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Oxford, United Kingdom

Reeve J.,Institute of Musculoskeletal Science | Loveridge N.,Orthopaedic Research Unit | Loveridge N.,MRC Human Nutrition Research
Bone | Year: 2014

Every hip fracture begins with a microscopic crack, which enlarges explosively over microseconds. Most hip fractures in the elderly occur on falling from standing height, usually sideways or backwards. The typically moderate level of trauma very rarely causes fracture in younger people. Here, this paradox is traced to the decline of multiple protective mechanisms at many length scales from nanometres to that of the whole femur. With normal ageing, the femoral neck asymmetrically and progressively loses bone tissue precisely where the cortex is already thinnest and is also compressed in a sideways fall. At the microscopic scale of the basic remodelling unit (BMU) that renews bone tissue, increased numbers of actively remodelling BMUs associated with the reduced mechanical loading in a typically inactive old age augments the numbers of mechanical flaws in the structure potentially capable of initiating cracking. Menopause and over-deep osteoclastic resorption are associated with incomplete BMU refilling leading to excessive porosity, cortical thinning and disconnection of trabeculae. In the femoral cortex, replacement of damaged bone or bone containing dead osteocytes is inefficient, impeding the homeostatic mechanisms that match strength to habitual mechanical usage. In consequence the participation of healthy osteocytes in crack-impeding mechanisms is impaired. Observational studies demonstrate that protective crack deflection in the elderly is reduced. At the most microscopic levels attention now centres on the role of tissue ageing, which may alter the relationship between mineral and matrix that optimises the inhibition of crack progression and on the role of osteocyte ageing and death that impedes tissue maintenance and repair. This review examines recent developments in the understanding of why the elderly hip becomes fragile. This growing understanding is suggesting novel testable approaches for reducing risk of hip fracture that might translate into control of the growing worldwide impact of hip fractures on our ageing populations. © 2014 The Authors. Source


Chapman K.,University of Oxford | Chapman K.,Institute of Musculoskeletal Science | Ferreira T.,University of Oxford | Morris A.,University of Oxford | And 2 more authors.
Genetic Epidemiology | Year: 2011

Large-scale meta-analyses of genome-wide association scans (GWAS) have been successful in discovering common risk variants with modest and small effects. The detection of lower frequency signals will undoubtedly require concerted efforts of at least similar scale. We investigate the sample size-dictated power limits of GWAS meta-analyses, in the presence and absence of modest levels of heterogeneity and across a range of different allelic architectures. We find that data combination through large-scale collaboration is vital in the quest for complex trait susceptibility loci, but that effect size heterogeneity across meta-analyzed studies drawn from similar populations does not appear to have a profound effect on sample size requirements. © 2011 Wiley Periodicals, Inc. Source


Brown C.P.,Institute of Musculoskeletal Science
Nature Reviews Rheumatology | Year: 2013

Nanoscience has arrived. Biological applications of nanoscience are particularly prominent and can be useful in a range of disciplines. Advances in nanoscience are underpinning breakthroughs in biomedical research and are beginning to be adopted by the rheumatology and musculoskeletal science communities. Within these fields, nanoscience can be applied to imaging, drug delivery, implant development, regenerative medicine, and the characterization of nanoscale features of cells, matrices and biomaterials. Nanoscience and nanotechnology also provide means by which the interaction of cells with their environment can be studied, thereby increasing the understanding of disease and regenerative processes. Although its potential is clear, nanoscience research tends to be highly technical, generally targeting an audience of physicists, chemists, materials scientists and engineers, and is difficult for a general audience to follow. This Review aims to step back from the most technical aspects of nanoscience and provide a widely accessible view of how it can be applied to advance the field of rheumatology, with an emphasis on technologies that can have an immediate impact on rheumatology and musculoskeletal research. © 2013 Macmillan Publishers Limited. Source


