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Background: Spinal cord injury (SCI) induces an acute alteration in bone metabolism. Although the aetiology of the bone disturbances is not precisely known, immobilisation reduces mechanical loading and the morphology of osteocytes, which are the primary mechanosensors. Periostin and sclerostin are secreted mostly by osteocytes and are involved in bone's mechanical response., Objective: The present study was conducted to determine whether individuals with SCI present alterations in serum periostin and sclerostin and to assess their relationships with bone mineral density, bone turnover markers, fracture status, time since injury, densitometric osteoporosis and paraplegic vs. tetraplegic status., Subjects and Methods: One hundred and thirty-one individuals with SCI (96 males and 35 females; 42.8 ± 13.7 yr old) with a mean 14.2 ± 12.1 years since the time of injury were evaluated and compared with 40 able-bodied controls in a cross-sectional study. Periostin and sclerostin were assayed by ELISA from Biomedica® (Vienna, Austria), and bone turnover markers and areal bone mineral density (aBMD) were concomitantly analysed., Results: Compared with controls, individuals with SCI presented higher periostin (p < 0.01), lower sclerostin (p < 0.001), similar markers of bone turnover levels and lower aBMD at the hip. Compared with chronic individuals, bone turnover markers, sclerostin excepted, values were higher as well as aBMD at hip in individuals with acute SCI. Moreover, the aBMD differences were more marked in tetraplegic than paraplegic individuals. Bone mineral density, fracture status, densitometric osteoporosis and paraplegia vs. tetraplegia did not seem to substantially influence the values of biological markers, sclerostin excepted., Conclusion: This study showed for the first time that individuals with SCI presented higher periostin levels than healthy controls only during the acute phase. Conversely, sclerostin levels are lower whatever the post-injury time. Fractures and densitometric osteoporosis were not associated with differences in these two biological markers, whereas paraplegia vs. tetraplegia and fragility fracture status seemed to influence sclerostin levels only., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The measurement of bone turnover markers is useful for the clinical investigation of patients with osteoporosis. Among the available biochemical markers, the measurements of serum procollagen type I N-terminal propeptide (PINP) and the crosslinked C-terminal telopeptide (serum CTX) have been recommended as reference markers of bone formation and bone resorption, respectively. The important sources of preanalytical and analytical variability have been identified for both markers, and precise measurement can now be obtained. Reference interval data for PINP and CTX have been generated across different geographical locations, which allows optimum clinical interpretation. However, conventional protein-based markers have some limitations, including a lack of specificity for bone tissue, and their inability to reflect osteocyte activity or periosteal metabolism. Thus, novel markers such as periostin, sclerostin and, sphingosine 1-phosphate have been developed to address some of these shortcomings. Recent studies suggest that the measurements of circulating microRNAs, a new class of marker, may represent early biological markers in osteoporosis. Bone markers have been shown to be a useful adjunct to bone mineral density for identifying postmenopausal women at high risk for fracture. Because levels of bone markers respond rapidly to both anabolic and anticatabolic drugs, they are very useful for investigating the mechanism of action of new therapies and, potentially, for predicting their efficacy to reduce fracture risk.

Over the last 15 years several biological markers of bone turnover have been developed with increased specificity and sensitivity. In osteoporosis clinical studies, the IOF and IFCC organizations have recently recommended the measurements of serum type I collagen N-propeptide (PINP) and the crosslinked C-terminal telopeptide (serum CTX) as markers of bone formation and bone resorption, respectively. However these markers have some limitations including a lack of specificity for bone tissue, their inability to reflect osteocyte activity or periosteal apposition. In addition they do not allow the investigation of bone tissue quality an important determinant of skeletal fragility. To address these limitations, new developments in markers of bone metabolism have been recently achieved. These include assays for periostin, a matricellular protein preferentially localized in the periosteal tissue, sphingosine 1-phosphate, a lipid mediator which acts mainly on osteoclastogenesis and the osteocyte factors such as sclerostin and FGF-23. Recent studies have shown an association between the circulating levels of these biological markers and fracture risk in postmenopausal women or elderly men, although data require confirmation in additional prospective studies. Finally, recent studies suggest that the measurements of circulating microRNAs may represent a novel class of early biological markers in osteoporosis. It is foreseen that with the use of genomics and proteomics, new markers will be developed to ultimately improve the management of patients with osteoporosis., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Osteoporosis diagnosis is based on bone mineral density (BMD) but bone remodeling is also a crucial issue. It can be assessed by bone turnover markers (BTMs). Their interest for the positive and etiological diagnosis of osteoporosis at baseline, and their predictive value for past asymptomatic vertebral fractures, were evaluated by a systematic review of the literature., Methods: Medline database was searched to identify all published reports analyzing BTMs and BMD or fractures. We conducted meta-analyses on BTMs levels according to osteoporotic status using random effects models., Results: Moderate and negative correlations were found, mainly in postmenopausal women, between BTMs and BMD, especially with bone alkaline phosphatase (bone ALP), osteocalcin, serum C-terminal and urine N-terminal crosslinking telopeptides of type I collagen (sCTX and uNTX). Bone ALP and sCTX levels are higher in osteoporotic patients compared to controls. High levels of bone ALP in primary hyperparathyroidism and low levels of osteocalcin in endogenous hypercorticism are the most relevant data reported in endocrine diseases associated with osteoporosis. High levels of BTMs, especially osteocalcin, bone ALP or sCTX, may be associated with prevalent vertebral fractures., Conclusion: The diagnosis value of BTMs at baseline in osteoporosis is very low. The interest of BTMs for the etiological diagnostic of secondary osteoporosis has not been demonstrated. Data are lacking to address the interest of BTMs assessment to screen for vertebral fractures in asymptomatic patients with high risk factors of fractures., (Copyright © 2011 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Unlabelled: The International Osteoporosis Foundation (IOF) and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) recommend that a marker of bone formation (serum procollagen type I N propeptide, s-PINP) and a marker of bone resorption (serum C-terminal telopeptide of type I collagen, s-CTX) are used as reference analytes for bone turnover markers in clinical studies., Introduction: Bone turnover markers (BTM) predict fracture risk, and treatment-induced changes in specific markers account for a substantial proportion of fracture risk reduction. The aims of this report were to determine their clinical potential in the prediction of fracture risk and for monitoring the treatment of osteoporosis and to set an appropriate research agenda., Methods: Evidence from prospective studies was gathered through literature review of the PUBMED database between the years 2000 and 2010 and the systematic review of the Agency for Healthcare Research and Quality up to 2001., Results: High levels of BTMs may predict fracture risk independently from bone mineral density in postmenopausal women. They have been used for this purpose in clinical practice for many years, but there is still a need for stronger evidence on which to base practice. BTMs provide pharmacodynamic information on the response to osteoporosis treatment, and as a result, they are widely used for monitoring treatment in the individual. However, their clinical value for monitoring is limited by inadequate appreciation of the sources of variability, by limited data for comparison of treatments using the same BTM and by inadequate quality control. IOF/IFCC recommend one bone formation marker (s-PINP) and one bone resorption marker (s-CTX) to be used as reference markers and measured by standardised assays in observational and intervention studies in order to compare the performance of alternatives and to enlarge the international experience of the application of markers to clinical medicine., Conclusion: BTM hold promise in fracture risk prediction and for monitoring treatment. Uncertainties over their clinical use can be in part resolved by adopting international reference standards.

