The contribution of serum osteoprotegerin to bone mass and vertebral fractures in postmenopausal women

Regulation of osteoclastic activity is critical for understanding bone loss associated with the postmenopausal period. In vitro and animal studies have revealed the role of OPG as a decoy receptor that neutralizes the effect of RANKL on the differentiation and activation of osteoclasts. However, the role of the OPG-RANKL system in postmenopausal osteoporosis is controversial. Thus, the aim of this study was to investigate the relationship among circulating levels of OPG, RANKL, bone turnover markers (BTM), bone mineral density (BMD) and vertebral fractures in postmenopausal women. We determined anthropometric parameters, circulating OPG and RANKL, BTM, estradiol, BMD by dual X-ray absorptiometry at the lumbar spine (LS) and femoral neck (FN), and pre-existing vertebral fractures in 206 ambulatory postmenopausal women of a mean age of 62 years (SD 7). Circulating OPG was significantly related to age ( r =0.158; P =0.023), years since menopause ( r =0.167; P =0.016) and BMD (LS Z-score: r =0.240; P =0.001, FN Z-score: r =0.156; P =0.025). Over half of the women had undetectable RANKL ( n =113; 54.9%). There were no significant differences in clinical variables, BTM or BMD among women with detectable vs. undetectable RANKL. OPG was found to be independently associated with osteoporosis (OR: 2.9, 1.4–5.9) and prevalent vertebral fractures (OR: 2.5, 1.2–5.4). We conclude that serum OPG levels are independently associated with bone mass and prevalent vertebral fractures in postmenopausal women.     

Relationships between insulin-like growth factor-I (IGF-I) and OPG, RANKL, bone mineral density in healthy Chinese women

Summary Serum IGF-I level was negatively correlated with OPG and OPG/RANKL ratio, but positively correlated with RANKL. Serum OPG level in the highest quintile of IGF-I was significantly lower than that in the lowest. We conclude that the effect of IGF-I on bone remodeling may be mediated by the OPG/RANKL system. Introduction Insulin-like growth factor I (IGF-I) is an important factor in coupling bone remodeling, activating both formation and resorption. Compared with the many studies on the role of IGF-I in bone formation, the information regarding its effects on bone resorption is limited and conflicting. The balance of the two peptides produced by osteoblasts, osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL), is critical for the bone resorption process. Our study was designed to analyze the relationships of serum concentrations of IGF-I with OPG, RANKL, OPG/RANKL ratio as well as BMDs in healthy Chinese women. Methods BMDs at lumbar spine and proximal femur in 504 pre- and postmenopausal women were measured by DXA. Serum levels of IGF-I, OPG and RANKL were also measured. Pearson’s correlation and partial correlation analysis, ANOVA, covariance analysis and stepwise multiple regression analysis were used as appropriate. Results Age was negatively correlated with serum levels of IGF-I (r = −0.702, p < 0.001). IGF-I was negatively correlated with OPG and OPG/RANKL ratio, but positively correlated with RANKL. The relationship between IGF-I and BMDs disappeared after adjustment for age. In postmenopausal women, IGF-I was lower in women with osteoporosis than in those with normal BMD (p = 0.056), but no differences were found among OPG, RANKL and OPG/RANKL ratio. Serum levels of OPG in the highest quintile of IGF-I were significantly lower than those in the lowest quintile of IGF-I, while no difference was found in RANKL. In the multiple regression analysis model, serum levels of IGF-I were the main determinants of the bone mass in Chinese women. Conclusions In conclusion, the relationship between decreasing IGF-I and BMDs in healthy Chinese women influenced by age, whereas the effect of IGF-I on bone remodeling (bone resorption) may be mediated by the OPG/RANKL system.     

Increased RANKL/OPG mRNA Ratio in Iliac Bone Biopsies From Women with Hip Fractures

RANKL (receptor activator of NF-B) is a potent physiological inducer of osteoclastogenesis. Its actions are blocked by the decoy receptor osteoprotegerin (OPG), and treatment with OPG blocks bone resorption in postmenopausal women. Both positive and negative associations between serum OPG and bone mineral density (BMD) have been reported in the literature. We hypothesized that decreased OPG production relative to RANKL within bone itself could lead to increased risk of osteoporotic fracture. We included ten women with hip fracture (age 76.3 ± 8.0 years, N.S, hip BMD 0.686 ± 1.3 g/cm2, P < 0.05) and 24 women with osteoarthrosis of the hip (age 72.8 ± 7.2 years, hip BMD 0.832 ± 1.1 g/cm²). Transiliac biopsies were obtained at the time of surgery. Total RNA was extracted from biopsies and reverse-transcribed. Real-time quantification of mRNA was performed with a SYBR Green I real time PCR assay, calculating relative gene expession with normalization of results for actin mRNA. Actin normalized mRNA levels for OPG and interleukin (IL)-6 were significantly lower in fracture patients, with a significantly higher RANKL/OPG ratio in patients with fractures. There was no significant difference in tumor necrosis factor (TNF), IL-1, IL-1ra, or IL-7 expression. IL-6 mRNA levels were lower in fracture patients (P < 0.05). The effect of increased RANKL/OPG ratio (Z = 2.08, P < 0.05) on fracture risk was additive to that of hip BMD T score (Z = –1.95, P < 0.05) when assessed using logistic regression. Elderly women with hip fractures exhibit an increased RANKL/OPG mRNA content of iliac bone. This is associated with increased fracture susceptibility, which is not in itself explained by low BMD.     

