Peter Alexandersen

New sequence variants associated with bone mineral density.

In an extended genome-wide association study of bone mineral density among 6,865 Icelanders and a follow-up in 8,510 subjects of European descent, we identified four new genome-wide significant loci. These are near the SOST gene at 17q21, the MARK3 gene at 14q32, the SP7 gene at 12q13 and the TNFRSF11A (RANK) gene at 18q21. Furthermore, nonsynonymous SNPs in the C17orf53, LRP4, ADAM19 and IBSP genes were suggestively associated with bone density.

Peripheral Adiposity Exhibits an Independent Dominant Antiatherogenic Effect in Elderly Women

Background—Although several lines of evidence point to an atherogenic role of central fat mass (CFM), few data are available to address the specific role played by peripheral fat mass (PFM). Methods and Results—This study was a cross-sectional analysis of 1356 women aged 60 to 85 years. Study variables were physical measures, CFM and PFM measured by DEXA, aortic calcification (AC) graded on lateral radiographs, lipid and glucose metabolites, blood pressure, and information on lifestyle factors and coronary disease. Peripheral fat mass showed independent negative correlation with both atherogenic metabolic risk factors and AC (P <0.001). The most severe insulin resistance-dyslipidemic syndrome and AC (score 5.10±0.76) was found in women with high central fat percentage (CF%, 21.7±0.2%) and low peripheral fat percentage (PF%, 18.3±0.2%, n=48). The least severe AC (score 2.45±0.31) was found in obese women with high CF% (21.6±0.1%) and high PF% (27.3±0.14%, n=112). The insulin resistance-dyslipidemic syndrome was also less severe compared with those with the same CF% but low PF%. The most favorable metabolic profile characterized women with low CF% (11.56±0.16%) and high PF% (26.86±0.33%, n=44). In women with a history of myocardial infarct (18.41±0.55%, n=45), CF% was significantly higher compared with women with no manifest coronary disease (16.48±0.12%, n=1210) without differences in PF%. Conclusions—In elderly women, localization of fat mass is apparently more important for atherosclerosis than obesity per se; although CFM is associated with atherogenic tendencies, PFM seems to exhibit an independent dominant antiatherogenic effect.

The relationship of natural androgens to coronary heart disease in males: a review

Published studies dealing with the relationship between circulating levels of testosterone and dehydroepiandrosterone (sulfate) (DHEA(S)) and coronary heart disease (CHD) in males, as well as corresponding experimental animal studies are reviewed. One randomized intervention study, eight prospective and 30 cross-sectional studies have evaluated this relationship. In the intervention study, testosterone undecanoate given orally significantly improved angina pectoris in 62 patients with CHD as compared to placebo. No significant association between serum testosterone and CHD was reported in the prospective studies, whereas those studies concerning DHEAS found either no or an inverse association with CHD. Of 30 cross-sectional studies, 18 reported reduced concentrations of testosterone (primarily), and/or DHEA(S) in CHD patients as compared to normals, 11 found similar circulating levels of these androgens in controls and patients with CHD, and one study found elevated levels of DHEA(S) in patients. Animal studies (six male rabbits and one in male chicks) suggest an anti-atherogenic effect of testosterone and DHEA. In conclusion, one intervention, eight cohort and several cross-sectional studies suggest either a neutral or a favourable effect of testosterone and DHEA(S) on CHD in males.

Natural Androgens Inhibit Male Atherosclerosis: A Study in Castrated, Cholesterol-Fed Rabbits

The effect of natural androgens on serum lipids and atherosclerosis is controversial. We therefore studied this important issue prospectively in an animal model of atherosclerosis. Eighty male rabbits were randomized to bilateral castration, and 20 animals were sham operated. The castrated rabbits were randomized to 500 mg oral dehydroepiandrosterone (DHEA) daily, 80 mg oral testosterone undecanoate (TU) daily, or 25-mg intramuscular injection of testosterone enanthate (TE) twice weekly, whereas the fourth castrated group (placebo) and the sham-operated rabbits did not receive any hormones. All animals were fed a cholesterol-rich diet during the 30-week treatment period. Average serum lipids and atherogenic lipoproteins were higher in the placebo group than in the other groups (ANOVA, P<0.0001). Aortic atherosclerosis, as evaluated by the cholesterol content (nmol/mg protein), was also highest in the placebo group (308+/-39) and lowest in the TE group (61+/-12), but was intermediate in the DHEA (155+/-30), TU (191+/-43), and sham operation (162+/-29) groups (ANOVA, P<0.0001). ANCOVA indicated that the androgen effect on aortic atherosclerosis was only in part explained by the changes in lipoproteins. Aortic estrogen receptor contents were significantly lower in the androgen-treated groups than in the control groups, whereas there was no difference in aortic androgen receptor contents between groups. Natural androgens inhibit aortic atherosclerosis in castrated male rabbits only partly through a lipid-mediated effect.

