Introduction
Background
A German radiologist, Albers-Schönberg, first described osteopetrosis in 1904.1
Osteopetrosis is a clinical syndrome characterized by the failure of osteoclasts to resorb bone. As a consequence, bone modeling and remodeling are impaired. The defect in bone turnover characteristically results in skeletal fragility despite increased bone mass, and it may also cause hematopoietic insufficiency, disturbed tooth eruption, nerve entrapment syndromes, and growth impairment. Human osteopetrosis is a heterogeneous disorder encompassing different molecular lesions and a range of clinical features. However, all forms share a single pathogenic nexus in the osteoclast.
Pathophysiology
To understand the pathophysiology of osteopetrosis, understanding the bone-remodeling cycle and the cell biology of osteoclasts is essential. In mice, many mutations result in osteopetrotic phenotypes (summarized in Table 1, below). Human homologs are known for some but not all of the murine lesions.
Bone cells and bone modeling and remodeling
In 1999, Baron clearly and concisely reviewed the cell biology of the bone remodeling.2 Osteoblasts synthesize bone matrix, which are composed of predominantly type I collagen and are found at the bone-forming surface. Osteoblasts are of fibroblastic origin. Extracellular matrix surrounds some osteoblasts, which become osteocytes. They are believed to play a critical role in the mechanotransduction of strain in bone remodeling.
In contrast, osteoclasts are derived from the monocyte/macrophage lineage. Osteoclasts can tightly attach to the bone matrix by integrin receptors to form a sealing zone, within which a sequestered compartment is acidified. Acidification promotes solubilization of the bone mineral in the sealing zone, and various proteases, notably cathepsin K, catalyze degradation of the matrix proteins.
Bone modeling and remodeling differ in that modeling implies a change in the shape of the overall bone and is prominent during childhood and adolescence. Modeling is the process by which the marrow cavity expands as the bone grows in length and diameter. Failure of modeling is the basis of hematopoietic failure in osteopetrosis. Remodeling, in contrast, involves the degradation of bone tissue from a preexisting bony structure and replacement of the degraded bone by newly synthesized bone. Failure of remodeling is the basis of the persistence of primary spongiosa and woven bone.
Osteoclast development and maturation
For precursor cells to mature, functional osteoclasts require the action of 2 distinct signals. The first is monocyte-macrophage–colony-stimulating factor (M-CSF), which is mediated by a specific membrane receptor and its signaling cascade. The second is the receptor activating NF-kappa B ligand (RANKL) acting through its cognate receptor, RANK. A soluble decoy receptor, osteoprotegerin, can bind RANKL, limiting its ability to stimulate osteoclastogenesis. In mouse models, disruption of these signaling pathways leads to an osteopetrotic phenotype.
Several excellent, detailed reviews of material presented here are available.3,4
Osteoclast function
After osteoclasts have formed, normal osteoclasts effectively dissolve existing bone matrix. For this to occur, the osteoclast must successfully create a sealing zone, acidify the contents of the sealing zone, and secrete cathepsin K. Disturbance of intrinsic osteoclast function is most commonly encountered in human osteopetrosis.
Table 1. Molecular Lesions Leading to Osteopetrosis in the Mouse
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Table
| Gene | Protein | Lesion | Phenotype | Human Equivalent | Key References |
|---|---|---|---|---|---|
| Csf1 | M-CSF | Naturally occurring op allele (frame shift) | Reduced size, short limbs, domed skull, absence of teeth, poor hearing, poor fertility, extramedullary hematopoiesis, rescued by administration of M-CSF | None known | Yoshida et al, 1990 |
| Csf1r | M-CSF receptor | Targeted disruption in exon 3 | Reduced size, short limbs, domed skull, absence of teeth, poor fertility, extramedullary hematopoiesis, slightly more severe than Csf1op phenotype | None known | Dai et al, 2002 |
| Tnfsf11 | RANKL | Targeted disruptions | Osteopetrosis, failure of lymph nodes to develop | None known | Kong et al, 1999; Kim et al, 2000 |
| Tnfrsf11a | RANK | Targeted disruptions | Osteopetrosis, failure of lymph nodes to develop | Duplications in exon 1 found in Paget disease and in familial expansile osteolysis | Li et al, 2000 |
