Pharmacokinetic profile and effect on bone markers and muscle strength of two daily dosage regimens of calcifediol in osteopenic/osteoporotic postmenopausal women.

BACKGROUND: At present, although cholecalciferol represents the form of vitamin D of choice for the treatment of vitamin D deficiency, there is a growing interest in calcifediol. AIMS: This study aimed to evaluate the efficacy and the safety of two different daily doses of calcifediol. METHODS: Fifty osteopenic/osteoporotic women with serum levels of 25-hydroxyvitamin D (25OHD) between 10 and 20 ng/ml were randomized to a 6-month treatment with oral calcifediol 20 µg/day (n = 25) or oral calcifediol 30 µg/day (n = 25). In all, we measured the time course of the levels of 25OHD and other biochemical parameters. Moreover, we evaluated handgrip strength and serum levels of myostatin. RESULTS: The peak increase in 25OHD levels was reached after 90 days of treatment in group 1 (59.3 ng/ml) and after only 60 days in group 2 (72.3 ng/ml); thereafter in both groups, the levels of 25OHD showed a tendency towards stabilization. After 30 days, all the patients treated with 30 µg/day had values of 25OHD > 30 ng/ml. Handgrip strength showed a modest but progressive increase which reached the statistical significance in the 30 µg/day group. This latter group also presented a modest and non-significant decrease in serum levels of myostatin. CONCLUSIONS: Calcifediol is able to rapidly normalize the vitamin D deficiency, and the 30 µg daily dosage could be suggested in those patients who need to rapidly reach optimal 25OHD levels. Moreover, the 6-month treatment with calcifediol at a dose of 30 µg results in a modest but significant increase in upper limb strength.

Infection by CagA-Positive Helicobacter pylori Strains and Bone Fragility: A Prospective Cohort Study.

Helicobacter pylori (HP) infection is a common and persistent disorder acting as a major cofactor for the development of upper gastrointestinal diseases and several extraintestinal disorders including osteoporosis. However, no prospective study assessed the effects of HP on bone health and fracture risk. We performed a HP screening in a population-based cohort of 1149 adults followed prospectively for up to 11 years. The presence of HP infection was assessed by serologic testing for serum antibodies to HP and the cytotoxin associated gene-A (CagA). The prevalence of HP infection did not differ among individuals with normal bone mineral density (BMD), osteoporosis, and osteopenia. However, HP infection by CagA-positive strains was significantly increased in osteoporotic (30%) and osteopenic (26%) patients respect to subjects with normal BMD (21%). Moreover, anti-CagA antibody levels were significantly and negatively associated with lumbar and femoral BMD. Consistent with these associations, patients affected by CagA-positive strains had a more than fivefold increased risk to sustain a clinical vertebral fracture (HR 5.27; 95% CI, 2.23-12.63; p < .0001) and a double risk to sustain a nonvertebral incident fracture (HR 2.09; 95% CI, 1.27-2.46; p < .005). Reduced estrogen and ghrelin levels, together with an impaired bone turnover balance after the meal were also observed in carriers of CagA-positive HP infection. HP infection by strains expressing CagA may be considered a risk factor for osteoporosis and fractures. Further studies are required to clarify in more detail the underlying pathogenetic mechanisms of this association. © 2020 American Society for Bone and Mineral Research (ASBMR).

Ultrasound indices of congestion in patients with acute heart failure according to body mass index.

