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SECTION Iv Investigation of Metabolic Diseases (Section Editor: Pierre Delmas)

29. DXA in Adults and Children ...... 152 Judith Adam and Nick Bishop 30. Quantitative Computed Tomography in Children and Adults ...... 158 Claus C. Gliier 31. Magnetic Resonance Imaging of Bone ...... 163 Sharmilla Majumdar 32. Radionuclide Scintigraphy in Metabolic Bone Disease ...... 166 Gopinath Gnanasegarun, Gary J. R. Cook, and Ignac Fogelman 33. Assessment of Fracture Risk ...... 170 John A. Kanis 34. Biochemical Markers of Bone Turnover in Osteoporosis ...... 174 Pawel Szulc and Pierre D. Delmcis 35. Bone Biopsy and Histomorphometry in Clinical Practice 180 Robert R. Recker 36. Vertebral Fracture Assessment ...... 186 Jackie A. Clowes and Richard Eustell 37. Molecular Diagnosis of Bone and Mineral Disorders ...... 193 Robert E Gagel and Gilbert J. Cote

0 2008 American Society for Bone and Mineral Research 151 Chapter 29. DXA in Adults and Children

Judith Adams' and Nick Bishop2 'Manchester Royal Infirmary, Imaging Science and Biomedical Engineering, University of Manchester, Manchester, United Kingdom; 'Academic Unit of Child Health. University of Sheffield, Shefjield Children's Hospital, Sheffield, United Kingdom

INTRODUCTION made in one site what the BMD will be in another site using DXA or other bone densitometry methods.(6) In research The first DXA scanners were introduced in the late 1980s, and studies, BMD measurements in different anatomical sites and DXA is now the most widely used and available bone densi- by various bone density methods (DXA, QCT, and quantita- tometry technique('.2); there are -27,000 central DXA scan- tive ultrasound [QUS]) may be complementary. ners worldwide. Dual-energy X-ray beams are required to cor- With appropriate software, whole body DXA scanning can rect BMD measurements for overlying soft tissue and are be performed, from which is extracted whole body and re- produced by a variety of techniques by different manufactur- gional BMC (g) and whole body and regional body composi- ers, and the energies are selected to optimize separation of tion (lean [muscle] and fat mass; Fig. 2).(2,3) mineralized and soft tissue components of the skeletal site analyzed.") If a single-energy photon beam is used, this is applicable only to peripheral skeletal sites that have to be Precision placed in a water bath to correct for overlying soft tissues. Precision measures the reproducibility of a bone densitom- etry technique and is usually expressed as a CV or standard- Technical Aspects and Developments ized CV (takes into account range of measurement^).('.^' Pre- cision for DXA total hip and lumbar spine DXA = 1-2%; Original DXA scanners used a pencil X-ray beam with a femoral neck and trochanter CV = 2.5%; and Ward's area = single detector, scanning in a rectilinear fashion across the ana- 2.555% (site not applied in clinical practice). In peripheral tomical site (scans times: 5-10 min; spatial resolution = l mm). sites, CV = 1% in the distal forearm, 2.5% in the ultra-distal Technical developments have taken place over recent forearm, and 1.4% in the calcaneus. Measurement sites gen- years,(4.') which include a fan-beam X-ray source and a bank erally used in clinical diagnosis (in contrast to research) are of detectors that enable faster scanning (1 min/site) with im- mean BMD for lumbar spine (L,-L,). femoral neck, and total proved image quality and spatial resolution (0.5 mm). hip"); in hyperparathyroidism (primary or secondary), a fore- arm measurement is relevant, because cortical bone can be lost Scanning Sites and Measurements Provided preferentially from this site. Precision is optimized by using the DXA can be applied to sites of the skeleton at which oste- minimum number of expert, highly motivated, and well- oporotic fractures occur; in the central skeleton, this includes trained technical staff; it is not ideal to have a large number of the lumbar spine (L,-L,; Fig. 1A) and proximal femur (total staff who rotate through different departments and perform hip, femoral neck, trochanter, and Ward's area; Fig. 1B). DXA BMD scanning only infrequently. can also be applied to peripheral skeletal sites (forearm and calcaneus), using either full-sized or dedicated peripheral Accuracy DXA scanners. Central DXA measures of lumbar spine, femo- ral neck, and total hip are currently used as the "gold stan- Accuracy is how close the BMD measured by densitometry dard" for the clinical diagnosis of osteoporosis by bone densi- is to the actual calcium content of the bone (ash weight). The tometry (Figs. 1A and 1B). accuracy of DXA lies in the region of 1&15'/0; the inaccuracies DXA X-ray attenuation values are converted to BMC (8); are related to marrow fat and DXA taking soft tissue as a bone area (BA; cm) is calculated by summing the pixels within reference.(32y)DXA makes some assumptions about body the bone edges (software algorithms detect the bone edges). composition and soft tissues, so inaccuracies may occur with "Areal" BMD (BMD,; g/cm2) is calculated by dividing BMC1 excessively under- or overweight subjects and with large BA.(3-') Because the DXA image is a 2D image of a 3D object, changes in weight between scans, but exactly how this can be the depth of is not taken into account. This fact results corrected for in adults is uncertain. in DXA being size-dependent, one of its significant limitations, particular in children in whom the bones change in size and Sensitivity shape during growth, and in patients whose disease might re- Sensitivity is the ability of the measurement to discriminate sult in small stature or slender bones. between patients with and without fractures and to measure DXA provides BMD, of integral (cortical and trabecular) small changes with time and/or treatment. A statistically sig- (501 bone. The cortical/trabecular ratios vary in different sites nificant change in BMD is calculated as 2.77 multiplied by 50 postero-anterior [PA] lumbar spine; 10190 lateral lumbar precision (CV) at the site of measurement to provide least spine; 60/40 total hip; 80120 total body; 5/95 calcaneus; 9515 significant change (LSC).("" LSC in the spine = 5.3%; total distal radius; 40/60 ultra-distal radius [depending on site of hip = 5.0% and femoral neck = 6.9%. Because changes in region of interest]). Because of the different composition of BMD are generally small, it is essential in an individual patient bones and rates of change in various skeletal sites, measure- to leave an adequate time interval between DXA measures, ments in different sites in the same individual will not give the usually 18-24 mo. same BMD results. Correlations between BMD measurements made in the same patient vary between r = 0.4 and r = 0.9; it is not possible to predict from a DXA BMD measurement Fracture Prediction Because whether a patient develops a fracture depends on Dr. Bishop has consulted for Procter & Gamble, Novartis, Roche. factors in addition to BMD (age, whether the patient falls, the and Alliance for Better Bone Health. Dr. Adams states that she has no nature of the fall, and the patient's response to the fall), it is conflicts of interest. impossible for BMD techniques to completely discriminate be-

