Important Determinant Of Bone Mass Research Articles

Strontium chloride improves bone mass by affecting the gut microbiota in young male rats.

Bone mass accumulated in early adulthood is an important determinant of bone mass throughout the lifespan, and inadequate bone deposition may lead to associated skeletal diseases. Recent studies suggest that gut bacteria may be potential factors in boosting bone mass. Strontium (Sr) as a key bioactive element has been shown to improve bone quality, but the precise way that maintains the equilibrium of the gut microbiome and bone health is still not well understood. We explored the capacity of SrCl2 solutions of varying concentrations (0, 100, 200 and 400 mg/kg BW) on bone quality in 7-week-old male Wistar rats and attempted to elucidate the mechanism through gut microbes. The results showed that in a Wistar rat model under normal growth conditions, serum Ca levels increased after Sr-treatment and showed a dose-dependent increase with Sr concentration. Three-point mechanics and Micro-CT results showed that Sr exposure enhanced bone biomechanical properties and improved bone microarchitecture. In addition, the osteoblast gene markers BMP, BGP, RUNX2, OPG and ALP mRNA levels were significantly increased to varying degrees after Sr treatment, and the osteoclast markers RANKL and TRAP were accompanied by varying degrees of reduction. These experimental results show that Sr improves bones from multiple angles. Further investigation of the microbial population revealed that the composition of the gut microbiome was changed due to Sr, with the abundance of 6 of the bacteria showing a different dose dependence with Sr concentration than the control group. To investigate whether alterations in bacterial flora were responsible for the effects of Sr on bone remodeling, a further pearson correlation analysis was done, 4 types of bacteria (Ruminococcaceae_UCG-014, Lachnospiraceae_NK4A136_group, Alistipes and Weissella) were deduced to be the primary contributors to Sr-relieved bone loss. Of these, we focused our analysis on the most firmly associated Ruminococcaceae_UCG-014. To summarize, our current research explores changes in bone mass following Sr intervention in young individuals, and the connection between Sr-altered intestinal flora and potentially beneficial bacteria in the attenuation of bone loss. These discoveries underscore the importance of the "gut-bone" axis, contributing to an understanding of how Sr affects bone quality, and providing a fresh idea for bone mass accumulation in young individuals and thereby preventing disease due to acquired bone mass deficiency.

Relationship between body composition and bone mass in normal-weight and overweight adolescents.

Adolescence is a period characterized by large accumulation of bone mass. Body composition is an important determinant of bone mass. This study aimed to assess the relationship of bone mass with lean mass (LM) and fat mass (FM) in normal-weight and overweight adolescents with consideration of sex, sexual maturation and physical activity covariates. A total of 118 adolescents (60 girls and 58 boys) aged between 10 and 14 years participated in the study. Individuals were classified as normal weight or overweight according to body mass index. Bone mineral density (BMD), bone mineral content (BMC), LM, and FM were measured by dual-energy X-ray absorptiometry. In normal-weight adolescents, LM (β=0.725, p < 0.001) and FM (β=0.185, p = 0.019) were associated with lumbar spine BMC, whereas in overweight adolescents only LM (β=0.736, p < 0.001) was associated with lumbar spine BMC. Furthermore, in the normal-weight group, FM and LM were associated with total body less head BMD (LM, β=0.792, p < 0.001; FM, β=0.257, p = 0.007) and lumbar spine BMD (LM, β=0.553, p < 0.001; FM, β=0.199, p < 0.035). In the overweight group, only LM was associated with total body less head BMD (β=0.682, p < 0.001) and lumbar spine BMD (β=0.528, p < 0.001). LM was the main predictor of bone mass in normal-weight and overweight adolescents. FM was associated with bone mass in normal-weight adolescents only. LM may be considered an important and useful marker in adolescents, when investigating bone health in this population. Activities that promote LM gain to reduce the risk of bone fractures and diseases in adulthood are recommended.

Adolescent undernutrition and early adulthood bone mass in an urbanizing rural community in India.