We used data from the Osteoporotic Fractures in Men (MrOS) study to test the hypothesis that men with higher levels of bone turnover would have accelerated bone loss and an elevated risk of fracture. MrOS enrolled 5995 subjects >65 yr; hip BMD was measured at baseline and after a mean follow-up of 4.6 yr. Nonspine fractures were documented during a mean follow-up of 5.0 yr. Using fasting serum collected at baseline and stored at -190 degrees C, bone turnover measurements (type I collagen N-propeptide [PINP]; beta C-terminal cross-linked telopeptide of type I collagen [betaCTX]; and TRACP5b) were obtained on 384 men with nonspine fracture (including 72 hip fractures) and 947 men selected at random. Among randomly selected men, total hip bone loss was 0.5%/yr among those in the highest quartile of PINP (>44.3 ng/ml) and 0.3%/yr among those in the lower three quartiles (p = 0.01). Fracture risk was elevated among men in the highest quartile of PINP (hip fracture relative hazard = 2.13; 95% CI: 1.23, 3.68; nonspine relative hazard = 1.57, 95% CI: 1.21, 2.05) or betaCTX (hip fracture relative hazard = 1.76, 95 CI: 1.04, 2.98; nonspine relative hazard = 1.29, 95% CI: 0.99, 1.69) but not TRACP5b. Further adjustment for baseline hip BMD eliminated all associations between bone turnover and fracture. We conclude that higher levels of bone turnover are associated with greater hip bone loss in older men, but increased turnover is not independently associated with the risk of hip or nonspine fracture.

The World Health Organization defines osteoporosis as a systemic disease characterized by decreased bone tissue mass and microarchitectural deterioration, resulting in increased fracture risk. Since this statement, a significant amount of data has been generated showing that these two factors do not cover all risks for fracture. Other independent clinical factors, such as age, as well as aspects related to qualitative changes in bone tissue, are believed to play an important role. The term "bone quality" encompasses a variety of parameters, including the extent of mineralization, the number and distribution of microfractures, the extent of osteocyte apoptosis, and changes in collagen properties. The major mechanism controlling these qualitative factors is bone remodeling, which is tightly regulated by the osteoclast/osteoblast activity. We focus on the relationship between bone remodeling and changes in collagen properties, especially the extent of one posttranslational modification. In vivo, measurements of the ratio between native and isomerized C-telopeptides of type I collagen provides an index of bone matrix age. Current preclinical and clinical studies suggests that this urinary ratio provides information about bone strength and fracture risk independent of bone mineral density and that it responds differently according to the type of therapy regulating bone turnover.

Background: Serum C-terminal cross-linked telopeptide of type I collagen (CTX-I), N-terminal propeptide of type I collagen (PINP), and osteocalcin (OC) are among the most sensitive bone turnover markers for evaluating osteoporosis. Each marker is currently measured individually by manual or automated immunoassays that are time consuming and require substantial sample volume. We evaluated the performance characteristics of a novel, fully automated, protein-array chip system that allows the simultaneous measurement of CTX-I, PINP, OC, and intact parathyroid hormone (PTH) in 20 microL of serum., Methods: We measured CTX-I, PINP, OC, and PTH using multiplex and corresponding automated single assays in 157 healthy premenopausal women, 74 healthy men, and 56 postmenopausal osteoporotic women before and 6 months after treatment with oral ibandronate (150 mg/month)., Results: Within- and between-run CVs of the multiplex assay were similar to those of single measurement assays (<10% for all markers), whereas the limit of quantification was lower, except for OC. Multiplex values highly correlated (r > 0.93, P < 0.0001 for all markers) with the corresponding single assays, and measured concentrations were comparable. After 6 months of ibandronate, CTX-I, PINP, and OC decreased by a median of 48%, 63%, and 52%, respectively (P < 0.0001 for all 3 markers), magnitudes similar to those of the corresponding single assays., Conclusions: The automated protein-array chip demonstrated similar analytical precision, improved analytical sensitivity, and comparable measured concentrations to those of single assays. The multiplex assay should be useful for assessing bone metabolism in large clinical studies, particularly when sample volume is limited.

