Alendronate prevents glucocorticoid-induced osteoporosis in patients with rheumatic diseases: A meta-analysis.
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SUBMITTER: Kan SL
PROVIDER: S-EPMC4998340 | biostudies-literature | 2016 Jun
REPOSITORIES: biostudies-literature
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Alendronate prevents glucocorticoid-induced osteoporosis in patients with rheumatic diseases: A meta-analysis.
Kan Shun-Li SL Yuan Zhi-Fang ZF Li Yan Y Ai Jie J Xu Hong H Sun Jing-Cheng JC Feng Shi-Qing SQ
Medicine 20160601 25
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 ...[more]
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Project description:BackgroundWhat affects the efficacy of alendronate for prevention of glucocorticoid-induced (GI) fractures remains unclear. We aimed to explore the factors affecting alendronate's efficacy, and further identify subgroup effects of alendronate in preventing GI fractures.MethodsWe searched 3 databases. Random-effects meta-analysis was conducted to synthesize risk ratio (RR) and 95% confidence interval (CI) for each endpoint. Meta-regression analysis was used to explore sources of heterogeneity, and subgroup analysis was used to address heterogeneity and evaluate subgroup effects. We detected publication bias using funnel plots and Egger tests.ResultsWe included 13 papers from 12 unique studies involving 46431 participants. Glucocorticoid (GC) dosage (P = .053) and proportion of previous vertebral fracture (PVF) (P = .047) were probably 2 sources of heterogeneity in meta-analysis for vertebral fractures, while GC duration (P = .020) was probably 1 for nonvertebral fractures. Alendronate reduced vertebral fractures in the high dosage subgroup (RR 0.61, 95% CI 0.44-0.86), but didn't in the low dosage subgroup (RR 1.56, 95% CI 0.20-12.02). Alendronate reduced vertebral fractures (RR 0.53, 95% CI 0.40-0.68) in the subgroup of PVF proportion <5%, but didn't (RR 0.76, 95% CI 0.42-1.37) in the subgroup of this proportion ≥5%. Alendronate reduced nonvertebral and hip fractures, whether in primary or in secondary prevention subgroup.ConclusionsThe findings in our study support that alendronate is used for the primary and secondary prevention of GI fractures, but do not support that alendronate is recommended as a first-line agent for patients receiving a low dose of GCs or patients with PVF.
| S-EPMC7571885 | biostudies-literature
Project description:The clinical utility of denosumab for the treatment of glucocorticoid-induced osteoporosis (GIOP) has yet to be established. This study aimed to compare the effects of denosumab on bone mineral density (BMD) and bone turnover markers to those of alendronate in patients with GIOP.A prospective, single-center study of 32 patients (18 men; median age, 66.0 years) with glomerular disease receiving prednisolone (PSL) who were diagnosed as having GIOP and had not received bisphosphonates before was conducted. Participants were randomized to either alendronate (35 mg orally once a week) or denosumab (60 mg subcutaneously once every 6 months), and all subjects received calcitriol. The primary endpoint was the percent change in lumbar spine (LS) BMD at 12 months of treatment.The demographic and clinical characteristics at baseline were not significantly different between the groups. Denosumab treatment markedly decreased serum levels of t-PINP, BAP, and TRACP-5b at 12 months compared to baseline (-57.4%, p<0.001; -30.9%, p<0.01; -57.7%, p<0.001, respectively). After 12 months of alendronate treatment, serum levels of t-PINP, BAP, and TRACP-5b were also significantly decreased compared to pretreatment (-38.9%, p<0.01; -16.3%, p<0.05; -43.5%, p<0.01, respectively). However, no significant differences in the changes of bone turnover markers were found between the two groups. As for the effects on BMD, denosumab treatment markedly increased LS BMD from 6 months compared to baseline, whereas no significant difference compared to pretreatment was found in the alendronate group during the study period. In the comparison of the two groups, a large increase of LS BMD was found in the denosumab treatment group compared to the alendronate treatment group at 12 months (p<0.05).In patients with GIOP, denosumab treatment markedly suppressed bone turnover, which led to a significantly greater increase in LS BMD than with alendronate treatment. These results suggest that denosumab is a therapeutic option for the treatment of GIOP.
