The main symptom of the patient is a serious lack of calcium in the body, resulting in insufficient bone density, leading to repeated fractures, and in severe cases, up to one hundred fractures in a lifetime. Children and their families due to surgery or fear of fracture, pain, do not dare to go down to the ground activities and overprotection, resulting in osteoporosis and more prone to fracture, very prone to fracture or bone deformation, height is also affected, the disease has no cure, the children and their families bring great pain. However, if the disease is found and treated in time, the condition can be improved, and the child can take care of himself or herself, or even be able to do some work within his or her ability. I. Etiology Most children with osteogenesis imperfecta have mutations in the gene encoding type I collagen, which is the main structural protein of bone, skin, tendon, tooth and sclera. type I collagen is a long triple-helical molecule consisting of two α1 chains and one α2 chain, with only slight amino acid sequence differences between the two chains. Both chains contain a repeating amino acid trimer GXY: G (Glycine, aminoacetic acid), X (Proline, proline), Y (hydroxyproline, hydroxyproline). The two residues spaced two residues apart are aminoacetic acid residues, which are essential for the formation of the helical structure because their side chains allow the formation of a tight heterotrimer. Substitution of any amino acid for aminoacetic acid disrupts the highly regular helical structure. More than 250 mutations in two genes of type I collagen have been reported to be associated with osteogenesis imperfecta in children with osteogenesis imperfecta. The majority of type I osteogenesis imperfecta is mutated with 1 allele quiescent, thus decreasing the normal amount of type I collagen. These mutations render the COL1A1 gene or COL1A2 gene nonfunctional or increase the number of abnormal collagen chains that cannot bind to normal collagen chains. There are multiple molecular mechanisms associated with this. The most common are failure point mutations, or one/two pairs of insertion/deletion mutations that produce premature abortive coding during RNA transcription. Another possibility is a bonding mutation, where the sequence is severed into an unstable protein that cannot participate in helix formation, or where the transcript is rapidly degraded within the cell, or remains located in the nucleus after transcription. Children with types II, III, and IV osteogenesis imperfecta have structural defects in one of the strands of type I collagen. The majority of these are point mutations (85%), in which aminoacetic acid is replaced by other amino acid residues, and in a few cases, bonding mutations. The mutated collagen chain is involved in helical structure formation, leading to structural alterations in type I collagen that are more clinically severe than those in which the collagen chain is completely nonfunctional. In most cases, there is often a concomitant decrease in the amount of collagen deposited into the bone because of instability and intracellular degradation. Methods of examining type I collagen for mutations have advanced considerably in recent years. There has been a shift from the need for skin biopsies and fibroblast cultures for RNA and protein analysis to drawing blood for direct DNA analysis. These changes have increased the speed and sensitivity of molecular analysis and have provided new methods for clinical diagnosis of atypical cases, genetic counseling, and prenatal diagnosis. However, recent scientific studies have confirmed that approximately 30% of children with severe osteogenesis imperfecta do not have structural or quantitative abnormalities of type I collagen. Other bone protein abnormalities may be present in these cases. Electron microscopy reveals that while normal bone is predominantly lamellar, children with osteogenesis imperfecta have more intertwined bone (immature, disorganized) than normal lamellar bone (mature, collagen fibers arranged in parallel). In addition, osteogenesis imperfecta bone is more mineralized than normal bone, making it harder and more brittle. Histologic examination of osteogenesis imperfecta reveals a decrease in both cortical and trabecular bone mass. The cortex is thinned, the trabeculae are also thinned and their number is reduced. Long bones with thinned cortex break easily. Vertebrae with reduced trabecular bone volume are prone to compression fractures. Histomorphometric studies of children with osteogenesis imperfecta have shown that although the productivity of each osteoblast is reduced, more osteoblasts are activated throughout the bone. At the same time, osteoclast activity is mildly increased, resulting in a faster than normal bone turnover rate. As a result, there is less trabecular bone formation than trabecular bone resorption during each remodeling cycle. The number of trabeculae in children with osteogenesis imperfecta does not increase with age as it does