Associations Between Plasma Growth and Differentiation Factor-15 with Aging Phenotypes in Muscle, Adipose Tissue, and Bone.

Growth and differentiation factor 15 (GDF-15) is associated with muscle, fat, and bone metabolism; however, this association has not been well characterized. Plasma GDF-15, appendicular skeletal muscle mass (ASM), fat mass (FM), and bone mineral density (BMD) were measured in 146 postmenopausal women. GDF-15 levels were higher in subjects with low Body Mass Index (BMI)-adjusted ASM than in those without (median [interquartile range] 831.3 [635.4-1011.4] vs. 583.8 [455.8-771.1] pg/mL, p = 0.018). The GDF-15 level was inversely correlated with BMI-adjusted ASM (r = - 0.377, p < 0.001) and BMD at femur neck (FN-BMD; r = - 0.201, p = 0.015), and positively correlated with percent FM (pFM; r = 0.328, p < 0.001). After adjusting for confounders, the GDF-15 level was inversely associated with BMI-adjusted ASM (ß = -0.250, p = 0.006) and positively associated with pFM (ß = 0.272, p = 0.004), and tended to be inversely associated with FN-BMD (ß = - 0.176, p = 0.076). The area under the receiver-operating characteristic curve of GDF-15 level > 618.4 pg/mL for sarcopenia was 0.706 (95% confidence interval (CI) 0.625-0.779) with a sensitivity of 83.3% and a specificity of 54.5%. Using a GDF-15 level of 618.4 pg/mL as a cut-off, the GDF-15 level was associated with a significantly greater likelihood of sarcopenia (odds ratio [OR] 2.35; 95% CI 1.00-5.51; p = 0.049), obesity (OR 3.28; 95% CI 1.48-7.27; p = 0.001), osteopenic obesity (OR 3.10; 95% CI 1.31-7.30; p = 0.010), and sarcopenic or osteosarcopenic obesity (OR 4.84; 95% CI 0.88-26.69; p = 0.070). These findings support the potential of GDF-15 as a biomarker for age-related changes in muscle, fat, and bone.

Associations of Circulating Levels of Sphingosine 1-Phosphate with the Trabecular Bone Score and Bone Mineral Density in Postmenopausal Women.

Despite the potential roles of sphingosine 1-phosphate (S1P) as a biomarker of osteoporotic fracture (OF), independent of bone mineral density (BMD) and clinical risk factors (CRFs), its association with bone microarchitecture, a key determinant of bone quality, have not been studied yet. We here investigated the association of S1P with the trabecular bone score (TBS), an index of the bone microarchitecture. The plasma S1P concentrations, TBS, and BMD were measured in the 339 postmenopausal women. The S1P level was inversely correlated with the TBS (γ=-0.096, p=0.049) and BMD at the femur neck (FN-BMD: γ=-0.122, p=0.025) and tended to be inversely correlated the BMD at the total hip (TH-BMD: γ=-0.096, p=0.079), but not at the lumbar spine (LS-BMD). After adjusting for fracture risk assessment tool probabilities of major OF from CRFs, the S1P level was inversely associated with the TBS (ß=-0.096, p=0.049) and FN-BMD (ß=-0.118, p=0.025) and tended to be inversely associated with the TH-BMD (ß=-0.092, p=0.083). Compared with subjects in the lowest S1P tertile, those in the highest S1P tertile had a significantly lower TBS (p=0.032) and BMD at femur (p=0.004-0.036). These findings indicated that a high S1P level in postmenopausal women was inversely associated with the both bone mass and microarchitecture, reflecting the compromised bone strength.

High Circulating Sphingosine 1-Phosphate is a Risk Factor for Osteoporotic Fracture Independent of Fracture Risk Assessment Tool.

