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).

Determinants of Bone Mass and Insulin Resistance in Korean Postmenopausal Women: Muscle Area, Strength, or Composition?

PURPOSE: Muscle mass, strength, and composition determine muscle quantity and quality. However, data on muscle properties in relation to bone mass or insulin resistance are limited in Asian populations. This study aimed to investigate the relative importance of muscle measurements in regards to their relationship with lower bone mass and insulin resistance. MATERIALS AND METHODS: In this study, 192 postmenopausal women (age, 72.39±6.07 years) were enrolled. We measured muscle cross-sectional area (CSA) and attenuation at the gluteus maximus and quadriceps muscles through quantitative computed tomography. Muscle strength and physical performance were evaluated with the hand grip test and Short Physical Performance Battery (SPPB). Pearson correlation analysis and linear regression were performed to evaluate the relationship between muscle properties and homeostatic model assessment-insulin resistance (HOMA-IR) or bone mineral density (BMD). RESULTS: Muscle CSA, hand grip strength, and SPPB score held positive correlations with spine and hip BMDs, but not with insulin resistance. In contrast, muscle attenuation of the gluteus maximus or quadriceps was inversely related to HOMA-IR (r=-0.194, p=0.018 and r=-0.292, p<0.001, respectively), but not BMD. Compared with the control group, muscle CSA was significantly decreased in patients with osteoporosis; however, decreased muscle attenuation, indicating high fat infiltration, was found only in patients with diabetes. CONCLUSION: Muscle mass, strength, and physical performance were associated with low bone mass, and accumulation of intramuscular fat, a histological hallmark of persistently damaged muscles, may play a major role in the development of insulin resistance in Korean postmenopausal women.

The novel myokine irisin: clinical implications and potential role as a biomarker for sarcopenia in postmenopausal women.

PURPOSE: To clarify the association of circulating irisin with muscle, liver and bone, and to evaluate irisin as a biomarker for sarcopenia in postmenopausal women. METHODS: Quadriceps cross-sectional area (QcCSA), bone mineral density (BMD), liver attenuation (measured in Hounsfield units (HU)) were assessed using quantitative computed tomography in 153 postmenopausal women, mean age of 72.20 ± 5.96 years. Muscle strength and physical performance were evaluated by handgrip test and short physical performance battery, respectively. Serum irisin was measured by an enzyme-linked immunosorbent assay kit. In addition, 147 young women were recruited as a reference group to define cut-off values for sarcopenia. RESULTS: Circulating irisin was positively correlated with QcCSA/body weight (BW) and liver HU even after adjusting for multiple covariates, and the serum level was significantly lower in the sarcopenia group (QcCSA/BW<-2SD of the mean values for young women) than in the presarcopenia (-2SD≤QcCSA/BW<-1SD) or control groups (1SD≤QcCSA/BW<2SD). Logistic regression models showed that the relationship between circulating irisin and prevalence of sarcopenia remained significant after adjusting for confounding factors (per 1.0 ng/mL decrease of irisin, odds-ratio = 1.95, 95% confidence interval 1.33-2.87, p-value = 0.001). CONCLUSIONS: In postmenopausal women, serum irisin may be used as a biomarker for sarcopenia, and we showed the potential for the development of irisin-based early screening and staging tool for sarcopenia.

The bone anabolic effects of irisin are through preferential stimulation of aerobic glycolysis.

