Impact of androgens, growth hormone, and IGF-I on bone and muscle in male mice during puberty.

The interaction between androgens and GH/IGF-I was studied in male GHR gene disrupted or GHRKO and WT mice during puberty. Androgens stimulate trabecular and cortical bone modeling and increase muscle mass even in the absence of a functional GHR. GHR activation seems to be the main determinant of radial bone expansion, although GH and androgens are both necessary for optimal stimulation of periosteal growth during puberty. INTRODUCTION: Growth hormone (GH) is considered to be a major regulator of postnatal skeletal growth, whereas androgens are considered to be a key regulator of male periosteal bone expansion. Moreover, both androgens and GH are essential for the increase in muscle mass during male puberty. Deficiency or resistance to either GH or androgens impairs bone modeling and decreases muscle mass. The aim of the study was to investigate androgen action on bone and muscle during puberty in the presence and absence of a functional GH/insulin-like growth factor (IGF)-I axis. MATERIALS AND METHODS: Dihydrotestosterone (DHT) or testosterone (T) were administered to orchidectomized (ORX) male GH receptor gene knockout (GHRKO) and corresponding wildtype (WT) mice during late puberty (6-10 weeks of age). Trabecular and cortical bone modeling, cortical strength, body composition, IGF-I in serum, and its expression in liver, muscle, and bone were studied by histomorphometry, pQCT, DXA, radioimmunoassay and RT-PCR, respectively. RESULTS: GH receptor (GHR) inactivation and low serum IGF-I did not affect trabecular bone modeling, because trabecular BMD, bone volume, number, width, and bone turnover were similar in GHRKO and WT mice. The normal trabecular phenotype in GHRKO mice was paralleled by a normal expression of skeletal IGF-I mRNA. ORX decreased trabecular bone volume significantly and to a similar extent in GHRKO and WT mice, whereas DHT and T administration fully prevented trabecular bone loss. Moreover, DHT and T stimulated periosteal bone formation, not only in WT (+100% and +100%, respectively, versus ORX + vehicle [V]; p < 0.05), but also in GHRKO mice (+58% and +89%, respectively, versus ORX + V; p < 0.05), initially characterized by very low periosteal growth. This stimulatory action on periosteal bone resulted in an increase in cortical thickness and occurred without any treatment effect on serum IGF-I or skeletal IGF-I expression. GHRKO mice also had reduced lean body mass and quadriceps muscle weight, along with significantly decreased IGF-I mRNA expression in quadriceps muscle. DHT and T equally stimulated muscle mass in GHRKO and WT mice, without any effect on muscle IGF-I expression. CONCLUSIONS: Androgens stimulate trabecular and cortical bone modeling and increase muscle weight independently from either systemic or local IGF-I production. GHR activation seems to be the main determinant of radial bone expansion, although GHR signaling and androgens are both necessary for optimal stimulation of periosteal growth during puberty.     

Growth hormone protects against ovariectomy‐induced bone loss in states of low circulating insulin‐like growth factor (IGF‐1)

Early after estrogen loss in postmenopausal women and ovariectomy (OVX) of animals, accelerated endosteal bone resorption leads to marrow expansion of long bone shafts that reduce mechanical integrity. Both growth hormone (GH) and insulin‐like growth factor (IGF‐1) are potent regulators of bone remodeling processes. To investigate the role of the GH/IGF‐1 axis with estrogen deficiency, we used the liver IGF‐1‐deficient (LID) mouse. Contrary to deficits in controls, OVX of LID mice resulted in maintenance of cortical bone mechanical integrity primarily owing to an enhanced periosteal expansion affect on cross‐sectional structure (total area and cortical width). The serum balance in LID that favors GH over IGF‐1 diminished the effects of ablated ovarian function on numbers of osteoclast precursors in the marrow and viability of osteocytes within the cortical matrix and led to less endosteal resorption in addition to greater periosteal bone formation. Interactions between estrogen and the GH/IGF‐1 system as related to bone remodeling provide a pathway to minimize degeneration of bone tissue structure and osteoporotic fracture. © 2010 American Society for Bone and Mineral Research     