Osteoporosis is a systemic disease characterized by low bone mass and microarchitectural deterioration of bone tissue, resulting in an increased risk of fracture. While the level of bone mass can be estimated by measuring bone mineral density (BMD) using dual X-ray absorptiometry (DXA), its measurement does not capture all the risk factors for fracture. Quantitative changes in skeletal turnover can be assessed easily and non-invasively by the measurement of serum and urinary biochemical markers; the most sensitive markers include serum osteocalcin, bone specific alkaline phosphatase, the N-terminal propeptide of type I collagen for bone formation, and the crosslinked C- (CTX) and N- (NTX) telopeptides of type I collagen for bone resorption. Advances in our knowledge of bone matrix biochemistry, most notably of post-translational modifications in type I collagen, are likely to lead to the development of new biochemical markers that reflect changes in the material property of bone, an important determinant of bone strength. Among those, the measurement of the urinary ratio of native (alpha) to isomerized (beta) CTX - an index of bone matrix maturation - has been shown to be predictive of fracture risk independently of BMD and bone turnover. In postmenopausal osteoporosis, levels of bone resorption markers above the upper limit of the premenopausal range are associated with an increased risk of hip, vertebral, and nonvertebral fracture, independent of BMD. Therefore, the combined use of BMD measurement and biochemical markers is helpful in risk assessment, especially in those women who are not identified as at risk by BMD measurement alone. Levels of bone markers decrease rapidly with antiresorptive therapies, and the levels reached after 3-6 months of therapy have been shown to be more strongly associated with fracture outcome than changes in BMD. Preliminary studies indicate that monitoring changes of bone formation markers could also be useful to monitor anabolic therapies, including intermittent parathyroid hormone administration and, possibly, to improve adherence to treatment. Thus, repeated measurements of bone markers during therapy may help improve the management of osteoporosis in patients.

Low body mass index (BMI) is a well-documented risk factor for future fracture. The aim of this study was to quantify this effect and to explore the association of BMI with fracture risk in relation to age, gender and bone mineral density (BMD) from an international perspective using worldwide data. We studied individual participant data from almost 60,000 men and women from 12 prospective population-based cohorts comprising Rotterdam, EVOS/EPOS, CaMos, Rochester, Sheffield, Dubbo, EPIDOS, OFELY, Kuopio, Hiroshima, and two cohorts from Gothenburg, with a total follow-up of over 250,000 person years. The effects of BMI, BMD, age and gender on the risk of any fracture, any osteoporotic fracture, and hip fracture alone was examined using a Poisson regression model in each cohort separately. The results of the different studies were then merged. Without information on BMD, the age-adjusted risk for any type of fracture increased significantly with lower BMI. Overall, the risk ratio (RR) per unit higher BMI was 0.98 (95% confidence interval [CI], 0.97-0.99) for any fracture, 0.97 (95% CI, 0.96-0.98) for osteoporotic fracture and 0.93 (95% CI, 0.91-0.94) for hip fracture (all p <0.001). The RR per unit change in BMI was very similar in men and women ( p >0.30). After adjusting for BMD, these RR became 1 for any fracture or osteoporotic fracture and 0.98 for hip fracture (significant in women). The gradient of fracture risk without adjustment for BMD was not linearly distributed across values for BMI. Instead, the contribution to fracture risk was much more marked at low values of BMI than at values above the median. This nonlinear relation of risk with BMI was most evident for hip fracture risk. When compared with a BMI of 25 kg/m(2), a BMI of 20 kg/m(2) was associated with a nearly twofold increase in risk ratio (RR=1.95; 95% CI, 1.71-2.22) for hip fracture. In contrast, a BMI of 30 kg/m(2), when compared with a BMI of 25 kg/m(2), was associated with only a 17% reduction in hip fracture risk (RR=0.83; 95% CI, 0.69-0.99). We conclude that low BMI confers a risk of substantial importance for all fractures that is largely independent of age and sex, but dependent on BMD. The significance of BMI as a risk factor varies according to the level of BMI. Its validation on an international basis permits the use of this risk factor in case-finding strategies.

Hip fractures are common among older women. At the present time, major efforts are being made to identify women with low bone mineral density (BMD). However, more than half of hip fractures occur in women who would not classically be considered osteoporotic by BMD. This study aimed to identify factors associated with hip fracture in women with high BMDs. A total of 7598 French women aged over 74 participated in the EPIDOS study and had BMD measured by dual energy X-ray absorptiometry. Analysis was carried out comparing women with and without hip fractures over more than 3 years of follow-up. The participants were divided into three groups based on femoral neck BMD, so as to have equal numbers in each group (cut-off points=0.601 g/cm(2), and 0.683 g/cm(2)). Multiple risk factors thought to be associated with hip fracture were tested in the high and low BMD groups to search for those whose effect was stronger in the high BMD group. Age adjusted Cox regression was used. Results for continuous variables are reported per standard deviation change. Positive interaction between higher BMD, hip fracture and the following factors were found: age (P<0.01), ultrasound attenuation (P<0.05), urinary deoxypyridinoline (DPD) (P<0.05), left quadriceps strength (P<0.05) and right and left foot coordination (P<0.05). The following factors had a larger hazards ratio in those in the upper third of BMD than the low and were statistically significant: femoral neck BMD, nulliparity, age, ultrasound attenuation and speed, prior fracture, urinary deoxypyridinoline, left grip strength and foot coordination. Multiple factors appear to be more strongly associated with hip fractures in women with high BMD than low. They appear to cluster as factors that may relate to bone turnover and architecture and others which are more subtle measures of left-sided coordination.

