Orthopedics - Oleksa A.P. 2006

Pathophysiology of Joints
Developmental Defects and Congenital Skeletal Anomalies
Osteogenesis Imperfecta

This disease has been known for a long time, as evidenced by a case described by Lusitanus in 1637 of a child born with bone fractures. Additionally, Schosie (1716) and Ammandt (1719) observed children with multiple bone fractures and attributed them to congenital Rickets.

In 1788, Parrot expressed the opinion that intrauterine fractures were the result of congenital Syphilis, arguing that intrauterine rickets does not exist. Over time, syphilis was also ruled out as a contributing factor to this condition.

In 1825, Lobstein reported on three patients of different ages who frequently suffered bone fractures without apparent cause, and proposed naming the condition "osteopsathyrosis idiopatica".

In 1849, Vrolik described a syndrome of bone fragility with multiple fractures occurring either intrauterinely or postnatally, and named it "osteogenesis imperfecta", a term that remains in use today.

Although the conditions described by Lobstein and Vrolik were initially considered distinct, Looser pointed out in 1906 that these variants share a common essence and suggested using the term "osteogenesis imperfecta congenita et tarda".

In 1938, Mastromarino convincingly demonstrated that both forms of this disease represent a single nosological entity with different clinical manifestations in terms of timing and varied prognoses.

Clinicians distinguish two forms of osteogenesis imperfecta: early (intrauterine, or prenatal), in which bone fractures occur in utero or during childbirth, and postnatal, or late, form.

Although children born with the prenatal form of the disease were traditionally considered nonviable and expected to die in the first months of life, many clinicians have pointed to the potential viability of these children (Bogdanov F.R., 1935; Ternovskiy S.D., 1953; Edelshtein B.M., 1955).

Volkov M.V. and Nefedieva N.M. (1974) suggested that one should speak of a wide spectrum of clinical manifestations of the disease. It is now firmly established that the earlier the disease manifests, the more severe its course and the poorer the prognosis.

In 1968, Gremlau (Gremlau J.L.) identified four stages in the course of osteogenesis imperfecta:

1) latent;

2) stage of bone fractures;

3) stage of Hearing loss;

4) stage of progressive Osteoporosis.

However, these classifications do not provide an adequate answer regarding the underlying causes of the disease. Unfortunately, there is currently no proper system for differentiating the clinical variants of osteogenesis imperfecta observed in children.

Based on genetic studies by numerous authors, Sillence (Sillence D., 1981) distinguished four types of the disease, which are accepted as the standard today:

1) Types I and IV — disorders with an Autosomal dominant inheritance pattern and a mild clinical course;

2) Type II — a severe form in which patients die shortly after birth or somewhat later due to multiple pathological fractures or pulmonary infectious complications;

3) Type III — a disorder with an Autosomal Recessive Inheritance pattern; affected individuals generally have a normal lifespan, with challenges primarily centered around the management of bone fractures.

Biochemical defects are localized in one or more mutated COL I A1 and COL I A2 genes, involving the a-1 and a-2 chains of type I Collagen. These variant Mutations result in Glycine substitution, thereby disrupting the native Structure of procollagen (Schtrolovics R., Glorieux F.H., Travers R. et al., 1994).

Considerable genetic and biochemical research in this field is still required to elucidate the specific pathological changes characteristic of this disease.

An improved Classification would enhance Diagnosis and Treatment by taking into account the identified biochemical deviations from the norm across heterogenetic patient groups.

Clinical Features of the disease.

Clinical manifestations of the disorder vary depending on the disease type, the patient's age, and their individual, genetically determined characteristics. As noted, in the prenatal form, infants are born very weak and sometimes nonviable. Despite normal labor, bone fractures occur during delivery. At birth, limb deformities resulting from the malunion of intrauterine fractures can sometimes be detected. Clinically, the diagnosis of osteogenesis imperfecta is primarily based on the presence of limb deformities caused by complete and incomplete bone fractures, Muscle atrophy, blue sclerae, and "amber-colored" Teeth. Later in life, bone fractures frequently occur during swaddling, bathing, or dressing the infant (putting on shirts or rompers). As a rule, fractures are subperiosteal, presenting with angular Displacement of the diaphyseal fragments of the Femur or humerus, and less commonly the BONES OF THE forearm and lower leg. Fractures of the pelvic bones and spine are observed on rare occasions. Because these fractures heal rapidly, treatment must be initiated immediately. It is worth noting that fractures of the hand and FOOT bones almost never occur. Furthermore, pseudoarthrosis does not develop following fractures, although R.M. Obakevich (1929) and V.M. Blokhin (1934) did describe them, which can be attributed to improper treatment.

