2012+ESCEO+欧洲绝经后妇女骨质疏松症诊断治疗指南

POSITION PAPER European guidance for the diagnosis and management of osteoporosis in postmenopausal women J. A. Kanis & E. V. McCloskey & H. Johansson & C. Cooper & R. Rizzoli & J.-Y. Reginster & on behalf of the Scientific Advisory Board of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF) Received: 25 June 2012 /Accepted: 25 June 2012 /Published online: 19 October 2012 # International Osteoporosis Foundation and National Osteoporosis Foundation 2012 Abstract Summary Guidance is provided in a European setting on the assessment and treatment of postmenopausal women at risk of fractures due to osteoporosis. Introduction The International Osteoporosis Foundation and European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis published guidance for the diagnosis and management of osteoporosis in 2008. This manuscript updates these in a European setting. Methods Systematic literature reviews. Results The following areas are reviewed: the role of bone mineral density measurement for the diagnosis of osteoporosis and assessment of fracture risk, general and pharmacological management of osteoporosis, monitoring of treatment, assess- ment of fracture risk, case finding strategies, investigation of patients and health economics of treatment. Conclusions A platform is provided on which specific guidelines can be developed for national use. Keywords Bone mineral density . Diagnosis of osteoporosis . Fracture risk assessment . FRAX . Health economics . Treatment of osteoporosis Introduction In 1997, the European Foundation for Osteoporosis and Bone Disease (subsequently the International Osteoporosis Foundation, IOF) published guidelines for the diagnosis and management of osteoporosis [1], subsequently updated in 2008 by the IOF and European Society for Clinical and Economic Evaluation of Osteoporosis and Osteoarthritis (ESCEO) [2]. Since then, there have been significant advan- ces in the field of osteoporosis. These include the develop- ment of new techniques for measuring bone mineral, improved methods of assessing fracture risk and new treat- ments that have been shown to significantly reduce the risk of fractures at vulnerable sites. Against this background, the Scientific Advisory Board of the ESCEO, in collaboration with the IOF, has recognised a need to update the guidance which is detailed below. The high societal and personal J. A. Kanis : E. V. McCloskey :H. Johansson WHO Collaborating Centre, UK University of Sheffield Medical School, Sheffield, UK C. Cooper MRC Lifecourse Epidemiology Unit, University of Southampton and NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK R. Rizzoli University Hospitals and Faculty of Medicine of Geneva, Geneva, Switzerland J.-Y. Reginster Department of Public Health, Epidemiology and Health Economics and HEC School of Management, University of Liège, Liège, Belgium J. A. Kanis (*) WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK e-mail: w.j.pontefract@sheffield.ac.uk Osteoporos Int (2013) 24:23–57 DOI 10.1007/s00198-012-2074-y www.medlive.cn costs of osteoporosis pose challenges to public health and physicians, particularly since most patients with osteoporo- sis remain untreated. Indeed, less than 20 % of patients with a fragility fracture receive therapy to reduce future fracture within the year following fracture [3–5]. The aim of this guidance is to stimulate a cohesive approach to the manage- ment of osteoporosis in Europe. The term guidance rather than guidelines is used, to avoid any prescriptive connota- tions since country- or region-specific guidelines are now widely available in many European countries and continue to evolve. Rather, the guidance can inform the development of new guidelines or the revision of existing guidelines. Whilst focussed on a European perspective and on postmen- opausal women, the principles may be of some assistance in other regions of the world and in men. Osteoporosis in Europe Osteoporosis is defined as a systemic skeletal disease characterised by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture [6]. Al- though the diagnosis of the disease relies on the quan- titative assessment of bone mineral density, which is a major determinant of bone strength, the clinical signifi- cance of osteoporosis lies in the fractures that arise. In this respect, there are some analogies with other multi- factorial chronic diseases. For example, hypertension is diagnosed on the basis of blood pressure whereas an important clinical consequence of hypertension is stroke. Because a variety of non-skeletal factors contribute to fracture risk [7–9], the diagnosis of osteoporosis by the use of bone mineral density (BMD) measurements is at the same time an assessment of a risk factor for the clinical outcome of fracture. For these reasons, there is a distinction to be made between the use of BMD for