Irisin, a recently identified hormone secreted by skeletal muscle in response to exercise, exhibits anabolic effects on the skeleton primarily through the stimulation of bone formation. However, the mechanism underlying the irisin-stimulated anabolic response remains largely unknown. To uncover the underlying mechanism, we biosynthesized recombinant irisin (r-irisin) using an Escherichia coli expression system and used it to treat several osteoblast cell types. Our synthesized r-irisin could promote proliferation and differentiation of osteoblasts as evidenced by enhanced expression of osteoblast-specific transcriptional factors, including Runt-related transcription factor-2 (Runx2), Oster (Osx), as well as early osteoblastic differentiation markers such as alkaline phosphatase (Alp) and collagen type I alpha 1 (Col1a1). Furthermore, we showed that the promotion of r-irisin on the proliferation and differentiation of osteoblast lineage cells are preferentially through aerobic glycolysis, as indicated by the enhanced abundance of representative enzymes such as lactate dehydrogenase A (LDHA) and pyruvate dehydrogenase kinase 1 (PDK1), together with increased lactate levels. Suppression of r-irisin-mediated aerobic glycolysis with Dichloroacetate blunted its anabolic effects. The favorite of the aerobic glycolysis after r-irisin treatment was then confirmed in primary calvarial cells by metabolic analysis using gas chromatography-mass spectrometry. Thus, our results suggest that the anabolic actions of r-irisin on the regulation of osteoblast lineage cells are preferentially through aerobic glycolysis, which may help to develop new irisin-based bone anabolic agents.

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.

Effects of Single Vitamin D3 Injection (200,000 Units) on Serum Fibroblast Growth Factor 23 and Sclerostin Levels in Subjects with Vitamin D Deficiency.

BACKGROUND: Vitamin D deficiency remains common in all age groups and affects skeletal and non-skeletal health. Fibroblast growth factor 23 is a bone-derived hormone that regulates phosphate and 1,25-dihydroxyvitamin D homeostasis as a counter regulatory factor. 1,25-Dihydroxyvitamin D stimulates fibroblast growth factor 23 synthesis in bone, while fibroblast growth factor 23 suppresses 1,25-dihydroxyvitamin D production in the kidney. The aim of this study was to evaluate the effects of vitamin D3 intramuscular injection therapy on serum fibroblast growth factor 23 concentrations, and several other parameters associated with bone metabolism such as sclerostin, dickkopf-1, and parathyroid hormone. METHODS: A total of 34 subjects with vitamin D deficiency (defined by serum 25-hydroxyvitamin D levels below 20 ng/mL) were randomly assigned to either the vitamin D injection group (200,000 units) or placebo treatment group. Serum calcium, phosphate, urine calcium/creatinine, serum 25-hydroxyvitamin D, fibroblast growth factor 23, sclerostin, parathyroid hormone, and dickkopf-1 levels were serially measured after treatment. RESULTS: Comparing the vitamin D injection group with the placebo group, no significant changes were observed in serum fibroblast growth factor 23, parathyroid hormone, or dickkopf-1 levels. Serum sclerostin concentrations transiently increased at week 4 in the vitamin D group. However, these elevated levels declined later and there were no statistically significant differences as compared with baseline levels. CONCLUSION: Serum fibroblast factor 23, sclerostin, parathyroid hormone, and dickkopf-1 levels were not affected significantly by single intramuscular injection of vitamin D3.

Significant liver fibrosis assessed using liver transient elastography is independently associated with low bone mineral density in patients with non-alcoholic fatty liver disease.

BACKGROUND: Metabolic bone disorders frequently occur in patients with chronic liver disease; however, the association between liver fibrosis and bone mineral density in patients with non-alcoholic fatty liver disease (NAFLD) is unclear. METHODS: This is a cross-sectional analysis of 231 asymptomatic subjects (160 women, 61.6 years old) from a university hospital setting, between February 2012 and December 2014. Bone mineral density (BMD) was measured at the lumbar spine, femur neck, and total hip using dual-energy X-ray absorptiometry (DXA). Liver fibrosis and steatosis were assessed using transient elastography. RESULTS: Among a total of 231 individuals, 129 subjects (55.8%) had NAFLD. BMDs at lumbar spine, femur neck, and total hip were significantly lower in patients having NAFLD with significant fibrosis, compared with patients having NAFLD without significant fibrosis (Ps<0.005). In patients with NAFLD, significant liver fibrosis revealed marked negative correlations with BMD at the lumber spine (r = -0.19, P = 0.032), femur neck (r = -0.19, P = 0.034), and total hip (r = -0.21, P = 0.016). A multivariate linear regression analysis revealed that significant liver fibrosis was independently correlated with low BMD at the femur neck (ß = -0.18, P = 0.039) and total hip (ß = -0.21, P = 0.005) after adjustment for age, sex, BMI, fasting plasma glucose, alanine aminotransferase, high-density lipoprotein cholesterol, and liver steatosis among patients with NAFLD. Using multivariable logistic regression, significant liver fibrosis was independently associated with overall osteopenia and osteoporosis in subjects having NAFLD (OR = 4.10, 95% CI = 1.02-16.45). CONCLUSION: The presence of significant liver fibrosis assessed via TE was independently associated with low BMD in NAFLD subjects.