In untreated children, fractures heal with angular deformities of the limb segments and pronounced, palpable hypertrophic callus formation. The limbs appear disproportionately short and deformed relative to the trunk.

As noted, due to frequent and sometimes multiple fractures and pulmonary inflammatory complications, infants with the early form of the disease typically die within the first days or months of life, and very few survive to the age of 10.

The late-onset form of osteogenesis imperfecta may manifest as bone fractures in children previously considered healthy, generally between the ages of 2 and 12, less commonly during adolescence, and occasionally in adults—although it is widely accepted that after Puberty, fractures become infrequent or cease altogether.

In the late form of osteogenesis imperfecta, the frequency of fractures varies widely, ranging from several to dozens, with diverse locations. In some cases, children exhibit spinal and lower limb deformities without a history of classic fractures, which results from microscopic bone cracks. Comminuted fractures do not occur in long bones, Ribs, or the clavicle due to the low magnitude of the applied force. The Nature of the bone fractures and their healing process do not differ from those observed in the early form of osteogenesis imperfecta, and pseudarthrosis is almost never seen. Fractures are typically accompanied by pain, Swelling, and bone fragment crepitus.

Patients with this condition consistently experience general malaise; muscle atrophy resulting from a sedentary lifestyle; and weakness of the ligamentous-capsular apparatus of the joints, leading to instability, subluxations, or even dislocations. Spinal curvatures and a Flat chest may also develop.

Diagnosis. Osteogenesis imperfecta is characterized by a classical triad of symptoms: bone fragility (brittle bones), blue sclerae, and hearing loss (deafness). Hearing loss develops gradually after puberty As a result of sclerotic changes and ankylosis of the Middle ear ossicles. However, deafness is not invariably present in cases of increased bone fragility. By contrast, blue sclerae are a permanent feature of the disease, caused by the thinning of the sclera and the underlying choroid pigment showing through.

Diagnosing osteogenesis imperfecta does not present significant difficulties. It is based on the aforementioned triad of symptoms, with the frequent fracturing of long tubular bones serving as the primary diagnostic indicator.

In some cases, the birth of an infant with the early form of the disease reveals a disproportion of short, curved limbs relative to a normal trunk, which may lead to a misdiagnosis of chondrodystrophy. However, a normal HEAD and face, along with the presence of thickened callus bone at sites of angular deformity resulting from the improper healing of intrauterine fractures, provide a solid basis for establishing the correct diagnosis.

In young children, osteogenesis imperfecta can be mistaken for rickets or the infantile form of Osteomalacia upon observing Chest deformities and curvature of the limbs and spine; however, a careful medical history and thorough examination rule out these pathologies.

The medical literature describes instances where the uneven ossification of a large hematoma formed after a bone fracture was mistakenly interpreted as a tumor, specifically a pseudosarcoma.

Radiological examination is a mandatory diagnostic Procedure for patients with osteogenesis imperfecta. Skeletal radiographs reveal a variety of pathological bone changes that depend on the patient's age, the clinical form, and the specific course of the disease. In the early form of the disease, radiological imaging is rarely required because a meticulous Clinical examination of the newborn by an orthopedic specialist provides sufficient grounds to establish or strongly suspect the correct diagnosis. Conversely, in children who survive, pathological bone fractures occur with such frequency that routine X-ray Diagnostics are rendered unnecessary.

For the late form of osteogenesis imperfecta, radiological examinations are performed on children, adolescents, and particularly adults presenting with bone fractures accompanied by fragment displacement or malunion, in order to determine the appropriate treatment strategy and deformity correction Methods.

On radiographs of children, long tubular bones exhibit a thinned cortical layer alongside a widened medullary cavity, with the cortex thickness potentially reduced to 0.3–0.1 cm. Osteoporosis is a characteristic feature; occasionally, a bone becomes so radiolucent that its shadow density is difficult to distinguish from that of soft Tissues. The spongy (cancellous) bone displays a wide-meshed, reticular structure. Epiphyses appear thickened relative to the diaphyses. Following numerous fractures, the bones exhibit deformities, significant callus formation, and osteosclerotic areas against a Background of osteoporosis. At the apex of angular deformities in long bones, Looser's zones of transformation—representing areas of structural bone remodeling—may be detected. T.P. Vinogradova (1951) suggested that Looser's zones arise as a result of microfractures occurring at sites of maximal biomechanical stress on the bone.

Although the structural Changes in the tubular bones of both the upper and lower extremities are identical, they are more pronounced in the lower limbs due to greater static and dynamic loads.

