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    Osteopetrosis: Pathophysiology, Symptom, and Treatment Options

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    - Describe the symptoms of that disease;
    - Explain the imbalance on the molecular, cellular and tissue levels;
    - Describe the current treatments and prognoses of those treatments;

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    Background on bone formation:

    Cellular level:

    Osteoblasts: cells responsible for creating new bone. Immature cells that lay down a protein mixture called 'osteoid' (matrix) which mineralizes to become bone. They also produce hormones, such as alkaline phosphatase, which is involved in mineralization. Osteoblasts become osteocytes once trapped in bone matrix.

    Osteoclasts: cells responsible for breaking down bone through a phagocytic-like process. The cells acidify the resorption pit, leading to digestion of bone. (Further info related to osteopetrosis below)

    Normal bone growth involves a balance between osteoblast and osteoclast function.

    Molecular level:

    Most bone is formed from bone matrix which is made up of hydroxyapatite and collagen. The matrix is produced as unmineralized osteoid from osteoblasts. Osteoblasts then secrete vesicles with alkaline phosphatase which cleaves phosphate groups which becomes a location for calcium and phosphates deposits. The vesicles rupture and allow crystals (hydroxyapatite) to grown.


    A group of rare genetic diseases in which there is reduced osteoclast bone resorption. The number of osteoclasts may be normal, increased or decreased depending of the type of osteopetrosis. Also referred to as "marble bone disease" as the bones become harder and denser.

    Some main types of osteopetrosis:

    1) Infantile malignant osteopetrosis
    2) Type 2 carbonic anhydrase deficiency
    3) autosomal-dominant types 1 and 2

    Exact pathophysiology for most types is unknown, but some are understood

    Carbonic anhydrase deficiency involves an absence of the enzyme, carbonic anhydrase 2. This enzyme is required by osteoclasts to excrete hydrogen ions, which in turn allows the cells to acidify the resorption pit and digest bone. Thus the lack of this enzyme will prevent osteoclasts from functioning properly, leading to an imbalance between bone growth and bone breakdown.

    Another form of the disease involves a mutation in a chloride channel gene. This mutation interferes with the proton pump of H+-ATPase and again prevents the osteoclasts from acidifying the resorption pit.


    Reduced osteoclast function results in bones that lack a medullary canal. The medullary canal has walls of spongy bone and is found within compact bone. In normal growth, the primary spongy bone is removed, creating a medullary canal that is then filled with bone marrow. In osteopetrosis, the primary spongy bone persists, filling the canal.

    There is a lack of bone remodeling, which results in woven bone which is structurally weak.


    Varies with type and severity of disease.

    - Stunted growth
    - Deformities
    - Increased fractures
    - Increased pressure on nerves due to excess bone - may lead to blindness, paralysis, deafness
    - Reduced medullary canal (ie: reduced space for bone marrow) leads to decreased hematopoiesis resulting in anemia (decreased production of red blood cells) and increased infections (decreased production of lymphocytes)
    - Extramedullary hematopoiesis may cause hepatosplenomegaly (enlarged liver and spleen). This is due to hematopoiesis occurring in areas outside of bone marrow.


    The only sustainable cure for osteopetrosis is a bone marrow transplant, as osteoclasts are derived from marrow monocyte precursors. This is primarily in infantile osteopetrosis and only helps if the underlying cause is decreased production of osteoclasts or production of abnormal osteoclasts.

    Vitamin D may stimulate osteoclasts; however there is only mild improvement and treatment is required indefinitely.

    Gamma interferon may improve white blood cell function decreasing the number of infections.

    Erythropoietin may be used to treat anemia.

    Surgical treatment is often needed for fractures and deformities.


    Kumar, V., Abbas. AK., Fausto, N (Eds). 2005. Robbins and Cotran Pathologic Basis of Disease, 7th Edition. Elsevier.

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