Bone Mineral Density of the Spine and Femur in Early Postmenopausal Turkish Women with Endemic Skeletal Fluorosis

The aim of this prospective, comparative study was to investigate the bone mineral density (BMD) changes in a group of early postmenopausal Turkish women with endemic skeletal fluorosis and to study effects of endemic fluorosis on BMD. Bone mineral density of L₂–L₄ vertebra, femur neck, femur trochanter, and Wards triangle were measured in 45 female patients with endemic skeletal fluorosis and 41 age-matched controls by dual X-ray absorbtiometry (DXA). The BMD of L₂–L₄ vertebra and Wards triangle were higher in the endemic fluorosis group than in the control group (P < 0.001). Patients with endemic fluorosis had higher femur neck and femur trochanter BMDs than did controls (P < 0.01 and P < 0.05, respectively). There was a positive correlation between serum fluoride content and BMD at the spine (r = 0.345, P = 0.001), femoral neck (r = 0.274, P = 0.011), Wards triangle (r = 0.295, P = 0.006), and trochanter (r = 0.217, P = 0.045). In conclusion, higher bone mineral density levels were seen in early postmenopausal women with endemic skeletal fluorosis. BMD measurement is a tool in the diagnosis and management of this preventable crippling disease.     

OPG and sRANKL Serum Concentrations in Osteopenic,Postmenopausal Women After 2‐Year Genistein Administration

Introduction : RANKL and its decoy receptor osteoprotegerin (OPG) constitute a complex physiological mediator system involved in the regulation of bone resorption and may be responsible for the homeostatic mechanism of normal bone remodeling. Genistein, an isoflavone representing 1–5% of total phytoestrogen content in soybean products, may positively regulate cellular bone metabolism, but its mechanism of action on bone is not yet fully understood. Materials and Methods : We studied the serum levels of both soluble RANKL (sRANKL) and OPG and the sRANKL/OPG ratio in 389 postmenopausal women (age, 49–67 yr) with a femoral neck BMD <0.795 g/cm² and no significant comorbid conditions after 24‐mo therapy with genistein, (n = 198; 54 mg/d) or placebo (n = 191). Both intervention and placebo contained calcium and vitamin D₃. All patients received dietary instruction in an isocaloric fat‐reduced diet. Results : In comparison with placebo, sRANKL level was lower (p < 0.001 versus placebo) and OPG higher in genistein recipients (p < 0.001 versus placebo) at 1 and 2 yr, respectively. Moreover, at the end of 24 mo, genistein produced a significant reduction in the sRANKL/OPG ratio compared with placebo (genistein = ?0.021, 95% CI, ?0.020 to ?0.022; placebo = +0.004, 95% CI, 0.003–0.005; difference = ?0.020, 95% CI, ?0.015 to ?0.025, p < 0.001). Conclusions : Our findings suggest that genistein plus calcium and vitamin D₃ as part of a healthy diet is able to positively modulate bone turnover in a cohort of osteopenic, postmenopausal women and improve sRANKL‐OPG balance after 24 mo of treatment.     

IL-17A-mediated sRANK ligand elevation involved in postmenopausal osteoporosis

Summary

The role of proinflammatory IL-17 cytokine was studied in postmenopausal bone loss between 31 osteopenic and 41 osteoporotic women. The effect of serum IL-17A, soluble receptor activator of NF-κB (sRANK) ligand, and osteoprotegerin (OPG) levels on lumbar bone mineral densities was measured. The results demonstrated an increased IL-17A-mediated sRANK ligand elevation in postmenopausal osteoporotic bone loss.

Introduction

IL-17 proinflammatory cytokine is a new inducer of bone loss. Postmenopausal osteoporosis represents a cross talk between estrogen deprivation and increased immune reactivity. The role of IL-17 was studied in the bone loss of postmenopausal osteoporosis.

