| 1. |
- Reginster, JY, et al.
(författare)
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Recommendations for an update of the current (2001) regulatory requirements for registration of drugs to be used in the treatment of osteoporosis in postmenopausal women and in men
- 2006
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Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 1433-2965 .- 0937-941X. ; 17:1, s. 41281-41281
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Recent advances in the understanding of the epidemiology of osteoporosis suggest that certain parts of the current European guidelines for the registration of drugs in osteoporosis might be no longer substantiated. The object of this review is to provide the European regulatory authorities with an evidence-based working document providing suggestions for the revision of the "Note for guidance for the approval of drugs to be used in postmenopausal osteoporosis" (CPMP/EWP/552/95). Following an extensive review of the literature (1990-2004), the Group for the Respect of Ethics and Excellence in Science (GREES) organized a workshop including European regulators, academic scientists and representatives of the pharmaceutical industry. The outcomes of this meeting reflect the personal views of those who attended and should not, in any case, be seen as an official position paper of any regulatory agency. The group identified a certain number of points that deserve discussion. They mainly relate to the nature of the indication being granted to new chemical entities (treatment of osteoporosis in women at high risk of fracture instead of prevention and treatment of osteoporosis), the requirements of showing an anti-fracture efficacy on all or on major nonvertebral fractures (instead of the hip), the duration of pivotal trials (2 years instead of 3) and the possibility of considering bridging studies for new routes of administration, new doses or new regimens of previously approved drugs. The group also recommends that an indication could be granted for the treatment of osteoporosis in males on the basis of a placebo-controlled study, with bone mineral density changes after 1 year as the primary endpoint, for medications approved in the treatment of osteoporosis in women at high risk of fractures.
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| 2. |
- Aapro, M, et al.
(författare)
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Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel
- 2008
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Ingår i: Annals of Oncology. - : Elsevier BV. - 1569-8041 .- 0923-7534. ; 19:3, s. 420-432
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Tidskriftsartikel (refereegranskat)abstract
- Bisphosphonates (BP) prevent, reduce, and delay cancer-related skeletal complications in patients, and have substantially decreased the prevalence of such events since their introduction. Today, a broad range of BP with differences in potency, efficacy, dosing, and administration as well as approved indications is available. In addition, results of clinical trials investigating the efficacy of BP in cancer treatment-induced bone loss (CTIBL) have been recently published. The purpose of this paper is to review the current evidence on the use of BP in solid tumours and provide clinical recommendations. An interdisciplinary expert panel of clinical oncologists and of specialists in metabolic bone diseases assessed the widespread evidence and information on the efficacy of BP in the metastatic and nonmetastatic setting, as well as ongoing research on the adjuvant use of BP. Based on available evidence, the panel recommends amino-bisphosphonates for patients with metastatic bone disease from breast cancer and zoledronic acid for patients with other solid tumours as primary disease. Dosing of BP should follow approved indications with adjustments if necessary. While i.v. administration is most often preferable, oral administration (clodronate, IBA) may be considered for breast cancer patients who cannot or do not need to attend regular hospital care. Early-stage cancer patients at risk of developing CTIBL should be considered for preventative BP treatment. The strongest evidence in this setting is now available for ZOL. Overall, BP are well-tolerated, and most common adverse events are influenza-like syndrome, arthralgia, and when used orally, gastrointestinal symptoms. The dose of BP may need to be adapted to renal function and initial creatinine clearance calculation is mandatory according to the panel for use of any BP. Subsequent monitoring is recommended for ZOL and PAM, as described by the regulatory authority guidelines. Patients scheduled to receive BP (mainly every 3-4 weeks i.v.) should have a dental examination and be advised on appropriate measures for reducing the risk of jaw osteonecrosis. BP are well established as supportive therapy to reduce the frequency and severity of skeletal complications in patients with bone metastases from different cancers.
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| 3. |
- Goldhahn, Jörg, et al.
(författare)
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Clinical evaluation of medicinal products for acceleration of fracture healing in patients with osteoporosis
- 2008
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 43:2, s. 343-347
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Tidskriftsartikel (refereegranskat)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. © 2008 Elsevier Inc. All rights reserved.
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| 4. |
- Goldhahn, Jörg, et al.
(författare)
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Critical issues in translational and clinical research for the study of new technologies to enhance bone repair
- 2008
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Ingår i: Journal of Bone and Joint Surgery. American volume. - : Journal of Bone and Joint Surgery. - 0021-9355 .- 1535-1386. ; 90:Supplement 1, s. 43-47
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Tidskriftsartikel (refereegranskat)abstract
- Osteoporosis increases fracture risk, especially in metaphyseal bone. Fractures seriously impair function and quality of life and incur large direct and indirect costs. Although the prevention of fractures is certainly the option, a fast and uneventful healing process is optimal when fractures do occur. Many new therapeutic strategies have been developed to accelerate fracture-healing or to diminish the complication rate during the course of fracture-healing. However, widely accepted guidelines are needed to demonstrate the positive or negative interactions of bioactive substances, drugs, and other agents that are being used to promote fracture-healing. For each study design, the primary study goal should be indicated. Outcome variables should include both objective and subjective parameters. The guidelines should be harmonized between European and American regulatory authorities to ensure comparability of results of studies and to foster global harmonization of regulatory requirements.
