Arrangement of one article: "Osseogenesis", a rare endocrine disease

Osteogenesis imperfecta (OI), also known as fragile bone disease, is the most common single-gene hereditary bone disease.
It is caused by a decrease in the quantity or quality of bone matrix protein due to mutations in multiple disease-causing genes, resulting in low bone mass.
, Bone diseases characterized by increased bone fragility and repeated fractures.

Most of the inheritance is autosomal dominant, a few are autosomal recessive, and X chromosome-associated inheritance is rare.

 Etiology and Epidemiology Bone is mainly composed of organic and inorganic matter.

Type Ⅰ collagen (collagen, COL1) is the most abundant component of bone organic matter, accounting for more than 90% of bone organic matter.
It is essential for maintaining the integrity of bone structure and bone biomechanical properties.

The pathogenesis of OI is that a variety of disease-causing gene mutations lead to abnormal metabolism of type I collagen, which is reduced in quantity or abnormal structure, causing thinning of cortical bone, slender trabecular bone, and irregular, grid-like or scaly trabecular bone , Which leads to a significant decrease in bone density, bone microstructure damage, abnormal bone biomechanical properties, and ultimately lead to repeated fractures and progressive bone deformities.

There are currently 21 OI pathogenic genes reported.
Among them, mutations in the α1 chain and α2 chain encoding genes COL1A1 or COL1A2 of type I collagen are the main cause of OI, and they are inherited in an autosomal dominant manner.

 The prevalence of neonatal OI is about 1/20000～1/15000, but the prevalence of OI in my country still needs further epidemiological investigation.

 Clinical manifestations Due to the complex and diverse spectrum of disease-causing genes and mutations of OI, the clinical phenotype of the disease varies.

The main clinical manifestations of the patient are repeated fractures, skeletal deformities, and varying degrees of activity limitation under mild external forces that have been onset since childhood.

Patients may have extra-skeletal manifestations such as blue sclera, loose ligaments, dysplasia of dentin, hearing loss, and heart valve disease.

The imaging features of OI mainly include: bone sparseness in many parts of the body; thinning of the skull plate, widening of fontanelles and cranial sutures, interstitial bones in the occiput, flat skull base; scoliosis or kyphotic deformity, vertebral body It is deformed and can have multiple vertebral compression fractures; the thorax can be twisted, deformed, or even collapsed; the long bones of the limbs are slender, the cortex is thin, the marrow cavity is relatively large, the metaphysis is widened, multiple long bone fractures, and bone bending deformities.

 According to the severity of the clinical condition, OI is divided into types I to V: type I is the lightest and most common; type II is the heaviest, usually perinatal death; type III is the most serious among the survivors, often short stature and skeletal deformities; IV; The severity of type is between type Ⅰ and type Ⅲ.

Type V OI has unique clinical features, including hypertrophic callus, dislocation of the radial head, calcification of the interosseous membrane of the forearm, and dense epiphyseal lines under the radial metaphysis.

Clinically, it can be judged based on fracture severity, time of onset, sclera color, and whether there is dentin hypoplasia.

In recent years, with the development of molecular biology, many new types of OI have been discovered.

 Diagnosis The clinical diagnosis of OI is mainly based on disease manifestations and imaging features.

The diagnosis basis mainly includes: childhood onset, history of repeated fragility fractures; blue sclera; dentinal dysplasia; hearing loss; family history of positive fractures.

The diagnosis of OI should be combined with bone imaging findings.

 OI patients can undergo bone density, bone X-ray, and bone metabolism biochemical indicators to assess the severity of the disease and help differential diagnosis.

If necessary, genetic mutation testing can be performed to further clarify molecular diagnosis.

Genetic diagnosis is an important means of precise diagnosis and treatment of OI, which is conducive to the identification of gene mutations, accurate classification of diseases, revealing pathogenesis, and promoting genetic counseling.

It is worth noting that, because the disease-causing genes of OI have not yet been fully discovered, genetic diagnosis cannot replace clinical diagnosis.