SummaryThe long-term effects on bone health of nutritional status in adolescence are unclear. The impact of adolescent and current body mass on bone mass in young adulthood in rural India was assessed. Current lean mass was a more important determinant of bone mass than thinness during adolescence in this population.Purpose/introductionAdolescence is a crucial period for skeletal growth. However, the long-term effects on bone health of nutritional status in adolescence, particularly in the context of nutritional transition, are unclear. The current manuscript assessed the impact of adolescent and current body size on bone mass in young adulthood in an Indian rural community that is undergoing rapid socioeconomic changes.MethodsThe Andhra Pradesh Children and Parents Study is a prospective cohort study in Hyderabad, India. In 2003–2005, the study collected anthropometric and cardiovascular data on adolescents (mean age = 16 years old). The second and third waves of the study in 2009–2012 collected data on current anthropometric measures, areal bone mineral density (aBMD) in hip and lumbar spine (L1–L4) measured by dual-energy X-ray absorptiometry, and living standards of the trial participants who were now young adults (mean age = 22 years old).ResultsThe median body mass index (BMI) of the 722 participants included in this analysis was 16.8 kg/m2 during adolescence, while the median BMI as young adults was 19.3 kg/m2. Lower aBMD during adulthood was associated with lower adolescent BMI (β (95 % confidence interval) for hip aBMD 0.017 (0.013 to 0.022) and LS aBMD 0.012 (0.008 to 0.016)). This association was attenuated upon adjustment for current fat and lean mass (β (95 % CI) for hip aBMD 0.00 (−0.005 to 0.005) and LS aBMD 0.005 (0.000 to 0.01)). There was clear evidence for positive associations between aBMDs and current lean mass.ConclusionsCurrent lean mass was a more important determinant of bone mass than thinness during adolescence in this population. Weight gain during late adolescence and young adulthood coupled with improvement in lean mass may help to mitigate any adverse effects that pre-adulthood undernutrition may have on bone mass accrual.

Life-course determinants of bone mass in young adults from a transitional rural community in India: the Andhra Pradesh Children and Parents Study (APCAPS)

Background: Undernutrition and physical inactivity are both associated with lower bone mass.Objective: This study aimed to investigate the combined effects of early-life undernutrition and urbanized lifestyles in later life on bone mass accrual in young adults from a rural community in India that is undergoing rapid socioeconomic development.Design: This was a prospective cohort study of participants of the Hyderabad Nutrition Trial (1987–1990), which offered balanced protein-calorie supplementation to pregnant women and preschool children younger than 6 y in the intervention villages. The 2009–2010 follow-up study collected data on current anthropometric measures, bone mineral density (BMD) measured by dual-energy X-ray absorptiometry, blood samples, diet, physical activity, and living standards of the trial participants (n = 1446, aged 18–23 y).Results: Participants were generally lean and had low BMD [mean hip BMD: 0.83 (women), 0.95 (men) g/cm2; lumbar spine: 0.86 (women), 0.93 (men) g/cm2]. In models adjusted for current risk factors, no strong evidence of a positive association was found between BMD and early-life supplementation. On the other hand, current lean mass and weight-bearing physical activity were positively associated with BMD. No strong evidence of an association was found between BMD and current serum 25-hydroxyvitamin D or dietary intake of calcium, protein, or calories.Conclusions: Current lean mass and weight-bearing physical activity were more important determinants of bone mass than was early-life undernutrition in this population. In transitional rural communities from low-income countries, promotion of physical activity may help to mitigate any potential adverse effects of early nutritional disadvantage.

Circulating Sclerostin in Children and Young Adults with Heritable Bone Disorders

Sclerostin is an inhibitor of bone formation and is an important determinant of bone mass. The role of sclerostin in heritable metabolic bone disorders has not been studied in detail. We evaluated serum sclerostin levels in patients with X-linked hypophosphatemic rickets (XLH) and osteogenesis imperfecta (OI) and analyzed the relationship of circulating sclerostin concentrations with lumbar spine areal bone mineral density (LS-aBMD). The study was conducted in the metabolic bone clinic of a pediatric orthopedic hospital. Participants were 128 individuals, including 30 patients with XLH, 76 patients with OI types I, III, and IV, and 22 healthy subjects. Sclerostin was quantified in serum samples. Patients with XLH had higher circulating sclerostin concentrations (mean [SD]: 30.2 [16.7] pmol/L) than healthy control subjects (21.4 [9.2] ng/mL) (P = .02), as well as relatively high LS-aBMD Z-scores (+1.1 [1.7]). In the XLH cohort, serum sclerostin levels were positively associated with the LS-aBMD Z-score (r = 0.56; P < .002) and with alkaline phosphatase (r = 0.45; P = .01). In patients with OI, sclerostin serum levels were similar to those of healthy control subjects despite low LS-aBMD. The elevated sclerostin serum levels in XLH and the normal concentrations in OI suggest that the bone mass abnormalities in these disorders are not caused by primary sclerostin dysregulation.

