New biochemical markers of bone turnover in serum

Measurement of serum NTx and serum CTx has been recently reported to be a sensitive for osteoporosis and metabolic bone disease. It indicates that the measurement of serum NTx and serum CTx, biochemical markers of bone resorption, predict long-term changes in vertebral BMD in elderly women receiving biophosphonate therapy and provide a useful tool to assess skeletal health.     

Relationship between serum hsCRP concentration and biochemical bone turnover markers in healthy pre- and postmenopausal women

OBJECTIVE: Although osteoporosis and atherosclerosis seem to be related, the mechanisms are not yet understood. We previously observed that women with higher serum concentrations of high sensitivity C-reactive protein (hsCRP), a strong risk factor for atherosclerosis, had lower bone mineral density (BMD). However, the relationship of hsCRP level with bone turnover rate, an independent risk factor for osteoporotic fracture, is not known. DESIGN: Cross-sectional hospital-based survey. PATIENTS: Apparently healthy pre- and postmenopausal women (n = 39 and 150, respectively). MEASUREMENTS: Urinary N-terminal telopeptide of type I collagen (NTx) and serum bone specific alkaline phosphatase (BALP) were measured using commercially available immunoassay kits. Serum hsCRP concentrations were measured by a particle-enhanced immunoturbidometric method. RESULTS: Both urinary NTx (gamma = 0.288, P < 0.001) and serum BALP (gamma = 0.260, P < 0.001) were positively correlated with serum hsCRP levels. Significance remained even after adjustment for age, body mass index and years since menopause (gamma = 0.257, P < 0.001, and gamma = 0.163, P = 0.027, respectively). Compared with subjects in the lowest hsCRP quartile (< or = 0.6 mg/l), those in the highest hsCRP quartile (> or = 1.6 mg/l) had significantly higher urinary NTx concentrations (P = 0.001) after adjustment for confounding variables. There was an increasing trend of serum BALP concentrations in the higher hsCRP quartile groups (P = 0.073). CONCLUSION: These findings suggest that low grade systemic inflammation may be a common linking factor between development of atherosclerosis and increased bone turnover rate.     

Urinary markers of adrenarche: reference values in healthy subjects, aged 3-18 years

Information on the urinary excretion of dehydroepiandrosterone (DHEA) and its direct metabolites is scarce for healthy subjects during growth. We used gas chromatography-mass spectrometry urinary steroid profiling to noninvasively study adrenarchal metabolome in 400 healthy subjects, aged 3-18 yr. Urinary 24-h excretion rates of DHEA did not increase significantly before age 7-8 yr. However, DHEA together with its 16alpha-hydroxylated downstream metabolites, 16alpha-hydroxy-DHEA and 3beta,16alpha,17beta-androstenetriol (DHEA&M), as well as the DHEA metabolite, 5-androstene-3beta,17beta-diol (ADIOL), and the sum of major urinary androgen metabolites (C19) rose consistently from the youngest to the oldest age group. The significant increases (P < 0.01) observed for 24-h excretion rates of C19, ADIOL, and DHEA&M were 2- to 4-fold in boys and girls between age 3 and 8 yr. DHEA&M, for example, rose from about 20 to 80 microg/d (P < 0.0001) during this period. Until the age of 16 yr, DHEA&M excretion also increased to nearly 1000 microg/d. Patterns of steroidogenic enzyme activities were assessed (from definite ratios of urinary steroid metabolites) for 21-hydroxylase, 3beta-hydroxysteroid dehydrogenase, 17beta-hydroxysteroid dehydrogenase, and 5alpha-reductase. Our results indicate for healthy boys and girls that adrenarche is a gradual process starting much earlier than hitherto believed. Efficient metabolism of DHEA, especially to 16-hydroxylated steroids, may explain the almost constant levels seen for this steroid until age 7-8 yr. The established reference values for DHEA, DHEA&M, ADIOL, C19 (including androsterone and etiocholanolone), and urinary parameters of steroidogenic enzyme activities could be useful to identify nutritional, environmental, and pathophysiological interrelations with the progressive maturational process of adrenarche. Our data may also be used as reference data for the diagnosis of steroid-related disorders.     

