Steroids - Exploitation

Corticosteroids, more specifically glucocorticoids are one of the most prescribed drugs. Corticosteroids are adrenal hormones that serve significant physiologic activities such as modulating glucose metabolism, protein catabolism, calcium metabolism, bone turnover control, immunosuppression, and down-regulation of inflammatory cascade. Corticosteroids are regarded life-saving due to their various effects and have been used therapeutically to treat broad range of auto-immune, rheumatologic, inflammatory, neoplastic, and viral illnesses.However, the therapeutic benefits of glucocorticoids are restricted by the adverse effects. The most serious side effects of corticosteroids are associated with the use of higher doses for longer periods and OTC availability in specific pharmacies, which leads to dependency, as well as its usage in mild and moderate server instances, which is contrary to guidelines. In the recent times the use of corticosteroids has been multiplied with the emergence of the Covid -19 pandemic. WHO and the standard guidelines has recommended the usage of corticosteroids in critically ill covid-19 patients but their usage in mild and moderate cases caused more harm than benefit. This illicit usage has resulted in the development of opportunistic fungal illnesses such as mucormycosis, posing an extra risk to patients in terms of quality of life and finances. Other adverse effects of systemic corticosteroids include morphological changes, increased blood sugar levels, delayed wound healing, infections, decreased bone density, truncal obesity, cataracts, glaucoma, blood pressure abnormalities, and muscle fibre atrophy.In this review we want to discuss the significance and detrimental effects of corticosteroids emphasizing on the recent times i.e., COVID-19.

Computational tools for aptamer identification and optimization

Aptamers are single-stranded DNA or RNA oligonucleotides that can selectively bind to a specific target. They are generally obtained by SELEX, but the procedure is challenging and time-consuming. Moreover, the identified aptamers tend to be insufficient in stability, specificity, and affinity. Thus, only a handful of aptamers have entered the practical use stage. Recently, computational approaches have demonstrated a significant capacity to assist in the discovery of high-performance aptamers. This review discusses the advances achieved in several aspects of computational tools in this field, as well as the new progress in machine learning and deep learning, which are used in aptamer identification and optimization. To illustrate these computationally aided processes, aptamer selections against SARS-CoV-2 are discussed in detail as a case study. We hope that this review will aid and motivate researchers to develop and utilize more computational techniques to discover ideal aptamers effectively. Copyright © 2022 Elsevier B.V.

Abstracts of the Joint Annual Meeting of the Swiss Society of Rheumatology and the Swiss Society of Physical Medicine and Rehabilitation

The proceedings contain 47 papers. The topics discussed include: increased humoral immune response after vaccination with mRNA-1273 vs BNT162b2 in patients with inflammatory rheumatic diseases;comparison of anti-fracture effectiveness of denosumab versus bisphosphonates in a registry-based, real-world cohort study;comparison of drug retention of TNF inhibitors, other biologics and JAK inhibitors in patients with rheumatoid arthritis who discontinued JAK inhibitor therapy;BRD3 regulates the inflammatory and stress response in rheumatoid arthritis synovial fibroblasts;effect of methotrexate and folic acid co-administration in arthritis;early anti-S antibody levels predict anti-SARS-CoV-2 neutralizing activity over 24 weeks in RA patients after SARS-CoV-2 mRNA vaccination;effect of zoledronate on bone mineral density and bone turnover markers after long-term denosumab therapy: observations in a real-world setting;and developing a screening tool for the detection of interstitial lung disease in systemic sclerosis: the ILD-RISC score.

Decrease in Bone Formation and Bone Resorption during Intravenous Methylprednisolone Pulse Therapy in Patients with Graves' Orbitopathy.

