Long-term Glucocorticoid Therapy Research Articles

Effect of long-term glucocorticoid therapy on cardiac functions in children with congenital adrenal hyperplasia.

Glucocorticoids play an important role in cardiac physiology. Chronic exposure and higher doses may cause adverse effects on the myocardium, especially in young patients receiving long-term therapy. To assess cardiac function in children with congenital adrenal hyperplasia (CAH) and its relation to glucocorticoid dose and therapy duration. Forty-seven patients with CAH due to 21-hydroxylase deficiency were compared to 47 controls. Patients were subdivided according to treatment duration (Group A: less than 6years, Group B: more than 6years). Mean daily glucocorticoid and cumulative glucocorticoid doses were calculated. Echocardiography was performed for patients and controls to evaluate cardiac functions, chamber dimensions and tissue Doppler valvular status. Compared to controls, patients had cardiac chamber hypertrophy reflected by higher M-mode dimensions. Patients had lower fractional shortening, defective ventricular relaxation, lower average mitral and tricuspid e´/a´ ratios (e´ early diastolic, a´ late diastolic) as well as s´ (systolic) velocities, higher average mitral E/e ratio and higher left ventricle TDI Tei index (P<.05). Group B had lower average mitral e´/a´ and tricuspid s´ velocities, and higher average mitral E/e ratio (P<.05). Cumulative glucocorticoid dose significantly correlated with different echocardiographic parameters. Long-term glucocorticoid therapy even within the recommended therapeutic range adversely affects cardiac functions in children with 21-hydroxylase deficiency.

Long-Term Glucocorticoid Use and Cancer Risk: A Population-Based Cohort Study in South Korea.

Long-term glucocorticoid (GC) exposure causes immunosuppression; therefore, the risk of cancer may be increased in long-term GC users. We investigated whether long-term GC use is associated with a higher risk of cancer in the population without cancer. A population-based cohort study using data from the National Health Insurance Service was conducted among the South Korean adult population in 2010. Long-term GC users were defined as those who were prescribed a continuous supply of oral GC for ≥30 days. The primary endpoint was a new cancer diagnosis from January 1, 2011, to December 31, 2015. Among 770,880 individuals included in the analysis, 1,602 (0.2%) were long-term GC users and 36,157 (4.7%) were newly diagnosed with cancer from January 2011 to December 2015. In the multivariable Cox regression analysis, the risk of cancer among long-term GC users was 1.23-fold higher than that of the unexposed individuals [95% confidence interval (CI), 1.06-1.43; P = 0.007]. In the competing risk analyses, the risks of liver cancer and lung cancer were 1.46-fold (95% CI, 1.03-2.07; P = 0.034) and 1.52-fold (95% CI, 1.04-2.21; P = 0.029) higher in the long-term GC users than that of the unexposed individuals, respectively. We found that long-term GC exposure might be associated with a higher risk of overall cancer, and this association was more evident for lung and liver cancer risk. However, because there might be unmeasured and potential confounders in this study, the results should be interpreted carefully, and future studies should be performed to confirm these findings. IMPACT: Long-term glucocorticoid therapy might be associated with a higher cancer risk. This association was more evident for lung and liver cancer risk. Our findings suggest that long-term prescriptions of glucocorticoids should be administered carefully considering the risk of cancer.

Daphnetin ameliorates glucocorticoid-induced osteoporosis via activation of Wnt/GSK-3β/β-catenin signaling

Glucocorticoids have been widely used in multiple inflammatory and autoimmune diseases. However, long-term glucocorticoid therapy may result in osteoporosis. The present study aimed to evaluate the potential therapeutic effects and investigate the underlying mechanisms of Daphnetin (Daph) on glucocorticoid-induced osteoporosis (GIOP). In vivo, male Sprague Dawley rats were intramuscularly injected with dexamethasone (DEX) to induce GIOP and Daph was given intraperitoneally. Bone histological changes, mineral content, microstructure parameters and bone turnover markers were detected. Gut microbiota composition and intestinal barrier function were further assessed. In vitro, MC3T3-E1 pre-osteoblasts were treated with DEX and the abilities of Daph on osteoblast proliferation, differentiation and mineralization were assessed. A Wnt signaling inhibitor, XAV939, was added additionally to evaluate the effect of Daph on Wnt signaling. The results showed that in vivo, Daph increased the DEX-induced reduction in body weight gain, bone mineral content and microstructure parameters and restored the levels of bone turnover markers in GIOP rats. In vitro, Daph promoted osteoblast proliferation, differentiation and mineralization in DEX-treated MC3T3-E1 pre-osteoblasts. Moreover, Daph activated the Wnt/GSK-3β/β-catenin signaling pathway. XAV939 successfully abolished the beneficial effects of Daph on GIOP in vitro. Besides, Daph showed improvement on gut microbiota disorder and intestinal barrier dysfunction post GIOP. Collectively, these data demonstrated that Daph effectively ameliorates GIOP and the possible mechanism may be that Daph activated Wnt/GSK-3β/β-catenin signaling.

