Bone Mass Accrual Research Articles

Reduced Bone Mass Accrual in Swim-Trained Prepubertal Mice

Clinical studies have found that nonimpact non-weight-bearing sports are associated with normal to low bone mineral densities. The objective of this study was to quantify structural bone adaptations of the mouse to swimming using in vivo micro-computed tomography. Prepubertal female mice underwent a 16-wk training program, in which they swam for progressively increasing durations up to 55 min for 5 d·wk(-1). A sham group was subjected to the water, but they did not perform the swimming exercise. Skeletal sites that were assessed included the proximal humerus, lumbar spine, midshaft and distal femur, proximal tibia, and the skull. Normal bone mass accrual was suppressed in the swim group during the initial 4 wk of training, during rapid growth. Swim mice gained 31.8% less (P = 0.001) and 16.7% less (P = 0.003) trabecular bone volume at the proximal tibial and humeral metaphyses, respectively. In the 12 wk that followed, low trabecular bone volume persisted in the swimmers (P < 0.001). Trabecular properties were reduced primarily at the metaphysis but not the epiphysis, and cortical bone was reduced at both compartments. At the femoral midshaft, swim mice had less cortical porosity (SHAM = 32% ± 3% vs SWIM = 22% ± 3%, P = 0.043). Despite the bone microarchitectural adaptations, swimming did not induce detectable changes to macroarchitecture, including bone length and total volume. Tissue mineral density was unaffected by swimming, suggesting that material changes did not occur. In conclusion, the response of prepubertal mice to swimming was adaptation at the bone microarchitectural level and resulted in an altered topology that was sustained until the end of the training program. Low bone mass was systemic throughout the mouse, with the largest depressions in the hindlimbs and spine.

Dietary patterns associated with fat and bone mass in young children

Obesity and osteoporosis have origins in childhood, and both are affected by dietary intake and physical activity. However, there is little information on what constitutes a diet that simultaneously promotes low fat mass and high bone mass accrual early in life. Our objective was to identify dietary patterns related to fat and bone mass in children during the age period of 3.8-7.8 y. A total of 325 children contributed data from 13 visits over 4 separate study years (age ranges: 3.8-4.8, >4.8-5.8, >5.8-6.8, and >6.8-7.8 y). We performed reduced-rank regression to identify dietary patterns related to fat mass and bone mass measured by dual-energy X-ray absorptiometry for each study year. Covariables included race, sex, height, weight, energy intake, calcium intake, physical activity measured by accelerometry, and time spent viewing television and playing outdoors. A dietary pattern characterized by a high intake of dark-green and deep-yellow vegetables was related to low fat mass and high bone mass; high processed-meat intake was related to high bone mass; and high fried-food intake was related to high fat mass. Dietary pattern scores remained related to fat mass and bone mass after all covariables were controlled for (P < 0.001-0.03). Beginning at preschool age, diets rich in dark-green and deep-yellow vegetables and low in fried foods may lead to healthy fat and bone mass accrual in young children.

The Central Regulation of Bone Mass, the First Link between Bone Remodeling and Energy Metabolism

Abstract Evolutionary consideration and clinical observations led us to hypothesize 10 yr ago that there may be a coordinated regulation, endocrine in nature, of bone remodeling and energy metabolism. The existence of this coordinated regulation is motivated by the energetic needs of the skeleton; therefore, this regulation relies on hormones that appear during evolution with the skeleton, not with energy metabolism. Leptin is such a hormone, and it is a critical regulator of bone mass as well as of appetite and energy expenditure. This review goes over the anatomical route and molecular pathways used by leptin to inhibit both bone mass accrual and appetite through its signaling in the brain.