Biological variability of biochemical markers of bone turnover in healthy women

To investigate day-to-day biological change of biochemical makers of bone turnover, we measured eight markers for 5 days in 10 healthy women. They aged 26-41 years (mean age; 31.1 years old), and had regular menstrual cycles. Fasting second void urine and blood was collected from them on five successive days. As serum marker, Estradiol (E2), intact PTH (i-PTH), Bone-specific alkaline phosphatase (BAP), and serum C-telopeptide (S-CTX) were measured. As urinary markers, urinary CTX (U-CTX), N-telopeptide (NTX), pyridinoline (Pyr) and deoxypyridinoline (Dpyr) were measured. Day-to-day physiological variations were different between bone markers. Variability of serum markers was less than that of urinary markers. Moreover, in the comparison of the same molecular marker, CTX, the variability of S-CTX was less than U-CTX. One should consider physiological variation of the marker to evaluate whether the change of the biochemical marker of bone turnover is significant or not.     

杭州地区2～6岁健康儿童血清垂体-甲状腺轴激素正常参考范围调查

用化学发光法检测592名杭州地区2～6岁健康儿童的血清TSH、T3、T4、FT3、FT4浓度并作统计分析,得出总人群的正常参考范围为:TSH 1.09～4.60 mIU/L,T3 1.17～1.95μg/L,T4 57.43～99.60μg/L,FT3 5.35～7.50 pmol/L,FT4 13.96～19.70 pmol/L.不同年龄、不同性别间比较,差异无统计学意义(P＞0.05).

Abstract：

Serum concentrations of TSH, total and free thyroxine, and total and free triiodothyronine in 592 healthy children aged 2-6 years were determined by means of ADVIA Centaur. The normal reference ranges were calculated. The reference ranges of TSH, T3, T4, FT3, and FT4 were 1.09-4.60 mIU/L, 1.17-1.95 μg/L,57.43-99.60 μg/L, 5.35-7.50 pmol/L, 13.96-19.70 pmol/L, respectively. There was no significant difference in the interval of thyroid hormones between males and females as well as among different age groups.     

Respiratory resistance and impedance magnitude in healthy children aged 2-18 years

Two hundred eighteen healthy children aged 2 to 18 years were studied using a modification of the forced oscillation technique. Reference values with height as predictor were determined for total respiratory resistance and impedance during inspiration, expiration, and throughout the whole respiratory cycle at an oscillation frequency of 4 Hz and, in a subpopulation of 61 children, at frequencies of 2 and 12 Hz. Mean total inspiratory resistance, determined at 4 Hz, decreased with growth from 1.3 kPa X 1(-1) X s at 2 years of age to 0.3 kPa X 1(-1) X s at 18 years. Variability in the results between individuals, expressed in terms of coefficient of variation, was found to be +27% and -21%, respectively, and within individuals, 9%. Resistance during expiration was on average 16% higher than during inspiration and the variability within individuals was 11%. A marked decrease in resistance was found in small children when the frequency was increased from 2 to 12 Hz. The frequency dependence of respiratory resistance observed in small children changes gradually with growth, in parallel with the reduction of total respiratory resistance, to an adult pattern in which no significant change in resistance can be noted between frequencies of 2 and 12 Hz.     

Bone turnover markers and bone mineral density in children with haemophilia

Summary. During childhood growth, bone undergoes modelling involving separate osteoblastic and osteoclastic processes. Markers of bone turnover circulate at high concentrations, parallel the childhood growth curve and correlate with height velocity. The aim of this study was to compare serum markers of bone turnover in children with haemophilia and normal bone mineral density (BMD) vs. those with low BMD. In a cross‐sectional study, 69 children with haemophilia were evaluated, 45 children with normal spine BMD vs. 24 with low BMD. Lumbar spine BMD was determined using dual X‐ray absorptiometry and Z‐scores were calculated. Serum samples of markers of bone turnover, osteocalcin (bone formation) and C‐telopeptide of type I collagen (bone resorption) were measured using ELISA. The mean BMD (g cm^?2) in the normal group was 0.656 ± 0.15 vs. 0.558 ± 0.12 in those with low BMD (P = 0.007), osteocalcin levels in children with normal BMD were 9.29 ± 4.97 vs. 7.06 ± 2.17 ng μL^?1 in the low BMD group (P = 0.012). C‐telopeptide levels in the normal group were 1.06 ± 1.4 vs. 0.74 ± 0.3 ng mL^?1 in the low BMD group (P = 0.169). Our results showed that low osteocalcin levels predominated in the group with low BMD, which indicates a diminished osteoblastic bone formation activity while there were no differences with regard to bone resorption markers. Moreover, osteocalcin levels explain 10% of the variation of lumbar spine Z‐score.     