Circulating sphingosine 1-phosphate (S1P) levels may be a biomarker for osteoporotic fracture (OF). This study assessed whether the addition of S1P levels to the fracture risk assessment tool (FRAX) could improve predictability of OF risk. Plasma S1P concentrations and FRAX variables were measured in 81 subjects with and 341 subjects without OF. S1P levels were higher in subjects with than those without OF (3.11 ± 0.13 µmol/L vs. 2.65 ± 0.61 µmol/L, P = 0.001). Higher S1P levels were associated with a higher likelihood of OF (odds ratio [OR] = 1.33, 95% confidence interval [CI] = 1.05-1.68), even after adjusting for FRAX probabilities. Compared with the lowest S1P tertile, subjects in the middle (OR = 3.37, 95% CI = 1.58-7.22) and highest (OR = 3.65, 95% CI = 1.66-8.03) S1P tertiles had higher rates of OF after adjustment. The addition of S1P levels to FRAX probabilities improved the area under the receiver-operating characteristics curve (AUC) for OF, from 0.708 to 0.769 (P = 0.013), as well as enhancing category-free net reclassification improvement (NRI = 0.504, 95% CI = 0.271-0.737, P < 0.001) and integrated discrimination improvement (IDI = 0.044, 95% CI = 0.022-0.065, P < 0.001). Adding S1P levels to FRAX probabilities especially in 222 subjects with osteopenia having a FRAX probability of 3.66-20.0% markedly improved the AUC for OF from 0.630 to 0.741 (P = 0.012), as well as significantly enhancing category-free NRI (0.571, 95% CI = 0.221-0.922, P = 0.001) and IDI (0.060, 95% CI = 0.023-0.097, P = 0.002). S1P is a consistent and significant risk factor of OF independent of FRAX, especially in subjects with osteopenia and low FRAX probability.

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.

The Association of Vitamin D With Femoral Neck Strength: An Additional Evidence of Vitamin D on Bone Health.

CONTEXT: Although bone mineral density (BMD) is a strong predictor of fracture risk, additional parameters, such as bone strength, are needed to predict future fracture risk because of the low sensitivity of BMD for predicting fracture risk. OBJECTIVE: The objective was to study the association of vitamin D with femoral neck (FN) strength. DESIGN AND SETTING: This was a population-based, cross-sectional study from Korea National Health and Nutrition Examination Surveys. PARTICIPANTS: A total of 1209 Koreans (586 men and 623 women) aged ≥50 years participated. MAIN OUTCOME MEASURES: We calculated composite indices of FN strength, such as the compression strength index, bending strength index (BSI), and impact strength index, by combining BMD, body weight, and height with the femoral axis length and width, which were measured by dual-energy x-ray absorptiometry. RESULTS: Multiple regression analysis demonstrated that serum 25-hydroxyvitamin D [25(OH)D] levels were associated with compression strength index, BSI, and impact strength index in both genders. When women were categorized into four quartiles of 25(OH)D, FN BMD and composite indices (except for BSI) significantly increased from the lowest (Q1) to the highest quartile (Q4) (P for trend = .001-.004). In contrast, there is no significant association of quartiles with composite indices in men. When women were divided into two groups according to their serum 25(OH)D levels, the composite indices as well as the FN BMD were markedly higher in subjects with higher 25(OH)D levels (≥51.5 nmol/L). CONCLUSION: These findings provide the first clinical evidence that high serum 25(OH)D levels exhibit higher composite indices of FN strength in a dose-dependent manner, especially in 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.

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.

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.

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.

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.

Clinical risk factors for osteoporotic fracture: a population-based prospective cohort study in Korea.

Clinical risk factors (CRFs), either alone or in combination with bone mineral density, are used to determine the fracture risk for clinical assessment and to determine intervention thresholds. Because fracture risk is strongly affected by ethnicity and population-specific differences, we sought to identify Korean-specific CRFs for fracture, in combination with quantitative ultrasound (qUS) measurements of the radius and tibia. A total of 9351 subjects (4732 men and 4619 women) aged 40 to 69 years were followed for a mean of 46.3 +/- 2.2 months. We obtained CRF information using a standardized questionnaire and measured anthropometric variables. Speed of sound at the radius (SoSR) and tibia (SoST) were measured by qUS. Fracture events were recorded using a questionnaire, and a height-loss threshold was used as an indicator of vertebral fracture. Relative risks were calculated by Cox regression analysis. A total of 195 subjects (61 men and 134 women) suffered low-trauma fractures. Older age, lower body mass index (BMI), and previous fracture history were positively associated with fracture risk in both sexes. Decreased hip circumference, lack of regular exercise, higher alcohol intake, menopause, and osteoarthritis history were further independent CRFs for fracture in women. However, neither SoSR nor SoST was independently associated with fracture risk. In this study, we identified the major Korean-specific CRFs for fracture and found that smaller hip circumference was a novel risk factor. This information will allow optimal risk-assessment targeting Koreans for whom treatment would provide the greatest benefit.