Osteoclast-secreted SLIT3 coordinates bone resorption and formation.

Coupling is the process that links bone resorption to bone formation in a temporally and spatially coordinated manner within the remodeling cycle. Several lines of evidence point to the critical roles of osteoclast-derived coupling factors in the regulation of osteoblast performance. Here, we used a fractionated secretomic approach and identified the axon-guidance molecule SLIT3 as a clastokine that stimulated osteoblast migration and proliferation by activating ß-catenin. SLIT3 also inhibited bone resorption by suppressing osteoclast differentiation in an autocrine manner. Mice deficient in Slit3 or its receptor, Robo1, exhibited osteopenic phenotypes due to a decrease in bone formation and increase in bone resorption. Mice lacking Slit3 specifically in osteoclasts had low bone mass, whereas mice with either neuron-specific Slit3 deletion or osteoblast-specific Slit3 deletion had normal bone mass, thereby indicating the importance of SLIT3 as a local determinant of bone metabolism. In postmenopausal women, higher circulating SLIT3 levels were associated with increased bone mass. Notably, injection of a truncated recombinant SLIT3 markedly rescued bone loss after an ovariectomy. Thus, these results indicate that SLIT3 plays an osteoprotective role by synchronously stimulating bone formation and inhibiting bone resorption, making it a potential therapeutic target for metabolic bone diseases.

Prediction of Future Osteoporotic Fracture Occurrence by Genetic Profiling: A 6-Year Follow-Up Observational Study.

CONTEXT: Heredity is an important risk factor for osteoporotic fracture, but it remains unclear whether genetic factors improve the predictability of future fracture occurrence. OBJECTIVE: To compare an integration model of genetic profiling with the current model for predicting future fracture occurrence. DESIGN AND SETTING: A retrospective observational cohort study. PARTICIPANTS: Postmenopausal women aged 45-93 years who were untreated (n = 117), hormone-treated (n = 491), or bisphosphonate (BP)-treated (n = 415), with a mean 6.1-year follow-up. MAIN OUTCOMES MEASURES: The main outcome was incident fractures. Ninety-five single nucleotide polymorphisms were genotyped. We calculated the Korean-specific genetic risk score 35 (GRS35) from 35 single nucleotide polymorphisms associated with osteoporosis-related traits at the baseline visit. RESULTS: Osteoporotic fracture occurred more frequently in the highest GRS35 tertile group than in the lower two tertile groups after adjustments for confounders (hazard ratio [HR], 1.73; 95% confidence interval [CI], 1.17-2.55). The associations of the GRS35 with incident fracture were only significant in the BP group (HR, 2.25; 95% CI, 1.28-3.95) and not in the untreated (HR, 1.26; 95% CI, 0.34-4.66) and hormone-treated (HR, 1.21; 95% CI, 0.62-2.36) groups. Integration of the GRS35 into the current model further improved its predictability for incident fracture occurrence by 6.3% (P = .010). CONCLUSIONS: Genetic profiling can more accurately predict future fracture risk, especially in individuals taking BPs.

Higher serum carcinoembryonic antigen levels associate with more frequent development of incident fractures in Korean women: a longitudinal study using the national health insurance claim data.

BACKGROUND: Pro-inflammatory cytokines play important roles in bone metabolism and several studies have shown that carcinoembryonic antigen (CEA) may promote inflammation. We investigated the association of serum CEA levels with the risk of osteoporosis and incident fracture. METHODS: We performed a small cross-sectional study with 302 Korean women and a large, longitudinal study with 7192 Korean women in an average 3-year follow-up period. For the cross-sectional study, bone mineral density (BMD) and bone turnover markers (BTMs) were measured. For the longitudinal study, incident fractures in the follow-up period were identified by using the selected International Classification of Diseases, 10th revision (ICD-10) codes and the nationwide claims database of the Health Insurance Review and Assessment Service of Korea. RESULTS: In the cross-sectional study, serum CEA levels correlated negatively with BMD at the lumbar spine (γ=-0.023; P=0.029) and positively with BTMs (γ=0.122 to 0.138, P=0.002 to P<0.001) after adjustment for confounding variables. In the longitudinal study, 254 (3.5%) women developed incident fractures in the follow-up period (2.8±1.3 years). After adjustment for potential confounders, the hazard ratio (HR) per 1 ng/mL increment of the baseline CEA level for the development of incident fracture was 1.22 [95% confidence interval (CI): 1.05-1.42]. The HR was markedly higher in subjects in the highest CEA quartile category compared with those in the lowest CEA quartile category (HR=1.54, 95% CI: 1.04-2.28). CONCLUSION: Therefore, serum CEA may be a biomarker of the risk of incident fracture in postmenopausal Korean women.