In severe forms of osteogenesis imperfecta, deformations of the vertebral bodies along with spinal curvature are observed. Vertebral bodies may become biconcave ("fish vertebrae") or compressed (platyspondyly) due to impaired enchondral vertical growth of the vertebral bodies. Pelvic bones are also frequently deformed on radiographs, manifesting as a reduction in pelvic conjugates and protrusio acetabuli of the hip joints. Following frequent fractures of the clavicles and ribs, the rib cage similarly becomes deformed.

Because such radiographic findings are typically present in all patients with osteogenesis imperfecta, further radiological investigations are generally unnecessary, although the literature contains reports on radioisotope studies and limb angiographies (M.V. Volkov, N.M. Nefedieva, 1974).

Laboratory Blood and urine tests in children with osteogenesis imperfecta do not reveal any specific pathognomonic signs of the disease. In some cases of fresh bone fractures, an elevated ERYTHROCYTE SEDIMENTATION RATE (ESR) has been noted. Biochemical serum analyses show that Calcium and phosphorus levels, as well as alkaline phosphatase activity, generally fall within normal limits across various age groups, although some researchers (Bethge J., 1962; Finke P., 1965) have detected elevated activities of acid and alkaline phosphatase. Volkov and Nefedieva observed a slight increase in alkaline phosphatase activity in patients with acute pathological bone fractures. Arnati et al. (1967) as well as Fricke and Jeanloz (1968) investigated protein-polysaccharide complexes as Key Components of Connective Tissue structures, while Volkov and Nefedieva studied serum protein-bound CARBOHYDRATES and the urinary excretion of glycopeptides. The results of these studies depended on the clinical form of osteogenesis imperfecta, pointing to metabolic disturbances, alterations in serum protein-Carbohydrate METABOLISM, and abnormal urinary excretion of Glycoproteins.

Collagen metabolism—as the primary protein comprising 95% of Bone tissue—was also investigated by measuring total urinary hydroxyproline excretion, as well as its levels in blood serum and bone biopsies obtained during surgery. It was established that the collagen content in bones and the urinary excretion of hydroxyproline were reduced.

M.V. Volkov and N.M. Nefedieva conducted hormonal studies in children with osteogenesis imperfecta. They determined that the glucocorticoid function of the adrenal cortex was somewhat impaired, though occasionally within normal limits. Furthermore, these hormonal alterations varied depending on the age of the children. An elevation in the biologically active fraction of plasma 11-oxycorticosteroids was more frequently observed in children under 10 years of age, whereas older children maintained normal levels. The authors attribute this to the varying frequency of bone fractures across different age groups.

Regarding the prognosis, it must be emphasized once again that in the early prenatal form of osteogenesis imperfecta, the majority of weakened infants die shortly after birth or During the first months of life due to frequent fractures and secondary inflammatory complications. The prognosis is considerably more favorable in the late form of the disease, as bone fractures occur with decreasing frequency during puberty and eventually disappear in adulthood.

Treatment. Given that frequent fractures in pathologically altered bones heal rapidly but with a strong tendency toward deformity, providing prompt emergency care and appropriate management is vital. The principles of treating fractures in osteogenesis imperfecta do not differ from standard traumatological practices. In cases of recurrent bone fractures, intramedullary metal osteosynthesis serves as a preventive measure against future fractures and angular deformities.

Because bone fractures in early childhood are typically managed using Conservative methods, angular deformities occasionally develop, which disrupt the static and dynamic function of the lower extremities and lead to secondary deforming osteoarthritis. Angular deformities in children and adults—especially in the lower limbs—must be corrected via corrective osteotomies combined with rod osteosynthesis. Closed osteoclaslasia is no longer employed because the bone typically breaks outside the apex of the deformity rather than at it. When necessary, children are advised to use orthopedic braces, and comprehensive rehabilitation is of paramount importance.

Preventing bone fractures is the single most critical aspect of managing osteogenesis imperfecta. Affected children require careful handling, a protective regimen, and general restorative therapy. The Use of calcium, phosphorus, iron, multivitamins, and vitamin D supplements is beneficial. Thymus extracts are prescribed in early childhood, while Sex Hormones are administered to older children to stimulate linear bone growth.

Ultraviolet (quartz) irradiation of children also plays a supportive role.

Patients are prescribed anabolic Steroids (such as nerobol per os in 4–6 week courses) and thyrocalcitonin (TCT), which inhibits bone resorption processes, accelerates regeneration, and promotes intensive calcium deposition within the protein matrix of the bones. The daily dose of thyrocalcitonin is 20 units for children under 10 and 30 units for older children, administered over a four-week course. Thyrocalcitonin therapy should be accompanied by high doses of calcium (calcium gluconate up to 2.0 g daily).

Children with osteogenesis imperfecta must be placed on dispensary medical registries and receive ongoing medical care. Guidance should be provided to steer them toward low-impact professions and appropriate career placement.