Pathology Research: Osteogenesis Imperfecta
Osteogenesis imperfecta (OI), or brittle bone disease, is a genetically determined disease, which is characterized by impaired production of type I collagen. It is a heterogeneous group of diseases with different types of inheritance, which leads to the fragility of bones, frequent fractures, bone deformities, and low bone mineral density. According to modern classifications, depending on the clinical manifestations and molecular defect, 15 types of OI, Bruck syndrome, and Cole-Carpenter syndrome are distinguished (Palomo et al., 2017). Accurate diagnosis is possible only using molecular genetic research methods in combination with radio imaging. This paper examines clinical indications, risk factors, diagnostics, prognosis, and treatment options for OI to better understand how to approach this disease.
Clinical Indications: Signs and Symptoms
To diagnose a patient with OI, a set of the most typical features should be identified based on recommendations from the International Osteoporosis Foundation (IOF). The hereditary history of OI or recurrent fractures, imperfect dentinogenesis, blue sclera, progressive hearing loss, and short stature can be noted (Marom et al., 2020). Another symptom is bone fractures with minimal or no trauma in the absence of other factors, such as maltreatment of children or other known pathology of bone tissues. Ligamentous weakness and other manifestations of connective tissue dysplasia, as well as multiple fractures for a long period and different stages of healing, should be mentioned. As stated by Marom et al. (2020), more than 90% of all patients have gene mutations in collagen COL1A1 and COL1A2. They are marked by an autosomal prevailing type of inheritance, while more than half of cases are new mutations.
The most widespread classification of OI is based on the clinical X-ray picture of the disease and includes types I, II, III, and IV of the disease, which are determined by an autosomal dominant manner of inheritance. Type V that is dominantly inherited presents the formation of volumetric hypertrophied, not prone to remodeling, was added (Marom et al., 2020). Type VI is probably recessively inherited, type VII has CRTAP gene mutation. There are also types that include patients with clinical and radiological manifestations of OI, but without disturbances in collagen synthesis of the first type. According to modern classifications, 15 types of OI are distinguished, depending on the clinical manifestations and molecular defect (Palomo et al., 2017). In addition, OI-like diseases are Bruck syndrome (congenital joint contractures because of a mutation of the PLOD2 gene) and Cole-Carpenter syndrome (craniostenosis).
Risk Factors
Heredity is the main risk factor since the most common types of OI are inherited. If one of the parents has this disease signs, there is a 50% probability that the child would also develop OI (Forlino & Marini, 2016). However, it should be emphasized that about 35% of children with OI have no family history, which means that mutation in genes is another major risk factor (Marini et al., 2017). In many cases, collagen defects lead to mutations, as it is the basic building block. To explain the causes of bone tissue disorder in hereditary diseases of the skeleton, growing attention is paid to the study of the role of growth factors, as well as markers of osteogenesis (Forlino & Marini, 2016). The issues of development, deposition, and the action of growth factors are complex, but they are of great importance for understanding the mechanisms of OI pathology and its potential prevention in the future.
Imaging Exam / Protocols to Best Diagnose Pathology
The study of skeletal mineralization is extensively conducted by the method of dual-energy X-ray absorptiometry of the lumbar spine L1-L4. Total Body and Total Body Less Head can be used to diagnose children based on models of densitometers equipped with a pediatric reference base. To assess the deficit in bone mineral density (BMD), the Z-score is used to measure standard deviations (SD) (Bregou Bourgeois et al., 2016). These methods allow for determining the presence of fractures, their stage, any deformations of long tubular bones, the presence of accessory bones of the skull, and the assessment of bone mineral density. A set of protocols is to be identified for every patient individually based on his or her history of fractures and traumas, heredity factors, and current condition.
Another method is an X-ray examination of the skeleton, namely, tubular bones and spine, which is performed to determine the state of the musculoskeletal system and conduct differential diagnostics with clinically similar conditions (Forlino & Marini, 2016). For example, fibrous dysplasia, rickets-like diseases, and other conditions are to be taken into account (Bregou Bourgeois et al., 2016). In addition, quantitative computed tomography allows spatially separating the trabecular and cortical bone and assessing BMD separately in each bone. Magnetic resonance imaging (MRI) of the brain and spine is regarded as a clarifying method to determine the presence of platybasia, indications for surgical treatment of scoliosis, and the risk of neurological complications (Eisenberg & Johnson, 2020). Genetic analysis is only required in some cases, for example, if a doctor suspects child abuse, as well as for prenatal diagnosis of OI and pregnancy planning.