BACKGROUND: Treatment with glucocorticoids (GCs) is associated with side effects. In contrast to the well-known negative impact on bone tissue exerted by oral GCs, few data are available regarding intravenous GCs. We investigated the influence of intravenous methylprednisolone (IVMP) on bone turnover markers (BTM): amino-terminal propeptide of type I procollagen (P1NP) and the C-terminal telopeptide of type I collagen (CTX), and on calcium metabolism parameters: 1,25-dihydroxyvitamin D (1,25(OH)2D), 25-hydroxyvitamin D (25(OH)D), calcium (Ca), phosphate (P), and intact parathormone (iPTH). METHODS: In a prospective study, 23 consecutive subjects with Graves' orbitopathy were included and treated with IVMP according to the European Group on Graves' Orbitopathy recommendations. We evaluated effects on BTM occurring during the first 7 days after 0.5 g IVMP, and after the therapy with 12 IVMP pulses with a cumulative dose of 4.5 g. RESULTS: We observed prompt but transient decrease of P1NP (p < 0.001) and the reduction of CTX (p = 0.02) after the first IVMP pulse. Following the full course of IVMP therapy, both P1NP and CTX were found decreased (p < 0.05 and p < 0.01, respectively). CONCLUSIONS: A single pulse of 0.5 g IVMP already decreases bone formation and resorption; however, this change is transient. The full therapy is associated with suppression of bone turnover.

Bone Turnover Markers After Six Nights of Insufficient Sleep and Subsequent Recovery Sleep in Healthy Men.

PURPOSE: The goal of this study was to determine the bone turnover marker (BTM) response to insufficient and subsequent recovery sleep, independent of changes in posture, body weight, and physical activity. METHODS: Healthy men (N = 12) who habitually slept 7-9 h/night were admitted to an inpatient sleep laboratory for a baseline 8 h/night sleep opportunity followed by six nights of insufficient sleep (5 h/night). Diet, physical activity, and posture were controlled. Serum markers of bone formation (osteocalcin, PINP) and resorption (ß-CTX) were obtained over 24 h at baseline and on the last night of sleep restriction, and on fasted samples obtained daily while inpatient and five times after discharge over 3 weeks. Maximum likelihood estimates in a repeated measures model were used to assess the effect of insufficient and subsequent recovery sleep on BTM levels. RESULTS: There was no statistically or clinically significant change in PINP (p = 0.53), osteocalcin (p = 0.66), or ß-CTX (p = 0.10) in response to six nights of insufficient sleep. There were no significant changes in BTMs from the inpatient stay through 3 weeks of recovery sleep (all p [Formula: see text] 0.63). On average, body weight was stable during the inpatient stay (Δweight = - 0.55 ± 0.91 kg, p = 0.06). CONCLUSION: No significant changes in serum BTMs were observed after six nights of insufficient or subsequent recovery sleep in young healthy men. Changes in weight and physical activity may be required to observe significant BTM change in response to sleep and circadian disruptions. Clinical Trials Registration Registered at ClinicalTrials.gov (NCT03733483) on November 7, 2018.

PETRAM RESULTS: BONE TURNOVER CHANGES on 18F-PET/CT after A RANDOMIZED SWITCH to TAF

Background: The mechanism of bone loss in antiretroviral-treated HIV-positive patients is poorly understood. Plasma bone turnover markers(BTMs) suggest uncoupling of bone resorption and formation by a treatment effect on bone cells. Switching away from TDF to TAF-containing regimens has been associated with bone mineral density(BMD) gains measured by dual-energy X-ray absorptiometry (DXA). One explanation is reversal of ongoing subclinical bone loss in the TDF to TAF switchers. Quantitative imaging with 18F-PET/CT allows assessment of regional bone formation at specific skeletal sites and can help differentiate if BMD changes are associated with increased bone formation or reduced bone loss. Methods: PETRAM, an open-label, randomised study conducted at a single UK site, enrolled non-osteoporotic virologically suppressed HIV-positive males, on >24 weeks rilpivirine/emtricitabine/TDF (RPV/FTC/TDF). They were randomised 1:1 to remain on RPV/FTC/TDF or switch to RPV/FTC/TAF. The protocol specified scanning by DXA (to measure BMD) and 18F-PET/CT at several regions of interest-with primary focus on the lumbar spine (LS) and total hip (TH)-at baseline, 24 weeks, and 48 weeks. However, the timing of scans was disrupted, and in some cases considerably delayed, by COVID-19. The primary analysis was therefore based on change between the baseline and final scans, adjusting for the interval between them. Regions of interest were drawn on the PET/CT images and the standardised uptake value (SUV) measured. A sample of 30 (15 per arm) was estimated to provide 90% power to detect a difference in change of 25% in SUV between the randomised groups. Results: 32 males, median age 51 years, 76% White ethnicity, median duration RPV/FTC/TDF of 49 months, BMI 25.5 kg/m2 were enrolled;27(16 TAF:11 TDF) were included in the final analysis. The interval between baseline and final scans ranged between 23-103 weeks (median 55 weeks). There was no significant difference in change in SUV(18F-PET/CT) at the LS or TH between the TAF and TDF arms (Table);there was a trend towards improved LS BMD, but not TH BMD, in the TAF arm. Conclusion: As measured by 18F-PET/CT, regional bone formation at the hip or LS in patients replacing TDF with TAF in their ART combination did not differ, and contrary to our hypothesis, switching to TAF vs. remaining on TDF over 23-103 weeks did not change BMD or SUV at these key skeletal sites. The improved LS BMD in those switching to TAF is consistent with findings from other TAF-switch studies.