diagnosis and for risk assessment. Common sites for osteoporotic fracture are the spine, hip, distal forearm and proximal humerus. The remaining life- time probability in women, at menopause, of a fracture at any one of these sites exceeds that of breast cancer (approx- imately 12 %), and the likelihood of a fracture at any of these sites is 40 % or more in Western Europe [10] (Table 1), a figure close to the probability of coronary heart disease. In the year 2000, there were estimated to be 620,000 new fractures at the hip, 574,000 at the forearm, 250,000 at the proximal humerus and 620,000 clinical spine fractures in men and women aged 50 years or more in Europe. These fractures accounted for 34.8 % of such fractures worldwide [11]. Osteoporotic fractures also occur at many other sites including the pelvis, ribs and distal femur and tibia. Collec- tively, all osteoporotic fractures account for 2.7 million fractures in men and women in Europe at a direct cost (2006) of €36 billion [12]. A more recent estimate (for 2010) calculated the direct costs at €29 billion in the five largest EU countries (France, Germany, Italy, Spain and UK) [13] and €38.7 billion in the 27 EU countries [14]. Osteoporotic fractures are a major cause of morbidity in the population. Hip fractures cause acute pain and loss of function, and nearly always lead to hospitalisation. Recov- ery is slow, and rehabilitation is often incomplete, with many patients permanently institutionalised in nursing homes. Vertebral fractures may cause acute pain and loss of function but may also occur without serious symptoms. Vertebral fractures often recur, however, and the consequent disability increases with the number of fractures. Distal radial fractures also lead to acute pain and loss of function, but functional recovery is usually good or excellent. It is widely recognised that osteoporosis and the consequent fractures are associated with increased mortality, with the exception of forearm fractures [15]. In the case of hip fracture, most deaths occur in the first 3–6 months following the event, of which 20–30 % are causally related to the fracture event itself [16]. In Sweden, the number of deaths that are causally related to hip fracture account for more than 1 % of all deaths, somewhat higher than the deaths attributed to pancreatic can- cer and somewhat lower than the deaths attributed to breast cancer [16]. In 2010, the number of deaths causally related to osteoporotic fractures was estimated at 43,000 in the European Union [14]. Approximately 50 % of fracture-related deaths in womenwere due to hip fractures, 28% to clinical vertebral and 22 % to other fractures. In Europe, osteoporosis accounted for more disability and life years lost than rheumatoid arthritis, but less than osteoarthritis. With regard to neoplastic diseases, the burden of osteoporosis was greater than for all sites of cancer, with the exception of lung cancers [11]. Bone mineral measurements The objectives of bone mineral measurements are to provide diagnostic criteria, prognostic information on the probability Table 1 Remaining lifetime probability of a major fracture at the age of 50 and 80 years in men and women from Sweden [10] (with kind permission from Springer Science and Business Media) Site At 50 years At 80 years Men Women Men Women Forearm 4.6 20.8 1.6 8.9 Hip 10.7 22.9 9.1 19.3 Spine 8.3 15.1 4.7 8.7 Humerus 4.1 12.9 2.5 7.7 Any of these 22.4 46.4 15.3 31.7 24 Osteoporos Int (2013) 24:23–57 www.medlive.cn of future fractures and a baseline on which to monitor the natural history of the treated or untreated patient. BMD is the amount of bone mass per unit volume (volumetric den- sity), or per unit area (areal density), and both can be measured in vivo by densitometric techniques. A wide variety of techniques is available to assess bone mineral that are reviewed elsewhere [17–19]. The most widely used are based on X-ray absorptiometry of bone, particularly dual energy X-ray absorptiometry (DXA), since the absorption of X-rays is very sensitive to the calcium content of the tissue of which bone is the most important source. Other techniques include quantitative ultrasound (QUS), quantitative computed tomography (QCT) applied both to the appendicular skeleton and to the spine, periph- eral DXA, digital X-ray radiogrammetry, radiographic absorptiometry, and other radiographic techniques. Other important determinants of bone strength for both cortical and trabecular bone include macro-and microarchitecture (e.g. cross-sectional moment of inertia, hip axis length, cortical thickness, trabecular bone score, Hurst parameters). X-ray-based technology is becoming available to estimate these components of bone strength which may have a future role in fracture risk assessment [20–23]. DXA is the most widely used bone densitometric tech- nique. It is versatile in the sense