The paradox of bone mineral density and fracture risk in type 2 diabetes.

Fracture risk in type 2 diabetes (T2D) patients is paradoxically increased despite no decrease in areal bone mineral density (BMD). This phenomenon, known as the "diabetic bone paradox", has been attributed to various factors including alterations in bone microarchitecture and composition, hyperinsulinemia and hyperglycemia, advanced glycation end products (AGEs), and comorbidities associated with T2D. Zhao et al. recently investigated the relationship between T2D and fracture risk using both genetic and phenotypic datasets. Their findings suggest that genetically predicted T2D is associated with higher BMD and lower fracture risk, indicating that the bone paradox is not observed when confounding factors are controlled using Mendelian randomization (MR) analysis. However, in prospective phenotypic analysis, T2D remained associated with higher BMD and higher fracture risk, even after adjusting for confounding factors. Stratified analysis revealed that the bone paradox may disappear when T2D-related risk factors are eliminated. The study also highlighted the role of obesity in the relationship between T2D and fracture risk, with BMI mediating a significant portion of the protective effect. Overall, managing T2D-related risk factors may be crucial in preventing fracture risk in T2D patients.

Role of Iron Accumulation in Osteoporosis and the Underlying Mechanisms.

Osteoporosis is prevalent in postmenopausal women. The underlying reason is mainly estrogen deficiency, but recent studies have indicated that osteoporosis is also associated with iron accumulation after menopause. It has been confirmed that some methods of decreasing iron accumulation can improve the abnormal bone metabolism associated with postmenopausal osteoporosis. However, the mechanism of iron accumulation-induced osteoporosis is still unclear. Iron accumulation may inhibit the canonical Wnt/ß-catenin pathway via oxidative stress, leading to osteoporosis by decreasing bone formation and increasing bone resorption via the osteoprotegerin (OPG)/receptor activator of nuclear factor kappa-B ligand (RANKL)/receptor activator of nuclear factor kappa-B (RANK) system. In addition to oxidative stress, iron accumulation also has been reported to inhibit either osteoblastogenesis or osteoblastic function as well as to stimulate either osteoclastogenesis or osteoclastic function directly. Furthermore, serum ferritin has been widely used for the prediction of bone status, and nontraumatic measurement of iron content by magnetic resonance imaging may be a promising early indicator of postmenopausal osteoporosis.

Computerized analysis of fetal heart rate pattern in the third trimester of low-risk pregnancy by long-range electronic fetal monitoring.

BACKGROUND: With computerized analysis of fetal heart rate(FHR) data from long-range monitoring, we aimed to comprehensively clarify the characteristics of FHR with increasing gestational age in low-risk pregnant women during the third trimester of pregnancy. METHODS: This was an observational study. 85 fetuses of low-risk pregnant women were included. The data covered 28 ∼ 40 weeks of gestation, and 125 cases of FHR monitoring from 85 fetuses were totally collected. The FHR baseline rate, variability, and acceleration were computationally calculated, analyzed and compared. RESULTS: The average effective monitoring time for each case was 13.9 ± 4.3 h. FHR baseline gradually decreased as the gestational age progressed, and the maximum FHR baseline appeared at 28-29 weeks, which was 137.5 (133.0, 141.3) bpm, whereas the minimum FHR baseline appeared at 38-39 weeks, that was 132.8 (128.1, 138.4) bpm. FHR variability fluctuated in (4-12）bpm. It gradually increased from 28 to 33 weeks of gestation, reached the maximum of 7.6 (6.0-9.4) bpm, and then decreased until full-term pregnancy. The moderate variability proportion of FHR gradually increased from 28 weeks of gestation, peaked at 32-33 weeks as 65.8%, and then gradually decreased to 56.2% at 37 weeks, which was maintained at this level until 39 weeks. The variation tendency of minimal variability proportion was opposite to moderate variability proportion. When it reached 40 weeks, the minimal and moderate variability proportions were 50.0% and 49.0%, respectively. The FHR acceleration area showed no trend change during the third trimester, while fluctuated in (29.5-42.4) lattices/h. CONCLUSION: This study revealed that the characteristics of FHR gradually changed with increasing gestational age, and the most obvious change was observed at 32-33 weeks, demonstrating that the specific gestational weeks may be an important period for the physiological bias of FHR tends to mature.

Evaluation of Clinical Graded Treatment of Acute Nonsuppurative Otitis Media in Children with Acute Upper Respiratory Tract Infection.