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| 5. |
- Janssen, S., et al.
(författare)
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Defining assessment projects and scenarios for policy support: Use of ontology in Integrated Assessment and Modelling
- 2009
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Ingår i: Environmental Modelling & Software. - : Elsevier BV. - 1873-6726 .- 1364-8152. ; 24:12, s. 1491-1500
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Konferensbidrag (refereegranskat)abstract
- Integrated Assessment and Modelling (IAM) provides an interdisciplinary approach to support ex-ante decision-making by combining quantitative models representing different systems and scales into a framework for integrated assessment. Scenarios in IAM are developed in the interaction between scientists and stakeholders to explore possible pathways of future development. As IAM typically combines models from different disciplines, there is a clear need for a consistent definition and implementation of scenarios across models, policy problems and scales. This paper presents such a unified conceptualization for scenario and assessment projects. We demonstrate the use of common ontologies in building this unified conceptualization, e.g. a common ontology on assessment projects and scenarios. The common ontology and the process of ontology engineering are used in a case study, which refers to the development of SEAMLESS-IF, an integrated modelling framework to assess agricultural and environmental policy options as to their contribution to sustainable development. The presented common ontology on assessment projects and scenarios can be reused by IAM consortia and if required, adapted by using the process of ontology engineering as proposed in this paper. (C) 2009 Elsevier Ltd. All rights reserved.
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| 6. |
- Lippuner, K, et al.
(författare)
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FRAX(R) assessment of osteoporotic fracture probability in Switzerland.
- 2009
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Ingår i: Osteoporosis international. - : Springer Science and Business Media LLC. - 1433-2965 .- 0937-941X.
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Tidskriftsartikel (refereegranskat)abstract
- A Swiss-specific FRAX(R) model was developed. Patient profiles at increased probability of fracture beyond currently accepted reimbursement thresholds for bone mineral density (BMD) measurement by dual X-ray absorptiometry (DXA), and osteoporosis treatment were identified. INTRODUCTION: This study aimed to determine which constellations of clinical risk factors, alone, or combined with BMD measurement by DXA, contribute to improved identification of Swiss patients with increased probability of fracture. METHODS: The 10-year probability of hip and any major osteoporotic fracture was computed for both sexes, based on Swiss epidemiological data, integrating fracture risk and death hazard, in relation to validated clinical risk factors, with and without BMD values. RESULTS: Fracture probability increased with age, lower body mass index (BMI), decreasing BMD T-score, and all clinical risk factors used alone or combined. Several constellations of risk factor profiles were identified, indicating identical or higher absolute fracture probability than risk factors currently accepted for DXA reimbursement in Switzerland. With identical sex, age and BMI, subjects with parental history of hip fracture had as high a probability of any major osteoporotic fracture as patients on oral glucocorticoids or with a prevalent fragility fracture. The presence of additional risk factors further increased fracture probability. CONCLUSIONS: The customised FRAX(R) model indicates that a shift from the current DXA-based intervention paradigm, toward a fracture risk continuum based on the 10-year probability of any major osteoporotic fracture may improve identification of patients at increased fracture risk.
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| 7. |
- Lippuner, K, et al.
(författare)
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Remaining lifetime and absolute 10-year probabilities of osteoporotic fracture in Swiss men and women.
- 2009
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Ingår i: Osteoporosis international. - : Springer Science and Business Media LLC. - 1433-2965 .- 0937-941X. ; 20:7, s. 1131-40
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Tidskriftsartikel (refereegranskat)abstract
- SUMMARY: Remaining lifetime and absolute 10-year probabilities for osteoporotic fractures were determined by gender, age, and BMD values. Remaining lifetime probability at age 50 years was 20.2% in men and 51.3% in women and increased with advancing age and decreasing BMD. The study validates the elements required to populate a Swiss-specific FRAX model. INTRODUCTION: Switzerland belongs to high-risk countries for osteoporosis. Based on demographic projections, burden will still increase. We assessed remaining lifetime and absolute 10-year probabilities for osteoporotic fractures by gender, age and BMD in order to populate FRAX algorithm for Switzerland. METHODS: Osteoporotic fracture incidence was determined from national epidemiological data for hospitalised fractured patients from the Swiss Federal Office of Statistics in 2000 and results of a prospective Swiss cohort with almost 5,000 fractured patients in 2006. Validated BMD-associated fracture risk was used together with national death incidence and risk tables to determine remaining lifetime and absolute 10-year fracture probabilities for hip and major osteoporotic (hip, spine, distal radius, proximal humerus) fractures. RESULTS: Major osteoporotic fractures incidence was 773 and 2,078 per 100,000 men and women aged 50 and older. Corresponding remaining lifetime probabilities at age 50 were 20.2% and 51.3%. Hospitalisation for clinical spine, distal radius, and proximal humerus fractures reached 25%, 30% and 50%, respectively. Absolute 10-year probability of osteoporotic fracture increased with advancing age and decreasing BMD and was higher in women than in men. CONCLUSION: This study validates the elements required to populate a Swiss-specific FRAX model, a country at highest risk for osteoporotic fractures.
