Pediatric reference values for tibial trabecular bone mineral density and bone geometry parameters using peripheral quantitative computed tomography.

The purpose of this study was to establish reference data, in relation to age and body height, for tibial trabecular and cortical volumetric bone mineral density, bone mineral content, and cross-sectional bone geometry in healthy children and adolescents using peripheral quantitative computed tomography (pQCT). Over a 2-year period, 432 (207 male and 225 female) healthy children, with an age range of 5 to 19 years, from 6 different geographic areas in Belgium were recruited. Multislice pQCT scanning (XCT2000(®), Stratec Medizintechnik, Pforzheim, Germany) was performed at the distal metaphysis (at the 4% site) and the distal diaphysis (14 and 38% sites) of the tibia of the dominant leg. Gender-specific centile curves in relation to age and body height were generated with the LMS method for total and trabecular volumetric bone mineral density (at 4% site), bone mineral content, total bone cross-sectional area, periosteal circumference (all at 4, 14, and 38% site), cortical volumetric bone mineral density, endosteal circumference, and cortical thickness (at the 14 and the 38% site). These centile curves can be used for the interpretation of pQCT results at the 4, 14, and 38% site of the tibia in European children and adolescents, at least when a similar methodology is used.

The relationship between circulating hormone levels, bone turnover markers and skeletal development in healthy boys differs according to maturation stage.

INTRODUCTION: This study investigates peri-pubertal changes in bone turnover markers, Wnt-signalling markers, insulin-like growth factor-1 (IGF-1) and sex steroid levels, and how they reflect skeletal development in peri-pubertal boys. MATERIALS AND METHODS: Population-based study in 118 peri-pubertal boys from the NINIOS cohort (age range at baseline 5.1-17.3 years) with repeated measurements at baseline and after two years. Serum levels of the classical bone turnover markers (BTM) procollagen type 1 N-terminal propeptide and carboxy-terminal collagen crosslinks, as well as sex-hormone binding globulin, IGF-1, osteoprotegerin, sclerostin and dickkopf-1 were measured using immunoassays. Sex steroids (estradiol, testosterone, and androstenedione) were measured using mass spectrometry and free fractions calculated. Dual energy x-ray absorptiometry was used for bone measurements at the lumbar spine and whole body. Volumetric bone parameters and bone geometry at the proximal and distal radius were assessed by peripheral QCT. Pubertal development was categorized based on Tanner staging. RESULTS: During puberty, sex steroid and IGF-1-levels along with most parameters of bone mass and bone size increased every next Tanner stage. In contrast, classical bone turnover markers and sclerostin peaked around mid-puberty, with subsequent declines towards adult values in late puberty. Especially classical BTM and sex steroid levels showed consistent associations with areal and volumetric bone parameters and bone geometry. However, observed associations differed markedly according to pubertal stage and skeletal site. CONCLUSION: Serum levels of sex steroids, IGF-1 and bone metabolism markers reflect skeletal development in peri-pubertal boys. However, skeletal development during puberty is nonlinear, and the relations between skeletal indices and hormonal parameters are nonlinear as well, and dependent on the respective maturation stage and skeletal site.

Growth, sexual and bone development in a boy with bilateral anorchia under testosterone treatment guided by the development of his monozygotic twin.

BACKGROUND: Sex steroids are essential for sexual maturation, linear growth and bone development. However, there is no consensus on the optimal timing, dosage and dosage interval of testosterone therapy to induce pubertal development and achieve a normal adult height and bone mass in children with hypogonadism. CASE PRESENTATION: A monozygotic monochorial male twin pair, of which one boy was diagnosed with anorchia at birth due to testicular regression syndrome was followed from the age of 3 until the age of 18 years. Low dose testosterone substitution (testosterone esters 25 mg/2 weeks) was initiated in the affected twin based on the start of pubertal development in the healthy twin and then gradually increased accordingly. Both boys were followed until age 18 and were compared as regards to linear growth, sexual maturation, bone maturation and bone development. Before puberty induction both boys had a similar weight and height. During puberty, a slightly faster weight and height gain was observed in the affected twin. Both boys ended up however, with a similar and normal (near) adult height and weight and experienced a normal development of secondary sex characteristics. At the age of 17 and 18 years, bone mineral density, body composition and volumetric bone parameters at the forearm and calf were evaluated in both boys. The affected boy had a higher lean mass and muscle cross-sectional area. The bone mineral density at the lumbar spine and whole body was similar. Trabecular and cortical volumetric bone parameters were comparable. At one cortical site (proximal radius), however, the affected twin had a smaller periosteal and endosteal circumference with a thicker cortex. CONCLUSIONS: In conclusion, a low dose testosterone substitution in bilateral anorchia led to a normal onset of pubertal development and (near) adult height. Furthermore, there was no difference in bone mineral density at the age of 17 and 18 years.

