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BACKGROUND: Genetic and environmental factors influence cognitive aging. The gene encoding dopamine beta-hydroxylase (DBH) could be one such factor since this hydroxylase converts dopamine to norepinephrine both of which are involved in cognition regulation. OBJECTIVE: To assess the effect of the 19bp insertion/deletion polymorphism in the 5' flank of the DBH gene on cognitive performance in elderly women relative to other factors of cognitive aging. METHODS: We examined a cross-sectional sample of 1371 postmenopausal women. Cognitive abilities were assessed by the 6-item orientation-memory-concentration test. The 19bp insertion/deletion polymorphism of the DBH gene was genotyped and apolipoprotein E (APOE) epsilon4 allele status was determined. In addition blood pressure, body fat mass and blood lipids were measured. Information was also obtained by personal interviews. Data were analyzed by regression analysis. RESULTS: Cognition was univariately associated with DBH genotype (p = 0.04). A univariate association of borderline significance was observed for APOE epsilon4 allele status (p = 0.07). Exclusion of women with severe cognition impairment did not alter the strength of the association with the DBH gene polymorphism markedly (p = 0.06) but obliterated the weak association between APOE epsilon4 allele status and cognition. The association of the DBH gene polymorphism with cognition persisted after adjustment for other variables (p = 0.03). CONCLUSIONS: The 19bp insertion/deletion polymorphism of the DBH gene influences cognition in elderly women and might have a stronger effect than APOE epsilon4 allele status on mild cognitive impairment. Both genetic polymorphisms had a significantly smaller impact on cognition than age, education, alcohol consumption and body fat measures. Copyright (c) 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Endometriosis requires medical management during a woman's reproductive years. Most treatments aim to create a hypoestrogenic milieu, but for patients wishing to conceive, drugs that allow normal ovarian function are needed. Targeting angiogenesis, a hallmark of the disease, using dopamine agonists (DAs) is a promising strategy for endometriosis treatment. Herein, we review experimental and clinical data that investigate this concept. In experimental models of endometriosis, DAs (bromocriptine, cabergoline, quinagolide) downregulate proangiogenic and upregulate antiangiogenic pathways in inflammatory, endothelial and endometrial cells, blocking cellular proliferation and reducing lesion size. Impaired secretion of vascular endothelial growth factor (VEGF) and inactivation of its receptor type-2 are key events. VEGF inhibition also reduces nerve fiber density in lesions. In humans, quinagolide shows similar effects on lesions, and DAs reduce pain and endometrioma size. Moreover, a 20-fold downregulation of Serpin-1, the gene that encodes for plasminogen activator inhibitor 1 (PAI-1), has been observed after DAs treatment. Pentoxifylline, a PAI-1, increases pregnancy rates in women with endometriosis. Thus, the data support the use of DAs in the medical management of endometriosis to reduce lesion size and pain while maintaining ovulation. A combined approach of DAs and pentoxifylline is perhaps a smart way of targeting the disease from a completely different angle than current medical treatments., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Depression has a multifactorial etiology which involves genetic factors and comorbid diseases., Methods: A cross-sectional sample of 1371 elderly women (mean age=69.2 years) was examined. Detailed information on their health was obtained. Cognitive functions were assessed by the Short Blessed Test and the Animal Naming Task. A 19 bp insertion/deletion polymorphism in the dopamine beta-hydroxylase (DBH) gene, the apolipoprotein (APOE) epsilon2/epsilon3/epsilon4 variation and 5-HTTLPR in the serotonin transporter gene were genotyped., Results: Depression was univariately associated with homozygosity for the DBH gene 19 bp deletion allele (odds ratio [OR]=1.96, 95% confidence intervals [95% CI]=1.17-3.29, p=0.01), family history of depression (OR=3.86, 95% CI=1.85-8.06, p=0.0003), a composite measure of cardiovascular diseases (OR=1.96, 95% CI=1.11-3.47, p=0.02), cognitive impairment assessed by the Short Blessed Test (OR=3.88, 95% CI=1.29-11.64, p=0.02) and performance on the Animal Naming Task (OR=0.74, 95% CI=0.59-0.93, p=0.01). The strength of the association of DBH genotype with depression essentially remained unchanged after correction for other variables in a multivariate model. This association may reflect noradrenaline dysfunction in the brain.

