Osteogenesis Imperfecta (OI)

Osteogenesis imperfecta (pronounced os-tee-uh-JEN-uh-sis im-per-FEK-tuh) means “imperfect bone formation” and is commonly known as “brittle bone disease” or OI. It is a rare genetic disorder that affects the protein collagen (pronounced KOL-uh-juhn), which is found in bone, teeth, skin, tendons, and parts of the eye. People with osteogenesis imperfecta have bones that can break easily, sometimes with no obvious cause. NICHD research has been instrumental in discovering the genes that cause some types of OI. The Institute continues to conduct and support research on many aspects of OI, including genetics and treatment. 

Common Name

  • Brittle bone disease

Medical or Scientific Name

  • Osteogenesis imperfecta, types I to XI

Osteogenesis Imperfecta (OI): Condition Information

What is OI?

OI, or “brittle bone disease,” is a condition causing fragile bones that break easily, sometimes for no obvious reason. Some people with OI have only a few fractures in their lifetimes. Others have hundreds.1 People who have severe forms of OI have fragile bones that are also deformed. Most people with OI experience physical disability. OI also can cause weak muscles, brittle teeth, a curved spine, and hearing loss. Most forms of OI are caused by abnormal genes that are passed down from one or both parents to their children.

There are currently 11 types of OI. Types I through IV are the most common. They are autosomal dominant forms of the disease. Autosomal dominance is a pattern of inheritance common to some genetic diseases. “Autosomal” means that the abnormal gene is located on one of the numbered, or non-sex, chromosomes. “Dominant” means that a single copy of the abnormal gene is enough to cause the disease; in other words, a person only needs to get the abnormal gene from one parent in order to inherit the disease, even though the matching gene from the other parent is normal. This is in contrast to an autosomal recessive disorder, where two copies of the mutation are needed to cause the disease; in other words, a person must inherit the abnormal gene from both parents in order to inherit the disease. Types VI through XI are autosomal recessive. 2,3,4

Citations

  1. National Library of Medicine, NIH, MedlinePlus. (2011). Osteogenesis imperfecta. Retrieved May 7, 2012, from http://www.nlm.nih.gov/medlineplus/osteogenesisimperfecta.html
  2. Forlino A, Cabral WA, Barnes AM, & Marini JC. (2011). New Perspectives on Osteogenesis Imperfecta. Nat Rev Endocrinol, Jun 14;7(9), 540-557. http://www.ncbi.nlm.nih.gov/pubmed/21670757
  3. Forlino, A., Cabral, W. A., Barnes, A. M., & Marini, J. C. (2011). New perspectives on osteogenesis imperfecta. Nature Reviews Endocrinology, 7, 540–557.
  4. Marini, J. C., Letocha, A. D., & Chernoff, E. J. (2005). Osteogenesis imperfecta. In S. B. Cassidy & J. E. Allanson (Eds.), Management of Genetic Syndromes. Hoboken, NJ: Wiley.

What causes osteogenesis imperfecta (OI)?

OI is caused by defects in or related to a protein called type 1 collagen (pronounced KOL-uh-juhn). Collagen is an essential building block of the body. The body uses type 1 collagen to make bones strong and to build tendons, ligaments, teeth, and the whites of the eyes.

Certain gene changes, or mutations, cause the collagen defects. Mutations in several genes can lead to OI. About 80%–90% of OI cases are caused by autosomal dominant mutations in the type 1 collagen genes, COL1A1 and COL1A2. Mutations in one or the other of these genes cause the body to make either abnormally formed collagen or too little collagen. Mutations in these genes cause OI Types I through IV.

The remaining cases of OI (types VI–XI) are caused by autosomal recessive mutations in any of six genes (SERPINF1, CRTAP, LEPRE1, PPIB, SERPINH1, and FKBP10) that code for proteins that help make collagen. These mutations also cause the body to make too little collagen or abnormally formed collagen.

