Osteopetrosis

Background

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]

Classification

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

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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.)

Epidemiology

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.

Prognosis

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.)

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Etiology

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

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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]

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History and Physical Examination

Infantile osteopetrosis

Infantile osteopetrosis (also called malignant osteopetrosis) is diagnosed early in life. Failure to thrive and growth retardation might be the initially presenting symptoms.

Bony defects and associated symptoms also occur, including the following:

• 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
• Other head manifestations include deafness, proptosis, and hydrocephalus
• Dentition may 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 suffer from anemia, easy bruising and bleeding (due to thrombocytopenia), as well as recurrent infections (due to inherent defects in the immune system)
• Extramedullary hematopoiesis may occur, with resultant hepatosplenomegaly, hypersplenism, and hemolysis
• Other manifestations include sleep apnea and blindness due to retinal degeneration

Adult osteopetrosis

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. (See Table 3, below.)^[21]  

Table 3. Types of Adult Osteopetrosis

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Approximately one half of patients are asymptomatic, and the diagnosis is made incidentally. The diagnosis is often made in late adolescence, because radiologic abnormalities start appearing only in childhood. In other patients, the diagnosis is based on family history, while some 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, or facial palsy), carpal tunnel syndrome, and osteoarthritis. Bones are fragile and may fracture easily. Approximately 40% of patients have recurrent fractures. Osteomyelitis of the mandible occurs in about 10% of patients.

Other manifestations include visual impairment due to retinal degeneration and psychomotor retardation. Bone marrow function is not compromised.

Physical examination

Physical findings are related to bony defects and include short stature, frontal bossing or large head, nystagmus, hepatosplenomegaly, and genu valgum in infantile forms of osteopetrosis.

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Radiography

Radiologic features of osteopetrosis are usually diagnostic. Because osteopetrosis encompasses a heterogeneous group of disorders, findings differ according to the variant.^[23]

Patients usually have generalized osteosclerosis. Bones may be uniformly sclerotic, but alternate sclerotic and lucent bands may be noted in iliac wings and near the ends of long bones. The bones may be clublike or may have the appearance of a bone within bone (endobone). Radiographs may also show evidence of fractures or osteomyelitis.

The entire skull is thickened and dense, especially at the base. Sinuses are small and underpneumatized. Vertebrae are usually extremely radiodense and they may show alternate bands, known as the rugger-jersey sign (see Table 3).

Differentiating type 1 from type 2 adult osteopetrosis

Two types of adult osteopetrosis are identified on the basis of radiographs. Typing the patient's disease may be important in predicting a fracture pattern, because type II disease appears to increase the risk of fracture (see Table 3). Radiographic characteristics of type I and type II disease are as follows:

• Type I disease - Sclerosis of the skull mainly affects the vault with marked thickening; the spine does not show much sclerosis.
• Type II disease - Sclerosis is found mainly in the base of the skull; the spine always has the rugger-jersey appearance, and the pelvis always shows subcristal sclerosis. Transverse banding of metaphysis is common in patients with type II disease but not in patients with type I disease - this finding confirms type II disease, but its absence does not necessarily indicate type I disease.

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Laboratory Studies

Laboratory studies

Laboratory studies include the following:

• Serum calcium
• Serum phosphorus 
• Serum creatinine
• 25-Hydroxy vitamin D
• Parathyroid hormone
• Complete blood cell count and differential
• BB isozyme of creatine kinase 
• Lactate dehydrogenase 
• Urinary calcium/creatinine ratio (random or 24 hour) at start of calcitriol therapy and every 3 months thereafter while on calcitriol 

Laboratory findings in adult osteopetrosis include the following:

• Acid phosphatase and CK-BB - Concentrations are often increased in type II disease

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Imaging Studies

MRI of the brain: Helps assess for cranial nerve involvement, hydrocephalus, and any vascular abnormalities.

CT scan of the brain: If cranial nerves are involved.

Bone biopsy and dual x-ray absorptiometry (DEXA) are not required for diagnosis. 

Renal ultrasound scan: Recommended every 12 months for patients who have CAII mutations and for patients on calcitriol therapy.^[24]

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Other Tests

Genetic screening

In addition to the routine laboratory investigations listed above, mutation screening of appropriate candidate genes should be undertaken in patients whose presentation corresponds to any of the known genetic lesions. Knowledge of the molecular basis of the osteopetrosis allows clinicians to provide informed genetic counseling and, in some cases, to choose appropriate therapy.

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Procedures

Procedures

Bone biopsy is not essential for diagnosis, because the radiographs usually are diagnostic. Histomorphometric studies of bone may be useful to predict the likelihood of the bone marrow transplantation (BMT) becoming successful. Patients with crowded bone marrow are less likely than others to respond to a transplant.

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Histologic Findings

Histologic findings

Failure of osteoclasts to resorb skeletal tissue is the pathognomonic feature of true osteopetrosis. Remnants of mineralized primary spongiosa are seen as islands of calcified cartilage within mature bone. Woven bone is also commonly seen. Osteoclasts can be increased, normal, or decreased in number.

Histologic analysis has revealed that type I adult-onset osteopetrosis is not a genuine form of osteopetrosis, because it lacks the characteristic findings.

