In silico discovery of quinoxaline derivatives as novel LRP5/6-sclerostin interaction inhibitors.

The Wnt/ß-catenin signaling pathway is a key regulator of bone homeostasis. Sclerostin act as an extracellular inhibitor of canonical Wnt signaling through high-affinity binding to the Wnt co-receptor LRP5/6. Disruption of the interaction between LRP5/6 and sclerostin has been recognized as a therapeutic target for osteoporosis. We identified a quinoxaline moiety as a new small-molecule inhibitor of the LRP5/6-sclerostin interaction through pharmacophore-based virtual screening, docking simulations, and in vitro assays. Structure-activity relationship studies and binding mode hypotheses were used to optimize the scaffold and yield the compound BMD4503-2, which recovered the downregulated activity of the Wnt/ß-catenin signaling pathway by competitive binding to the LRP5/6-sclerostin complex. Overall, this study showed that the optimized structure-based drug design was a promising approach for the development of small-molecule inhibitors of the LRP5/6-sclerostin interaction. A novel scaffold offered considerable insights into the structural basis for binding to LRP5/6 and disruption of the sclerostin-mediated inhibition of Wnt signaling.

The systemic effects of sclerostin overexpression using ΦC31 integrase in mice.

Sclerostin, encoded by the Sost gene, is mainly produced by osteocytes in bone and antagonizes the Wnt/ß-catenin signaling pathway, which is a requisite for bone formation. Currently, human anti-sclerostin antibodies are being tested in phase III clinical trials. In addition, serum sclerostin levels are reported to be associated with bone mineral density and fracture risk in normal individuals; however, the correlation between serum sclerostin and bone mass remains controversial. To study the effects of the continuous exposure of exogenous sclerostin on bone, a ΦC31 integrase system, which has the characteristics of site-specificity and efficiency, was applied for the delivery of the Sost gene in this study. We injected Sost-attB plasmid with or without ΦC31 integrase plasmid into the mouse tail vein using a hydrodynamic-based method. The site-specific integration of the Sost gene into the mouse genome was confirmed by examining a pseudo-attP site on the hepatic genomic DNA. Sclerostin was expressed in the hepatocytes, secreted into the blood flow, and maintained at high concentrations in the mice with both Sost-attB plasmid and ΦC31 integrase plasmid injections, which was observed by serial measurement. Moreover, the mice with long-term high levels of serum sclerostin showed trabecular bone loss on micro-CT analysis. Peripheral B cell populations were not affected. Our results suggested that sclerostin could be expressed in the liver and sustained successfully at high levels in the blood by using the ΦC31 integrase system, leading to trabecular bone loss. These findings may help to further ascertain the effects of sclerostin introduced exogenously on the skeleton.

Z-score discordance and contributing factors in healthy premenopausal women with low bone mineral density: the Korean National Health and Nutrition Examination Survey 2008-9.

The premenopausal period is important for bone health and prevention of future fractures, but measuring bone mineral density (BMD) at only one site may not be sufficient to determine therapeutic strategies for low BMD in premenopausal women due to the presence of Z-score discordance. In this study, we investigated Z-score discordance in addition to contributing factors of idiopathic low BMD in healthy premenopausal Korean women. We studied 3003 premenopausal women aged 18-50 years, without secondary causes for low BMD and history of fragility fracture, who had participated in the Fourth Korean National Health and Nutrition Examination Surveys (2008-2009). Low body mass index (BMI), low vitamin D level, and low body muscle mass were associated with low BMD even in premenopausal women. Risk factors differed depending on the anatomic site. Low BMI and low vitamin D level were risk factors for low femoral neck BMD (FN-BMD), but not for low lumbar spine BMD (LS-BMD). Only total muscle mass had a slight effect on low LS-BMD. Z-score discordance was much higher than expected, in 75 and 73.8 % of the low LS-BMD and low FN-BMD groups, respectively. Our findings suggest the need to consider BMD discordance in premenopausal women and also to provide information on correctable factors affecting low BMD in younger populations. Long-term follow-up is needed to evaluate the possible effect of Z-score discordance on the prognosis of osteoporosis and subsequent fracture risk.

The transcription factor protein Sox11 enhances early osteoblast differentiation by facilitating proliferation and the survival of mesenchymal and osteoblast progenitors.

