Bone 42 (2008) 467 475 www.elsevier.

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Review

A reference standard for the description of osteoporosis

John A. Kanis a,, Eugene V. McCloskey b , Helena Johansson c , Anders Oden c , L. Joseph Melton III d , Nikolai Khaltaev e
a

WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield Medical School, UK b Osteoporosis Centre, Northern General Hospital, Sheffield, UK c Consulting Statistician, Gothenburg, Sweden d Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA e Non-communicable Diseases, WHO, Geneva, Switzerland Received 7 June 2007; revised 31 October 2007; accepted 5 November 2007 Available online 17 November 2007

Abstract In 1994, the World Health Organization published diagnostic criteria for osteoporosis. Since then, many new technologies have been developed for the measurement of bone mineral at multiple skeletal sites. The information provided by each assessment will describe the clinical characteristics, fracture risk and epidemiology of osteoporosis differently. Against this background, there is a need for a reference standard for describing osteoporosis. In the absence of a true gold standard, this paper proposes that the reference standard should be based on bone mineral density (BMD) measurement made at the femoral neck with dual-energy X-ray absorptiometry (DXA). This site has been the most extensively validated, and provides a gradient of fracture risk as high as or higher than that of many other techniques. The recommended reference range is the NHANES III reference database for femoral neck measurements in women aged 2029 years. A similar cut-off value for femoral neck BMD that is used to define osteoporosis in women can be used for the diagnosis of osteoporosis in men namely, a value for BMD 2.5 SD or more below the average for young adult women. The adoption of DXA as a reference standard provides a platform on which the performance characteristics of less well established and new methodologies can be compared. 2007 Elsevier Inc. All rights reserved.
Keywords: Diagnosis of osteoporosis; Bone mineral density; Men; Reference standard; Osteopenia

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . Methods of assessment . . . . . . . . . . . . . . . . . . . Performance characteristics of bone mineral measurements Diagnosis of osteoporosis . . . . . . . . . . . . . . . . . Diagnostic thresholds. . . . . . . . . . . . . . . . . . Choice of reference site and technology . . . . . . . . . . Diagnostic criteria for men . . . . . . . . . . . . . . . . . Diagnostic criteria for non-white women . . . . . . . . . Normative reference ranges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468 468 468 469 470 470 471 471 471

Corresponding author. WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK. Fax: +44 114 285 1813. E-mail address: w.j.pontefract@shef.ac.uk (J.A. Kanis). 8756-3282/$ - see front matter 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.bone.2007.11.001

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Measurement of multiple Osteopenia . . . . . . . Limitations . . . . . . . Acknowledgments. . . . References . . . . . . .

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Introduction The internationally agreed description of osteoporosis is: 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 [1]. This description captures the notion that low bone mass is an important component of the risk of fracture, but that other abnormalities occur in the skeleton that contribute to skeletal fragility. Thus, ideally, clinical assessment of the skeleton should capture all these aspects of fracture risk. At present, however, the assessment of bone mineral is the only aspect that can be readily measured in clinical practice, and it now forms the cornerstone for the general management of osteoporosis. In 1994, the World Health Organization (WHO) published diagnostic criteria for osteoporosis in postmenopausal women, intended primarily for descriptive epidemiology [2,3]. These criteria have since been widely accepted and are commonly used to provide intervention thresholds, treatment and inclusion criteria for drug trials, and a basis for health technology assessments. The strength of these diagnostic categories as a reference standard has been the fashioning of a common approach to describe the disease. Developments since 1994, however, have eroded their value. These include the development of many new technologies for the measurement of bone mineral, the plethora of skeletal sites available for assessment, an increased understanding of osteoporosis in men (not provided for in the WHO reports) and the move towards risk-based assessment. The objectives of bone mineral measurement are to provide diagnostic criteria, prognostic information on the risk of future fractures, and a baseline on which to monitor the natural history of the treated or untreated patient. The multiple sites and technologies available have increased the armamentarium at our disposal for clinical research and for the management of patients. This is important because no one site or technique subserves all the clinical requirements of a bone mineral measurement. For example, even with dual-energy X-ray absorptiometry (DXA), the use of measurements at a single site is problematic. Whereas hip fracture risk is more accurately assessed by DXA at the hip than by DXA at the forearm, measurement at the forearm may detect skeletal losses earlier in secondary causes of osteoporosis than measurements at the spine or hip; neither the hip nor forearm is a particularly responsive site for monitoring of treatment. Thus, each site and technique has its own unique performance characteristics, and the information provided by each will describe the clinical characteristics, fracture risk and epidemiology of osteoporosis differently. Against this background, there is a need for a reference standard for describing osteoporosis. In the absence of

