Chronic Glucocorticoid Use Research Articles

Osteocyte: the unrecognized side of bone tissue

Osteocytes represent 95% of all bone cells. These cells are old osteoblasts that occupy the lacunar space and are surrounded by the bone matrix. They possess cytoplasmic dendrites that form a canalicular network for communication between osteocytes and the bone surface. They express some biomarkers (osteopontin, beta3 integrin, CD44, dentin matrix protein 1, sclerostin, phosphate-regulating gene with homologies to endopeptidases on the X chromosome, matrix extracellular phosphoglycoprotein, or E11/gp38) and have a mechano-sensing role that is dependent upon the frequency, intensity, and duration of strain. The mechanical information transmitted into the cytoplasm also triggers a biological cascade, starting with NO and PGE(2) and followed by Wnt/beta catenin signaling. This information is transmitted to the bone surface through the canalicular network, particularly to the lining cells, and is able to trigger bone remodeling by directing the osteoblast activity and the osteoclastic resorption. Furthermore, the osteocyte death seems to play also an important role. The outcome of micro-cracks in the vicinity of osteocytes may interrupt the canalicular network and trigger cell apoptosis in the immediate surrounding environment. This apoptosis appears to transmit a message to the bone surface and activate remodeling. The osteocyte network also plays a recognized endocrine role, particularly concerning phosphate regulation and vitamin D metabolism. Both the suppression of estrogen following menopause and chronic use of systemic glucocorticoids induce osteocyte apoptosis. On the other hand, physical activity has a positive impact in the reduction of apoptosis. In addition, some osteocyte molecular elements like sclerostin, connexin 43, E11/gp38, and DKK1 are emerging as promising targets for the treatment of various osteo-articular pathologies.

Chronic Prednisolone Treatment Reduces Hepatic Insulin Sensitivity while Perturbing the Fed-to-Fasting Transition in Mice

Chronic glucocorticoid use for treatment of inflammatory diseases is accompanied by severe side effects in humans (e.g. hyperglycemia and insulin resistance). The present studies were conducted to characterize consequences of chronic treatment with the synthetic glucocorticoid prednisolone on insulin sensitivity and blood glucose kinetics in mice. Prednisolone treatment increased fasting blood glucose and plasma insulin concentrations, but this apparently reduced insulin sensitivity could not be confirmed in hyperinsulinemic euglycemic clamp studies. Therefore, a novel method to study whole body glucose kinetics was used. This method revealed that prednisolone-treated mice show an increased hepatic glucose production (HGP). The increased HGP was accompanied by elevated plasma insulin concentrations, indicating reduced insulin sensitivity of hepatic glucose metabolism in prednisolone-treated mice. Compared with vehicle, prednisolone-treated mice had lower blood glucose concentrations, higher plasma free fatty acids, and higher plasma fibroblast growth factor-21 concentrations in the fed condition, i.e. mimicking a fasting situation. Next, the effects of 24-h fasting on energy metabolism were studied. Compared with controls, fasted prednisolone-treated mice had higher blood glucose concentrations and lower plasma beta-hydroxybutyrate concentrations. In conclusion, these results indicate that chronic prednisolone treatment reduces insulin sensitivity of HGP, induces a fasting-like phenotype in fed mice, and perturbs the fed-to-fasting transition.

Exercício físico previne alterações cardiometabólicas induzidas pelo uso crônico de glicocorticóides

Chronically, glucocorticoids induce adverse cardiometabolic alterations including insulin resistance, diabetes, dyslipidemia, liver steatosis and arterial hypertension.To evaluate the effect of regular practice of aerobic exercise on cardiometabolic alterations induced by chronic administration of dexamethasone (Dex - 0.5 mg/kg/day ip) in rats.Male Wistar rats (n = 24) were divided in four groups: Control group; Trained group; Treated with Dex group and Treated with Dex and trained group. The exercise training (initiated 72 hours after the first dose of Dex) was carried out three times a week until the end of the treatment. At the end of this period, the following biochemical assessments were performed: fasting glycemia, oral glucose tolerance test and analysis of the blood lipid profile that included total cholesterol (TC), LDL-c, HDL-c, VLDL-c and triglycerides (TG). The weight of the gastrocnemius muscle, the histopathological analysis of the liver and cardiometabolic indices (TC/HDL-c, LDL-c/HDL-c and TG/HDL-c) were also performed.Hyperglycemia, lower glucose tolerance, increased TC, LDL-c, VLDL-c, TG, CT/HDL-c, LDL-c/HDL-c and TG/HDL-c, decreased HDL-c, presence of liver steatosis and muscular hypotrophy were observed in the animals treated with Dex. The exercise training reduced hyperglycemia, improved glucose tolerance, decreased dyslipidemia and prevented liver steatosis, muscular hypotrophy and reduced CT/HDL-c, LDL-c/HDL-c and TG/HDL-c ratios. However, there was no significant effect on HDL-c.The aerobic exercise training have a protective effect against the cardiometabolic alterations induced by the chronic use of glucocorticoids.