Elevated serum IGF‐1 levels synergize PTH action on the skeleton only when the tissue IGF‐1 axis is intact

There is growing evidence that insulin‐like growth factor 1 (IGF‐1) and parathyroid hormone (PTH) have synergistic actions on bone and that part of the anabolic effects of PTH is mediated by local production of IGF‐1. In this study we analyzed the skeletal response to PTH in mouse models with manipulated endocrine or autocrine/paracrine IGF‐1. We used mice carrying a hepatic IGF‐1 transgene (HIT), which results in a threefold increase in serum IGF‐1 levels and normal tissue IGF‐1 expression, and Igf1 null mice with blunted IGF‐1 expression in tissues but threefold increases in serum IGF‐1 levels (KO‐HIT). Evaluation of skeletal growth showed that elevations in serum IGF‐1 in mice with Igf1 gene ablation in all tissues except the liver (KO‐HIT) resulted in a restoration of skeletal morphology and mechanical properties by adulthood. Intermittent PTH treatment of adult HIT mice resulted in increases in serum osteocalcin levels, femoral total cross‐sectional area, cortical bone area and cortical bone thickness, as well as bone mechanical properties. We found that the skeletal response of HIT mice to PTH was significantly higher than that of control mice, suggesting synergy between IGF‐1 and PTH on bone. In sharp contrast, although PTH‐treated KO‐HIT mice demonstrated an anabolic response in cortical and trabecular bone compartments compared with vehicle‐treated KO‐HIT mice, their response was identical to that of PTH‐treated control mice. We conclude that (1) in the presence of elevated serum IGF‐1 levels, PTH can exert an anabolic response in bone even in the total absence of tissue IGF‐1, and (2) elevations in serum IGF‐1 levels synergize PTH action on bone only if the tissue IGF‐1 axis is intact. Thus enhancement of PTH anabolic actions depends on tissue IGF‐1. © 2010 American Society for Bone and Mineral Research.     

Caloric Restriction Decreases Cortical Bone Mass but Spares Trabecular Bone in the Mouse Skeleton: Implications for the Regulation of Bone Mass by Body Weight

Introduction: Body weight is positively correlated with bone mass and density, and both muscle mass and body fat are thought to play a role in regulating bone metabolism. We examined bone metabolism in calorically restricted mice to determine how alterations in soft tissue mass affect bone mass, density, and strength. Materials and Methods: Caloric restriction (CR) was initiated in male mice at 14 wk of age at 10% restriction, increased to 25% restriction at 15 wk, and then increased to 40% restriction at 16 wk, where it was maintained until 24 wk of age when the study was terminated. Control mice were fed ad libitum (AL). Body composition, BMD, and BMC were measured by DXA, BMD and BMC in the femoral metaphysis were measured by pQCT, femora were tested in three‐point bending, serum leptin and IGF‐1 were measured using immunoassay, and osteoblast and osteoclast numbers were determined using histomorphometry. Results: Body weight, lean mass, fat mass, percent body fat, serum leptin, and serum IGF‐1 were all significantly lower in CR mice than AL mice. Whole body BMC and BMD did not differ significantly between the two groups. Femur BMC, BMD, cortical thickness, and fracture strength decreased significantly in CR mice, but trabecular bone volume fraction in the femur did not change with food restriction. Vertebral cortical thickness also decreased with caloric restriction, whereas spine BMC, BMD, and trabecular bone volume fraction were significantly increased with caloric restriction. Conclusions: Caloric restriction and its related weight reduction are associated with marked decreases in lean mass, fat mass, serum leptin and IGF‐1, and cortical bone mass. Consistent with the opposite effects of leptin on cortical and cancellous bone, trabecular bone mass is spared during food restriction.     

