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Objective: The threefold aim was to (1) compare areal bone mineral density (aBMD), bone turnover markers, and periostin levels in young women with either anorexia nervosa (AN) or obesity (OB) and controls (CON); (2) model the profiles according to age; and (3) determine the parameters associated with aBMD., Subjects and Methods: One hundred and fifty-two young women with ages ranging from 16.0 to 27.0 years were subdivided into 3 groups (AN, OB, CON). The CON group was age-matched by ±6 months. aBMD, bone turnover markers, and periostin levels were evaluated., Results: aBMD modeling showed that hip aBMD was higher in OB than in the other 2 groups from 19 years, and AN presented lower values than CON from 21 years. aBMD at the lumbar spine was higher in older OB and CON women, starting from 20 to 22 years, but in AN the difference with the other 2 groups increased with age. Periostin levels were lower in OB than in AN or CON, but no variation with age was observed. Compared with controls, OB and AN presented similarly lower markers of bone formation, although markers of bone resorption were lower in OB and higher in AN. A modeling approach showed that markers of bone formation and resorption were lower in older than in younger CON, whereas the values of these bone markers remained relatively constant in AN and OB. In all groups, lean body mass (LBM) was the parameter most positively correlated with aBMD., Conclusion: This study demonstrated that weight extremes (AN or OB) influence aBMD, bone remodeling and periostin profiles. Moreover, factors related to aBMD were specific to each condition, but LBM was the parameter most consistently associated with aBMD., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Periostin is a matricellular protein involved in bone formation and bone matrix organization, but it is also produced by other tissues. Its circulating levels have been weakly associated with bone microstructure and prevalent fractures, possibly because periostin measured by the current commercial assays does not specifically reflect bone metabolism. In this context, we developed a new ELISA for a periostin fragment resulting from cathepsin K digestion (K-Postn). We hypothesized that circulating K-Postn levels could be associated with bone fragility. A total of 695 women (age 65.0 ± 1.5 years), enrolled in the Geneva Retirees Cohort (GERICO), were prospectively evaluated over 4.7 ± 1.9 years for the occurrence of low-trauma fractures. At baseline, we measured serum periostin, K-Postn, and bone turnover markers (BTMs), distal radius and tibia microstructure by HR-pQCT, hip and lumbar spine aBMD by DXA, and estimated fracture probability using the Fracture Risk Assessment Tool (FRAX). Sixty-six women sustained a low-trauma clinical fracture during the follow-up. Total periostin was not associated with fractures (HR [95% CI] per SD: 1.19 [0.89 to 1.59], p = 0.24). In contrast, K-Postn was significantly higher in the fracture versus nonfracture group (57.5 ± 36.6 ng/mL versus 42.5 ± 23.4 ng/mL, p < 0.001) and associated with fracture risk (HR [95%CI] per SD: 2.14 [1.54 to 2.97], p < 0.001). After adjustment for aBMD, FRAX, bone microstructure, or BTMs, K-Postn remained significantly associated with fracture risk. The performance of the fracture prediction models was improved by adding K-Postn to aBMD or FRAX (Harrell C index for fracture: 0.70 for aBMD + K-Post versus 0.58 for aBMD alone, p = 0.001; 0.73 for FRAX + K-Postn versus 0.65 for FRAX alone, p = 0.005). Circulating K-Postn predicts incident fractures independently of BMD, BTMs, and FRAX in postmenopausal women. Hence measurement of a periostin fragment resulting from in vivo cathepsin K digestion may help to identify subjects at high risk of fracture. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Bone is a complex tissue constituted by a collagen matrix filled in with crystal of hydroxyapatite (HAP). Bone mechanical properties are influenced by the collagen matrix which is organized into hierarchical structures from the individual type I collagen heterotrimer flanked by linear telopeptides at each end to the collagen fibrils that are interconnected by enzymatic and non-enzymatic cross-links. Although most studies focused on the role of collagen cross-links in bone strength, other organizational features may also play a role. At the molecular level it has been shown that homotrimer of type I collagen found in bone tissue of some patients with osteogenesis imperfecta (OI) is characterized by decreased mechanical competence compared to the regular heterotrimer. The state of C-telopeptide isomerization-which can be estimated by the measurement in body fluids of the native and isomerized isoforms-has also been shown to be associated with bone strength, particularly the post-yield properties independent of bone size and bone mineral density. Other higher hierarchical features of collagen organization have shown to be associated with changes in bone mechanical behavior in ex vivo models and may also be relevant to explain bone fragility in diseases characterized by collagen abnormalities e.g., OI and Paget's disease. These include the orientation of collagen fibrils in a regular longitudinal direction, the D-spacing period between collagen fibrils and the collagen-HAP interfacial bonding. Preliminary data indicate that some of these organizational features can change during treatment with bisphosphonate, raloxifene, and PTH suggesting that they may contribute to their anti-fracture efficacy. It remains however to be determined which of these parameters play a specific and independent role in bone matrix properties, what is the magnitude of mechanical strength explained by collagen organization, whether they are relevant to explain osteoporosis-induced bone fragility, and how they could be monitored non-invasively to develop efficient bone quality biomarkers.