BACKGROUND: The inverse relationship between body mass index (BMI) and natriuretic peptide levels complicates the diagnosis of heart failure (HF) in obese patients. Assessment of congestion with ultrasound could facilitate HF diagnosis but it is unclear if any relationship exists amongst BMI, inferior vena cava (IVC) diameter and the number of B-lines. METHODS: We performed a comprehensive echocardiographic evaluation within 24 h from hospital admission in patients with HF, including lung B-lines and IVC diameter, and studied their relationship with BMI and outcome. RESULTS: 216 patients (median age 81 (77-86) years) were enrolled. Median number of B-lines was 31 (IQR 26-38), median IVC diameter was 23 (22-25) mm and median BNP 991 (727-1601) pg/mL. BMI was inversely correlated with B-lines (r = - 0.50, p < 0.001), but not with IVC diameter (r = - 0.04, p = 0.58). Compared to overweight patients (BMI 25-29.9 kg/m2; n = 100) or with a normal BMI (BMI < 25 kg/m2; n = 59), obese patients (BMI ≥ 30 kg/m2; n = 57) had lower B-lines [28 (24-33) vs 30 (26-35), and vs 38 (32-42), respectively; p < 0.001] but similar IVC diameter. During the first 60 days of follow-up, there were 53 primary events: 29 patients died and 24 had a HF-related hospitalisation. B-lines and IVC diameter were independently associated with an increased risk. However, B-lines were less likely to predict outcome in the subgroup of patients with a BMI ≥ 30 kg/m2. CONCLUSIONS: Assessment of IVC diameter or B-lines in patients admitted with AHF identifies those at greater risk of death or HF readmission. However, assessment of B-lines might be influenced by BMI.

Preventive Role of Vitamin D Supplementation for Acute Phase Reaction after Bisphosphonate Infusion in Paget's Disease.

CONTEXT: Intravenous aminobisphosphonates (N-BPs) can induce an acute phase reaction (APR) in up to 40% to 70% of first infusions, causing discomfort and often requiring intervention with analgesics or antipyretics. OBJECTIVE: Our aim was to explore the risk factors of APR in a large sample of patients with Paget's disease of bone (PDB) and to assess the possible preventive effects of vitamin D administration. METHODS: An observational analysis was performed in 330 patients with PDB at the time of N-BP infusion. Then, an interventional study was performed in 66 patients with active, untreated PDB to evaluate if vitamin D administration (oral cholecalciferol 50 000 IU/weekly for 8 weeks before infusion) may prevent APR. RESULTS: In a retrospective study, APR occurred in 47.6% and 18.3% of naive or previously treated patients, respectively. Its prevalence progressively increased in relation to the severity of vitamin D deficiency, reaching 80.0% in patients with 25-hydroxyvitamin D (25OHD) levels below 10 ng/mL (relative risk (RR) = 3.7; 95% confidence interval (CI) 2.8-4.7, P < .0001), even in cases previously treated with N-BPs. Moreover, APR occurred more frequently in patients who experienced a previous APR (RR = 2.8; 95% CI 1.5-5.2; P < .001) or in carriers of SQSTM1 mutation (RR = 2.3; 95% CI 1.3-4.2; P = .005). In the interventional study, vitamin D supplementation prevented APR in most cases, equivalent to a RR of 0.31 (95% CI 0.14-0.67; P < .005) with respect to prevalence rates of the observational cohort. A similar trend was observed concerning the occurrence of hypocalcemia. CONCLUSIONS: The achievement of adequate 25OHD levels is recommended before N-BP infusion in order to minimize the risk of APR or hypocalcemia in PDB.

Combination of ST2 and B-type natriuretic peptide in diabetic patients with acute heart failure: relation with ventricular stiffness and outcome.

