Influence of Obesity on Bone Turnover Markers and Fracture Risk in Postmenopausal Women.

Background and aims: The relationship between obesity and bone metabolism is controversial. In recent decades, the protective role of obesity in the development of osteoporosis is questioned. The aims of this study are the following: to evaluate the differences in bone turnover markers between postmenopausal women with and without obesity and to compare the risk of fracture at five years between these groups. Methods: An observational longitudinal prospective cohort study of postmenopausal women with obesity (O) (body mass index (BMI) > 30 kg/m2) and non-obesity (NoO) (BMI < 30 kg/m2) is designed. 250 postmenopausal women are included in the study (NoO: 124 (49.6%) and O: 126 (50.4%)). It measures epidemiological variables, dietary variables (calcium intake, vitamin D intake, smoking, alcohol consumption, and physical activity), biochemicals (ß-crosslap, type I procollagen amino-terminal peptide (P1NP), 25OH-vitamin D, and parathyroid hormone (PTH)), anthropometric variables, and fracture data five years after the start of the study. The mean age is 56.17 (3.91) years. Women with obesity showed lower levels of vitamin D (O: 17.27 (7.85) ng/mL, NoO: 24.51 (9.60) ng/mL; p < 0.01), and higher levels of PTH (O: 53.24 (38.44−65.96) pg/mL, NoO: 35.24 (25.36−42.40) pg/mL; p < 0.01). Regarding the bone formation marker (P1NP), it was found to be high in women without obesity, O: 45.46 (34.39−55.16) ng/mL, NoO: 56.74 (45.34−70.74) ng/mL; p < 0.01; the bone resorption marker (ß-crosslap) was found to be high in women with obesity, being significant in those older than 59 years (O: 0.39 (0.14) ng/mL, NoO 0.24 (0.09) ng/mL; p < 0.05). No differences are observed in the risk of fracture at 5 years based on BMI (OR = 0.90 (95%CI 0.30−2.72); p = 0.85). Conclusions: Postmenopausal women with obesity showed lower levels of bone formation markers; older women with obesity showed higher markers of bone resorption.

Estrogen receptor genes polymorphisms determine serum lipid profile in healthy postmenopausal women treated with calcium, vitamin D, and genistein.

Cardiovascular risk increases in women after menopause. Unfavorable lipid-lipoprotein changes due to a lack of estrogens may have an important role in this context. Estrogen actions are mainly mediated by their binding to two estrogen receptors (ERs) whose signaling may be conditioned by different factors. Calcium, vitamin D, and genistein, among others, cause a beneficial effect on serum lipid profile by its modulation. Some genetic factors can also determine this signal. We determined the possible additive effect of genistein on calcium and vitamin D supplementation regarding serum lipid profile changes and whether ER polymorphisms may mediate in this effect. We performed a prospective, double blind study in which women were randomized in two groups: one group received calcium and vitamin D and the other group received calcium, vitamin D and genistein. Subsequently, we studied rs9340799, rs928554, and rs4986938 ER polymorphisms in both groups. Our results showed that being a carrier of the variant allele G of rs928554 polymorphism was associated with a greater decrease in triglyceride levels and that the homozygous AA genotype of rs9340799 polymorphism was associated with a greater decrease in total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels after calcium, vitamin D, and genistein supplementation. This is the first report showing an association between polymorphisms in ER genes and an improvement of the serum lipid profile after taking calcium, vitamin D, and genistein supplementation in postmenopausal women. It reinforces the hypothesis that genetic factors are crucial in ER signalling.

Impact of obesity on bone metabolism. / Influencia de la obesidad sobre el metabolismo óseo.

High weight is a protective factor against osteoporosis and risk of fracture. In obesity, however, where overweight is associated to excess fat, this relationship does not appear to be so clear, excess weight has sometimes been associated to decreased bone mass. Obesity interferes with bone metabolism through mechanical, hormonal, and inflammatory factors. These factors are closely related to weight, body composition, and dietary patterns of these patients. The net beneficial or harmful effect on bone mass or risk of fracture of the different components of this condition is not well known. We need to recognize patients at a greater risk of bone disease related to obesity to start an adequate intervention.