Objective: To treat children with acute nonsuppurative otitis media induced by acute upper respiratory tract infection of varying severity and evaluate its therapeutic effects. Materials and Methods: Patients from the emergency department with acute nonsuppurative otitis media were followed up between September 2015 and December 2018. A total of 420 patients were classified into grades I to III according to tympanic membrane intactness and systemic reactions and treated according to grading. Results: Grade I patients showed no significant difference in the recovery of acute symptoms whether antibiotics are used or not. Grade II patients, after 3 months of follow-up, showed no tympanic membrane perforation, and 9 cases of binaural B-type children did not improve but were cured by operation. In grade III patients, after treatment for 4 hours in the experimental group 3, the earache subsided, 1 case had tympanic membrane perforation, and the patients recovered after 2 weeks (64/92) and after 3 months (28/92) of drug treatment. After treatment for 4 h in the control group 3, the earache eased, and 3 patients developed tympanic membrane perforation and were treated for 3 months. 4 binaural B-type children did not improve but recovered after surgical treatment. Conclusion: Grade I patients could be closely followed up by clinical observation. For anti-inflammatory patients with grade II disease, treatment has therapeutic significance. For patients with grade III, some patients still have TMP, but the use of cephalosporin third-generation drugs plus an appropriate amount of hormone therapy is effective in reducing symptoms and tympanic local reactions.

[Percutaneous pedicle screw fixation combined with vertebroplasty for the treatment of Genant â ¢ degree osteoporotic vertebral compression fractures].

OBJECTIVE: To investigate the clinical effect of percutaneous pedicle screw fixation(PPSF) combined with percutaneous vertebroplasty (PVP) in the treatment of Genant Ⅲ degree osteoporotic vertebral compression fractures (OVCFs). METHODS: The hospitalized 83 patients with Genant Ⅲ degree OVCFs treated by PPSF combined with PVP from June 2015 to June 2017 were retrospectively analyzed, and 83 patients treated by PVP alone from January 2013 to June 2016 were randomly selected as the control group. There were 19 males and 64 females with an average age of (73.6±11.0) years in combined group with treatment of PPSF and PVP. There were 15 malesand 68 females with an average age of (75.5±10.6) years in control group. The anterior edge height of the vertebral body and Cobb angle before operation, 1 day, and 6, 12, 24 months after operation were compared between two groups. Visual analogue scale(VAS) and Oswestry Disability Index (ODI) were used to assess the pain level and daily lumbar dysfunction for patients, respectively. The complications were observed. RESULTS: The follow-up time of all patients was more than 2 years. The combined group and control group were (24.3±10.2) months and (27.5±14.8) months, respectively. There were no statistically significant differences in the anterior edge height of the vertebral body and Cobb angle at 1 day after surgery between two groups (P>0.05), and there were statistically significant differences at 6, 12, 24 months after surgery between two groups (P<0.01). The difference in ODI and VAS scores at 6 and 12 months after operation between two groups was statistically significant (P<0.05). Postoperative complications incontrol group were higher than those in the combined group. CONCLUSION: PPSF combined with PVP for the treatment of Genant Ⅲ degree OVCFs is superior to PVP alone in terms of vertebral height loss, patient satisfaction, and complications.

Reducing iron accumulation: A potential approach for the prevention and treatment of postmenopausal osteoporosis.

Postmenopausal osteoporosis (PMOP) is a systemic bone metabolism disease, characterized by progressive bone loss following menopause and a subsequent increase in fracture risk. Estrogen deficiency as a result of menopause is known to increase bone resorption and accelerate bone loss. Furthermore, postmenopausal women may exhibit iron accumulation, in addition to estrogen deficiency. Elevated iron levels are a risk factor for PMOP in postmenopausal women, and reducing the iron overload has been demonstrated to benefit bone cell metabolism in vitro and improve the bone in vivo by normalizing osteoclastic bone resorption and formation. The identification of hepcidin was a key development in the field of iron metabolism in the previous decade. We hypothesize that hepcidin may aid in the prevention and treatment of PMOP due to its capacity to control body iron stores and its intrinsic effects on osteoblast function. The aim of the current review was to highlight the role of iron accumulation in the pathogenesis of PMOP and to evaluate the possible use of hepcidin as a potential therapy for this condition.

Local bone interaction between renin-angiotensin system and kallikrein-kinin system in diabetic rat.

OBJECTIVE: This study was performed to investigate bone deteriorations and the involvement of skeletal renin-angiotensin system (RAS) and kallikrein-kinin system (KKS) of male rat in response to the hyperglycemia. METHODS: The biomarkers in serum and urine were measured by ELISA kit, and tibias were taken for the measurement on gene, protein expression and histological analysis, femurs were taken for the measurement on biomechanical parameters and micro-CT. RESULTS: The DM1 showed the decreased level of osteocalcin, testosterone and FGF-23, and the increased level of serum CTX as compared to those of vehicle group. The H&E staining showed remarkable bone deteriorations, including increased disconnections and separation of trabecular bone among growth plate and joint cartilage in DM1 group. Biomechanically, the maximum load, maximum stress, and strain parameter of DM1 group was significantly lower than control group. Type 1 diabetic mice displayed bone loss shown the reduction of bone volume/total volume, trabecular number, trabecular thickness and bone mineral density. The STZ injection significantly up-regulated mRNA expression of AT1R, AGT, renin, renin-receptor, and ACE, and the expression of AT2R, B1R and B2R were down-regulated in tibia of rat in hyperglycemia group. The protein expression of renin, ACE and Ang II were significantly up-regulated, and AT2R, B1R and B2R were down-regulated in DM1 group. CONCLUSIONS: The treatment of hyperglycemia was detrimental to bone as compared to the vehicle group, and the underlying mechanism was mediated, at least partially, through down-regulation of KSS activity and up-regulation of RAS activity in local bone.

