Early-Onset Osteoporosis

Mäkitie, Outi; Zillikens, M. Carola

doi:10.1007/s00223-021-00885-6

Cited by 50 publications

(36 citation statements)

References 112 publications

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“…To further investigate the function of the WNT11 mutation, we wondered whether its effect could be driven by R-Spondin 2 (RSPO2), an activator of the canonical Wnt signaling pathway. In osteoblasts, RSPO2 acts as a ligand for LGR4–6 receptors and is known to promote osteoblast maturation and mineralization via WNT11 ( 26 ). The expression of RSPO2 was decreased by 55.8% in WNT11 mutant cells as compared with control cells ( P < 0.01) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

WNT11, a new gene associated with early onset osteoporosis, is required for osteoblastogenesis

Silva

Edouard

Fradin

et al. 2021

Human Molecular Genetics

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Monogenic early-onset osteoporosis (EOOP) is a rare disease defined by low bone mineral density (BMD) that results in increased risk of fracture in children and young adults. Although several causative genes have been identified, some of the EOOP causation remains unresolved. Whole-exome sequencing revealed a de novo heterozygous loss-of-function mutation in WNT11 (NM_004626.2:c.677_678dup p.Leu227Glyfs*22) in a 4-year-old boy with low BMD and fractures. We identified two heterozygous WNT11 missense variants (NM_004626.2:c.217G > A p.Ala73Thr) and (NM_004626.2:c.865G > A p.Val289Met) in a 51-year-old woman and in a 61-year-old woman respectively, both with bone fragility. U2OS cells with heterozygous WNT11 mutation (NM_004626.2:c.690_721delfs*40) generated by CRISPR-Cas9 showed reduced cell proliferation (30%) and osteoblast differentiation (80%) as compared with wild-type U2OS cells. The expression of genes in the Wnt canonical and non-canonical pathways was inhibited in these mutant cells, but recombinant WNT11 treatment rescued the expression of Wnt pathway target genes. Furthermore, the expression of RSPO2, a WNT11 target involved in bone cell differentiation, and its receptor LGR5, was decreased in WNT11 mutant cells. Treatment with WNT5A and WNT11 recombinant proteins reversed LGR5 expression, but WNT3A recombinant protein treatment had no effect on LGR5 expression in mutant cells. Moreover, treatment with recombinant RSPO2 but not WNT11 or WNT3A activated the canonical pathway in mutant cells. In conclusion, we have identified WNT11 as a new gene responsible for EOOP, with loss-of-function variant inhibiting bone formation via Wnt canonical and non-canonical pathways. WNT11 may activate Wnt signaling by inducing the RSPO2–LGR5 complex via the non-canonical Wnt pathway.

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Section: Resultsmentioning

confidence: 99%

WNT11, a new gene associated with early onset osteoporosis, is required for osteoblastogenesis

Silva

Edouard

Fradin

et al. 2021

Human Molecular Genetics

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“…We also repeated the main analysis of fracture rates stratified by affected body parts that are known to be more fractured by accidental injury, non-accidental injury, and decreased bone density in children. [14][15][16]…”

Section: Discussionmentioning

confidence: 99%

Association of clinical and social factors with risk of fracture in children with atopic dermatitis