Common and rare variants in the exons and regulatory regions of osteoporosis-related genes improve osteoporotic fracture risk prediction.

CONTEXT: Osteoporotic fracture risk is highly heritable, but genome-wide association studies have explained only a small proportion of the heritability to date. Genetic data may improve prediction of fracture risk in osteopenic subjects and assist early intervention and management. OBJECTIVE: To detect common and rare variants in coding and regulatory regions related to osteoporosis-related traits, and to investigate whether genetic profiling improves the prediction of fracture risk. DESIGN AND SETTING: This cross-sectional study was conducted in three clinical units in Korea. PARTICIPANTS: Postmenopausal women with extreme phenotypes (n = 982) were used for the discovery set, and 3895 participants were used for the replication set. MAIN OUTCOME MEASURE: We performed targeted resequencing of 198 genes. Genetic risk scores from common variants (GRS-C) and from common and rare variants (GRS-T) were calculated. RESULTS: Nineteen common variants in 17 genes (of the discovered 34 functional variants in 26 genes) and 31 rare variants in five genes (of the discovered 87 functional variants in 15 genes) were associated with one or more osteoporosis-related traits. Accuracy of fracture risk classification was improved in the osteopenic patients by adding GRS-C to fracture risk assessment models (6.8%; P < .001) and was further improved by adding GRS-T (9.6%; P < .001). GRS-C improved classification accuracy for vertebral and nonvertebral fractures by 7.3% (P = .005) and 3.0% (P = .091), and GRS-T further improved accuracy by 10.2% (P < .001) and 4.9% (P = .008), respectively. CONCLUSIONS: Our results suggest that both common and rare functional variants may contribute to osteoporotic fracture and that adding genetic profiling data to current models could improve the prediction of fracture risk in an osteopenic individual.

Association between metabolic syndrome and incident fractures in Korean men: a 3-year follow-up observational study using national health insurance claims data.

CONTEXT: Although the prevalence of both metabolic syndrome (MetS) and fractures increases with advancing age, studies on possible associations between these conditions in men are limited and the results are inconsistent. OBJECTIVE: The objective of the study was to clarify the impact of MetS on the male risk of incident fractures. DESIGN AND SETTING: This was a large, longitudinal study with an average 3-year follow-up period. PARTICIPANTS: Korean men (n = 16 078) aged 50 years or older who had undergone comprehensive routine health examinations participated in the study. MAIN OUTCOME MEASURES: Incident fractures found after baseline examinations were identified using selected International Classification of Diseases, tenth revision, codes in the nationwide claims database of the Health Insurance Review and Assessment Service of Korea. RESULTS: In total, 158 men (1.0%) developed incident fractures. The fracture event rates for subjects with and without MetS were 26.2 and 35.7 per 10 000 person-years, respectively. After adjustment for potential confounders, subjects with MetS had a much lower risk of incident fractures than subjects without MetS (hazard ratio 0.662, 95% confidence interval 0.445-0.986). Furthermore, subjects with three and four or more MetS components had a 49.4% and 50.4% lower risk, respectively, of incident fractures compared with the subjects without any MetS components. Importantly, additional adjustment for body mass index eliminated the statistical significance of these associations. CONCLUSION: Our current results indicate that the beneficial effects of MetS in reducing fracture risk could be explained by the general obesity that accompanies MetS, although other related factors, such as greater padding effect, peripheral aromatization, or adipokine changes, may also contribute.

