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Disruption of insulin-like growth factor-I expression in type IIalphaI collagen-expressing cells reduces bone length and width in mice. Govoni Kristen E,Lee Seong Keun,Chung Yoon-Sok,Behringer Richard R,Wergedal Jon E,Baylink David J,Mohan Subburaman Physiological genomics It is well established that insulin-like growth factor (IGF)-I is critical for the regulation of peak bone mineral density (BMD) and bone width. However, the role of systemic vs. local IGF-I is not well understood. To determine the role local IGF-I plays in regulating BMD and bone width, we crossed IGF-I flox/flox mice with procollagen, typeIIalphaI-Cre mice to generate conditional mutants in which chondrocyte-derived IGF-I was disrupted. Bone parameters were measured by dual X-ray absorptiometry at 2, 4, 8, and 12 wk of age and peripheral quantitative computed tomography at 12 wk of age. Body length, areal BMD, and bone mineral content (BMC) were reduced (P < 0.05) between 4 and 12 wk in the conditional mutant mice. Bone width was reduced 7% in the vertebrae and femur (P < 0.05) of conditional mutant mice at 12 wk. Gains in body length and total body BMC and BMD were reduced by 27, 22, and 18%, respectively (P < 0.05) in conditional mutant mice between 2 and 4 wk of age. Expression of parathyroid hormone related protein, parathyroid hormone receptor, distal-less homeobox (Dlx)-5, SRY-box containing gene-9, and IGF binding protein (IGFBP)-5 were reduced 27, 36, 45, 33, and 45%, respectively, in the conditional mutant cartilage (P < 0.05); however, no changes in Indian hedgehog, Dlx-3, growth hormone receptor, IGF-I receptor, and IGFBP-3 expression were observed (P > or = 0.20). In conclusion, IGF-I from cells expressing procollagen type IIalphaI regulates bone accretion that occurs during postnatal growth period. 10.1152/physiolgenomics.00022.2007
Low IGF-I Bioavailability Impairs Growth and Glucose Metabolism in a Mouse Model of Human PAPPA2 p.Ala1033Val Mutation. Fujimoto Masanobu,Andrew Melissa,Liao Lihong,Zhang Dongsheng,Yildirim Gozde,Sluss Patrick,Kalra Bhanu,Kumar Ajay,Yakar Shoshana,Hwa Vivian,Dauber Andrew Endocrinology Bioactive free IGF-I is critically important for growth. The bioavailability of IGF-I is modulated by the IGF-binding proteins (IGFBPs) and their proteases, such as pregnancy-associated plasma protein-A2 (PAPP-A2). We have created a mouse model with a specific mutation in PAPPA2 identified in a human with PAPP-A2 deficiency. The human mutation was introduced to the mouse genome via a knock-in strategy, creating knock-in mice with detectable protein levels of Papp-a2 but without protease activities. We found that the Pappa2 mutation led to significant reductions in body length (10%), body weight (10% and 20% in males and females, respectively), and relative lean mass in mice. Micro-CT analyses of Pappa2 knock-in femurs from adult mice showed inhibited periosteal bone expansion leading to more slender bones in both male and female mice. Furthermore, in the Pappa2 knock-in mice, insulin resistance correlated with decreased serum free IGF-I and increased intact IGFBP-3 concentrations. Interestingly, mice heterozygous for the knock-in mutation demonstrated a growth rate for body weight and length as well as a biochemical phenotype that was intermediate between wild-type and homozygous mice. This study models a human PAPPA2 mutation in mice. The mouse phenotype closely resembles that of the human patients, and it provides further evidence that the regulation of IGF-I bioavailability by PAPP-A2 is critical for human growth and for glucose and bone metabolism. 10.1210/en.2018-00755
Impact of Lean Body Mass and Insulin Sensitivity on the IGF-1-Bone Mass Axis in Adolescence: the EPICOM Study. Jensen Rikke Beck,Bytoft Birgitte,Lohse Zuzana,Johnsen Sine Knorr,Nielsen Morten Frost,Oturai Peter Sandor,Højlund Kurt,Damm Peter,Clausen Tine D,Jensen Dorte M The Journal of clinical endocrinology and metabolism CONTEXT:Insulin-like growth factor-1 (IGF-1) is involved in the growth of muscle and bone mass and contributes to glucose homeostasis. The offspring of mothers with diabetes during pregnancy have an increased risk of insulin resistance (IR). OBJECTIVE:We hypothesized that bone mass was decreased in the offspring of mothers with type 1 diabetes (T1D), and that the IGF-1-bone mass relationship would be negatively influenced by IR. DESIGN:Data from the Epigenetic, Genetic and Environmental Effects on Growth, Metabolism and Cognitive Functions in Offspring of Women with Type 1 Diabetes (EPICOM) study performed from 2012 to 2013 were included. SETTING:This work is a follow-up study of a nationwide register study. PATIENTS:A total of 278 adolescent index offspring whose mothers had T1D and 303 matched controls were studied. MAIN OUTCOME MEASURE:Bone mineral content (BMC) determined by a dual-energy x-ray absorptiometry scan and the interaction with IGF-1 and insulin sensitivity were measured. RESULTS:There was no difference in BMC, bone mineral density, height (SD score [SDS]), or BMC/height between index and control offspring. IGF-1 (SDS) did not differ between the groups but insulin-like growth factor-binding protein 3 (SDS) was higher in index boys compared to controls (B = .31 [95% CI, 0.06-0.57], P = .02). The statistical path analysis showed that IGF-1 predicted BMC/height (B = .24 [95% CI, 0.02-0.45], P = .03), but lean mass was a mediator of this. IGF-1 and the homeostatic model assessment of IR were positively associated (B = .75 [95% CI, 0.37-1.12], P < .001). There was no moderating effect of the interaction between IR and IGF-1 on lean mass in the entire cohort (B = .005 [95% CI, -0.03 to 0.04], P = .81) or when analyzing index cases and controls separately. CONCLUSION:We found that lean mass was an intermediary factor in the IGF-1-bone mass relationship in a large cohort of adolescents, and this relationship was not moderated by IR. 10.1210/clinem/dgaa861
Expression of the components of the insulin-like growth factor axis across the growth-plate. Olney R C,Mougey E B Molecular and cellular endocrinology Linear bone growth occurs as the result of proliferation and differentiation of growth-plate chondrocytes. These two phases of chondrocyte growth are regulated separately, with insulin-like growth factor I (IGF-I) being the primary stimulator of proliferation. We studied the expression of the components of the growth hormone GH/IGF system to learn if this proliferative signal is altered as chondrocytes undergo differentiation. Growth-plate chondrocytes were isolated from fetal cows and fractionated on discontinuous Percoll gradients. Five populations were recovered, ranging from high density cells (proliferative chondrocytes) to low density cells (hypertrophic chondrocytes). Messenger RNAs (mRNAs) were analyzed by a reverse transcriptase/quantitative polymerase chain reaction (RT/qPCR) technique. Results showed that mRNA of IGF-I and IGF-II in proliferative chondrocytes was 32 and five fold more abundant, respectively, than in hypertrophic chondrocytes. Of the four major IGF-I mRNA transcripts, the class 1-Ea transcript was predominant. Messenger RNA levels for IGFBP-3, -4, and -5 were also reduced in hypertrophic chondrocytes. Levels of GH receptor, the type 1 IGF receptor, and IGF binding protein-2 (IGFBP-2) mRNAs were unchanged across the growth-plate. Since IGF-I and -II are potent stimulators of proliferation, the down-regulation of these genes may be necessary in order for hypertrophy to proceed.
Age related secretary pattern of growth hormone, insulin-like growth factor-I & insulin-like growth factor binding protein-3 in postmenopausal women. Aliasgarzadeh Akbar,Ghojazadeh Morteza,Haji-Hoseini Reza,Mehanfar Faezeh,Piri Reza,Naghavi-Behzad Mohammad,Nezami Nariman The Indian journal of medical research BACKGROUND & OBJECTIVES:After menopause in women, loss of bone density increases rapidly with estrogen deficiency. Evidence has revealed that this deficiency may be directly correlated with growth hormone (GH) level declining with age. The present study was designed to evaluate the age dependant patterns of GH, insulin-like growth factor-1 (IGF1-1) and insulin-like growth factor binding protein-3 (IGFBP-3) endogenous secretion in postmenopausal women. METHODS:During this prospective study in a 12-month period, 150 postmenopausal women were enrolled who were referred to the densitometry unit of bone research centre of Tabriz University of Medical Sciences for assessing bone mineral density. Serum levels of basal and clonidine stimulated GH were measured using radioimmunoassay while IGF-1 and IGFBP-3 were measured by ELISA. Post stimulation over 3 to 6 fold increase in GH over the baseline level was considered normal response and less increase was considered abnormal. RESULTS:There were no significant differences in the mean levels of GH0, GH60 and GH90 in different age groups of postmenopausal women. No significant difference in the mean IGFBP-3 and IGF-1 levels was seen in different age groups of postmenopausal women. The number of postmenopausal women with abnormal response to stimulation by clonidine in 61-70 and > 70 yr age groups was higher than in other groups (P< 0.05). INTERPRETATION & CONCLUSIONS:Despite the higher rate of abnormal response to stimulation by clonidine in women aged more than 60 yr, the current study showed no significant correlation between age, and the basal and stimulated GH secretion rate and serum levels of IGF-1 and IGFBP-3 in postmenopausal women.
Recombinant IGF-1 Induces Sex-Specific Changes in Bone Composition and Remodeling in Adult Mice with Deficiency. Rubio Leticia,Vargas Antonio,Rivera Patricia,López-Gambero Antonio J,Tovar Rubén,Christians Julian K,Martín-de-Las-Heras Stella,Rodríguez de Fonseca Fernando,Chowen Julie A,Argente Jesús,Suárez Juan International journal of molecular sciences Deficiency of pregnancy-associated plasma protein-A2 (PAPP-A2), an IGF-1 availability regulator, causes postnatal growth failure and dysregulation of bone size and density. The present study aimed to determine the effects of recombinant murine IGF-1 (rmIGF-1) on bone composition and remodeling in constitutive knock-out (ko/ko) mice. To address this challenge, X-ray diffraction (XRD), attenuated total reflection-fourier transform infra-red (ATR-FTIR) spectroscopy and gene expression analysis of members of the IGF-1 system and bone resorption/formation were performed. mice (both sexes) had reduced body and bone length. Male mice had specific alterations in bone composition (mineral-to-matrix ratio, carbonate substitution and mineral crystallinity), but not in bone remodeling. In contrast, decreases in collagen maturity and increases in , (resorption) and (formation) characterized the bone of females. A single rmIGF-1 administration (0.3 mg/kg) induced short-term changes in bone composition in mice (both sexes). rmIGF-1 treatment in females also increased collagen maturity, and , , and expression. In summary, acute IGF-1 treatment modifies bone composition and local IGF-1 response to bone remodeling in mice with deficiency. These effects depend on sex and provide important insights into potential IGF-1 therapy for growth failure and bone loss and repair. 10.3390/ijms22084048
Comparative analysis of clinical, biochemical and genetic aspects associated with bone mineral density in small for gestational age children. Silvano Liliana,Miras Mirta,Pérez Adriana,Picotto Gabriela,Díaz de Barboza Gabriela,Muñoz Liliana,Martin Silvia,Sobrero Gabriela,Armelini Pedro,Mericq Verónica,Tolosa de Talamoni Nori, Journal of pediatric endocrinology & metabolism : JPEM Clinical, biochemical and genetic analysis related to bone mineral density (BMD) were carried out in children born small for gestational age (SGA) that failed to achieve postnatal catch-up growth (CUG), SGA children that completed CUG and adequate for gestational age (AGA) children. Serum IGF-I, IGF-II, IGF binding protein-3 and acid-labile subunit were lower in the SGA-CUG children as compared with the other groups. Frequencies of polymorphic variants of vitamin D receptor, estrogen receptor and collagen genes were similar among groups. The genotype 194-192 of the IGF-I gene was higher in the SGA-CUG and 196-192 was higher in the SGA+CUG group. In the SGA-CUG group, the genotype SS of the COLIA1 gene was associated with lower BMD. Therefore, IGF system and COLIA1 polymorphism distinguish prepubertal SGA-CUG children from the SGA+CUG children of the same age. Furthermore, COLIA1 polymorphism could be useful to predict osteopenia in SGA-CUG children.
Serum complexes of insulin-like growth factor-1 modulate skeletal integrity and carbohydrate metabolism. Yakar Shoshana,Rosen Clifford J,Bouxsein Mary L,Sun Hui,Mejia Wilson,Kawashima Yuki,Wu Yingjie,Emerton Kelly,Williams Valerie,Jepsen Karl,Schaffler Mitchell B,Majeska Robert J,Gavrilova Oksana,Gutierrez Mariana,Hwang David,Pennisi Patricia,Frystyk Jan,Boisclair Yves,Pintar John,Jasper Héctor,Domene Horacio,Cohen Pinchas,Clemmons David,LeRoith Derek FASEB journal : official publication of the Federation of American Societies for Experimental Biology Serum insulin-like growth factor (IGF) -1 is secreted mainly by the liver and circulates bound to IGF-binding proteins (IGFBPs), either as binary complexes or ternary complexes with IGFBP-3 or IGFBP-5 and an acid-labile subunit (ALS). The purpose of this study was to genetically dissect the role of IGF-1 circulatory complexes in somatic growth, skeletal integrity, and metabolism. Phenotypic comparisons of controls and four mouse lines with genetic IGF-1 deficits-liver-specific IGF-1 deficiency (LID), ALS knockout (ALSKO), IGFBP-3 (BP3) knockout, and a triply deficient LID/ALSKO/BP3 line-produced several novel findings. 1) All deficient strains had decreased serum IGF-1 levels, but this neither predicted growth potential or skeletal integrity nor defined growth hormone secretion or metabolic abnormalities. 2) IGF-1 deficiency affected development of both cortical and trabecular bone differently, effects apparently dependent on the presence of different circulating IGF-1 complexes. 3) IGFBP-3 deficiency resulted in increased linear growth. In summary, each IGF-1 complex constituent appears to play a distinct role in determining skeletal phenotype, with different effects on cortical and trabecular bone compartments. 10.1096/fj.08-118976
Pycnodysostosis: A Growth Hormone Responsive Skeletal Dysplasia. AACE clinical case reports OBJECTIVE:Pycnodysostosis is commonly associated with growth hormone (GH) deficiency and responds well to GH therapy with achievement of normal or near-normal height and restoration of body proportions. CASE REPORT:A 22-month-old extremely short (-4.05 height standard deviation score) disproportionate boy with skeletal dysplasia presented to clinic. Skeletal survey, genetic panel, magnetic resonance imaging, and an insulin-like growth factor generation tests were performed. RESULTS:Skeletal survey showed increased bone density with classic features of pycnodysostosis, subsequently confirmed to be due to a deleterious homozygous frameshift mutation in . Uniquely among skeletal dysplasias, GH deficiency is a common association, secondary to pituitary hypoplasia. Magnetic resonance imaging confirmed pituitary hypoplasia and he subsequently underwent an insulin-like growth factor generation test that demonstrated biochemical responsiveness to GH therapy. This was thought to be safer than a classic GH stimulation test, in view of his very small size. Subsequently, his height has markedly improved on GH therapy. His height is now -2.25 SD, with an annualized growth velocity of 9.65 cm/y over a period of 18 months . CONCLUSION:It is important to consider GH therapy in children with pycnodysostosis, with the greatest benefit seen in children started at a young age. 10.1016/j.aace.2021.02.006
The relation between 25-hydroxyvitamin D with peak bone mineral density and body composition in healthy young adults. Boot Annemieke M,Krenning Eric P,de Muinck Keizer-Schrama Sabine M P F Journal of pediatric endocrinology & metabolism : JPEM OBJECTIVE:The associations between peak bone mineral density (BMD) and body composition with 25 hydroxyvitamin D (25OHD) levels in healthy young adults were evaluated. METHODS:The number of participants was 464; 347 women and 117 men. The mean age was 24.3 years (range 17-31 years). BMD of the lumbar spine, total body and femoral neck (FN) and body composition were measured by dual energy X-ray absorptiometry. Volumetric BMD, bone mineral apparent density (BMAD), of the lumbar spine and FN was calculated. RESULTS:In females, 25OHD level was positively associated with FN BMD and BMAD (both p<0.01) and negatively with percentage body fat (p<0.001). In males, 25OHD levels had a positive association with total body BMD and lean body mass (p=0.03 and p=0.01). CONCLUSIONS:25OHD level is a determinant of peak BMD in both sexes. Vitamin D status was associated with body fat in females and with lean body mass in males.
Circulating levels of IGF-1 directly regulate bone growth and density. Yakar Shoshana,Rosen Clifford J,Beamer Wesley G,Ackert-Bicknell Cheryl L,Wu Yiping,Liu Jun-Li,Ooi Guck T,Setser Jennifer,Frystyk Jan,Boisclair Yves R,LeRoith Derek The Journal of clinical investigation IGF-1 is a growth-promoting polypeptide that is essential for normal growth and development. In serum, the majority of the IGFs exist in a 150-kDa complex including the IGF molecule, IGF binding protein 3 (IGFBP-3), and the acid labile subunit (ALS). This complex prolongs the half-life of serum IGFs and facilitates their endocrine actions. Liver IGF-1-deficient (LID) mice and ALS knockout (ALSKO) mice exhibited relatively normal growth and development, despite having 75% and 65% reductions in serum IGF-1 levels, respectively. Double gene disrupted mice were generated by crossing LID+ALSKO mice. These mice exhibited further reductions in serum IGF-1 levels and a significant reduction in linear growth. The proximal growth plates of the tibiae of LID+ALSKO mice were smaller in total height as well as in the height of the proliferative and hypertrophic zones of chondrocytes. There was also a 10% decrease in bone mineral density and a greater than 35% decrease in periosteal circumference and cortical thickness in these mice. IGF-1 treatment for 4 weeks restored the total height of the proximal growth plate of the tibia. Thus, the double gene disruption LID+ALSKO mouse model demonstrates that a threshold concentration of circulating IGF-1 is necessary for normal bone growth and suggests that IGF-1, IGFBP-3, and ALS play a prominent role in the pathophysiology of osteoporosis. 10.1172/JCI15463
The influence of serum ghrelin, IGF axis and testosterone on bone mineral density in boys at different stages of sexual maturity. Pomerants Triin,Tillmann Vallo,Jürimäe Jaak,Jürimäe Toivo Journal of bone and mineral metabolism The aim of our study was to examine the relationship between bone mineral density (BMD) and serum ghrelin, insulin-like growth factor-1 (IGF-1), IGF-binding protein 3 (IGFBP-3), and testosterone levels in boys at different stages of puberty. The study included 60 healthy nonobese Estonian schoolboys at the age of 10-18 years. Subjects were divided in three groups (20 boys in each) based on the results of self-assessment using illustrated questionnaire of pubertal stage (G1, I; G2-G3, II; G3-G4, III). Morning fasting blood samples were collected for analysis of ghrelin, testosterone, IGF-1, and IGFBP-3. Total body BMD, lumbar BMD, lumbar apparent volumetric BMD (BMAD), and bone mineral content (BMC) were measured by DXA. Serum testosterone concentration was the most important biochemical predictor of BMD in the total group, explaining 48.8% of variability in total body BMD, 51.4% in lumbar BMD, and 36.8% in lumbar BMAD. Body mass and height were both related to BMD and BMC throughout puberty. The serum IGF-1/IGFBP-3 ratio was correlated with serum testosterone (r = 0.69) and ghrelin (r = -0.58) levels, but also with total BMD (r = 0.39), lumbar BMD (r = 0.42; P < 0.001 in all cases), BMAD (r = 0.29; P < 0.01), and total BMC (r = 0.48; P < 0.001). We conclude that serum testosterone concentration and serum IGF-1/IGFBP-3 molar ratio are the major determinants of bone mineral density in boys at different pubertal stages. Serum ghrelin concentration did not appear to have a direct independent effect on BMD. If present, the association may be mediated through sex hormones and the GH-IGF-I axis. 10.1007/s00774-006-0744-6
Associations of insulin-like growth factor-I and insulin-like growth factor binding protein-3 with bone quality in the general adult population. Böker J,Völzke H,Nauck M,Hannemann A,Friedrich N Clinical endocrinology OBJECTIVE:Growth hormone (GH) and its main mediator, insulin-like growth factor-I (IGF-I), play a significant role in bone metabolism. The relations between IGF-I and bone mineral density (BMD) or osteoporosis have been assessed in previous studies but whether the associations are sex-specific remains uncertain. Moreover, only a few studies examined bone quality assessed by quantitative ultrasound (QUS). We aimed to investigate these associations in the general population of north-east Germany. DESIGN AND MEASUREMENTS:Data from 1759 men and 1784 women who participated in the baseline examination of the Study of Health in Pomerania (SHIP)-Trend were used. IGF-I and IGF-binding protein-3 (IGFBP-3) concentrations were measured on the IDS-iSYS multidiscipline automated analyser (Immunodiagnostic Systems Limited). QUS measurements were performed at the heel (Achilles InSight, GE Healthcare). Sex-specific linear and multinomial logistic regression models adjusted for potential confounders were calculated. RESULTS:Linear regression analyses revealed significant positive associations between IGF-I and IGF-I/IGFBP-3 ratio, a marker for free IGF-I, with all QUS parameters in men. Among women, we found an inverse association between IGF-I and the QUS-based fracture risk but no association with any other QUS parameter. There was no association between IGFBP-3 and the QUS-based fracture risk. CONCLUSIONS:Our data suggest an important role of IGF-I on bone quality in men. The observed association of IGF-I with the QUS-based stiffness index and QUS-based fracture risk in this study might animate clinicians to refer patients with low IGF-I levels, particularly men, to a further evaluation of risk factors for osteoporosis and a detailed examination of the skeletal system. 10.1111/cen.13588
The role of insulin-like growth factor I components in the regulation of vitamin D. Gómez José Manuel Current pharmaceutical biotechnology Several factors are known to be involved in the regulation of vitamin D and sunlight and diet are the two sources in humans, but the relative importance of each of them is not well defined. Vitamin D, parathyroid hormone and serum insulin-like growth factor-I (IGF-I) were found to be independent predictors of total bone density. Thus, the growth hormone (GH)/IGF-I is thought to play an important role in the regulation of bone mineral density and the skeleton is second only to the liver as a source of circulating levels of IGF-I. The mechanisms by which IGF-I may influence bone metabolism is not fully understood but they are a predictor of bone mass density and are positively associated with vitamin D concentrations. There is a physiological decline of the GH/IGF axis with ageing. The high affinity IGF-binding proteins (IGFBP-I to 6) have also been involved in IGF-I regulation, and it is important to include the IGF-independent properties, particularly those of IGFBP3 that may be involved in the osteoblastic differentiation observed in human bone marrow stromal cell cultures. These hormones have been shown to up regulate each other. 1,25-(OH) D(3) has been shown to promote the action of IGF-I by increasing IGF-I receptors and IGF-I can also elevate 1,25-(OH) D(3) concentrations by stimulating the hydroxylation of 25-(OH) D(3) in the active 1,25-(OH) D(3) hormone. Both GH and IGF-I significantly increased renal 1alpha-hydroxylase expression and serum 1, 25-(OH) D(3) concentrations. In prostate cells, 1,25-(OH) D(3) is growth inhibitory for many established cell lines and the role of IGFBPs, especially IGFBP-3, can be growth inhibitory or stimulatory and IGFBP-3 expression increases in response to 1,25-(OH) D(3), or its analogs, in established prostate cancer cell lines. Body fat is inversely associated with 25-(OH) D(3) in relation to with anthropometric measures, indicating a specific role of adipose tissue. IGF-I may be involved in both normal and abnormal fetal growth and stimulation of IGF-I synthesis during normal pregnancy may be associated with an increase in GH production by the placenta. Thus, maternal and umbilical cord serum IGF-I and 1,25-(OH) D(3) concentrations are lower in preeclampsia and umbilical cord serum IGF-I, IGFBP-1 and IGFBP-3 concentrations are associated with low newborn birth weights.