BACKGROUND: Diabetes is a common disease in heart failure and its prevalence ranges from 10 to 30%. ST-2 is a novel biomarker of myocardial fibrosis and remodelling in heart failure and may be involved in the inflammatory process of diabetes mellitus. In this study, we sought: to evaluate levels of ST-2 and B-type natriuretic peptide (BNP) in groups with acute heart failure with and without diabetes; to analyse the prognostic impact of ST-2 over a 6-month follow-up period. METHODS: We performed an echocardiographic examination and measured ST-2 and BNP within 24 h of hospital admission. Patients were classified as heart failure with reduced ejection fraction {HFrEF [left ventricular ejection fraction (LVEF) <50%]} or heart failure with preserved ejection fraction (HFpEF, LVEF ≥50%). We defined diastolic function according to recent guidelines, and we calculated left ventricular stiffness was assessed by the ratio between E/e' (index of left ventricular filling pressure) and left ventricular diastolic diameter (LVEDD) (index of left ventricular volume). The sum of death and rehospitalization due to cardiovascular causes was considered in the composite outcome. RESULTS: Of 121 patients enrolled, 58 experienced diabetes and 63 had normal glucose levels. Sixty patients showed HFrEF and 61 HFpEF. Among patients with diabetes, we observed significantly increased levels of serum ST-2 with respect to patients without diabetes [89 (29-147) 72 ±â€Š42 vs. 48 (29-80) 59 ±â€Š33 ng/ml; P = 0.04]. No differences were found between the two groups in terms of BNP levels, risk factors, renal function and echocardiographic measurements. Conversely, BNP was significantly higher in HFrEF with respect to HFpEF [786 (344-1390) vs. 423 (195-796) pg/ml; P = 0.004]. A significant correlation between ST-2 and BNP in diabetic patients (r = 0.50; P < 0.001) compared with nondiabetic patients (r = 0.40; P = 0.001) was found. ST-2 showed a numerically greater correlation with left ventricular stiffness in patients with diabetes (r = 0.56; P < 0.001) than patients without (r = 0.29; P = 0.04). Moreover, in all patients, ST-2 demonstrated a significant correlation with glycated glycosylated haemoglobin HbA1c (r = 0.40; P < 0.001). Univariate analysis demonstrated that both ST-2 more than 54 ng/ml and BNP more than 567 pg/ml were related to adverse events occurrence within 6 months [hazard ratio (HR): 3.64 (1.90-6.94), P < 0.001; HR: 2.21 (1.20-4.07), P = 0.01, respectively]. After adjustment for potential confounding factors, the multivariable analysis showed that only ST-2 levels greater than 54 ng/ml were associated with poor prognosis [HR: 3.56 (1.66-7.62); P = 0.001]. CONCLUSION: ST-2 confirmed its prognostic power independently of diabetes and LVEF. Patients with diabetes showed higher levels of ST-2. However, the mechanism related to ST-2 increase needs to be better understood, although increased left ventricle stiffness and filling pressure seem to be the most important causative factors. CLINICAL TRIAL REGISTRATION: www.clinicaltrial.gov Diur-HF Trial (Trial ID: NCT01441245).

Different trajectories and significance of B-type natriuretic peptide, congestion and acute kidney injury in patients with heart failure.

The exact relationship existing among congestion status, brain natriuretic peptide (BNP) changes and acute kidney injury (AKI) has not been elucidated in patients with acute heart failure (AHF). The aims of this study are: to investigate the relation and prognostic role of BNP, AKI and clinical congestion after discharge; to define the exact BNP cut off value or a BNP in-hospital reduction to identify patients with higher risk during vulnerable post-discharge phase. We consecutively enrolled 157 patients with a diagnosis of AHF. BNP and creatinine were measured in all patients, and degree of failure was assessed. AKI was defined as a creatinine increase ≥0.3 mg/dL or eGFR reduction ≥20% during hospitalization. All patients were followed for 1 and 3 months. Of 146 included patients, 110 patients (75%) displayed effective decongestion, 116 (79%) showed a BNP decrease ≥30%, and 28 (19%) developed in-hospital AKI. BNP in-hospital decrease ≥30% was found more often in patients who showed good decongestion in comparison to patients in persistent failure (63 vs 22%; p < 0.001). The ROC curve analyses at 3 months show that both BNP reduction of 30% between admission and discharge and decongestion at discharge identifies patients with a reduced incidence of cardiovascular events (AUC = 0.79, confidence interval 0.68-0.90, sensibility 90%, sensitivity 50% p < 0.001). Kaplan-Meier survival plots show a better outcome in patients with a BNP decrease ≥30% and good decongestion at discharge (p = 0.03). BNP reduction in AHF is associated with decongestion. BNP reduction associated with decongestion at discharge is a favorable prognostic indicator at 90-day survival irrespective of the AKI occurrence.