Genome-wide association study for radiographic vertebral fractures: a potential role for the 16q24 BMD locus.

Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged > 55 years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey­Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey­Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han­Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p < 5 × 10− 8. In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p = 4.6 × 10− 8. However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% CI: 0.98­1.14; p = 0.17), displaying high degree of heterogeneity (I2 = 57%; Qhet p = 0.0006). Under Han­Eskin alternative random effects model the summary effect was significant (p = 0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size > 1.25) may still be consistent with an effect size < 1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.

A higher serum gamma-glutamyl transferase level could be associated with an increased risk of incident osteoporotic fractures in Korean men aged 50 years or older.

Oxidative stress has detrimental effects on bone metabolism, and gamma-glutamyl transferase (GGT) is known to play an important role in the generation of free radical species through the extra-cellular hydrolysis of glutathione, the main cellular antioxidant. We performed a large longitudinal study with an average follow-up period of 3 years to investigate the association between baseline serum GGT levels and the development of future osteoporotic fractures (OFs) in men. A total of 16,036 Korean men aged 50 years or older who had undergone comprehensive routine health examinations were enrolled. Incident fractures at osteoporosis-related sites (e.g., hip, spine, distal radius, and proximal humerus) that occurred after baseline examinations were identified from the nationwide claims database of the Health Insurance Review and Assessment Service of Korea using selected ICD-10 codes. Among the study subjects, 156 cases (1.0%) developed incident OFs during the study period. The event rate was 32.7 (95% CI = 28.0-38.3) per 10,000 person-years. Multivariable adjusted Cox proportional hazard analyses adjusted for age, body mass index, lifestyle factors, and medical and drug histories revealed that the hazard ratio per standard deviation increase of the baseline GGT levels for the development of incident fractures was 1.115 (95% CI = 1.011-1.230). These data provide the first epidemiological evidence, in support of previous in vitro and animal studies, of the harmful effects of GGT on bone metabolism, and indicate that the serum GGT level may be a useful biomarker of poor bone health outcomes in men.

Multiple gene polymorphisms can improve prediction of nonvertebral fracture in postmenopausal women.

Clinical risk factors (CRFs), with or without bone mineral density (BMD), are used to determine the risk of osteoporotic fracture (OF), which has a heritable component. In this study we investigated whether genetic profiling can additionally improve the ability to predict OF. Using 1229 unrelated Korean postmenopausal women, 39 single-nucleotide polymorphisms (SNPs) in 30 human genomic loci were tested for association with osteoporosis-related traits, such as BMD, osteoporosis, vertebral fracture (VF), nonvertebral fracture (NVF), and any fracture. To estimate the effects of genetic profiling, the genetic risk score (GRS) was calculated using five prediction models: (Model I) GRSs only; (Model II) BMD only; (Model III) CRFs only; (Model IV) CRFs and BMD; and (Model V) CRFs, BMD, and GRS. A total of 21 SNPs within 19 genes associated with one or more osteoporosis-related traits and were included for GRS calculation. GRS associated with BMD before and after adjustment for CRFs (p ranging from <0.001 to 0.018). GRS associated with NVF before and after adjustment for CRFs and BMD (p ranging from 0.017 to 0.045), and with any fracture after adjustment for CRFs and femur neck BMD (p = 0.049). In terms of predicting NVF, the area under the receiver operating characteristic curve (AUC) for Model I was 0.55, which was lower than the AUCs of Models II (0.60), III (0.64), and IV (0.65). Adding GRS to Model IV (in Model V) increased the AUC to 0.67, and improved the accuracy of NVF classification by 11.5% (p = 0.014). In terms of predicting any fracture, the AUC of Model V (0.68) was similar to that of Model IV (0.68), and Model V did not significantly improve the accuracy of any fracture classification (p = 0.39). Thus, genetic profiling may enhance the accuracy of NVF predictions and help to delineate the intervention threshold.

High serum total bilirubin as a protective factor against hip bone loss in healthy middle-aged men.