Perturbations in bone formation and resorption in insulin-like growth factor binding protein-3 transgenic mice. Silha Josef V,Mishra Suresh,Rosen Clifford J,Beamer Wesley G,Turner Russell T,Powell David R,Murphy Liam J Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research UNLABELLED:IGF-I and their binding proteins are important in bone health. Examination of BMD, osteoblast proliferation, and markers of bone resorption in transgenic mice that constitutively overexpress IGFBP-3 indicates that overexpression of IGFBP-3 increases osteoclast number and bone resorption, impairs osteoblast proliferation, and has a significant negative effect on bone formation. INTRODUCTION:Low serum insulin-like growth factor I (IGF-I) levels correlate with an increased risk of osteoporotic fractures. Serum IGF-I is largely bound to IGF-binding protein-3 (IGFBP-3), which can inhibit IGF-I action and enhance delivery of IGF-I to tissues. Its role in bone biology is unclear. METHODS:Bone mineral density (BMD), osteoblast proliferation, and markers of bone resorption were examined in transgenic (Tg) mice that constitutively overexpressed human IGFBP-3 cDNA driven by either the cytomegalovirus (CMV) or phosphoglycerate kinase (PGK) promoter. RESULTS:Cultured calvarial osteoblasts from Tg mice expressed the transgene and grew more slowly than cells from wild-type (Wt) mice, and the mitogenic response to IGF-I was attenuated in osteoblasts from Tg mice. Total volumetric BMD and cortical BMD, measured in the femur using peripheral quantitative computed tomography (pQCT) were significantly reduced in both Tg mouse strains compared with Wt mice. PGKBP-3 Tg mice showed the most marked reduction in bone density. Osteocalcin levels were similar in Wt and CMVBP-3 Tg mice but were significantly reduced in PGKBP-3 Tg mice. Urinary deoxypyridinoline and osteoclast perimeter, markers of bone resorption, were significantly increased in both Tg mouse strains compared with Wt mice. Using double labeling with tetracycline, we demonstrated that pericortical and endocortical mineral apposition rate was significantly reduced in PGKBP-3 Tg mice compared with Wt mice. CONCLUSIONS:These data show that overexpression of IGFBP-3 increases osteoclast number and bone resorption, impairs osteoblast proliferation, and has a significant negative effect on bone formation. 10.1359/jbmr.2003.18.10.1834
Serum levels of insulin-like growth factor (IGF); IGF-binding proteins-3, -4, and -5; and their relationships to bone mineral density and the risk of vertebral fractures in postmenopausal women. Yamaguchi T,Kanatani M,Yamauchi M,Kaji H,Sugishita T,Baylink D J,Mohan S,Chihara K,Sugimoto T Calcified tissue international We previously found that serum levels of insulin-like growth factor I (IGF-I) and IGF-binding protein (IGFBP)-3, but not IFGBP-2, were associated with bone mineral density (BMD) and the risk of vertebral fractures. The aim of the present study was to investigate the roles of IGFBP-4 and -5 in age-dependent bone loss and vertebral fracture risk in postmenopausal Japanese women and to compare them with those of IGF-I and IGFBP-3. One hundred and ninety-three Japanese women aged 46-88 years (mean 62.5) were enrolled in the cross-sectional study. BMD was measured at the lumbar spine, femoral neck, ultradistal radius (UDR), and total body by dual-energy X-ray absorptiometry. Serum levels of IGFBP-4 and -5 as well as IGF-I and IGFBP-3 were measured by radioimmunoassay. Serum levels of IGF-I, IGFBP-3, and IGFBP-5 declined with age, while serum IGFBP-4 increased with age. Multiple regression analysis was performed between BMD at each skeletal site and serum levels of IGF-I and IGFBPs adjusted for age, body weight, height, and serum creatinine. BMD at the UDR was significantly and positively correlated with all serum levels of IGF-I and IGFBPs measured (P < 0.01), while BMD at the femoral neck was correlated with none of them. Serum IGF-I level was significantly and positively correlated with BMD at all sites except the femoral neck (P < 0.01), while serum IGFBP-3 and -4 levels were significantly and positively correlated with only radial BMD (P < 0.01). Serum IGFBP-5 level was positively correlated with UDR BMD (P < 0.001) and negatively correlated with total BMD (P < 0.05). Serum IGF-I, IGFBP-3, and IFGBP-5 levels were significantly lower in women with vertebral fractures than in those without fractures (mean +/- SD: 97.1 +/- 32.1 vs. 143.9 +/- 40.9 ng/dl, P < 0.0001; 2.18 +/- 1.02 vs. 3.23 +/- 1.07 microg/ml, P < 0.0001; 223.6 +/- 63.3 vs. 246.5 +/- 71.5 ng/ml, P = 0.0330, respectively). When multivariate logistic regression analysis was performed with the presence of vertebral fractures as a dependent variable and serum levels of IGF-I and IGFBPs adjusted for age, body weight, height, serum creatinine, and serum alubumin as independent variables, IGF-I and IGFBP-3 were selected as indices affecting the presence of vertebral fractures [odds ratio (OR) = 0.29, 95% confidential interval (CI) 0.15-0.57 per SD increase, P = 0.0003 and OR = 0.31, 95% CI 0.16-0.61 per SD increase, P = 0.0007, respectively]. To compare the significance values, IGF-I, IGFBP-3, and age were simultaneously added as independent variables in the analysis. IGFBP-3 was more strongly associated with the presence of vertebral fractures than IGF-I and age (P = 0.0006, P = 0.0148, and P = 0.0013, respectively). Thus, after comprehensive measurements of serum levels of IGF-I and IGFBPs, it seems that serum IGF-I level is most efficiently associated with bone mass and that serum IGFBP-3 level is most strongly associated with the presence of vertebral fractures in postmenopausal women among the IGF system components examined. 10.1007/s00223-005-0163-z
Serum insulin-like growth factor-I, insulin-like growth factor binding protein-3, sex steroids, osteocalcin and bone mineral density in male and female rats. Fukuda R,Usuki S,Mukai N,Amagai H,Hayashi K,Takamatsu K Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology Although it has been reported that the rate of weight gain and linear growth increases markedly during puberty in rats, little is known about the relationship between endocrine changes and bone mineral density (BMD) changes upon sexual maturation in these animals. The aim of this study was to examine the levels of serum insulin-like growth factor-I (IGF-I), IGF binding protein (IGFBP)-3, sex steroids and osteocalcin, and the changes in BMD in normal aging male and female rats. Male rats exhibited increases in serum IGF-I and IGFBP-3 concentrations before increases in serum testosterone levels. IGF-I and testosterone peaked at 9 weeks of age, and thereafter remained in a steady state, whereas IGFBP-3 reached a peak at 7 weeks of age, and then gradually declined. A strong correlation between serum IGF-I and IGFBP-3 levels was found in subjects 3-9 weeks old. A highly significant correlation between serum IGF-I and testosterone levels was also found. In females, serum 17 beta-estradiol, IGF-I and IGFBP-3 levels increased gradually from 3 to 5 weeks old, peaked at 9 weeks, and then decreased slowly thereafter. The correlation coefficient between serum IGF-I and IGFBP-3 was highly significant. The correlation coefficient between serum IGF-I and 17 beta-estradiol levels was weak, although it was strongest when the subjects were 3-9 weeks old. Serum osteocalcin is a marker of bone formation; its level remained relatively high from 3 to 9 and from 3 to 7 weeks of age in males and females, respectively, although osteocalcin in both sexes declined gradually with age. As for bone mass, sharp increases in BMD in the tibia, femur and lumbar vertebrae appeared earlier in female than in male rats, and the BMD in females tended to be higher than in males between 5 and 9 weeks old. After 9 weeks of age, BMD in males was higher than that in females, as BMD in males continued to increase whereas females tended to remain in a steady state after this stage. The correlation coefficients between tibial BMD and serum IGF-I or IGFBP-3 levels were highly significant when the subjects were from 3 to 9 weeks old. Taken together, these results suggest that BMD development occurs earlier in female than in male rats. This sex-related difference in changes in the BMD pattern may result from the earlier onset of puberty in females, and from sex-specific differences in concentrations of IGF-I, IGFBP-3 and sex steroids during maturation. 10.3109/09513599809012830
Insulin growth factor binding protein-3 enhances dental implant osseointegration against methylglyoxal-induced bone deterioration in a rat model. Journal of periodontal & implant science PURPOSE:The aim of this study was to determine the effect of insulin growth factor binding protein-3 (IGFBP-3) on the inhibition of glucose oxidative stress and promotion of bone formation near the implant site in a rat model of methylglyoxal (MGO)-induced bone loss. METHODS:An study was performed in MC3T3 E1 cells treated with chitosan gold nanoparticles (Ch-GNPs) conjugated with cDNA followed by MGO. An study was conducted in a rat model induced by MGO administration after the insertion of a dental implant coated with . RESULTS:MGO treatment downregulated molecules involved in osteogenic differentiation and bone formation in MC3T3 E1 cells and influenced the bone mineral density and bone volume of the femur and alveolar bone. In contrast, IGFBP-3 inhibited oxidative stress and inflammation and enhanced osteogenesis in MGO-treated MC3T3 E1 cells. In addition, IGFBP-3 promoted bone formation by reducing inflammatory proteins in MGO-administered rats. The application of Ch-GNPs conjugated with as a coating of titanium implants enhanced osteogenesis and the osseointegration of dental implants. CONCLUSIONS:This study demonstrated that IGFBP-3 could be applied as a therapeutic component in dental implants to promote the osseointegration of dental implants in patients with diabetes, which affects MGO levels. 10.5051/jpis.2101200060
Influence of insulin-like growth factor binding protein (IGFBP)-1 and IGFBP-3 on bone health: results from the European Male Ageing Study. Pye Stephen R,Almusalam Bader,Boonen Steven,Vanderschueren Dirk,Borghs Herman,Gielen Evelien,Adams Judith E,Ward Kate A,Bartfai Gyorgy,Casanueva Felipe F,Finn Joseph D,Forti Gianni,Giwercman Aleksander,Han Thang S,Huhtaniemi Ilpo T,Kula Krzysztof,Labrie Fernand,Lean Michael E J,Pendleton Neil,Punab Margus,Silman Alan J,Wu Frederick C W,O'Neill Terence W, Calcified tissue international The aim of this study was to determine the influence of insulin-like growth factor binding protein (IGFBP)-1, IGFBP-3, and IGF-I on calcaneal ultrasound parameters in middle-aged and elderly European men. Men aged 40-79 years were recruited from population registers for participation in the European Male Ageing Study (EMAS). Subjects were invited by letter to complete a postal questionnaire and to attend for an interviewer-assisted questionnaire, quantitative ultrasound (QUS) of the calcaneus, and a fasting blood sample from which serum levels of IGFBP-1, IGFBP-3, IGF-I, estradiol (E(2)), and SHBG were assayed. The questionnaires included the Physical Activity Scale for the Elderly (PASE) and questions about smoking and alcohol consumption. Estimated bone mineral density (eBMD) was derived as a function of the QUS parameters speed of sound and broadband ultrasound attenuation. Height and weight were measured in all subjects. 3057 men, mean age 59.7 years (standard deviation 11.0) were included in the analysis. After adjusting for age, center, and BMI, higher levels of IGFBP-1 were associated with lower eBMD. Higher levels of both IGFBP-3 and IGF-I were associated with higher eBMD. After further adjustment for PASE score, current smoking, alcohol consumption, free E(2), and SHBG, IGFBP-3 and IGF-I, though not IGFBP-1, remained significantly associated with eBMD. IGFBP-1 was associated with bone health, though the effect could be explained by other factors. IGFBP-3 and IGF-I were independent determinants of bone health in middle-aged and elderly European men. 10.1007/s00223-011-9484-2
Potential role of rhIGF-I/IGFBP-3 in maintaining skeletal mass in space. Tanaka H,Moriwake T,Matsuoka Y,Nakamura T,Seino Y Bone Bone loss during space flight may be induced by decreased activity of bone formation. To explore a new method for the bone loss in microgravity, the effects of insulin-like growth factor I (IGF-I), a potent stimulator for osteoblast activities, were studied in in vitro and in vivo system. The complex of IGF-I and its specific binding protein, IGFBP-3, may stimulate the osteoblastic activities via prolonged serum half life and increased cellular association of IGF-I. In an ovariectomy combined with neurectomy model, this complex stimulated bone turnover. IGF-I/IGFBP-3 may be a candidate for the treatment of bone loss induced by the microgravity.
Circulating PTH, Vitamin D and IGF-I levels in relation to bone mineral density in elderly women. Lumachi Franco,Camozzi Valentina,Doretto Paolo,Tozzoli Renato,Basso Stefano M M In vivo (Athens, Greece) Age and reduced bone mineral density (BMD) represent major risk factors for vertebral fracture risk, especially in pos-tmenopausal women, and measurement of BMD is currently considered of value in estimating bone mineralization. BMD correlates with demographics and anthropometric parameters, as well as with several markers of bone metabolism and calcium-regulating hormones, such as leptin, osteoprotegerin, parathyroid hormone (PTH), vitamin D, insulin-like growth factor-I (IGF-I) and sex steroid hormones. The aim of this study was to evaluate the relationship between PTH, 25(OH) vitamin D [25(OH)D], IGF-I and BMD in a selected group of elderly women. Thirty-one post-menopausal women over the age of 65, who were not estrogen, vitamin D or bisphosphonate users and did not have a history of fracture, bone disease or malignancy, were prospectively enrolled in the study. All the patients underwent lumbar spine dual-energy x-ray absorptiometry (DXA) and serum calcium, creatinine, PTH, 25(OH)D and IGF-I measurements. As expected, a weakly-inverse correlation between age and 25(OH)D (R=-0.50, p=0.020), and between BMD and PTH (R=-0.48, p=0.027) was found. There was a strong relationship between IGF-I and BMD (R=0.64, p=0.0016), and between age and IGF-I (R=-0.70, p<0.001), while IGF-I did not correlate with 25(OH)D (R=-0.16, p=0.48) or BMI (R=-0.089, p=0.70). In conclusion, in this selected group of elderly women, we found a strong relationship of increased bone resorption, expressed as BMD, to calcium-regulating hormones PTH and IGF-I, while 25(OH)D and BMI seem to be independent of bone mineralization status.
The dietary protein, IGF-I, skeletal health axis. Bonjour Jean-Philippe Hormone molecular biology and clinical investigation Dietary protein represents an important nutrient for bone health and thereby for the prevention of osteoporosis. Besides its role as a brick provider for building the organic matrix of skeletal tissues, dietary protein stimulates the production of the anabolic bone trophic factor IGF-I (insulin-like growth factor I). The liver is the main source of circulating IGF-I. During growth, protein undernutrition results in reduced bone mass and strength. Genetic defect impairing the production of IGF-I markedly reduces bone development in both length and width. The serum level of IGF-I markedly increases and then decreases during pubertal maturation in parallel with the change in bone growth and standing height velocity. The impact of physical activity on bone structure and strength is enhanced by increased dietary protein consumption. This synergism between these two important environmental factors can be observed in prepubertal boys, thus modifying the genetically determined bone growth trajectory. In anorexia nervosa, IGF-I is low as well as bone mineral mass. In selective protein undernutrition, there is a resistance to the exogenous bone anabolic effect of IGF-I. A series of animal experiments and human clinical trials underscore the positive effect of increased dietary intake of protein on calcium-phosphate economy and bone balance. On the contrary, the dietary protein-induced acidosis hypothesis of osteoporosis is not supported by several experimental and clinical studies. There is a direct effect of amino acids on the local production of IGF-I by osteoblastic cells. IGF-I is likely the main mediator of the positive effect of parathyroid hormone (PTH) on bone formation, thus explaining the reduction in fragility fractures as observed in PTH-treated postmenopausal women. In elderly women and men, relatively high protein intake protects against spinal and femoral bone loss. In hip fracture patients, isocaloric correction of the relatively low protein intake results in: increased IGF-I serum level, significant attenuation of postsurgical bone loss, improved muscle strength, better recovery, and shortened hospital stay. Thus, dietary protein contributes to bone health from early childhood to old age. An adequate intake of protein should be recommended in the prevention and treatment of osteoporosis. 10.1515/hmbci-2016-0003
Potential applications for rhIGF-I: Bone disease and IGFI. Bahamonde Marisol,Misra Madhusmita Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society Growth hormone (GH) and insulin like growth factor-I (IGFI) are key bone trophic hormones, whose rising levels during puberty are critical for pubertal bone accrual. Conditions of GH deficiency and genetic resistance impact cortical and trabecular bone deleteriously with reduced estimates of bone strength. In humans, conditions of undernutrition (as in anorexia nervosa (AN), or subsequent to chronic illnesses) are associated with low IGF-I levels, which correlate with disease severity, and also with lower bone mineral density (BMD), impaired bone structure and lower strength estimates. In adolescents and adults with AN, studies have demonstrated a nutritionally acquired GH resistance with low IGF-I levels despite high concentrations of GH. IGF-I levels go up with increasing body weight, and are associated with rising levels of bone turnover markers. In short-term studies lasting 6-10 days, recombinant human IGF-I (rhIGF-I) administration in physiologic replacement doses normalized IGF-I levels and increased levels of bone formation markers in both adults and adolescents with AN. In a randomized controlled trial in adults with AN in which participants were randomized to one of four arms: (i) rhIGF-I with oral estrogen-progesterone (EP), (ii) rhIGF-I alone, (iii) EP alone, or (iv) neither for 9 months, a significant increase in bone formation markers was noted in the groups that received rhIGF-I, and a significant decrease in bone resorption markers in the groups that received EP. The group that received both rhIGF-I and EP had a significant increase in bone density at the spine and hip compared to the group that received neither. Side effects were minimal, with no documented fingerstick glucose of <50 mg/dl. These data thus suggest a potential role for rhIGF-I administration in optimizing bone accrual in states of undernutrition associated with low IGF-I. 10.1016/j.ghir.2020.101317
IGF-I improved bone mineral density and body composition of weaver mutant mice. Yao Weiguo,Zhong Jin,Yu Jun,Warner Therry,Bozic Tomica,Ye Ping,D'Ercole A Joseph,Hock Janet M,Lee Wei-Hua Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society Our recent report on a parallel decrease in the body weights and serum IGF-I levels of weaver mice suggests that IGF-I's endocrine function may be impaired in neurodegenerative diseases. To further understand the overall effects of IGF-I deficiency on the postnatal growth, we measured bone mineral density (BMD), bone mineral content (BMC), lean body mass (LBM) and fat mass in male and female weaver mice and wild-type littermates on D21 (prepuberty), D45 (puberty), and D60 (postpuberty) using dual-energy X-ray absorptiometry (DEXA). In both male and female weaver mice, we found that the levels of circulating IGF-I paralleled those of BMD, BMC, and LBM, but not the fat mass. Male weaver mice have normal fat mass at all three ages studied, whereas female weaver mice showed a trend to increase their fat mass as they mature. To determine whether circulating IGF-I is a determinant of body composition, we crossbred IGF-I transgenic mice with homozygous weaver mice, which resulted in a significant increase in circulating IGF-I levels in both male and female weaver mice and normalization of their BMD, BMC and body weights. In summary, our results demonstrated that normal circulating IGF-I levels are important in maintaining BMD, BMC, and body composition in neurodegenerative diseases, such as hereditary cerebellar ataxia. 10.1016/j.ghir.2008.04.006
Hip fracture patients, a group of frail elderly people with low bone mineral density, muscle mass and IGF-I levels. Hedström M Acta physiologica Scandinavica Elderly women with hip fractures constitute an increasing group of patients in many western countries. The most significant of many factors contributing to the incidence of hip fractures are neuromuscular impairment and low bone mineral density (BMD). Both bone mass and muscle strength decrease during ageing as well as growth hormone (GH) and the anabolic, insulin-like growth factor I (IGF-I). We have found a lower IGF-I level and lower bone and lean body mass in hip fracture patients than in an age-matched group of patients. This sign of catabolism seems to continue postoperatively, with a significant decrease of both BMD and lean body mass possibly indicating GH/IGF-I therapy together with adequate nutrition to preserve bone and muscle losses in elderly patients with hip fractures. 10.1046/j.1365-201x.1999.00626.x
Role of IGF-I signaling in muscle bone interactions. Bikle Daniel D,Tahimic Candice,Chang Wenhan,Wang Yongmei,Philippou Anastassios,Barton Elisabeth R Bone Skeletal muscle and bone rely on a number of growth factors to undergo development, modulate growth, and maintain physiological strength. A major player in these actions is insulin-like growth factor I (IGF-I). However, because this growth factor can directly enhance muscle mass and bone density, it alters the state of the musculoskeletal system indirectly through mechanical crosstalk between these two organ systems. Thus, there are clearly synergistic actions of IGF-I that extend beyond the direct activity through its receptor. This review will cover the production and signaling of IGF-I as it pertains to muscle and bone, the chemical and mechanical influences that arise from IGF-I activity, and the potential for therapeutic strategies based on IGF-I. This article is part of a Special Issue entitled "Muscle Bone Interactions". 10.1016/j.bone.2015.04.036
Insulin-like Growth Factor-1, Bone Mineral Density, and Fracture: A Mendelian Randomization Study. Yuan Shuai,Wan Zi-Hao,Cheng Shi-Le,Michaëlsson Karl,Larsson Susanna C The Journal of clinical endocrinology and metabolism CONTEXT:The associations of circulating insulin-like growth factor-1 (IGF-1) levels with bone mineral density and fracture risk are inconclusive in observational studies. OBJECTIVE:We conducted a mendelian randomization study to assess the associations of serum IGF-1 levels with estimated bone mineral density (eBMD) and fracture. METHODS:Genetic instruments for IGF-1 were selected at the genome-wide significance level (P < 5 × 10-8) from a genome-wide association study including 358 072 individuals of European ancestry. Summary-level data for eBMD (426 824 individuals) and fracture (53 184 fracture cases and 373 611 noncases) were obtained from the UK Biobank study. Univariable and multivariable mendelian randomization analyses methods were used to estimate the associations of IGF-1 with eBMD and fracture. The main outcome measure included the change of eBMD and odds ratio of fracture per genetically predicted 1-SD increase of serum IGF-1 levels. RESULTS:For 1-SD increase in IGF-1, the change of eBMD levels was 0.04 g/cm2 (95% CI, 0.01-0.07; P = .011) and the odds ratio of fracture was 0.94 (95% CI, 0.91-0.98; P = .003). The associations persisted with similar magnitude after adjustment for height. The association was consistent for fracture but not for eBMD after excluding genetic instruments that might directly influence these outcomes. The association between IGF-1 and fracture was somewhat attenuated after adjustment for eBMD (odds ratio 0.96; 95% CI, 0.92-0.99; P = .012). CONCLUSION:The present study supports a role for IGF-1 in preventing fracture, possibly and partly mediated by greater bone mineral density. 10.1210/clinem/dgaa963
Endocrine consequences of anorexia nervosa. Misra Madhusmita,Klibanski Anne The lancet. Diabetes & endocrinology Anorexia nervosa is prevalent in adolescents and young adults, and endocrine changes include hypothalamic amenorrhoea; a nutritionally acquired growth-hormone resistance leading to low concentrations of insulin-like growth factor-1 (IGF-1); relative hypercortisolaemia; decreases in leptin, insulin, amylin, and incretins; and increases in ghrelin, peptide YY, and adiponectin. These changes in turn have harmful effects on bone and might affect neurocognition, anxiety, depression, and the psychopathology of anorexia nervosa. Low bone-mineral density (BMD) is particularly concerning, because it is associated with changes in bone microarchitecture, strength, and clinical fractures. Recovery leads to improvements in many--but not all--hormonal changes, and deficits in bone accrual can persist. Oestrogen-replacement therapy, primarily via the transdermal route, increases BMD in adolescents, although catch-up is incomplete. In adults, oral oestrogen--combined with recombinant human IGF-1 in one study and bisphosphonates in another--increased BMD, but not to the normal range. More studies are necessary to investigate the optimum therapeutic approach in patients with, or recovering from, anorexia nervosa. 10.1016/S2213-8587(13)70180-3
About adverse effects of high-dose vitamin D supplementation on volumetric bone density. Boucher Barbara J Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 10.1002/jbmr.4252
Vitamin D status of Icelandic children and its influence on bone accrual. Hauksson Haukur Heidar,Hrafnkelsson Hannes,Magnusson Kristjan Thor,Johannsson Erlingur,Sigurdsson Emil L Journal of bone and mineral metabolism The importance of vitamin D for children's bone health has been well established, but the effects of less severe deficiency are not fully known. The main objective of this study was to assess the vitamin D status of Icelandic children at the age of 7, and again at 9 years of age, and the association of vitamin D status with bone mineral content and bone accrual over 2 years. We invited 321 children to participate in this study, and 267 (83 %) took part; 211 (79 %) underwent a DXA scan and 164 were again scanned 2 years later; 159 (60 %) vitamin D samples were measured and 119 (75 %) were measured again 2 years later. At age 7, 65 % of the children had vitamin D concentrations <50 nmol/l, and at age 9 this figure was 60 %. At age 7, 43 % of the children had insufficient amounts of vitamin D (37.5-50 nmol/l), and 22 % had a vitamin D deficiency (<37.5 nmol/l). In linear regression analysis, no association was found between vitamin D and bone mineral content. Furthermore, there was no significant difference in bone accrual over 2 years for the children with insufficient or deficient vitamin D at both ages, compared to those having more than 50 nmol/l at both time points. More than 60 % of Icelandic children have inadequate concentrations of vitamin D in serum repeatedly over a 2-year interval. However, vitamin D in the range did not have a significant effect on bone mineral content or accrual at ages 7 and 9. 10.1007/s00774-015-0704-0
Vitamin D and bone density, fractures, and falls: the end of the story? Gallagher J Chris The lancet. Diabetes & endocrinology 10.1016/S2213-8587(18)30269-9
Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis. Bolland Mark J,Grey Andrew,Avenell Alison The lancet. Diabetes & endocrinology BACKGROUND:The effects of vitamin D on fractures, falls, and bone mineral density are uncertain, particularly for high vitamin D doses. We aimed to determine the effect of vitamin D supplementation on fractures, falls, and bone density. METHODS:In this systematic review, random-effects meta-analysis, and trial sequential analysis, we used findings from literature searches in previously published meta-analyses. We updated these findings by searching PubMed, Embase, and Cochrane Central on Sept 14, 2017, and Feb 26, 2018, using the search term "vitamin D" and additional keywords, without any language restrictions. We assessed randomised controlled trials of adults (>18 years) that compared vitamin D with untreated controls, placebo, or lower-dose vitamin D supplements. Trials with multiple interventions (eg, co-administered calcium and vitamin D) were eligible if the study groups differed only by use of vitamin D. We excluded trials of hydroxylated vitamin D analogues. Eligible studies included outcome data for total or hip fractures, falls, or bone mineral density measured at the lumbar spine, total hip, femoral neck, total body, or forearm. We extracted data about participant characteristics, study design, interventions, outcomes, funding sources, and conflicts of interest. The co-primary endpoints were participants with at least one fracture, at least one hip fracture, or at least one fall; we compared data for fractures and falls using relative risks with an intention-to-treat analysis using all available data. The secondary endpoints were the percentage change in bone mineral density from baseline at lumbar spine, total hip, femoral neck, total body, and forearm. FINDINGS:We identified 81 randomised controlled trials (n=53 537 participants) that reported fracture (n=42), falls (n=37), or bone mineral density (n=41). In pooled analyses, vitamin D had no effect on total fracture (36 trials; n=44 790, relative risk 1·00, 95% CI 0·93-1·07), hip fracture (20 trials; n=36 655, 1·11, 0·97-1·26), or falls (37 trials; n=34 144, 0·97, 0·93-1·02). Results were similar in randomised controlled trials of high-dose versus low-dose vitamin D and in subgroup analyses of randomised controlled trials using doses greater than 800 IU per day. In pooled analyses, there were no clinically relevant between-group differences in bone mineral density at any site (range -0·16% to 0·76% over 1-5 years). For total fracture and falls, the effect estimate lay within the futility boundary for relative risks of 15%, 10%, 7·5%, and 5% (total fracture only), suggesting that vitamin D supplementation does not reduce fractures or falls by these amounts. For hip fracture, at a 15% relative risk, the effect estimate lay between the futility boundary and the inferior boundary, meaning there is reliable evidence that vitamin D supplementation does not reduce hip fractures by this amount, but uncertainty remains as to whether it might increase hip fractures. The effect estimate lay within the futility boundary at thresholds of 0·5% for total hip, forearm, and total body bone mineral density, and 1·0% for lumbar spine and femoral neck, providing reliable evidence that vitamin D does not alter these outcomes by these amounts. INTERPRETATION:Our findings suggest that vitamin D supplementation does not prevent fractures or falls, or have clinically meaningful effects on bone mineral density. There were no differences between the effects of higher and lower doses of vitamin D. There is little justification to use vitamin D supplements to maintain or improve musculoskeletal health. This conclusion should be reflected in clinical guidelines. FUNDING:Health Research Council of New Zealand. 10.1016/S2213-8587(18)30265-1
Vitamin D and bone health in children. Shaw Nick BMJ (Clinical research ed.) 10.1136/bmj.d192
Efficacy of vitamin D fortified foods on bone mineral density and serum bone biomarkers: A systematic review and meta-analysis of interventional studies. Tangestani Hadith,Djafarian Kurosh,Emamat Hadi,Arabzadegan Niloufar,Shab-Bidar Sakineh Critical reviews in food science and nutrition Vitamin D fortified foods (VDFs) were taken into consideration due to the high prevalence of osteoporosis worldwide. However, the efficacy of VDFs on bone health has not been fully examined. The current meta-analysis was conducted in order to summarize the impacts of VDFs on serum 25-hydroxyvitamin D (25(OH)D), bone mineral density (BMD), and bone turnover markers (BTM). A systematic search up to October 2017 was done via PubMed and Scopus search engines. To pool mean differences, random-effects model (the DerSimonian-Laird estimator) was used. Heterogeneity among studies was examined by Cochrane Q test. 20 trials involving 1786 subjects were included in this meta-analysis. Based on random effect model, there were significant effects of VDFs on serum 25(OH)D (MD:16.94 nmol/L 95% CI: 13.38, 20.50;  < 0.001,  = 99.0%), BMD (MD: 0.03 gr/cm; 95% CI: (0.02, 0.05);  < 0.001,  = 58.8%) and paratormone hormone (PTH; MD:-9.22; 95% CI: (-14.97, -3.46);  = 0.002,  = 98.8%). VDFs may increase serum 25(OH)D and BMD while decrease serum PTH levels. We did not find any beneficial effect of VDFs on BTM. 10.1080/10408398.2018.1558172
Does vitamin D supplementation improve bone density in vitamin D-deficient children? Protocol for an individual patient data meta-analysis. Winzenberg Tania,Lamberg-Allardt Christel,El-Hajj Fuleihan Ghada,Mølgaard Christian,Zhu Kun,Wu Feitong,Riley Richard D BMJ open INTRODUCTION:Our previous study-level (aggregate data) meta-analysis suggested that vitamin D supplements may be beneficial for bone density specifically in children with vitamin D deficiency. However, the misclassification of vitamin D status inherent in study-level data means that the results are not definitive and cannot provide an accurate assessment of the size of any effect. Therefore, we propose to undertake an individual patient data (IPD) meta-analysis to determine whether the effect of vitamin D supplementation on bone density in children differs according to baseline vitamin D status, and to specifically estimate the effect of vitamin D in children who are vitamin D deficient. METHODS AND ANALYSIS:This study has been designed to adhere to the Preferred Reporting Items for Systematic Review and Meta-Analyses of IPD statement. We will include randomised placebo-controlled trials of vitamin D supplementation reporting bone density outcomes at least 6 months after the study commenced in children and adolescents (aged <20 years) without coexistent medical conditions or treatments causing osteoporosis. We will update the search of the original review to cover the period 2009-2017, using the same methods as the original review. Fully anonymised data on all randomised patients will be requested. Outcomes will be femoral neck, total hip, lumbar spine and proximal and distal forearm bone mineral density, and total body bone mineral content. A two-stage IPD meta-analysis will be used to examine the effect of baseline serum 25-hydroxyvitamin D (25(OH)D) on treatment effect for each bone density outcome. Restricted maximum likelihood will be used to estimate the random-effects meta-analysis models, with 95% CI for summary effects. Heterogeneity will be assessed by I and potential publication bias (small-study effects) and availability bias by funnel plots, Egger's test and Peter's test. ETHICS AND DISSEMINATION:Ethics approval will not be required as the data are to be used for the primary purpose for which they were collected and all original individual studies had ethics approval. Results of the IPD meta-analysis will be submitted for publication in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER:CRD42017068772. 10.1136/bmjopen-2017-019584
The Effect of Calcium or Calcium and Vitamin D Supplementation on Bone Mineral Density in Healthy Males: A Systematic Review and Meta-Analysis. Silk Leslie N,Greene David A,Baker Michael K International journal of sport nutrition and exercise metabolism Research examining the preventative effects of calcium and vitamin D supplementation has focused on children and females, leaving the effects on male bone mineral density (BMD) largely unexplored. Thus, the aim of this systematic review and meta-analysis is to examine the efficacy of calcium supplementation, with or without vitamin D for improving BMD in healthy males. Medline, EMBASE, SPORTDiscus, Academic Search Complete, CINHAHL Plus and PubMed databases were searched for studies including healthy males which provided participants calcium supplementation with or without vitamin D and used changes to BMD as the primary outcome measure. Between trial standardized mean differences of percentage change from baseline in BMD of femoral neck, lumbar spine, total body and total hip sites were calculated. Nine studies were included in the systematic review with six references totaling 867 participants contributing to the meta-analysis. Significant pooled effects size (ES) for comparison between supplementation and control groups were found at all sites included in the meta-analysis. The largest effect was found in total body (ES = 0.644; 95% CI = 0.406-0.883; p < .001), followed by total hip (ES = 0.483, 95% CI= 0.255-0.711, p < .001), femoral neck (ES = 0.402, 95% CI = 0.233-0.570, p = .000) and lumbar spine (ES = 0.306, 95% CI = 0.173-0.440,p < .001). Limited evidence appears to support the use of calcium and vitamin D supplementation for improving BMD in older males. There is a need for high quality randomized controlled trials, especially in younger and middle-aged male cohorts and athletic populations to determine whether supplementation provides a preventative benefit. 10.1123/ijsnem.2014-0202
Vitamin D supplementation for improving children with bone mineral density: A protocol for systematic review and meta-analysis. Medicine BACKGROUND:Osteoporosis is usually one of the less perceived complications of chronic illness among children. Previous studies have shown that vitamin D supplementation may be valuable to bone density, especially among children with a deficiency of vitamin D. Yet, the results often remain inconsistent. Therefore, the present study investigates the clinical therapeutic effects of vitamin D supplementation to enhance children with bone mineral density. METHODS:We will search the randomised controlled experiment literature of vitamin D supplementation for bone mineral density, focusing on children, in 3 distinct English databases (EMBASE, MEDLINE via PubMed, and Cochrane Library) and 2 specific Chinese databases (China National Knowledge Infrastructure (CNKI) and WanFang databases). Additionally, we intend to explore the Clinical Trials.gov, reference lists of identified publication and the grey literature. Accordingly, we will use 2 independent authors to screen the literature, extract data, and research quality assessment. We will carry out all statistical analyses using RevMan 5.3 software. RESULTS:We will systematically evaluate the clinical therapeutic effects of vitamin D supplementation to enhance children with bone mineral density. CONCLUSION:The present study will summarise the currently published pieces of evidence of vitamin D supplementation for bone mineral density in children to further comprehend its promotion and application. ETHICS AND DISSEMINATION:The present study is a systematic review and meta-analysis founded upon existing or published studies; therefore, ethical approval is not applicable. OSF REGISTRATION NUMBER:October 24, 2020. osf.io/7vtey. (https://osf.io/7vtey/). 10.1097/MD.0000000000023475
Associations between serum calcium, 25(OH)D level and bone mineral density in adolescents. Pan Kaiyu,Tu Rongliang,Yao Xiaocong,Zhu Zhongxin Advances in rheumatology (London, England) BACKGROUNDS:It is important to improve our understanding of the roles of calcium and vitamin D in bone health for preventing osteoporosis. We aimed at exploring the associations between serum calcium, vitamin D level, and bone mineral density (BMD) in adolescents included in the National Health and Nutrition Examination Survey (NHANES) 2001-2006. METHODS:Weighted multivariate linear regression models were used to estimate the associations of serum calcium, 25(OH)D level with total BMD. Smooth curve fitting was used to explore the potential non-linear relationship. RESULTS:A total of 5990 individuals aged between 12 and 19 years were included in this study. The fully-adjusted model showed serum calcium positively correlated with total BMD. However, an inverted U-shaped relationship was found when we performed the smooth curve fitting method, and the inflection point was calculated at 9.6 mg/dL using the two-piecewise linear regression model. In contrast, there was a positive correlation between serum 25(OH)D and total BMD after adjusting for potential confounders. CONCLUSIONS:The present study revealed a positive correlation between serum 25(OH)D level and total BMD, and an inverted U-shaped relationship between serum calcium and total BMD. 10.1186/s42358-021-00174-8
Effects of vitamin D supplementation on bone density in healthy children: systematic review and meta-analysis. Winzenberg Tania,Powell Sandi,Shaw Kelly Anne,Jones Graeme BMJ (Clinical research ed.) OBJECTIVE:To determine the effectiveness of vitamin D supplementation for improving bone mineral density in children and adolescents and if effects vary with factors such as vitamin D dose and vitamin D status. DESIGN:Systematic review and meta-analysis. DATA SOURCES:Cochrane Central Register of Controlled Trials, Medline (1966 to present), Embase (1980 to present), CINAHL (1982 to present), AMED (1985 to present), and ISI Web of Science (1945 to present), last updated on 9 August 2009, and hand searching of conference abstracts from key journals. Study selection Placebo controlled randomised controlled trials of vitamin D supplementation for at least three months in healthy children and adolescents (aged 1 month to <20 years) with bone density outcomes. Two authors independently assessed references for inclusion and study quality and extracted data. DATA SYNTHESIS:Standardised mean differences of the percentage change from baseline in bone mineral density of the forearm, hip, and lumbar spine and total body bone mineral content in treatment and control groups. Subgroup analyses were carried out by sex, pubertal stage, dose of vitamin D, and baseline serum vitamin D concentration. Compliance and allocation concealment were also considered as possible sources of heterogeneity. RESULTS:From 1653 potential references, six studies, totalling 343 participants receiving placebo and 541 receiving vitamin D, contributed data to meta-analyses. Vitamin D supplementation had no statistically significant effects on total body bone mineral content or on bone mineral density of the hip or forearm. There was a trend to a small effect on lumbar spine bone mineral density (standardised mean difference 0.15, 95% confidence interval -0.01 to 0.31; P=0.07). Effects were similar in studies of participants with high compared with low serum vitamin D levels, although there was a trend towards a larger effect with low vitamin D for total body bone mineral content (P=0.09 for difference). In studies with low serum vitamin D, significant effects on total body bone mineral content and lumbar spine bone mineral density were roughly equivalent to a 2.6% and 1.7% percentage point greater change from baseline in the supplemented group. CONCLUSIONS:It is unlikely that vitamin D supplements are beneficial in children and adolescents with normal vitamin D levels. The planned subgroup analyses by baseline serum vitamin D level suggest that vitamin D supplementation of deficient children and adolescents could result in clinically useful improvements, particularly in lumbar spine bone mineral density and total body bone mineral content, but this requires confirmation. 10.1136/bmj.c7254
Effects of vitamin D supplements on bone density. Reid Ian R Journal of endocrinological investigation 10.1007/s40618-014-0127-0
Vitamin D supplementation for improving bone mineral density in children. Winzenberg Tania M,Powell Sandi,Shaw Kelly A,Jones Graeme The Cochrane database of systematic reviews BACKGROUND:Results of randomised controlled trials (RCTs) of vitamin D supplementation to improve bone density in children are inconsistent. OBJECTIVES:To determine the effectiveness of vitamin D supplementation for improving bone mineral density in children, whether any effect varies by sex, age or pubertal stage, the type or dose of vitamin D given or baseline vitamin D status, and if effects persist after cessation of supplementation. SEARCH STRATEGY:We searched the Cochrane Central Register of Controlled Trials (CENTRAL Issue 3, 2009), MEDLINE (1966 to present), EMBASE (1980 to present), CINAHL (1982 to present), AMED (1985 to present) and ISI Web of Science (1945 to present) on 9 August 2009, and we handsearched key journal conference abstracts. SELECTION CRITERIA:Placebo-controlled RCTs of vitamin D supplementation for at least three months in healthy children and adolescents (aged from one month to < 20 years) with bone density outcomes. DATA COLLECTION AND ANALYSIS:Two authors screened references for inclusion, assessed risk of bias, and extracted data. We conducted meta-analyses and calculated standardised mean differences (SMD) of the percent change from baseline in outcomes in treatment and control groups. We performed subgroup analyses by sex, pubertal stage, dose of vitamin D and baseline serum vitamin D and considered these as well as compliance and allocation concealment as possible sources of heterogeneity. MAIN RESULTS:We included six RCTs (343 participants receiving placebo and 541 receiving vitamin D) for meta-analyses. Vitamin D supplementation had no statistically significant effects on total body bone mineral content (BMC), hip bone mineral density (BMD) or forearm BMD. There was a trend to a small effect on lumbar spine BMD (SMD 0.15, 95% CI -0.01 to 0.31, P = 0.07). There were no differences in effects between high and low serum vitamin D studies at any site though there was a trend towards a larger effect with low vitamin D for total body BMC (P = 0.09 for difference). In low serum vitamin D studies, significant effects on total body BMC and lumbar spine BMD were approximately equivalent to a 2.6% and 1.7 % percentage point greater change from baseline in the supplemented group. AUTHORS' CONCLUSIONS:These results do not support vitamin D supplementation to improve bone density in healthy children with normal vitamin D levels, but suggest that supplementation of deficient children may be clinically useful. Further RCTs in deficient children are needed to confirm this. 10.1002/14651858.CD006944.pub2
Vitamin D Effect on Bone Mineral Density and Fractures. Reid Ian R Endocrinology and metabolism clinics of North America One hundred years ago, vitamin D was identified as the cause and cure of osteomalacia. This role remains firmly established. Vitamin D influences skeletal mineralization principally through the regulation of intestinal calcium absorption. It has been proposed that vitamin D has direct beneficial effects on bone (besides the prevention of osteomalacia), but these have been difficult to establish in clinical trials. Meta-analyses of vitamin D trials show no effects on bone density or fracture risk when the baseline 25-hydroxyvitamin D is >40 nmol/L. A daily dose of 400 to 800 IU vitamin D is usually adequate to correct such deficiency. 10.1016/j.ecl.2017.07.005
Associations of serum vitamins levels with bone mineral density in the different race-ethnicities US adults. Li Xiang,Liu Xun BMC musculoskeletal disorders BACKGROUND:The conclusions on the associations of specific vitamin levels with bone mineral density (BMD) were controversial. Therefore, the aims of this study were to examine the associations of serum vitamins levels with BMD and the modified effect of race/ ethnicity on these associations in the US adults. METHODS:This study was from the third National Health and Nutrition Examination Survey. All participants aged ≥18 years with complete data were eligible. Serum vitamins A, B9, B12, C, and E levels were assayed using the Quantaphase II Radioassay Kit (Bio-Rad). Dual-energy X-ray absorptiometry was employed to measure BMD, including femur neck and the total hip. RESULTS:There were 6023 participants included in the final analysis. Serum folate, vitamins A and C levels were positively associated with BMD. No significant associations of serum vitamins B12 and E levels with BMD were observed. There were positive associations of serum folate level (β = 0.00027 and 0.00032; and 95% CI: 0.00002-0.00057 and 0.00002-0.00063, respectively), vitamin A level (β = 0.01132 and 0.01115; and 95% CI: 0.00478-0.01787 and 0.00430-0.01799, respectively), and vitamin C level (β = 0.00027 and 0.00029; and 95% CI: 0.00012-0.00042 and 0.00013-0.00045, respectively) with BMD at femur neck and the total hip only in the Not Hispanic participants. CONCLUSION:Elevated serum folate, vitamins A and C levels were associated with a higher BMD. Furthermore, sex and race/ ethnicity modified the associations of serum vitamins levels with BMD. 10.1186/s12891-021-03997-0
Retinoid receptors in bone and their role in bone remodeling. Henning Petra,Conaway H Herschel,Lerner Ulf H Frontiers in endocrinology Vitamin A (retinol) is a necessary and important constituent of the body which is provided by food intake of retinyl esters and carotenoids. Vitamin A is known best for being important for vision, but in addition to the eye, vitamin A is necessary in numerous other organs in the body, including the skeleton. Vitamin A is converted to an active compound, all-trans-retinoic acid (ATRA), which is responsible for most of its biological actions. ATRA binds to intracellular nuclear receptors called retinoic acid receptors (RARα, RARβ, RARγ). RARs and closely related retinoid X receptors (RXRα, RXRβ, RXRγ) form heterodimers which bind to DNA and function as ligand-activated transcription factors. It has been known for many years that hypervitaminosis A promotes skeleton fragility by increasing osteoclast formation and decreasing cortical bone mass. Some epidemiological studies have suggested that increased intake of vitamin A and increased serum levels of retinoids may decrease bone mineral density and increase fracture rate, but the literature on this is not conclusive. The current review summarizes how vitamin A is taken up by the intestine, metabolized, stored in the liver, and processed to ATRA. ATRA's effects on formation and activity of osteoclasts and osteoblasts are outlined, and a summary of clinical data pertaining to vitamin A and bone is presented. 10.3389/fendo.2015.00031
Bone Mineral Density and Fat-Soluble Vitamin Status in Adults with Cystic Fibrosis Undergoing Lung Transplantation: A Pilot Study. Hubert Grace,Chung Theresa Tam,Prosser Connie,Lien Dale,Weinkauf Justin,Brown Neil,Goodvin Marianne,Jackson Kathy,Tabak Joan,Salgado Josette,Alzaben Abeer Salman,Mager Diana R Canadian journal of dietetic practice and research : a publication of Dietitians of Canada = Revue canadienne de la pratique et de la recherche en dietetique : une publication des Dietetistes du Canada PURPOSE:Patients with cystic fibrosis (CF) often experience low bone mineral density (BMD) pre- and post-lung transplantation (LTX). The study purpose was to describe BMD and micronutrient status in adults with CF pre- and post-LTX. METHODS:Twelve patients with CF (29 ± 8 years) were recruited from the CF clinic at the University of Alberta Lung Transplant Program. BMD and vitamins A, D, E, K status, and parathyroid hormone were measured pre- and post-LTX. RESULTS:No significant differences pre- and post-LTX were observed at the different bone sites measured (lumber-spine, femoral-neck (FN), hip, and femoral-trochlea) (P > 0.05). BMD T-scores (<-2) was present in lumbar-spine, FN, hip, and femoral-trochlea in 33%, 17%, 17%, and 25% of individuals pre-LTX and 58%, 33%, 58%, and 33% of individuals post-LTX, respectively. More than 50% of patients had suboptimal vitamin K levels (PIVKA-II values >3 ng/mL) pre- and post-LTX. CONCLUSION:Adults with CF pre- and post-LTX had reduced BMD and suboptimal vitamin K status. 10.3148/cjdpr-2016-014
Association of dietary consumption and serum levels of vitamin A and β-carotene with bone mineral density in Chinese adults. Chen Geng-Dong,Zhu Ying-Ying,Cao Yi,Liu Jun,Shi Wen-Qi,Liu Zhao-Min,Chen Yu-Ming Bone BACKGROUND:Former studies suggested an adverse effect of hypervitaminosis A on bone health, while the effects of retinol and its precursor (β-carotene) remain uncertain in populations consuming vitamin A (VA) mainly from plant sources. OBJECTIVE:We investigated the association of serum, dietary retinol, and β-carotene with bone mineral density (BMD) in Chinese adults. METHODS:We recruited 2101 women and 1053 men (aged 40-75 years) in Guangzhou, China. Dietary intake was assessed through face-to-face interviews with food-frequency questionnaires at baseline and 3 years later. Serum levels of retinol and β-carotene were determined by HPLC using a baseline specimen, and the BMD for the whole body (WB), lumbar spine (LS), total hip (TH), and femur neck (FN) were measured using dual energy X-ray absorptiometry at follow-up. RESULTS:In general, greater levels of serum retinol, β-carotene, and the β-carotene-to-retinol ratio were associated with a higher BMD after adjustment for potential covariates in the total sample. BMD values in the top (vs. bottom) quartile were increased by 2.06% (TH) for retinol; 2.87% (WB), 2.51% (LS), 3.10% (FN) for β-carotene; 2.21% (WB) and 2.05% (FN) for the β-carotene-to-retinol ratio in the total sample (all p<0.05). A significant positive association with BMD was observed for dietary intake of β-carotene and total VA in retinol equivalents at the hip sites in the total sample. CONCLUSION:Higher circulating and dietary levels of VA and β-carotene and higher serum β-carotene-to-retinol ratios were positively associated with BMD in Chinese adults consuming relatively low levels of VA, mainly from plant foods. 10.1016/j.bone.2015.05.028
Associations between Dietary Antioxidant Vitamin Intake and the Changes in Bone Mass in Chinese Adolescents: A 2.5-Year Longitudinal Study. Nutrients (1) Background: Optimal bone mass accumulation during adolescence is crucial for maximising peak bone mass during adulthood. Dietary antioxidant vitamins may contribute to bone mass accumulation. This 2.5-year-long longitudinal study aimed to evaluate the relationships between dietary vitamin A, C, and E intakes and the annual changes in bone parameters among Chinese adolescents. (2) Method: Subjects aged 10-18 years ( = 1418) were recruited from a secondary school in Jiangmen, China. Dietary vitamin A, C, and E intakes were assessed using 24 h dietary records over 3 consecutive days. The Sahara Clinical Bone Sonometer was used to measure the broadband ultrasound attenuation (BUA) and the speed of sound (SOS). Their annual changes were then calculated (i.e., BUA%/year, SOS%/year). The associations were detected after adjusting for the baseline bone phenotype; age; sex; weight; height; pubertal stage; physical activity; and dietary intakes of vitamin D, calcium and energy. (3) Results: A curvilinear relationship was found between the dietary intake of vitamin C and BUA%/year ( = 0.026); further analyses in the subgroups revealed that this relationship was observed in male adolescents ( = 0.012). A positive association was observed only in boys with a dietary vitamin C intake of ≥159.01 mg/day (β = 0.395, = 0.036). Moreover, a linear positive association was shown between the dietary intake of vitamin E and BUA%/year in female adolescents (β = 0.082, = 0.033). (4) Conclusion: Our findings indicated that dietary vitamin C intake has a threshold effect on bone mass gain in male adolescents and that dietary vitamin E intake could be a positive predictor of bone mass gain in female adolescents. 10.3390/nu14194187
Vitamin a: history, current uses, and controversies. Chapman M Shane Seminars in cutaneous medicine and surgery Vitamin A is required for the proper functioning of many important metabolic and physiologic activities, including vision, gene transcription, the immune system and skin cell differentiation. Both excessive and deficient levels of vitamin A lead to poor functioning of many human systems. The biologically active form, retinoic acid, binds to nuclear receptors that facilitate transcription that ultimately leads to it's physiological effects. Retinoids are derivatives of vitamin A that are medications used to treat acne vulgaris, psoriasis, ichthyosis (and other disorders of keratinization), skin cancer prevention as well as several bone marrow derived neoplasias. Systemic retinoids are teratogenic and have to be prescribed with caution and close oversight. Other potential adverse events are controversial. These include the relationship of retinoid derivatives in sunscreens, their effects on bone mineral density, depression and suicidal ideation and inflammatory bowel disease. These controversies will be discussed in detail. 10.1016/j.sder.2011.11.009
Vitamins and bone health: beyond calcium and vitamin D. Ahmadieh Hala,Arabi Asma Nutrition reviews Osteoporosis is a major health disorder associated with an increased risk of fracture. Nutrition is among the modifiable factors that influence the risk of osteoporosis and fracture. Calcium and vitamin D play important roles in improving bone mineral density and reducing the risk of fracture. Other vitamins appear to play a role in bone health as well. In this review, the findings of studies that related the intake and/or the status of vitamins other than vitamin D to bone health in animals and humans are summarized. Studies of vitamin A showed inconsistent results. Excessive, as well as insufficient, levels of retinol intake may be associated with compromised bone health. Deficiencies in vitamin B, along with the consequent elevated homocysteine level, are associated with bone loss, decreased bone strength, and increased risk of fracture. Deficiencies in vitamins C, E, and K are also associated with compromised bone health; this effect may be modified by smoking, estrogen use or hormonal therapy after menopause, calcium intake, and vitamin D. These findings highlight the importance of adequate nutrition in preserving bone mass and reducing the risk of osteoporosis and fractures. 10.1111/j.1753-4887.2011.00372.x