Radiographic Appearance
Osteopenia, bone deformities, and bone fractures are the main radiographic characteristics of OI (Forlino & Marini, 2016). The radiographic examinations show that the cortical layer of long bones in OI patients is thinned, and the medullary canal is enlarged in diameter. The cancellous bone structure can be sparse, having an irregular reticular pattern. In patients with more serious disorders, individual bone trabeculae can be completely underdeveloped. In the most severe cases, the bones are likely to be light so that they do not stand out in any way against the background of soft tissues (Marini et al., 2017). Accordingly, they are available for radiological determination only due to the thin lines of the cortical layer bordering them. A mild or severe thinning in metatarsal bones is another common appearance (Forlino & Marini, 2016). It should also be stressed that radiographic appearance differs depending on the type of OI, the age of a patient, and concomitant diseases.
Prognosis
The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) and the International Osteoporosis Foundation (IOF) recommend determining the signs of bone formation and bone resorption. It is expected to predict the risk of possible fractures and assess changes in bone parameters in response to ongoing therapy for OI. Bregou Bourgeois et al. (2016) found that higher bone resorption values ​​in persons with low bone mineral density correlate with the greater risk of fractures. In general, the incidence of OI is approximately one case per 10–20 thousand live births (Palomo et al., 2017). However, with a mild course, the disease often remains undiagnosed due to the mild severity of clinical manifestations, which means that the actual prevalence of the disease may be higher.
The possibility of effective therapy, adequate surgical correction, and physical rehabilitation helps to reduce skeletal deformities. Nevertheless, some patients have pronounced kyphoscoliotic deformities of the spine, which can lead to severe complications from the cardiovascular and bronchopulmonary systems (Bregou Bourgeois et al., 2016). Prolonged immobilization and a lack of active movements in patients who do not receive active rehabilitation can be the cause of urolithiasis and renal dysfunction. Platybasia associated with spinal deformity often leads to basilar impression, promoting severe neurological complications (Bregou Bourgeois et al., 2016). Timely observation by specialists of an interdisciplinary group specializing in the treatment of OI contributes to the early detection and prevention of complications, adequate treatment, and improvement of the quality of life of patients with OI.
Treatment Options
Since OI is a genetic disorder, the possible forms of therapy are often limited to symptomatic treatments. To eliminate further bone loss, the therapy with drugs from the bisphosphonate group is performed. These drugs are administered intravenously, over three consecutive days, every 3-4 months, depending on the patient’s age (Marom et al., 2020). The side effects of pamidronic acid are usually mild and transient. The most common side effects are flu-like symptoms and low-grade fever, usually developing in the first 48 hours after drug infusion (Marom et al., 2020). Clinically pronounced hypocalcemia is quite rare; also, in complex therapy, children should receive calcium and vitamin D preparations in age-specific dosages. Orthopedic surgery, physical therapy, and occupational therapy help prevent fractures and improve function (Eisenberg & Johnson, 2020). Also, cochlear implantations are recommended in the cases with hearing loss.
The therapy for patients with OI should be aimed at increasing their motor activity, reducing the frequency of fractures, pain management, and social adaptation. Patients with OI have high intelligence, normal life expectancy, and with adequate treatment, they can be active and independent members of society (Marom et al., 2020). When treating children and adults with OI, an interdisciplinary approach must be used (Eisenberg & Johnson, 2020). It is identified by the clinical manifestations of this disease, which include not only damage to the musculoskeletal system, but also other organs and systems, including endocrine, cardiovascular, vision, hearing, and so on (Bregou Bourgeois et al., 2016). In this connection, a full adaptation is also impossible without the participation of a psychologist, physical therapist, rehabilitation therapist, and professionals in the selection and making of auxiliary equipment, such as walkers, orthoses, et cetera.
References
Bregou Bourgeois, A., Aubry-Rozier, B., Bonafé, L., Laurent-Applegate, L. A., Pioletti, D., & Zambelli, P. Y. (2016). Osteogenesis imperfecta: From diagnosis and multidisciplinary treatment to future perspectives. Swiss Medical Weekly, 146, 1-10.
Eisenberg, R. L., & Johnson, N. M. (2020). Comprehensive radiographic pathology (7th ed.). Elsevier Health Sciences.
Forlino, A., & Marini, J. C. (2016). Osteogenesis imperfecta. The Lancet, 387(10028), 1657-1671.
Marini, J. C., Forlino, A., Bächinger, H. P., Bishop, N. J., Byers, P. H., De Paepe, A., & Semler, O. (2017). Osteogenesis imperfecta. NatureRreviews Disease Primers, 3(1), 1-19.
Marom, R., Rabenhorst, B. M., & Morello, R. (2020). Osteogenesis imperfecta: An update on clinical features and therapies. European Journal of Endocrinology, 183(4), 95-106.
Palomo, T., Vilaça, T., & Lazaretti-Castro, M. (2017). Osteogenesis imperfecta: Diagnosis and treatment. Current Opinion in Endocrinology & Diabetes and Obesity, 24(6), 381-388.