These gene changes are inherited, or passed down from parents to their children; people who have OI are born with it. However, in some cases, the gene mutation is not inherited and occurs after conception.1,2,3,4

Citations

  1. Forlino A, Cabral WA, Barnes AM, & Marini JC. (2011). New Perspectives on Osteogenesis Imperfecta. Nat Rev Endocrinol, Jun 14;7(9), 540-557. http://www.ncbi.nlm.nih.gov/pubmed/21670757
  2. Forlino, A., Cabral, W. A., Barnes, A. M., & Marini, J. C. (2011). New perspectives on osteogenesis imperfecta. Nature Reviews Endocrinology, 7, 540–557.
  3. Marini, J. C., Letocha, A. D., & Chernoff, E. J. (2005). Osteogenesis imperfecta. In S. B. Cassidy & J. E. Allanson (Eds.), Management of genetic syndromes. Hoboken, NJ: Wiley.
  4. National Institute of Arthritis and Musculoskeletal and Skin Diseases. (2009). What is osteogenesis imperfecta? Fast facts: An easy to read series of publications for the public. Retrieved June 2, 2102, from http://www.niams.nih.gov/Health_Info/bone/Osteogenesis_Imperfecta/osteogenesis_imperfecta_ff.asp

How many people are affected by or at risk of osteogenesis imperfecta (OI)?

Infants who have recognizable OI at birth make up about 1 in every 16,000 to 20,000 births. The incidence rate is similar in people with milder forms of OI that become apparent later in life.

OI affects all genders, races and ethnic groups equally.1

Citations

  1. Forlino A, Cabral WA, Barnes AM, & Marini JC. (2011). New Perspectives on Osteogenesis Imperfecta. Nat Rev Endocrinol, Jun 14;7(9), 540-557. http://www.ncbi.nlm.nih.gov/pubmed/21670757

What are the symptoms of osteogenesis imperfecta (OI)?

All types of OI have some degree of bone fragility and fracturing, and many have some degree of bone deformity.

The symptoms of OI vary by type:

  • Type I
    • Most common and mildest form of OI. It can be so mild that health care providers do not diagnose it in some people until they are adults.
    • Bone fractures occur mostly in years before puberty and decrease in frequency after puberty.
    • Normal height; a few inches shorter than same gender relatives
    • Little or no bone deformity
    • Brittle teeth in rare cases
    • Hearing loss in some cases
    • Blue sclera (whites of the eyes)
    • Easy bruising
    • Mild delay in motor skills
  • Type II
    • Severe; usually results in stillborn birth or death in the first months of life
    • Severe bone deformity
  • Type III
    • Most severe, nonlethal form
    • Hundreds of fractures starting very early in life
    • Severe bone deformities and physical disability that worsen over time
    • Sclera may be blue or grey
    • Triangular face and prominent forehead
    • Scoliosis (abnormal curving of the spine)
    • Sunken or protruding chest wall
    • Brittle teeth
    • Hearing loss
    • Very short height
    • Motor skill delays
    • Usually need wheelchairs
  • Type IV
    • Similar to type I but with mild to moderate bone deformity
    • Dozens of fractures on average, most of which occur before puberty or after middle age
    • Motor skill delays
    • People with type IV often need braces or crutches to walk
    • Short height
    • Brittle teeth
    • Hearing loss in some cases
    • White or blue sclera
    • Scoliosis
    • Large head
    • Easy bruising
  • Type V
    • Identical symptoms to Type IV except:
      • Normal sclera
      • Normal teeth
      • Severely limited ability to twist forearms clockwise or counterclockwise
    • Distinguished from Type IV by differing bone features at microscopic level
  • Type VI
    • Identical symptoms to Type IV except:
      • Normal teeth
      • Greater frequency of fractures
    • Distinguished from Type IV by differing bone features at microscopic level
  • Type VII and VIII
    • Similar to Types II and III
    • Severe or lethal bone deformity
    • Type VII can also involve small head, blue sclera, bulging eyes
    • Some people with Type VIII have lived into their second or third decade
  • Type IX
    • Moderate to severe bone deformity and similar to Types III and IV
    • White sclera
    • Short height
  • Type X
    • Severe and often leads to death.
  • Type XI
    • Bone deformities worsen over time

The bone deformities and collagen defects common to OI can affect various internal organs, leading to secondary problems. These include:

Lung Problems

People with OI are more vulnerable to lung problems, including asthma and pneumonia. Viral and bacterial infections can become severe. In fact, respiratory failure is the most common cause of death in people with OI.