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| 8. |
- Rizzoli, R, et al.
(författare)
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Risk factors for vitamin D inadequacy among women with osteoporosis : an international epidemiological study
- 2006
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Ingår i: International journal of clinical practice (Esher). - : Hindawi Limited. - 1368-5031 .- 1742-1241. ; 60:8, s. 1013-1019
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Tidskriftsartikel (refereegranskat)abstract
- A serum 25-hydroxyvitamin D [25(OH)D] level of 75 nmol/l (30 ng/ml) has been proposed as the minimum for adequate vitamin D nutrition as lower levels are associated with increases in serum parathyroid hormone in otherwise healthy adults. Amongst 2589 community-dwelling, postmenopausal women with osteoporosis from 18 countries, recruited to determine risk factors for vitamin D inadequacy, 64% had vitamin D inadequacy. General health, education, ethnicity, sun exposure, skin reactivity, diet, recent travel to sunny climates, vitamin D supplementation, body mass index (BMI), season and latitude were assessed using logistic regression models. Asian ethnicity, BMI >= 30 kg/m(2), living in non-equatorial countries, inadequate vitamin D supplementation, poor/fair health, no education about vitamin D, skin reactivity and no recent travel to sunny areas were significant predictors. Several modifiable risk factors are associated with vitamin D inadequacy worldwide, suggesting potentially simple ways to increase vitamin D and improve bone health in postmenopausal women.
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| 9. |
- van der Wal, T., et al.
(författare)
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Trade-offs in the design of cross-disciplinary software systems
- 2005
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Ingår i: MODSIM 2005 - International Congress on Modelling and Simulation : Advances and Applications for Management and Decision Making, Proceedings - Advances and Applications for Management and Decision Making, Proceedings. - 0975840029 - 9780975840023 ; , s. 732-737
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Konferensbidrag (refereegranskat)abstract
- As researchers we are often faced with the difficult and demanding task of preparing models, and their computer implementations, for decision making, or, more recently, for integrated assessment. Such assessment often involves large scale problems, where the decisions to be made can deeply affect the environment, the social context and the economic background of regions and even nations. Yet, we face the grim reality that a model is a focused representation of the world, and it is always a result of several compromises in terms of details and structure, leading to trade-offs in terms of complexity, flexibility and performance. This trade-off becomes an essential design property. We often wish our models to be as simple as possible, balancing transparency, understandability and level of detail. Now, we are involved in the SEAMLESS project, an EU FP6 Integrated Project, aims at generating an integrated framework of computer models. This framework can be used for assessment of how future alternative agricultural and environmental polices affect sustainable development in Europe. Thus, we are designing a cross disciplinary software system to deal with different simulation domains. In this, we need to take care of many differences between the different modeling societies. We decided to apply an architecture centric development method and evaluated this with stakeholders based on a so-called Architecture Trade-off Analysis method. When prioritizing the requirements we used a cost-benefit analysis as a weighting factor for deciding what to do first. Requirements were grouped in user-roles, that appeal to differences in user-interface options. The resulting software architecture identified the necessity to identify two major blocks: the modeling environment, to be used by a number of user roles, mostly modelers and coders, and the processing environment, which is oriented towards the needs of those user roles more focused on system analysis, rather than design and implementation. Another key factor of our architecture is the knowledge base, which provides a common repository for all knowledge, data, model sources which are shared by the two environments. When moving on from architecture to design and implementation, we tried to steer clear of the risk of inventing another modelling framework, and therefore in our prototype we use different existing frameworks for different tasks in the overall design. This means that we discussed the view that 'one tool fixes everything', and we chose to rely on specific frameworks for specific needs. We chose a modelling framework with a track record in crop modeling, to target our biophysical modeling needs, and we selected a de facto standard framework for economic modeling to solve agri-economic modelling problems. All of this comes at a price, that is the extra effort required to integrate different frameworks. We chose therefore to develop an evolution of the OpenMI integration framework to target this issue. In this article we describe all the risks we have identified as associated to our architecture centric approach and how we dealt with them. This article describes the design of the modeling framework for SEAMLESS. A first prototype is ready in January 2006.
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