La double vie de la sérotonine ou quand la génétique découvre la physiologie

During the last 20 years, the emergence of sophisticated genetic tools has extraordinarily improved our understanding of a large number of physiological functions, among which the physiology of the skeleton. Bone, recently described as an endocrine organ, has the ability to constantly renew itself through bone remodeling, which requires a constant supply of energy. Hence, we hypothesized that there must be a coregulation of bone mass and energy metabolism, and focused on leptin, an adipocyte-derived hormone, which regulates both energy metabolism and bone remodeling through a central relay. Through a careful analysis of leptin neuronal targets, we unraveled that leptin regulation of bone mass occurs indirectly by inhibiting serotonin release and synthesis in neurons of the brainstem. Surprisingly, we observed that the other pool of serotonin, produced in enterochromaffin cells of the duodenum, negatively regulates bone mass accrual. Thus, serotonin is a molecule with two distinct functional identities depending on its site of synthesis. Finally, a recent study provides a proof of principle that inhibiting gut-derived serotonin (GDS) biosynthesis could become a new anabolic treatment for osteoporosis. double dagger.

Bone mineral density in partially recovered early onset anorexic patients - a follow-up investigation

Background and aimsThere still is a lack of prospective studies on bone mineral development in patients with a history of early onset Anorexia nervosa (AN). Therefore we assessed associations between bone mass accrual and clinical outcomes in a former clinical sample. In addition to an expected influence of regular physical activity and hormone replacement therapy, we explored correlations with nutritionally dependent hormones.Methods3-9 years (mean 5.2 ± 1.7) after hospital discharge, we re-investigated 52 female subjects with a history of early onset AN. By means of a standardized approach, we evaluated the general outcome of AN. Moreover, bone mineral content (BMC) and bone mineral density (BMD) as well as lean and fat mass were measured by dual-energy x-ray absorptiometry (DXA). In a substudy, we measured the serum concentrations of leptin and insulin-like growth factor-I (IGF-I).ResultsThe general outcome of anorexia nervosa was good in 50% of the subjects (BMI ≥ 17.5 kg/m2, resumption of menses). Clinical improvement was correlated with BMC and BMD accrual (χ2 = 5.62/χ2 = 6.65, p = 0.06 / p = 0.036). The duration of amenorrhea had a negative correlation with BMD (r = -.362; p < 0.01), but not with BMC. Regular physical activity tended to show a positive effect on bone recovery, but the effect of hormone replacement therapy was not significant. Using age-related standards, the post-discharge sample for the substudy presented IGF-I levels below the 5th percentile. IGF-I serum concentrations corresponded to the general outcome of AN. By contrast, leptin serum concentrations showed great variability. They correlated with BMC and current body composition parameters.ConclusionsOur results from the main study indicate a certain adaptability of bone mineral accrual which is dependent on a speedy and ongoing recovery. While leptin levels in the substudy tended to respond immediately to current nutritional status, IGF-I serum concentrations corresponded to the individual's age and general outcome of AN.

Osteocyte Wnt/β-Catenin Signaling Is Required for Normal Bone Homeostasis

Beta-Catenin-dependent canonical Wnt signaling plays an important role in bone metabolism by controlling differentiation of bone-forming osteoblasts and bone-resorbing osteoclasts. To investigate its function in osteocytes, the cell type constituting the majority of bone cells, we generated osteocyte-specific beta-catenin-deficient mice (Ctnnb1(loxP/loxP); Dmp1-Cre). Homozygous mutants were born at normal Mendelian frequency with no obvious morphological abnormalities or detectable differences in size or body weight, but bone mass accrual was strongly impaired due to early-onset, progressive bone loss in the appendicular and axial skeleton with mild growth retardation and premature lethality. Cancellous bone mass was almost completely absent, and cortical bone thickness was dramatically reduced. The low-bone-mass phenotype was associated with increased osteoclast number and activity, whereas osteoblast function and osteocyte density were normal. Cortical bone Wnt/beta-catenin target gene expression was reduced, and of the known regulators of osteoclast differentiation, osteoprotegerin (OPG) expression was significantly downregulated in osteocyte bone fractions of mutant mice. Moreover, the OPG levels expressed by osteocytes were higher than or comparable to the levels expressed by osteoblasts during skeletal growth and at maturity, suggesting that the reduction in osteocytic OPG and the concomitant increase in osteocytic RANKL/OPG ratio contribute to the increased number of osteoclasts and resorption in osteocyte-specific beta-catenin mutants. Together, these results reveal a crucial novel function for osteocyte beta-catenin signaling in controlling bone homeostasis.