that it can be used to assess bone mineral density/bone mineral content of the whole skeleton as well as specific sites, including those most vulnerable to fracture [17, 24, 25]. Areal density (in grams per square centimetre) rather than a true volumetric density (in grams per cubic centimetre) is measured since the scan is two dimensional. Areal BMD accounts for about two thirds of the variance of bone strength as determined in vitro on isolated bones, such as the vertebral body or proximal femur. DXA can also be used to visualise lateral images of the spine from T4 to L4 to detect deformities of the vertebral bodies [26–30]. Vertebral fracture assessment (VFA) may improve fracture risk evaluation, since many patients with vertebral fracture may not have a BMD T- score classified as osteoporosis. This procedure involves less radiation and is less expensive than a conventional X-ray examination. Whereas whole body bone, fat and lean mass can also be measured using DXA, these measurements are useful for research; they do not assist in the routine diagnosis or assessment of osteoporosis. The performance characteristics of many measure- ment techniques have been well documented [31, 32]. For the purpose of risk assessment and for diagnosis, a characteristic of major importance is the ability of a technique to predict fractures. This is traditionally expressed as the increase in the relative risk of fracture per standard deviation unit decrease in bone mineral measurement—termed the gradient of risk. Limitations of BMD There are a number of technical limitations in the general application of DXA for diagnosis which should be recog- nised [1, 33]. The presence of osteomalacia, a complication of poor nutrition in the elderly, will underestimate total bone matrix because of decreased mineralization of bone. Osteo- arthrosis or osteoarthritis at the spine or hip are common in the elderly and contribute to the density measurement, but not necessarily to skeletal strength. Heterogeneity of density due to osteoarthrosis, previous fracture or scoliosis can often be detected on the scan and in some cases excluded from the analysis. Some of these problems can be overcome with adequately trained staff and rigorous quality control. Diagnosis of osteoporosis Bone mineral density is most often described as a T- or Z- score, both of which are units of standard deviation (SD). The T-score describes the number of SDs by which the BMD in an individual differs from the mean value expected in young healthy individuals. The operational definition of osteoporosis is based on the T-score for BMD [7, 34] assessed at the femoral neck and is defined as a value for BMD 2.5 SD or more below the young female adult mean (T-score less than or equal to −2.5 SD) [8, 35]. The Z-score describes the number of SDs by which the BMD in an individual differs from the mean value expected for age and sex. It is mostly used in children and adolescents. The reference range recommended by the IOF, ISCD,WHO and NOF for calculating the T-score [8, 36] is the National Health and Nutrition Examination Survey (NHANES) III ref- erence database for femoral neck measurements in Caucasian women aged 20–29 years [37]. Note that the diagnostic criteria for men use the same female reference range as that forwomen. This arises fortuitously because for any age and BMD at the femoral neck, the risk of hip fracture or a major osteoporotic fracture is the same in men and women [38–40]. However, the T-score cannot be used interchangeably with different techni- ques and at different sites, since the prevalence of osteoporosis and proportion of individuals allocated to any diagnostic cat- egory would vary (Table 2), as does the risk of fracture. These considerations have led to the adoption of the femoral neck as the reference site [36], but do not preclude the use of other sites and technologies in clinical practice, though it should be recognised that the information derived from the T-score will differ from that provided by BMD at the femoral neck. Measurement of multiple skeletal sites A number of guidelines favour the concurrent use of BMD at the proximal femur and at the lumbar spine for patient Osteoporos Int (2013) 24:23–57 25 www.medlive.cn assessment. Patients are defined as having osteoporosis on the basis of the lower of two T-scores [41, 42]. The prediction of fracture is, however, not improved overall by the use of multiple sites [43–45]. Selection of patients on the basis of a minimum value from two or more tests will, however, increase the number of patients selected. The same result can be achieved by less stringent criteria for the definition of osteoporosis, by defining osteoporosis, for example, as a T-score of ≤−2.0 SD rather than ≤−2.5 SD. Notwithstanding, the measurement of more than one site can aid in the assessment of individuals (discussed below). Osteopenia