Jay R. Shapiro MD - Osteogenesis Imperfecta: A Translational Approach to Brittle Bone Disease

This is a present day story of osteogenesis imperfecta (OI). Also known as the brittle bone syndrome, it describes what we now know of this rare experiment of nature and how investigation has yielded important insights into bone biology, genetics and collagen chemistry. In so doing, it has also fully confirmed the rewards which come from the study of rare diseases. For many, research has been driven primarily by the catastrophic lifelong disability which this inherited bony fragility can cause. Known, and described, for centuries as an orthopedic oddity, it was the parallel advances in genetic description and collagen biochemistry which led the way to significant progress. OI now stands center stage as the first of the new metabolic bone diseases. Importantly, increased understanding of the abnormal bone cell biology suggested new ways in which OI might be treated. This book describes these aspects in detail. It also deals with the effect of collagen gene mutations in nonskeletal tissues and with some apparent overlap syndromes. In so doing, its many authors provide a wide and firm base for research.

Early descriptions of the brittle bone syndrome recognized that skeletal and nonskeletal manifestations varied widely in severity but two major groups, mild and severe, could be identified. Some variants, such as those with blindness (subsequently the osteoporosis pseudoglioma syndrome), were later separated off. It was also recognized (by the prescient term hypoplasia of the mesenchyme) that collagen in the skeleton and soft tissues was likely to be defective. When it became possible to study the different collagens and their genes, haploinsufficiency and triple helical glycine mutations defined the major groups. Recently, very rare recessive OI variants, such as those with defective prolyl-3 mutations, provide a fascinating goldmine for collagen chemists and those with noncollagen gene mutations (such as Type V with hyperplastic callus) continue to mystify.

Interpretation of the appearance of OI bone itself has not been easy, especially in the growing skeleton, and quantitative histomorphometry has a language of its own. However, it was here that we began to understand what effects collagen gene mutations have on the skeleton and how they might be dealt with. The simple explanation of the abnormal fragile bone of OI is that the osteoblastic production of collagen is variably reduced and that OI is a disorder of bone formation. One might then reasonably wonder why in some circumstances (particularly in children) OI can respond positively to bisphosphonates, universal antiresorptive agents. This conundrum receives full attention. Theoretically, a more logical approach to the treatment of OI is so-called gene therapy, with the replacement or elimination of the offending gene according to the type of mutation and its effects. This is an oversimplification and, so far, a practical minefield, but some progress has been made in experimental systems. Although the main burden of the collagen gene mutations falls upon the skeleton, defects in other collagen-containing tissues such as the teeth, ears, skin and cardiovascular system complete the brittle bone syndrome.

To get some idea of how much advance has been made and, indeed, how much still remains to be done, the reader should enter the clinic. For the new OI patient of whatever age the diagnosis, type, likely mutation, form of inheritance and prognosis can now be reasonably assessed by the informed physician and confirmed by any necessary investigation, but uncertainties remain, particularly with treatment. Orthopaedic surgery and specialized rehabilitation remain as they have done for many previous decades the cornerstone of skeletal management. In a perfect world, the care of the OI patient should involve many disciplines, but this is not always possible. This is exactly where this book will be most valuable in providing all that is currently known about OI in one place.