Smurf1 inhibits mesenchymal stem cell proliferation and differentiation into osteoblasts through JunB degradation

Ubiquitin ligase Smurf1-deficient mice develop an increased-bone-mass phenotype in an age-dependent manner. It was reported that such a bone-mass increase is related to enhanced activities of differentiated osteoblasts. Although osteoblasts are of mesenchymal stem cell (MSC) origin and MSC proliferation and differentiation can have significant impacts on bone formation, it remains largely unknown whether regulation of MSCs plays a role in the bone-mass increase of Smurf1-deficient mice. In this study we found that bone marrow mesenchymal progenitor cells from Smurf1−/− mice form significantly increased alkaline phosphatase–positive colonies, indicating roles of MSC proliferation and differentiation in bone-mass accrual of Smurf1−/− mice. Interestingly, Smurf1−/− cells have an elevated protein level of AP-1 transcription factor JunB. Biochemical experiments demonstrate that Smurf1 interacts with JunB through the PY motif and targets JunB protein for ubiquitination and proteasomal degradation. Indeed, Smurf1-deficient MSCs have higher proliferation rates, consistent with the facts that cyclin D1 mRNA and protein both are increased in Smurf1−/− cells and JunB can induce cyclinD1 promoter. Moreover, JunB overexpression induces osteoblast differentiation, shown by higher expression of osteoblast markers, and JunB knock-down not only decreases osteoblast differentiation but also restores the osteogenic potential to wild-type level in Smurf1−/− cells. In conclusion, our results suggest that Smurf1 negatively regulates MSC proliferation and differentiation by controlling JunB turnover through an ubiquitin-proteasome pathway. © 2010 American Society for Bone and Mineral Research.

Adiponectin and its association with bone mass accrual in childhood

Circulating adiponectin levels are inversely related to bone mineral density (BMD) in humans and animal models. Previous studies in humans have been confined largely to adult populations, and whether adiponectin influences bone mass accrual in childhood is unclear. We examined this question using the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort by investigating relationships between circulating adiponectin levels at a mean age of 9.9 years, indices of bone mass as measured by total-body dual-energy X-ray absorptiometry (DXA) at ages 9.9 and 15.5 years, and cortical bone parameters as measured by peripheral quantitative computed tomography (pQCT) of the midtibia at age 15.5 years. A total of 4927 children were included at age 9.9 years, of whom 97% and 90% of boys and girls, respectively, were in prepuberty or early puberty, as defined by Tanner stage 1-2. A total of 2754 children were included at age 15.5 years, of whom 95% and 97% of boys and girls, respectively, were in late puberty, as defined by Tanner stage 4-5. Circulating adiponectin was found to be related to fat mass, lean mass, and, to a lesser extent, height, so analyses were adjusted for these three variables to identify possible independent effects of adiponectin on bone development. Adiponectin was inversely related to total-body-less-head bone mineral content (BMC; -3.0%), bone area (BA; -1.8%), BMC divided by BA (BMD; -4.8%), and BMC adjusted for BA by linear regression (aBMC; -5.6%), as measured at age 9.9 years (coefficients show change per doubling in adiponectin concentration, p < .001). Consistent with these results, inverse associations also were seen between adiponectin and cortical BMC (-4.8%) and cortical bone area (-4.7%), as measured by tibial pQCT at age 15.5 years (p < .001). Further pQCT results suggested that this inverse association of adiponectin with skeletal development predominantly involved a negative association with endosteal relative to periosteal expansion, as reflected by cortical thickness (-6.0%, p < .001). We conclude that, independent of fat mass, lean mass, and height, adiponectin is associated with lower bone mass in childhood predominantly owing to an influence on relative endosteal expansion. Since these associations were observed before and after puberty, this suggests that setting of adiponectin levels in midchildhood has the potential to exert long-term effects on bone strength and fracture risk.