Cyclized Oligopeptide Targeting LRP5/6-DKK1 Interaction Reduces the Growth of Tumor Burden in a Multiple Myeloma Mouse Model.

PURPOSE: Dickkopf 1 (DKK1) has been extensively investigated in mouse models of multiple myeloma, which results in osteolytic bone lesions. Elevated DKK1 levels in bone marrow plasma and serum inhibit the differentiation of osteoblast precursors. Present pharmaceutical approaches to target bone lesions are limited to antiresorptive agents. In this study, we developed a cyclized oligopeptide against DKK1-low density lipoprotein receptor-related protein (LRP) 5/6 interaction and tested the effects of the oligopeptide on tumor burden. MATERIALS AND METHODS: A cyclized oligopeptide based on DKK1-LRP5/6 interactions was synthesized chemically, and its nuclear magnetic resonance structure was assessed. Luciferase reporter assay and mRNA expressions of osteoblast markers were evaluated after oligopeptide treatment. MOPC315.BM.Luc cells were injected into the tail vein of mice, after which cyclized oligopeptide was delivered subcutaneously 6 days a week for 4 weeks. RESULTS: The cyclized oligopeptide containing NXI motif bound to the E1 domain of LRP5/6 effectively on surface plasmon resonance analysis. It abrogated the Wnt-ß-catenin signaling inhibited by DKK1, but not by sclerostin, dose dependently. RT-PCR and alkaline phosphatase staining showed increased expressions of osteoblast markers according to the treatment concentrations. Bioluminescence images showed that the treatment of cyclized oligopeptide reduced tumor burden more in oligopeptide treated group than in the vehicle group. CONCLUSION: The cyclized oligopeptide reported here may be another option for the treatment of tumor burden in multiple myeloma.

Site-Specific Difference of Bone Geometry Indices in Hypoparathyroid Patients.

BACKGROUND: Hypoparathyroid patients often have a higher bone mineral density (BMD) than the general population. However, an increase in BMD does not necessarily correlate with a solid bone microstructure. This study aimed to evaluate the bone microstructure of hypoparathyroid patients by using hip structure analysis (HSA). METHODS: Ninety-five hypoparathyroid patients >20 years old were enrolled and 31 of them had eligible data for analyzing bone geometry parameters using HSA. And among the control data, we extracted sex-, age-, and body mass index-matched three control subjects to each patient. The BMD data were reviewed retrospectively and the bone geometry parameters of the patients were analyzed by HSA. RESULTS: The mean Z-scores of hypoparathyroid patients at the lumbar spine, femoral neck, and total hip were above zero (0.63±1.17, 0.48±1.13, and 0.62±1.10, respectively). The differences in bone geometric parameters were site specific. At the femoral neck and intertrochanter, the cross-sectional area (CSA) and cortical thickness (C.th) were higher, whereas the buckling ratio (BR) was lower than in controls. However, those trends were opposite at the femoral shaft; that is, the CSA and C.th were low and the BR was high. CONCLUSION: Our study shows the site-specific effects of hypoparathyroidism on the bone. Differences in bone components, marrow composition, or modeling based bone formation may explain these findings. However, further studies are warranted to investigate the mechanism, and its relation to fracture risk.