a true gold standard, this paper argues the case that the reference standard should be based on bone mineral density (BMD) measured at the femoral neck. Methods of assessment Bone mineral density is the amount of bone mass per unit volume (volumetric density, g/cm3), or per unit area (areal density, g/cm2), 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 [4]. The most widely used techniques are based on X-ray absorptiometry in bone, particularly DXA, since the absorption of X-rays is very sensitive to the calcium content of tissue, of which bone is the most important source. Other techniques include quantitative ultrasound (QUS), quantitative computed tomography (QCT) applied both to the spine and hip and to the appendicular skeleton (pQCT), peripheral DXA, digital X-ray radiogrammetry, radiographic absorptiometry, and other radiographic techniques. Of these, DXA is the most widely used bone densitometric technique. It is versatile in the sense that it can be used to assess bone mineral content of the whole skeleton as well as specific sites, including those most vulnerable to fracture [5,6,7]. The widespread clinical use of DXA, particularly at the proximal femur and lumbar spine (central DXA), arises from many prospective studies that have documented a strong gradient of risk for fracture prediction. For example, a widely cited meta-analysis [8] indicated that the risk of hip fracture increased 2.6-fold for each standard deviation (SD) decrease in femoral neck BMD. This gradient of risk is as high as or higher than that of many other techniques, and the use of central DXA predicts other types of fracture with as high a gradient of risk as other techniques. The vast amount of information available for central DXA has meant that it has now become the de facto reference standard for assessment of osteoporosis and fracture risk [9,10,11]. The formal adoption of DXA as a reference standard provides a platform on which the performance characteristics of less well established methodologies can be compared as reviewed below. Performance characteristics of bone mineral measurements The performance characteristics of many measurement techniques have been well documented [2,7,8]. For the purpose of risk assessment and for diagnosis, the characteristic of major importance is the ability of a technique to predict future fractures. This is traditionally expressed as the increase in relative risk of fracture per unit SD decrease in bone mineral measurements termed the gradient of risk.

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There are 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 [8]. For example, BMD assessments by DXA to predict hip fracture are better when measurements are made at the hip rather than at the spine or forearm (Table 1). For the prediction of hip fracture, the gradient of risk provided by hip BMD is 2.6, i.e., 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 (3 SD lower than the average for age and sex) would have a 2.63 or greater than 15-fold higher risk than an individual of the same age with an average BMD (Z-score of 0). Where the intention is to predict any osteoporotic fracture, rather than hip fracture alone, the commonly used techniques are comparable: The risk of fracture increases approximately 1.6-fold for each SD decrement in the measurement. Thus, an individual with a measurement of 3 standard deviations below the average value for age would have a 1.63 or greater than 4-fold higher risk than an individual with an average BMD. Note that an individual with an average value for BMD has a lower fracture risk than the risk for the population, since BMD is normally distributed whereas the risk of fracture increases exponentially with decreasing BMD. These considerations indicate the importance of the gradient of risk in evaluating densitometry techniques. Consider, for example, two techniques which at the same site give a gradient for hip fracture risk of 1.6 and 2.6 as mentioned above (Fig. 1). Assume that it might be considered desirable to intervene in individuals with a risk of fracture that was three times that of the average population of the same age. In the former scenario with a gradient of risk of 1.6/SD, almost no patients (0.5% of the population) would exceed this risk and be selected for treatment, but a substantial minority (5%) would be detected using a test with the higher (2.6/SD) gradient of risk. Moreover the relative risk of fracture within the selected population would be higher using the test with the higher gradient of risk (4.9 versus 3.5). The formalisation of the relationship between gradient of risk and the population selected for treatment is discussed elsewhere [12]. A further point of relevance is the level of evidence on which information about the performance characteristics of a given technique has been obtained. The most secure level of evidence comes from population-based prospective studies. Less reliance can be made on retrospective cohort studies and cross-sectional or case-control studies. It is also important to know whether the risk identified by a given technique identifies a risk that is

