Thomas N. Hangartner

Height Adjustment in Assessing Dual Energy X- Ray Absorptiometry Measurements of Bone Mass and Density in Children

CONTEXT In children, bone mineral content (BMC) and bone mineral density (BMD) measurements by dual-energy x-ray absorptiometry (DXA) are affected by height status. No consensus exists on how to adjust BMC or BMD (BMC/BMD) measurements for short or tall stature. OBJECTIVE The aim of this study was to compare various methods to adjust BMC/BMD for height in healthy children. DESIGN Data from the Bone Mineral Density in Childhood Study (BMDCS) were used to develop adjustment methods that were validated using an independent cross-sectional sample of healthy children from the Reference Data Project (RDP). SETTING We conducted the study in five clinical centers in the United States. PARTICIPANTS We included 1546 BMDCS and 650 RDP participants (7 to 17 yr of age, 50% female). INTERVENTION No interventions were used. MAIN OUTCOME MEASURES We measured spine and whole body (WB) BMC and BMD Z-scores for age (BMC/BMD(age)), height age (BMC/BMD(height age)), height (BMC(height)), bone mineral apparent density (BMAD(age)), and height-for-age Z-score (HAZ) (BMC/BMD(haz)). RESULTS Spine and WB BMC/BMD(age)Z and BMAD(age)Z were positively (P < 0.005; r = 0.11 to 0.64) associated with HAZ. Spine BMD(haz) and BMC(haz)Z were not associated with HAZ; WB BMC(haz)Z was modestly associated with HAZ (r = 0.14; P = 0.0003). All other adjustment methods were negatively associated with HAZ (P < 0.005; r = -0.20 to -0.34). The deviation between adjusted and BMC/BMD(age) Z-scores was associated with age for most measures (P < 0.005) except for BMC/BMD(haz). CONCLUSIONS Most methods to adjust BMC/BMD Z-scores for height were biased by age and/or HAZ. Adjustments using HAZ were least biased relative to HAZ and age and can be used to evaluate the effect of short or tall stature on BMC/BMD Z-scores.

Revised Reference Curves for Bone Mineral Content and Areal Bone Mineral Density According to Age and Sex for Black and Non-Black Children: Results of the Bone Mineral Density in Childhood Study

CONTEXT Deficits in bone acquisition during growth may increase fracture risk. Assessment of bone health during childhood requires appropriate reference values relative to age, sex, and population ancestry to identify bone deficits. OBJECTIVE The objective of this study was to provide revised and extended reference curves for bone mineral content (BMC) and areal bone mineral density (aBMD) in children. DESIGN The Bone Mineral Density in Childhood Study was a multicenter longitudinal study with annual assessments for up to 7 yr. SETTING The study was conducted at five clinical centers in the United States. PARTICIPANTS Two thousand fourteen healthy children (992 males, 22% African-Americans) aged 5-23 yr participated in the study. INTERVENTION There were no interventions. MAIN OUTCOME MEASURES Reference percentiles for BMC and aBMD of the total body, lumbar spine, hip, and forearm were obtained using dual-energy x-ray absorptiometry for Black and non-Black children. Adjustment factors for height status were also calculated. RESULTS Extended reference curves for BMC and aBMD of the total body, total body less head, lumbar spine, total hip, femoral neck, and forearm for ages 5-20 yr were constructed relative to sex and age for Black and non-Black children. Curves are similar to those previously published for 7-17 year olds. BMC and aBMD values were greater for Black vs. non-Black children at all measurement sites. CONCLUSIONS We provide here dual-energy x-ray absorptiometry reference data on a well-characterized cohort of 2012 children and adolescents. These reference curves provide the most robust reference values for the assessment and monitoring of bone health in children and adolescents in the literature to date.