Additional value of Galectin-3 to BNP in acute heart failure patients with preserved ejection fraction.

BACKGROUND: Almost half of patients with acute heart failure have preserved ejection fraction (HFpEF). HFpEF is a diagnostic challenge using traditional investigation tools; Galectin-3 (Gal-3) is an emerging biomarker useful in individuals at risk for HF. The aim of our study is to analyse the relation and prognostic value of Gal-3, BNP and renal dysfunction in patients with HFpEF compared to patients with reduced ejection fraction (HFrEF). METHODS: We enrolled 98 patients with acute heart failure (AHF) and measured Gal-3, BNP, and estimated glomerular filtration rate (eGFR) within 12h of hospital admission. On the basis of echocardiographic findings we divided our sample into two groups: patients with HFrHF (ejection fraction<50%) or HFpEF (ejection fraction>50%). Patients were followed up at 6months. RESULTS: No differences in Gal-3 levels were found in the two subgroups (HFrEF: 19.5±5.1ng/mL; HFpEF: 20.5±8.7, p=0.56). Gal-3 was inversely related to renal dysfunction (LogGal-3 vs eGFR: r=-0.30, p=0.01) but did not correlate with LogBNP levels (r=0.07, p=0.55). Gal-3 was associated with more advanced diastolic dysfunction in HFpEF (p=0.009). In addition LogGal-3 was related to diastolic LV stiffness (all patients: r=0.45, p<0.001; HFpEF: r=0.64, p<0.001). Cox regression analysis showed that LogGal-3>1.30 was related to poor outcome independently from renal dysfunction and other risk factors only in HFpEF (univariate HR 23.98 [3.03-89.45]; p<0.001). Adjusted for renal dysfunction (HR 16.32 [1.98-34.09]; p=0.009). CONCLUSIONS: Gal-3 is not able to distinguish between HFrEF and HFpEF patients. However it is related to diastolic dysfunction severity and LV stiffness in HFpEF. Gal-3 demonstrates a prognostic role independently from renal dysfunction in subjects with HFpEF.

Admission plasma neutrophil gelatinase associated lipocalin (NGAL) predicts worsening renal function during hospitalization and post discharge outcome in patients with acute heart failure.

UNLABELLED: Abstract Background: The role of neutrophil gelatinase-associated lipocalin (NGAL) has been described in chronic heart failure (HF), however less data are available in patients admitted for acute HF. METHODS: We evaluated the role of NGAL in predicting in-hospital worsening renal function (WRF) and post-discharge follow-up during six months period in patients with acute HF. All patients were submitted to creatinine, estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN) and B-type natriuretic peptide (BNP) measurement during hospitalization and before discharge. RESULTS: Patients with chronic kidney dysfunction (CKD) demonstrated higher NGAL respect to subject with preserved renal function (241 ± 218 and 130 ± 80 ng/ml; P = 0.0001). In subgroup that developed WRF during hospitalization, NGAL levels were significantly increased respect to patients without WRF (272 ± 205 versus 136 ± 127 ng/ml; P = 0.0001). A cut off of 134 ng/ml has been related to WRF with good sensibility and specificity (92% and 71% AUC 0.83; P = 0.001). Multivariable Cox regression analysis showed that cut-off of 134 ng/ml was the only marker related to death (HR: 1.75; 95% CI: 1.24-2.45; P < 0.001). Follow-up analysis confirmed that NGAL > 130 ng/ml was associated with adverse events during a six-month period. CONCLUSION: Admission NGAL measurement appears a sensible tool for in-hospital WRF prediction as well as an early marker for adverse outcome during post discharge vulnerable phase.

Patients with cardiorenal syndrome revealed increased neurohormonal activity, tubular and myocardial damage compared to heart failure patients with preserved renal function.

