Integrative Analysis for Elucidating Transcriptomics Landscapes of Glucocorticoid-Induced Osteoporosis.
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ABSTRACT:
SUBMITTER: Ying X
PROVIDER: S-EPMC7176994 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Glucocorticoids (GC) are an important risk factor for bone fragility in children with serious illnesses, largely due to their direct adverse effects on skeletal metabolism. To better appreciate the natural history of fractures in this setting, over a decade ago the Canadian STeroid-associated Osteoporosis in the Pediatric Population ("STOPP") Consortium launched a 6 year, multi-center observational cohort study in GC-treated children. This study unveiled numerous key clinical-biological principles about GC-induced osteoporosis (GIO), many of which are unique to the growing skeleton. This was important, because most GIO recommendations to date have been guided by adult studies, and therefore do not acknowledge the pediatric-specific principles that inform monitoring, diagnosis and treatment strategies in the young. Some of the most informative observations from the STOPP study were that vertebral fractures are the hallmark of pediatric GIO, they occur early in the GC treatment course, and they are frequently asymptomatic (thereby undetected in the absence of routine monitoring). At the same time, some children have the unique, growth-mediated ability to restore normal vertebral body dimensions following vertebral fractures. This is an important index of recovery, since spontaneous vertebral body reshaping may preclude the need for osteoporosis therapy. Furthermore, we now better understand that children with poor growth, older children with less residual growth potential, and children with ongoing bone health threats have less potential for vertebral body reshaping following spine fractures, which can result in permanent vertebral deformity if treatment is not initiated in a timely fashion. Therefore, pediatric GIO management is now predicated upon early identification of vertebral fractures in those at risk, and timely intervention when there is limited potential for spontaneous recovery. A single, low-trauma long bone fracture can also signal an osteoporotic event, and a need for treatment. Intravenous bisphosphonates are currently the recommended therapy for pediatric GC-induced bone fragility, typically prescribed to children with limited potential for medication-unassisted recovery. It is recognized, however, that even early identification of bone fragility, combined with timely introduction of intravenous bisphosphonate therapy, may not completely rescue the osteoporosis in those with the most aggressive forms, opening the door to novel strategies.
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Project description:Glucocorticoid-induced osteoporosis (GIOP) is a serious problem for patients with rheumatic diseases requiring long-term glucocorticoid treatment. Alendronate, a bisphosphonate, has been recommended in the prevention of GIOP. However, the efficacy and safety of alendronate in preventing GIOP remains controversial. We performed a meta-analysis to investigate the efficacy and safety of alendronate in preventing GIOP in patients with rheumatic diseases.We retrieved randomized controlled trials from PubMed, EMBASE, and the Cochrane Library. Two reviewers extracted the data and evaluated the risk of bias and quality of the evidence. We calculated the risk ratio (RR) with a 95% confidence interval (CI) for dichotomous outcomes, and the mean difference (MD) with a 95% CI for continuous outcomes using Review Manager, version 5.3.A total of 339 studies were found, and 9 studies (1134 patients) were included. Alendronate was not able to reduce the incidence of vertebral fractures (RR = 0.63, 95% CI: 0.10-4.04, P = 0.62) and nonvertebral fractures (RR = 0.40, 95% CI: 0.15-1.12, P?=?0.08). Alendronate significantly increased the percent change in bone mineral density (BMD) at the lumbar spine (MD?=?3.66, 95% CI: 2.58-4.74, P?<?0.05), total hip (MD?=?2.08, 95% CI: 0.41-3.74, P?<?0.05), and trochanter (MD?=?1.68, 95% CI: 0.75-2.61, P?<?0.05). Significant differences were not observed in the percent change in BMD at the femoral neck (MD?=?-0.33, 95% CI: -2.79 to 2.13, P?=?0.79) and total body (MD?=?0.64, 95% CI: -0.06 to 1.34, P?=?0.07). No significant differences in the adverse events were observed in patients treated with alendronate versus the controls (RR?=?1.00, 95% CI: 0.94-1.07, P?=?0.89). The odds of gastrointestinal adverse events were significantly reduced (RR?=?0.77, 95% CI: 0.62-0.97, P?<?0.05).Our analysis suggests that alendronate can increase the percent change in BMD at the lumbar spine, total hip, and trochanter, and is not associated with an increased incidence of gastrointestinal adverse events; however, the vertebral and nonvertebral fractures cannot be reduced. However, the results should be interpreted with caution due to the poor statistical power.
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Project description:Background: Several medications have been used for glucocorticoids-induced osteoporosis (GIO). However, the best therapeutic option for GIO is still controversial. A Bayesian network meta-analysis was conducted to compare the efficacy and safety of denosumab, teriparatide and bisphosphonates for patients with GIO. Methods: Relevant randomized controlled trials published in PubMed, Embase, Cochrane Library and ClinicalTrials.gov up to August 2023 were searched. The following efficiency and safety outcomes were extracted for comparison: bone mineral density (BMD) percentage changes in lumbar spine, femur neck and total hip, and incidences of adverse events (AEs), serious adverse events (SAEs), vertebrae and non-vertebrae fracture. Bayesian random effects models were used for multiple treatment comparisons. Results: 11 eligible RCTs involving 2,877 patients were identified. All the six medications including alendronate, risedronate, etidronate, zoledronate, teriparatide, and denosumab and were effective in increasing BMD. Teriparatide and denosumab were more effective in improving lumbar spine and femur neck BMD, and reducing vertebrae fracture. Alendronate and denosumab were more effective in improving total hip BMD. Alendronate and teriparatide had the lowest incidences of AEs and SAEs. Conclusion: Teriparatide denosumab and the bisphosphonates are all effective in improving BMD for GIO patients. Based on this network meta-analysis, teriparatide and denosumab have higher efficiency in improving lumbar spine and femur neck BMD, and reducing vertebrae fracture. Systematic Review Registration: 10.17605/OSF.IO/2G8YA, identifier CRD42023456305.
