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Osteogenesis imperfecta is an autosomal dominant disorder of the connective tissue, which is also known as "brittle-bone disease" because it renders those affected susceptible to fractures after minimal trauma. Clinically and biochemically, osteogenesis imperfecta is a generalized disorder of the connective tissue, characterized by various combinations of blue sclerae, triangular facies, macrocephaly, hearing loss, defective dentition, barrel chest, vertebral compression and scoliosis, progressive limb deformity and bowing, joint laxity, and varying degrees of growth retardation. The currently accepted classification of the disease includes four types defined according to clinical and radiographic features, with some overlap among them. (1) Type I is the mildest form of the disorder. Affected patients have prepubertal fractures from mild trauma, osteopenia, and slight growth retardation. Type II is the lethal perinatal form. Infants with this condition have a relatively large, soft cranium, short limbs, and a narrow thoracic cavity. On radiographs, the long bones appear crumpled and the ribs beaded by callus from fractures sustained in utero. The two forms in the middle of the clinical spectrum -- the progressive deforming type III and the moderately severe type IV -- are nonlethal but carry a heavy clinical burden in the form of recurrent fractures, limited ability to walk, limb deformity, severe growth deficiency, deformity of the pectus, and scoliosis. All types of osteogenesis imperfecta are caused by defects in type I collagen, the major structural protein of the extracellular matrix of bone, skin, and tendons. Type I collagen is a long, helical molecule composed of two copies of the (alpha)1 chain and one copy of the (alpha)2 chain. Each chain contains 338 uninterrupted repeats of the triplet GXY, where G is glycine, X is often proline, and Y is often hydroxyproline. The presence of glycine at every third residue is crucial to the formation and function of the helix, because its small side chain can be accommodated in the sterically hindered central region of the helix. (2) The mutations of collagen that cause osteogenesis imperfecta can be categorized into two groups. Most patients with type I osteogenesis imperfecta produce structurally normal collagen in reduced amounts because of a null (alpha)1(I) allele. (3) Patients with types II, III, and IV osteogenesis imperfecta have structural defects in one of the chains of collagen. The majority of the mutations (85 percent) result in the substitution of another amino acid for a glycine residue, and a smaller group (11 percent) is caused by single-exon splicing defects. The structural mutations affect connective tissue through a dominant negative mechanism, in which the presence of the mutant chain in the extracellular matrix directly disorganizes and weakens the matrix. In addition, although type I collagen is abundant in the skin and vascular walls, osteogenesis imperfecta is predominantly a bone disease. Several factors may be involved; for example, the mutant collagen may undergo less intracellular degradation and more secretion by osteoblasts than by fibroblasts, as well as more efficient incorporation into bone matrix. (4) The management of osteogenesis imperfecta focuses on minimizing fractures and maximizing function, (5) because there is no therapy that effectively reverses the osteopenia, normalizes the histologic features of connective tissue, or reverses the secondary features of this condition. Physical therapy beginning in early childhood is the mainstay of management. It should focus on isotonic strengthening of the muscles, stabilization of the joints, and aerobic conditioning. Many patients with type III osteogenesis imperfecta are confined to wheelchairs but still have recurrent fractures. For these patients, the combination of rehabilitation and selective orthopedic procedures can improve their ability to care for themselves and increase their independence. Most patients with type IV and many with type III osteogenesis imperfecta can walk with the use of a combination of bracing, surgery, and physical therapy to strengthen hip-girdle muscles and increase stamina. (6) The placement of intramedullary rods in femurs or tibias may be indicated if the bowing deformity is greater than 40 degrees, to adjust alignment of the limbs and provide some internal support for weight bearing. (7) However, even for patients who can walk, this approach does not decrease the rate of fracture or the scoliosis-related cardiopulmonary morbidity of osteogenesis imperfecta. As for drug therapy, treatment with fluoride and calcitonin has proved unsuccessful. In this issue of the Journal, Glorieux and colleagues report on an uncontrolled trial of the bisphosphonate pamidronate in children with type III and IV osteogenesis imperfecta. (8) The bisphosphonates are synthetic analogues of pyrophosphate, a natural inhibitor of osteoclastic bone resorption. These drugs are effective in patients with osteoporosis, Paget's disease, and fibrous dysplasia, and they have few side effects. (9) Previously, only a handful of patients with osteogenesis imperfecta had been treated with one of these drugs, with reported benefit. In the study by Glorieux et al., in which 30 children who were 3 to 16 years of age were treated with intravenous pamidronate at four-to-six-month intervals, chronic bone pain decreased, motor function improved, bone mineral density