Previous fracture is a well-documented risk factor for future fracture. The aim of this study was to quantify this risk on an international basis and to explore the relationship of this risk with age, sex, and bone mineral density (BMD). We studied 15259 men and 44902 women from 11 cohorts comprising EVOS/EPOS, OFELY, CaMos, Rochester, Sheffield, Rotterdam, Kuopio, DOES, Hiroshima, and two cohorts from Gothenburg. Cohorts were followed for a total of 250000 person-years. The effect of a prior history of fracture on the risk of any fracture, any osteoporotic fracture, and hip fracture alone was examined using a Poisson model for each sex from each cohort. Covariates examined were age, sex, and BMD. The results of the different studies were merged by using the weighted beta-coefficients. A previous fracture history was associated with a significantly increased risk of any fracture compared with individuals without a prior fracture (RR = 1.86; 95% CI = 1.75-1.98). The risk ratio was similar for the outcome of osteoporotic fracture or for hip fracture. There was no significant difference in risk ratio between men and women. Risk ratio (RR) was marginally downward adjusted when account was taken of BMD. Low BMD explained a minority of the risk for any fracture (8%) and for hip fracture (22%). The risk ratio was stable with age except in the case of hip fracture outcome where the risk ratio decreased significantly with age. We conclude that previous history of fracture confers an increased risk of fracture of substantial importance beyond that explained by measurement of BMD. Its validation on an international basis permits the use of this risk factor in case finding strategies.

Biochemical markers of bone turnover have for several years been considered as valuable parameters in research clinical studies, but their use in individual patients is still debated. Recently several position papers have proposed guidelines for their use in clinical practice in patients with post menopausal osteoporosis. In the present article, we report the results of a survey which aims at comparing the actual modalities of prescription of French physicians with the above-mentioned recommendations. We contacted by phone clinical chemists from 158 different hospitals and asked them to transmit to the concerned physicians of their hospital a detailed questionnaire for assessing which bone marker(s) is (are) prescribed and for which purpose (s), and if not prescribed, the reason of non prescription. We were able to analyze 309 questionnaires from 89 hospitals including 5 specialties, rheumatology (35.9%), endocrinology (18.1%), gynecology (11.0%), internal medicine (22.0%) and geriatry (12.9%). The results showed large discrepancies between the mode of prescription of a subset of physicians and the guidelines. The most often evoked reason for non prescription was a lack of information about bone markers suggesting a need for teaching courses. This survey has also shown that many physicians do not know exactly which parameters are effectively measured in their hospital and which are addressed to specialized laboratories underlining the importance of the dialogue between clinicians and clinical chemists. We propose that in a given hospital, the present article may serve as a basis for a discussion between clinicians and biologists about the development and/or the optimization of the measurements of these markers of bone turnover.

Background: Biochemical markers of bone turnover can provide prognostic information about the risk of osteoporotic fracture and are useful tools for monitoring efficacy of antiresorptive therapy. A serum-based automated assay may be of better clinical value than urinary markers because of lower imprecision and day-to-day within-person variability. Our aim was to evaluate the technical and clinical performances of a new, fully automated assay for serum C-terminal cross-linking telopeptide of type I collagen (CTX), a marker of bone resorption., Methods: Serum CTX was measured on the Elecsys 2010 automated analyzer (Roche). Results were compared with those of the manual ELISA. We measured serum CTX concentrations in 728 healthy women, ages 31-89 years. We investigated the ability of this assay to predict the rate of postmenopausal forearm bone loss evaluated by four repeated bone mineral density measurements using dual-x-ray absorptiometry in 305 women followed prospectively for 4 years. Finally, in a cohort of healthy, untreated, postmenopausal women, we compared baseline serum CTX in 55 women who subsequently had a fracture (20 vertebral and 35 peripheral fractures) with values in the 380 women who did not fracture during a mean 5 years of follow-up., Results: The within- (n = 21) and between-run (n = 21) CVs were <4.1% and 5.7%, respectively. In 728 healthy women, serum CTX concentrations (automated) correlated with those of the manual ELISA (r = 0.82; P<0.0001). The median long-term within-person variability assessed by four repeated measurements over 3 months in 18 postmenopausal women was 9.4%. Compared with 254 premenopausal women, serum CTX was 39% (P<0.0001) higher in 45 perimenopausal women and 86% (P<0.0001) higher in 429 postmenopausal women (mean age, 64 years). Baseline serum CTX correlated negatively with changes of bone mass measured at the mid (r = -0.23; P<0.0001) and distal (r = -0.27; P<0001) radius. Postmenopausal women with serum CTX greater than the mean + 2 SD values in premenopausal women accounted for 42% of the population, lost bone at the mid radius on average eightfold more rapidly than the other women (-0.27% +/- 2.92% vs. -2.25% +/- 3.95%; P<0.0001), and had increased risk of fracture with a relative risk (95% confidence interval) of 1.8 (1.01-3.1) after adjustment for physical activity., Conclusions: The automated assay for serum CTX is precise and predicts rate of bone loss and fracture risk in postmenopausal women. Because it is convenient to use and has high throughput, this serum bone resorption marker may be useful for the investigation of patients with osteoporosis.