Effect of vitamin A, calcium and vitamin D fortification and supplementation on nutritional status of women: an overview of systematic reviews. Systematic reviews BACKGROUND:Micronutrient deficiency affects the health and development of vulnerable population such as children and pregnant women. Measures such as fortification of food and supplementation have been implemented to prevent or control deficiencies related to micronutrients. OBJECTIVE:To assess the effect of vitamin A, vitamin D, and calcium fortification and supplementation on nutritional status of women in reproductive age group. To assess the toxicities and adverse events related to intervention. METHODOLOGY:Systematic reviews including RCTs on women of reproductive age group provided with vitamin A, vitamin D, and calcium supplementation or fortified food were included, to report all malnutrition-related outcomes due to deficiency of the abovementioned micronutrients. The Cochrane Database of Systematic Reviews, EPPI Centre, Campbell Collaboration, PubMed, Web of Science, and Scopus were searched electronically for English language publications, until 31 March 2018. Hand searching of the articles was done from the Journal of Food Science and Technology. Two independent reviewers selected the systematic reviews, extracted data, and assessed for the quality. RESULTS:A total of 16 systematic reviews were included in narrative synthesis. Supplementation of vitamin A was reported to result in increased maternal serum retinol concentrations and increased breast milk retinol concentration. It reduced the risk of anemia (Hb < 11 g/dL) and reduced maternal clinical infection. Vitamin D supplementation increased 25-hydroxy vitamin D levels. There was insufficient evidence for the effect on bone mineral density and serum calcium levels. Calcium supplementation did not have any significant effect on body weight, weight gain, and body mass index of the participants. CONCLUSION:This overview of systematic reviews reiterates the nutritional importance of vitamin A, vitamin D, and calcium supplementation for the reproductive age women. However, there was no empirical evidence available for fortification of food with vitamin A, vitamin D, and calcium and nutritional benefits of the same for reproductive age women, therefore thrusting upon the need of conducting future quality research, i.e., clinical trials and systematic reviews for food fortification. SYSTEMATIC REVIEW REGISTRATION:A priori protocol for this overview of systematic reviews was registered in PROSPERO with registration number CRD42018089403 . 10.1186/s13643-020-01501-8
Vitamin A decreases the anabolic bone response to mechanical loading by suppressing bone formation. Lionikaite Vikte,Henning Petra,Drevinge Christina,Shah Furqan A,Palmquist Anders,Wikström Pernilla,Windahl Sara H,Lerner Ulf H FASEB journal : official publication of the Federation of American Societies for Experimental Biology Increased vitamin A consumption is associated with decreased cortical bone mass and increased fracture risk in humans. Rodent studies have demonstrated that hypervitaminosis A increases cortical bone resorption, whereas the importance of the effects on bone formation is less well defined. We used an experimental model of increased bone formation by loading of the tibiae to investigate the effect of vitamin A on bone formation. Control [retinol activity equivalents (RAE) 4.5 µg/g chow] or vitamin A (RAE 60 µg/g chow) diets were given to female C57BL/6N mice for 4 wk, after which the tibiae were subjected to axial loading on alternate days for 2 wk, while the diets were continued. Vitamin A inhibited the loading-induced increase in trabecular and cortical bone volume. This was attributed to inhibition of loading-induced increase in osteoblast number and activity, and expression of osteoblastic genes Sp7, Alpl, and Col1a1 in cortical bone. Vitamin A, loading, and combination thereof also resulted in site-specific effects on bone composition measured by Raman spectroscopy. In summary, a clinically relevant dose of vitamin A suppresses the loading-induced gain of bone mass by decreasing bone formation. These observations may have implications for regulation of bone mass caused by physical activity and the risk of osteoporosis in humans.-Lionikaite, V., Henning, P., Drevinge, C., Shah, F. A., Palmquist, A., Wikström, P., Windahl, S. H., Lerner, U. H. Vitamin A decreases the anabolic bone response to mechanical loading by suppressing bone formation. 10.1096/fj.201802040R
Vitamin A intake, serum vitamin D and bone mineral density: analysis of the Korea National Health and Nutrition Examination Survey (KNHANES, 2008-2011). Joo Nam-Seok,Yang Sung-Won,Song Byeng Chun,Yeum Kyung-Jin Nutrients The association of high vitamin A intake and low bone mineral density (BMD) is still controversial. To determine the association of dietary vitamin A intake and serum 25-hydroxyvitamin D (25(OH)D) concentration with BMD, a total of 6481 subjects (2907 men and 3574 women) aged ≥50 years from the Korean National Health and Nutrition Examination Survey (2008-2011) were divided into groups according to dietary vitamin A intake (tertiles) and serum 25(OH)D (<50, 50-75, >75 nmol/L), and evaluated for BMD after adjusting for relevant variables. Mean dietary vitamin A intakes were 737 and 600 μg RE (Retinol Equivalents) in men and women, respectively. Total hip and femoral neck BMD in men and lumbar spine BMD in women were both positively correlated with dietary vitamin A intake in subjects with serum 25(OH)D >75 nmol/L. Among men with serum 25(OH)D <50 nmol/L, both the top (mean 1353 μg RE) and bottom (mean 218 μg RE) tertiles of dietary vitamin A intake had lower BMD than the middle group (mean 577 μg RE). In this population, BMD was the highest among men and women with serum 25(OH)D = 50-75 nmol/L and that there were no differences in BMD by vitamin A intake in these vitamin D adequate groups. This cross-sectional study indicates that vitamin A intake does not affect bone mineral density as long as the serum 25(OH)D concentration is maintained in the moderate level of 50-75 nmol/L. 10.3390/nu7031716
Vitamin A Nutritional Status Is a Key Determinant of Bone Mass in Children. Nutrients The bone mass increases that occur during the period of childhood are of great significance for maximizing the peak bone mass in adults and preventing for osteoporosis. Studies have reported that VA can improve the bone health in adults. Moreover, limited studies have assessed such associations in children. In this cross-sectional study including 426 children, we assessed the children's plasma retinol concentration by liquid chromatography-mass spectrometry and the dietary intake of VA and carotenoids using a structured Food Frequency Questionnaire. Their bone mineral content and bone mineral density (BMD) were measured using dual-energy X-ray absorptiometry. After adjusting for potential confounders, the restricted cubic spline revealed an inverted U-shaped association between plasma retinol concentration and BMD; the estimated effects on the TBLH BMD per μmol/L increase in the plasma retinol concentration were 1.79 × 10 g/cm below 1.24 μmol/L and -5.78 × 10 g/cm above this point ( for non-linearity = 0.046). A multiple linear regression analysis revealed a positive association between the plasma retinol concentration and the TBLH BMC ( = 1.89, 95% CI: 1.64 × 10-3.62, = 0.032). In conclusion, an appropriate plasma retinol concentration and greater intakes of dietary VA and β-carotene may enhance the bone mineral status of children who are aged 6-9 years. 10.3390/nu14214694
Vitamin A: is it a risk factor for osteoporosis and bone fracture? Ribaya-Mercado Judy D,Blumberg Jeffrey B Nutrition reviews Results from observational studies of the association between vitamin A intake or serum concentration and bone mineral density or fracture are mixed. The inconsistencies may be due, in part, to difficulties in obtaining an accurate assessment of vitamin A intake or status. Serum retinol is a poor measure of vitamin A status because it is subject to homeostatic control. Stable-isotope-dilution methodology gives a validated assessment of the total-body and liver vitamin A stores and is recommended in future studies on vitamin A status and osteoporosis. The potential for exacerbating an already serious public health problem with intakes of vitamin A currently considered safe indicates further research into this matter is warranted. 10.1111/j.1753-4887.2007.tb00268.x
Vitamin A and bone health: the balancing act. Tanumihardjo Sherry A Journal of clinical densitometry : the official journal of the International Society for Clinical Densitometry The role of vitamin A status as it relates to bone health is historical yet controversial. Population-based studies have linked high dietary intake of preformed vitamin A, which is obtained from animal-source foods, fortified foods, and some supplements, to greater risk of osteoporosis and hip fracture. In contrast, carotenoids, some of which are vitamin A precursors from plants, are associated with improved bone health. Carotenoids may be a biomarker that reflects a generally healthy lifestyle, which includes fruit and vegetable consumption. Current dietary recommendations to increase fruit and vegetable intake in the Dietary Guidelines for Americans will result in greater intakes of provitamin A carotenoids if consumers comply. This could lead to artificially high intakes of vitamin A in dietary analyses. However, multiple factors affect the bioconversion of provitamin A carotenoids to the active form of vitamin A. The human body will strive to maintain vitamin A balance by down-regulating provitamin A carotenoid bioconversion. If high preformed vitamin A intake is associated with poor bone health and provitamin A carotenoids are protective, future studies are needed to clarify the associations between total body stores of vitamin A, dietary intake of the pre- and pro-forms, and bone health throughout the life cycle. 10.1016/j.jocd.2013.08.016
Vegan Diet and Bone Health-Results from the Cross-Sectional RBVD Study. Menzel Juliane,Abraham Klaus,Stangl Gabriele I,Ueland Per Magne,Obeid Rima,Schulze Matthias B,Herter-Aeberli Isabelle,Schwerdtle Tanja,Weikert Cornelia Nutrients Scientific evidence suggests that a vegan diet might be associated with impaired bone health. Therefore, a cross-sectional study ( = 36 vegans, = 36 omnivores) was used to investigate the associations of veganism with calcaneal quantitative ultrasound (QUS) measurements, along with the investigation of differences in the concentrations of nutrition- and bone-related biomarkers between vegans and omnivores. This study revealed lower levels in the QUS parameters in vegans compared to omnivores, e.g., broadband ultrasound attenuation (vegans: 111.8 ± 10.7 dB/MHz, omnivores: 118.0 ± 10.8 dB/MHz, = 0.02). Vegans had lower levels of vitamin A, B2, lysine, zinc, selenoprotein P, n-3 fatty acids, urinary iodine, and calcium levels, while the concentrations of vitamin K1, folate, and glutamine were higher in vegans compared to omnivores. Applying a reduced rank regression, 12 out of the 28 biomarkers were identified to contribute most to bone health, i.e., lysine, urinary iodine, thyroid-stimulating hormone, selenoprotein P, vitamin A, leucine, α-klotho, n-3 fatty acids, urinary calcium/magnesium, vitamin B6, and FGF23. All QUS parameters increased across the tertiles of the pattern score. The study provides evidence of lower bone health in vegans compared to omnivores, additionally revealing a combination of nutrition-related biomarkers, which may contribute to bone health. Further studies are needed to confirm these findings. 10.3390/nu13020685
Vitamin A and its dervatives effect on bone mineral density, a systematic review. Journal of family medicine and primary care BACKGROUND:Even though vitamin A (Vit A) is one of the essential vitamins required for bone growth and development, it is still uncertain whether its effect on bone mineral density (BMD) is beneficial or harmful. AIM:To assess Vit A's effect and its derivatives on BMD and the risk of developing osteoporosis. DATA SOURCES:PubMed, Cochrane Library, Science Direct, Embase, and Google Scholar were searched in February 2019 and updated in November 2020. METHODS:Conducted following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. RESULTS:A total of 13 studies were included in this report out of 9,124 citations. Five of them were cross-sectional studies, and nine were cohort studies. Three out of five cross-sectional studies showed an increase in BMD, while two showed a decrease in BMD. Four out of eight cohort studies found an increase in BMD; two studies found no association between vitamin A level and BMD; one showed an inverse U-shape association of vitamin A with BMD, suggesting that both the increase or decrease levels of vitamin A affect BMD, while only one study showed a decrease in BMD. CONCLUSION:Although most of the included studies showed a favorable effect of Vit A on BMD, Vit A's role or its derivatives on BMD change remains unclear. 10.4103/jfmpc.jfmpc_663_21
Association between lumbar bone mineral density and serum uric acid in postmenopausal women: a cross-sectional study of healthy Chinese population. Han Wen,Bai Xiaojuan,Wang Nan,Han Lulu,Sun Xuefeng,Chen Xiangmei Archives of osteoporosis Partial correlation and regression analyses were used in this study. We showed that there is a linear relationship between bone mineral density and serum uric acid within the normal physiologic range, and higher serum uric acid levels had a protective effect on bone loss in postmenopausal osteoporosis. PURPOSE:The significance of the relationship between lumbar bone mineral density BMD) and serum uric acid (SUA) levels is unclear. The aims of this study were to investigate on a population-level the association between lumbar BMD and SUA within the normal physiologic range and to determine whether SUA plays a protective role in bone loss in healthy postmenopausal Chinese women. METHODS:This was a community-based cross-sectional study involving 390 healthy postmenopausal women, 47-89 years of age, conducted in Shenyang, China. The BMD was measured at the lumbar spine using dual-energy X-ray absorptiometry (DXA). The SUA levels were obtained at each DXA visit. Partial correlation and regression analyses were applied to determine the associations. RESULTS:The SUA levels were significantly different between the normal BMD, osteopenia, and osteoporosis groups. The lumbar BMD was positively correlated with SUA in postmenopausal women after adjustment for age (r = 0.212). After adjustment for age, body mass index, systolic blood pressure, diastolic blood pressure, hip circumference, cigarette smoking, alcohol consumption, milk intake, physical exercise, fracture history, total protein, total bilirubin, triglycerides, total cholesterol, high-density lipoprotein cholesterol, fasting blood glucose, serum calcium, and estimated glomerular filtration rate, the lumbar BMD was associated with SUA and the odds ratio of the third SUA quartile was 0.408 (95%CI, 0.198-0.841, P = 0.015), compared to the first quartile of SUA levels. CONCLUSION:The lumbar BMD was linearly associated with SUA levels within the normal physiologic range of postmenopausal women. Higher SUA levels had a protective effect on bone loss in postmenopausal osteoporosis. 10.1007/s11657-017-0345-0
Positive association between serum uric acid and bone mineral density in Chinese type 2 diabetes mellitus stratified by gender and BMI. Xu Mingxin,Su Junlei,Hao Jie,Zhong Ni,Zhang Zhiyin,Cui Ran,Li Feng,Sheng Chunjun,Zhang Ge,Sheng Hui,Qu Shen Journal of bone and mineral metabolism Accumulating evidence has demonstrated that serum uric acid (UA), a natural powerful antioxidant, plays a beneficial role in bone health in the general population. However, few reports are available on the association between serum UA and bone in patients with type 2 diabetes mellitus (T2DM). We therefore investigated whether the benefit of serum UA for bone health was still present in those patients. 626 males and 609 postmenopausal females with T2DM were enrolled in this cross-sectional study. Serum UA concentrations and bone mineral density (BMD) measured at lumbar spine, femoral neck and total hip by dual-energy X-ray absorptiometry were obtained from all subjects. Meanwhile, data on osteoporosis prevalence, glucose metabolism, bone turnover markers and other serum biochemical indexes were collected. After adjustment for potential confounders, the results suggested that serum UA was positively associated with BMD in patients with normal weight, but this positive association varied by gender and skeletal sites in overweight T2DM patients [body mass index (BMI) ≥ 25 kg/m]. Moreover, significantly lower odds ratios (ORs) for osteoporosis were found in postmenopausal patients with the highest UA tertile and male patients with medium UA tertile [adjusted OR 0.315, 95% confidence interval (CI) 0.170-0.581 for postmenopausal patients; adjusted OR 0.464, 95% CI 0.225-0.955 for male patients]. The positive association between serum UA and BMD found in Chinese T2DM patients may imply that relatively high UA is a protective factor for bone in these patients. Large intervention studies are needed to further confirm the outcomes and provide possible explanations. 10.1007/s00774-017-0877-9
Specific higher levels of serum uric acid might have a protective effect on bone mineral density within a Chinese population over 60 years old: a cross-sectional study from northeast China. Chen Feng,Wang Yingfang,Guo Yan,Wang Jiabei,Yang Aolin,Lv Qingqing,Liu Yixuan,Ma Guojing,Liu Ying,Wang Difei Clinical interventions in aging Oxidative stress has been demonstrated to be a mechanism that leads to bone mass reduction, and according to many studies, serum uric acid (UA) is a strong endogenous antioxidant that can protect bone mineral density (BMD). To date, there have been no large-scale, cross-sectional studies based on the population in northeast China to assess the relationship between serum UA and BMD. Therefore, we examined the association between serum UA and BMD among a Chinese population older than 60 years old in northeast China. This research was a cross-sectional study of 3465 Chinese individuals over 60 years old in nine communities from the city of Shenyang, which is the capital of northeast China's Liaoning Province. Participants were stratified into three groups by serum UA or BMD levels, and then Pearson's correlation analysis and multiple regression analysis were used to study the relationship between serum UA and BMD. We found that participants with higher serum UA levels had significantly greater BMD and T-values compared to those of participants with lower serum UA levels. After adjusting for confounding factors, Pearson's correlation analysis and multiple regression analysis showed that higher serum UA levels remained associated with higher BMD levels (<0.05). In different models, the prevalence of osteoporosis (OP) among participants with higher serum UA levels was reduced by 23% to 26% (<0.05) compared to that in individuals with lower serum UA levels. In addition, serum UA levels were negatively correlated with estimated glomerular filtration rate (eGFR) and positively correlated with 25-hydroxy vitamin D [25-(OH)D] (<0.05). We concluded that higher serum UA levels are associated with greater BMD, and serum UA might have a protective effect on bone metabolism due to its antioxidant properties. 10.2147/CIA.S186500
Association between Uric Acid and Bone Mineral Density in Postmenopausal Women with Type 2 Diabetes Mellitus in China: A Cross-Sectional Inpatient Study. Journal of diabetes research OBJECTIVE:To analyze the association between uric acid levels and bone mineral density in postmenopausal women with type 2 diabetes mellitus. METHODS:We retrospectively analyzed 262 postmenopausal women with type 2 diabetes mellitus, to assess uric acid levels and bone mineral density using the score of dual-energy X-ray absorptiometry. RESULTS:(1) Women in the osteoporosis group demonstrated higher uric acid levels and lower estimated glomerular filtration rate ( < 0.05, respectively). (2) Uric acid levels were positively correlated with the hip and lumbar spine bone mineral density and score ( = 0.17, < 0.05; = 0.25, < 0.05; = 0.17, < 0.05; and = 0.28, < 0.05, respectively). Meanwhile, there was a positive relation between estimated glomerular filtration rate and hip bone mineral density ( = 0.22, < 0.05). (3) Logistic regression analysis showed that age, body mass index, and diabetic duration are independent risk factors for osteoporosis in postmenopausal women with type 2 diabetes mellitus. The level of estimated glomerular filtration rate and uric acid levels were not independent effect factors for osteoporosis in menopausal women. CONCLUSION:Uric acid levels are neither a protective factor nor a risk factor for osteoporosis in women with type 2 diabetes mellitus. 10.1155/2020/3982831
Review of the Literature Examining the Association of Serum Uric Acid with Osteoporosis and Mechanistic Insights into Its Effect on Bone Metabolism. Kaushal Neelam,Vohora Divya,Jalali Rajinder K,Jha Sujeet Endocrine, metabolic & immune disorders drug targets BACKGROUND AND OBJECTIVE:Osteoporosis is a common bone disorder that increases susceptibility to fragility bone fractures. The clinical and public health repercussions of osteoporosis are huge due to the morbidity, mortality, and cost of medical care linked with fragility fractures. Clinical assessment of osteoporotic risk factors can help to identify candidates at an early stage that will benefit from medical intervention and potentially lowering the morbidity and mortality seen with fractures and complications. Given this, research is ongoing to evaluate the association of osteoporosis with some novel or less well-studied risk factors/bio-markers such as uric acid (UA). DISCUSSION:Uric acid's antioxidant activity has been proposed to be one of the factors responsible for increasing longevity and lowering rates of age-related cancers during primate evolution, the level of which increased markedly due to loss of uricase enzyme activity (mutational silencing). Accumulated evidence shows that oxidative stress is the fundamental mechanism of age-related bone loss and acts via enhancing osteoclastic activity and increasing bone resorption. Antioxidant substances such as ascorbic acid scavenge free radicals are positively related to bone health. Thus, it is hypothesized that uric acid holds bone-protective potential owing to its potent antioxidative property. Several correlation studies have been conducted globally to investigate the relationship between serum uric acid with bone mineral density and osteoporosis. Few pre-clinical studies have tried to investigate the interaction between uric acid and bone mineral density and reported important role played via Runt-related transcription factor 2 (RUNX2)/core-binding factor subunit alpha-1 (CBF-alpha-1), Wingless-related integration site (Wnt)-3a/β-catenin signaling pathway and 11β Hydroxysteroid Dehydrogenase type 1. CONCLUSION:In this review, the authors provided a comprehensive summary of the literature related to association studies reported in humans as well work done until date to understand the potential cellular and molecular mechanisms that interplay between uric acid and bone metabolism. 10.2174/1871530318666181102115106
Effect of High-Dose Vitamin D Supplementation on Volumetric Bone Density and Bone Strength: A Randomized Clinical Trial. JAMA Importance:Few studies have assessed the effects of daily vitamin D doses at or above the tolerable upper intake level for 12 months or greater, yet 3% of US adults report vitamin D intakes of at least 4000 IU per day. Objective:To assess the dose-dependent effect of vitamin D supplementation on volumetric bone mineral density (BMD) and strength. Design, Setting, and Participants:Three-year, double-blind, randomized clinical trial conducted in a single center in Calgary, Canada, from August 2013 to December 2017, including 311 community-dwelling healthy adults without osteoporosis, aged 55 to 70 years, with baseline levels of 25-hydroxyvitamin D (25[OH]D) of 30 to 125 nmol/L. Interventions:Daily doses of vitamin D3 for 3 years at 400 IU (n = 109), 4000 IU (n = 100), or 10 000 IU (n = 102). Calcium supplementation was provided to participants with dietary intake of less than 1200 mg per day. Main Outcomes and Measures:Co-primary outcomes were total volumetric BMD at radius and tibia, assessed with high resolution peripheral quantitative computed tomography, and bone strength (failure load) at radius and tibia estimated by finite element analysis. Results:Of 311 participants who were randomized (53% men; mean [SD] age, 62.2 [4.2] years), 287 (92%) completed the study. Baseline, 3-month, and 3-year levels of 25(OH)D were 76.3, 76.7, and 77.4 nmol/L for the 400-IU group; 81.3, 115.3, and 132.2 for the 4000-IU group; and 78.4, 188.0, and 144.4 for the 10 000-IU group. There were significant group × time interactions for volumetric BMD. At trial end, radial volumetric BMD was lower for the 4000 IU group (-3.9 mg HA/cm3 [95% CI, -6.5 to -1.3]) and 10 000 IU group (-7.5 mg HA/cm3 [95% CI, -10.1 to -5.0]) compared with the 400 IU group with mean percent change in volumetric BMD of -1.2% (400 IU group), -2.4% (4000 IU group), and -3.5% (10 000 IU group). Tibial volumetric BMD differences from the 400 IU group were -1.8 mg HA/cm3 (95% CI, -3.7 to 0.1) in the 4000 IU group and -4.1 mg HA/cm3 in the 10 000 IU group (95% CI, -6.0 to -2.2), with mean percent change values of -0.4% (400 IU), -1.0% (4000 IU), and -1.7% (10 000 IU). There were no significant differences for changes in failure load (radius, P = .06; tibia, P = .12). Conclusions and Relevance:Among healthy adults, treatment with vitamin D for 3 years at a dose of 4000 IU per day or 10 000 IU per day, compared with 400 IU per day, resulted in statistically significant lower radial BMD; tibial BMD was significantly lower only with the 10 000 IU per day dose. There were no significant differences in bone strength at either the radius or tibia. These findings do not support a benefit of high-dose vitamin D supplementation for bone health; further research would be needed to determine whether it is harmful. Trial Registration:ClinicalTrials.gov Identifier: NCT01900860. 10.1001/jama.2019.11889
Bone mineral status in prepubertal children with constitutional delay of growth and puberty. Moreira-Andrés M N,Cañizo F J,de la Cruz F J,Gómez-de la Cámara A,Hawkins F G European journal of endocrinology OBJECTIVE:We wished to clarify whether the osteopenia reported in adult men with a history of constitutional delay of growth and puberty (CDGP) could be due to the delayed puberty or an independent predisposition to osteoporosis in this condition. DESIGN:Short prepubertal children with CDGP and children with familial short stature (FSS) were matched for height and other auxological variables. The FSS children served as a control group. METHODS:We measured spinal (L1-L4) bone mineral content (BMC) and bone mineral density (BMD) by dual energy X-ray absorptiometry (Hologic QDR 1000/w) in 56 children aged 5-11 years. All children had height below the 10th percentile for chronological age (CA), and bone age (BA) less than 10 years, 29 of them with clinical diagnosis of possible CDGP and 27 of them with FSS. The BMD standard deviation scores (SDS) relative to the values for normal height children were obtained. RESULTS:The mean (+/-S.D.) spinal BMD was significantly lower in the children with CDGP than in the FSS group (0.534+/-0.059 vs 0.623+/-0.060 g/cm2, P< 0.001). Both groups had negative mean lumbar BMD SDS, but in the CDGP group it was significantly lower than in the FSS group as well when the SDS was based on the CA (-1.41+/-0.61 vs -0.38+/-0.51, P< 0.001) and when it was related to BA (-0.78+/-0.64 vs -0.17+/-0.52, P< 0.01). BMC was significantly lower in the CDGP than in the FSS group, when multiple regression analysis was performed by using scanned bone area, body weight and height, sex and BA as independent variables (P = 0.0005). CONCLUSION:The finding of decreased mineralization in prepubertal children with CDGP before the age of puberty suggests that they may have an inherent predisposition to osteopenia.