| Ostm1 | Osteopetrosis-associated transmembrane protein 1 | Naturally occurring deletion | Abnormal coat color, short lifespan, chondrodysplasia, failure of tooth eruption, osteopetrosis | Infantile malignant osteopetrosis | Chalhoub et al, 2003 |
| Acp5 | Tartrate resistant acid phosphatase (acid phosphatase 5) | Targeted disruption | Chondrodysplasia, osteopetrosis | None known | Hayman et al, 1996 |
| Car2 | Carbonic anhydrase 2 | N -ethyl-N -nitrosourea (ENU) mutagenesis | No skeletal phenotype in mouse, renal tubular acidosis, growth retardation | Osteopetrosis with renal tubular acidosis | Lewis et al, 1988 |
| Clcn7 | Chloride channel 7 | Targeted disruptions | Chondrodysplasia, osteopetrosis, failure of tooth eruption, optic atrophy, retinal degeneration, premature death | Autosomal dominant type 2 osteopetrosis, autosomal recessive osteopetrosis | Kornak et al, 2001; Cleiren et al, 2001 |
| Ctsk | Cathepsin K | Targeted disruption | Osteopetrosis with increased osteoclast surface | Pycnodysostosis | Saftig et al, 1998; Kiviranta et al, 2005 |
| Gab2 | Grb2 -associated binder 2 | Targeted disruption | Osteopetrosis, defective osteoclast maturation | None known | Wada et al, 2005 |
| Mitf | Micro-ophthalmia–associated transcription factor | Spontaneous mutations, ENU mutagenesis, radiation mutagenesis, targeted disruption, untargeted insertional mutagenesis | Pigmentation failure, failure of tooth eruption, osteopetrosis, microphthalmia, infertility in both sexes | Waardenburg syndrome, type 2a; Tietz syndrome, ocular albinism with sensorineural deafness | Hodgkinson et al, 1993; Steingrimsson et al, 1994 |
| Src | c-SRC | Targeted disruption | Osteopetrosis, failure of tooth eruption, premature death, reduced body size, female infertility, poor nursing | None known | Soriano et al, 1991 |
| Tcirg1 | 116-kD subunit of vacuolar proton pump | Spontaneous deletion, targeted disruption | Osteopetrosis, failure of tooth eruption, chondrodysplasia, small size, premature death | Autosomal recessive osteopetrosis | Li et al, 1999; Scimeca et al, 2000; Frattini et al, 2000 |
| Traf6 | Tumor necrosis factor (TNF)-receptor–associated factor 6 | Targeted disruptions | Osteopetrosis, failure of tooth eruption, decreased body size, premature death, impaired maturation of dendritic cells | None known | Naito et al, 1999; Lomaga et al, 1999; Kobayashi et al, 2003 |
| Gene | Protein | Lesion | Phenotype | Human Equivalent | Key References |
|---|---|---|---|---|---|
| Csf1 | M-CSF | Naturally occurring op allele (frame shift) | Reduced size, short limbs, domed skull, absence of teeth, poor hearing, poor fertility, extramedullary hematopoiesis, rescued by administration of M-CSF | None known | Yoshida et al, 1990 |
| Csf1r | M-CSF receptor | Targeted disruption in exon 3 | Reduced size, short limbs, domed skull, absence of teeth, poor fertility, extramedullary hematopoiesis, slightly more severe than Csf1op phenotype | None known | Dai et al, 2002 |
| Tnfsf11 | RANKL | Targeted disruptions | Osteopetrosis, failure of lymph nodes to develop | None known | Kong et al, 1999; Kim et al, 2000 |
| Tnfrsf11a | RANK | Targeted disruptions | Osteopetrosis, failure of lymph nodes to develop | Duplications in exon 1 found in Paget disease and in familial expansile osteolysis | Li et al, 2000 |
| Ostm1 | Osteopetrosis-associated transmembrane protein 1 | Naturally occurring deletion | Abnormal coat color, short lifespan, chondrodysplasia, failure of tooth eruption, osteopetrosis | Infantile malignant osteopetrosis | Chalhoub et al, 2003 |
| Acp5 | Tartrate resistant acid phosphatase (acid phosphatase 5) | Targeted disruption | Chondrodysplasia, osteopetrosis | None known | Hayman et al, 1996 |
| Car2 | Carbonic anhydrase 2 | N -ethyl-N -nitrosourea (ENU) mutagenesis | No skeletal phenotype in mouse, renal tubular acidosis, growth retardation | Osteopetrosis with renal tubular acidosis | Lewis et al, 1988 |
| Clcn7 | Chloride channel 7 | Targeted disruptions | Chondrodysplasia, osteopetrosis, failure of tooth eruption, optic atrophy, retinal degeneration, premature death | Autosomal dominant type 2 osteopetrosis, autosomal recessive osteopetrosis | Kornak et al, 2001; Cleiren et al, 2001 |
| Ctsk | Cathepsin K | Targeted disruption | Osteopetrosis with increased osteoclast surface | Pycnodysostosis | Saftig et al, 1998; Kiviranta et al, 2005 |
