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Osteopenia and bone fractures are significant causes of morbidity in children with cholestatic liver disease. Dual-energy X-ray absorptiometry (DXA) analysis was performed in children with intrahepatic cholestatic diseases who were enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis in the Childhood Liver Disease Research Network. DXA was performed on participants aged >5 years (with native liver) diagnosed with bile acid synthetic disorder (BASD), alpha-1 antitrypsin deficiency (A1AT), chronic intrahepatic cholestasis (CIC), and Alagille syndrome (ALGS). Weight, height, and body mass index Z scores were lowest in CIC and ALGS. Total bilirubin (TB) and serum bile acids (SBA) were highest in ALGS. Bone mineral density (BMD) and bone mineral content (BMC) Z scores were significantly lower in CIC and ALGS than in BASD and A1AT (P < 0.001). After anthropometric adjustment, bone deficits persisted in CIC but were no longer noted in ALGS. In ALGS, height-adjusted and weight-adjusted subtotal BMD and BMC Z scores were negatively correlated with TB (P < 0.001) and SBA (P = 0.02). Mean height-adjusted and weight-adjusted subtotal BMC Z scores were lower in ALGS participants with a history of bone fractures. DXA measures did not correlate significantly with biliary diversion status. Conclusion: CIC patients had significant bone deficits that persisted after adjustment for height and weight and generally did not correlate with degree of cholestasis. In ALGS, low BMD and BMC reference Z scores were explained by poor growth. Anthropometrically adjusted DXA measures in ALGS correlate with markers of cholestasis and bone fracture history. Reduced bone density in this population is multifactorial and related to growth, degree of cholestasis, fracture vulnerability, and contribution of underlying genetic etiology.

Perfluoroalkyl substances (PFASs), including perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA), have been associated with adverse bone, and metabolic changes in adults. However association of PFASs with bone health in children is understudied. Considering their role as endocrine disruptors, we examined relationships of four PFASs with bone health in children.In a cross sectional pilot study, 48 obese children aged 8-12 years were enrolled from Dayton's Children Hospital, Ohio. Anthropometric, clinical and biochemical assessments of serum were completed. Serum PFASs were measured by UPLC-ESI-MS/MS. In a subset of 23 children, bone health parameters were measured using calcaneal quantitative ultrasound (QUS).While PFASs exposure was associated with a consistent negative relationship with bone health parameters, among four PFASs tested, only PFNA showed a significant negative relationship with bone parameter (β [95% CI], = - 72.7 [- 126.0, - 19.6], p = .010). PFNA was also associated with raised systolic blood pressure (p = .008), low density lipoprotein cholesterol (LDL-C; p.001), and total cholesterol (TC; p = .014). In addition, both PFOA and PFOS predicted elevation in LDL-C, and PFOA predicted increased TC, as well. In this analysis, PFASs were not strongly related to thyroid hormones, 25-hydroxy vitamin D, liver enzymes, or glucose homeostasis.PFASs exposure in obese children may play a role in adverse skeletal and cardiovascular risk profiles.

Anthropometric adjustments of bone measurements are necessary in Prader-Willi syndrome patients to correctly assess the bone status of these patients. This enables physicians to get a more accurate diagnosis of normal versus abnormal bone, allow for early and effective intervention, and achieve better therapeutic results. Bone mineral density (BMD) is decreased in patients with Prader-Willi syndrome (PWS). Because of largely abnormal body height and weight, traditional BMD Z-scores may not provide accurate information in this patient group. The goal of the study was to assess a cohort of individuals with PWS and characterize the development of low bone density based on two adjustment models applied to a dataset of BMD and bone mineral content (BMC) from dual-energy X-ray absorptiometry (DXA) measurements. Fifty-four individuals, aged 5–20 years with genetically confirmed PWS, underwent DXA scans of spine and hip. Thirty-one of them also underwent total body scans. Standard Z-scores were calculated for BMD and BMC of spine and total hip based on race, sex, and age for all patients, as well as of whole body and whole-body less head for those patients with total-body scans. Additional Z-scores were generated based on anthropometric adjustments using weight, height, and percentage body fat and a second model using only weight and height in addition to race, sex, and age. As many PWS patients have abnormal anthropometrics, addition of explanatory variables weight, height, and fat resulted in different bone classifications for many patients. Thus, 25–70 % of overweight patients, previously diagnosed as normal, were subsequently diagnosed as below normal, and 40–60 % of patients with below-normal body height changed from below normal to normal depending on bone parameter. This is the first study to include anthropometric adjustments into the interpretation of BMD and BMC in children and adolescents with PWS. This enables physicians to get a more accurate diagnosis of normal versus abnormal BMD and BMC and allows for early and effective intervention.

Gaucher disease (GD) is a lysosomal storage disorder; symptomatic patients with type 1 GD need long-term disease-specific therapy of which the standard of care has been enzyme replacement therapy (ERT). Thirty-eight of 40 patients (aged 9–71 years) clinically stable on ERT with imiglucerase, safely switched to a comparable dose of velaglucerase alfa (units/kg) during TKT034, a 12-month, open-label clinical study, and for 10–50 months in an extension study. The most common adverse events (AEs) judged to be drug-related in the extension were fatigue and bone pain. No drug-related serious AEs were reported. No AEs led to study withdrawal. At 24 months from baseline (baseline being TKT034 week 0), patients had generally stable hemoglobin, platelet, spleen, liver, and bone density parameters. Nevertheless, dose adjustment based on the achievement of therapeutic goals was permitted, and 10 patients, including seven patients who had platelet counts