Influence of fat on bone measurements with dual-energy absorptiometry

In order to investigate the influence of fat on bone in dual-energy absorptiometry measurements, we evaluated a special phantom on the three scanners: Lunar DP3, Lunar DPX and Hologic QDR-1000. The phantom employed hydroxyapatite blocks of various thicknesses to simulate bone, water to simulate muscle and lucite to simulate fat. The lucite plates were arranged in one and two layers in three different configurations: over the whole measurement area, over the hydroxyapatite blocks only and at both sides of the hydroxyapatite blocks. For all scanners, no influence of fat could be demonstrated if it was homogeneously distributed over the whole measurement area. However, changes in area bone-density were observed if fat was distributed inhomogeneously over the measurement area. Fat over only the bone area reduced the measured bone values by 0.051 g/cm2 per cm fat layer. Fat over only the soft-tissue area increased the measured bone values by the same amount. These results apply to the Lunar DPX scanner. The results for the Lunar DP-3 scanner are similar; those for the Hologic QDR-1000 show a slightly smaller fat dependence of 0.044 g/cm2 per cm fat layer. The fat influences are not dependent on the amount of bone and only minimally on the soft-tissue thickness. A change of 50% in the fat content of the bone marrow will change the measured area bone-density of an averaged sized vertebra by 5-6% depending on scanner model. Inhomogeneous fat distribution in soft tissue, resulting in a difference of 2 cm fat layer between soft-tissue area and bone area, will influence the measured area bone-density by 9-10%.

Effect of enzyme replacement therapy with imiglucerase on BMD in type 1 Gaucher disease.

The effect of ERT with imiglucerase on BMD in type 1 GD was studied using BMD data from the International Collaborative Gaucher Group Gaucher Registry. Data were analyzed for 160 untreated patients and 342 ERT‐treated patients. Imiglucerase significantly improves BMD in patients with GD, with 8 years of ERT leading to normal BMD.

Risedronate in children with osteogenesis imperfecta: a randomised, double-blind, placebo-controlled trial

BACKGROUND Children with osteogenesis imperfecta are often treated with intravenous bisphosphonates. We aimed to assess the safety and efficacy of risedronate, an orally administered third-generation bisphosphonate, in children with the disease. METHODS In this multicentre, randomised, parallel, double-blind, placebo-controlled trial, children aged 4-15 years with osteogenesis imperfecta and increased fracture risk were randomly assigned by telephone randomisation system in a 2:1 ratio to receive either daily risedronate (2·5 or 5 mg) or placebo for 1 year. Study treatment was masked from patients, investigators, and study centre personnel. Thereafter, all children received risedronate for 2 additional years in an open-label extension. The primary efficacy endpoint was percentage change in lumbar spine areal bone mineral density (BMD) at 1 year. The primary efficacy analysis was done by ANCOVA, with treatment, age group, and pooled centre as fixed effects, and baseline as covariate. Analyses were based on the intention-to-treat population, which included all patients who were randomly assigned and took at least one dose of assigned study treatment. The trial is registered with ClinicalTrials.gov, number NCT00106028. FINDINGS Of 147 patients, 97 were randomly assigned to the risedronate group and 50 to the placebo group. Three patients from the risedronate group and one from the placebo group did not receive study treatment, leaving 94 and 49 in the intention-to-treat population, respectively. The mean increase in lumbar spine areal BMD after 1 year was 16·3% in the risedronate group and 7·6% in the placebo group (difference 8·7%, 95% CI 5·7-11·7; p<0·0001). After 1 year, clinical fractures had occurred in 29 (31%) of 94 patients in the risedronate group and 24 (49%) of 49 patients in the placebo group (p=0·0446). During years 2 and 3 (open-label phase), clinical fractures were reported in 46 (53%) of 87 patients in the group that had received risedronate since the start of the study, and 32 (65%) of 49 patients in the group that had been given placebo during the first year. Adverse event profiles were otherwise similar between the two groups, including frequencies of reported upper-gastrointestinal and selected musculoskeletal adverse events. INTERPRETATION Oral risedronate increased areal BMD and reduced the risk of first and recurrent clinical fractures in children with osteogenesis imperfecta, and the drug was generally well tolerated. Risedronate should be regarded as a treatment option for children with osteogenesis imperfecta. FUNDING Alliance for Better Bone Health (Warner Chilcott and Sanofi).

