Congenital Metabolic Bone Disorders's Fragility

Congenital Metabolic Bone Disorders's Fragility: History

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Subjects: Endocrinology & Metabolism | Genetics & Heredity

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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.

congenital metabolic bone disorders
skeletal development
bone turnover
mineral metabolism
bone mineralization
bone fragility
pathological fractures

1. Introduction

Despite its inert appearance, bone is a highly active tissue, continuously undergoing a remodeling process, by which the old tissue is replaced by new bone, granting the skeleton the ability to adapt to mechanical use, correct calcium and phosphate homeostasis, and to heal fractures. The correct equilibrium between bone resorption and new bone formation is necessary for skeletal health. An imbalance between these two phases results in bone fragility, a pathological condition in which the correct bone microarchitecture is altered, the strength of bone tissue is reduced, and the skeleton is prone to deformities and fractures, even in the presence of low-impact traumas or with no trauma [2^[1]].

Skeletal development and life-long bone turnover are two finely and complexly regulated processes, in which numerous local and systemic factors participate (chemokines, cytokines, hormones, intracellular signals, and biomechanical stimulation) [3^[2],^[3]]. A variety of genes and epigenetic factors concur for the correct modeling and remodeling of the skeleton. As a consequence, a defect of expression and/or activity in one of these key factors can alter normal bone turnover and be responsible for bone fragility.

At the cellular level, bone fragility can be caused by excessive osteoclast-driven bone resorption that is not balanced by a corresponding amount of bone formation, which leads to bone mass loss and “porous bone” (osteoporosis), or by disfunctions specifically affecting the correct mineralization process of the extracellular matrix leading to “soft bone” (a pathological condition named osteomalacia in adults and rickets in children), or by an excessive bone mass (osteopetrosis) being the outcome of an enhanced osteoblast-driven mineralized bone deposition or a reduced resorption activity by the osteoclasts. Despite their different molecular causes and histological manifestations, these bone pathological conditions confer an elevated rate of deformities to the tissue and notably increase the risk of fragility fractures. In osteoporosis and osteomalacia, bone fragility is caused by quantitatively low bone mass or by poorly mineralized bone, respectively. Conversely, in osteopetrosis, bone fragility can be caused by excessive bone formation and mineralization density, which, rather than conferring additional strength, lead to a lack of normal tissue turnover and bone repair, with consequent structural brittleness, predisposing the bone to fracture [5^[4]].

Clinically, the most common cause of bone fragility is idiopathic osteoporosis of the elderly. Aging is the main cause of progressive bone mass reduction, acting in synergy with pre-existent endogenous (genetic and epigenetic signatures) and exogenous (lifestyle and diet) risk factors. Osteoporosis is defined, according to the World Health Organization criteria, as a bone mineral density (BMD) value that is more than 2.5 standard deviations below that of the mean level for a young adult reference population [6^[5]]. Fragility fractures, occurring prevalently at wrists, vertebrae, and proximal femur, but also at ribs and humerus, represent the clinical endpoint of this pathological condition. Osteoporosis can also manifest as a secondary consequence to a varied spectrum of diseases, affecting organs other than the skeleton, which alter mineral metabolism, and indirectly, correct bone homeostasis [7^[6]].

In addition, bone fragility can manifest at any age, as a consequence of a wide spectrum of rare congenital metabolic bone disorders, in which the inherited genetic defect compromises the correct bone tissue modeling and remodeling, causing bone deformities and fragility fractures.

2. Bone Fragility in Rare Congenital Metabolic Bone Disorders

The most recent taxonomic classification of human rare congenital skeletal metabolic diseases, prepared by the Skeletal Rare Diseases Working Group of the International Osteoporosis Foundation, and based on the genetic defect and the deranged bone metabolic activity causing the disease, reported a total of 116 Mendelian-inherited clinical phenotypes, and 86 mutated causative genes, involved in the regulation of bone and mineral metabolism homeostasis [8^[7]]. According to this taxonomy, congenital metabolic bone diseases can be divided into four major groups, based on their primary pathogenic molecular mechanisms: (1) disorders due to altered activity of bone cells (osteoclasts, osteoblasts, or osteocytes); (2) disorders due to altered bone extracellular matrix proteins; (3) disorders due to altered bone microenvironmental regulators; and (4) disorders due to altered activity of calciotropic and phosphotropic hormones/regulators.

Inheritance is variable among diseases; it can be autosomal dominant, autosomal recessive, or in rare cases, follows X-linked modes. Mutations are usually inherited from one or both parents; however, more rarely, they may occur de novo at the embryo level [9^[8]]. They can be inactivating mutations, leading to a loss-of-function of the encoded protein, or activating mutations, resulting in a gain-of-function of the encoded protein.

2.1. Bone Fragility in Bone Disorders Due to Altered Activity of Bone Cells

Alterations in number, differentiation, and/or activity of bone cells are causes of abnormal bone tissue homeostasis. Disorders caused by genetic defects altering the correct functions of bone-forming and bone-reabsorbing cells consist of numerous different rare phenotypes (Table 1), which can be further divided into four subgroups: (1) diseases characterized by low bone resorption (Table 1, Subgroup 1a), (2) diseases characterized by high bone resorption (Table 1, Subgroup 1b), (3) diseases characterized by low bone formation (Table 1, Subgroup 1c), and (4) diseases caused by high bone formation (Table 1, Subgroup 1d).