During recent years, experimental data, case reports, and epidemiological studies have suggested an important role for estradiol in bone metabolism in men. In a cohort of 596 men, aged 51-85 yr, we measured bone mineral density (BMD) of the lumbar spine, hip, total body, and forearm; serum levels of sex steroid hormones [total and free testosterone, total estradiol (17betaE(2)), bioavailable estradiol (bio-17betaE(2)), androstenedione, and sex hormone-binding globulin]; and markers of bone turnover [serum osteocalcin, bone alkaline phosphatase, N-terminal extension propeptide of type I collagen, and beta-isomerized C-terminal telopeptide of collagen type I (betaCTX)], as well as urinary excretion of betaCTX and deoxypyridinoline (DPyr). An age-related decrease was found for bio-17betaE(2) (r = -0.16; P < 0.001), free testosterone (r = -0.25; P < 0.001), free testosterone index (r = -0.32; P < 0.001), and androstenedione (r = -0.22; P < 0.001), but not for total 17betaE(2) or total testosterone. 17betaE(2) and bio-17betaE(2), but not other hormones, were correlated with BMD after adjustment for age and body weight. In men with a bio-17betaE(2) level in the lowest quartile, the average BMD was lower than in men having a bio-17betaE(2) level in the highest quartile by 6.6-8.7% according to the site of measurement, which corresponded to 0.45-0.65 SD. In age- and body weight-adjusted models, bio-17betaE(2), but not other hormones, was negatively correlated with bone markers (e.g., osteocalcin: r = -0.14; P < 0.001; urinary betaCTX: r = -0.20; P = 0.0001; DPyr: r = -0.14; P < 0.001). In men with the lowest concentration of bio-17betaE(2) (first quartile), the concentrations of markers of bone turnover were higher by 11-35% (or 0.4-0.7 SD) than in men having the highest bio-17betaE(2) level (upper quartile). In men in the lowest quartile for bio-17betaE(2) and in the highest quartile for urinary DPyr or betaCTX, the BMD of total hip and that of distal forearm were 8% and 10% lower than in men in the highest quartile for bio-17betaE(2) and in the lowest quartile for DPyr or ssCTX. In the age- and body weight-adjusted multiple regression models, bio-17betaE(2) contributed significantly to the explanation for the variability in all markers. In summary, we found in a cross-sectional analysis of a cohort of men that low levels of bio-17betaE(2) are associated with high bone turnover and low BMD. These data suggest that the age-related decrease in bio-17betaE(2) contributes to bone loss in elderly men by increasing bone turnover. Low 17betaE(2) levels may be an important risk factor for osteoporosis in men.

Biochemical markers of bone turnover have been developed over the past 20 years that are more specific for bone tissue than conventional ones such as total alkaline phosphatase and urinary hydroxyproline. They have been widely used in clinical research and in clinical trials of new therapies as secondary end points of treatment efficacy. Most of the interest has been devoted to their use in postmenopausal osteoporosis, a condition characterized by subtle modifications of bone metabolism that cannot be detected readily by conventional markers of bone turnover. Although several recent studies have suggested that biochemical markers may be used for the management of the individual patient in routine clinical practice, this has not been clearly defined and is a matter of debate. Because of the crucial importance to clarify this issue, the Société Francaise de Biologie Clinique prompted an expert committee to summarize the available data and to make recommendations. The following paper includes a review on the biochemical and analytical aspects of the markers of bone formation and resorption and on the sources of variability such as sex, age, menstrual cycle, pregnancy and lactation, physical activity, seasonal variation and effects of diseases and treatments. We will also describe the effects of pre-analytical factors on the measurements of the different markers. Finally based on that review, we will make practical recommendations for the use of these markers in order to minimize the variability of the measurements and improve the clinical interpretation of the data.

Hormone replacement therapy (HRT) induces a rapid decrease in biochemical markers of bone turnover that correlate with a subsequent increase in bone mineral density (BMD). To determine the utility of bone markers in the management of postmenopausal women receiving HRT, we analyzed the relationship between changes in four markers (serum osteocalcin and bone alkaline phosphatase [BAP], serum and urinary C-telopeptide of type I collagen [CTX]) and changes in spine BMD in 569 women treated for 2 years with different doses of a matrix transdermal 17beta-estradiol patch in two placebo-controlled trials. Using a logistic regression model, we found that both the percent change from baseline and the actual value of resorption markers at 3 and 6 months of treatment were predictive of BMD response at 2 years. Comparable results were obtained with formation markers at 6 months only. We determined the sensitivity, probably of positive BMD response, and corresponding cutoff value of markers at 3 and 6 months with a specificity set at a level of 0.90, so that <10% of women classified with markers as responders, i.e., as having a subsequent increase in BMD at 2 years >/=2.26%, would be false positive. All markers provided a high probability of positive BMD response ranging from 0.82 to 0.91, with a sensitivity higher for resorption than for formation markers, and sometimes improved in a model combining the percent change and the actual value of marker under HRT. For example, a decrease in serum CTX >/= 33% at 3 months of HRT provided a 68% sensitivity and 87% probability of positive BMD response at 2 years for a 90% specificity. At 6 months, a decrease in urinary CTX >/= 53% provided a 68% sensitivity and 91% probability of a positive BMD response for a 90% specificity. Half of false-negative cases at 3 months will be correctly identified by a subsequent urinary CTX measurement at 6 months. We conclude that the short-term change in bone markers reflects long-term changes of BMD in postmenopausal women treated with HRT. Our data suggest that bone turnover markers can be used to monitor the BMD response to HRT at the individual level. Whether such monitoring could improve long-term compliance to HRT should be tested prospectively.