Osteopenia in Gaucher disease develops early in life: Response to imiglucerase enzyme therapy in children, adolescents and adults

BACKGROUND In Gaucher disease (GD), acid-β-glucosidase (GBA1) gene mutations result in defective glucocerebrosidase and variable combinations of hematological, visceral, and diverse bone disease. Osteopenia is highly prevalent, but its age of onset during the natural course of GD is not known. It is also unclear if the degree of improvement in osteopenia, secondary to imiglucerase enzyme therapy, differs by the age of the patient. OBJECTIVE We hypothesized that osteopenia develops early in life, during the natural course of type 1 Gaucher disease (GD1), and that its response to treatment is maximal during this period. METHODS We examined data from the International Collaborative Gaucher Group (ICGG) Gaucher Registry of patients treated with imiglucerase between the ages of 5 and 50 years. Lumbar spine bone mineral density (BMD) (determined by dual-energy X-ray absorptiometry (DXA) and expressed as Z-scores) at baseline and for up to 10 years on imiglucerase were analyzed in children (ages ≥ 5 to <12 years), adolescents (≥ 12 to <20 years), young adults (≥ 20 to < 30 years), and older adults (≥ 30 to < 50 years). BMD was correlated with other disease characteristics. Pre-treatment, descriptive statistics were applied to 5-year age categories. Non-linear mixed effects regression models were used to analyze DXA Z-scores over time after treatment with imiglucerase. RESULTS Pre-treatment, low BMD was prevalent in all age groups, most strikingly in adolescents. DXA Z-scores were at or below -1 in 44% of children (n=43), 76% of adolescents (n=41), 54% of young adults (n=56) and 52% of older adults (n=171). The most common GBA1 genotype was N370S heteroallelic. Baseline hematological and visceral manifestations in the 4 age groups were similar. In children with DXA Z-scores ≤-1 at baseline, imiglucerase therapy for 6 years resulted in improvement of mean DXA Z-scores from -1.38 (95% CI -1.73 to -1.03) to -0.73 (95% CI -1.25 to -0.21); in young adults DXA Z-scores improved from -1.95 (95% CI -2.26 to -1.64) to -0.67 (95% CI -1.09 to -0.26). BMD also improved in older adults, but the magnitude of the improvement was lower compared to younger patients. CONCLUSIONS Low bone density is common in GD1 with the highest prevalence rate in adolescence, a developmental period critical to attainment of peak bone mass. Imiglucerase results in amelioration of osteopenia in all age groups, with the greatest improvements in younger patients.

The Official Positions of the International Society for Clinical Densitometry: Acquisition of Dual-Energy X-Ray Absorptiometry Body Composition and Considerations Regarding Analysis and Repeatability of Measures

In preparation for the International Society for Clinical Densitometry Position Development Conference of 2013 in Tampa, Florida, Task Force 2 was created as 1 of 3 task forces in the area of body composition assessment by dual-energy X-ray absorptiometry (DXA). The assignment was to review the literature, summarize the relevant findings, and formulate positions covering (1) accuracy and precision assessment, (2) acquisition of DXA body composition measures in patients, and (3) considerations regarding analysis and repeatability of measures. There were 6 primary questions proposed to the task force by the International Society for Clinical Densitometry board and expert panel. Based on a series of systematic reviews, 14 new positions were developed, which are intended to augment and define good clinical practice in quantitative assessment of body composition by DXA.

Temporary Brittle Bone Disease: Association with Decreased Fetal Movement and Osteopenia