Introduction and Hypothesis: Epidemiological observations suggest links between osteoporosis and risk of acute cardiovascular events and vice versa. Whether the two clinical conditions are linked by common pathogenic factors or atherosclerosis per se remains incompletely understood. We investigated whether serum lipids and polymorphism in the ApoE gene modifying serum lipids could be a biological linkage., Methods: This was an observational study including 1176 elderly women 60-85 years old. Women were genotyped for epsilon (epsilon) allelic variants of the ApoE gene, and data concerning serum lipids (total cholesterol, triglycerides, HDL-C, LDL-C, apoA1, ApoB, Lp(a)), hip and spine BMD, aorta calcification (AC), radiographic vertebral fracture and self-reported wrist and hip fractures, cardiovascular events together with a wide array of demographic and lifestyle characteristics were collected., Results: Presence of the ApoE epsilon 4 allele had a significant impact on serum lipid profile, yet no association with spine/hip BMD or AC could be established. In multiple regression models, apoA1 was a significant independent contributor to the variation in AC. However, none of the lipid components were independent contributors to the variation in spine or hip BMD. When comparing the women with or without vertebral fractures, serum triglycerides showed significant differences. This finding was however not applicable to hip or wrist fractures. After adjustment for age, severe AC score (>or=6) and/or manifest cardiovascular disease increased the risk of hip but not vertebral or wrist fractures., Conclusion: The contribution of serum lipids to the modulators of BMD does not seem to be direct but rather indirect via promotion of atherosclerosis, which in turn can affect bone metabolism locally, especially when skeletal sites supplied by end-arteries are concerned. Further studies are needed to explore the genetic or environmental risk factors underlying the association of low triglyceride levels to vertebral fractures.

Objective: To investigate associations among body composition, cardiovascular risk factors, and atherosclerosis in middle-aged and elderly men for the identification of potential pathogenic links., Research Methods and Procedures: The study included 168 white men 44 to 86 years old. Severity of aortic calcification (AC) was graded on lateral radiographs, and body fat and lean mass were measured by DXA. Information on demographic and lifestyle characteristics also was gathered., Results: A strong and independent inverse association was found between AC and peripheral lean mass (PLM), even after adjusting for age and BMI (p < 0.05). Independently of the influence of PLM, AC was directly correlated with truncal fat mass (p < 0.05). Furthermore, AC was inversely associated with tertiles of the free androgen index (p < 0.05). In a multiple regression model, age and serum cholesterol (p < 0.01) contributed directly, and truncal fat mass tended also to contribute directly (p = 0.09), whereas PLM contributed borderline inversely (p = 0.06) to the variation of AC (R = 0.635, p < 0.0001)., Discussion: Severity of AC is strongly dependent on age and further modulated by an array of traditional cardiovascular risk factors. Sarcopenia and truncal fat mass are reciprocal correlates of atherosclerosis of borderline statistical significance in multivariate models. To clarify whether sarcopenia is an atherogenic risk factor or rather a parallel consequence of low-grade inflammation also promoting atherogenic trends, further longitudinal studies in larger sample sizes of men and women are needed.

Objective: Calcitonin was recently reported to counter progression of cartilage degradation in an experimental model of osteoarthritis, and the effects were primarily suggested to be mediated by inhibition of subchondral bone resorption. We investigated direct effects of calcitonin on chondrocytes by assessing expression of the receptor and pharmacological effects on collagen type II degradation under ex vivo and in vivo conditions., Methods: Localization of the calcitonin receptor on articular chondrocytes was investigated by immunohistochemistry, and the expression by reverse transcriptase polymerase chain reaction (RT-PCR). In bovine articular cartilage explants, cartilage degradation was investigated by release of C-terminal telopeptides of collagen type II (CTX-II), induced by tumor necrosis factor-alpha (TNF-alpha) [20 ng/ml] and oncostatin M (OSM) [10 ng/ml], with salmon calcitonin [0.0001-1 microM]. In vivo, cartilage degradation was investigated in ovariectomized (OVX) rats administered with oral calcitonin [2 mg/kg calcitonin] for 9 weeks., Results: The calcitonin receptor was identified in articular chondrocytes by immunohistochemistry and RT-PCR. Calcitonin concentration-dependently increased cAMP levels in isolated chondrocytes. Explants cultured with TNF-alpha and OSM showed a 100-fold increase in CTX-II release compared to vehicle-treated controls (P<0.001). The degradation of type II collagen in these explants was concentration-dependently inhibited by calcitonin, 65% protection at 10 nM calcitonin (P<0.01). TNF-alpha and OSM induced a pronounced increase in matrix metalloproteinase (MMP) activity, which was strongly inhibited by calcitonin. In vivo, administration of salmon calcitonin to OVX rats resulted in significant (P<0.001) decrease in CTX-II levels., Conclusion: These results are the first evidence of calcitonin receptor expression on articular chondrocytes and that the chondroprotective effects of calcitonin might involve the inhibition of MMP expression.

