Mary Brock Discovery Fund.

Target Values and Daytime Variation of Bone Turnover Markers in Monitoring Osteoporosis Treatment After Fractures.

ABSTRACTThe serum bone turnover markers (BTM) procollagen type 1 N‐terminal propeptide (P1NP) and C‐terminal cross‐linking telopeptide of type 1 collagen (CTX) are recommended for monitoring adherence and response of antiresorptive drugs (ARD). BTM are elevated about 1 year after fracture and therefore BTM target values are most convenient in ARD treatment follow‐up of fracture patients. In this prospective cohort study, we explored the cut‐off values of P1NP and CTX showing the best discriminating ability with respect to adherence and treatment effects, reflected in bone mineral density (BMD) changes. Furthermore, we explored the ability of BTM to predict subsequent fractures and BTM variation during daytime in patients using ARD or not. After a fragility fracture, 228 consenting patients (82.2% women) were evaluated for ARD indication and followed for a mean of 4.6 years (SD 0.5 years). BMD was measured at baseline and after 2 years. Serum BTM were measured after 1 or 2 years. The largest area under the curve (AUC) for discrimination of patients taking ARD or not was shown for P1NP <30 μg/L and CTX <0.25 μg/L. AUC for discrimination of patients with >2% gain in BMD (lumbar spine and total hip) was largest at cut‐off values for P1NP <30 μg/L and CTX <0.25 μg/L. Higher P1NP was associated with increased fracture risk in patients using ARD (hazard ratio [HR]logP1NP = 15.0; 95% confidence interval [CI] 2.7–83.3), p = 0.002. P1NP and CTX were stable during daytime, except in those patients not taking ARD, where CTX decreased by 21% per hour during daytime. In conclusion, P1NP <30 μg/L and CTX <0.25 μg/L yield the best discrimination between patients taking and not taking ARD and the best prediction of BMD gains after 2 years. Furthermore, higher P1NP is associated with increased fracture risk in patients on ARD. BTM can be measured at any time during the day in patients on ARD. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Relationships of Serum Bone Turnover Markers With Metabolic Syndrome Components and Carotid Atherosclerosis in Patients With Type 2 Diabetes Mellitus

ObjectiveThis study aimed to investigate the association of serum bone turnover markers (BTMs) with metabolic syndrome components and carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM).MethodsWe performed a cross-sectional based study in T2DM populations. Serum BTMs including N-terminal osteocalcin (N-MID), β-cross-linked C-telopeptide of type I collagen (β-CTX), and procollagen type I N-terminal propeptide (PINP) were measured by immunoassay method. Carotid artery intima-media thickness and carotid artery plaque (CAP) were measured by B-mode ultrasound.ResultsThe serum N-MID, PINP, and β-CTX levels significantly lower in the CAP group compared with the non-CAP group. N-MID and PINP levels were inversely associated with fasting blood glucose, HOMA-IR, CRP, eGFR, and triglycerides (all P < 0.05), whereas β-CTX levels were negatively associated with triglycerides (P < 0.05). After multiple adjustment, the odds ratios (ORs) were substantially higher for CAP with decreased N-MID level (OR = 0.958; 95% CI = 0.926–0.991; P = 0.013). However, serum levels of PINP and β-CTX were not associated with the presence of CAP. Multivariate logistic regression analysis further revealed that serum N-MID, PINP, and β-CTX levels were significantly associated with hypertriglyceridemia, whereas serum N-MID and β-CTX levels were associated with overweight/obesity risk.ConclusionsThese findings indicated that serum N-MID level was an independent risk factor for carotid atherosclerosis, whereas BTM levels were associated with other metabolic syndrome components in a T2DM population.

The Brown Algae Ishige sinicola Extract Ameliorates Ovariectomy-Induced Bone Loss in Rats and Suppresses Osteoclastogenesis through Downregulation of NFATc1/c-Fos.