Fig. 1. Relationship between relative risk of fracture and Z-score with the use of two tests with a gradient of fracture risk of 1.6 or 2.6. The horizontal dashed line is set at an arbitrary treatment threshold (RR = 3). The y-axis gives the Z-score and the proportion (%) of the population. For each test (1.6 and 2.6), the inset gives the Z-score at the intervention threshold, the proportion of the population detected to be at high risk and the average RR in the population detected.

responsive to any intended treatment. The grading of levels of evidence for prognostic risk factors, including BMD, are reviewed elsewhere [4], and the quality of the data for these issues is greatest for DXA. The gradient of risk depends on the technique used, the site measured and the fracture of interest. In general, site-specific measurements show the higher gradients of risk for fractures at their respective sites. For example, measurements at the hip predict hip fracture with greater power than do measurements at the heel, lumbar spine or forearm [8,13]. For other combinations of measurement sites and fractures, gradients of risk range from 1.5 to 3.0 for each SD decrease in bone mineral measurement (see Table 1). The performance characteristics of ultrasound are similar. Most studies suggest that measurements of broadband ultrasound attenuation or speed of sound at the heel are associated with a 1.5- to 2-fold increase in risk for each SD decrease [7]. Comparative studies indicate that these gradients of risk are also very similar to those provided by peripheral assessment of BMD at appendicular sites by absorptiometric techniques to predict any osteoporotic fracture [8,14]. Diagnosis of osteoporosis Total skeletal mass and density remain relatively constant once growth has ceased, until the age of 50 years or so [15]. The distribution of bone mineral content or density in young healthy adults (peak bone mass) is approximately normally distributed, irrespective of the measurement technique used. Because of this normal distribution, bone density values in individuals may be expressed in relation to a reference population in standard deviation units. This reduces the problems associated with differences in calibration between instruments. When SDs are calculated in relation to the mean of a young healthy population, this is referred to as the T-score.

Table 1 Age-adjusted increase in relative risk of specific fractures (with 95% confidence interval) in women for every 1 SD decrease in bone mineral density (by absorptiometry) below the mean value for age (adapted from [8]) Site of measurement Distal radius Femoral neck Lumbar spine Forearm fracture Hip fracture Vertebral fracture 1.7 (1.42.1) 1.8 (1.12.7) 2.3 (1.92.8) All fractures 1.4 (1.31.6) 1.6 (1.41.8) 1.5 (1.41.7)

1.7 (1.42.0) 1.8 (1.42.2) 1.4 (1.41.6) 2.6 (2.03.5) 1.5 (1.31.8) 1.6 (1.22.2)

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J.A. Kanis et al. / Bone 42 (2008) 467475 Table 2 Estimate of the average T-score at the age of 65 in women (from [10] with kind permission from Springer Science and Business Media) Measurement site Spine Spine Heel Spine Forearm Femoral neck Total hip Heel Technique QCT Lateral DXA Achilles DXA DXA DXA DXA Sahara T-score at age 60 years 2.5 2.2 1.5 1.3 1.4 1.2 0.9 0.7