Abstract. Infants who present with multiple unexplained fractures pose a difficult diagnostic dilemma of child abuse versus intrinsic bone disease. Temporary brittle bone disease is a recently described disease characterized by a transient bone weakness in the first year of life which presents with multiple, unexplained fractures that can be confused with child abuse. The purpose of this study was to determine if there are common, historical features in infants with unexplained fractures that might suggest a basis for the fractures, and to determine if bone density measurements might indicate that such infants have low bone density. Medical records were reviewed in 33 infants who were referred for consultation for multiple unexplained fractures in which the parents and other caregivers denied wrongdoing. In 9 of the infants, radiographic absorptiometry and/or computed tomography bone density studies were performed. In 26 of these infants the diagnosis of temporary brittle bone disease was made. A normal collagen test was found in 17 of the 26 infants studied; 9 infants did not have a collagen test because the diagnosis of osteogenesis imperfecta was considered highly unlikely. In 25 of them there was a history of decreased fetal movement and/or intrauterine confinement. Bone density, as judged by plain X-ray films, was normal in all 26 cases, but when formally measured by radiographic absorptiometry or computed tomography, the bone density measurements were low in 8 of the 9 infants studied. These findings implicate decreased fetal movement and intrauterine confinement as contributing factors to temporary brittle bone disease and suggest that normal, unconstrained fetal movement during pregnancy is important for normal fetal bone formation. These findings support the model that bone formation and strength are dependent on the mechanical load placed on the bone. The results also demonstrate the usefulness of bone density measurements in evaluating the infant with multiple unexplained fractures to help distinguish nonaccidental injury from intrinsic bone disease.

Recommendations for Thresholds for Cortical Bone Geometry and Density Measurement by Peripheral Quantitative Computed Tomography

Peripheral quantitative computed tomography (pQCT) is widely used for clinical and research purposes. For accurate determination of bone geometry (bone cross-sectional area, cortical thickness, and cortical area), volumetric bone mineral density (vBMD) and cortical bone mineral content (BMC), it is important to select the appropriate thresholds. A Stratec XCT-2000 scanner was used to compare current standard practice with new optimized thresholds. Currently, a single threshold of 710 mg/mL for the measurement of cortical vBMD and geometry is used. We hypothesised that this threshold may not be optimal and used the European Forearm Phantom (EFP) and patient data to test more appropriate thresholds. A single slice (1.2 mm width, 0.4 mm pixel size) was made at section 4 of the EFP (representing the diaphyseal portion of a long bone). The EFP has a known cortical thickness of 2.5 mm and, therefore, the correct threshold for geometry would be that which measures cortical thickness as 2.5 mm. Thresholds were altered at approximately the 50% value between soft tissue (60 mg/mL) and peak density (879 mg/mL), and cortical thickness versus threshold was plotted; the correct threshold for geometry was 460 mg/mL. By expressing this threshold as a percentage of the range of density values in the EFP ([460–60]/[879–60] = 49%) and then applying this percentage to in vivo data, the optimum threshold for geometry can be determined: ([1240−79] × 0.49) + 79 = 648 mg/mL. For cortical vBMD of in vivo bone measurements at the midshaft site of the radius, thresholds were varied around the peak value (1240 mg/mL), and the threshold was set to that which gave a cortical density of 1240 mg/mL; the threshold for cortical density was, therefore, 1200 mg/mL. A subset of radius scans from a population of young healthy females was analyzed using the new thresholds (648 mg/mL for bone geometry, 1200 mg/mL for cortical vBMD) versus the current threshold (710 mg/mL). For bone geometry, the mean difference between the analysis based on the new threshold and that based on the manufacturer-recommended threshold ranged between 2.1% and 14% (total area = 2.1%, cortical thickness = 14%, cortical area = 3.7%). Although there was a 10% difference between the analysis based on the new threshold and that based on the manufacturer-recommended threshold, this difference was not systematic. Thresholds will significantly affect results obtained from pQCT. The current threshold of 710 mg/mL is inadequate for accurate determination of bone geometry and cortical vBMD. New thresholds of 648 mg/mL for geometry and 1,200 mg/mL for cortical vBMD should be used.

Quantitative Measurement of Bone Density Using Gamma-Ray Computed Tomography

A special purpose gamma-ray computed tomography scanner has been developed for precise measurements of bone density in the human appendicular skeleton. Details of the scanners hardware and of the software organization for system control and data analysis are given, together with an outline of the theoretical basis for conversion of measured linear attenuation coefficients to physical bone densities. Performance of the system was evaluated on bone-like phantoms. Clinically, a precision of ± 0.5% is obtained for bone density determinations. This device is being used in experimental studies and clinical investigations.