Summary: Sclerostin is a key regulator of bone formation. In a population of 572 postmenopausal women (mean age, 67 years) followed prospectively for a median of 6 years, there was no significant association between baseline levels of serum sclerostin and incidence of all fractures which occurred in 64 subjects., Introduction: Sclerostin, an osteocyte soluble factor, is a major negative regulator of osteoblastic activity. Circulating sclerostin levels were reported to increase with age and to be modestly associated with bone mineral density (BMD) and bone turnover, but there are no data on the association with fracture risk., Methods: We investigated 572 postmenopausal women (mean age, 67 ± 8.5 years) from the OFELY population-based cohort. The associations of serum sclerostin measured with a new two-site ELISA and spine and hip BMD by DXA, serum β-isomerized C-terminal crosslinking of type I collagen (CTX), intact N-terminal propeptide of type I collagen (PINP), intact PTH, 25-hydroxyvitamin D [25(OH)D], estradiol, testosterone, and fracture risk were analyzed. At the time of sclerostin measurements, 98 postmenopausal women had prevalent fractures. After a median of 6 years (interquartile range, 5-7 years) follow-up, 64 postmenopausal sustained an incident fracture., Results: Serum sclerostin correlated positively with spine (r = 0.35, p < 0.0001) and total hip (r = 0.25, <0.0001) BMD. Conversely, serum sclerostin was weakly negatively associated with the bone markers PINP (r = -0.10, p = 0.014) and CTX (r = -0.13, p = 0.0026) and with intact PTH (r = -0.13, p = 0.0064). There was no significant association of serum sclerostin with 25(OH)D, estradiol, free estradiol index, or testosterone. Serum sclerostin considered as a continuous variable or in quartiles was not significantly associated with the risk of prevalent or incident fracture., Conclusion: Serum sclerostin is weakly correlated with BMD, bone turnover, and PTH in postmenopausal women. It was not significantly associated with the risk of all fractures, although the number of incident fractures recorded may not allow detecting a modest association.

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 © 2011 Elsevier Inc. All rights reserved.)

Surrogate markers of fracture risk--bone turnover markers (BTMs) and bone mineral density (BMD)--can be used to monitor treatment response. We assessed whether changes in these markers greater than the least significant change (LSC) were associated with fracture risk reduction and greater adherence. This secondary analysis of the Improving Measurements of Persistence on ACtonel Treatment (IMPACT) study--a multinational prospective, open-label, cluster-randomized study of postmenopausal women on oral risedronate 5 mg/d for 52 weeks-assessed adherence by electronic monitors. Urinary N-terminal cross-linked telopeptide of type 1 collagen (uNTX) and serum C-terminal cross-linked telopeptide of type 1 collagen (sCTX) levels were assessed at baseline and weeks 10 and 22, and BMD at baseline and week 52. Fractures were recorded as adverse events. In 2302 women, responses beyond LSC in BTMs (uNTX and sCTX) and BMD (spine only) were associated with a reduced risk of nonvertebral fractures (NVFs) and all fractures. NVF incidence was about 50% lower in patients with 30% or more of uNTX reduction at week 22 (1.6%) than in those with less than 30% reduction (3.2%, p = .015). NVFs also were reduced in patients with more than 3% spine BMD increase at 52 weeks than those with 3% or less. Responses greater than LSC in BTMs and BMD were associated with greater adherence, but there was no association between adherence and fracture outcomes at 52 weeks. Changes greater than the LSC in BTMs and BMD reflect better treatment adherence, were associated with fracture risk reduction, and identify differences in individual responsiveness to risedronate., (Copyright © 2011 American Society for Bone and Mineral Research.)

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.

Introduction: Vitamin D status is considered as an important determinant of bone health but supplementation trials with vitamin D(3) 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.

Context: Treatment of osteoporotic women with PTH increases biochemical markers of bone turnover, increases axial bone mineral density (BMD), and reduces fracture risk., Objective: Our objective was to determine the relationship between levels of baseline turnover before PTH therapy and short-term changes in turnover during PTH therapy and subsequent changes in areal and volumetric BMD., Design and Setting: We conducted a randomized, placebo-controlled trial at four academic centers., Patients: Patients included 238 postmenopausal women with low hip or spine BMD., Intervention: Subjects were randomized to sc PTH (1-84), 100 mug/d (119 women), for 1 yr., Main Outcome Measure: Bone turnover markers were measured in fasting blood samples collected before therapy and after 1 and 3 months. Areal and volumetric BMD at the spine and hip were assessed by dual-energy x-ray absorptiometry and quantitative computed tomography (QCT) after 1 yr of therapy., Results: Among women treated with PTH alone, the relationships between baseline turnover and 1-yr changes in dual-energy x-ray absorptiometry and QCT BMD were inconsistent. Greater 1- and 3-month increases in turnover, particularly the formation marker N-propeptide of type I collagen, were associated with greater increases in areal BMD. When volumetric hip and spine BMD were assessed by QCT, greater short-term increases in turnover were even more positively associated with 1-yr increases in BMD. Each sd increase in the 3-month change of N-propeptide of type I collagen was associated with an a 21% greater increase in QCT spine trabecular BMD., Conclusions: Greater short-term changes in turnover with PTH therapy are associated with greater 1-yr increases in spine and hip BMD among postmenopausal osteoporotic women.