Lung problems result from a combination of factors. If the ribs and spine do not develop normally, there may be less space for the lungs to expand. Collagen also is an important building block of connective tissue in the lungs. If the body does not make enough collagen, or makes abnormal collagen, the lungs do not work properly. This makes it difficult for people with OI to get enough oxygen through their bodies. In addition, they may have problems coughing effectively to clear away mucus.1

Heart Problems

Heart problems, such as incorrectly working valves and arteries, sometimes occur in people with OI.

Neurological Problems

People with OI often have enlarged heads, called macrocephaly (pronounced mak-roh-SEF-uh-lee). They can also have a condition called hydrocephalus (pronounced hahy-druh-SEF-uh-luhs), in which fluid builds up inside the skull, causing the brain to swell.

People with severe OI often have basilar (BAS-uh-ler) invagination (pronounced in-vaj-uh-NEY-shuhn), a malformation of the spinal column that puts pressure on the spinal cord and brain stem. It worsens over time and can cause severe headaches, changes in facial sensation, lack of control over muscle movements, and difficulty swallowing. If untreated, basilar invagination can lead to rapid neurological decline and inability to breathe.2,3,4

Citations

  1. Osteogenesis Imperfecta Foundation. (2008). Respiratory issues in osteogenesis imperfecta. Retrieved May 7, 2012, from https://oif.org/wp-content/uploads/2019/08/Respiratory_Issues.pdf External Web Site Policy
  2. Forlino A, Cabral WA, Barnes AM, & Marini JC. (2011). New Perspectives on Osteogenesis Imperfecta. Nat Rev Endocrinol, Jun 14;7(9), 540-557. http://www.ncbi.nlm.nih.gov/pubmed/21670757
  3. Forlino, A., Cabral, W. A., Barnes, A. M., & Marini, J. C. (2011). New perspectives on osteogenesis imperfecta. Nature Reviews Endocrinology, 7, 540–557.
  4. Marini, J. C., Letocha, A. D., & Chernoff, E. J. (2005). Osteogenesis imperfecta. In S. B. Cassidy & J. E. Allanson (Eds.), Management of genetic syndromes. Hoboken, NJ: Wiley.

How do health care providers diagnose osteogenesis imperfecta (OI)?

If OI is moderate or severe, health care providers usually diagnose it during prenatal ultrasound at 18 to 24 weeks of pregnancy.

If a parent or sibling has OI, a health care provider can test the DNA of the fetus for the presence of an OI mutation. In this case, a health care provider obtains a sample of fetal cells by chorionic villus (pronounced KOHR-ee-on-ik VILL-uhs) sampling (CVS) or amniocentesis (pronounced am-nee-oh-sen-TEE-sis). The fetal cells can also be tested for the presence of abnormal collagen.

For amniocentesis, a health care provider takes a small amount of fluid from the sac surrounding the fetus for testing. He or she takes the sample by inserting a thin needle into the uterus through the abdomen. For CVS, a health care provider uses a similar procedure to take a sample of tissue from the placenta for testing.