Childhood and adolescence are critical periods of bone mineral content (BMC) accrual that may have long-term consequences for osteoporosis in adulthood. Adequate dietary calcium intake and weight-bearing physical activity are important for maximizing BMC accrual. However, the relative effects of physical activity and dietary calcium on BMC accrual throughout the continuum of pubertal development in childhood remains unclear. The purpose of this study was to determine the effects of self-reported dietary calcium intake and weight-bearing physical activity on bone mass accrual across the five stages of pubertal development in a large, diverse cohort of US children and adolescents. The Bone Mineral Density in Childhood study was a mixed longitudinal study with 7393 observations on 1743 subjects. Annually, we measured BMC by dual-energy X-ray absorptiometry (DXA), physical activity and calcium intake by questionnaire, and pubertal development (Tanner stage) by examination for up to 7 years. Mixed-effects regression models were used to assess physical activity and calcium intake effects on BMC accrual at each Tanner stage. We found that self-reported weight-bearing physical activity contributed to significantly greater BMC accrual in both sexes and racial subgroups (black and nonblack). In nonblack males, the magnitude of the activity effect on total body BMC accrual varied among Tanner stages after adjustment for calcium intake; the greatest difference between high- and low-activity boys was in Tanner stage 3. Calcium intake had a significant effect on bone accrual only in nonblack girls. This effect was not significantly different among Tanner stages. Our findings do not support differential effects of physical activity or calcium intake on bone mass accrual according to maturational stage. The study demonstrated significant longitudinal effects of weight-bearing physical activity on bone mass accrual through all stages of pubertal development.

Translational evaluation of disease progression and treatment response is critical to the development of therapies for osteoporosis. In this study, longitudinal in-vivo monitoring of odanacatib (ODN) treatment efficacy was compared to alendronate (ALN) in ovariectomized (OVX) non-human primates (NHPs) using high-resolution peripheral computed tomography (HR-pQCT). Treatment effects were evaluated using several determinants of bone strength, density and quality, including volumetric bone mineral density (vBMD), three-dimensional structure, finite element analysis (FEA) estimated peak force and biomechanical properties at the ultradistal (UD) radius at baseline, 3, 6, 9, 12, and 18 months of dosing in three treatment groups: vehicle (VEH), low ODN (2 mg/kg/day, L-ODN), and ALN (30 μg/kg/week). Biomechanical axial compression tests were performed at the end of the study. Bone strength estimates using FEA were validated by ex-vivo mechanical compression testing experiments. After 18 months of dosing, L-ODN demonstrated significant increases from baseline in integral vBMD (13.5%), cortical thickness (24.4%), total bone volume fraction BV/TV (13.5%), FEA-estimated peak force (26.6%) and peak stress (17.1%), respectively. Increases from baseline for L-ODN at 18 months were significantly higher than that for ALN in DXA-based aBMD (7.6%), cortical thickness (22.9%), integral vBMD (12.2%), total BV/TV (10.1%), FEA peak force (17.7%) and FEA peak stress (11.5%), respectively. These results demonstrate a superior efficacy of ODN treatment compared to ALN at the UD radii in ovariectomized NHPs.

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.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.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; p0·0001). 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.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.Alliance for Better Bone Health (Warner Chilcott and Sanofi).

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.

This study aimed to validate finite element analysis (FEA) estimation of strength, identify high-resolution peripheral quantitative computed tomography (HR-pQCT) measures correlating with strength, and evaluate the precision of HR-pQCT measurements to longitudinally monitor effects of osteoporosis treatment in ovariectomized (OVX) non-human primates (NHPs). HR-pQCT images were acquired in three groups of NHPs: Intact (n=10), OVX-odanacatib treated (OVX-ODN 30 mg/kg, n=10) and OVX-vehicle treated (OVX-Veh, n=10) at the ultradistal (UD) and distal 1/3 radii and tibia at 12, 16 and 20 months. FEA estimates of bone strength using the Pistoia criterion were validated by ex-vivo mechanical compression (r(2)=0.95) of the UD radius. Single linear regressions of FEA-determined ultimate stress showed high correlation with HR-pQCT derived parameters: integral vBMD (r(2)=0.86), bone volume fraction (r(2)=0.84) and cortical thickness (r(2)=0.79). Precision of HR-pQCT measurements, obtained from an excised radius and tibia, showed low variation (CV=0.005%-5.6%) and helped identify possible sources of error. Comparison of OVX-Veh and Intact groups showed decreases in bone parameters demonstrating trends consistent with bone loss. Comparison of OVX-ODN and OVX-Veh groups showed a treatment effect with increases in bone parameters: integral vBMD (477±27 vs. 364±22 mgHA/cm(3)) and cortical thickness (Ct.Th) (0.90±0.07 vs. 0.64±0.04 mm) at the UD radius, Ct.Th (2.15±0.28 vs. 1.56±0.08 mm) at the distal 1/3 radius. Axial compression peak stress calculated and obtained experimentally showed the OVX-ODN group was 33% stronger than the OVX-Veh group. We conclude that HR-pQCT and FEA serve as robust techniques to longitudinally monitor bone parameters and strength in NHP's.

Finite element (FE) models of long bones constructed from computed-tomography (CT) data are emerging as an invaluable tool in the field of bone biomechanics. However, the performance of such FE models is highly dependent on the accurate capture of geometry and appropriate assignment of material properties. In this study, a combined numerical–experimental study is performed comparing FE-predicted surface strains with strain-gauge measurements. Thirty-six major, cadaveric, long bones (humerus, radius, femur and tibia), which cover a wide range of bone sizes, were tested under three-point bending and torsion. The FE models were constructed from trans-axial volumetric CT scans, and the segmented bone images were corrected for partial-volume effects. The material properties (Young’s modulus for cortex, density–modulus relationship for trabecular bone and Poisson’s ratio) were calibrated by minimizing the error between experiments and simulations among all bones. The R2 values of the measured strains versus load under three-point bending and torsion were 0.96–0.99 and 0.61–0.99, respectively, for all bones in our dataset. The errors of the calculated FE strains in comparison to those measured using strain gauges in the mechanical tests ranged from −6% to 7% under bending and from −37% to 19% under torsion. The observation of comparatively low errors and high correlations between the FE-predicted strains and the experimental strains, across the various types of bones and loading conditions (bending and torsion), validates our approach to bone segmentation and our choice of material properties.

