Osteoporosis in Children with Chronic Disease

Högler, Wolfgang; Ward, Leanne M.

doi:10.1159/000381045

Cited by 29 publications

(20 citation statements)

References 153 publications

(224 reference statements)

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“…Although osteotoxic side effects of GCs are observed across the lifespan, children are an exceptionally vulnerable population. Children treated with chronic, high‐dose steroids have an equally observed incidence/prevalence of osteoporosis relative to adults, plus impairment of linear growth . Physiologic cortisol in humans, including children is 5 to 7 mg/m 2 /day .…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoids Disrupt Skeletal Angiogenesis Through Transrepression of NF-κB–Mediated Preosteoclast Pdgfb Transcription in Young Mice

Peng

et al. 2020

Journal of Bone and Mineral Research

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In the growing skeleton, angiogenesis is intimately coupled with osteogenesis. Chronic, high doses of glucocorticoids (GCs) are associated with decreased bone vasculature and induce osteoporosis and growth failure. The mechanism of GC‐suppression of angiogenesis and relationship to osteoporosis and growth retardation remains largely unknown. Type H vessels, which are regulated by preosteoclast (POC) platelet‐derived growth factor–BB (PDGF‐BB), are specifically coupled with bone formation and development. We determined the effect of GCs on POC synthesis of PDGF‐BB in relation to type H vessel formation, bone mass, and bone growth in the distal femur of 2‐week‐old young mice receiving prednisolone or vehicle for 2, 4, or 6 weeks. After 2 weeks of prednisolone, the number of POCs were unchanged while POC synthesis of PDGF‐BB was reduced. Longer treatment with prednisolone reduced POCs numbers and PDGF‐BB. These changes were associated with a reduction in type H vessels, bone formation rate, bone mass, and bone length at each time point. In vitro, excessive concentrations of prednisolone (10−6M) resulted in decreased PDGF‐BB concentration and POC numbers. Conditioned medium from POC cultures treated with control concentration of prednisolone (10−7M) or recombinant PDGF‐BB stimulated endothelial tube formation, whereas conditioned medium from control concentration of prednisolone‐treated POC cultures neutralized by PDGF‐BB antibody or excessive prednisolone inhibited endothelial tube formation. Administration of excessive prednisolone attenuated the P65 subunit of nuclear factor kappa B (NF‐κB) binding to the Pdgfb promoter, resulting in lower Pdgfb transcription. Co‐treatment with excessive prednisolone and the glucocorticoid receptor (GR) antagonist (RU486), GR siRNA, or TNFα rescued NF‐κB binding to the Pdgfb promoter and endothelial tube formation. These results indicate that PDGF‐BB synthesis in POCs is suppressed by GCs through transrepression of GR/NF‐κB, thus inhibiting type H vessel formation and associated osteoporosis and growth failure. © 2020 American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 99%

Glucocorticoids Disrupt Skeletal Angiogenesis Through Transrepression of NF-κB–Mediated Preosteoclast Pdgfb Transcription in Young Mice

Peng

et al. 2020

Journal of Bone and Mineral Research

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“…The detailed demographic and clinical information were listed in Table 1. In general, since other chronic diseases than osteoporosis might also lead to osteoporotic fractures, subjects with chronic disorders or taking medicine were excluded from this present study 16, 17 . Written informed consent was obtained from all the enrolled subjects, and this study was approved by the Ethics Committee of the Central Hospital of Lishui City, Wenzhou Medical University.…”

Section: Methodsmentioning

confidence: 99%

Common Variants in OPG Confer Risk to Bone Mineral Density Variation and Osteoporosis Fractures

Sheng

Cai

Gong

et al. 2017

Sci Rep

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Although many common variants have been identified for bone mineral density (BMD) and osteoporosis fractures, all the identified risk variants could only explain a small portion of heritability of BMD and osteoporosis fractures. OPG belongs to the tumor necrosis factor receptor superfamily, which plays a crucial role in bone remodeling and is thus a promising candidate gene of osteoporosis. Several studies have explored the association of OPG variants with BMD or osteoporosis fractures, however, the results remain inconsistent among different populations. In the study, we first assessed the relationship between OPG variants and BMD or osteoporosis fractures in our sample size (227 subjects with postmenopausal osteoporosis and 189 controls), and then performed a systematic meta-analysis. Among the nine SNPs genotyped, rs6469804 and rs2073618 showed significant associations with both BMD and osteoporotic fractures, while rs3102735 was only associated with BMD in our samples (P < 0.05). For meta-analyses, data for a total of 12 SNPs were pooled (4725 patients and 37804 controls), and five SNPs, including rs6993813, rs6469804, rs3134070, rs2073618 and rs3102734, showed association with osteoporosis fractures (P < 0.05). On light of the above analysis, we believe that OPG is one promising susceptibility gene of BMD or osteoporotic fractures.

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“…A relative increase in resorption and/or decrease in formation lead to a net loss in bone mass, changes in bone microarchitecture, and increased risk of fracture. These are common processes in children with chronic illnesses, who have multiple risk factors related to mobility, nutrition, and exposure to bone-toxic therapies [3]. In addition, osteolytic disorders such as primary tumors and metastases result in bone destruction through localized activation of osteoclasts [4].…”

Section: The Role Of Rankl In Bone Modeling and Remodelingmentioning

confidence: 99%

Denosumab: an Emerging Therapy in Pediatric Bone Disorders

Boyce

2017

Curr Osteoporos Rep

118

102

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Purpose of Review Denosumab is an inhibitor of receptor activator of nuclear factor kappa-B ligand (RANKL), and has emerged as an important novel therapy for skeletal disorders. This article examines the use of denosumab in children. Recent findings Considerable safety and efficacy data exists for denosumab treatment of adults with osteoporosis, bone metastases, and giant cell tumors. Pediatric data is limited; however, evidence suggests denosumab may be beneficial in decreasing bone turnover, increasing bone density, and preventing growth of certain skeletal neoplasms in children. Denosumab’s effect on bone turnover is rapidly reversible after drug discontinuation, representing a key difference from bisphosphonates. Rebound increased bone turnover has led to severe hypercalcemia in several pediatric patients. Summary Denosumab is a promising therapy for pediatric skeletal disorders. At present, safety concerns related to rebounding bone turnover and mineral homeostasis impact use of denosumab in children. Research is needed to determine if and how these effects can be mitigated.

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Osteoporosis in Children with Chronic Disease

Cited by 29 publications

References 153 publications

Glucocorticoids Disrupt Skeletal Angiogenesis Through Transrepression of NF-κB–Mediated Preosteoclast Pdgfb Transcription in Young Mice

Glucocorticoids Disrupt Skeletal Angiogenesis Through Transrepression of NF-κB–Mediated Preosteoclast Pdgfb Transcription in Young Mice

Common Variants in OPG Confer Risk to Bone Mineral Density Variation and Osteoporosis Fractures

Denosumab: an Emerging Therapy in Pediatric Bone Disorders

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