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 are very rare. Only a few cases of intermediate autosomal osteopetrosis have been reported in the medical literature.
Types of Osteopetrosis
Three distinct forms of the disease are recognized
- Infantile – seen in infancy
- Intermediate – seen in childhood
- Adult onset — seen in adulthood
- Autosomal dominant
- No bone marrow failure
- Often diagnosed incidentally
- Good prognosis
- Autosomal recessive
- Severe bone marrow failure
- Poor prognosis
- Usually diagnosed before age 1y
- Autosomal recessive/dominant
- No bone marrow failure
- Poor prognosis
- Not applicable
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 bone forming cells 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 causes 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 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 with renal tubular acidosis and cerebral calcification.
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.
- Dlayed dentition
- Fragile bones that fracture easily
- Bone marrow failure as defective osseous tissue replaces bone marrow – causes pancytopenia
- Easy bruising and bleeding due to thrombocytopenia
- Recurrent infections due to defects in the immune system
- Extramedullary hematopoiesis
- Sleep apnea
- Blindness due to retinal degeneration
- Osteomyelitis of mandible
Adult osteopetrosis is also called benign osteopetrosis is diagnosed in late adolescence or adulthood.
Two types have been recognized.
- Marked sclerosis mainly of the vault
- Spine does not show much sclerosis
- No endobones in pelvis
- Transverse metaphysic banding absent
- Serum acid phosphatase is normal
- Carries low risk of fracture
- Sclerosis mainly of the base of 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
- Recurrent fractures.
- Osteomyelitis of the mandible
- Impairment due to retinal degeneration
- Psychomotor retardation
Bone marrow is not compromised.
- 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.
- Myeloproliferative Disease
- Lead Toxicity in children
- 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
- 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.
Radiographic features are more pronounced in type II
- Appearance of a bone within 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 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
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 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 is be used to correct anemia. It stimulates the bone marrow to produc more red blood cells.
Corticosteroids increase red blood cells and also stimulate bone resorption. But steroids are not the preferred because they need to be given for 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.
Fractures occurring in these patients are treated as per need and surgery might be necessary in some cases.
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.
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