Helen Woodhead

Importance of lean mass in the interpretation of total body densitometry in children and adolescents

OBJECTIVE Most studies that use total body dual energy x-ray absorptiometry (DEXA) in children rely on areal bone mineral density (BMD=bone mineral content [BMC]/bone area [BA]) and compare the output with age- and sex-specific normative data. Because this approach is prone to size-related misinterpretation, this study focuses on the interrelations among BMC, body size (height), and lean tissue mass (LTM). STUDY DESIGN This cross-sectional study presents normative total body LTM data in relation to height and BMC for 459 healthy white subjects (249 female), 3 to 30 years of age. Guidelines for DEXA interpretation in children are provided and illustrated for patients with growth hormone deficiency (n=5) and anorexia nervosa (n=5). RESULTS LTM/height tended to be greater in male than in girls. The BMC/LTM ratio was greater in female than in boys (P<.001), even after adjustment for age and height. Sex-specific reference curves were created for LTM/height, the BMC/LTM ratio, BA/height, and BMC/BA. CONCLUSIONS We recommend that total body DEXA in children should be interpreted in 4 steps: (1) BMD or BMC/age, (2) height/age, (3) LTM/height, and (4) BMC/LTM ratio for height. This allows differentiation of the origin of a low BMD or BMC/age, for example, short stature and primary, secondary, and mixed bone defects.

The re-emerging burden of rickets: a decade of experience from Sydney

Aim: To define the demographics and clinical characteristics of cases presenting with nutritional rickets to paediatric centres in Sydney, Australia. Methods: Retrospective descriptive study of 126 cases seen from 1993 to 2003 with a diagnosis of vitamin D deficiency and/or confirmed rickets defined by long bone x ray changes. Results: A steady increase was seen in the number of cases per year, with a doubling of cases from 2002 to 2003. Median age of presentation was 15.1 months, with 25% presenting at less than 6 months of age. The most common presenting features were hypocalcaemic seizures (33%) and bowed legs (22%). Males presented at a younger age, with a lower weight SDS, and more often with seizures. The caseload was almost exclusively from recently immigrated children or first generation offspring of immigrant parents, with the region of origin predominantly the Indian subcontinent (37%), Africa (33%), and the Middle East (11%). Seventy nine per cent of the cases were born in Australia. Eleven cases (all aged <7 months) presented atypically with hyperphosphataemia. Conclusions: This large case series shows that a significant and increasing caseload of vitamin D deficiency remains, even in a developed country with high sunlight hours. Cases mirror recent immigration trends. Since birth or residence in Australia does not appear to be protective, screening of at risk immigrant families should be implemented through public health policies.

Mid-femur geometry and biomechanical properties in 15- to 18-yr-old female athletes

PURPOSE Right-leg mid-femur geometry and biomechanical indices of bone strength were compared among elite cyclists (CYC), runners (RUN), swimmers (SWIM), triathletes (TRI), and controls (C)-10 subjects per group. METHODS Bone cross-sectional areas (CSA), volumes (Vol), and cross-sectional moments of inertia (CSMI) were assessed by magnetic resonance imaging (MRI), and cortical volumetric bone density (volBMD) was determined as the quotient of DXA-derived bone mineral content (BMC) and MRI-derived cortical bone volume. Bone strength index (BSI) was calculated as the product of cortical volBMD and CSMI. RESULTS RUN had higher (P < 0.05) size- (femur length and body mass) adjusted (ANCOVA) cortical CSA than C, SWIM, and CYC; and higher size, age, and years of sport-specific training- (YST) adjusted cortical CSA than SWIM and CYC. TRI had higher (P < 0.05) size-adjusted CSA than SWIM. SWIM and CYC had significantly larger (P < 0.05) size-adjusted medullary cavity CSA than RUN and TRI, and the difference between CYC and RUN persisted after additional adjustment for age and YST. RUN had significantly (P < 0.05) greater size-adjusted CSMI and BSI than C, SWIM, and CYC; and higher size, age, and YST-adjusted CSMI and BSI than SWIM and CYC. Mid-femur areal bone mineral density (BMD) was significantly (P < 0.05) higher for RUN compared with CYC only, but there were no other differences among groups for BMC, bone volumes, or volumetric total or cortical BMD. CONCLUSIONS Running, a weight-bearing exercise, is associated with more favorable geometric and biomechanical characteristics in relation to bone strength, compared with the weight supported activities of swimming and cycling. Differences may reflect skeletal adaptations to the specific mechanical-loading patterns inherent in these sports.