Methods

Serum IL-17A, sRANK ligand, and OPG levels were investigated on bone mineral densities (BMDs) in the total lumbar (L1–L4) region in 18 pre- and 72 postmenopausal women. IL-17A, sRANK ligand, OPG levels, and BMDs were measured with enzyme-linked immunosorbent assay (ELISA) and dual-energy X-ray absorptiometry (DXA).

Results

Increased serum IL-17A, sRANK ligand, and OPG levels were demonstrated in postmenopausal osteoporotic women compared to osteopenic women (3.65?±?0.61 vs 3.31?±?0.43 ng/ml for IL-17A, P?<?0.007; 2.88?±?0.84 vs 2.49?±?0.61 ng/ml for sRANK ligand, P?<?0.027; and 1.43?±?0.07 vs 1.39?±?0.07 ng/ml for OPG, P?<?0.038). In postmenopausal women, IL-17A levels correlated inversely with total lumbar BMDs (P?<?0.008, r?=??0.279) and positively with sRANK ligand levels (P?<?0.0001, r?=?0.387) or the ratio of sRANK ligand and OPG (P?<?0.013, r?=?0.261), but did not with OPG levels alone.

Conclusion

Increased IL-17A levels are involved in postmenopausal osteoporosis, playing a role in the bone-resorpting processes.     

Assessment of the bone status of Nigerian women by ultrasound and biochemical markers

Ultrasound analysis of the calcaneus and serum markers of bone turnover were used to examine the bone status of healthy Nigerian women who reside in an area of the world where dietary calcium intake is generally low and estrogen replacement therapy is not widely available. A total of 218 women (108 premenopausal and 110 postmenopausal) between the ages of 16 and 95 years were enrolled in the study. Broadband ultrasound attenuation (BUA) and speed of sound velocity (SOS) were measured and used to calculate the stiffness index (SI) of the calcaneus. In this cross-sectional study, the Nigerian women exhibited a marked age-dependent decline in SI that was defined by the regression equation SI=105.9–6.62E-3×Age². SI was significantly correlated with age (r=−0.41,P<0.001) and with serum NTx concentrations (r=−0.26,P<0.001), but not with serum levels of bone specific alkaline phosphatase (BSAP). Years since menopause was also significantly correlated with SI (r=0.40,P<0.001). A significant increase in serum NTx concentration occurred at least a decade before a significant decline in SI was evident. In the total study group, 24% of the women had T-scores indicative of osteopenia and 9% had T-scores indicative of osteoporosis, based on US reference data. Although the reported current incidence of fracture is low in women in sub-Saharan West Africa, these data show that after menopause Nigerian women have a decline in bone quality and increase in bone turnover similar to North American Caucasian women.     

Serum Levels of Pyridinium Crosslinks in Postmenopausal Women and in Paget's Disease of Bone

The purpose of this study was to measure pyridinium crosslinks in serum by high performance liquid chromatography (HPLC) and to correlate levels with urinary excretion in patients with different osteometabolic conditions. Blood and spot urine samples were collected between 9 and 11 A.M. in 92 early postmenopausal, untreated women (age 52.3 ± 2.6 years, months since menopause 20.4 ± 9.6), 17 patients with active Paget's disease (10 males, aged 65.1 ± 12.6) and 24 healthy premenopausal women (aged 28.4 ± 4.2). Urinary excretion of the total fraction (free + peptide bound) of pyridinolines (Pyr, Dpyr) was measured by HPLC. Before HPLC analysis, serum samples were submitted to a clean-up procedure by ultrafiltration. In 42 postmenopausal women, bone loss was calculated from two bone mass measurements (L2–L4, DXA), performed at study entry and after 12 months. Statistical analysis was performed by Student's t test for independent samples and linear regression analysis. In pagetic patients' serum levels of Pyr and Dpyr were more than threefold increased over the mean observed in healthy controls and were closely correlated with total alkaline phosphatase levels (Pyr: r = 0.73; Dpyr: r = 0.72, P < 0.0005). Compared with controls, postmenopausal women had significantly increased levels of both urinary and serum Pyr and Dpyr (P < 0.003). In pagetic patients and postmenopausal women, crosslinks serum levels were correlated with their urinary excretion with r values ranging from 0.46 to 0.84. In postmenopausal women, only serum Dpyr correlated with the rate of bone loss (r =−0.36, P= 0.02). The data suggest that serum levels of pyridinium cross-links are correlated with urinary excretion in patients with different osteometabolic conditions. The determination of serum levels prevents limitations related to urinary specimen collection and may be a more practical method for routine application, avoiding corrections for urinary creatinine which could be misleading. Received: 13 August 1996 / Accepted: 25 April 1997     

Influence of Body Mass Index on the Age-related Slope of Total and Regional Bone Mineral Content