Proandrogenic and Antiandrogenic Progestins in Transgender Youth: Differential Effects on Body Composition and Bone Metabolism.

Context: Progestins can be used to attenuate endogenous hormonal effects in late-pubertal transgender (trans) adolescents (Tanner stage B4/5 and G4/5). Currently, no data are available on the effects of progestins on the development of bone mass or body composition in trans youth. Objective: To study prospectively the evolution of body composition and bone mass in late-pubertal trans adolescents using the proandrogenic or antiandrogenic progestins lynestrenol (L) and cyproterone acetate (CA), respectively. Design and Outcome Measurements: Forty-four trans boys (Tanner B4/5) and 21 trans girls (Tanner G4/5) were treated with L or CA for 11.6 (4 to 40) and 10.6 (5 to 31) months, respectively. Anthropometry, grip strength, body composition, and bone mass, size, and density were determined by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography before the start of progestin and before addition of cross-sex hormones. Results: Using L, lean mass [+3.2 kg (8.6%)] and grip strength [+3 kg (10.6%)] significantly increased, which coincided with a more masculine body shape in trans boys. Trans girls showed loss of lean mass [-2.2 kg (4.7%)], gain of fat mass [+1.5 kg (9.4%)], and decreased grip strength Z scores. CA limited normal bone expansion and impeded pubertal bone mass accrual, mostly at the lumbar spine [Z score: -0.765 to -1.145 (P = 0.002)]. L did not affect physiological bone development. Conclusion: Proandrogenic and antiandrogenic progestins induce body composition changes in line with the desired appearance within 1 year of treatment. Bone health, especially at the lumbar spine, is of concern in trans girls, as bone mass accrual is severely affected by androgen suppressive therapy.

Androgens and obesity in male adolescents.

PURPOSE OF REVIEW: Data on sex steroid levels and pubertal development in obese adolescent boys are scarce and contrasting. The present review summarizes the most recent results obtained with improved methodology to measure low sex steroid levels in children. RECENT FINDINGS: Obese pubertal boys have lower serum sex hormone-binding globulin and consequently lower total testosterone levels compared to normal-weight peers. However, during pubertal development, free testosterone levels in obese adolescents are not different from controls, indicating preserved androgen exposure as is additionally suggested by similar clinical genital staging (Tanner), serum gonadotropins levels, and serum prostate-specific antigen concentrations compared to nonobese adolescents. In pre and early puberty, total testosterone levels is not decreased, notwithstanding low sex hormone-binding globulin, and free testosterone is slightly increased in obese boys. This may result from increased adrenal activity as revealed by elevated serum androstenedione and dehydroepiandrosterone sulfate. In obese adolescent boys, increased aromatization of testosterone to estradiol tends to accelerate skeletal maturation. SUMMARY: In obese adolescent boys, free testosterone is a better index than total testosterone levels of androgen status, which is not different from nonobese controls. Increased aromatization of testosterone to estradiol underlies the dissociation between normal clinical sexual maturation and advanced skeletal maturation in the obese adolescent.

Genetic variations in the androgen receptor are associated with steroid concentrations and anthropometrics but not with muscle mass in healthy young men.