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.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.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 to12 years), adolescents (≥ 12 to20 years), young adults (≥ 20 to30 years), and older adults (≥ 30 to50 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.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.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.

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.The aim of this study was to compare various methods to adjust BMC/BMD for height in healthy children.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).We conducted the study in five clinical centers in the United States.We included 1546 BMDCS and 650 RDP participants (7 to 17 yr of age, 50% female).No interventions were used.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)).Spine and WB BMC/BMD(age)Z and BMAD(age)Z were positively (P0.005; 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 (P0.005; r = -0.20 to -0.34). The deviation between adjusted and BMC/BMD(age) Z-scores was associated with age for most measures (P0.005) except for BMC/BMD(haz).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.

The purpose of this study was to determine the minimum thickness of cortical bone required for the accurate measurement of cortical material density by computed tomography (CT) and to establish normal reference values. A phantom with several wall thicknesses of bone-like material was constructed to simulate various cortical widths. The CT density at each level of thickness was measured on a GE 9800 CT scanner and on the OsteoQuant, a special CT scanner optimized for the measurement of bone in the extremities. The minimum width required to attain the correct material density was determined for each scanner. Additionally, the material density and width of the cortex in the radius and/or femur were measured by CT in 761 healthy subjects, ages 4-84 years. The minimum thickness necessary for an accurate density evaluation of the walls of the phantom by CT was 2-2.5 mm; below these thresholds the values fell in a linear way relative to width. In humans, the material density of cortical bone in the appendicular skeleton was not influenced by height or weight, and the values were similar for all subjects, as long as the cortical width was above 2-2.5 mm. The cortical width increased with age up to 30 years and decreased from 50 years on. We conclude that the material density of cortical bone in the appendicular skeleton can be measured accurately by CT if the thickness of the cortex exceeds 2-2.5 mm.

Differences in osteoporotic hip fracture incidence between American whites and blacks and between women and men are considered to result, in part, from differences in bone mineral density and geometry at the femur. The aim of this study was to quantify differences in femoral bone density and geometry between a large sample of healthy American white and black women and men.Healthy American white (n=612) and black (n=164) premenopausal women, aged 23 to 57 years, and healthy American white (n=492) and black (n=169) men, aged 20 to 63 years, had volumetric bone mineral density (vBMD) and geometry variables measured at the femur by computerized tomography (CT), and areal bone mineral density (aBMD) at femoral neck measured by dual X-ray absorptiometry (DXA).American blacks had higher vBMD at the femoral neck and femoral shaft cortex than American whites whereas femoral axis length and femoral neck area were not different. Men had lower vBMD at the femoral neck and femoral cortex than women but had greater femoral axis length and femoral neck area than women. The higher aBMD in American blacks than whites persisted after correction for measured area whereas the higher aBMD in men than women disappeared.At the femoral neck, American whites have lower bone density than American blacks but similar geometry. Women have higher bone density than men in both races but have smaller geometry variables. The differences in bone density may account in part for the differences in hip fracture incidence between American blacks and whites, whereas the differences in femur size may account for the differences in hip fracture rates between men and women.

Gaucher disease (GD), the most common of the lysosomal storage disorders, results from mutations in the gene for acid β-glucosidase (glucocerebrosidase, GBA) leading to insufficient enzyme activity [1]. Glucocerebroside accumulation in the lysosomes of various cell types is responsible for the clinical manifestations of GD, which may include hepatomegaly, splenomegaly, anemia, thrombocytopenia, and bone marrow infiltration by lipid-engorged “Gaucher cells.” Occurring panethnically, type 1 (non-neuronopathic) is the most prevalent form of GD, while the less frequent type 2 (acute neuronopathic) and type 3 (chronic neuronopathic) are characterized by neurological involvement. More than half of type 1 patients are diagnosed in childhood and an earlier age of onset is indicative of more severe disease due to its progressive nature. Affecting both the marrow and mineral compartments, GD-related bone disease is the most significant cause of morbidity and long-term disability for patients. GD-related bone disease in children is a major cause for concern as it puts them at risk of developing irreversible and debilitating bone complications and interferes with normal growth and achievement of optimal bone mass during a critical period of growth. Timely initiation of appropriate disease management is necessary to avoid serious long-term complications such as growth retardation, osteoporosis, and fractures, and includes an initial radiological assessment and ongoing monitoring of both the bone marrow and mineral components. General guidelines for the monitoring of skeletal disease in children with type 1 GD recommend magnetic resonance imaging (MRI) of the spine and femora; radiography of the spine (when clinically indicated), chest, pelvis, and long bones; and dual-energy X-ray absorptiometry (DXA) of the spine and hips at baseline and every 12–24 months [2, 3]. However, these recommendations require further clarification in view of the challenges associated with their use in children with GD, especially since the use of conventional radiography is limited by a high burden of radiation and lack of sensitivity and specificity. The current standard of care for type 1 GD is enzyme replacement therapy (ERT) with imiglucerase (Cerezyme®; Genzyme Corporation, Cambridge, MA, USA). Oral substrate reduction therapy with miglustat (Zavesca®; Actelion, San Francisco, CA, USA) is also available for the treatment of patients with mild to moderate GD for whom ERT is not an option. The availability of therapy that may prevent or reverse GD-related bone disease heightens the need for early diagnosis and initiation of disease management in children. A Working Group of international experts met in October 2006 to recommend evidence- and consensus-based guidelines to facilitate the assessment and monitoring of bone disease in children with type 1 or type 3 GD.