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Project description:Anti-osteoporosis medication (AOM) use in patients exposed to glucocorticoids is thought to reduce fractures. We found post-menopausal women using glucocorticoids for at least 90 days who also used an AOM within 90 days had 48 % fewer fractures by 1 year and 32 % fewer fractures by 3 years compared to non-AOM users.The purpose of this study is to explore the effectiveness of adherence to quality measures by estimating the effect of anti-osteoporosis medication (AOM) initiation within 90 days after chronic (?90 days) glucocorticoid (GC) therapy on osteoporotic fracture.A new-user cohort was assembled using the MarketScan databases between 2000 and 2012. Included patients were female, age ?50 at GC initiation, had a first GC fill daily dose ?10 mg and persisted for at least 90 days. During a 365-day baseline period, patients were excluded for prior GC or AOM (bisphosphonate, denosumab, teriparatide) use, fracture, or cancer diagnosis. Initiators of an AOM in the 14 days pre- or 90 days post-GC fill were characterized as AOM users; those without, AOM non-users. Follow-up began 91 days after GC fill with patients followed until fracture, loss of continuous enrollment, initiation of AOM by AOM non-users, or end of study period. A propensity score was estimated for AOM receipt using all measured covariates and converted to a stabilized inverse probability of treatment weights (IPTW). Weighted hazard ratios (HR) and associated 95% confidence intervals (95% CI) were estimated using weighted Cox proportional hazard models.Of the 7885 women eligible for the study, 12.1% were AOM users. AOM use was associated with lower fracture incidence: weighted HR of 0.52 (95% CI 0.29, 0.94) at 1 year and weighted HR of 0.68 (95% CI 0.47, 0.99) at 3 years.AOM initiation within 90 days of chronic GC use was associated with a fracture reduction of 48% at 1 year and 32% at 3 years.
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Project description:Glucocorticoids (GC) are widely used clinically, despite the presence of significant side effects, including glucocorticoid-induced osteoporosis (GIOP). While GC are believed to act directly on osteoblasts and osteoclasts to promote osteoporosis, the detailed underlying molecular mechanism of GC-induced osteoporosis is still not fully elucidated. Here, we show that lymphocytes play a pivotal role in regulating GC-induced osteoporosis. We show that GIOP could not be induced in SCID mice that lack T cells, but it could be re-established by adoptive transfer of splenic T cells from wild-type mice. As expected, T cells in the periphery are greatly reduced by GC; instead, they accumulate in the bone marrow where they are protected from GC-induced apoptosis. These bone marrow T cells in GC-treated mice express high steady-state levels of NF-κB receptor activator ligand (RANKL), which promotes the formation and maturation of osteoclasts and induces osteoporosis. Taken together, these findings reveal a critical role for T cells in GIOP.
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Project description:BackgroundHuman genomic variations, including single nucleotide polymorphisms (SNPs) and copy number variations (CNVs), are associated with several phenotypic traits varying from mild features to hereditary diseases. Several genome-wide studies have reported genomic variants that correlate with gene expression levels in various tissue and cell types.ResultsWe studied human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) measuring the SNPs and CNVs with Affymetrix SNP 6 microarrays and expression values with Affymetrix Exon microarrays. We computed the linear relationships between SNPs and expression levels of exons, transcripts and genes, and the associations between gene CNVs and gene expression levels. Further, for a few of the resulted genes, the expression value was associated with both CNVs and SNPs. Our results revealed altogether 217 genes and 584 SNPs whose genomic alterations affect the transcriptome in the same cells. We analyzed the enriched pathways and gene ontologies within these groups of genes, and found out that the terms related to alternative splicing and development were enriched.ConclusionsOur results revealed that in the human pluripotent stem cells, the expression values of several genes, transcripts and exons were affected due to the genomic variation.
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Project description:Glucocorticoids are effective drugs used for the treatment of inflammatory diseases such as rheumatoid arthritis or asthma. Furthermore, they regulate various physiological processes, including bone remodeling. However, long-term high- and even low-dose glucocorticoid use is associated with a compromised bone quality and an increased fracture risk. At the cellular level, glucocorticoids suppress bone formation and stimulate bone resorption, which leads to loss of bone mass. To investigate the underlying mechanisms and new therapeutic strategies, the in vivo model for glucocorticoid-induced bone loss is widely used. This protocol outlines the common procedure that is currently used for the induction of bone loss in mice using glucocorticoids. It further provides useful hints and highlights possible pitfalls to take into account before starting an experiment.
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