Unlabelled: A 3-year, randomized, double-blind, placebo-controlled trial evaluated the effect of oral alendronate on the BMD of 64 adult patients with osteogenesis imperfecta. The mean increases in the lumbar spine BMD were 10.1 +/- 9.8% (p < 0.001) and 0.7 +/- 5.7% in the alendronate and placebo groups, respectively. Oral alendronate increases BMD in adult patients with osteogenesis imperfecta., Introduction: This study evaluated the effect of oral alendronate on the BMD of adult patients with osteogenesis imperfecta., Materials and Methods: We carried out a 3-year, randomized, double-blind, placebo-controlled trial of oral alendronate in 64 adult patients with osteogenesis imperfecta. The primary endpoint was the difference between the groups in the mean percent change in lumbar spine BMD at 3 years. Secondary outcomes included changes in BMD of total hip, vertebral and peripheral fracture incidence, pain, hearing loss, and bone turnover biochemical markers. Patients were treated daily with either placebo or 10 mg alendronate. All received 1 g of calcium and 800 IU of vitamin D daily., Results: The mean +/- SD increases in the lumbar spine BMD were 10.1 +/- 9.8% (p < 0.001) and 0.7 +/- 5.7% in the alendronate and placebo groups, respectively. Hip BMD increased in the alendronate group by 3.3 +/- 0.5% (p = 0.001) and decreased in the placebo group by 0.3 +/- 0.6%. The sample size was not sufficient to determine an effect of alendronate on fracture rate. A significant increase of the pain score was noted in the alendronate group (p = 0.04) in the intent-to-treat analysis but not in the per protocol analysis. There was no change in hearing in either group. Bone resorption and formation biochemical markers were significantly decreased in the alendronate group (p < 0.001). There were no differences in severe adverse effects between the groups, but there was an increase in nonsevere upper gastrointestinal effects in the alendronate group (p = 0.003)., Conclusions: Oral alendronate increases BMD and increase nonsevere gastrointestinal adverse effects but does not modify the hearing loss in adult patients with osteogenesis imperfecta. More studies are needed to evaluate an effect on the fracture rate.

Unlabelled: The influence of pretreatment bone turnover on alendronate efficacy is not known. In the FIT, we examined the effect of pretreatment bone turnover on the antifracture efficacy of daily alendronate given to postmenopausal women. The nonspine fracture efficacy of alendronate was significantly greater among both osteoporotic and nonosteoporotic women with higher baseline levels of the bone formation marker PINP., Introduction: Previous trials have shown that high bone turnover is associated with greater increases in BMD among bisphosphonate-treated women. The influence of pretreatment bone turnover levels on antifracture efficacy has not been well studied., Materials and Methods: We randomized women 55-80 years of age with femoral neck BMD T scores < or = -1.6 to alendronate (ALN), 5-10 mg/day (n = 3105), or placebo (PBO; n = 3081). At baseline, 3495 women were osteoporotic (femoral neck BMD T score < or = -2.5 or prevalent vertebral fracture), and 2689 were not osteoporotic (BMD T score > -2.5 and no prevalent vertebral fracture). Pretreatment levels of bone-specific alkaline phosphatase (BSALP), N-terminal propeptide of type 1 collagen (PINP), and C-terminal cross-linked telopeptide of type 1 collagen (sCTx) were measured in all participants using archived serum (20% fasting). The risk of incident spine and nonspine fracture was compared in ALN- and PBO-treated subjects stratified into tertiles of baseline bone marker level., Results and Conclusions: During a mean follow-up of 3.2 years, 492 nonspine and 294 morphometric vertebral fractures were documented. Compared with placebo, the reduction in nonspine fractures with ALN treatment differed significantly among those with low, intermediate, and high pretreatment levels of PINP levels (p = 0.03 for trend). For example, among osteoporotic women in the lowest tertile of pretreatment PINP (<41.6 ng/ml), the ALN versus PBO relative hazard for nonspine fracture was 0.88 (95% CI: 0.65, 1.21) compared with a relative hazard of 0.54 (95% CI: 0.39, 0.74) among those in the highest tertile of PINP (>56.8 ng/ml). Results were similar among women without osteoporosis at baseline. Although they did not reach statistical significance, similar trends were observed with baseline levels of BSALP. Conversely, spine fracture treatment efficacy among osteoporotic women did not differ significantly according to pretreatment marker levels. Spine fracture treatment efficacy among nonosteoporotic women was related to baseline BSALP (p = 0.05 for trend). In summary, alendronate nonspine fracture efficacy is greater among both osteoporotic and nonosteoporotic women with high pretreatment PINP. If confirmed in other studies, these findings suggest that bisphosphonate treatment may be most effective in women with elevated bone turnover.

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.

Unlabelled: About one-half of women with incident fractures have BMD above the WHO diagnostic threshold of osteoporosis. In the OFELY study, low BMD, increased markers of bone turnover, and prior fracture could be used to identify, within osteopenic women, those at high risk of fracture., Introduction: Recent data suggest that about one-half of women with incident fractures have BMD above the World Health Organization (WHO) diagnostic threshold of osteoporosis (T score

Objectives: To determine the changes in body weight, body composition, and bone turnover in patients with spondyloarthropathy (SpA) treated with anti-tumour necrosis factor alpha (TNFalpha)., Patients and Methods: 19 patients with SpA (2 women, 17 men), aged 21-71 years, were studied in a 1 year prospective open study. 17 patients received infliximab: 3 or 5 mg/kg/infusion at weeks 0, 2, 6 and infusions in the case of a relapse (n = 14) or systematically (n = 3); 2 patients received etanercept (25 mg twice a week). Body weight, body composition (lean mass, fat mass), and bone mineral density (BMD; using dual energy x ray absorptiometry) were measured at baseline and at months 6 and 12. Serum insulin-like growth factor-I (IGF-I), bone markers (carboxy terminal telopeptide of collagen Iota (CTX) and procollagen type Iota N terminal propeptide (PINP)) were measured at baseline and months 3, 6, and 12., Results: In 1 year there was a significant increase in body weight (mean (SD) 2.24 (3.1) kg, p = 0.0004), and in lean mass (1.4 (1.69) kg, p = 0.005), but no changes in fat mass. BMD increased at the spine (5.6%, p = 0.0005) and total femur (2.6%, p = 0.01). CTX decreased from the third month (-50%, p = 0.005) up to 1 year (-30%, p = 0.012), and a trend for an increase in PINP (10%, p = 0.06) and in IGF-I (15%, p = 0.04) was seen at month 3., Conclusion: These data confirm that treatment with anti-TNFalpha in SpA is associated with an increase of BMD, which results from a decrease of bone resorption. Increase in body weight and lean mass is observed in parallel with an increase in IGF-1.