Background: A variety of factors contribute to the development of cognitive impairment in elderly people. Previous studies have focused upon a single or a few risk factors. In this study we assessed and compared the significance of a wide variety of potential risk factors for cognitive impairment in postmenopausal women., Methods: A total of 208 pairs of elderly women (mean age = 73.2 years) were examined in a cross-sectional case-control study. Each pair consisted of a case (with impaired cognition) and a control subject matched by age and educational status. Cognitive functions were determined using a modified version of the Blessed test. Participants were also subjected to a general clinical examination and they were interviewed to collect information on lifestyle practices and comorbid disorders. Genotypes for the apolipoprotein E (APOE) epsilon4, catechol-O-methyltransferase (COMT) Val/Met, and brain-derived neurotropic growth factor (BDNF) Val/Met polymorphisms were determined. Data were analyzed by conditional logistic regression., Results: We identified a set of risk factors for age-related cognitive impairment. A statistical model for assessment of the importance of these factors was constructed. The factors in this model were physical exercise (odds ratio [OR] = 0.50, 95% confidence interval [CI] = 0.32-0.78), regular alcohol consumption (OR = 0.49, 95% CI = 0.29-0.83), metabolic syndrome (OR = 2.83, 95% CI = 1.26-6.39), depression (OR = 3.24, 95% CI = 1.28-8.22), and the APOE epsilon4 allele (OR = 1.76, 95% CI = 1.09-2.83). Also COMT genotype was present as a risk factor in the statistical model (p = 0.08)., Conclusions: Lifestyle risk factors, comorbid disorders, and genetic factors contribute to development of age-related cognitive impairment. The two former groups of risk factors appear to be particular important in this respect.

Objective: To investigate whether aorta calcification (AC) - a surrogate marker of atherosclerosis - is an independent indicator of low bone mass density (BMD), accelerated bone loss, and risk of future fractures in postmenopausal women., Design: A prospective epidemiological study. Follow-up period was 7.5 years., Setting: Community-based sample followed by a research institute., Subjects: A total of 2662 generally healthy postmenopausal women with a mean age of 65.0 +/- 7.1 years at baseline., Main Outcome Measures: Annual rate of changes in BMD (DEXA) and AC (X-rays), vertebral fractures (X-rays), hip fractures (questionnaire)., Results: Advanced AC at baseline was significantly associated with lower BMD and accelerated bone loss from the proximal femur. In a multivariate logistic regression model, age (OR 1.1, 95% CI 1.0-1.2, P = 0.02), body mass index (BMI; OR 0.9, 95% CI 0.8-1.0, P = 0.03) and the severity of AC (OR 2.3, 95% CI 1.1-4.8, P = 0.03) were independent predictors of hip fractures. Adjusted OR for vertebral fracture was 1.2 (95% CI 1.0-1.5, P = 0.12)., Conclusions: Aorta calcification seems to independently contribute to the development of osteoporosis in the proximal femur. Further studies are needed to clarify whether effective atherosclerosis prevention lowers hip fracture risk.

The estrogen receptor alpha (ESR1) gene has been implicated in the process of cognitive impairment in elderly women. In a paired case-control study, we tested whether two ESR1 gene polymorphisms (the XbaI and PvuII sites) are risk factors for cognitive impairment as measured by the six-item Orientation-Memory-Concentration test in postmenopausal Danish women. Hormone replacement therapy, age and executive cognitive ability were examined as covariates for ESR1 gene effects on cognitive impairment. The XbaI polymorphism showed a marginal effect on cognitive abilities (P=0.054) when adjusted for executive cognitive ability. Using a dominant genetic model for the X allele, we found an elevated risk (executive cognitive ability adjusted P=0.033) for cognitive impairment. Hormone replacement therapy also had a borderline effect on cognitive ability (P=0.049) and this effect was reflected in executive cognitive ability. These data support that the ESR1 gene variants affect cognitive functioning in postmenopausal women.

Objective: The effect of hormone replacement therapy (HRT) on cardiovascular risk is intensely debated. The aim of this study was to investigate the long-term effects of HRT given for a few years on all-cause and cardiovascular mortality and the severity of atherosclerosis., Methods: This analysis was based on a cohort of 1,458 postmenopausal women (55.8 +/- 6.1 years old) who previously participated in a number of randomized, placebo-controlled, clinical trials assessing the efficacy of 2-3 years of therapy with various estrogen plus progestin combinations for preventing bone loss. Women were followed on average for 9.8 years and came for a follow-up visit. Outcome variables were all-cause and cardiovascular mortality and the severity of atherosclerosis, as estimated by semi-quantitative scoring of vascular calcification in the lumbar aorta on lateral radiographs., Results: A total of 174 women died during the observation period. All-cause mortality was decreased by 30% in the HRT+ group compared with the HRT- group (hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.50-0.97) after adjusting for age, body mass index and smoking. Under the same conditions, similar results characterized mortality from cardiovascular disease (n = 61 deaths; 35.1% of all deaths) and coronary heart disease (n = 39 deaths; 22.4% of all deaths), which were decreased by 46% (HR 0.54, 95% CI 0.29-0.98, p = 0.045) and 53% (HR 0.47, 95% CI 0.21-1.03, p = 0.062), respectively. Furthermore, the mean severity score of aortic calcification at follow-up was significantly lower in hormone-treated compared to non-treated women (p < 0.0001)., Conclusion: Women who receive 2-3 years of HRT after menopause do not have increased all-cause mortality, and results of the present study suggest relative cardiovascular benefits compared to those who had not used hormones.

