THE CHALLENGE OF DIAGNOSISDXA in AdultsIn adults, the advent of noninvasive bone densitometry has offered a means to identifyand treat individuals with bone fragility before they fracture and to monitor their responseto therapy with parameters other than fracture. Of the available densitometry techniques,DXA is currently the preferred method for detecting adults at risk for osteoporosis. Itswidespread use as a clinical tool is in part because of its low radiation exposure, excellentprecision, ease of testing, and affordability.For postmenopausal women, much work has been done to establish disease severitythresholds and even fracture risk based on DXA. In this group, fracture risk has beencorrelated to low bone density as measured by DXA. The World Health Organization hasdeveloped criteria for the diagnosis of osteoporosis in postmenopausal Caucasianwomen based on a BMD that is 2.5 standard deviations or more below the average valuefor a young adult (i.e., T-score < 2.5).A significant limitation of DXA is that while it uses density as a surrogate for strength,it does not truly measure all parameters of bone that determine fracture risk. For example,the reduction in fracture rates observed after initiation of bisphosphonate therapy exceedsthat predicted by gains in BMD (7981). This observation illustrates the importance offactors other than bone mineral that contribute to bone strength. The size, shape, geometry,microarchitecture of bone and the rates of bone turnover are important modifiers ofbone strength and fracture risk.In contrast to that of postmenopausal women, the diagnosis of bone fragility in men,younger women, and especially children is more complex and controversial (82). Theindications for bone DXA in these patients and the clinical implications of their resultsare still being debated. Experts in the bone field have proposed guidelines for testing andinterpreting DXA results in men, young women, and children, based on opinion wheredata were lacking (83). Another panel of bone experts have criticized these recommendations,citing the lack of objective data to support the opinions (84). In short, considerablecontroversy surrounds the optimal approach to identify risk for bone fragility in menand younger individuals.DXA in Children and AdolescentsChildren present the most challenging population for assessing skeletal health, primarilybecause of the numerous variables of growth. Measurement techniques in the pediatricsetting would ideally be safe, painless, of short duration, and would provide valuableinformation. In comparison with other bone measurement systems, DXA best fits thesecriteria. However, there are difficulties that are unique to children and adolescents whenusing this tool. This discussion serves as a very brief introduction to topics that are thefocus of this text.Bones change in size, shape, and mass throughout the first two decades of life, and thetempo of change varies by skeletal site and individual. Measurements of bone mass byDXA are two-dimensional (i.e., areal) and are strongly influenced by bone size, pubertalstage, and bone age (85,86). Children with smaller bones may appear to have low BMD,and, in serial testing, changes resulting from increased bone size can be misconstrued forincreased bone density. For this reason, areal BMD can be a source of confusion in thepediatric population, and the concept of volumetric density may be more appropriate.When using DXA with children, it may be that different units of measurement will bemore useful than those for adults. For example, BMC and BMD are often used interchangeablyto denote mass, although they are very different parameters. It appears thatBMC measured by DXA is more sensitive to change in bone acquisition than is arealBMD, especially in early- and prepubertal children (86).Another difficulty encountered in the use of DXA is the lack of universal pediatricreference data for determining normal from abnormal bone mass. Until recently, DXAsoftware programs automatically generated a T-score, comparing the data of the subject,regardless of his or her age, with that of healthy young adults. This is an inappropriatecomparison for those under age 20 who have not yet achieved PBM.Even when comparing children to their age- and gender-matched peers, there is difficultybecause the tempo of growth, sexual maturation, and bone mineral accrual canvary among individuals and can be altered by chronic illness. These factors must beconsidered as well in determining if bone mineral is normal.The complexity of obtaining and interpreting bone densitometry in children andadolescents has led to confusion and misdiagnoses in children. In one recent study, morethan half of the subjects referred for a evaluation of pediatric osteoporosis had beenmisdiagnosed with low bone mass, with the most frequent error resulting from the use ofa T-score in pediatric patients (87). As this is a developing field, DXAs are frequentlyperformed and interpreted by specialists with expertise in adult osteoporosis but