Sox11 deletion mice are known to exhibit developmental defects of craniofacial skeletal malformations, asplenia, and hypoplasia of the lung, stomach, and pancreas. Despite the importance of Sox11 in the developing skeleton, the role of Sox11 in osteogenesis has not been studied yet. In this study, we identified that Sox11 is an important transcription factor for regulating the proliferation and survival of osteoblast precursor cells as well as the self-renewal potency of mesenchymal progenitor cells via up-regulation of Tead2. Furthermore, Sox11 also plays an important role in the segregation of functional osteoblast lineage progenitors from osteochondrogenic progenitors. Facilitation of osteoblast differentiation from mesenchymal cells was achieved by enhanced expression of the osteoblast lineage specific transcription factors Runx2 and Osterix. Morpholino-targeted disruption of Sox11 in zebrafish impaired organogenesis, including the bones, which were under mineralized. These results indicated that Sox11 plays a crucial role in the proliferation and survival of mesenchymal and osteoblast precursors by Tead2, and osteogenic differentiation by regulating Runx2 and Osterix.

The anabolic effect of teriparatide is undermined by low levels of high-density lipoprotein cholesterol.

Intermittent parathyroid hormone (PTH) administration has a potent ability to increase bone mass, regardless of underlying conditions or species. A recent study using LDLR(-/-) mice showed that the anabolic effect of PTH was blunted by hyperlipidemia, whereas PTH anabolism was rescued by enhancement of high-density lipoprotein cholesterol (HDL-C) function. We conducted a retrospective longitudinal study to determine whether lipid profiles also affect the anabolic effect of intermittent PTH treatment in humans. Fifty-two patients (8 males and 44 females, ages 38-85 years) with severe osteoporosis who had been treated with teriparatide (TPTD, recombinant human PTH(1-34) for 12 months were studied at Severance Hospital, Yonsei University. C-telopeptide (CTX) and osteocalcin (OCN) were measured at 0, 3, and 12 months; and total cholesterol, triglycerides, and HDL-C were measured at baseline. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry at 0 and 12 months. Lumbar spine BMD increased significantly after 12 months of treatment with TPTD (10.0 ± 9.3%, p < 0.001). Initial 3-month changes in CTX and OCN levels revealed positive correlations with the increase in lumbar BMD (r = 0.546, p = 0.001 and r = 0.500, p = 0.006, respectively). Moreover, percentage change in lumbar BMD at 12 months showed a negative correlation with baseline total cholesterol (r = -0.438, p = 0.009) and a positive correlation with HDL-C (r = 0.498, p = 0.016). A smaller 3-month increase in OCN and a lower HDL-C level at baseline were associated with a smaller lumbar BMD increase after TPTD treatment, even after adjustment for age, sex, and other confounding factors (ß = 0.462, p = 0.031 for ΔOCN and ß = 0.670, p = 0.004 for HDL-C). Plasma levels of lipids, especially HDL-C, seem to be associated with the extent of osteoanabolic effects of TPTD in humans.

Effect of liver dysfunction on circulating sclerostin.

Sclerostin is a Wnt inhibitor produced specifically by osteocytes. It decreases bone formation by repressing osteoblast differentiation and proliferation. Whether circulating sclerostin level is affected by liver function is not currently clear. The aim of the study was to evaluate this relationship. Our cross-sectional study included 47 patients with liver cirrhosis and 50 healthy controls. Serum sclerostin level was analyzed by ELISA. Serum sclerostin levels were significantly higher in patients with cirrhosis than in controls (50.8 ± 38.2 vs. 35.1 ± 8.8 pmol/L, p = 0.008). After further adjustment for age, sex, body mass index, serum creatinine, and presence of diabetes, cirrhosis patients had higher sclerostin than controls. Subgroup analysis found that patients with Child-Pugh class B or C had higher sclerostin levels than patients with class A or controls after adjusting for multiple confounding factors. Multiple regression analysis showed that gender (p = 0.022), presence of diabetes (p < 0.001), albumin (p = 0.010), and serum creatinine (p = 0.037) were independent factors for circulating sclerostin level. Circulating sclerostin was higher in patients with advanced liver cirrhosis than in healthy controls or patients with early liver cirrhosis. The elevated sclerostin levels clearly correlated with markers of liver dysfunction such as albumin. The relationship between circulating sclerostin and liver function indicates a possible role of the liver in sclerostin metabolism.

High prevalence of spine­femur bone mineral density discordance and comparison of vertebral fracture risk assessment using femoral neck and lumbar spine bone density in Korean patients.

