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Osteopetrosis is a congenital disorder characterized by defective or absent osteoclasts, the cells that break down bone. In healthy bone, a balance is achieved between the production of bone by osteoblasts, and the break down of bone by osteoclasts. In osteopetrosis, osteoclasts don’t function normally, and the production of bone by osteoblasts leads to bones that are abnormally dense and brittle.

In severe osteopetrosis, the bone marrow space within the bone is markedly reduced limiting the production of new blood cells. Anemia (low numbers of red blood cells), thrombocytopenia (decreased platelets, cells important for blood clotting) and low numbers of white blood cells, can occur in patients with the severe form of the disease. Bleeding may occur when the platelet number is very low, or infections may occur if the number of white blood cells is reduced. These factors can result in the death of patients with severe osteopetrosis in the first few years of life.

Other complications can result from severe osteopetrosis such as enlargement of the liver and spleen as the body attempts to make blood cells in locations other than the bone marrow. Overgrowth of bone may also occur and can result in limited space for nerves and blood vessels to pass through, especially those coming through the skull. The constriction of these nerves and their blood vessels can affect their function, which can result in loss of vision or complete blindness in infancy for severely affected children.

What Causes Osteopetrosis?

Osteopetrosis may result from conditions which interfere with the production of osteoclasts and their ability to remove bone. In the vast majority of cases, the problem relates to an inability of the osteoclasts to produce acid on the surface of the bone. Normally, the cells make the acid internally and move it outside the cell, which begins the process of bone digestion. Defects in the production of the acid, or in the movement of the acid across the cell membrane next to the bone, have been shown to result in osteopetrosis.

The genes related to osteopetrosis have been described only recently. The most common genetic defect seen in severe osteopetrosis is a “proton pump” present only in osteoclasts, which moves the acid (proton) across the cell membrane. This gene is called ATP6i or TCIRG1, and defects in this gene are seen in 50-60% of severe osteopetrosis.

Another gene needed to move protons across the cell membrane is a “chloride channel,” called ClCN7. This is the second most common gene seen in osteopetrosis, accounting for about 15% of severe osteopetrosis cases. Interestingly, mutations in this gene are also responsible for less severe osteopetrosis.

What Treatments Are Available for Osteopetrosis?

The treatments for autosomal dominant osteopetrosis have traditionally been more supportive, taking care of problems (issues with vision, teeth, infections, fractures, etc.) as they arise.

Management of malignant infantile osteopetrosis includes more aggressive therapy such as the following:

  • Interferon gamma is a drug given by injection that may delay the progression of the disease, and is the only therapy specifically approved for osteopetrosis by U.S. Food and Drug Administration (FDA). There is also strong evidence that Interferon (Actimmune) reduces the chance of serious infection in people with osteopetrosis. However, it is not a cure, and patients may continue to progress while on treatment.
  • Calcitrol, the active form of Vitamin D, is a potent stimulator of osteoclasts. When high doses are taken by mouth, calcitrol can help improve the blood counts and the amount of bone marrow space. While some of the problems caused by osteopetrosis may improve, calcitriol doesn’t represent a cure for the disease, as the changes are not permanent, and patients may begin to worsen despite continuing on calcitriol.
  • Prednisone is a synthetic steroid hormone that has been found to improve blood counts in some patients with osteopetrosis that have anemia (too few red blood cells) and low numbers of platelets. The drug, which is taken orally, may work by slowing the destruction of blood cells in the spleen. However, if taken over a long period of time, prednisone may increase the chance of infection.
  • Bone marrow transplantation (BMT) is a procedure that replaces abnormal osteoclasts with normal cells. It is the only therapy that can completely cure the blood related issues and bone abnormalities in people with osteopetrosis. Unfortunately, BMT is very risky. Only 40 to 70 percent of patients are long-term survivors of the procedure. To some degree the outcome relies on how well the patient going through transplant is tissue-type matched with a possible donor. Individuals with osteopetrosis do better if they have a brother or sister that is “matched”. Unrelated donors, who are people from outside the family can also be used, but the complication rate is higher. Because the risk of transplant is high, transplant is only used in patients who are seriously affected by osteopetrosis.
  • Physical and Occupational Therapy. Children with severe osteopetrosis have a heavy skeleton that causes delays in the development of physical abilities such as walking. The disease’s impact on vision and hearing can also slow the rate at which other skills, such as the ability to speak, are mastered. Physical and occupational therapy helps children with osteopetrosis develop motor and other skills, greatly enhancing their ability to reach their full developmental potential.