in normal children, but rather deviates from normal values. There is also a decrease in the number of new trabeculae produced by the growth plate, which relies on endochondral ossification, which also leads to a decrease in bone mass. In normal development, cortical bone continually increases in width and cross-sectional area. This is dependent on the relationship between new bone formation in the periosteum and resorption in the endosteum, with more lateral than medial bone formation. In children with osteogenesis imperfecta, osteoblasts are not active enough, and thus lateral bone formation is reduced. At the same time, medial bone resorption continues and even increases. The combined result of these factors is thinning of the cortical bone of the long bones and a decrease in the cross-sectional area. Muscle size and strength contribute to bone formation. In children with osteogenesis imperfecta, prolonged and repeated braking due to fractures, surgery, chronic bone pain, and parental overprotection decreases trabecular volume and cortical thickness, resulting in a vicious cycle – “fracture-brake-fracture “. The only way to improve the strength of long tubular bones with thinned cortex and fragile bone is to increase their diameter. But unfortunately, as mentioned earlier, in most children with osteogenesis imperfecta their long bone diaphragm diameter decreases. This further reduces the strength of the long bones. Other common morphologic problems in children with osteogenesis imperfecta are curvature deformities of the limbs, which are prone to recurrent fractures at the apex of the deformity, and only surgical orthopedics can reduce this risk. Types of osteogenesis imperfecta Sillence (1979) genetically categorized the disease into 4 types: type I is autosomal dominant, showing only blue sclera, mild symptoms, no or mild skeletal deformities, and normal or near-normal height. type II dies perinatally or is born with multiple fractures or skeletal deformities. type III is the type with the worst manifestations after survival. These children have short stature, abnormal epiphyseal plates, and progressive limb and spine deformities due to multiple fractures.Type IV presents with mild to moderate skeletal deformities and varying degrees of short stature.DNA studies have shown that almost all type I osteogenesis imperfecta and 70-75% of type II-IV osteogenesis imperfecta are caused by mutations in the genes that encode type I collagen. Mutations in the genes encoding type I collagen. There are more than 250 types of mutations in these genes, resulting in a wide range of clinical presentations, from death at birth to lifelong asymptomatic. Thus, the four phenotypes do not better reflect the clinical and molecular diversity of osteogenesis imperfecta. Recently, three different types of osteogenesis imperfecta with unique clinical and histologic features have been identified. None of them have type I collagen mutations and are non-collagen mutant osteogenesis imperfecta, and their respective underlying genetic defects remain to be investigated. Children with type V osteogenesis imperfecta are prone to post-fracture hyperplastic bone scabs, early calcification of the forearm interosseous membrane, and metaphyseal sclerotic bands. Children with V-type osteogenesis imperfecta do not have blue sclera or hypodontia. Histologic studies of the ilium show irregular arrangement of lamellar bone (fishnet), whereas collagen fibers in typical type IV osteogenesis imperfecta are arranged parallel to each other. The type of inheritance is autosomal dominant, and the clinical manifestations vary in severity, with most cases being moderately severe. Type VI osteogenesis imperfecta is a mineralization disorder. Children are prone to multiple fractures, vertebral compression, and long tubular bone deformities. There is normal scleral color, no dental hypoplasia, and mildly elevated serum alkaline phosphatase levels. Bone density is decreased. Cranial seamless interosseous bone formation. Lax bands due to bone softening are seen in the scapula, long bones and ribs, but do not involve the epiphyseal plates as in rickets. The most typical histologic change is an abundance of osteoid (unmineralized bone matrix) without metabolic disorders such as hypocalcemia, hypophosphatemia, or Vit D deficiency in the child. In addition, the loss of lamellar arrangement is observed under polarized light microscopy, often in a fish-scale arrangement. Type VII osteogenesis imperfecta is seen in the northern Quebec population. Typical manifestations are shortened limbs and hip inversion. Other clinical and histologic manifestations are similar to those of typical type IV osteogenesis imperfecta. The type of inheritance is autosomal recessive. This type of osteogenesis imperfecta is not a type I collagen disease because it can develop with a mutation in one allele of the structural protein. Because the common characteristics of osteogenesis imperfecta are bone fragility and bone loss, the principle of