| Gab2 | Grb2 -associated binder 2 | Targeted disruption | Osteopetrosis, defective osteoclast maturation | None known | Wada et al, 2005 |
| Mitf | Micro-ophthalmia–associated transcription factor | Spontaneous mutations, ENU mutagenesis, radiation mutagenesis, targeted disruption, untargeted insertional mutagenesis | Pigmentation failure, failure of tooth eruption, osteopetrosis, microphthalmia, infertility in both sexes | Waardenburg syndrome, type 2a; Tietz syndrome, ocular albinism with sensorineural deafness | Hodgkinson et al, 1993; Steingrimsson et al, 1994 |
| Src | c-SRC | Targeted disruption | Osteopetrosis, failure of tooth eruption, premature death, reduced body size, female infertility, poor nursing | None known | Soriano et al, 1991 |
| Tcirg1 | 116-kD subunit of vacuolar proton pump | Spontaneous deletion, targeted disruption | Osteopetrosis, failure of tooth eruption, chondrodysplasia, small size, premature death | Autosomal recessive osteopetrosis | Li et al, 1999; Scimeca et al, 2000; Frattini et al, 2000 |
| Traf6 | Tumor necrosis factor (TNF)-receptor–associated factor 6 | Targeted disruptions | Osteopetrosis, failure of tooth eruption, decreased body size, premature death, impaired maturation of dendritic cells | None known | Naito et al, 1999; Lomaga et al, 1999; Kobayashi et al, 2003 |
In humans, three distinct forms of the disease are based on age and clinical features and account for most cases. These are adult onset, infantile, and intermediate (see Table 2). Other rare forms have been described (eg, lethal, transient, postinfectious, acquired).
A distinct form of osteopetrosis occurs in association with renal tubular acidosis and cerebral calcification due to carbonic anhydrase isoenzyme II deficiency. This enzyme catalyzes the formation of carbonic acid from water and carbon dioxide. Carbonic acid dissociates spontaneously to release protons, which are essential for creating an acidic environment required for dissolution of bone mineral in the resorption lacunae. Lack of this enzyme results in impaired bone resorption. Clinical features vary considerably among individuals who are affected.
Table 2. Clinical Classification of Human Osteopetrosis
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Table
| Characteristic | Adult onset | Infantile | Intermediate |
|---|---|---|---|
Inheritance | Autosomal dominant | Autosomal recessive | Autosomal recessive |
Bone marrow failure | None | Severe | None |
Prognosis | Good | Poor | Poor |
Diagnosis | Often diagnosed incidentally | Usually diagnosed before age 1 y | Not applicable |
| Characteristic | Adult onset | Infantile | Intermediate |
|---|---|---|---|
Inheritance | Autosomal dominant | Autosomal recessive | Autosomal recessive |
Bone marrow failure | None | Severe | None |
Prognosis | Good | Poor | Poor |
Diagnosis | Often diagnosed incidentally | Usually diagnosed before age 1 y | Not applicable |
The classification of osteopetrosis shown above is purely clinical and must be supplemented by the molecular insights gained from animal models (see Table 1).
Frequency
United States
Epidemiologic data are not available.
International
Overall incidence of the disease is estimated to be 1 case in 100,000-500,000 population.5 However, the actual incidence is unknown because epidemiologic studies have not been conducted.
Mortality/Morbidity
- If untreated, infantile osteopetrosis usually results in death by the first decade of life due to severe anemia, bleeding, or infection.
- Adults with osteopetrosis are usually asymptomatic and have good long-term survival rates.
Age
Three variants of the disease are diagnosed in infancy, childhood (intermediate), or adulthood.
Clinical
History
- Infantile osteopetrosis (also called malignant osteopetrosis) is diagnosed early in life. Its clinical manifestations are described below.
- Failure to thrive and growth retardation are symptoms.
- Bony defects occur. Nasal stuffiness due to mastoid and paranasal sinus malformation is often the presenting feature of infantile osteopetrosis. Neuropathies related to cranial nerve entrapment occur due to failure of the foramina in the skull to widen completely. Manifestations include deafness, proptosis, and hydrocephalus. Dentition might be delayed. Osteomyelitis of the mandible is common due to an abnormal blood supply. Bones are fragile and can fracture easily.
