Abstract
The genetic architecture of skeletal biomechanical performance has tremendous potential to advance our knowledge of the biological mechanisms that drive variation in skeletal fragility and osteoporosis risk. Research using traditional approaches that focus on specific gene pathways is increasing our understanding of how and to what degree those pathways may affect population-level variation in fracture susceptibility, and shows that known pathways may affect bone fragility through unsuspected mechanisms. Non-traditional approaches that incorporate a new appreciation for the degree to which bone traits co-adapt to functional loading environments, using a wide variety of redundant compensatory mechanisms to meet both physiological and mechanical demands, represent a radical departure from the dominant reductionist paradigm and have the potential to rapidly advance our understanding of bone fragility and identification of new targets for therapeutic intervention.
Highlights
Skeletal biomechanics are at the very heart of osteoporosis fracture risk
Bone mineral density (BMD) was the initial focus of much bone biomechanics research aimed at understanding osteoporosis fracture risk at the exclusion of many other vital contributors to bone fragility, but great strides have since been made in identifying a vast number of morphologic and compositional bone properties that contribute to fracture resistance, and like BMD, are influenced by genetic variation
Some research groups are applying approaches that represent this new paradigm of phenotypic integration and, in so doing, are (1) addressing gaps in our knowledge as to how complex bone traits work in concert to confer robust bone strength and fracture resistance, and (2) investigating the genetics of skeletal biomechanics in a way that is likely to quickly and significantly advance the field, and, ideally, our ability to develop focused treatments that target specific deficits that render individuals more susceptible to osteoporotic fracture
Summary
Skeletal biomechanics are at the very heart of osteoporosis fracture risk. Susceptibility of a bone to fracture results directly from biomechanical properties that are maintained, in the face of changing, and sometimes competing, physiological and mechanical demands, by elegant co-adaptation of a myriad of traits at all of bone’s hierarchical levels of organization. Bone mineral density (BMD) was the initial focus of much bone biomechanics research aimed at understanding osteoporosis fracture risk at the exclusion of many other vital contributors to bone fragility, but great strides have since been made in identifying a vast number of morphologic and compositional bone properties that contribute to fracture resistance, and like BMD, are influenced by genetic variation. Genetic studies of bone biomechanics designed to capture variability in the ways that co-adaptation of traits to habitual loading leads to bones that vary significantly in fracture resistance, hold the promise of leading us to the molecular biological mechanisms that drive the coadaptation process itself, and that are likely to be central mediators of fracture susceptibility. Study designs that treat skeletal biomechanical phenotypes as multifactorial and reflect their true composite nature represent the beginnings of an exciting and necessary new paradigm in the genetics of skeletal fragility
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