withlimited experience with pediatric densitometry. Misleading information about bone masscan result from the use of inappropriate software or improper positioning during acquisition,as well as from an interpretation of results that does not account for known confoundingvariables.The consequences of these errors can be costly. Pediatric patients may be inappropriatelylabeled as osteoporotic, producing anxiety in parents and children. Physiciansmay respond to these reports by restricting physical activity or by prescribing drugs forosteoporosis that are, to date, untested for safety and efficacy in children. In addition, ifthe results of these studies are confusing or are thought to be unreliable, the clinician is less likely to initiate skeletal health assessment in children using DXA, missing anopportunity to identify and correct deficits in developing bone.SUMMARYThere is an ever-expanding body of knowledge regarding the positive and negativeinfluences on developing bone. Despite this, we are observing worrisome trends in childhoodsuch as poor nutrition, sedentary lifestyle, and obesity, all of which are associatedwith low bone mass. Beyond that, increasing rates of childhood fractures have beenreported on several continents. In addition, more children are surviving significant illnessesand treatment regiments that can have profound deleterious effects on bone.Aside from immediate concerns in children, the model of PBM as a determinant ofadult osteoporosis and fragility fracture implies that the first two decades of life representa window of opportunity in which to implement upstream prevention and interventionstrategies that may impart enduring effects on the bone health of an individual.It follows that this same period represents a window of vulnerability and a timeduring which increased scrutiny of bone development is essential.It is therefore critical that we expand our ability to measure bone health parameters inthe growing patient, to identify markers of inadequate gain, and to monitor effectivenessof interventions. This requires a noninvasive, safe, and available instrument with goodprecision, short test time, and useful output. As DXA, even with its limitations, is currentlythe best fit for bone health assessment in children, it is imperative that the clinicalutility of DXA be maximized so that we can recognize indications of bone fragility andidentify trajectories of bone acquisition that may predispose a child to a lifetime of poorbone health.Development of these guidelines for the clinical use of DXA in pediatric patients willhopefully improve the quality of densitometry data and reduce the frequency of misdiagnosisin the clinical setting while research continues to advance the usefulness of thisand other tools.WHAT ARE WE MEASURING WITH BONE DENSITOMETRY?Bone densitometry offers a tool with which pediatric bone status can be assessed. Asthe child grows, the skeleton will increase in size and mineral content and will change inshape. When interpreting measurements from bone densitometry scanners, it is imperativethat these changes in bone size, shape, and mass are taken into account (20,21). For example, changes in bone density over time could reflect changes in bone size, mineralcontent, or a combination of these. The quantitative measures that can be obtained frommost densitometry techniques include bone area (BA; cm2), bone mineral content (BMC; g),and bone mineral density (BMD; g/cm2).A model based on the biological organization of bone was proposed by Rauch andSchonau (22) to help in understanding and interpreting the measurements obtained frombone densitometry and to relate these changes to the physiological changes that occurduring bone development (see Fig. 1). The model describes separate definitions for thematerial, compartment, and total densities of bone, and each of these will be discussedbriefly:1. Material mineral density. This reflects the degree of mineralization of the organic bonematrix. Material density can be determined only within a very small volume occupiedonly by bone matrix, exclusive of marrow spaces, osteonal canals, lacunae, and canaliculi.The resolution required to measure BMDmaterial is not possible with currentnoninvasive densitometric techniques; BMDmaterial can be determined from specimenstaken at bone biopsy, an invasive procedure. These specimens can be analyzed by mineral/ash weight, contact radiography, backscatter electron microscopy, or laser-ablatedmass spectrometry. Measurement of BMDmaterial is not routinely assessed in clinicalpractice.2. Compartment mineral density. The BMDcompartment is the amount of mineral containedwithin the trabecular or cortical compartments (i.e., the mass of mineral per unit volumeof trabecular or cortical bone). Quantitative computed tomography (QCT) measurescortical and trabecular bone separately, and can therefore measure BMDcompartment in bothtypes of bone. DXA measurements are a composite of trabecular and cortical bone, andso the technique is not able to separate the