Trpv6 mediates intestinal calcium absorption during calcium restriction and contributes to bone homeostasis

Energy-dependent intestinal calcium absorption is important for the maintenance of calcium and bone homeostasis, especially when dietary calcium supply is restricted. The active form of vitamin D, 1,25-dihydroxyvitamin D 3 [1,25(OH) 2D 3], is a crucial regulator of this process and increases the expression of the transient receptor potential vanilloid 6 ( Trpv6) calcium channel that mediates calcium transfer across the intestinal apical membrane. Genetic inactivation of Trpv6 in mice ( Trpv6 −/− ) showed, however, that TRPV6 is redundant for intestinal calcium absorption when dietary calcium content is normal/high and passive diffusion likely contributes to maintain normal serum calcium levels. On the other hand, Trpv6 inactivation impaired the increase in intestinal calcium transport following calcium restriction, however without resulting in hypocalcemia. A possible explanation is that normocalcemia is maintained at the expense of bone homeostasis, a hypothesis investigated in this study. In this study, we thoroughly analyzed the bone phenotype of Trpv6 −/− mice receiving a normal (∼ 1%) or low (∼ 0.02%) calcium diet from weaning onwards using micro-computed tomography, histomorphometry and serum parameters. When dietary supply of calcium is normal, Trpv6 inactivation did not affect growth plate morphology, bone mass and remodeling parameters in young adult or aging mice. Restricting dietary calcium had no effect on serum calcium levels and resulted in a comparable reduction in bone mass accrual in Trpv6 +/+ and Trpv6 −/− mice (− 35% and 45% respectively). This decrease in bone mass was associated with a similar increase in bone resorption, whereas serum osteocalcin levels and the amount of unmineralized bone matrix were only significantly increased in Trpv6 −/− mice. Taken together, our findings indicate that TRPV6 contributes to intestinal calcium transport when dietary calcium supply is limited and in this condition indirectly regulates bone formation and/or mineralization.

Low-dose Oral Contraceptives in Adolescents: How Low Can You Go?

Context The use of combined oral contraception (COC) before the accrual of peak bone mass in adolescents is common. Despite the tendency to prescribe lower ethinyl estradiol concentrations so as to reduce thromboembolic complications, concerns have developed as to whether low-dose COC provides sufficient estrogen supplementation for adequate adolescent bone development. Objective This paper reviews the available literature on bone mineral density (BMD) and low-dose COC in adolescents in an effort to determine whether adult-oriented recommendations for the lowest tolerated estrogen dose should apply to adolescent populations. Design A MEDLINE search of all English-language literature (1966 to January 2008) was performed using the terms “adolescent,” “oral contraception,” and “BMD.” Bibliographies were reviewed to extract additional relevant sources. Articles were selected based on pertinence to BMD changes in association with low-dose (20 μg ethinyl estradiol) hormonal contraception with emphasis on adolescent study groups. Results A limited number of studies examining 20-ug preparations in adolescents have demonstrated a significantly smaller mean percentage BMD acquisition in COC groups vs untreated controls. Bone mineral density decreases appeared to positively correlate with early gynecological age of first COC use and treatment duration. Conclusions Loss of bone mass as a result of hormonal contraceptive use may have serious long-term implications in the adolescent population, who have yet to achieve peak bone density. Both age at first COC use and cumulative estrogen dose appear to be important factors in determining skeletal development in adolescents. Further studies are warranted to inform specific prescribing practices for this population.

Signaling through the M 3 Muscarinic Receptor Favors Bone Mass Accrual by Decreasing Sympathetic Activity

Bone remodeling is regulated by various neuronal inputs, including sympathetic tone, which is known to inhibit bone mass accrual. This aspect of sympathetic nervous system function raises the prospect that the other arm of the autonomic nervous system, the parasympathetic nervous system, may also affect bone remodeling. Here, we use various mutant mouse strains, each lacking one of the muscarinic receptors that mediate parasympathetic activity, to show that the parasympathetic nervous system acting through the M(3) muscarinic receptor is a positive regulator of bone mass accrual, increasing bone formation and decreasing bone resorption. Gene expression studies, cell-specific gene deletion experiments, and analysis of compound mutant mice showed that the parasympathetic nervous system favors bone mass accrual by acting centrally and by decreasing the sympathetic tone. By showing that both arms of the autonomic nervous system affect bone remodeling, this study further underscores the importance of neuronal regulation of bone.