The aim of our study was to describe cross-sectional and longitudinal bone mineral decrease in pre-, peri-, and postmenopausal healthy women using a monoenergy X-ray densitometer specifically designed for forearm assessement. Measurements were performed on the most distal part of the radius (ultradistal, 55% of trabecular bone and 45% of trabecular bone), and on the distal part (distal, 13% of trabecular bone and 87% of cortical bone). A specific trabecular-rich region of interest (nROI) comprising two trapezoids regions of interest located proximally to the endplates of the radius and ulna was also investigated. From a large prospective study (OFELY study), 455 women were measured once a year for 2 years (three measurements). The proportion of postmenopausal women classified as having osteoporosis (i.e., a T score <-2.5) was 33% for the distal region, 44% for the ultradistal region, and 45% for the nROI. No significant bone mineral decrease was found over the 2-year period in premenopausal women (n = 138). In perimenopausal (n = 48) women, a bone loss of 1% was found at the distal site. In the 269 postmenopausal women, a significant decrease was observed at all sites, ranging from 2.14% for the nROI to 2.68% for the ultradistal part. Bone loss was greater in the first 5 years after menopause in trabecular sites and decreased thereafter. For the distal site, bone loss remained stable during the postmenopausal period. We conclude that this small and portable forearm densitometer is suitable for the diagnosis of osteoporosis, and provides information on the rate of bone loss in peri- and postmenopausal women in trabecular and cortical compartments of bone.

The recent discovery of specific and sensitive biochemical markers reflecting the overall rate of bone formation and bone resorption has markedly improved the noninvasive assessment of bone turnover in various metabolic bone diseases, especially in osteoporosis. The immunoassay of human osteocalcin, recognizing the intact molecule and its major proteolytic fragment, and assays for bone alkaline phosphatase and the intact form of the N-terminal extension propeptide of type I collagen are currently the most sensitive markers for assessing bone formation. The best indices of bone resorption are the new immunoassays for pyridinoline cross-links and type I collagen-related peptides in urine and, recently, in serum. Several studies indicate that screening for these bone markers may be useful for improving the prognostic assessment of postmenopausal women in combination with bone mass measurement, that is, their risk for osteoporosis and, ultimately, for fractures and to monitor rapidly the efficacy of antiresorptive drugs.

We have previously shown that hip bone mineral density (BMD), heel broadband ultrasound attenuation (BUA) and bone resorption markers are independent predictors of hip fracture in elderly women. We investigated whether a combination of these three parameters could improve the predictive value of a single test in a nested case-control analysis (75 hip fractures and 228 age-matched controls) of the EPIDOS prospective study comprising 7598 healthy women 75 years of age and older followed prospectively for a mean 22 months. At baseline, prior fracture, femoral neck BMD by dual-energy X-ray absorptiometry (DXA), heel BUA and urinary type I collagen C-telopeptide breakdown products (CTX) were assessed. The area under the receiver operating characteristic curve was significant for the three diagnostic tests, heel BUA being the best single predictor. The added value of urinary CTX to either BMD or BUA depends on the cutoff point chosen to define patients at risk and on the therapeutic strategy that is considered. Defining patients at risk as those with low BMD (or low BUA) or high CTX resulted in a significant increase in the sensitivity compared with BMD or BUA alone--a strategy that could be applied when a broad treatment is considered. However, this increased sensitivity was also obtained simply by increasing the BMD and BUA cutoffs, suggesting that a combination of CTX with BMD/BUA is not useful for that type of treatment strategy. Conversely, defining patients at risk as those with both low BMD and high CTX increases the specificity (88% vs 78%) with a similar number of hip fracture patients being identified (30% vs 32%)--a combination that could be useful when the strategy is to target treatment to a subset of high-risk patients. This strategy appears to be more cost-effective than bone mass measurement alone as indicated by the 37% fewer patients who need to be treated to avoid one fracture per year. If DXA or ultrasound is not available, the combination of a bone resorption marker with a history of any type of fracture after the age of 50 years gave a predictive value similar to that obtained with femoral neck BMD or heel BUA alone, for both types of treatment strategy. We conclude that the combination of urinary CTX with hip BMD could be useful for the identification of elderly women at high risk for hip fracture, resulting in higher specificity for a given sensitivity threshold than BMD measurement alone. If DXA is not available, the combination of history of fracture and urinary CTX performs as well as hip BMD to assess hip fracture risk in elderly women.

Osteoporosis, one of the most prevalent diseases associated with aging, is characterized by a low bone mass and microarchitectural deterioration of bone tissue leading to increased susceptibility of fracture. The management of osteoporotic patients relies especially on the static measurement of bone mass as bone mineral and dynamic changes of bone turn over. New developments of bone mineral density measurement techniques and biochemical markers of bone turnover are reviewed. Their clinical uses for the management of patients with osteoporosis are discussed.

The recent development of specific and sensitive biochemical markers reflecting the overall rate of bone formation and bone resorption, has markedly improved the non-invasive assessment of bone turnover in various metabolic bone diseases, especially osteoporosis. The immunoassay of human osteocalcin recognizing the intact molecule and its major proteolytic fragment, along with that of bone alkaline phosphatase, are currently the most sensitive markers to assess bone formation. For bone resorption, the total urinary excretion of pyridinoline crosslinks measured by high pressure liquid chromatography has shown its superiority over all other markers for the clinical assessment of osteoporosis. The recent development of immunoassays recognizing either the free pyridinoline crosslinks or pyridinoline crosslinked-type I collagen peptides in urine and serum should allow a broad use of this sensitive resorption marker. Recent studies, some of them still in progress, define the clinical use of these markers: first, to improve the prognostic assessment of post-menopausal women in combination with bone mass measurement, i.e. their risk of developing osteoporosis and, ultimately, fractures and, second, to monitor the efficacy of anti-resorption drugs.

