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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 (β = -0.250, p = 0.006) and positively associated with pFM (β = 0.272, p = 0.004), and tended to be inversely associated with FN-BMD (β = - 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.

Despite many studies about local and systemic interactions between bone and muscle, the more dominant interaction remains unclear. We aimed to compare the association of skeletal muscle mass with bone mineral density (BMD) at the femur, which seemed more likely affected by local interaction, and the association of skeletal muscle mass with BMD at the lumbar spine (LS-BMD) and the trabecular bone score (TBS), which seemed more likely affected by systemic interaction. In 279 women, we measured the femoral neck BMD (FN-BMD), total hip BMD (TH-BMD), LS-BMD, and TBS. Appendicular skeletal muscle mass (ASM), lean mass (LM), and other LM (OLM; remaining LM excluding ASM) were measured using bioelectrical impedance analysis. ASM (β = 0.008–0.014, p

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

As populations continue to age worldwide, sarcopenic obesity has heightened interest due to its medical importance. Although much evidence now indicates that n-3 fatty acids (FAs) may have beneficial effects on body composition including fat and muscle, their exact mechanisms have not yet been elucidated. Because free FA receptor 4 (FFA4) has been reported to be a receptor for n-3 FAs, we hypothesized that the protective role of n-3 FAs on body composition could be mediated by FFA4. To test this possibility, we generated mice overexpressing n-3 FAs but lacking FFA4 by crossing fat-1 transgenic (fat-1 Tg+) and FFA4 knockout (Ffar4 -/-) mice. Because fat-1 Tg+ mice, in which n-6 is endogenously converted into n-3 FAs, contain high n-3 FA levels, they could be a good animal model for studying the effects of n-3 FAs in vivo. Male and female littermates were included in high-fat-diet- (HFD) and ovariectomy-induced models, respectively. In the HFD model, male fat-1 Tg+ mice had a lower percentage of fat mass and a higher percentage of lean mass than their wild-type littermates only when they had the Ffar4 +/+ not the Ffar4 -/- background. Female fat-1 Tg+ mice showed less increase of fat mass percentage and less decrease of lean mass percentage after ovariectomy than wild-type littermates. However, these effects on body composition were attenuated in the Ffar4 -/- background. Taken together, our results indicate that the beneficial effects of n-3 FAs on body composition were mediated by FFA4 and thus suggest that FFA4 may be a potential therapeutic target for modulating sarcopenic obesity.

Although sclerostin (SOST) and Dickkopf-related protein 1 (DKK1) are major regulators in bone metabolism, their associations with osteoporotic fracture (OF) in Asians are inconclusive. Furthermore, there have been no clinical studies separately considering non-vertebral and vertebral fractures in terms of the blood levels of SOST and DKK1. Among 513 consecutive postmenopausal Korean women, we identified 103 cases defined as subjects with OF (i.e., non-vertebral and/or vertebral fractures). The controls were randomly selected from the remaining 410 subjects and matched 1:1 to cases according to both age and body mass index. Non-vertebral and morphological vertebral fractures were identified by an interviewer-assisted questionnaire and lateral thoracolumbar radiographs, respectively. Bone mineral density (BMD) and plasma levels of SOST and DKK1 were measured. Plasma SOST levels were lower in subjects with OF than in the control group. Each standard deviation decrement of plasma SOST concentration was associated with a multivariable-adjusted odds ratio of 1.77 for any prevalent OF type. The odds for OF was 2.97-fold higher in subjects in the lowest SOST tertile compared with subjects in the highest SOST tertile. These associations remained significant when the non-vertebral and vertebral fractures were analyzed separately. However, prevalent OF was not associated with plasma DKK1 levels, regardless of the type of fracture and the adjustment model employed. Consistently, plasma SOST levels were positively related with BMD values at all measured skeletal sites, although this was not observed for DKK1. Circulating SOST but not DKK1 may be a potential biomarker for predicting bone health in Asians.

Despite the beneficial role and plausible mechanism of vitamin D on skeletal muscle in animal studies, its association in humans remains a controversial issue due to inconsistent clinical results, especially in older Asians. This was a population-based, cross-sectional study from the Korea National Health and Nutrition Examination Surveys, which enrolled 354 men aged ≥ 50 years and 328 postmenopausal women. Hand grip strength (HGS) was measured using a digital grip strength dynamometer. Low muscle strength was defined based on Korean-specific cut-off point of HGS. Serum 25-hydroxyvitamin D [25(OH)D] levels were 19.4 ± 6.7 and 17.1 ± 7.2 ng/mL in men and women, respectively. Among covariates including age, body mass index, lifestyle factors, and protein intake, age was inversely associated with HGS in both men and women, and protein intake (g/day) was positively associated with HGS only in men. However, the independent correlation between serum 25(OH)D and HGS was not observed, regardless of gender. When subjects were divided into three groups [deficient (25(OH)D

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.

Parkinson's disease (PD) patients have been reported to have lower bone mineral density (BMD) and higher fracture risk than individuals without PD. We assessed the association between hyperhomocysteinemia due to levodopa intake and BMD in PD patients. We measured serum homocysteine (Hcy) concentrations and BMD in the proximal femur and lumbar spine of PD patients aged 55 years or older (n = 95) and three age-/gender-matched control subjects (n = 285). The prevalence of osteoporosis was higher in both men (2.5-fold) and women (1.7-fold) with PD than in controls, and adjusted odds ratios for osteoporosis were 3.57 (95% confidence interval [CI], 1.25-10.20) for men and 2.54 for women (95% CI, 1.31-4.93) with PD. Serum Hcy concentrations were significantly higher in PD patients (median = 13.0 micromol/l) than controls (median = 11.5 micromol/l) (P = 0.005). Serum Hcy concentrations were independently associated with BMD values at all proximal femur sites in all subjects (P = 0.005 to 0.012). In PD patients, higher serum Hcy concentrations were independently associated with higher fracture risk (P = 0.029). PD patients taking higher doses of levodopa had significantly higher serum Hcy concentrations (P = 0.013), and greater levodopa intake was associated with lower BMD values in some areas (P = 0.008 to 0.029). In conclusion, these findings indicate that hyperhomocysteinemia due to levodopa intake may be one additional risk factor for osteoporosis and fracture in PD patients. Reducing Hcy may be a therapeutic modality for treating osteoporosis in PD patients taking levodopa.