Patients with high-bone-mass phenotype owing to Lrp5-T253I mutation have low plasma levels of serotonin

The Lrp5 gene is a major determinant of bone mass accrual. It has been demonstrated recently to achieve this function by hampering the synthesis of gut-derived serotonin, which is a powerful inhibitor of bone formation. In this study we analyzed plasma serotonin levels in patients with a high-bone-mass (HBM) phenotype owing to gain-of-function mutation of Lrp5 (T253I). A total of 9 HBM patients were compared with 18 sex- and age-matched controls. In HBM patients, the serotonin concentrations in platelet-poor plasma were significantly lower than in the controls (mean +/- SEM: 2.16 +/- 0.28 ng/mL versus 3.51 +/- 0.49 ng/mL, respectively, p < .05). Our data support the hypothesis that circulating serotonin levels mediate the increased bone mass resulting from gain-of-function mutations in Lrp5 in humans.

Low-density lipoprotein receptor-related protein 5 ( LRP5) variation in fracture prone children

Objective Recent studies have confirmed that the low-density lipoprotein receptor-related protein 5 gene ( LRP5), plays a role in bone mass accrual and in susceptibility to osteoporotic fractures in adults. This study evaluated whether LRP5 variation is implicated in childhood fractures. Patients and methods During an epidemiological study on childhood fractures, comprising 1390 consecutive Finnish children with an acute fracture, we recruited fracture-prone 4–16 years old children, who had a history of at least two low-energy long bone fractures before age 10 years or three low-energy long bone fractures before age 16 years, and/or at least one low-energy vertebral compression fracture. A total of 72 (5.2%) children fulfilled these inclusion criteria; DNA samples were obtained for 66 of them. All 23 exons and exon–intron boundaries of the LRP5 gene were sequenced; the identified variants were analyzed in 235 healthy Finnish control samples. Results Sequencing revealed 15 coding region missense or silent variants with unknown functional consequences. No obvious loss-of-function mutations such as deletions, insertions, or changes resulting in premature termination codon or altered splicing were identified. Phenotyping of the proband and parents, and genotyping of the parents, in 9 families with novel or rare variants showed no obvious correlation between any of the LRP5 variants and fractures. Conclusions Our study shows that in children LRP5 mutations are not a common cause of increased fractures. The observed rare LRP5 variants may together with unfavorable environmental and other genetic factors contribute to childhood fractures, but further studies are needed to confirm their functional significance and biological pathways through which this may occur. Our findings suggest that systematic LRP5 screening is not indicated in children with recurrent fractures.

Fat Mass Exerts a Greater Effect on Cortical Bone Mass in Girls than Boys

It is unclear whether fat mass (FM) and lean mass (LM) differ in the way they influence cortical bone development in boys and girls. The aim of the study was to investigate the contributions of total body FM and LM to parameters related to cortical bone mass and geometry. We conducted a longitudinal birth cohort study, the Avon Longitudinal Study of Parents and Children. A total of 4005 boys and girls (mean age, 15.5 yr) participated in the study. We measured cortical bone mass, cortical bone mineral content (BMC(C)), cortical bone mineral density, periosteal circumference (PC), and endosteal circumference by tibial peripheral quantitative computed tomography. LM had a similar positive association with BMC(C) in boys and girls [regression coefficients with 95% confidence interval (CI); P for gender interactions: boys/girls, 0.952 (0.908, 0.997); P = 0.85]. However, the mechanisms by which LM influenced bone mass differed according to gender because LM was positively associated with PC more strongly in girls [boys, 0.579 (0.522, 0.635); girls, 0.799 (0.722, 0.875); P < 0.0001], but was only associated with cortical bone mineral density in boys [boys, 0.443 (0.382, 0.505); girls, 0.014 (-0.070, 0.097); P < 0.0001]. There was a stronger positive association between FM and BMC(C) in girls [boys, 0.227 (0.185, 0.269); girls, 0.355 (0.319, 0.392); P < 0.0001]. This reflected both a greater positive association of FM with PC in girls [boys, 0.213 (0.174, 0.253); girls, 0.312 (0.278, 0.347); P = 0.0002], and a stronger negative association with endosteal circumference(PC) [boys, -0.059 (-0.096, 0.021); girls, -0.181 (-0.215, -0.146); P < 0.0001]. Whereas LM stimulates the accrual of cortical bone mass to a similar extent in boys and girls, FM is a stronger stimulus for accrual of cortical bone mass in girls, reflecting a greater tendency in females for FM to stimulate periosteal growth and suppress endosteal expansion.

