Zvi Zadik

Consensus Development for the Supplementation of Vitamin D in Childhood and Adolescence

aMeyer Children Hospital, Haifa, Israel; bMarmara University, Istanbul, Turkey; cUniversity of North Carolina, Chapel Hill, N.C., USA; dVrije Universiteit, Amsterdam, The Netherlands; eAcademic Hospital V.V.B., Brussels, Belgium; fJohns Hopkins University, Baltimore, Md., USA; gBirmingham Children’s Hospital, Birmingham, UK; hUniversitatskinderklinik, Cologne, Germany; iDana Children’s Hospital, Tel Aviv, Israel; jKaplan Hospital Rehovot, Israel

Pediatric reference curves for multi-site quantitative ultrasound and its modulators.

More than 85% of peak skeletal mass is accrued by the age of 18 years, making bone growth during childhood and adolescence a critical process. The purpose of this study is to establish pediatric reference curves for bone Speed of Sound (SOS) as measured by multi-site quantitative ultrasound. Analysis was performed on a total of 1085 healthy subjects ages 0–18 years (595 females, 490 males). Demographic and anthropometric parameters (height and weight), as well as data on calcium intake and physical activity, were collected. Ultrasound bone measurements were performed at the mid-shaft tibia and the distal third of the radius (Sunlight Omnisense® 7000P). An age-related speed of sound (SOS) curve that describes SOS changes at the tibia and radius in both genders was demonstrated. SOS showed a steep increase during the first 5 years of life in both genders at the tibia and radius. The period between the ages of 6–11 years is characterized with a very shallow increase in SOS at both sites. Thereafter, during the pubertal period, there is a second growth burst in SOS, starting at age 11 for girls and age 14 for boys. No significant meaningful correlation was found between the anthropometric parameters (height, weight and BMI) and the SOS measurements after the age parameter was controlled. Subjects who reported low physical activity levels were found to have lower Z-scores than their counterparts (P<0.05). The SOS of pre-menarche girls was significantly lower than that of post-menarche girls at the radius and tibia (P<0.05). The level of calcium intake did not correlate with bone SOS. Intra-operator precision measurements were 0.36% (0.25–0.47%) at radius and 0.30% (0.20–0.40%) at the tibia. To date, there is no widely accepted classification or clinical working guidelines for childrens bone health assessment or prediction of fracture risk based on bone strength measurements in children. This study establishes a pediatric reference curve for the Omnisense, and therefore supports the feasibility of using Sunlight Omnisense® 7000P, a multi-site bone sonometer, for the assessment of pediatric bone properties. Further studies mainly in different diseased children groups should further support the use of such a basic tool for clinical evaluation, assisting the physician to work towards healthy bones for his patients.

From Bone Biology to Bone Analysis

Bone development is one of the key processes characterizing childhood and adolescence. Understanding this process is not only important for physicians treating pediatric bone disorders, but also for clinicians and researchers dealing with postmenopausal and senile osteoporosis. Bone densitometry has great potential to enhance our understanding of bone development. The usefulness of densitometry in children and adolescents would be increased if the physiological mechanisms and structural features of bone were given more consideration in the design and interpretation of densitometric studies. This review gives an overview on the most relevant techniques of quantitative noninvasive bone analysis. Furthermore it describes the relationship between bone biology, selected surrogates describing the biological processes and the possibilities of measuring these surrogates specifically and precisely by the different devices. The overall recommendation for researchers in this field is to describe firstly the biological process to be analyzed (bone growth in length, remodeling or modeling, or all together), secondly the bone parameter which describes this process, and thirdly the reason for selecting a special device.