The aim of this study was to evaluate the prevalence of spine­femur discordance, and to compare the effectiveness of femoral neck (FN) and lumbar spine (LS) bone mineral density (BMD) for estimation of the risk of vertebral fractures. Women who were evaluated with dual energy X-ray absorptiometry between January 2001 and December 2005 were enrolled in this study. Vertebral fracture risk was calculated using initial FN and LS BMD. The follow-up vertebral X-rays from all subjects were reviewed, and the calculated estimated risk using the Fracture Risk Assessment Tool (FRAX(®)) was compared with the actual prevalence of vertebral fractures during the follow-up period. Among a total of 443 women with a mean age of 58.5 years, 130 women (29.3 %) demonstrated femur­spine discordance (i.e., a difference between FN and LS BMD of [1 SD). Most subjects having discordance showed lower LS BMD (73.1 %) compared to FN BMD. During the mean 7-year follow-up period, 12 (2.7 %) vertebral fractures occurred. In cases with high estimated fracture risk ([20 % for estimated fracture risk), using LSBMD significantly reflected the actual vertebral fracture in total subjects [odds ratio (OR) 19.29, 95 % confidence interval (CI) 4.21­88.46], in subjects with spine­femur discordance (OR 16.00, 95 % CI 1.91­134.16), and in subjects with spine­femur discordance having lower LSBMD (OR 20.67, 95 % CI 1.63­262.71). In comparison, the estimated risk using FN BMD did not reflect the actual occurrence of vertebral fractures. In conclusion, a significant number of Korean subjects exhibited spine­femur discordance, and LS BMD might be more appropriate for estimation of vertebral fracture risk.

The association between bone mineral density and metabolic syndrome: a Korean population-based study.

This study was conducted to investigate the association between the metabolic syndrome (MS), which includes a cluster of major risk factors for cardiovascular diseases, and bone mineral density (BMD) from a population-based study. This cross-sectional study was based on a nationwide representative survey data from the Korean National Health and Nutrition Examination Survey (KNHANES) 2008. A total of 3,207 subjects were included from the KNHANES 2008 and composed of men (mean age 48.4 years), premenopausal women (mean age 36.5 years) and postmenopausal women (mean age 64.8 years). The MS was identified according to the new criteria from a joint scientific statement endorsed by major organizations including the National Heart, Lung, and Blood Institute. The mean age of study participants was significantly different according to MS status (58.2 years in the MS group vs. 45.7 years in the non-MS group, P < 0.001). The association between MS and BMD at the lumbar spine and proximal femur was analyzed with adjustment for potential confounders. Although the adjusted BMD at all skeletal sites was not significantly different between participants with and without MS, an increased number of MS components was associated with low adjusted femoral neck (FN) BMD only in men (P = 0.01). After adjusting confounding factors, the triglyceride component of MS was related to low FN BMD in men, but to high BMD at all of the skeletal sites measured in postmenopausal women. The glucose component of MS showed an association with high adjusted BMD at total hip in men. Men with MS had significantly higher odds for pooled osteopenia and osteoporosis (odds ratio: 1.49, 95 % confidence interval: 1.04-2.14). In conclusion, low BMD is associated with MS in Korean men, and the association between the MS component and the BMD is different according to gender.

The prevalence and risk factors of vertebral fractures in Korean patients with type 2 diabetes.

Although type 2 diabetes mellitus (T2DM) has been associated with an increase in fracture risk, there is no data regarding the prevalence of vertebral fractures or its risk factors for patients with T2DM in Korea. In this cross-sectional study, we recruited postmenopausal women with T2DM from 24 tertiary hospital diabetes clinics in Korea. Prevalent vertebral fractures were identified on lateral spinal radiographs of thoracolumbar vertebrae by vertebral morphometry. Demographic and biochemical characteristics related to diabetes were obtained, and bone mineral density of the lumbar spine and femoral neck, which was available in 752 (33.6 %) and 675 (30.1 %) patients, respectively, was also analyzed. Of the 2239 subjects recruited (mean age 63.9 years), a total of 970 (43.3 %) subjects had vertebral fractures. In the bivariate analysis, history of fragility fractures after 50 years of age, microalbuminuria, presence of cardiovascular disease (myocardial infarction, angina, cerebrovascular complications of cardiovascular disease), and presence of osteoporosis at the total hip were significantly associated with the presence of vertebral fractures, after adjusting for age. In the multivariate analysis, the presence of cardiovascular diseases in addition to advancing age and history of fragility fractures was significantly associated with increased odds of vertebral fractures. Vertebral fractures were highly prevalent in postmenopausal women with T2DM in this study conducted in Korea, and the presence of cardiovascular disease, in addition to older age and history of fragility fractures, was significantly associated with the presence of vertebral fractures.