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.

Antiresorptive agents are effective in preventing and treating postmenopausal osteoporosis, provided they are taken as directed. Regular physical examinations including height measurements may fail to ensure optimal compliance. Bone mineral density (BMD) measurement is indispensable for determining whether treatment is warranted. The measurement can be repeated after 2 years at least, provided quality-control procedures are adequate. BMD changes over time should be compared to the least significant change calculated from the in vivo BMD reproducibility at the measurement center. However, BMD changes are not correlated with the fracture risk reduction induced by antiresorptive treatment. Biochemical markers for bone turnover can be monitored after only 3-6 months provided steps are taken to control for intraindividual variability. They are useful when patient compliance is poor or the treatment response inadequate.

Objective: To assess in post-menopausal women the efficacy and tolerability of a continuous oestradiol/intermittent norgestimate HRT regimen to prevent and to reverse post-menopausal loss of bone mineral density (BMD) and to determine the effects on serum bone turnover markers markers., Methods: A 1-year, multicentre, international, placebo-controlled, randomised, double-blind clinical trial was conducted in 146 post-menopausal women with an intact uterus in order to assess the effect on bone loss of continuous oral 17beta-oestradiol (1 mg per day) combined with norgestimate (90 microg per day), for 3 consecutive days out of every 6-day treatment period (E2/iNGM). During a second year extension, all women agreeing to continue were on the E2/iNGM regimen. BMD was assessed prior to treatment and after 1 and 2 years or at the end of treatment in women stopping participation prematurely after at least 6 months of treatment. Serum bone turnover markers were determined prior to and at 1 year of treatment Adverse events were collected at three-monthly intervals during clinic visits over the treatment period., Results: BMD in the lumbar spine, the primary endpoint, was evaluable in 117 subjects completing >6 months of treatment. BMD increased on average by 2.4% in women on the intermittent progestin regimen. It decreased by 1.4% in placebo treated women. The change from baseline and the difference between active and placebo treatment (Delta placebo) were highly significant (P < 0.0001). On E2/iNGM, also the BMD in the total hip increased (+1.49%, Delta placebo 3.73%, P < 0.0001). The serum markers for bone formation osteocalcin and type I collagen N-propeptide were significantly reduced compared to baseline by 31 and 44%, respectively and the bone resorption marker C-terminal crosslinked telopeptide of type I collagen by 59%. Minor increases (<10%) of markers in the placebo group were not significant. During a second year extension of the trial, all subjects were on active treatment. Subjects on placebo who lost (median+/-CI 95%) 0.66% (-2.3 to +0.5) of spine BMD during the first year now gained 4.41% (2.7-7.6). They also gained 1.6% (0.1-0.3.6) in the total hip. Subjects continuously on oestradiol/intermittent norgestimate (E2/iNGM) gained an additional 5.7% (2.3-13.5) in the lumbar spine and +0.1% (-0.6 to +2.2) at the total hip. Side effects reported by women on the intermittent progestin regimen significantly in excess over reports from the placebo group were uterine bleeding, abdominal and breast pain, but not headache. Back pain and weight gain was reported by significantly fewer women on active treatment compared to placebo., Conclusion: The continuous oestradiol/intermittent norgestimate HRT regimen is well tolerated, reduces bone turnover and prevents post-menopausal bone loss in healthy post-menopausal women.

In osteoporosis, the main cause for concern is the increase in the risk of fractures. The level of bone mineral density (BMD) measured by various techniques has been shown to be a strong predictor of fracture risk in postmenopausal women. However, half of patients with incident fractures have BMD value above the diagnostic threshold of osteoporosis defined as a T-score of -2.5 SD or more below the average value of young healthy women. Clearly there is a need for improvement in the identification of patients at risk for fracture. Several prospective studies have shown that an increased bone resorption evaluated by specific biochemical markers was associated with increased risk of the hip, spine and non-vertebral fractures independently of BMD. The use of bone markers in individual patients may be appropriate in some situations, especially in women who are not detected at risk by BMD measurements. For example, in the OFELY study including 668 postmenopausal women followed prospectively over 9 years, we found that among the 115 incident fractures, 54 (47%) actually occurred in non-osteoporotic women. Among these women, the combination of bone markers and history of previous fracture was highly predictive of fracture risk. Thus, bone markers may be used in the assessment of fracture risk in selected cases in which BMD and clinical risk factors are not enough to take a treatment decision. Advances in our knowledge of bone matrix biochemistry, most notably of post-translational modifications in type I collagen, may allow identification of biochemical markers that reflect changes in the material property of bone, which is an important determinant of bone strength. Preliminary in vitro studies indicate that the extent of post-translational modifications of collagen--which can be reflected in vivo by the measurement of the urinary ratio between native and isomerised type I collagen--play a role in determining the mechanical competence of cortical bone, independently of BMD. Further studies in osteoporosis should explore the changes in these biochemical parameters of bone matrix as they may represent a key component of bone quality.