Diagnostic thresholds The following four general descriptive categories are proposed for adult men aged 50 years or more and postmenopausal women using measurements of DXA at the femoral neck. Normal. A value for BMD that is higher than 1 SD below the young adult female reference mean (T-score greater than or equal to 1 SD). Low bone mass (osteopenia). A value for BMD more than 1 SD below the young female adult mean, but less than 2.5 SD below this value (T-score b 1 and N 2.5 SD). Osteoporosis. 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). Severe osteoporosis (established osteoporosis). A value for BMD 2.5 SD or more below the young female adult mean in the presence of 1 or more fragility fractures. The recommended reference range is the Third National Health and Nutrition Examination Survey (NHANES III) reference database for femoral neck measurements in white women aged 2029 years [16,17], as previously recommended by the International Osteoporosis Foundation and the International Society of Clinical Densitometry [9,10]. These diagnostic criteria for osteoporosis are similar to those previously proposed by the WHO in 1994 [2,3], but differ by specifying a reference site (the femoral neck), providing a young normal reference range, and by accommodating diagnostic criteria for non-white women and for men. The reasons for these clarifications are reviewed briefly below. Choice of reference site and technology The original 1994 WHO criteria provided for diagnosis of osteoporosis at the hip, lumbar spine or forearm. With the techniques available for measuring bone mineral at that time, the prevalence of osteoporosis was roughly equal at any one of these

Fig. 2. Bone mineral density T-scores measured at the total hip and lumbar spine in a sequential series of postmenopausal women referred for BMD tests. Despite a significant correlation between measurements at the two sites, the correlation is not sufficiently close to predict one value from another. For example, with a T-score of 0 SD at the spine, the T-score at the hip varied from 1 to +1 SD.

sites, and this sufficed for the descriptive epidemiology of osteoporosis. Since introduction of the WHO working definition of osteoporosis, much attention has focussed on its application to clinical trials and patient care, and several problems have emerged. The first is that a large number of new measurement techniques have been applied to many different skeletal sites. It is now clear that the same T-score derived from different sites and techniques yields different information on the prevalence of osteoporosis and on fracture risk. Reasons relate to differences in the gradient of risk for techniques to predict fracture [10,18], discrepancies in the population SD at different sites and with different equipment [19,20], and differences in the apparent rate of bone loss with age from different skeletal sites [21]. A second problem that arises is that the inter-site correlations, though of statistical significance, are inadequate for predictive purposes (Fig. 2) [14,22,23]. This arises from biological variations that occur in the composition of bone between sites, as well as technical errors of accuracy in the various measurements [10]. For these reasons, it is evident that the T-score cannot be used interchangeably with different techniques and at different skeletal sites. For example, in Caucasian women at the age of 60 years, the T-score may vary from 0.7 to 2.5, depending on the technique used [10,21] (Table 2). These considerations indicate that a reference standard should be adopted in terms of skeletal site and measurement technology. DXA is the most widely available and validated technique. Measurements with DXA at the femoral neck have the highest predictive value for hip fracture, and this has been well established in many prospective studies [8,24]. Moreover, the hip is the site of highest clinical relevance, since hip fracture is the dominant complication of osteoporosis in terms of morbidity and cost [25]. The choice of a reference site holds true in principle for many other multifactorial diseases. For example, in essential hypertension, measurements made at the leg may differ substantially from measurements made at the arm. In the field of osteoporosis, as for hypertension, it is appropriate to select a standardised site for the purposes of diagnosis. There is, however, an argument to be made for using the total hip measurement, since this site has a better reproducibility than measurements made at the femoral neck because a larger area of bone is involved. Reference data are also available for the total hip [17], but the evidence to date does not suggest any improvement in fracture prediction [26]. A similar argument can be raised for the diagnostic use of measurements of BMD at the

