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E. Anders Kolb, M.D. Normal bone growth is a balance between bone building and bone remodeling. Osteoblasts are cells that deposit minerals and osteoid to make bone. Osteoclasts remodel the mineral and osteoid to provide structure and strength for the bone while also building spaces for bone marrow to grow. Bone marrow is the red cellular material inside of bones that manufactures the cells in our blood. In osteopetrosis, osteoclasts do not function normally. Bone is deposited by osteoblasts, but not remodeled by osteoclasts. The results are dense hard bones that are actually more brittle because they lack the osteoclast-designed lattice work. Fractures can occur because the bones are brittle, and healing may be delayed because of impaired bone remodeling. In its most severe form, abnormal bone growth may impair the function of cranial nerves and the normal flow of spinal fluid. X-rays of bones will show sclerotic or dense bones with minimal or no bone marrow space. Bones usually consist of a dense outer layer call the cortex, and an internal cavity made of a latticework of remodeled bone. Usually contained within this cavity is the bone marrow. In patients with osteopetrosis, this internal latticework may appear as dense as the cortex. Additional studies may include:
Genetic Testing is now the gold-standard for diagnosis of osteopetrosis. Connective Tissue Gene Tests (http://www.ctgt.net) is an excellent lab equipped for and experienced in diagnosing osteopetrosis. They and other labs offer tests to identify known mutations in genes that can cause osteoclast dysfunction. Not all genes have been identified. Some patients may still be diagnosed by x-ray. However, confirmation of genetic mutations is crucial in defining the cause of the disease and in counseling patients on their risk of passing the gene to their children. Internationally, the incidence of osteopetrosis is estimated to be about 1 in 100,000 to 1 in 500,000. Epidemiological studies have not been conducted to confirm these estimates. In the United States it is estimated that there on only about 40 children born each year with the most severe from of osteopetrosis (autosomal recessive osteopetrosis). Treatment High doses of vitamin D may increase osteoclast absorption of bone. Gamma interferon may increase bone resportion, increase bone marrow production of blood cells and increase white blood cells function. Corticosteroids may reduce bone density. These therapies alone or in combination may be effective in alleviating symptoms in patients with autosomal dominant osteopetrosis, and slowing the progression of symptoms in patients with autosomal recessive osteopetrosis. However, the only cure for osteopetrosis is bone marrow transplant. Bone marrow transplant (aka stem cell transplant, hematopoietic progenitor cell transplant) may only be indicated for the most severe forms of osteopetrosis. Osteoclasts are a type of cell call a macrophage it is it derived from cells in the bone marrow. By replacing a patient’s bone marrow with that of a donor marrow, you are effectively destroying the abnormal cells and replacing them with functional osteoclasts. Improvement in symptoms is dependent on the bone marrow engrafting (i.e. in accepts its new home and starts producing new blood cells and osteoclasts) and the new donor-derived osteoclasts slowly remodeling the abnormal bones. There are numerous publications and reports on the success of bone marrow transplant in halting the progression of abnormal bone formation and allowing for new bone formation. Information on bone marrow transplantation for this and other diseases can be found through the National Marrow Donor Program (www.marrow.org). To identify a bone marrow or stem cell donor, the patient will need to have a blood test to identify their human leukocyte antigen (HLA) types. This typing can be used by a bone marrow transplant program to search donor registries through the National Marrow Donor Program (NMDP). The NMDP has access to millions of potential adult donors and cord blood units worldwide. For infants with autosomal recessive osteopetrosis (MIOP), the chances of finding a reasonable match through the NMDP is excellent. Once a donor is found the bone marrow transplant physician will discuss with you the transplant treatment plan. In general, the goal is to give chemotherapy and rarely radiation therapy to destroy the patient’s bone marrow and immune system so that the patient accepts the new transplanted bone marrow and immune system. Included in that new bone marrow will be normal osteoclasts that may take several weeks to months time to affect change in bone density. As the bone is repaired, many of the symptoms that lead to the initial diagnosis of osteopetrosis may start to diminish. Bone marrow transplant is not a simple procedure, but it is a potential cure. The NMDP and your transplant physician will be excellent resources to educate you about the process. Other Considerations Patients with osteopetrosis may have significant orthopedic problems and concerns. Treatment by physicians familiar with the disease is important. Infants with osteopetrosis (MIOP) should receive specialized care immediately. |
Types of Osteopetrosis In general terms there are 2 different kinds of osteopetrosis: Autosomal Dominant Osteopetrosis and Autosomal Recessive Osteopetrosis. Autosomal Dominant Osteopetrosis means that the person inherited a single copy of the abnormal gene from a parent or there was a spontaneous mutation in one copy of the gene. This means that there may be a second functioning gene occasionally resulting in some osteoclast activity and a less severe form of the disease. Patients with Autosomal dominant osteopetrosis may have mild, moderate or severe disease. In most forms, affected patients are diagnosed late in childhood or in adulthood. Genes involved in autosomal dominant osteopetrosis include:
Autosomal Recessive Osteopetrosis means that the person inherited 2 abnormal copies of the gene and have little or no normal osteoclast activity. Autosomal recessive osteopetrosis is also called malignant infantile osteopetrosis (MIOP). Patients with Autosomal recessive osteopetrosis may be fatal without aggressive treatment. Cranial nerve compression, increased spinal fluid pressure, low blood counts, and enlargement of the liver and spleen are common findings at diagnosis. Low calcium may be present at birth and is a clue to the diagnosis of osteopetrosis. Genes involved in autosomal recessive osteopetrosis include:
Other Resources Clinical Trials: http://www.clinicaltrials.gov/ct2/show/NCT00775931?term=osteopetrosis&rank=2 http://www.clinicaltrials.gov/ct2/show/NCT00145886?term=osteopetrosis&rank=7
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