In computed tomography (CT), the representation of edges between objects of different densities is influenced by the limited spatial resolution of the scanner. This results in the misrepresentation of density of narrow objects, leading to errors of up to 70% and more. Our interest is in the imaging and measurement of narrow bone structures, and the issues are the same for imaging with clinical CT scanners, peripheral quantitative CT scanners or micro CT scanners. Mathematical models, phantoms and tests with patient data led to the following procedures: (i) extract density profiles at one-degree increments from the CT images at right angles to the bone boundary; (ii) consider the outer and inner edge of each profile separately due to different adjacent soft tissues; (iii) measure the width of each profile based on a threshold at fixed percentage of the difference between the soft-tissue value and a first approximated bone value; (iv) correct the underlying material density of bone for each profile based on the measured width with the help of the density-versus-width curve obtained from computer simulations and phantom measurements. This latter curve is specific to a certain scanner and is not dependent on the densities of the tissues within the range seen in patients. This procedure allows the calculation of the material density of bone. Based on phantom measurements, we estimate the density error to be below 2% relative to the density of normal bone and the bone-width error about one tenth of a pixel size.

Adjuvant therapy for hormone receptor (HR) positive postmenopausal breast cancer patients includes aromatase inhibitors (AI). While both the non-steroidal AI letrozole and the steroidal AI exemestane decrease serum estrogen concentrations, there is evidence that exemestane may be less detrimental to bone. We hypothesized that single nucleotide polymorphisms (SNP) predict effects of AIs on bone turnover. Early stage HR-positive breast cancer patients were enrolled in a randomized trial of exemestane versus letrozole. Effects of AI on bone mineral density (BMD) and bone turnover markers (BTM), and associations between SNPs in 24 candidate genes and changes in BMD or BTM were determined. Of the 503 enrolled patients, paired BMD data were available for 123 and 101 patients treated with letrozole and exemestane, respectively, and paired BTM data were available for 175 and 173 patients, respectively. The mean change in lumbar spine BMD was significantly greater for letrozole-treated (-3.2 %) compared to exemestane-treated patients (-1.0 %) (p = 0.0016). Urine N-telopeptide was significantly increased in patients treated with exemestane (p = 0.001) but not letrozole. Two SNPs (rs4870061 and rs9322335) in ESR1 and one SNP (rs10140457) in ESR2 were associated with decreased BMD in letrozole-treated patients. In the exemestane-treated patients, SNPs in ESR1 (Rs2813543) and CYP19A1 (Rs6493497) were associated with decreased bone density. Exemestane had a less negative impact on bone density compared to letrozole, and the effects of AI therapy on bone may be impacted by genetic variants in the ER pathway.

Background Gaucher Disease type 1 (GD1) often manifests in childhood. Early treatment with enzyme replacement therapy (ERT) may prevent disease complications. We report the assessment of velaglucerase alfa ERT in pediatric GD1 patients who participated in a long-term extension study (HGT-GCB-044, ClinicalTrials.gov Identifier NCT00635427). Methods Safety and efficacy were evaluated in pediatric patients receiving velaglucerase alfa 30–60U/kg by intravenous infusion every other week. In addition to key hematological and visceral efficacy assessments, exploratory assessments conducted specifically in pediatric patients included evaluation of height, bone age, bone marrow burden, and Tanner stage of puberty. Results The study included 24 pediatric patients. Fifteen patients were naive to ERT on entry into the preceding trials TKT032 (12-month trial) or HGT-GCB-039 (9-month trial): in the preceding trials, ten of these 15 patients received velaglucerase alfa and five patients received imiglucerase ERT. Nine patients in the study were previously treated with imiglucerase for >30months and were switched to velaglucerase alfa in the preceding trial TKT034 (12-month trial). Cumulative ERT exposure in the clinical studies ranged from 2.0 to 5.8years. Three serious adverse events, including a fatal convulsion, were reported; none were deemed related to velaglucerase alfa. One patient tested positive for anti-velaglucerase alfa antibodies. An efficacy assessment at 24months showed that velaglucerase alfa had positive effects on primary hematological and visceral parameters in treatment-naive patients, which were maintained with longer-term treatment. Disease parameters were stable in patients switched from long-term imiglucerase ERT. Exploratory results may suggest benefits of early treatment to enable normal growth in pediatric patients. Conclusion The safety profile and clinical response seen in pediatric patients are consistent with results reported in adults.

