Association between a variation in the phosphodiesterase 4D gene and bone mineral density

BACKGROUND: Fragility fractures caused by osteoporosis are a major cause of morbidity and mortality in aging populations. Bone mineral density (BMD) is a useful surrogate marker for risk of fracture and is a highly heritable trait. The genetic variants underlying this genetic contribution are largely unknown. METHODS: We performed a large-scale association study investigating more than 25,000 single nucleotide polymorphisms (SNPs) located within 16,000 genes. Allele frequencies were estimated in contrasting DNA pools from white females selected for low (<0.87 g/cm(2), n = 319) and high (> 1.11 g/cm(2), n = 321) BMD at the lumbar spine. Significant findings were verified in two additional sample collections. RESULTS: Based on allele frequency differences between DNA pools and subsequent individual genotyping, one of the candidate loci indicated was the phosphodiesterase 4D (PDE4D) gene region on chromosome 5q12. We subsequently tested the marker SNP, rs1498608, in a second sample of 138 white females with low (<0.91 g/cm(2)) and 138 females with high (>1.04 g/cm(2)) lumbar spine BMD. Odds ratios were 1.5 (P = 0.035) in the original sample and 2.1 (P = 0.018) in the replication sample. Association fine mapping with 80 SNPs located within 50 kilobases of the marker SNP identified a 20 kilobase region of association containing exon 6 of PDE4D. In a second, family-based replication sample with a preponderance of females with low BMD, rs1498608 showed an opposite relationship with BMD at different sites (p = 0.00044-0.09). We also replicated the previously reported association of the Ser37Ala polymorphism in BMP2, known to interact biologically with PDE4D, with BMD. CONCLUSION: This study indicates that variants in the gene encoding PDE4D account for some of the genetic contribution to bone mineral density variation in humans. The contrasting results from different samples indicate that the effect may be context-dependent. PDE4 inhibitors have been shown to increase bone mass in normal and osteopenic mice, but up until now there have been no reports implicating any member of the PDE4 gene family in human osteoporosis

Correlation of estrogen receptor beta gene polymorphisms with spinal bone mineral density in peri- and post-menopausal Greek women

Estrogens play a significant role in bone physiology. Their action is mainly exerted through their receptors. Estrogen receptor alpha (ER alpha) plays a major role in bone homeostasis and there is evidence suggesting that estrogen receptor beta (ER beta) has also an effect on BMD. We investigated the possible effect of two ER beta gene polymorphisms on spinal bone mineral density (BMD) and metabolic bone markers in Greek women. Spine BMD as well as biochemical bone markers were measured in 147 healthy peri- and post-menopausal women [mean age (S.D.) 54 (7.9) years]. Genotyping was performed for two restriction fragment length polymorphisms (RFLPs) of ER beta gene, Rsal in exon 5 and Alul in exon 8. For each polymorphism studied the cohort was divided into two groups: the '' wild-type '' group (RR and AA, respectively) and the '' carrier '' group including subjects with at least one allele with the restriction site (Rr&rr and Aa&aa, respectively). The distribution of Rsal genotypes was RR: 91.2% (n = 134). Rr: 8.2% (n = 12), and rr: 0.6% (n = 1) and of Alul genotypes AA: 36.7% (n = 54), Aa: 57.2% (n = 84), and aa: 6.1 % (n = 9). No linkage disequilibrium was found between the two polymorphic sites studied. Spine BMD did not differ significantly in the two groups of either polymorphism, after adjusting for age, weight, height, and years since menopause [mean BMD (S.D.) for RR 0.841 (0.17) g/cm(2) versus Rr&rr 0.798 (0.13) g/cm(2), p = 0.25, and mean BMD (S.D.) for AA 0.828 (0.16) g/cm(2) versus Aa&aa 0.848 (0.17) g/cm(2), p = 0.32]. No significant differences were noted We in metabolic bone markers except for a marginal difference of RR versus Rr/rr in urinary hydroxyproline/creatinine ratio [median (IQR) 3.88 (6.04) mu mol/mmol in RR versus 8.2 (4.32) mu mol/mmol in Rr/rr, p = 0.05]. Furthermore, no interaction between the two polymorphisms on BMD was found. In conclusion, in a Greek female post-menopausal population, the two ER beta gene polymorphisms were not associated with BMD, or metabolic bone markers. (c) 2005 Elsevier Ireland Ltd. All rights reserved