Bilirubin is known to have a physiologic role as an antioxidant that efficiently scavenges peroxyl radicals and suppresses oxidation, and oxidative stress has detrimental effects on bone metabolism. In the present study, we performed a 3-year longitudinal study of healthy middle-aged men, investigating the association between serum total bilirubin concentrations and annualized changes in bone mineral density (BMD). The study enrolled a total of 917 Korean men aged 40 years or older who had undergone comprehensive routine health examinations with an average follow-up interval of 3 years. BMD at proximal femur sites was measured with dual-energy X-ray absorptiometry using the same equipment at baseline and follow-up. The overall mean annualized rates of bone loss at the total femur, femoral neck, and trochanter were -0.25 %/year, -0.34 %/year, and -0.44 %/year, respectively. After adjustment for potential confounders, the rates of bone loss at all proximal femur sites were significantly attenuated in a dose-response fashion across increasing bilirubin concentrations (P = 0.006-0.046). Moreover, compared to subjects in the lowest bilirubin quartile category, those in the highest bilirubin quartile category showed significantly less bone loss at all proximal femur sites after adjustment for confounding factors (P = 0.010-0.048). This study provides the first clinical evidence that serum total bilirubin could be a protective marker against future bone loss, especially in subjects without liver diseases.

Meta-analysis identifies a MECOM gene as a novel predisposing factor of osteoporotic fracture.

BACKGROUND: Osteoporotic fracture (OF) as a clinical endpoint is a major complication of osteoporosis. To screen for OF susceptibility genes, we performed a genome-wide association study and carried out de novo replication analysis of an East Asian population. METHODS: Association was tested using a logistic regression analysis. A meta-analysis was performed on the combined results using effect size and standard errors estimated for each study. RESULTS: In a combined meta-analysis of a discovery cohort (288 cases and 1139 controls), three hospital based sets in replication stage I (462 cases and 1745 controls), and an independent ethnic group in replication stage II (369 cases and 560 for controls), we identified a new locus associated with OF (rs784288 in the MECOM gene) that showed genome-wide significance (p=3.59×10(-8); OR 1.39). RNA interference revealed that a MECOM knockdown suppresses osteoclastogenesis. CONCLUSIONS: Our findings provide new insights into the genetic architecture underlying OF in East Asians.

High serum total homocysteine levels accelerate hip bone loss in healthy premenopausal women and men.

INTRODUCTION: Despite extensive evidence demonstrating the direct, detrimental role of homocysteine on bone metabolism, the effects of serum total homocysteine (tHcy) on bone loss are still equivocal. In the present study, we performed a longitudinal study on healthy participants of various ages of both sexes in order to investigate the association between serum tHcy concentrations and annualized changes in bone mineral density (BMD). METHODS: A total of 460 Koreans ≥ 30 years of age received comprehensive, routine health examinations for an average period of 3 years. The BMD at proximal femur sites was measured with dual-energy X-ray absorptiometry using the same equipment at baseline and follow-up. RESULTS: After adjusting for potential confounders, the rates of bone loss at the proximal femur sites were significantly accelerated in a dose-response fashion across increasing tHcy concentrations in premenopausal women and men, but not in postmenopausal women. Consistently, compared with subjects in the lowest tHcy quartile, premenopausal women in the third and/or highest tHcy quartile and men in the highest tHcy quartile showed significantly higher rates of bone loss at all proximal femur sites (p=0.015-0.048) and at the total femur and femur neck (p=0.008-0.013), respectively. In contrast, there were no differences in terms of bone loss among the tHcy quartiles for postmenopausal women. CONCLUSION: These data provide the first clinical evidence that increased tHcy levels could be an independent risk factor for the future deterioration of bone mass in premenopausal women and men.

Association of Bone Marrow Sphingosine 1-phosphate Levels with Osteoporotic Hip Fractures.