Sexual dimorphism in cortical bone size and strength but not density is determined by independent and time‐specific actions of sex steroids and IGF‐1: Evidence from pubertal mouse models

Although it is well established that males acquire more bone mass than females, the underlying mechanism and timing of this sex difference remain controversial. The aim of this study was to assess the relative contribution of sex steroid versus growth hormone–insulin‐like growth factor 1 (GH–IGF‐1) action to pubertal bone mass acquisition longitudinally in pubertal mice. Radial bone expansion peaked during early puberty (3 to 5 weeks of age) in male and female mice, with significantly more expansion in males than in females (+40%). Concomitantly, in 5 week old male versus female mice, periosteal and endocortical bone formation was higher (+70%) and lower (?47%), respectively, along with higher serum IGF‐1 levels during early puberty in male mice. In female mice, ovariectomy increased radial bone expansion during early puberty as well as the endocortical perimeter. In male mice, orchidectomy reduced radial bone expansion only during late puberty (5 to 8 weeks of age), whereas combined androgen and estrogen deficiency modestly decreased radial bone expansion during early puberty, accompanied by lower IGF‐1 levels. GHRKO mice with very low IGF‐1 levels, on the other hand, showed limited radial bone expansion and no skeletal dimorphism. From these data we conclude that skeletal sexual dimorphism is established during early puberty and depends primarily on GH–IGF‐1 action. In males, androgens and estrogens have stimulatory effects on bone size during late and early puberty, respectively. In females, estrogens limit bone size during early puberty. These longitudinal findings in mice provide strong evidence that skeletal dimorphism is determined by independent and time‐specific effects of sex steroids and IGF‐1. © 2010 American Society for Bone and Mineral Research     

Serum IGF‐1 Determines Skeletal Strength by Regulating Subperiosteal Expansion and Trait Interactions

Strong correlations between serum IGF‐1 levels and fracture risk indicate that IGF‐1 plays a critical role in regulating bone strength. However, the mechanism by which serum IGF‐1 regulates bone structure and fracture resistance remains obscure and cannot be determined using conventional approaches. Previous analysis of adult liver‐specific IGF‐1–deficient (LID) mice, which exhibit 75% reductions in serum IGF‐1 levels, showed reductions in periosteal circumference, femoral cross‐sectional area, cortical thickness, and total volumetric BMD. Understanding the developmental sequences and the resultant anatomical changes that led to this adult phenotype is the key for understanding the complex relationship between serum IGF‐1 levels and fracture risk. Here, we identified a unique developmental pattern of morphological and compositional traits that contribute to bone strength. We show that reduced bone strength associated with low levels of IGF‐1 in serum (LID mice) result in impaired subperiosteal expansion combined with impaired endosteal apposition and lack of compensatory changes in mineralization throughout growth and aging. We show that serum IGF‐1 affects cellular activity differently depending on the cortical surface. Last, we show that chronic reductions in serum IGF‐1 indirectly affect bone strength through its effect on the marrow myeloid progenitor cell population. We conclude that serum IGF‐1 not only regulates bone size, shape, and composition during ontogeny, but it plays a more fundamental role—that of regulating an individual's ability to adapt its bone structure to mechanical loads during growth and development.     

Impact of Pregnancy‐Associated Plasma Protein‐A Deletion on the Adult Murine Skeleton