To examine the relationships between serum leptin and bone metabolism, we measured bone mineral density (BMD) at the spine and the hip, fasting serum leptin, and osteocalcin and urinary excretion of C-terminal crosslinking telopeptide of type I collagen (CTX), as markers of bone formation and resorption, respectively, in 121 postmenopausal women aged 54 +/- 5 years. These parameters were also assessed at 6 months and 2 years of treatment with either 2.5 mg tibolone (n = 34), 1.25 mg tibolone (n = 45), or 2 mg estradiol plus 1 mg norethindrone acetate (n = 42). At baseline, serum leptin correlated positively with spine (r = 0.21, P = 0.02) and total hip (r = 0.26, P = 0.0044) BMD and negatively with CTX (r = -0.38, P < 0.0001) and osteocalcin (r = 0.21, P = 0.025). After adjustment for BMI and for fat mass, the association between serum leptin and CTX persisted with a partial correlation coefficient of -0.18 (P = 0.046) and of -0.22 (P = 0.03), respectively. Women in the highest quartile of leptin levels had 11% higher total hip (P = 0.0039) and lumbar spine BMD (P = 0.016), 21% lower osteocalcin (P = 0.01), and 38% lower CTX (P = 0.0005) than women in the lowest quartile (P < 0.05). During treatment, serum leptin levels increased (+14.7 +/- 47.3%, P = 0.019), without significant difference between the groups. This increase correlated with the increase in body weight (r = 0.46, P < 10(-4)). No correlation was found between the changes in leptin and the changes in bone parameters. In conclusion, leptin may play a role as a determinant of bone resorption in healthy, untreated postmenopausal women, but the effect of estradiol or tibolone on bone are not mediated by leptin.

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.

Measurement of microstructural parameters of trabecular bone noninvasively in vivo is possible with high-resolution magnetic resonance (MR) imaging. These measurements may prove useful in the determination of bone strength and fracture risk, but must be related to other measures of bone properties. In this study in vivo MR imaging was used to derive trabecular bone structure measures and combined with micro-finite element analysis (microFE) to determine the effects of trabecular bone microarchitecture on bone mechanical properties in the distal radius. The subjects were studied in two groups: (I) postmenopausal women with normal bone mineral density (BMD) (n = 22, mean age 58 +/- 7 years) and (II) postmenopausal women with spine or femur BMD -1 SD to -2.5 SD below young normal (n = 37, mean age 62 +/- 11 years). MR images of the distal radius were obtained at 1.5 T, and measures such as apparent trabecular bone volume fraction (App BV/TV), spacing, number and thickness (App TbSp, TbN, TbTh) were derived in regions of interest extending from the joint line to the radial shaft. The high-resolution images were also used in a micro-finite element model to derive the directional Young's moduli (E1, E2 and E3), shear moduli (G12, G23 and G13) and anisotropy ratios such as E1/E3. BMD at the distal radius, lumbar spine and hip were assessed using dual-energy X-ray absorptiometry (DXA). Bone formation was assessed by serum osteocalcin and bone resorption by serum type I collagen C-terminal telopeptide breakdown products (serum CTX) and urinary CTX biochemical markers. The trabecular architecture displayed considerable anisotropy. Measures of BMD such as the ultradistal radial BMD were lower in the osteopenic group (p<0.01). Biochemical markers between the two groups were comparable in value and showed no significant difference between the two groups. App BV/TV, TbTh and TbN were higher, and App TbSp lower, in the normal group than the osteopenic group. All three directional measures of elastic and shear moduli were lower in the osteopenic group compared with the normal group. Anisotropy of trabecular bone microarchitecture, as measured by the ratios of the mean intercept length (MIL) values (MIL1/MIL3, etc.), and the anisotropy in elastic modulus (E1/E3, etc.), were greater in the osteopenic group compared with the normal group. The correlations between the measures of architecture and moduli are higher than those between elastic moduli and BMD. Stepwise multiple regression analysis showed that while App BV/TV is highly correlated with the mechanical properties, additional structural measures do contribute to the improved prediction of the mechanical measures. This study demonstrates the feasibility and potential of using MR imaging with microFE modeling in vivo in the study of osteoporosis.

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.

Bone loss before and around the time of menopause is not well characterized by longitudinal studies. We measured bone mineral density at various skeletal sites--total body, femoral neck, trochanter, anteroposterior (AP) and lateral spine, and forearm--with dual-energy X-ray absorptiometry in a large prospective cohort of 272 untreated pre- and perimenopausal women aged 31-59 years, at 1 year intervals for 3 years. Sex steroids and the following markers of bone remodeling were measured: serum osteocalcin (OC), procollagen I carboxyterminal extension peptide, bone alkaline phosphatase (BAP) and urinary crosslinks (CTX and NTX). Seventy-six women were classified as perimenopausal and 196 as premenopausal. Over the 3 years, premenopausal women had no significant bone loss at any site and a small but significant increase in bone mineral density at the trochanter, total hip, AP spine and radius. Perimenopausal women significantly lost bone from cancellous and cortical sites, i.e., the femoral neck, trochanter and lumbar spine. In perimenopausal women with increased follicle stimulating hormone, the rate of bone loss at the femoral neck correlated negatively with OC and BAP. In perimenopausal women, serum estradiol levels decreased during the 3 years of follow-up and bone loss from the trochanter and the AP spine was correlated with serum estradiol after 3 years. In conclusion, among premenopausal women there is no bone loss. In contrast, there is a rapid and diffuse bone loss in perimenopausal women, related to decreased estrogen secretion. Bone markers may be useful to identify these women losing bone.

