The Relationship Between Calciotropic Hormones, IGF-1, and Bone Mass Across Pubertal Stages.

BACKGROUND: Little is known about the changes in calciotropic hormones during puberty and their relationship to bone mass during this critical period for skeletal accretion. OBJECTIVES: Investigate changes in calciotropic hormones, IGF-1, body composition, and their associations with bone metabolism in adolescents. METHODS: Post hoc analyses were performed from data on 335 healthy school children, ages 10-17 years, with hypovitaminosis D who participated in a vitamin D randomized controlled trial. Baseline serum biochemistries; hormonal studies; densitometry at the spine, hip, and total body; and body composition were used. ANOVA and regression analyses were implemented to evaluate changes in variables of interest across pubertal stages, within and between genders. RESULTS: Bone mass and body composition parameters increased substantially across Tanner stages in both genders. Serum calcium, 1,25-dihydroxyvitamin D, and 25-hydroxyvitamin D levels did not vary by Tanner stages in both genders. Conversely, serum phosphorus, alkaline phosphatase, IGF-1, PTH, and osteocalcin peaked for the most part at Tanner stage II in girls and stage III in boys. 1,25-Dihydroxyvitamin D correlations with bone mass were not consistent, whereas IGF-1 was the most robust correlate of bone mass at several skeletal sites in early Tanner stages in both genders (R = 0.3-0.6). CONCLUSION: Serum phosphorus, alkaline phosphatase, IGF-1, PTH, and osteocalcin, but not calcium or 1,25-dihydroxyvitamin D, increased significantly in early puberty, with gender difference except for PTH, peaking earlier in girls than in boys. IGF-1 is a robust predictor of bone mass, an effect mediated in large part by increments in lean mass.

Activating BRAF Mutations Detected in Mixed Hürthle Cell Carcinoma and Multifocal Papillary Carcinoma of the Thyroid Gland: Report of an Unusual Case and Review of the Literature.

Despite the increase in the incidence of thyroid carcinomas, the occurrence of collision tumors in the thyroid remains a rare event. We present the case of a 69-year-old female who presented to the emergency department with a chief complaint of painful neck swelling. Imaging revealed a large right hemithyroid mass and a left hemithyroid nodule. Fine needle aspiration of the lesions and subsequent total thyroidectomy revealed a Hürthle cell carcinoma in the right lobe and bilateral multicentric papillary carcinoma foci, including 2 foci with a classical pattern and 1 encapsulated follicular variant in the isthmus. BRAF gene mutation analysis revealed V600E gene mutation in the classical variants of papillary carcinoma and in the Hürthle cell carcinoma. The focus of follicular variant of papillary carcinoma in the isthmus and a sample from normal thyroid tissue did not harbor BRAF mutations. This case is remarkable in being an unusual report of a follicular Hürthle cell carcinoma harboring the BRAF V600E mutation and occurring in collision with multifocal papillary carcinoma. Documentation of such cases is important as it helps better understand the pathogenesis, clinical behavior, and radiologic findings of such rare lesions and to determine the optimal treatment modalities.

Persistent Effect of Vitamin D Supplementation on Musculoskeletal Parameters in Adolescents One Year After Trial Completion.

We showed a beneficial effect of vitamin D supplementation on musculoskeletal parameters in adolescent girls in a 1-year, randomized, double-blinded placebo-controlled trial (RCT). Our objective for this study was to investigate the residual effect of vitamin D supplementation on bone mineral content (BMC), bone mineral density (BMD), at the lumbar spine and hip, lean mass, and height, 1 year after trial completion. We performed post hoc analyses in 167 adolescents, 86 girls and 81 boys, age 13.9 ± 2 years, who received vitamin D or placebo during the trial, and continued into the follow-up trial. Musculoskeletal parameters were measured at baseline, 12 months (intervention), and 24 months (follow-up). ANOVA and t tests were used to compare results between the placebo group and the merged vitamin D arms (200 or 2000 IU/day), by gender. Baseline characteristics were comparable between treatment groups at entry into the extension. Girls who had received vitamin D during the trial, had significantly larger hip BMC increments compared to those assigned to placebo, at 24 months compared to study entry, but not 24 compared to 12 months, which persisted in adjusted analyses. There were no significant differences in bone mass changes between treatment groups in boys, at 24 months compared to 12 months or to baseline. The beneficial effect of vitamin D supplementation on hip bone mass, achieved in girls during the trial, persisted 1 year after trial completion. These net cumulative increments, 1 year after discontinuation of supplementation, may have important implications on optimizing peak bone mass accretion in adolescent girls. © 2016 American Society for Bone and Mineral Research.