Introduction : The metalloproteinase, pregnancy‐associated plasma protein‐A (PAPP‐A) functions to enhance local insulin‐like growth factor (IGF)‐I bioavailability through cleavage of inhibitory IGF binding proteins. Because IGF‐I is an important regulator of skeletal growth and remodeling and PAPP‐A is highly expressed by osteoblastic cells, we hypothesized that, in the absence of PAPP‐A, bone physiology would be compromised because of a blunting of local IGF‐I action even in the presence of normal circulating IGF‐I levels. Materials and Methods : pQCT, μCT, histomorphometry, and mechanical strength testing were performed on bones from PAPP‐A knockout (KO) mice and wildtype (WT) littermates at 2–12 mo of age. IGF‐I levels and bone formation and resorption markers were determined in sera from these animals. Results : Volumetric BMD in PAPP‐A KO mice measured by pQCT at the femoral midshaft, which is primarily cortical bone, was 10% less than WT at 2 mo. This difference was maintained at 4, 6, and 12 mo. Cortical thickness at this site was similarly decreased. On the other hand, trabecular bone at the distal femur (pQCT) and in the tibia (μCT) showed age‐progressive decreases in bone volume fraction in PAPP‐A KO compared with WT mice. Tibial μCT indicated a 46% relative decrease in trabecular bone volume/total volume (BV/TV) and a 28% relative decrease in trabecular thickness in PAPP‐A KO compared with WT mice at 6 mo. These trabecular deficiencies in PAPP‐A KO mice corresponded to a weakening of the bone. Serum markers and bone histomorphometry indicated that the primary impact of PAPP‐A is on skeletal remodeling resulting in a state of low‐turnover osteopenia in adult PAPP‐A KO mice. Circulating IGF‐I levels were not altered in PAPP‐A KO mice. Conclusions : PAPP‐A is a bone growth regulatory factor in vivo and, in its absence, mice show skeletal insufficiency in mass, density, architecture, and strength. The data suggest a primary role for PAPP‐A in modulating local IGF bioavailability for trabecular bone remodeling.     

Growth hormone mediates pubertal skeletal development independent of hepatic IGF‐1 production

Deficiencies in either growth hormone (GH) or insulin‐like growth factor 1 (IGF‐1) are associated with reductions in bone size during growth in humans and animal models. Liver‐specific IGF‐1‐deficient (LID) mice, which have 75% reductions in serum IGF‐1, were created previously to separate the effects of endocrine (serum) IGF‐1 from autocrine/paracrine IGF‐1. However, LID mice also have two‐ to threefold increases in GH, and this may contribute to the observed pubertal skeletal phenotype. To clarify the role of GH in skeletal development under conditions of significantly reduced serum IGF‐1 levels (but normal tissue IGF‐1 levels), we studied the skeletal response of male LID and control mice to GH inhibition by pegvisomant from 4 to 8 weeks of age. Treatment of LID mice with pegvisomant resulted in significant reductions in body weight, femur length (Le), and femur total area (Tt.Ar), as well as further reductions in serum IGF‐1 levels by 8 weeks of age, compared with the mean values of vehicle‐treated LID mice. Reductions in both Tt.Ar and Le were proportional after treatment with pegvisomant. On the other hand, the relative amount of cortical tissue formed (RCA) in LID mice treated with pegvisomant was significantly less than that in both vehicle‐treated LID and control mice, indicating that antagonizing GH action, either directly (through GH receptor signaling inhibition) or indirectly (through further reductions in serum/tissue IGF‐1 levels), results in disproportionate reductions in the amount of cortical bone formed. This resulted in bones with significantly reduced mechanical properties (femoral whole‐bone stiffness and work to failure were markedly decreased), suggesting that compensatory increases of GH in states of IGF‐1 deficiency (LID mice) act to protect against a severe inhibition of bone modeling during growth, which otherwise would result in bones that are too weak for normal and/or extreme loading conditions. © 2011 American Society for Bone and Mineral Research.     

An O‐Glycosylation of Fibronectin Mediates Hepatic Osteodystrophy Through α4β1 Integrin

