Association of bone turnover biomarkers with severe intracranial and extracranial artery stenosis in type 2 diabetes mellitus patients

BACKGROUND Intracranial and extracranial artery stenosis is associated with cerebral infarction.Vascular calcification and atherosclerosis are the main causes of stenosis and major risk factors for cardiovascular and cerebrovascular events in patients with type 2 diabetes mellitus(T2DM).Bone turnover biomarkers(BTMs)are associated with vascular calcification,atherosclerosis,glucose,and lipid metabolism.AIM To investigate the association of circulating BTM levels with severe intracranial and extracranial artery stenosis in patients with T2DM.METHODS For this cross-sectional study including 257 T2DM patients,levels of the BTMs serum osteocalcin(OC),C-terminal cross-linked telopeptide of type I collagen(CTX),and procollagen type I N-peptide were measured by electrical chemiluminescent immunoassay,and artery stenosis was assessed by color Doppler and transcranial Doppler.Patients were grouped according to the existence and location(intracranial vs.extracranial)of artery stenosis.Correlations between BTM levels,previous stroke,stenosis location,and glucose and lipid metabolism were analyzed.RESULTS T2DM patients with severe artery stenosis had a higher frequency of previous stroke and levels of all three tested BTMs(all P<0.05)than patients without.Some differences in OC and CTX levels were observed according to the location of artery stenosis.Significant associations were also observed between BTM levels and some glucose and lipid homeostasis parameters.On multivariate logistic regression analysis,all BTMs were significant predictors of artery stenosis in T2DM patients with and without adjustment for confounding factors(all P<0.001),and receiver operating characteristic curve analysis demonstrated the ability of BTM levels to predict artery stenosis in T2DM patients.CONCLUSION BTM levels were found to be independent risk factors for severe intracranial and extracranial artery stenosis and were differentially associated with glucose and lipid metabolism in patients with T2DM.Therefore,BTMs may be promising biomarkers and potential therapeutic targets for artery stenosis.

Assessment of bone turnover and bone quality in type 2 diabetic bone disease： current concepts and future directions

Substantial evidence exists that in addition to the well-known complications of diabetes, increased fracture risk is an important morbidity. This risk is probably due to altered bone properties in diabetes. Circulating biochemical markers of bone turnover have been found to be decreased in type 2 diabetes （T2D） and may be predictive of fractures independently of bone mineral density （BMD）. Serum sclerostin levels have been found to be increased in T2D and appear to be predictive of fracture risk independent of BMD. Bone imaging technologies, including trabecular bone score （TBS） and quantitative CT testing have revealed differences in diabetic bone as compared to non-diabetic individuals. Specifically, high resolution peripheral quantitative CT （HRpQCT） imaging has demonstrated increased cortical porosity in diabetic postmenopausal women. Other factors such as bone marrow fat saturation and advanced glycation endproduct （AGE） accumulation might also relate to bone cell function and fracture risk in diabetes. These data have increased our understanding of how T2D adversely impacts both bone metabolism and fracture risk.

Correlation of Serum Leptin Level with Bone Mineral Density and Bone Turnover Markers in Chinese Adolescent Dancers

Objective To investigate plasma leptin concentrations in adolescent female dancers and to determine whether leptin has some effects on their bone mineral density （BMD） and bone turnover markers. Methods Sixty dancers aged 15-17 years and 77 healthy controls were enrolled in the study. Bone mineral density （BMD） and body composition were detected by dual energy X-ray absorptiometry. Serum leptin concentrations were measured by radioimmunoassay （RIA）. Two bone turnover markers, bone-specific alkaline phosphatase （BAP） and tartrate-resistant acid phosphatase（TRACP）, were determined by ELISA. Results The dancers had a lower fat mass and a lower leptin level than the controls, while they had a relatively higher BMD of the total body and legs after adjustment for BMI and age. The levels of bone resorption and formation of markers were higher in the dancers than in the controls. Leptin was positively correlated with BMI, body weight, fat mass, and percentage of body fat. In dancers, Leptin was positively correlated with the BMD of the total body and the left leg. However, after adjustment for BMI, no correlation of serum leptin concentrations with BMD values was found in either dancers or controls. Nor correlation was found between leptin and bone turnover markers after adjustment for BMI. Conelusion The leptin profile is different between the controls and the dancers with a lower BMI and a lower fat mass. Circulating plasma leptin level depends on BMI and is not a direct determinant of BMD in Chinese adolescent dancers.

