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Background and Objective: Leptin is an hormone resulting from the obesity gene. Their actions could be important in the pathogenesis of the osteoporosis. The aim of this study is to analyse the influence of tobacco on serum leptin levels, and its relationship with bone mineral density (BMD) and steroid hormones., Subjects and Method: A group of healthy volunteers were recruited and classified as smokers or non-smokers. A subgroup of smokers ceased smoking during one month. Serum leptin and steroids hormones levels were analysed, and a baseline BMD was measured. In the abstinent group the analysis was repeated at the end of the study., Results: Fifty-nine healthy volunteers were included (22 of which were smokers). Fifteen smokers remained abstinent for a month. Both groups were similar except in age, being smokers older. Male smokers had lower lumbar BMD (p = 0.017). After adjusting by age, serum leptin levels were higher in smokers than in non-smokers, with statistical differences in women (p = 0.049). Abstinence increased leptin levels, though not reaching statistical significance. An inverse correlation between leptin levels and androstendione in men (r = -0.622; p = 0.001), and a positive correlation with testosterone in women (r = 0.405; p = 0.019) were found. After adjusting by body mass index, only the correlation of leptin levels with androstendione persisted., Conclusions: Leptin negatively correlate with sex hormones in young men and is influenced by smoking in young women. Thus, the hormone could be relevant for bone mass regulation in smoker persons.

Background: Polymorphisms of the vitamin D receptor (VDR) gene have been implicated in the genetic regulation of bone mineral density (BMD). However, the clinical impact of these variants remains unclear., Objective: To evaluate the relation between VDR polymorphisms, BMD, and fractures., Design: Prospective multicenter large-scale association study., Setting: The Genetic Markers for Osteoporosis consortium, involving 9 European research teams., Participants: 26,242 participants (18,405 women)., Measurements: Cdx2 promoter, FokI, BsmI, ApaI, and TaqI polymorphisms; BMD at the femoral neck and the lumbar spine by dual x-ray absorptiometry; and fractures., Results: Comparisons of BMD at the lumbar spine and femoral neck showed nonsignificant differences less than 0.011 g/cm2 for any genotype with or without adjustments. A total of 6067 participants reported a history of fracture, and 2088 had vertebral fractures. For all VDR alleles, odds ratios for fractures were very close to 1.00 (range, 0.98 to 1.02) and collectively the 95% CIs ranged from 0.94 (lowest) to 1.07 (highest). For vertebral fractures, we observed a 9% (95% CI, 0% to 18%; P = 0.039) risk reduction for the Cdx2 A-allele (13% risk reduction in a dominant model)., Limitations: The authors analyzed only selected VDR polymorphisms. Heterogeneity was detected in some analyses and may reflect some differences in collection of fracture data across cohorts. Not all fractures were related to osteoporosis., Conclusions: The FokI, BsmI, ApaI, and TaqI VDR polymorphisms are not associated with BMD or with fractures, but the Cdx2 polymorphism may be associated with risk for vertebral fractures.

Osteoporosis is a common disease of bone possessing a strong genetic component. Cytochrome P450 aromatase, which is encoded by the CYP19A1 gene, converts androgens to estradiol. Considerable evidence suggests that extragonadal estrogens play an important role in determining bone mineral density (BMD) in postmenopausal women, and, among them, those synthesized in bone cells may also be important for the determination of bone phenotype. Therefore, CYP19A1 is an excellent candidate gene for osteoporosis. Since a region upstream of exon I.3, including exon I.6, was identified as containing repressor elements of promoter pII, we conducted a search for SNPs in this region of CYP19A1. Two SNPs [Aro1(rs4775936) and Aro2] located in exon I.6 and promoter I.6, respectively, were identified and their association with BMD analyzed in a cohort of 256 Spanish postmenopausal women. Aro1(rs4775936), but not Aro2, was associated with lumbar spine BMD (P = 0.029). Homozygotes AA (16% of the women) exhibited significantly higher lumbar spine BMD, compared with GG or GA individuals. Therefore, this study describes the Aro1 polymorphism which lies within a regulatory region and which may be a functional polymorphism, partially responsible for the bone phenotype it is associated with.

Context: Both bone mineral density (BMD) and fracture risk have a strong genetic component. Estrogen receptor alpha (ESR1) is a candidate gene for osteoporosis, but previous studies of ESR1 polymorphisms in this field were hampered by small sample size, lack of standardization, and inconclusive results., Objective: To generate large-scale evidence on whether 3 common ESR1 polymorphisms (intron 1 polymorphisms XbaI [dbSNP: rs9340799] and PvuII [dbSNP: rs2234693] and promoter TA repeats microsatellite) and haplotypes thereof are associated with BMD and fractures., Design and Setting: Meta-analysis of individual-level data involving standardized genotyping of 18 917 individuals in 8 European centers., Main Outcome Measures: BMD of femoral neck and lumbar spine; all fractures and vertebral fractures by genotype., Results: No between-center heterogeneity was observed for any outcome in any genetic contrast. None of the 3 polymorphisms or haplotypes had any statistically significant effect on BMD in adjusted or unadjusted analyses, and estimated differences between genetic contrasts were 0.01 g/cm2 or less. Conversely, we found significant reductions in fracture risk. In women homozygous for the absence of an XbaI recognition site, the adjusted odds of all fractures were reduced by 19% (odds ratio, 0.81 [95% CI, 0.71-0.93]; P = .002) and vertebral fractures by 35% (odds ratio, 0.65 [95% CI, 0.49-0.87]; P = .003). Effects on fractures were independent of BMD and unaltered in adjusted analyses. No significant effects on fracture risk were seen for PvuII and TA repeats., Conclusions: ESR1 is a susceptibility gene for fractures, and XbaI determines fracture risk by mechanisms independent of BMD. Our study demonstrates the value of adequately powered studies with standardized genotyping and clinical outcomes in defining effects of common genetic variants on complex diseases.

Single-nucleotide polymorphisms (SNPs) in regulatory regions of candidate genes may determine variability in bone mineral density (BMD) because they may be responsible for differences in levels of a gene product in response to external signals. Under this hypothesis, we scanned an 800-base pair (bp) region within the COL1A1 promoter, known to harbor cis elements important for in vivo expression, and we found two new polymorphisms: -1663indelT and -1997 G/T. The G to T transversion at -1997 was associated with lumbar spine BMD (p = 0.015) when tested in a cohort of 256 postmenopausal women after adjusting by age, body weight, and years since menopause; a lower degree of association was detected also for femoral neck BMD in a subgroup of 146 women in univariate analysis and after adjusting by age (p = 0.044). The polymorphism -1663indelT, which corresponds to a deletion of a T in a tract of eight T residues (-1670 to -1663), did not show significant association with BMD. Interestingly, -1663indelT is in strong linkage disequilibrium (LD) with the previously described Sp1 polymorphism of intron 1, which in this study did not show association with BMD either. Significant interaction between -1997 G/T and -1663indelT (p = 0.019), and between -1997 G/T and Sp1 (p = 0.045) was observed also. Individuals heterozygous for the three polymorphisms showed the highest mean BMD value. Gel retardation assays showed that oligonucleotides containing either the -1663 or the -1997 polymorphic sites specifically bind primary osteoblast nuclear proteins. We named these binding sites as PCOL1 and PCOL2, respectively. In summary, this study describes two new SNPs in the COL1A1 promoter, which may affect bone mass determination.