two components at most sites. BMDcompartmentcan be determined by DXA in skeletal sites such as the diaphyses of the femur and theradius, both of which are comprised of cortical bone. Radiogrammetry measures thecortical BMDcompartment of the metacarpals.3. Total mineral density. BMDtotal is the mineral density of all of the material containedwithin the periosteal envelope and articular surfaces. QCT and DXA measure BMDtotal.Calculations are required to estimate bone volume from DXA scans because this techniquemeasures areal density only. Bone mineral apparent density (BMAD) is an example of a volumetric density calculated using BMDtotal. This density is sometimes inappropriatelyreferred to in the literature as true bone density.Table 3 summarizes which of the aforementioned BMD measurements can be determinedusing the densitometry techniques discussed in this chapter; quantitative ultrasound(QUS) and magnetic resonance imaging (MRI) do not measure BMDCOMPARISON BETWEEN CENTRAL AND PERIPHERALTECHNIQUESIn adults, measurements of bone mass at both axial and peripheral sites have provento predict future osteoporotic fracture (128). In older adults, osteoporosis is defined interms of bone densitometry as a T-score (i.e., the SD from the mean of ethnic- and sexmatchedpeak BMD) of 2.5 or below using axial DXA in the lumbar spine and proximalfemur. The agreement in classification by the various densitometric techniques has beenstudied in adults (129131), and each performs well in differentiating osteoporosis orosteopenia from normal bone status. However, each technique identifies different peopleas osteoporotic or osteopenic; hence, the diagnostic agreement among the methods is poor (i.e., a * score of 0.4). As an exception to the rule, several studies have shown thatthe agreement between trabecular vBMD (measured by QCT) and lateral DXA BMD hasa score of 0.75 (131). The reasons for poor agreement among different bone densitymethods and at different sites are likely to include differences in the ability of the techniqueto measure integral or separate cortical and trabecular bone (132,133), differingpatterns of regional bone loss (e.g., in the spine versus the radius), and differential disease-specific effects on bone. Differences in scanner technology will also be relevant incontributing to the poor agreement among methods. Whether BMD is measured in adultsor in children, the agreement among different techniques is likely to be of similar magnitude(r between 0.4 and 0.9).Because there may be regional differences in bone mass and strength, selection ofskeletal site to scan is important. For example, in children with juvenile idiopathic arthritis,who are most likely to suffer a vertebral crush fracture (134,135), measurement ofspinal trabecular bone should be a priority. Any measurement that does not include thespine is less likely to be sensitive to the bone changes that occur. Diagnostic agreementbetween axial and peripheral skeletal sites may also differ depending on the childs phaseof skeletal development. A large change in DXA spinal BMD with no change in radiustrabecular BMD may be caused by the increase in bone size due to the pubertal growthspurt rather than being due to the change in volumetric bone mineral density. The relationshipbetween the peripheral and axial bone densitometry techniques and fractures hasnot been studied in children.Several studies have been performed that investigate the ability of peripheral measurementto predict osteoporotic fracture in adults (128,136,137). Site-specific measurementshave proven to be the best predictors of fractures at that site; for example, hip BMDwill predict hip fracture better than radial or spinal BMD measurements. However, BMDmeasurements by peripheral techniques do predict spine and hip fracture in adults, thusproviding useful information if an axial BMD measurement is not available.The forearm is the most common site of fracture in children. Goulding et al. (138) haveshown that children who have had fractures generally have lower BMD in the wholeskeleton. Some studies have confirmed an association between low BMD and all upperlimb fractures (139), whereas others have observed reductions in hip and spine but notwhole-body bone measurements in children who have fractured (140,141). In the onlyprospective study of childhood fracture to date, low BMD, as measured by axial DXA,was predictive of the likelihood of a child to refracture within 4 yr of the initial fracturedate (142). The correlation between BMD and childhood fractures has been reviewed(143). In young people, lower bone density at the spine or whole body has been linkedto fractures only at the forearm but not at other skeletal sites. These findings suggest thatlow BMD may be a contributing factor to childhood fracture, just as it is in adults.However, there are insufficient data to establish a fracture threshold in children andyoung adults. Furthermore, comparisons among different scanning techniques for childhoodfractures have not yet been made.