The effect of growth hormone and IGF-I on clonogenic growth of hematopoietic cells in leukemic patients during active disease and during remission - a preliminary report

The number of survivors of childhood leukemia treated with growth hormone for growth retardation is increasing. The debate about the direct or indirect relationship of GH and insulin-like growth factor I (IGF-I) to the occurrence or recurrence of malignancy, especially in the case of GH therapy in patients with leukemia, is still unresolved. We, therefore, studied the effect of GH and IGF-I on bone marrow of patients with acute leukemia (ALL and AML) in diagnosis and recurrence and in chronic leukemia patients (CML) in remission. GH increased blast colony numbers by a mean of 68% and 77% at GH concentrations of 250 and 300 ng/ml, respectively. IGF-I increased blast colony numbers in ALL patients by 50, 93 and 105%, and in AML patients by 33, 58 and 65%, at IGF-I concentrations of 0.05, 0.25 and 0.5 ng/ml, respectively. In 3 CML patients in remission a granulocyte-macrophage colony forming assay did not reveal stimulation of peripheral blood blast colony formation by GH or IGF-I. Our in vitro data (as previously reported) suggest that GH and IGF-I may promote blast cell proliferation, and the supplemental administration of these peptides in leukemia patients in remission must be carefully monitored for early relapse. Additional studies on bone marrow cells of leukemic patients in remission are needed in order to examine the effects of GH and IGF-I on these cells.

Breast Development in the First 2 Years of Life: An Association With Soy-based Infant Formulas

Objective: To evaluate the estrogenic effect of soy-based formulas in female infants. These formulas contain significant amounts of phytoestrogens, compounds with structural similarity to estradiol. Patients and Methods: A cross-sectional study consisting of 694 female infants ages 3 to 24 months that consecutively attended 10 general pediatric clinics, none of them having been referred for breast development. The presence of breast buds served as a marker for the endocrine effect of soy-derived phytoestrogens. Results: Of the participants, 92 had consumed soy formulas for more than 3 months. Breast tissue was more prevalent in the second year of life in infants fed soy-based formula vs those that were breast-fed and those fed dairy-based formula (22.0% vs 10.3%; P = 0.02) with an odds ratio of 2.45 (95% confidence interval 1.11–5.39). No differences in breast bud prevalence were observed during the first year of life. Unlike infants on dairy-based formulas and breast-feeding, infants fed a soy-based formula did not demonstrate a decline in the prevalence of breast during the second year of life. Conclusions: We suggest that phytoestrogens impose a preserving effect on breast tissue that is evolved in early infancy, leading eventually to a slower waning of infantile breast tissue.

Cognitive impairment is prevalent in pseudohypoparathyroidism type Ia, but not in pseudopseudohypoparathyroidism: possible cerebral imprinting of Gsα

Objective  Pseudohypoparathyroidism type Ia (PHP‐Ia) is a hereditary disorder characterized by resistance to multiple hormones that work via cAMP such as PTH and TSH, accompanied by typical skeletal features including short stature and brachydactyly, termed Albright hereditary osteodystrophy (AHO). In affected kindreds, some members may have AHO but not hormone resistance; they are termed as pseudopseudohypoparathyroidism (PPHP). The molecular basis for the disorder is heterozygous inactivating mutation of the Gsα gene. In affected families, subjects with both PHP‐Ia and PPHP have the same Gsα mutations. The skeletal features common to PPHP and PHP‐Ia are presumably caused by tissue‐specific Gsα haploinsufficiency. Other features that distinguish between PPHP and PHP‐Ia, such as the multihormone resistance, are presumably caused by tissue‐specific paternal imprinting of Gsα. This suggests that major differences in phenotype between PHP‐Ia and PPHP point to specific tissues with Gsα imprinting. One such major difference may be cognitive function in PHP‐Ia and PPHP.

Effect of Growth Hormone Treatment on Quality of Life of Short-Stature Children

While enhanced growth velocity is a well-established benefit following the initiation of growth hormone treatment (GHT), the potential benefit of GHT on quality of life (QOL) of short-stature children has not yet been documented. We compare QOL of two groups of short-stature children who attended the Endocrine Unit (EU) and were 2 SD or more below the average for age and gender. The first group included 96 patients of whom 65 were without any underlying disease, 15 had classical GH deficiency and 16 had Turner syndrome or renal disease. These patients were on GHT for at least 2 years. The other group included 33 patients. Owing to lack of resources to include these 33 patients in a clinical trial, they did not get GHT. They were normal variant of short stature, and their height was similar to the height of the 65 children included in the first group. QOL was assessed using self-administered questionnaires, which were filled out by the patients on their regular visit to the EU. QOL was defined in terms of school achievements, leisure activities, emotional and physical self-esteem, relationships with peers and family members. No significant differences were found between the two groups. The mean scores for the different domains of QOL ranged between 2.6 and 3.8 on a scale ranging from 1 (very pessimistic view) to 4 (very optimistic view).