The Role of Piper sarmentosum Aqueous Extract as a Bone Protective Agent, a Histomorphometric Study.

Glucocorticoids are one of the causes of secondary osteoporosis. The aqueous extract of Piper sarmentosum contains flavonoids that possess antioxidant effects. In this study, we determined the effects of aqueous Piper sarmentosum leaf extract on structural, dynamic and static histomorphometric changes from osteoporotic bones of rats induced with glucocorticoids. Thirty-two Sprague-Dawley rats were divided equally into four groups—Sham control group given vehicles (intramuscular (IM) olive oil and oral normal saline); AC: Adrenalectomised (Adrx) control group given IM dexamethasone (DEX) (120 μg/kg/day) and vehicle (oral normal saline); AP: Adrx group administered IM DEX (120 μg/kg/day) and aqueous Piper sarmentosum leaf extract (125 mg/kg/day) orally; and AG: Adrx group administered IM DEX (120 μg/kg/day) and oral glycyrrhizic acid (GCA) (120 mg/kg/day). Histomorphometric measurements showed that the bone volume, trabecular thickness, trabecular number, osteoid and osteoblast surfaces, double-labelled trabecular surface, mineralizing surface and bone formation rate of rats given aqueous Piper sarmentosum leaf extract were significantly increased (p < 0.05), whereas the trabecular separation and osteoclast surface were significantly reduced (p < 0.05). This study suggests that aqueous Piper sarmentosum leaf extract was able to prevent bone loss in prolonged glucocorticoid therapy. Thus, Piper sarmentosum has the potential to be used as an alternative medicine against osteoporosis and osteoporotic fractures in patients undergoing long-term glucocorticoid therapy.

Skeletal health in patients following allogeneic hematopoietic cell transplantation.

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative approach for patients with certain hematological diseases, including several forms of lymphoma and leukemia. Besides several treatment-associated risks, transplanted patients are at an increased risk of developing osteoporosis. The underlying pathophysiology is complex and includes factors influenced directly by the disease as well as applied therapies like irradiation, chemotherapy and adjuvant immunosuppressive agents. In addition, patients are prone to secondary hypogonadism, and many patients will require long-term glucocorticoid therapy to mitigate graft-versus-host reactions. All these factors contribute to bone loss, but the individual risk profile may vary greatly. This review summarizes our knowledge on bone loss following allogenic HCT and provides screening and treatment recommendations.

