Congenital Metabolic Bone Disorders as a Cause of Bone Fragility

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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Osteoporosis in Skin Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms21134749 ◽

2020 ◽

Vol 21 (13) ◽

pp. 4749 ◽

Cited By ~ 4

Author(s):

Maria Maddalena Sirufo ◽

Francesca De Pietro ◽

Enrica Maria Bassino ◽

Lia Ginaldi ◽

Massimo De Martinis

Keyword(s):

Bone Resorption ◽

Bone Formation ◽

Skin Diseases ◽

Public Health Problem ◽

Bone Fragility ◽

Skeletal Disease ◽

Metabolic Bone ◽

Systemic Treatments ◽

Increased Risk ◽

Skeletal Homeostasis

Osteoporosis (OP) is defined as a generalized skeletal disease characterized by low bone mass and an alteration of the microarchitecture that lead to an increase in bone fragility and, therefore, an increased risk of fractures. It must be considered today as a true public health problem and the most widespread metabolic bone disease that affects more than 200 million people worldwide. Under physiological conditions, there is a balance between bone formation and bone resorption necessary for skeletal homeostasis. In pathological situations, this balance is altered in favor of osteoclast (OC)-mediated bone resorption. During chronic inflammation, the balance between bone formation and bone resorption may be considerably affected, contributing to a net prevalence of osteoclastogenesis. Skin diseases are the fourth cause of human disease in the world, affecting approximately one third of the world’s population with a prevalence in elderly men. Inflammation and the various associated cytokine patterns are the basis of both osteoporosis and most skin pathologies. Moreover, dermatological patients also undergo local or systemic treatments with glucocorticoids and immunosuppressants that could increase the risk of osteoporosis. Therefore, particular attention should be paid to bone health in these patients. The purpose of the present review is to take stock of the knowledge in this still quite unexplored field, despite the frequency of such conditions in clinical practice.

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Metabolic bone tissue disorders in patients with long bone fractures complicated by chronic osteomyelitis

Genij Ortopedii ◽

10.18019/1028-4427-2019-25-2-149-155 ◽

2019 ◽

Vol 25 (2) ◽

pp. 149-155 ◽

Cited By ~ 2

Author(s):

A.V. Tsiskarashvili ◽

◽

S.S. Rodionova ◽

S.P. Mironov ◽

K.M. Bukhtin ◽

...

Keyword(s):

Bone Tissue ◽

Chronic Osteomyelitis ◽

Bone Fractures ◽

Long Bone ◽

Long Bone Fractures ◽

Metabolic Bone

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A pragmatic window of opportunity to minimise the risk of MRONJ development in individuals with osteoporosis on Denosumab therapy: a hypothesis

Head & Face Medicine ◽

10.1186/s13005-021-00280-4 ◽

2021 ◽

Vol 17 (1) ◽

Author(s):

Giuseppina Campisi ◽

Rodolfo Mauceri ◽

Francesco Bertoldo ◽

Vittorio Fusco ◽

Alberto Bedogni

Keyword(s):

Tooth Extraction ◽

Oral Surgery ◽

Metastatic Cancer ◽

Bone Fragility ◽

Osteonecrosis Of The Jaw ◽

Time Interval ◽

Dental Surgery ◽

Metabolic Bone ◽

Increased Risk

Abstract Denosumab is associated with the development of medication-related osteonecrosis of the jaw (MRONJ), an uncommon but severe oral side effect with a higher prevalence in metastatic cancer patients than in patients with metabolic bone fragility. Although several oral triggers can initiate MRONJ, invasive oral treatments and tooth extraction still remain the most common precipitating event. In general, tooth extraction and oral surgery should be avoided in patients at increased risk of MRONJ, while extraction of non-restorable teeth should be performed based on specific risk reduction protocols to eliminate dental/periodontal infections, still protecting from MRONJ onset. Based on the different pharmacological activity of denosumab and nitrogen-containing bisphosphonates, it is likely that the MRONJ risk profile of patients with osteoporosis could somewhat vary. We hypothesize the chance to maximize the pharmacokinetic of denosumab 60 mg (Prolia®) and identify a time interval in which invasive oral treatments can ideally take place without restrictions in patients with metabolic bone fragility, We propose that dental surgery (e.g. tooth extraction) may be safely performed without additional intra or peri-operative procedures in osteoporosis patients using denosumab provided that careful case selection, adequate communication among specialists, planning of a delayed dosing window (1-month deferral) and rigorous postoperative follow-up are granted. Graphical abstract