The noninvasive assessment of bone turnover has markedly improved in the past few years with the development of sensitive and specific markers of bone formation and bone resorption. Markers of bone formation in serum include total and bone-specific alkaline phosphatase, osteocalcin, and type I collagen carboxyterminal extension peptide. Assessment of bone resorption can be achieved by measuring plasma tartrate-resistant acid phosphate and the urinary excretion (and possibly serum levels) of bone type I collagen degradation products: hydroxyproline, hydroxylysine glycosides, and, more recently, the pyridinium crosslinks (pyridinoline and deoxypyridinoline) and associated peptides. The immunoassay of human osteocalcin and bone alkaline phosphatase for formation and the pyridinoline crosslinks measured by high-pressure liquid chromatography or by immunoassay for bone resorption are currently the most sensitive and specific markers of bone turnover for the clinical assessment of osteoporosis. Using these new markers, several studies have shown that bone turnover increases after the menopause and remains elevated in late postmenopausal and elderly women. An increased bone turnover rate is related to a high rate of bone loss in postmenopausal women and to a decreased bone mass in elderly women. Recent data suggest that some of the new immunoassays for pyridinoline crosslinks could predict the subsequent risk of hip fracture in elderly women. Thus, bone markers might be used in combination with bone mass measurement to improve the prognostic assessment of postmenopausal women, i.e., their risk of developing osteoporosis and ultimately fractures. Treatment of postmenopausal women with antiresorptive drugs such as estrogens, bisphosphonates, and calcitonin induces a rapid decrease in the levels of bone markers that is correlated with the long-term effect of such treatments on bone mass. Thus, bone markers should be very useful in monitoring treatment efficacy in patients with osteoporosis.

In order to validate a new technique to measure bone mineral density (BMD) of the forearm with a single X-ray absorptiometry device (DTX 100), we have measured the BMD of 195 women, aged 32 to 83 years, free of metabolic bone disease, simultaneously on two devices: 1. BMD of the ultradistal radius and of the distal radius and ulna on DTX 100, Osteometer, 2. BMD of the lumbar spine, of the proximal femur, of the whole body and of the distal and ultradistal radius by dual X-ray absorptiometry (DXA) on an Hologic 2000 device. The precision of DTX, assessed by 5 repeated measurements on 9 volunteers, was 1% for the distal site and 2% for the ultradistal site. There was a high correlation (r = 0.93) between radial BMD measurement by DTX and Hologic 2000. Correlations between forearm BMDs measured by DTX and whole body BMD were as high (r = 0.80-0.82) as between whole body BMD and lumbar spine (r = 0.82), femoral neck (r = 0.77) and femoral trochanter (r = 0.76). Age-related bone loss measured by DTX was 27% and 31% at the distal and ultra distal radius respectively, as compared to 17% for the lumbar spine, 21% for the femoral neck and 16% for the whole body BMD. In a group of 20 untreated osteoporotic women with vertebral fractures, forearm BMD was as sensitive (T score of -3.1 and -2.9 for distal and ultra distal) as was lumbar spine (T = -2.9) and femoral neck (T = -2.5).(ABSTRACT TRUNCATED AT 250 WORDS)

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Objectives: Serum bone turnover markers (sBTM) are used in clinical practice for patients undergoing postmenopausal osteoporosis therapy. The aim of this study was to systematically analyze the literature on the ability of sBTM to monitor therapy, focusing on the following 5 objectives: (1) pretreatment values and treatment choice; (2) short-term changes and clinical response; (3) sBTM effect on persistence to therapy; (4) sBTM ability to predict fracture risk after withdrawal of therapy; and (5) the prediction of serious adverse effects. Methods: A systematic search on Medline completed manually was performed until November 2010 and was limited to postmenopausal osteoporosis and marketed therapies. Results: Following the PRISMA statement for systematic reviews, 48 studies were selected. Baseline sBTM levels were not able to predict fracture risk reduction with either treatment. There was more evidence for the prediction of fracture risk reduction with bone formation sBTM including PINP than with sCTX. Most of the studies found correlations between sBTM and bone mineral density (BMD) changes under antiresorptive therapies, although inconsistently. The only published study on the impact of sBTM on persistence to therapy showed negative results. There was no evidence that sBTM allow the prediction of adverse effects, especially osteonecrosis of the jaw. Conclusions: sBTM reflect the skeletal effects of anti-osteoporotic treatments. Pretreatment values are not recommended for selecting therapy. Short-term changes are significantly correlated with BMD variation, but there is no published evidence that they predict benefit on fracture risk at the individual level. [Copyright &y& Elsevier]

Abstract: Introduction : Vitamin D status is considered as an important determinant of bone health but supplementation trials with vitamin D3 have yielded conflicting results. The aim of this study was to investigate the associations between serum 25-hydroxyvitamin D (25-OH D), bone turnover markers, bone mineral density (BMD), radius bone loss and incidence of fracture in postmenopausal women. Methods : 669 postmenopausal women (mean age: 62.2 years) belonging to a population-based cohort were followed prospectively for a median of 11.2 years. At baseline, 25-OH D levels, BMD, bone turnover markers and clinical risk factors of osteoporosis were assessed. BMD loss at the radius was estimated by annual measurements of BMD and all incident fractures which occurred in 134 women were confirmed by radiographs. Results : 73% and 35% of women had serum 25-OH D levels below 75 and 50 nmol/l which correspond respectively to the median and lowest optimal values recently proposed for fracture prevention. 11% of women had levels below 30 nmol/l. Serum 25-OH D correlated modestly with intact PTH (r 2 =0.023, p <0.0001), but not with bone turnover markers or BMD at the hip and radius after adjustment for age. When levels of 25-OH D were considered as a continuous variable, there was no significant association between 25-OH D levels and radius BMD loss or fracture risk. After adjustment for age, there was no significant difference in incidence of fracture, BMD, radius BMD loss, bone turnover markers, grip strength and the percentage of fallers in the previous year between women with 25-OH D levels below or above 75, 50 or 30 nmol/l. Conclusions: In a population of home-dwelling healthy postmenopausal women with few of them with severe vitamin D deficiency, vitamin D status may not be an important determinant of bone health. [Copyright &y& Elsevier]