Low Dentin Matrix Protein 1 Is Associated With Incident Cardiovascular Events in Peritoneal Dialysis Patients.

Recent reports demonstrated that dentin matrix protein 1 (DMP1) acts as an inhibitor of vascular calcification and might be a potential biomarker for chronic kidney disease-mineral and bone disorder; however, no clinical investigations regarding DMP1 have been performed in dialysis patients. We investigated the prognostic value of DMP1 on cardiovascular outcomes in prevalent peritoneal dialysis patients. We recruited 223 prevalent peritoneal dialysis patients and divided them into high and low DMP1 groups according to log-transformed plasma DMP1 levels. Lateral lumbar spine radiographs were used for measurement of vascular calcification. Major cardiovascular events were compared between the two groups. A Cox proportional hazards analysis determined DMP1 was independently associated with cardiovascular outcomes. In vitro mouse osteocytes were cultured in media containing indoxyl sulfate (IS), and the expressions of DMP1 were examined. The mean age was 52.1 ± 11.8 years, and 116 (52.0%) patients were male. The median value of log DMP1 was 0.91 (0.32-2.81 ng/mL). The multiple logistic regression analysis indicated that DMP1 levels were independently associated with the presence of vascular calcification after adjustment for multiple confounding factors (odds ratio = 0.719; 95% confidence interval [CI] 0.522-0.989; p = 0.043). During a mean follow-up duration of 34.6 months, incident cardiovascular events were observed in 41 (18.4%) patients. A Kaplan-Meier plot showed that the low DMP1 group had a significantly higher rate of incident cardiovascular events compared with the high DMP1 group (log-rank test, p = 0.026). In addition, multiple Cox analysis showed that low DMP1 was significantly associated with incident cardiovascular events (log 1 increase: hazard ratio = 0.855; 95% CI 0.743-0.984; p = 0.029) after adjustment for multiple confounding factors. In IS-stimulated osteocytes, mRNA and protein expression levels of DMP1 were significantly decreased compared with control osteocytes. We showed that low DMP1 levels were significantly associated with presence of vascular calcification and were independently associated with the incident cardiovascular events in prevalent peritoneal dialysis patients. DMP1 might be a potential factor contributing to cardiovascular complications in dialysis patients. © 2016 American Society for Bone and Mineral Research.

A Novel Human PTH Analog [Cys25]hPTH(1-34) Restores Bone Mass in Ovariectomized Mice.

CONTEXT: Recently, an arginine-to-cysteine homozygous mutation at position 25 in mature PTH was reported in a Korean patient with hypoparathyroidism. OBJECTIVE: To clarify whether the high bone mass phenotype observed in this patient was related to the hypoparathyroidism itself or to chronic elevation of mutant PTH. METHODS: A series of in vitro and in vivo experiments were performed in MC3T3E1, ROS 17/2.8, and SAOS2 cells treated with human (h)PTH(1-34), Cys25hPTH(1-34), Ala1Cys25hPTH(1-34), and Bpa1Cys25hPTH(1-34). The peptides were then sc delivered to ovariectomized mice as daily single injections. RESULTS: Compared with hPTH(1-34) and Ala1Cys25hPTH(1-34), treatment with Cys25hPTH(1-34) or Bpa1Cys25hPTH(1-34) resulted in decreases in the cAMP response and promoter-cAMP-response element luciferase reporter activity. Although the cAMP response was sustained with hPTH(1-34) in MC3T3E1 cells, such response was not observed with the other mutated peptides. Meanwhile, all PTH analogues exhibited ERK phosphorylation and cytoplasmic Ca++ signals comparable with hPTH(1-34). On microcomputed tomography analyses, trabecular and cortical bone parameters improved after 6 weeks of respective treatments as follows: hPTH(1-34) (80 µg/kg) = Ala1Cys25hPTH(1-34) (80 µg/kg) = Cys25hPTH(1-34) (80 µg/kg) > Bpa1Cys25hPTH(1-34) (80 µg/kg) > hPTH(1-34) (40 µg/kg). The increment of RANKL to OPG mRNA ratio in the MC3T3E1 cells after 6 hours of treatment of Cys25hPTH(1-34), AL1Cys25hPTH(1-34), and Bpa1Cys25hPTH(1-34) was less than that was obtained after hPTH(1-34) treatment. On bone histomorphometric analysis, AL1Cys25hPTH(1-34) increased the bone formation rate in both trabecular and periosteal bones compared with the control group. CONCLUSION: The high bone mass phenotype observed in this patient with hypoparathyrodism caused by a Cys mutation at the 25th residue of hPTH(1-84) may have arisen from both direct and indirect effects exerted by the mutant PTH itself on bone.