Patients with cholestatic liver disease experience increased fracture risk. Higher circulating levels of a fibronectin isoform called oncofetal fibronectin (oFN) were detected in a subset of such patients. Administering this isoform to mice suppresses osteoblast differentiation and diminishes bone mineral density in vivo, suggesting it is responsible for bone loss in cholestatic liver disease. The aim of this study was to define the mechanism by which oFN affects osteoblast function and evaluate possible modifiers in experimental hepatic osteodystrophy. The fibronectin isoform oFN is characterized by the presence of various glycosylations. In line with this, adding oFN that underwent enzymatic O‐deglycosylation to osteoblasts normalized nodule formation in vitro. Of three possible O‐glycosylation sites in oFN, only a mutation at AA 33 of the variable region or binding of this glycosylated site with an antibody normalized osteoblast differentiation. Because the responsible site is located in the variable region of fibronectin, which binds to α4β1 or α4β7 integrins, these integrins were evaluated. We show that integrin α4β1 mediates the inhibitory effect of oFN both in vitro as well as in vivo. In a hepatic osteodystrophy mouse model, we demonstrate that liver fibrosis is associated with increased circulating oFN and diminished BMD. In addition, trabecular bone loss induced by oFN injection or fibrosis induction could be prevented by either administering an antibody that binds to α4 integrin (PS/2) or the CS1 peptide, which contains a binding site for α4β1 integrin. In summary, oFN inhibits osteoblast activity. This is because of an O‐glycosylation in the variable region that results in decreased integrin‐mediated signaling. This deleterious effect can be thwarted by binding α4β1 integrin. Thus, we have characterized the defect and the receptor mediating bone loss in patients with hepatic osteodystrophy and evaluated possible therapeutic interventions in a murine model. © 2016 American Society for Bone and Mineral Research.     

Growth hormone regulates the balance between bone formation and bone marrow adiposity

Cancellous bone decreases and bone marrow fat content increases with age. Osteoblasts and adipocytes are derived from a common precursor, and growth hormone (GH), a key hormone in integration of energy metabolism, regulates the differentiation and function of both cell lineages. Since an age‐related decline in GH is associated with bone loss, we investigated the relationship between GH and bone marrow adiposity in hypophysectomized (HYPOX) rats and in mice with defects in GH signaling. HYPOX dramatically reduced body weight gain, bone growth and mineralizing perimeter, serum insulin‐like growth factor 1 (IGF‐1) levels, and mRNA levels for IGF‐1 in liver and bone. Despite reduced body mass and adipocyte precursor pool size, HYPOX resulted in a dramatic increase in bone lipid levels, as reflected by increased bone marrow adiposity and bone triglyceride and cholesterol content. GH replacement normalized bone marrow adiposity and precursor pool size, as well as mineralizing perimeter in HYPOX rats. In contrast, 17β ‐estradiol, IGF‐1, thyroxine, and cortisone were ineffective. Parathyroid hormone (PTH) reversed the inhibitory effects of HYPOX on mineralizing perimeter but had no effect on adiposity. Finally, bone marrow adiposity was increased in mice deficient in GH and IGF‐1 but not in mice deficient in serum IGF‐1. Taken together, our findings indicate that the reciprocal changes in bone and fat mass in GH signaling‐deficient rodents are not directly coupled with one another. Rather, GH enhances adipocyte as well as osteoblast precursor pool size. However, GH increases osteoblast differentiation while suppressing bone marrow lipid accumulation. © 2010 American Society for Bone and Mineral Research     

Fetal Growth Velocity,Size in Early Life and Adolescence,and Prediction of Bone Mass: Association to the GH–IGF Axis