UNLABELLED 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. INTRODUCTION The objective was to determine the effect of enzyme replacement therapy (ERT; Cerezyme, imiglucerase) on BMD in type 1 Gaucher disease (GD). MATERIALS AND METHODS The study population included all adults (men, 18-70 years; women, 18-50 years) enrolled in the International Collaborative Gaucher Group (ICGG) Gaucher Registry for whom lumbar spine BMD measurements were available. BMD data with up to 8 years of follow-up were analyzed for 160 patients who received no ERT and 342 patients treated with ERT alone. BMD was assessed by DXA of the lumbar spine. Z scores for patients with GD were compared with a reference population. From the model's estimate, percent of patients by age and sex with osteoporosis (T score < or = -2.5) were calculated. RESULTS DXA Z scores for patients with GD in the no ERT (untreated) group were significantly below normal (y intercept = -0.80 Z score units, p < 0.001) and remained approximately 1 SD below the reference population over time (slope = -0.010 Z score units per year, p = 0.68). The DXA Z scores for patients with GD who received ERT at a dose of 60 U/kg/2 weeks were significantly lower than the reference population at baseline (y-intercept = -1.17 Z score units, p < 0.001), but improved significantly over time (slope = +0.132 Z score units per year, p < 0.001). A significant dose-response relationship was noted for the ERT group, with the slopes for the three main dosing groups of 15, 30, and 60 U/kg/2 weeks of +0.064, +0.086, and +0.132 Z score units per year, respectively. The BMD of patients with GD treated with ERT increased to -0.12 (60 U/kg/2 weeks), -0.48 (30 U/kg/2 weeks), and -0.66 (15 U/kg/2 weeks) SD of the mean of the reference population after 8 years of ERT, approaching the reference population. Estimated risk of osteoporosis of this GD population, if left untreated, ranged from approximately 10 to 30% in women and 10% to 25% in men. CONCLUSIONS ERT with imiglucerase (Cerezyme) may increase BMD in patients with GD. Response to treatment with imiglucerase is slower for BMD than for hematologic and visceral aspects of GD. A normal (age- and sex-adjusted) BMD should be a therapeutic goal for patients with type 1 GD.

The International Society for Clinical Densitometry (ISCD) Committee on Standards of Bone Measurement (CSBM) consists of experts in technical aspects of bone densitometry. The CSBM recently reviewed the scientific literature on cross-calibration and precision assessment. A report with recommendations was presented at the 2005 ISCD Position Development Conference (PDC). Based on a thorough review of the data by the ISCD Expert Panel during the conference, the ISCD adopted Official Positions with respect to (1) cross-calibration when changing or replacing hardware; (2) the approach to cross-calibration when an entire system is changed to one made by either the same or a different manufacturer; (3) when no cross-calibration study or bone mineral density (BMD) comparison is done between facilities; and (4) the minimum acceptable precision for an individual technologist. We present here the ISCD Official Positions on these topics that were established as a result of the 2005 PDC, together with the associated rationales and supportive evidence.

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] x 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.

Background: Short-term studies established that calcium influences bone accretion during growth. Whether long-term supplementation influences bone accretion in young adults is not known. Objective: This study evaluated the long-term effects of calcium supplementation on bone accretion among females from childhood to young adulthood. Design: A 4-y randomized clinical trial recruited 354 females in pubertal stage 2 and optionally was extended for an additional 3 y. The mean dietary calcium intake of the participants over 7 y was approximately 830 mg/d; calcium-supplemented persons received an additional approximately 670 mg/d. Primary outcome variables were distal and proximal radius bone mineral density (BMD), total-body BMD (TBBMD), and metacarpal cortical indexes. Results: Multivariate analyses of the primary outcomes indicated that calcium-supplementation effects vary over time. Follow-up univariate analyses indicated that all primary outcomes were significantly larger in the supplemented group than in the placebo group at the year 4 endpoint. However, at the year 7 endpoint, this effect vanished for TBBMD and distal radius BMD. Longitudinal models for TBBMD and proximal radius BMD, according to the time since menarche, showed a highly significant effect of supplementation during the pubertal growth spurt and a diminishing effect thereafter. Post hoc stratifications by compliance-adjusted total calcium intake and by final stature or metacarpal total cross-sectional area showed that calcium effects depend on compliance and body frame. Conclusions: Calcium supplementation significantly influenced bone accretion in young females during the pubertal growth spurt. By young adulthood, significant effects remained at metacarpals and at the forearm of tall persons, which indicated that the calcium requirement for growth is associated with skeletal size. These results may be important for both primary prevention of osteoporosis and prevention of bone fragility fractures during growth.

A constrained least-squares technique to correct diagnostic x-ray tube energy spectra for inherent blurring by scintillation detectors was developed. The measured detector response function to monoenergetic sources was used to construct a matrix that modeled the energy broadening in the crystal. This blurring operator, along with an estimate of statistical noise in the count data, comprised the a priori system knowledge required for application of the method. Tungsten anode spectra up to 90 kVp were acquired with a Nal-photomultiplier detector system at a source-to-detector distance of 30 cm. X-ray tube output was collimated at the detector by a 0.5 mm diameter pinhole collimator. Measured Nal spectra were compared to both published reference data and to spectra acquired in our laboratory with a Ge detector system. Application of the constrained least-squares technique involved first defining a criterion function that combined an assessment of the goodness of fit with a weighted measure of the smoothness of the solution. Minimization of this function resulted in the corrected spectrum. While it is not possible to recover the characteristic tungsten peaks, the success of our method in deconvolving the measured spectra was demonstrated by a significant improvement in agreement with reference data. To provide a measure of this agreement, a histogram of the differences between the two curves was generated. The full width at half maximum (FWHM) of the Gaussian distribution fit to the histogram was used to quantify the similarity between the spectra and the reference data, both before and after correction. As spectral agreement improves, the FWHM becomes smaller. We show that application of the constrained least-squares technique improved spectral matching by 20%-60%.

An instrument is demonstrated whereby radiographic images of a sample's electron density are compiled from the information encoded in the energy spectra of gamma rays backscattered from one side of the sample. It is assumed that access is restricted to only one surface of the object under inspection. Use of energy coding allows imaging in a fan beam rather than independent interrogation of individual volume elements. The Multiplexed Compton Scatter Tomograph instrument consists of an array of high-energy-resolution detectors and fan beam collimators. Instrument signals are converted to electron density images using a penalized weighted least squares image reconstruction algorithm coupled with a deterministic system model that includes effects of Doppler broadening. The proof-of-principle instrument is demonstrated on aluminum samples. In an 8 mm thick sample with a 4 mm void in its center, contrast recovery of 90% is achieved. In a 10 mm thick sample with a 3 mm void at the back about 85% of the contrast is recovered.