Primary Hyperparathyroidism Corrected by Vitamin D supplementation: A Rare Presentation

Introduction: Primary hyperparathyroidism (PHTP) is a common endocrine disorder characterized by high parathyroid hormone (PTH) and calcium levels, commonly detected incidentally. A common concurrent finding is vitamin D deficiency, with a reported incidence of as high 91%. Vitamin D administration in PHPT is controversial due to a risk of exacerbating hypercalcemia, though some studies have shown that this may in fact be beneficial by suppressing PTH levels and decreasing bone demineralization. We present an interesting case of a 45-year-old male presenting with asymptomatic PHPT which was successfully managed solely with vitamin D administration. Case Description: Our patient is a 45-year-old male who was seen for an incidentally detected elevated calcium level of 10.4 mg/dl and a PTH level of 146.3 pg/ml. The patient denied a history of nephrolithiasis, polyuria, bone pain, or other hypercalcemia symptoms. A Computed Tomography scan of his neck followed by a Single Proton Emission Computerized Tomography (SPECT) demonstrated a potential right sided parathyroid adenoma. The rest of his workup was notable only for a severely decreased vitamin D level of 10.7 ng/ml. Although he qualified for surgical intervention based on his age, a decision regarding surgery was deferred because of the COVID pandemic. Vitamin D supplementation was started at 1000 units daily. Subsequent labs showed an initial increase in PTH to 189 pg/ml, later trending down to 155 pg/ml after his vitamin D dose was increased from 1000 U to 5000 U at 3 months. At 6 months, both PTH and calcium levels showed significant improvement coming down to 80 ng/ml and 9.3 mg/dl, respectively, in concert with improving Vitamin D levels. Discussion: Vitamin D deficiency often coexists with PHPT and is associated with both more severe disease and worse outcomes after parathyroidectomy. Correction of vitamin D deficiency in PHPT is controversial and is feared to worsen underlying hypercalcemia. Two meta-analyses, done in 2014 and 2021, have however demonstrated that vitamin D supplementation can be safely used and lowers PTH levels without causing hypercalcemia or hypercalciuria. Potentially, this could be due to a reduction in bone turnover due to the reduction in PTH, though at present this remains an area for further study. Our case represents only the second reported case of a patient with PHPT who, when treated with vitamin D, showed improvement in both hypercalcemia and PTH levels. Therefore, we postulate that it may be reasonable to defer the decision about surgery in asymptomatic patients with PHPT and concurrent vitamin D deficiency until after the vitamin D deficiency has been corrected.

Vitamin D Status Is Negatively Related to Insulin Resistance and Bone Turnover in Chinese Non-Osteoporosis Patients With Type 2 Diabetes: A Retrospective Cross-Section Research.

