Long bone fragility in NF1 is due to deficiency of architecture, micro-structure and matrix mineralization

Abstract The last 2 decades have seen growing recognition of the need to appropriately identify and treat children with osteoporotic fractures. This focus stems from important advances in our understanding of the genetic basis of bone fragility, the natural history and predictors of fractures in chronic conditions, the use of bone-active medications in children, and the inclusion of bone health screening into clinical guidelines for high-risk populations. Given the historic focus on bone densitometry in this setting, the International Society for Clinical Densitometry published revised criteria in 2013 to define osteoporosis in the young, oriented towards prevention of overdiagnosis given the high frequency of extremity fractures during the growing years. This definition has been successful in avoiding an inappropriate diagnosis of osteoporosis in healthy children who sustain long bone fractures during play. However, its emphasis on the number of long bone fractures plus a concomitant bone mineral density (BMD) threshold ≤ −2.0, without consideration for long bone fracture characteristics (eg, skeletal site, radiographic features) or the clinical context (eg, known fracture risk in serious illnesses or physical-radiographic stigmata of osteoporosis), inappropriately misses clinically relevant bone fragility in some children. In this perspective, we propose a new approach to the definition and diagnosis of osteoporosis in children, one that balances the role of BMD in the pediatric fracture assessment with other important clinical features, including fracture characteristics, the clinical context and, where appropriate, the need to define the underlying genetic etiology as far as possible.

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AB0728 OSTEOGENESIS IMPERFECTA: ABOUT 12 CASES

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2364 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 1395.1-1395

Author(s):

O. Jomaa ◽

J. Mahbouba ◽

S. Zrour ◽

I. Bejia ◽

M. Touzi ◽

...

Keyword(s):

Lumbar Spine ◽

Osteogenesis Imperfecta ◽

Bone Densitometry ◽

Calcium Supplementation ◽

Hereditary Disease ◽

Bone Fragility ◽

Lower Limbs ◽

Long Bone ◽

Z Score ◽

Average Serum

Background:Osteogenesis imperfecta (OI), is a rare hereditary disease characterized by bone fragility and low bone mass. The clinical presenatation is various with varying severity skeletal signs and inconstant extra-skeletal signs. Type 1 is the most common form (60% of cases).Objectives:Our objective is to describe the various clinical features observed over a period of 15 years.Methods:This is a retrospective descriptive study including 12 patients followed for OI, hospitalized in the Rheumatology Department at Fattouma Bourguiba Hospital Monastir TUNISIA between 2006 and 2019. Files were collected and analyzed.Results:They are 9 boys and 3 girls with an average age of 14.9 ± 8.6 years. Consanguinity was reported in 25% of cases. The reason leading to consultation was, recurrent fractures (75%), blue sclera (16.7), and bone deformity (8.3%). The number of previous fractures was on average of 5, all of which were caused by a low energy trauma. Similar family cases were noted in 41.6%. The mean age of the first fracture was 4.41 ± 3.2 years. The most frequent fracture sites were respectively: femur (7/12), leg (6/12), tibia (3/12), humerus (4/12), ankle (2/12), and forearm (2/12). A deformity was noted in 58.3% of the cases: lumbar kyphosis (2), exaggerated dorsal kyphosis (2), femurs in parenthesis (2), and an anarchic deformity of 2 lower limbs (1). Imperfect dentinogenesis was found in 8.3% of cases, while ENT examination revealed conductive and sensorineural hearing loss in 2 patients each. The main radiological abnormalities were diffuse bone demineralization (9 patients), cortical thinning (5 patients), vertebral compression (3 patients), and fracture (2 patients). The bone densitometry showed a mean Z score of 3.49±1.4 in the lumbar spine. The average serum calcium level was 2.38±1.15, alkaline phosphatases were elevated in all cases with an average of 756±624.9. The vitamin D level was deficient in all cases with an average of 22.75±5.3. All patients received in addition to the vitamin-calcium supplementation, pamidronate intravenously at a dose of 9mg/kg/year with a mean number of 6 cures. The main side effects observed during the infusion were abdominal pain, polyarthralgia and asthenia (1 patient), chest pain (1 patient) and fever and chills (1 patient). The control bone densitometry showed a mean Z score of 1.81±1.2 in the lumbar spine.Conclusion:Despite advances in the OI diagnosis and treatment, more research is needed. Bisphosphonate treatment decreases long-bone fracture rates, but such fractures are still frequent. New antiresorptive and anabolic agents are being investigated but efficacy and safety of these drugs, especially in children, need to be better established before they can be used in clinical practice.References:[1]https://doi.org/10.1097/med.0000000000000367Disclosure of Interests:None declared