Chronic obstructive pulmonary disease is associated with osteoporosis and low levels of vitamin D

We did a cross-sectional analysis of chronic pulmonary obstructive disease (COPD) patients without chronic use of systemic glucocorticoids (CUG). Osteoporosis was found in 51% and bone mineral density (BMD) was correlated with severity of disease. Low levels of vitamin D were found in 94%. All COPD patients may benefit from vitamin D supplementation and screening for low BMD. Patients with chronic pulmonary obstructive disease have low bone mineral density, caused by chronic use of systemic glucocorticoids and hypovitaminosis D. However, patients without CUG may also have low BMD. We performed a cross-sectional analysis in 49 patients (21 men, 28 postmenopausal women), with COPD without CUG, from Brazil (25 degrees 25' S). Several markers of bone metabolism were measured, plus BMD. Osteoporosis risk factors and history of fractures were investigated. Respiratory function was assessed by venous gasometry, spirometry, and oximetry. BMD results were compared to those of 40 healthy non-smokers controls. COPD patients had lower BMD at all sites (p < 0.01). Osteoporosis was observed in 51%. BMD independently correlated with stage of disease (lumbar spine, R = 0.38, p = 0.01; total femur, R = 0.36, p = 0.01; femoral neck, R = 0.40, p < 0.01). Ninety-four percent had low levels of vitamin D (<30 ng/mL) and 67% had secondary hyperparathyroidism. Vitamin D was correlated with oxygen saturation (R = 0.36, p = 0.01), with lower levels in those with saturation <88% (p = 0.01). Patients with COPD without CUG have increased risk for osteoporosis. Such patients have hypovitaminosis D, which is correlated with the severity of disease. Screening for low BMD and vitamin D supplementation may be warranted to all COPD patients.

Bisphosphonates for Glucocorticoid Users: Yearly or Daily?

Chronic glucocorticoid use is associated with osteoporosis and excess risk for fractures. In an international, randomized, double-blind, double-dummy trial sponsored by the manufacturer of zoledronic acid (Reclast), investigators assessed the efficacy and safety of a single 5-mg intravenous infusion of zoledronic acid compared with 5-mg oral risedronate daily for 1 year. Before randomization, all 833 participants (68% of whom were women and 40% of whom used …

Adenosine receptor agonists for promotion of dermal wound healing

Wound healing is a dynamic and complex process that involves a well-coordinated, highly regulated series of events including inflammation, tissue formation, revascularization and tissue remodeling. However, this orderly sequence is impaired in certain pathophysiological conditions such as diabetes mellitus, venous insufficiency, chronic glucocorticoid use, aging and malnutrition. Together with proper wound care, promotion of the healing process is the primary objective in the management of chronic poorly healing wounds. Recent studies have demonstrated that A 2A adenosine receptor agonists promote wound healing in normal and diabetic animals and one such agonist, Sonedenoson, is currently being evaluated as a prospective new therapy of diabetic foot ulcers. We will review the mechanisms by which adenosine receptor activation affects the function of the cells and tissues that participate in wound healing, emphasizing the potential beneficial impact of adenosine receptor agonists in diabetic impaired healing.

