Osteopetrosis I
INTRODUCTION ¡@

Background: Osteopetrosis is a rare hereditary bone disease of heterogeneous pathophysiology in which failure of osteoclastic bone resorption leads to increased bone mass. However, the bone has poor mechanical properties. A German radiologist, Albers-Schönberg, first described osteopetrosis in 1904.

Pathophysiology: The primary underlying defect in all types of osteopetrosis is failure of the osteoclasts to reabsorb bone. This results in thickened sclerotic bones, which have poor mechanical properties. Increased bone fragility results from a failure of the collagen fibers to connect osteons properly and from defective remodeling of woven bone to compact bone.

Three distinct forms of the disease are based on age and clinical features. These are adult onset, infantile, and intermediate (see Table 1). Other rare forms have been described (eg, lethal, transient, postinfectious).

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. Considerable variability exists in the clinical features amongst the individuals who are affected.

Table 1. Types of Osteopetrosis

CharacteristicsAdult onsetInfantileIntermediate
InheritanceAutosomal dominantAutosomal recessiveAutosomal recessive
Bone marrow failureNoneSevereNone
PrognosisGoodPoorPoor
DiagnosisOften diagnosed incidentallyUsually diagnosed before age 1 y

Frequency:

Mortality/Morbidity:

  • Adult patients with osteopetrosis usually are asymptomatic and have good long-term survival rates.

Age: Three variants of the disease are diagnosed in infancy, childhood (intermediate), or adulthood.
CLINICAL ¡@

History:

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:

WORKUP ¡@

Lab Studies:

  • 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.
    • Creatinine kinase (CK-BB) is increased due to increased release from defective osteoclasts.
  • Adult osteopetrosis
    • Acid phosphatase and CK-BB often are increased in type II disease.
    • Serum bone-specific alkaline phosphatase also may be increased in various types of the disease.

Imaging Studies:

  • Radiological features usually are 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 appear clublike or show an appearance of a bone within bone (endobone).
  • Radiographs may show evidence of fractures or osteomyelitis.
  • Two types of adult osteopetrosis are identified on the basis of radiographs. Typing patients might be important to predict a fracture pattern because type II patients appear to be at higher risk of fracture (see Table 2).
    • 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 shows the rugger jersey appearance, and the pelvis always shows subcristal sclerosis. Transverse banding of metaphysis is commonly seen in patients with type II disease, but not in patients with type I disease. Their presence confirms type II disease, but their absence does not necessarily indicate type I disease.
  • MRI can be used to follow bones 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 chances of success of a BMT. Patients with more crowded bone marrow are less likely 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 commonly is seen. Osteoclasts can be increased, normal, or decreased in number.

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

TREATMENT ¡@

Medical Care:

Surgical Care:

  • For infantile osteopetrosis, BMT remarkably has been shown to improve osteopetrosis in some cases.
    • It can cure both bone marrow failure and metabolic abnormalities.
    • Patients with severely crowded bone marrow appear less likely to benefit; thus, histologic analysis of the bone may help identify patients who will benefit from BMT and also predict the chances of success.
    • BMT is the only curative treatment for this disease. However, the use of BMT may be limited to only a few patients because an appropriate bone marrow donor cannot always be found. Also, BMT carries considerable risk because of the necessity for profound immunosuppression and the possibility of a graft-versus-host reaction.
  • In adult osteopetrosis, surgical treatment may be needed for aesthetic reasons (in patients with significant facial deformity) or functional reasons (for multiple fractures with 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.

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 other hand, patients might need calcium if hypocalcemia or rickets becomes a problem.

Activity: Counsel patients to avoid activities that might increase the risk of fractures.
MEDICATION ¡@

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 -- Increase serum calcium levels by increasing calcium absorption from the GI tract.
Drug Name
 Calcitriol (Rocaltrol, Calcijex) -- Calcitriol in large doses, along with restricted calcium intake, occasionally improves osteopetrosis dramatically. It can be used for treatment of infantile osteopetrosis and appears to help by stimulating dormant osteoclasts and, thus, bone resorption. Markers of bone turnover (eg, serum osteocalcin, bone specific alkaline phosphatase, urine hydroxyproline levels) increase during therapy. Usually, produces only a modest clinical improvement, which is not sustained after discontinuation of therapy.
Pediatric Dose 15 ng/kg/d PO initially, followed by a maintenance dose of 5-40 ng/kg/d PO
Contraindications Documented hypersensitivity; hypercalcemia; hypercalciuria
Interactions Cholestyramine and colestipol decrease absorption of calcitriol; magnesium-containing antacids and thiazide diuretics can increase effects of calcitriol
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions May need to restrict calcium intake to avoid hypercalcemia; maintain adequate fluid intake
FOLLOW-UP ¡@

Deterrence/Prevention:

Complications:

Prognosis:

MISCELLANEOUS ¡@

Medical/Legal Pitfalls:

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