- Defective osseous tissue tends to replace bone marrow, which can cause bone marrow failure with resultant pancytopenia. Patients might have anemia, easy bruising and bleeding (due to thrombocytopenia), and recurrent infections (due to inherent defects in the immune system). Extramedullary hematopoiesis might occur with resultant hepatosplenomegaly, hypersplenism, and hemolysis.
- Other manifestations include sleep apnea and blindness due to retinal degeneration.
- Adult osteopetrosis (also called benign osteopetrosis) is diagnosed in late adolescence or adulthood.
- Two distinct types have been described, type I and type II, on the basis of radiographic, biochemical, and clinical features.6
- Table 3. Types of Adult Osteopetrosis
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[ CLOSE WINDOW ]Table
Characteristic Type I Type II Skull sclerosis Marked sclerosis mainly of the vault Sclerosis mainly of the base Spine Does not show much sclerosis Shows the rugger-jersey appearance Pelvis No endobones Shows endobones in the pelvis Transverse banding of metaphysis Absent May or may not be present Risk of fracture Low High Serum acid phosphatase Normal Very high Characteristic Type I Type II Skull sclerosis Marked sclerosis mainly of the vault Sclerosis mainly of the base Spine Does not show much sclerosis Shows the rugger-jersey appearance Pelvis No endobones Shows endobones in the pelvis Transverse banding of metaphysis Absent May or may not be present Risk of fracture Low High Serum acid phosphatase Normal Very high - Recent work has demonstrated that the clinical syndrome of adult type I osteopetrosis is not true osteopetrosis, but rather, increased bone mass due to activating mutations of LRP5.7 These mutations cause increased bone mass but no associated defect of osteoclast function. Instead, some have hypothesized that the set point of bone responsiveness to mechanical loading is altered, resulting in an altered balance between bone resorption and deposition in response to weight bearing and muscle contraction.
- Some cases of type II osteopetrosis result from mutations of CLCN7, the type 7 chloride channel.8,9 However, in other families with the clinical syndrome of type II adult osteopetrosis, linkage to other distinct genomic regions have been demonstrated. Therefore, the clinical syndrome is genetically heterogeneous.
- Approximately one half of patients are asymptomatic, and the diagnosis is made incidentally, often in late adolescence because radiologic abnormalities start appearing only in childhood. In other patients, the diagnosis is based on family history. Still other patients might present with osteomyelitis or fractures.
- Many patients have bone pains. Bony defects are common and include neuropathies due to cranial nerve entrapment (eg, with deafness, with facial palsy), carpal tunnel syndrome, and osteoarthritis. Bones are fragile and might fracture easily. Approximately 40% of patients have recurrent fractures. Osteomyelitis of the mandible occurs in 10% of patients.
- Bone marrow function is not compromised.
- Other manifestations include visual impairment due to retinal degeneration and psychomotor retardation.
Physical
Physical findings are related to bony defects and include short stature, frontal bossing, a large head, nystagmus, hepatosplenomegaly, and genu valgum in infantile osteopetrosis.
Causes
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. The exact molecular defects or sites of these mutations largely are unknown. The defect might lie in the osteoclast lineage itself or in the mesenchymal cells that form and maintain the microenvironment required for proper osteoclast function. The following is a review of some of the evidence suggesting disease etiology and heterogeneity of these causes:
- The specific genetic defect in humans is known only in osteopetrosis caused by carbonic anhydrase II deficiency.
- Infantile osteopetrosis seems to be transmitted as an autosomal recessive manner based on its inheritance pattern.
- Viruslike inclusions have been reported in osteoclasts of some patients with benign osteopetrosis, but the clinical significance remains uncertain.
- Absence of biologically active colony-stimulating factor (CSF-1) due to a mutation in its coding gene causes impairment of osteoclastic function in the osteopetrotic (Op/Op) mouse. Altered CSF-1 production also has been shown in toothless (tl) osteopetrotic rats. Knockout mice of some proto-oncogenes have been shown to have osteopetrosis.
More on Osteopetrosis |
 Overview: Osteopetrosis |
| Differential Diagnoses & Workup: Osteopetrosis |
| Treatment & Medication: Osteopetrosis |
| Follow-up: Osteopetrosis |
| References |
| Next Page » |
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Further Reading
Keywords
Albers-Schönberg disease, marble bone disease, osteopetrosis generalisata, hereditary bone disease, osteoclastic bone resorption, infantile osteopetrosis, malignant osteopetrosis, adult osteopetrosis, benign osteopetrosis, skeletal fragility, fragile skeleton, easily broken bones, disturbed tooth eruption, nerve entrapment syndromes, growth impairment
