1. Osteogenesis imperfecta Osteogenesis imperfecta (literally means "imperfectly formed bone." People with osteogenesis imperfecta have a genetic defect that impairs the body's ability to make strong bones. Some people have a more severe form of the condition. Their bones break easily and they may break hundreds of bones during their lives. Many people, however, have a milder form of OI, and go through life with few fractures

2. Cause In people with osteogenesis imperfecta, one of the genes that tells the body how to make a specific protein does not function. This protein (type I collagen) is a major component of the connective tissues in bones. Type I collagen is also important in forming ligaments, teeth, and the white outer tissue of the eyeballs (sclera). As a result of the defective gene, not enough type I collagen is produced, or the collagen that is produced is of poor quality. In either case, the result is fragile bones that break easily but can heal at a normal rate.

3. In most cases of OI, children inherit the defective gene from one of their parents. But, the child's symptoms and the degree of disability can be very different from that of the parent. In some children, neither parent has osteogenesis imperfecta. In these cases, the genetic defect is a spontaneous mutation (change) in the gene, and it stops functioning correctly. There are different types of osteogenesis imperfecta with symptoms that range from mild to severe. Each person with the condition may have a different combination of symptoms. All people with OI, however, have weaker bones. Description

4. Description This 16-year-old boy has bone deformities in both his shinbones that have not yet been straightened with surgery.

5. In many children with osteogenesis imperfecta, the number of times their bones fracture decreases significantly as they mature. However, osteogenesis imperfecta may become active again after menopause in women or after the age of 60 in men. Scoliosis, or curvature of the spine, is a problem for many children with osteogenesis imperfecta. There are several types of osteogenesis imperfecta and they vary in severity and characteristics. As scientists have discovered new genetic problems causing OI, new types of the disorder have been recognized. All types of the disorder, however, have symptoms and severity that fall somewhere within the range of the first four types recognized. These four types are described below

6. Type I Osteogenesis Imperfecta Type I osteogenesis imperfecta is the most common and mildest type of this disease. While the structure of the collagen is normal, there is less collagen than there should be. There is little or no bone deformity, although the bones are fragile and easily broken. The effects of osteogenesis imperfecta may extend to the teeth, making them prone to cavities and cracking. The whites of the eyes may have a blue, purple, or gray tint.

7. Type II Osteogenesis Imperfecta Type II osteogenesis imperfecta is the most severe form of the disease. The collagen does not form properly. Bones may break even while the fetus is in the womb. Many infants with type II osteogenesis imperfecta do not survive.

8. Type III Osteogenesis Imperfecta Type III osteogenesis imperfecta also has improperly formed collagen and often severe bone deformities, plus additional complications. The infant is often born with fractures. The whites of the eyes may be white, blue, purple, or gray. People with type III osteogenesis imperfecta are generally shorter than average. They may have spinal deformities, respiratory complications, and brittle teeth

9. Type IV Osteogenesis Imperfecta Type IV osteogenesis imperfecta is moderately severe, with improperly formed collagen. Bones fracture easily, but the whites of the eyes are normal. Some people with type IV osteogenesis imperfecta may be shorter than average and may have brittle teeth. Bone deformities are mild to moderate. In many cases, broken bones that occur with little or no force are the first sign of osteogenesis imperfecta, and will cause your doctor to suspect the condition

10. Medical History and Physical Examination Because osteogenesis imperfecta is often inherited, your doctor will discuss family medical history in addition to your child's medical history. Your doctor will also complete a thorough physical examination that includes checking your child's eyes and teeth.

11. Tests X-rays will provide your doctor with clear images of your child's bones, showing fractures as well as malformations of bone. Your doctor may take blood or tissue samples for genetic testing. In many cases, these tests are able to identify the mutation, particularly if the parent's mutation is also known. Ultrasound can often detect severe cases of osteogenesis imperfecta during pregnancy.