treatment is to increase bone strength, prevent fracture, improve the gravity line, and improve function. Recently, bisphosphonates have been used both at home and abroad to treat osteogenesis imperfecta with relatively satisfactory efficacy. Bisphosphonates are synthetic pyrophosphonate analogs that bind to hydroxyapatite in bone and specifically block osteoclast-mediated bone resorption. Bisphosphonates are pyrophosphonate analogs in which the oxygen atom in the center of the molecule is prevented from degradation by replacing it with a carbon atom. Two phosphate groups are directly attached to the charcoal atom, from which two side chains, R1 and R2, extend simultaneously.The R1 side chain is usually a hydroxyl group, which, together with the phosphate group, is known as the bone hook.The difference in the R2 side chain results in different potencies for different molecules. Older generation bisphosphonates such as Etidronate and Clodronate form cytotoxic non-cyclic ATP analogs after uptake from the bone surface into the cell via cell phagocytosis, which accumulate inside the cell and lead to apoptosis. Recently nitrogen-containing bisphosphonate drugs inhibit farnesyl bisphosphate synthase activity. This inhibition results in the inability to isoprenylate (transfer fatty acid side chains) a variety of intracellular proteins, particularly small GTP-binding proteins such as Ras, Rab, Rho, and Rac. The inability of these small proteins to isoprenylate results in their inability to ectopically enter the cell membrane. This interference with cellular processes leads to early apoptosis in certain cells, including osteoclasts. At the cellular level, loss of osteoclast function leads to decreased bone resorption, which subsequently triggers a series of changes. The increase in bone mineral content is more pronounced in children with lower bone mineral content at the start of treatment (bone mineral content).Glorieux et al. were the first to use bisphosphonates in the treatment of osteogenesis imperfecta. The first child was treated with pamidronate (a second-generation bisphosphonate) at Shriners Hospitals in Montreal in 1992. At the time of publication in 1998, a total of 30 children over 3 years of age with osteogenesis imperfecta had been treated for 1.3-5 years. Z-scores of lumbar spine bone density improved from -5.3 ± 1.2 to -3.4 ± 1.5, a 42% increase. The cortical width of the metacarpals increased by 27.0 ± 20.2% per year compared to 8C9% per year in normal children. Increased vertebral volume indicated new bone formation. The annual fracture rate decreased by 1.7%, and walking function improved in half of the children, with 13% of those who were previously wheelchair-dependent being able to walk independently after treatment. Chronic musculoskeletal pain and easy fatigue improved in all children. The urinary NTx/creatinine ratio (N-terminal telopeptide of type I collagen, a marker of bone resorption) was 132% before treatment, and decreased to 49% at 4 years of treatment (compared with controls of the same age and sex). Treatment of 11 cases of type V brittle bone disease, age at start of treatment 1.8-15.0 years, 6 females. 50% reduction in N-terminal telopeptide, increase in lumbar spine bone density (Size and volumetric ) iliac biopsy showed an 86% increase in cortical thickness, and fracture rate was reduced from 1.5/year to 0.5/year. Subsequently, the age of treatment was advanced to infancy with the aim of preventing the development of short stature, spinal curvature and limb deformities. The results of treatment in children under 2 years of age have recently been reported in the literature. The control group consisted of children with osteogenesis imperfecta of similar age and severity, who were not treated with pamidronate but received the same physiotherapy. There was a significant increase in BMD Z-scores in the treatment group and no increase in the control group. Vertebral coronal plane area was increased in the treated group but decreased in the untreated group. The fracture rate was low in the treated group (annual fracture rate 2.6±2.5 in the treated group and 6.3±1.6 in the control group).Children younger than 2 years of age responded more rapidly and significantly to treatment than older children, with a reduction in bone pain and an increase in mobility on the day of treatment initiation. Although early bisphosphonate treatment does not completely prevent bending deformities of the long bones. However, it can significantly reduce the severity of osteogenesis imperfecta by increasing vertebral height, growth improvement and decreasing fracture rates. There are now several papers in the world reporting the efficacy of pamidronate, which can achieve better results in type I, type III, type IV and type V brittle bone disease. The current dosage is generally as follows: under 2 years of age, 0.5mg/kg/day for 3 consecutive days, once in February, the first 0.25mg/kg/day; 2-3 years of age, 0.75mg/kg/day for 3 consecutive days, once in March, the