Poor growth in early life is associated with numerous adverse outcomes later in life. In 123 adolescents 16–18 yr of age, the previous findings of a positive relation between size in early life and later bone mass was confirmed. These associations were mediated by the current height and weight, but it was not confirmed that alterations of the GH–IGF axis cause this. Introduction: Numerous studies have found associations between low birth weight and disease later in life, including decreased bone mass. Materials and Methods: A longitudinal cohort of 16‐ to 19‐year‐old adolescents (n = 123) with data on third trimester fetal growth velocity (FGV) was assessed by serial ultrasound measurements, birth weight (BW), and weight at 1 yr. A follow‐up study included DXA scan, anthropometric measurements, and measurements of the growth hormone (GH) –IGF‐I axis in a representative subpopulation (n = 30). Results: BW and weight at 1 yr were positively associated with whole body BMC (p = 0.02 and p < 0.0001, respectively), lumbar spine BMC (p = 0.001 and p = 0.03, respectively), and lumbar spine BMD (p = 0.04). After correction for adolescent height and weight, no association remained significant. There was no relation between IGF‐I and IGF binding protein 3 (IGFBP‐3) levels in adolescence and size in early life or bone mass. In the subpopulation, GH secretion (median, 2.58 versus 4.05), GH pulse mass (median, 10.7 versus 19.4 mU/liter), and total GH (median, 74.9 versus 108.8 mU/liter/12 h) were decreased in the small for gestational age (SGA) group compared with the appropriate for gestational age (AGA) group; this did not reach statistical significance. Likewise, there were no differences in IGF‐I, IGF‐II, and IGFBP‐1, ?2, and ?3 levels between the SGA and AGA groups. A statistically significant positive association between FGV and adolescent IGF‐II was found (B = 199.9, p = 0.006). Significant negative associations between GH measurement and BMC, as well as BMD, were found (B = ?0.008, p = 0.005 and B = ?0.008, p = 0.006, respectively). Conclusions: This study confirms the previous findings of a positive relation between size in early life and later BMC, an association apparently independent of the distal part of the GH/IGF‐I axis. However, this association may be mediated mainly by postnatal growth determining size of the skeletal envelope rather than an effect of fetal programming on bone mass per se.     

A structural approach to the assessment of fracture risk in children and adolescents with chronic kidney disease

Children with chronic kidney disease (CKD) have multiple risk factors for impaired accretion of trabecular and cortical bone. CKD during childhood poses an immediate fracture risk and compromises adult bone mass, resulting in significantly greater skeletal fragility throughout life. High-turnover disease initially results in thickened trabeculae, with greater bone volume. As disease progresses, resorption cavities dissect trabeculae, connectivity degrades, and bone volume decreases. Increased bone turnover also results in increased cortical porosity and decreased cortical thickness. Dual-energy X-ray absorptiometry (DXA)-based measures of bone mineral density (BMD) are derived from the total bone mass within the projected bone area (g/cm²), concealing distinct disease effects in trabecular and cortical bone. In contrast, peripheral quantitative computed tomography (pQCT) estimates volumetric BMD (vBMD, g/cm³), distinguishes between cortical and trabecular bone, and provides accurate estimates of cortical dimensions. Recent data have confirmed that pQCT measures of cortical vBMD and thickness provide substantially greater fracture discrimination in adult dialysis patients compared with hip or spine DXA. The following review considers the structural effects of renal osteodystrophy as it relates to fracture risk and the potential advantages and disadvantages of DXA and alternative measures of bone density, geometry, and microarchitecture, such as pQCT, micro-CT (μCT), and micro magnetic resonance imaging (μMRI) for fracture risk assessment.     

Special aspects of renal osteodystrophy in children

Renal osteodystrophy represents a spectrum of skeletal lesions that range from high-turnover to low-turnover bone disease. Similar factors are involved in the pathogenesis of renal osteodystrophy in adult and pediatric patients with chronic kidney disease (CKD). However, growth retardation and the development of bone deformities are specific complications that occurred in pediatric patients with CKD. Metabolic acidosis, renal osteodystrophy, malnutrition, and disturbances in the insulin growth factor (IGF)/growth hormone (GH) are among the main factors involved and they are discussed briefly in this article. In addition to disturbances in bone remodeling, longitudinal bone growth occurs at the growth plate cartilage by endochondral ossification. Although young rats with experimental CKD have growth retardation, the characteristics of the growth plate are markedly different between animals with severe secondary hyperparathyroidism and those with calcium-induced adynamic osteodystrophy. These disturbances may suggest potential molecular mechanisms by which endochondral bone formation may be altered in renal failure, consequently leading to growth retardation.     