BACKGROUND: Cardiorenal syndrome (CRS) is associated with increased cardiovascular morbidity and mortality; still, its biomarker pattern has been poorly evaluated so far. The aim of this study was to measure the inflammatory activation, neurohormonal status and kidney and myocardial damage in patients with CRS compared to patients with heart failure (HF) without renal impairment (RI). METHODS: We analyzed 246 patients on the basis of renal function (group 1: 120 HF patients without RI; group 2: 126 CRS patients). In each group, interleukin-6, tumor necrosis factor-α, B-type natriuretic peptide (BNP), neutrophil gelatinase-associated lipocalin (NGAL), troponin T (TnT), osteoprotegerin and blood urea nitrogen (BUN) were measured. The diagnostic power of all laboratory parameters to detect CRS was evaluated by the receiver operating characteristic (ROC) curve and logistic regression analysis. RESULTS: A significant increase in BNP [626.4 pg/ml, confidence interval (CI) 518-749 vs. 487.8 pg/ml, CI 411-578; p < 0.05], NGAL (156 ng/ml, CI 129-186 vs. 89.1 ng/ml, CI 72-109; p < 0.0001), BUN (108.9 mg/dl, CI 98-120 vs. 51 mg/dl, CI 46-55; p < 0,0001) and TnT (0.62 ng/ml, CI 0.51-0.75 vs. 0.21 ng/ml, CI 0.15-0.28; p < 0.001) was seen in CRS patients compared to HF patients without RI. ROC curve analysis showed that only NGAL, BUN, BUN/creatinine ratio and TnT can discriminate patients with CRS from patients without RI. CONCLUSIONS: In CRS patients, renal tubular damage and neurohormonal and cardiac injury activation are increased compared to patients without RI. The current biomarker pattern could be used for an early diagnosis of RI in acute and chronic HF.

Serum relaxin in systemic sclerosis.

OBJECTIVE: To evaluate serum levels of relaxin (RLX), a hormone with acknowledged antifibrotic activity, in patients with systemic sclerosis (SSc). METHODS: We performed a pilot study of 50 outpatients with SSc and 50 healthy subjects. Serum RLX was measured using the relaxin ELISA. Statistical analysis was performed using Student's t test. RESULTS: Serum RLX appeared to be significantly higher (p < 0.001) in patients with SSc compared to controls. RLX appeared significantly increased (p < 0.001) in male patients compared to male controls, and in female patients compared to female controls. RLX was significantly higher (p < 0.001) in female patients and female controls compared to male patients and male controls. CONCLUSION: In patients with SSc, the increased level of RLX represents a defensive response against the fibrotic process.

A polymorphic CYP19 TTTA repeat influences aromatase activity and estrogen levels in elderly men: effects on bone metabolism.

Current evidence suggests that estrogen plays a dominant role in determining bone mineral density (BMD) in men, and inactivating mutations in the aromatase CYP19 gene have been associated with low bone mass in young males. We previously reported an association between a TTTA repeat polymorphism in intron 4 of the CYP19 gene and osteoporotic risk in postmenopausal females. Here we explore the role of this polymorphism as a genetic determinant of BMD in a sample of elderly males who were recruited by direct mailing and followed longitudinally for 2 (n = 300) and 4 (n = 200) yr. Six different allelic variants, containing seven, eight, nine, 10, 11, and 12 TTTA repeats, were detected. There was a bimodal distribution of alleles, with two major peaks at seven and 11 repeats and a very low distribution of the nine-repeat allele. Men with a high-repeat genotype (>nine repeats) showed higher lumbar BMD values, lower bone turnover markers, higher estradiol levels, and a lower rate of BMD change than men with a low-repeat genotype (25), suggesting that the effect of CYP19 genotypes on bone may be masked by the increase in fat mass. Moreover, the high-repeat genotype was less represented, although not significantly, in the vertebral fracture group with respect to the nonvertebral fracture group. Functional in vitro analysis after incubation with [3H]-androstenedione showed a higher aromatase activity in fibroblasts from subjects with a high-repeat genotype than in fibroblasts from subjects with a low-repeat genotype. In conclusion, differences in estrogen levels due to polymorphism at the aromatase CYP19 gene may predispose men to increased age-related bone loss and fracture risk.