A comparison of bone geometry and cortical density at the mid-femur between prepuberty and young adulthood using magnetic resonance imaging

In upper extremity bones, a sexual dimorphism exists in the development of periosteal and endocortical bone surfaces during growth. Little is known about developmental patterns of bone geometry at weight-bearing bones like the femur. Using MRI and dual energy X-ray absorptiometry (DXA), this study assessed the differences in mid-femoral total (TA), cortical (CA) and medullary areas (MA), cortical thickness, and cortical density (BMD(compartment)) between prepuberty and young adulthood in 145 healthy subjects (94 females) 6 to 25 years old. Additionally, agreement between mid-femoral total bone volume (TV) measurements by DXA and MRI were investigated. In both sexes, TA, CA, MA, and cortical thickness were significantly larger in adults compared to prepubertal subjects (P < 0.001), and males had greater values than females. This sex difference persisted for TA, CA, and cortical thickness (P < 0.05), but not MA, after adjusting for femur length and weight. Mean (SD) cortical BMD increased from 1.05 (0.07) and 1.09 (0.10) g/cm(3) in prepubertal children to 1.46 (0.14) and 1.42 (0.1) g/cm(3) in young adults, females and males, respectively (P < 0.001). TV measurements by DXA were significantly greater than by MRI (P < 0.001) in young adults. In conclusion, periosteal and endocortical expansion and increasing cortical BMD are the growth processes found at the mid-femur in both sexes. Our findings contrast to that in upper extremity bones, where MA is constant in females during growth. The difference in femoral bone development may be due to higher strains caused by weight bearing and genetic factors. DXA, in contrast to MRI, is inaccurate in the determination of mid-femoral TV measures.

Homozygous Thyroid Hormone Receptor β-Gene Mutations in Resistance to Thyroid Hormone: Three New Cases and Review of the Literature

CONTEXT The most common cause of resistance to thyroid hormone (RTH) is heterozygous thyroid hormone receptor β (THRB) gene mutations. Homozygous mutations in the THRB gene are a rare event. OBJECTIVE In this study, the clinical findings of three new patients (belonging to two families) homozygous for mutations in the THRB gene are compared to three other families in which affected individuals lack a normal TRβ. METHODS We conducted clinical studies and genetic analyses. RESULTS The clinical presentation in all three homozygous subjects was unusually severe; their phenotype was characterized by compromised intellectual development, tachycardia, goiter, growth retardation, and hearing loss. This was comparable with one other reported patient homozygous for mutant TRβ, but not in RTH due to THRB gene deletions. CONCLUSION We report three new subjects, from two families, in whom RTH was associated with homozygous mutations in the THRB gene. They represent an important addition to the single known patient homozygous for a mutant TRβ. The clinical and laboratory abnormalities indicate a strong dominant-negative effect and are in agreement with data obtained from mice expressing a mutant Thrb in both alleles. This report strengthens the concept that the mutated TRβ interferes with the function of the TRα1 in humans.

Early Determinants of Fractures in Rett Syndrome

OBJECTIVES. The goals were to compare the fracture incidence in Rett syndrome with that in the general population and to investigate the impact of genotype, epilepsy, and early motor skills on subsequent fracture incidence in girls and young women with Rett syndrome. METHODS. The Australian Rett syndrome study, a population-based study operating since 1993, investigated Australian subjects with Rett syndrome born since 1976. The 234 (81.2%) of 288 verified cases in the Australian Rett syndrome database in 2004 whose families had completed follow-up questionnaires and provided information about fracture history were included in the analyses. The main outcomes were fracture incidence in the Rett syndrome population and fracture risk according to genotype, presence of epilepsy, and early motor profile. RESULTS. Fracture incidence in this cohort was 43.3 episodes per 1000 person-years, nearly 4 times greater than the population rate. Risk was increased specifically in cases with p.R270X mutations and in cases with p.R168X mutations. Having epilepsy also increased fracture risk, even after adjustment for genotype. CONCLUSIONS. Girls and young women with Rett syndrome are at increased risk of fracture. Those with mutations found previously to be more severe and those with epilepsy have an increased propensity toward fractures. Improved understanding of the risk factors for fracture could contribute to better targeting of interventions to decrease fracture incidence in this vulnerable population.