New models describing anthropometrically adjusted normal values of bone mineral density and content in children have been created for the various measurement sites. The inclusion of multiple explanatory variables in the models provides the opportunity to calculate Z-scores that are adjusted with respect to the relevant anthropometric parameters.Previous descriptions of children's bone mineral measurements by age have focused on segmenting diverse populations by race and sex without adjusting for anthropometric variables or have included the effects of a single anthropometric variable.We applied multivariate semi-metric smoothing to the various pediatric bone-measurement sites using data from the Bone Mineral Density in Childhood Study to evaluate which of sex, race, age, height, weight, percent body fat, and sexual maturity explain variations in the population's bone mineral values. By balancing high adjusted R(2) values with clinical needs, two models are examined.At the spine, whole body, whole body sub head, total hip, hip neck, and forearm sites, models were created using sex, race, age, height, and weight as well as an additional set of models containing these anthropometric variables and percent body fat. For bone mineral density, weight is more important than percent body fat, which is more important than height. For bone mineral content, the order varied by site with body fat being the weakest component. Including more anthropometrics in the model reduces the overlap of the critical groups, identified as those individuals with a Z-score below -2, from the standard sex, race, and age model.If body fat is not available, the simpler model including height and weight should be used. The inclusion of multiple explanatory variables in the models provides the opportunity to calculate Z-scores that are adjusted with respect to the relevant anthropometric parameters.

The objectives of this study were (1) to determine whether there are differences in bone density in children versus adults with osteogenesis imperfecta type I (OI-type I) using computed tomography (CT) bone density measurements, (2) to determine whether there are differences in bone density between normal infants and infants with OI-type I using CT bone density measurements and (3) to determine whether CT bone density measurements could be helpful in investigating the infant with unexplained fractures. CT bone density measurements determine both the cortical bone density (CBD) and the trabecular bone density (TBD). CT bone density was determined using the OsteoQuant in 14 individuals with OI-type I who ranged in ages from 8 months to 45 years. The control groups consisted of over 1000 normal individuals, mostly adults, and included 7 normal infants who ranged in age from 10 months to 27 months. One of the individuals with OI-type I was a 4-month-old infant with multiple, unexplained fractures who had no other features of OI-type I and whose parents were accused of child abuse. Infants and children with OI-type I had low CBD and low TBD compared with normal controls, whereas adults with OI-type I had low TBD and high CBD when compared with controls. The one infant with multiple unexplained fractures and no other features of OI-type I had a bone density profile suggesting OI-type I with a low TBD and low CBD. Subsequent collagen analysis showed biochemical evidence of OI-type I. Individuals with OI-type I have abnormal CT bone density profiles that evolve over time from a low CBD and low TBD during infancy and childhood to a high CBD and low TBD during adulthood. This may explain the decreased frequency of fractures in individuals with OI-type I in adulthood compared with childhood. Individuals with OI-type I can present with only multiple unexplained fractures and have no other clinical features to strongly suggest the diagnosis. CT bone density measurements can be helpful in these atypical cases of OI-type I and should be considered in the investigation of the infant with unexplained fractures to help distinguish intrinsic bone disease from child abuse.

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.

Odanacatib (ODN) is a selective and reversible Cathepsin K (CatK) inhibitor currently being developed as a once weekly treatment for osteoporosis. Here, effects of ODN compared to alendronate (ALN) on bone turnover, DXA-based areal bone mineral density (aBMD), QCT-based volumetric BMD (vBMD) and geometric parameters were studied in ovariectomized (OVX) rhesus monkeys. Treatment was initiated 10 days after ovariectomy and continued for 20 months. The study consisted of four groups: L-ODN (2 mg/kg, daily p.o.), H-ODN (8/4 mg/kg daily p.o.), ALN (15 μg/kg, twice weekly, s.c.), and VEH (vehicle, daily, p.o.). L-ODN and ALN doses were selected to approximate the clinical exposures of the ODN 50-mg and ALN 70-mg once-weekly, respectively. L-ODN and ALN effectively reduced bone resorption markers uNTx and sCTx compared to VEH. There was no additional efficacy with these markers achieved with H-ODN. Conversely, ODN displayed inversely dose-dependent reduction of bone formation markers, sP1NP and sBSAP, and L-ODN reduced formation to a lesser degree than ALN. At month 18 post-OVX, L-ODN showed robust increases in lumbar spine aBMD (11.4%, p

Background: Although it is widely accepted that dietary calcium intake (CaI) and weight-bearing physical activity (WBA) increase bone mass accrual during growth, few prospective studies have followed children from early childhood to sexual maturity to evaluate this relationship.

Objective. To evaluate the association between chronological age, skeletal age, pubertal stage, and basic anthropometry with bone mass of the total body, forearm, and second metacarpal bone in 456 healthy Caucasian females, aged 8–13 years. Design. Total body and forearm bone measurements were performed by dual X-ray absorptiometry, while bone mass of the second metacarpal was assessed by radiogrammetry. Skeletal age (SA) was assessed by the FELS method and pubertal stage was self-determined by selecting corresponding illustrations of breast and pubic hair development. The C p criterion was used to select the best multiple regression model containing the subset of independent variables with the least bias and best predictive ability for each of the measured bone mass variables. Results. Of all the independent variables, weight, stature, and SA emerged as the most significant predictors for almost all the bone mass variables. Multiple regression models were created based on the C p criterion with the resulting R 2 (adjusted) for bone mineral content of total body, proximal forearm, ultradistal forearm, length of second metacarpal, as well as of total, medullary, and cortical areas: 0.793, 0.523, 0.390, 0.602, 0.232, 0.073, and 0.264, respectively. The measured bone variables were also regressed on SA using either quadratic or linear equations, depending on the shape of the cubic splines used for the best curve fitting. Significant positive association (p