first 0.38mg/kg/day. over 3 years of age, 1mg/kg/day for 3 consecutive days, once in April, the first 0.5mg/kg/day. Once, first 0.5mg/kg/day. Rauch observed the effect of long-term sodium pamiphosphate treatment on the morphology of bone tissue in children.25 children with moderate to severe osteogenesis imperfecta, 7 girls and 18 boys, aged 1.4 to 15.3 years. Iliac bone biopsies and vertebral bone densitometry were performed before the start of treatment and after 2.7 +/- 0.5 and 5.5 +/- 0.7 years of treatment. Bone density increased by 72% at the second measurement but only by 24% at the third measurement. Bone cortical width and cancellous bone volume increased by 87% and 38%, respectively, at the second examination. Subsequently, the increase in cortical width was insignificant, but the amount of cancellous bone was mildly increased. This shows that the maximum effect of sodium pamiphosphate is achieved within 2-4 years of starting treatment. Rauch also looked at the response to discontinuation of sodium pamiphosphate in osteogenesis imperfecta for more than 3 years. 12 pairs of children, each with similar age, severity, and duration of treatment, were treated, and one group was discontinued and the other group continued the drug. Bone resorption activity increased 2 years after discontinuation. Bone mineral mass increased between both groups. Bone mineral density Z value decreased in the untreated group and increased in the continued treatment group. Fracture rates and functional levels were similar between the two groups. Although bone resorption activity increased after discontinuation of the drug, it was still significantly lower than in the untreated group with sodium pamidophosphate; bone mineral content and bone mineral density remained increased, but bone mineral density Z-values decreased. The changes were significant in children who continued to grow. It can be seen that 2 years after discontinuation of the drug, bone metabolism remained suppressed and bone mass continued to increase, but lumbar spine bone density increased less compared with healthy individuals. The extent of these changes was influenced by growth. The following side effects of pamidronate have been reported in the literature. The most common is an acute febrile reaction, usually seen at the time of the first injection, in about 85% of cases. Mild hypocalcemia, leukopenia and transient bone pain and vomiting have also been reported. Four infants with respiratory disease developed respiratory failure at the time of the first injection. Large doses at high concentrations can lead to renal failure. Therefore, pamidronate should only be administered slowly intravenously at low concentrations (no more than 0.12 mg/ml). Rarely, pamidronate may cause scleritis with or without anterior uveitis. Bronchial stenosis due to pamidronate has also been reported. However, these serious side effects have not been seen in children with osteogenesis imperfecta treated with pamidronate for more than 8 years, with the exception of one case of bronchial stenosis, and the relationship between bronchial stenosis and the drug is uncertain. The safety of bisphosphonate medication in the treatment of childhood diseases has been demonstrated, with no effect on growth, no change in epiphyseal plate morphology, and no effect on fracture healing. The effects of bisphosphonate therapy in young girls have not been systematically studied, but no side effects have been reported in case reports. Animal studies have shown that although bisphosphonates are not teratogenic at therapeutic doses, they can cross the placenta and accumulate in the fetus, especially in bone tissue. Since bisphosphonates are present in the body throughout life, long follow-up studies are needed to exclude delayed side effects of these drugs in patients and offspring. The main effect of bisphosphonate therapy in children with osteogenesis imperfecta is to increase cortical bone thickness. This is the result of blocking bone resorption by endosteal osteoclasts without interfering with new bone formation by osteoblasts on the surface of long bones. Cortical thickening strengthens the bone, thus allowing the child to undergo orthopedic surgery for intramedullary fixation and rehabilitation (physiotherapy and occupational therapy). However, bisphosphonate medications do not cure osteogenesis imperfecta, and most children with severe disease and some with mild disease require intramedullary metal fixation to support the long bones. Due to the low bone strength of the child, plate fixation cannot be utilized as screw fixation is not secure and there is a high rate of fracture at the upper and lower stresses of the plate. Therefore, central fixation is required. Traditionally, in children with severe osteogenesis imperfecta, intramedullary fixation of the lower limbs should be performed before they begin to stand and are able to walk independently to prevent lower limb deformity. However, after initiation of treatment with pamidronate, intramedullary