Hormonal and biochemical parameters correlated with bone densitometric markers in prepubertal Hungarian children

BackgroundThe conditions that define bone development in prepuberty profoundly influence bone health later in life. We aimed to reveal important determinants of bone mass in Tanner stage I. MethodsWe studied 84 healthy children (43 girls and 41 boys) aged 7 to 11years. Serum estradiol (E2), 25-hydroxyvitamin D3-vitamin [25(OH)D3], intact parathyroid hormone (PTHi), osteocalcin (OC) and β-crosslaps (CTXs) were longitudinally analyzed (Roche Diagnostics System). Total and spine bone mineral content (tBMC and LBMC) and density (tBMD and LBMD) were assessed, and total fat body mass index (FBMi) was calculated (DXA Lunar Prodigy). ResultsThe serum PTHi, OC and LBMD values were significantly higher in girls than in boys. The mean 25(OH)D3 level was lower but not significantly in girls compared to boys. Significant negative correlation was found between PTHi and 25(OH)D3 levels (r=−0.28; p=0.011) when tested in all subjects, but no correlation was detected when the gender groups were separately tested. There was a trend for higher E2 levels in girls. Significant positive correlation (r=0.32; p=0.042) was detected between FBMi and E2 concentration in girls only. A significant negative correlation was found between E2 and 25(OH)D3 levels (r=−0.37, p<0.05) in girls with elevated (>3.6pmol/l) PTHi and with suboptimal (<75nmol/l) 25(OH)D3 levels. Furthermore, positive correlations were noted between E2 and CTXs and OC (r=0.54, p<0.01 and r=0.39, p<0.03) and a marginally significant positive correlation (r=0.33; p=0.06) was detected between OC and PTHi levels in girls. However, we detected no correlations when these markers were analyzed in boys. There was a significant correlation between E2 and all BMC and LBMD values in both genders. The tBMD, LBMD and tBMC values showed weak, but significant negative associations with 25OHD3 levels (β=−0.44 to −0.55; p<0.001) in girls only. All BMD and BMC values were positively predicted by OC levels, but not by CTXs, in both genders. Among the biochemical markers, E2 was the only factor correlating with all dependent variables (BMCs and BMDs) in both genders. Among all parameters analyzed, FBMi (β=0.64) showed the strongest influence on tBMC characteristically in girls only. ConclusionsOur results support that 1.) E2 levels play a key role in defining bone turnover and bone mass in both genders already in prepuberty; 2.) high PTHi levels in childhood should be evaluated with caution, because the normal range for serum PTHi in different Tanner stage groups is not well established; and 3.) the negative correlation between 25(OH)D and E2 and the positive correlation between PTHi and OC suggest that estrogens regulate PTHi indirectly and cause lower circulating 25(OH)D3 levels. We propose that the decreased levels of 25(OH)D3 reflect not the real vitamin supply, but may rather be the result of E2 regulation. Therefore, the actual serum 25OHD levels may underestimate the availability of factors supporting bone formation.

Alterations in the Synthesis of IL-1β, TNF-α, IL-6, and Their Downstream Targets RANKL and OPG by Mouse Calvarial Osteoblasts In vitro: Inhibition of Bone Resorption by Cyclic Mechanical Strain

Mechanical strain is an important determinant of bone mass and architecture, and the aim of this investigation was to further understand the role of the cell–cell signaling molecules, IL-1β, TNF-α, and IL-6 in the mechanobiology of bone. Mouse calvarial osteoblasts in monolayer culture were subjected to a cyclic out-of-plane deformation of 0.69% for 6 s, every 90 s for 2–48 h, and the levels of each cytokine plus their downstream targets RANKL and OPG measured in culture supernatants by ELISAs. Mouse osteoblasts constitutively synthesized IL-1β, TNF-α, and IL-6, the production of which was significantly up-regulated in all three by cyclic mechanical strain. RANKL and OPG were also constitutively synthesized; mechanical deformation however, resulted in a down-regulation of RANKL and an up-regulation OPG synthesis. We next tested whether the immunoreactive RANKL and OPG were biologically active in an isolated osteoclast resorption pit assay – this showed that culture supernatants from mechanically deformed cells significantly inhibited osteoclast-mediated resorptive activity across the 48 h time-course. These findings are counterintuitive, because IL-1β, TNF-α, and IL-6 have well-established reputations as bone resorptive agents. Nevertheless, they are pleiotropic molecules with multiple biological activities, underlining the complexity of the biological response of osteoblasts to mechanical deformation, and the need to understand cell–cell signaling in terms of cytokine networks. It is also important to recognize that osteoblasts cultured in vitro are deprived of the mechanical stimuli to which they are exposed in vivo – in other words, the cells are in a physiological default state that in the intact skeleton leads to decreased bone strains below the critical threshold required to maintain normal bone structure.

