Bone adapts its mass and architecture in response to its mechanical environment. Yet control of this process by mechanical cues is poorly understood, particularly for unloading. Defining the fundamental mechanoregulation of bone adaptation is critical for the better understanding and mitigation of bone loss in astronauts as well as clinical conditions such as spinal cord injury, stroke, muscular dystrophy, and bed rest. The overall goal of this work was to study skeletal adaptation to varying amounts of reduced loading to help delineate the relationship between mechanical stimuli and skeletal adaptation. We first examined the relative contribution of muscle and gravitational forces to the maintenance of skeletal health in mice, using botulinum toxin (BTX) to induce muscle paralysis and hindlimb unloading to eliminate external loading on the hindlimbs, alone and in combination. BTX led to greater bone loss than hindlimb unloading, while the combination of interventions led to the most detrimental effects overall, suggesting that both muscle and gravitational forces play a role in skeletal maintenance, with greater contributions from muscle forces. We then characterized skeletal adaptation to controlled reductions in mechanical loading of varying degrees employing a novel model that enables long-term exposure of mice to partial weightbearing (PWB). We found that declines in bone mass and architecture were linearly related to the degree of unloading. Even mice bearing 70% of their body weight exhibited significant bone loss, suggesting that the gravity of the moon (0.16 G) and Mars (0.38 G) will not be sufficient to prevent bone loss on future exploration missions. Finally, since bone remodeling is highly site-specific, we used gait analysis and inverse dynamics to determine the mechanical environment during PWB, and then developed a finite element model of the tibia to resolve the local strain-related stimulus proposed to drive changes in bone mass. We found modest correlations between cortical bone architecture at different PWB levels and strain energy density. Altogether this work provides a critical foundation and rationale for future studies that incorporate detailed quantification of the mechanical stimuli and longitudinal changes in bone architecture to further advance our understanding of the skeletal response to reduced loading.
Bones and joints are always under mechanical loading a key concept in understanding bone metabolism. Among the most common diseases of bones and joints in the elderly are osteoporosis and joint osteoarthritis. Dynamic changes in mechanical loading give rise to problems resulting in stenosis of the spinal column at the cervical, thoracic, and lumbar levels. Mechanical loading also accelerates joint destruction caused by inflammation from such conditions as chronic rheumatoid arthritis. An understanding of mechanical loading is essential therefore to clinicians, basic researchers, and engineers working with bones and joints. Providing up-to-date research and clinical findings, the contents of this volume are from the papers, symposia, and special lectures presented at the 12th Annual Meeting of the Orthopaedic Research Meeting of the Japanese Orthopaedic Association in Niigata, in October 1997.
Osteoporosis causes over 2 million skeletal fractures every year in people 50 years of age or older. Fractures predominantly happen at corticocancellous sites, such as the hip and spine. Due to lower accrual of bone mass during growth and rapid bone loss following menopause, 71% of these fractures occur in women. Mechanical loading, which stimulates bone formation, is a potential anabolic therapy for pathological bone loss. Determining the parameters of mechanical loading that stimulate osteogenesis in cancellous bone is critical for harnessing the therapeutic potential of mechanical stimuli. In this thesis, the effects of sex, aging, and estrogen deficiency on the adaptive response of cancellous bone were examined using in vivo tibial compression applied to mice. The effect of sex on the cancellous adaptive response to tibial loading was investigated in growing mice. The magnitude of peak applied loads that corresponded to +1200 [mu][epsilon]at the tibial mid-shaft was determined to be -11.5 N in both males and females from in vivo strain gauging. This peak load resulted in similar peak cancellous tissue strains of ~-2400 [mu][epsilon]in females and ~-2100 [mu][epsilon]. Following 2 weeks of tibial compression, male and female mice increased cancellous bone mass 73% in the proximal tibia, primarily through increased trabecular thickening (+75%). Tissue mineral density increased 18% and trabecular separation decreased 19% as well. As a result of adaptation, the proportion of the applied load carried by the cancellous compartment, rather than by the cortical shell, increased. In addition, the metaphyseal stiffness of the loaded limbs was greater than in control limbs. None of these loadinginduced changes differed by sex. Next, the effect of aging on the cancellous adaptive response was investigated in adult, osteopenic female mice, and this response was compared to that observed previously in growing mice. We applied the same peak compressive loads (-11.3 N) to one group of adult female mice (Load-Matched), which corresponded to +2200 [mu][epsilon]mid-diaphyseal strains and peak cancellous tissue strains of -2257 [mu][epsilon]. We applied the same peak mid-diaphyseal strains (+1200 [mu][epsilon]) to a second group of adult female mice (Strain-Matched), engendered by -5.9 N peak applied load, which corresponded to peak cancellous tissue strains of -1112 [mu][epsilon]. In the LM group, cancellous bone mass increased 49% through increased trabecular thickening (+64%), and cortical mass increased 41% through medullary contraction (-19%). These adaptive changes increased the metaphyseal stiffness of loaded limbs relative to control limbs (IMAX +88%, IMIN +54%). No adaptive response was observed in the SM group. The response in the cancellous compartment was reduced relative to that observed in growing mice. However, tibial loading recovered age-related loss to levels equivalent to control limbs of young animals, supporting the use of mechanical loading as a therapeutic intervention against osteoporotic fractures. In contrast, the response in the cortical compartment was enhanced relative to that in young mice. While both young and adult mice similarly increased IMAX and cortical area, adult mice underwent enhanced medullary contraction. Finally, tibial compression was applied to osteopenic, estrogen-deficient adult female mice to demonstrate that mechanical loading can stimulate cancellous bone formation following estrogen withdrawal. Loading was applied immediately following ovariectomy (OVX) or sham (Sham) surgery and lasted 1, 2, and 6 weeks to characterize the adaptive response over time. Estrogen deficiency did not inhibit the adaptive response of cancellous bone in adult females. After 6 weeks of loading, cancellous bone mass increased similarly in Sham and OVX groups. Cancellous bone mass exhibited a bimodal change with loading due to the different effects of loading and estrogen deficiency, acting at different rates, on cancellous architecture. Loading primarily increased trabecular thickness while estrogen deficiency primarily increased separation. No differences in the control limbs between Sham and OVX groups were observed within the 6 week time period. In summary, tibial compression elicited a robust anabolic response in cancellous bone, which increased mass in growing young male and female mice, and in osteopenic and estrogen deficient adult female mice. Cancellous mass occurred primarily through trabecular thickening and resulted in an overall stiffer tibia metaphysis. Tibial compression recovered age-related bone loss in osteopenic adult female mice to levels equivalent to the control limbs of young mice, even following estrogen withdrawal. These results demonstrate that mechanical loading can be targeted to corticocancellous sites to increase bone mass, improve structural integrity, and reduce risk for fracture. Additionally, these results demonstrate that mechanical loading can be implemented as a preventative measure, either in growing children, or pre- and peri-menopausal women, to increase peak bone mass and reduce risk of fracture.
