Quantifying the material and structural determinants of bone strength

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742 is no more that 20%, and around 40–59% for hip fractures. Moreover, no drugs have been shown to reduce the risk of hip fractures in women or men over 75 years of age [2]. In addition, access to and compliance with osteoporosis therapies are poor [3]. Osteoporosis is defined as ‘‘a disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk.’’[4] A fracture occurs when the external force applied to a bone exceeds its strength. For a given loading condition, the ability of a bone to resist fracture depends on the amount of bone, the spatial distribution of the bone mass and the intrinsic properties of the materials that comprise the bone [5]. Presently, diagnosis of osteoporosis is based on measurement of areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry (DXA). While aBMD is a predictor of fracture risk [6], it lacks sensitivity and specificity; most women with osteoporosis do not sustain a fracture and over 50% of women who sustain a fracture do not have osteoporosis [7–9]. Moreover, changes in BMD following therapy explain only 4–30% of the fracture risk reduction [10–13]. These observations have focussed attention on other factors that influence bone strength [14,15] and have motivated development of new technologies to assess these factors. In this review, the general considerations for the non-invasive assessment of the material and structural determinants of bone strength are presented and developments in this area are critically reviewed. The focus of attention here is on technologies that can be applied clinically. Criteria for evaluating new technologies Imaging technologies must be accurate and precise and must have established quality control procedures, standardised data acquisition and analysis, as well as methods for cross-calibration of devices at different clinical centres [16]. Data that help define the clinical utility of a new imaging technique include: (1) sex- and age-specific reference data; (2) assessment of disease severity; (3) associations with fracture risk in untreated subjects; and (4) changes in the measurement with worsening of the disease or with therapeutic intervention. Ultimately, imaging techniques must have clinical utility d they must identify individuals at risk for fracture with high sensitivity, assist in monitoring of therapy and provide potential surrogates for anti-fracture efficacy. The techniques should also provide insights into the pathogenesis of disease. This is a particularly important concern because some techniques rely on models which simplify the structure of bone. As such these simplifications may produce misleading notions regarding the pathogenesis of disease and the effects of treatment. There are many examples of this, and these limitations are discussed in this article. Imaging Techniques M.L. Bouxsein, E. Seeman / Best Practice & Research Clinical Rheumatology 23 (2009) 741–753 Dual-energy X-ray absorptiometry (DXA) and aBMD Introduced about 25 years ago, dual-energy X-ray absorptiometry (DXA) provides a quantitative assessment of mineralised bone mass at the axial and appendicular skeleton in vivo. This technique measures the attenuation of photons of two different energies during radiation transmission. Bone mineral content (BMC, g) and aBMD (g cm –2 ) of a region of interest are obtained. As low aBMD is a strong risk factor for fractures [17], this technique provided the basis for the World Health Organization (WHO)’s guidelines for diagnosis of osteoporosis [18]. Advantages to DXA include a low radiation exposure, excellent precision, low cost, ease of use and short measurement times. However, the measurements are two-dimensional (2D) so larger bones may have higher aBMD than smaller bones because of differences in size [19]; the bone with the lower BMD may not have gained less or lost more bone. DXA also does not distinguish cortical and cancellous bone. Nor do changes in aBMD provide information regarding the morphological basis of that change; aBMD may decrease more in one person than another because resorption from the endosteal envelope is greater and/or periosteal apposition is less. Bone loss may occur mainly from trabecular bone or from the intracortical or endocortical surfaces or from both. DXA cannot assess 3D geometry or trabecular architecture. Furthermore, measurements are subject to artefacts due to degenerative changes such as osteophytes and aortic calcification. Thus,
M.L. Bouxsein, E. Seeman / Best Practice & Research Clinical Rheumatology 23 (2009) 741–753 743 although DXA is currently the gold standard for clinical assessment of fracture risk, its shortcomings are increasingly being recognised. DXA in the assessment of bone structure d hip structural analysis (HSA) Bone geometry, an important determinant of bone strength, has been assessed non-invasively by several methods including radiogrammetry, automated DXA-based analysis of X-ray attenuation profiles (termed ‘hip structural analysis’, HSA) and 3D imaging methods such as computed tomography or magnetic resonance imaging. HSA has been widely used because structural properties can be estimated from routine DXA scans, and the software needed to compute these variables is now provided by several of the DXA manufacturers. HSA uses data from 2D DXA scans to derive measurements of bone geometry at the proximal femur, including the amount and distribution of bone mass, bone morphology and indices of bone strength such as section modulus (an index of resistance to bending), buckling ratio and bone area (an index of resistance to compression) [20]. However, some of these indices are derived under the assumption that the bone cross section is circular at the femoral neck and shaft, and elliptical at the inter-trochanteric region, that the tissue mineral density is constant and that cortical and trabecular bone in the cross section are a constant proportion [21]. Moreover, the method is limited to analyses of a single plane. HSA has been used to examine effects of anti-resorptive and anabolic therapies on femoral geometry [21–25]. However, anti-resorptive therapies increase tissue mineral density [26–29], whereas teriparatide may decrease it [30]. An increase in the amount of mineral per unit bone volume is ‘seen’ by HSA as an increase in the cross-sectional area of bone material, leading an investigator to infer that there has either been periosteal apposition and/or endocortical apposition produced by antiresorptive agents; effects that are not produced by this class of drug. Thus, interpretation of HSA from studies where mineralisation density changes is difficult and suspect. Several studies have used this method to provide information regarding age-, race- and sex-related differences in femoral geometry that may contribute to hip fracture risk [31–39]; effects of physical activity and hormone status on femoral geometry [40,41]; and genetic determinants of femoral structure [42–44]. Because some of the assumptions underlying HSA have not been tested across ages and populations, conclusions from these studies should be viewed with caution. Several prospective studies report that HSA-derived measures of femoral geometry are associated with risk of hip fracture [45–48]. However, it is unclear whether HSA provides information about fracture risk that is independent of BMD. This is likely because femoral BMD and HSA-derived structural properties are highly correlated because the same attenuation profile is used to compute the measurements. Thus, conclusions regarding independent contributions of bone density and geometry to femoral fragility are problematic using HSA. We do not recommend the use of this technique because of the uncertainties and the potentially misleading notions of bone physiology that can arise if the results are accepted on face value. Moreover, other options are available for directly measuring the 3D geometry, such as magnetic resonance imaging (MRI), computed tomography (CT) and high-resolution peripheral quantitative computed tomography (HR-pQCT). These are being used in clinical studies to identify the relationships between geometry, bone density and fracture risk. Quantitative computed tomography (QCT) In QCT, the X-ray source and detector rotate in synchronised fashion around the subject. Algorithms are used to reconstruct the attenuation data into 3D images. Use of a bone mineral (or hydroxyapatite) phantom allows calibration of the data, providing a measurement of bone density that is independent of bone size. The cortical and trabecular compartments are measured separately (Fig. 1). QCT-based bone measurements have been used to evaluate sex-, age- and ethnic-related differences in vertebral and femoral geometry and density, providing insights into the development of skeletal fragility [49– 52]. As the variance in measures of vBMD by QCT are greater than by using DXA, particularly for cancellous bone, changes expressed in percentage terms are greater than changes observed by DXA. Accelerated decrease in trabecular bone is observed with greater decreases in women than men in
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