Osteopetrosis

Synonyms: marble bone disease, Albers-Schönberg's disease^[1]

Osteopetrosis is a clinical syndrome characterised by the failure of osteoclasts to resorb bone, leading to impairment of bone modelling and remodelling.^[2] This results in skeletal fragility despite increased bone mass, and it may also cause bone marrow failure, disturbed tooth eruption, nerve entrapment syndromes and growth impairment.

Osteopetrosis is a heterogeneous disorder encompassing different molecular lesions and a range of clinical features. Two main forms exist:

• Recessively inherited severe osteopetrosis.^[3]
• Dominantly inherited mild form.^[4]

Epidemiology

Overall incidence is estimated to be 1 case in 100,000-500,000.^[1]

Presentation

Severe osteopetrosis

• An infant is short with a large head and frontal bossing, knock knees.
• Nerve compression causes blindness and deafness.^[2]
• Reduction in bone marrow space causes anaemia.
• There may also be hydrocephalus, delayed eruption of teeth, fractures.

Mild petrosis

• This ranges from asymptomatic and discovered incidentally on X-ray to multiple fractures of both the long bones and the small bones of the hands and feet, with mild anaemia.
• Patients may present with osteoarthritis or osteomyelitis.^[5]
• Rarely, a more severe form produces nerve compression with deafness and blindness.

Differential diagnosis

• Myelofibrosis
• Renal glomerular osteodystrophy
• Inherited hypophosphataemia
• Fluorosis in adults
• Hypoparathyroidism
• Pseudohypoparathyroidism
• Lead toxicity

Investigations

• Diagnosis is made by X-rays which are usually diagnostic:^[6]
  • Generalised osteosclerosis; bones may be uniformly sclerotic, but alternating sclerotic and lucent bands may be noted in the iliac wings and near the ends of long bones.
  • Bones may be club-like or appear like a bone within bone.
  • The entire skull is thickened and dense, especially at the base.
  • Sinuses are small.
  • Vertebrae are very radiodense and may show alternating bands (rugger-jersey sign).
  • There may be evidence of fractures or osteomyelitis.
  • Severe osteopetrosis:
    • Characteristic changes ('Erlenmeyer flask deformity' of the metaphyses) on X-ray.
  • Mild osteopetrosis:
    • X-ray shows generalised increase in bone density and clubbing of metaphyses.
    • In vertebral bodies, alternating lucent and dense bands cause a sandwich-like appearance.
• CT scans may occasionally be required and the use of MRI tends to be limited to imaging of the marrow in the severe, recessive disease, which is usually fatal without marrow transplantation.^[6]
• In severe osteopetrosis, the plasma calcium is reduced, and acid phosphatase and calcitriol are raised.

Associated diseases

Deficiency of carbonic anhydrase can cause petrosis associated with renal tubular acidosis, cerebral calcification, growth failure and mental retardation.

Management

Infantile osteopetrosis requires treatment. Adult osteopetrosis requires no treatment unless complications arise which do require treatment. No specific medical treatment exists for the adult type.
Management is mainly focused on correcting complications and improving the quality of life. The gene defects have not yet been identified.^[7] Management of complications includes treatment of fractures, and joint replacements.^[5] Management of infantile osteopetrosis includes the following:

• Vitamin D appears to help by stimulating dormant osteoclasts and therefore bone resorption.
• Large doses of calcitriol, along with restricted calcium intake, sometimes improve osteopetrosis dramatically but usually produce only modest clinical improvement, which is not sustained after therapy is discontinued.^[8]
• Gamma interferon:
  • This has produced long-term benefits.
  • It improves white blood cell function and so decreases infections. Trabecular bone volume substantially decreases and volume of bone marrow increases. This leads to an increase in haemoglobin, platelet count and survival rates.
  • Combination therapy with calcitriol is superior to calcitriol alone.
• Erythropoietin can be used to correct anaemia.
• Corticosteroids have been used to stimulate bone resorption and treat anaemia but may be required for months or years and are not the preferred treatment option.
• Bone marrow transplant:
  • Improves some cases of infantile osteopetrosis.
  • Can cure both bone marrow failure and metabolic abnormalities in patients whose disease arises from an intrinsic defect of the osteoclast lineage.^[9]
  • Bone marrow transplant is the only curative treatment but it may be limited to those patients whose defects are extrinsic to the osteoclast lineage.
• Surgery:
  • In infantile osteopetrosis, surgical treatment is sometimes necessary because of fractures.
  • In adult osteopetrosis, surgical treatment may be needed for aesthetic reasons (eg in patients with notable facial deformity), functional reasons (eg in patients with multiple fractures, deformity, and loss of function) or for severe related degenerative joint disease.

Complications

• Bone marrow failure, with severe anaemia, bleeding and infections.
• Growth restriction and failure to thrive.

Prognosis

• If untreated, infantile osteopetrosis usually results in death by the first decade of life due to severe anaemia, bleeding or infection.
• Adults with osteopetrosis are usually asymptomatic and have good long-term survival rates.