Identification of Anabolic Selective Androgen Receptor Modulators with Reduced Activities in Reproductive Tissues and Sebaceous Glands

Androgen replacement therapy is a promising strategy for the treatment of frailty; however, androgens pose risks for unwanted effects including virilization and hypertrophy of reproductive organs. Selective Androgen Receptor Modulators (SARMs) retain the anabolic properties of androgens in bone and muscle while having reduced effects in other tissues. We describe two structurally similar 4-aza-steroidal androgen receptor (AR) ligands, Cl-4AS-1, a full agonist, and TFM-4AS-1, which is a SARM. TFM-4AS-1 is a potent AR ligand (IC(50), 38 nm) that partially activates an AR-dependent MMTV promoter (55% of maximal response) while antagonizing the N-terminal/C-terminal interaction within AR that is required for full receptor activation. Microarray analyses of MDA-MB-453 cells show that whereas Cl-4AS-1 behaves like 5alpha-dihydrotestosterone (DHT), TFM-4AS-1 acts as a gene-selective agonist, inducing some genes as effectively as DHT and others to a lesser extent or not at all. This gene-selective agonism manifests as tissue-selectivity: in ovariectomized rats, Cl-4AS-1 mimics DHT while TFM-4AS-1 promotes the accrual of bone and muscle mass while having reduced effects on reproductive organs and sebaceous glands. Moreover, TFM-4AS-1 does not promote prostate growth and antagonizes DHT in seminal vesicles. To confirm that the biochemical properties of TFM-4AS-1 confer tissue selectivity, we identified a structurally unrelated compound, FTBU-1, with partial agonist activity coupled with antagonism of the N-terminal/C-terminal interaction and found that it also behaves as a SARM. TFM-4AS-1 and FTBU-1 represent two new classes of SARMs and will allow for comparative studies aimed at understanding the biophysical and physiological basis of tissue-selective effects of nuclear receptor ligands.

Leptin-dependent co-regulation of bone and energy metabolism

The adipocyte-derived hormone leptin inhibits appetite and bone mass accrual. To fulfill these two functions leptin requires the integrity of hypothalamic neurons but not the expression of its receptor, ObRb on these neurons. These results suggested that leptin acts first elsewhere in the brain to mediate these functions. However, this neuroanatomical site of leptin action in the brain remained elusive. Recent mouse genetic, electrophysiological and neuroanatomical studies provide evidence that leptin inhibits appetite and bone mass accrual through a two-step pathway: it decreases synthesis and the release by brainstem neurons of serotonin that in turn targets hypothalamic neurons to regulate appetite and bone mass accrual.

The association between dietary protein intake and bone mass accretion in pubertal girls with low calcium intakes

To assess the association between protein intakes and bone mass accrual in girls, data were analysed for 757 pre-pubertal girls (mean age 10.1 years) in urban Beijing, China, who participated in a 5-year study including 2 years of milk supplementation (intervention groups only) and 3 years of follow-up study. At 0, 12, 24, 48 and 60 months from the baseline, bone mass of the proximal or distal forearm (PF or DF) and total body (TB) was measured with dual energy X-ray absorptiometry; dietary intakes were assessed by a 3-d food record (including two weekdays and one weekend day). Linear mixed models were used and continuous variables were logarithm transformed. The mean longitudinal Ca intake (432-675 mg/d on average) positively influenced bone mineral content (BMC) at TB, PF and DF after controlling for baseline bone mass and other possible confounders. However, negative associations were observed between protein intake (55.9-61.0 g/d on average) and BMC accrual at TB, PF or DF (beta = - 1.92, - 10.2 or - 4.82, respectively, P < 0.01) after adjustment. When protein intake was considered according to animal or plant food sources, protein from animal foods, particularly meat, had significant negative effects on BMC accrual at DF or PF after adjustment. It was concluded that higher protein intake, especially from animal foods, appeared to have a negative effect on bone mass accrual in Chinese pubertal girls with low Ca intakes.