fixation is generally no longer performed in children before standing. If the child’s medullary cavity is not wide enough, the child may be temporarily braced for protection until the cavity permits intramedullary fixation. Mild osteogenesis imperfecta, no deformity of the lower limb, and a very low fracture rate do not require intramedullary fixation. At present, intramedullary fixation for osteogenesis imperfecta can be divided into Rush nail and extendable nail. Extendable intramedullary nails can be lengthened with bone growth and are mainly used in the femur.Dubow-Bailey type extendable intramedullary nails have been used as a standard technique for decades. However, it has a high complication rate (displacement, T-shank dislodgement).Fassier and Duval proposed a new concept to minimize its mechanical complications. This intramedullary nail does not require a knee osteotomy, but is inserted through the greater trochanter, as in the treatment of adult fractures. Fassier used a minimally invasive technique to place the Dubow-Bailey intramedullary nail. This is used in cases where the femur is wide and cortically thin. The technique utilizes two incisions: proximal via the greater trochanter and distal via the knee to place the male and female rods, respectively. One or more percutaneous osteotomies are made to correct the deformity. The procedure has less bleeding, reduced operative time, quicker return to activity after surgery, and less skin scarring. However, the learning curve for this procedure is steeper. The possibility of Dubow-Bailey intramedullary nail fixation of the tibia is controversial because of the damage to the ligaments and the articular surface of the distal tibia. The tibia is usually fixed with Rush nails, which can be replaced if there is flexion or fracture with growth (usually 2-3 years). The duration of postoperative braking should be minimized to avoid postoperative bone loss. Unless the osteotomy is very unstable, immobilization in plaster pants is usually not used. To avoid rotation of the femoral osteotomy, both lower extremities may be immobilized in long leg casts and connected by crossbars, as in an A-frame. The child can sit up. Generally 3 weeks after the operation, the cast is removed, the brace is worn, and upright weight-bearing is gradually started. The indications for intramedullary fixation of the upper limb are mainly two: (1) upper limb dysfunction due to deformity, inability to use braces, walkers, and impeded activities of the child (2) repeated fractures. The forearm can be fixed with thin Kirschner pins, and in the humerus can be fixed with Kirschner pins or extendable intramedullary nails. Comparative studies of extendable and non-extendable intramedullary nails have found that about 20-40% of extendable nails need to be replaced again, while 50% of non-extendable nails need to be replaced again surgically, with a complication rate of 72% in the former and 50% in the latter. In a recent analysis of 82 children with intramedullary nail fixation at Shriners Hospitals in Montreal, 51% of non-extendable intramedullary nails were reoperated on and 27% of extendable nails required reoperation. The complication rate was 55% in both groups. Thus, extendable intramedullary nails can reduce the number of surgeries, while their complications are not higher than those of conventional intramedullary nails. Pamidronate treatment can improve bone quality and make intramedullary nail fixation more stable, and the improvement of intramedullary nailing also reduces the mechanical complications at the same time. Correction of spinal deformity in osteogenesis imperfecta Type III, 100% of children with osteogenesis imperfecta older than 7 years of age have scoliosis greater than 30°. Because of the fragility of the rib cage and its inability to effectively transmit pressure to the spine, the use of braces to correct osteogenesis imperfecta scoliosis is ineffective and may result in thoracic deformity. Indications for spinal deformity surgery: mild cases of osteogenesis imperfecta with progressive scoliosis greater than 45°, heavy cases with curvature greater than 30°-35°, and those whose bone quality allows internal fixation. Because children with type III and type IV osteogenesis imperfecta have a low growth potential of the spine, surgery can be performed as early as 7-8 years of age. Spinal fusion can be used to treat the condition, and most scholars recommend segmental internal fixation, as different internal fixation devices usually do not provide adequate stability. In type III osteogenesis imperfecta, newer instruments such as small hooks and clips, pedicle hooks are more stable than sublaminar wire fixation. Because the iliac crest is small and fragile, intraoperative bone grafting with allograft or synthetic bone should be used. If in situ bone grafting is used, postoperative head ring-plaster fixation is helpful, but a CT scan of the head should be performed before head ring fixation to determine pin placement. It