Relationship of serum GDF11 levels with bone mineral density and bone turnover markers in postmenopausal Chinese women

Growth differentiation factor 11 （GDF11） is an important circulating factor that regulates aging. However, the role of GDF11 in bone metabolism remains unclear. The present study was undertaken to investigate the relationship between serum GDF11 level, bone mass, and bone turnover markers in postmenopausal Chinese women. Serum GDF11 level, bone turnover biochemical markers, and bone mineral density （BMD） were determined in 169 postmenopausal Chinese women （47-78 years old）. GDF11 serum levels increased with aging. There were negative correlations between GDF11 and BMD at the various skeletal sites. After adjusting for age and body mass index （BMI）, the correlations remained statistically significant. In the multiple linear stepwise regression analysis, age or years since menopause, BMI, GDF11, and estradiol were independent predictors of BMD. A significant negative correlation between GDF11 and bone alkaline phosphatase （BAP） was identified and remained significant after adjusting for age and BMI. No significant correlation was noted between cross-linked N-telopeptides of type I collagen （NTX） and GDF11. In conclusion, GDF11 is an independent negative predictor of BMD and correlates with a biomarker of bone formation, BAP, in postmenopausal Chinese women. GDF11 potentially exerts a negative effect on bone mass by regulating bone formation.

Association of Bone Turnover Levels with MTHFR Gene Polymorphisms among Pregnant Women in Wuhan, China

Pregnancy is a critical stimulator of bone mineral resorption. We used to find the MTHFR gene polymorphisms are related with blood lead levels among pregnant women. Pregnancy-stimulated bone turnover may be associated with MTHFR gene polymorphisms too. In this article, we aimed to determine the relationship between MTHFR gene polymorphisms and bone turnover rates among the pregnant women. The participants including pregnant and non-pregnant women were selected and recruited during their routine prenatal or physical examination from July to October in 2012. A total of 1000 participants, including 250 pregnant women in the first, second, and third trimesters and 250 non-pregnant women, were enrolled in the study. Finally, after excluding 27 participants unable to provide blood samples, 973 eligible participants （i.e., 234, 249, and 248 pregnant women in the first, second, and third trimesters, respectively, and 242 non-pregnant women） were included in the research. The MTHFR gene 1298CC homozygote carriers were more susceptible to yield higher plasma homocysteine levels than the 1298AA/AC carriers, with standardized coefficients of 0.086 （P〈0.05） and 0.104 （P〈0.01） of all the participants and the pregnant women, respectively. The MTHFR gene 1793AA homozygote carriers more likely showed higher plasma osteocalcin levels （standardized β=0.091, P〈0.01） than the 1793GG/GA carriers among all the subjects. Plasma homocysteine levels were positively correlated with blood lead levels among the participants and the pregnant women with standardized coefficients of 0.320 （P〈0.01） and 0.179 （P〈0.01）, respectively. Plasma osteocalcin levels were positively associated with blood lead levels among pregnant and non-pregnant women with standardized coefficients of 0.084 （P〈0.05） and 0.125 （P〈0.01）, respectively. In conclusion, homocysteine and osteocalcin contents in plasma are associated with the MTHFR gene A1298C polymorphism and blood lead levels among pregnant women. The MTHFR gene A1298C polymorphism-related homocysteine is a possible risk factor for increased blood lead levels among Chinese women.

Effect of Chongcao Bushen Capsule on bone turnover markers in patients with diabetic osteoporosis

Objective:To study the effect of Chongcao Bushen Capsules on bone turnover markers in patients with diabetic osteoporosis.Methods:107 patients with diabetic osteoporosis treated in the Hospital from December 2016 to November 2019were enrolled.They were divided into a control group(n=54)and an observation group(n=53)by random number table.The control group was treated with calcium carbonate,and the observation group was treated with Chongcao Bushen Capsules.The treatment effects,TCM syndrome scores,and bone turnover markers[including osteocalcin,type 1 procollagen amino-terminal propeptide(tP1NP),parathyroid hormone(PTH),25-hydroxyvitamin D,andβ-isomerized c-terminal peptide(β-CTx)],and the incidence of adverse reactions in the two groups were observed and compared.Results:After treatment,the total effective rate of treatment in the observation group(94.44%)was higher than that in the control group(73.58%),and the difference was statistically significant(P<0.05).The scores of symptoms including waist and knee weakness,back and waist pain,lower limb weakness,fatigue and tiredness,difficult walking and dizziness in the observation group were shown to be lower than the control group,and the difference was statistically significant(P<0.05).The levels of osteocalcin,PTH,tP1NP,andβ-CTx in the observation group were lower than those in the control group,and the difference was statistically significant(P<0.05).The 25-hydroxyvitamin D in the observation group was higher than the control group,and the difference was statistically significant(P<0.05).Bone density in both male and female in the observation group was higher than that in the control group,and the difference was statistically significant(P<0.05).Conclusion:For patients with diabetic osteoporosis,Chongcao Bushen Capsule can help improve their clinical symptoms,bone density and the level of bone turnover markers.