The influence of body mass index (BMI) on T scores for total body bone mineral content (TBBMC) and regional bone mineral content (RBMC) was studied in 186 healthy women: 100 postmenopausal, 35 perimenopausal, and 51 premenopausal. The three groups were divided by BMI >25 kg/m² and BMI <25 kg/m² and the postmenopausal women were further subdivided by years since menopause (YSM): <10, 10–20, and >20. Tartrate-resistant acid phosphatase (TRAP) concentration was higher in perimenopausal and postmenopausal women with BMI <25 kg/m² (P < 0.001). T scores for TBBMC and for axial or peripheral RBMC differed (P < 0.05 in all) between women with BMI >25 kg/m² and BMI <25 kg/m². The rate of perimenopausal and postmenopausal age-related slope of BMC, as reflected in all measurements, differed with BMI. In the overall group of women, the T score for TBBMC correlated significantly with BMI (r = 0.46, P < 0.0001); this correlation increased when adjusted for age (r = 0.62, P < 0.0001). BMI correlated with TRAP only in postmenopausal women (r = 0.57, P < 0.0001). Yearly TBBMC decline was twice as high in postmenopausal women with BMI <25 kg/m² (P= 0.0004) than in those with BMI >25 kg/m²; the decline of trunk RBMC was more significant (P < 0.0001). These findings confirm the influence of BMI and gonadal status on bone mass. Received 20 February 1996 / Accepted 31 December 1996     

Specific Changes of Urinary Excretion of Cross-Linked N-Telopeptides of Type I Collagen in Pre- and Postmenopausal Women: Correlation with Other Markers of Bone Turnover

Urinary excretion of cross-linked N-telopeptide of type I collagen (NTx) has been reported to be a specific marker of bone resorption [18]. We assessed a new immunoassay for NTx as an indicator of changes in bone resorption caused by spontaneous menopause and compared cross-sectionally the levels of urinary NTx, hydroxylysylpyridinoline (HP), lysylpyridinoline (LP), hydroxyproline (OH-Pr), other serum biochemical indices, and lumbar spine and proximal femur bone mineral density (BMD). Eighty-one Japanese women aged 22–77 participated in this study; 36 were premenopausal and 45 were postmenopausal. Urinary HP, LP, and NTx stayed at low levels in the premenopausal period and rose 21%, 30%, and 67% in the postmenopausal period, respectively. The rise in LP and NTx was statistically significant (P < 0.01), suggesting that NTx is mostly released from bone matrix when bone resorption is accelerated. When premenopausal women were divided into two age groups and postmenopausal women were divided into two groups according to years since menopause (YSM) there were significant differences in LP and NTx between women <4 YSM and women aged <40 and those women aged 41+ (P < 0.01 and P < 0.05, respectively). A significant 110% increase in urinary NTx and a 48% increase in urinary LP were observed in postmenopausal women compared with age-matched premenopausal women aged 45–55. All biochemical markers other than serum PTH correlated significantly with each other (r = 0.243–0.858, P < 0.05–0.0001). Urinary NTx inversely correlated with lumbar spine BMD. When postmenopausal women were divided into three groups, the correlation between bone resorption and formation markers in women 0-1 YSM was greater than in women 2–10 YSM and in women 11 + YSM, indicating that resorption and formation are coupled at the early postmenopausal period. We conclude that urinary NTx is responsive to changes in bone metabolism caused by estrogen deficiency and may be a more sensitive and specific marker than HP, LP, or OH-Pr in the early postmenopausal years. Received: 15 February 1995 / Accepted: 18 October 1996     

Differential Bone Metabolism Between Postmenopausal Women With Osteoarthritis and Osteoporosis

