AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

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

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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

    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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Osteoblastic metastases
Pyknodysostosis
Fluoride poisoning
Beryllium poisoning
Leukemia
Sickle cell diseases

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Findings in infantile osteopetrosis
• • Serum calcium generally reflects oral intake. Hypocalcemia can occur and cause rickets if it is severe enough.
  • Parathyroid hormone (PTH) often is elevated (secondary hyperparathyroidism).
  • Acid phosphatase is increased due to increased release from defective osteoclasts.
  • Levels of creatinine kinase isoform BB (CK-BB) is increased due to increased release from defective osteoclasts.
• Findings in adult osteopetrosis
• • Acid phosphatase and CK-BB concentrations are often increased in type II disease.
• • Serum bone-specific alkaline phosphatase values may also be increased in various types of the disease.
• Other findings
• • In addition to the results of routine laboratory investigations listed above, mutation screening of appropriate candidate genes should be undertaken in patients whose presentations correspond 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.

Imaging Studies

• Radiologic features are usually diagnostic. Because the disease is a heterogeneous group of disorders, the findings vary depending on the subtype.
• Patients usually have generalized osteosclerosis. Bones may be uniformly sclerotic, but alternating sclerotic and lucent bands may be noted in iliac wings and near ends of long bones. The bones might be clublike or appear like a bone within bone (endobone).
• The entire skull is thickened and dense, especially at the base. Sinuses are small and underpneumatized. Vertebrae are extremely radiodense. They may show alternating bands, known as the rugger-jersey sign (see Table 3 in History).
• Radiographs may show evidence of fractures or osteomyelitis.
• Two types of adult osteopetrosis are identified on the basis of radiographs. Typing the patient's disease might be important to predict a fracture pattern because type II disease appears to increase the risk of fracture (see Table 3 in History).
• • 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.
• MRI can be used to assess bones over time after bone marrow transplantation (BMT).

Procedures

• Bone biopsy is not essential for diagnosis because radiographs usually are diagnostic.
• Histomorphometric studies of bone might be useful to predict the likelihood that BMT will succeed. Patients with crowded bone marrow are less likely than others to respond to a transplant.

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 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.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Infantile osteopetrosis warrants treatment because of the adverse outcome associated with the disease.
• • At a recent symposium, researchers described current thinking regarding its pathogenesis and treatment.¹⁰
  • Vitamin D (calcitriol) appears to help by stimulating dormant osteoclasts and thus stimulate bone resorption. Large doses of calcitriol, along with restricted calcium intake, sometimes improve osteopetrosis dramatically.¹¹ It usually produces only modest clinical improvement, which is not sustained after therapy is discontinued.
  • Treatment with gamma interferon has produced long-term benefits. It improves WBC function, tremendously decreasing the incidence of new infections. With treatment, trabecular bone volume substantially decreases, and bone-marrow volume increases. This effect increases in hemoglobin, platelet counts, and survival rates. Combination therapy with calcitriol is clearly superior to calcitriol alone.
  • Erythropoietin can be used to correct anemia.
  • Corticosteroids have been used to stimulate bone resorption and treat anemia. In 1 study, corticosteroids resulted in a striking increase in RBC mass and platelet count, but failed to improve bone mass. This effect on blood cells is due to reduced destruction in the reticuloendothelial system. Prednisone 1-2 mg/kg/d is usually administered for months to years. Steroids are not the preferred treatment option.
• Adult osteopetrosis requires no treatment by itself, though complications of the disease might require intervention. No specific medical treatment exists for the adult type.

Surgical Care

• BMT markedly improves some cases of infantile osteopetrosis.
• • BMT can cure both 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 to 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.
• In pediatric osteopetrosis, surgical treatment is sometimes necessary because of fractures. This constellation of problems and prevailing opinions regarding management has been reviewed.¹²
• 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.

Consultations

Refer patients to an endocrinologist with special interest and experience in bone and mineral metabolism. A patient-oriented Web site, Osteopetrosis Web site, provides the names of several experts in the field.

Diet

Nutritional support is important to improve growth of patients. It also enhances responsiveness to other treatment options. Calcium deficient diet has shown some success in these patients. On the contrary, patients might need calcium if hypocalcemia or rickets becomes a problem.

Activity

Counsel patients to avoid activities that might increase their risk of fractures.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Some of the medications include vitamin-D supplements, corticosteroids, interferon, and erythropoietin.

Drug Category: Vitamin-D supplements

These supplements increase serum calcium levels by increasing calcium absorption from the GI tract.

Drug Category: Interferons

These agents delay disease progression in severe, malignant osteopetrosis.¹³ Combined with calcitriol, interferons are substantially more effective than calcitriol alone. The combination reduces incidence of severe infections, the number of transfusions needed, and the patient’s bone mass considerably more than calcitriol alone. The US Food and Drug administration approved in 2000 for use in children with osteopetrosis.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Deterrence/Prevention

• Counsel patients on appropriate lifestyle modifications to prevent fractures.
• Provide genetic counseling to patients to allow appropriate family planning.

Complications

• Infantile osteopetrosis
• • Bone marrow failure may occur, resulting in severe anemia, bleeding, or infections.
  • Growth retardation and failure to thrive can occur.

Prognosis

• Infantile osteopetrosis
• • If untreated, infantile osteopetrosis usually results in death by the first decade of life due to severe anemia, bleeding, or infections.
  • Patients fail to thrive, have growth retardation, and increased morbidity.
  • The prognosis of some patients can markedly change after BMT.
• Adult osteopetrosis: Patients have good long-term survival rates.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• In the differential diagnosis, include conditions that can result in diffuse osteosclerosis.
• Such conditions may include congenital disorders (eg, pyknodysostosis, hypoparathyroidism, pseudohypoparathyroidism), chemical poisoning (eg, fluoride, lead, beryllium), malignancies (leukemia, myeloproliferative diseases), and sickle cell disease.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Sep 19, 2007