Osteoporosis: Marsh D

Compston J, Cooper A, Cooper C, Francis R, Kanis JA, Marsh D, McCloskey EV, Reid DM, Selby P, Wilkins M, Anonymous00031. · University of Cambridge School of Clinical Medicine, Department of Medicine, Cambridge, United Kingdom. · Maturitas. · Pubmed #19135323 No free full text.

Abstract: In 1999 and 2000 the Royal College of Physicians published guidelines for the prevention and treatment of osteoporosis [Royal College of Physicians. Osteoporosis: clinical guidelines for the prevention and treatment. London: Royal College of Physicians; 1999; Royal College of Physicians and Bone and Tooth Society of Great Britain. Update on pharmacological interventions and an algorithm for management. London, UK: Royal College of Physicians; 2000.; Royal College of Physicians. Glucocorticoid-induced osteoporosis. Guidelines on prevention and treatment; Bone and Tooth Society of Great Britain, National Osteoporosis Society and Royal College of Physicians. London, UK: Royal College of Physicians; 2002]. Since then, there have been significant advances in the field of osteoporosis including the development of new techniques for measuring bone mineral density, improved methods of assessing fracture risk and new treatments that have been shown to significantly reduce the risk of fractures. Against this background, the National Osteoporosis Guideline Group (NOGG), in collaboration with many Societies in the UK, have updated the original guidelines [Royal College of Physicians, National Osteoporosis Guideline Group on behalf of the Bone Research Society, British Geriatrics Society, British Orthopaedic Association, British Society of Rheumatology, National Osteoporosis Society, Osteoporosis 2000, Osteoporosis Dorset, Primary Care Rheumatology Society, Society for Endocrinology. Osteoporosis. Clinical guideline for prevention and treatment, Executive Summary. University of Sheffield Press; 2008], a practical summary of which is detailed below. The management algorithms are underpinned by a health economic analysis applied to the epidemiology of fracture in the UK.

Goldhahn J, Scheele WH, Mitlak BH, Abadie E, Aspenberg P, Augat P, Brandi ML, Burlet N, Chines A, Delmas PD, Dupin-Roger I, Ethgen D, Hanson B, Hartl F, Kanis JA, Kewalramani R, Laslop A, Marsh D, Ormarsdottir S, Rizzoli R, Santora A, Schmidmaier G, Wagener M, Reginster JY. · Schulthess Clinic Zurich and Clinical Priority Program Fracture Fixation in Osteoporotic, Bone of AO Foundation, Davos, Switzerland. · Bone. · Pubmed #18544475 No free full text.

Abstract: Pre-clinical studies indicate that pharmacologic agents can augment fracture union. If these pharmacologic approaches could be translated into clinical benefit and offered to patients with osteoporosis or patients with other risks for impaired fracture union (e.g. in subjects with large defects or open fractures with high complication rate), they could provide an important adjunct to the treatment of fractures. However, widely accepted guidelines are important to encourage the conduct of studies to evaluate bioactive substances, drugs, and new agents that may promote fracture union and subsequent return to normal function. A consensus process was initiated to provide recommendations for the clinical evaluation of potential therapies to augment fracture repair in patients with meta- and diaphyseal fractures. Based on the characteristics of fracture healing and fixation, the following study objectives of a clinical study may be appropriate: a) acceleration of fracture union, b) acceleration of return to normal function and c) reduction of fracture healing complications. The intended goal(s) should determine subsequent study methodology. While an acceleration of return to normal function or a reduction of fracture healing complications in and of themselves may be sufficient primary study endpoints for a phase 3 pivotal study, acceleration of fracture union alone is not. Radiographic evaluation may either occur at multiple time points during the healing process with the aim of measuring the time taken to reach a defined status (e.g. cortical bridging of three cortices or disappearance of fracture lines), or could be obtained at a single pre-determined timepoint, were patients are expected to reach a common clinical milestone (i.e. pain free full weight-bearing in weight-bearing fracture cases). Validated Patient Reported Outcomes (PRO's) measures will need to support the return to normal function co-primary endpoints. If reduction of complication rate (e.g. non-union) is the primary objective, the anticipated complications must be defined in the study protocol, along with their possible associations with the specified fracture type and fixation device. The study design should be randomized, parallel, double-blind, and placebo-controlled, and all fracture subjects should receive a standardized method of fracture fixation, defined as Standard of Care.

Heyburn G, Beringer T, Elliott J, Marsh D. · Fracture Unit, Royal Victoria Hospital, Belfast BT12 6BA, Northern Ireland. · Clin Orthop Relat Res. · Pubmed #15292785 No free full text.