An unusual case of autonomous hyperparathyroidism in a patient with X-linked hypophosphatemic rickets and Kallmann syndrome.

We are reporting an unusual patient who presented to our medical center at 18 years of age for evaluation of disabling bilateral lower extremity deformity and delayed puberty. Extensive clinical, laboratory, and radiologic evaluation confirmed the coexistence of 2 X-linked inherited disorders, X-linked hypophosphatemic rickets (XLH) and Kallmann syndrome (KS). Treatment with oral phosphate and calcitriol along with intramuscular testosterone injections was initiated. Despite a dramatic response, the course of treatment was complicated by secondary hyperparathyroidism and, 13 years later, by the development of an autonomous parathyroid adenoma that was surgically resected. Furthermore, the coexistence of XLH and KS has not been reported before. We believe that the proximity of the KAL-1 gene (Xp 22.3), involved in the pathogenesis of KS, to the phosphate regulating endopeptidase on the X chromosome gene (Xp 22.1-22.2), involved in XLH, might be responsible for this association.

Disruption of POF1B binding to nonmuscle actin filaments is associated with premature ovarian failure.

Premature ovarian failure (POF) is characterized by elevated gonadotropins and amenorrhea in women aged <40 years. In a Lebanese family with five sisters who received the diagnosis of POF, we established linkage to the long arm of the X chromosome (between Xq21.1 and Xq21.3.3), using whole-genome SNP typing and homozygosity-by-descent mapping. By sequencing one candidate gene within that region, POF1B, we identified a point mutation localized in exon 10. This substitution of a nucleotide (G-->A), at position 1123, results in an arginine-->glutamine mutation of the protein sequence at position 329 (mutation R329Q). All the affected family members were homozygous for the mutation, whereas the unaffected members were heterozygous. Because POF1B shares high homology with the tail portion of the human myosin, we assessed the ability of both wild-type and mutant POF1B proteins to bind nonmuscle actin filaments in vitro. We found that the capacity of the mutant protein to bind nonmuscle actin filaments was diminished fourfold compared with the wild type, suggesting a function of POF1B in germ-cell division. Our study suggests that a homozygous point mutation in POF1B influences the pathogenesis of POF by altering POF1B binding to nonmuscle actin filaments.

Effect of vitamin D replacement on musculoskeletal parameters in school children: a randomized controlled trial.

BACKGROUND: Despite the high prevalence of hypovitaminosis D in children and adolescents worldwide, the impact of vitamin D deficiency on skeletal health is unclear. METHODS: One hundred seventy-nine girls, ages 10-17 yr, were randomly assigned to receive weekly oral vitamin D doses of 1,400 IU (equivalent to 200 IU/d) or 14,000 IU (equivalent to 2,000 IU/d) in a double-blind, placebo-controlled, 1-yr protocol. Areal bone mineral density (BMD) and bone mineral content (BMC) at the lumbar spine, hip, forearm, total body, and body composition were measured at baseline and 1 yr. Serum calcium, phosphorus, alkaline phosphatase, and vitamin D metabolites were measured during the study. RESULTS: In the overall group of girls, lean mass increased significantly in both treatment groups (P < or = 0.05); bone area and total hip BMC increased in the high-dose group (P < 0.02). In premenarcheal girls, lean mass increased significantly in both treatment groups, and there were consistent trends for increments in BMD and/or BMC at several skeletal sites, reaching significance at lumbar spine BMD in the low-dose group and at the trochanter BMC in both treatment groups. There was no significant change in lean mass, BMD, or BMC in postmenarcheal girls. CONCLUSIONS: Vitamin D replacement had a positive impact on musculoskeletal parameters in girls, especially during the premenarcheal period.

Sex differences in the effect of body-composition variables on bone mass in healthy children and adolescents.

