Updated: Oct 07, 2022
  • Author: Kanisha Desai, DO; Chief Editor: George T Griffing, MD  more...
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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. (See Etiology and Presentation.)

Although human osteopetrosis is a heterogeneous disorder encompassing different molecular lesions and a range of clinical features, all forms share a single pathogenic nexus in the osteoclast. [1] Osteopetrosis was first described in 1904, by German radiologist Albers-Schönberg. (See Etiology.) [2]


In humans, three distinct clinical forms of the disease—infantile, intermediate, and adult onset—are identified based on age and clinical features. These variants, which are diagnosed in infancy, childhood, or adulthood, respectively, account for most cases. (See Table 1, below.)

Table 1. Clinical Classification of Human Osteopetrosis (Open Table in a new window)


Adult onset




Autosomal dominant [3]

Autosomal recessive

Autosomal recessive

Bone marrow failure









Often diagnosed incidentally

Usually diagnosed before age 1y

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 2, in Etiology).

Other, rare forms of osteopetrosis 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. (See Etiology.)


Overall incidence of osteopetrosis is difficult to estimate. Autosomal recessive has an incidence of about 1 in 250,000 births, and autosomal dominant has an incidence of about 5 in 100,000 births. [1, 4] However, the actual incidence is unknown, because epidemiologic studies have not been conducted.


In infantile osteopetrosis, bone marrow failure may occur. If untreated, infantile osteopetrosis usually results in death by the first decade of life due to severe anemia, bleeding, or infections. Patients with this condition fail to thrive, have growth retardation, and suffer increased morbidity. The prognosis of some patients with infantile osteopetrosis can markedly change after bone marrow transplantation (BMT). Patients with adult osteopetrosis have good long-term survival rates. (See Treatment and Medication.)

Patient education

General counseling of patients with osteopetrosis should be offered on appropriate lifestyle modifications to prevent fractures as well as genetic counseling to allow appropriate family planning. (See Treatment.)



To understand the etiology of osteopetrosis, it is very essential to understand the bone-remodeling cycle and the cell biology of osteoclasts.

Bone cells and bone modeling and remodeling

In 1999, Baron clearly and concisely reviewed the cell biology of the bone remodeling. [5] Osteoblasts synthesize bone matrix, which is composed predominantly of type I collagen and is found at the bone-forming surface. Osteoblasts are of fibroblastic origin. Osteoblasts arise from multipotent mesenchymal stem cells. [6] Extracellular matrix surrounds some osteoblasts, which become osteocytes. They are believed to play a critical role in the mechanotransduction of strain in bone remodeling. Osteoblasts are responsible for synthesizing bone matrix and thereby creating an environment that supports the growth, maturation, and function of osteoclasts. [7]

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 is a sequestered, acidified compartment. [8] 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 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 woven bone.

Osteoclast development and maturation

For precursor cells to mature, functional osteoclasts require the action of 2 distinct signals. The first signal is monocyte-macrophage–colony-stimulating factor (M-CSF), which is mediated by a specific membrane receptor and its signaling cascade. The second signal 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. [9, 7, 10, 11]

Genetic and molecular defects in osteopetrosis

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 may 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 with osteopetrosis is caused by carbonic anhydrase II deficiency (discussed below)

  • Based on its inheritance pattern, infantile osteopetrosis seems to be transmitted in an autosomal recessive manner

  • 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, and also osteopetrosis developed in knockout mice of some proto-oncogenes.

Research has demonstrated that the clinical syndrome of adult type I osteopetrosis is not true osteopetrosis, with the increased bone mass of this condition being due to activating mutations of LRP5. [12] 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 changed, 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. [13, 14, 15] However, in other families with the clinical syndrome of type II adult osteopetrosis, linkage to other distinct genomic regions has been demonstrated. Therefore, the clinical syndrome is genetically heterogeneous.

In mice, many mutations result in osteopetrotic phenotypes (summarized in Table 2, below). Human homologs are known for only some of the murine lesions.

Table 2. Molecular Lesions Leading to Osteopetrosis in the Mouse (Open Table in a new window)





Human Equivalent

Key References



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


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 Csf1opphenotype

None known

Dai et al, 2002



Targeted disruptions

Osteopetrosis, failure of lymph nodes to develop

None known

Kong et al, 1999; Kim et al, 2000



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


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


Tartrate resistant acid phosphatase (acid phosphatase 5)

Targeted disruption

Chondrodysplasia, osteopetrosis

None known

Hayman et al, 1996


Carbonic anhydrase II

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


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


Cathepsin K

Targeted disruption

Osteopetrosis with increased osteoclast surface


Saftig et al, 1998; Kiviranta et al, 2005


Grb2 -associated binder 2

Targeted disruption

Osteopetrosis, defective osteoclast maturation

None known

Wada et al, 2005


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



Targeted disruption

Osteopetrosis, failure of tooth eruption, premature death, reduced body size, female infertility, poor nursing

None known

Soriano et al, 1991


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


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

Osteopetrosis in carbonic anhydrase isoenzyme II deficiency

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.

Mutations in known genes 

The TCIRG1 (T-cell immune regulator 1) gene encodes the a3-subunit of the ATP-dependent vacuolar proton pump.

In the recent years, new CLCN7 (chloride voltage-gated channel 7) mutations have also been reported. The second most frequent form of osteopetrosis is caused by mutations in the CLCN7 gene. [16, 17]

The SNX10 (sorting nexin 10) gene encodes a protein that belongs to the SNX family of cytoplasmic and membrane-bound proteins.

The OSTM1 (osteopetrosis-associated transmembrane protein 1) gene encodes a protein that helps stabilize CLCN7 and protects it from degradation. OSTM1 also plays an important role in the central nervous system. [18]

The PLEKHM1 (pleckstrin homology domain-containing family M-with RUN domain-member 1) gene encodes a cytosolic protein that plays a role in endosomal trafficking pathways. [19]

The CAII gene encodes a cytoplasmic enzyme that catalyzes the formation of H2CO3 from H2O and CO2.

The FERMT3 (fermitin family member 3) gene encodes kindlin-3, which comprises three focal adhesion proteins involved in integrin activation.

The RANKL (receptor activator of nuclear kappa B ligand) gene encodes a protein that plays an integral role in signaling cascade driving osteoclast differentiation and activation.

The RANK (receptor activator of nuclear kappa B) gene encodes the receptor for RANKL.

The SLC29A3 gene encodes a lysosomal nucleoside transporter highly. This gene plays a role in dysosteosclerosis, which is a rare form of osteopetrosis that presents in infancy with distinct skeletal features.

SLC4A2 (solute carrier family 4 member 2) deficiency can also cause autosomal recessive osteopetrosis. Loss of function mutations in SLC4A2 have been shown to cause osteopetrosis in mice and cattle. 

Other genes have been found that are reported in newly recognized forms of osteopetrosis. These include TRAF6 gene inactivation, LRRK1, MITF (microphthalmia-associated transcription factor), CSF1R, and C16orf57. [20]