| S-EPMC5854344 | biostudies-literature
Project description:BackgroundWhile bisphosphonates (BPs) are commonly used in clinical treatment for osteoporosis, their roles on osteoporosis treatment for rheumatic patients remain unclear. We performed a meta-analysis to evaluate the efficacy of BPs on fractures prevention and bone mass preserving in rheumatic patients.Methodology/principal findingsWe searched PubMed, EmBase, and the Cochrane Central Register of Controlled Trials for relevant literatures with a time limit of Jan. 6, 2012. All randomized clinical trials of BPs for adult rheumatic patients with a follow-up of 6 months or more were included. We calculated relative risks (RRs) for fractures and weighted mean difference (WMD) for percent change of bone mineral density (BMD). Twenty trials were included for analysis. The RR in rheumatic patients treated with BPs was 0.61 (95%CI [0.44, 0.83], P?=?0.002) for vertebral fractures, and 0.49 (95%CI [0.23, 1.02], P?=?0.06) for non-vertebral fractures. The WMD of BMD change in the lumbar spine was 3.72% (95%CI [2.72, 4.72], P<0.001) at 6 months, 3.67% (95%CI [2.84, 4.50], P<0.001) at 12 months, 3.64% (95%CI [2.59, 4.69], P<0.001) at 24 months, and 5.87% (95%CI [4.59, 7.15], P<0.001) at 36 months in patients using BPs, as compared with those treated with calcium, vitamin D or calcitonin. In subgroup analyses, rheumatic patients using BPs for osteoporosis prevention had greater WMD than those using BPs for treating osteoporosis at 6 months (4.53% vs. 2.73%, P?=?0.05) and 12 months (4.93% vs. 2.91%, P?=?0.01).Conclusions/significanceIn both short-term and middle-term, BPs can preserve bone mass and reduce the incidence of vertebral fractures in rheumatic patients, mainly for those who have GC consumption. The efficacy of BPs is better when using BPs to prevent rather than to treat osteoporosis in rheumatic patients.
| S-EPMC3855695 | biostudies-literature
Project description:Alendronate (ALN) is a key therapeutic used to treat glucocorticoid-induced osteoporosis (GIOP), but may induce severe side effects. We showed earlier that plastrum testudinis extracts (PTE) prevented and treated GIOP in vivo. However, clinically, PTE is seldom used alone. Herein, we reveal the synergistic effect of ALN and PTE can treat GIOP of the rat spine and define the mechanism. Sprague-Dawley rats were randomly assigned to four groups: a vehicle group, a GIOP group, an ALN group, and an ALN+PTE group. Each group was further divided into two experimental phases, including dexamethasone (DXM) intervention and withdrawal. Bone mass, microarchitecture, biomechanics, bone-turnover markers, and histomorphology were evaluated. The mRNA and protein expression levels of CTSK and Runx2 were detemined. We found that ALN+PTE improved bone quantity and quality, bone strength, bone turnover; and mitigated histological damage during glucocorticoid intervention and withdrawal. The therapeutic effect was better than that afforded by ALN alone. ALN+PTE reduced CTSK protein expression, promoted Runx2 mRNA and protein expression to varying extents, and more strongly inhibited bone resorption than did ALN alone. Overall, the synergistic effect mediated by ALN+PTE reversed GIOP during DXM intervention and withdrawal via affecting CTSK and Runx2 expression at mRNA and protein levels.