The effects of 17 beta-estradiol (E2) 1 mg combined with low doses of norethisterone acetate (NETA) on postmenopausal bone loss and turnover were investigated in a 2-year, randomized, double-masked, placebo-controlled trial. A total of 135 postmenopausal women with a lumbar spine bone mineral density (BMD) T-score between -2 and +2 were randomized to daily treatment with an oral tablet of either placebo, E2 1 mg/NETA 0.25 mg, or E2 1 mg/NETA 0.5 mg. Significant (p < 0.001) increases in BMD at the lumbar spine (L1-4) were observed with E2 1 mg/NETA 0.25 mg (5.2%) and E2 1 mg/NETA 0.5 mg (5.4%) compared with placebo (-0.9%). The total hip BMD increased significantly in the E2 1 mg/NETA 0.25 mg (3.1%) and E2 1 mg/NETA 0.5 mg groups (3.3%) compared with placebo. At the femoral trochanter, the increase in BMD in the E2 1 mg/NETA 0.5 mg group (6.3%) was significantly different from the placebo group (0.8%), while that in the E2 1 mg/NETA 0.25 mg group (3.3%) was not. No statistical differences were found between the active groups and placebo for the change in BMD at the femoral neck. Significant increases in BMD at the distal radius and total body were found for both E2 1 mg/NETA 0.25 mg (0.9% and 2.5%, respectively) and E2 1 mg/NETA 0.5 mg (2.1% and 3.0%, respectively) compared with placebo (-0.7% and 0.4%, respectively). At the end of the treatment, urinary pyridinoline type I collagen C-telopeptide had decreased by 65% and 60% in the E2 1 mg/NETA 0.25 mg and E2 1 mg/NETA 0.5 mg groups, respectively, while the mean serum concentrations of osteocalcin had decreased by 39% and 34%, bone-specific alkaline phosphatase by 32% and 29%, and C-terminal propeptide of type I collagen by 21% and 19% had decreased by 34-39%, 29-32%, and 19-21% in the E2 1 mg/NETA 0.25 mg and E2 1 mg/NETA 0.25 mg groups, respectively. In conclusion, combinations of E2 1 mg and NETA 0.25 or 0.5 mg prevent bone loss in postmenopausal women at the lumbar spine, hip, distal radius and total body, and normalize bone turnover.

The ability of biochemical markers to predict the rate of postmenopausal bone loss is still controversial. To investigate this issue further, baseline levels of a panel of specific and sensitive biochemical bone markers were correlated to the rate of change of forearm bone mineral density (BMD) assessed by four measurements over a 4-year period using dual-energy X-ray absorptiometry in a large population-based prospective cohort of 305 women aged 50-88 years (mean 64 years), 1-38 years postmenopausal. In the whole population, higher baseline levels of bone formation (serum osteocalcin and serum type I collagen N-terminal propeptide) and bone resorption markers (urinary N-telopeptides; urinary and serum C-telopeptides) were significantly associated with faster BMD loss (r = -0.19 to -0.30, p < 0.001), independently of age. In women within 5 years of menopause that have the highest rate of bone loss, the predictive value of bone markers was increased with correlation coefficients reaching 0.53. Women with an abnormally high bone turnover, i.e., with levels of bone markers at baseline 2 SD above the mean of premenopausal women, had a rate of bone loss that was 2- to 6-fold higher than women with a low turnover (p = 0.01-0.0001) according to the marker. When the population was categorized according to quartiles of bone markers at baseline, a similar relationship between increased levels of bone markers and faster rate of bone loss was found (p = 0.008-0.0001). In the logistic regression model, the odds-ratio of fast bone loss, defined as the rate of bone loss in the upper tertile of the population, was increased by 1.8- to 3.2-fold for levels of biochemical markers in the high turnover group compared with levels within the premenopausal range, with, however, a limited value for identifying individual fast bone losers. We conclude that increased levels of some of the new biochemical markers of bone turnover are associated with greater radial bone loss. Because increased bone loss is associated with an increased risk of fracture, bone turnover markers may be useful to improve the prediction of the risk of osteoporosis in postmenopausal women.

Bone mineral density (BMD) is under strong genetic control. Recent work has suggested that a polymorphism affecting an Sp1 binding site in the collagen I (COLI) A1 gene is associated with BMD and vertebral fracture in postmenopausal women. We analyzed this polymorphism in relation to BMD and bone turnover in 220 healthy premenopausal women aged 31-57 years. There were 61% SS homozygotes, 35% Ss heterozygotes, and 4% ss homozygotes, genotype frequencies similar to those previously reported in other Caucasian populations. Women in the three genotype groups were matched for age, body weight, physical activity, smoking habits, and oral contraceptive use, but height was greatest in the SS group and lowest in the ss group (p = 0.03). Between-group comparisons by analysis of variance (ANOVA) showed that COLI A1 genotype was significantly associated with spine BMD (p = 0.05), total body BMD (p = 0.046), and total body bone mineral content (BMC) (p = 0.02), but the differences between extreme genotypes were small (4, 5, and 10%, for spine BMD, total body BMD, and total body BMC, respectively). After adjustment for height, the differences between genotypes decreased and were no longer significant by ANOVA (p = 0.08, 0.17, and 0.33 for spine BMD, total body BMD, and total body BMC). Furthermore, no significant difference between genotypes was observed for femoral neck, trochanter, Ward's triangle, or forearm BMD. COLI A1 genotype was associated with serum C-terminal extension propeptide of type I collagen (p = 0.04), with lowest levels in ss individuals, but not with any other marker of bone formation (osteocalcin, alkaline phosphatase, and type I collagen N-terminal extension propeptide) or bone resorption (urinary excretion of type I collagen C and N telopeptide breakdown products). The COLI A1 Sp1 polymorphism is associated with height, peak total body BMD and BMC, and spine BMD. The genotype-specific differences account for only a small proportion of variance in BMD at these sites and are not significant after adjustment for height, suggesting that part of the effect on bone mass may be due to differences in body size. Our data support the view that COLI A1 may be a candidate gene for regulation of bone mass, but our results must be treated with caution, in view of the small number of ss individuals, and will require confirmation in larger studies.