The Role of Nuclear Factor-E2-Related Factor 1 in the Oxidative Stress Response in MC3T3-E1 Osteoblastic Cells.

BACKGROUND: Reactive oxygen species (ROS) and antioxidants are associated with maintenance of cellular function and metabolism. Nuclear factor-E2-related factor 1 (NFE2L1, Nrf1) is known to regulate the expression of a number of genes involved in oxidative stress and inflammation. The purpose of this study was to examine the effects of NFE2L1 on the response to oxidative stress in osteoblastic MC3T3-E1 cells. METHODS: The murine calvaria-derived MC3T3-E1 cell line was exposed to lipopolysaccharide (LPS) for oxidative stress induction. NFE2L1 effects were evaluated using small interfering RNA (siRNA) for NFE2L1 mRNA. ROS generation and the levels of known antioxidant enzyme genes were assayed. RESULTS: NFE2L1 expression was significantly increased 2.4-fold compared to the control group at 10 µg/mL LPS in MC3T3-E1 cells (P<0.05). LPS increased formation of intracellular ROS in MC3T3-E1 cells. NFE2L1 knockdown led to an additional increase of ROS (20%) in the group transfected with NFE2L1 siRNA compared with the control group under LPS stimulation (P<0.05). RNA interference of NFE2L1 suppressed the expression of antioxidant genes including metallothionein 2, glutamatecysteine ligase catalytic subunit, and glutathione peroxidase 1 in LPS-treated MC3T3-E1 cells. CONCLUSION: Our results suggest that NFE2L1 may have a distinct role in the regulation of antioxidant enzymes under inflammation-induced oxidative stress in MC3T3-E1 osteoblastic cells.

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.

Serum γ-Glutamyl Transferase Is Inversely Associated with Bone Mineral Density Independently of Alcohol Consumption.

BACKGROUND: γ-Glutamyl transferase (GGT) is a well-known marker of chronic alcohol consumption or hepatobiliary diseases. A number of studies have demonstrated that serum levels of GGT are independently associated with cardiovascular and metabolic disorders. The purpose of this study was to test if serum GGT levels are associated with bone mineral density (BMD) in Korean adults. METHODS: A total of 462 subjects (289 men and 173 women), who visited Severance Hospital for medical checkup, were included in this study. BMD was measured using dual energy X-ray absorptiometry. Cross-sectional association between serum GGT and BMD was evaluated. RESULTS: As serum GGT levels increased from the lowest tertile (tertile 1) to the highest tertile (tertile 3), BMD decreased after adjusting for confounders such as age, body mass index, amount of alcohol consumed, smoking, regular exercise, postmenopausal state (in women), hypertension, diabetes mellitus, and hypercholesterolemia. A multiple linear regression analysis showed a negative association between log-transformed serum GGT levels and BMD. In a multiple logistic regression analysis, tertile 3 of serum GGT level was associated with an increased risk for low bone mass compared to tertile 1 (odds ratio, 2.271; 95% confidence interval, 1.340 to 3.850; P=0.002). CONCLUSION: Serum GGT level was inversely associated with BMD in Korean adults. Further study is necessary to fully elucidate the mechanism of the inverse relationship.