152 0 2008 American Society for Bone and Mineral Research DXA IN ADULTSAND CHILDRENI 153

FIG. 1. (A) DXA of normal lumbar spine L,-L,. Re- sults are generally expressed as a mean “areal” density (BMD,; g/cm2) for all four vertebrae. (B) DXA of left hip; although BMD, is provided in a number of different sites (femoral neck, oblong box; Ward‘s area, small box; tro- chanter; and total hip). for clinical diagnosis of osteopo- rosis (WHO T-score at or below -2.5), femoral neck and A B total hip are used. tween those with and without fractures. However, the lower in the path of the X-ray beam will contribute to measured the DXA BMD, the more at risk the patient is of suffering a BMD. If there is degenerative disc disease with osteophytes, fracture.‘”) DXA BMD measurements made in any skeletal osteoarthritis with hyperostosis of facet , or vertebral site (central and peripheral) are predictive of fracture, with the fracture (same amount of calcium before fracture contained in risk of fracture increased in individuals with the lower BMD. The relative risk (RR) of fracture per 1 SD decrease in BMD below the age-adjusted mean varies between 1.4 and 2.6.‘“’ This reduction in BMD in predicting fracture is as good as a rise of 1 SD in blood pressure is in predicting stroke and a 1 SD rise in cholesterol is in predicting myocardial infarction. Site- specific measurements are best in predicting fracture in that particular anatomical place. Radiation Doses DXA involves very low radiation doses (pDXA: calcaneus, 0.03 pSv; forearm, 0.5 pSv; spine, 24pSv; femur, 2-5 pSv; whole body, 1-3 pSv) that are similar to those of natural back- ground radiation (2400 pSv/yr; -7 pSv/d).(’2,13) Clinical Applications There has been much debate concerning the appropriate use of bone densitometry, particularly in population screening in women at menopause, and the cost-effectiveness of such a program has not been established. However, there is consensus that central DXA bone densitometry is the “gold standard” measurement to make in appropriate individuals to assess frac- ture risk and make the diagnosis of osteoporosis in terms of bone den~itometry.(’”~’Bone densitometry has high specific- ity but low sensitivity. Selection of patients who would most appropriately be referred for DXA bone densitometry is based on a case-finding strategy in those who have had a fragility (low-trauma) fracture or have other strong risk factors (estro- gen/testosterone deficiency, primary hypogonadism, height loss, low trauma fractures, radiographic osteopenia, oral glu- cocorticoid therapy [prednisolone > 7.5 mg/d for >3 mo], rheu- matoid arthritis, and other secondary causes of osteoporosis). There may be national differences in such referral guidelines based on local reimbursement policies and economic con- straints. Artefacts FIG. 2. Whole body DXA (in a child) is obtained in -1 min on fan These can cause inaccuracies in DXA and are most common beam scanners and provides total and regional information about the in the lumbar spine in the elderly population. All the calcium skeleton (less head) and body composition (lean muscle and fat mass).