Bala Y.,University of Melbourne | Chapurlat R.,French Institute of Health and Medical Research | Cheung A.M.,A+ Network | Felsenberg D.,Charite - Medical University of Berlin | And 10 more authors.
Journal of Bone and Mineral Research | Year: 2014

During early menopause, steady-state bone remodeling is perturbed; the number of basic multicellular units (BMUs) excavating cavities upon the endosteal surface exceeds the number (generated before menopause) concurrently refilling. Later in menopause, steady-state is restored; the many BMUs generated in early menopause refill as similarly large numbers of BMUs concurrently excavate new cavities. We hypothesized that risedronate reduces the number of cavities excavated. However, in younger postmenopausal women, the fewer cavities excavated will still exceed the fewer BMUs now refilling, so net porosity increases, but less than in controls. In older postmenopausal women, the fewer cavities excavated during treatment will be less than the many (generated during early menopause) now refilling, so net porosity decreases and trabecular volumetric bone mineral density (vBMD) increases. We recruited 324 postmenopausal women in two similarly designed double-blind placebo-controlled studies that included 161 younger (Group 1, ≤ 55 years) and 163 older (Group 2, ≥ 55 years) women randomized 2:1 to risedronate 35 mg/week or placebo. High-resolution peripheral computed tomography was used to image the distal radius and tibia. Cortical porosity was quantified using the StrAx1.0 software. Risedronate reduced serum carboxyterminal cross-linking telopeptide of type 1 bone collagen (CTX-1) and serum amino-terminal propeptide of type 1 procollagen (P1NP) by ∼50%. In the younger group, distal radius compact-appearing cortex porosity increased by 4.2% ± 1.6% (p = 0.01) in controls. This was prevented by risedronate. Trabecular vBMD decreased by 3.6% ± 1.4% (p = 0.02) in controls and decreased by 1.6% ± 0.6% (p = 0.005) in the risedronate-treated group. In the older group, changes did not achieve significance apart from a reduction in compact-appearing cortex porosity in the risedronate-treated group (0.9% ± 0.4%, p = 0.047). No between-group differences reached significance. Results were comparable at the distal tibia. Between-group differences were significant for compact-appearing cortex porosity (p = 0.005). Risedronate slows microstructural deterioration in younger and partly reverses it in older postmenopausal women, features likely to contribute to antifracture efficacy. © 2014 American Society for Bone and Mineral Research. © 2014 American Society for Bone and Mineral Research. Source


Ackermann P.W.,Karolinska University Hospital | Franklin S.L.,Institute of Musculoskeletal Science | Dean B.J.F.,Institute of Musculoskeletal Science | Carr A.J.,Institute of Musculoskeletal Science | And 2 more authors.
Frontiers in Bioscience - Landmark | Year: 2014

The regulatory mechanisms involved in tendon homeostasis and repair are not fully understood. Accumulating data, however, demonstrate that the nervous system, in addition to afferent (sensory) functions, through efferent pathways plays an active role in regulating pain, inflammation, and tissue repair. In normal-, healing- and tendinopathic tendons three neurosignalling pathways consisting of autonomic, sensory and glutamatergic neuromediators have been established. In healthy tendons, neuromediators are found in the paratenon, whereas the proper tendon is practically devoid of nerves, reflecting that normal tendon homeostasis is regulated by pro- and antiinflammatory mediators from the tendon surroundings. During tendon repair, however, there is extensive nerve ingrowth into the tendon proper and subsequent timedependent appearance of sensory, autonomic and glutamatergic mediators, which amplify and fine-tune inflammation and tendon regeneration. In tendinopathy, excessive and protracted sensory and glutamatergic signalling may be involved in inflammatory, painful and hypertrophic tissue reactions. As our understanding of these processes improves, neuronal mediators may prove to be useful in the development of targeted pharmacotherapy and tissue engineering approaches to painful, degenerative and traumatic tendon disorders. Source

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