Standard reference for the six-minute-walk test in healthy children aged 7 to 16 years

RATIONALE: We have previously reported that the six-minute-walk test (6MWT) is a reliable and valid functional test for assessing exercise tolerance and endurance. There is a lack of pediatric standard reference for the 6MWT. OBJECTIVES: To construct height-specific standards for the 6MWT for children aged 7 to 16 years. METHODS: The anthropometric data, spirometric lung function, and six-minute-walk distance (6MWD) of Chinese children aged 7 to 16 years were prospectively measured using standardized protocols. The findings were used to construct height-specific standards for the 6MWT. The least mean square (LMS) method using maximum penalized likelihood was used to facilitate model fitting. Factors significantly associated with 6MWD were also determined. MEASUREMENTS AND MAIN RESULTS: From January 2005 to April 2006, a total of 1,445 subjects were studied. The measured variables showed a normal distribution. Height-specific reference standards for 6MWT were constructed for both male and female children. Forward stepwise multiple regression analysis revealed height and difference in heart rate before and after the walk test to be important clinical variables associated with 6MWD. CONCLUSIONS: These 6MWD standards will provide useful references for the care of pediatric patients.     

9月龄～6岁健康儿童麻疹和风疹抗体水平监测

目的 了解新疆阿克苏地区9月龄～6岁健康儿童麻疹和风疹抗体水平,及时发现免疫薄弱人群,采取针对性免疫措施.方法 采用分层随机抽样法,采集839名9月龄～6岁健康儿童血清标本,采用酶联免疫吸附试验(ELISA)检测麻疹和风疹IgG抗体.结果 839名儿童麻疹抗体阳性率为94.3％,抗体几何平均滴度(GMT)为1 541.2 mIU/ml;风疹抗体阳性率为92.1％,抗体几何平均滴度(GMT)为958.4 mIU/ml.不同免疫剂次和不同年龄组儿童麻疹、风疹抗体阳性率和GMT水平不同,差异有统计学意义(P＜0.05).结论 阿克苏地区9月龄～6岁健康儿童麻疹、风疹IgG抗体水平总体较高,但仍存在薄弱环节,1岁以下儿童是麻疹和风疹的高危人群,应加强此部分人群的针对性免疫策略.     

An assessment of genetic markers as predictors of bone turnover in healthy adults

In 1992 a significant relationship between bone turnover and the vitamin D receptor (VDR) genotype was reported in Australian subjects of UK-Irish decent. Since then, several groups have investigated the relationship between VDR and other bone-related genotypes, bone mass and bone turnover in several populations. However, the results of these studies are conflicting. Therefore, our aim was to determine bone-related genotypes in a population of healthy Irish adults and relate these genotypes to the rate of bone turnover. One hundred and eighteen healthy Irish adults (aged 19-67 yr) were recruited and fasting blood and first void urines were collected from each subject. Bone-related genotype frequencies in healthy Irish adults were similar to those reported in other Caucasian populations and were in Hardy-Weinberg equilibrium. Estrogen receptor (Pvu II or Xba I), apolipoprotein E and collagen IA1 genotypes were not related to bone turnover. The tt VDR genotype was associated with significantly higher serum osteocalcin (29% and 40%) compared with the Tt and TT genotypes, respectively. The ff VDR genotype was associated with significantly higher urinary pyridinoline (by approximately 44% and approximately 29%) and deoxypyridinoline (by approximately 76% and approximately 58%) levels and higher serum osteocalcin (by approximately 25% and approximately 53%) compared with the Ff or FF genotypes, respectively. These findings suggest that healthy Irish adults with either the tt or ff VDR genotype have higher rates of bone turnover than those with Tt or TT, or Ff or FF genotypes, respectively, and therefore may have a higher risk of low bone mineral density and osteoporosis in later life.     