| S-EPMC5587701 | biostudies-literature
Project description:BackgroundBisphosphonates are recommended for use as first-line therapy for the prevention and treatment of glucocorticoid-induced osteoporosis in adults. However, the appropriate usage of bisphosphonates for the prevention or treatment of glucocorticoid-induced osteoporosis in children remains unclear.MethodsWe performed a cross-sectional study to clarify the factors associated with the development of glucocorticoid-induced bone loss and osteoporosis in patients with childhood-onset rheumatic disease and to investigate the impact of the early use of alendronate. We recruited 39 patients with childhood-onset rheumatic disease who were evaluated to detect bone loss or osteoporosis at 3 months to 1.5 years after the initiation of treatment. The primary outcome of the study was the presence of bone loss or osteoporosis at the initial evaluation of the bone mineral density after at least 3 months of glucocorticoid therapy.ResultsBone loss and a history of fracture were found in 56 and 18% of the participants, respectively. Weekly oral alendronate therapy (median, 25.4 mg/m2) had been started by the time of the evaluation of osteoporosis in 46% of the participants and within 3 months after the start of glucocorticoid in 31% of the participants. There were no significant differences between the participants with bone loss (wBL group) and without bone loss (w/oBL group) in terms of gender, primary disease, or the age at the onset of primary disease. In terms of glucocorticoid use, there was no significant difference in the age at the start of glucocorticoid therapy, the length of glucocorticoid use, or the dose of glucocorticoids. The proportion of patients in the w/oBL group who received alendronate within 3 months after the start of glucocorticoid therapy was significantly greater than that in the wBL group. In the logistic regression analysis, only "alendronate therapy within 3 months after the start of glucocorticoid therapy" had a statistically significant effect on the development of bone loss (OR, 0.08; 95% CI, 0.02-0.43). The analysis did not reveal any factors associated with the development of osteoporosis.ConclusionsThe early use of alendronate may have a preventive effect against the development of bone loss in glucocorticoid-treated patients with childhood-onset rheumatic disease.
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Project description:Unlabelled: Gene-modified mesenchymal stem cell (MSC)-like cells with enhanced bone marrow homing and osteogenesis have been used in treating glucocorticoid-induced murine osteoporosis (GIOP). Recent preclinical studies have further demonstrated the immunomodulatory and anticatabolic potential of allogeneic MSCs in treating osteoporosis under inflammatory and autoimmune conditions. In this study, we investigated whether systemic infusion of allogeneic MSCs without genetic manipulation could prevent GIOP, whether anabolic and anticatabolic effects existed, and whether homing or immunomodulation underlay the putative therapeutic effects. Allogeneic bone marrow-derived MSCs (BMMSCs) were isolated, identified, and systemically infused into mice treated with excessive dexamethasone. We revealed that allogeneic MSC transplantation prevented the reduction of bone mass and strength in GIOP. Bone histomorphometric analyses of bone remodeling demonstrated the maintenance of bone formation and osteoblast survival after MSC therapy. Using green fluorescent protein (GFP)-labeled BMMSCs, we showed that donor BMMSCs(GFP) homed and inhabited recipient bone marrow for at least 4 weeks and prevented recipient bone marrow cell apoptosis, as shown by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Furthermore, donor BMMSCs(GFP) committed to Osterix (Osx)(+) osteoblast progenitors and induced recipient osteoblastogenesis, as exhibited by GFP-Osx double-labeling immunofluorescence analysis. No anticatabolic effects or systemic immunomodulatory effects of infused BMMSCs were detected. These findings demonstrated that allogeneic MSC therapy prevented GIOP by inhabiting and functioning in recipient bone marrow, which promoted osteoblastogenesis, which in turn maintained bone formation. Our findings provide important information regarding cell-based anabolic therapy for GIOP and uncover MSC behaviors following the homing event.SignificanceThis study revealed the therapeutic potential of systemically infused, genetically unmodified allogeneic MSCs in glucocorticoid-induced osteoporosis. The donor MSCs inhabited recipient bone marrow and promoted osteoblastogenesis. The therapeutic effects were based on maintenance of bone formation. These results provide important information regarding cell-based anabolic therapy for glucocorticoid-induced osteoporosis and uncover previously unrecognized mesenchymal stem cell behaviors following a homing event. The current study also indicates that minimizing the time of cell culture confers an advantage for increasing transplanted mesenchymal stem cells to the targeted organ to promote therapeutic effects.
| S-EPMC4996443 | biostudies-literature
Project description:Osteoporosis is the most common bone metabolic disease, characterized by bone mass loss and bone microstructure changes due to unbalanced bone conversion, which increases bone fragility and fracture risk. Glucocorticoids are clinically used to treat a variety of diseases, including inflammation, cancer and autoimmune diseases. However, excess glucocorticoids can cause osteoporosis. Herein we performed an integrated analysis of two glucocorticoid-related microarray datasets. The WGCNA analysis identified 3 and 4 glucocorticoid-related gene modules, respectively. Differential expression analysis revealed 1047 and 844 differentially expressed genes in the two datasets. After integrating differentially expressed glucocorticoid-related genes, we found that most of the robust differentially expressed genes were up-regulated. Through protein-protein interaction analysis, we obtained 158 glucocorticoid-related candidate genes. Enrichment analysis showed that these genes are significantly enriched in the osteoporosis related pathways. Our results provided new insights into glucocorticoid-induced osteoporosis and potential candidate markers of osteoporosis.