BACKGROUND: Prophylactic interventions against osteoporosis require a determination of the factors that influence the accumulation of bone mass during growth. OBJECTIVE: The objective was to determine the independent sex-specific contribution of lean mass and fat mass to bone mineral content (BMC), after adjustment for anthropometric variables and lifestyle factors, in healthy children and adolescents. DESIGN: Healthy schoolchildren (184 boys and 179 girls) aged 10-17 y (x+/- SD: 13.0 +/- 2.1 y) participated in this cross-sectional study. Total and regional (lumbar spine, femoral neck, and distal one-third of the radius) BMC and body composition were measured by dual-energy X-ray absorptiometry. RESULTS: A significant effect of anthropometric variables and lifestyle factors on BMC was observed at all skeletal sites. Lean mass and fat mass showed robust correlations with BMC, even after adjustment for anthropometric variables and lifestyle factors. Lean mass contributed to 6-12% of the variance in BMC in boys and to 4-10% in girls. Fat mass accounted for 0.1-2% of BMC variance in boys and to 0.1-6.5% in girls. CONCLUSIONS: Both lean mass and fat mass are consistent predictors of BMC at multiple skeletal sites in healthy children and adolescents. The contribution of lean mass to BMC variance was larger in boys than in girls. In both sexes, the highest contribution of lean mass to BMC was observed at the femoral neck.

Bone mineral density by age, gender, pubertal stages, and socioeconomic status in healthy Lebanese children and adolescents.

Gender, ethnicity, and lifestyle factors affect bone mass acquisition during childhood, thus the need for age- and sex-adjusted Z scores using ethnic-specific data for bone mineral density (BMD) measurement. This study aimed at establishing normative data for BMD in healthy Lebanese children and adolescents. Three hundred sixty-three healthy children aged 10 to 17 years (mean+/-SD: 13.1+/-2.0) were studied. BMD, bone mineral content (BMC), and lean mass were measured by dual-energy X-ray absorptiometry (DXA) using a Hologic 4500A device, and apparent volumetric BMD (BMAD) of the lumbar spine and the femoral neck were calculated. BMD, BMC, and BMAD were expressed by age groups and Tanner stages for boys and girls separately. There was a significant effect of age and puberty on all bone parameters, except at the femoral neck BMAD in boys. BMC and BMD were higher at cortical sites in boys, including subtotal body and hip; whereas, in girls, it was higher at a site more enriched in trabecular bone, namely the lumbar spine. At several skeletal sites, girls had significantly higher BMD adjusted for lean mass than boys. By the end of puberty, adolescents had a mean BMD that was 43-66% higher at the lumbar spine and 25-41% higher at cortical sites than pre-pubertal children, depending on the gender. Mean BMD values in the study group were significantly lower (P<0.01) than Western normative values, with Z scores ranging between -0.2 and -1.1. In both genders, children of lower socioeconomic status tended to have lower BMD than those from a higher socioeconomic background. This study allows additional insight into gender dimorphism in mineral accretion during puberty. It also provides a valuable reference database for the assessment of BMD in children with pubertal or growth disorders who are of Middle Eastern origin.

Effect of gender, puberty, and vitamin D status on biochemical markers of bone remodedeling.

Peak bone mass, a determinant of osteoporosis at older ages, is affected by genetic, nutritional, lifestyle, and hormonal factors. Adolescence is a critical time for peak bone mass accrual, and boys achieve a higher peak bone mass than girls. We have reported vitamin D insufficiency in adolescents in our population, but its impact on bone remodeling is unclear. We systematically evaluated the impact of puberty, gender, and vitamin D status on biochemical markers of bone remodeling. Serum osteocalcin (OC), bone alkaline phosphatase (BAP), C-terminal telopeptide of type I collagen crosslinks (S-CTX), and 25 OH vitamin D were measured in 172 healthy students from private schools in the fall of 1999: There were 92 girls and 80 boys, age 10-17 years. In girls, all markers of bone turnover changed significantly with pubertal stage, were maximal at midpuberty, and decreased toward adult levels by Tanner stage V. Conversely in boys, these markers increased during early pubertal stages but had not normalized by Tanner stage V. Levels of all biochemical markers were significantly higher in boys compared to girls even after adjustment for age, body weight, and Tanner stage, P < 0.0001. In the subgroup of girls, those with vitamin D insufficiency, serum levels of BAP and S-CTX were highest. However, in multiple regression analyses, gender was the only consistent correlate of all three markers of bone remodeling. In conclusion, after adjusting for age, weight, and Tanner stages, changes in bone remodeling markers were most powerfully affected by gender. The latter may have important implications on gender differences in peak bone mass.