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plies such normal reference databases. These databases are predominantly, but not exclusively, drawn from a white Overestimation of BMD American-based population. There is a paucity of appropriate Spinal degeneration and hyperostosis (osteophytes) reference ranges for children and certain ethnic minorities Vertebral fracture (e.g., Asians). A patient's results can be interpreted in terms of Extraneous calcification (lymph nodes, aortic calcification) the SD from the mean of either sex-matched peak bone mass Overlying metal (navel rings, surgical rodsiplates, Myodil) (PBM; T-score) or age-matched BMD (Z-score). Sclerotic metastases Vertebral hemangioma The World Health Organization (WHO) has defined oste- Ankylosing spondylitis with paravertebral ossification oporosis in terms of bone densitometry as a T-score at or Poor positioning of femoral neck (inadequate internal rotation) below -2.5 in the lumbar spine, femoral neck, and total fe- Excessive body weight m~r.''~)The definition applies to DXA of lumbar spine, proxi- Strontium ranelate therapy mal femur (femoral neck), and the distal third of the forearm Underestimation of BMD but not to other techniques (e.5.. QCT: QUS) or other ana- Laminectomy tomical sites (e.g., caIcaneus),(l8 nor IS it yet confirmed to be Lytic metastases applicable to younger women and men. Until PBM has been Low body weight reached (i.c., in children and young adults up to -20 yr), in- Other terpretation can be made only by comparison with age- DXA will not differentiate low calcium content in bone being matched mean (Z-score).'1y-2'' Variations in the mean and SD caused by osteoporosis (reduced amount of bone; quantitative of reference ranges may alter the number of patients identified abnormality) and osteomalacia (reduced calcium/osteoid ratio: as osteoporotic; in DXA of the hip, use of the NHANES ref- qualitative abnormality) erence database is preferred for whites.'2') Although there is consensus on the definition of osteoporo- sis in bone densitometry (WHO T-score below -2.5), there is as yet no consensus on levels of BMD that justify therapeutic which is reduced in area) present, BMD will be falsely interventions that are cost-effective. This is perhaps not sur- elevated.'") Other etiologies can also cause false elevation or prising, because it is the individual patient that is being treated underestimation of BMD measured by DXA (Table 1; Figs. and not the BMD result, and age is a strong independent pre- 3A and 3B): it is essential that DXA images be scrutinized for dictor of fracture. Other factors (e.g., age, previous low trauma such artefacts. Vertebra affected significantly by artefact fracture over age SO, parental hip fracture, glucocorticoid should be excluded from analysis; however, for clinical diag- therapy, rheumatoid arthritis, smoking, alcohol consumption) nosis, a minimum of two vertebrae must be available for analy- contribute to prediction of fracture risk. The WHO has re- sis. Strontium ranelate is a relatively new oral therapy for os- cently published algorithms for calculating 10-yr fracture risk teoporosis; some of the apparent increase in BMD is for patients from such clinical risk factors that will make the artefactual, related to the high atomic number of strontium decision to instigate therapy more c~st-effective.''~) that accumulates in bone and contributes to X-ray attenuation; methods to correct for this have been proposed.'") It is im- portant to note that DXA will not differentiate low calcium Monitoring Change in BMD content in bone being caused by osteoporosis (reduced amount Whether DXA should be used to monitor change in BMD of bone; quantitative abnormality) and osteomalacia (reduced with time and therapy is contentious and varies between dif- calcium/osteoid ratio; qualitative abnormality). ferent countries and their guidelines. In calculating change To overcome the problems of degenerative disc disease and over time, the absolute BMD values (g/cm2) should be used; hyperostosis in PA DXA of the spine, lateral DXA has been statistically significant change is 2.77 x CV%. In longitudinal developed. On scanners with "C" arms, lateral scanning can be studies in an individual patient, an adequate interval of time performed with the patient remaining in the supine position: (18-24 mo) between measures is required to show significant otherwise, the patient has to be repositioned in the lateral change, unless large changes in BMD are anticipated (e.g., decubitus position, which limits its clinical practicality and pre- after organ transplantation together with large doses of gluco- cision (CV = 2.8-5.9% in lateral decubitus position, 1.6-2% in corticoids).("" L, L, the supine position). Because and may have ribs super- Different manufacturers use different edge detection algo- imposed and L, is overlain by the iliac crest, L, may be the rithms and analyze different regions of interest (ROIs) for only vertebra that can be analyzed in lateral DXA. Therefore, analysis in the hip, so results from different scanners are not although lateral DXA may be a more sensitive predictor of interchangeable. In longitudinal studies, it is vital to use the vertebral fracture than PA spinal DXA, its limited precision same scanner and software program. With technical develop- and impracticality means that it is not often performed in clini- ments, it may become necessary to replace a scanner. To cross- cal practice. calibrate between the old and new scanner, scanning patients Because of these artefacts on PA DXA of lumbar spine, it (-100. with a spread of BMD from high to low) and phantoms has been suggested that, in the elderly population (>65 yr of (scanner manufacturer or European Spine Phantom) will gen- age), only the proximal femur (femoral neck, total hip) should erally allow the required calculations to be be scanned. However, monitoring change is performed opti- mally in the lumbar spine if there are no artefacts.'") Research Application Interpretation There are other scanning capabilities on central DXA scan- When a BMD measurement has been made, this has to be ners, which currently remain as research applications. These interpreted as normal or abnormal and a report must be for- include whole body scanning for total and regional BMC, lean mulated that will be of assistance to the referring clinician.'16' muscle, and fat mass (Fig. 2) in adults, children, and neo- For this, it is essential that age-, sex-, and ethnically matched nate~."~'Software programs are available for measuring BMD reference data are available. The scanner manufacturer sup- around prostheses after hip and knee , in bone