北京市部分老年男性25羟维生素D水平及其与骨代谢的关系

目的探讨北京市部分老年男性维生素D水平及其与骨代谢指标的关系。方法采用化学发光法测定血清25羟化维生素D3（25OHD₃）、甲状旁腺素（PTH）、β-Ⅰ型胶原C端肽（β-CTX）、骨钙素（osteocalcin）、1型原胶原分子N一端前肽（PINP）水平。根据血清25OHD3水平分为维生素D严重缺乏（<10ng/mL）、缺乏（≥10<20ng/mL）、不足（≥20<30ng/mL）和充足（≥30ng/mL）。结果 2010年5月至6月入选564名老年受试者,平均年龄（73.7±8.5）岁。≥60～70岁为老年1组、≥70～80岁为老年2组,≥8O岁为老年3组。老年男性总体25OHD3水平为（14.57±5.95）ng/mL,均为维生素D缺乏。各组受试者血清PTH平均水平为（34.85±12.23）ng/mL,骨钙素平均水平为（13.49±4.81）ng/mL,β-CTX平均水平为（0.30±0.15）ng/mL。K-S检验结果表明,上述骨代谢指标均呈正态分布。各年龄组25OHD3、PTH、骨钙素、PINP、β-CTX水平差异均无统计学意义（P>0.05）。老年男性维生素D严重缺乏、缺乏、不足、充足的比例分别为23.4%（132/564）,56.6%（319/564）,18.4%（104/564）,1.6%（9/564）。不同年龄组间低维生素D状态的比例差异无统计学意义（F=15.57,P=0.076）。相关分析结果表明,25OHD3水平与PTH呈负相关（r=-0.240,P=0.000）;与骨钙素呈负相关（r=-0.080,P=0.034）;与β-CTX无显著相关（r=-0.044,P=0.252）。LOESS回归分析显示,25OHD3水平为9.8～15.6ng/mL时,血清PTH出现平台期。25OHD3与骨钙素尽管有较弱的负相关,但未出现明显平台期。结论北京市部分老年男性人群存在严重维生素D缺乏和不足状况。老年男性的维生索D状态与PTH、骨形成指标骨钙素水平有一定关联,但与I型胶原蛋白的形成与吸收可能无直接关系,有必要进一步探讨维生素D与骨转换的关系。     

Short-term changes in growth and urinary growth hormone, insulin-like growth factor-I and markers of bone turnover excretion in healthy prepubertal children.

Childhood growth is a non-linear process. To assess whether there is a biochemical correlate of non-linear growth, we have measured free pyridinoline (fPYR) and deoxypyridinoline (fDPYR) excretion in seven healthy prepubertal children, aged 6.1-7.7 years. To examine the link between short-term growth and hormone output, urinary growth hormone (uGH) and insulin-like growth factor-I (uIGF-I) were also measured. Height and weight were measured and a timed overnight urine was collected three times per week from September to July, with results expressed as a weekly change in height (Dheight(w)) or weight (Dweight(w)), and as weekly average hormone or bone marker excretion (uGH(w), uIGF-I(w), fPYR(w), fDPYR(w)). Subject specific SD scores (SDS) were derived for each variable.Dheight(w)and Dweight(w)did not correlate to uGH(w), uIGF-I(w), fPYR(w)or fDPYR(w). Dheight(w)SDS was weakly but significantly correlated to fPYR(w)SDS (r = +0.16;P<0.05) and fDPYR(w)SDS (r = +0.15;P<0.05). The percentage of high frequency (2-4 weeks) variation in uGH(w)excretion, as defined by time series analysis, was correlated with the mean uIGF-I(w)(r = +0.81;P<0.05), which in turn was significantly reduced (92 +/- 38 vs 120 +/- 47 ng;P<0.001) during periods of slow growth (Dheight(w)< 0.05 cm/week).We conclude that in normal children the amount of urinary fPYR, fDPYR, GH and IGF-I does not provide a direct biochemical correlate of growth from week to week. However good growth is associated with a relative increase in fPYR and fDPYR excretion, while poor growth is associated with reduced IGF-I excretion, which in turn is influenced by the temporal secretory pattern of GH over 2-4 weeks.     

Raloxifene lowers serum calcium and markers of bone turnover in postmenopausal women with primary hyperparathyroidism