Osteoporosis is characterized by reduction in bone mass and microarchitectural deterioration of the bone, which causes bone fragility and fracture susceptibility. Ishige sinicola, a brown alga, reportedly affects osteoblast differentiation. However, its protective effect on estrogen deficiency-induced bone loss has not been elucidated. This study aimed to investigate the effect of I. sinicola extract (ISE) on ovariectomy (OVX)-induced bone loss in vivo and osteoclastogenesis in vitro. Female Sprague-Dawley rats were randomly assigned to the sham-operated (SHAM) group and four OVX subgroups: SHAM, OVX, ISE20 (20 mg/kg), ISE200 (200 mg/kg), and estradiol (10 μg/kg). After 6 weeks of treatment, the bone mineral density (BMD), femur indices, and serum biomarker levels were measured. Furthermore, the effects of ISE on osteoclastogenesis and the expression of osteoclast-specific markers were measured. ISE administration improved the trabecular bone structure, bone biomechanical properties, BMD, and bone mineralization degree. In addition, the levels of serum bone turnover markers were decreased in the ISE group compared with those in the OVX group. Moreover, ISE inhibited osteoclast formation by downregulating NFATc1, TRAP, c-Src, c-Fos, and cathepsin K without any cytotoxic effects on RANKL-induced osteoclast formation. Therefore, we suggest that ISE has therapeutic potential in postmenopausal osteoporosis.

Effects of prior osteoporosis treatment on the treatment response of romosozumab followed by denosumab in patients with postmenopausal osteoporosis.

To investigate the effects of prior osteoporosis treatment on the response to treatment with romosozumab (ROMO) followed by denosumab (DMAb) in patients with postmenopausal osteoporosis. In this prospective, observational, multicenter study, treatment-naïve patients (Naïve; n = 55) or patients previously treated with bisphosphonates (BP; n = 37), DMAb (DMAb; n = 45) or teriparatide (TPTD; n = 17) (mean age, 74.6years; T-scores of the lumbar spine [LS] - 3.2 and total hip [TH] - 2.6) were switched to ROMO for 12months, followed by DMAb for 12months. Bone mineral density (BMD) and serum bone turnover markers were evaluated for 24months. A BMD increase was observed at 12 and 24months in the following patients: Naïve (18.2% and 22.0%), BP (10.2% and 12.1%), DMAb (6.6% and 9.7%), and TPTD (10.8% and 15.0%) (P < 0.001 between the groups at both 12 and 24months) in LS and Naïve (5.5% and 8.3%), BP (2.9% and 4.1%), DMAb (0.6% and 2.2%), and TPTD (4.3% and 5.4%) (P < 0.01 between the groups at 12months and P < 0.001 at 24months) in TH, respectively. The BMD increase in LS from 12 to 24months was negatively associated with the levels of bone resorption marker at 24months. Incidences of major fragility fractures for the respective groups were as follows: Naïve (5.5%), BP (16.2%), DMAb (11.1%), and TPTD (5.9%). Previous treatment affected the BMD increase of following treatment with ROMO, although it did not affect that of following treatment with DMAb after ROMO.

Chronic and acute hypervitaminosis A are associated with suboptimal anthropometric measurements in a cohort of South African preschool children

Excessive vitamin A (VA) can cause bone resorption and impair growth. Government-mandated VA supplementation (VAS) and adequate intake through dietary fortification and liver consumption led to excessive VA in South African children. We evaluated the relation between VAS and underlying hypervitaminosis A assessed by retinol isotope dilution (RID) with measures of growth and bone turnover in this cohort. Primary outcomes in these children (n=94, 36-60 mo) were anthropometric measurements [height-for-age (HAZ), weight-for-age (WAZ), and weight-for-height (WHZ) z scores], serum bone turnover markers [C-terminal telopeptide of type I collagen (CTX) and N-terminal propeptide of type I procollagen (P1NP)], and inflammation defined as C-reactive protein (CRP; ≥5mg/L) and/or α1-acid glycoprotein (AGP; ≥1g/L). VA status was previously measured by RID-estimated total body VA stores (TBSs) and total liver VA reserves (TLRs), and serum retinol and carotenoid concentrations, before and 4 wk after children were administered 200,000 IU VAS. Serum 25-hydroxyvitamin D3 was measured by ultra-performance LC. In this largely hypervitaminotic A cohort, HAZ, WAZ, and WHZ were negatively associated with increasing TLRs, where TLRs predicted 6-10% of the variation before VAS (P < 0.05), increasing to 14-19% 4 wk after VAS (P < 0.01). Bone resorption decreased after VAS (P < 0.0001), whereas formation was unaffected. Neither CTX nor P1NP were correlated with TLRs at either time. Serum carotenoids were low. One child at each time point was vitamin D deficient (<50nmol/L). CRP and AGP were not associated with growth measurements. Excessive TLRs due to dietary VA intake and VAS are associated with lower anthropometric measures and bone resorption decreased after supplementation. VA supplementation programs should monitor VA status with biomarkers sensitive to TLRs to avoid causing negative consequences in children with hypervitaminosis A. This trial is registered at clinicaltrials.gov as NCT02915731.