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FIG. 3. Artefacts on DXA. (A) Lumbar spine verte- bral fracture of L, and L,. BMD at these levels will be falsely elevated (same BMC as nonfractured vertebra but in a smaller projected area. giving higher apparent BMD). (B) Laminectomy L,. Removal of the laminae and spinous process will falsely reduce the BMD of this vertebra. DXA images must be carefully scruti- nized for such artefacts, and affected vertebra should be excluded from analysis. A minimum of two verte- A B brae are required for classificationhnterpretation. specimens and small animals, and application in novel ana- and avoiding problems of the divergent X-ray beam of radi- tomical sites (hand, mandible).(27-2y)Although there may be ography that can distort vertebral shape causing apparent bi- no specific commercial software program available for scan- concavity of endplates-DXA uses a lateral scan projection ning such sites, programs for scanning conventional sites (e.g., method. with simultaneous movement of X-ray source and forearm) can be used, with analysis being performed by hand- detectors along the spine, so the X-ray beam is always parallel placed ROIs; these would not be as precise as automated to the vertebral endplates and avoids the “bean can” artefact ROIs. of vertebral endplates caused by the parallax effect on radio- Anatomical measurements can also be derived from DXA. graphs. Guidelines suggest that elderly patients (women >70 The hip axis length (HAL) has been found to be predictive of yr; men >80 yr) who have low BMD with historical height loss hip fracture; normal HAL in postmenopausal women is 10.5 f of 4 cm (1.6 in) in women (6 cm; 2.4 in in men) or prospective 0.62 cm; HAL of 11.0 cm increased hip fracture 2-fold, and height loss of >2 cm (0.8 in) in women (3 cm; 1.2 in in men) and HAL of 11.5 cm increased the risk 4-f0ld.(~~)’HAL is the dis- other risk factors should undergo vertebral fracture assessment tance from the inner margin of the bony pelvis to the lateral using lateral vertebral assessment (LVA) or instantaneous ver- border of the femur along a line drawn through the midline of tebral assessment (IVA) by DXA to detect vertebral frac- the femoral neck and parallel to its margins. There will be tures.(2’)The method has been shown to be satisfactory for some magnification of the hip geometry with fan-beam scan- excluding vertebral fractures being present.““’ However, more ners, so that corrections have to be applied. Structural compo- scientific studies are required to confirm the exact clinical role nents of the proximal femur (size and shape), in combination of this alternative technology to conventional spinal radiogra- with BMD, have been found to improve fracture risk predic- phy for the identification of vertebral fractures. tion.(”) Hip structure analysis (HSA) has been introduced to extract geometric strength information from hip DXA, by DXA IN CHILDREN making mathematical calculations of the distribution of cal- cium in DXA cross-sections in the femoral neck, trochanteric The purpose of any assessment of bone size or mass in chil- region, and proximal femoral shaft(”) and has been applied dren is to provide data relevant to the current, or future, health retrospectively in several large research studies. Its application of the skeleton. DXA is the most widely used quantitative in clinical practice is still to be defined. bone imaging technique in pediatric practice, but many aspects of its use, and the interpretation of the data obtained, remain contentious,(1 ‘)-22.37.38) Vertebral Fracture Assessment DXA provides estimates of bone size in two dimensions and Lateral views of thoracic and lumbar spine (T4-L4) can be bone mass within that envelope, the value of bone mass ad- obtained with fan-beam scanners, using dual- or single-energy justed for size being BMD, (g/cm2). To overcome this limita- scanning, with the patient either in the supine (“C” arm scan- tion to some extent, a “calculated volumetric BMD” (bone ners) or lateral decubitus position (Fig. 4). From these, a visual mineral apparent density [BMAD; g/cm”]) can be made in the assessment for vertebral fractures or morphometric assessment spine and femoral Although in adult practice there of vertebral shape can be Such morphometric is general acceptance that DXA BMD below certain absolute analysis has the potential for automation by application of values are associated with increased fracture risk, there is no computer analysis techniques (e.g., active shape and appear- such absolute threshold for children. The fact that this is re- ance models) that may potentially make them more practical flected in manufacturer-provided reference values for BMD,, for use in a clinical setting.‘”) Vertebral fracture assessment which increase in a similar way to height and weight during (VFA) has several advantages over conventional radiography: childhood and adolescence, clearly indicate that DXA is not lower dose of ionizing radiation (12 ~SVsingle energy; 42 pSv) measuring true volumetric BMD, but some composite measure