Those with a negative genetic test cannot rule out the possibility of OI.

 Differential diagnosis As there are many kinds of bone diseases in children, including hereditary bone disease, metabolic bone disease, tumor bone disease, etc.
, before the diagnosis of OI, it should be related to achondroplasia, low phosphorus rickets, pseudo-vitamin D-dependent rickets, Fanconi syndrome, bone fibrous heteroplasia, hypophosphatase, osteosarcoma, lymphoma, leukemia-related bone disease, joint hypermobility syndrome and other diseases are distinguished.
The following examinations are helpful for the differential diagnosis: 1.
Skeleton X In patients with OI, the bones in many parts of the whole body are sparse; the skull plate is thinned, the fontanelles and cranial sutures are widened, the occiput may have interstitial bones, and the skull base is flat; scoliosis or kyphosis deformity, vertebral deformation, and multiple vertebrae Compression fractures of the body; the thorax can be distorted, deformed, or even collapsed; the long bones of the limbs are slender, the cortical bone is thin, the marrow cavity is relatively large, the metaphysis is widened, multiple long bone fractures, and bone bending deformities.

 2.
Bone density The bone density of OI patients is often significantly lower than that of normal people of the same age and sex.

 3.
Biochemical examination OI patients often have normal serum calcium, phosphorus, and alkaline phosphatase concentrations.

 4.
Detection of pathogenic gene mutations by detecting mutations in type I collagen encoding genes or their metabolism-related pathogenic genes to help diagnosis and differential diagnosis.

 Treatment 1.
Specific treatment method There is no mature and effective treatment method for OI disease-causing gene mutations.
The existing treatment is only symptomatic treatment, which aims to increase bone density and reduce fracture rate.

 Appropriate amount of calcium and vitamin D is the basic treatment of OI, which can provide the nutrients needed by the bones, but cannot effectively reduce the fracture rate.

At present, the most effective drugs for the treatment of OI are bisphosphonates, and promising therapeutic drugs in the future include the N-terminal 1-34 fragment of parathyroid hormone (PTH1-34), targeting RANKL, osteosclerosin, and transforming growth factor- β (TGF-β) monoclonal antibody, etc.

 Bisphosphonates (BPs) for the treatment of OI have not been approved by the U.
S.
and my country's Drug Administration, and are still experimental treatments.

It can effectively inhibit the activity of osteoclasts, thereby inhibiting bone resorption, increasing bone density, and reducing fracture rate.
However, whether it can improve the growth and development of patients and reduce the fracture rate of patients with severe OI has not yet reached a consensus.

The appropriate dosage, frequency of use, and duration of drug treatment of BPs for OI need to be further explored.

 It is worth noting that BPs are mainly excreted through the kidneys, and those with a creatinine clearance rate of less than 35ml/min are prohibited from BPs.

Common adverse reactions of BPs in the treatment of OI include: the first intravenous infusion of BPs often presents acute-phase reactions, including fever, headache, nausea, myalgia, arthralgia and hypocalcemia, etc.
, which usually occur within 24 hours after the first infusion , Relieved in about 3 days, and those with obvious symptoms can be treated symptomatically with non-steroidal anti-inflammatory drugs.

The common adverse reaction of oral BPs is gastrointestinal discomfort, and those with digestive system diseases should be used with caution.

 2.
Comprehensive treatment Orthopedic treatment is required for fragility fractures, OI patients with severe bone deformities, and patients with delayed or nonunion fractures that significantly affect the quality of life of the patients.

OI's orthopedic treatment mainly includes rehabilitation treatment and surgical treatment.

Surgical treatment mainly includes fracture surgery, joint surgery and orthopedic surgery.

Surgery is usually combined with medication and rehabilitation training to achieve better results.

 Figure 1 The diagnosis and treatment process of osteogenesis imperfecta The above content is extracted from: The National Health Commission of the People's Republic of China.
Guidelines for the diagnosis and treatment of rare diseases (2019 edition) [J].
The official website of the National Health Commission of the People's Republic of China.