12. Treatment While there is no cure for osteogenesis imperfecta, there are ways to improve a child's quality of life. Treatment is individualized and depends on the severity of the disease and the age of the patient. Care is provided by a team of healthcare professionals, including several types of doctors, a physical therapist, a nurse-clinician, and a social worker. Support from a social worker or psychologist is very helpful for both the child and the family, and often becomes even more important during adolescence

13. Nonsurgical Treatment In most cases, treatment is nonsurgical. Medication. Medical bisphosphonates, given to the child either by mouth or intravenously, slow down bone resorption. In children with more severe osteogenesis imperfecta, bisphosphonate treatment often reduces the number of fractures and bone pain. These medications must be administered by properly trained doctors and require close monitoring. Immobilization. Casting, bracing, or splinting fractures is necessary to keep the bones still and in line so that healing can occur. Exercise. After a fracture, movement and weight bearing are encouraged as soon as the bone has healed. Specific exercises will increase mobility and decrease the risk of future fractures. Low-impact exercise, such as swimming and walking, can help strengthen bones and the muscles that support them. Exercise is part of a healthy lifestyle for every child.

14. Surgical Treatment Surgery may be recommended in cases of: Repeated fractures of the same bone Fractures that do not heal properly Bone deformity, such as scoliosis

15. This 14-year-old boy with osteogenesis imperfecta has scoliosis. Scoliosis is a sideways curve of the spine. Instead of a straight line down the middle of the back, this spine has two curves. Courtesy of Texas Scottish Rite Hospital for Children.

16. Rodding. Metal rods may be inserted in the long bones of the arms and legs to help reinforce the bone, and subsequently lessen the number of fractures. Some rods are a fixed length and must be replaced as a child grows. Other rods are designed like telescopes, and they expand as a child's bones grow. There are,however, other complications that may occur with telescoping rods. Do not hesitate to ask your orthopaedic surgeon about both rodding options

17. Spinal fusion for scoliosis. Although bracing is the usual treatment for scoliosis, it is not often effective in children with osteogenesis imperfecta because the ribs will become deformed from the brace, without preventing the scoliosis from worsening. Spinal fusion, a surgery in which the bones of the spine are realigned and fused together, may be recommended when the scoliosis becomes severe

18. Living with Ostogenesis Imperfecta Below are some tips developed by the Osteogenesis Imperfecta Foundation for taking care of children with osteogenesis imperfecta. Most importantly, do not feel guilty if your child breaks a bone. Children must grow and develop, and fractures will occur no matter

19. how careful you are Do not be afraid to touch or hold an infant with osteogenesis imperfecta, but be careful. To lift an infant with osteogenesis imperfecta, spread your fingers apart and put one hand between the legs and under the buttocks, and place the other hand behind the shoulders, neck, and head. Never lift a child with osteogenesis imperfecta by holding him or her under the armpits. Do not pull on arms or legs or, in those with severe osteogenesis imperfecta, lift the legs by the ankles to change a diaper. Select an infant car seat that reclines. It should be easy to place or remove your child in the seat. Consider padding the seat with foam and using a layer of foam between your child and the harness. Be sure your stroller is large enough to accommodate casts. Do not use a sling- or umbrella-type stroller. Follow your doctor's instructions carefully, especially with regard to cast care and mobility exercises. Swimming and walking are often recommended as safe exercises. Adults with OI should avoid activities such as smoking, drinking, and taking steroids because they have a negative impact on bone density. Increasing awareness of child abuse and a lack of awareness about osteogenesis imperfecta may lead to inaccurate conclusions about a family situation. Always have a letter from your family doctor and a copy of your child's medical records handy.

