Osteopetrosis or Marble Bone Disease

Osteopetrosis is also called stone bone or marble bone disease. It is also known by the name of Albers-Schönberg disease.

It is an inherited disorder characterized by hard dense bones due to by the failure of osteoclasts to resorb bone leading to impairment of modeling and remodeling.

Osteopetrosis is a rare disease. Autosomal dominant is the most common form of the disorder, affecting about 1 in 20,000 people. Autosomal recessive is rarer, occurring in an estimated 1 in 250,000 people.

Other forms of osteopetrosis are very rare.

Osteopetrosis of femur with fracture, Note the obliterated medullary cavity

Types of Osteopetrosis

Three distinct forms of the disease are recognized

• Infantile
  • Seen in infancy
  • Autosomal recessive
  • Severe bone marrow failure
  • Poor prognosis
  • Usually diagnosed before age 1y
• Intermediate
  • Seen in childhood
  • Autosomal recessive/dominant
  • No bone marrow failure
  • Poor prognosis
  • Not applicable
• Adult-onset
  • Seen in adulthood
  • Autosomal dominant
  • No bone marrow failure
  • Often diagnosed incidentally
  • Good prognosis

Other, rare forms that have been described are lethal, transient, postinfectious and acquired. A distinct form of osteopetrosis that occurs in association with renal tubular acidosis and cerebral calcification due to carbonic anhydrase isoenzyme II deficiency is also described.

Pathophysiology of Osteopetrosis

[For details on bone physiology and remodeling, please refer to Bone Anatomy and Physiology]

Osteoblasts are the bone-forming cells of fibroblastic origin. Extracellular matrix surrounds some osteoblasts, which become osteocytes.

Osteoclasts are derived from the monocyte/macrophage lineage. Osteoclasts can tightly attach to the bone matrix and cause solubilization of the bone mineral.

Bone modeling is the process by which the marrow cavity expands as the bone grows in diameter. Remodeling involves the removal of bone tissue from a preexisting bone and replacement by newly synthesized bone.

Failure of modeling is the basis of hematopoietic failure in osteopetrosis. Failure of remodeling is the basis of the persistence of woven bone.

The primary underlying defect in all types of osteopetrosis is the failure of the osteoclasts to reabsorb bone.

A number of heterogeneous molecular or genetic defects can result in impaired osteoclastic function thought the exact molecular defects or sites are largely are unknown.

The defect may lie in the osteoclast lineage itself or in the mesenchymal cells required for proper osteoclast function.

[The differentiation is important because  only defects with osteoclast lineage would be benefited by bone marrow transplant]

Osteopetrosis in carbonic anhydrase isoenzyme II deficiency

Carbonic anhydrase isoenzyme II catalyzes the formation of carbonic acid from water and carbon dioxide. Carbonic acid dissociates spontaneously to release protons. These protons help in forming acidic environment required for resorption by osteoclast.

Lack of this enzyme results in impaired bone resorption. This type of osteopetrosis is associated with renal tubular acidosis and cerebral calcification.

Clinical Presentation

Infantile osteopetrosis

Infantile osteopetrosis is also called malignant osteopetrosis. It is diagnosed early in life and is often associated with failure to thrive and growth retardation.

Following are the clinical features

• Nasal stuffiness due to mastoid and paranasal sinus malformation
• Cranial nerve entrapment neuropathy
• Deafness, proptosis, and hydrocephalus.
• Delayed dentition
• Fragile bones that fracture easily
• Bone marrow failure as defective osseous tissue replaces bone marrow  – causes pancytopenia
  • Anemia
  • Easy bruising and bleeding due to thrombocytopenia
  • Recurrent infections due to defects in the immune system
• Extramedullary hematopoiesis
  • Hepatosplenomegaly
  • Hypersplenism
  • Hemolysis
• Sleep apnea
• Blindness due to retinal degeneration
• Osteomyelitis of mandible

Adult Osteopetrosis

Adult osteopetrosis is also called benign osteopetrosis is diagnosed in late adolescence or adulthood.

Two types have been recognized.

Type I

• Marked sclerosis mainly of the vault
• The spine does not show much sclerosis
• No endobones in pelvis
• Transverse metaphysic banding absent
• Serum acid phosphatase is normal
• Carries low risk of fracture

Type II

• Sclerosis mainly of the base of the skull
• Spine shows the rugger-jersey appearance
• Shows endobones in the pelvis [bone within bone appearance]
• Transverse metaphysic banding may or may not be present
• Serum acid phosphatase is high
• Carries very high risk of fracture

In adult osteopetrosis, approximately one-half of patients are asymptomatic, and the diagnosis is made incidentally.

