The cellular activities of bone modeling and remodeling determine the material composition and structure of bone. Bone modeling refers to the deposition of new bone without prior bone resorption. Bone remodeling is characterized by the appearance of focally and temporally distinct regions of resorption followed by bone formation that constitutes the basic multicellular units (BMUs).The purpose of bone modeling and remodeling during growth is to build peak bone strength. After the completion of growth, bone modeling continues in adulthood modestly to increase bone size further, whereas bone remodeling maintains bone strength by removal of microdamage.The concept of peak bone mass more broadly captures peak bone strength, which is characterized by mass, density, microarchitecture, microrepair mechanisms and the geometric properties that provide structural strength. If the magnitude of peak bone mass attained in young adulthood is an important predictor of osteoporosis later in life, then the timing of peak bone mass is also important because it defines the lifecycle phase during which peak bone mass can be optimized Although bone mineral density (BMD) is among the strongest risk factors for fracture, a number of clinical studies have demonstrated the limitations of bone mineral density measurements in assessing fracture risk and monitoring the response to the therapy. These observations have brought renewed attention to the broader array of factors that influence skeletal fragility, including bone size, shape, microarchitecture and bone quality. Bone fragility can be defined by biomechanical parameters, including ultimate force, ultimate displacement and energy absorption.The biomechanical definition of bone fragility includes at least three components: strength, brittleness and work to failure. A fourth biomechanical measure, stiffness, also is used to assess mechanical integrity of bones, but is not a direct measure of fragility. There are at least three ways to make the skeleton stronger. First, increase bone masslarger bones can carry more load. Second, distribute bone mass effectively, i.e. put bone tissue where the mechanical demand are greatest. Third, improve the material properties of bone tissue such that the bone is stronger at a tissue-level.The causes of bone fragility are: abnormal collagen (Osteogenesis imperfecta, Paget's disease of bone), mineralization defect (osteomalacia), abnormal remodeling rate and balance (turnover) [A. High bone turnover with negative BMU balance-postmenopausal osteoporosis, hyperparathyroidism, B. Other abnormalities of bone turnover with negative BMU balance-osteoporosis in men, corticosteroid-induced osteoporosis]The genetic basis of osteoporosis has been difficult to identify. Nevertheless, several approaches have been undertaken in the past decades in order to identify candidate genes for bone fragility, including the study of rare monogenic syndromes with striking phenotypes (Osteogenesis imperfecta and osteopetrosis), the analysis of individuals or families with ext...