IDIOPATHIC PULMONARY HEMOSIDEROSIS IN A DOWN SYNDROME PATIENT

SESSION TITLE: Fellows Diffuse Lung Disease Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Idiopathic Pulmonary Hemosiderosis (IPH) is a rare disease found primarily in children characterized by recurrent episodes of diffuse alveolar hemorrhage. The exact etiology and pathogenesis of IPH is unknown. Patients with Down Syndrome have a higher risk of developing pulmonary hemosiderosis. Additionally, in this population IPH manifests more severely. CASE PRESENTATION: Patient is 25 months old ex 36-week female with history of Trisomy 21, Atrial septal defect (ASDs) who has had a history of recurrent hemoptysis, anemia, and pulmonary infiltrates. Patient underwent extensive work-up including bronchoscopy and lung biopsy with the final diagnosis of Idiopathic Pulmonary Hemosiderosis (IPH). The patient presented to our PICU with acute alveolar hemorrhage and severe anemia secondary to RSV pneumonia and IPH recurrence despite being on maintenance therapy of prednisone and hydroxychloroquine. Patient required advanced respiratory support and was treated with a short course of pulse steroids. Patient eventually was placed on Azathioprine instead of Hydroxychloroquine with an increased Prednisone maintenance dose. DISCUSSION: IPH generally occurs in children below the age of 10 years, most commonly from 1 to 7 years. The classical triad of anemia, hemoptysis, and pulmonary infiltrates is a distinguishing characteristic of this disease; however, any one of them could be the initial manifestation. The estimated prevalence of IPH reaches 1.85 per 1,000,000 children, compared to 138.5 per 1,000,000 children with Down Syndrome. Patients with Down Syndrome tend to present earlier and more severely; they experience more dyspnea at diagnosis, more frequent secondary pulmonary hypertension (PAH), and an increased risk of fatal evolution. Systemic glucocorticoids are the mainstay of therapy for acute alveolar hemorrhage due to IPH. In a prior series of 23 children with IPH, low-dose oral prednisone was associated with prolonged survival compared with historical controls. In another series of 17 patients, long-term glucocorticoid therapy was associated with a five-year survival of 86 percent. The duration of corticosteroid treatment was variable among the patients based on clinical, radiological (alveolar infiltrates), and biological (hemoglobin, reticulocytes) evolution. Currently, there are no definitive guidelines directing use or choice of steroid-sparing medications in IPH; however, a few case reports describe the use of an immunosuppressant (cyclophosphamide, hydroxychloroquine, mycophenolate mofetil, azathioprine) in conjunction with oral glucocorticoids in the setting of respiratory failure. CONCLUSIONS: Additional studies investigating different therapeutic options are critical in order to reduce overall morbidity & mortality, particularly in children with Down Syndrome who are more predisposed to IPH relapse. Reference #1: Dr. Inderpal Randhawa Reference #2: Dr. Bugsu Ovunc Reference #3: Dr. Cyrus Shahriary DISCLOSURES: No relevant relationships by Yaron Fireizen, source=Web Response No relevant relationships by Nastasia Nianiaris, source=Web Response No relevant relationships by Inderpal Randhawa, source=Web Response No relevant relationships by Cyrus Shahriary, source=Web Response No relevant relationships by Dibanni Vasquez, source=Web Response

Long-term systemic glucocorticoid therapy and weight gain: a population-based cohort study.

To describe the variation in weight gain in people chronically exposed to systemic glucocorticoids in primary care and to identify the risk factors for weight gain. Data were analysed from the British database, The Health Improvement Network. Body weight variations of individuals prescribed systemic glucocorticoids for at least 3 months at a mean dose ≥10 mg/day were described. The risk factors associated with weight gain ≥10% of the usual weight were assessed. A total of 31516 adults prescribed glucocorticoids and 26967 controls were included in the study. During glucocorticoid exposure, only 12475 (39.6%) individuals gained >2 kg compared with their usual weight. Younger women were more likely to gain weight (mean weight gain in 18-39-year-old glucocorticoid-exposed women: 3.6 kg (s.d. 8.6) compared with 2 kg (s.d. 7.3) in the control group; the absolute mean difference was 1.6 kg (95% CI 0.9, 2.2; P < 0.001). Weight gain ≥10% of the usual weight was observed in 10.2% (n = 3208) of those chronically exposed to glucocorticoids. Women, younger people, those living in areas of higher deprivation, smokers, those on higher doses of the drug and those previously exposed to glucocorticoids were at higher risk. The risk was lower in people prescribed glucocorticoids for an inflammatory condition when compared with asthma or chronic obstructive pulmonary disease. After taking into account usual weight rather than weight just before glucocorticoid initiation and the natural history of weight variation, the amount of weight gain induced by systemic glucocorticoids as prescribed in primary care is less than usually thought. 18THIN081.

High fracture risk patients with glucocorticoid-induced osteoporosis should get an anabolic treatment first.

Long-term glucocorticoid (GC) therapy induces glucocorticoid-induced osteoporosis (GIOP) and its associated fractures. Most specialty organizations recommend bisphosphonates as first-line therapies based only on bone mineral density efficacy data. Effective treatment of GIOP based on head-to-head trials with fracture endpoint has not yet been established. The pathophysiologic mechanisms of GIOP that lead to the detrimental effects on bone are not yet fully elucidated. Although GCs in an early and transitory period promote osteoclastic activity, in the current paper, we outline why GIOP is in fact a disease of the bone formation and then provide the rationale for the use of bone-forming agents as first-line therapy for patients with high fracture risk in GIOP.

Safety and efficacy of teriparatide treatment for severe osteoporosis in patients with Duchenne muscular dystrophy.

