Disorganization and Musculoskeletal Diseases: Novel Insights into the Enigma of Unexplained Bone Abnormalities and Fragility Fractures.

Purpose of review: Describe the potential contribution of disorganized tissue to the pathogenesis of bone abnormalities and fractures. Especially, fractures that are unexplained by bone loss (osteoporosis) or structural deterioration.

Recent findings: Currently, bone fragility is primarily viewed as due to loss, or decay (osteoporosis). However, it is also acknowledged that this view is limited because it does not explain many fractures or abnormalities such as necrosis, sclerosis, or infarcts. Atypical femoral fractures (AFFs) during antiresorptive therapy are an example. Hence, it is proposed that another distinct mechanism is responsible for bone diseases. A remarkable bone property distinct from mass and decay is the organization (arrangement) of its components. Components must be perfectly assembled or well-stacked to ensure "the right amount of bone, at the right place". Disorganization is an aberration that is conspicuous in many diseases, more so in conditions poorly associated with bone mass and decay such as osteogenesis imperfecta, hypophosphatasia, and AFFs. However, despite the likely critical role of disorganization, this feature has received limited clinical attention. This review focuses on the potential contribution of disorganization to bone in health and diseases. Particularly, we propose that disorganization, by causing ineffective transfer of loads, may produce not only bone abnormalities (pain, necrosis, infarct, sclerosis, delayed healing) but also fractures, especially AFFs or stress fractures. A disorganized element is one that is where it shouldn't be (improperly stacked elements). Hence, disorganization can be measured by quantifying the extent to which a tissue (pixel within an image) is at an incorrect location.