Type I collagen fragments are the most sensitive markers of bone resorption in osteoporosis. Currently, all available type I collagen-related bone resorption markers detect in serum and/or urine fragments arising from the telopeptide region of the molecule. Our aim was to evaluate the technical and clinical performances of a new assay detecting in urine a degradation fragment originating from the helical part of type I collagen and consisting of the 620–633 sequence of the α1 chain. Urinary helical peptide was measured with a new ELISA (Metra Helical peptide, Quidel Corporation). Results were compared with those of urinary C-terminal cross-linking type I collagen of type I collagen (CTX), an established bone resorption marker. We measured urinary helical peptide levels in 89 healthy women (age 31–89 years) and in 59 postmenopausal women involved in two randomized studies of the efficacy of alendronate (10 mg/day; n = 20) and transdermal 17β estradiol (50 μg/day; n = 39). The within-run and between-run CVs were ≤ 7.3 and 8.7%, respectively. In 59 healthy women, urinary helical peptide levels highly correlated with those of urinary CTX (r = 0.78, P < 0.0001). The long-term intraindividual variability assessed over 6 months in 18 untreated postmenopausal women was 24%. Compared to 24 premenopausal women, urinary helical peptide was 42% (P < 0.0001) higher in 65 postmenopausal women (mean age, 60 years), an increase comparable to that of urinary CTX (+ 47%, P < 0.0001). Urinary helical peptide levels decreased by 72% (P < 0.0001) after 3 months of alendronate treatment and by 59% (P < 0.0001) after 6 months of transdermal estrogen therapy. These changes were of similar magnitude to those of urinary CTX (−69 and −62%, respectively; NS compared with changes in helical peptide). In women treated with transdermal 17β estradiol, the percentage of change of urinary helical peptide and urinary CTX at 6 months significantly correlated with the change in spinal bone mineral density after 2 years (r = −0.58, P = 0.002, and r = −0.52, P = 0.006, for urinary helical peptide and CTX, respectively). This new assay for type I collagen helical peptide has demonstrated adequate analytical performance and was highly correlated with urinary CTX, an established type I collagen C-telopeptide bone resorption marker. The test was a sensitive indicator of the antiresorptive effects of bisphosphonate and estrogens in postmenopausal women. This new bone resorption marker should be useful for the clinical investigation of patients with osteoporosis. [Copyright &y& Elsevier]

Genetic factors play an important role in determining bone mass and several genes are involved in this process. Interleukin-6 (IL-6) is a candidate gene for regulation of bone mineral density (BMD) and it has been suggested recently that novel IL-6 −174 G/C allelic variants may be associated with peak BMD in young men and with bone resorption in elderly women. In this study, we assessed the relationships between IL-6 gene polymorphism, peak BMD, rate of postmenopausal BMD loss, and bone turnover in women. BMD was measured by dual-energy X-ray absorptiometry in 255 healthy premenopausal women, aged 31–57 years. BMD loss at the forearm was measured over 4 years in 298 healthy untreated postmenopausal women, 50–88 years (mean 64 years). We also measured levels of serum osteocalcin, bone alkaline phosphatase, and N-propeptide of type I collagen for bone formation and three markers of bone resorption, including urinary and serum C-terminal cross-linking telopeptide of type I collagen and urinary N-terminal telopeptide of type I collagen, in both pre- and postmenopausal women at baseline. In premenopausal women we found a significant association between IL-6 genotypes and BMD at the whole body (analysis of variance [ANOVA], p = 0.03), femoral neck (p = 0.03), trochanter (p = 0.014), Ward’s triangle (p = 0.03), and total hip (p = 0.006), with subjects having the CC genotype showing 3%–7% higher BMD levels than their GG counterparts. However, after matching women with CC and GG genotypes for body height the differences decreased (2%–4%), and were no longer significant (p = 0.10–0.23). In postmenopausal women the mean rate of loss at the ultradistal radius was significantly associated with IL-6 genotypes (ANOVA, p = 0.049), with women having the CC genotype showing a significantly greater rate of bone loss (p < 0.05) compared with their GC and GG counterparts. After adjustment for weight changes, the difference in the rate of ultradistal radius bone loss between genotypes decreased and was not significant (p = 0.06 for CC vs. GG). A similar trend was observed for distal radius bone loss (p = 0.10, ANOVA), but not for the middle radius. We found no significant association between genotypes, bone turnover markers in premenopausal women, and either bone turnover or BMD in postmenopausal women. We conclude that this new functional IL-6 polymorphism was weakly associated with level of peak BMD and the rate of forearm trabecular postmenopausal bone loss in this cohort of healthy French women. IL-6 genotypes accounted only for a small proportion of the interindividual variation of both peak BMD and rate of bone loss and were not significant after adjustment for height and changes in body weight, respectively, suggesting that part of the effect may have been due to the differences in body size. Larger long-term studies are necessary to assess adequately the relationships between IL-6 genotype, rate of bone loss, and risk of fracture. [Copyright &y& Elsevier]