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lumbar spine, which are widely used in clinical practice. The principal reason why these still are not considered is that their ability to predict fracture has not been as adequately validated as BMD measurements derived from the femoral neck. Moreover, an important source of accuracy error in lumbar spine BMD is aortic calcification and osteoarthrosis that increase progressively with age. These considerations should not be taken to infer that the use of other techniques or other sites do not have clinical utility for the management of patients where they have been shown to provide information on fracture risk. Diagnostic criteria for men Suitable diagnostic cut-off values for osteoporosis in men are less well defined than those for white women. Many studies that have examined fracture risk in men and women have come to disparate conclusions concerning the relationship between fracture risk and BMD [2731]. There are several reasons for these discrepancies: Firstly, the relation between BMD and fracture risk changes with age [32,33], so that age-adjustment is required. Second, a difference between sexes in the gradient of risk (relative risk per SD decrease in BMD) could be the result of differences in the SD of measurements [34]. Third, data derived from referral populations of osteoporotic men and women are likely to be biased. However, the few studies available show that the risk of hip fracture is similar in men and women for any given absolute value for BMD measured at the hip [24,32,35,36]. Likewise, the risk of vertebral fracture is also similar in men and women for any given BMD [29,37]. These studies indicate that a similar cut-off value for hip BMD that is used in women can be used in the diagnosis of osteoporosis in men namely, a value for BMD 2.5 SD or more below the average for young adult women. If a male reference range was used instead, it would increase the apparent prevalence of osteoporosis in that group. For example, the prevalence of osteoporosis in Swedish men aged 70 years is 7.6%, but increases to 8.6% using male values to derive the diagnostic threshold [38]. Diagnostic criteria for non-white women Within the US the prevalence rates for osteoporosis are 6% for black women and 14% for Mexican Americans compared to 17% in postmenopausal white women when NHANES III refTable 3 Prevalence (%) of osteoporosis at the age intervals shown in Sweden using femalederived reference ranges at the femoral neck ([38], with permission from Elsevier) Age range (years) Men % of population 2.5 3.5 5.8 7.4 7.8 10.3 16.6 6.3 Number affected (000) 7.0 7.6 11.4 14.2 14.6 13.7 14.7 83.2 Women % of population 6.3 9.6 14.3 20.2 27.9 37.5 47.2 21.2 Number affected (000) 17.0 21.1 30.0 43.7 63.0 68.3 67.8 310.9

Table 4 Prevalence (%) of osteoporosis in population-based cohorts from different regions of the world (from [4], with permission) Study Region Age (years) 50 Men EVOS CaMos Rotterdam Dubbo Rochester Hiroshima All cohorts Women EVOS CaMos Rotterdam Dubbo Rochester Hiroshima All cohorts Europe Canada Netherlands Australia USA Japan 0.6 0.5 1.0 0.5 1.0 0.9 0.6 60 1.4 1.5 2.2 1.4 2.0 2.2 1.7 70 3.7 4.3 4.8 4.1 4.1 5.1 4.3 80 9.2 11.6 10.4 11.4 8.2 11.4 10.4 90 21.0 27.9 20.8 28.2 15.7 23.5 22.6

Europe Canada Netherlands Australia USA Japan

3.8 2.9 4.0 3.6 1.9 5.6 3.4

8.5 7.8 9.2 8.8 6.2 10.7 8.5

17.9 19.1 19.8 20.0 18.8 19.5 19.2

33.9 39.8 37.6 39.1 44.8 32.8 37.7

54.6 64.9 59.4 62.2 73.9 49.7 61.3

erence values are used [16]. The use of race-specific reference ranges would minimise the differences in prevalence of osteoporosis among women of different races, in contrast to the marked differences in their fracture risk [39]. Moreover, there is substantial heterogeneity in fracture risk even within populations of a given race or ethnicity, making the use of sex- and racespecific reference ranges even more problematic [40,41]. Consequently, the use of reference ranges in whites in the US accommodates the higher bone mass and lower fracture risk in blacks [16]. Normative reference ranges The prevalence of osteoporosis, as defined by the T-score, depends critically upon the reference range adopted. As noted above, it is suggested that the US reference data generated from the NHANES III study [17] serve as a reference standard for the proximal femur. Thus, the threshold for diagnosing osteoporosis using DXA at the femoral neck is 0.577 g/cm2 derived from the young white female population aged 2029 years. The NHANES III data are derived using Hologic equipment and appropriate standardisation is required with some other densitometers [42]. By this criterion, approximately 10 million men and women over the age of 50 years have osteoporosis in the US. The prevalence of osteoporosis for Sweden using this criterion is shown in Table 3 [38] and for some other regions in Table 4 [4]. Approximately 6% of men and 21% of women aged 5084 years are classified as having osteoporosis. The prevalence of osteoporosis in men over the age of 50 years is about one third that in women [38] comparable to the difference in lifetime risk of an osteoporotic fracture in men and women [2]. In the US, the prevalence of osteoporosis in postmenopausal white women is 17% compared with 21% in the UK and approximately 8% in Canada [43]. These differences may explain in part regional differences in fracture rates, and support the need for a standardised normative reference range.