A comparative study of bone metabolism between postmenopausal women with osteoarthritis and osteoporosis showed that differential levels of bone remodeling markers, leptin, free leptin index, and osteoprotegerin might partly contribute to the proposed inverse relationship in bone mass between postmenopausal women with osteoarthritis and osteoporosis. Introduction : Osteoarthritis (OA) and osteoporosis (OP) are two common disorders affecting the quality of life in the elderly. The association between OA and OP has always been debated. The objective of this study was to compare bone metabolism between postmenopausal women with OA and OP. Materials and Methods : A total of 120 postmenopausal women with OA and OP (n = 60, respectively) were included in this comparative study. Anthropometric parameters and BMD at the spine and the proximal femur were measured. Serum leptin, soluble leptin receptor (sLR), osteoprotegerin (OPG), and bone remodeling markers, including bone‐specific alkaline phosphatase (BALP), osteocalcin (OC), deoxypyridinoline cross‐links (DPD), and cross‐linked N‐telopeptides of type I collagen (NTX), were quantified with commercial ELISA or EIA kits. Free leptin index (FLI) was also calculated by the ratio between serum leptin and sLR levels. Results : Postmenopausal women with OA had higher body weight, body mass index, fat mass, and percentage of fat than those suffered from OP. Compared with the patients in OP group, the patients in OA group had significantly higher BMD values at all sites measured. Higher serum leptin and FLI and lower OPG levels were shown in the OA group (leptin: 31.22 ± 6.4 versus 26.50 ± 9.27 ng/ml, p < 0.001; FLI: 3.20 ± 1.02 versus 2.50 ± 0.95, p < 0.05; OPG: 4.75 ± 1.97 versus 6.96 ± 2.75 pM, p < 0.001), whereas lower serum OC and higher urine DPD were noted in the OP group (OC: 16.45 ± 8.45 versus 13.06 ± 6.25 ng/ml, p < 0.05; DPD: 10.83 ± 7.12 versus 15.29 ± 6.65 nM BCE/mM Cr, p < 0.001). Serum OPG levels negatively correlated with BMD at all sites assessed. However, no correlation was found between leptin and BMD. Only in the OA group di positive correlations exist between FLI and Z‐score at the femoral neck and Ward's triangle region. After stepwise regression analysis, it was found that differential factors were able to predict the variance of BMD at different sites to a certain extent. Conclusions : Our study suggests that there are significant differences in bone metabolism between postmenopausal women with OA and OP and provides evidence for the inverse relationship between OA and OP. Differential levels of bone remodeling markers, leptin, FLI, and OPG may partly contribute to the proposed inverse relationship. Roles of leptin and its soluble receptor in bone metabolism regulation should be explored further.     

Comparison of vitamin D metabolism in early healthy and late osteoporotic postmenopausal women

Summary We studied 20 healthy premenopausal women aged 36.5±4.0 years (mean±1 SD), 123 healthy postmenopausal women aged 50.0±2.4 years, and 103 postmenopausal women aged 65.1±5.6 years with symptomatic osteoporosis (forearm and spinal fracture). Serum levels of vitamin D metabolites [25(OH)D, 24,25(OH)₂D₃, and 1,25(OH)₂D] were compared with (1) bone mass in the forearm (single photon absorptiometry) and in the spine (dual photon absorptiometry); (2) biochemical indices of bone formation (serum alkaline phosphatase, plasma bone Gla protien), and bone resorption (fasting urinary hydroxyproline); and (3) other biochemical estimates of calcium metabolism (serum calcium, serum phosphate, 24-hour urinary calcium, intestinal absorption of calcium). The present study revealed no difference in any of the vitamin D metabolites between the premenopausal women, the healthy postmenopausal women and the osteoporotic women as a group. The concentrations of 1,25(OH)₂D and 25(OH)D were significantly lower in patients with spinal fracture than in those with forearm fracture. In the early postmenopausal women, serum 1,25(OH)₂D was related to forearm bone mass (r=−0.20;P<0.05), intestinal calcium absorption (r=0.18;P<0.05), and 24-hour urinary calcium (r=0.21;P<0.05); serum 25(OH)D was related to spinal bone mass (r=0.23;P<0.01). In the osteoporotic women, serum vitamin D metabolites were not related to bone mass, but 1,25(OH)₂D was related to bone Gla protein (r=0.33;P<0.001), serum phosphate (r=−0.27;P<0.01), and 24-hour urinary calcium (r=0.43;P<0.001). The present study demonstrates that in a population that is apparently not deficient in vitamin D, a disturbance of the vitamin D metabolism is not likely to play a pathogenetic role in early postmenopausal bone loss. Patients with spinal fractures have low levels of vitamin D metabolites, which may aggravate their osteoporosis.     

Association between bone mineral densities and serum lipid profiles of pre- and post-menopausal rural women in South Korea