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Project description:BACKGROUND:Rare diseases (RDs) in rheumatology as a group have a high prevalence, but randomized controlled trials are hampered by their heterogeneity and low individual prevalence. To survey the current evidence of pharmacotherapies for rare rheumatic diseases, we conducted a systematic review and meta-analysis. Randomized controlled trials (RCTs) of RDs in rheumatology for different pharmaco-interventions were included into this meta-analysis if there were two or more trials investigating the same RD and using the same assessment tools or outcome parameters. The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PUBMED were searched up to April 2nd 2020. The overall objective of this study was to identify RCTs of RDs in rheumatology, evaluate the overall quality of these studies, outline the evidence of pharmacotherapy, and summarize recommended therapeutic regimens. RESULTS:We screened 187 publications, and 50 RCTs met our inclusion criteria. In total, we analyzed data of 13 different RDs. We identified several sources of potential bias, such as a lack of description of blinding methods and allocation concealment, as well as small size of the study population. Meta-analysis was possible for 26 studies covering six RDs: Hunter disease, Behçet's disease, giant cell arteritis, ANCA-associated vasculitis, reactive arthritis, and systemic sclerosis. The pharmacotherapies tested in these studies consisted of immunosuppressants, such as corticosteroids, methotrexate and azathioprine, or biologicals. We found solid evidence for idursulfase as a treatment for Hunter syndrome. In Behçet's disease, apremilast and IF-? showed promising results with regard to total and partial remission, and Tocilizumab with regard to relapse-free remission in giant cell arteritis. Rituximab, cyclophosphamide, and azathioprine were equally effective in ANCA-associated vasculitis, while mepolizumab improved the efficacy of glucocorticoids. The combination of rifampicin and azithromycin showed promising results in reactive arthritis, while there was no convincing evidence for the efficacy of pharmacotherapy in systemic sclerosis. CONCLUSION:For some diseases such as systemic sclerosis, ANCA-associated vasculitis, or Behcet's disease, higher quality trials were available. These RCTs showed satisfactory efficacies for immunosuppressants or biological drugs, except for systemic sclerosis. More high quality RCTs are urgently warranted for a wide spectrum of RDs in rheumatology.
| S-EPMC7603763 | biostudies-literature
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 the second most leading cause of osteoporosis. We have identified a compound, a benzofuran pyran hybrid compound 4e that has osteogenic potential and we wanted to assess its efficacy in GIOP in male mice. We assessed the effect of dexamethasone and compound 4e on primary osteoblasts using various cell based and immunofluorescence assays. For in vivo studies we administered methylprednisolone and compound 4e as a prophylactic measure in male Balb/c mice for 28 days and then evaluated the effect on bone microarchitecture by microCT, bone formation by histology along with clinically relevant bone markers. Compound 4e preserved osteoblast differentiation as evident by higher ALP positive cells and mineralization in compound treated groups. Compound 4e also increased the expression of osteogenic genes. This compound guarded β-catenin expression both in vitro and in vivo as confirmed by western blot and immunofluorescence assays. This led to the preservation of bone microarchitecture and cortical thickness at 2.5 mg kg-1 and 5 mg kg-1 doses. Further compound 4e enhanced bone formation rate and regulated osteocyte death. The osteogenic potential of compound 4e was reflected by an increased level of serum marker osteocalcin and decreased levels of SOST and CTX-I. Overall, Compound 4e is able to overcome the catabolic effect of dexamethasone on bone by targeting the canonical WNT/β-catenin signaling as evidenced by both in vitro and in vivo studies.
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