Effect of HMB Supplementation on Body Composition, Fitness, Hormonal Profile and Muscle Damage Indices

There is a huge market for ergogenic supplements for athletes. However, only a few products have been proven to have ergogenic effects and to be effective at improving muscle strength and body composition. One such supplement is beta-hydroxy beta-methylbutyrate (HMB). Derived from the amino acid leucine and its keto acid alpha-ketoisocaproate (KIC), HMB has been well documented as an oral ergogenic supplement commonly used by athletes. Several studies have shown that combining exercise training with HMB supplementation leads to increased muscle mass and strength, and there is some anecdotal evidence of aerobic improvement. However, HMB supplementation has been found to be effective mainly for untrained individuals. While previous reviews have emphasized three main pathways for HMBs mode of action: 1) enhancement of sarcolemmal integrity via cytosolic cholesterol, 2) inhibition of protein degradation via proteasomes, and 3) increased protein synthesis via the mTOR pathway, more recent studies have suggested additional possible mechanisms for its physiological effects. These include decreased cell apoptosis and enhanced cell survival, increased proliferation, differentiation and fusion via the MAPK/ERK and PI3K/Akt pathways, and enhanced IGF-I transcription. These are described here, and hormonal interactions are discussed, along with HMB dosage and safety issues.

Urinary free cortisol values in children under stress

Children with adrenocortical insufficiency are commonly instructed to increase their baseline glucocorticoid replacement doses by three to five times during periods of stress such as surgery or febrille illness. We conducted this to determine whether these recommendations reflect the actual change in urinary free cortisol (UFC) output during stress. The 24-hour UFC excretion was determined in 78 children who were admitted to a general pediatric department or intensive care unit with temperature > 38.7 degrees C, after major surgery, or during status epilepticus; we reevaluated 43 of the patients 2 weeks after recovery. In addition, the 24-hour UFC levels were determined in 127 healthy children aged 1.8 to 17 years. The UFC level positively correlated with age (r = 0.254; p < 0.001). The amount of UFC per gram of creatinine was inversely correlated with age (r = 0.255; p < 0.001). The amount of UFC per surface area was independent of age. The mean change in the level of UFC per square meter surface area was highest among children who had cardiothoracic surgery and those with multiple trauma. The increase in UFC level during bacterial infection was significantly greater than that during viral infection. The current recommendation to increase the dose to three to five times the baseline glucocorticoid dose during times of stress may underestimate the changes in UFC found in some patients with major surgery, trauma, or certain serious bacterial infections. Production rate studies are needed to prove this point.

Final height after growth hormone therapy in peripubertal boys with a subnormal integrated concentration of growth hormone.

The aim of this study was to test the effect of growth hormone (GH) therapy on final height in peripubertal boys with idiopathic short stature in whom a subnormal integrated concentration of GH (< 3.2 micrograms/l) was found. Twenty-eight peripubertal children were studied. Height was below 2 SD for age, growth velocity was < 4.5 cm/year, bone age was more than 2 SD below mean for age and GH response to provocative tests was more than 10 micrograms/l. Eleven subjects (group B) were treated with recombinant GH 0.75 unit/kg/week, divided into 3 weekly doses for 2 years, and then the same weekly dose divided into daily injections was administered until final height was attained. Seventeen untreated children (group A) who were followed until cessation of growth served as controls. The GH-treated patients reached their target heights (-2.1 +/- 0.5, mean +/- SD in SDS) and predicted heights (-1.8 +/- 0.8) determined by the Bayley and Pinneau method, while the final heights of the untreated patients were significantly lower than their target heights and their predicted final heights (-2.7 +/- 0.7, -1.8 +/- 1.0 and -2.7 +/- 0.7, respectively). The main effect of GH was observed during the 1st year of treatment when height velocity was significantly higher in the GH-treated group than in the untreated one (9.3 +/- 2.1 vs. 5.3 +/- 1.1, respectively, p < 0.001). The high cost of the treatment in this specific age group should be weighed against the results.