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 - Another agent that can be used against anemia
- Gamma interferon - Improves white blood cell function, greatly decreasing the incidence of new infections
Vitamin D Analogs
Class Summary
These supplements increase serum calcium levels by increasing calcium absorption from the gastrointestinal tract.
Calcitriol (Rocaltrol, Calcijex, Vectical)
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.
Corticosteroids
Class Summary
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.
Prednisone
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.
Hematopoietic Growth Factors
Class Summary
These agents are used to manage anemia related to chronic renal failure, rheumatoid arthritis, and AIDS.
Epoetin alfa (Procrit, Epogen)
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.
Darbepoetin (Aranesp)
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.
Immunomodulators
Class Summary
These agents delay disease progression in severe, malignant osteopetrosis.[20] 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.
Gamma-1b interferon (Actimmune)
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.
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| Characteristic | Adult onset | Infantile | Intermediate |
| Inheritance | Autosomal dominant | Autosomal recessive | Autosomal recessive |
| Bone marrow failure | None | Severe | None |
| Prognosis | Good | Poor | Poor |
| Diagnosis | Often diagnosed incidentally | Usually diagnosed before age 1y | Not applicable |
| Gene | Protein | Lesion | Phenotype | Human Equivalent | Key References |
| Csf1 | M-CSF | 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 |
| 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 | Infantile malignant osteopetrosis | Chalhoub et al, 2003 |
| Acp5 | Tartrate resistant acid phosphatase (acid phosphatase 5) | Targeted disruption | Chondrodysplasia, osteopetrosis | None known | Hayman et al, 1996 |
| Car2 | 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 |
| Clcn7 | 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 |
| Ctsk | Cathepsin K | Targeted disruption | Osteopetrosis with increased osteoclast surface | Pycnodysostosis | Saftig et al, 1998; Kiviranta et al, 2005 |
| Gab2 | Grb2 -associated binder 2 | Targeted disruption | Osteopetrosis, defective osteoclast maturation | None known | Wada et al, 2005 |
| Mitf | 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 |
| Src | c-SRC | Targeted disruption | Osteopetrosis, failure of tooth eruption, premature death, reduced body size, female infertility, poor nursing | None known | Soriano et al, 1991 |
| Tcirg1 | 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 |
| Traf6 | 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 |
| 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 |
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