Longitudinal association between sex hormone levels, bone loss, and bone turnover in elderly men.

Male osteoporosis is an increasingly important health problem. It is known that sex steroid hormones play an important role in regulating bone turnover and bone mass in males as well as in females. However, the exact mechanism of bone loss in men remains unknown. In the present study, 200 elderly men (age range, 55-85 yr) were followed for 4 yr to evaluate the relationships between hormone levels, bone turnover markers, bone mineral density, and rates of bone loss. Femoral and lumbar bone mineral density, bone ultrasound parameters at the os calcis, serum testosterone (T), serum estradiol (E(2)), SHBG levels, and bone turnover markers (urinary crosslaps and bone alkaline phosphatase) were evaluated for each man at enrollment and 4 yr afterward. The free androgen index (FAI) and free estrogen index (FEI) as well as measures of the bioavailable sex hormones [calculated bioavailable E(2) (c-bioE(2)) and T (c-bioT)] were calculated from total hormone levels and SHBG. In the total population, T, c-bioT, c-bioE(2), FAI, and FEI, but not E(2), decreased significantly with age, whereas SHBG increased significantly. Subjects with FEI, c-bioE(2), and E(2) levels below the median showed higher rates of bone loss at the lumbar spine and the femoral neck as well as higher speed-of-sounds decrease at the calcaneus with respect to men with FEI, c-bioE(2), and E(2) levels above the median. Serum bone alkaline phosphatase and urinary crosslaps were significantly higher in men with FEI, c-bioE(2), and E(2) in the lower quartile than in men with FEI, c-bioE(2), and E(2) levels in the higher quartile. No statistically significant differences were observed in relation to T, c-bioT, or FAI levels. Finally, the ratio between E(2) and T, an indirect measure for aromatase activity, increased significantly with age and was higher in normal than in osteoporotic subjects. In conclusion, results from the present study indicate an important role of estrogens, and particularly of the ability to aromatize T to E(2), in the regulation of bone loss and bone metabolism in elderly men.

Anthropometric, haemodynamic, humoral and hormonal evaluation in patients with incidental adrenocortical adenomas before and after surgery.

OBJECTIVE: To compare clinical and humoral parameters before and after surgery in patients with incidental adrenocortical adenomas. DESIGN: Six patients with subclinical Cushing's syndrome and nine with non-functioning adenomas were investigated before and 12 Months after removal of the mass. METHODS: Anthropometric (body weight, body mass index and waist to hip ratio), haemodynamic (blood pressure and heart rate), metabolic (lipids and oral glucose tolerance test (OGTT)), hormonal (cortisol, plasma renin activity, aldosterone, androgens and catecholamines) and bone metabolism (hydroxyproline, parathyroid hormone, osteocalcin and ostase) parameters were evaluated. RESULTS: In the whole group, a significant decrease in body weight (69.7+/-3.5 vs 70.8+/-3.5 kg, P<0.03), in systolic (135.3+/-5.1 vs 145.6+/-4.9 mmHg, P<0.009) and diastolic (83.7+/-1.9 vs 91.0+/-3.5 mmHg, P<0.03) blood pressure and in glucose levels in response to OGTT (106.4+/-9.6 vs 127.5+/-6.5 mg/dl, P<0.05) was observed after surgery. All other parameters examined did not change significantly. This trend was also found in both groups separately. Analytical data showed a high frequency of overweight/obesity (66.6%), hypertension (66.6%) and impaired glucose profile (26.6%) in our patients, with a greater prevalence of these cardiovascular risk factors in the subclinical Cushing's syndrome group. After surgery, values normalized or improved in eight out of ten hypertensive patients and in three out of four patients with impaired glucose profile. CONCLUSIONS: Solid adrenocortical incidentalomas are associated with some cardiovascular risk factors which may be corrected after removal of the mass. Therefore, surgery may be an appropriate choice in patients with subclinical Cushing's syndrome but also in those with solid non-functioning adenomas and coexistent cardiovascular risk factors.