A longer interval without GH replacement and female gender are associated with lower bone mineral density in adults with childhood-onset GH deficiency: a KIMS database analysis. Tritos Nicholas A,Hamrahian Amir H,King Donna,Greenspan Susan L,Cook David M,Jönsson Peter J,Wajnrajch Michael P,Koltowska-Häggstrom Maria,Biller Beverly M K European journal of endocrinology OBJECTIVE:Childhood-onset GH deficiency (COGHD) is associated with low bone mineral density (BMD). Adults with persistent COGHD may be at risk for insufficient bone accrual or bone loss during adulthood. The purpose of this study was to identify BMD predictors and to characterize the effects of GH replacement on BMD in COGHD adults with persistent GHD. DESIGN:Retrospective analysis of the KIMS database. METHODS:Variables predicting standardized BMD (sBMD) were identified. The effect of GH replacement (3 years) on BMD was examined. RESULTS:Three hundred and fourteen COGHD adults (148 women, 166 men; 62 non-naïve, 178 semi-naïve, and 74 true naïve, depending on length and timing of previous GH replacement), who had BMD measured in lumbar spine (LS) and femoral neck (FN) at study entry. In semi-naïve subjects, a longer gap in GH replacement between childhood and adulthood was predictive of lower sBMD in the FN (r=-0.18, P=0.038). TSH deficiency predicted lower sBMD in the LS (r=-0.16, P=0.052). In true naïve patients, a longer gap between onset of pituitary disease and study entry (r=-0.35, P=0.012), and female gender (r=-0.27, P=0.043) independently predicted lower sBMD in the FN. There were no differences in BMD increases between non-naïve, semi-naïve, and true naïve subjects on GH replacement. CONCLUSIONS:In semi-naïve subjects a longer interval off GH replacement was associated with lower sBMD in the FN. Among true naïve patients, a longer gap between the onset of pituitary disease and GH replacement, and female gender predicted lower sBMD in the FN. 10.1530/EJE-12-0070
Growth, puberty, and bone health in children and adolescents with inflammatory bowel disease. Jin Hye-Young,Lim Jae-Sang,Lee Yena,Choi Yunha,Oh Seak-Hee,Kim Kyung-Mo,Yoo Han-Wook,Choi Jin-Ho BMC pediatrics BACKGROUND:Endocrine complications such as impaired growth, delayed puberty, and low bone mineral density (BMD) can be associated with inflammatory bowel disease (IBD) in children and adolescents. This study was performed to investigate the frequency, characteristics, and outcomes of endocrine complications of IBD in children and adolescents. METHODS:This study included 127 patients with IBD diagnosed before 18 years of age [117 with Crohn disease (CD) and 10 with ulcerative colitis (UC)]. Growth profiles, pubertal status, 25-hydroxyvitamin D [25(OH)D] levels, and BMD were reviewed retrospectively. RESULTS:Short stature was observed in 14 of 127 (11.0 %) with a mean height-SDS of -2.31 ± 0.72. During a 2-year follow-up period, height-SDS did not significantly improve, while weight-SDS significantly improved. Among 109 patients who were older than 13 (girls) or 14 (boys) years of age during the study period, 11 patients (10.1 %) showed delayed puberty, which was associated with low weight-SDS. Vitamin D deficiency was documented in 81.7 % (94/115) with the average 25(OH)D level of 14.5 ± 7.0 ng/mL. Lumbar BMD Z-score was below - 2 SDS in 25 of 119 patients (21.0 %). Height-SDS, weight-SDS, and body mass index (BMI)-SDS were lower in patients with osteoporosis than those without osteoporosis. When pediatric CD activity index scores were high (≥ 30), weight-SDS, BMI-SDS, insulin-like growth factor 1 (IGF-1)-SDS, and testosterone levels were significantly decreased. CONCLUSIONS:Vitamin D deficiency and osteoporosis are common in pediatric IBD patients. As disease severity deteriorates, weight-SDS, IGF-1-SDS, and testosterone levels were decreased. Optimal pubertal development is necessary for bone health. 10.1186/s12887-021-02496-4
Lactose intolerance: lack of evidence for short stature or vitamin D deficiency in prepubertal children. Setty-Shah Nithya,Maranda Louise,Candela Ninfa,Fong Jay,Dahod Idris,Rogol Alan D,Nwosu Benjamin Udoka PloS one BACKGROUND:The health consequences of lactose intolerance (LI) are unclear. AIMS:To investigate the effects of LI on stature and vitamin D status. HYPOTHESES:LI subjects will have similar heights and vitamin D status as controls. SUBJECTS AND METHODS:Prepubertal children of ages 3-12 years with LI (n=38, age 8.61 ± 3.08y, male/female 19/19) were compared to healthy, age- and gender-matched controls (n=49, age 7.95±2.64, male/female 28/21). INCLUSION CRITERIA:prepubertal status (boys: testicular volume <3cc; girls: Tanner 1 breasts), diagnosis of LI by hydrogen breath test, and no history of calcium or vitamin D supplementation. Vitamin D deficiency was defined as 25-hydroxyvitamin D [25(OH)D] <50 nmol/L. Gender-adjusted midparental target height (MPTH) z-score was calculated using NCHS data for 18 year-old adults. Data were expressed as mean ± SD. RESULTS:There was no significant difference in 25(OH)D between the LI and non-LI subjects (60.1±21.1, vs. 65.4 ± 26.1 nmol/L, p = 0.29). Upon stratification into normal weight (BMI <85(th) percentile) vs. overweight/obese (BMI ≥85(th) percentile), the normal weight controls had significantly higher 25(OH)D level than both the normal weight LI children (78.3 ± 32.6 vs. 62.9 ± 23.2, p = 0.025), and the overweight/obese LI children (78.3±32.6 vs. 55.3±16.5, p = 0.004). Secondly, there was no overall difference in height z-score between the LI children and controls. The normal weight LI patients had similar height as normal controls (-0.46 ± 0.89 vs. -0.71 ± 1.67, p = 0.53), while the overweight/obese LI group was taller than the normal weight controls (0.36 ± 1.41 vs. -0.71 ± 1.67, p = 0.049), and of similar height as the overweight/obese controls (0.36 ± 1.41 vs. 0.87 ± 1.45, p = 0.28). MPTH z-score was similar between the groups. CONCLUSION:Short stature and vitamin D deficiency are not features of LI in prepubertal children. 10.1371/journal.pone.0078653
Currently used growth-promoting treatment of children results in normal bone mass and density. A prospective trial of discontinuing growth hormone treatment in adolescents. Fors H,Bjarnason R,Wirént L,Albertsson-Wikland K,Bosaeust L,Bengtsson B A,Johannsson G Clinical endocrinology BACKGROUND AND AIMS:The need for continued GH replacement in patients with childhood-onset GH deficiency (GHD) into adulthood has been recognized. The consequences of discontinuing GH treatment on bone mineralization in adolescent patients with GHD and short stature were examined over a period of 2 years. PATIENTS:Forty adolescents (aged 16-21 years) treated with GH for more than 3 years and 16 closely matched healthy controls were studied. After a baseline visit, GH treatment was discontinued. The patients were then re-examined with the same protocol after 1 and 2 years. Twenty-one patients had continuing severe GHD into adulthood, while 19 patients were regarded as having sufficient endogenous GH secretion (GHS). RESULTS:At baseline, there were no differences between the groups in total bone mineral content (BMC) or bone mineral density (BMD). After 2 years without GH treatment, BMC increased similarly in the GHD and GHS groups. BMC of the lumbar spine (L2-L4) increased only in the GHD group. Lumbar spine BMD increased in the GHD and the GHS groups. No changes were observed in the femoral neck region. Biochemical measurements showed that carboxy-terminal cross-linked telopeptide of type I collagen (ICTP) and bone specific alkaline phosphates (ALP) were higher in the GHD and GHS groups at baseline compared with controls. Osteocalcin, carboxy-terminal propeptide of type I procollagen (PICP), ICTP and ALP decreased during the 2 years off treatment in both the GHD and GHS groups. PICP was also lower after 2 years in the GHD group compared with both the GHS group and controls. CONCLUSIONS:After discontinuation of GH therapy in adolescents at or near final height, there was a continued increase in BMC and BMD both for adolescents with growth hormone deficiency and for those classified as growth hormone sufficient. These groups did not differ from controls at baseline or after 2 years. In the growth hormone deficiency group, biochemical markers for bone formation decreased to levels below those in the growth hormone sufficient and healthy control groups. Although the number of patients and controls in this study were small, the results indicate that the present treatment of Swedish GH-deficient children to final height results in normal BMD.
Growth hormone therapy improves bone mineral density in children with cerebral palsy: a preliminary pilot study. Ali Omar,Shim Melanie,Fowler Eileen,Greenberg Marcia,Perkins Donna,Oppenheim William,Cohen Pinchas The Journal of clinical endocrinology and metabolism CONTEXT:Cerebral palsy is associated with osteopenia, increased fracture risk, short stature, and decreased muscle mass, whereas GH therapy is associated with increased bone mineral density (BMD) and linear growth and improvement in body composition. OBJECTIVE:We conducted a pilot study to evaluate the effect of 18 months of GH therapy on spinal BMD, linear growth, biochemical markers, and functional measures in children with cerebral palsy. DESIGN AND SETTING:The study was a randomized control trial, conducted from 2002-2005 at the University of California, Los Angeles, Orthopedic Hospital's Center for Cerebral Palsy. PATIENTS:Patients included 12 males with cerebral palsy, ages 4.5-15.4 yr. INTERVENTION:We compared 18 months of GH (50 microg daily) vs. no treatment. PRIMARY OUTCOME MEASURES:Spinal BMD (dual-energy x-ray absorptiometry scan), height, growth factors, and bone markers were assessed. RESULTS:Ten subjects (five in each group) completed the study. Pre- and post-average height z-scores were -1.47 +/- 0.23 and 0.8 +/- 0.2 (GH-treated group) vs. -1.35 +/- 1.26 and -1.36 +/- 1.27 (control group) (Delta SD score, 0.67 vs. -0.01; P = 0.01). Average change in spinal BMD z-score (Delta SD score corrected for height) was 1.169 +/- 0.614 vs. 0.24 +/- 0.25 in the treated and control groups, respectively (P = 0.03). Osteocalcin, IGF-I, and IGF-binding protein 3 levels increased during GH therapy. There was no change in quality of life scores as measured by the Pediatric Orthopedic Disability Inventory. CONCLUSIONS:This small pilot study suggests that 18 months of GH therapy is associated with statistically significant improvement in spinal BMD and linear growth. 10.1210/jc.2006-0385
Growth Hormone Deficiency in the Transition Age. Loche Sandro,Di Iorgi Natascia,Patti Giuseppa,Noli Serena,Giaccardi Marta,Olivieri Irene,Ibba Anastasia,Maghnie Mohamad Endocrine development Growth hormone (GH) is essential not only for normal growth during childhood, but also for the acquisition of bone mass and muscle strength in both sexes. This process is completed after the achievement of adult height in the phase of transition from adolescence to adulthood. Adolescents with childhood onset GH deficiency (GHD) show reduction of bone mineral density, decrease in lean body mass, increase in fat mass, and deterioration of the lipid profile. For this reason, continuation of GH replacement therapy in the transition age is recommended in all patients with a confirmed diagnosis of GHD. To confirm the diagnosis of GHD, GH treatment should be discontinued for at least 1 month after the attainment of adult height, and the patient should be re-evaluated for GH secretion. Current guidelines indicate that retesting is not required for those with a transcription factor mutation, more than 3 pituitary hormone deficits, or isolated GHD associated with an identified mutation. The key predictors of persistent GHD are its severity, the presence of additional pituitary hormone deficits, low insulin-like growth factor I (IGF-I) concentration, and the presence of structural hypothalamic-pituitary abnormalities Treatment should be initiated with a low dose (0.2-0.5 mg/day s.c.) and then adjusted according to IGF-I concentrations. 10.1159/000487525
16q24.3 Microduplication in a Patient With Developmental Delay, Intellectual Disability, Short Stature, and Nonspecific Dysmorphic Features: Case Report and Review of the Literature. Bucerzan Simona,Miclea Diana,Lazea Cecilia,Asavoaie Carmen,Kulcsar Andrea,Grigorescu-Sido Paula Frontiers in pediatrics We describe the case of a seven-year-old female patient who presented in our service with severe developmental delay, intellectual disability, facial dysmorphism, and femur fracture, observed in the context of very low bone mineral density. Array-based single nucleotide polymorphism (SNP array) analysis identified a 113 kb duplication involving the morbid OMIM genes: (exon1), , and genes. ANKRD11 deletions are frequently described in association with KBG syndrome, the duplications being less frequent (one case described before). The exome sequencing was negative for pathogenic variants or of uncertain significance in genes possibly associated with this phenotype. The patient presented subtle signs of KBG syndrome. It is known that the phenotype of KBG syndrome has a wide clinical spectrum, this syndrome being often underdiagnosed due to overlapping features with other conditions, also characterized by multiple congenital anomalies and intellectual disability. The particularity of this case is represented by the very low bone mineral density in a patient with 16q24.3 duplication. ANKRD11 haploinsufficiency is known to be associated with skeletal involvement, such as short stature, or delayed bone age. An effect on bone density has been observed only in experimental studies on mice with induced missense mutations in the gene. This CNV also involved the duplication of the very conserved gene, which could have a role for the skeletal phenotype of this patient, knowing the high level of gene expression in bone tissue and also the association with spondyloepimetaphyseal dysplasia Isidor Toutain type, in case of splicing mutations. 10.3389/fped.2020.00390
Low birth weight, bone metabolism and fracture risk. Dötsch Jörg Dermato-endocrinology As for other diseases of higher age, low birth weight was expected to be a risk factor for an altered bone metabolism and osteoporosis.ON THE FIRST GLANCE THIS EXPECTATION APPEARS TO BE CONFIRMED BY ANIMAL DATA: rats with intrauterine growth restriction following maternal protein malnutrition show a reduction of bone mineral density going in line with a decrease in serum vitamin D concentrations.HOWEVER, THE SITUATION IS LESS CLEAR IN NEWBORNS WITH LOW BIRTH WEIGHT: Some studies show a relation of birth weight and bone mineral density whereas others don't. The older the former low birth weight patients the fainter the effect seems to be. In fact young adults with idiopathic short stature have a low bone mineral density than the low birth weight group irrespective of whether they have experienced catch-up growth or not. As a consequence low birth weight is can not be identified as a relevant risk factor for hip fractures in menopausal women. Postmenopausal women with low birth weight even show higher vitamin D concentrations than normal birth weight individuals.In conclusion, there is no consistent long term effect of low birth weight on bone mineral density or hip fracture risk later in life. Whether methodological weaknesses in the studies performed so far are causal or whether postnatal factors such as physical activity and nutrition are of higher importance can only be speculated upon at present. 10.4161/derm.3.4.14636
[Comparative study of bone mineralization in children and adolescents with familial short stature and a control group]. Armadá Maresca M I,Alonso Ortiz T,Viña Simón E,Bueno Lozano G,Ruibal Francisco J L,Zuluaga P,Lozano Tonkín C,Casado de Frías E Anales espanoles de pediatria OBJECTIVE:Our objective was to study children with familial short stature (FSS) to observe whether they develop bone mineralization similar to that seen in healthy children with an adequate height for their age and sex. PATIENTS AND METHODS:The study included 70 FSS patients (39 boys and 31 girls) between 6 and 20 years of age and 246 control patients with the same mean age and sex of the study group. Bone mineral density was measured in the lumbar spine and forearm by performing dual energy X-ray absorptiometry using a Hologic ADR-1000. RESULTS:The main difference between the FSS population and the control group was in the final adult bone mass, which was 20% less in the lumbar spine and 15% less in the forearm in the FSS group. CONCLUSIONS:A large difference in bone mineralization was observed among the FSS population compared to the control group during infancy and adolescence and this becomes accentuated with age or growth resulting in bone mineralization that is not optimum for facing the losses which occur during adulthood.
The Impact of congenital, severe, untreated growth hormone (GH) deficiency on bone size and density in young adults: insights from genetic GH-releasing hormone receptor deficiency. Maheshwari Hiralal G,Bouillon Roger,Nijs Jos,Oganov Victor S,Bakulin Alexej V,Baumann Gerhard The Journal of clinical endocrinology and metabolism GH and IGF-I have well recognized effects on bone elongation during development, but their importance for bone mineralization and structure during the growth phase are less well understood. Because children with GH deficiency are generally treated with GH, little detailed information exists in humans about the effects of long-term GH deficiency on bone development. The recently described syndrome of genetic GHRH receptor deficiency in Pakistan (dwarfism of Sindh) affords a unique opportunity to examine the question of GH deficiency on bone development because the affected patients have congenital, severe, isolated GH deficiency, which had never been treated because of societal reasons. We performed dual energy x-ray absorptiometry scans in four adult males (age, 23-30 yr) to address the question of bone mineralization. Areal bone mineral density (BMD) was low (mean Z scores: -3.3, -2.1, -3.7, and -1.7) in the lumbar spine, femoral neck, forearm, and total skeleton, respectively. This low areal BMD is in part caused by the small bone size in these dwarfed patients. When corrected for size, volumetric BMD (bone mineral apparent density) was normal to near normal (mean Z scores: -1.2, +0.8, and +0.8 for lumbar spine, femoral neck and total skeleton, respectively). We conclude that GH/IGF-I deficiency has relatively little impact on bone mineralization during the bone accretion phase. This is in marked contrast to their effect on bone elongation and overall bone size. 10.1210/jc.2002-021120
The insulin-like growth factor system in bone: basic and clinical implications. Endocrinology and metabolism clinics of North America The insulin-like growth factor (IGF) regulatory system is critical for skeletal growth and maintenance. Initially there was great hope that the recombinant IGFs might be used clinically for disorders ranging from short stature to fracture repair and osteoporosis. Although this potential was not realized, basic and translational studies have continued, providing significant insights into the role of this family of growth factors in skeletal homeostasis and the pathophysiology of several bone disorders. This article reviews the importance of the IGF regulatory system in skeletal growth and maintenance. 10.1016/j.ecl.2012.04.013
Children with severe Osteogenesis imperfecta and short stature present on average with normal IGF-I and IGFBP-3 levels. Hoyer-Kuhn Heike,Höbing Laura,Cassens Julia,Schoenau Eckhard,Semler Oliver Journal of pediatric endocrinology & metabolism : JPEM BACKGROUND:Osteogenesis imperfecta (OI) is characterized by bone fragility and short stature. Data about IGF-I/IGFBP-3 levels are rare in OI. Therefore IGF-I/IGFBP-3 levels in children with different types of OI were investigated. METHODS:IGF-I and IGFBP-3 levels of 60 children (male n=38) were assessed in a retrospective cross-sectional setting. RESULTS:Height/weight was significant different [height z-score type 3 versus type 4: p=0.0011 and weight (p≤0.0001)] between OI type 3 and 4. Mean IGF-I levels were in the lower normal range (mean±SD level 137.4±109.1 μg/L). Mean IGFBP-3 measurements were in the normal range (mean±SD 3.105±1.175 mg/L). No significant differences between OI type 3 and 4 children have been observed (IGF-I: p=0.0906; IGFBP-3: p=0.2042). CONCLUSIONS:Patients with different severities of OI have IGF-I and IGFBP-3 levels in the lower normal range. The type of OI does not significantly influence these growth factors. 10.1515/jpem-2015-0385
Height adjustment in assessing dual energy x-ray absorptiometry measurements of bone mass and density in children. Zemel Babette S,Leonard Mary B,Kelly Andrea,Lappe Joan M,Gilsanz Vicente,Oberfield Sharon,Mahboubi Soroosh,Shepherd John A,Hangartner Thomas N,Frederick Margaret M,Winer Karen K,Kalkwarf Heidi J The Journal of clinical endocrinology and metabolism CONTEXT: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. OBJECTIVE:The aim of this study was to compare various methods to adjust BMC/BMD for height in healthy children. DESIGN: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). SETTING:We conducted the study in five clinical centers in the United States. PARTICIPANTS:We included 1546 BMDCS and 650 RDP participants (7 to 17 yr of age, 50% female). INTERVENTION:No interventions were used. MAIN OUTCOME MEASURES: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)). RESULTS:Spine and WB BMC/BMD(age)Z and BMAD(age)Z were positively (P < 0.005; 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 (P < 0.005; r = -0.20 to -0.34). The deviation between adjusted and BMC/BMD(age) Z-scores was associated with age for most measures (P < 0.005) except for BMC/BMD(haz). CONCLUSIONS: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. 10.1210/jc.2009-2057
The effects of growth hormones on the growth velocities and serum index expressions in short stature children. Zhou Ping,Lv Qing American journal of translational research OBJECTIVE:To study the effect of recombinant human growth hormone (rhGH) treatment on the growth velocities and serum index expressions of short stature children. METHODS:56 short stature children admitted to our hospital from January 2018 to January 2020 were recruited as the study cohort. All the children were treated with rhGH. After six months of treatment, their serum indicators [ghrelin, Nesfatin-1, bone-specific alkaline phosphate (BAP), insulin-like growth factor 1 (IGF-1)], their growth velocity indicators [body mass index (BMI), height, growth velocity (GV)], their blood lipid levels [triglycerides (TG), total cholesterol (TC), low density lipoprotein (LDL), high and low density lipoprotein (HDL)], their insulin statuses [fasting insulin (FINS), their homeostasis model assessment of insulin resistance (HOMA-IR)], and their thyroid function index [thyroid stimulating hormone (TSH), 3'-triiodothyronine (T3), 4'-triiodothyronine (T4)] level changes before and after the treatment were compared. RESULTS:(1) After the treatment, the children's serum ghrelin and IGF-1 levels increased in comparison with their pre-treatment levels (P<0.05), and their nesfatin-1 levels decreased (P<0.05). (2) After the treatment, the children's BMI, height, and GV increased in comparison with their pre-treatment levels (P<0.05). (3) After the treatment, the children's TG levels were noticeably higher than they were before the treatment (P<0.05), and the TC and LDL levels were remarkably lower than they were before the treatment (P<0.05). (4) After the treatment, the children's T3 and T4 levels were significantly higher compared to their levels before the treatment (P<0.05). CONCLUSION:GH can promote the development and growth of short stature children, improve their related serum indicator levels, and does not induce metabolic dysfunction.
