Osteopetrosis

Thickening of the bones which become abnormally dense due an inherited defect in bone resorption -- the process in which old bone is broken down and removed so that new bone can be added to the skeleton.

Osteoclasts are the cells responsible for bone resorption.

In osteopetrosis the osteoclasts do not perform normally.

This flaw in bone resorption results in bones that are abnormally dense, yet are fragile and easily broken.

Men and women are equally affected by the disease.</P> The increased bone mass in individuals with osteopetrosis can limit the amount of available space within the bone marrow.

Since the bone marrow is responsible for the production of blood cells, impaired bone marrow function can produce several clinical problems.

For example, interference with red blood cell production can lead to anemia.

Impairment of white blood cell production can limit the body's ability to fight infection.

When platelet production is suppressed, individuals are prone to bleeding since platelets are essential for clotting blood.

Anemia, infection, and bleeding are just some of the symptoms that individuals with osteopetrosis can experience --blindness, deafness and even stroke can occur when the skeleton is so dense that blood vessels and nerves cannot pass through the bones.</P> Three major types of osteopetrosis have been identified:</P> > >Malignant infantile form -- this disease is usually discovered in the first months of life.

Hence the term 'infantile.' The children have the full disease and, in addition, they may have significant delays in psychomotor and tooth development.

This form of the disease can be severe, often resulting in death during the first decade of life.

This disease is inherited as an autosomal recessive trait -- so brothers and sisters of a patient are each at 25% risk to have the same disease.

The gene has been found on chromosome 11 in region 11q13.4-q13.5 and is a mutation in what is called the TCIRG1 subunit of the vacuolar proton pump.

>Adult form -- this form is milder and more benign than the infantile form.

It generally does not alter life expectancy.

Many of the individuals with it have few or no symptoms.

It is inherited from generation to generation as an autosomal dominant trait.

Males and females with it have a 50% chance of transmitting the gene to each of their children.

The gene is on chromosome 1 in region 1p21. >Intermediate form-- this type of the disease is found in children younger than 10. It tends to be less severe than the malignant infantile form, but more severe than the adult form.

Individuals with this type of osteopetrosis generally do not have a reduced life expectancy.

</LI></UL> The diagnosis of osteopetrosis is usually made when dense bones are discovered on x-rays.

A bone biopsy can confirm the presence of the disease.

Confirming the specific subtype of the disease is important so that individuals can receive the most appropriate treatment.

Various therapies have been used in the treatment of osteopetrosis.

The US Food and Drug Administration (FDA) has approved Actimmune (interferon gamma-1b) for delaying disease progression in patients with severe malignant osteopetrosis.

Actimmune is the only therapy approved specifically for the treatment of osteopetrosis.

Adult and pediatric patients may benefit.

In addition to the approved indication, there is also strong evidence to suggest that Actimmune reduces the chance for serious infection in osteopetrosis.

Bone marrow transplantation (BMT) allows the abnormal osteoclasts to be replaced with normal cells.

BMT is the only approach that has resulted in a cure of the malignant infantile form of the disease.

BMT replaces the abnormal osteoclasts with normal cells, curing the defect if the transplantation, or engraftment, is successful.

Because of its high failure rate and because of its side-effects, BMT tends to be reserved for only the most severe cases of osteopetrosis.

The survival rate after BMT in children with osteopetrosis is 40 to 70 % depending on how well matched the donor is to the patient.

Young human leukocyte antigen-matched siblings provide marrow with the best chance for engraftment and cure of osteopetrosis.

High doses of Calcitrol (the active form of vitamin D) have been used to stimulate osteoclast function in individuals with osteopetrosis.

Calcitrol has been shown to significantly reduce symptoms in people who have mild or severe forms of the disease, though it is not approved by the FDA for this purpose.</P> Large doses of glucocorticoid drugs (such as prednisone) may be given for short periods of time to patients with impaired red blood cell or platelet production.

Prednisone improves blood counts in patients with anemia and low platelet counts and slows blood cell destruction.

However, if continued for long periods, prednisone may reduce the growth velocity of children and predispose patients to infection.</P> Good nutrition is important to ensure normal growth and development of children with osteopetrosis.

Physical and occupational therapy are also extremely useful in helping children to reach their full developmental potential.

Even children with severe osteopetrosis frequently (about 80% of the time) have a normal intellectual level.

The heavy skeleton results in gross motor delays.

Blindness can delay speech.

The average severely affected child walks at about 2 years and begins to speak at age 20 to 24 months.</P> Osteopetrosis is also known as marble bone disease and Albers-Schonberg disease.