Osteogenesis Imperfecta (OI)

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

OI is caused by defects in or related to a protein called type 1 collagen. 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

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

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 healthcare 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. They can also have a condition called hydrocephalus, in which fluid builds up inside the skull, causing the brain to swell.

People with severe OI often have basilar invagination, 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

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

If a parent or sibling has OI, a healthcare provider can test the DNA of the fetus for the presence of an OI mutation. In this case, a healthcare provider obtains a sample of fetal cells by chorionic villus sampling (CVS) or amniocentesis. The fetal cells can also be tested for the presence of abnormal collagen.

For amniocentesis, a healthcare 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 healthcare 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 healthcare provider may notice symptoms in an infant or child. The healthcare 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

Healthcare 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

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
• Physical therapy
• Bracing
• Surgical procedures
• Medication
• Treatments for Related Conditions

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. Healthcare 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 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