Chronic Sleep Deprivation Impaired Bone Formation in Growing Rats and Down-Regulated PI3K/AKT Signaling in Bone Tissues.

BackgroundThis study aimed to assess the effects of chronic sleep deprivation (CSD) on bone metabolism in growing rats and the likely underlying mechanism.MethodsTwenty 5-week-old male Wistar rats and randomly divided into the CSD and normal control (NC) groups after one-week acclimatization. After a 6-week intervention of sleep deprivation, the distal femurs of both groups were harvested for micro-computed tomography scans and histological analysis. Meanwhile, the femur tissues were measured the mRNA and protein expression via RNA sequencing and immunohistochemical analysis. Serum bone turnover markers were evaluated at 0, 2, 4, and 6 weeks.ResultsCSD impaired the bone growth, showing an imbalance of bone turnover status, dysphasia in the metaphysis growth plate, and deterioration of bone microarchitecture. Further, CSD suppressed bone formation, showing that the expression of osteogenesis-related proteins (col1α1 and osteocalcin) and mRNA (igf1, bglap, runx2, col1α1, pth1r) are down-regulated. Differentially expressed genes were detected, and functional enrichment analyses revealed that the PI3K/AKT pathway was significantly down-regulated in the CSD group.ConclusionThese results suggest that CSD can significantly impaire bone health, and it may exert these effects in part by suppressing bone formation and osteoblast differentiation, and inactivating the PI3K/AKT signaling pathway.

Zoledronic Acid Ameliorates the Bone Turnover Activity and Periprosthetic Bone Preservation in Cementless Total Hip Arthroplasty.

The administration of zoledronic acid (ZA) to patients who received cementless total hip arthroplasty (THA) has been reported to reduce bone turnover markers (BTMs) and increase bone mineral density (BMD). The effects of two-dose ZA versus placebo on cementless THA patients were analyzed in this five-year extension study. Alkaline phosphatase (ALP), osteocalcin (OC), procollagen 1 intact N-terminal propeptide (P1NP), serum calcium, renal function, radiological findings, and functional outcomes were compared in 49 patients, and the periprosthetic BMD of seven Gruen zones were compared in 19 patients. All the patients had normal renal function and calcium levels at their final follow-up. The mean ALP level in the ZA group was significantly lower at the fifth year, mean OC levels were significantly lower at the second and fifth year, and mean P1NP levels were significantly lower from 6 weeks to 5 years as compared with the control group. Fifth-year BMD levels were not found to be different between the ZA and control groups. The BMD Change Ratios in the ZA group were significantly increased in Gruen zone 6 at 1, 2, and 5 years. Our study results suggest that short-term ZA treatment with a subsequent 4-year drug holiday may inhibit serum BTMs and provide periprosthetic bone preservation at five years without adverse events.

Bone biopsy findings in patients receiving long-term bisphosphonate therapy for glucocorticoid-induced osteoporosis.