Strategies for maximizing growth in puberty in children with short stature. Mauras Nelly Pediatric clinics of North America The approach to the child with growth retardation who is in puberty remains an important clinical challenge. The use of high-dose growth hormone (GH), suppression of puberty with GnRH analogs in combination with GH, and the use of selective inhibitors of the aromatase enzyme with aromatase inhibitors (also in combination with GH) are all therapeutic choices that have been studied. Aromatase blockade effectively blocks estrogen production in males with a reciprocal increase in testosterone, and a new generation of aromatase inhibitors, including anastrozole, letrozole and exemestane, is under investigation in adolescent subjects with severe growth retardation. This class of drugs, if judiciously used for a window of time, offers promise as an adjunct treatment of growth delay in pubertal patients with GH deficiency, idiopathic short stature, testotoxicosis, and other disorders of growth. These evolving uses of aromatase inhibitors, however, represent off-label use of the product, and definitive data on their efficacy are not available for each of the conditions mentioned. Safety issues regarding bone health also require further study. 10.1016/j.pcl.2011.07.007
Bone mineral accretion and its relationship to growth, sexual maturation and body composition during childhood and adolescence. Zemel Babette World review of nutrition and dietetics Bone mineral accretion during childhood and adolescence is subject to a number of influences, including body composition changes, sexual maturation and growth. Bone mass and density increase with age and vary by sex, so bone health must be evaluated like other growth outcomes, i.e. in relation to age- and sex-specific reference ranges. Peak bone mass, the amount of bone acquired at the end of skeletal development is an important determinant of lifelong skeletal health. The timing of puberty is inversely related to peak bone mass, such that individuals who experience puberty at older ages have lower bone mass in young adulthood. Height, an indicator of skeletal size, is correlated with bone mineral content and density. Even more importantly, children who are tall for their age have greater bone mass and density than children of average or short stature. Body composition, particularly lean body mass, has a positive effect on bone accretion because of the mechanical strains of muscle mass on bone accretion. The effect of height growth is positively associated with bone accretion, but the magnitude of the effect is not the same at all pubertal stages; in Tanner stage 5, height growth has a more pronounced effect on bone accretion than at the beginning of puberty. Understanding these complex relationships is essential to understanding bone metabolism during this part of the life cycle and the challenges of assessing bone health in children with medical conditions that threaten bone health. 10.1159/000342601
The effect of vitamin D supplementation and nutritional intake on skeletal maturity and bone health in socio-economically deprived children. European journal of nutrition PURPOSE:1. To determine the effect of vitamin D supplementation on bone age (BA), a marker of skeletal maturity, and Bone Health Index (BHI), a surrogate marker of bone density. 2. To characterise the differences in nutritional intake and anthropometry between children with advanced vs. delayed BA. METHODS:The current study is a post hoc analysis of radiographs obtained as part of a randomised controlled trial. In this double-blind, placebo-controlled trial, deprived Afghan children (n = 3046) aged 1-11 months were randomised to receive six doses of oral placebo or vitamin D3 (100,000 IU) every 3 months for 18 months. Dietary intake was assessed through semi-quantitative food frequency questionnaires at two time points. Anthropometric measurements were undertaken at baseline and 18 months. Serum 25OHD was measured at five time points on a random subset of 632 children. Knee and wrist radiographs were obtained from a random subset (n = 641), of which 565 wrist radiographs were digitised for post-hoc analysis of BA and BHI using BoneXpert version 3.1. RESULTS:Nearly 93% (522, male = 291) of the images were analysable. The placebo (n = 258) and vitamin D (n = 264) groups were comparable at baseline. The mean (± SD) age of the cohort was 2 (± 0.3) years. At study completion, there was no difference in mean 25-hydroxy vitamin D concentrations [47 (95% CI 41, 56) vs. 55 (95% CI 45, 57) nmol/L, p = 0.2], mean (± SD) BA SDS [- 1.04 (1.36) vs. - 1.14 (1.26) years, p = 0.3] or mean (± SD) BHI SDS [- 0.30 (0.86) vs. - 0.31 (0.80), p = 0.8] between the placebo and vitamin D groups, respectively. Children with advanced skeletal maturity (BA SDS ≥ 0) when compared to children with delayed skeletal maturity (BA SDS < 0), had consumed more calories [mean (± SD) calories 805 (± 346) vs 723 (± 327) kcal/day, respectively, p < 0.05], were significantly less stunted (height SDS - 1.43 vs. - 2.32, p < 0.001) and underweight (weight SDS - 0.82 vs. - 1.45, p < 0.001), with greater growth velocity (11.57 vs 10.47 cm/ year, p < 0.05). CONCLUSION:Deprived children have significant delay in skeletal maturation but no substantial impairment in bone health as assessed by BHI. BA delay was influenced by total calorie intake, but not bolus vitamin D supplementation. 10.1007/s00394-021-02511-5
Bone health in adolescence. Ambrosio Maria R,Aliberti Ludovica,Gagliardi Irene,Franceschetti Paola,Zatelli Maria C Minerva obstetrics and gynecology Adolescence is a fundamental period for the formation of the skeleton, because is the stage in which bones grow more in both size and strength, laying a solid foundation for the future health of the skeleton. Any condition interfering with optimal peak bone mass accrual can increase fracture risk later in life. Up to 80% of peak bone mass is genetically determined while the remaining 20% is modulated by environmental factors that, if deleterious, may result in low bone mineral density (BMD) and an increased risk of fracture. The preferred test to assess bone health is dual-energy x-ray absorptiometry (spine or total body less head) using Z scores instead of T scores, even though in short stature or growth delay, should be used the height Z-score. The correction of risk factors is the first treatment for low BMD in children and adolescents. It's necessary having a correct lifestyle for preserving bone health: a proper nutrition, an adequate physical weight-bearing activity and avoidance of alcohol intake and tobacco smoke. Bisphosphonates could be used in children who sustained osteoporotic fractures, impairing quality of life, when spontaneous recovery is low for the persistence of osteoporosis risk factors. This clinical review discusses factors affecting bone health during childhood and adolescence and deals with diagnosis and treatment of low bone mass or osteoporosis in this age group. 10.23736/S2724-606X.20.04713-9
Vitamin D and Parathyroid Hormone during Growth Hormone Treatment. Children (Basel, Switzerland) Background. There is some controversy concerning a potential interaction between vitamin D and PTH and the GH/IGF-1 axis. The goal of this study is to assess vitamin D and PTH status in children with GH deficiency at diagnostic and during treatment with rhGH. Methods. Longitudinal and descriptive study in 110 patients, aged 3.3−9.1 years, with GH deficiency (GHD group) treated with rhGH. At diagnosis and after 12, 24, 36, and 48 months of treatment, a clinical (height, weight, and bone age) and laboratory (phosphorus, calcium, calcidiol, PTH, IGF-1) evaluation was performed. Concurrently, 377 healthy children, aged 3.8−9.7 years, were enrolled and constituted a control group. Vitamin D status was stated in accordance to the U.S. Endocrine Society criteria. Results. No significant differences were found in the prevalence of vitamin D deficiency among control (11.43%) and GHD (13.6%) groups at the moment of diagnosis, remaining without significant changes at 12 (12.9%), 24 (14.6%), 36 (13.1%), and 48 months (13.3%) of treatment. There were not any significant differences in serum levels of calcium, phosphorus, and calcidiol, but a steady increase (p < 0.001) in PTH was detected. Conclusions. Prepubertal patients with GH deficient do not appear to have a higher risk of vitamin D deficiency than healthy subjects, and with treatment with rhGH, no changes in the organic content of vitamin D were observed although a significant increase in PTH levels was detected. 10.3390/children9050725
Impaired Height Growth Associated with Vitamin D Deficiency in Young Children from the Japan Environment and Children's Study. Nutrients Vitamin D is essential for calcium absorption and bone homeostasis. Although short-stature children were reported to have low vitamin D concentrations, there is no clear evidence of a link between vitamin D and height growth in young children not limited to those with short stature. We collected height and weight data at 2 and 4 years of age, serum vitamin D concentrations at 4 years, and questionnaire results on sun exposure from the Japan Environment and Children’s Study (JECS). We then analyzed the relationship between vitamin D deficiency and height growth. We also analyzed the correlation between serum vitamin D concentration and sun exposure. Overall, 3624 participants from JECS were analyzed. We identified cases of subclinical vitamin D deficiency and insufficiency. We further found that definitive vitamin D deficiency (<10 ng/mL) impaired height growth by 0.6 cm per year even in young children not limited to those with short stature. Furthermore, we clarified that children with vitamin D deficiency had reduced outdoor activity, especially during winter. In children with either short or normal stature, definitive vitamin D deficiency was associated with height growth decline, and reduction in outdoor activity, especially during winter, was a risk factor for vitamin D deficiency. 10.3390/nu14163325
Effects of oral vitamin D supplementation on linear growth and other health outcomes among children under five years of age. The Cochrane database of systematic reviews BACKGROUND:Vitamin D is a secosteroid hormone that is important for its role in calcium homeostasis to maintain skeletal health. Linear growth faltering and stunting remain pervasive indicators of poor nutrition status among infants and children under five years of age around the world, and low vitamin D status has been linked to poor growth. However, existing evidence on the effects of vitamin D supplementation on linear growth and other health outcomes among infants and children under five years of age has not been systematically reviewed. OBJECTIVES:To assess effects of oral vitamin D supplementation on linear growth and other health outcomes among infants and children under five years of age. SEARCH METHODS:In December 2019, we searched CENTRAL, PubMed, Embase, 14 other electronic databases, and two trials registries. We also searched the reference lists of relevant publications for any relevant trials, and we contacted key organisations and authors to obtain information on relevant ongoing and unpublished trials. SELECTION CRITERIA:We included randomised controlled trials (RCTs) and quasi-RCTs assessing the effects of oral vitamin D supplementation, with or without other micronutrients, compared to no intervention, placebo, a lower dose of vitamin D, or the same micronutrients alone (and not vitamin D) in infants and children under five years of age who lived in any country. DATA COLLECTION AND ANALYSIS:We used standard Cochrane methodological procedures. MAIN RESULTS:Out of 75 studies (187 reports; 12,122 participants) included in the qualitative analysis, 64 studies (169 reports; 10,854 participants) contributed data on our outcomes of interest for meta-analysis. A majority of included studies were conducted in India, USA, and Canada. Two studies reported for-profit funding, two were categorised as receiving mixed funding (non-profit and for-profit), five reported that they received no funding, 26 did not disclose funding sources, and the remaining studies were funded by non-profit funding. Certainty of evidence varied between high and very low across outcomes (all measured at endpoint) for each comparison. Vitamin D supplementation versus placebo or no intervention (31 studies) Compared to placebo or no intervention, vitamin D supplementation (at doses 200 to 2000 IU daily; or up to 300,000 IU bolus at enrolment) may make little to no difference in linear growth (measured length/height in cm) among children under five years of age (mean difference (MD) 0.66, 95% confidence interval (CI) -0.37 to 1.68; 3 studies, 240 participants; low-certainty evidence); probably improves length/height-for-age z-score (L/HAZ) (MD 0.11, 95% CI 0.001 to 0.22; 1 study, 1258 participants; moderate-certainty evidence); and probably makes little to no difference in stunting (risk ratio (RR) 0.90, 95% CI 0.80 to 1.01; 1 study, 1247 participants; moderate-certainty evidence). In terms of adverse events, vitamin D supplementation results in little to no difference in developing hypercalciuria compared to placebo (RR 2.03, 95% CI 0.28 to 14.67; 2 studies, 68 participants; high-certainty evidence). It is uncertain whether vitamin D supplementation impacts the development of hypercalcaemia as the certainty of evidence was very low (RR 0.82, 95% CI 0.35 to 1.90; 2 studies, 367 participants). Vitamin D supplementation (higher dose) versus vitamin D (lower dose) (34 studies) Compared to a lower dose of vitamin D (100 to 1000 IU daily; or up to 300,000 IU bolus at enrolment), higher-dose vitamin D supplementation (200 to 6000 IU daily; or up to 600,000 IU bolus at enrolment) may have little to no effect on linear growth, but we are uncertain about this result (MD 1.00, 95% CI -2.22 to 0.21; 5 studies, 283 participants), and it may make little to no difference in L/HAZ (MD 0.40, 95% CI -0.06 to 0.86; 2 studies, 105 participants; low-certainty evidence). No studies evaluated stunting. As regards adverse events, higher-dose vitamin D supplementation may make little to no difference in developing hypercalciuria (RR 1.16, 95% CI 1.00 to 1.35; 6 studies, 554 participants; low-certainty evidence) or in hypercalcaemia (RR 1.39, 95% CI 0.89 to 2.18; 5 studies, 986 participants; low-certainty evidence) compared to lower-dose vitamin D supplementation. Vitamin D supplementation (higher dose) + micronutrient(s) versus vitamin D (lower dose) + micronutrient(s) (9 studies) Supplementation with a higher dose of vitamin D (400 to 2000 IU daily, or up to 300,000 IU bolus at enrolment) plus micronutrients, compared to a lower dose (200 to 2000 IU daily, or up to 90,000 IU bolus at enrolment) of vitamin D with the same micronutrients, probably makes little to no difference in linear growth (MD 0.60, 95% CI -3.33 to 4.53; 1 study, 25 participants; moderate-certainty evidence). No studies evaluated L/HAZ or stunting. In terms of adverse events, higher-dose vitamin D supplementation with micronutrients, compared to lower-dose vitamin D with the same micronutrients, may make little to no difference in developing hypercalciuria (RR 1.00, 95% CI 0.06 to 15.48; 1 study, 86 participants; low-certainty evidence) and probably makes little to no difference in developing hypercalcaemia (RR 1.00, 95% CI 0.90, 1.11; 2 studies, 126 participants; moderate-certainty evidence). Four studies measured hyperphosphataemia and three studies measured kidney stones, but they reported no occurrences and therefore were not included in the comparison for these outcomes. AUTHORS' CONCLUSIONS:Evidence suggests that oral vitamin D supplementation may result in little to no difference in linear growth, stunting, hypercalciuria, or hypercalcaemia, compared to placebo or no intervention, but may result in a slight increase in length/height-for-age z-score (L/HAZ). Additionally, evidence suggests that compared to lower doses of vitamin D, with or without micronutrients, vitamin D supplementation may result in little to no difference in linear growth, L/HAZ, stunting, hypercalciuria, or hypercalcaemia. Small sample sizes, substantial heterogeneity in terms of population and intervention parameters, and high risk of bias across many of the included studies limit our ability to confirm with any certainty the effects of vitamin D on our outcomes. Larger, well-designed studies of long duration (several months to years) are recommended to confirm whether or not oral vitamin D supplementation may impact linear growth in children under five years of age, among both those who are healthy and those with underlying infectious or non-communicable health conditions. 10.1002/14651858.CD012875.pub2
Vitamin D: Giveth to Those Who Needeth. Lips Paul,Bilezikian John P,Bouillon Roger JBMR plus Severe vitamin D deficiency may cause rickets. While this point is not disputed, the use of vitamin D in the elderly to prevent fractures has been challenged recently by a meta-analysis of 81 RCTs, suggesting that the effects of vitamin D were trivial. As is true for any review of the literature, the interpretation of a meta-analysis can be confounded by the choice of publications to include or exclude. Indeed, the authors excluded RCTs with combined vitamin D and calcium supplementation, included futile studies of very short duration, or studies with high bolus doses known to transiently increase fracture risk. The best available data show that calcium and vitamin D supplementation of elderly subjects can decrease the risk of hip and other non-vertebral fractures, especially in institutionalized subjects or elderly subjects with poor calcium and vitamin D status. Vitamin D deficiency is associated with many chronic diseases. The VIDA and VITAL trials did not show a protective effect on cardiovascular diseases and cancer. The D2d study also did not influence the progress of prediabetes to diabetes. However, the baseline 25OHD concentrations of the majority of the participants of all these trials were essentially normal. Post-hoc analysis of these studies suggest some possibly beneficial health outcomes in vitamin D deficient subjects. A meta-analysis suggested that vitamin D could partly prevent upper respiratory infections. Mendelian randomization studies suggest a causal link between lifelong low vitamin D status and multiple sclerosis. A vitamin D supplement in pregnant women may decrease maternal morbidity and improve the health of their offspring. Better-designed studies are needed to answer all outstanding questions. However, based on all available data, it seems that correction of vitamin D and/or calcium deficiency of infants, pregnant women and elderly subjects can improve their health. © 2019 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research. 10.1002/jbm4.10232
Analysis of the Influence of High-Dose rhGH Therapy on Serum Vitamin D and IGF-1 Levels in School-Age Children with Idiopathic Short Stature. Evidence-based complementary and alternative medicine : eCAM OBJECTIVE:To discuss the influence of high-dose recombinant human growth hormone (rhGH) therapy on serum vitamin D and insulin-like growth factor-1 (IGF-1) levels in school-age children with idiopathic short stature (ISS). METHOD:A total of 103 school-age children with ISS were selected from June 2016 to June 2020 in our hospital. The enrolled cases were divided into the low-dose group ( = 59) and high-dose group ( = 44) according to the treatment dose of rhGH. After the treatment, the height (Ht), height standard deviation score (Ht SDS), growth velocity (GV), and other indicators were recorded. The serum 25-hydroxy vitamin D [25-(OH)D] and IGF-1 levels of the two groups were tested, and the occurrence of adverse reactions was recorded. RESULTS:After treatment, the high-dose group outperformed the low-dose group in various growth effect indicators such as Ht, Ht SDS, and GV ( < 0.05). After treatment, the serum 25-(OH)D of children with ISS in the two groups increased significantly, but there was no significant difference between the two groups ( > 0.05). After treatment, the serum IGF-1 of children with ISS in the two groups increased significantly, but there was no significant difference between the two groups ( > 0.05). For children with ISS, adverse reactions induced by rhGH therapy were very rare. There was no significant difference in the incidence of adverse reactions induced by different doses of rhGH in the treatment of ISS ( > 0.05). CONCLUSION:rhGH has definite efficacy in the treatment of ISS children, for it can significantly increase the annual growth rate of ISS children in a dose-dependent manner. High-dose rhGH for ISS has a better therapeutic effect. At the same time, regardless of the dose level of rhGH, serum 25-(OH)D and IGF-1 levels in children with ISS were increased, with less adverse reactions and higher safety. 10.1155/2021/5776487
Vitamin D, calcium and phosphorus status in children with short stature - effect of growth hormone therapy. Klatka Maria,Partyka Małgorzata,Polak Agnieszka,Terpiłowska Barbara,Terpiłowski Michał,Chałas Renata Annals of agricultural and environmental medicine : AAEM OBJECTIVE:The aim of the study was to assess the level of calcium, phosphorus and vitamin D in the blood of patients treated for short stature (SS). MATERIAL AND METHODS:The study encompassed 110 children treated for somatotropin hypopituitarism (SHP) in the Department of Paediatric Endocrinology and Diabetology at the Medical University of Lublin. The levels of calcium, phosphorus and vitamin D were marked for both groups in the peripheral blood collected on a routine basis for diagnostic examinations. The parameters were compared within the group of children with SHP, both the patients who were about to start the therapy and those in the course of the therapy as well as between the research group (110 children) and the control group. RESULTS:The results obtained were compared with the results in the control group that comprised 41 children with a general good health status, although with nasal septum deviation treated in the Department of Paediatric Otolaryngology at the Medical University of Lublin. CONCLUSIONS:On the basis of the research performed, the following conclusions were drawn: 1) children with SHP were characterised with calcium-phosphorus imbalance. The level of calcium, phosphorus and vitamin D was diminished. The values did not change due to a several-year hormone growth treatment (HGT). 2) the level of calcium and phosphorus was appropriate in the control group children, but the vitamin D level was considerably lowered. This shows the necessity for vitamin D control and supplementation, not only in children with SS. 10.26444/aaem/139569
Association between Insulin-Like Growth Factor-1 and Uric Acid in Chinese Children and Adolescents with Idiopathic Short Stature: A Cross-Sectional Study. Wang Panpan,Ji Baolan,Shao Qian,Zhang Mei,Ban Bo BioMed research international OBJECTIVE:The aim of this study was to examine the relationship between insulin-like growth factor-1 (IGF-1) and serum uric acid (UA) in Chinese children and adolescents with idiopathic short stature (ISS). METHODS:A cross-sectional study of 91 Chinese children and adolescents with ISS was performed. Anthropometric measurements and biochemical parameters were tested. The standard deviation score of IGF-1 (IGF-1 SDS) was calculated. RESULTS:A univariate analysis displayed a significant positive correlation between IGF-1 SDS and UA ( = 0.004). In multivariate piecewise linear regression, the levels of IGF-1 SDS increased with the elevation of UA when UA was between 168 mol/L and 301 mol/L ( 0.010, 95% CI 0.004-0.017; = 0.002). The levels of IGF-1 SDS decreased with the elevation of UA when UA was either less than 168 mol/L (  -0.055, 95% CI -0.081--0.028; < 0.001) or more than 301 mol/L (  -0.005, 95% CI -0.013-0.002; = 0.174). CONCLUSIONS:This study demonstrated a nonlinear relationship between IGF-1 and UA levels in Chinese children and adolescents with ISS. This finding suggests that either high or low levels of UA may have an adverse effect on IGF-1, whereas appropriate UA levels have a beneficial effect. 10.1155/2018/4259098
Growth hormone therapy in children; research and practice - A review. Collett-Solberg Paulo Ferrez,Jorge Alexander A L,Boguszewski Margaret C S,Miller Bradley S,Choong Catherine Seut Yhoke,Cohen Pinchas,Hoffman Andrew R,Luo Xiaoping,Radovick Sally,Saenger Paul Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society Short stature remains the most common reason for referral to a pediatric Endocrinologist and its management remains a challenge. One of the main controversies is the diagnosis of idiopathic short stature and the role of new technologies for genetic investigation of children with inadequate growth. Complexities in management of children with short stature includes selection of who should receive interventions such as recombinant human growth hormone, and how should this agent dose be adjusted during treatment. Should anthropometrical data be the primary determinant or should biochemical and genetic data be used to improve growth response and safety? Furthermore, what is considered a suboptimal response to growth hormone therapy and how should this be managed? Treatment of children with short stature remains a "hot" topic and more data is needed in several areas. These issues are reviewed in this paper. 10.1016/j.ghir.2018.12.004
Using height association studies to gain insights into human idiopathic short and syndromic stature phenotypes. Lettre Guillaume Pediatric nephrology (Berlin, Germany) Variation in adult height is not the most clinically relevant human quantitative trait, yet its study provides the foundation of many quantitative genetics theories and important statistical concepts (e.g. regression). Even today, the analysis of adult height by genome-wide association studies (GWAS) continues to significantly impact human genetics: these studies have led to the discovery of >200 loci associated with variation in adult height and have highlighted the very polygenic nature of human continuous traits. In this brief review, I discuss and provide examples on how such genetic associations, identified in individuals of normal height, could help understand the complex genetics behind such phenotypes as idiopathic short stature (ISS) or extreme/syndromic height phenotypes of unknown cause. 10.1007/s00467-012-2301-y
Zinc deficiency in Japanese children with idiopathic short stature. Yoshida Kei,Urakami Tatsuhiko,Kuwabara Remi,Morioka Ichiro Journal of pediatric endocrinology & metabolism : JPEM Background and methods We investigated the frequency of zinc deficiency in Japanese children with idiopathic short stature, and evaluated whether serum zinc levels correlated with background factors, including age and standard deviation scores (SDSs) for height and serum insulin-like growth factor (IGF)-1 levels. The study subjects consisted of 89 Japanese children. Results The mean serum zinc level was 79 ± 12 (49-108) μg/dL. Of all the children, 48.3% had a low zinc level, in the 60-80 μg/dL range, and 6.7% had zinc deficiency with a zinc level below 60 μg/dL. The majority with a low zinc level and zinc deficiency were asymptomatic other than for short stature. We found no significant correlations of serum zinc with age, or the SDSs for height and serum IGF-1 levels, in either the entire subject population or those with a zinc level below 80 μg/dL. Conclusions We found a low zinc level to be common in Japanese children with idiopathic short stature, whereas actual zinc deficiency was rare. However, other as yet unknown mechanisms not associated with the growth hormone (GH)-IGF-1 axis could be involved in growth retardation in idiopathic short stature. 10.1515/jpem-2019-0129
Association between systolic blood pressure and uric acid in Chinese children and adolescents with idiopathic short stature: a cross-sectional study. Kou Shuang,Zhang Mei,Ji Baolan,Zhao Qianqian,Li Yanying,Pan Hui,Ban Bo,Li Ping Journal of human hypertension The purpose of this study was to investigate the relationship between systolic blood pressure (SBP) and uric acid (UA) in patients with idiopathic short stature (ISS). The present study was a cross-sectional study. A total of 210 Chinese children and adolescents with ISS were included, and their anthropometrics and biochemical parameters were measured. Growth hormone peak levels were assessed after provocation tests with L-dopa and insulin. The univariate analysis results showed a significant positive association between UA and SBP levels (P < 0.001). Furthermore, a non-linear relationship was detected between UA and SBP. In multivariate piecewise linear regression, the inflection point of UA was 4.13 mg/dl (95% CI 3.28, 6.65; P = 0.03), the levels of SBP increased with the increase in UA when the UA level was >4.13 mg/dl (β 2.63, 95% CI: 0.94, 4.31; P = 0.002). However, we did not observe a significant relationship between UA and SBP when the UA level was <4.13 mg/dl (β -2.72, 95% CI -6.89, 1.45; P = 0.202). Our study found a nonlinear relationship between UA and SBP in Chinese children and adolescents with ISS and showed that SBP levels were associated positively with the rise of UA levels when the UA levels reached the inflection point. 10.1038/s41371-020-0362-0
GH Resistance Is a Component of Idiopathic Short Stature: Implications for rhGH Therapy. Savage Martin O,Storr Helen L Frontiers in endocrinology Idiopathic short stature (ISS) is a term used to describe a selection of short children for whom no precise aetiology has been identified. Molecular investigations have made notable discoveries in children with ISS, thus removing them from this category. However, many, if not the majority of children referred with short stature, are designated ISS. Our interest in defects of GH action, i.e. GH resistance, has led to a study of children with mild GH resistance, who we believe can be mis-categorised as ISS leading to potential inappropriate management. Approval of ISS by the FDA for hGH therapy has resulted in many short children receiving this treatment. The results are extremely variable. It is therefore important to correctly assess and investigate all ISS subjects in order to identify those with mild but unequivocal GH resistance, as in cases of PAPP-A2 deficiency. The correct identification of GH resistance defects will direct therapy towards rhIGF-I rather than rhGH. This example illustrates the importance of recognition of GH resistance among the very large number patients referred with short stature who are labelled as 'ISS'. 10.3389/fendo.2021.781044
[Idiopathic short stature and treatment with biosynthetic growth hormone: clinical and ethical reflections on an arbitrary diagnosis]. Soriano-Guillén L,Argente J Anales de pediatria (Barcelona, Spain : 2003) 10.1016/j.anpedi.2011.10.009
Relationship between hemoglobin and insulin-like growth factor-1 in children and adolescents with idiopathic short stature. Zhao Qianqian,Zhang Mei,Ji Baolan,Chu Yuntian,Pan Hui,Yan Wenhua,Ban Bo BMC endocrine disorders BACKGROUND:The growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis is critical for the regulation of children's growth and development. Serum IGF-1 concentrations are usually low in individuals with idiopathic short stature (ISS) despite normal endogenous GH levels, and the associated underlying factors are unknown. This study aimed to explore the relationship between IGF-1 and hemoglobin (Hb) in children with ISS. METHODS:A cross-sectional analysis was performed including 178 children and adolescents with ISS who were enrolled from March 2013 to February 2019. The related clinical and biochemical parameters were evaluated for each patient. Univariate analysis, smooth curve fitting and multivariate piecewise linear regression were performed. RESULT:The mean levels of IGF-1 standard deviation scores (SDS) and Hb were - 0.99 (- 1.60 - -0.09) and 131.81 ± 9.36 g/L, respectively. Univariate analysis displayed a significant positive association between Hb and IGF-1 SDS (P < 0.001). After adjusting for potential confounding factors, the positive relationship between Hb and IGF-1 SDS remained (P = 0.001). Furthermore, there was an inflection point for Hb in the curve. In a multivariate piecewise linear regression model, IGF-1 SDS was significantly positively associated with Hb when Hb concentrations were lower than 145 g/L (B 0.05; 95% CI 0.02, 0.07; P < 0.001). However, IGF-1 SDS decreased with increasing Hb levels when Hb concentrations were greater than 145 g/L (B -0.15; 95% CI -0.23, - 0.06; P = 0.001). CONCLUSION:This study demonstrated that Hb is associated with IGF-1 in Chinese children and adolescents with ISS. The levels of IGF-1 increased with the elevation of Hb, but when the concentration of Hb exceeded a certain range, with the increase of Hb, IGF-1 decreased instead. 10.1186/s12902-020-00600-w
Common VDR polymorphisms and idiopathic short stature in children from northern Greece. Emmanouilidou E,Galli-Tsinopoulou A,Kyrgios I,Gbandi E,Goulas A Hippokratia BACKGROUND:A Vitamin D Receptor gene (VDR) polymorphism, rs10735810 (Fok1), has been associated in the past with idiopathic short stature (ISS) in a linkage study. We have investigated the association of the same, as well as a different polymorphism in the same gene [rs731236 (Taq1)] with ISS, in an independent study in Greek children. METHODS:The VDR rs10735810 (Fok1) and rs731236 (Taq1) polymorphisms were genotyped in a group of ISS children (n= 47) and an age and sex-matched group of normal height children (n= 60) from northern Greece. Genotyping was accomplished through established PCR-RFLP methods. RESULTS:An association trend of rs10735810 with ISS was observed, with the TT (ff) genotype being apparently underrepresented among ISS children compared to controls (p= 0.076; OR= 0.165, 95% CI= 0.025-1.094). CONCLUSIONS:The above results, together with recent evidence related to the functionality of the rs10735810 polymorphism, cannot exclude an involvement of VDR in the pathogenesis of ISS. Hippokratia 2015, 19 (1): 25-29.