BACKGROUND AND OBJECTIVES: Vitamin D status is closely related to blood glucose and bone metabolism in patients with type 2 diabetes (T2DM). Vitamin D affects bone density and bone metabolism, leading to osteopenia and osteoporosis. Insulin resistance increases the risk of osteoporosis in patients with T2DM. Our previous studies have shown a negative correlation between insulin resistance and 25-hydroxy vitamin D [25(OH)D] levels. The aim of the present study was to determine the association between vitamin D status and insulin resistance and bone metabolism in patients with T2DM. SUBJECTS AND METHODS: A retrospective cross-section research was carried out among 109 non-osteoporosis patients with T2DM. Their fasting blood glucose (FBG), 25(OH)D, fasting blood insulin (FINS), glycosylated hemoglobin (HbA1c), serum creatinine (SCr), calcium (Ca), phosphorus (P), insulin-like growth factor-1 (IGF-1), bone alkaline phosphatase (BALP), body mass index (BMI), glomerular filtration rate (eGFR), homeostatic model estimates of insulin resistance (HOMA-IR), and calcium-phosphorus product were measured routinely. RESULTS: Both in men and women, 25(OH)D was negatively correlated with BALP (ß = -0. 369, p ≤ 0.001)and HOMA-IR (ß = -0.349, p ≤ 0.001), and positively associated with IGF-1(ß = 0.672, p ≤ 0.05). There was a negative correlation between HOMA-IR and IGF-1 (ß = -0.464, p ≤ 0.001), and a positive correlation between HOMA-IR and BALP (ß = 0.344, p ≤ 0.05), adjusted by confounding factors. CONCLUSION: Our study demonstrates that 25(OH)D concentrations are negatively correlated with insulin resistance and bone turnover. Insulin resistance increases with the decrease of 25(OH)D concentration, which can enhance bone turnover, and increases the risk of osteoporosis in non-osteoporosis patients with T2DM. This is the first study to clarify the relationship between serum vitamin D status, insulin resistance, and bone metabolism in non-osteoporosis patients with T2DM in China.

MACHINE LEARNING AND RADIOMICS IDENTIFY NOVEL BIOMARKERS OF BONE LOSS

Purpose: Altered bone turnover is a factor in many diseases including osteoarthritis (OA), osteoporosis, inflammation, and viral infection. The absence of obvious symptoms and insufficiently sensitive biomarkers in the early stages of bone loss limits early diagnosis and treatment. Therefore, it is urgent to identify novel, more sensitive, and easy-to-detect biomarkers which can be used in the diagnosis and prognosis of bone health. Our previous data using standard micro-computed tomography (μCT) measurements showed that SARS-CoV-2 infection in mice significantly decreased trabecular bone volume at the lumbar spine, suggesting that decreased bone mass, increased fracture risk, and OA may be underappreciated long-haul comorbidities for COVID patients. In this study, we applied integrated state-of-the-art radiomics and machine learning models to identify more sensitive image-based biomarkers of SARS-CoV-2-induced bone loss from μCT images. These radiomic biomarkers can potentially provide a non-invasive way of quantifying and monitoring systemic bone loss and evaluating treatment efficacy in both research and clinical practices. Methods: All animal use was performed with approval of the Institutional Animal Care and Use Committee. To quantify SARS-CoV-2-induced bone loss, 6-week-old transgenic mice (16 male, 16 female) expressing humanized ACE2 receptors were inoculated with a 2020 strain of SARS-CoV-2 or phosphate-buffered saline (Control) [Fig. A]. Viral infection was confirmed by detection of infectious SARS-CoV-2 in throat swabs and histological identification of SARS-CoV-2 labeled cells. At 6-14 days post-infection, lumbar vertebral bodies (L5) were scanned with μCT (μCT 35, SCANCO Medical AG;6 μm nominal voxel size). The open-source research platform 3D Slicer v2020 with a built-in Python console v3.8 was used for medical image computing and fully automated segmentation of cortical and trabecular bone. Standard μCT assessment of bone microstructure was performed. Radiomic feature extraction and data processing were performed using python based PyRadiomics v3.0.1. A total of 120 radiographic features were extracted from the segmented images [Fig. B]. Principle component analysis (PCA) for feature selection, a support vector machine learning (SVML) predictive model for classification, holdback method for model validation, and all statistical analyses (significance at p<0.05) were performed using JMP Pro v15 (SAS). Results: Using standard μCT methods, SARS-CoV-2 infection significantly reduced the bone volume fraction (BV/TV) by 10 and 10.5% (p= 0.04) and trabecular thickness (Tb.Th) by 8 and 9% (p= 0.02) in male and female mice, respectively, compared to PBS control mice [Fig. C]. Radiomics detected a 20-fold greater magnitude in change over standard methods. SARS-CoV-2 infection significantly changed radiographic parameters with the largest change being a 300% increase in the second-order parameter: cluster shade [Fig. D]. The 45 radiomic features comprising the first 3 principal components were selected for inclusion in the SVML model. The SVML Model (radial basis function kernel;cost = 4.8;gamma = 0.46) produced an area under the receiver operating characteristic curve (AUC) of 1.0 which reflects a perfectly accurate test [Fig. E]. Conclusions: SARS-CoV-2 infection of humanized ACE2 expressing mice caused significant bone changes, suggesting that decreased bone mass, increased fracture risk, OA, and other musculoskeletal complications could be long-term comorbidities for people infected with COVID-19. We developed an open-source, fully automated segmentation and radiomics system to assess systemic bone loss using μCT images. When coupled with machine learning, this system was able to identify novel radiographic biomarkers of bone loss that better discriminate differences in bone microstructure between SARS-CoV-2 infected and control mice than standard bone morphometric indices. The high accuracy of the SVML model in classifying SARS-CoV-2 infected mice opens the possibility of translating these biom rkers to the clinical setting for early detection of skeletal changes associated with long-haul COVID. The methods presented here were demonstrated using SARS-CoV-2 as a model system and can also be adapted to other diseases associated with altered bone turnover. Development of machine-learning methods for radiomic applications is a crucial step toward clinically relevant radiomic biomarkers of bone health and provides a non-invasive way of quantifying and monitoring systemic bone loss and evaluating treatment efficacy. [Formula presented]