Bisphosphonates (BPs) have been shown to reduce the incidence of vertebral fractures during the first year or two of glucocorticoid (GC) treatments and are therefore recommended as a first-line treatment for GC-induced osteoporosis (GIO). However, there are theoretical concerns about the long-term use of BPs in low-turnover osteoporosis caused by chronic GC therapy. We analyzed the trabecular microarchitecture, bone metabolism, and material strength of iliac crest bone biopsy samples from 10 female patients with rheumatoid arthritis who received an average of 6.7years of BP therapy for GIO (GIOBP group), compared with those of 10 age- and bone mineral density (BMD)-matched non-rheumatoid arthritis postmenopausal women (reference group). Patients in the GIOBP group had a significantly greater fracture severity index, as calculated from the number and the extent of vertebral fractures compared with the reference patients. Micro-computed tomography analysis showed that the degree of mineralization and trabecular microarchitecture were significantly lower in the GIOBP group than in the reference patients. Patients in the GIOBP group exhibited lower bone contact stiffness, determined by micro-indentation testing, than in the reference group. The contact stiffness of the bone was negatively correlated with the fracture severity index and the daily prednisolone dosage. Immunohistochemistry and serum bone turnover markers showed decreased osteoclastic activity, impaired mineralization, and an increased fraction of empty lacunae in the GIOBP group. Our findings indicate that patients receiving long-term BP for GIO are still at high risk for fragility fractures because of poor bone quality.

Combined growth hormone and insulin-like growth factor-1 rescues growth retardation in glucocorticoid-treated mdxmice but does not prevent osteopenia.

Short stature and osteoporosis are common in Duchenne muscular dystrophy (DMD) and its pathophysiology may include an abnormality of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis, which is further exacerbated by long-term glucocorticoid (GC) treatment. Hence, an agent that has anabolic properties and may improve linear growth would be beneficial in this setting and therefore requires further exploration. A 5-week-old x-linked muscular dystrophy (mdx) mice were used as a model of DMD. They were treated with prednisolone ± GH + IGF-1 for 4 weeks and then compared to control mdx mice to allow the study of both growth and skeletal structure. GC reduced cortical bone area, bone fraction, tissue area and volume and cortical bone volume, as assessed by micro computed tomography (CT) In addition, GC caused somatic and skeletal growth retardation but improved grip strength. The addition of GH + IGF-1 therapy rescued the somatic growth retardation and induced additional improvements in grip strength (16.9% increase, P < 0.05 compared to control). There was no improvement in bone microarchitecture (assessed by micro-CT and static histomorphometry) or biomechanical properties (assessed by three-point bending). Serum bone turnover markers (Serum procollagen 1 intact N-terminal propeptide (P1NP), alpha C-terminal telopeptide (αCTX)) also remained unaffected. Further work is needed to maximise these gains before proceeding to clinical trials in boys with DMD.

Bone Turnover Markers After Six Nights of Insufficient Sleep and Subsequent Recovery Sleep in Healthy Men.

The goal of this study was to determine the bone turnover marker (BTM) response to insufficient and subsequent recovery sleep, independent of changes in posture, body weight, and physical activity. Healthy men (N = 12) who habitually slept 7-9h/night were admitted to an inpatient sleep laboratory for a baseline 8h/night sleep opportunity followed by six nights of insufficient sleep (5h/night). Diet, physical activity, and posture were controlled. Serum markers of bone formation (osteocalcin, PINP) and resorption (β-CTX) were obtained over 24 h at baseline and on the last night of sleep restriction, and on fasted samples obtained daily while inpatient and five times after discharge over 3weeks. Maximum likelihood estimates in a repeated measures model were used to assess the effect of insufficient and subsequent recovery sleep on BTM levels. There was no statistically or clinically significant change in PINP (p = 0.53), osteocalcin (p = 0.66), or β-CTX (p = 0.10) in response to six nights of insufficient sleep. There were no significant changes in BTMs from the inpatient stay through 3weeks of recovery sleep (all p [Formula: see text] 0.63). On average, body weight was stable during the inpatient stay (Δweight = - 0.55 ± 0.91kg, p = 0.06). No significant changes in serum BTMs were observed after six nights of insufficient or subsequent recovery sleep in young healthy men. Changes in weight and physical activity may be required to observe significant BTM change in response to sleep and circadian disruptions. Clinical Trials Registration Registered at ClinicalTrials.gov (NCT03733483) on November 7, 2018.