To assess the value of computed tomographic (CT) measurements of cortical bone in children with osteopenia.The area and density of cortical bone in the midshaft of the femur were measured with CT in 37 children with osteopenia. Twenty had osteoporosis in one leg, nine had osteogenesis imperfecta (IO), and eight had vitamin D-resistant rickets. Comparisons were made between the CT measurements of the normal and abnormal extremities and between patients with OI or rickets and a group of 17 healthy, matched children.Sex, age, height, and weight did not influence cortical bone density; values were similar for the 17 control subjects. Children with osteoporosis and IO had reduced bone area but normal bone density. Compared with control subjects, patients with rickets had similar bone area but reduced bone density (869 mg/cm3 K2HPO4 +/- 79 [standard deviation] vs 1,132 mg/cm3 K2HPO4 +/- 41).CT measurements of area and density of cortical bone aided the differentiation of the various disorders that cause osteopenia in children.

Unloading of bones because of bed rest, paralysis, and immobilization results eventually in osteoporosis and fractures. This loss is particularly apparent in the trabecular compartment of weightbearing bones but includes most parts of the skeleton in its severe forms. Quantitative bone measurements can identify the site of major losses and provide a loss progression.

We hypothesized that overall disease activity or the severity of involvement of individual disease compartments, as measured by clinical and surrogate markers, predict the risk of avascular osteonecrosis (AVN) or fractures in type 1 Gaucher disease (GD1). We applied our risk-set matched case-control method to identify four patient groups within the International Collaborative Gaucher Group (ICGG) Gaucher Registry based on the presence and absence of AVN and fractures. Characteristics of GD1 were examined by comparing the distributions of each risk factor in cases versus matched controls using conditional logistic regression to calculate adjusted odds ratios (OR). Potential risk factors included hematological and visceral parameters, GD1 biomarkers, white blood cells, GBA1 genotype, and spine and femur dual-energy X-ray absorptiometry (DXA) Z-scores. In the total population of 5894 ICGG Gaucher Registry patients, 544 experienced at least one episode of AVN; 2008 reported no history of AVN. Clinical and surrogate markers of disease activity were similar in patients with and without AVN; patients with AVN were 1.6 times more likely to be anemic compared to matched controls (OR = 1.59; 95% confidence interval [CI], 1.06-2.38, p 0.05). For fractures, 319 patients suffered fractures and 1233 had no prior history of fractures. Clinical and surrogate markers of disease in patients with and without fractures were similar, except for mean lumbar spine DXA Z-scores. Among patients with fractures, 49.3% had DXA Z-scores ≤ -1 compared to 31.0% in the control group. Compared to controls with Z-scores -1.0, GD1 patients exhibiting Z-scores ≤ -1 had an OR of 5.55 (95% CI, 1.81-17.02, p 0.01) for fracture. In GD1, after controlling for gender, year of birth, treatment status, and splenectomy status, we identified new risk factors for AVN and fractures. Concurrent anemia was associated with an increased risk for AVN. Low bone mineral density of the lumbar spine was a strong risk factor for fractures of the spine and femur in GD1.

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.

The monitoring time interval (MTI) is the expected time in years necessary to identify a change between two measures that exceeds the measurement error. Our purpose was to determine MTI values for dual-energy X-ray absorptiometry (DXA) scans in normal healthy children, according to age, sex, and skeletal site. 2014 children were enrolled in the Bone Mineral Density in Childhood Study and had DXA scans of the lumbar spine, total hip, nondominant forearm, and whole body. Measurements were obtained annually for seven visits from 2002 to 2010. Annualized rates of change were calculated by age and sex for all bone regions. A subgroup of 155 children ages 6 to 16 years (85 boys) had duplicate scans for calculation of scan precision. The bone mineral density (BMD) regions of interest included the spine, total body less head (TBLH), total hip, femoral neck, and one-third radius. Bone mineral content (BMC) was also evaluated for the spine and TBLH. The percent coefficient of variation (%CV) and MTI were calculated for each measure as a function of age and sex. The MTI values were substantially less than 1 year for the TBLH and spine BMD and BMC for boys ≤ 17 years and girls ≤ 15 years. The hip and one-third radius MTIs were generally 1 year in the same group. MTI values as low as 3 months were found during the peak growth years. However, the MTI values in late adolescence for all regions were substantially longer and became nonsensical as each region neared the age for peak bone density. All four DXA measurement sites had reasonable (1 year) MTI values for boys ≤ 17 years and girls ≤ 15 years. MTI was neither useful nor stable in late adolescence and young adulthood. Alternative criteria to determine scan intervals must be used in this age range.

The aim of this study was to develop quantitative computed-tomography (QCT)-based bone-strength indicators that highly correlate with finite-element (FE)-based strength. Transaxial QCT scans were obtained from 36 major, cadaveric, long bones (humerus, radius, femur and tibia) from 4 females and 2 males, 53 to 86 years old. These images were used to construct the FE models and to develop the QCT-based bone strength indicators under every-day, simplified loading conditions. We have evaluated the performance of area-weighted (AW), density-weighted (DW) and modulus-weighted (MW) rigidity measures as well as popular strength indicators like section modulus (Z) and stress–strain index (SSI). We have also developed a novel strength metric, the centroid deviation, which analyzes the spatial distribution of the centroids along the length of the bone. The correlation results show that the MW polar moment of inertia and the MW moment of inertia are the two top-performers for all bones and loading conditions (average r > 0.89). The MW centroid deviations correlated highly with the estimated load to fracture for all bones under compression (r > 0.83), except for the humerus (r = 0.67). Consistently DW or MW rigidity measures produced a statistically significant improvement in capturing bone strength compared to AW rigidity measures. As expected, MW rigidity measures showed a higher correlation with the FE-based fracture load than the DW rigidity measures; however, the improvement was not statistically significant. Through this study we present a short-list of useful QCT-based strength parameters that correlate well with FE-based fracture load. Although a few parameters perform reasonably well across most bones and loading conditions, a judicious assessment of bone strength should include multiple parameters evaluated at multiple critical locations in the long bones, with attention to the type of loading and bone type.

