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DNA methylation changes are a constant feature of acute myeloid leukemia. Hypomethylating drugs such as azacitidine are active in acute myeloid leukemia (AML) as monotherapy. Azacitidine monotherapy is not curative. The AML-AZA trial tested the hypothesis that DNA methyltransferase inhibitors such as azacitidine can improve chemotherapy outcome in AML. This randomized, controlled trial compared the efficacy of azacitidine applied before each cycle of intensive chemotherapy with chemotherapy alone in older patients with untreated AML. Event-free survival (EFS) was the primary end point. In total, 214 patients with a median age of 70 years were randomized to azacitidine/chemotherapy (arm-A) or chemotherapy (arm-B). More arm-A patients (39/105; 37%) than arm-B (25/109; 23%) showed adverse cytogenetics (P=0.057). Adverse events were more frequent in arm-A (15.44) versus 13.52 in arm-B, (P=0.26), but early death rates did not differ significantly (30-day mortality: 6% versus 5%, P=0.76). Median EFS was 6 months in both arms (P=0.96). Median overall survival was 15 months for patients in arm-A compared with 21 months in arm-B (P=0.35). Azacitidine added to standard chemotherapy increases toxicity in older patients with AML, but provides no additional benefit for unselected patients.Leukemia advance online publication, 1 December 2015; doi:10.1038/leu.2015.306. © 2015 Macmillan Publishers Limited Source

Szulc P.,University of Lyon | Hawa G.,BioMedica | Boutroy S.,University of Lyon | Vilayphiou N.,University of Lyon | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Context: Osteoprotegerin (OPG) is an inhibitor of bone resorption, but its relationship to bone microarchitecture remains unclear. Objective: Our objective was to study the relationship between OPG concentration and bone microarchitecture in men. Design, Setting, and Participants: We conducted a cross-sectional study of a population-based cohort of 1149 men aged 20-87 yr. Interventions: We assessed bone microarchitecture at the distal radius and tibia by high-resolution peripheral quantitative computed tomography (XtremeCT Scanco) and measured serum OPG concentration and bone turnover markers: osteocalcin, bone-specific alkaline phosphatase, N-terminal extension type I collagen propeptide, C-terminal type 1 collagen telopeptide, and urinary deoxypyridinoline. Main outcome measures: Differences were assessed in bone microarchitectural parameters across the OPG quartiles in the models adjusted for age, weight, height, physical activity, ischemic heart disease, diabetes mellitus, calcium intake, serum levels of free testosterone, bioavailable 17β-estradiol, PTH, 25-hydroxycholecalciferol, and creatinine. Results: After adjustment for the confounders, men in the highest (fourth) quartile of OPG levels (>4.55pmol/liter)hadhighertotal cross- sectionalareaandtrabecularareaatthedistalradiusanddistal tibia (3.3-6.0%, P < 0.05). At both skeletal sites, the highest OPG quartile was associated with lower cortical thickness (8.2%, P < 0.001, and 3.7%, P < 0.05) and volumetric bone mineral density (vBMD, 2.7%, P < 0.001, and 1.6%, P < 0.005) compared with the three lower quartiles combined. Associations of OPG level with trabecular vBMD, number, thickness, and distribution were not significant. Men in the fourth OPG quartile had higher levels of bone resorption markers (11.8-13.1%, P < 0.01-0.001). Conclusions: Men with higher serum OPG concentration had lower cortical thickness and vBMD, probably due to accelerated endo- and intracortical bone turnover, but higher cross-sectional area possibly due to periosteal apposition. Copyright © 2011 by The Endocrine Society. Source

Mazziotti G.,University of Brescia | Maffezzoni F.,University of Brescia | Doga M.,University of Brescia | Hofbauer L.C.,Dresden University Medical Center | And 2 more authors.
Bone | Year: 2014

Over the last few years, there has been experimental evidence for the existence of cross-talking between bone remodeling and glucose metabolism. Whether this experimental model can be translated to humans is still debated, and it is also unclear whether the modulation of bone turnover by anti-osteoporotic drugs may lead to changes in glucose metabolism. The aim of this 12-month prospective study was to investigate whether treatment of glucocorticoid-induced osteoporosis (GIO) with bipshosphonates or teriparatide may influence serum glycated hemoglobin (HbA1c) and fasting plasma glucose. One-hundred-eleven patients (70 F, 41 M, median age 70, range: 55-89) chronically treated with glucocorticoids were evaluated for changes in serum HbA1c and fasting plasma glucose during treatment with bisphosphonates (45 cases) or teriparatide (33 cases) as compared to those occurring during treatment with calcium and vitamin D alone (33 cases). In patients treated with teriparatide, but not in those treated with bisphosphonates or calcium and vitamin D alone, a statistically significant (p=0.01) decrease in serum HbA1c was observed during the follow-up, the change being greater (p= 0.01) in patients with diabetes as compared to those without diabetes. In most cases, the decrease of serum HbA1c was relatively limited and in some patients the improvement of glucose homeostasis was concomitant with implementation of anti-diabetic treatments. Fasting plasma glucose did not change significantly during either bisphosphonates or teriparatide treatments. In conclusion, currently used bone active drugs may produce limited effects on glucose metabolism in patients with GIO. Interestingly, the bone anabolic drug teriparatide was shown to be associated with some improvement in serum HbA1c in this clinical context. © 2014 Elsevier Inc. Source