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.

Previous studies have demonstrated an association between bone mineral density (BMD) and a start codon polymorphism (SCP) of the vitamin D receptor (VDR) gene in pre- and postmenopausal Caucasian and Japanese women. The SCP can be determined by a restriction fragment length polymorphism defined by the FokI restriction endonuclease. VDR alleles containing the FokI site are denoted by f and alleles lacking the site by F. In this study, the association between BMD and the SCP was examined in a group of 174 premenopausal French women who previously had been studied for a relationship between BMD and the VDR BsmI polymorphism. The SCP genotypes of the French women were FF 40%, Ff 44%, and ff 16% and they were independent of the BsmI genotype. BMD was measured by dual-energy X-ray absorptiometry at the lumbar spine, proximal femur, forearm, and total body. In contrast to previous reports, there was no association of BMD with SCP genotype in this group of Caucasian women at any site. We also measured several biochemical indices of calcium homeostasis and bone turnover. We found no statistically significant associations between SCP genotype and calcium, parathyroid hormone, or vitamin D levels. There was a 33.5% higher level of the skeletal resorption marker N-telopeptides of type I collagen in the women with the ff genotype when compared with women with the FF genotype (p = 0.004). Other bone turnover markers failed to show an association with SCP genotype. In summary, the SCP genotype may not be associated with reduced BMD in all geographical or ethnic populations.

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.

We measured the bone mineral density (BMD) at various skeletal sites (total body, hip, anteroposterior [AP] and lateral [lat] spine, and forearm) in a large population-based cohort of women aged 31-89 years (the OFELY cohort), and results were analyzed according to age and postmenopausal years. A significant apparent bone loss was found before the menopause in cancellous bone, i.e., at the lat spine and Ward's triangle (-10%; p < 0.05-0.001). Cross-sectional analysis indicated that, after the menopause, apparent bone loss was accelerated within the 10 years following menopause, continued thereafter at all sites except the AP spine, and was again accelerated in elderly menopausal for more than 25 years. Between 30 and 80 years, BMD decreased by 15 to 44% (T score -1.6 to -3.4) according to the site. The amount of apparent bone loss was highest at the Ward's triangle when expressed in percentage (44%) and at the mid- and distal radius when expressed in number of standard deviations from the peak bone mass (-3.4). As a result, the percentage of women classified as osteoporotic according to the World Heath Organization, i.e., with a T score < or = -2.5, varied substantially from site to site and was highest at the radius (37% and 46%) and lateral spine (25-31%), intermediate at the Ward's triangle, AP spine, and whole body BMD, and lowest at the whole body bone mineral content, femoral neck, and trochanter (10-12%). In conclusion, this cross-sectional but large study suggests that there is a moderate apparent premenopausal bone loss that occurs only at cancellous bone sites and that apparent bone loss is accelerated at most skeletal sites after the age of 75 years. Because of the highly variable coefficient of variation of the peak bone mass at various skeletal sites, the percentage of postmenopausal women identified as being osteoporotic varies widely according to the site of measurement.

Changes of bone turnover with aging are responsible for bone loss and play a major role in osteoporosis. Although an increase of bone turnover has been documented at the time of menopause, the subsequent abnormalities of bone resorption and formation and their potential role in determining bone mass in the elderly have not been investigated. To address this issue, we have measured a battery of new sensitive and specific markers of bone turnover in a population-based study of 653 healthy women analyzed cross-sectionally, including 432 women postmenopausal from 1 to 40 years, and the data were correlated with bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) at different skeletal sites. Bone formation was assessed by serum osteocalcin (OC), serum bone-specific alkaline phosphatase (B-ALP), serum C-propeptide of type I collagen (PICP), and bone resorption by the urinary excretion of two pyridinoline cross-linked peptides (NTX and CTX). Bone turnover increased in perimenopausal women with both irregular menses and elevated serum follicle stimulating hormone (FSH). Menopause induced a 37-52% and 79-97% increase in the bone formation and bone resorption marker levels, respectively (p < 0.0001 except for PICP). In postmenopausal women, bone formation markers did not decrease with age. When resorption markers were corrected by whole body bone mineral content (BMC), the fraction of bone resorbed per day was not correlated with age in postmenopausal women and remained elevated for up to 40 years after menopause. In premenopausal women, the bone turnover rate accounted for only 0-10% of the variation in whole body BMC, total hip, distal radius, and lumbar spine BMD. With increasing time after menopause, the importance of the bone turnover rate as a determinant of bone mass increased at all sites and accounted for up to 52% of the BMD variance in elderly women. Thus, in women 20 years or more postmenopause, bone turnover was higher in those in the lowest quartile than in those in the highest quartile of BMD. In elderly women, 20 years since menopause and over, but not in younger ones, serum PTH was negatively correlated with serum 25-hydroxyvitamin D (r = -0.22, p < 0.05) and explained only 5-8% of the bone turnover variance (p < 0.01-0.001). These data indicate that the overall rates of both bone formation and bone resorption remain high in elderly women. The rate of bone turnover appears to play an increasing role as a determinant of bone mass with increasing time since menopause with a high bone turnover rate being associated with a low bone mass. Thus assessing bone marker levels may be useful in the evaluation of osteoporosis risk. In elderly women, secondary hyperparathyroidism caused in part by reduced serum 25-hydroxyvitamin D appears to be a marginal determinant of an increased bone turnover rate.