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FIG. 4. VFA can be made on DXA scanners on (A) single-energy and (B) dual-energy images (grade 3 severe crush fracture of Tx) at much lower radiations doses (li 100th to l/SOth) than in conventional spinal radiographs; some of the thoracic vertebrae are better visualized on dual, than on single, energy images. Six-point morphom- etry (MXA) and visual assessment of the vertebrae can be made. Aortic calcification can also be visualized and A B graded. of bone size and mass. This is not necessarily a disadvantage tation; and thalassemia major. Other requests come when a because bone size, especially in the tubular bones that children child has recurrent fractures in the absence of an obvious un- are most prone to fracture, is an important predictor of bone derlying predisposition. strength. In children, when should a DXA scan be performed and Advantages of DXA in children are short scan time, low should it be repeated? Although there are many studies using radiation dose, and general widespread availability. DXA DXA to show efficacy of a specific intervention in children, measures of bone mass in healthy children are predictive of little has been published about the practical application of fracture risk both at the measurement site (in the forearm) and DXA in the clinical setting. It can be reasonably assumed that elsewhere; total body less head (TBLH; Fig. 2) BMC, adjusted a DXA would be only part of an assessment of bone health and for weight, height, and bone area, is the measure that has been would be undertaken either because of a perceived increase in found, in a prospective cohort study at age 9.9 yr, to be most fracture risk or because of bone disease. strongly associated with fracture risk over the following 2 Measurement sites for DXA in children are typically the yr.(42)However, there are no data for the predictive value of lumbar spine (L,-L4) and total body, where precision is similar DXA at other ages in apparently healthy children and no simi- to that achieved in adults. Forearm and proximal femur have lar data for children with bone disease. been used in some studies, as has the lateral distal femur where Children are a difficult group to study, because as they grow, deformity and contracture preclude use of DXA in the normal their bone mass should increase. They also fracture fre- measurement sites. Normative reference data are available for quently-by the end of teenage years, up to one half of all boys spine, femoral neck, total body, and lateral distal fem~r.(~'.~') and one third of girls will have sustained a fra~ture.(~~.~~'A T-scores must not be used in children who have not yet single fracture in an otherwise healthy child should not there- reached PBM; measurements are usually reported as sex spe- fore require study of skeletal health. Most requests for DXA in cific and in relation to age (Z-score; at or below -2.0 being children will be in the groups thought to be at increased risk of reduced in children who are normal in size for their age). The fracture. These include children with primary bone diseases diagnosis of osteoporosis in children should not be made on such as osteogenesis imperfecta and idiopathic juvenile osteo- the basis of densitometric criteria alone. Terminology such as porosis; chronic immobilization (cerebral palsy and Duchenne "low BMD for chronological age" may be used if the Z-score dystrophy); inflammatory conditions (Crohn's disease, cystic is below -2.0; terms such as osteoporosis and osteopenia fibrosis, and juvenile idiopathic arthritis); endocrine disorders should not be ~sed."~.~')Adjustments have been made in re- such as anorexia nervosa and Cushing's syndrome (but not search studies in healthy children to account for the assumed Turner's syndrome); after chemotherapy or organ transplan- shape of vertebrae (cylindrical, cuboidal) and the femoral