20. Osteopetrosis What is osteopetrosis? Osteopetrosis is a bone disease that makes bones abnormally dense and prone to breakage (fracture). Researchers have described several major types of osteopetrosis, which are usually distinguished by their pattern of inheritance: autosomal dominant, autosomal recessive, or X- linked. The different types of the disorder can also be distinguished by the severity of their signs and symptoms

21. Autosomal dominant osteopetrosis (ADO), which is also called Albers- Schönberg disease, is typically the mildest type of the disorder. Some affected individuals have no symptoms. In these people, the unusually dense bones may be discovered by accident when an x-ray is done for another reason. In affected individuals who develop signs and symptoms, the major features of the condition include multiple bone fractures, abnormal side-to-side curvature of the spine (scoliosis) or other spinal abnormalities, arthritis in the hips, and a bone infection called osteomyelitis. These problems usually become apparent in late childhood or adolescence

22. Autosomal recessive osteopetrosis (ARO) is a more severe form of the disorder that becomes apparent in early infancy. Affected individuals have a high risk of bone fracture resulting from seemingly minor bumps and falls. Their abnormally dense skull bones pinch nerves in the head and face (cranial nerves), often resulting in vision loss, hearing loss, and paralysis of facial muscles. Dense bones can also impair the function of bone marrow, preventing it from producing new blood cells and immune system cells. As a result, people with severe osteopetrosis are at risk of abnormal bleeding, a shortage of red blood cells (anemia), and recurrent infections. In the most severe cases, these bone marrow abnormalities can be life- threatening in infancy or early childhood.

23. Other features of autosomal recessive osteopetrosis can include slow growth and short stature, dental abnormalities, and an enlarged liver and spleen (hepatosplenomegaly). Depending on the genetic changes involved, people with severe osteopetrosis can also have brain abnormalities, intellectual disability, or recurrent seizures (epilepsy). A few individuals have been diagnosed with intermediate autosomal osteopetrosis (IAO), a form of the disorder that can have either an autosomal dominant or an autosomal recessive pattern of inheritance. The signs and symptoms of this condition become noticeable in childhood and include an increased risk of bone fracture and anemia. People with this form of the disorder typically do not have life-threatening bone marrow abnormalities. However, some affected individuals have had abnormal calcium deposits (calcifications) in the brain, intellectual disability, and a form of kidney disease called renal tubular acidosis.

24. Rarely, osteopetrosis can have an X-linked pattern of inheritance. In addition to abnormally dense bones, the X-linked form of the disorder is characterized by abnormal swelling caused by a buildup of fluid (lymphedema) and a condition called anhydrotic ectodermal dysplasia that affects the skin, hair, teeth, and sweat glands. Affected individuals also have a malfunctioning immune system (immunodeficiency), which allows severe, recurrent infections to develop. Researchers often refer to this condition as OL-EDA-ID, an acronym derived from each of the major features of the disorder.

25. How common is osteopetrosis? Autosomal dominant osteopetrosis is the most common form of the disorder, affecting about 1 in 20,000 people. Autosomal recessive osteopetrosis is rarer, occurring in an estimated 1 in 250,000 people. Other forms of osteopetrosis are very rare. Only a few cases of intermediate autosomal osteopetrosis and OL-EDA-ID have been reported in the medical literature.

26. What genes are related to osteopetrosis? Mutations in at least nine genes cause the various types of osteopetrosis. Mutations in the CLCN7 gene are responsible for about 75 percent of cases of autosomal dominant osteopetrosis, 10 to 15 percent of cases of autosomal recessive osteopetrosis, and all known cases of intermediate autosomal osteopetrosis. TCIRG1 gene mutations cause about 50 percent of cases of autosomal recessive osteopetrosis. Mutations in other genes are less common causes of autosomal dominant and autosomal recessive forms of the disorder. The X-linked type of osteopetrosis, OL-EDA-ID, results from mutations in the IKBKG gene. In about 30 percent of all cases of osteopetrosis, the cause of the condition is unknown.

