Editorial: Osteoporosis in Children: Still a Diagnostic Challenge

Myriad challenges confront clinicians caring for children at risk for bone fragility. Despite the consensus that chronic illness, undernutrition, immobilization, and genetic bone disorders can compromise bone health, there is little agreement about how best to identify and treat these conditions (1–3). For adult patients, dual energy x-ray absorptiometry (DXA) is the principal diagnostic tool to assess risk of fracture, select patients for therapy, and monitor the response to intervention. In fact, bone mineral density (BMD) is sufficiently predictive of fracture risk in the elderly that DXA measurements alone have been used to establish the diagnosis of osteoporosis. A postmenopausal woman with a BMD T-score (sd scores from the mean for healthy young adults) at or below 2.5 has been classified as “osteoporotic” by World Health Organization criteria (4). However, fractures occur in many adults with normal BMD values because bone fragility is modulated by age, gender, weight, alcohol consumption, smoking history, glucocorticoid therapy, and personal or family fracture history (4). Models of absolute fracture risk include both BMD values and these relevant clinical factors. The role of densitometry in evaluating the skeletal status of children continues to evolve. DXA is considered the preferred method of assessing bone mineral status in clinical practice because of its speed, precision, and low radiation exposure (2, 3). Unfortunately, the acquisition and interpretation of DXA data in growing children is far more complex than in adults. Failure to recognize the myriad pitfalls in pediatric densitometry leads to misdiagnosis and potentially unwarranted intervention. A recent study by Gafni et al. (5) provides a clear cautionary note. Of the children referred for a drug treatment trial, 62% were mislabeled as “osteoporotic” because their BMD values had been compared with adult rather than pediatric norms. When DXA scans were reevaluated using appropriate controls, only 26% of the subjects had low BMD values. A key barrier to interpretation of densitometry in children has been the lack of standardized pediatric reference data. Calculation of T-scores is not appropriate in younger patients who have not yet reached their adult (peak) bone mass. Instead, DXA results must be compared with normative data derived from healthy children of similar age and maturity to derive a Z-score. Until recently, the only available pediatric reference data came from relatively small, convenience samples of 200–400 subjects measured using older DXA equipment and software versions. Only lately have reference data emerged from larger cohorts collected on newer Hologic (6) and GE/Lunar (7) DXA equipment. The selection of a reference data set has important implications because the differing means and sd scores will alter the Z-score. In particular, failure to use gender-specific reference data can result in the misdiagnosis of low bone mass in boys during adolescence when they lag behind girls in growth and puberty (8). The Bone Mineral Density in Childhood Study (BMDCS) addresses the need for improved pediatric DXA norms. The goal was to approximate the characteristics of an optimal reference data set (9). The cohort was comprised of healthy youth, representative of the general population, drawn from multiple regions (to address local differences in ethnicity and lifestyle), and sufficiently large to encompass the variability due to age, gender, race, and ethnicity. A total of 1554 healthy, ethnically diverse youth (ages 6–16 yr at entry) were recruited from five leading pediatric bone centers. The latest DXA equipment and software were used to reduce systematic differences between reference data and the DXA machines currently in clinical use. Results were analyzed using a statistical model that captures the nonlinear patterns of gains in bone size and mineral content and the increasing variability with age. In this issue, Kalkwarf et al. (10) report the results from baseline and yr 1 and 2 of this 5-yr study. These data should be considered as the best available pediatric DXA norms for interpreting Hologic DXA scans for this cohort’s age group. The rigor that went into selection of subjects, cross-calibration of DXA scanners from multiple sites, assessment of bone age and pubertal stage, and statistical modeling are unparalleled. The authors acknowledge the relatively small numbers of Asians and Hispanics in the cohort. An earlier study in healthy 9to 25-yr-old subjects found significant differences between Blacks and non-Blacks (non-Hispanic Caucasians, Asians, and Hispanics) but not between the three nonBlack groups (2). For this reason, the BMDCS data are likely the best available reference source for Asian and Hispanic youth. Despite the progress made by this important study, many challenges and controversies remain. Pediatric reference data from the BMDCS were collected only on Hologic DXA scanners. These values cannot be used to interpret data obtained from GE/Lunar or Norland densitometers because of systematic differences in software. Although formulae have been developed to convert DXA results from the differing machines into “universal” BMD values, these assumptions have not been adequately tested in children and adolescents. BMDCS reference data are available only for ages 7–17 yr, and norms for older and younger youth are needed. Until these become available, reference data for ages 17–20 yr can be found in the literature (6); standard adult reference data Abbreviations: BMAD, Bone mineral apparent density; BMC, bone mineral content; BMD, bone mineral density; DXA, dual energy x-ray absorptiometry; QCT, quantitative computed tomography.