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Fragility fractures and bone remodeling in type 2 diabetes mellitus

Obesity and metabolism ◽

10.14341/omet2017311-18 ◽

2017 ◽

Vol 14 (3) ◽

pp. 11-18 ◽

Cited By ~ 1

Author(s):

Tatiana O. Yalochkina ◽

Zhanna E. Belaya

Keyword(s):

Risk Factors ◽

Bone Mineral Density ◽

Type 2 Diabetes ◽

Bone Tissue ◽

Bone Mineral ◽

Bone Fragility ◽

Mineral Density ◽

Severe Diabetes ◽

Increased Risk

Fracture risk is significantly increased in both type 1 and type 2 diabetes and individuals with diabetes experience worse fracture outcomes compared to normoglycemic individuals. Patients with T1DM have decreased bone mineral density (BMD), whereas patients with T2DM demonstrate increased BMD compared to healthy control. The latest studies show increased incidence of low-traumatic fractures in patients with T2DM instead of high bone mineral density (BMD). The risk of osteoporotic fractures in patients with T2DM can be explained by disease complications and increased risk of falls and consequent trauma. However, the most important cause of bone fragility in T2DM is the deterioration in bone microarchitecture, the mechanism of which is not completely understood. High BMD in patients with T2DM does not allow us to use dual-energy X-ray-absorptiometry as a gold standard test for diagnosticsof osteoporosis. Consequently,new risk factors and diagnostic algorithm as well as treatment strategy should be developed for patients with T2DM. In addition to this, some researchers considered that the group of T2DM is geterogenous and physicians might face patients with osteoporosis and mild diabetes that add very little to bone fragility; patients with osteoporosis and moderate or severe diabetes which also affects bone tissue diabetoosteoporosis; and patients without osteoporosis but severe diabetes which cause bone tissue deterioration with the development of diabetic bone disease. New diagnostic tools and algorithm and new experimental research are needed for better understanding bone deterioration in patients with T2DM. This review summarizes our current knowledge on fracture rate, risk factors for fractures and causes of bone deterioration in subjects with T2DM.

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The roles of miRNA, lncRNA and circRNA in the development of osteoporosis

Biological Research ◽

10.1186/s40659-020-00309-z ◽

2020 ◽

Vol 53 (1) ◽

Cited By ~ 3

Author(s):

Yang Yang ◽

Wang Yujiao ◽

Wang Fang ◽

Yuan Linhui ◽

Guo Ziqi ◽

...

Keyword(s):

Environmental Factors ◽

Bone Fragility ◽

Circular Rnas ◽

Therapeutic Approaches ◽

Control Of Gene Expression ◽

Metabolic Bone ◽

Increased Risk ◽

Non Coding Rnas ◽

Genetic And Environmental Factors

Abstract Osteoporosis is a common metabolic bone disease, influenced by genetic and environmental factors, that increases bone fragility and fracture risk and, therefore, has a serious adverse effect on the quality of life of patients. However, epigenetic mechanisms involved in the development of osteoporosis remain unclear. There is accumulating evidence that epigenetic modifications may represent mechanisms underlying the links of genetic and environmental factors with increased risk of osteoporosis and bone fracture. Some RNAs, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have been shown to be epigenetic regulators with significant involvement in the control of gene expression, affecting multiple biological processes, including bone metabolism. This review summarizes the results of recent studies on the mechanisms of miRNA-, lncRNA-, and circRNA-mediated osteoporosis associated with osteoblasts and osteoclasts. Deeper insights into the roles of these three classes of RNA in osteoporosis could provide unique opportunities for developing novel diagnostic and therapeutic approaches to this disease.

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Calcium Sensing Receptors: Coordinators of Mineral Metabolism and Therapeutic Targets for Metabolic Bone Disorders

The Physiological Basis of Metabolic Bone Disease ◽

10.1201/b16906-8 ◽

2014 ◽

pp. 80-115

Keyword(s):

Mineral Metabolism ◽

Therapeutic Targets ◽

Bone Disorders ◽

Calcium Sensing ◽

Metabolic Bone

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Genetic Determinants of Inherited Endocrine Tumors: Do They Have a Direct Role in Bone Metabolism Regulation and Osteoporosis?