Dissimilarity of femur aging in men and women from a Nationwide Survey in Korea (KNHANES IV).

In light of the differences in hip fracture rates between men and women of different ages, age-related changes in bone structure that lead to bone fragility might differ depending on both age and gender. To investigate age-related bone loss and geometric deterioration of the femur, hip scans of 1,504 men and 2,076 women aged 19-92 years acquired during the Fourth Korean National Health and Nutrition Examination Survey (KNHANES IV) using dual-energy X-ray absorptiometry (DXA) were analyzed with a structural analysis program. Cross-sectional area and cortical thickness with bone mineral density in men started to decline from the third decade and continued to decline at a constant rate. However, in women, these parameters remained nearly constant until the fifth decade and then declined at a more rapid rate than that seen in men. Consequently, changes in the buckling ratio, earlier onset, and continuation of increase over the lifetime were observed in men. A relatively later onset with a greater acceleration with aging was observed in women. Taken together, there were obvious gender and age differences in structural trends with age. Bone aging, i.e., bone loss and geometric deterioration, actually begins at a young age, especially in men, and osteoporosis prevention strategies should target not only the elderly but also younger individuals.

Efficacy of a combined alendronate and calcitriol agent (Maxmarvil®) in Korean postmenopausal women with early breast cancer receiving aromatase inhibitor: a double-blind, randomized, placebo-controlled study.

The use of aromatase inhibitor (AI) in postmenopausal women with hormone receptor (HR)-positive early breast cancer (EBC) produces a deleterious effect on bone mass and an increase in fractures. Several studies using intravenous bisphosphonates have shown effective management of AI-induced bone loss. To determine whether a lower dosage in oral form combined with calcitriol can effectively manage AI-induced bone loss, we performed a randomized, double-blind, prospective, placebo-controlled 24-week trial with a combination of alendronate and 0.5-µg of calcitriol daily to HR-positive EBC patients. A total of 98 Korean postmenopausal women with HR-positive EBC who received daily AI, calcium and vitamin D were randomly assigned to 5-mg of alendronate and 0.5-µg of calcitriol (Maxmarvil®) or placebo groups. The bone mineral density (BMD) and turnover markers were measured. At week 24, the difference in lumbar BMD between the groups was 3.0% (p < 0.005). The increase in C-telopeptide after 24 weeks was significantly less in the Maxmarvil group compared to that in the placebo group (35.2 ± 17.5% vs. 109.8 ± 28.6%, p < 0.05). Our study demonstrates that a combination of 5-mg alendronate and 0.5-µg calcitriol is effective to prevent bone loss due to AI in Korean postmenopausal women with EBC.

Ultraviolet B activated 1,25(OH)(2)D affects the level of fibroblast growth factor-23 in human.

Fibroblast growth factor 23 (FGF-23) is known as a phosphaturic factor regulating phosphate homeostasis. Several studies suggest that dietary phosphate, serum phosphate and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] are candidate regulators of FGF-23. While the human studies, which modulated the dietary or serum phosphate showed in rather controversial results, manipulation of the active vitamin D definitely affected FGF-23 in animals. This study was conducted to elucidate the relationship between active vitamin D directly stimulated by ultraviolet B (UVB) exposure and FGF-23 level in human. Ten healthy young adults were recruited to get the UVB exposure thrice a week at sub-minimal erythemal dose with gradual increment by 10% only for 4 weeks. Serum calcium, phosphate, mineral-related hormones and bone turnover markers were analyzed before and after the UVB exposure every 4 week for 12 whole weeks. Twenty five-hydroxyvitamin D [25(OH)D] increased by 115% (19.8 ng/mL to 40.5 ng/mL, p < 0.001) after 4 weeks of UVB exposure. While 1,25(OH)(2)D increased by 75% (49.9 pg/mL to 64.4 pg/mL, p < 0.001) then both level decreased after 4 weeks of withdrawal. C-telopeptide peaked at 2nd week then decreased, while osteocalcin increased gradually. FGF-23 started to increase from the 4th week of UVB exposure then significantly at the 4th week after withdrawal of UVB (27.8 pg/mL to 41.4 pg/mL, p < 0.05). UVB exposure effectively increased 1,25(OH)(2)D with delayed stimulatory effect on FGF-23. This result could support the regulatory loop of 1,25(OH)(2)D and FGF-23 in human, FGF-23 regulation by 1,25(OH)(2)D.