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Approach Considerations

Treatment approach

The following have been used in the treatment of patients with osteopetrosis:

• • Goal 25-hydroxy vitamin D is >30
  • Supplementation of calcium may be necessary if dietary intake is below the daily recommended amount

   

  

   
• • This is needed for patients who have symptomatic anemia

   

  

   
• • Studies have shown that treatment with interferon gamma can increase leukocyte superoxide activity and hematologic recovery and decrease trabecular bone volume. However, interferon gamma-1b failed to increase bone turnover markers in autosomal dominant osteopetrosis type 2 and is unlikely to be effective in decreasing bone mass in this population.^[25]

   

  

   
• • There is lack of evidence at this time to support the routine use of steroids
  • Case reports have shown that steroid use in infantile osteopetrosis can lead to regression of the disease and prevent the need for bone marrow transplant

   

  

   
• • Patients aged younger than 1 year and patients with bone marrow failure should be referred for HSCT
  • For patients with malignant infantile osteopetrosis, HSCT may correct bone metabolism, but this condition needs to be identified promptly^[26]
  • Haploidentical stem cell transplantation with post-transplant cyclophosphamide can be used for pediatric patients who have non-malignant disease in the absence of a matched donor^[27]
  • Compared to patients with malignant infantile osteopetrosis, indications for HSCT in patients who have the indeterminate form of osteopetrosis are less clear. A study showed that HSCT alleviated symptoms and improved quality of life in patients aged older than 5 years with the intermediate form of osteopetrosis^[28]

   

  

   

Surgical treatment

In pediatric osteopetrosis, surgical treatment is sometimes necessary because of fractures. The constellation of problems associated with this condition and the prevailing opinions regarding their management have been reviewed.^[29]

In adult osteopetrosis, surgical treatment may be needed for aesthetic reasons (eg, in patients with notable facial deformity) or for functional reasons (eg, in patients with multiple fractures, deformity, and loss of function). Severe, related degenerative joint disease may warrant surgical intervention as well.

Fractures most commonly involve long bones such as the femur, tibia, humerus, and foot bones. Historically, fractures have been treated nonsurgically due to challenges associated with surgical treatment. Preoperative planning with orthopedic surgery is necessary to evaluate the best course of surgical management.^[30]

Consultations

A multidisciplinary approach may be needed for patients with osteopetrosis. Depending on the clinical symptoms and organ involvement, patients may need to be followed by an ophthalmologist, dentist, orthopedics specialist, neurologist, otolaryngologist, hematologist, or nephrologist.

Diet

Nutritional support is important to improve patient growth. It also enhances responsiveness to other treatment options. A calcium-deficient diet has shown some success in patients. However, patients may need calcium if hypocalcemia or rickets becomes a problem.

Long-term monitoring

Measurement of serum calcium, phosphorus, 25-hydroxy vitamin D, and parathyroid hormone levels and a complete blood cell count every 6-12 months is generally recommended.

Patients who are receiving calcitriol therapy may require more frequent monitoring with serum calcium, serum phosphorus, serum creatinine, and a urinary calcium/creatinine ratio every 3 months and renal ultrasonography every 12 months during therapy. 

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Bone Marrow Transplantation

BMT markedly improves some cases of infantile osteopetrosis.^[31] BMT can cure bone marrow failure and metabolic abnormalities in patients whose disease arises from an intrinsic defect of the osteoclast lineage.

BMT is the only curative treatment for this disease. However, BMT may be limited in a subset of patients whose defects are extrinsic to the osteoclast lineage and whose condition is unlikely to respond. Moreover, this approach is limited, because an appropriate bone marrow donor is not always found. Also, BMT poses considerable risk because of the necessity for profound immunosuppression and the possibility of a graft-versus-host reaction. Magnetic resonance imaging (MRI) can be used to assess bones over time after BMT.

Hypercalcemia in bone marrow transplantation

Hypercalcemia can occur following hematopoietic cell transplantation (HCT), owing to the engraftment of osteoclasts arising from precursor cells. In a study of 15 patients with osteopetrosis, Martinez et al found that posttransplantation hypercalcemia developed in 40% of these individuals, occurring primarily in patients over age 2 years at the time of the HCT; the median time to onset was 23 days.^[32] The hypercalcemia resolved following treatment with isotonic saline, furosemide, and subcutaneous calcitonin.

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Guidelines Summary

Consensus guidelines from the Osteopetrosis Working Group give recommendations for patients with less severe forms of osteopetrosis where hematopoietic cell transplantation is not the standard treatment. The recommendations include^[24] :

• A diagnosis can be made by characteristic radiographic findings.
• Genetic testing can identify mutations associated with unique disease complications.
• Patients should be continually monitored for changes in mineral metabolism and other complications including cranial nerve impingement, anemia, leukopenia, and dental disease.
• Calcitriol should not be used in high doses and symptom-based supportive therapy is recommended for disease complications as there is no effective treatment for non-infantile osteopetrosis.

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Medication Summary

Medications administered in osteopetrosis include the following:

• Vitamin-D supplements: Appear to help by stimulating dormant osteoclasts, thus stimulating bone resorption
• Corticosteroids: Have also been used to stimulate bone resorption and to treat anemia
• Erythropoietin: Is another agent that can be used against anemia
• Gamma interferon: Improves white blood cell function, greatly decreasing the incidence of new infections

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