If OI is not detected prenatally, parents or a health care provider may notice symptoms in an infant or child. The health care provider may perform the following:

  • Physical exam, which includes:
    • Measuring the length of limbs
    • Measuring the head circumference
    • Examining the eyes and teeth
    • Examining the spine and rib cage
  • Personal and family medical history, which include questions about:
    • Broken bones
    • Hearing loss
    • Brittle teeth
    • Adult height
    • Racial background
    • Whether close relatives have had children together
  • X-ray
  • Bone density test
  • Bone biopsy, in some cases

Health care providers may send blood or skin samples to a lab for collagen or genetic testing. These tests usually confirm whether a person has OI.1,2,3

Citations

  1. Forlino A, Cabral WA, Barnes AM, & Marini JC. (2011). New Perspectives on Osteogenesis Imperfecta. Nat Rev Endocrinol, Jun 14;7(9), 540-557. http://www.ncbi.nlm.nih.gov/pubmed/21670757
  2. Forlino, A., Cabral, W. A., Barnes, A. M., & Marini, J. C. (2011). New perspectives on osteogenesis imperfecta. Nature Reviews Endocrinology, 7, 540–557.
  3. Marini, J. C., Letocha, A. D., & Chernoff, E. J. (2005). Osteogenesis imperfecta. In S. B. Cassidy & J. E. Allanson (Eds.), Management of genetic syndromes. Hoboken, NJ: Wiley.

What are the treatments for osteogenesis imperfecta (OI)?

OI treatments are designed to prevent or control symptoms and vary from person to person. Early intervention is important to ensure optimal quality of life and outcomes. Treatment for OI and its related symptoms may include:

Fracture Care

Casting, splinting, and bracing fractured bones can help them heal properly. However, bones may weaken if they are held in one place for long periods. Health care providers try to strike a balance between healing fractures and maintaining bone strength.

Physical Therapy

Physical therapy aims to maintain functioning in as many aspects of life as possible. A usual program combines muscle strengthening with aerobic conditioning. Many children with OI have delayed motor skills because their muscles are weak. A physical rehabilitation program can include strengthening of deltoids, biceps, and important lower muscles, such as the gluteus maximus, gluteus medius, and trunk extensors. When these muscles are strong, children can lift their arms and legs against the pull of gravity and get around independently.1

Bracing

For some people with OI, wearing braces on the legs can provide support for weak muscles, decrease pain, and keep joints properly aligned. Braces can allow people to get around and function more easily.

Surgical Procedures

Some people with OI undergo surgery to correct bone deformities, including scoliosis and basilar invagination. A common surgical procedure for OI patients, “rodding,” is the placement of metal rods in the long bones of the legs. This strengthens them and helps prevent fractures. Some rods get longer as the legs grow. But they also can work their way out of the bone.1 Surgery can also be performed to improve hearing loss.

Medication

Bisphosphonates (pronounced bis-FOS-foh-neyts) are drugs used to treat osteoporosis. They also are useful for OI, especially in children. These drugs do not build new bone, but they slow the loss of existing bone. They have been shown to reduce vertebral compressions and some long bone fractures.2 However, controlled trials show no improvement in motor skill or decrease in bone pain.3

Treatments for Related Conditions

Although these treatments are not specifically for OI, individuals with OI might rely on the following to address conditions related to OI:

  • Hearing aids for hearing loss
  • Crowns and similar dental devices for brittle teeth
  • Oxygen administration for people with lung problems4

Citations

  1. Marini, J. (2010). Osteogenesis imperfecta. In F. Singer (Ed.), Diseases of bone and metabolism. Retrieved May 29, 2012, from http://www.endotext.org/chapter/osteogenesis-imperfecta/ External Web Site Policy (Free Registration Required)
  2. National Library of Medicine. (2011).Osteogenesis imperfecta. Retrieved May 7, 2012, from http://www.nlm.nih.gov/medlineplus/ency/article/001573.htm
  3. Marini, J. C. (2009). Bone: Use of bisphosphonates in children—proceed with caution. Nature Reviews. Endocrinology, 5(5), 241–243. PMID: 19444252
  4. Marini, J.C ., Letocha, A. D., & Chernoff, E. J. (2005). Osteogenesis imperfecta. In S. B. Cassidy & J. E. Allanson (Eds.), Management of genetic syndromes. Hoboken, NJ: Wiley.