Calcium-fortified fresh milk ameliorates postmenopausal osteoporosis via regulation of bone metabolism and gut microbiota in ovariectomized rats

The aging of the global population has made postmenopausal osteoporosis prevention essential;however,pharmacological treatments are limited.Herein,we evaluate the effect of calcium-fortified fresh milk(FM)in ameliorating postmenopausal osteoporosis in a rat model established using bilateral ovariectomy.After 3 months of FM(containing vitamin D,and casein phosphopeptides,1000 mg Ca/100 g)or control milk(110 mg Ca/100 g milk)supplementation,bone changes were assessed using dual-energy X-ray absorptiometry,microcomputed tomography,and bone biomechanical testing.The results revealed that FM can regulate bone metabolism and gut microbiota composition,which act on bone metabolism through pathways associated with steroid hormone biosynthesis,relaxin signaling,serotonergic synapse,and unsaturated fatty acid biosynthesis.Furthermore,FM administration significantly increased bone mineral content and density in the lumbar spine and femur,as well as femoral compressive strength,while improving femoral trabecular bone parameters and microarchitecture.Mechanistically,we found that the effects may be due to increased levels of estrogen,bone formation marker osteocalcin,and procollagen typeⅠN-propeptide,and decreased expression of the bone resorption marker C-telopiptide and tartrate-resistant acid phosphatase 5b.Overall,the findings suggest that FM is a potential alternative therapeutic option for ameliorating postmenopausal osteoporosis.

Bone Loss in Women with Type 1 Diabetes

Background: Although osteoporosis has been investigated and debated in the diabetic population over the past decades, very little is known about the spontaneous changes in bone mineral density (BMD) and biochemical markers of bone turnover in pre- and postmenopausal type 1 diabetic (T1DM) women over time. Aim: To measure spontaneous changes in BMD and biochemical markers of bone turnover in pre- and postmenopausal T1DM women. Subjects: 53 T1DM women (31 premenopausal and 22 postmenopausal) from the outpatient clinic were enrolled in the study in 1993 and 35 (22 premenopausal, 13 postmenopausal) were reexamined in 1997. Method: BMD was measured at femoral neck (f.n.), spine (L2 - L4), total body and forearm with DXA or SXA in 53 T1DM women. 4 years later a re-scan was carried out on 35 T1DM. Results: In premenopausal subjects a yearly decrease less than 1% at f.n., spine, forearm and total body was observed, though only statistically significant (s.s.) at f.n., p ≤ 0.05. In postmenopausal subjects a s.s. decrease less than 2% was observed at f.n., forearm and total body, p ≤ 0.05. In general, osteopenic or osteoporotic values were observed at the measured skeletal sites. Only at f.n. a lower s.s. BMD compared to age-matched reference women was seen. Conclusion: Small or non-significant changes in BMD and biochemical markers of bone turnover were observed in pre- and postmenopausal T1DM subjects after a 4-year period.

Effect of chronic sleep deprivation on peak bone mass in rats: An experimental study

Objective:To investigate the effects of chronic sleep deprivation(CSD)on bone microstructure and peak bone mass(PBM)in SD rats.Methods:Twenty-four SD rats were randomly divided into CSD group and control group.In the CSD group,a CSD model was established using a new sleep deprivation instrument for rats and mice,and intervened for 5 weeks.Bone turnover markers including P1NP and CTX-1 before and after the experiment were observed.After the experiment,the left femur were scanned by Micro-CT,and the cortical bone and bone trabecula were three-dimensionally reconstructed,respectively.The bone mineral density(BMD)and relevant parameters were detected.Results:CT images of the femur(proximal ends)showed significant trabecular loss in CSD rats.Trabecular parameters including bone volume fraction(BV/TV),trabecular number(Tb.N)and trabecular separation(Tb.Sp)in the CSD group were all lower than those in the control group.The bone cortex of the middle segment of the femur and tibia in CSD rats was also lower than that in the control group.The parameters of bone cortex including total tissue area(Tt.Ar),cortical bone area(Ct.Ar)and cortical bone thickness(Ct.Th)in the CSD group were significantly lower than those in the control group(P<0.01).After chronic CSD,BMD of both bone trabecula and bone cortex of the femur was lower,while the corresponding P1NP and CTX-1 were significantly higher than those in the control group.Conclusion:Sleep plays an important role in PBM formation.CSD accelerates bone turnover and thus significantly reducing PBM in SD rats.