0 2008 American Society for Bone and Mineral Research DXA IN ADULTSAND CHILDRENI 157 neck,(3y-41) and some reference data using these have been REFERENCES published‘45’ or the expected relationship of bone size and 1. Blake GM. Fogelman I2007 The role of DXA bone density scans mass with body size or elements of body composition such as in the diagnosis and treatment of osteoporosis. Postgrad Med J lean body Some of the current generation of scan- 83:509-5 17. ners provide methods of adjusting for body size at both the 2. Adams JE 2008 Dual energy X-ray absorptiometry. In: Grampp S spine and total body, but there is a lack of information cur- (ed.) Radiology of Osteoporosis, 2nd ed. Springer-Verlag. Berlin, rently as to which adjustment (if any) should be used in clinical Germany, pp. 105-124. 3. Blake CM. Wahner HW, Fogelman I (eds.) 1999 The Evaluation practice. In some studies, adjustment for bone age or pubertal of Osteoporosis: Dual Energy X-ray Absorptiometry and Ultra- status has been undertaken, but estimation of bone age is a sound in Clinical Practice. Martin Dunitz, London, UK. specialized technique, and there is more than one method of 4. Engelke K, Gluer CC 2006 Quality and performance measures in assessment in common use. There is a lack of data for ethnic bone densitometry: Part 1: Errors and diagnosis. Osteoporos Int subgroups. It is unclear from the published data whether any 17:1283-1292. 3. Fogelman I, Blake GM 2005 Bone densitometry; and update. Lan- one of the proposed adjustments is optimal in terms of either cet 366:2068-2070. fracture prediction or skeletal health assessment. 6. Grampp S. Genant HK, Mathur A, Lang P, Jergas M, Takada M. In diseases in childhood in which fracture risk is increased, Gluer CC. Lu Y, Chavez M 1997 Comparisons of non-invasive initiation of DXA BMD should be at the discretion of the bone mineral measurements in assessing age-related loss, fracture discrimination and diagnostic classification. J Bone Miner Res treating clinician, and the monitoring interval should reflect 12:697-7 I I. the severity of the disease. There is little evidence to support 7. Gluer CC, Blake G, Blunt BA, Jergas M, Genant HK 1995 Accu- monitoring at intervals of <6 mo in any setting. Although there rate assessment of precision errors: How to measure the repro- is increased risk of fracture for children receiving glucocorti- ducibility of bone densitometry techniques. Osteoporos Int 5:262- coid therapy, it is difficult to disentangle the effects of these 270. 8. Kanis JA, Gluer C for the Committee of the Scientific Advisors, from those of the underlying bone disease. Currently it does International Osteoporosis Foundation 2000 An update in the di- not seem appropriate that DXA should be any more frequent agnosis and assessment of osteoporosis with densitometry. Osteo- in children receiving such therapy. poros Int 11:192-202. Interpretation of DXA results depends on the clinical con- 9. Blake GM, Fogelman I 2008 How important are BMD accuracy errors for the clinical interpretation of DXA scans? J Bone Miner text. A diagnosis of osteoporosis should not be made on the Rcs 23:457-462. basis of a bone mass measurement in isolation. If a child 10. Gluer CC 1999 Monitoring skeletal changes by radiological tech- presents with recurrent fractures but no clinically apparent niques. J Bone Miner Res 14:1952-1962. underlying disease and bone mass is within the expected range, 11. Marshall D, Johncll 0. Wedel H 1996 Meta-analysis of how well reassurance can be offered. If there is an underlying problem, measures of bone density predict occurrence of osteoporotic frac- tures. BMJ 312:1254-1259. further monitoring and additional imaging may be required. 12. Kalender WA 1992 Effective dose values in bone mineral mea- Such a clinical setting would be a child with apparently mild surements by photon absorptiometry and computed tomography. osteogenesis imperfecta with bone mass in the normal range Ostcoporos Int 2:82-87. who may have occult fractures of thoracic vertebrae. Low bone 13. Blake GM, Naeem M, Boutros M 2006 Comparison of effective mass in the presence of vertebral, or recurrent, fractures re- dose to children and adults from dual energy X-ray absorptiom- etry examinations. Bone 38:935-942. sulting in loss of independent mobility and chronic bone pain 14. Compston J 2005 Guidelines for the management of osteoporosis: should prompt evaluation of the need for active intervention. The present and the future. Osteoporos Int 16:1173-1176. 15. Blake GM. Fogelman I 2007 The correction of BMD measure- ments for bone strontium content. J Clin Densitom 10:259-265. CONCLUSIONS 16. Miller P, Bonnick SL, Rosen CJ 1996 Consensus of an interna- tional panel on the clinical utility of bone mass measurements in DXA offers a precise technique, with acceptable accuracy, the detection of low bone mass in the adult population. Calcif for measuring BMD in central and peripheral skeletal sites in Tissue Int 58:207-214. adults and children, using very low doses of radiation (similar 17. World Health Organization Study Group 1994 Assessment of to levels of natural background radiation). DXA is currently Fracture Risk and Its Application to Screening for Postmeno- pausal Osteoporosis. World Health Organization. Geneva. Swit- regarded as the “gold standard” for BMD measurements for zerland. the diagnosis of osteoporosis in adults. However, there are 18. Miller P 2000 Controversies in bone mineral densitvII diagnostic some important limitations (BMD,, size dependency, mea- classification. Calcif Tissue Int 66:317-319. surement of integral [cortical and trabecular] bone), of which 19. National Osteoporosis Society 2004 A Practical Guide to Bone Ilcnsitometry in Children. National Osteoporosis Society, Camer- users and operators need to be aware. Good precision depends ton, UK. on scanners being operated by skilled and appropriately 20. Faulkner RA, Bailey DA, Drinkwater DT, Wilkinson AA. Hous- trained staff and quality assurance protocols being in place. ton CS. McKay HA 1993 Regional and total body bone mineral DXA can be used in adults to diagnose osteoporosis using the content. bone mineral density, and total body tissue composition WHO threshold (T-score = -2.5 or below in lumbar spine in children 8-16 years of age. Calcif Tissue Int 53:7-12. L,-L,, femoral neck, and total hip), predict fractures, contrib- 21. International Society for Clinical Densitometry 2005 ISCD. Avail- able at www.ISCD.org. Accessed March 30, 2008. ute to decisions on patient management and therapeutic inter- 22. Sawyer AJ, Bachrach LK, Fung EB (eds.) 2006 Bone Densitom- vention, and perhaps also monitor change in BMD (except in etry in Growing Patients; Guidelines for Clinical Practice. Hu- the forearm). There is potential for visual and morphometric mana Press. Totowa, NJ, USA. assessment of vertebral fractures from lateral DXA images. 23. Lookcr AC, Wahner HW, Dunn WL, Calvo MS, Harris TB, Heyse There are increasing, and varied, applications of DXA in re- SP. Johnston CC Jr. Lindsay R 1998 Updated data on proximal US search studies in novel sites and in both humans and animals. femur bone mineral levels of adults. Ostcoporos Int 8:468489. 24. World Health Organisation (WHO) Fracture Risk Assessment There are particular issues for DXA in children in whom the Tool (FRAX) Available at http://www.shef.ac.uk/FRAX/. Ac- size dependency is a limitation, and to date, there is no con- cessed March 28, 2008. sensus on whether size correction should be applied and which 25. Genant HK, Grampp S. Glueer CC, Faulkner KG, Jergas M, En- method is optimum. gelke K, Hagiwara s, van Kuijk C 1994 Universal standardisation