Circulating sclerostin and estradiol levels are associated with inadequate response to bisphosphonates in postmenopausal women with osteoporosis.

INTRODUCTION: The biological mechanisms associated with an inadequate response to treatment with bisphosphonates are not well known. This study investigates the association between circulating levels of sclerostin and estradiol with an inadequate clinical outcome to bisphosphonate therapy in women with postmenopausal osteoporosis. METHODS: This case-control study is based on 120 Spanish women with postmenopausal osteoporosis being treated with oral bisphosphonates. Patients were classified as adequate responders (ARs, n=66, mean age 68.2±8 years) without incident fractures during 5 years of treatment, or inadequate responders (IRs, n=54, mean age 67±9 years), with incident fractures between 1 and 5 years of treatment. Bone mineral density (DXA), structural analysis of the proximal femur and structural/fractal analysis of the distal radius were assessed. Sclerostin concentrations were measured by ELISA and 17ß-estradiol levels by radioimmunoassay based on ultrasensitive methods. RESULTS: In the ARs group, sclerostin serum levels were significantly lower (p=0.02) and estradiol concentrations significantly higher (p=0.023) than in the IRs group. A logistic regression analysis was performed, including as independent variables in the original model femoral fracture load, 25 hydroxyvitamin D, previus history of fragility fracture, sclerostin and estradiol. Only previous history of fragility fracture (OR 14.04, 95% CI 2.38-82.79, p=0.004) and sclerostin levels (OR 1.11, 95% CI 1.02-1.20, p=0.011), both adjusted by estradiol levels remained associated with IRs. Also, sclerostin concentrations were associated with the index of resistance to compression (IRC) in the fractal analysis of the distal radius, a parameter on bone microstructure. CONCLUSIONS: Sclerostin and estradiol levels are associated with the response to bisphosphonate therapy in women with postmenopausal osteoporosis.

Expression of genes related to energy metabolism (osteocalcin, FOXO1, insulin receptor, and SOST) in bone cells of Goto-Kakizaki rats and response to bariatric surgery.

OBJECTIVES: The aim of this experimental study was to evaluate the expression of 4 genes (osteocalcin, sclerostin (SOST), insulin receptor, and transcription factor forkhead box protein (FOXO1) in the bone cells of Goto-Kakizaki (GK) rats and the expression of these genes in response to bariatric surgery. METHODS: We designed an experimental study with 3 arms (Wistar rats, nonoperated GK rats, and GK rats with gastrojejunal bypass). Gene expression (osteocalcin, insulin receptor, FOXO1, SOST) was measured at baseline and after surgery. Plasma levels of glucose, insulin, homeostasis model assessment (HOMA), glucagon-like peptide 1 (GLP-1), and the production of insulin were measured at baseline and at 60 minutes by pancreatic islets. RESULTS: GK rats had decreased levels of expression of osteocalcin (50.86 ± 19.21 versus 16.78 ± 22.11, P = .031), insulin receptor (1.45 ± .44 versus .54 ± .35, P = .020), and SOST (.92 ± .05 versus .43 ± .47, P = .048) compared with Wistar rats. Gene expression in GK rats, operated and nonoperated, was similar. In nonoperated GK rats, there was a negative correlation between the SOST gene and plasma insulin (r:-.786, P = .021) and the production of insulin by pancreatic islets at 60 minutes (r:-0.857, P = .014). GLP-1 increased after surgery. CONCLUSION: Diabetic GK rats presented a reduced expression of the osteocalcin, insulin receptor, and SOST genes. There was an inverse relationship between SOST and plasma and local insulin. We found no changes in the expression of bone genes that regulate energy metabolism after gastrojejunal bypass.