Estrogen replacement therapy (ERT) decreases total serum calcium by about 0.5 mg/dl in postmenopausal women with primary hyperparathyroidism (PHPT). We investigated the ability of raloxifene, which has skeletal antiresorptive properties similar to those of ERT, to decrease serum calcium concentrations and markers of bone turnover in PHPT. Eighteen postmenopausal women with asymptomatic PHPT were randomized to 8 wk of raloxifene (60 mg/d) or placebo, followed by a 4-wk washout. At baseline, the groups were well matched. The calcium concentration decreased significantly by 8 wk of raloxifene administration (10.8 +/- 0.2 to 10.4 +/- 0.2 mg/dl; P < 0.05), as did markers of bone resorption and formation [osteocalcin, 11.4 +/- 1.6 to 9.9 +/- 1.6 nmol/liter (P < 0.05); serum N-telopeptide, 21.2 +/- 3.4 to 17.3 +/- 2.8 nmol bone collagen equivalents/liter (P < 0.05)]. Four weeks after raloxifene was discontinued, indices were indistinguishable from baseline. Raloxifene administration did not affect serum PTH, 1,25-dihydroxyvitamin D, total alkaline phosphatase, or urinary calcium excretion. Calcium and bone marker changes were therefore similar to those observed with ERT in PHPT. This short-term study suggests that raloxifene may be a useful approach to the treatment of postmenopausal women with mild PHPT.     

Pegvisomant-induced serum insulin-like growth factor-I normalization in patients with acromegaly returns elevated markers of bone turnover to normal

Active acromegaly is associated with increased biochemical markers of bone turnover. Pegvisomant is a GH receptor antagonist that normalizes serum IGF-I in 97% of patients with active acromegaly. We evaluated the effects of pegvisomant-induced serum IGF-I normalization on biochemical markers of bone and soft tissue turnover, as well as levels of PTH and vitamin D metabolites, in 16 patients (nine males; median age, 52 yr; range, 28-78 yr) with active acromegaly (serum IGF-I at least 30% above upper limit of an age-related reference range). Serum procollagen III amino-terminal propeptide (PIIINP) and type I procollagen amino-terminal propeptide, osteocalcin (OC), bone-related alkaline phosphatase, C-terminal cross-linked telopeptide of type I collagen (CTx), albumin-corrected calcium, intact PTH, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D [1,25-(OH)(2) vit D], urinary type 1 collagen cross-linked N-telopeptide/creatinine ratio, and urinary calcium (24 h collection) were measured (single-batch analysis) at study entry and after IGF-I normalization, along with sera from 32 age- and sex-matched controls. Compared with controls, PIIINP, OC, and CTx were significantly elevated in patients at baseline. Pegvisomant-induced serum IGF-I normalization (699 +/- 76 to 242 +/- 28 micro g/liter, P < 0.001) was associated with a significant decrease in PIIINP, markers of bone formation (type I procollagen amino-terminal propeptide, OC, and bone-related alkaline phosphatase), and resorption (CTx and urinary type 1 collagen cross-linked N-telopeptide/creatinine ratio). 1,25-(OH)(2) vit D decreased and intact PTH increased significantly, but 25-hydroxy vitamin D was unaffected. A significant decline in calculated calcium clearance was observed. The decrease in serum IGF-I correlated positively with the decrease of serum PIIINP (r = 0.7, P < 0.01). After normalization of serum IGF-I, there was no statistical difference between patients and controls for any parameters for which control data were available. In conclusion, GH excess is associated with increased bone and soft tissue turnover. Pegvisomant-induced normalization of serum IGF-I results in a decrease in markers of bone and soft tissue turnover to levels observed in age-matched controls, and these changes are accompanied by an increase in PTH and a decrease in 1,25-(OH)(2) vit D. These data provide further evidence of the effectiveness of pegvisomant in normalizing the altered biological effects of GH hypersecretion.     

Association between serum leptin concentrations and bone mineral density, and biochemical markers of bone turnover in adult men.

Leptin, the product of the ob gene, has been shown to inhibit bone formation in mice. We addressed whether leptin has any role in the regulation of bone mineral density (BMD) in humans. Subjects were 221 adult men with a mean (+/-SD) age and body mass index of 52.1 +/- 8.7 yr and 23.6 +/- 2.8 kg/m2. Serum leptin, carboxyterminal propeptide of type 1 procollagen (PICP; a marker of bone formation), and cross-linked carboxyterminal teleopeptide of type 1 collagen (a marker of bone resorption) were measured by RIA. BMD was assessed by single photon absorptiometry, and total fat mass was determined by bioimpedance analysis. BMD was inversely associated with serum leptin concentrations and total fat mass after adjustment for body weight. PICP, but not cross-linked carboxyterminal teleopeptide of type 1 collagen, was inversely correlated with serum leptin. These results may suggest that an increase in serum leptin reduces bone formation and decreases BMD in adult men. Leptin may be a regulator of BMD in humans.