Although the utility of bone mass measurements has been the subjects of extensive investigations, the number of studies comparing the predictive value of bone mass measurement at different skeletal sites in the same cohort with a large number of clinically verified endpoints is limited. Furthermore, scant information is available on how age at the time of diagnosis influence the risk of future fractures posed by low bone mineral density (BMD). We have followed 5,564 Danish postmenopausal women for a mean period of 7.3 years. Bone mineral content (BMC) at the forearm and BMD at the spine and hip were assessed at baseline. Vertebral fractures were assessed on digitalized images of lateral X-rays of the thoracic and lumbar spine, whereas non-vertebral fractures were self-reported. At follow-up, 17.6% of the women revealed an incidental vertebral fracture and 14.2% reported a new non-vertebral fracture. The absolute risk per 1,000 person-years of osteoporotic fracture increased significantly with decreasing bone mass at all three skeletal sites (P<0.001). Osteoporotic BMD (T-score < or =-2.5) had similar predictive values of fractures regardless of the skeletal site of measurement. Furthermore, the absolute risk of osteoporotic fractures increased significantly with increasing age at the same level of bone mass. Interestingly, the relative risk (RR) of vertebral fracture accompanying 1 SD decrease in spine BMD was similar across different age groups: <55 years (RR:2.1, 95% CI 1.3-3.3), 55-64 years (RR:2.3, 95%CI 1.7-3.2), 65-74 years (RR:2.0; 95%CI 1.5-2.6). Furthermore, women with any prior osteoporotic fracture had a 2.4-fold (95% CI 2.01-2.75, P<0.001) increased risk of a new vertebral fracture. Both age and prior fracture are strong predictors of future fractures. The long-term predictive value of bone mass measurement is independent of the site of measurement and the age at diagnosis.

The objective of this study was to evaluate the utility of the quantitative ultrasound (QUS) technique for the identification of subjects with spine fracture or low bone mineral density (BMD) previously determined by dual energy X-ray absorptiometry (DEXA). QUS of the phalanges in 1,350 postmenopausal women (60-83 years old) was compared with DEXA measurements of four skeletal sites (lumbar spine, total hip, femoral neck, and distal radius) of the same subjects. The contribution of body mass index (BMI) was also assessed. Amplitude dependent speed of sound (AD-SoS), ultrasound bone profile index (UBPI), and BMD of all anatomical regions, except for the spine, decreased significantly with increasing age quartiles. QUS parameters correlated weakly but significantly with BMD ( r =0.21-0.31, p <0.01). After adjustment for BMI, the association between QUS parameters and BMD remained unchanged. UBPI was found to be independent of BMI. All techniques and all sites were able to significantly discriminate fractured from non-fractured subjects by receiver operating characteristic (ROC) analysis (area under the curve [AUC]> or =0.60, p <0.0001). AD-SoS and UBPI showed similar fracture discrimination ability of spine, distal radius and total body BMD in terms of odds ratios, but BMD of the total hip and femoral neck showed the best performance in discriminating fractured from non-fractured subjects. In conclusion, QUS assessment of the phalanges correlates moderately with BMD of all skeletal sites and is able to effectively discriminate fractured from non-fractured subjects.

Objective: To assess the efficacy of 3 months of oral salmon calcitonin (sCT) on cartilage degradation as estimated by the changes in the urinary excretion of C-terminal telopeptide of collagen type II (CTX-II), and to investigate whether the response of oral sCT to urinary CTX-II depends on the baseline level of cartilage turnover., Methods: This was a randomized, double blind, placebo-controlled clinical setting including 152 Danish postmenopausal women aged 55-85. The subjects received treatment with the different doses of sCT (0.15, 0.4, 1.0, or 2.5 mg) combined with Eligen technology-based carrier molecule (200 mg), or placebo for 3 months. The efficacy parameter was the changes in the 24-h excretion of urinary CTX-I/II corrected for creatinine excretion at month 3., Results: sCT induced a significant dose-dependent decrease in 24-h urinary CTX-II excretion. Similar dose-dependent responses were found in 24-h urinary CTX-I. When stratifying the study population into tertiles of baseline urinary CTX-II, the present osteoarthritic symptoms and definite cases of osteoarthritis (OA) were significantly more frequent in women in the highest tertile of CTX-II (mean 391 +/- 18 ng/mmol). Women who received 1.0 mg of sCT and had the highest cartilage turnover presented the greatest decrease in urinary CTX-II after 3 months of treatment., Conclusion: In addition to its pronounced effect on bone resorption, this novel oral sCT formulation may also reduce cartilage degradation and thereby provide therapeutic benefit in terms of chondroprotection. Women with high cartilage turnover are more likely to benefit from oral sCT treatment.