OBJECTIVE: The relationship between serum testosterone (T) levels, muscle mass and muscle force in eugonadal men is incompletely understood. As polymorphisms in the androgen receptor (AR) gene cause differences in androgen sensitivity, no straightforward correlation can be observed between the interindividual variation in T levels and different phenotypes. Therefore, we aim to investigate the relationship between genetic variations in the AR, circulating androgens and muscle mass and function in young healthy male siblings. DESIGN: 677 men (25-45 years) were recruited in a cross-sectional, population-based sibling pair study. METHODS: Relations between genetic variation in the AR gene (CAGn, GGNn, SNPs), sex steroid levels (by LC-MS/MS), body composition (by DXA), muscle cross-sectional area (CSA) (by pQCT), muscle force (isokinetic peak torque, grip strength) and anthropometrics were studied using linear mixed-effect modelling. RESULTS: Muscle mass and force were highly heritable and related to age, physical activity, body composition and anthropometrics. Total T (TT) and free T (FT) levels were positively related to muscle CSA, whereas estradiol (E2) and free E2 (FE2) concentrations were negatively associated with muscle force. Subjects with longer CAG repeat length had higher circulating TT, FT, and higher E2 and FE2 concentrations. Weak associations with TT and FT were found for the rs5965433 and rs5919392 SNP in the AR, whereas no association between GGN repeat polymorphism and T concentrations were found. Arm span and 2D:4D finger length ratio were inversely associated, whereas muscle mass and force were not associated with the number of CAG repeats. CONCLUSIONS: Age, physical activity, body composition, sex steroid levels and anthropometrics are determinants of muscle mass and function in young men. Although the number of CAG repeats of the AR are related to sex steroid levels and anthropometrics, we have no evidence that these variations in the AR gene also affect muscle mass or function.

Estrogen-specific action on bone geometry and volumetric bone density: longitudinal observations in an adult with complete androgen insensitivity.

INTRODUCTION: Sex steroids have distinct effects on bone growth and maintenance in men and women, mediated through their respective steroid receptors. Though most evidence is derived from animal studies, several concepts have been confirmed in humans by detection of specific mutations. In this report we describe changes in bone size and volumetric bone density in a complete androgen insensitive subject (CAIS) due to a mutation in the androgen receptor during 5 years of estrogen treatment. MATERIALS AND METHODS: We present a case report of a 31 year old XY female with CAIS with a longitudinal follow-up for 5 years of areal and volumetric bone parameters. Areal and volumetric bone parameters were determined using dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT). Sex steroids, LH, FSH and IGF-I were determined by immunoassay. RESULTS: Complete androgen insensitivity syndrome was genetically confirmed by detection of the mutation Asp767Tyr in the androgen receptor gene. Bone size at presentation was found to be intermediate between male and female reference values. Low areal and volumetric bone density (both trabecular and cortical) was observed at baseline and improved gradually with estrogen treatment (+2% to 6.5%). Upon estrogen treatment, endosteal contraction (-1%) was demonstrated, with increasing cortical thickness (+3%), cortical area (+5%) and unchanged periosteal circumference. CONCLUSIONS: During adult life, estrogens mediate endosteal bone apposition and volumetric bone density, without marked influence on periosteal bone apposition. The finding of a bone size intermediate between male and female supports testosterone as an essential mediator for periosteal bone expansion, but not as the sole stimulus for bone expansion during growth.

Vitamin D binding protein, a new nutritional marker in cystic fibrosis patients.

BACKGROUND: Vitamin D binding protein (DBP) is a multifunctional transport protein with a decreased serum concentration in cystic fibrosis (CF). The present study investigates the importance of DBP and its role as an alternative nutritional marker in CF. METHODS: DBP phenotypes of 116 CF patients were determined electrophoretically. Serum DBP was measured by immunonephelometry. Parathormone was assessed by an immunoradiometric assay. Serum 25OH vitamin D(3), 1,25(OH)(2) vitamin D(3) and leptin concentrations were determined by a radioimmunoassay. Serum alpha-tocopherol was measured by HPLC. Routine chemistry parameters were assessed using commercial methods. The Prognostic Inflammatory and Nutritional Index was calculated. RESULTS: Decreased serum DBP concentrations were observed in the CF group. Total cholesterol, low-density lipoprotein (LDL)-cholesterol, triglyceride concentration, alpha-tocopherol and a low nutritional status correlated positively with DBP. Lipoprotein precipitation demonstrated a partial presence of DBP in very-low-density lipoprotein and LDL. Furthermore, DBP was positively correlated with serum leptin concentration. CONCLUSIONS: The present study demonstrates a positive correlation between DBP and serum lipids. Serum DBP concentration can be considered as a nutritional marker (especially for lipids).