OPPORTUNITY™

The mortality rate of maintenance hemodialysis (MHD) patients remains high. Measures of protein-energy wasting, including hypoalbuminemia, are strongly associated with their high mortality. Growth hormone (GH) may improve lean body mass (LBM) and serum albumin levels, and health-related quality of life (HRQoL), which are significantly and positively associated with survival in MHD patients. The OPPORTUNITY Trial will examine whether GH reduces mortality and morbidity and improves overall health in hypoalbuminemic MHD patients. The primary hypothesis is that daily recombinant human GH injections, compared with placebo, improve survival in hypoalbuminemic MHD patients. Secondary hypotheses are that GH improves morbidity and health, including number of hospitalized days, time to cardiovascular events, LBM, serum protein and inflammatory marker levels, exercise capacity, and HRQoL, and has a favorable safety profile. This is a prospective, double-blind, multicenter, randomized clinical trial involving 2500 MHD patients, up to 50% with diabetes mellitus, from 22 countries. Patients are randomized in a 1:1 ratio to receive daily injections of GH (20 microg/kg per day) or placebo for 104 weeks. Key inclusion criteria include clinically stable and well-dialyzed (Kt/V > or =1.2) adult MHD patients with serum albumin <4.0 g/dl. Exclusion criteria include active malignancy, active proliferative or severe nonproliferative diabetic retinopathy, uncontrolled hypertension, chronic use of high-dose glucocorticoids, or immunosuppressive agents and pregnancy. The OPPORTUNITY Trial is the first large-scale randomized clinical trial in adult MHD patients evaluating the response to GH of such clinical endpoints as mortality, morbidity, markers of body protein mass, inflammation, exercise capacity, and HRQoL.

Cushing Syndrome and Suppression of the Hypothalamic-Pituitary-Adrenal Axis After Chronic Use of Topical Glucocorticoids

Topical and inhaled corticoids are considered to be safe even though some reports point out the risks, especially in children. We describe 2 adults in whom the chronic use of topical steroids led to Cushing syndrome. Patients treated with potent topical corticoids should be informed about the possibility of developing Cushing syndrome. Adrenal reserve should be monitored in those patients treated with glucocorticoids for long periods, regardless of the administration route.

Impact of Growth Hormone and Dehydroepiandrosterone on Protein Metabolism in Glucocorticoid-Treated Patients

Chronic pharmacological glucocorticoid (GC) use causes substantial morbidity from protein wasting. GH and androgens are anabolic agents that may potentially reverse GC-induced protein loss. Our objective was to assess the effect of GH and dehydroepiandrosterone (DHEA) on protein metabolism in subjects on long-term GC therapy. This was an open, stepwise GH dose-finding study (study 1), followed by a randomized cross-over intervention study (study 2). The studies were performed at a clinical research facility. In study 1, six subjects (age 69+/-4 yr) treated with long-term (>6 months) GCs (prednisone dose 8.3+/-0.8 mg/d) were studied before and after two sequential GH doses (0.8 and 1.6 mg/d) for 2 wk each. In study 2, 10 women (age 71+/-3 yr) treated with long-term GCs (prednisone dose 5.4+/-0.5 mg/d) were studied at baseline and after 2-wk treatment with GH 0.8 mg/d, DHEA 50 mg/d, or GH and DHEA (combination treatment). Changes in whole body protein metabolism were assessed using a 3-h primed constant infusion of 1-[13C]leucine, from which rates of leucine appearance, leucine oxidation, and leucine incorporation into protein were estimated. In study 1, GH 0.8 and 1.6 mg/d significantly reduced leucine oxidation by 19% (P=0.03) and 31% (P=0.02), and increased leucine incorporation into protein by 10% (P=0.13) and 19% (P=0.04), respectively. The lower GH dose did not cause hyperglycemia, whereas GH 1.6 mg/d resulted in fasting hyperglycemia in two of six subjects. In study 2, DHEA did not significantly change leucine metabolism alone or when combined with GH. Blood glucose was not affected by DHEA. GH, at a modest supraphysiological dose of 0.8 mg/d, induces protein anabolism in chronic GC users without causing diabetes. DHEA 50 mg/d does not enhance the effect of GH. GH may safely prevent or reverse protein loss induced by chronic GC therapy.

The near absence of osteoporosis treatment in older men with fractures

The burden of osteoporotic fractures in older men is significant. The objectives of our study were to: (1) characterize older men with fractures associated with osteoporosis, (2) determine if medication treatment rates for osteoporosis are improving and (3) identify patient, healthcare benefit and utilization, and clinician characteristics that are significantly associated with treatment. This retrospective cohort study assessed 1,171 men aged 65 or older with any new fracture associated with osteoporosis between 1 January 1998 and 30 June 2001 in a non-profit health maintenance organization in the United States. Multiple logistic regression was used to evaluate pre-fracture factors for their association with osteoporosis treatment in the 6-month post-fracture period. The main outcome measure was pharmacologic treatment for osteoporosis in the 6 months after the index fracture. Subjects' average age was 76.7 years; 3.3% had a diagnosis of osteoporosis and 15.2% a diagnosis or medication associated with secondary osteoporosis. Only 7.1% of the study population and 16.0% of those with a hip or vertebral fracture received a medication for osteoporosis following the index fracture, and treatment rates did not improve over time. In the multivariate model, factors significantly associated with drug treatment were a higher value on the Charlson Comorbidity Index (odds ratio 1.26, 95% confidence interval 1.05-1.51), having an osteoporosis diagnosis (odds ratio 8.11, 95% confidence interval 3.08-21.3), chronic glucocorticoid use (odds ratio 5.37, 95% confidence interval 2.37-12.2) and a vertebral fracture (odds ratio 16.6, 95% confidence interval 7.8-31.4). Bone mineral density measurement was rare (n =13, 1.1%). Our findings suggest that there is under-ascertainment and under-treatment of osteoporosis and modifiable secondary causes in older men with fractures. Information systems merging diagnostic and treatment information can help delineate gaps in patient management. Interventions showing promise in other conditions should be evaluated to improve care for osteoporosis.