27. The genes associated with osteopetrosis are involved in the formation, development, and function of specialized cells called osteoclasts. These cells break down bone tissue during bone remodeling, a normal process in which old bone is removed and new bone is created to replace it. Bones are constantly being remodeled, and the process is carefully controlled to ensure that bones stay strong and healthy. Mutations in any of the genes associated with osteopetrosis lead to abnormal or missing osteoclasts. Without functional osteoclasts, old bone is not broken down as new bone is formed. As a result, bones throughout the skeleton become unusually dense. The bones are also structurally abnormal, making them prone to fracture. These problems with bone remodeling underlie all of the major features of osteopetrosis

28. How do people inherit osteopetrosis? Osteopetrosis can have several different patterns of inheritance. Most commonly, the disorder has an autosomal dominant inheritance pattern, which means one copy of an altered gene in each cell is sufficient to cause the disorder. Most people with autosomal dominant osteopetrosis inherit the condition from an affected parent. Osteopetrosis can also be inherited in an autosomal recessive pattern, which means both copies of a gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. OL-EDA-ID is inherited in an X-linked recessive pattern. The IKBKG gene is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons..

29. Paget's disease of bone bone is a localized disorder of bone remodeling. Increased number s of larger than normal osteoclasts initiate the process at affected skeletal sites, and the increase in bone resorption is followed by an increase in new bone formation, altering bone architecture. The signs and symptoms of Paget's disease are varied, depending in part on the location of the involved sites and the degree of increased bone turnover. Recent progress in Paget's disease research includes new data regarding the etiology of this disorder and the ongoing development of more effective therapies. Although the cause of Paget's disease remains unproven, the creation of pagetic osteoclasts seems ever more likely to result from both genetic and environmental factors. Many studies indicate that in patients with Paget's disease, both osteoclasts and their precursors harbor evidence of a paramyxovirus infection, although not all studies confirm this finding. Very recent genetic investigations hav

30. identified one candidate gene on chromosome 18q, although genetic heterogeneity is almost certainly present. Advances in treatment have resulted from the availability of several potent bisphosphonate compounds (e.g., pamidronate, alendronate, and risedronate) that, unlike earlier treatments, produce normal or near normal bone turnover indices in a majority of patients. New bone formation after such treatment has a more normal, lamellar pattern, and mineralization abnormalities are rare to absent with the newer compounds. The availability of such agents has prompted a more aggressive management philosophy in which both symptomatic disease and also asymptomatic disease at sites with a risk of progression and future complications are viewed as clear indications for pharmacologic intervention. INTRODUCTION Top of page Abstract INTRODUCTION STUDIES OF THE ETIOLOGY OF PAGET'S DISEASE TREATMENT OF PAGET'S DISEASE: NEW THERAPIES AND NEW PRINCIPLES FOR MANAGEMENT

31. PAGET'S DISEASE OF BONE is a localized disorder of bone remodeling estimated to occur in 2– 3% of individuals in the U.S. over age 60. Increased numbers of larger than normal and supernucleated osteoclasts initiate the remodeling abnormality with increased bone resorption at affected sites. Coupled to this initially osteolytic process is a secondary increase in new bone formation, with the deposition of architecturally disorganized new bone. As a consequence of this localized increase in bone turnover, there is a characteristic radiographic appearance of bone that may show areas of osteolysis juxtaposed to regions with irregular cortical thickening, trabecular coarsening, and an overall sclerotic appearance. Elevated biochemical markers of bone turnover such as serum total (SAP) or bone-specific alkaline phosphatase and urinary hydroxyproline or collagen cross-links and associated peptides reflect the ongoing increased bone remodeling that defines this disorder

32. On physical examination, pagetic bone may appear to be perfectly normal if the changes are early or mild, or the bone may be enlarged and obviously deformed with more advanced disease. Pagetic bone and overlying skin may be warm to the touch in regions such as the tibia or skull due to increased vascularity when turnover is high. Pagetic bone deformity may include such findings as an enlarged skull, kyphosis, and bowing of affected limbs. Clinical symptoms and complications of Paget's disease include bone pain; secondary osteoarthritis from deformity of bone near major joints such as the hip, knee, or ankle; gait disturbances due to a shortened bowed femur or tibia; fractures of long bones or vertebrae; headache or hearing loss with extensive skull involvement; and lumbar spinal stenosis or other syndromes of neural compression with attendant sensory or motor deficits. A recent study has indicated that these complications have a striking impact on the overall quality of life for many patients