ReviewA reference standard for the description of osteoporosis
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.
Section snippets
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
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”.
There are significant differences in the performance of different techniques at
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
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 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
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 [27], [28], [29], [30], [31]. 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
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 reference 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
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 20–29 years. The NHANES III data are derived using Hologic equipment and appropriate
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 neck,
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
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
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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