is preferable to use 6-8 pins for fixation rather than the traditional 4 nails to minimize torque. Anterior vertebral fusion has only been reported in a few cases. The risks of anesthesia in children with severe osteogenesis imperfecta are high: airway problems, restrictive lung disease, cranial base entrapment, difficulty with intubation, risk of fracture during revision, and risk of hyperthermia and profuse sweating. If the child has airway problems, there is also a high risk of prone positioning of the child during posterior surgical spinal fusion. Miniaturization of endoprostheses, segmental fixation, and improvement in bone quality after pamidronate treatment have made surgical orthopedic treatment of previously untreatable spinal deformities in osteogenesis imperfecta now possible. V. PRINCIPLES OF REHABILITATION FOR OSTEOPATHIC INCOMPLETENESS A systematic rehabilitation program had been developed prior to the initiation of bisphosphonate drug therapy. Rehabilitation is now more effective as pamidronate therapy reduces bone fragility, better prognosis for standing and walking. Children with osteogenesis imperfecta may have long bone curvature deformities, vertebral compression, spondylolisthesis, wasting muscle atrophy, oblique head deformity, hip external rotation flexion deformity, and horseshoe foot deformity. These disorders can interfere with the child’s motor function, especially head and trunk control, sitting, climbing, standing, and walking. Parental fear of handling and overprotection can also hinder the child’s ability to live independently. The main goals of rehabilitation for children with osteogenesis imperfecta are (1) to promote the development of gross motor function, (2) to assist in a variety of safe and active activities, and (3) to promote independent functioning to improve quality of life. The rehabilitation program varies with age. In early infancy, parents are encouraged to gently care for their children. Taking turns lying on the right and left sides helps to prevent occipital flattening, cervical dystocia, and hip flexor external rotation deformity. The prone position should be adopted only when the child is awake. Parents should learn how to stimulate active movement of the upper and lower extremities. Parents can assist the child with gentle active activities, but vigorous diagonal and rotational activities should be avoided to avoid fractures. During crawling segments, all forms of segmental movement (sliding, snaking, alternating crawling) are encouraged. Although alternate crawling is not important for the child’s eventual standing and walking, weight-bearing on the upper extremities will help with later wheelchair propulsion, or walking with crutches. At the onset of standing, children with type III and type IV osteogenesis imperfecta who are able to stand with support should undergo intramedullary fixation of the femur and tibia to prevent fractures and deformities. Early postoperative knee-ankle-foot brace immobilization facilitates early uprighting on a sloping table and subsequent return to walking function. Walking is encouraged whenever possible. Weight-bearing in a pool, pedaling a tricycle, walking under a walker, or quadrupedal crutches are all viable rehabilitative treatments. Exercise the hip extensor muscles and quadriceps in the prone position to prevent the development of hip flexion contractures. If the child’s quadriceps muscle strength is adequate, knee-ankle-foot braces are replaced with ankle-foot braces to prevent tibial flexion deformity. Physical therapy also includes a fitness program to train flexibility, endurance, and strength. VI FUTURE TREATMENT Bisphosphonates are not a cure for osteogenesis imperfecta; they do not alter the genetic defect. Bone marrow transplantation has been tried for osteogenesis imperfecta with mixed results. Firstly, the grafting ability of osteoblasts is not strong, thus studies have been done to isolate and expand osteoblasts prior to importation. The second problem is the use of immunosuppressive agents, which also have a destructive effect on bone. Others have isolated mutated osteoblasts from affected children, genetically modified them and then infused them back into the body. Nucleases have also been used to specifically inactivate mutant collagen genes. Alternatively, transfer RNA splicing or RNACDNA oligonucleotide chimeras have been utilized. However, these gene therapy methods cannot be applied to the clinic for a short period of time. In the past 10 years, there has been great progress in the treatment of osteogenesis imperfecta. The mechanisms of osteogenesis imperfecta have been better understood. New non-collagenous osteogenesis imperfecta have been identified, attracting inquiry into new mutational modalities leading to this inherited disease. Early application of bisphosphonate drugs, prompt surgical treatment and rehabilitation have altered the natural course of osteogenesis imperfecta. New treatments such as gene therapy require further research.