Despite standard therapy with vitamin D and bisphosphonates (BP), many patientswith Duchenne muscular dystrophy (DMD) continue to sustain fragility fractures due to long-term glucocorticoidtreatment and limited mobility. We aimed toevaluate the safety and efficacy of teriparatide for the treatment of severe osteoporosis in adolescent and young adult patients with DMD. We prospectively treated 6 patients with DMD who had severe osteoporosis with teriparatide 20mcg subcutaneously daily for 1-2years. Inclusion criteria were long-term glucocorticoid therapy, and severe osteoporosis despite treatment with BP, or intolerance to BP. We examined long bone and vertebral fracture outcomes, including vertebral morphometry measures, bone mineral density and content, bone formation markers, safety indices, and adverse events. The mean age at teriparatide start was 17.9years (range 13.9-22.1years). All 6 patients were on daily glucocorticoids (mean ± SD; duration 10.9 ± 2.5years) and 5 were non-ambulatory. Five patients had been treated with BP for 7.9 ± 4.2years. All had vertebral and a history of long bone fragility fractures at baseline. Vertebral heights and Genant fracture grading remained stable. Long bone fracture rate appeared to decrease (from 0.84/year to 0.09/year); one patient sustained a long bone fracture at 6months of treatment. Trajectories for change in bone mineral density and content were not different post- vs. pre-teriparatide. Procollagen type 1 amino-terminal propeptide (P1NP) increased, while laboratory safety indices remained stable and non-concerning. No adverse events were observed. In six patients with DMD treated with teriparatide for severe osteoporosis, we observed stable bone health and modest increases in P1NP, without safety concerns. Further studies are needed to better understand teriparatide efficacy for treatment of osteoporosis in patients with DMD.

Predictors of long-term therapy with glucocorticoid in polymyalgia rheumatica

Objectives To investigate the response of glucocorticoid (GC) therapy for patients with polymyalgia rheumatica (PMR) and predictive factors which correspond to the long-term GC. Methods We reviewed 93 patients with PMR who were treated with GC for more than 6 months. We compared the clinical findings between patients who achieved remission within 24 months (early-remission group, n = 40) and those who required GC therapy for more than 24 months (long-therapy group, n = 24). Results Among 93 patients, 49 have achieved a remission, 35 were undergoing treatment, and 9 have transferred to other hospitals or died. Rate of remission of patients treated for one year GC therapy was in 12% and 53% after 2 years. Serum CRP of long-therapy group was significantly higher than those of the early-remission group. The ratio of patients who experienced more than one relapse within 6 months was 37.5% of long-therapy group and 7.5% of early-remission group. Multivariate logistic regression analysis showed that the history of relapse until 6 months was a significant predictor of long therapy. Conclusions Some patients need the long-term therapy for more than 4 years. The history of relapse till 6 months is a significant predictor of the long-term GC therapy.

MON-189 Evaluation of Adrenal Insufficiency and Recovery in Rheumatology Patients on Long-Term Glucocorticoid Therapy