Effect of two types of bariatric surgery (gastrojejunal bypass and sleeve gastroplasty) on gene expression of bone remodeling markers in Goto-Kakizaki rats.

BACKGROUND: The aim of this study was to evaluate gene expression of bone remodeling markers in type 2 diabetic Goto-Kakizaki (GK) nonobese rats after gastrojejunal bypass and sleeve gastroplasty and their relationship with hormonal parameters. METHODS: We designed an experimental study in three groups of GK rats (nonoperated gastrojejunal bypass and sleeve gastroplasty). Gene expression of markers of bone remodeling and levels of insulin, leptin, and glucagon-like peptide-1 (GLP-1) were determined. RESULTS: GK rats had decreased levels of osteocalcin expression compared with Wistar rats. Gene expression of markers of bone remodeling in GK rats was similar in the three groups studied, although there was a trend to decreased receptor activator for nuclear factor κ B ligand (RANKL) in gastroplasty rats. Significant differences in the osteocalcin/RANKL ratio were observed between controls and gastrojejunal bypass rats compared with gastroplasty rats. The behavior of gastrointestinal hormones was antagonistic (GLP-1 gastrojejunal bypass 1.54 ± 0.24 ng/ml vs. GLP-1 gastroplasty 0.673 ± 0.09, p = 0.0001; leptin gastrojejunal bypass 1,178 ± 0.474 pg/ml vs. leptin gastroplasty 7,391 ± 4,054 pg/ml, p = 0.002). There was a reduction in leptin in the bypass group associated with an increase in gastrectomized rats. In gastrectomized rats, there was a trend toward an inverse relationship between leptin and RANKL (r = -0.771, p = 0.072). This relationship was more marked in the totality of operated rats, n = 12 (r = -0.608, p = 0.036). CONCLUSION: Our results show a more favorable profile of sleeve gastroplasty on bone remodeling. There was a trend to an increase in the expression of the osteocalcin gene, which is probably mediated by increased expression of leptin that inhibits the expression of RANKL.

Genetic polymorphisms of the Wnt receptor LRP5 are differentially associated with trochanteric and cervical hip fractures.

Epidemiological studies suggest that cervical and trochanteric hip fractures have different pathogenesis. We tested the hypothesis that genetic factors have different influences on both types of fractures. Ten polymorphisms of genes known to play an important role in skeletal homeostasis [estrogen receptor alpha (ESR1), aromatase (CYP19A1), type I collagen (COL1A1), and lipoprotein receptor-related protein 5 (LRP5)] were analyzed in 471 Spanish patients with fragility hip fractures. Two polymorphisms of the LRP5 gene (rs7116604 and rs3781600) were associated with the type of fracture (P = 0.0085 and 0.0047, respectively). The presence of rare alleles at each locus was associated with trochanteric fractures over cervical fractures (OR = 1.7 in individuals with at least one rare allele at rs7116604 or rs3781600 loci in comparison with the common homozygotes). Considering individuals bearing the four common alleles as reference, the OR for trochanteric fractures was 1.6 in those with one or two rare alleles and 7.5 in those with three or four rare alleles (P for trend = 0.0074), which is consistent with an allele-dosage effect. There were no significant differences in the frequency distributions of the ESR1, CYP19A1, and COL1A1 genotypes between trochanteric and cervical fractures in either the original group or an extended group of 818 patients. These results suggest that LRP5 alleles influence the type of hip fractures. They support the view that different genetic factors are involved in cervical and trochanteric fractures, which should be taken into consideration in future genetic association studies.

Haplotypes of intron 4 of the estrogen receptor alpha gene and hip fractures: a replication study in Caucasians.

