Sclerostin inhibition reverses systemic, periarticular and local bone loss in arthritis

Chen, Xiaoxiang; Baum, Wolfgang; Dwyer, Denise; Stöck, Michael; Schwabe, K; Ke, H.Z.; Stolina, Marina; Schett, Georg; Bözec, Aline

doi:10.1136/annrheumdis-2013-203345

Cited by 82 publications

(59 citation statements)

References 18 publications

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“…TNF-α transgenic mice are models of osteoporosis with dramatic decrease in bone mass and deterioration of bone microarchitecture. In addition, an over-expression of a Wnt inhibitor, sclerostin, has been observed in these models, with a consequence of inflammation-related decrease in bone formation (43). Moreover, alterations in other Wnt inhibitors, such as DKK1, might be involved in inflammation-related bone loss (44).…”

Section: N Discussion and Conclusionmentioning

confidence: 99%

Prevalence and incidence of osteoporotic fractures in patients on long-term glucocorticoid treatment for rheumatic diseases: the Glucocorticoid Induced OsTeoporosis TOol (GIOTTO) study

et al. 2017

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SUMMARYOsteoporosis and fractures are common and invalidating consequences of chronic glucorticoid (GC) treatment. Reliable information regarding the epidemiology of GC induced osteoporosis (GIOP) comes exclusively from the placebo group of randomized clinical trials while observational studies are generally lacking data on the real prevalence of vertebral fractures, GC dosage and primary diagnosis. The objective of this study was to evaluate the prevalence and incidence of osteoporotic fractures and to identify their major determinants (primary disease, GC dosage, bone mineral density, risk factors, specific treatment for GIOP) in a large cohort of consecutive patients aged >21 years, on chronic treatment with GC (≥5 mg prednisone -PN -equivalent) and attending rheumatology centers located all over Italy. Glucocorticoid Induced OsTeoporosis TOol (GIOTTO) is a national multicenter cross-sectional and longitudinal observational study. 553 patients suffering from Rheumatoid Arthritis (RA), Polymyalgia Rheumatica (PMR) and Connective Tissue Diseases (CTDs) and in chronic treatment with GCs were enrolled. Osteoporotic BMD values (T score <-2.5) were observed in 28%, 38% and 35% of patients with CTDs, PMR or RA at the lumbar spine, and in 18%, 29% and 26% at the femoral neck, respectively. Before GC treatment, prevalent clinical fractures were reported by 12%, 37% and 17% of patients with CTDs, PMR, or RA, respectively. New clinical fragility fractures during GC treatment were reported by 12%, 10% and 23% of CTDs, PMR and RA patients, respectively. Vertebral fractures were the prevailing type of fragility fracture. More than 30% of patients had recurrence of fracture. An average of 80% of patients were in supplementation with calcium and/or vitamin D during treatment with GCs. Respectively, 64%, 80%, and 72% of the CTDs, PMR and RA patients were on pharmacological treatment for GIOP, almost exclusively with bisphosphonates. The GIOTTO study might provide relevant contributions to clinical practice, in particular by highlighting and quantifying in real life the prevalence of GIOP and relative fractures, the frequency of the main risk factors, and the currently sub-optimal prevention. Moreover, these results emphasize the importance of the underlying rheumatic disease on the risk of GIOP associated fractures.

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Section: N Discussion and Conclusionmentioning

confidence: 99%

Prevalence and incidence of osteoporotic fractures in patients on long-term glucocorticoid treatment for rheumatic diseases: the Glucocorticoid Induced OsTeoporosis TOol (GIOTTO) study

et al. 2017

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“…Therefore, sclerostin inhibition is considered as a potential, powerful tool to enhance bone repair in inflammatory arthritis. 47 In a research study on an experimental model in mice, Yao et al showed that treatment with monoclonal antibody against sclerostin (Scl-Ab) prevented glucocorticoid (GC)-induced reduction in both trabecular and cortical bone mass and strength, and appeared to maintain osteoblast activity through autophagy. 48 Glucocorticoids increase the expression of Wnt signaling antagonists (sclerostin and Dkk-1) in experimental studies on rodents.…”