The Role of GH/IGF-I-Mediated Mechanisms in Sex Differences in Cortical Bone Size in Mice

Cortical bone dimensions are important determinants of bone strength. Gender differences in cortical bone size caused by greater periosteal expansion in males than in females during the pubertal growth spurt are well established both in humans and in experimental animal models. However, the mechanism by which gender influences cortical bone size is still a matter of investigation. The role of androgens and estrogen in pubertal bone growth has been examined in human disorders as well as animal models, such as gonadectomized or sex steroid receptor knockout mice. Based on the findings that growth hormone (GH) and insulin-like growth factor I (IGF-I) are major regulators of postnatal skeletal growth, we and others have predicted that sex hormones interact with the GH/IGF-I axis to regulate cortical bone size. However, studies conflict as to whether estrogen and androgens impact cortical bone size through the canonical pathway, through GH without IGF-I mediation, through IGF-I without GH stimulation, or independent of GH/IGF-I. We review recent data on the impact of sex steroids and components of the GH/IGF axis on sexual dimorphism in bone size. While the GH/IGF-I axis is a major player in regulating peak bone size, the relative contribution of GH/IGF-dependent mechanisms to sex differences in cortical bone size remains to be established.     

Overexpression of Human Hydroxysteroid (17β) Dehydrogenase 2 Induces Disturbance in Skeletal Development in Young Male Mice

To understand the function of human hydroxysteroid (17β) dehydrogenase 2 (HSD17B2) in the peripheral tissues in vivo, we studied the bone development in transgenic male mice ubiquitously expressing human HSD17B2. Bones of HSD17B2TG and WT males (26 days and 2 and 6 mo old) were analyzed by pQCT and histomorphometry, and data were correlated with serum testosterone (T), IGF‐I, and osteocalcin concentrations. At the age of 26 days, the body weight of HSD17B2TG males was significantly lower, and the lengths of the tibia and femur of the HSD17B2TG males were significantly shorter. Histomorphometric and pQCT analyses showed lower trabecular and cortical BMD, a markedly smaller area of cortical bone at both of the diaphyses, and a smaller percentage of trabecular bone volume and thickness in the HSD17B2TG males. The data suggested slower osteoblast differentiation and a slower bone formation rate of femoral diaphysis on the periosteum but faster on the endocortical surface in HSD17B2TG males. The altered bone parameters were correlated with low serum T, IGF‐I, and osteocalcin concentrations at the prepubertal age. Interestingly, after puberty, the bone parameters analyzed in the adult HSD17B2TG males were mostly normal, consistent with the normal body weight and normalized serum concentrations of IGF‐I and T. In conclusion, HSD17B2TG males presented with growth retardation and a decreased bone formation rate at prepubertal age. These changes were associated with lower serum IGF‐I, osteocalcin, and T concentrations. It is concluded that the enforced constitutive expression of HSD17B2 disturbs the coordinated action of IGF‐I and sex steroids essential for pubertal bone growth.     

Caloric restriction leads to high marrow adiposity and low bone mass in growing mice

The effects of caloric restriction (CR) on the skeleton are well studied in adult rodents and include lower cortical bone mass but higher trabecular bone volume. Much less is known about how CR affects bone mass in young, rapidly growing animals. This is an important problem because low caloric intake during skeletal acquisition in humans, as in anorexia nervosa, is associated with low bone mass, increased fracture risk, and osteoporosis in adulthood. To explore this question, we tested the effect of caloric restriction on bone mass and microarchitecture during rapid skeletal growth in young mice. At 3 weeks of age, we weaned male C57Bl/6J mice onto 30% caloric restriction (10% kcal/fat) or normal diet (10% kcal/fat). Outcomes at 6 (n = 4/group) and 12 weeks of age (n = 8/group) included body mass, femur length, serum leptin and insulin‐like growth factor 1 (IGF‐1) values, whole‐body bone mineral density (WBBMD, g/cm²), cortical and trabecular bone architecture at the midshaft and distal femur, bone formation and cellularity, and marrow fat measurement. Compared with the normal diet, CR mice had 52% and 88% lower serum leptin and 33% and 39% lower serum IGF‐1 at 6 and 12 weeks of age (p < .05 for all). CR mice were smaller, with lower bone mineral density, trabecular, and cortical bone properties. Bone‐formation indices were lower, whereas bone‐resorption indices were higher (p < .01 for all) in CR versus normal diet mice. Despite having lower percent of body fat, bone marrow adiposity was elevated dramatically in CR versus normal diet mice (p < .05). Thus we conclude that caloric restriction in young, growing mice is associated with impaired skeletal acquisition, low leptin and IGF‐1 levels, and high marrow adiposity. These results support the hypothesis that caloric restriction during rapid skeletal growth is deleterious to cortical and trabecular bone mass and architecture, in contrast to potential skeletal benefits of CR in aging animals. © 2010 American Society for Bone and Mineral Research.     