Animal experiments revealed conflicting results as to the impact of bisphosphonate treatment on atherosclerosis and related vascular calcification. The effect of long-term treatment with clinical doses of bisphosphonates on aortic calcification (AC) in an "at-risk" population of osteoporotic elderly women has not been assessed systematically. In the present analysis including 474 women (55-80 years) participating in two 3-year randomized, placebo-controlled clinical trials, we assessed the simultaneous impact of ibandronate given either orally (2.5 mg daily or 20 mg intermittently) or intravenously (0.5 mg or 1.0 mg IV every 3 months) on bone mass and AC. All women received calcium and vitamin D supplements. Bone mineral density (BMD) was measured at the lumbar spine and the total hip using dual-energy X-ray absorptiometry (DXA). Calcified deposits of the lumbar aorta (L1-L4) were visualized on lateral radiographs and severity was graded by a validated scoring system. Measurements were performed at baseline and at years 1, 2, and 3. At baseline, there was a significant inverse correlation between the severity of AC and BMD at the hip (r=-0.151, P=0.003), but not at the lumbar spine. The two oral doses and the 1.0 mg IV dose evoked statistically significant increases in both hip and spine BMD compared with placebo, whereas the effect of 0.5 mg was significant only at the hip (P<0.05). No differences in the yearly rate of progression or the 3-year change in AC was observed between the different intervention groups. Furthermore, there were no statistically significant correlations between the 3-year change in BMD and the simultaneous change in AC. These findings thus suggest that 3-year treatment with effective doses of ibandronate does not pose any cardiovascular risk in terms of altering vascular calcification.

Objective: To investigate how body fat mass, an established source of endogenous estrogen after menopause, influences cognitive impairment in elderly women., Research Methods and Procedures: Study participants were 5607 generally healthy postmenopausal women with mean age of 63.8 years at baseline followed for an average of 7.3 years. Cognitive function assessed at follow-up using the short Blessed test was related to baseline body weight, the yearly change in weight, and follow-up measures of body fat depots assessed by DXA. Cognitive function was also related to various surrogates of lifetime estrogen exposure., Results: Women with the worst cognitive performance (score >or= 9) at follow-up were the ones who lost the most body weight and revealed the lowest central fat mass (CFM). The association of weight loss with worse cognitive performance was apparent across all age groups except for those more than 80 years old. In the multivariate logistic model, the risk of cognitive impairment was 18% lower in women in the second quartile of CFM (p = 0.14), 32% lower in the third (p = 0.01), and 48% lower in the fourth (p < 0.001) compared with those in the first quartile. CFM showed significant correlation with the simultaneously measured serum estradiol (r = 0.25; p < 0.001). Cognitive score showed an inverse linear relationship with the duration of reproductive period and bone mineral density assessed at follow-up., Discussion: These findings argue for a protective association of body fat mass with cognitive impairment in elderly women. This association seems to involve a more prominent exposure to endogenous estrogens.

Unlabelled: Oral administration of calcitonin could improve compliance to long-term treatment. Efficacy and safety of a novel oral formulation was assessed on 277 postmenopausal women. The results show (1) effective enteral absorption, (2) marked inhibition of bone resorption with minimal alteration of formation, and (3) reproducibility of responses over 3 months., Introduction: We have recently introduced an Eligen technology-based oral formulation of salmon calcitonin (sCT) that effectively delivers the hormone to the circulation. The efficacy and safety during longer-term administration, however, has not been investigated in the target population., Materials and Methods: This was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging clinical trial including 277 healthy postmenopausal women 55-85 years of age. Women received treatment with either daily (0.15, 0.4, 1.0, or 2.5 mg) or intermittent doses (1.0 mg, every other day) of sCT combined with the delivery agent (8-[N-2-hydroxi-5-chloro-benzoyl]-amino-caprylic acid, 200 mg) or placebo for 3 months. All participants received 1,000 mg calcium plus 400 IU vitamin D daily throughout the study. Efficacy parameters were the acute and/or pre-dose changes in serum and urinary C-terminal telopeptide of type I collagen (CTx), N-mid osteocalcin (OC), bone-specific alkaline phosphatase (BSALP), calcium, and parathyroid hormone (PTH) measured by established immunoassays., Results: After the first dose, sCT evoked dose-dependent decreases in serum CTx (-60.8% to -81.8% from baseline) compared with placebo, reaching nadirs 2-3 h after drug intake, after which, gradual increases were observed. The simultaneous acute changes in OC were statistically nonsignificant. Area under the curve (AUC) of serum CTx responses at months 1 and 3 showed strong correlation with those at baseline (both r = 0.78, p < 0.001). At month 3, the placebo-corrected changes in the pre-dose value of serum and urinary CTx were significant only in the 1.0-mg dose group (-18.9% and -20.5%, respectively, p < 0.05). The placebo-corrected change in OC was -8.6 (p = 0.09), whereas the change in BSALP was -7.3 (p = 0.02). The oral formulation was well tolerated, with mild to moderate gastrointestinal and skin manifestations apparent mainly in the high-dose groups., Conclusion: The results of this 3-month trial show that the novel Eligen technology-based oral formulation of sCT has potential to become a safe and effective treatment for postmenopausal bone loss. Future trials are needed to assess the impact of long-term administration on changes in BMD and fracture risk.

