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, 3 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 estimated to be 1 case per 100,000-500,000 population.[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
Counsel patients with osteopetrosis on appropriate lifestyle modifications to prevent fractures. Provide genetic counseling to patients to allow appropriate family planning. (See Treatment.)
To understand the etiology of osteopetrosis, understanding the bone-remodeling cycle and the cell biology of osteoclasts is essential.
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 are composed predominantly of 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[6] to form a sealing zone, within which is a sequestered, acidified compartment. 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 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.[7, 8, 9, 10]
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 is known only in osteopetrosis 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 knockout mice of some proto-oncogenes have been shown to have osteopetrosis
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.[11] 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.[12, 13, 14] 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.
Infantile osteopetrosis (also called malignant osteopetrosis) is diagnosed early in life. Failure to thrive and growth retardation are symptoms.
Bony defects and associated symptoms 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
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), and 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.)[15]
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 often made 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 may fracture easily. Approximately 40% of patients have recurrent fractures. Osteomyelitis of the mandible occurs in 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, a large head, nystagmus, hepatosplenomegaly, and genu valgum in infantile osteopetrosis.
Laboratory findings in infantile osteopetrosis include the following:
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 - Increased due to increased release from defective osteoclasts
Creatinine kinase isoform BB (CK-BB) - levels are increased due to increased release from defective osteoclasts
Laboratory findings in adult osteopetrosis include the following:
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
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.
Procedures
Bone biopsy is not essential for diagnosis, because radiographs usually are diagnostic. Histomorphometric studies of bone may 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.
Radiologic features of osteopetrosis are usually diagnostic. Because osteopetrosis encompasses a heterogeneous group of disorders, findings differ according on the variant.[17]
Patients usually have generalized osteosclerosis. Bones may be uniformly sclerotic, but alternating 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 extremely radiodense. They may show alternating 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)
Infantile osteopetrosis warrants treatment because of the adverse outcome associated with the disease.[18] Vitamin D (calcitriol) appears to help by stimulating dormant osteoclasts, thus stimulating bone resorption. Large doses of calcitriol, along with restricted calcium intake, sometimes improve osteopetrosis dramatically.[19] However, calcitriol 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 white blood cell function, greatly decreasing the incidence of new infections. With treatment, trabecular bone volume substantially decreases and bone-marrow volume increases. This results in 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 also been used to treat anemia, as well as to stimulate bone resorption. In one study, corticosteroids resulted in a striking increase in red blood cell 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/day is usually administered for months to years. Steroids are not the preferred treatment option.
Adult osteopetrosis
Adult osteopetrosis requires no treatment by itself, although complications of the disease may require intervention. No specific medical treatment exists for the adult type.
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.[20]
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 provides the names of several experts in the field.
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.
BMT markedly improves some cases of infantile osteopetrosis.[21] 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 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. 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.[22] The hypercalcemia resolved following treatment with isotonic saline, furosemide, and subcutaneous calcitonin.
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[23] :
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
Clinical Context:
In large doses, with restricted calcium intake, calcitriol sometimes improves osteopetrosis dramatically. It can be used to treat 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. However, calcitriol usually produces only modest clinical improvement, which is not sustained after discontinuation.
Clinical Context:
Prednisone is an immunosuppressant used for the treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity. The drug stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.
Clinical Context:
Epoetin alfa is a purified glycoprotein produced from mammalian cells modified with gene coding for human erythropoietin (EPO). The amino acid sequence is identical to that of endogenous EPO. Biological activity mimics human urinary EPO, which stimulates division and differentiation of committed erythroid progenitor cells and induces the release of reticulocytes from bone marrow into the blood stream.
Clinical Context:
Darbepoetin is an erythropoiesis-stimulating protein closely related to erythropoietin, a primary growth factor produced in kidney that stimulates development of erythroid progenitor cells. Its mechanism of action is similar to that of endogenous erythropoietin, which interacts with stem cells to increase red cell production.
Darbepoetin contains 5 N-linked oligosaccharide chains, whereas epoetin alfa contains 3 such chains. Darbepoetin has longer a half-life than epoetin alfa and may be administered weekly or biweekly.
Clinical Context:
Gamma-1b interferon is synthesized by eukaryotic cells in response to viruses and a variety of natural and synthetic stimuli. It possesses antiviral, immunomodulatory, and antiproliferative activity. Gamma interferon has potent phagocyte-activating effects not seen with other interferon preparations. It works by stimulating osteoclast activity.
These agents delay disease progression in severe, malignant osteopetrosis.[24] Combined with calcitriol, interferons are substantially more effective than calcitriol alone. The combination reduces the incidence of severe infections, the number of transfusions needed, and the patient’s bone mass considerably more than calcitriol alone. The FDA approved interferon in 2000 for use in children with osteopetrosis.
Robert Blank, MD, PhD, Professor of Medicine, Cell Biology, and Physiology, Chief, Division of Endocrinology, Metabolism, and Clinical Nutrition, Director, TOPS Obesity Center, Medical College of Wisconsin; Staff Physician, Clement J Zablocki Veterans Affairs Medical Center
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Bristol-Myers Squibb.
Coauthor(s)
Anuj Bhargava, MD, MBA, Adjunct Assistant Professor, Drake College of Pharmacy; Co-Director, Diabetes Institute, Mercy Medical Center; President, Iowa Diabetes and Endocrinology Research Center; President, My Diabetes Home, LLC
Disclosure: Received honoraria from Merck for speaking, research trials; Received honoraria from Novo Nordisk for speaking and teaching; Received honoraria from Sanofi for speaking and teaching; Received honoraria from takeda for speaking and teaching; Received honoraria from Abbott for speaking and teaching; Received grant/research funds from Lilly for research trials; Received grant/research funds from Gilead for research trials; Received grant/research funds from Novartis for research trials; Received gr.
Chief Editor
George T Griffing, MD, Professor Emeritus of Medicine, St Louis University School of Medicine
Disclosure: Nothing to disclose.
Acknowledgements
Romesh Khardori, MD, PhD, FACP Former Professor, Department of Medicine, Former Chief, Division of Endocrinology, Metabolism, and Molecular Medicine, Southern Illinois University School of Medicine
Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, and Endocrine Society
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Stanley Wallach, MD Executive Director, American College of Nutrition; Clinical Professor, Department of Medicine, New York University School of Medicine
Stanley Wallach, MD is a member of the following medical societies: American College of Nutrition, American Society for Bone and Mineral Research, American Society for Clinical Investigation, American Society for Clinical Nutrition, American Society for Nutritional Sciences, Association of American Physicians, and Endocrine Society
Baron R. Anatomy and Ultrastructure of Bone. Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 4th ed. Philadelphia, Pa: Lippincott, Williams, and Wilkins; 1999. 3-10.
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 Csf1opphenotype
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