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Mechanical stimulation by intermittent compression stimulates sulfate incorporation and matrix mineralization in fetal mouse long-bone rudiments under serum-free conditions

Calcified Tissue International ◽

10.1007/bf02556004 ◽

1989 ◽

Vol 45 (6) ◽

pp. 342-347 ◽

Cited By ~ 36

Author(s):

Č. Bagi ◽

E. H. Burger

Keyword(s):

Mechanical Stimulation ◽

Long Bone ◽

Matrix Mineralization ◽

Serum Free ◽

Fetal Mouse ◽

Intermittent Compression ◽

Sulfate Incorporation ◽

Serum Free Conditions

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Unique occurrence of long bone fragility with cranial hyperostosis: Searching for the genetic culprit

Bone Abstracts ◽

10.1530/boneabs.4.p108 ◽

2015 ◽

Author(s):

Adalbert Raimann ◽

Uwe Wintergerst ◽

Paul Roschger ◽

Rainer Stelzl ◽

Rainer Biedermann ◽

...

Keyword(s):

Bone Fragility ◽

Long Bone

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Glucocorticoid-Induced Osteoporosis: Why Kids Are Different

Frontiers in Endocrinology ◽

10.3389/fendo.2020.00576 ◽

2020 ◽

Vol 11 ◽

Author(s):

Leanne M. Ward

Keyword(s):

Vertebral Body ◽

Vertebral Fractures ◽

Early Identification ◽

Treatment Strategies ◽

Bone Fragility ◽

Bisphosphonate Therapy ◽

Growth Potential ◽

Long Bone ◽

Osteoporosis Therapy ◽

Poor Growth

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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Novel Intramedullary-Fixation Technique for Long Bone Fragility Fractures Using Bioresorbable Materials

PLoS ONE ◽

10.1371/journal.pone.0104603 ◽

2014 ◽

Vol 9 (8) ◽

pp. e104603 ◽

Cited By ~ 8

Author(s):

Takanobu Nishizuka ◽

Toshikazu Kurahashi ◽

Tatsuya Hara ◽

Hitoshi Hirata ◽

Toshihiro Kasuga

Keyword(s):

Fragility Fractures ◽

Bone Fragility ◽

Intramedullary Fixation ◽

Long Bone ◽

Fixation Technique

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Gnathodiaphyseal Dysplasia: A Syndrome of Fibro-Osseous Lesions of Jawbones, Bone Fragility, and Long Bone Bowing

Journal of Bone and Mineral Research ◽

10.1359/jbmr.2001.16.9.1710 ◽

2001 ◽

Vol 16 (9) ◽

pp. 1710-1718 ◽

Cited By ~ 45

Author(s):

Mara Riminucci ◽

Michael T. Collins ◽

Alessandro Corsi ◽

Alan Boyde ◽

Mark D. Murphey ◽

...

Keyword(s):

Bone Fragility ◽

Long Bone

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Congenital Metabolic Bone Disorders as a Cause of Bone Fragility

International Journal of Molecular Sciences ◽

10.3390/ijms221910281 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10281

Author(s):

Francesca Marini ◽

Francesca Giusti ◽

Teresa Iantomasi ◽

Maria Luisa Brandi

Keyword(s):

Bone Tissue ◽

Mineral Metabolism ◽

Genetic Defect ◽

Bone Fragility ◽

Long Bone ◽

Bone Modeling ◽

Primary Osteoporosis ◽

Bone Disorders ◽

Metabolic Bone ◽

Increased Risk

Bone fragility is a pathological condition caused by altered homeostasis of the mineralized bone mass with deterioration of the microarchitecture of the bone tissue, which results in a reduction of bone strength and an increased risk of fracture, even in the absence of high-impact trauma. The most common cause of bone fragility is primary osteoporosis in the elderly. However, bone fragility can manifest at any age, within the context of a wide spectrum of congenital rare bone metabolic diseases in which the inherited genetic defect alters correct bone modeling and remodeling at different points and aspects of bone synthesis and/or bone resorption, leading to defective bone tissue highly prone to long bone bowing, stress fractures and pseudofractures, and/or fragility fractures. To date, over 100 different Mendelian-inherited metabolic bone disorders have been identified and included in the OMIM database, associated with germinal heterozygote, compound heterozygote, or homozygote mutations, affecting over 80 different genes involved in the regulation of bone and mineral metabolism. This manuscript reviews clinical bone phenotypes, and the associated bone fragility in rare congenital metabolic bone disorders, following a disease taxonomic classification based on deranged bone metabolic activity.

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