Osteogenesis Imperfecta (OI): NICHD Research Goals

The NICHD conducts research on osteogenesis imperfecta in order to clarify the ways in which the primary gene defect causes skeletal fragility and other connective-tissue symptoms. The Institute also aims to apply this knowledge to the treatment of children with these conditions.

Following the discovery of the genetic source of recessive OI, NICHD researchers now are working to advance understanding of its cellular and biochemical mechanisms. Parallel to this are studies with mouse models for OI to study disease pathogenesis and the skeletal matrix of OI, the effects of pharmacological therapies, and approaches to gene therapy.

Clinical studies are also a significant piece of the NICHD’s OI research effort. In particular, these focus on children with types II and IV OI.

Osteogenesis Imperfecta (OI): Research Activities and Scientific Advances

Through its intramural and extramural organizational units, the NICHD conducts and supports research on OI.

Institute Activities and Advances

Medications for OI

NICHD researchers from the Bone and Extracellular Matrix Branch (BEMB) are conducting clinical studies of a bisphosphonate drug called pamidronate (pronounced pam-id-ROH-neyt) in children who have type III or type IV OI. The studies will compare different doses of the drug by itself or in combination with growth hormone. The aim is to test whether bone mineral density is improved and determine whether there are changes in motor function, muscle strength, or bone pain.1

NICHD researchers are exploring additional therapies for treating OI, including medications that build bone mass. One potential treatment, sclerostin antibody (Scl-Ab) therapy, improved bone mass in mice.2

In a recent study using a mouse model for OI generated at the NICHD, BEMB researchers and their colleagues characterized the differentiation of bone marrow stem cells in adult mice into other cell types. They found that the ability of the stem cells to turn into bone cells was impaired, shunting the precursor cells into the pathway to become fat cells. Researchers then treated the OI mouse model with bortezomib (Btz), which the Food and Drug Administration has approved for treating a cancer (myeloma) that begins in certain bone marrow cells. Treating the OI mouse model with Btz improved the capacity for bone marrow stem cells to turn into bone cells and improved whole bone properties. Although Btz itself is not a suitable therapy for OI, given these study findings, future research may target bone marrow stem cells as an approach to treat OI.3

Bone Marrow Transplants for OI

Over the past several years, NICHD researchers from the Section of Physical Biochemistry (SPB) and BEMB, along with university colleagues, have suggested that transplanting healthy bone marrow into mice with OI may someday lead to an effective treatment for people.

In 2009, a group published the results of a study in which bone marrow was transplanted in utero to mice with lethal OI mutations. About 2% of the transplanted cells remained after birth. These cells produced normal collagen, which accounted for about 20% of all type I collagen in the mice. About 3 in 10 mice not only survived birth but also had only mild OI symptoms.4,5,6 These studies, as well as gene therapy studies, may one day lead to treatments for OI.

Natural History of OI

BEMB researchers are recruiting patients for a long-term study of types III and IV OI from birth to age 25. They aim to assess the natural history of the disease, including any symptoms that affect the teeth, heart, lungs, brain, and hearing. Heart and lung problems are a major cause of disability and death in adults with OI, but it’s not known how these complications develop or whether susceptible people can be identified early in childhood. The study also will include research on the genetics of OI; participants and their parents will be tested for OI gene mutations.7

Studies of Recessive OI

NICHD researchers have discovered three of the known genes that cause recessive OI. Recessive OI is caused by mutations in genes that code for parts of a protein complex. The complex folds and shapes collagen before it is sent out of a cell. Researchers supported by the NICHD’s Developmental Biology and Structural Variation Branch are using human tissues and novel mouse models to better understand how recessive OI comes about and how to distinguish it from the more common dominant OI.8

NICHD researchers in the SPB are focusing on how specific recessive mutations affect the shape of the collagen protein. They have found that mutations that affect a section of collagen called the “N-anchor” result in the loose joints that are common in people with OI. Mutations that affect another section, called the “C-anchor,” seem to result in lethal OI. The group also is studying how protein folding goes awry in recessive OI, and how the stress of improper folding affects the body’s bone-forming cells.5

In 2010, NICHD researchers in the BEMB found a new mutation that is responsible for some recessive forms of OI. The newly identified mutation is in the gene that contains the information needed to make the protein cyclophilin B. This protein is part of a complex of three proteins that modifies collagen, folding it into a precise molecular configuration, before it is secreted from cells.