Impact of serum calcium and phosphate on coronary atherosclerosis detected by cardiac computed tomography.

AIMS: High calcium (Ca), phosphate (P), and Ca-P product (CPP) are associated with cardiovascular disease in patients with chronic kidney disease. Whether this relationship persists in individuals with normal kidney function is not yet elucidated. We explored the relationship of serum Ca, P, and CPP to coronary atherosclerosis assessed by cardiac computed tomography angiography (cCTA) in participants with normal kidney function. METHODS AND RESULTS: This study included 7553 participants (52 ± 10 years, male 57%) with near-normal kidney function (estimated glomerular filtration rate > 60 mL/min/1.73 m2) who underwent cCTA. The relationship of Ca, P, and CPP to coronary atherosclerosis [coronary artery Ca score (CACS) >100 and the presence of coronary artery disease (CAD)] was evaluated. Higher Ca, P, and CPP were significantly associated with CACS > 100 continuously [adjusted odds ratio (OR) per mg/dL: Ca 1.21, P = 0.026; P 1.29, P < 0.001; CPP 1.03, P < 0.001]. However, they correlate only weakly with the presence of CAD (OR: Ca 1.17, P = 0.001; P 1.05, P = 0.173; CPP 1.01, P = 0.034). This discrepancy was because calcified or mixed plaque and non-calcified plaque (NCP) were included in CAD. A significant relationship was demonstrated between calcified or mixed plaque and Ca, P, and CPP (OR: Ca 1.20, P = 0.001; P 1.13, P = 0.003; CPP 1.02, P = 0.001), but not NCP. CONCLUSION: Elevated serum levels of Ca, P, and CPP are significantly associated with the presence of calcified coronary atherosclerotic plaque. It is unclear if there is a causal relationship. This relationship is thought to contribute to vascular calcification, but is less closely associated with NCP.

Aortic calcification and bone metabolism: the relationship between aortic calcification, BMD, vertebral fracture, 25-hydroxyvitamin D, and osteocalcin.

The aim of this study was to investigate the relationship between aortic calcification (AC) and low bone mineral density (BMD), 25(OH)D, C-terminal telopeptide (CTx), and osteocalcin levels in Asian women. We also tried to find the association between AC and the risk of vertebral fracture. We included 769 patients in this study. All patients underwent QCT. Aortic calcium score (ACS) was quantified by the Agatston scoring method. Spinal fracture was defined by lumbar spine radiography. Among 769 subjects, 96 had at least one vertebral fracture and 345 had AC. ACS positively correlated with age. Osteocalcin, CTx, 25(OH)D, total-hip trabecular BMD (tBMD), femoral neck tBMD, and vertebral tBMD were inversely related with ACS. However, cortical BMD (cBMD) did not correlate with ACS. Among these parameters, only osteocalcin significantly correlated with ACS, even after adjusting for age. We divided the subjects into two groups based on the presence of AC to determine the association between AC and vertebral fracture. Multivariate logistic regression analysis showed that age, tBMD of each site, and AC were associated with vertebral fractures. After adjusting for confounding factors, patients with AC had more than a threefold increased risk of vertebral fracture (OR = 3.29-3.57, P < 0.05 according to site). This study suggests that high ACS is related to low tBMD but not cBMD. Furthermore, our findings indicate that this relationship is definitely age-dependent. Finally, we found that AC is significantly associated with the prevalence of vertebral fracture in Asian women.

Effect of teriparatide on pregnancy and lactation-associated osteoporosis with multiple vertebral fractures.