BACKGROUND: Sphingosine 1-phosphate (S1P) has been discovered to be a critical regulator of bone metabolism. Very recently, we found that higher circulating S1P levels were associated with higher rate of prevalent osteoporotic fracture in human. METHODS: This was a cross-sectional study of 16 patients who underwent hip replacement surgeries. Bone marrow fluids were obtained during hip surgeries, and the S1P levels were measured using a competitive enzyme-linked immunosorbent assay (ELISA) assay. Bone mineral densities (BMDs) at various skeletal sites were obtained using dual energy X-ray absorptiometry. RESULTS: Among 16 patients, 4 patients were undergone operations due to hip fractures, and the others were done by any other causes. Bone marrow S1P levels were significantly lower in patients with hip fractures than in those without, before and after adjusting for confounding factors (P=0.047 and 0.025, respectively). We failed to demonstrate significant associations between bone marrow S1P levels and any BMD values (γ=0.026-0.482, P=0.171-0.944). CONCLUSIONS: In conjunction with our previous findings, these suggest that the effects of gradient between peripheral blood and bone marrow, but not S1P itself, may be the most critical on bone metabolism.

Plasma sphingosine 1-phosphate levels and the risk of vertebral fracture in postmenopausal women.

CONTEXT: Although sphingosine 1-phosphate (S1P) plays diverse roles in bone metabolism, the most prominent role seems to be the augmentation of bone resorption. OBJECTIVE: The objective of the study was to investigate the possibility of using S1P as a predictor for osteoporotic vertebral fracture (VF) risk. DESIGN AND SETTING: This was a case-control study conducted in a clinical unit in Korea. PARTICIPANTS: Sixty-nine cases having radiological VF and 69 age- and body mass index-matched controls among 460 eligible postmenopausal women participated in the study. MAIN OUTCOME MEASURES: Lateral thoracolumbar radiographs, bone mineral density (BMD), bone turnover markers, and plasma S1P levels were obtained from all subjects. RESULTS: S1P levels were markedly higher in subjects with VF (7.49±3.44 µmol/liter) than in those without VF (5.58±2.01 µmol/liter; P=0.001) and increased in a dose-response manner as the number of VF increased (P for the trend<0.001), even after adjustment for lumbar spine BMD and potential confounders. The odds ratio for VF was markedly higher in subjects in the highest S1P quartile category compared with those in the lowest S1P quartile category after adjustment for confounders (odds ratio 9.33, 95% confidence interval 2.68-32.49). S1P levels were inversely correlated with BMD at various sites (P=0.015 to 0.044), whereas they were positively correlated with bone resorption markers (P=0.016 to 0.098). CONCLUSION: These findings suggest that plasma S1P may be a potential biomarker for the risk of VF, independent of BMD, in postmenopausal women.

Afamin secreted from nonresorbing osteoclasts acts as a chemokine for preosteoblasts via the Akt-signaling pathway.

Although it is well known that osteoclastic bone resorption is followed by osteoblastic bone formation, questions remain as to when coupling factors are produced during bone resorption and which stages of bone formation are affected by these factors. To clarify these mechanisms, we established an in vitro system to investigate the coupling phenomenon. We obtained conditioned media (CM) from osteoclasts in the early and late stages of differentiation and from bone resorption stages. The collected CM was used to treat primary mouse calvarial osteoblasts and preosteoblastic MC3T3-E1 cells and to evaluate its influence on the migration, viability, proliferation, and differentiation of osteoblasts. We found that CM from osteoclasts in the early stage of differentiation predominantly stimulated the migration of osteoblastic lineages. By further performing fractional analyses of the CM with liquid chromatography-tandem mass spectrometry, we identified afamin, which has binding activity with vitamin E, as a possible coupling factor. The CM collected from afamin siRNA-transfected osteoclasts significantly suppressed preosteoblast migration. Afamin activated Akt in preosteoblasts, and pretreatment with Akt inhibitor significantly blocked afamin-stimulated preosteoblast migration. In conclusion, these results indicate that osteoclasts themselves play a central role in the coupling of bone resorption and formation by stimulating preosteoblast migration. In addition, we identified afamin as one of osteoclast-derived chemokines that affect preosteoblasts through the activation of the Akt-signaling pathway.

TNF-α mediates the stimulation of sclerostin expression in an estrogen-deficient condition.