Hormone replacement therapy (HRT) is often prescribed for a few years to suppress menopausal symptoms. Although its long-term use of HRT for the primary prevention of osteoporosis is not currently recommended, the long-term skeletal benefits of the limited therapy are of great interest. To determine whether administration of HRT for 2-3 years in the early postmenopausal years provides long-term benefits, such as prevention of bone loss and osteoporotic fractures, we studied a group of 347 healthy postmenopausal women with normal bone mass who had earlier completed one of four placebo-controlled HRT trials and who were reexamined 5, 11, or 15 years after stopping HRT. Of these women, 263 received either HRT or placebo for 2-3 years with no further bone-sparing treatment until follow-up, and the remaining 84 women reported either prolonged or current use of HRT at reexamination. Bone mineral density (BMD) at the spine (L1-L4) and bone mineral content (BMC) in the forearm were measured at baseline, the end of the trials, and follow-up. At follow-up, we assessed the radiological presence of vertebral fracture and collected information on the new incidence of nonvertebral fractures. Compared with that of the placebo-treated women, the BMD and BMC of HRT-treated women continued to show significantly higher values (>5%) even many years after stopping HRT. After stopping treatment, the rate of bone loss returned to normal postmenopausal rates. The preservation of bone mass in the HRT group was accompanied by a significantly reduced risk of all osteoporotic fractures as compared with the placebo group [OR = 0.48 (95% CI, 0.26-0.88)]. 'Fast losers' on placebo had more than a 4-fold higher risk of fractures than had the women on limited HRT with a normal rate of bone loss after withdrawal. In conclusion, limited HRT administered in the early postmenopausal years offers long-lasting benefits for the prevention of postmenopausal bone loss and osteoporotic fracture.

The aim of this study was to evaluate the efficacy of pulsed estrogen therapy (intranasal 17beta-estradiol) in the prevention of postmenopausal bone loss. A total of 386 women (40-65 years old), less than 5 years past menopause, were randomized to intranasal placebo, 17beta-estradiol 150 micro g, or 300 micro g daily for 2 years. Women with an intact uterus received micronised progesterone 200 mg per day, 14 days of each 28-day cycle. Women randomised to placebo-treatment received placebo progesterone. The primary endpoints were changes in BMD at the spine (L2-L4) and femoral neck. Secondary endpoints were changes in bone turnover markers: serum osteocalcin (sOC) as a marker of bone formation and urinary C-terminal telopeptides (uCTX) as a marker of bone resorption. BMD increased at all measured sites in women receiving active treatment in a dose-related manner, the difference compared to placebo being 5.2% and 6.7% at the spine, and 3.2% and 4.7 % at the hip, respectively, with 150 microg and 300 microg ( P<0.001). On the other hand, a decrease versus baseline of -3.2% and -3.3% at the spine and hip, respectively, was observed in women receiving placebo ( P<0.001). In the patients with at least one risk factor for osteoporotic fracture, the difference between placebo and 150 microg or 300 micro g was even higher at the spine (5.4% and 7.4%, respectively), and at the femoral neck (4.0% and 5.2%, respectively). Correspondingly, uCTX decreased from baseline by 39% and 46 %, and sOC by 22% and 27%, in the 150 micro g group and 300 micro g group (all P<0.001 versus placebo). A strong correlation was found between variations of bone turnover markers after 1 year and BMD after 2 years, emphasizing that bone markers can predict BMD response during hormonal treatment. Acceptability and general tolerance were good. This study demonstrates that pulsed estrogen therapy at the dose of 150 microg and 300-microg per day prevents bone loss in a dose-dependant manner at each site studied, and normalizes bone turnover markers to premenopausal levels.