5054 5559 6064 6569 7074 7579 8084 5080

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J.A. Kanis et al. / Bone 42 (2008) 467475 Table 6 Gradient of risk (with 95% confidence intervals) for each SD decrease in BMD at the femoral neck, lumbar spine or the minimum of the two sites in men and women combined ([58,60] with kind permission from Springer Science and Business Media) Outcome fracture Femoral neck RR Any fracture Any osteoporotic fracture Hip fracture Vertebral fracture a
a

The NHANES III data come from a large study of a representative sample of the US population. The use of this reference population implies that different countries or different races should not utilize their own reference ranges. Normal ranges for DXA are available for many countries including the Netherlands [36,44], the UK [4547], Germany [48], France [22], and several other countries [49], where differences in the mean BMD and the SDs used are relatively small. Differences in BMD in different regions of the world only vary by approximately one SD [50] (Table 5). Such variations in BMD between populations appear to be substantially less therefore than variations in fracture risk. Indeed, age- and sexspecific risks of hip fracture differ more than 10-fold, even within Europe [5154]. These differences are very much larger than can be accounted for by any differences in BMD between communities. In Asia, hip fracture risk is lower than in Northern Europe or the US, but BMD is also lower [50,55,56]. In view of the disparity between population fracture risks and BMD, it is uncertain whether reference ranges drawn from local populations would be of any added value. It would seem appropriate to use the large and adequately sampled NHANES III reference values until further research tempers this view [10]. A caveat, however, is that the same BMD in different geographic locations does not necessarily carry the same risk of fracture. Measurement of multiple skeletal sites A number of investigators favour the concurrent use of BMD at the proximal femur and at the lumbar spine for patient assessment, with patients defined as having osteoporosis on the basis of the lower of two T-scores. For example, the International Society for Clinical Densitometry recommends that patients who have a BMD test receive scans of both the lumbar spine and hip [9,57]. Patients are characterised as having osteoporosis where the T-score is 2.5 SD or less at the spine, femoral
Table 5 Mean (SD) spine and femoral neck BMD (g/cm2) adjusted using linear regression to age 35 years, height 170 cm and weight 70 kg in men, and age 35 years, height 160 cm and weight 60 kg for women Men Spine Mean Ankara Beijing Cape Town Debrecen Manila Moscow Obninsk Santiago Sao Paulo Shanghai Singapore Toronto Zagreb 1.060 1.082 1.077 0.967 1.054 1.067 1.132 1.080 0.957 0.992 1.058 1.062 0.998 SD 0.147 0.128 0.172 0.124 0.144 0.152 0.139 0.137 0.166 0.103 0.148 0.159 0.144 Femoral neck Mean 0.946 0.908 0.898 0.874 0.920 0.969 0.950 0.935 0.852 0.832 0.920 0.882 0.854 SD 0.139 0.121 0.131 0.137 0.134 0.144 0.115 0.128 0.147 0.094 0.133 0.183 0.110 Women Spine Mean 1.037 1.115 1.109 1.033 1.055 1.058 1.085 1.103 0.998 1.000 1.083 1.139 1.042 SD 0.130 0.105 0.150 0.104 0.143 0.136 0.129 0.126 0.151 0.117 0.135 0.148 0.099 Femoral neck Mean 0.872 0.857 0.864 0.818 0.817 0.868 0.849 0.874 0.840 0.793 0.842 0.860 0.850 SD 0.109 0.102 0.115 0.087 0.111 0.131 0.111 0.110 0.142 0.105 0.119 0.123 0.114