Therapeutic effect of deferoxamine on iron overload-induced inhibition of osteogenesis in a zebrafish model.

Osteoporosis results from an imbalance in bone remodeling, in which osteoclastic bone resorption exceeds osteoblastic bone formation. Iron has recently been recognized as an independent risk factor for osteoporosis. Reportedly, excess iron could promote osteoclast differentiation and bone resorption through the production of reactive oxygen species (ROS). We evaluated the effect of iron on osteoblast differentiation and bone formation in zebrafish and further investigated the potential benefits of deferoxamine (DFO), a powerful iron chelator, in iron-overloaded zebrafish. The zebrafish model of iron overload described in this study demonstrated an apparent inhibition of bone formation, accompanied by decreased expression of osteoblast-specific genes (runx2a, runx2b, osteocalcin, osteopontin, ALP, and collagen type I). The negative effect of iron on osteoblastic activity and bone formation could be attributed to increased ROS generation and oxidative stress. Most importantly, we revealed that DFO was capable of removing whole-body iron and attenuating oxidative stress in iron-overloaded larval zebrafish, which facilitated larval recovery from the reductions in bone formation and osteogenesis induced by iron overload.

Iron overload inhibits osteoblast biological activity through oxidative stress.

Iron overload has recently been connected with bone mineral density in osteoporosis. However, to date, the effect of iron overload on osteoblasts remains poorly understood. The purpose of this study is to examine osteoblast biological activity under iron overload. The osteoblast cells (hFOB1.19) were cultured in a medium supplemented with different concentrations (50, 100, and 200 µM) of ferric ammonium citrate as a donor of ferric ion. Intracellular iron was measured with a confocal laser scanning microscope. Reactive oxygen species (ROS) were detected by 2,7-dichlorofluorescin diacetate fluorophotometry. Osteoblast biological activities were evaluated by measuring the activity of alkaline phosphatase (ALP) and mineralization function. Results indicated that iron overload could consequently increase intracellular iron concentration and intracellular ROS levels in a concentration-dependent manner. Additionally, ALP activity was suppressed, and a decline in the number of mineralized nodules was observed in in vitro cultured osteoblast cells. According to these results, it seems that iron overload probably inhibits osteoblast function through higher oxidative stress following increased intracellular iron concentrations.

A comparison of the biological activities of human osteoblast hFOB1.19 between iron excess and iron deficiency.

Bone metabolism has a close relationship with iron homeostasis. To examine the effects of iron excess and iron deficiency on the biological activities of osteoblast in vitro, human osteoblast cells (hFOB1.19) were incubated in a medium supplemented with 0-200 µmol/L ferric ammonium citrate and 0-20 µmol/L deferoxamine. The intracellular iron was measured by a confocal laser scanning microscope. Proliferation of osteoblasts was evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Apoptotic cells were detected using annexin intervention V/PI staining with a flow cytometry. Alkaline phosphatase (ALP) activity was measured using an ALP assay kit. The number of calcified nodules and mineral area was evaluated by von Kossa staining assay. The expressions of type I collagen and osteocalcin of cultured osteoblasts were detected by reverse transcriptase polymerase chain reaction and Western blot. Intracellular reactive oxygen species (ROS) was measured using the oxidation-sensitive dye 2,7-dichlorofluorescin diacetate by flow cytometry. The results indicated that excessive iron inhibited osteoblast activity in a concentration-dependent manner. Low iron concentrations, in contrast, produced a biphasic manner on osteoblasts: mild low iron promoted osteoblast activity, but serious low iron inhibited osteoblast activity. Osteogenesis was optimal in certain iron concentrations. The mechanism underlying biological activity invoked by excessive iron may be attributed to increased intracellular ROS levels.

Effect of hepcidin on intracellular calcium in human osteoblasts.

Hepcidin is known to increase intracellular iron through binding to and degrading ferroportin, which is a transmembrane protein that transports iron from the intracellular to the outside. However, it is not clear whether hepcidin has a similar effect on intracellular calcium. Here, we investigated the influence of hepcidin on intracellular calcium in human osteoblasts, with or without high environmental iron concentrations. Our data showed that hepcidin (<100 nmol/L) could increase intracellular calcium, and this effect was more significant when cells were exposed to high environmental iron concentrations. To further explore its underlying mechanisms, we pretreated human osteoblasts with Nimodipine, a L-type calcium channel blocker, and Dantrolene, a ryanodine receptor antagonist to inhibit abnormal calcium release from the sarco-endoplasmic reticulum. These treatments had not resulted in any alteration of intracellular calcium in human osteoblasts. Thus, these findings indicate that the increase of intracellular calcium induced by hepcidin is probably due to calcium release from endoplasmic reticulum, which is triggered by calcium influx.