Effects of denosumab treatment in chronic liver disease patients with osteoporosis

BACKGROUND Effective treatment of osteoporosis is essential for improving morbidity and health-related quality of life in chronic liver disease(CLD)patients.Denosumab has been shown to increase bone mineral density(BMD)and decrease the risk of osteoporotic fracture in the general population.However,there are few reports evaluating the efficacy of denosumab in CLD patients.AIM To investigated the effects and safety of denosumab in CLD patients with osteoporosis.METHODS Sixty CLD patients with osteoporosis were subcutaneously administered denosumab once every 6 mo.The study period for evaluating efficacy and safety was 12 mo.Changes from baseline in BMD at the lumbar spine,femoral neck,and total hip were evaluated at 12 mo of denosumab treatment.Bone turnover and quality were assessed by measuring serum tartrate-resistant acid phosphatase-5b(bone resorption marker),serum total procollagen type I N-terminal propeptide(bone formation maker),and plasma pentosidine(bone quality marker).RESULTS Among the 405 CLD patients,138(34.1%)patients were diagnosed with osteoporosis;among these,78 patients met the exclusion criteria and thus 60 patients were finally included in the present study.The median percentage changes from baseline to 12 mo of denosumab treatment in BMD at the lumbar spine,femoral neck,and total hip were+4.44%,+3.71%,and+4.03%,respectively.Denosumab significantly improved BMD,regardless of sex,patient age,and presence of liver cirrhosis.Serum tartrate-resistant acid phosphatase-5b and procollagen type I N-terminal propeptide levels constantly and significantly declined after denosumab treatment(P<0.001).Plasma pentosidine levels were also significantly lower at 12 mo of treatment(P=0.010).No patients experienced fractures and moderate-to-severe adverse events,except for transient hypocalcemia.CONCLUSION Denosumab treatment was safe and increased BMD,suppressed bone turnover,and improved bone quality marker levels in CLD patients with osteoporosis,irrespective of differences in baseline characteristics.

Dietary supplementation of 25-hydroxycholecalciferol increases tibial mass by suppression bone resorption in meat ducks

Leg problems often result from the rapid weight gain and poor bone quality in modern ducks,leading to a high risk of fractures and continuous pain.We hypothesized that improving bone quality in combination with delaying weight gain via a low nutrient density(LND)diet probably reverses these skeletal abnormalities.Studies indicated that 25-hydroxycholecalciferol(25-OH-D3),a vitamin D3 metabolite,is effective in treating bone-related disorders.Therefore,Exp.1 evaluated the effects of 25-OH-D3 on tibial mass of meat ducks.Male meat ducklings were fed a standard nutrient density diet(containing a regular vitamin regimen)without or with 25-OH-D3 at 0.069 mg/kg for 35 d.The results showed that 25-OH-D3 supplementation improved the mineral content,microarchitecture and mechanical properties of tibias,and this companied by a decreased serum bone resorption marker and a concomitant decrement in osteoclast-specific marker genes expression.Subsequently,Exp.2 was conducted to examine the impacts of 25-OH-D3 incorporating an LND diet on tibial quality of ducks under 2 different vitamin regimens(regular and high).Ducklings were allocated to a 2*2 factorial arrangement with 2 kinds of vitamin premixes and without or with 25-OH-D3 at 0.069 mg/kg in LND diets.The high premix had higher levels of all vitamins except biotin than the regular premix.The results demonstrated that high vitamin diets exhibited more significant effects than regular vitamin diets on inhibiting bone turnover and increasing minerals deposition.Tibial mineral content,microarchitecture,and strength of birds under the regular vitamin regimen were increased by 25-OH-D3 supplementation;However,these positive effects were not observed in ducks under the high vitamin regimen.To conclude,25-OH-D3 supplementation improves tibial mass by suppressing osteoclast-mediated bone resorption in meat ducks,and this positive impact only was observed in regular but not high vitamin regimen when birds fed an LND diet.

Urinary cross-linked N-telopeptides of type Ⅰ collagen and bone metabolic diseases

Objective To evaluate the type I collagen cross linked N telopeptide (NTx) levels in human urine as an indicator of bone resorption rate in different ages, sex and in bone metabolic diseases.Methods Urinary NTx was determined by immunoassay in 591 Beijing healthy subjects aged from 0 to 86 years and 379 patients with bone metabolic diseases.Results The levels of urinary NTx were significantly higher in children than in adults (P<0.001) and higher in boys than in girls (P<0.01) and increased 1.4-2.2 times in postmenopausal females than in men and premenopausal women. Urine NTx had a positive linear correlation with urine HOP/Cr (r= 0.778, P< 0.01) and Ca/Cr ratio (r=0.320, P< 0.01 ), and a negative linear correlation with age (r= -0.523, P<0.01) and lumbar spine BMD (r= -0.426, P<0.01). The levels of urine NTx increased for 3.6 times in pregnancy, 1.5 times in osteoporosis, 1.9 times in fragility fracture, 3.6 times in chronic renal failure, 2.1 times in rickets and 7.2 times in multiple myeloma compared to age matched controls.Conclusions NTx in urine is a specific and sensitive indicator of bone resorption and is able to distingish normal premenopause from late osteoporotic patients. NTx could be used as diagnostic information about metabolic bone diseases, and to monitor antiresorptive therapy.