BackgroundLong-term glucocorticoid (GC) therapy is commonly used to treat rheumatological conditions. This may result in tertiary adrenal insufficiency, as a result of suppression of the HPA axis, when GC doses are weaned/withdrawn. There is little published data about tertiary adrenal insufficiency in this group. This study aims to further evaluate prevalence, characteristics and recovery of adrenal insufficiency in these patients at a large UK teaching hospital.MethodsWe retrospectively identified patients seen in outpatient clinics between January 2014 and September 2019 who had received tapering doses of long-term GC to treat their underlying condition (largely patients with polymyalgia rheumatica, giant cell arteritis or other vasculitis) and had either had a 9am cortisol or short synacthen test (SST). Data were collected using a standardised proforma.ResultsThere was a total of 238 patients, median age of 71 years with a female preponderance (75%). Mean duration of glucocorticoid use was 63.3 months. Mean peak dose of glucocorticoid was 29.2mg.142 patients had 9am cortisol as the first line test to assess adrenal function. 65% of these were considered sub-optimal based on local protocol (cortisol <350nmol/L). 38% of these patients went on to have SST, of which 56% continued to show evidence of sub-optimal cortisol production. All patients where baseline 9am cortisol was <100nmol/L failed to reach stimulated cortisol of >500nmol/L on SST, whereas 31% failed SST if 9am cortisol was 250-350 nmol/L.In total 138 SSTs were performed of which 51% (n=70) were abnormal (cortisol <500nmol/L post synacthen). When baseline cortisol was <100nmol/L on SST, all patients had a suboptimal peak response. However, where baseline cortisol on SST was >350 nmol/L only 3% had a sub-optimal peak cortisol.32 of these patients with an abnormal baseline SST went on to have a repeat SST within 2 years. 50% (n=16) continued to be suboptimal. Of the 32 patients, 38% (n=12) were switched to hydrocortisone with 33% showing complete adrenal recovery, average time to recovery of 25 months. 62% (n=20) patients did not switch, with 60% demonstrating recovery within the same time period (p=0.05). Mean ACTH levels in patients who had sub-optimal SST were 23.1 ng/L (n=19). ACTH levels were not different between those who recovered and those who did not (p=0.23).ConclusionOur study suggests that tertiary adrenal insufficiency is highly prevalent in this cohort of patients with rheumatological conditions requiring long-term glucocorticoid therapy. A 9am cortisol threshold of greater than 350nmol/L excludes most patients with adrenal insufficiency. These data also suggest no significant difference in adrenal recovery if switched to hydrocortisone versus continuing on prednisolone. ACTH levels were not fully suppressed in patients with adrenal insufficiency and did not predict recovery.

Recent advances in the diagnosis and management of giant cell arteritis.

Giant cell arteritis (GCA) has classically been diagnosed by temporal artery biopsy and treated with high-dose, long-term glucocorticoid therapy. Noninvasive imaging increasingly is employed for diagnostic purposes, but further studies are needed to determine the role of imaging in monitoring longitudinal disease activity. Glucocorticoid-sparing therapy mitigates the numerous adverse effects of glucocorticoids. This review addresses new developments in these areas. For diagnosis, when performed at a center with expertise in its use, temporal artery ultrasound has an estimated sensitivity and specificity of 78 and 79%, respectively. State-of-the-art time-of-flight positron emission tomography/computed tomography (PET/CT) has an estimated sensitivity and specificity of 71 and 91%, respectively. The sensitivities of both imaging modalities decrease following glucocorticoid administration. Tocilizumab is an effective glucocorticoid-sparing therapy, demonstrating sustained glucocorticoid-free remission in 56% of patients receiving weekly tocilizumab compared with 18% of patients receiving a 52-week prednisone taper. The traditional acute phase reactants are of no value in patients treated with interleukin-6 receptor (IL6-R) blockade, and thus, the development of new biomarkers is an important priority in the field. Noninvasive imaging techniques are increasingly used in the absence of temporal artery biopsy to confirm diagnostic suspicions of GCA. Tocilizumab reduces the cumulative glucocorticoid exposure and increases the rate of sustained remission. Ongoing efforts are directed towards new methods to identify disease flares.

Associated factors of poor treatment outcomes in patients with giant cell arteritis: clinical implication of large vessel lesions

BackgroundRelapses frequently occur in giant cell arteritis (GCA), and long-term glucocorticoid therapy is required. The identification of associated factors with poor treatment outcomes is important to decide the treatment algorithm of GCA.MethodsWe enrolled 139 newly diagnosed GCA patients treated with glucocorticoids between 2007 and 2014 in a retrospective, multi-center registry. Patients were diagnosed with temporal artery biopsy, 1990 American College of Rheumatology classification criteria, or large vessel lesions (LVLs) detected by imaging based on the modified classification criteria. Poor treatment outcomes (non-achievement of clinical remission by week 24 or relapse during 52 weeks) were evaluated. Clinical remission was defined as the absence of clinical signs and symptoms in cranial and large vessel areas, polymyalgia rheumatica (PMR), and elevation of C-reactive protein (CRP) levels. A patient was determined to have a relapse if he/she had either one of the signs and symptoms that newly appeared or worsened after achieving clinical remission. Re-elevation of CRP without clinical manifestations was considered as a relapse if other causes such as infection were excluded and the treatment was intensified. Associated factors with poor treatment outcomes were analyzed by using the Cox proportional hazard model.ResultsCranial lesions, PMR, and LVLs were detected in 77.7%, 41.7%, and 52.5% of the enrolled patients, respectively. Treatment outcomes were evaluated in 119 newly diagnosed patients who were observed for 24 weeks or longer. The mean initial dose of prednisolone was 0.76 mg/kg/day, and 29.4% received any concomitant immunosuppressive drugs at baseline. Overall, 41 (34.5%) of the 119 patients had poor treatment outcomes; 13 did not achieve clinical remission by week 24, and 28 had a relapse after achieving clinical remission. Cumulative rates of the events of poor treatment outcomes in patients with and without LVLs were 47.5% and 17.7%, respectively. A multivariable model showed the presence of LVLs at baseline was significantly associated with poor treatment outcomes (adjusted hazard ratio [HR] 3.54, 95% CI 1.52–8.24, p = 0.003). Cranial lesions and PMR did not increase the risk of poor treatment outcomes.ConclusionThe initial treatment intensity in the treatment algorithm of GCA could be determined based upon the presence or absence of LVLs detected by imaging at baseline.