Body Composition and Bone Mineral Density in Children with Premature Adrenarche and the Association of LRP5 Gene Polymorphisms with Bone Mineral Density

Precocious increase in adrenal androgen production is the hallmark of premature adrenarche (PA). Adrenal androgens have anabolic properties. The objective of the study was to test whether body composition and bone mineral density (BMD) are altered in PA and study whether genetic variation in low-density lipoprotein receptor-related protein 5 (LRP5) affects BMD in PA. This was a cross-sectional study. The study was conducted at a university hospital. The study included 126 prepubertal children (64 with PA, 10 boys; 62 non-PA controls, 10 boys). Femoral neck and lumbar spine areal and calculated volumetric BMD (dual energy X-ray absorptiometry), body composition (bioimpedance), serum 25-hydroxyvitamin D, and markers of bone turnover and calcium homeostasis were compared between the PA and control groups. Single-nucleotide polymorphisms of LRP5 were determined and associated with BMD. Children with PA had higher femoral neck and lumbar spine BMD(areal) than the controls (Z-score 0.56 vs. -0.09, P < 0.001, and 0.20 vs. -0.31, P = 0.009, respectively). However, the mean BMDs did not differ significantly between the groups when adjusted for height or bone size. BMD(areal) correlated strongly with height sd score in both groups. Among the PA children, LRP5 single-nucleotide polymorphism E644E minor variant was associated with lower and F549F minor variant with higher BMD. Total body fat mass, fat percent, serum PTH, and alkaline phosphatase concentrations were higher and 25-hydroxyvitamin D lower in the PA group. Prepubertal children with PA had higher BMD(areal) compared with healthy controls. This was mainly explained by their increased height. LRP5 polymorphisms may contribute to bone mass accrual in prepubertal PA children.

A Serotonin-Dependent Mechanism Explains the Leptin Regulation of Bone Mass, Appetite, and Energy Expenditure

Leptin inhibition of bone mass accrual requires the integrity of specific hypothalamic neurons but not expression of its receptor on these neurons. The same is true for its regulation of appetite and energy expenditure. This suggests that leptin acts elsewhere in the brain to achieve these three functions. We show here that brainstem-derived serotonin (BDS) favors bone mass accrual following its binding to Htr2c receptors on ventromedial hypothalamic neurons and appetite via Htr1a and 2b receptors on arcuate neurons. Leptin inhibits these functions and increases energy expenditure because it reduces serotonin synthesis and firing of serotonergic neurons. Accordingly, while abrogating BDS synthesis corrects the bone, appetite and energy expenditure phenotypes caused by leptin deficiency, inactivation of the leptin receptor in serotonergic neurons recapitulates them fully. This study modifies the map of leptin signaling in the brain and identifies a molecular basis for the common regulation of bone and energy metabolisms. For a video summary of this article, see the PaperFlick file with the Supplemental Data available online.

Decreased Bone Mineral Density in Adults Born with Very Low Birth Weight: A Cohort Study

Very-low-birth-weight (VLBW, <1,500 g) infants have compromised bone mass accrual during childhood, but it is unclear whether this results in subnormal peak bone mass and increased risk of impaired skeletal health in adulthood. We hypothesized that VLBW is associated with reduced bone mineral density (BMD) in adulthood. The Helsinki Study of Very Low Birth Weight Adults is a multidisciplinary cohort study representative of all VLBW births within the larger Helsinki area from 1978 to 1985. This study evaluated skeletal health in 144 such participants (all born preterm, mean gestational age 29.3 wk, birth weight 1,127 g, birth weight Z score 1.3), and in 139 comparison participants born at term, matched for sex, age, and birth hospital. BMD was measured by dual energy X-ray absorptiometry at age 18.5 to 27.1 y. Adults born with VLBW had, in comparison to participants born at term, a 0.51-unit (95% confidence interval [CI] 0.28-0.75) lower lumbar spine Z score and a 0.56-unit (95% CI 0.34-0.78) lower femoral neck Z score for areal BMD. These differences remained statistically significant after adjustment for the VLBW adults' shorter height and lower self-reported exercise intensity. Young adults born with VLBW, when studied close to the age of peak bone mass, have significantly lower BMD than do their term-born peers. This suggests that compromised childhood bone mass accrual in preterm VLBW children translates into increased risk for osteoporosis in adulthood, warranting vigilance in osteoporosis prevention.