Abstract: How are we to cope with the complex problems that now surround elderly patients with fractures? What are these problems and what systems should be in place to address them? No matter how successful we may be in treatment of osteoporosis and prevention of falls, it is inevitable that a massive worldwide increase in incidence of fragility fractures will occur in the next 50 years. It is crucial that we upgrade our systems to cope with this, if severe disruption of health services is to be avoided. This review considers the topics of falls, osteoporosis, and impact modification. We review the major medical issues that should be addressed in delivering hospital care that is efficient and of high quality. Various models for organizing the necessary liaison between fracture staff and medical or geriatric staff are examined and the current literature regarding orthogeriatric care is reviewed. We propose that the model of continuous orthogeriatric care, as practiced in Belfast, may be the way forward in addressing the complex problems associated with elderly patients with fractures. A system of ongoing audit of treatment outcomes and the journey of care for elderly patients with fractures of the proximal femur is necessary as a monitoring tool in developing the optimal system for orthogeriatric liaison.

McCann RM, Colleary G, Geddis C, Clarke SA, Jordan GR, Dickson GR, Marsh D. · Queen's University Belfast, Division of Surgery and Perioperative Care, Department of Orthopaedic Surgery, Musgrave Park Hospital, Stockman's Lane, Belfast, Ulster BT9 7JB, United Kingdom. · J Orthop Res. · Pubmed #17960650 No free full text.

Abstract: Osteoporosis (OP) is one of the most prevalent bone diseases worldwide with bone fracture the major clinical consequence. The effect of OP on fracture repair is disputed and although it might be expected for fracture repair to be delayed in osteoporotic individuals, a definitive answer to this question still eludes us. The aim of this study was to clarify the effect of osteoporosis in a rodent fracture model. OP was induced in 3-month-old rats (n = 53) by ovariectomy (OVX) followed by an externally fixated, mid-diaphyseal femoral osteotomy at 6 months (OVX group). A further 40 animals underwent a fracture at 6 months (control group). Animals were sacrificed at 1, 2, 4, 6, and 8 weeks postfracture with outcome measures of histology, biomechanical strength testing, pQCT, relative BMD, and motion detection. OVX animals had significantly lower BMD, slower fracture repair (histologically), reduced stiffness in the fractured femora (8 weeks) and strength in the contralateral femora (6 and 8 weeks), increased body weight, and decreased motion. This study has demonstrated that OVX is associated with decrease in BMD (particularly in trabecular bone) and a reduction in the mechanical properties of intact bone and healing fractures. The histological, biomechanical, and radiological measures of union suggest that OVX delayed fracture healing.

Dixon N, Páli T, Kee TP, Ball S, Harrison MA, Findlay JB, Nyman J, Väänänen K, Finbow ME, Marsh D. · University of Leeds, School of Chemistry and School of Biochemistry and Molecular Biology, Leeds, United Kingdom. · Biophys J. · Pubmed #17872954 links to  free full text

Abstract: The osteoclast variant of the vacuolar H(+)-ATPase (V-ATPase) is a potential therapeutic target for combating the excessive bone resorption that is involved in osteoporosis. The most potent in a series of synthetic inhibitors based on 5-(5,6-dichloro-2-indolyl)-2-methoxy-2,4-pentadienamide (INDOL0) has demonstrated specificity for the osteoclast enzyme, over other V-ATPases. Interaction of two nitroxide spin-labeled derivatives (INDOL6 and INDOL5) with the V-ATPase is studied here by using the transport-active 16-kDa proteolipid analog of subunit c from the hepatopancreas of Nephrops norvegicus, in conjunction with electron paramagnetic resonance (EPR) spectroscopy. Analogous experiments are also performed with vacuolar membranes from Saccharomyces cerevisiae, in which subunit c of the V-ATPase is replaced functionally by the Nephrops 16-kDa proteolipid. The INDOL5 derivative is designed to optimize detection of interaction with the V-ATPase by EPR. In membranous preparations of the Nephrops 16-kDa proteolipid, the EPR spectra of INDOL5 contain a motionally restricted component that arises from direct association of the indolyl inhibitor with the transmembrane domain of the proteolipid subunit c. A similar, but considerably smaller, motionally restricted population is detected in the EPR spectra of the INDOL6 derivative in vacuolar membranes, in addition to the larger population from INDOL6 in the fluid bilayer regions of the membrane. The potent classical V-ATPase inhibitor concanamycin A at high concentrations induces motional restriction of INDOL5, which masks the spectral effects of displacement at lower concentrations of concanamycin A. The INDOL6 derivative, which is closest to the parent INDOL0 inhibitor, displays limited subtype specificity for the osteoclast V-ATPase, with an IC(50) in the 10-nanomolar range.

Wright SA, McNally C, Beringer T, Marsh D, Finch MB. · No affiliation provided · Rheumatol Int. · Pubmed #15798908 No free full text.

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