Role of gastrointestinal hormones in postprandial reduction of bone resorption.

Collagen type I fragments, reflecting bone resorption, and release of gut hormones were investigated after a meal. Investigations led to a dose escalation study with glucagon like peptide‐2 (GLP‐2) in postmenopausal women. We found a dose‐dependent effect of GLP‐2 on the reduction of bone resorption.

Enlarged Waist Combined With Elevated Triglycerides Is a Strong Predictor of Accelerated Atherogenesis and Related Cardiovascular Mortality in Postmenopausal Women

Background—Upward trends of obesity urge more effective identification of those at cardiovascular risk. A simple dichotomous indicator, enlarged waist (≥88 cm) combined with elevated triglycerides (≥1.45 mmol/L) (EWET), was shown to offer advantages in identifying individuals with atherogenic “lipid overaccumulation” compared with other indicators, including the metabolic syndrome defined by the National Cholesterol Education Program (MS-NCEP). Whether EWET offers superior disease and event prediction in postmenopausal women, however, remains unknown. Methods and Results—A community-based sample of 557 women (48 to 76 years of age) were followed up for 8.5±0.3 years to assess the utility of EWET and MS-NCEP in estimating the risk of all-cause and cardiovascular mortality and the annual progression rate of aortic calcification. At baseline, 15.8% of women had EWET and 17.6% had MS-NCEP. All-cause mortality and cardiovascular mortality were increased in carriers of the dichotomous indicators (P<0.001). After adjustment for age, smoking, and LDL cholesterol, presence of EWET was associated with a 4.7-fold (95% CI, 2.2 to 9.8; P<0.001) increased risk and presence of MS-NCEP was associated with a 3.2-fold (95% CI, 1.5 to 6.5; P<0.001) increased risk for fatal cardiovascular events. Exclusion of women with prevalent diabetes did not change these trends; respective hazard ratios were 4.2 (95% CI, 1.9 to 9.3; P<0.001) and 2.5 (95% CI, 1.1 to 5.5; P<0.05). Among those who were discordant for EWET and MS-NCEP at baseline, those who had EWET alone (n=21) had a higher annual progression rate of aortic calcification compared with those who had MS-NCEP alone (n=31; P<0.05). Conclusions—The combined presence of EWET may be the best indicator of cardiovascular risk in postmenopausal women. Other components of the MS-NCEP add little medical value to screening in general practices.

Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche

Earlier menarche correlates with shorter adult height and higher childhood body fat. We conducted a genome-wide association study of age at menarche (AAM) on 15,297 Icelandic women. Combined analysis with replication sets from Iceland, Denmark and the Netherlands (N = 10,040) yielded a significant association between rs314280[T] on 6q21, near the LIN28B gene, and AAM (effect = 1.2 months later per allele; P = 1.8 × 10−14). A second SNP within the same linkage disequilibrium (LD) block, rs314277, splits rs314280[T] into two haplotypes with different effects (0.9 months and 1.9 months per allele). These variants have been associated with greater adult height. The association with adult height did not account for the association with AAM or vice versa. Other variants, previously associated with height, did not associate significantly with AAM. Given the link between body fat and AAM, we also assessed 11 variants recently associated with higher body mass index (BMI) and 5 of those associated with earlier AAM.

Sequence variants in the CLDN14 gene associate with kidney stones and bone mineral density

Kidney stone disease is a common condition. To search for sequence variants conferring risk of kidney stones, we conducted a genome-wide association study in 3,773 cases and 42,510 controls from Iceland and The Netherlands. We discovered common, synonymous variants in the CLDN14 gene that associate with kidney stones (OR = 1.25 and P = 4.0 × 10−12 for rs219780[C]). Approximately 62% of the general population is homozygous for rs219780[C] and is estimated to have 1.64 times greater risk of developing the disease compared to noncarriers. The CLDN14 gene is expressed in the kidney and regulates paracellular permeability at epithelial tight junctions. The same variants were also found to associate with reduced bone mineral density at the hip (P = 0.00039) and spine (P = 0.0077).