Associations of Estrogen Receptor Alpha and Beta Gene Polymorphisms with Sex Steroid Levels and Body Fat Content in Men

Objective: Estrogens play an important role in male physiology. We investigated the possible association of four single nucleotide polymorphisms in Estrogen Receptor alpha (ESR1) and Estrogen Receptor beta (ESR2) genes with circulating levels of sex steroids and Sex Hormone Binding Globulin (SHBG) in men. Design and Methods: SHBG, total and calculated free testosterone (TT and cal FT), estradiol (E2) and free Estradiol (FE2) were determined in a population-based cohort of 170 apparently healthy Greek men. Body mass index (BMI), waist circumference (WC) and percentage of body fat (%fat) content were measured in all participants. Genotyping for the Pvu II and Xba I polymorphisms of the ESR1 gene and for the Rsa I and Alu I polymorphisms of the ESR2 gene was performed. Results: Pvu II showed an association with E2 levels [median (IQR) pp 58.5 (42.1-73.4) pg/ml vs. Pp 48.8 (42.9-60.1) and PP 57.7 (44-70.5),p = 0.032], and with %fat [mean +/- SD pp 24.6 +/- 5.3 vs. Pp 22.4 +/- 5.2 and PP 21.2 +/- 6.7, p = 0.044], after adjustment for age and WC. Furthermore, the effect of Pvu II on E2 was independent of %fat (p = 0.038). A synergistic effect of the two ESR1 polymorphisms on E2 (p = 0.023), FE2 (p = 0.03) and %fat (p = 0.004) was present. Finally, a synergistic effect of the ESR1 and ESR2 genes on TT (p = 0.009), independent of age, WC and %fat also emerged. Conclusions: Genetic variation in ESR1 is associated with serum estradiol levels and body fat content regulation in men. Furthermore, a synergistic effect of ESR1 and ESR2 genes is exerted on serum testosterone levels

Effect of Exogenous Intermittent Recombinant Human PTH 1-34 Administration and Chronic Endogenous Parathyroid Hormone Excess on Glucose Homeostasis and Insulin Sensitivity

We aimed to evaluate the effects of exogenous intermittent teriparatide (rhPTH 1-34) administration versus the chronic exposure to excess endogenous parathyroid hormone (PTH), as in pHPT, on glucose homeostasis. Two patient groups were studied: Group 1 included 25 normocalcemic women with postmenopausal osteoporosis (age 65.2 +/- 1.6 years) studied before and six months after teriparatide initiation; Group 2 included 19 postmenopausal women with pHPT (age 55.2 +/- 2.5 years) studied before and six months after successful parathyroidectomy. Calcium - total (Ca) and corrected (CCa) - ALP, PTH, as well as glucose and insulin concentrations during an oral glucose tolerance test (OGTT) were determined before and six months after either intervention. Area under the curve for glucose (AUCglu) and insulin (AUCins) were calculated. Delta Ins30'/Delta Glu30' was applied as an index of insulin secretion. The HOmeostasis Model of Assessment (HOMA) and Matsuda ISI (Insulin Sensitivity Index) were used to calculate insulin resistance (IR) and whole body insulin sensitivity, respectively. In Group I no difference was found in any OGTT-derived parameter. In Group 2 significant reductions in AUCins and Delta Ins30'/Delta Glu30' were observed. No correlation between the change in Delta CCa or Delta PTH Delta AUCglu or Delta AUCins was found in either group. Our data suggest that while subtle transient alterations of Ca and PTH within the normal range as in exogenous rhPTH 1-34 administration do not affect glucose homeostasis, the continuously elevated Ca and endogenous PTH levels as in pHPT affect insulin sensitivity and result in increased insulin secretion

Associations of Estrogen Receptor Alpha and Beta Gene Polymorphisms with Lipid Levels and Insulin Resistance in Men