Alendronate has been shown to reduce bone turnover and increase bone mass. However, little is known about the duration of the effect on bone after treatment withdrawal. The aim of this study was to investigate the long-term effects on bone mineral density (BMD) and bone turnover of various alendronate regimens after treatment withdrawal. In this study, we followed 203 postmenopausal women who previously participated in two alendronate randomized placebo-controlled trials. Daily oral treatment with various doses of alendronate (2.5-20 mg) were given for 2, 4, or 6 yr followed by no treatment for 7, 5, or 3 yr, respectively. Bone mineral density of the lumbar spine, hip, and forearm was measured by dual-energy x-ray absorptiometry. Biochemical markers of bone turnover were induced serum C-terminal telopeptides of type I collagen (CTX) and osteocalcin. Women who received alendronate (2.5-10 mg per day) for 2 yr had a 3.8% higher BMD compared to those receiving placebo when assessed 7 yr after withdrawal. The residual effect was proportionally larger in women who had received treatment for 4 (5.9%, P=0.02) or 6 yr (8.6%, P=0.002), respectively. However, the largest residual effect was found in women treated with alendronate 20 mg per day for 2 yr (9.7%, P=0.01 vs. placebo). The rate of bone loss after alendronate withdrawal was comparable to the bone loss observed in the placebo group. Bone markers tended to reverse back to normal levels, but were still affected even several years after withdrawal of treatment. This study has demonstrated that the efficacy of alendronate in preventing bone loss was proportional to the duration of treatment. The rate of bone loss after withdrawal of alendronate corresponded to the normal postmenopausal rate of bone loss. A residual effect on BMD was found up to 7 yr after treatment withdrawal.

Aim: To investigate the long-term effects of central fat mass (CFM) and peripheral fat mass (PFM) on atherogenic risk profile and the progression of aortic calcification (AC) in postmenopausal women., Methods and Results: Participants were 316 women aged 50-76 years, who were followed for 7.7 years. CFM and PFM were measured at baseline by DXA and related to follow-up measures of atherogenic metabolites, blood pressure, and the progression of AC assessed on lateral radiographs. CFM and PFM independently of each other exhibited contrasting influence on follow-up measures of atherogenic risk factors and the progression of AC. In a multiple regression model, the negative contribution of PFM (P<0.05), but not the adverse contribution of CFM, was independent of confounders. When comparing different extreme forms of obesity, women with central obesity showed the greatest (2.36+/-0.60, n=11), whereas those with peripheral obesity the smallest changes in AC (0.50+/-0.34, n=10) over the study period. Women with general obesity also tended to show less progression of AC compared with women with central obesity (1.23+/-0.42, n=21)., Conclusions: This study provides direct support for the independent anti-atherogenic influence of PFM and calls on further research to define the adipocyte-derived factors involved in this favourable effect.

Previous studies indicate that low bone mineral density (BMD) in the hip is a useful predictor of cardiovascular mortality among the elderly. The objective of this study was to investigate whether low hip BMD is directly associated with the severity of atherosclerosis. The per-protocol population consisted of 963 women aged 60-85 years. Study variables were aortic calcification (AC) graded on lateral lumbar radiographs, BMD at various anatomic sites (distal radius, lumbar spine, proximal femur) measured by DXA, information on various risk factors, and medical history. After adjustment for age, BMD at the proximal femur, but not at the radius or spine BMD, showed statistically significant association with the severity of AC (r = -0.12-17, P < 0.001). Age, years since menopause, BMI, level of education, current and previous smoking, and weekly fitness activity were significant common risk factors (all P < 0.05) with contrasting influence on AC and hip BMD. In a multiple regression model, AC contributed significantly and independently to the variation in hip BMD (beta = -0.10, P = 0.004). Impaired blood flow represented by 40 women with documented history of intermittent claudication was not an independent contributor and did not alter the association between AC and hip BMD. However, AC and demineralization in the hip was particularly severe in women with intermittent claudication accompanied by a higher prevalence of coronary heart disease compared with age-matched controls (all P < 0.001). In conclusion, severe osteoporosis in the hip may indicate advanced atherosclerosis and thereby an increased risk for not only hip fractures but also for coronary heart disease. The results further emphasize that osteoporosis in the hip and peripheral vascular disease are linked by common risk factors and pathomechanisms.

Recent in vitro and animal studies suggest that cholesterol and its metabolites inhibit the functional activity of osteoblasts and thereby induce reduced bone mineralization. However, scant information is available on the clinical implication of these findings with special regard to postmenopausal bone loss. Therefore, the aim of the present study was to investigate cross-sectional and longitudinal associations between serum cholesterol, bone mineral density (BMD), and bone turnover in 340 postmenopausal women aged 50-75 years (mean 59 years), who were followed for 8.3 +/- 1.1 years. BMD in the lumbar spine, distal forearm, and total hip was measured by dual energy X-ray absorptiometry. Other study variables were physical measures, serum cholesterol, serum markers of bone turnover, and self-reported information on various risk factors for osteoporosis. At baseline, serum cholesterol showed significant negative correlation with BMD at the lumbar spine (r = -0.21, P < 0.0001) and distal forearm (r = -0.14, P = 0.013), but not at the hip. No associations of serum cholesterol with serum osteocalcin (r = 0.054, P = 0.317) and CTX (r = -0.027, P = 0.623) were, however, noted. After adjustment for age and BMI, the negative correlation remained significant at the lumbar spine (r = -0.16, P = 0.004), but not at the distal forearm (r = -0.018, P = 0.738). At the end of the 8-year follow-up, the correlation between serum cholesterol and spine BMD was not observed. Those with the largest increases in serum cholesterol, however, showed the greatest decreases in spine BMD independently of the changes in BMI (r = -0.16, P = 0.004). The correlation between the changes in serum cholesterol and the simultaneous changes in osteocalcin (r = 0.081, P = 0.140) and CTX (r = 0.042, P = 0.441) were statistically insignificant. Thus, our results suggest that the weak associations between spine BMD and serum cholesterol can be explained by the fact that both variables are simultaneously affected by estrogen deficiency rather than by a direct influence of serum cholesterol on osteoblast function.