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for the dual X-ray absorptiometry: Patient and phantom cross- Bone Densitometry in Growing Patients; Guidelines for Clinical calibration results. J Bone Miner Res 9:1503-1514. Practice. Humana Press. pp. 41-58. 26. Kalender WA, Felsenberg D, Genant HK, Dequeker J, Reeve J 39. Carter DR, Bouxsein ML, Marcus R 1992 New approaches for 1995 The European Spine Phantom: A tool for standardisation interpreting projected bone densitometry data. J Bone Miner Res and quality control in spinal bone mineral measurement by DXA 7:137-145. and QCT. Eur J Radiol 20:83-92. 40. Kroger H, Kotaniemi A, Vainio P, Alhava E 1992 Bone densi- 27. Khoo WW 2000 Body composition measurements during infancy. tometry of the spine and femur in children by dual-energy x-ray Ann N Y Acad Sci 904:383-392. absorptiometry. Bone Miner 17:75-85. 28. Drage NA, Palmer RM, Blake GM, Wilson R, Crane F, Fogelman 41. Lu PW, Cowell CT, Lloyd-Jones SA, Briody J, Howman-Giles R I2007 A comparison of bone mineral density in the spine, hip and 1996 Volumetric bone mineral density in normal subjects, aged jaw of edentulous subjects. Clin Oral Implants Res 18:496-500. 5-27 years. J Clin Endocrinol Metab 81:1586-1590. 29. Haugeberg G, Emery P 2005 Value of dual-energy X-ray absorp- 42. Clark EM, Ness AR, Bishop NJ, Tobias JH 2006 Association be- tiometry as a diagnostic tool in early rheumatoid arthritis. Rheum tween bone mass and fractures in children: A prospective cohort Dis Clin North Am 31:715-728. study. J Bone Miner Res 21:1489-1495. 30. Faulkner KG, McClung M, Cummings SR 1994 Automated evalu- 43. Cooper C, Dennison EM. Leulkens HG, Bishop N, van Staa TP ation of hip axis length for predicting hip fracture. J Bone Miner 2004 Epidemiology of childhood fractures in Britain: A study using Res 9:1065-1070. the general practice research database. J Bone Miner Res 31. Gregory JS, Stewart A, Undrill PE, Reid DM, Aspden RM 2005 19: 1976-1981. Bone shape, structure and density as determinants of osteoporotic 44. Jones IE, Williams SM, Dow N, Goulding A 2002 How many hip fracture: A pilot study investigating the combination of risk children remain fracture-free during growth? a longitudinal study fracture. Invest Radiol 40591-597. of children and adolescents participating in the Dunedin Multidis- 32. Beck TJ 2007 Extending DXA beyond bone mineral density: Un- ciplinary Health and Development Study. Osteoporos Int 13:99& derstanding hip structure analysis. Curr Osteoporos Rep 5:49-55. 995. 33. Link TM, Guglielmi G, van Kuijk C, Adam JE 2005 Radiologic 45. Ward KA, Ashby RL, Roberts SA, Adam JE, Mughal MZ 2007 assessment of osteoporotic fracture: Diagnostic and prognostic im- UK reference data for the Hologic QDR Discovery dual energy plications. Eur Radiol 158:1521-1532. X-rav absorutiometrv scanner in healthv children aeed" 6-17 vcars. Arch Dis Child 9253-59. 34. Ferrar L, Jiang G, Adams J, Eastell R 2005 Identification of ver- 46. Prentice A. Parsons TJ. Cole TJ 1994 Uncritical use of bone min- tebral fractures: An update. Osteoporos Int 16:717-728. eral density in absorptiometry may lead to size-related artifacts in 35. Roberts MG, Cootes TF, Pacheco EM, Adam JE 2007 Quantita- the identification of bone mineral determinants. Am J Clin Nutr tive fracture detection on Dual Energy X-ray Absorptiometry 605337-842. (DXA) images using shape and appearance models. Acad Radiol 47. Warner JT. Cowan FJ, Dunstan FD, Evand WD, Webb DK, Greg- 14:1166-1178. ory JW 1998 Measured and predicted bone mineral content in 36. Rea JA, Li J, Blake GM, Steiger P, Genant HK, Fogelman I 2000 healthy boys and girls aged 6-18 years: Adjustment for body size Visual assessment of vertebral deformity by X-ray absorptiometry: and puberty. Acta Paediatr 87:244-249. A highly predictive method to exclude vertebral deformity. Os- 48. Molgaard C, Thomsen BL, Prentice A, Cole TJ, Michaelsen KF teoporos Int 11:660-668. 1997 Whole body bone mineral content in healthy children and 37. van Rijn RR, Van DS, I, Link TM, Grampp S, Guglielmi G, Imhof adolescents. Arch Dis Child 76:9-15. H, Glucr C, Adam JE, van Kuijk C 2003 Bone densitometry in 49. Crabtree NJ. Kibirige MS, Fordham J, Banks LM, Muntoni F, children: A critical appraisal. Eur Radiol 13:700-710. Chinn D, Boivin CM, Shaw NJ 2004 The relationship between lean 38. Crabtree NJ, Leonard MB, Zemel BS 2006 Dual energy X-ray body mas and bone mineral content in paediatric health and dis- absorptiometry. In: Sawyer AJ, Bachrach LK, Fung EB (eds.) ease. Bone 35:965-972.