Effect of Calcium Supplementation in Glucocorticoid-Induced Osteoporosis

The commonest secondary cause of osteoporosis is Glucocorticoid-induced osteoporosis (GIO) which is also the commonest cause of iatrogenic osteoporosis. Chronic glucocorticoids (GCs) treatment may cause fractures in 30-50% of patients. Fracture risk is increased among those using oral glucocorticoids. On long-term glucocorticoids therapy, deterioration of cortical bone progressively detected and long bones became increasingly fragile. Any patient with chronic glucocorticoids therapy should be expected as suffering from GIO. Patients on glucocorticoids should receive supplementation with calcium. These deleterious influences are the result of suppression of bone formation that occurs with an early but temporal rise in the process of bone resorption. Numbers of osteoclast also rapidly rise, and accompanied by inactivation of osteoblast and decline of bone formation, these changes cause the fastest bone loss during the initial phase disease. Glucocorticoids cause inhibition of osteoblasts replication and function and accelerate their apoptosis. Calcium is fundamental for bone, and assuring sufficient calcium intake is important. It is said that when children and adolescents ingest large amount of calcium could result in a decrease in the danger of developing osteoporosis when they got old, however, some researches propose that solitary use of calcium supplementation might not be enough for lowering the danger for fracture. Conflicting results were reported about the effects of the use of supplemental calcium on the bone mineral content in those taking glucocorticoids therapy. Whereas, calcium supplementations were used in most bone protective treatment trials and therefore should be used as an adjunct to GIO therapy.

Pulsed electromagnetic fields modify the adverse effects of glucocorticoids on bone architecture, bone strength and porous implant osseointegration by rescuing bone-anabolic actions.

Long-term glucocorticoid therapy is known to induce increased bone fragility and impaired skeletal regeneration potential. Growing evidence suggests that pulsed electromagnetic fields (PEMF) can accelerate fracture healing and increase bone mass both experimentally and clinically. However, how glucocorticoid-treated bone and bone cells respond to PEMF stimulation remains poorly understood. Here we tested the effects of PEMF on bone quantity/quality, bone metabolism, and porous implant osseointegration in rabbits treated with dexamethasone (0.5mg/kg/day, 6weeks). The micro-CT, histologic and nanoindentation results showed that PEMF ameliorated the glucocorticoid-mediated deterioration of cancellous and cortical bone architecture and intrinsic material properties. Utilizing the new porous titanium implant (Ti2448) with low toxicity and low elastic modulus, we found that PEMF stimulated bone ingrowth into the pores of implants and enhanced peri-implant bone material quality during osseous defect repair in glucocorticoid-treated rabbits. Dynamic histomorphometric results revealed that PEMF reversed the adverse effects of glucocorticoids on bone formation, which was confirmed by increased circulating osteocalcin and P1NP. PEMF also significantly attenuated osteocyte apoptosis, promoted osteoblast-related osteocalcin, Runx2 and Osx expression, and inhibited osteocyte-specific DKK1 and Sost expression (negative regulators of osteoblasts) in glucocorticoid-treated skeletons, revealing improved functional activities of osteoblasts and osteocytes. Nevertheless, PEMF exerted no effect on circulating bone-resorbing cytokines (serum TRAcP5b and CTX-1) or skeletal gene expression of osteoclast-specific markers (TRAP and cathepsin K). PEMF also significantly upregulated skeletal gene expression of canonical Wnt ligands (Wnt1, Wnt3a and Wnt10b), whereas PEMF did not alter non-canonical Wnt5a expression. This study demonstrates that PEMF treatment improves bone mass, strength and porous implant osseointegration in glucocorticoid-treated rabbits by promoting potent bone-anabolic action, which is associated with canonical Wnt-mediated improvement in osteoblast and osteocyte functions. This study provides a new treatment alternative for glucocorticoid-related bone disorders in a convenient and non-invasive manner.

