New Mechanisms of Osteopetrosis

Osteopetroses are rare genetic disorders characterized by sclerosis of the skeleton due to reduced or complete lack of osteoclast function and, as a consequence, impairment of bone resorption. Osteoclast failure causes persistence of old bone, an increase in bone density and obstruction of the internal cavities containing vital organs such as the bone marrow and the nervous system. Short stature, deformities and pathological fractures are typical symptoms, along with severe hematological and neural failures. In humans, several types can be distinguished and their classification is based on their mode of inheritance, age of onset, severity and associated clinical symptoms. The best-known osteopetroses are the severe and intermediate autosomal recessive forms and the milder autosomal dominant subtype. Besides these forms, a restricted number of cases has been reported in which patients present with additional clinical features unrelated to the skeletal phenotype. Over the last few years, molecular genetic studies have resulted in the identification of mutations in genes whose function is associated with bone resorption or with osteoclast differentiation, but about 30% of patients still remain without a recognized molecular defect. At present, therapy is unsatisfactory and effort is necessary both to unravel the gene defects yet unrecognized and to identify new treatments to improve the phenotype and save lives. Nevertheless, significant advances have been made in recent years and the disease now seems better understood both genetically and clinically. This review will summarize recent knowledge on the pathogenesis of osteopetrosis and will discuss future challenges and developments for therapy. IBMS BoneKEy. 2009 January;6(1):16-28. ©2009 International Bone & Mineral Society