Variation in childhood skeletal robustness is an important determinant of cortical area in young adults

A better understanding of bone growth will benefit efforts to reduce fracture incidence, because variation in elderly bone traits is determined primarily by adulthood. The natural variation in robustness was used as a model to understand how variable growth patterns define adult bone morphology. Longitudinally acquired hand radiographs of 29 boys and 30 girls were obtained from the Bolton-Brush study for 6 time points spanning 8 to 18 years of age. Segregating individuals into tertiles based on robustness revealed that the biological activity underlying bone growth varied significantly with the natural variation in robustness. For boys, slender metacarpals used an osteoblast-dependent growth pattern to establish function, whereas robust metacarpals used an osteoclast-dependent growth pattern. In contrast, differences in biological activity between girls with slender and robust metacarpals were largely based on the age at which the marrow surface changed from expansion to infilling. Importantly, cortical area for slender metacarpals was as much as 19.7% and 32.2% lower than robust metacarpals for boys and girls, respectively, indicating that robustness was a major determinant of adult cortical area. Finally, after accounting for robustness and body weight effects, we found that the inter-individual variation in cortical area was established as early as 8 years of age. While variation in the amount of bone acquired during growth has primarily been attributed to factors like nutrition, exercise, and genetic background, we showed that the natural variation in robustness was also a major determinant of cortical area, which is an important determinant of bone mass. This predictable relationship between robustness and cortical area should be incorporated into clinical diagnostic measures and experimental studies.

Estimating Calcium Intake at Time of Dual Energy X-Ray Absorptiometry (DXA) Scan

Background: Calcium intake, whether from diet or supplementation, is an important determinant of bone mass and an adjunct to all treatments for osteoporosis. Recommended daily allowance for calcium is 800 mg; for patients with osteoporosis on treatment a higher intake of 1200 mg is advocated. As part of our DXA service, we estimate calcium intake from dairy sources, which accounts for about 80% of dietary calcium intake. Methods: We studied our computerised records of estimated daily calcium intake in our DXA database over a 2 year period (n 5 5982) according to the following categories: women (premenopausal and postmenopausal) and men (under 50 years and over 50 years). We determined the frequency of subjects with estimated calcium intake below 400 mg/d, 800 mg/d and 1200 mg/d. Results: About 69% of adults have calcium intake below recommended intake of 800 mg/d. If patients had a diagnosis of osteoporosis, then about 90% would need a prescription for a calcium supplement in order to achieve a daily calcium intake in excess of 1200 mg/d. Conclusion: An estimate of calcium intake should be made at the time of DXA testing in order to identify subjects who would benefit from advice about augmenting their dietary intake of calcium, and if necessary to make a suggestion to the referring clinician about prescribing calcium supplements.

Lumbar spine peak bone mass and bone turnover in men and women: a longitudinal study

Peak bone mass is an important determinant of bone mass in later life, but the age of peak bone mass is still unclear. We found that bone size and density increase and bone turnover decreases until age 25. It may be possible to influence bone accrual into the third decade. Peak bone mass is a major determinant of bone mass in later life. Bone growth and maturation is site-specific, and the age of peak bone mass is still unclear. It is important to know the age to which bone accrual continues so strategies to maximise bone mass can be targeted appropriately. This study aims to ascertain the age of lumbar spine peak bone mass. We measured lumbar spine BMC, estimated volume and BMAD by DXA and biochemical markers of bone turnover in 116 healthy males and females ages 11 to 40, followed up at an interval of five to nine years. The majority of peak bone mass was attained by the mid-twenties. Increases in BMC in adolescents and young adults were mostly due to increases in bone size. Bone turnover markers decreased through adolescence and the third decade and the decreasing rate of change in bone turnover corresponded with the decreasing rate of change in lumbar spine measurements. Skeletal maturation and bone mineral accrual at the lumbar spine continues into the third decade.

