What is Osteopetrosis

Osteopetrosis is a congenital condition present at birth in which the bones are overly dense. This results from an imbalance between the formation of bone and the breakdown of bone, both of which are necessary in the development and maintenance of normal bone. In osteopetrosis, the cells that break down bone, or the osteoclasts, usually are either fewer in number or are ineffective in breaking down bone. When an individual has osteopetrosis, all of his or her bones are affected. They are overly dense and the skeleton is extremely heavy.

Three Forms of the Disease

There are three major types of osteopetrosis:

* Malignant Infantile Form: This type of osteopetrosis is very severe. It is inherited when both parents have an abnormal gene that is passed to the child. The disease is apparent from birth and frequently ends in death. Despite its name, the disease is not related to cancer.

* Intermediate Form: This type of osteopetrosis is less severe than the malignant infantile form. Found in children younger than 10 years old, it is more severe than the adult form of osteopetrosis, but usually does not shorten life expectancy.

* Adult Form: This is a milder type of osteopetrosis that is found in adults between 20 and 40 years old. This form rarely causes a significant reduction in life expectancy.

Symptoms

Malignant Infantile Form

This is the most severe form of osteopetrosis. Children with this type have:

* Anemia (and frequently complete marrow failure).

* Frequent infections due to a reduction in white blood cells (the cells that fight infection) and to inactive white cells.

* No tooth eruption or inadequate tooth eruption from the gums.

* Increased pressure within the skull.

* Failure to thrive.

* Delays in psychomotor development, including delays in sitting, walking and talking.

* Blindness, deafness and other nerve problems within the head.

* Death during the first 10 years of life in 30 percent of these children.

Intermediate and Adult Forms

Symptoms are:

* Fractures: because the bones, although dense, are also weak.

* Frequent infections: due to problems with the bone marrow that impair white blood cell production.

* Blindness, deafness and strokes: overgrowth of bone may damage nerves and blood vessels.

Who is Affected

The adult form of osteopetrosis occurs in about one in 20,000 people. There are about 1,250 people with the adult form of osteopetrosis in the United States. The malignant infantile form of osteopetrosis is seen in between 1 in 100,000 to 1 in 500,000 births. In other words, only 8 to 40 children with this severe form of osteopetrosis are born per year in the United States.

The adult form of osteopetrosis is inherited as an "autosomal dominant trait," meaning that it can be passed from generation to generation and children can inherit osteopetrosis even if only one parent is affected. There is a 50 percent chance that a child of someone with adult osteopetrosis will have the disease. Many cases, however, occur without a family history. It is possible that these cases are new or spontaneous gene mutations.

The severe malignant infantile form is inherited as an "autosomal recessive disorder," meaning that both parents have an abnormal gene that is passed to the affected child. Because the gene is recessive, each parent will be normal, not showing any symptoms of the disease. Usually, there is no history of severe, congenital osteopetrosis in the family prior to the diagnosis of the first child. If parents have one child with severe osteopetrosis, there is a 1 in 4 chance for each pregnancy that a subsequent child will be affected. A sibling of a parent known to carry the abnormal gene (i.e., the aunt or uncle of the affected child) has a 50 percent chance that he or she also carries the gene.

The intermediate form may be inherited in either an autosomal recessive or an autosomal dominant fashion. Most cases occur sporadically, however, with no known inheritance pattern.

Diagnosis

Diagnosis for osteopetrosis is made when dense bones are found on X-rays. The diagnosis usually is confirmed by taking a sample of the bone to determine the precise nature of the disease. A variety of additional studies are done to look for any problems, such as hearing and vision testing, X-rays, blood counts and brain imaging.

Treatment

Types of Physicians

The physicians who usually treat osteopetrosis include

* Hematologists

* Endocrinologists

* Orthopedic surgeons

Treatments for osteopetrosis include:

* Actimmune® (Interferon gamma-1b). The U.S. Food and Drug Administration (FDA) recently approved Actimmune® (Interferon gamma-1b) Injection for delaying the progression of the disease in patients with severe malignant osteopetrosis. Actimmune® is the only therapy approved specifically for the treatment of osteopetrosis. Both adult and pediatric patients may benefit from Actimmune®.