In symptomatic patients following symptoms are noted.

• Bone pains
• Neuropathies due to nerve entrapment
  • Deafness
  • Facial palsy
  • Carpal tunnel syndrome
• Osteoarthritis
• Recurrent fractures.
• Osteomyelitis of the mandible
• Impairment due to retinal degeneration
• Psychomotor retardation

Bone marrow is not compromised.

Intermediate Osteopetrosis

• Autosomal dominant or an autosomal recessive
• Signs noticeable in childhood
• Increased risk of bone fracture and anemia
• Abnormal calcium deposits (calcifications) in the brain
• Intellectual disability
• Renal tubular acidosis.

Differential Diagnoses

• Hypoparathyroidism
• Myeloproliferative Disease
• Lead Toxicity in children
• Pseudohypoparathyroidism

Lab Investigations

• Decreased calcium
• Elevated parathyroid hormone
• Increased acid phosphatase – due to increased release from defective osteoclasts
• Increased creatinine kinase isoform due to increased release from defective osteoclasts

Radiography

Infantile

• Generalized osteosclerosis- Weak and dense skeleton which may have multiple healed fractures.
• Metaphyseal splaying may also be apparent
• Mandible: characteristic triangular opacity representing calcification within the secondary condylar cartilage ossification centre
• Defective dentition with incomplete enamel formation and/or cavities
• Paranasal sinuses: poorly pneumatised (ethmoid sinuses least severely affected)
• Hair-on-end appearance: areas of increased hematopoietic activity
• Thickening of skull especially at the base.

Adult

Radiographic features are more pronounced in type II

• The appearance of a bone within the bone (endobone)
• Extremely radiodense vertebrae. May show alternating bands, known as the rugger-jersey sign
• Fractures or osteomyelitis.
• Alternating radiolucent metaphyseal bands

Treatment of osteopetrosis

Adult osteopetrosis

Adult osteopetrosis requires no treatment by itself, although complications of the disease may require intervention. No specific medical treatment exists for the adult type.

Surgical treatment may be needed for deformities and fractures

Infantile osteopetrosis

Vitamin D

Vitamin D stimulates dormant osteoclasts, and thus bone resorption. Large doses of calcitriol, along with restricted calcium intake, sometimes improve osteopetrosis though modestly and till the treatment is given.

Gamma Interferon

Gamma interferon leads to long-term benefits.

• It improves hemoglobin, platelet counts and white blood cell function, thus decreases susceptibility against infections.
• Trabecular bone volume substantially decreases and bone-marrow volume increases.
• Provides better results in combination therapy with calcitriol

Erythropoietin

Erythropoietin is be used to correct anemia. It stimulates the bone marrow to produce more red blood cells.

Corticosteroids

Corticosteroids increase red blood cells and also stimulate bone resorption. But steroids are not preferred because they need to be given for a long time.

Bone Marrow Transplantation

Bone marrow transplantation can cure bone marrow failure and metabolic abnormalities in patients whose disease arises from an intrinsic defect of the osteoclast lineage.

Bone marrow transplantation is the only cure  for this disease.

Other Treatments

Fractures occurring in these patients are treated as per need and surgery might be necessary in some cases.

Prognosis

By the age of 6 years, 70% of the affected will die. Rest have a very poor quality of life with death resulting by the age of ~10 years.

Death is usually due to severe anemia, bleeding, or infections.

The prognosis of some patients with infantile osteopetrosis can markedly change after bone marrow transplantation.

Patients with adult osteopetrosis have good long-term survival rates.

References

• Gerritsen EJ, Vossen JM, Van loo IH et-al. Autosomal recessive osteopetrosis: variability of findings at diagnosis and during the natural course. Pediatrics. 1994;93 (2): 247-53.
• Tolar J, Teitelbaum SL, Orchard PJ. Osteopetrosis. N Engl J Med. 2004 Dec 30. 351(27):2839-49.
• el-Tawil T, Stoker DJ. Benign osteopetrosis: a review of 42 cases showing two different patterns. Skeletal Radiol. 1993 Nov. 22(8):587-93.
• Key L, Carnes D, Cole S, et al. Treatment of congenital osteopetrosis with high-dose calcitriol. N Engl J Med. 1984 Feb 16. 310(7):409-15.
• Armstrong DG, Newfield JT, Gillespie R. Orthopedic management of osteopetrosis: results of a survey and review of the literature. J Pediatr Orthop. 1999 Jan-Feb. 19(1):122-32.
• Key LL Jr, Rodriguiz RM, Willi SM, et al. Long-term treatment of osteopetrosis with recombinant human interferon gamma. N Engl J Med. 1995 Jun 15. 332(24):1594-9