Association of genetic variations of genes encoding thrombospondin, type 1, domain-containing 4 and 7A with low bone mineral density in Japanese women with osteoporosis

Twins and family studies have shown that genetic factors are important determinants of bone mass. Important aspects of bone mineral density (BMD) regulation are endocrine systems, notably hormonal regulation of adrenal corticoids, as indicated by clinical knowledge of glucocorticoid-induced osteoporosis. Glucocorticoid is known to negatively regulate bone mass in vivo, and glucocorticoid increases thrombospondin messenger ribonucleic acid (mRNA) levels. We studied single nucleotide polymorphisms (SNPs) in genes encoding thrombospondin, type 1, domain-containing 4 and 7A (THSD4 and THSD7A) for possible association with lumbar and femoral BMD among 337 Japanese women with osteoporosis who participated in the BioBank Japan project. Genetic variations of THSD4 and THSD7A loci displayed significant association with lumbar and femoral BMD. Most significant correlation was observed for THSD7A SNP rs12673692 with lumbar BMD (P = 0.00017). Homozygous carriers of the major (G) allele had the highest BMD [0.886 +/- 0.011 g/cm2, mean +/- standard deviation (SD)], whereas heterozygous carriers were intermediate (0.872 +/- 0.013 g/cm2) and homozygous A-allele carriers had the lowest (0.753 +/- 0.023 g/cm2). THSD4 SNP rs10851839 also displayed strong association with lumbar BMD (P = 0.0092). In addition, both THSD7A and THSD4 displayed significant association with femoral BMD in a recessive model (P = 0.036 and P = 0.0046, respectively). Results suggest that variations of THSD7A and THSD4 loci may be important determinants of osteoporosis in Japanese women.

Osteoblast expression of an engineered G s -coupled receptor dramatically increases bone mass

Osteoblasts are essential for maintaining bone mass, avoiding osteoporosis, and repairing injured bone. Activation of osteoblast G protein-coupled receptors (GPCRs), such as the parathyroid hormone receptor, can increase bone mass; however, the anabolic mechanisms are poorly understood. Here we use "Rs1," an engineered GPCR with constitutive G(s) signaling, to evaluate the temporal and skeletal effects of G(s) signaling in murine osteoblasts. In vivo, Rs1 expression induces a dramatic anabolic skeletal response, with midfemur girth increasing 1,200% and femur mass increasing 380% in 9-week-old mice. Bone volume, cellularity, areal bone mineral density, osteoblast gene markers, and serum bone turnover markers were also elevated. No such phenotype developed when Rs1 was expressed after the first 4 weeks of postnatal life, indicating an exquisite temporal sensitivity of osteoblasts to Rs1 expression. This pathway may represent an important determinant of bone mass and may open future avenues for enhancing bone repair and treating metabolic bone diseases.

The RANKL/RANK/OPG pathway

Understanding of osteoclast formation and activation has advanced considerably since the discovery of the RANKL/RANK/OPG system in the mid 1990s. Osteoblasts and stromal stem cells express receptor activator of NF-jB ligand (RANKL), which binds to its receptor, RANK, on the surface of osteoclasts and their precursors. This regulates the differentiation of precursors into multinucleated osteoclasts and osteoclast activation and survival both normally and in most pathologic conditions associated with increased bone resorption. Osteoprotegerin (OPG) is secreted by osteoblasts and osteogenic stromal stem cells and protects the skeleton from excessive bone resorption by binding to RANKL and preventing it from interacting with RANK. The RANKL/OPG ratio in bone marrow is thus an important determinant of bone mass in normal and disease states. RANKL/RANK signaling also regulates lymph node formation and mammary gland lactational hyperplasia in mice, and OPG protects large arteries of mice from medial calcification. This article reviews the roles of the RANKL/RANK/OPG system in bone and other tissues.