Bone mineral density (BMD) is under strong genetic control. Polymorphisms at the vitamin D receptor (VDR) gene have been recently suggested to account for up to 75% of this genetic effect. We analyzed these polymorphisms, i.e., that of BsmI, TaqI, and ApaI restriction enzymes by PCR of the DNA in 189 healthy premenopausal women aged 31 to 57 years. For the BsmI polymorphism they were 17% BB homozygotes, 51% Bb heterozygotes, and 32% bb homozygotes, genotype frequencies that are very similar to those previously reported in other Caucasian populations of north European ancestry. Women in the three genotypes for any of the three polymorphisms were matched for age and did not differ in body weight, height, physical activity, nor smoking habits. We found no relationship between the genotype for any of the three polymorphisms nor bone formation and resorption rate assessed by five specific biochemical markers of bone turnover nor with BMD measured at the spine, proximal femur, forearm, and whole body by dual-energy X-ray absorptiometry (DXA). We concluded that these polymorphisms are not predictive of bone turnover nor BMD in a sample of healthy premenopausal women drawn from the French population.

The objective of this study was to determine the effect of oral contraceptive pills on bone turnover. The design consisted of a cross-sectional analysis of a prospective cohort. There were 52 women taking oral contraceptives and 156 nonuser controls from a large cohort of 1039 healthy women, aged 31-89 years (OFELY study). Most users were taking combined oral contraceptives containing 30 micrograms ethinyl estradiol and the mean duration of pill use was 6.7 +/- 6.4 years. Users and nonusers were matched for age [mean age (years): 39.3 +/- 3.5 vs. 40.5 +/- 4.3, range 35-49 years for both]. Main outcome measures included three markers of bone formation (serum osteocalcin, bone-specific alkaline phosphatase, and C-terminal propeptide of type I collagen) and two markers of bone resorption that are pyridinoline crosslinked peptides (Crosslaps and NTX). Users and nonusers did not differ for weight, height, alcohol and tobacco use, dietary calcium intake, parity, exercise activity, body fat and lean composition, and calcium chemistry tests. In pill users all bone formation and resorption markers were decreased compared with controls: osteocalcin, 7.7 +/- 2.7 vs. 10.1 +/- 3.1 ng/mL (-24%, p < 0.001); bone-specific alkaline phosphatase, 7.5 +/- 2.3 vs. 8.8 +/- 2.7 ng/mL (-15%, p < 0.003); C-terminal propeptide of type I collagen, 77.2 +/- 93.1 vs. 93.1 +/- 31.9 ng/mL (-17%, p = 0.001); Crosslaps: 175 +/- 91 vs. 211 +/- 105 micrograms/mmol Cr (-17%, p = 0.03); and NTX, 16.2 +/- 5.9 vs. 22.5 +/- 9.4 nmol of bone collagen equivalent/mmol Cr (-28%, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

We performed repeated ultrasound measurements approximately 2 years apart (average 23 months +/- 3 months) on the os calcis of 113 healthy postmenopausal women recruited from two large prospective cohort studies named OFELY and EPIDOS. Group A (from OFELY) consisted of 88 women aged 52-72 (63 +/- 5) years, randomly selected from a large insurance company, and group B (from EPIDOS) consisted of 25 women aged 75-88 (80 +/- 4) years, randomly selected from the voting lists. We obtained broadband ultrasonic attenuation (BUA) and speed of sound (SOS) measurements, as well as the Stiffness index, with a Lunar Achilles ultrasound machine. We performed dual energy X-ray absorptiometry (DXA) measurements of femoral neck bone mineral density (neck BMD) with a Hologic QDR 2000 for group A and with a Lunar DPX Plus for group B. The decrease that we observed over 2 years was on average +/- 1 SD: -1.01 +/- 4.6 dB/MHz (p = 0.02) for BUA (which is approximately equal to the long-term precision error in vitro), -11.3 +/- 9.2 m/s (p = 0.0001) for SOS (approximately 5 times the precision error), -3.8 +/- 4.2% YA (p = 0.0001) for Stiffness (2.5 times the precision error) and -0.01 +/- 0.03 g/cm2 (p = 0.0001) for neck BMD (approximately equal to the precision error). In terms of percentage change this represents: -1.0% +/- 4.3% for BUA, -0.8% +/- 0.6% for SOS and -1.85% +/- 4.4% for neck BMD. At the individual level, most SOS and Stiffness values were consistent with a decrease, whereas BUA and neck BMD values were spread out above and below the zero line of no change. The decreases in SOS and Stiffness were significantly larger in the early postmenopause (< or = 20 years since menopause [YSM]) than in the late postmenopause (> 20 YSM). We observed a similar trend for BUA and BMD but this did not reach statistical significance. We found a weak but significant correlation between changes in ultrasound variables and changes in neck BMD. However, the 2-year changes observed in SOS were not significantly correlated with changes in BUA. This study suggests that the heel ultrasound measurements of SOS and Stiffness are valuable indices of postmenopausal bone loss, and could be used for follow-up in therapeutic trials.

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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