Lumbar spine RR 1.42 1.47 1.57 1.84 95% CI 1.351.49 1.381.56 1.361.82 1.192.85

Minimum value RR 1.45 1.55 2.11 1.75 95% CI 1.381.52 1.451.64 1.812.45 1.232.49

95% CI 1.371.51 1.421.61 2.102.87 1.793.42

1.43 1.51 2.45 2.47

Risk ratio (RR) comparing women with and without osteoporosis [60].

Differences between centres are highly significant (p b 0.001 for all) ([49], with permission).

neck, or total hip. This is presumably to increase diagnostic sensitivity, but the combined use of two or more sites does not improve prognostic ability [58]. A recent meta-analysis undertaken on 7 population-based cohorts showed that for the prediction of any osteoporotic fracture, the gradient of risk provided by femoral neck BMD was 1.51/SD. That provided by BMD at the lumbar spine was 1.47/SD, and that provided by the minimum value at either site was 1.55/SD [59]. Thus, using the minimum value does not improve the gradient of risk. The same pertains to the prediction of hip fracture [60] (Table 6). This suggests that there is no diagnostic advantage for combining sites in this way. This view is supported by an independent study of the predictive value of hip, spine or the combination for vertebral fracture risk in the placebo arm of a large multicentre intervention study of vertebral fracture. In this instance, the combined measurements gave lower risk ratios than for measurements either at the lumbar spine or the femoral neck [61]. In a further cross-sectional study, the sensitivity for vertebral fracture was increased using the lowest T-score of each of the four lumbar vertebral bodies assessed rather than the average value of the lumbar spine, but at the expense of reduced specificity [62]. Selection of patients on the basis of a minimum value from 2 or more tests will, however, increase the number of patients selected for treatment. For example, the correlation coefficient between BMD at the lumbar spine and femoral neck was 0.638 in the 19,000 patients assessed in the meta-analysis described in Table 6 [59]. From the correlation coefficient, if 10% of individuals in a population were characterised as having osteoporosis on the basis of BMD at the femoral neck, the prevalence of osteoporosis would increase to 15% with the addition of lumbar spine measurements and taking the minimum value to dichotomise an osteoporotic population. Where 50% of the population are characterised by a single technique to have osteoporosis, the apparent prevalence increases to 64% with the additional measurement. Thus, the sole effect of utilizing this approach is to increase the apparent prevalence of osteoporosis and the cost of patient management, but not to improve fracture prediction. The apparent prevalence would increase still further with the minimum value from multiple sites. The same result can be achieved by using less stringent criteria for the definition of osteoporosis, for example, by defining osteoporosis as a T-score of b 2.0 SD rather than b 2.5 SD. This would undermine, however, the value of a single diagnostic threshold.