The primary objective of this study was to investigate whether changes in the serum level of an endometrial secretory protein, placental protein 14 (PP14), can reflect endometrial adverse events induced by selective oestrogen receptor modulators (SERMs). A randomized, double-blind, placebo-controlled trial was used. Participants were healthy postmenopausal women aged 45-65 years, who received either various doses of raloxifene (30, 60 or 150 mg day-1) or levormeloxifene (1.25, 5, 10 or 20 mg day-1) or placebo for 12 months. Serum PP14 and endometrial thickness (ET) were monitored by radio-immunoassay and transvaginal ultrasonography, respectively. In the levormeloxifene trial, endometrial status at 12 months was assessed by hysteroscopy. Raloxifene induced only slight increases in serum PP14 and ET. Levormeloxifene, however, induced marked increases in both study parameters at all the does tested. The 6 month changes in PP14 showed a positive correlation with both the 6 and 12 month changes in ET (P < 0.001). Marked stromal oedema, pseudocysticity with or without hypervascularity and endometrial proliferation were seen on hysteroscopy in those showing the largest increases in serum PP14. These results suggest that the PP14 assay used on a group basis may provide useful information on the endometrial effects of SERMs administered in a given dose range, and thereby could assist future clinical trials aiming to find the optimal dose range of new SERMs.

Objective: To investigate the polymorphisms of the vitamin D receptor (VDR) and estrogen receptor (ER) genes in relation to biochemical markers of bone turnover (serum osteocalcin and urinary collagen type I degradation products (CrossLaps), and to study ER genotypes in relation to serum lipoproteins, blood pressure, or changes in these parameters after 2 years of hormone replacement therapy (HRT) in 499 Danish postmenopausal women., Methods: The VDR gene polymorphisms were determined by means of the three restriction enzymes, i.e. BsmI, ApaI and TaqI, while the ER gene polymorphisms were determined by means of the PvuII and XbaI restriction enzymes. Serum osteocalcin, urinary CrossLaps and the lipoproteins were also assessed. Body mass index was recorded., Results: The VDR or ER genotypes did not differ significantly with respect to age, age at menopause or body mass index. No significant effect of VDR or ER genotype on bone turnover was found. Furthermore, we were unable to find any relationship between ER genotype and lipoproteins or blood pressure at baseline, or changes in these parameters during HRT., Conclusion: A clinically significant relationship between VDR and ER genotypes and biochemical markers of bone turnover or serum lipoproteins could not be demonstrated in healthy Danish postmenopausal women.

The polymorphisms of the estrogen receptor (ER) gene defined by the restriction enodonucleases PvuII and XbaI have recently been reported to be associated with bone mineral density (BMD) in postmenopausal women. To investigate the possible relation of the PvuII and XbaI restriction fragment-length polymorphisms of the ER gene with BMD in Danish postmenopausal women, two studies were undertaken: 1) a cross-sectional study of 499 postmenopausal women, where the ER genotypes and alleles were related to BMD of the hip, spine, and lower forearm; and 2) a longitudinal study of 101 postmenopausal women followed up for 18 years. In the latter study, late postmenopausal bone loss in the hip and spine was determined over a period of 6 years in women (mean age of 63 to 69 years), and long-term postmenopausal bone loss in the lower forearm was determined over a period of 18 years in women (mean age of 51 to 69 years). Genotyping was performed through the restriction cleavage of polymerase chain reaction-amplified genomic DNA with the two restriction enzymes, PvuII and XbaI. Restriction fragment-length polymorphisms were represented as P or p (PvuII) and X or x (XbaI), with the lower case letters signifying the presence of the restriction site. The frequencies of the ER genotypes were similar to previously published genotype frequencies in Caucasian and Asian populations. No significant effect of the ER genotypes or alleles on BMD was found at any site, nor was there a relation between ER genotypes and the rate of bone loss either in the hip and spine over 6 years, or in the lower forearm over 18 years. In conclusion, we could not demonstrate any major effect of the ER gene polymorphisms on BMD or rate of bone loss in healthy postmenopausal Danish women.

Crossed immunoelectrophoresis was applied to purify Y. enterocolitica common antigen by precipitation with monospecific rabbit anti-P. aeruginosa CA antibody. Monoclonal antibodies against Y. enterocolitica CA were then raised by immunization of mice with these immunoprecipitates. This method provides the possibility of producing a panel of anti-CA monoclonal antibodies from a large number of bacterial species.