Effect of long-term glucocorticoid therapy on bone mineral density of the patients with congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) is characterized by androgen excess which should be treated with life-long glucocorticoid therapy, thus can affect bone mineralization. We aimed to evaluate the bone mineral density (BMD) and determine the factors affecting bone mineralization in patients with CAH. This prospective case-control study was conducted in children, adolescents and young adults with classical 21-hydroxylase CAH, and age-, sex-, and pubertal stage matched healthy controls. Lumbar1-4 BMD was determined by dual-energy X-ray absorptiometry. BMD z-score was calculated using national standards with respect to height age and was referred as `low BMD` if z-score < -1 SD. Univariate analyses were performed between low BMD and normal BMD groups, and multivariate logistic regression analysis was performed to assess the independent predictors of low BMD. Correlations of Body Mass Index (BMI)-z-score, average serum 17-hydroxyprogesterone level, duration of treatment, average and cumulative glucocorticoid doses with BMD z-score were evaluated with Spearman analyses. Each group included 37 cases. BMD z-score of patients with CAH [0.47 (-0.04 - 1.56)] was higher than control group [-0.43 (-0.82 -0.05)]; p= < 0.001. Number of patients with low BMD was similar in both groups; [CAH: 6(16.2%), control: 5(13.5%); p= 0.744]. BMI- z-score was higher in patients with CAH when compared to control group; p= < 0.001. BMI z-score was lower in low BMD group as comparison to normal BMD group; p= 0.041. Each 1.0 decrease in BMI z-score, risk of having low BMD was found to increase by 1.79 (%95 CI: 1.03- 3.12, p= 0.040). BMI-z-score, average serum 17-hydroxyprogesterone level, duration of treatment, average and cumulative glucocorticoid doses were not found to be correlated with BMD z-score. Long-term glucocorticoid therapy did not have negative effect on BMD of patients with CAH. Higher BMI z-score in patients with CAH may have a positive effect on preserving bone health. Precautions should be taken for increased risk of obesity.

Effect of glucocorticoids on mortality in patients with acute respiratory distress syndrome: A meta-analysis.

To date, the efficacy of glucocorticoid therapy to reduce mortality in patients with acute respiratory distress syndrome (ARDS) has remained controversial among the studies available. The present meta-analysis study aimed to further clarify the impact of glucocorticoid therapy on mortality in patients with ARDS by performing a pooled analysis of the previous data. The PubMed, Chinese Knowledge Infrastructure, Wanfang and Cochrane trials databases were searched for relevant studies published between 1966 and 2016. Randomized controlled trials (RCTs) that included the use of glucocorticoids in patients with ARDS and had reported on mortality were included. Odds ratios (OR) and 95% confidence intervals (CI) for mortality were calculated. A total of 10 RCTs were included in the meta-analysis. Of these, 4 studies used high-dose glucocorticoid therapy, while 6 used low-dose glucocorticoid therapy. In the pooled analysis, glucocorticoids were indicated to significantly reduce ARDS-associated mortality (OR=0.64, 95% CI: 0.48-0.85, P=0.002). Further subgroup analysis indicated the following: i) Long-term low-dose glucocorticoid therapy reduced ARDS-associated mortality compared with that in the control group (OR=0.60, 95% CI: 0.44-0.82, P=0.001), whereas high-dose short-term glucocorticoid therapy did not reduce mortality (OR=0.82, 95% CI: 0.43-1.57, P=0.55). ii) Early initiation of glucocorticoid therapy was associated with reduced mortality compared with that in the control group (OR=0.60, 95% CI: 0.44-0.83, P=0.002); however, late initiation did not reduce mortality (OR=0.36, 95% CI: 0.03-3.76, P=0.39). iii) Therapeutic rather than preventive use of glucocorticoids reduced mortality (OR=0.65, 95% CI: 0.49-0.86, P=0.003). Overall, the present meta-analysis suggests that early initiation of long-term low-dose glucocorticoid therapy reduces mortality of patients with ARDS.