What Are the Types of Osteopetrosis?

A diagnosis of osteopetrosis is made clinically, when dense bones are revealed by X-ray images. The findings on history and physical examination are commonly vision problems, a large liver/spleen, low blood counts, low calcium levels, and other symptoms, which help to confirm the diagnosis. Bone sampling and genetic testing may also be helpful.

Several forms of osteopetrosis exist.

The most common form is autosomal dominant osteopetrosis. In this form, the affected person generally inherits the disease from their mother or father, who also has the disease. Interestingly, there is substantial variability in manifestation of the disease person to person.

The gene causing autosomal dominant osteopetrosis(CLCN7) appears to be the same gene responsible for severe osteopetrosis, but in adult osteopetrosis only one copy of the gene is abnormal. In severe osteopetrosis caused by mutations in this gene, both copies of the gene are affected. The gene encodes a “chloride channel” important in the production of acid by osteoclasts, as osteoclasts use acid to digest the bone. Because it is an autosomal dominant disorder, there is a 50 percent chance (for each pregnancy) that the offspring of a person with autosomal dominant osteopetrosis will have the disorder.

While this form of osteopetrosis tends to be relatively mild, many people with this form of the disease suffer from many fractures. They may have many dental problems, and sometimes bone infections are seen, especially in the jaw. Some people also have difficulty with loss of vision as well.

No therapy has been shown to effectively impact the course of autosomal dominant osteopetrosis, and generally none is needed based on the relatively lower number of symptoms associated with this disease. However, assistance from an orthopedic expert knowledgeable in this problem can be helpful with the many fractures that may occur. Ear, nose and throat, and dental specialists can help with issues related to the teeth and jaw infections. Ophthalmologists (eye specialists) may also be important in assessing changes in vision. More rarely, blood counts can be affected, and transfusions may be necessary. In very severe autosomal dominant osteopetrosis, bone marrow transplantation could be considered, but is not ordinarily performed.

The most severe form of osteopetrosis is termed infantile osteopetrosis, as affected individuals usually have difficulties soon after birth. This form is also called malignant osteopetrosis, not because of a relationship to cancer, but because of the severity of the disease.

This disorder is inherited in an autosomal recessive pattern, which means that both parents have one abnormal gene, but do not have any characteristics of the disease. When these parents have children, the chance that a particular child will receive the abnormal gene from both parents (and therefore have osteopetrosis) is 1 in 4. The disease is very rare, with about 1 in 300,000 children having severe osteopetrosis.

Children with osteopetrosis present with a number of characteristics. Some develop seizures due to low calcium levels in the blood. Others don’t appear to be able to see normally, and still others are noted to have an enlarged liver or spleen on an examination. Some children have blood counts that are abnormal, or an X-ray is done and bones characteristic of osteopetrosis are found. The heads of children with osteopetrosis are often enlarged, and on scans sometimes have increased size of the fluid-filled spaces in the brain.

Most children with severe osteopetrosis will develop life-threatening complications related to difficulties in the production of blood cells. Many die of infections or bleeding as infants. Another problem is that their teeth don’t emerge from the gums normally. Many children with osteopetrosis have developmental delays due to the increased weight of their skull, or due to vision or hearing problems. Some develop increased pressure in their heads because of interruption of the normal flow of spinal fluid from the brain to the spinal cord by the overgrowth of bone.

Looking for information for adult patients? Visit The U of M Adult Blood and Marrow Transplant Program