The objectives of this population-based study were to investigate the potential association between bone mineral density (BMD) and serum lipid profiles and to compare the effects of serum lipids on BMD at various skeletal sites in pre- and post-menopausal women. In July and August of 2004, BMD was measured at a variety of skeletal sites [lumbar spine (L_1–4), femoral neck, trochanter, Wards triangle, shaft and proximal total hip] using the GE/Bravo Lunar DPX dual-energy X-ray absorptiometer in a South Korean population-based sample of 375 pre-menopausal and 355 post-menopausal rural women aged 19–80 years. The levels of serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were inversely associated with BMD in both pre- and post-menopausal women. In the pre-menopausal women, correlations were shown only for lumbar 1–4 (TC: r =–0.12, P <0.05; LDL-C: r =–0.12, P <0.05), whereas in the post-menopausal women, no correlation was evident for the lumbar sites. In the post-menopausal subjects, the TC levels showed significant correlations with the BMD values at the trochanter ( r =–0.15, P <0.01), shaft ( r =–0.16, P <0.001) and proximal total hip ( r =–0.15, P <0.01) sites, while the LDL-C levels showed significant correlations with the BMD values at the neck ( r =–0.13, P <0.05), trochanter ( r =–0.21, P <0.001), shaft ( r =–0.20, P <0.001) and proximal total hip ( r =–0.20, P <0.001) sites. The levels of triglyceride (TG) were shown to have a significant positive correlation with BMD values at the trochanter site ( r =0.11, P =0.05) in the post-menopausal women; by contrast, subjects in a higher quartile of TG levels show lower lumbar BMD values in the pre-menopausal women. The levels of high-density lipoprotein cholesterol (HDL-C) were not associated with BMD values at any of the sites in the pre- and post-menopausal subjects. Our data indicate a relationship between BMD values and serum lipid levels and suggest differences between pre- and post-menopausal women in terms of the effects of serum lipids on BMD at various skeletal sites.     

IGF-1 as an early marker for low bone mass or osteoporosis in premenopausal and postmenopausal women

To find out which of the following parameters—serum levels of insulin-like growth factor 1 (IGF-1), osteoprotegerin (OPG), leptin, osteocalcin (OC), and urinary excretion of N-terminal telopeptide of type I collagen (NTx), can be used as an early marker for osteopenia/osteoporosis in women diagnosed by dual-energy X-ray absorptiometry (DXA), 282 premenopausal and 222 postmenopausal women aged 20–75 years were investigated by the measurement of bone mineral densities (BMDs) at lumbar spine (LS) and femoral neck (FN) by DXA, together with serum concentrations of IGF-1, OPG, leptin, OC, and urinary NTx. The characteristics of the earliest marker(s) were tested with the receiver operating characteristic (ROC) analysis. The area under the curve (AUC), sensitivity, and specificity parameters were determined. It was revealed that serum levels of IGF-1 and leptin changed the earliest, with both markers significantly decreasing (P < 0.0001) or increasing (P = 0.020), respectively, at age 30. However, in ROC analysis, IGF-1 was the only early parameter that had the capacity to differentiate the low bone mass/osteoporosis women from the normal ones (P < 0.0001). If the serum level of IGF-1 at 1.5 SD below its peak was adopted as a cutoff point, it could identify women with low bone mass/osteoporosis with a sensitivity of 73% and specificity of 67%. In the premenopausal women subgroup analysis, the low bone mass women (30/282, 10.6%) were older (38.2 ± 1.7 vs. 34.5 ± 0.5 years; P = 0.026), with lower serum levels of IGF-1 (215.1 ± 22.4 vs. 278.8 ± 9.4 ng/ml; P = 0.02) and less lean mass (33.1 ± 0.6 vs. 34.8 ± 0.2 kg; P = 0.010) than the normal ones. After controlling for age, the serum level of IGF-1 had a weak, but still significant, positive correlation with lean mass (r = 0.17, P < 0.001). In conclusion, measurement of serum IGF-1 in young women may help in the early identification of those at risk for developing low bone mass and osteoporosis.     

Plasma Leptin Values in Relation to Bone Mass and Density and to Dynamic Biochemical Markers of Bone Resorption and Formation in Postmenopausal Women

After the menopause it has been noted that heavier women conserve bone better than those with lower body weight. The protective effect of obesity on bone mass has been ascribed to a high body fat content. The present study of 54 postmenopausal women was undertaken to determine whether circulating plasma levels of leptin, the newly described hormone produced in adipocytes, were correlated with age-adjusted total body bone mineral content (BMC) or bone mineral density (BMD), or with dynamic biochemical markers of bone resorption or of bone formation. Leptin values were strongly correlated with all measures of adiposity (P < 0.001). Age-adjusted values for BMC and BMD, respectively, were also positively correlated (P < 0.001) with body weight (r = 0.643, r = 0.502), total fat mass (r = 0.557, r = 0.510) and with plasma leptin concentrations (r = 0.480, r = 0.551), confirming a positive relationship between fat mass and bone mass. By contrast, no significant correlations were observed between plasma leptin and dynamic markers of bone resorption (urinary deoxypyridinoline/creatinine r =−0.105, hydroxyproline/creatinine r =−0.193) or formation (plasma osteocalcin r = 0.103). Because there was no evidence for an association between ciculating plasma levels of leptin and biochemical markers of either osteoclastic or osteoblastic activity we conclude it is unlikely that circulating leptin plays any significant direct role in controlling bone cell activity. Our results do not support the hypothesis that leptin mediates the bone-sparing effects of obesity. Received: 23 September 1997 / Accepted: 11 May 1998     