Chapter 30. Quantitative Computed Tomography in Children and Adults

Claus C. Gluer Medizinische Physik, Klinik fur Diagnostische Radiologie, Universitatsklinikurn Schleswig-Holstein, Kid, Germany

INTRODUCTION pressed as CT number measured in Hounsfield units (HUs), but for QCT, a reference phantom of known composition is BMD is one of the strongest predictors of fracture risk, but scanned together with the patient that allows conversion of today's standard densitometric method, DXA, has limitations, HUs into calcium-hydroxyapatite (Ca-HAP) equivalent BMD. particularly for characterizing changes in bone status in sub- For earlier measurements that were calibrated to K,HPO,, a jects on treatment. QCT is a potential alternative for the fu- correction factor needs to be applied to express results in Ca- ture. Technical and clinical considerations are outlined in this HAP, an issue important, for example, for comparison with chapter. published reference ranges. Unlike DXA, BMD measured by QCT reflects volumetric BMD and not an areal projection. METHODOLOGY Single-energy QCT was initially applied to the radius by Ruegsegger et a].(')followed by measurements at the spine by X-ray-based CT provides 3D morphological and composi- Genant and Boyd.'" Dual-energy approaches improve tional information. On the reconstructed CT images, tissue QCT contrast is predominantly determined by X-ray absorption of its heavier elements (e.g., calcium). Image gray values are ex- Key words: BMD, absorptiometry. QCT, pQCT, Calibration, refer- ence data. radiation exposure, error sources, T-scores, Z-scores, Tan- ner stage, mineralization, fracture risk, diagnosis, monitoring, bone The author states that he has no conflict of interest. geometry, microstructure, finite element analysis, quality assurance

0 2008 American Society for Bone and Mineral Research