This guide to the disease is written by Dr. Colin Steward, Reader in Stem cell Transplantation at the Royal Hospital for Children, Bristol and Medical Advisor to the OST. The opinions expressed are personal and do not necessarily represent those of the Osteopetrosis Support Trust.

He would value input from both families and health professionals if you know of any factual inaccuracy or have suggestions for improvements


What Is Osteopetrosis?

Osteopetrosis is a term used to describe a range of diseases in which bone density is increased. In the worst forms children are diagnosed soon after birth, but in others diagnosis may only be made when an X-ray is taken to investigate a broken bone as an adult. All of the forms of osteopetrosis are thought to be due to defects in the formation or function of osteoclasts, cells responsible for breaking down bone.


The picture on the left above shows an X-ray of the leg bones in a baby with osteopetrosis. In comparison to the more normal appearances on the right (in a child who has undergone successful bone marrow transplantation) the bones are a dense, chalky white colour. This explains the alternative name of “marble bone disease”. The bone ends are also frayed, an early sign of rickets. The commonest cause of rickets is dietary calcium or vitamin D deficiency but in osteopetrosis body calcium stores are high but calcium cannot be released from the bones due to defective function of osteoclasts

WHAT ARE OSTEOCLASTS?

At every stage of life we need to mould and strengthen bones so that they:

  1. Stay strong but light, resisting stresses and small fractures
    In order to maximise the ratio of strength to weight most bones have a hollow or tubular structure.

  2. Grow as a child grows
    This is extremely important and one of the main problems in a young child with osteopetrosis. The bone needs to be hollowed out from the centre and grow at the edges if they are to get bigger but stay light. This "remodelling" is especially important in the skull where nerves pass through small holes (foramina) to the eyes, ears and muscles of the face, and where the spinal nerves pass through the bottom of the skull into the spine. If these holes do not grow at the same rate as the nerves the bone exerts pressure on the nerves and this can damage them.

  3. House the bone marrow
    The bone marrow, the factory for the blood, is housed in the cavities in the centre of bones. If the bones stay solid, blood is produced mainly in the liver and spleen - the same as occurs in a young foetus. This causes swelling of the liver and spleen which can in turn lead to excessive destruction of blood cells and the need for transfusions.

  4. Maintain blood levels of calcium and phosphate
    The levels of these chemicals need to be held in a narrow range in our blood in order for the electrical systems which allow our nerves to work to operate correctly. For example if the levels of calcium fall by just 25% irritability, jittering, fits and tetany can occur. Since most of the body's stores of these chemicals are held in the bones it is crucial that these are released in carefully controlled amounts.


All of these aims are achieved by co-ordinated activity of cells called osteoclasts and osteoblasts. The osteoblasts build up bone, using calcium and phosphate (as well as other chemicals) as building blocks. Their activity is balanced by osteoclasts, large cells which are formed by the fusion of a number of smaller cells. This fusion results in the cell having multiple nuclei (the nucleus is the central part of the cell where the genes are held).

Osteoclasts are formed from cells which start life in the bone marrow and migrate to the bone - this is why bone marrow transplantation (BMT) is used to treat severe forms of the disease in children. Once formed the osteoclasts seal tightly to an area of bone and release chemicals which dissolve the bone.

One chemical involved in dissolving the bone appears to be hydrochloric acid (hydrogen chloride). This is made up of hydrogen ions (protons) and chloride ions which are pumped out of osteoclasts onto the bone surface through ion channels. In 2000 it was shown that mutations in the gene (variously called ATP6i or TCIRG1) which codes for the ion channels which pump hydrogen ions was responsible for osteopetrosis in almost one half of all children with the disease. It has since been shown that defects in a chloride pump gene, ClCN7, explain some cases of infantile and most cases of adult osteopetrosis.

The surface of osteoclasts is folded in waves (like the surface of the small intestine in the gut) in order to maximise the area of contact with the bone. This is called the ruffled border. When an area of bone has been dissolved they then crawl out of the pit they have created (called a Howship's lacuna) to a new area of bone. The picture below is a very detailed view of an osteoclast moving out of a lacuna taken using an electron microscope.

In osteopetrosis osteoclasts may either be absent, be present but unable to make ruffled borders or be increased in number. The last is the commonest appearance in children with severe disease. Presumably in the last case, the bone recognises that its osteoclasts are not working properly and instructs them to multiply, whereas in other cases osteoclasts simply cannot be formed.