Severe, malignant osteopetrosis is a rare life-threatening congenital disorder that occurs in approximately 1 in 300,000 births.1 It is characterized by the development of abnormally dense and brittle bone structures, which compromises bone marrow space and impairs cranial nerve function. As a result, patients have an increased risk of anemia, blindness, hearing loss, and infection.

The term osteopetrosis refers to a group of heritable disorders that can be distinguished according to the pattern of inheritance and the genetic profile of the patient.^{1, 2} Broadly speaking, there are three major types of osteopetrosis:

• Malignant osteopetrosis: Inherited in an autosomal recessive pattern, this form is apparent from birth and frequently shortens life expectancy. Despite its name, it is not related to cancer.²
• Intermediate autosomal recessive osteopetrosis: Like malignant osteopetrosis, this form is inherited in an autosomal recessive pattern. Generally found in children younger than 10 years of age, it is more severe than the adult form, but less severe than the malignant infantile form.
• Autosomal dominant benign osteopetrosis: Also known as adult-onset osteopetrosis, this form is milder than the malignant and intermediate forms, and symptoms may not appear until adolescence or adulthood.

Pathogenesis
Human bone is a dynamic tissue that undergoes a continuous cycle of remodeling in which old bone is removed and replaced by newly formed bone. There are two primary types of cells that mediate this process. Osteoclasts remove old bone cells through a process called resorption, while osteoblasts replace them with new cells in a process called deposition. In normal bone, the two processes remain in balance; as bone is remodeled, there is no net change in the total amount of bone tissue (Figure 1).

Figure 1. Normal human bone homeostasis.

In osteopetrosis, there is an imbalance between the resorption of old bone and the deposition of new bone. While osteoblasts deposit new bone cells at a normal rate, a defect in the osteoclasts prevents the efficient removal of old bone cells. The result of this imbalance is an increase in bone mass, which reduces the space available for bone marrow and narrows the pathways through which nerves pass in the skull. As cranial nerves become compressed, vision and hearing are impaired, while restriction of the marrow cavity limits the development of new blood cells, placing patients at risk for anemia and infection. Additionally, since osteopetrotic bones are very brittle, patients are susceptible to frequent and recurrent fractures.^{2, 3}

Treatment
The primary goals of therapy in patients with severe malignant osteopetrosis are to prolong survival, delay disease progression, and manage secondary complications. Presently, bone marrow transplantation is the only potentially curative therapy; however, successful transplantation is dependent on the availability of a suitably matched donor, which can be found for only 20-40% of patients.^{3, 4} For the remaining majority of patients, therapy is aimed at slowing the progression of disease and managing secondary complications like anemia and recurrent infection.

Several drugs, including Calcitriol (active vitamin D), corticosteroids, and Actimmune^® (interferon gamma-1b), have been reported to be of some benefit in slowing the progression of disease.⁴ Among these, only Actimmune^® has been approved by the U.S. Food and Drug Administration for the treatment of patients with osteopetrosis.

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In addition to drugs that are used to treat the primary condition, patients may require treatment for a number of common secondary complications.4 Blood transfusions and drugs like erythropoietin (Epogen®, Procrit®) may be used to treat anemia, while pain medications are frequently needed to manage the pain associated with bone fractures. Since children with severe malignant osteopetrosis often have an abnormal head shape, surgery may be required to relieve intracranial pressure or release compressed nerves. Finally, nutritional support and physical therapy are generally recommended in order to help children reach their full developmental potential.

The health information contained herein is provided for educational purposes only and is not intended to replace discussions with a healthcare provider. All decisions regarding patient care must be made with a healthcare provider, considering the unique characteristics of patients.

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References
1. Tolar J, Teitelbaum S, Orchard P. Mechanisms of Disease: Osteopetrosis. N Eng J Med 2004; 351: 2839-49.
2. Balemans W, Van Wesenbeeck L, Van Hul W. A Clinical and Molecular Overview of the Human Osteopetroses. Calcif Tissue Int. 2005;77: 263-274.
3. Key LL Jr, Rodriguiz RM, Willi SM, et al. Long-term treatment of osteopetrosis with recombinant human interferon gamma. N Engl J Med. 1995; 24:1594-1599.
4. Wilson CJ, Vellodi A. Autosomal recessive osteopetrosis: diagnosis, management, and outcome. Arch Dis Child 2000; 83:449-452.