Kim

Kwak

et al. 2022

Pediatric Allergy Immunology

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Background Children with atopic dermatitis (AD) have multiple risk factors for accidental fractures, injuries that can lead to significant morbidity and mortality. However, little is known about the factors that mediate the relationship between AD and fracture in children. Objective Our purpose was to examine the association of AD with fracture and to identify potential mediating factors. Methods This retrospective cohort study examined children with and without AD from a longitudinal matched cohort database of 353,040 children registered in the national health insurance service and participated in the national health‐screening program of Korea. We defined AD using medical claims and medication prescription records. We investigated accidental fracture events between the index date and the end of follow‐up in a propensity score–matched cohort. Pre‐specified subgroup analyses considered fractures in four different regions of the body. The mediating effects of 10 possible clinical factors (including the use of antihistamines and systemic corticosteroids) and social factors (including nutritional status and parental safety awareness) were determined. Results There were 145,704 participating children, 20% with AD and 49% girls. Fractures occurred in 6,652 of the children with AD (23%, mean age: 64.6 ± 29.2 months) and in 24,698 of the control group (21%, mean age 65.0 ± 28.9 months). Children with AD had an 8% greater risk of fracture events overall (adjusted relative risk [aRR]: 1.08, 95% CI: 1.05–1.10). In subgroup analysis, AD was related to increased rates of skull and facial bone fracture (aRR: 1.09, 95% CI: 1.04–1.14), for trunk including vertebrae (aRR: 1.58, 95% CI: 1.22– 2.05), and for distal limbs (aRR: 1.11, 95% CI: 1.07–1.15). However, the relationship with proximal limb fracture was insignificant. Duration of systemic corticosteroid prescription was the largest mediating factor, followed by duration of antihistamine prescription, and infant feeding practices. In particular, the duration of systemic corticosteroid prescription was significantly associated with fracture events (incidence: 20.1% at the 25th percentile and 23.6% at the 75th percentile; difference: 3.4% [95% CI: 2.8–4.0%]). Conclusions Children with AD were related to increased fracture events. The key factors with mediating effects were systemic use of corticosteroid and antihistamine. Infant feeding practices had weaker mediating effects.

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“…These conditions result in severe bone disease and low bone mass accrual. Timely recognition is therefore important to initiate treatment and specialist care [ 33 – 35 ].…”

Section: Primary Osteoporosismentioning

confidence: 99%

Osteoporosis in children and adolescents: when to suspect and how to diagnose it

et al. 2022

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Early recognition of osteoporosis in children and adolescents is important in order to establish an appropriate diagnosis of the underlying condition and to initiate treatment if necessary. In this review, we present the diagnostic work-up, and its pitfalls, of pediatric patients suspected of osteoporosis including a careful collection of the medical and personal history, a complete physical examination, biochemical data, molecular genetics, and imaging techniques. The most recent and relevant literature has been reviewed to offer a broad overview on the topic. Genetic and acquired pediatric bone disorders are relatively common and cause substantial morbidity. In recent years, there has been significant progress in the understanding of the genetic and molecular mechanistic basis of bone fragility and in the identification of acquired causes of osteoporosis in children. Specifically, drugs that can negatively impact bone health (e.g. steroids) and immobilization related to acute and chronic diseases (e.g. Duchenne muscular dystrophy) represent major risk factors for the development of secondary osteoporosis and therefore an indication to screen for bone mineral density and vertebral fractures. Long-term studies in children chronically treated with steroids have resulted in the development of systematic approaches to diagnose and manage pediatric osteoporosis.Conclusions: Osteoporosis in children requires consultation with and/or referral to a pediatric bone specialist. This is particularly relevant since children possess the unique ability for spontaneous and medication-assisted recovery, including reshaping of vertebral fractures. As such, pediatricians have an opportunity to improve bone mass accrual and musculoskeletal health in osteoporotic children. What is Known:• Both genetic and acquired pediatric disorders can compromise bone health and predispose to fractures early in life.• The identification of children at risk of osteoporosis is essential to make a timely diagnosis and start the treatment, if necessary. What is New:• Pediatricians have an opportunity to improve bone mass accrual and musculoskeletal health in osteoporotic children and children at risk of osteoporosis.• We offer an extensive but concise overview about the risk factors for osteoporosis and the diagnostic work-up (and its pitfalls) of pediatric patients suspected of osteoporosis.

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Early-Onset Osteoporosis

Cited by 50 publications

References 112 publications

WNT11, a new gene associated with early onset osteoporosis, is required for osteoblastogenesis

WNT11, a new gene associated with early onset osteoporosis, is required for osteoblastogenesis

Association of clinical and social factors with risk of fracture in children with atopic dermatitis

Osteoporosis in children and adolescents: when to suspect and how to diagnose it

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