increased, and bone resorption decreased. There was a decrease in radiologically confirmed fractures of 1.7 fractures per year; the healing of fractures was not altered. These results are cause for cautious optimism. They warrant further studies to determine the long-term effect of bisphosphonate therapy on the density, histologic features, and biomechanical properties of bone. It will be especially important to determine whether bisphosphonate-treated bone has improved functional properties despite the presence of mutant collagen in its matrix. There are prospects for gene therapy in the treatment of osteogenesis imperfecta. Two alternative approaches are being investigated. One is replacement of mutant cells with normal cells through bone marrow transplantation. The principal challenge of this approach is how to target mesenchymal precursor cells to become osteoblasts that reside in the skeleton. The second approach, involving the suppression of mutant genes, aims to decrease the expression of the mutant allele by introducing ribozymes into the cells to cleave the mutant gene product while leaving the normal gene product intact. (10) If successful, this method should change a structural defect in collagen to a quantitative defect in normal collagen, with a correspondingly milder phenotype. For now, however, we need to find ways to increase bone strength and function. This initial study by Glorieux et al. indicates that pamidronate, although not a cure for osteogenesis imperfecta, may be a way to bring about such increases. Joan C. Marini, M.D., Ph.D. National Institutes of Health Bethesda, MD 20892-1830 References 1. Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet 1979;16:101-16. Return to Text 2. Prockop DJ, Kivirikko KI. Collagens: molecular biology, diseases, and potentials for therapy. Annu Rev Biochem 1995;64:403-34. Return to Text 3. Willing MC, Deschenes SP, Scott DA, et al. Osteogenesis imperfecta type I: molecular heterogeneity for COL1A1 null alleles of type I collagen. Am J Hum Genet 1994;55:638-47. Return to Text 4. Sarafova AP, Choi H, Forlino A, et al. Three novel type I collagen mutations in osteogenesis imperfecta type IV probands are associated with discrepancies between electrophoretic migration of osteoblast and fibroblast collagen. Hum Mutat 1998;11:395-403. Return to Text 5. Marini JC. Osteogenesis imperfecta: comprehensive management. Adv Pediatr 1988;35:391-426. Return to Text 6. Marini JC, Gerber NL. Osteogenesis imperfecta: rehabilitation and prospects for gene therapy. JAMA 1997;277:746-50. Return to Text 7. Reing CM. Report on new types of intramedullary rods and treatment effectiveness data for selection of intramedullary rodding in osteogenesis imperfecta. Connect Tissue Res 1995;31:Suppl:S77-S79. Return to Text 8. Glorieux FH, Bishop NJ, Plotkin H, Chabot G, Lanoue G, Travers R. Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med 1998;339:947-52. Return to Text 9. Liberman UA, Weiss SR, Broll J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995;333:1437-43. Return to Text 10. Grassi G, Forlino A, Marini JC. Cleavage of collagen RNA transcripts by hammerhead ribozymes in vitro is mutation-specific and shows competitive binding effects. Nucleic Acids Res 1997;25:3451-8.

Severe osteogenesis imperfecta is a disorder characterized by osteopenia, frequent fractures, progressive deformity, loss of mobility, and chronic bone pain. There is no effective therapy for the disorder. We assessed the effects of treatment with a bisphosphonate on bone resorption. Methods. In an uncontrolled observational study involving 30 children who were 3 to 16 years old and had severe osteogenesis imperfecta, we administered pamidronate intravenously (mean [±SD] dose, 6.8±1.1 mg per kilogram of body weight per year) at 4-to-6-month intervals for 1.3 to 5.0 years. Clinical status, biochemical characteristics reflecting bone turnover, the bone mineral density of the lumbar spine, and radiologic changes were assessed regularly during treatment. Results. Administration of pamidronate resulted in sustained reductions in serum alkaline phosphatase concentrations and in the urinary excretion of calcium and type I collagen N-telopeptide. There was a mean annualized increase of 41.9±29.0 percent in bone mineral density, and the deviation of bone mineral density from normal, as indicated by the z score, improved from -5.3±1.2 to -3.4±1.5. The cortical width of the metacarpals increased by 27.0±20.2 percent per year. The increases in the size of the vertebral bodies suggested that new bone had formed. The mean incidence of radiologically confirmed fractures decreased by 1.7 per year (P<0.001). Treatment with pamidronate did not alter the rate of fracture healing, the growth rate, or the appearance of the growth plates. Mobility and ambulation improved in 16 children and remained unchanged in the other 14. All the children reported substantial relief of chronic pain and fatigue. Conclusions. In children with severe osteogenesis imperfecta, cyclic administration of intravenous pamidronate improved clinical outcomes, reduced bone resorption, and increased bone density. (N Engl J Med 1998;339:947-52.) Source Information From the Genetics Unit, Shriners Hospital for Children (F.H.G., N.J.B., H.P., G.C., G.L., R.T.), and the Departments of Surgery and Pediatrics (F.H.G., N.J.B.), McGill University, Montreal. Address reprint requests to Dr. Glorieux at the Genetics Unit, Shriners Hospital for Children, 1529 Cedar Ave., Montreal, QC H3G 1A6, Canada.