Hyperbilirubinemia is not a major contributing factor to altered bone mineral density in patients with chronic liver disease.

Reduced bone density is commonly encountered in patients with chronic liver disease. Prior studies have shown that unconjugated bilirubin inhibits osteoblast activity and function in vitro and in animal models of bone mineralization. To determine whether hyperbilirubinemia promotes the development of hepatic osteodystrophy, bone mineral density (BMD) was measured by dual energy X-ray absorptiometry in a cohort of 86 consecutive patients with chronic liver disease referred for liver transplant evaluation. The mean age of the study population was 52 years (range, 22-73), in which 52% were female and 90% were white. Average bone density values were significantly lower than expected for age, race, and sex, with Z-scores for the femoral neck and spine of -0.50 (95% confidence interval [CI] -0.63 to -0.37; p=0.0003) and -0.69 (95% CI -0.85 to -0.52; p=0.0001), respectively. Sixty-one subjects (71%) exhibited reduced BMD (T-score of femoral neck or spine相似文献   

Effect of long-term growth hormone treatment on bone mass and bone metabolism in growth hormone-deficient men.

Long-term GH treatment in GH-deficient men resulted in a continuous increase in bone turnover as shown by histomorphometry. BMD continuously increased in all regions of interest, but more in the regions with predominantly cortical bone. INTRODUCTION: Adults with growth hormone (GH) deficiency have reduced rates of bone turnover and subnormal BMD. GH treatment is effective in enhancing bone turnover as shown by biochemical markers and bone histomorphometric studies. However, it is uncertain whether long-term treatment will result in higher bone mass. In this study, we present BMD and histomorphometric data on 5 years of GH treatment in GH-deficient men. MATERIALS AND METHODS: Thirty-eight adult men with childhood onset GH deficiency (20-35 years) were included in the study. Twenty-six of these had multiple pituitary hormone deficiencies and were on stable conventional hormone replacement. BMC (total body) and BMD (lumbar spine and hip) were measured before and after 1, 2, 3, 4, and 5 years of treatment. BMD in various regions of the total body was calculated by computer software (head, trunk, arms, and legs). Transiliac bone biopsies were obtained before and after 1 and 5 years of GH treatment. RESULTS: Total body BMC increased 18% after 5 years of treatment. This increase was observed in all regions of interest: head, 13.7%; trunk, 27.8%; arms, 24.4%; legs, 13.8%. BMD also increased in all separately measured regions: lumbar spine, 9%; femoral neck, 11%; femoral trochanter, 16%. Lumbar spine area significantly increased (p=0.0002). Histomorphometric data showed increased osteoid surface (p<0.02), osteoid volume (p<0.01), and activation frequency (p<0.006), but trabecular bone volume did not increase significantly. Qualitative assessment of the cortical bone showed endosteal and periosteal bone formation. CONCLUSIONS: In conclusion, GH considerably increases BMC after long-term treatment. The combination of BMD and histomorphometric data suggests that GH has a greater effect on cortical than on trabecular bone.