Anestesia para cesariana em paciente com hiperplasia adrenal congênita: relato de caso

The purpose of this case report is to illustrate the anesthetic management of a Cesarean section in a patient with non-classic congenital adrenal hyperplasia (CAH) and to review the clinical features and management of various forms of CAH during pregnancy. A 32-year-old primigravida, diagnosed with non-classic CAH, was admitted with intrauterine growth retardation at 28 weeks of gestation. Clinical features included morbid obesity, mild hypertension and chronic use of glucocorticoids. An emergency Cesarean section was performed at 29 weeks of gestation under uneventful spinal anesthesia with perioperative steroid coverage. Both mother and neonate had good outcome. The management of patients with CAH presenting for labour or operative delivery should include the understanding of the effects of chronic steroid therapy, signs of adrenal insufficiency and perioperative steroid coverage. Anesthetic considerations should include issues related to obesity and hypertension. A multidisciplinary approach is required to ensure successful outcome.

Osteoporosis Before Lung Transplantation: Association with Low Body Mass Index, but Not with Underlying Disease

Due to progress in lung transplantation, post-transplantation osteoporosis becomes an important problem. We determined bone mineral density (BMD) in 74 lung transplantation candidates, among them 24 patients with cysticfibrosis, 16 with chronic obstructive pulmonary disease, 14 with pulmonary fibrosis, and 11 with pulmonary hypertension. The mean T score (+/- SD) was -2.6 +/- 1.3 at femoral neck (FN), -2.2 +/- 1.6 at Ward's triangle (WT) and -2.3 +/- 1.5 at lumbar spine (LS). Osteoporosis was found in 61% of the patients at FN, 45% at WT and 50% at LS. Patients with different underlying lung diseases were similarly affected, not only those with cystic fibrosis but also others, including patients with pulmonary hypertension. No association was found between BMD and age, gender, menstrual condition in women and testosterone level in men. A negative correlation was found between chronic glucocorticoid use and T scores. Body mass index correlated positively (p < 0.01) with T scores at any site and the correlation was also significant for the 2 largest subgroups. Loss of lung function (FEV1) also was associated with lower T scores. No correlation was found between BMD and biochemical indices of bone turnover. Multivariate analysis revealed BMI and glucocorticoid use as independent risk factors. We conclude that osteoporosis is a very common condition in patients with end-stage pulmonary disease, independent of the underlying diagnosis. In view of additional bone loss under immunosuppressive treatment after lung transplantation, early diagnosis and prevention of osteoporosis in the pretransplant period should receive high priority.

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Background/Aim: Prolonged use of glucocorticoids (GC) in glioma treatment can lead to adrenal insufficiency (AI) and subsequent steroid dependence due to suppression of the hypothalamic-pituitary-adrenal (HPA) axis. This is challenging to diagnose due to its nonspecific clinical symptoms erroneously ascribed to treatment. This study aimed to evaluate the risk factors predisposing patients with gliomas to develop AI. Patients and Methods: Charts in the neuro-oncology clinic from July 2018 to March 2019 were reviewed. Inclusion criteria included &gt;18 y/o with WHO Grade II-IV gliomas, and secondary AI. Demographic profile, tumor characteristics, and treatment profile were compared. Results: The majority of patients were started on high dose dexamethasone at &gt;8 mg daily, and were on dexamethasone for 4-8 months. The minimum dose needed to prevent symptoms was 0.5 mg to 2 mg daily. The majority received standard radiation doses ranging from 54-60 Gy. Most patients had radiation exposure to the HPA axis within the prescription isodose levels. Conclusion: Prolonged steroid dependency can result from chronic GC use in patients with glioma. Dose and duration of GC are risk factors for its development. Radiation exposure to the HPA axis may also be a contributing factor.