Correlates of Osteoprotegerin Levels in Women and Men

Osteoprotegerin (OPG) is a potent antiresorptive molecule that binds the final effector for osteoclastogenesis, receptor activator of NF-kB ligand (RANK-L). OPG production is regulated by a number of cytokines and hormones, including sex steroids, but there are few data on age and gender effects on circulating serum OPG levels, as well as possible relationships between OPG levels and bone turnover markers or bone mineral density (BMD). Thus, we measured serum OPG levels in an age-stratified, random sample of men (n= 346 age range, 23–90 years) and women (n= 304; age range 21–93 years) and related them to sex steroid levels, bone turnover markers and BMD. Serum OPG levels increased with age in both men (R= 0.39, p<0.001) and women (R= 0.18, p<0.01). Premenopausal women had higher OPG levels than men under age 50 years (171 ± 6 pg/ml vs 134 ± 6 pg/ml, respectively, p<0.001), whereas serum OPG levels were no different in postmenopausal women compared with men = 50 years (195 ± 7 pg/ml vs 188 ± 7 pg/ml, respectively, p= 0.179). OPG levels correlated inversely with serum bioavailable testosterone levels in men = 50 years (R=–0.27, p<0.001), but no associations were present with either estrogen or testosterone levels in the women. In the men, there was a trend for OPG levels to be associated positively with bone resorption markers and inversely with BMD. Collectively, the gender difference in OPG levels suggests that sex steroids may regulate OPG production in vivo, as has been found in vitro. Moreover, OPG production may also rise with increases in bone turnover, probably as a homeostatic mechanism to limit bone loss. Further studies directly testing these hypotheses should provide additional insights into the potential role of OPG in bone loss related to aging and sex steroid deficiency. Received: 14 August 2001 / Accepted: 20 November 2001     

Association Between Female Sex Hormones and Biochemical Markers of Bone Turnover in Peri- and Postmenopausal Women

In an epidemiological study, markers of bone formation (serum osteocalcin and C-terminal propeptide of type I collagen) and bone resorption [urinary type I collagen peptides (Crosslaps), urinary total pyridinoline (TPYRI), urinary deoxypyridinoline (DPYRI) as well as female sex hormones (serum estradiol)], follicle-stimulating hormone (FSH) and luteinizing hormone were measured in 237 women. This cohort aged 44–66 years, came for their first medical examination since menopause to the outpatient menopause clinic at the Kaiser-Franz-Josef-Hospital, Vienna. The women were all 0.5–5.0 years since cessation of menses and were not taking medications other than hormone replacement therapy [52 cases, 21.9%)] and had no diseases known to affect bone and mineral metabolism. The best correlation was found between urinary DPYRI and urinary TPYRI (r = 0.63, P= 0.0001), followed by urinary Crosslaps and urinary DPYRI (r = 0.47, p = 0.0001). Only weak but significant correlations between E₂ and urinary Crosslaps (r =−0.21, P < 0.0001) as well as serum E₂ and serum osteocalcin (r =−0.16, P= 0.0007), were observed. Of the 237 women 53% suffered from a severe E₂ deficiency (E₂ < 10.0 ng/liter). In these patients, urinary Crosslaps (+48%) and serum osteocalcin (+22%) were significantly higher (P < 0.0001) compared with those patients with E₂ levels > 10 ng/liter. Women with E₂ levels >10 ng/liter were further subdivided into those with and without sex hormone replacement therapy, whereby no statistical differences in any of the biochemical markers could be observed between these groups. We could clearly demonstrate that in postmenopausal women suffering from severe E₂ deficiency (E₂ < 10 ng/liter), urinary Crosslaps and serum osteocalcin are significantly increased, indicating in principle a clear correlation between E₂ deficiency and these markers of bone turnover. Received: 3 February 1997 / Accepted: 15 October 1997     

Low bone density and abnormal bone turnover in patients with atherosclerosis of peripheral vessels.