Genes ◽

10.3390/genes12081286 ◽

2021 ◽

Vol 12 (8) ◽

pp. 1286

Author(s):

Francesca Marini ◽

Francesca Giusti ◽

Teresa Iantomasi ◽

Maria Luisa Brandi

Keyword(s):

Clinical Features ◽

Current Knowledge ◽

Mineral Metabolism ◽

Genetic Defect ◽

In Vivo Studies ◽

Bone Modeling ◽

Endocrine Tumors ◽

Direct Role ◽

Primary Tumors ◽

Metabolism Regulation

Endocrine tumors are neoplasms originating from specialized hormone-secreting cells. They can develop as sporadic tumors, caused by somatic mutations, or in the context of familial Mendelian inherited diseases. Congenital forms, manifesting as syndromic or non-syndromic diseases, are caused by germinal heterozygote autosomal dominant mutations in oncogenes or tumor suppressor genes. The genetic defect leads to a loss of cell growth control in target endocrine tissues and to tumor development. In addition to the classical cancer manifestations, some affected patients can manifest alterations of bone and mineral metabolism, presenting both as pathognomonic and/or non-specific skeletal clinical features, which can be either secondary complications of endocrine functioning primary tumors and/or a direct consequence of the gene mutation. Here, we specifically review the current knowledge on possible direct roles of the genes that cause inherited endocrine tumors in the regulation of bone modeling and remodeling by exploring functional in vitro and in vivo studies highlighting how some of these genes participate in the regulation of molecular pathways involved in bone and mineral metabolism homeostasis, and by describing the potential direct effects of gene mutations on the development of skeletal and mineral metabolism clinical features in patients.

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

Bone Abstracts ◽

10.1530/boneabs.1.pp454 ◽

2013 ◽

Author(s):

Jirko Kuhnisch ◽

Jong Seto ◽

Claudia Lange ◽

Susanne Schrof ◽

Sabine Stumpp ◽

...

Keyword(s):

Bone Fragility ◽

Long Bone ◽

Micro Structure ◽

Matrix Mineralization

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Management of primary and secondary osteoporosis in children

Therapeutic Advances in Musculoskeletal Disease ◽

10.1177/1759720x20969262 ◽

2020 ◽

Vol 12 ◽

pp. 1759720X2096926

Author(s):

Sophia D. Sakka ◽

Moira S. Cheung

Keyword(s):

Bone Fractures ◽

Bone Biopsy ◽

Treatment Options ◽

Quantitative Computed Tomography ◽

Fragility Fractures ◽

Secondary Osteoporosis ◽

Long Bone ◽

Vertebral Fracture Assessment ◽

Primary Osteoporosis ◽

Mineral Density

Osteoporosis in children differs from adults in terms of definition, diagnosis, monitoring and treatment options. Primary osteoporosis comprises primarily of osteogenesis imperfecta (OI), but there are significant other causes of bone fragility in children that require treatment. Secondary osteoporosis can be a result of muscle disuse, iatrogenic causes, such as steroids, chronic inflammation, delayed or arrested puberty and thalassaemia major. Investigations involve bone biochemistry, dual-energy X-ray absorptiometry scan for bone densitometry and vertebral fracture assessment, radiographic assessment of the spine and, in some cases, quantitative computed tomography (QCT) or peripheral QCT. It is important that bone mineral density (BMD) results are adjusted based on age, gender and height, in order to reflect size corrections in children. Genetics are being used increasingly for the diagnosis and classification of various cases of primary osteoporosis. Bone turnover markers are used less frequently in children, but can be helpful in monitoring treatment and transiliac bone biopsy can assist in the diagnosis of atypical cases of osteoporosis. The management of children with osteoporosis requires a multidisciplinary team of health professionals with expertise in paediatric bone disease. The prevention and treatment of fragility fractures and improvement of the quality of life of patients are important aims of a specialised service. The drugs used most commonly in children are bisphosphonates, that, with timely treatment, can give good results in improving BMD and reshaping vertebral fractures. The data regarding their effect on reducing long bone fractures are equivocal. Denosumab is being used increasingly for various conditions with mixed results. There are more drugs trialled in adults, but these are not yet licenced for children. Increasing awareness of risk factors for paediatric osteoporosis, screening and referral to a specialist team for appropriate management can lead to early detection and treatment of asymptomatic fractures and prevention of further bone damage.

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