Efficacy and safety of vitamin D3 B.O.N intramuscular injection in Korean adults with vitamin D deficiency.

OBJECTIVE: There has been no prospective study that examined intramuscular injection of high-dose vitamin D in Korean adults. The aim of this study was to assess the efficacy and safety of high-dose vitamin D3 after intramuscular injection in Korean adults with vitamin D deficiency. METHOD: This study was a 24-week, prospective, multicenter, randomized, double-blind, placebo-controlled trial. A total of 84 subjects ≥19 and <65 years of age were randomly allocated to either the vitamin D3 or placebo group in a 2:1 ratio. After randomization, a single injection of plain vitamin D3 200,000 IU or placebo was intramuscularly administered. If serum 25-hydroxyvitamin D (25[OH]D) concentrations were <30 ng/mL on week 12 or thereafter, a repeat injection was administered. RESULTS: After a single intramuscular injection of vitamin D3 to adults with vitamin D deficiency, the proportion of subjects with serum 25(OH)D concentrations ≥30 ng/mL within 12 weeks was 46.4% in the vitamin D3 group and 3.6% in the placebo group (p < 0.0001). The proportion of subjects with serum 25(OH)D concentrations ≥30 ng/mL within 24 weeks was 73.2% in the vitamin D3 group and 3.6% in the placebo group (p < 0.0001). Mean change in serum 25(OH)D concentrations at weeks 12 and 24 after vitamin D3 injection was 12.8 ± 8.1 and 21.5 ± 8.1 ng/mL, respectively, in the vitamin D3 group, with no significant changes in the placebo group. Serum parathyroid hormone concentrations showed a significant decrease in the vitamin D3 group but no change in the placebo group. CONCLUSION: Intramuscular injection of vitamin D3 200,000 IU was superior to placebo in terms of its impact on serum 25(OH)D concentrations, and is considered to be safe and effective in Korean adults with vitamin D deficiency.

The Effects of a High Fat Diet Containing Diacylglycerol on Bone in C57BL/6J Mice.

PURPOSE: In epidemiologic and animal studies, a high fat diet (HFD) has been shown to be associated with lower bone mineral density (BMD) and a higher risk of osteoporotic fractures. Meanwhile, consuming a HFD containing diacylglycerol (DAG) instead of triacylglycerol (TAG) is known to offer metabolically beneficial effects of reductions in body weight and abdominal fat. The purpose of this study was to investigate the effects of a HFD containing DAG (HFD-DAG) on bone in mice. MATERIALS AND METHODS: Four-week-old male C57BL/6J mice (n=39) were divided into three weight-matched groups based on diet type: a chow diet group, a HFD containing TAG (HFD-TAG) group, and a HFD-DAG group. After 20 weeks, body composition and bone microstructure were analyzed using dual energy X-ray absorptiometry and micro-computed tomography. Reverse transcription-polymerase chain reaction (PCR) and real-time PCR of bone marrow cells were performed to investigate the expressions of transcription factors for osteogenesis or adipogenesis. RESULTS: The HFD-DAG group exhibited lower body weight, higher BMD, and superior microstructural bone parameters, compared to the HFD-TAG group. The HFD-DAG group showed increased expression of Runx2 and decreased expression of PPARgamma in bone marrow cells, compared to the HFD-TAG group. The HFD-DAG group also had lower levels of plasma glucose, insulin, total cholesterol, and triglyceride than the HFD-TAG group. CONCLUSION: Compared to HFD-TAG, HFD-DAG showed beneficial effects on bone and bone metabolism in C57BL/6J mice.