Bone strength index in adolescent girls: does physical activity make a difference?

Background: Bone strength index (BSI) combines bone mineral and bone biomechanical properties to measure resistance to bending. This index may have greater clinical significance than the more often described markers of bone mineral content (BMC), areal density, or geometry alone and, in turn, may show a stronger relation to fracture risk. The BSI is the product of volumetric cortical bone mineral density (BMD) and cross sectional moment of inertia within a region of interest. Calculations combine dual energy x ray absorptiometry and magnetic resonance imaging technologies and provide a useful, non-invasive measure of in vivo bone strength. Objectives: (a) To compare BSI in adolescent female middle distance runners and age matched controls; (b) to examine factors predictive of BSI in adolescent girls. Methods: Twenty adolescent female middle distance runners (mean (SD) age 16 (1.7) years, physical activity 8.9 (2.1) hours a week) and 20 female controls (age 16 (1.8) years, physical activity 2.0 (0.07) hours a week) were recruited. To calculate BSI, a region of interest representing 10% of the mid-distal tibia was analysed for dual energy x ray absorptiometry derived BMC and was combined with bone geometry and biomechanical properties obtained by magnetic resonance imaging assessments. Potential predictors of BSI were also examined. Results: Independent t tests showed that BMC (p  =  0.028), cortical bone volume (p  =  0.002), volumetric cortical BMD (p  =  0.004), cross sectional moments of inertia (p  =  0.005), and BSI (p  =  0.002) were higher in the distal tibia of athletes than of controls. The strongest predictor of BSI was hours of physical activity a week (R2  =  0.46). Conclusions: Athletes habitually exposed to high training loads displayed greater BSI at the distal tibia than controls. The results further confirm BSI as a significant and discerning marker in musculoskeletal health in adolescent girls engaged in high and low mechanical loading.

Measurement of midfemoral shaft geometry: Repeatability and accuracy using magnetic resonance imaging and dual-energy X-ray absorptiometry

Although macroscopic geometric architecture is an important determinant of bone strength, there is limited published information relating to the validation of the techniques used in its measurement. This study describes new techniques for assessing geometry at the midfemur using magnetic resonance imaging (MRI) and dual‐energy X‐ray absorptiometry (DXA) and examines both the repeatability and the accuracy of these and previously described DXA methods. Contiguous transverse MRI (Philips 1.5T) scans of the middle one‐third femur were made in 13 subjects, 3 subjects with osteoporosis. Midpoint values for total width (TW), cortical width (CW), total cross‐sectional area (TCSA), cortical cross‐sectional area (CCSA), and volumes from reconstructed three‐dimensional (3D) images (total volume [TV] and cortical volume [CVol]) were derived. Midpoint TW and CW also were determined using DXA (Lunar V3.6, lumbar software) by visual and automated edge detection analysis. Repeatability was assessed on scans made on two occasions and then analyzed twice by two independent observers (blinded), with intra‐ and interobserver repeatability expressed as the CV (CV ± SD). Accuracy was examined by comparing MRI and DXA measurements of venison bone (and Perspex phantom for MRI), against “gold standard” measures made by vernier caliper (width), photographic image digitization (area) and water displacement (volume). Agreement between methods was analyzed using mean differences (MD ± SD%). MRI CVs ranged from 0.5 ± 0.5% (TV) to 3.1 ± 3.1% (CW) for intraobserver and 0.55 ± 0.5% (TV) to 3.6 ± 3.6% (CW) for interobserver repeatability. DXA results ranged from 1.6 ± 1.5% (TW) to 4.4 ± 4.5% (CW) for intraobserver and 3.8 ± 3.8% (TW) to 8.3 ± 8.1% (CW) for interobserver variation. MRI accuracy was excellent for TV (3.3 ± 6.4%), CVol (3.5 ± 4.0%), TCSA (1.8 ± 2.6%), and CCSA (1.6 ± 4.2%) but not TW (4.1 ± 1.4%) or CW (16.4 ± 14.9%). DXA results were TW (6.8 ± 2.7%) and CW (16.4 ± 17.0%). MRI measures of geometric parameters of the midfemur are highly accurate and repeatable, even in osteoporosis. Both MRI and DXA techniques have limited value in determining cortical width. MRI may prove valuable in the assessment of surface‐specific bone accrual and resorption responses to disease, therapy, and variations in mechanical loading.