Serum CrossLaps for monitoring the response in individuals undergoing antiresorptive therapy

The Serum CrossLaps (CTx) enzyme-linked immunosorbent assay (ELISA) is specific for a cross-linked, beta-aspartate-isomerized form of the epitope EKAHDGGR derived from the carboxyterminal telopeptide region of type I collagen alpha(1) chain. Collagen type I fragments reactive in the CTx assay are released during osteoclastic bone resorption and can be used as a measure of bone resorption activity. Our objectives were to assess the intraindividual variation of serum CTx concentration as well as the clinical value of the serum CTx assay for monitoring antiresorptive therapy in individual patients. The influence of the sampling time and fasting on the serum CTx measurements was studied with the aim of determining an optimal sampling protocol. Studies of circadian variation in serum CTx concentration in 15 postmenopausal women showed that fasting significantly reduced the average circadian variation of the marker from 36% to 8.7%. This was further supported by assessing short-term (2 weeks) intraindividual variation in ten postmenopausal women who were sampled in the morning, either fasting or nonfasting. The average short-term intraindividual coefficient of variation (CV) was 7.9% in the samples obtained from fasting women, and 14.3% in the samples obtained from nonfasting women. The long-term intraindividual biological variation was 13.4% in 44 postmenopausal women sampled every 6 months (fasting morning samples) over a 1 year period. The ability of the serum CTx assay to monitor individual responses to antiresorptive therapy was assessed in studies of the effects of hormone replacement therapy (HRT) and bisphosphonate (alendronate). Serum samples (morning fasting) were obtained from postmenopausal women treated with either bisphosphonate or HRT at baseline and then after various timepoints of therapy. Spine bone mineral density (BMD) measurements were carried out and the annual percentage change in spine BMD (alphaBMD) was calculated. Sixteen of 17 (94%) of the HRT-treated and 12 of 13 (92%) of the bisphosphonate-treated women showed a decrease in serum CTx after 6 months that was greater than the calculated least significant change (LSC) of the marker (LSC(CTx)). In contrast, only 59% of the HRT-treated and 64% of the bisphosphonate-treated women showed a response in spine BMD greater than the LSC(BMD) 0%) from women with a loss in spine BMD (alphaBMD < 0%). In conclusion, the serum CTx showed high specificity and sensitivity for monitoring individual responses to antiresorptive therapy. More than 92% of the treated women showed significant responses in serum CTx measurements after 6 months.

Mechanism of circadian variation in bone resorption

The diurnal variation in bone resorption markers is poorly understood and may contain essential information about regulation of bone resorption. To explore the acute regulation of bone resorption we studied bone turnover in 14 postmenopausal women during a randomized, crossover, 24 h study of oral glucose tolerance test (OGTT), normal diet, or fasting. Whereas fasting counteracted variation in bone resorption, as measured by serum C-telopeptide fragments of collagen type 1 degradation (s-CTx), OGTT and normal diet induced a 50% reduction (p < 0.001) over 2 h. For OGTT, s-CTx reverted to baseline levels after 6 h, and for normal diet s-CTx remained suppressed during the afternoon and returned to baseline overnight. Repeated OGTT at 8:00 A.M. and 8:00 P.M. in nine postmenopausal women demonstrated that identical reductions in s-CTx could be obtained at both timepoints with an intermediate return to baseline between tests. A 2 h randomized, crossover study of OGTT and fasting in 23 men and premenopausal women similarly revealed a 50% decrease in s-CTx. A randomized, crossover 2 h study of insulin tolerance test compared with fasting in six men and premenopausal women demonstrated a 20%-30% decrease in s-CTx (p < 0.01-0.05). Nine hour follow-up of ten healthy individuals during a crossover experiment of OGTT, protein, and fat intake revealed a comparable 50% reduction in s-CTx, but distinct profiles of serum glucose and serum insulin. Bone resorption was reduced by intake of food, glucose, fat, and protein and counteracted by fasting, and this seems to have been be independent of age and gender. Both exogenous and endogenous insulin stimulation tests induced a reduction in bone resorption, but this was only partial when compared with the reduction observed during food intake.