Ghrelin and Growth. Perchard Reena,Clayton Peter E Endocrine development Ghrelin is a pleiotropic hormone, whose effect on growth hormone secretion, through the growth hormone secretagogue (GHS) receptor, is one of its many actions. Relationships between GHS receptor gene variants and human height, both in healthy individuals and in patients with growth disorders have been identified. These include constitutional delay in growth and puberty, idiopathic short stature, and isolated growth hormone deficiency. In this review, we provide an overview of the role of ghrelin in growth. 10.1159/000475732
Association between uric acid and height during growth hormone therapy in children with idiopathic short stature. Frontiers in endocrinology Background:Serum uric acid (UA) within appropriate levels is reported to be beneficial in patients with idiopathic short stature (ISS). This study aimed to evaluate the association between serum UA levels and height standard deviation scores (SDS) in patients with ISS during growth hormone (GH) therapy. Methods:A longitudinal study (LG Growth Study) of 182 children (mean age: 7.29±2.60 years) with ISS was performed. All participants were in the prepubertal stage and treated with GH, and the data within a treatment period of 30 months were analyzed. Results:In the adjusted Pearson's correlation, UA was significantly correlated with height SDS after controlling for sex, age, and body mass index (BMI) SDS (r=0.22, p=0.007). In the adjusted multiple regression analyses, the height SDS was significantly associated with UA after controlling for sex, age, and BMI SDS (β=0.168, p=0.007). Within the 30-month treatment period, the UA levels significantly increased as the height SDS increased, and the mean UA levels at baseline and 30 months after treatment were 3.90±0.64 mg/dL and 4.71±0.77 mg/dL, respectively (p=0.007). Discussion:In conclusion, UA is related to height SDS, and GH treatment leads to a significant increase in UA without hyperuricemia. Elevated UA is considered a favorable outcome of GH therapy, and further studies are needed to determine its role as a monitoring tool. 10.3389/fendo.2022.1025005
Next-generation sequencing-based mutational analysis of idiopathic short stature and isolated growth hormone deficiency in Korean pediatric patients. Ahn Jungmin,Oh Jiyoung,Suh Junghwan,Song Kyungchul,Kwon Ahreum,Chae Hyun Wook,Oh Jun Suk,Lee Hae In,Lee Myeong Seob,Kim Ho-Seong Molecular and cellular endocrinology We investigated the distribution of short stature-associated mutations in Korean pediatric patients with idiopathic short stature (ISS) and isolated growth hormone deficiency (IGHD) via targeted next-generation sequencing (TNGS). We employed a 96-gene TNGS panel for short stature in a total of 144 patients (5-19 years-old) previously diagnosed with ISS or IGHD and identified heterozygous pathogenic or likely pathogenic genetic variants in 14 (10%) patients. Of the mutated genes, PROKR2 (n = 3) is associated with gonadotropin-releasing hormone deficiency or hypopituitarism, while FGFR1 (n = 1) and NPR2 (n = 3) encode growth plate paracrine factors. FBN1 (n = 1), COL9A1 (n = 1), MATN3 (n = 1), and ACAN (n = 3) regulate the cartilage extracellular matrix, while PTPN11 (n = 1) controls intracellular pathways. Six patients had IGHD, and eight patients had ISS. The current findings highlight the utility of TNGS for determining the genetic etiology in these patients. 10.1016/j.mce.2021.111489
Growth Hormone Treatment for Idiopathic Short Stature. Cutfield Wayne S,Albert Benjamin B Pediatric endocrinology reviews : PER ISS is the commonest cause of short stature and poor growth and is arbitrarily defined as a height < -2 SDS without an identified cause. ISS consists largely of normal children with the remainder unrecognised conditions, mainly syndromes and genetic (monogenic and polygenic) causes. Growth response to rhGH is widely variable reflecting the heterogeneity of ISS. Further identification of genetic causes of ISS will better characterise treatment response. rhGH during childhood has been shown in RCTs to improve adult height by approximately 4 cm which is less than seen in other treated growth disorders. Factors that influence response include; younger age, longer birth length, lower height compared to mid-parental height, delayed bone age and larger rhGH dose. The evidence that short stature is associated with psychological well-being and quality of life is minimal and that rhGH could improve this is scant. Further research in this area is urgently required. 10.17458/per.vol16.2018.ca.ghidiopathicshortstature
Dilemmas of growth hormone treatment for GH deficiency and idiopathic short stature: defining, distinguishing, and deciding. Halas Julia G,Grimberg Adda Minerva pediatrica Worrisome growth can be a sign of underlying pathology but usually reflects healthy variation. It is often recognized through short stature, which is defined by arbitrarily separating height, a physical trait on a continuum, into "normal" and "abnormal." In some cases of worrisome growth, recombinant human growth hormone (rhGH) treatment is indicated to hasten growth/increase height. This review addresses the two most frequently treated indications for rhGH, growth hormone deficiency (GHD) and idiopathic short stature (ISS). A review of worrisome growth itself, of the history of GH treatment, of the blurry line between partial GHD and ISS, of the GH stakeholders, and of the outside pressures involved in these cases demonstrates the ambiguous platform upon which treatment decisions are made. The rhGH treatment decision process can be examined further by considering the three most impactful factors on parental height-related medical decision-making: treatment characteristics, child health, and psychosocial function. While it is important to note that treatment for classical GHD is uncontroversial and supported, treatment decisions for partial GHD and ISS are more complicated and require careful evaluation of both patient needs and the supporting evidence. As the rhGH community grows, physicians, parents, and patients are encouraged to engage in a shared decision-making process to navigate the many challenges facing the GH field. Although this review addresses GHD and ISS specifically, the issues discussed are often applicable to pediatrics as a whole. 10.23736/S0026-4946.20.05821-1
Clinical Indications for Growth Hormone Therapy. Advances in pediatrics Growth hormone (GH) is an injectable medication originally used to replace the deficiency of the hormone, but has expanded to treating conditions that may reduce growth and adult height even when the body maintains endogenous GH production. In the United States, there are 8 Food and Drug Administration (FDA)-approved indications for pediatric GH therapy: GH deficiency, Prader-Willi Syndrome, small for gestational age (SGA) without catch-up growth, idiopathic short stature, Turner syndrome, SHOX gene haploinsufficiency, Noonan Syndrome, and chronic renal insufficiency. We characterize the growth patterns and effects of GH treatment in each of these indications. We also review patterns of growth that warrant referral to a pediatric endocrinologist, as well as safety updates. This review is intended to guide practitioners on the initial evaluation and management of patients with short stature, and the indications for GH therapy. 10.1016/j.yapd.2022.03.005
Effects of Single Vitamin D₃ Injection (200,000 Units) on Serum Fibroblast Growth Factor 23 and Sclerostin Levels in Subjects with Vitamin D Deficiency. Zhang Dongdong,Seo Da Hea,Choi Han Seok,Park Hye Sun,Chung Yoon Sok,Lim Sung Kil Endocrinology and metabolism (Seoul, Korea) BACKGROUND:Vitamin D deficiency remains common in all age groups and affects skeletal and non-skeletal health. Fibroblast growth factor 23 is a bone-derived hormone that regulates phosphate and 1,25-dihydroxyvitamin D homeostasis as a counter regulatory factor. 1,25-Dihydroxyvitamin D stimulates fibroblast growth factor 23 synthesis in bone, while fibroblast growth factor 23 suppresses 1,25-dihydroxyvitamin D production in the kidney. The aim of this study was to evaluate the effects of vitamin D₃ intramuscular injection therapy on serum fibroblast growth factor 23 concentrations, and several other parameters associated with bone metabolism such as sclerostin, dickkopf-1, and parathyroid hormone. METHODS:A total of 34 subjects with vitamin D deficiency (defined by serum 25-hydroxyvitamin D levels below 20 ng/mL) were randomly assigned to either the vitamin D injection group (200,000 units) or placebo treatment group. Serum calcium, phosphate, urine calcium/creatinine, serum 25-hydroxyvitamin D, fibroblast growth factor 23, sclerostin, parathyroid hormone, and dickkopf-1 levels were serially measured after treatment. RESULTS:Comparing the vitamin D injection group with the placebo group, no significant changes were observed in serum fibroblast growth factor 23, parathyroid hormone, or dickkopf-1 levels. Serum sclerostin concentrations transiently increased at week 4 in the vitamin D group. However, these elevated levels declined later and there were no statistically significant differences as compared with baseline levels. CONCLUSION:Serum fibroblast factor 23, sclerostin, parathyroid hormone, and dickkopf-1 levels were not affected significantly by single intramuscular injection of vitamin D₃. 10.3803/EnM.2017.32.4.451
Parathyroid function and vitamin D metabolism during human growth hormone replacement. Gertner J M,Horst R L,Broadus A E,Rasmussen H,Genel M The Journal of clinical endocrinology and metabolism Changes in calcium and phosphorus metabolism were studied in nine children with GH deficiency before and during human GH replacement therapy. Parathyroid function and serum concentrations of physiologically important vitamin D metabolites were examined to determine their relationship to changes in mineral metabolism. By comparison with pretreatment values, the GH-treated children showed significant increases in growth rate and renal tubular phosphate reabsorption and a significant decrease in urinary calcium excretion after a standardized oral load. There was no significant change in serum concentrations of parathyroid hormone, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, or 24,25-dihydroxyvitamin D or in nephrogenous cAMP excretion. Although GH has been proposed as a regulator of vitamin D metabolism, the present study demonstrates that the anabolic changes in calcium and phosphorus metabolism accompanying GH therapy are not mediated via changes in parathyroid hormone or vitamin D status. 10.1210/jcem-49-2-185
TRABECULAR BONE SCORE CHANGE DIFFERS WITH REGARD TO 25(OH)D LEVELS IN PATIENTS TREATED FOR ADULT-ONSET GROWTH HORMONE DEFICIENCY. Kužma Martin,Binkley Neil,Bednárová Adriana,Killinger Zdenko,Vaňuga Peter,Payer Juraj Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists OBJECTIVE:Vitamin D is important in bone health. However, potential relationships of concomitant vitamin D deficiency with growth hormone deficiency (GHD) and the possibility that vitamin D inadequacy may alter the skeletal effects of growth hormone (GH) replacement therapy have not been adequately evaluated. METHODS:A prospective study was conducted in adult-onset GHD patients treated with recombinant human GH (rhGH) for 2 years. Trabecular bone score (TBS), lumbar spine (LS) bone mineral density (BMD), total hip (TH) BMD, and 25-hydroxyvitamin D (25(OH)D) levels were assessed at baseline and 24 months. The study cohort was divided based on 25(OH)D levels into 2 groups with the cutoff defined as the 50(th) percentile at each follow-up time point. RESULTS:Fifty-seven patients (29 males/28 females, mean age 34.4 years) were studied. After 24 months of GH replacement, LS BMD increased by 7.6% and TH BMD increased by 4.5% (both P<.05), with no difference according to 25(OH)D levels. TBS increased (+1.39 ± 3.6%) in those whose 25(OH)D was above the 50(th) percentile but decreased (-1.36 ± 5.6%, P<.05) in the cohort below the 50(th) percentile of 25(OH)D. Positive correlations were observed between baseline levels of IGF-1 and 25(OH)D (R = 0.37, P<.001) and between 24-month 25(OH)D and TBS (R = 0.25, P<.05). CONCLUSION:A differential effect of GH on TBS change was observed; TBS increased only in the cohort with 25(OH)D above the 50(th) percentile. Vitamin D sufficiency may be required to obtain optimal effects of GH treatment on bone quality, as assessed by TBS, in GHD adults. ABBREVIATIONS:AO-GHD = adult-onset GHD BMD = bone mineral density BMI = body mass index Ca = calcium CTx = carboxyterminal collagen crosslinks CV = coefficient of variation DXA = dual energy X-ray absorptiometry ECLIA = enzyme-labeled chemiluminescent immunometric assay GH = growth hormone GHD = growth hormone deficiency IGF-1 = insulin-like growth factor 1 LS BMD = lumbar spine BMD OC = osteocalcin 25(OH)D = 25-hydroxyvitamin D P = phosphorus PTH = parathyroid hormone rhGH = recombinant human GH TBS = trabecular bone score TH BMD = total hip BMD. 10.4158/EP151183.OR
Serum transforming growth factor-beta levels in patients with vitamin D deficiency. Isik Serhat,Ozuguz Ufuk,Tutuncu Yasemin Ates,Erden Gonul,Berker Dilek,Acar Kadir,Aydin Yusuf,Akbaba Gulhan,Helvaci Nafiye,Guler Serdar European journal of internal medicine BACKGROUND:Transforming growth factor-beta 1 (TGF-β1) contributes to tissue repair by promoting tissue fibrosis, and elevations have been reported in patients with bone marrow fibrosis. The aim of this study was to evaluate the relationship between TGF-β1 levels and vitamin D deficiency. METHODS:All patients presenting to the outpatient Endocrinology and Metabolic Diseases clinic between June and September of 2008 were approached, and consenting patients who were deemed suitable candidates were enrolled. Hematological parameters were measured, along with serum levels of total and ionized calcium, phosphorus, parathyroid hormone, iron, folic acid vitamin B12 levels, 25 OH vitamin D3 (25OHD(3)) and TGF-β1. RESULTS:A total of 132 patients were included in the study. Patients were divided into 4 groups based on levels of 25OHD(3) [group 1 (<5 ng/ml), 20 patients; group 2 (5-15 ng/ml), 38 patients; group 3 (16-30 ng/ml); and group 4 (>30 ng/ml), 28 patients]. TGF-β1 levels were higher in patients in group 1 compared to the other groups. Transforming growth factor-beta levels correlated negatively with vitamin D3 and positively with leukocyte count, platelet count, of MCV and MCH. Multiple regression analyses revealed TGF-β1 levels to be associated with 25OHD(3) as well as with platelet count. CONCLUSIONS:Results of this study are suggestive of the presence of a significant relationship between TGF-β and vitamin D deficiency. Increased TGF-β1 and platelet count may be an early indicator of bone marrow fibrosis in patients with vitamin D deficiency. 10.1016/j.ejim.2011.09.017
Association Between Vitamin D and Carboxy-Terminal Cross-Linked Telopeptide of Type I Collagen in Children During Growth Hormone Replacement Therapy. Witkowska-Sędek Ewelina,Stelmaszczyk-Emmel Anna,Kucharska Anna,Demkow Urszula,Pyrżak Beata Advances in experimental medicine and biology Growth hormone and insulin-like growth factor-1 (IGF-1) play a crucial role in the regulation of bone turnover. Adequate vitamin D status supports proper bone remodeling, leading to normal longitudinal bone growth and normal peak bone mass. The aim of this study was to evaluate the association between serum 25-hydroxyvitamin D [25(OH)D] and carboxy-terminal cross-linked telopeptide of type I collagen (ICTP) in children and adolescents with growth hormone deficiency at baseline and during recombinant human growth hormone (rhGH) replacement therapy. The study was prospective and included 30 children and adolescents aged 5 to 17 years. Concentrations of 25(OH)D, ICTP, and IGF-1 were measured at baseline and during the first year of rhGH therapy. Baseline serum 25(OH)D concentration correlated with ICTP concentrations during the first trimester of rhGH therapy (r = 0.38, p < 0.050); the correlation was stronger in the second trimester of therapy (r = 0.6, p = 0.002). We conclude that proper vitamin D status is important in reaching the adequate dynamics of bone remodeling during growth, which is essential to achieve a catch-up growth during rhGH therapy. 10.1007/5584_2017_109
Clinical Implications of Growth Hormone Deficiency for Oral Health in Children: A Systematic Review. Journal of clinical medicine Growth hormone (GH) is involved in the regulation of the postnatal dental and skeletal growth, but its effects on oral health have not been clearly defined. This paper aims to provide a review of current clinical knowledge of dental caries, tooth wear, developmental enamel defects, craniofacial growth and morphology, dental maturation, and tooth eruption in growth hormone deficient (GHD) children. A systematic review was carried out using Scopus, MEDLINE-EbscoHost and Web of Science from 2000 to May 2021. PRISMA guidelines for reporting systematic reviews were followed. All the selected studies involved groups under eighteen years of age, covering a total of 465 GHD patients. The studies that were selected provide reliable evidence for delayed dental maturity and orthodontic disturbances in GHD patients. Data on dental hard tissues pathology are scarce and are limited to occurrences of dental caries. GHD children showed abnormal craniofacial morphology with reduced mandibular dimensions, with a resulting tendency towards Angle's Class II occlusion, which affected up to 31% of patients. Dental age has been shown to be delayed in GHD patients by about 1 to 2 years. Moreover, the risk of dental caries in children with GHD decreases with increasing levels of vitamin D. Hence, further studies would be valuable for evaluating the risk of various oral health problems and to organize targeted dental care for this vulnerable group. 10.3390/jcm10163733
Vitamin D deficiency and fetal growth. Brunvand L,Quigstad E,Urdal P,Haug E Early human development Vitamin D deficiency in pregnancy has been associated with decreased fetal growth, but previous studies have found no direct relation between the weight of the new-born child and the maternal serum level of 25-hydroxyvitamin D3 (calcidiol). The aim of this study was to evaluate the relation between maternal serum calcium and parathyroid hormone with reduced fetal growth in vitamin D deficient pregnant women. Thirty Pakistani women were included in the study at delivery. Only mothers without known chronic diseases who delivered vaginally after an uncomplicated pregnancy were included. Anthropometric data were recorded, and blood samples were drawn from the mothers 1-4 h after delivery. Nearly all (29/30) the Pakistani women had low (< 30 nmol/l) serum levels of 25-hydroxyvitamin D3. Thirteen of the mothers had high serum parathyroid hormone (PTH) levels (> 5.5 pmol/l). The median (range) level of ionised calcium in serum was 1.23 (1.15-1.28) nmol/l. A positive correlation was found between the level of ionised calcium in maternal serum and the crown-heel length of the infant (Spearman's rho = 0.65, P = 0.002, n = 20). The maternal serum PTH was related inversely to the crown-heel length (Spearman's rho = -0.47, P = 0.01, n = 30). No confounding effect of gestational age, sex of the infant, maternal height and body mass index (BMI) was found. The study indicates that vitamin D deficiency affects fetal growth through an effect on maternal calcium homeostasis.
Incidence rate of vitamin D deficiency and FGF23 levels in 12- to 13-year-old adolescents in Japan. Koyama Satomi,Kubota Takuo,Naganuma Junko,Arisaka Osamu,Ozono Keiichi,Yoshihara Shigemi Journal of bone and mineral metabolism INTRODUCTION:The incidence rate of vitamin D deficiency is increasing throughout the world. We measured the incidence rate of vitamin D deficiency and fibroblast growth factor 23 (FGF23) levels in 12- to 13-year-old adolescents in Japan. MATERIALS AND METHODS:A total of 492 adolescents (247 boys and 245 girls) from Japanese community enrolled in this study. 25 hydroxyvitamin D (25(OH)D) was measured with radioimmunoassay. In the subjects with low 25(OH)D levels (≦ 20 ng/ml), intact parathyroid hormone (iPTH), calcium (Ca), phosphorus (P), albumin (Alb), alkaline phosphatase (ALP) and FGF23 were measured. RESULTS:25(OH)D levels were significantly lower in girls (20.9 ± 3.1 ng/ml) than in boys (22.2 ± 3.3 ng/ml) (p < 0.0001). Fifty-five boys (22.3%) and 83 (33.9%) girls showed vitamin D deficiency (< 20 ng/ml). One-hundred eighty-six (75.3%) boys and 162 (66.1%) girls showed vitamin D insufficiency (≧ 20 ng/ml, < 30 ng/ml). In the subjects whose 25(OH)D levels were ≦ 20 ng/ml, the levels of iPTH, Ca, P, Alb, ALP and FGF23 were 22.3 ± 9.0 pg/ml, 9.5 ± 0.4 mg/dl, 4.7 ± 0.6 mg/dl, 4.6 ± 0.3 g/dl, 920.8 ± 339.3 U/l and 42.6 ± 26.0 pg/ml, respectively. There was a significant negative association between serum 25(OH)D levels and iPTH [r =  - 0.290 (p < 0.0001)]. There was no significant association between serum 25(OH)D levels and FGF23. CONCLUSION:We show that 28% of Japanese 12- to 13-year-old early adolescents suffer from vitamin D deficiency. Findings from this study indicate that vitamin D deficiency requires close oversight in public health during adolescence to ensure proper bone health. 10.1007/s00774-020-01173-3
Vitamin D levels in primary growth hormone deficiency disorder Prader-Willi syndrome. Purtell Louise,Viardot Alexander,Campbell Lesley V Endocrine 10.1007/s12020-016-0889-6
The relationship between alkaline phosphatase and bone alkaline phosphatase activity and the growth hormone/insulin-like growth factor-1 axis and vitamin D status in children with growth hormone deficiency. Witkowska-Sędek Ewelina,Stelmaszczyk-Emmel Anna,Majcher Anna,Demkow Urszula,Pyrżak Beata Acta biochimica Polonica The relationships between bone turnover, the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis and vitamin D are complex, but still not fully explained. The GH/IGF-1 axis and vitamin D can mutually modulate each other's metabolism and influence the activation of cell proliferation, maturation, and mineralization as well as bone resorption. The aim of this study was to evaluate the reciprocal associations between bone formation markers [alkaline phosphatase (ALP), bone alkaline phosphatase (BALP)], the GH/IGF-1 axis and 25-hydroxyvitamin D [25(OH)D] in children with growth hormone deficiency at baseline and during recombinant human growth hormone (rhGH) therapy. ALP, BALP, 25(OH)D and IGF-1 levels were evaluated in 53 patients included in this prospective three-year study. ALP, BALP and IGF-1 increased during rhGH therapy. Baseline ALP activity correlated positively with baseline height velocity (HV). ALP and BALP activity at 12 months correlated positively with HV in the first year of therapy. We found positive correlations between ALP and IGF-1 at baseline and during the first year of therapy, between BALP activity at 12 months and rhGH dose in the first year of therapy, and between doses of cholecalciferol in the first year of rhGH therapy and early changes in BALP activity during rhGH therapy. Our results indicate that vitamin D supplementation enhances the effect of rhGH on bone formation process, which could improve the effects of rhGH therapy. ALP and BALP activity are useful in the early prediction of the effects of rhGH therapy, but their utility as long-term predictors seemed insufficient. 10.18388/abp.2017_2541
Relationship Between 25(OH)D and IGF-I in Children and Adolescents with Growth Hormone Deficiency. Witkowska-Sędek E,Kucharska A,Rumińska M,Pyrżak B Advances in experimental medicine and biology Recent studies have shown that vitamin D has an impact on the production and secretion of IGF-I in the liver. The aim of our study was to investigate the relationship between the concentrations of 25-hydroxy vitamin D [25(OH)D] and insulin-like growth factor I (IGF-I) in growth hormone deficient children and adolescents before recombinant human growth hormone (rhGH) treatment. The study was retrospective and included 84 children and adolescents aged 4-17. Prior to initiating rhGH therapy, concentrations of 25(OH)D and IGF-I were measured in all patients. IGF-I concentrations were normalized for bone age. The studied group was divided into two subgroups according to serum 25(OH)D levels. Significant positive correlations between 25(OH)D concentration and IGF-I SDS-normalized for bone age were observed in both studied subgroups. The results of our study suggest that vitamin D deficiency could influence IGF-I concentrations in children and adolescents with growth hormone deficiency, and vitamin D deficiency should be normalized before the measurement of IGF-I concentrations to obtain the reliable and unbiased IGF-I values. 10.1007/5584_2016_212
The role of parathyroid hormone during pregnancy on the relationship between maternal vitamin D deficiency and fetal growth restriction: a prospective birth cohort study. Meng Deng-Hong,Zhang Ying,Ma Shuang-Shuang,Hu Hong-Lin,Li Jing-Jing,Yin Wan-Jun,Tao Rui-Xue,Zhu Peng The British journal of nutrition Previous studies have shown conflicting findings regarding the relationship between maternal vitamin D deficiency (VDD) and fetal growth restriction (FGR). We hypothesised that parathyroid hormone (PTH) may be an underlying factor relevant to this potential association. In a prospective birth cohort study, descriptive statistics were evaluated for the demographic characteristics of 3407 pregnancies in the second trimester from three antenatal clinics in Hefei, China. The association of the combined status of vitamin D and PTH with birth weight and the risk of small for gestational age (SGA) was assessed by a multivariate linear and binary logistic regression. We found that declined status of 25-hydroxyvitamin D is associated with lower birth weight (for moderate VDD: adjusted β = -49·4 g, 95 % CI -91·1, -7·8, P < 0·05; for severe VDD: adjusted β = -79·8 g, 95 % CI -127·2, -32·5, P < 0·01), as well as ascended levels of PTH (for elevated PTH: adjusted β = -44·5 g, 95 % CI -82·6, -6·4, P < 0·05). Compared with the non-VDD group with non-elevated PTH, pregnancies with severe VDD and elevated PTH had the lowest neonatal birth weight (adjusted β = -124·7 g, 95 % CI -194·6, -54·8, P < 0·001) and the highest risk of SGA (adjusted risk ratio (RR) = 3·36, 95 % CI 1·41, 8·03, P < 0·01). Notably, the highest risk of less Ca supplementation was founded in severe VDD group with elevated PTH (adjusted RR = 4·67, 95 % CI 2·78, 7·85, P < 0·001). In conclusion, elevated PTH induced by less Ca supplementation would further aggravate the risk of FGR in pregnancies with severe VDD through impaired maternal Ca metabolism homoeostasis. 10.1017/S0007114520001105
Cardiovascular risk factors in growth hormone deficiency: is vitamin D a new kid on the block? Isgaard Jörgen Endocrine 10.1007/s12020-016-0860-6
Does Vitamin D Status Correlate with Cardiometabolic Risk Factors in Adults with Growth Hormone Deficiency? Uzunova Ivayla,Kirilov Georgi,Zacharieva Sabina,Zlatareva Naydenka,Kalinov Krasimir Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme Apart from being individually associated with cardiometabolic health, 25(OH)D and IGF-1 interplay with a positive correlation between them, which raises questions about the role of vitamin D for the adverse cardiovascular (CV) risk profile in hyposomatotropism. Thus, we aimed to investigate vitamin D status in GH deficiency (GHD) and the association between 25(OH)D and metabolic syndrome (MetS), its components, and other surrogate markers of CV risk. A total of 129 GHD adults (childhood-onset GHD, 41.9%) underwent blood testing (glucose, insulin, lipid profile, uric acid); blood pressure, anthropometric and bioelectrical-impedance measurements. Other CV risk markers were examined in a subsample of the initial population - hsCRP, adiponectin, and asymmetric dimethylarginine (n=88); carotid intima-media thickness (n=44). Total serum 25(OH)D, measured by electro-chemiluminescence binding assay, was used for vitamin D status assessment (adequate,≥30 ng/ml; insufficient, 20-29.9 ng/ml; deficient,<20 ng/ml). Data demonstrated high prevalence of hypovitaminosis D in GHD (deficiency 79.1%; insufficiency 14.7%), with lower 25(OH)D among adult-onset GHD subjects (14.0±7.2 vs. 16.8±8.0 ng/ml, p=0.039) and patients with MetS (11.8±4.5 vs. 16.3±8.1 ng/ml, p<0.0001). 25(OH)D correlated negatively and weakly with BMI, waist circumference, percent body fat, visceral fat area, and systolic BP. Regardless of whether vitamin D is a cause or a consequence of these metabolic abnormalities, 25(OH)D testing in hyposomatotropism is advisable. Normalization of vitamin D status is not proven to improve CV outcomes in general population, but it might have favorable effects in GHD, as its benefits might be restricted to patients with both low 25(OH)D and certain risk factors. 10.1055/s-0043-100114
Dental caries and vitamin D3 in children with growth hormone deficiency: A STROBE compliant study. Wójcik Dorota,Krzewska Aleksandra,Szalewski Leszek,Pietryka-Michałowska Elżbieta,Szalewska Magdalena,Krzewski Szymon,Pels Elżbieta,Beń-Skowronek Iwona Medicine Vitamin D may prevent dental caries. To date, no attempts have been made to examine the correlation between the incidence of caries and the concentrations of vitamin D in children with pituitary growth hormone deficiency.The study observed patients of the Department of Endocrinology and Diabetology of the University Paediatric Hospital of the Medical University of Lublin treated with human recombinant growth hormone for pituitary growth hormone deficiency (GHD). The study was conducted between October 2014 and June 2015. The study group consisted of 121 children and adolescents (6-17 years old), including 56 children from rural areas and 65 children from urban areas. The study group was stratified by area of residence.In our study, the increase in vitamin D3 [25(OH)D] levels reduced the D component by 0.66 per each 10 ng/mL of vitamin D3 concentration. The percentage of children with active caries in rural areas is 91.07% (n = 51), which is significantly higher than the percentage of children with active caries in urban areas (81.54%, n = 53).To date, information regarding the potential possibility of reducing the incidence of dental caries by means of increasing the levels of vitamin D was sidelined by paediatricians and dentists alike. Therefore, this aspect of caries prevention should be highlighted. 10.1097/MD.0000000000009811