Bauer S.,University of Marburg | Hofbauer L.C.,Dresden University Medical Center | Rauner M.,Dresden University Medical Center | Strzelczyk A.,University of Marburg | And 4 more authors.
Epilepsy Research | Year: 2013

Purpose: To determine early changes in bone turnover markers induced by treatment with oxcarbazepine or valproate. Methods: In this prospective study, 31 adults with newly diagnosed epilepsy were included who were started on therapy with either oxcarbazepine (OXC, n=16, mean age 45.6 years, 37.5% female) or valproate (VPA, n=15, mean age 42.2 years, 33.3% female). Clinical characteristics were obtained at baseline, after 2 weeks and 3 months. In addition, blood samples were drawn at each visit. Calcium, phosphate, alkaline phosphatase (AP), receptor activator of NF-κB ligand (RANKL), osteoprotegerin (OPG), osteocalcin (OC) and cathepsin K were determined. Results: In OXC treated patients, OPG increased by 0.06. pmol/L (p= 0.0004) after 2 weeks and remained elevated by 0.05. pmol/L (p=0.02) after 3 months. Between 2 weeks and 3 months of OXC treatment, OC increased by 1.98. ng/mL (p=0.02). During the first 3 months of OXC treatment, total serum AP increased by 11%. ±. 9% (p=0.02). Compared to baseline, serum calcium raised by 0.06. mmol/L (p=0.04) after 2 weeks and by 0.07. mmol/L (p=0.004) after 3 months of OXC treatment. In VPA treated patients, a late OPG increase by 0.07. pmol/L (p=0.007) occurred after 3 months. During the first 3 months of OXC treatment, total serum AP decreased by by 7%. ±. 15% (p=0.03). No changes in OC or calcium were seen. RANKL was below detection limit in 16 out of 31 patients (52%) and did not change significantly during treatment. Cathepsin K was below detection limit at baseline in 27 out of 31 patients (87%) and was therefore not further evaluated. Phosphate did not change during treatment. Conclusion: Increased bone turnover can be measured within few weeks of newly started treatment with OXC, while significant changes under VPA treatment occurred only after 3 months. Our data suggest distinct mechanisms of increased bone turnover in different anticonvulsants. These variable mechanisms may require individual prevention and treatment strategies. © 2013 Elsevier B.V. Source

Szulc P.,University of Lyon | Schoppet M.,University of Marburg | Goettsch C.,Dresden University Medical Center | Rauner M.,Dresden University Medical Center | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: Myostatin is expressed mainly in skeletal muscle cells and acts as an inhibitor of muscle growth and differentiation. However, data on the determinants of serum myostatin concentrations in humans are limited. Objective: The aim of the study was to assess the correlates of serum myostatin concentrations in men. Design: We conducted a cross-sectional analysis of the STRAMBO cohort. Setting: Men holding private health insurance coverage with Mutuelle de Travailleurs de la Région Lyonnaise were included in the study. Participants: A total of 1121 male volunteers aged 20-87 yr participated in the study. Interventions: Nonfasting blood samples were collected. Main Outcome Measures: We measured the association of the investigated variables with circulating myostatin levels. Results: Serum myostatin levels increased slightly with age until 57 yr and then decreased. Circulating myostatin levels showed circannual variation, with the highest concentration in spring. In men older than 57 yr, serum myostatin levels decreased across increasing quartiles of body mass indexandof total central and peripheral fat mass (P < 0.05 to < 0.001). Serum myostatin levels were positively correlated with serum levels of 25-hydroxycholecalciferol (25OHD), even after adjustment for season. Average myostatin levels were 0.47 SD higher in men with 25OHD above 40 ng/ml, compared with those with 25OHD below 20 ng/ml (P < 0.05). Current smokers had lower myostatin concentration. Neither current physical activity nor serum levels of PTH, testosterone, and 17β-estradiol were associated with myostatin concentrations. Conclusions: In men, circulating myostatin levels show seasonal changes and are associated with age, body mass index, fat mass, smoking, and 25OHD levels. Copyright © 2012 by The Endocrine Society. Source

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