BACKGROUND: Despite their great impact, few genetic association studies have used hip fractures as an endpoint. However, the association of two polymorphisms on intron 4 of estrogen receptor alpha (ESR1) with hip fractures was recently reported in a Chinese population. The aim of this study was to investigate whether such association is also present in Caucasians. METHODS: We analyzed those two SNPs and another neighbour SNP located on the exon 4 of ESR1 in 787 patients with hip fractures and 953 controls from Spain. RESULTS: The allelic frequencies differed markedly from those reported in Asian populations. Nevertheless, haplotypes including the rs3020314 and rs1884051 loci in intron 4 showed a significant association with hip fractures (omnibus test p = 0.006 in the whole group and 0.00005 in women). In the sex-stratified analysis, the association was significant in females, but not in males. In women, the CA haplotype appeared to have a protective influence, being present in 6.5% of the controls, but only in 3% of patients with fractures (odds ratio 0.39; 95% confidence interval 0.26-0.59; estimated population preventive fraction 3.5%). The inclusion of the rs1801132 SNP of exon 4 further increased the statistical significance of the association (odds ratio 0.17; 95% CI 0.08-0.37; p = 0.00001). Each SNP appeared to contribute independently to the association. No genotype-related differences in gene expression were found in 42 femoral bone samples. CONCLUSIONS: This study confirms the association of some polymorphisms in the region of exon 4/intron 4 of ESR1 and hip fractures in women. However, there are marked differences in allele frequencies between Asian and Caucasian populations.

Polymorphisms of the WNT10B gene, bone mineral density, and fractures in postmenopausal women.

Wnt ligands are important regulators of skeletal homeostasis. Wnt10B tends to stimulate the differentiation of common mesenchymal precursors toward the osteoblastic lineage, while inhibiting adipocytic differentiation. Hence, we decided to explore the association of WNT10B allelic variants with bone mineral density and osteoporotic fractures. A set of tag SNPs capturing most common variations of the WNT10B gene was genotyped in 1438 Caucasian postmenopausal women, including 146 with vertebral fractures and 432 with hip fractures. We found no association between single SNPs and spine or hip bone mineral density (BMD). In the multilocus analysis, some haplotypes showed a slight association with spine BMD (P = 0.03), but it was not significant after multiple-test correction. There was no association between genotype and vertebral or hip fractures. Transcripts of WNT10B and other Wnt ligands were detected in human bone samples by real-time PCR. However, there was no relationship between genotype and RNA abundance. Thus, WNT10B is expressed in the bone microenvironment and may be an important regulator of osteoblastogenesis, but we have not found evidence for a robust association of common WNT10B gene allelic variants with either BMD or fractures in postmenopausal women.

Ghrelin and bone mass in postmenopausal hypertensive women.

BACKGROUND: Ghrelin, a recently discovered peptide mainly secreted by the stomach, has an orexigenic effect which stimulates secretion of the growth hormone. It also has vasodilator effects which reduce blood pressure and stimulate in vitro, bone formation. OBJECTIVES: To evaluate the effect of ghrelin on bone mass and bone remodeling markers in postmenopausal hypertensive women. MATERIAL AND METHODS: 25 postmenopausal hypertensive women, light to moderate based on the JNC-VII criteria, were studied. They had a mean age of 58 +/- 8 years, a body mass index of 28 +/- 6 and a hypertension development time of 65 +/- 84 months. Osteocalcin, PTHi, 25-vitamin D, ghrelin in serum and deoxypiridinoline in urine were determined in all patients. A lumbar spine densitometer was made (DXP Lunar, Madison, Wisc., USA). RESULTS: Diminished levels of ghrelin were observed in the osteoporotic group (40 +/- 19 vs. 78 +/- 40, p = 0.027). When the patients were separated according to ghrelin tertiles, a greater bone mass was observed in the upper tertiles, which was associated with a decrease in the urinary deoxypiridinoline. When the total population was analyzed, no relation between the ghrelin and bone mass was found, nor with any of the parameters of calcium metabolism. Only a statistically significant relation between ghrelin and deoxypiridinoline was observed (r = -0.428, p = 0.026). CONCLUSIONS: In postmenopausal hypertensive women, ghrelin may produce a protecting effect over bone mass through an anticatabolic mechanism manifested by a decrease of bone resorption.