* Bone Marrow Transplantation (BMT). BMT is the only therapy that has resulted in a complete cure of the severe malignant infantile form of osteopetrosis. BMT replaces the abnormal osteoclasts, or cells that breakdown bones, with normal cells. This process cures the defect if the transplantation is successful. The survival rate after BMT in children who have osteopetrosis is 40 to 70 percent depending on how well matched the donor is to the patient. BMT is only used in severely affected patients, because of the high risk of failure with the potential of a fatal outcome.

* High Dose Calcitriol. Calcitriol is the active form of vitamin D and stimulates the bone destructing function of the osteoclasts. Given orally in high doses, it can reverse some of the problems of severe osteopetrosis and significantly improve the adult form. High dose calcitriol is not FDA-approved for treatment of osteopetrosis presently.

* Prednisone. Given orally, Prednisone has improved blood counts in patients with anemia and low platelet counts as it may slow blood cell destruction. Prednisone treatment provides a short-term boost to the blood system, allowing other therapies to continue. If taken for long periods, however, prednisone may actually reduce the growth rate of children and predispose patients to infection.

* Nutrition. Good nutrition is vital to ensure normal growth and development of children with osteopetrosis.
* Physical and Occupational Therapy. Physical and occupational therapy are extremely useful in helping children with osteopetrosis reach their full developmental potential. The heavy skeleton results in gross motor delays and blindness can delay speech. The average severely affected child walks at about two years and begins to speak between 20 to 24 months old. Even children with severe osteopetrosis frequently (about 80 percent of the time) have a normal intellectual level.

Prognosis

Patients with the adult form of osteopetrosis have a normal life span. The major complications are fractures and compression of the cranial nerves, or those nerves pertaining to the bones of the head. These complications can lead to blindness, deafness and facial nerve paralysis.

Less than 30 percent of all children with the severe malignant infantile form of osteopetrosis survive to their tenth birthday, unless they are treated with BMT or a combination of interferon gamma and calcitriol. Only 10 percent of infants who have blindness and anemia before six months old survive more than one year unless they are successfully treated.

Glossary of Terms

Anemia: Having too few red blood cells. Symptoms include tiredness, weakness and shortness of breath.

Antigen: A substance capable of stimulating an immune response.

Autosomal dominant trait: One parent has an abnormal gene that is passed to the affected child.

Autosomal recessive disorder: Both parents have an abnormal gene that is passed to the affected child.

Calcitriol: The active form of vitamin D, which is generated by chemical alterations in the liver and kidney. Calcitriol stimulates calcium absorption, bone formation and removal of calcium from bones.

Carbonic Anhydrase: An enzyme that aids in the breakdown of bicarbonate into carbon dioxide and water. This enzyme is crucial to the ability of cells to get rid of hydrogen ions and maintain the level of cell acidity.

Congenital: Present at birth.

Cranial: Pertaining to the bones of the head.

Endocrinologists: Physicians who specialize in hormonal and metabolic disorders.

Engraftment: Successful transplantation of cells from one individual to another.

Enzyme: A protein that helps a chemical reaction to take place. Enzymes are responsible for controlling and facilitating the chemical processes that allow cells to grow, develop and function.

Human Leukocyte Antigen (HLA): These antigens are present on the surface of white blood cells and are used to determine if the body's immune system will detect a cell(s) as foreign or self. Identity of these major histocompatability antigens between cells being transplanted and the individual into whom they are being transplanted is crucial to the success of the engraftment.

Hematologists: Physicians who study and treat diseases of the blood.

Interferon gamma: A substance made by lymphocytes in the body, which stimulates an immune response. Interferon gamma has been used to stimulate improved immunity in patients with white cell defects. The U.S. Food and Drug Administration (FDA) approved Actimmune® (Interferon gamma-1b) Injection in 2000 for delaying the time to disease progression in patients with severe malignant osteopetrosis.

Lymphocytes: Blood cells that help fight infection.

Osteoclasts: Cells that break down bone.

This fact sheet was adapted from The Paget Foundation publication
Questions & Answers about Osteopetrosis
with support from the
NIH Osteoporosis and Related Bone Diseases~National Resource Center.

For more information about Osteopetrosis, contact:

The Paget Foundation for Paget's Disease of Bone
and Related Disorders
120 Wall Street, Suite 1602, New York, NY 10005-4001
Toll-free: 800-23-PAGET · Phone: 212-509-5335
Fax: 212-509-8492
E-Mail: pagetfdn@aol.com
Internet: www.paget.org