The adult skeleton regenerates by temporary cellular structures that comprise teams of juxtaposed osteoclasts and osteoblasts and replace periodically old bone with new. A considerable body of evidence accumulated during the last decade has shown that the rate of genesis of these two highly specialized cell types, as well as the prevalence of their apoptosis, is essential for the maintenance of bone homeostasis; and that common metabolic bone disorders such as osteoporosis result largely from a derangement in the birth or death of these cells. The purpose of this article is 3-fold: 1) to review the role and the molecular mechanism of action of regulatory molecules, such as cytokines and hormones, in osteoclast and osteoblast birth and apoptosis; 2) to review the evidence for the contribution of changes in bone cell birth or death to the pathogenesis of the most common forms of osteoporosis; and 3) to highlight the implications of bone cell birth and death for a better understanding of the mechanism of action and efficacy of present and future pharmacotherapeutic agents for osteoporosis.

/pdf/birth-and-death-of-bone-cells-basic-regulatory-mechanisms-3uf3t3e9wv.pdf

Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis.

Reports linking long-term use of bisphosphonates (BPs) with atypical fractures of the femur led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address key questions related to this problem. A multidisciplinary expert group reviewed pertinent published reports concerning atypical femur fractures, as well as preclinical studies that could provide insight into their pathogenesis. A case definition was developed so that subsequent studies report on the same condition. The task force defined major and minor features of complete and incomplete atypical femoral fractures and recommends that all major features, including their location in the subtrochanteric region and femoral shaft, transverse or short oblique orientation, minimal or no associated trauma, a medial spike when the fracture is complete, and absence of comminution, be present to designate a femoral fracture as atypical. Minor features include their association with cortical thickening, a periosteal reaction of the lateral cortex, prodromal pain, bilaterality, delayed healing, comorbid conditions, and concomitant drug exposures, including BPs, other antiresorptive agents, glucocorticoids, and proton pump inhibitors. Preclinical data evaluating the effects of BPs on collagen cross-linking and maturation, accumulation of microdamage and advanced glycation end products, mineralization, remodeling, vascularity, and angiogenesis lend biologic plausibility to a potential association with long-term BP use. Based on published and unpublished data and the widespread use of BPs, the incidence of atypical femoral fractures associated with BP therapy for osteoporosis appears to be very low, particularly compared with the number of vertebral, hip, and other fractures that are prevented by BPs. Moreover, a causal association between BPs and atypical fractures has not been established. However, recent observations suggest that the risk rises with increasing duration of exposure, and there is concern that lack of awareness and underreporting may mask the true incidence of the problem. Given the relative rarity of atypical femoral fractures, the task force recommends that specific diagnostic and procedural codes be created and that an international registry be established to facilitate studies of the clinical and genetic risk factors and optimal surgical and medical management of these fractures. Physicians and patients should be made aware of the possibility of atypical femoral fractures and of the potential for bilaterality through a change in labeling of BPs. Research directions should include development of animal models, increased surveillance, and additional epidemiologic and clinical data to establish the true incidence of and risk factors for this condition and to inform orthopedic and medical management. © 2010 American Society for Bone and Mineral Research.

https://asbmr.onlinelibrary.wiley.com/doi/pdf/10.1002/jbmr.416

Atypical subtrochanteric and diaphyseal femoral fractures: Report of a task force of the american society for bone and mineral Research

Forces in Joints, Skeletal Biology, Analysis of Bone Remodeling, Mechanical Properties of Bone, Fatigue and Fracture Resistance of Bone, Mechanical Adaptation of the Skeleton, Synovial Joint Mechanics, Mechanical Properties of Ligament and Tendon

Skeletal Tissue Mechanics

Introduction: Reports linking long-term use of bisphosphonates (BPs) with atypical fractures of the femur led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a Task Force to address key questions related to this problem. Methods: A multi-disciplinary expert group reviewed pertinent published reports concerning atypical femur fractures, as well as pre-clinical studies that could provide insight into their pathogenesis. Results and Conclusions: A case definition was developed so that subsequent studies report on the same condition. The Task Force defined major and minor features of complete and incomplete atypical femoral fractures and recommends that all major features, including their location in the subtrochanteric region and femoral shaft, transverse or short oblique orientation, minimal or no associated trauma and absence of comminution, be present to designate a femoral fracture as atypical. Minor features include their associations with cortical thickening, a periosteal reaction of the lateral cortex, a medial spike when the fracture is complete, prodromal pain, bilaterality, comorbid conditions and concomitant drug exposures, including BPs, other antiresorptive agents, glucocorticoids and proton pump inhibitors. Preclinical data evaluating the effects of BPs on collagen cross-linking and maturation, accumulation of microdamage and advanced glycation end-products, mineralization, remodeling, vascularity and angiogenesis, lend biological plausibility to a potential association with long-term BP use. Based on published and unpublished data and the widespread use of BPs, the incidence of atypical femoral fractures associated with BP therapy for osteoporosis appears to be very low, particularly compared to the number of vertebral, hip and other fractures that are prevented by BPs. Moreover, a causal association between BPs and atypical fractures has not been established. However, recent observations suggest that the risk rises with increasing duration of exposure and there is concern that lack of awareness and under-reporting may mask the true incidence of the problem. Recommendations: Given the relative rarity of atypical femoral fractures, the Task Force recommends that specific diagnostic and procedural codes be created and that an international registry be established to facilitate studies of the clinical and genetic risk factors and optimal surgical and medical management of these fractures. Physicians and patients should be made aware of the possibility of atypical femoral fractures and of the potential for bilaterality through a change in labeling of BPs. Research directions should include development of animal models, increased surveillance and additional epidemiological and clinical data to establish the true incidence of and risk factors for this condition and to inform orthopaedic and medical management.

Atypical Subtrochanteric and Diaphyseal Femoral Fractures: Report of a Task Force of the American Society for Bone and Mineral Research Running Title: Atypical Femoral Fractures Task Force Report

Trabecular bone is a complex material with substantial heterogeneity Its elastic and strength properties vary widely across anatomic sites, and with aging and disease Although these properties depend very much on density, the role of architecture and tissue material properties remain uncertain It is interesting that the strains at which the bone fails are almost independent of density Current work addresses the underlying structure-function relations for such behavior, as well as more complex mechanical behavior, such as multiaxial loading, time-dependent failure, and damage accumulation A unique tool for studying such behavior is the microstructural class of finite element models, particularly the "high-resolution" models It is expected that with continued progress in this field, substantial insight will be gained into such important problems as osteoporosis, bone fracture, bone remodeling, and design/analysis of bone-implant systems This article reviews the state of the art in trabecular bone biomechanics, focusing on the mechanical aspects, and attempts to identify important areas of current and future research

Biomechanics of trabecular bone.

Trabecular bone volume and microdamage accumulation in the femoral heads of women with and without femoral neck fractures

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Trabecular bone volume and microdamage accumulation in the femoral heads of women with and without femoral neck fractures