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Osteopenia It is recommended that diagnostic criteria be reserved for osteoporosis and that osteopenia (or low bone mass) should not be considered to be a disease category. Provision is still, however, made for the description of osteopenia in epidemiologic studies. The original intention of the WHO was to choose a threshold that would make osteopenia and osteoporosis uncommon at the time of the menopause, on the assumption that bone loss began at that time. It is now evident that bone loss from the proximal femur begins at a much earlier age [63]. If peak bone mass was constant up to the average age of menopause, then the expected frequency of osteopenia would be 16% at the age of 50 years, whereas it is actually much higher. By the age of 50 years, the prevalence of osteopenia is 35.5% in women and 21.8% in men (Table 7) [38]. Nonetheless, the identification of osteopenia will capture the majority of individuals who will develop osteoporosis in the next 10 years [64] in the same sense that prehypertension and prediabetes [65,66] predict an increased risk of hypertension and diabetes, respectively. Limitations There are a number of limitations in the general application of DXA for the diagnosis of osteoporosis which should be recognised [67]. The presence of osteomalacia, a complication of poor nutrition in the elderly, will underestimate total bone mass because of decreased mineralization of bone. Osteoarthrosis at the spine or osteoarthritis at the hip is common in the elderly, and contributes 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 [57]. As mentioned, the DXA image is two dimensional and therefore provides an areal BMD rather than a true volumetric BMD. As a consequence, the computation of BMD is sensitive to changes in bone size. For example, areal bone density will overestimate true volumetric bone density in individuals with large bones. In adults, this error is fortuitously beneficial since larger bones in general also have higher strength. Thus, this error may improve fracture prediction in adults. The clinical consequences of osteoporosis are fragility fractures, the causation of which is multifactorial. This includes
Table 7 The prevalence (%) of osteopenia and the relative risk (RR) of hip fracture compared to the general population at the BMD threshold for osteopenia (T-score =1 SD) at the ages shown in Swedish men and women ([38], with permission from Elsevier) Age (years) 50 55 60 65 70 75 80 Men Prevalence (%) 21.8 24.7 27.6 29.4 33.8 39.1 45.9 RR 1.2 1.1 1.0 0.9 0.8 0.7 0.6 Women Prevalence % 35.5 44.8 49.2 51.8 55.6 64.3 49.5 RR 0.8 0.6 0.5 0.4 0.3 0.2 0.2

factors related to falls as well as additional skeletal factors not captured by BMD, such as the microarchitectural organisation of bone. For example, the incidence of hip fracture increases about 40-fold between the ages of 50 and 80 years in many countries. Over the same interval, BMD decreases. From the change in BMD and the known relationship between BMD and fracture risk, hip fractures would be expected to increase only about 4-fold [38]. Thus, the contribution of BMD to hip fracture risk is a relatively small component of age-dependent risk. The contribution of BMD to other fracture outcomes is even less, because the gradient of risk per SD change is lower than that at the hip for hip fracture prediction. These limitations of BMD indicate that BMD will never discriminate completely between patients who will be or have been fractured from those without fracture. This provides the rationale for incorporating independent clinical risk factors to improve fracture prediction by BMD [4,6871]. Although the sensitivity of BMD for fracture prediction is low over most reasonable assumptions, the specificity is high [69,72]. Thus, many fractures will occur in individuals with BMD values in the normal range, but fracture risk there is quite low. By contrast, fracture risk is very high in individuals with osteoporosis. There is an appropriate analogy with several other multifactorial diseases, such as hypertension and stroke. Hypertension is continuously distributed in the population (as is BMD) and hypertension is an important cause of stroke (high specificity). But many individuals with stroke are normotensive (low sensitivity). There is a growing awareness that treatments should be targeted on the basis of fracture risk rather than solely on the information provided by a BMD test. As mentioned, several clinical risk factors provide information on fracture risk over and above that captured by BMD [4,61,69]. The measurement of risk most suited for their integration is the absolute risk, expressed as the probability of fracture within a given time frame, e.g. the 10year fracture probability in %. Thus, intervention thresholds will be based on fracture risk and differ, therefore, from diagnostic thresholds. In this context, it is relevant to question the need for diagnostic criteria when the field is moving towards risk-based assessment and intervention. These developments will certainly decrease the clinical utility of the T-score, but they will, however, take time to implement into routine clinical practice. Notwithstanding, diagnostic criteria remain of value in quantifying the burden of disease and the development of strategies to combat osteoporosis in the foreseeable future. The present paper updates guidance provided 13 years ago and is likely to change again as the technology improves. The development of new techniques with higher performance characteristics than BMD, or that add significant information to BMD, would be a welcome stimulus to revise the reference standards. Acknowledgments The programme of work has been supported by unrestricted grants from: Alliance for Better Bone Health, Hologic, IGEA, Lilly, Lunar, Merck Research Laboratories, Novartis, Pfizer, Roche, Servier and Wyeth.

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