2.2. Bone Fragility in Bone Disorders Due to Altered Extracellular Matrix Proteins

Currently, all the known inherited diseases of the bone matrix affect collagen type 1. These can be divided into the following subgroups: (1) disease caused by genetic defects affecting the collagen type 1 synthesis and structure (Table 2, Subgroup 2a), (2) disease caused by gene mutations altering the post-translational collagen modification (Table 2, Subgroup 2b), and (3) diseases caused by gene mutations involved in the processing and crosslink of collagen (Table 2, Subgroup 2c). All together, these diseases include 16 genetically heterogeneous clinical forms of Osteogenesis imperfecta, Bruck syndromes type 1 and type 2 (caused by loss-of-function mutations in two genes encoding proteins involved in the regulation of folding and crosslinking of procollagen type 1), and two Osteogenesis imperfecta-like syndromes (Cole-Carpenter syndromes type 1 and type 2) [8^[7]]. Despite these clinical forms distinguished by their clinical severity, bone characteristic features commonly overlap. People with these conditions have fragile bones, prone to deformities, that fracture easily, often from a mild trauma or with no apparent cause. Additional pathognomonic bone features may include short stature, curvature of the spine (scoliosis), joint deformities (contractures), and dentinogenesis imperfecta. The severe forms show marked growth deficiency and multiple fractures that may occur even before birth. Conversely, patients with milder forms are usually of normal or near normal height, and show only a few fractures during their lifetime, manifesting prevalently during childhood and adolescence as the result of minor trauma.

2.3. Bone Fragility in Bone Disorders Due to Altered Bone Microenvironmental Regulators

The regulation of bone remodeling is both systemic and local. Local regulation of bone homeostasis includes cytokines and growth factors that modulate bone cell functions, or enzymes involved in the control of bone and mineral metabolism, such as alkaline phosphatase (ALP).

According to the genetic defects affecting the bone microenvironmental regulators, these disorders can primarily be divided into the following subgroups: (1) diseases due to altered ALP activity (Table 3, Subgroup 3a), and (2) diseases due to alterations in bone-regulating cytokines and growth factors [8^[7]]. The latter can be further divided into: (1) diseases due to alterations of the RANK/RANKL/OPG system (Table 3, Subgroup 3b), (2) diseases due to alterations of the glycosylphosphatidylinositol (GPI) biosynthesis pathway (Table 3, Subgroup 3c), (3) diseases due to alterations of LRP5-Wnt signaling (Table 3, Subgroup 3d), and (4) diseases due to alteration of the bone morphogenetic protein receptor (BMPR) (Table 3, Subgroup 3e).

2.4. Bone Fragility in Bone Disorders Due to Altered Activity of Calciotropic and Phosphotropic Hormones/Regulators

Calcium ion and phosphate are the two components of hydroxyapatite crystals of bone mineralized matrix. The appropriate regulation of calcium ion and phosphate homeostasis and their correct availability are fundamental aspects for the mineralization process to properly take place. Calciotropic and phosphotropic hormones are the endocrine effectors regulating the systemic homeostasis of calcium and phosphate, respectively. Calciotropic hormones include the parathyroid hormone (PTH) and the active form of vitamin D (1,25-dihydroxyvitamin D), while the only phosphotropic hormone is the fibroblast growth factor 23 (FGF23).

Diseases affecting the correct regulation of calcium and/or phosphate homeostasis, and, subsequently, bone mineralization, can be classified into: (1) disorders due to an excess or a deficiency of PTH secretion by the parathyroid glands (named hyperparathyroidism and hypoparathyroidism, respectively); (2) disorders caused by abnormal PTH receptor signaling (pseudohypoparathyroidism); (3) disorders due to altered vitamin D metabolism and activity (Table 4); and (4) congenital disorders of the phosphate homeostasis (Table 5).

3. Conclusions

To date, over 100 different congenital metabolic bone disorders involving abnormalities of cartilage and bone have been reported, with skeletal phenotypes often overlapping among these rare conditions. As a consequence, a differential diagnosis may require a thorough medical evaluation, including personal and family medical histories, anthropometric evaluation, radiological imaging, biochemical measurements, and genetic counseling, carried out by specialists with specific expertise. The identification of the precise causative genetic variant is of key importance for the diagnosis and clinical management of the patient, since knowing the deregulated pathway(s) responsible for disease development may help personalize clinical care, to choose a specific medical treatment, if available, and to determine the eligibility of the patient to participate in clinical trials underway for novel target therapies.

Multigenic panel testing using next-generation sequencing technique, which allows the simultaneous screening of genes responsible for congenital metabolic bone disorders, including the high-resolution analysis of copy number variants, can provide rapid and comprehensive diagnostic and therapeutic benefits to clinicians and patients, and therefore should become part of the medical work-up for patients.

This entry is adapted from the peer-reviewed paper 10.3390/ijms221910281

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