Bone Repair Biomaterials: Regeneration and Clinical Applications, Second Edition, provides comprehensive reviews on materials science, engineering principles and recent advances. Sections review the fundamentals of bone repair and regeneration, discuss the science and properties of biomaterials used for bone repair, including metals, ceramics, polymers and composites, and discuss clinical applications and considerations, with chapters on such topics as orthopedic surgery, tissue engineering, implant retrieval, and ethics of bone repair biomaterials. This second edition includes more chapters on relevant biomaterials and a greatly expanded section on clinical applications, including bone repair applications in dental surgery, spinal surgery, and maxilo-facial and skull surgery. In addition, the book features coverage of long-term performance and failure of orthopedic devices. It will be an invaluable resource for researchers, scientists and clinicians concerned with the repair and restoration of bone. - Provides a comprehensive review of the materials science, engineering principles and recent advances in this important area - Presents new chapters on Surface coating of titanium, using bone repair materials in dental, spinal and maxilo-facial and skull surgery, and advanced manufacturing/3D printing - Reviews the fundamentals of bone repair and regeneration, addressing social, economic and clinical challenges - Examines the properties of biomaterials used for bone repair, with specific chapters assessing metals, ceramics, polymers and composites
This first-ever Surgeon General's Report on bone health and osteoporosis illustrates the large burden that bone disease places on our Nation and its citizens. Like other chronic diseases that disproportionately affect the elderly, the prevalence of bone disease and fractures is projected to increase markedly as the population ages. If these predictions come true, bone disease and fractures will have a tremendous negative impact on the future well-being of Americans. But as this report makes clear, they need not come true: by working together we can change the picture of aging in America. Osteoporosis, fractures, and other chronic diseases no longer should be thought of as an inevitable part of growing old. By focusing on prevention and lifestyle changes, including physical activity and nutrition, as well as early diagnosis and appropriate treatment, Americans can avoid much of the damaging impact of bone disease and other chronic diseases. This Surgeon General's Report brings together for the first time the scientific evidence related to the prevention, assessment, diagnosis, and treatment of bone disease. More importantly, it provides a framework for moving forward. The report will be another effective tool in educating Americans about how they can promote bone health throughout their lives. This first-ever Surgeon General's Report on bone health and osteoporosis provides much needed information on bone health, an often overlooked aspect of physical health. This report follows in the tradition of previous Surgeon Generals' reports by identifying the relevant scientific data, rigorously evaluating and summarizing the evidence, and determining conclusions.
Every year workers' low-back, hand, and arm problems lead to time away from jobs and reduce the nation's economic productivity. The connection of these problems to workplace activities-from carrying boxes to lifting patients to pounding computer keyboards-is the subject of major disagreements among workers, employers, advocacy groups, and researchers. Musculoskeletal Disorders and the Workplace examines the scientific basis for connecting musculoskeletal disorders with the workplace, considering people, job tasks, and work environments. A multidisciplinary panel draws conclusions about the likelihood of causal links and the effectiveness of various intervention strategies. The panel also offers recommendations for what actions can be considered on the basis of current information and for closing information gaps. This book presents the latest information on the prevalence, incidence, and costs of musculoskeletal disorders and identifies factors that influence injury reporting. It reviews the broad scope of evidence: epidemiological studies of physical and psychosocial variables, basic biology, biomechanics, and physical and behavioral responses to stress. Given the magnitude of the problem-approximately 1 million people miss some work each year-and the current trends in workplace practices, this volume will be a must for advocates for workplace health, policy makers, employers, employees, medical professionals, engineers, lawyers, and labor officials.
Intracellular cell signaling is a well understood process. However, extracellular signals such as hormones, adipokines, cytokines and neurotransmitters are just as important but have been largely ignored in other works. Aimed at medical professionals and pharmaceutical specialists, this book integrates extracellular and intracellular signalling processes and offers a fresh perspective on new drug targets.
The book is a collection of original research and review articles addressing the intriguing field of the cellular and molecular players involved in muscle homeostasis and regeneration. One of the most ambitious aspirations of modern medical science is the possibility of regenerating any damaged part of the body, including skeletal muscle. This desire has prompted clinicians and researchers to search for innovative technologies aimed at replacing organs and tissues that are compromised. In this context, the papers, collected in this book, addressing a specific aspects of muscle homeostasis and regeneration under physiopathologic conditions, will help us to better understand the underlying mechanisms of muscle healing and will help to design more appropriate therapeutic approaches to improve muscle regeneration and to counteract muscle diseases.