Pregnancy and lactation-associated osteoporosis (PLO) is very rare, but it can cause severe vertebral compression fractures with disabling back pain. PLO patients have commonly been treated with antiresorptive agents against high bone turnover. There are, however, some concerns regarding the use of bisphosphonates: (1) PLO occurs during the first pregnancy with a high possibility of recurrence during the second pregnancy, (2) long-term outcomes of bisphosphonates in PLO are lacking, and (3) there is a possibility of bisphosphonates accumulated in the bones crossing the placenta. Therefore, alternative therapies must be considered. We analyzed the effect of teriparatide (TPTD), the human recombinant parathyroid hormone (1-34), for 18 months in three women with PLO. Multiple vertebral fractures with severe back pain appeared within 6 months after their first childbirth. Two of them had a family history of osteoporosis. Lactation was discontinued immediately after diagnosis of PLO. Calcium carbonate, cholecalciferol, and TPTD were prescribed. The back pain immediately resolved. Bone mineral density (BMD) increased by 14.5-25.0% (mean 19.5%) at the lumbar spine and by 9.5-16.7% (mean 13.1%) at the femoral neck, after 18 months of treatment. The final Z scores in these PLO patients were nearly normalized. Two women had a second baby without any complication. BMD significantly improved after 18 months of treatment with TPTD without further fractures. In conclusion, TPTD should be considered to avoid long-term morbidity in young patients with PLO and is highly encouraged for use in PLO patients with multiple vertebral fractures.

Low serum vitamin D is associated with high risk of diabetes in Korean adults.

Vitamin D may play a role in glucose metabolism. A low vitamin D level has been associated with increased risk of diabetes mellitus, but the association has not been confirmed in Asians. Our objective was to examine the association of serum 25-hydroxyvitamin D [25(OH)D] levels with insulin resistance and diabetes mellitus in Korean adults based on a large population-based survey. Cross-sectional analyses were carried out on 5787 Korean adults (2453 men and 3334 women) who were 20 y or older and participated in the Fourth Korea NHANES conducted in 2008. Diabetes mellitus was defined as fasting plasma glucose ≥7 mmol/L or current use of oral hypoglycemic agents or insulin. Insulin resistance was estimated by homeostatic model assessment for insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI). Compared to individuals with a sufficient serum 25(OH)D concentration ≥75 nmol/L, the OR (95% CI) for diabetes mellitus were 1.73 (1.09-2.74), 1.30 (0.91-1.84), and 1.40 (0.99-1.98) for serum 25(OH)D concentrations <25, 25 to <50, and 50 to <75 nmol/L, respectively, after multiple adjustments (P-trend < 0.0001). Furthermore, the serum 25(OH)D level was inversely associated with HOMA-IR (ß = -0.061; P = 0.001) and positively associated with QUICKI (ß = 0.059; P = 0.001) in overweight or obese participants. In conclusion, a low serum vitamin D concentration is associated with a high risk of diabetes mellitus in Korean adults and the concentration is inversely associated with insulin resistance in those who are overweight or obese.

Characteristics of body fat, body fat percentage and other body composition for Koreans from KNHANES IV.

Accurate measurement of fat mass has become increasingly important with the increasing incidence of obesity. We assessed fat and muscle mass of Koreans with the Korea National Health and Nutrition Examination Survey IV (KNHANES IV). We studied 10,456 subjects (aged 20 to 85 yr; 4,476 men, 5,980 women). Fat and muscle mass were measured by dual-energy x-ray absorptiometry. Reference values of body compositions were obtained using the LMS method. The fat mass index (FMI, body fat mass/height(2); kg/m(2)) of Korean men did not correlate with age (P = 0.452), but those of Korean women (P < 0.001) did. The ratio of percentage of fat in the trunk and legs was positively related with age in both the genders. The appendicular lean mass/height(2) (kg/m(2)) of Korean men was negatively related to age (P < 0.001). In women, this ratio increased with age (P < 0.001). When we defined obesity according to the FMI classification, the rates of obesity were 6.1% (FMI > 9 kg/m(2)) in men and 2.7% (FMI > 13 kg/m(2)) in women. It is concluded that the muscle mass decreases and obesity increases with aging in Korean men, whereas both fat mass and obesity increase with aging in Korean women.

Romosozumab in Postmenopausal Korean Women with Osteoporosis: A Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study.