Evaluation of densitometric bone–muscle relationships in Crohn's disease

Background Patients with Crohn's disease (CD) are 1.4 to 2.5 times more likely than the normal population to sustain a fracture but the factors involved in the pathogenesis are not clearly understood. Bone mass is affected both by nutrition and by muscular activity. Trauma excepted, the largest voluntary loads on bones come from muscle contraction, not body weight. Aim To assess the relationship between bone mass (bone mineral content) and muscle mass (lean mass) in CD patients. Methods Adult CD patients who had had a whole body, lumbar and hip densitometric evaluation were selected. Information regarding age, gender, weight, duration of CD, age at diagnosis, use of glucocorticoids and disease activity during the year before densitometric evaluation and laboratory parameters were collected. Results Data from 65 patients (28.8 ± 10.6 years, F = 44, M = 21) were analyzed. Lumbar bone mineral content (BMC), BMC in both hips, total and regional BMC significantly correlated with body weight and total and regional lean mass (LM). In multiple regression analysis, only total LM was shown to be independently associated with lumbar BMC, BMC in both hips and total BMC. LM in upper and lower limbs was shown to be independently associated with BMC in upper and lower limbs, respectively. Conclusions These results suggest that muscular mass and activity, rather than overall body weight, are important determinants of bone mass and, hence of bone strength in Crohn's disease. Thus, the management of bone loss in inflammatory bowel disease should address the effects of both nutrition and exercise on muscle mass.

Childhood Bone Mass Acquisition and Peak Bone Mass May Not Be Important Determinants of Bone Mass in Late Adulthood

During childhood and adolescence, bone mass acquisition occurs primarily through skeletal growth. It is widely assumed that bone mass acquisition throughout childhood is an important determinant of the risk of osteoporosis in late adulthood; bone mass is thought to resemble a bank account in which deposits persist indefinitely. However, several well-controlled clinical studies suggest that increasing bone mass acquisition during childhood will have only transient effects. A likely explanation is that bone mass is governed by a homeostatic system that tends to return to a set point after any perturbation and, therefore, bone mass depends primarily on recent conditions, not those in the distant past. Indeed, in an animal model, we have shown evidence that bone mass acquisition in early life has no effect on bone mass in adulthood, in part because many areas of the juvenile skeleton are replaced in toto through skeletal growth. Therefore, it should not be assumed that alterations in childhood bone mass acquisition will affect bone mass many decades later in late adulthood. This issue remains open and the solution may depend on the type of childhood condition (for example calcium intake versus exercise) and its magnitude, timing, and duration. To date, both animal studies and clinical studies suggest that much of the effect of early bone mass acquisition does not persist.

Biology of RANK, RANKL, and osteoprotegerin

The discovery of the receptor activator of nuclear factor-κB ligand (RANKL)/RANK/osteoprotegerin (OPG) system and its role in the regulation of bone resorption exemplifies how both serendipity and a logic-based approach can identify factors that regulate cell function. Before this discovery in the mid to late 1990s, it had long been recognized that osteoclast formation was regulated by factors expressed by osteoblast/stromal cells, but it had not been anticipated that members of the tumor necrosis factor superfamily of ligands and receptors would be involved or that the factors involved would have extensive functions beyond bone remodeling. RANKL/RANK signaling regulates the formation of multinucleated osteoclasts from their precursors as well as their activation and survival in normal bone remodeling and in a variety of pathologic conditions. OPG protects the skeleton from excessive bone resorption by binding to RANKL and preventing it from binding to its receptor, RANK. Thus, RANKL/OPG ratio is an important determinant of bone mass and skeletal integrity. Genetic studies in mice indicate that RANKL/RANK signaling is also required for lymph node formation and mammary gland lactational hyperplasia, and that OPG also protects arteries from medial calcification. Thus, these tumor necrosis factor superfamily members have important functions outside bone. Although our understanding of the mechanisms whereby they regulate osteoclast formation has advanced rapidly during the past 10 years, many questions remain about their roles in health and disease. Here we review our current understanding of the role of the RANKL/RANK/OPG system in bone and other tissues.

Bone mass in young adults: relationship with gender, weight and genetic factors

To determine the relationship of the bone mass attained in young adults with anthropometric and genetic factors. Cross-sectional study of normal individuals. We studied 341 healthy subjects between 22 and 45 years of age. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) and correlated with body weight, height and nine polymorphisms in six genes involved in sex steroid metabolism (17-hydroxylase, aromatase and 5-reductase) and activity (oestrogen receptors (ER)-alpha and -beta, and androgen receptor). The BMD was higher in men than in women (spine: 1.048 +/- 0.120 vs. 1.034 +/- 0.112; hip: 0.907 +/- 0.131 vs. 0.822 +/- 0.104 g cm(-2), P < 0.001). However, the difference was due, at least in part, to the larger body size in men and diminished markedly after height adjustment. There was a negative correlation between age and hip BMD. Body weight was the single most influential factor on spine and hip BMD in both sexes, explaining 8-9% of BMD variance. Amongst the genetic factors studied, a common CA repeat polymorphism in ER-beta showed a significant association with BMD in women (P = 0.03 at the spine, and 0.008 at the hip). The relationship between ER-beta genotype and BMD persisted after adjustment by body weight and age, explaining a further 2-3% of BMD variance. Allelic variants of other genes studied were not related with BMD. Body weight and allelic variants of ER-beta are associated with BMD in young adults.