Patients with vascular calcifications often have low bone mineral density (BMD), but it is still uncertain if osteoporosis and peripheral vascular disease (VD) are interrelated and linked by a common pathomechanism. Moreover, data on bone turnover in patients with advanced atherosclerosis are lacking. We measured BMD by dual-energy X-ray absorptiometry (DXA) and quantitative bone ultrasound (QUS), as well as the serum levels of osteocalcin (OC), bone-specific alkaline phosphatase (BAP), osteoprotegerin (OPG) and its ligand RANKL, and the urinary concentration of the C-terminal telopeptides of type I collagen (CrossLaps), in 36 patient (20 male and 16 female) with serious atherosclerotic involvement of the carotid and/or femoral artery to investigate the underlying mechanism of vascular and osseous disorders. Thirty age-matched and gender matched healthy individuals served as controls. After adjustment for age, BMD was significantly reduced at the lumbar spine in 23/36 (63%) patients (mean T score –1.71±1.42) and at the proximal femur in 34/36 (93%) patients (neck mean T score –2.5±0.88). Ten patients (27%) had abnormal QUS parameters. Gender and diabetes had no effect on the relationship between vascular calcification and bone density at any site measured. VD subjects had OC and BAP serum levels lower than controls (13.3±3.1 vs 27.7±3.3 ng/ml, P<0.01, and 8.4±2.3 vs 12.5±1.4 g/l, P<0.01, respectively). Urinary CrossLaps excretion was not significantly different in patients with VD and in controls (257.9±138.9 vs 272.2±79.4 µg/mmol Cr, respectively). Serum OPG and RANKL levels were similar in patients and in controls (3.5±1.07 vs 3.4±1.05 pmol/l, and 0.37±0.07 vs 0.36±0.06 pmol/l, respectively). We proved high occurrence of osteoporosis in VD, with evidence of age and gender independence. Negative bone remodelling balance would be a consequence of reduced bone formation, with no apparent increased activation of the OPG–RANKL system.     

Higher circulating hsCRP levels are associated with lower bone mineral density in healthy pre- and postmenopausal women: evidence for a link between systemic inflammation and osteoporosis

Factors involved in inflammation are linked with those critical for bone remodeling. We examined the association between serum high sensitivity C-reactive protein (hsCRP) levels and bone mineral density (BMD) in healthy women. Serum concentrations of hsCRP and total alkaline phosphatase (ALP) were measured in premenopausal ( n =3,662) and postmenopausal ( n =1,031) women aged 30 years or older. BMD was measured at the femoral neck and lumbar spine using dual energy X-ray absorptiometry. According to the WHO definition, osteopenia was diagnosed at –2.5< T -score <–1.0 SD, and osteoporosis was diagnosed at T -score –2.5 SD at any sites. Compared with normal subjects, log-transformed serum hsCRP levels were higher in osteopenic and osteoporotic subjects (all, P <0.001) with linearity ( P for trend <0.001), after adjustment for age, BMI and menopausal status. Menopausal status did not have a significant interaction on the association ( P =0.457). In both premenopausal and postmenopausal women, serum total ALP levels were higher in the subjects with higher hsCRP quintiles than those with the lowest quintile (all, P for trend <0.001). Multivariate-adjusted odds ratio (OR) for osteoporosis and osteopenia were 1.35 (95% CI, 1.08 to 1.68) in the highest hsCRP quintile of premenopausal women, and OR for osteoporosis was 1.54 (95% CI, 1.10 to 2.53) in the highest hsCRP quintile of postmenopausal women. These findings suggest that subclinical systemic inflammation may be associated with bone turnover rate and bone mass in healthy women.     

Genetic Polymorphisms of OPG, RANK, and ESR1 and Bone Mineral Density in Korean Postmenopausal Women

To evaluate the effects of genetic polymorphisms of OPG, RANK, and ESR1, which regulate osteoclastogenesis, on bone mineral density (BMD), a cross-sectional study was conducted in 650 Korean postmenopausal women. BMDs of the distal radius and the calcaneus were measured by dual energy X-ray absorptiometry (DXA). Genetic polymorphisms of OPG 163 A > G, 1181 G > C; RANK 421 C > T, 575 T > C; and ESR1 1335 C > T, 2142 G > A were determined by matrix-assisted laser desorption/ionization—time of flight (MALDI-ToF) mass spectrometry. The differences between the BMDs of the genotypes of OPG, RANK, and ESR1 were analyzed by multiple linear regression model adjusted for age and body mass index. Women with the OPG 1181 CC genotype had higher BMDs at the distal radius (7%) and calcaneus (10%) than those with the GG genotype; and these differences were statistically significant (P = 0.001 and P = 0.007, respectively). A significant association was also observed between RANK 575 T > C and calcaneus BMD (P for trend = 0.017). No significant association was observed between BMDs and the polymorphisms of ESR1. The association between OPG 1181 G > C and BMD was profound in subjects with the RANK 575 TT or ESR1 2142 GG genotypes; women with OPG 1181 CC had higher BMDs at the distal radius (11%) and calcaneus (11%) than those with OPG 1181 GG only in women with RANK 575 TT genotype (P = 0.002 and P = 0.021, respectively). These results suggest that OPG genetic polymorphisms, especially with the RANK 575 TT or ESR1 2142 GG genotypes, are related to low BMD in postmenopausal Korean women.