Objective. The association of four single nucleotide polymorphisms in estrogen receptor alpha (ESR1) and beta (ESR2) genes with lipid levels and insulin resistance in men. Design and methods. Lipids, glucose, insulin and HOMA-IR were determined, in a population-based, cross-sectional, cohort of 170 apparently healthy middle-aged Greek men, along with body mass index (BMI), waist circumference (WC) and percentage of body fat content (%fat). Genotyping of ESR1 for Pvull and XbaI and ESR2 for RsaI and AluI polymorphisms was performed. Results. Associations of AluI with LDL-Chol (mean +/- SD, aa 4.3 +/- 1.1 vs. Aa 3.7 +/- 1.0 and AA 4.2 +/- 1.1, p = 0.023) and RsaI with HOMA-IR [median (IQR), RR 1.55 (0.88-2.49) vs. Rr/rr 1.69 (0.72-2.29), p = 0.032] were found. Synergistic effects of RsaI and AluI of ESR2 gene on LDL-Chol levels, %fat and WC, as well as a synergistic effect of both ESR1 and ESR2 genes on levels of TChol (p = 0.01) and LDL-Chol (p = 0.027) were also shown. These findings remained significant after adjustment for potential confounders. Significant independent associations of PvuII with %fat (mean +/- SD, pp 24.6 +/- 5.3 vs Pp 22.4 +/- 5.2 and PP 21.2 +/- 6.7, p = 0.044), and RsaI with %fat (RR 22.6 +/- 5.5 vs. Rr/rr 25.2 +/- 6.3, p = 0.015) and WC (mean +/- SD, RR 97.4 +/- 10.4 vs. Rr/rr 102.6 +/- 12.6, p = 0.013) were found. Synergistic effects on %fat, between the ESR1 polymorphisms (p = 0.004), between the ESR2 polymorphisms and among all four ESR polymorphisms studied were also present. Conclusions. ESR2 is associated with LDL-Chol levels and HOMA-IR in men independently of confounders. Body fat is affected by both genes. Furthermore, a synergistic effect of ESR1 and ESR2 on TChol, LDL-Chol and %fat, was shown. (C) 2015 Elsevier Inc. All rights reserved

Endogenous intact PTH is suppressed during teriparatide (rhPTH 1-34) administration in postmenopausal women with established osteoporosis

Introduction: Teriparatide (recombinant human PTH 1-34/TPTD) is an osteoanabolic agent available for osteoporosis treatment. The aim of this prospective trial was to evaluate the acute and chronic effects of TPTD in endogenous intact PTH (iPTH) levels in postmenopausal women with established osteoporosis. Materials and methods: Thirty-six postmenopausal Caucasian women (age 66.6 +/- 1.4 years) with established osteoporosis received TPTD 20 mu g once daily for eighteen months. Follow-up was continued for another six months after treatment discontinuation for a total of 24 months. Serum calcium, phosphate, total alkaline phosphatase (ALP) and iPTH were obtained from all women before and one hour, one day, as well as one, six, twelve, 18 and 24 months after treatment initiation. Lumbar spine bone mineral density was measured before, as well as twelve and eighteen months after treatment initiation. Results: iPTH levels decreased from the first hour of treatment, remained suppressed as long as TPTD was administered and increased after treatment discontinuation (p < 0.001). Total ALP followed an opposite pattern. Serum calcium remained within normal range. Conclusions: iPTH levels are suppressed rapidly and persistently during TPTD administration whereas they return to baseline after treatment discontinuation; therefore, they can serve as an index of patient's compliance to treatment

Oxidative Stress and Reduced Antioxidative Status, along with Endothelial Dysfunction in Acromegaly