Interleukin-15 (IL-15) has been suggested to participate in bone metabolism by stimulating osteoclast differentiation and mediating inflammatory bone loss. This study investigated the effect of IL-15 gene polymorphisms on the bone mineral density (BMD) and bone fracture rates of postmenopausal women. Sequencing of the IL-15 gene in 24 Koreans revealed 16 single-nucleotide polymorphisms (SNPs), of which five were selected for further study. Postmenopausal Korean women (n = 844) were genotyped for these SNPs, and their BMDs and risk of fractures were assessed. It was found that the +20A > G, +13467C > A, +13653A > T, and +13815A > T IL-15 gene polymorphisms were significantly associated with the BMD of the lumbar spine and femoral neck and that their effects were gene-dose dependent. BMD was reduced when the minor allele of +13467A and +13653T or the common allele of +20A and +13815A was present. Haplotype (ht) analyses revealed that ht1 (GCAT) and ht2 (AATA) were associated with BMD of the lumbar spine and femoral neck. However, there was no association between the risk of fracture and IL-15 SNPs or hts. These results suggest that the +20A > G, +13467C > A, +13653A > T, and +13815A > T SNPs in the IL-15 gene affect BMD and, thus, could be genetic markers of osteoporosis.

Osteoporosis is characterized by impaired osteoblastogenesis. Bone mineral density (BMD) is a major determinant of bone strength. RUNX2 is an osteoblast-specific transcription factor involved in osteoblast differentiation and ossification. To determine whether RUNX2 is associated with BMD in an ethnically distinct population, we investigated SNPs within the two RUNX2 promoters (P1 and P2) using the Illuminar GoldenGate system in 729 postmenopausal Korean women. Subjects bearing the minor homozygote genotype (CC) at the RUNX2 −1025 T > C SNP (rs7771980) located in P2 showed a significant association with reduced lumbar spine BMD (p = 0.02) and BMDs at proximal femur sites (trochanter, p = 0.05; total femur, p = 0.04) compared with subjects carrying the major homozygote genotype (TT) or the heterozygote genotype (TC), respectively. These results present an interesting genotype association complementary to the previously reported association of BMD with the RUNX2 −1025 T > C P2 SNP in Spanish and Australian cohorts. Therefore, we suggest that the RUNX2 P2 polymorphism (−1025 T > C) may be a useful genetic marker for bone metabolism and may play an important role in BMD in postmenopausal Korean women.

Previously, we showed that AMP-activated protein kinase (AMPK) negatively regulates receptor activator of nuclear factor-κB ligand-induced osteoclast formation in vitro. The present study investigated the effect of (-)-epigallocathechin-3-gallate (EGCG), an AMPK activator, on ovariectomy (OVX)-induced bone loss in mice. Female mice subjected to OVX were administered EGCG for 8 weeks. We measured total-body bone mineral density (BMD) before and after the operation at an interval of 4 weeks. We performed micro-computed tomography (micro-CT) of the tibia and bone histomorphometric examination of the femur. Western blot analysis was additionally performed, to detect levels of the phosphorylated and total forms of AMPK-α in calvarial extracts. EGCG prevented OVX-induced body weight gain. The OVX control did not show a significant increase in BMD values at baseline and after treatment, unlike the sham control. EGCG attenuated OVX-induced bone loss. Micro-CT experiments revealed that EGCG induced a significant increase in trabecular bone volume and trabecular number and a decrease in trabecular spacing compared to the OVX control. Histomorphometric analyses further showed that EGCG suppressed osteoclast surface and number. Phosphorylated AMPK expression was significantly elevated in bone following EGCG treatment. Our findings collectively indicate that EGCG decreases OVX-induced bone loss via inhibition of osteoclasts.

Cardiovascular disease and osteoporosis are thought to share common risk factors, and metabolic syndrome (MS) is composed of major risk factors for cardiovascular disease. This study was performed to investigate the relationships between specific MS components and bone mineral density (BMD). BMD was measured at the femoral neck of Korean men aged 40 years or more (n = 1,780) and postmenopausal women (n = 1,108) using dual-energy X-ray absorptiometry. We identified subjects with MS as defined by two criteria, International Diabetes Federation (IDF) and American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI). Body fat and lean mass were measured via bioimpedance analysis. The prevalence of MS was 19.8% and 7.7% in men and 20.8% and 11.6% in postmenopausal women according to the AHA/NHLBI definition and the IDF definition, respectively. After multivariate adjustment, femoral neck BMD was significantly lower in subjects with MS regardless of diagnostic criteria. BMD decreased as the number of MS components increased (P < 0.001 for trends in both sexes). Among MS components, waist circumference was the most important factor in this negative association. When multiple linear regression models were applied to each 5-kg weight stratum to test for a linear trend, waist circumference and fat mass were negatively associated with BMD and lean mass was positively associated with BMD in men but not in women. MS was associated with a lower BMD in Korean men and postmenopausal women, suggesting that visceral fat may lead to bone loss, especially in men.