Although recent clinical studies have suggested a possible role for sclerostin, a secreted Wnt antagonist, in the pathogenesis of postmenopausal osteoporosis, the detailed mechanisms how estrogen deficiency regulates sclerostin expression have not been well-elucidated. Bilateral ovariectomy or a sham operation in female C57BL/6 mice and BALB/c nude mice was performed when they were seven weeks of age. The C57BL/6 mice were intraperitoneally injected with phosphate-buffered serum (PBS), 5 µg/kg ß-estradiol five times per week for three weeks, or 10 mg/kg TNF-α blocker three times per week for three weeks. Bony sclerostin expression was assessed by immunohistochemistry staining in their femurs. The activity and expression of myocyte enhancer factors 2 (MEF2), which is essential for the transcriptional activation of sclerostin, in rat UMR-106 osteosarcoma cells were determined by luciferase reporter assay and western blot analysis, respectively. Bony sclerostin expression was stimulated by estrogen deficiency and it was reversed by estradiol supplementation. When the UMR-106 cells were treated with well-known, estrogen-regulated cytokines, only TNF-α, but not IL-1 and IL-6, increased the MEF2 activity. Consistently, TNF-α also increased the nuclear MEF2 expression. Furthermore, the TNF-α blocker prevented the stimulation of bony sclerostin expression by ovariectomy. We also found that there was no difference in sclerostin expression between ovariectomized nude mice and sham-operated nude mice. In conclusion, these results suggest that TNF-α originating from T cells may be at least in part responsible for stimulating the sclerostin expression observed in an estrogen-deficient condition.

Higher circulating sphingosine 1-phosphate levels are associated with lower bone mineral density and higher bone resorption marker in humans.

CONTEXT: Several in vivo and in vitro studies suggest that sphingosine-1-phosphate (S1P) is known to act as a coupling factor, to stimulate osteoclastogenesis, to control the migration of osteoclast precursors between the blood and bone, and to stimulate the proliferation, migration, and survival of osteoblasts. OBJECTIVE: Using the determination of circulating S1P levels, we investigated which kinds of processes may be primarily affected by S1P in humans. DESIGN AND SETTING: This was a cross-sectional study conducted in two clinical units in Korea. PARTICIPANTS: Men (n = 86), premenopausal women (n = 94), and postmenopausal women (n = 357) participated in the study. MAIN OUTCOME MEASURES: We measured S1P levels and their relationships with bone mineral density, biochemical bone turnover markers, and uncoupling indices. RESULTS: S1P levels were significantly higher in the postmenopausal women than in the premenopausal women and men. High S1P concentrations were significantly associated with low bone mineral density values at some femur sites in the postmenopausal women (P = 0.015 to 0.049), at the lumbar spine in the premenopausal women (P = 0.017), and at all sites in men (P = 0.001 to 0.036) after adjustments with multiple covariates. S1P levels were positively correlated with bone resorption markers (P = 0.003 to 0.049), but not with formation markers in postmenopausal women. Higher S1P levels were associated with lower uncoupling indices (P = <0.001 to 0.048) in postmenopausal women. CONCLUSION: These findings suggest that S1P may primarily affect bone resorption, resulting in bone loss.

Iron overload accelerates bone loss in healthy postmenopausal women and middle-aged men: a 3-year retrospective longitudinal study.