OBJECTIVE We attempted to design and construct a computed tomography scanner with an in vivo precision of better than 0.5% for trabecular bone density of the radius. MATERIALS AND METHODS A number of considerations involving physical limitations, stability of the system, and cost led to the development of the OsteoQuant, an isotope-based computed tomography scanner working on the translate-rotate principle. With 16 detectors providing a total of 128 projections and 256 data points per projection, the measurement time for one cross section is typically 90 s. Optimal for bone measurements in arms and legs, 125I was chosen as the photon source. The detectors are photomultipliers with Nal(TI) crystals employed in the counting mode. Usually, six to ten slices are measured at a given site, 2 mm apart from each other, and bone density is calculated for trabecular, subcompact, and compact bone. For repeat measurements, the evaluation sites are carefully matched, and the same volume of bone is analyzed at each measurement occasion. RESULTS The long-term precision of the scanner, measured with a water cylinder, is 0.03%. This error includes the performance of the scanner hardware, calibration of the photon count rates, and reconstruction process. In vivo precision is influenced by additional factors such as slice positioning, patient cooperation, and bone contour detection. At the distal end of the tibia, trabecular bone density can be measured with a precision of 0.1%. The error for trabecular bone density in the radius is 0.3%. CONCLUSION The OsteoQuant surpasses the design goals and represents an ideal instrument to assess small changes in bone density over time.

Context: Whether a child with low bone mineral density (BMD) at one point in time will continue to have low BMD, despite continued growth and maturation, is important clinically. The stability of a characteristic during growth is referred to as “tracking.” Objective: We examined the degree of tracking in bone mineral content (BMC) and BMD during childhood and adolescence and investigated whether tracking varied according to age, sexual maturation, and changes in growth status. Design: We conducted a longitudinal study with measurements at baseline and annually for 3 yr. Setting: The Bone Mineral Density in Childhood Study was conducted at five clinical centers in the United States. Study Participants: A total of 1554 girls and boys, ages 6–16 yr at baseline, participated in the study. Main Outcome Measures: Whole body, spine, hip, and forearm BMC and BMD were measured by dual-energy x-ray absorptiometry, and age-, sex-, and race-specific Z-scores were calculated. Deviation from tracking was calculated as the Z-score at yr 3 minus baseline. Results: Correlations between Z-scores at baseline and yr 3 ranged from 0.76–0.88. Among children with a Z-score below −1.5 at baseline, 72–87% still had a Z-score below −1 after 3 yr. Age, sexual maturation, and deviations in growth status (P < 0.01) were associated with deviation from tracking; however, tracking was strongly evident even after adjusting for the effects of age, maturation, and growth. Conclusions: Bone density showed a high degree of tracking over 3 yr in children and adolescents. Healthy children with low bone density will likely continue to have low bone density unless effective interventions are instituted.

A new model describing normal values of bone mineral density in children has been evaluated, which includes not only the traditional parameters of age, gender, and race, but also weight, height, percent body fat, and sexual maturity. This model may constitute a better comparative norm for a specific child with given anthropometric values. Previous descriptions of children’s bone mineral density (BMD) by age have focused on segmenting diverse populations by race and gender without adjusting for anthropometric variables or have included the effects of anthropometric variables over a relatively homogeneous population. Multivariate semi-metric smoothing (MS2) provides a way to describe a diverse population using a model that includes multiple effects and their interactions while producing a result that can be smoothed with respect to age in order to provide connected percentiles. We applied MS2 to spine BMD data from the Bone Mineral Density in Childhood Study to evaluate which of gender, race, age, height, weight, percent body fat, and sexual maturity explain variations in the population’s BMD values. By balancing high adjusted R 2 values and low mean square errors with clinical needs, a model using age, gender, race, weight, and percent body fat is proposed and examined. This model provides narrower distributions and slight shifts of BMD values compared to the traditional model, which includes only age, gender, and race. Thus, the proposed model might constitute a better comparative standard for a specific child with given anthropometric values and should be less dependent on the anthropometric characteristics of the cohort used to devise the model. The inclusion of multiple explanatory variables in the model, while creating smooth output curves, makes the MS2 method attractive in modeling practically sized data sets. The clinical use of this model by the bone research community has yet to be fully established.

The goal of this study was to evaluate a number of modern multi-slice helical CT scanners with respect to random and systematic errors in the measurement of bone density. For this purpose, a rod phantom was designed to mimic a patient with various amounts of bone, and scans of the rod phantom along with the Mindways calibration phantom were taken using General Electric, Siemens and Toshiba 4-, 16- and 64-slice CT scanners.

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%.

A patient's bone status is commonly assessed by radiologic methods. Although the desired information concentrates on the probability of future fractures, the radiologic density is widely used as a surrogate for bone strength. There have been attempts to develop new parameters that have a closer relationship with bone strength, but the investigators tend to use a linear relationship between measured density and their strength-related parameter. We briefly discuss the background of mechanical deformation as it relates to bone and point out some of the basic principles involved in the assessment of strength. We then show that the relevant connection between strength and density makes use of the elastic modulus, which relates to density in a power law with an exponent of close to 2. We suggest modifications of some of the widely used strength-related parameter expressions that follow the theory more closely and will, thus, have the potential to better reflect the patient's bone status.