Recently, BEMB researchers and their colleagues conducted a study to determine the prevalence of one of these recessive OI mutations among Mid-Atlantic African Americans, African immigrants, West Africans, and Africans from areas beyond West Africa. The mutation is in the LEPRE1 gene, which codes for a protein known as P3H1 that is part of the collagen-folding complex. The investigators screened DNA from the target populations and estimated that 0.4% of Mid-Atlantic African Americans carry the genetic mutation, affecting 1 in 260,000 births. The prevalence is higher in West Africa—1.48% of people in Nigeria and Ghana carry the genetic mutation, affecting 1 in 18,260 births. The researchers estimated that the mutation originated between 650 and 900 years ago in this part of West Africa (they did not find it in neighboring countries). Taken together, these findings suggest that the mutation for this type of recessive OI was introduced to populations in the United States during the Atlantic slave trade.9

Other Activities and Advances

OI Mutation Consortium

The BEMB leads an international consortium of connective tissue laboratories that compile and analyze information on mutations in type I collagen. The first analysis of the consortium’s database, published in 2007, listed more than 830 mutations. The database now contains more than 1,570 mutations from nine international laboratories.5

Citations

  1. NIH. (2012). Pamidronate to treat osteogenesis imperfecta in children. Retrieved May 7, 2012, from http://clinicaltrials.gov/ct2/show/NCT00005901
  2. Sinder, B. P., Eddy, M. M., Ominsky, M. S., Caird, M. S., Marini, J. C., & Kozloff, K. M. (2013). Sclerostin antibody improves skeletal parameters in a Brtl/+ mouse model of osteogenesis imperfecta. Journal of Bone Mineral Research, 28(1); 73–80.
  3. Gioia, R., Panaroni, C., Besio, R., Palladini, G., Merlini, G., Giansanti, V., et al. (2012). Impaired osteoblastogenesis in a murine model of dominant osteogenesis imperfecta: A new target for osteogenesis imperfecta pharmacological therapy. Stem Cells, 30, 1465–1476.
  4. Panaroni, C., Gioia, R., Lupi, A., Besio, R., Goldstein, S. A., Kreider, J., et al. (2009). In utero transplantation of adult bone marrow decreases perinatal lethality and rescues the bone phenotype in the knockin murine model of classical, dominant osteogenesis imperfecta. Blood, 114, 459–468.
  5. NICHD. (2011).2011 Annual report of the Division of Intramural Research. Retrieved May 7, 2012, from https://annualreport.nichd.nih.gov/2011/spb2.html
  6. NICHD. (2011). 2011 Annual report of the Division of Intramural Research. Retrieved May 7, 2012, from https://annualreport.nichd.nih.gov/2011/bemb.html
  7. NIH. (2012). Evaluation and intervention for the effects of osteogenesis imperfecta. Retrieved May 7, 2012, from http://clinicaltrials.gov/ct2/show/NCT00001594
  8. Research Portfolio Online Reporting Tools. (n.d.). Pathogenesis of novel forms of osteogenesis imperfecta (project information 1P01HD070394-01). Retrieved May 7, 2012, from https://projectreporter.nih.gov/project_info_description.cfm?aid=8196080&icde=11963151
  9. Cabral, W. A., Barnes, A. M., Adeyemo, A., Cushing, K., Chitayat, D., Porter, F. D., et al. (2012). A founder mutation in LEPRE1 carried by 1.5% of West Africans and 0.4% of African Americans causes lethal recessive osteogenesis imperfecta. Genetics in Medicine, 14, 543–551.
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