Despite extensive experimental and animal evidence about the detrimental effects of iron and its overload on bone metabolism, there have been no clinical studies relating iron stores to bone loss, especially in nonpathologic conditions. In the present study, we performed a large longitudinal study to evaluate serum ferritin concentrations in relation to annualized changes in bone mineral density (BMD) in healthy Koreans. A total of 1729 subjects (940 postmenopausal women and 789 middle-aged men) aged 40 years or older who had undergone comprehensive routine health examinations with an average 3 years of follow-up were enrolled. BMD in proximal femur sites (ie, the total femur, femur neck, and trochanter) was measured with dual-energy X-ray absorptiometry using the same equipment at baseline and follow-up. The mean age of women and men in this study was 55.8 ± 6.0 years and 55.5 ± 7.8 years, respectively, and serum ferritin levels were significantly higher in men than in women (p < 0.001). The overall mean annualized rates of bone loss in the total femur, femur neck, and trochanter were -1.14%/year, -1.17%/year, and -1.51%/year, respectively, in women, and -0.27%/year, -0.34%/year, and -0.41%/year, respectively, in men. After adjustment for potential confounders, the rates of bone loss in all proximal femur sites in both genders were significantly accelerated in a dose-response fashion across increasing ferritin quartile categories (p for trend = 0.043 to <0.001). Consistently, compared with subjects in the lowest ferritin quartile category, those in the third and/or highest ferritin quartile category showed significantly faster bone loss in the total femur and femur neck in both genders (p = 0.023 to <0.001). In conclusion, these data provide the first clinical evidence that increased total body iron stores could be an independent risk factor for accelerated bone loss, even in healthy populations.

Efficacy of intravenously administered ibandronate in postmenopausal Korean women with insufficient response to orally administered bisphosphonates.

We investigated rates of insufficient and over-responsiveness to orally administered bisphosphonates in postmenopausal women, and tested the efficacy of intravenous ibandronate in patients with insufficient response to orally administered bisphosphonates. Postmenopausal women were treated with either alendronate (70 mg/week; n = 88) or risedronate (35 mg/week; n = 84) for 1 year, and their response to orally administered bisphosphonates was assessed using serum C-telopeptide (CTX) levels. Insufficient responders were changed to once-quarterly intravenous ibandronate 3 mg injection (n = 13) or maintained on orally administered bisphosphonates (n = 19), according to patients' preference, for an additional 1 year. There was no significant difference in baseline characteristics between two orally administered bisphosphonate groups except the bone mineral density values at the lumbar spine. Insufficient rate was higher in the risedronate group (19.0 %) than in the alendronate group (8.0 %), using the premenopausal serum CTX median as a cut-off (P = 0.043). The over-response rate among the alendronate group (59.1 %) was significantly higher than that in the risedronate group (38.1 %), based on a serum CTX cut-off value of 0.100 ng/ml (P = 0.006). Intravenous ibandronate suppressed serum CTX levels to a significantly greater degree at 7 days after the second dosing (0.191 ± 0.110 ng/mL; P < 0.001) and 3 months after the fourth dosing (0.274 ± 0.159 ng/mL; P = 0.004) among insufficient responders, compared with post-oral/pre-intravenous levels (0.450 ± 0.134 ng/mL). Rates of insufficient and over-responsiveness to orally administered bisphosphonates were considerable, and a change to intravenous bisphosphonates may be considered in patients showing an insufficient response to orally administered bisphosphonates.

Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

Association of ADIPOR1 polymorphisms with bone mineral density in postmenopausal Korean women.

Adiponectin may affect bone through interactions with two known receptors, adiponectin receptors (ADIPOR) 1 and 2. We examined the association between polymorphisms of ADIPOR1 and ADIPOR2 and bone mineral density (BMD) in postmenopausal Korean women. Six polymorphisms in ADIPOR1 and four polymorphisms in ADIPOR2 were selected and genotyped in all study participants (n = 1,329). BMD at the lumbar spine and femur neck were measured using dual-energy X-ray absorptiometry. Lateral thoracolumbar (T4-L4) radiographs were obtained for vertebral fracture assessment and the occurrence of non-vertebral fractures examined using self-reported data. P values were adjusted for multiple testing using Bonferroni correction (P(corr)). ADIPOR1 rs16850799 and rs34010966 polymorphisms were significantly associated with femur neck BMD (P(corr) = 0.036 in the dominant model; P(corr) = 0.024 and P(corr) = 0.006 in the additive and dominant models, respectively). Subjects with the rare allele of each polymorphism had lower BMD, and association of rs34010966 with BMD showed a gene dosage effect. However, ADIPOR2 single nucleotide polymorphisms and haplotypes were not associated with BMD at any site. Our results suggest that ADIPOR1 polymorphisms present a useful genetic marker for BMD in postmenopausal Korean women.