BACKGROUND: This phase 3 study evaluated the efficacy and safety of 6-month treatment with romosozumab in Korean postmenopausal women with osteoporosis. METHODS: Sixty-seven postmenopausal women with osteoporosis (bone mineral density [BMD] T-scores ≤-2.5 at the lumbar spine, total hip, or femoral neck) were randomized (1:1) to receive monthly subcutaneous injections of romosozumab (210 mg; n=34) or placebo (n=33) for 6 months. RESULTS: At month 6, the difference in the least square (LS) mean percent change from baseline in lumbar spine BMD (primary efficacy endpoint) between the romosozumab (9.5%) and placebo (-0.1%) groups was significant (9.6%; 95% confidence interval, 7.6 to 11.5; P<0.001). The difference in the LS mean percent change from baseline was also significant for total hip and femoral neck BMD (secondary efficacy endpoints). After treatment with romosozumab, the percent change from baseline in procollagen type 1 N-terminal propeptide transiently increased at months 1 and 3, while that in C-terminal telopeptide of type 1 collagen showed a sustained decrease. No events of cancer, hypocalcemia, injection site reaction, positively adjudicated atypical femoral fracture or osteonecrosis of the jaw, or positively adjudicated serious cardiovascular adverse events were observed. At month 9, 17.6% and 2.9% of patients in the romosozumab group developed binding and neutralizing antibodies, respectively. CONCLUSION: Treatment with romosozumab for 6 months was well tolerated and significantly increased lumbar spine, total hip, and femoral neck BMD compared with placebo in Korean postmenopausal women with osteoporosis (ClinicalTrials.gov identifier NCT02791516).

Relationship between visceral adiposity and bone mineral density in Korean adults.

The objective of the study was to investigate the relationship between visceral and subcutaneous adiposity measured by computed tomography and bone mineral density (BMD) and to identify the metabolic factors associated with BMD. We studied 461 subjects recruited from the health-care center at Severance Hospital, Yonsei University College of Medicine. Multivariate regression analyses were conducted to examine the cross-sectional associations between body composition-related or metabolic parameters and BMD. After adjusting for body weight and other confounders, visceral fat area had an inverse association with BMD in men (beta = -0.133, P = 0.049 for lumbar spine; beta = -0.135, P = 0.037 for femoral neck; beta = -0.179, P = 0.005 for total hip) and women (beta = -0.424, P < 0.001 for lumbar spine; beta = -0.302, P = 0.005 for femoral neck; beta = -0.274, P = 0.014 for total hip). However, the subcutaneous fat area showed no statistically significant relationship with BMD at most sites. Among the metabolic parameters, HDL cholesterol was positively associated with BMD, while LDL cholesterol was negatively associated with BMD in men. In women, total and LDL cholesterol were negatively associated with BMD at the lumbar spine. We conclude that visceral adiposity is inversely associated with BMD after adjusting for confounders and that metabolic factors may partly contribute to this inverse relation.

Biopsy of thyroid nodules: comparison of three sets of guidelines.

OBJECTIVE: The purpose of this study was to compare the results with three sets of guidelines for fine-needle aspiration biopsy of thyroid nodules. MATERIALS AND METHODS: A total of 1,398 nodules confirmed with fine-needle aspiration biopsy or surgery were included in the study. We compared the diagnostic value of three sets of guidelines for ultrasound findings that should lead to fine-needle aspiration biopsy of a nodule. According to the Kim criteria, a nodule should have at least one of the following findings: marked hypoechogenicity, irregular or microlobulated margins, microcalcifications, or length greater than width. According to the Society of Radiologists in Ultrasound, biopsy should be performed on a nodule 1 cm in diameter or larger with microcalcifications, 1.5 cm in diameter or larger that is solid or has coarse calcifications, and 2 cm in diameter or larger that has mixed solid and cystic components, and a nodule that has undergone substantial growth or is associated with abnormal cervical lymph nodes. According to the American Association of Clinical Endocrinologists, a hypoechoic nodule with at least one additional feature, such as irregular margins, length greater than width, and microcalcifications, should be biopsied. RESULTS: For all nodules, the diagnostic accuracy of the Kim (area under the receiver operating characteristic curve [Az]=0.868) and American Association of Clinical Endocrinologists (Az=0.850) criteria was greater than that of the Society of Radiologists in Ultrasound criteria (Az=0.551). The number of nodules for which fine-needle aspiration biopsy was recommended (25.6%) was smallest with use of the American Association of Clinical Endocrinologists criteria, and the smallest number (7.3%) of missed malignant lesions was associated with use of the Kim criteria. The results did not change for the subgroup with nodules larger than 1 cm. CONCLUSION: The Kim and American Association of Clinical Endocrinologists criteria are more accurate than the Society of Radiologists in Ultrasound criteria. The American Association of Clinical Endocrinologists guidelines are recommended for achieving high specificity, and the Kim criteria may be chosen for higher sensitivity.