Increased sclerostin levels after further ablation of remnant estrogen by aromatase inhibitors.

BACKGROUND: Sclerostin is a secreted Wnt inhibitor produced almost exclusively by osteocytes, which inhibits bone formation. Aromatase inhibitors (AIs), which reduce the conversion of steroids to estrogen, are used to treat endocrine-responsive breast cancer. As AIs lower estrogen levels, they increase bone turnover and lower bone mass. We analyzed changes in serum sclerostin levels in Korean women with breast cancer who were treated with an AI. METHODS: We included postmenopausal women with endocrine-responsive breast cancer (n=90; mean age, 57.7 years) treated with an AI, and compared them to healthy premenopausal women (n=36; mean age, 28.0 years). The subjects were randomly assigned to take either 5 mg alendronate with 0.5 µg calcitriol (n=46), or placebo (n=44) for 6 months. RESULTS: Postmenopausal women with breast cancer had significantly higher sclerostin levels compared to those in premenopausal women (27.8±13.6 pmol/L vs. 23.1±4.8 pmol/L, P<0.05). Baseline sclerostin levels positively correlated with either lumbar spine or total hip bone mineral density only in postmenopausal women (r=0.218 and r=0.233; P<0.05, respectively). Serum sclerostin levels increased by 39.9%±10.2% 6 months after AI use in postmenopausal women; however, no difference was observed between the alendronate and placebo groups (39.9%±10.2% vs. 55.9%±9.13%, P>0.05). CONCLUSION: Serum sclerostin levels increased with absolute deficiency of residual estrogens in postmenopausal women with endocrine-responsive breast cancer who underwent AI therapy with concurrent bone loss.

Concurrent bisphosphonate-related bilateral atypical subtrochanteric fractures and osteonecrosis of the jaw on bone scintigraphy.

An 82-year-old woman presented with bilateral thigh pain. She had pain in her right thigh operated for a low-trauma fracture 2 years earlier and newly developed pain in her left thigh without trauma. A whole-body bone scan revealed increased tracer uptake in her bilateral subtrochanteric femoral shafts and in the right mandible without evidence of metastatic bone disease. She had been taking bisphosphonates for 7 years to treat osteoporosis and was soon diagnosed with atypical subtrochanteric fractures and bisphosphonate-related osteonecrosis of the jaw. The bone scan simultaneously identified 2 serious adverse effects of long-term use of bisphosphonates.

Comparison of Buckling Ratio and Finite Element Analysis of Femoral Necks in Post-menopausal Women.

OBJECTIVES: Osteoporosis is a prevalent problem amongst the elderly. Bone mineral density (BMD) obtained from dual X-ray absorptiometry (DXA) is the gold standard in diagnosing osteopenia (-1.0 < t < -2.5) and osteoporosis (t > -2.5). However, following osteoporosis therapy, increases in BMD may be unreliable. Although hip fracture risk can be reduced with the aid of drugs, treated patients still face considerable risk as most people who sustain hip fracture do not have generalized osteoporosis. A study of the local distribution of bone mass was necessary as they contribute to the geometry and consequently the bone strength. METHODS: By identifying the respective regions in the femoral neck, the geometric changes were localized and differed between each patient, proving that drug treatment elicits local changes in mean outer radius and mean cortical thickness. Numerical analysis also validated the above findings, where critical strain regions were predicted at similar zones and this is coherent with the fact that reduced thickness of the cortical bone has been related to increased risk of fracture initiation. RESULTS: Hence, from individual radar plots, we can determine if the effect of drugs had outweighed the effect of aging. We can then propose a course of treatment drug better suited for the patient in the clinical scenario. CONCLUSION: Clinically, little conclusion can be drawn from just the BMD in osteopenic / osteoporotic patients. This emphasizes the necessity of using geometry and structure to predict fracture risk. Focusing on a patient specific analysis at a local level will improve diagnosis of osteoporosis and ultimately fracture prediction.