Acromegaly is characterized by high cardiovascular morbidity and mortality. Oxidative stress and endothelial dysfunction are underlying mechanisms of atherosclerosis. The aim of this study was to evaluate the blood redox status and endothelial function by means of nitric oxide (NO) levels in patients with acromegaly. Total antioxidant capacity (TAC), catalase activity and glutathione concentration (GSH), as measures of antioxidative capacity, total oxidized glutathione (GSSG) and thiobarbituric acid reactive substances (TBARS), as indices of oxidative stress, and NO levels were assessed in 15 patients with acromegaly (age 55.4 +/- 10.5 years; 6 males) and 15 age-and sex-matched controls (age 58.4 +/- 8.1 years; 7 males). Active disease was present in 12 patients: 11 on current pharmacotherapy and 1 newly diagnosed. Three acromegalics were in remission after successful treatment. Acromegalics as compared with controls had significantly lower levels of catalase activity (8.2 +/- 5.8 vs. 51.3 +/- 29.1 mmol/ml/min, p < 0.001), GSH (0.97 +/- 0.54 vs. 1.41 +/- 0.35 mmol/l, p = 0.006), GSSG (0.27 +/- 0.19 vs. 2.04 +/- 1.32 mmol/l, p = 0.002) and NO levels (6.0 +/- 3.1 vs. 43.0 +/- 29.8 mmol/l, p < 0.001), but higher TBARS (16.3 +/- 8.9 vs. 10.1 +/- 10.8, nmol/ml, p = 0.019). After adjustment for confounders, differences in catalase activity, NO levels and TBARS remained signifi cant (p = 0.004, p < 0.001 and p = 0.025, respectively). No association between IGF-I/GH and oxidative stress markers was noticed, except for a positive correlation between nadir GH and GSSG (r(2) = 0.563, p = 0.036). Acromegaly is associated with increased levels of oxidative stress coupled by diminished antioxidant capacity and endothelial dysfunction indicated by the presence of decreased NO levels

Profound hypocalcemia following effective response to zoledronic acid treatment in a patient with juvenile Paget&apos;s disease

Juvenile Paget&apos;s disease (JPD) is a rare, autosomal recessive osteopathy. Although it has phenotypic overlap with Paget&apos;s disease of bone (PDB), it is probably a distinct entity. Because of its rarity, optimal disease management has not yet been established by randomized controlled trials. However, clinical, biochemical, and radiographic improvement has been reported after treatment with antiresorptive agents, including calcitonin and bisphosphonates (BPs). Compared with other BPs, zoledronic acid (ZOL) has a higher affinity to bone mineral and is a stronger inhibitor of the enzyme farnesyl pyrophosphate synthase (the main target of nitrogen-containing BPs), properties that explain the prolonged effect of ZOL on bone turnover and render it a therapeutic option for JPD, similar to PDB. We describe hereby, for the first time in the literature, the case of a patient with JPD who developed severe hypocalcemia and secondary hyperparathyroidism following effective treatment with ZOL. © 2010 The Japanese Society for Bone and Mineral Research and Springer

Head-to-head comparison of risedronate vs. teriparatide on bone turnover markers in women with postmenopausal osteoporosis: a randomised trial

Aims: We aimed to compare the effect of risedronate (RIS) and teriparatide (TPTD) (recombinant human parathyroid hormone 1-34) on bone turnover markers in women with postmenopausal osteoporosis. Methods: Forty-four Caucasian women (age 65.1 +/- 1.6 years) with postmenopausal osteoporosis were randomly assigned to receive either RIS 35 mg once weekly (n = 22) or TPTD 20 mu g once daily (n = 22) for 12 months. Serum N-terminal propeptide of type 1 collagen (P1NP), C-terminal telopeptide of type 1 collagen (CTx), total alkaline phosphatase (ALP) and intact parathyroid hormone (iPTH) were obtained from all women before, 3 and 6 months after treatment initiation. Lumbar spine bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry before and 12 months after treatment initiation. Results: P1NP, CTx and total ALP levels decreased in RIS group (p < 0.001) and increased in TPTD group (p < 0.001) throughout the treatment. iPTH increased significantly in RIS group (p < 0.05) and decreased in TPTD group (p < 0.001). Finally, lumbar spine BMD increased significantly in both RIS (p = 0.003) and TPTD groups (p < 0.001) without significant differences between them. Conclusions: Our data suggest that both serum P1NP and CTx are reliable markers of RIS and TPTD action in women with postmenopausal osteoporosis. In a similar way, serum total ALP can be used as an alternative marker for monitoring both RIS and TPTD action, while iPTH can be used only for TPTD-treated women. The increase in P1NP and CTx after 3 months of treatment with RIS or TPTD can predict the increase in BMD after 12 months of treatment