Effects of early vitamin D deficiency rickets on bone and dental health, growth and immunity. Zerofsky Melissa,Ryder Mark,Bhatia Suruchi,Stephensen Charles B,King Janet,Fung Ellen B Maternal & child nutrition Vitamin D deficiency is associated with adverse health outcomes, including impaired bone growth, gingival inflammation and increased risk for autoimmune disease, but the relationship between vitamin D deficiency rickets in childhood and long-term health has not been studied. In this study, we assessed the effect of early vitamin D deficiency on growth, bone density, dental health and immune function in later childhood to determine if children previously diagnosed with rickets were at greater risk of adverse health outcomes compared with healthy children. We measured serum 25-hydroxyvitamin D, calcium, parathyroid hormone, bone mineral density, anthropometric measures, dietary habits, dental health, general health history, and markers of inflammation in 14 previously diagnosed rickets case children at Children's Hospital Oakland Research Center. We compared the findings in the rickets cases with 11 healthy children selected from the population of CHO staff families. Fourteen mothers of the rickets cases, five siblings of the rickets cases, and seven mothers of healthy children also participated. Children diagnosed with vitamin D deficiency rickets had a greater risk of fracture, greater prevalence of asthma, and more dental enamel defects compared with healthy children. Given the widespread actions of vitamin D, it is likely that early-life vitamin D deficiency may increase the risk of disease later in childhood. Further assessment of the long-term health effects of early deficiency is necessary to make appropriate dietary recommendations for infants at risk of deficiency. 10.1111/mcn.12187
Vitamin D status in prepubertal children with isolated idiopathic growth hormone deficiency: effect of growth hormone therapy. Hamza Rasha Tarif,Hamed Amira I,Sallam Mahmoud T Journal of investigative medicine : the official publication of the American Federation for Clinical Research Few studies, and with controversial results, analyzed vitamin D status in children before and after growth hormone (GH) treatment. Thus, we aimed to assess vitamin D status in prepubertal children with idiopathic growth hormone deficiency (GHD), and to evaluate the effect of GHD and GH treatment on vitamin D levels. Fifty prepubertal children with isolated GHD were compared with 50 controls. All were subjected to history, anthropometric assessment and measurement of 25 hydroxyvitamin D (25(OH)D), serum calcium, phosphorous, alkaline phosphatase and parathyroid hormone (PTH) at diagnosis and 1 year after GH therapy. Serum 25(OH)D levels <30 ng/mL and 20 ng/mL were defined as vitamin D insufficiency and deficiency, respectively. 25(OH)D was lower in cases than controls. Forty per cent of children with GHD were 25(OH)D insufficient and 44% deficient, while 16% were sufficient at baseline. There was a positive correlation between 25(OH)D and peak GH levels. Peak GH was a significant predictor of 25(OH)D levels. After 1 year of GH therapy, 25(OH)D increased (18.42±5.41 vs 34.5±10.1 ng/mL; P<0.001). Overall, 22% of cases remained insufficient and 24% deficient, with an increase in prevalence of children with normal levels (54%; P<0.001). 25(OH) correlated negatively with PTH (r=-0.71, P=0.01). In conclusion, hypovitaminosis D is prevalent in children with GHD and significantly improved 1 year after GH therapy. 25(OH)D should be assessed in children with GHD at diagnosis and during follow-up. 10.1136/jim-2017-000618
Vitamin D status and response to growth hormone treatment in prepubertal children with growth hormone deficiency. Durá-Travé T,Gallinas-Victoriano F,Moreno-González P,Urretavizcaya-Martinez M,Berrade-Zubiri S,Chueca-Guindulain M J Journal of endocrinological investigation PURPOSE:To analyze whether vitamin D deficiency could condition the growth response to GH therapy, as well as to analyze if GH treatment modifies both seasonal variations and vitamin D levels in these patients. METHODS:Retrospective study in 98 prepubertal children with GH deficiency (GHD), aged 4.1-8.9 years treated with GH. Growth rate and blood testing (calcium, phosphorus, IGF-I, 25(0H)D and PTH) were monitored at diagnostic and every six months until 24 months of treatment. A control group was recruited (247 healthy children, aged 3.8-9.7 years). The criteria of the US Endocrine Society were used for the definition of hypovitaminosis D. RESULTS:There were no significant differences in vitamin D deficiency among control (12.5%) and GHD groups (15.3%) before starting treatment. Growth rate and IGF-1 and PTH increased (p < 0.05) during GH treatment, but there were no significant differences in calcium, phosphorus and 25(OH)D. There were no significant differences in growth rate and IGF-1, calcium and phosphorus levels in relation to the seasons along GH treatment. There was no correlation between 25(OH)D and IGF-1 during GH therapy. In every programmed control, patients with vitamin D deficiency showed lower growth rate (p < 0.05) compared to patients with vitamin D insufficiency or sufficiency. CONCLUSION:GH treatment, at least during the first two years, does not modify the vitamin D levels. Vitamin D deficiency could condition the response to GH therapy so vitamin D monitoring should be considered as part of the routine evaluation of children with GH treatment. 10.1007/s40618-020-01227-3
Functions of vitamin D in bone. Goltzman D Histochemistry and cell biology Vitamin D, synthesized in the skin or absorbed from the diet, undergoes multi-step enzymatic conversion to its active form, 1,25-dihydroxy vitamin D [1,25(OH)D], followed by interaction with the vitamin D receptor (VDR), to modulate target gene expression. Loss-of function mutations in the genes encoding the enzymes regulating these processes, or in the VDR, result in human diseases, which have demonstrated the paramount role of 1,25(OH)D in mineral and skeletal homeostasis. Mouse genetics has been used to create disease phenocopies which have produced considerable insight into the mechanisms of 1,25(OH)D regulation of mineral and skeletal metabolism. Hypophosphatemia resulting from 1,25(OH)D deficiency or resistance can inhibit apoptosis in hypertrophic chondrocytes leading to abnormal development of the cartilaginous growth plate in rickets. Decreased 1,25(OH)D may also cause decreased vascular invasion associated with reduced chondroclast and osteoclast activity and thereby contribute to growth plate abnormalities. Reduced 1,25(OH)D-mediated intestinal and renal calcium transport can reduce calcium availability, increase parathyroid hormone secretion and phosphaturia, and impair mineral availability for normal matrix mineralization, resulting in reduced growth plate mineralization and osteomalacia. 1,25(OH)D may exert an anabolic effect in bone, apparently via the VDR in mature osteoblasts, by increasing osteoblast activity and reducing osteoclast activity. High ambient levels of exogenous 1,25(OH)D, or of elevated endogenous 1,25(OH)D in the presence of reduced calcium balance, can enhance bone resorption, and apparently prevent mineral deposition in bone. These actions demonstrate the critical role of vitamin D in regulating skeletal homeostasis both indirectly and directly via the 1,25(OH)D/VDR system. 10.1007/s00418-018-1648-y
ANALYSIS OF THE VITAMIN D RECEPTOR BSMI GENE POLYMORPHISM IN CHILDREN WITH GROWTH HORMONE DEFICIENCY. Bolshova Elena V,Ryznychuk Mariana A,Kvacheniuk Dmitry A Wiadomosci lekarskie (Warsaw, Poland : 1960) OBJECTIVE:The aim: The objective of the study was to investigate the polymorphism of the vitamin D receptor (VDR) BsmI gene in children with growth hormone deficiency and the level of their vitamin D supply. PATIENTS AND METHODS:Materials and methods: Sixteen children diagnosed with of growth hormone deficiency who were treated at the State Institution «V.P. Komisarenko Institute of Endocrinology and Metabolism of the National Academy of Medical Sciences of Ukraine» were examined. The patient's gender and age, the anthropometric data, the vitamin D level in the blood, the bone age, the GH level, the IGF-1 levels, the level of calcium in the blood and VDR gene polymorphism were taken into account. RESULTS:Results: It was shown that in the presence of the G/A genotype, the risk of growth hormone deficiency development was increased OR = 1,096 (95% CI 0.39-3.02; p = 0.86). For BsmI, mean values of height, body mass, height SDS, serum 25(OH)D, in the studied population (16 children) were 123.49 ± 19.62 cm, 26.96 ± 11.11 kg, -2.25 ± 0.85, 48.86 ± 16.71 nmol/l, respectively; total calcium level consisted of 2.40 ± 0.12 mmol/l, serum phosphorus - 1.43 ± 0.11 mmol/l. CONCLUSION:Conclusions: The allele frequency of the VDR BsmI polymorphism was 62.5% for the G allele (n = 20) and 37.5% for the allele A (n = 12). The G allele carrier of the polymorphic locus BsmI rs1544410 of the VDR gene (rs11568820) is associated with an increased risk of growth hormone deficiency development OR = 1.31 (95% CI 0.62-2.75; p = 0.47).
Vitamin D in children with growth hormone deficiency due to pituitary stalk interruption syndrome. Delecroix Cécile,Brauner Raja,Souberbielle Jean-Claude BMC pediatrics BACKGROUND:Recent studies have shown a relationship between vitamin D status and growth hormone (GH) and insulin-like growth factor 1 (IGF1). The objective of this study was to assess vitamin D status in children with GH deficiency due to pituitary stalk interruption syndrome (PSIS) and to investigate the relationship between 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D (1,25 (OH) D) serum levels and patient characteristics. METHODS:A retrospective single-center study of 25OHD and 1,25(OH)D serum concentrations in 50 children with PSIS at the initial evaluation before treatment. RESULTS:Mean concentrations of 33.2 ± 18.0 ng/mL for 25OHD and 74.5 ± 40.7 ng/L for 1,25(OH)D were measured. Additionally, 25OHD concentrations were significantly higher in boys than in girls (p = 0.04) and lower in the cold season than in the sunny season (p = 0.03). Significant positive correlations were observed between the GH peak and serum 1,25 (OH) D concentrations (Rho = 0.35; p = 0.015) and the 1,25(OH)D/25OHD ratio (Rho = 0.29; p < 0.05). No correlation was found for other characteristics, including IGF1. CONCLUSIONS:Vitamin D status in children with hypothalamic-pituitary deficiency due to PSIS was similar to that reported in national and European studies in healthy children. The positive significant correlations between the GH peak and the 1,25 (OH)D concentration as well as with the 1,25 (OH)D/25OHD ratio suggest that even in these patients who had severely impaired GH secretion and low IGF1 levels, an interplay between the GH/IGF1 axis and the vitamin D system still exists. 10.1186/s12887-018-0992-3
Vitamin D and Dental Caries in Children with Growth Hormone Deficiency. Wójcik Dorota,Szalewski Leszek,Pietryka-Michałowska Elżbieta,Borowicz Janusz,Pels Elżbieta,Beń-Skowronek Iwona International journal of endocrinology Vitamin D deficiency is a common risk factor for multifactorial diseases, and it seems to be associated with growth hormone deficiency (GHD). Vitamin D could prevent dental caries. The goal of this study was to identify whether there is an association between hormonal therapy with growth hormone (GH), vitamin D supplementation, vitamin D levels, and the occurrence of caries among children affected by GHD. The study group consisted of patients from the Department of Endocrinology and Diabetology of the University Paediatric Hospital at the Medical University of Lublin treated with recombinant human GH for pituitary GHD. It was conducted between October 2014 and June 2015. The study group included 121 children and adolescents aged 6 to 18 years, with 56 children from rural areas and 65 from urban areas. The study group was stratified by the area of residence. We found the statistically significant impact of vitamin D concentration on the average value of the DMFT (decayed, missed, and filled teeth) index and its component-DT (decayed teeth), which was noted in subjects from rural areas. Among patients from urban areas, we found a statistically significant correlation between duration of therapy and the DMFT index. An increase in duration of GH therapy by 10 months leads to a mean increase in DMFT index by 0.70. Based on multiple regression analysis, we developed the following model: value of DT = 3.10 - 0.73category of vitamin D concentration - 0.07duration of supplementation (in months). In this model, variables with a significant impact on the value of DT in the group of patients from rural areas include time of vitamin D supplementation and category of vitamin D concentration. Greater emphasis should be placed on promoting vitamin D as a potentially effective agent reducing the number of dental caries, especially among patients with GHD. 10.1155/2019/2172137
Effect of Vitamin D Combined with Recombinant Human Growth Hormone in Children with Growth Hormone Deficiency. Disease markers Objective:Growth hormone deficiency (GHD) refers to the complete or partial lack of pituitary growth hormone synthesis and secretion. This study is aimed at investigating the efficacy of vitamin D and recombinant human growth hormone (rhGH) in children with GHD. Methods:A total of 100 children with GHD at our hospital were included between 1 January 2018 and 31 October 2020. The patients were divided into a study group ( = 70, received vitamin D combined with rhGH) and a control group ( = 30, received rhGH). The growth and development (bone age, growth rate, and height), bone metabolism (bone alkaline phosphatase (BAP), -collagen degradation product (-CTX), osteocalcin (OC), and amino-terminal propeptide type I procollagen (PINP)), insulin-like growth factor 1 (IGF-1), ghrelin, and adverse reactions in the two groups were measured before and 12 months after treatment. Results:There were no significant differences in the bone age, growth rate, and height between the two groups before treatment. After 12 months of treatment, the bone age, growth rate, and height of the study group were significantly higher than those of the control group. After 12 months of treatment, the levels of serum BAP, PINP, and OC in the study group were significantly higher than those in the control group, while the levels of -CTX in the study group were significantly lower than those in the control group. The serum IGF-1 level in the study group was significantly higher than that in the control group, while the ghrelin level in the study group was lower. There was no significant difference in the incidence of adverse reactions between the two groups. Conclusion:Combined rhGH and vitamin D treatment can promote growth and development, improve bone metabolism, and regulate IGF-1 and ghrelin levels. 10.1155/2022/7461958
Vitamin D and growth hormone in children: a review of the current scientific knowledge. Esposito Susanna,Leonardi Alberto,Lanciotti Lucia,Cofini Marta,Muzi Giulia,Penta Laura Journal of translational medicine BACKGROUND:Human growth is a complex mechanism that depends on genetic, environmental, nutritional and hormonal factors. The main hormone involved in growth at each stage of development is growth hormone (GH) and its mediator, insulin-like growth factor 1 (IGF-1). In contrast, vitamin D is involved in the processes of bone growth and mineralization through the regulation of calcium and phosphorus metabolism. Nevertheless, no scientific study has yet elucidated how they interact with one another, especially as a dysfunction in which one influences the other, even if numerous biochemical and clinical studies confirm the presence of a close relationship. MAIN BODY:We reviewed and analyzed the clinical studies that have considered the relationship between vitamin D and the GH/IGF-1 axis in pediatric populations. We found two main areas of interest: the vitamin D deficiency status in patients affected by GH deficit (GHD) and the relationship between serum vitamin D metabolites and IGF-1. Although limited by some bias, from the analysis of the studies presented in the scientific literature, it is possible to hypothesize a greater frequency of hypovitaminosis D in the subjects affected by GHD, a reduced possibility of its correction with only substitution treatment with recombinant growth hormone (rGH) and an improvement of IGF-1 levels after supplementation treatment with vitamin D. CONCLUSIONS:These results could be followed by preventive interventions aimed at reducing the vitamin D deficit in pediatric age. In addition, further research is needed to fully understand how vitamin D and growth are intertwined. 10.1186/s12967-019-1840-4
Vitamin D physiology. Lips P Progress in biophysics and molecular biology Vitamin D3 is synthesized in the skin during summer under the influence of ultraviolet light of the sun, or it is obtained from food, especially fatty fish. After hydroxylation in the liver into 25-hydroxyvitamin D (25(OH)D) and kidney into 1,25-dihydroxyvitamin D (1,25(OH)2D), the active metabolite can enter the cell, bind to the vitamin D-receptor and subsequently to a responsive gene such as that of calcium binding protein. After transcription and translation the protein is formed, e.g. osteocalcin or calcium binding protein. The calcium binding protein mediates calcium absorption from the gut. The production of 1,25(OH)2D is stimulated by parathyroid hormone (PTH) and decreased by calcium. Risk factors for vitamin D deficiency are premature birth, skin pigmentation, low sunshine exposure, obesity, malabsorption and advanced age. Risk groups are immigrants and the elderly. Vitamin D status is dependent upon sunshine exposure but within Europe, serum 25(OH)D levels are higher in Northern than in Southern European countries. Severe vitamin D deficiency causes rickets or osteomalacia, where the new bone, the osteoid, is not mineralized. Less severe vitamin D deficiency causes an increase of serum PTH leading to bone resorption, osteoporosis and fractures. A negative relationship exists between serum 25(OH)D and serum PTH. The threshold of serum 25(OH)D, where serum PTH starts to rise is about 75nmol/l according to most surveys. Vitamin D supplementation to vitamin D-deficient elderly suppresses serum PTH, increases bone mineral density and may decrease fracture incidence especially in nursing home residents. The effects of 1,25(OH)2D and the vitamin D receptor have been investigated in patients with genetic defects of vitamin D metabolism and in knock-out mouse models. These experiments have demonstrated that for active calcium absorption, longitudinal bone growth and the activity of osteoblasts and osteoclasts both 1,25(OH)2D and the vitamin D receptor are essential. On the other side, bone mineralization can occur by high ambient calcium concentration, so by high doses of oral calcium or calcium infusion. The active metabolite 1,25(OH)2D has its effects through the vitamin D receptor leading to gene expression, e.g. the calcium binding protein or osteocalcin or through a plasma membrane receptor and second messengers such as cyclic AMP. The latter responses are very rapid and include the effects on the pancreas, vascular smooth muscle and monocytes. Muscle cells contain vitamin D receptor and several studies have demonstrated that serum 25(OH)D is related to physical performance. The active metabolite 1,25(OH)2D has an antiproliferative effect and downregulates inflammatory markers. Extrarenal synthesis of 1,25(OH)2D occurs under the influence of cytokines and is important for the paracrine regulation of cell differentiation and function. This may explain that vitamin D deficiency can play a role in the pathogenesis of auto-immune diseases such as multiple sclerosis and diabetes type 1, and cancer. In conclusion, the active metabolite 1,25(OH)2D has pleiotropic effects through the vitamin D receptor and vitamin D responsive elements of many genes and on the other side rapid non-genomic effects through a membrane receptor and second messengers. Active calcium absorption from the gut depends on adequate formation of 1,25(OH)2D and an intact vitamin D receptor. Bone mineralization mainly depends on ambient calcium concentration. Vitamin D metabolites may play a role in the prevention of auto-immune disease and cancer. 10.1016/j.pbiomolbio.2006.02.016
AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY GUIDELINES FOR MANAGEMENT OF GROWTH HORMONE DEFICIENCY IN ADULTS AND PATIENTS TRANSITIONING FROM PEDIATRIC TO ADULT CARE. Yuen Kevin C J,Biller Beverly M K,Radovick Sally,Carmichael John D,Jasim Sina,Pantalone Kevin M,Hoffman Andrew R Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists The development of these guidelines is sponsored by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPG). Recommendations are based on diligent reviews of clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols. The Executive Summary of this 2019 updated guideline contains 58 numbered recommendations: 12 are Grade A (21%), 19 are Grade B (33%), 21 are Grade C (36%), and 6 are Grade D (10%). These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world care of patients. The evidence base presented in the subsequent Appendix provides relevant supporting information for the Executive Summary recommendations. This update contains 357 citations of which 51 (14%) are evidence level (EL) 1 (strong), 168 (47%) are EL 2 (intermediate), 61 (17%) are EL 3 (weak), and 77 (22%) are EL 4 (no clinical evidence). This CPG is a practical tool that practicing endocrinologists and regulatory bodies can refer to regarding the identification, diagnosis, and treatment of adults and patients transitioning from pediatric to adult-care services with growth hormone deficiency (GHD). It provides guidelines on assessment, screening, diagnostic testing, and treatment recommendations for a range of individuals with various causes of adult GHD. The recommendations emphasize the importance of considering testing patients with a reasonable level of clinical suspicion of GHD using appropriate growth hormone (GH) cut-points for various GH-stimulation tests to accurately diagnose adult GHD, and to exercise caution interpreting serum GH and insulin-like growth factor-1 (IGF-1) levels, as various GH and IGF-1 assays are used to support treatment decisions. The intention to treat often requires sound clinical judgment and careful assessment of the benefits and risks specific to each individual patient. Unapproved uses of GH, long-term safety, and the current status of long-acting GH preparations are also discussed in this document. This updated guideline provides evidence-based recommendations regarding the identification, screening, assessment, diagnosis, and treatment for a range of individuals with various causes of adult growth-hormone deficiency (GHD) and patients with childhood-onset GHD transitioning to adult care. The update summarizes the most current knowledge about the accuracy of available GH-stimulation tests, safety of recombinant human GH (rhGH) replacement, unapproved uses of rhGH related to sports and aging, and new developments such as long-acting GH preparations that use a variety of technologies to prolong GH action. Recommendations offer a framework for physicians to manage patients with GHD effectively during transition to adult care and adulthood. Establishing a correct diagnosis is essential before consideration of replacement therapy with rhGH. Since the diagnosis of GHD in adults can be challenging, GH-stimulation tests are recommended based on individual patient circumstances and use of appropriate GH cut-points. Available GH-stimulation tests are discussed regarding variability, accuracy, reproducibility, safety, and contraindications, among other factors. The regimen for starting and maintaining rhGH treatment now uses individualized dose adjustments, which has improved effectiveness and reduced reported side effects, dependent on age, gender, body mass index, and various other individual characteristics. With careful dosing of rhGH replacement, many features of adult GHD are reversible and side effects of therapy can be minimized. Scientific studies have consistently shown rhGH therapy to be beneficial for adults with GHD, including improvements in body composition and quality of life, and have demonstrated the safety of short- and long-term rhGH replacement. = American Association of Clinical Endocrinologists; = American College of Endocrinology; = alpha-2-HS-glycoprotein; = adult-onset growth hormone deficiency; = arginine; = best evidence level; = bone mineral density; = body mass index; = confidence interval; = childhood-onset growth hormone deficiency; = clinical practice guideline; = C-reactive protein; = diabetes mellitus; = dual-energy X-ray absorptiometry; = evidence level; = Food and Drug Administration; = fixed-dose glucagon stimulation test; = Genetics and Neuroendocrinology of Short Stature International Study; = growth hormone; = growth hormone deficiency; = growth hormone-releasing hormone; = glucagon stimulation test; = high-density lipoprotein; = Hypopituitary Control and Complications Study; = insulin-like growth factor-1; = insulin-like growth factor-binding protein; = isolated growth hormone deficiency; = insulin tolerance test; = Kabi International Metabolic Surveillance; = long-acting growth hormone; = low-density lipoprotein; = leukemia inhibitory factor; = multiple pituitary hormone deficiencies; = magnetic resonance imaging; = procollagen type-III amino-terminal pro-peptide; = pituitary hormone deficiencies; = quality of life; = recombinant human growth hormone; = receiver operating characteristic; = relative risk; = subarachnoid hemorrhage; = standard deviation score; = standardized incidence ratio; = secondary neoplasms; = triiodothyronine; = traumatic brain injury; = vitamin D-binding protein; = World Anti-Doping Agency; = weight-based glucagon stimulation test. 10.4158/GL-2019-0405
Vitamin D. Dusso Adriana S,Brown Alex J,Slatopolsky Eduardo American journal of physiology. Renal physiology The vitamin D endocrine system plays an essential role in calcium homeostasis and bone metabolism, but research during the past two decades has revealed a diverse range of biological actions that include induction of cell differentiation, inhibition of cell growth, immunomodulation, and control of other hormonal systems. Vitamin D itself is a prohormone that is metabolically converted to the active metabolite, 1,25-dihydroxyvitamin D [1,25(OH)(2)D]. This vitamin D hormone activates its cellular receptor (vitamin D receptor or VDR), which alters the transcription rates of target genes responsible for the biological responses. This review focuses on several recent developments that extend our understanding of the complexities of vitamin D metabolism and actions: the final step in the activation of vitamin D, conversion of 25-hydroxyvitamin D to 1,25(OH)(2)D in renal proximal tubules, is now known to involve facilitated uptake and intracellular delivery of the precursor to 1alpha-hydroxylase. Emerging evidence using mice lacking the VDR and/or 1alpha-hydroxylase indicates both 1,25(OH)(2)D(3)-dependent and -independent actions of the VDR as well as VDR-dependent and -independent actions of 1,25(OH)(2)D(3). Thus the vitamin D system may involve more than a single receptor and ligand. The presence of 1alpha-hydroxylase in many target cells indicates autocrine/paracrine functions for 1,25(OH)(2)D(3) in the control of cell proliferation and differentiation. This local production of 1,25(OH)(2)D(3) is dependent on circulating precursor levels, providing a potential explanation for the association of vitamin D deficiency with various cancers and autoimmune diseases. 10.1152/ajprenal.00336.2004
Vitamin D across growth hormone (GH) disorders: From GH deficiency to GH excess. Ciresi A,Giordano C Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society The interplay between vitamin D and the growth hormone (GH)/insulin-like growth factor (IGF)-I system is very complex and to date it is not fully understood. GH directly regulates renal 1 alpha-hydroxylase activity, although the action of GH in modulating vitamin D metabolism may also be IGF-I mediated. On the other hand, vitamin D increases circulating IGF-I and the vitamin D deficiency should be normalized before measurement of IGF-I concentrations to obtain reliable and unbiased IGF-I values. Indeed, linear growth after treatment of nutritional vitamin D deficiency seems to be mediated through activation of the GH/IGF-I axis and it suggests an important role of vitamin D as a link between the proliferating cartilage cells of the growth plate and GH/IGF-I secretion. Vitamin D levels are commonly lower in patients with GH deficiency (GHD) than in controls, with a variable prevalence of insufficiency or deficiency, and this condition may worsen the already known cardiovascular and metabolic risk of GHD, although this finding is not common to all studies. In addition, data on the impact of GH treatment on vitamin D levels in GHD patients are quite conflicting. Conversely, in active acromegaly, a condition characterized by a chronic GH excess, both increased and decreased vitamin D levels have been highlighted, and the interplay between vitamin D and the GH/IGF-I axis becomes even more complicated when we consider the acromegaly treatment, both medical and surgical. The current review summarizes the available data on vitamin D in the main disorders of the GH/IGF-I axis, providing an overview of the current state of the art. 10.1016/j.ghir.2017.02.002