Section: Inflammatory Diseases Related To Disorders Of Sclerostinmentioning

confidence: 99%

Sclerostin: Intracellular mechanisms of action and its role in the pathogenesis of skeletal and vascular disorders

Pietrzyk¹,

Smertka²,

Chudek³

2017

Adv Clin Exp Med

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Sclerostin is a glycoprotein involved in the regulation of bone metabolism, exclusively secreted by osteocytes. It affects the activity of bone morphogenetic proteins (BMPs) and is an inhibitor of the Wnt/β-catenin metabolic pathway in bone cells. Osteocytes reduce the release of sclerostin in response to mechanical stimuli acting on bone, and thus promote the activation of osteogenic pathway Wnt/β-catenin in osteoblasts. This signaling pathway plays a key role in osteogenesis and bone turnover. Loss of sclerostin gene function is related to 3 different craniotubular hyperostosis processes: sclerosteosis, craniodiaphyseal dysplasia, and van Buchem disease. Additionally, experimental and clinical studies suggest that sclerostin may promote vascular calcification. Antibodies directed against sclerostin stimulate bone formation and represent a new therapeutic option in the treatment of diseases with increased bone resorption, such as osteoporosis and inflammatory diseases where there is generalized bone loss, periarticular osteoporosis, and cartilage damage, such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), and glucocorticoid-induced osteoporosis (GIO). Antibody use has the potential to offer new therapeutic approaches in the therapy of mineral and bone disorders resulting from chronic kidney disease (CKD-MBD) and vascular calcifications.

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“…However, the role of sclerostin blockade in AS is not entirely clear, as patients with AS can also develop articular erosions. In arthritic hTNFtg mice, sclerostin blockade was shown to inhibit the local bone and cartilage damage that occurred in inflamed joints [133]. Therefore, sclerostin blockade may alleviate the bone erosions seen in erosive inflammatory arthritis.…”

Section: Mechanisms Of Bone Formation In Asmentioning

confidence: 99%

Bone as a Target Organ in Rheumatic Disease: Impact on Osteoclasts and Osteoblasts

Baum

Gravallese

2015

Clinic Rev Allerg Immunol

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Dysregulated bone remodeling occurs when there is an imbalance between bone resorption and bone formation. In rheumatic diseases, including rheumatoid arthritis (RA) and seronegative spondyloarthritis, systemic and local factors disrupt the process of physiologic bone remodeling. Depending upon the local microenvironment, cell types, and local mechanical forces, inflammation results in very different effects on bone, promoting bone loss in the joints and in periarticular and systemic bone in RA and driving bone formation at enthesial and periosteal sites in diseases such as ankylosing spondylitis (AS), included within the classification of axial spondyloarthritis. There has been a great deal of interest in the role of osteoclasts in these processes and much has been learned over the past decade about osteoclast differentiation and function. It is now appreciated that osteoblast-mediated bone formation is also inhibited in the RA joint, limiting the repair of erosions. In contrast, osteoblasts function to produce new bone in AS. The Wnt and BMP signaling pathways have emerged as critical in the regulation of osteoblast function and the outcome for bone in rheumatic diseases, and these pathways have been implicated in both bone loss in RA and bone formation in AS. These pathways provide potential novel approaches for therapeutic intervention in diseases in which inflammation impacts bone.

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Sclerostin inhibition reverses systemic, periarticular and local bone loss in arthritis

Cited by 82 publications

References 18 publications

Prevalence and incidence of osteoporotic fractures in patients on long-term glucocorticoid treatment for rheumatic diseases: the Glucocorticoid Induced OsTeoporosis TOol (GIOTTO) study

Prevalence and incidence of osteoporotic fractures in patients on long-term glucocorticoid treatment for rheumatic diseases: the Glucocorticoid Induced OsTeoporosis TOol (GIOTTO) study

Sclerostin: Intracellular mechanisms of action and its role in the pathogenesis of skeletal and vascular disorders

Bone as a Target Organ in Rheumatic Disease: Impact on Osteoclasts and Osteoblasts

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