Zolendronic acid after teriparatide: Pandemic observations

Objective: Teriparatide for sever osteoporosis is followed by antiresorptive drugs, and one option in patients with gastric intolerance is zolendronic acid or denosumab (1-5). During pandemic lockdown, the access to bone assessment was limited (1-5). Type 1 diabetic patients are particularly at risk for bone loss, but also for COVID-19 infection, thus the importance of respecting the pandemic rules (1-5). We aim to introduce a female case diagnosed with severe menopausal osteoporosis that was followed during post-teriparatide sequence of medication, including during pandemic days. Case report: This is a type 1 diabetic female of 77 y who was first diagnosed with menopausal osteoporosis 8 y ago (lumbar T-score of-3.1 SD) and started medication with weekly alendronate in addition to vitamin D supplements. After 3 y, she suffered a single spontaneous vertebral fracture thus teriparatide was initiated for 2 y (with good tolerance): lumbar T-score went from -3.1 to -1.9 SD. In the meantime, due to bilateral coxarthrosis she needed bilateral hip replacement. Further on, she continued with biannually denosumab for 8 injections, reaching a lumbar BMD-DXA 0.942 g/cm2, T-score of -2 SD, Z-score of -0.8 SD so an intravenous perfusion with zolendronic acid 5 mg was administered plus vitamin D supplements. While she had no additional fracture and glycated haemoglobin A1c remained around 6.2-6.4%, one year later, the pandemic started, so only bone turnover markers (BTM) were assessed, not DXA: suppressed CrossLaps=0.22 ng/mL (normal: 0.33-0.782 ng/ mL), osteocalcin=11 ng/mL (normal: 15-46 ng/mL), P1NP=27 pg/mL (normal: 15-45 pg/mL). She continued with vitamin D, and 20 months after injection CrossLaps remained low (=22 ng/mL) with normal osteocalcin (=15 ng/mL), P1NP (=28 pg/mL) and stationary BMD. Conclusion: Zolendronic acid effect in osteoporotic patients is easy to access by blood assays if DXA is not available, while lack of BTM increase is suggestive for a good outcome.