Osteogenesis Imperfecta

Osteogenesis imperfecta (OI, or Brittle Bone Disease) is a clinically and genetically heterogeneous group of heritable disorders of connective tissue. The incidence of forms recognizable at birth is 1:10-20,000. The hallmark feature of OI is bone fragility, with susceptibility to fracture from minimal trauma, as well as bone deformity and growth deficiency. OI has multiple secondary features, including macrocephaly, blue sclerae, dentinogenesis imperfecta, hearing loss, neurological defects (macrocephaly and basilar invagination), and cardiopulmonary complications (the major cause of mortality directly related to OI). The current paradigm of OI is that of a collagen-related disorder. The classical Sillence types of OI (types I-IV) with autosomal dominant inheritance comprise about 80-85% of cases and are caused by mutations in the genes that encode type I collagen, COL1A1 and COL1A2. These types encompass the full spectrum of OI severity, from perinatal lethal type II to progressively deforming type III to mild and diagnostically delayed type I. The rare forms of OI (types V-XVIII) delineated in the last decade have (except for type V and some XV) autosomal recessive inheritance and are caused by mutations in genes whose protein products interact with collagen for post-translational modification or folding. OI, regardless of etiology, requires clinical management and genetic analysis. Most individuals with OI have significant physical disabilities. The diagnostic work-up focuses on the skeletal system, including age-specific physical exam, a thorough family pedigree, radiographic examination, and DEXA. Differential diagnosis (child maltreatment, thanatophoric dysplasia, achondrogenesis type I, campomelic dysplasia, hypophosphatasia, osteoporosis) varies with patient age and OI severity. Genetic counseling, nonsurgical (e.g., rehabilitation, bracing, splinting), surgical, and pharmacological (bisphosphonates, anti-RANK ligand antibody, recombinant human parathyroid hormone analog, growth hormone) management are essential components of complete care for individuals who have OI. Fractures should be evaluated with standard x-rays and managed with reduction and realignment, as needed, to prevent loss of function and to interrupt a cycle of refracturing. Two pharmacologic treatment modalities target osteoclast bone resorption. Bisphosphonates (synthetic analogs of pyrophosphate) induce osteoclast apoptosis. Maximum effects on bone histology and density occur within the first year following treatment. Meta-analyses do not support significant reduction in long bone fractures in bisphosphonate-treated children. Anti-RANK ligand antibody improves bone mineral density in individuals with OI types I, III, IV and VI without accumulating in the bone matrix. Disturbance of calcium homeostasis is a clinically significant side effect. Anabolic therapy with growth hormone to ameliorate short stature in OI is successful for type I and about half of type IV OI children; responders also have improved bone histology, increased bone density and fewer fractures. Two antibody-based drugs with anabolic action on bone: anti-sclerostin, a negative regulator of bone formation in the Wnt pathway, and anti-TGF-β, a coordinator of bone remodeling produced by osteoblasts, have shown promising efficacy in early phase clinical trials and animal studies, respectively. Overall, a multidisciplinary approach to management of this set of disorders is most beneficial, with care centered on maximizing patient quality of life. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.