Weight gain in childhood and bone mass in female college students

The attainment of maximal peak bone mass early on in life is one of the most important strategies for the prevention of osteoporosis in women. The aim of this study was to clarify the correlation between gains in body size in all growth phases in childhood and adult bone mass in women. The subjects were 86 female first-year university students, aged 18-21 years. We measured the subjects' bone mineral content (BMC) and bone mineral density (BMD) at the lumbar spine and the left hip, including the femoral neck, with dual energy X-ray absorptiometry. Each subject was measured for current height and weight. Height and weight at birth, and at 1.5, and 3 years were obtained from each maternity record book, and those between 6 and 18 years were obtained from their school health records. Other information, including physical activity and calcium intake, was obtained through an interview. Bivariate analysis showed that weight gains during the periods from birth to 1.5 years and from 9 to 12 years significantly correlated with both BMC and BMD values at any site. The stepwise method of multiple regression analysis showed that a weight gain during the period from birth to 1.5 years was significantly associated with BMC at the lumbar spine (P = 0.0001) and at the femoral neck (P = 0.0290) and with BMD at the lumbar spine (P = 0.0387). Birth weight was significantly associated with BMC at the lumbar spine (P = 0.0474) and the total hip (P = 0.0352), and weight gain during the period from 9 to 12 years was significantly associated with BMC at the femoral neck (P = 0.0376). In conclusion, birth weight and weight gain in infancy are important determinants of bone mass in young women. Additionally, a girl's prepubertal growth spurt is likely to be a key phase for the acquisition of bone mass in relation to body weight. Our findings suggest that osteoporosis prevention programs may need to start very early in the life cycle.

Association of genetic variation of the RIL gene, encoding a PDZ-LIM domain protein and localized in 5q31.1, with low bone mineral density in adult Japanese women.

Twin and family studies had shown that genetic factors are important determinants of bone mass. Multiple genes might be involved. One candidate gene, the reversion-induced LIM gene ( RIL), is a PDZ and LIM-domain-containing protein and has been localized within the cytokine cluster of chromosome 5 (5q31.1). In a genetic study of 370 adult Japanese women, we investigated the correlation between radial bone mineral density (BMD) and a genetic variation (-3333T-->C) of the 5'-flanking region of RIL gene. A significant association was identified between the RIL variation -3333T-->C and radial BMD ( r=0.15, P=0.003). The variation of the RIL locus may be an important determinant of osteoporosis.

Modeling of cross-sectional bone size, mass and geometry at the proximal radius: a study of normal bone development using peripheral quantitative computed tomography.

It is becoming increasingly accepted that bone size is an important determinant of bone mass. Studies on the development of bone size may therefore promote a better understanding of the basis of diseases which are due to low bone mass. Here, we characterize the temporal changes in cross-sectional bone size, geometry and mass at the radial diaphysis in healthy subjects from 6 to 40 years of age (n = 469; 273 females). Peripheral quantitative computed tomography was used to measure total and cortical cross-sectional area, bone mineral content (BMC) and volumetric bone mineral density (BMD) at the site of the forearm whose distance from the ulnar styloid process corresponded to 65% of forearm length. Over the age range of the study, total cross-sectional area increased by 39 mm2 (50%) in females and by 85 mm2 (116%) in males. Cortical area increased to a similar extent in both sexes. Between 6-7 years and adulthood, BMC increased by 52 mg/mm (111%) in females and by 73 mg/mm (140%) in males and was significantly higher in males after the age of 15 years. Volumetric BMD increased by 246 mg/cm3 (48%) in females but by only 132 mg/cm3 (23%) in males and was significantly higher in women than in men. In summary, these data show that BMC in men is higher than in women, because periosteal modeling continues longer in boys than in girls. Volumetric BMD is higher in women, partly because the size of the marrow cavity does not increase in girls as it does in boys.