It is recommended that diagnostic criteria be reserved for osteoporosis and that osteopenia should not be con- sidered a disease category. Rather, the description of osteopenia is solely intended for purposes of epidemio- logical description. Prevalence of osteoporosis Because the distribution of BMD in the young healthy population is normally distributed and bone loss occurs with advancing age, the prevalence of osteoporosis increases with age. The prevalence of osteoporosis in the largest countries in the EU (Germany, France, Italy, Spain and UK) using the WHO criteria is shown for women in Table 3 [13, 46]. Approximately 21 % of women aged 50–84 years are classified as having oste- oporosis accounting for more than 12 million women in these countries. These data assume that the distribution of femoral neck BMD is the same in these index countries. There may be small differences in the age- and sex-specific BMD in different European countries as well as within countries. If so, these differences in BMD are relatively small and insuf- ficient to account for the observed differences in fracture rates (see below). Risk factors for fracture BMD Assessment of BMD has provided a crucial determinant of fracture risk, and many guidelines have used BMD thresholds to determine whether treatments should be recommended. Intervention thresholds have ranged from T-scores of −3 SD to −1.5 SD depending on the clinical context, the country or health economic factors [1, 47–51]. The use of bone mass measurements for prognosis depends upon accuracy. Accura- cy in this context is the ability of the measurement to predict fracture. In general, all densitometric techniques have high specificity but low sensitivity which varies with the cutoff chosen to designate high risk. At the age of 50 years, for example, the proportion of women with osteoporosis who will fracture their hip, spine, forearm or proximal humerus in the next 10 years (i.e. positive predictive value) is approximately 45 %. Despite this, the overall detection rate for these fractures (sensitivity) is low, and 96 % of fractures at the spine, hip, forearm or proximal humerus will occur in women without osteoporosis [52]. The low sensitivity is one of the reasons why widespread population-based screening with BMD is not widely recom- mended in women at the time of the menopause [7]. Table 2 Estimates of T-scores and the prevalence of osteopo- rosis according to site and tech- nique [36] Measurement site Technique T-score at 60 years WHO classification Prevalence of osteoporosis (%) Spine QCT −2.5 Osteoporosis 50 Spine Lateral DXA −2.2 Low bone mass 38 Spine DXA −1.3 Low bone mass 14 Forearm DXA −1. 4 Low bone mass 12 Heel Achilles −1.5 Low bone mass 11 Total hip DXA −0.9 Normal 6 Heel Sahara −0.7 Normal 3 Table 3 Number (in thousands) of women with osteoporosis accord- ing to age in the EU5 using female-derived reference ranges at the femoral neck [13] Age group (years) France UK Germany Italy Spain EU5 50–54 135 127 192 128 95 695 55–59 200 175 265 180 126 974 60–64 286 276 328 276 175 1,385 65–69 271 308 489 335 215 1,672 70–74 364 365 718 464 270 2,236 75–79 484 411 672 546 368 2,543 80–84 526 417 686 558 357 2,612 50–84 2,266 2,079 3,350 2,487 1,606 12,117 26 Osteoporos Int (2013) 24:23–57 www.medlive.cn Many cross-sectional and prospective population studies indicate that the risk for fracture increases by a factor of 1.5 to 3.0 for each standard deviation decrease in bone mineral density [31]. The ability of bone mineral density to predict fracture is comparable to the use of blood pressure to predict stroke and substantially better than serum cholesterol to predict myocardial infarction [7]. There are, however, significant differences in the performance of different techniques at different skeletal sites. In addition, the performance depends on the type of fracture that one wishes to predict [31, 53]. For example, BMD assessments by DXA to predict hip fracture are more predictive when measurements are made at the hip rather than at the spine or forearm (Table 4). For the prediction of hip fracture, the gradient of risk provided by hip BMD in a meta-analysis is 2.6 [31]. In other words, the fracture risk increases 2.6-fold for each SD decrease in hip BMD. Thus, an individual with a Z-score of −3 at the hip would have a 2.63 or greater than 15-fold higher risk than an individual of the same age with a Z-score of 0. Where the intention is to predict any osteoporotic fracture, the com- monly used techniques are comparable: The risk of fracture increases approximately 1.5-fold for each standard deviation decrease in the measurement so that an individual with a mea- surement of 3 standard deviations below the average value for age would have a 1.53 or greater than 3-fold higher risk than an individual with an average BMD. Note that the risk of fracture in