Adipocyte-Derived Periostin Mediates Glucocorticoid-Induced Hepatosteatosis in Mice

Long-term glucocorticoids (GCs) therapy usually cause many metabolic side effects, including fatty liver, hyperglycemia and insulin resistance. However, the molecular mechanisms contributing to GCs-induced metabolic disorders remain poorly understood. In the present study, we show that treatment of dexamethasone (DEX), a synthetic analog of GCs, led to the accumulation of triglycerides in the livers of mice, but not in the cultured hepatocytes, suggesting that GCs may promote liver steatosis through integrative organ crosstalk mediated by systemic factors. We further show that DEX could upregulate the expression levels of Periostin in white adipose tissues, which in turn induce liver steatosis and hyperglycemia. Both administration of a Periostin-neutralizing antibody and genetic ablation of Periostin largely attenuated DEX-induced hepatic steatosis. Therefore, our findings identify an important role for Periostin in the regulation of GCs-induced negative side effects. Funding Statement: This study was supported by Project of Clinical Medical Plateau Discipline Construction in Shanghai Pudong New Area (No. PWYgy2018-07) by J.W., the National Natural Science Foundation of China (No. 81500663), the Shanghai Outstanding Young Doctor Training and Funding Program, and the Shanghai Health and Family Planning Commission Outstanding Youth Program by B.L. Declaration of Interests: The authors stated: No potential conflict of interest relevant to this article was reported. Ethics Approval Statement: The animal protocol was reviewed and approved by the animal care committees of Shanghai Pudong New Area People's Hospital and XinHua Hospital.

Detection of Atypical Femur Fractures

The 2019 International Society for Clinical Densitometry (ISCD) Position Development Conference Task Force for monitoring with dual-energy X-ray absorptiometry (DXA) identified detection of atypical femur fractures (AFFs) as an important topic and established this working group to answer key questions in this area. The authors conducted a systematic review of the literature and deliberated on proposed ISCD positions, which were then reviewed by an external expert panel and vetted at the 2019 ISCD Position Development Conference in Kuala Lumpur on March 23, 2019. This paper summarizes the final ISCD positions and the rationale for supporting these positions. Default-length femur imaging or extended-length femur imaging as well as full-length femur imaging (FFI), both single-energy and dual-energy scans, by DXA can detect abnormalities in the spectrum of AFF. It is important to visually inspect all DXA scans of the hip and femur, and report on findings of focal periosteal and endosteal thickening at the lateral cortex (grade: Good, A, W). FFI is the preferred DXA scan mode for detecting abnormalities in the spectrum of AFF. The FFI report should state the absence or presence of abnormalities in the spectrum of AFF. If focal thickening is present on the lateral cortex, the report should state whether a lucent line is seen (grade: Fair, C, W). The ISCD recommends considering the use of bilateral FFI in patients who are currently or have been in the past year on potent antiresorptive therapy (ie, oral or intravenous bisphosphonate or subcutaneous denosumab therapy) for a cumulative period of 3 or more years, especially those on long-term glucocorticoid therapy (grade: Fair, B, W). More research is needed to determine the role of repeat testing and the optimal time interval for follow-up DXA scans, whether an automated measuring tool would perform better than visual inspection, whether FFI would change patient management and outcomes, and the cost-effectiveness of FFI.

Growth Hormone Increases Bone Toughness and Decreases Muscle Inflammation in Glucocorticoid-Treated Mdx Mice, Model of Duchenne Muscular Dystrophy.

The absence of functional dystrophin with mutations of the dystrophin-encoding gene in Duchenne muscular dystrophy (DMD) results in muscle inflammation and degeneration, as well as bone fragility. Long-term glucocorticoid therapy delays the muscular disease progression but suppresses growth hormone secretion, resulting in short stature and further deleterious effects on bone strength. This study evaluated the therapeutic potential of daily growth hormone therapy in growing mdx mice as a model of DMD. Growth hormone treatment on its own or in combination with glucocorticoids significantly improved muscle histology and function and decreased markers of inflammation in mdx mice. Glucocorticoid treatment thinned cortical bone and decreased bone strength and toughness. Despite the minimal effects of growth hormone on bone microarchitecture, it significantly improved biomechanical properties of femurs and vertebrae, even in the presence of glucocorticoid treatment. Together these studies suggest that the use of growth hormone in DMD should be considered for improvements to muscle and bone health. © 2019 American Society for Bone and Mineral Research.