Clinical guidelines for management of bone health in Rett syndrome based on expert consensus and available evidence

Objectives We developed clinical guidelines for the management of bone health in Rett syndrome through evidence review and the consensus of an expert panel of clinicians. Methods An initial guidelines draft was created which included statements based upon literature review and 11 open-ended questions where literature was lacking. The international expert panel reviewed the draft online using a 2-stage Delphi process to reach consensus agreement. Items describe the clinical assessment of bone health, bone mineral density assessment and technique, and pharmacological and non-pharmacological interventions. Results Agreement was reached on 39 statements which were formulated from 41 statements and 11 questions. When assessing bone health in Rett syndrome a comprehensive assessment of fracture history, mutation type, prescribed medication, pubertal development, mobility level, dietary intake and biochemical bone markers is recommended. A baseline densitometry assessment should be performed with accommodations made for size, with the frequency of surveillance determined according to individual risk. Lateral spine x-rays are also suggested. Increasing physical activity and initiating calcium and vitamin D supplementation when low are the first approaches to optimizing bone health in Rett syndrome. If individuals with Rett syndrome meet the ISCD criterion for osteoporosis in children, the use of bisphosphonates is recommended. Conclusion A clinically significant history of fracture in combination with low bone densitometry findings is necessary for a diagnosis of osteoporosis. These evidence and consensus-based guidelines have the potential to improve bone health in those with Rett syndrome, reduce the frequency of fractures, and stimulate further research that aims to ameliorate the impacts of this serious comorbidity.

Sex-specific developmental changes in muscle size and bone geometry at the femoral shaft

INTRODUCTION When expressed as a percentage of the average result in young adults, bone mineral content lags behind bone length before puberty. Even though this observation has led to speculation about bone fragility in children, such relationships could simply be due to scaling effects when measures with different geometrical dimensions are compared. METHODS The study population comprised 145 healthy subjects (6-25 years, 94 females). Magnetic resonance imaging and dual-energy X-ray absorptiometry were used to determine femur length, bone mineral content, cortical bone mineral density, cross-sectional bone geometry (bone diameter; cortical thickness; total, cortical and medullary areas; cross-sectional and polar moments of area; bone strength index) and muscle area at the proximal one-third site of the femur. Results were dimensionally scaled by raising two-, three- and four-dimensional variables to the power of 1/2, 1/3 and 1/4, respectively. Sex-differences were also assessed before and after functionally adjusting variables for femur length and weight or muscle size. RESULTS In prepubertal children, unscaled results expressed as percentages of adult values were lowest for variables with the highest dimensions (e.g., moments of area<bone mineral content<cross-sectional areas<femur length). However, when dimensionally scaled, results in children represented similar percentages of the respective average adult values, even after functional adjustments. Before puberty, there was no sex-difference in adjusted bone or muscle variables. After puberty, males had greater total and cortical bone area, bone diameter, moments of area, bone strength index and muscle area than women, both in absolute terms as well as adjusted for femur length and weight. The largest sex-difference was found for muscle area. When compared relative to muscle size, young adult women attained greater total and cortical bone area than men. CONCLUSIONS Growth in femoral length, diameter, mass and strength appears well coordinated before puberty. Postpubertal females have narrower femora, less bone strength and muscle size than males. However, when muscle size is taken into account, females have a larger femoral bone cross-section and more cortical bone. These sex-differences likely result from a combination of mechanical and hormonal effects occurring during puberty.