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This study investigated the association between body composition and risk of atrial fibrillation (AF) in postmenopausal women. In a retrospective analysis we assessed data from 5704 postmenopausal women (age 70.7 ± 6.5 yrs.) who in 1999-2001 participated in The Prospective Epidemiological Risk Factor study with body composition assessed by dual-energy X-ray absorptiometry. Outcomes were obtained from Danish Health Registries and body composition association to risk of AF was evaluated by univariable and multivariable Cox Hazard regression. 850 women developed AF after baseline. High lean body mass was associated with increased risk of AF in multivariable analyses, adjusting for body mass index (BMI), height or weight (adjusted for: BMI, hazard ratio (HR) 1.49, 95% Confidence Interval (1.22-1.80); height, HR 1.27 (1.03-1.56); weight, 1.33 (1.06-1.65)). Height and weight were associated with increased risk of AF in multivariable analyses adjusting for body composition measures. When adjusting for total lean mass, only height remained statistically significant (HR 1.34 (1.09-1.64)). In a cohort of elderly Caucasian women, high lean body mass, height and weight were associated with increased risk of AF and the variables remained significant after adjusting for age and other known risk factors of AF.

Background: The relationship between levels of extracellular matrix (ECM) turnover and mortality is currently unknown. The study aimed to determine if levels of ECM turnover are predictors of all-cause mortality in a large cohort of postmenopausal women., Methods: 5,855 postmenopausal Danish women enrolled in the Prospective Epidemiologic Risk Factor (PERF) study. Baseline demographics and serum were collected at registration. Dates of death were obtained from the Danish Death Registry. ECM turnover was evaluated by serological biomarkers measuring bone (telopeptide of type I collagen [CTX-1] and osteocalcin) and soft tissue (formation of type VI collagen [PRO-C6], MMP-degraded type IV collagen [C4M], formation of type III collagen [PRO-C3], and MMP-degraded type I collagen [C1M]) turnover. Multivariate Cox analyses were performed with 3, 5, and 15 years of follow-up., Results: The association of bone turnover (CTX-1 and osteocalcin) with all-cause mortality was U-shaped for all time periods. After adjustment for possible confounders, the lowest quintile of bone formation and degradation remained significant for all time periods. We observed J-shaped association between all-cause mortality and PRO-C6, C4M, and PRO-C3, and there was a linear association between C1M and all-cause mortality. After adjustment for possible confounders, the highest quintile of the soft tissue turnover biomarkers (PRO-C6, C4M, PRO-C3, and C1M) remained significantly associated with all-cause mortality for all time periods., Conclusion: Both low and high levels of tissue turnover were associated with increased risk of all-cause mortality in postmenopausal women. Overall, these results highlight the importance of bone and soft tissue homeostasis., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: An altered tumor microenvironment is one of the earliest signs of cancer and an important driver of the disease. We have seen previously that biomarkers reflecting tumor microenvironment modifications, such as matrix metalloproteinase (MMP)-degraded type 1 collagen (C1M), MMP-degraded type IV collagen (C4M), and citrullinated and MMP-degraded vimentin (VICM), were higher in the serum of cancer patients than in healthy controls. However, it is not known if these biomarkers could predict an increased risk of cancer. The aim of this study was to investigate whether C1M, C4M, and VICM were elevated prior to diagnosis of solid cancers in a large prospective study., Methods: Between 1999 and 2001, 5,855 postmenopausal Danish women ages 48 to 89 years enrolled in the Prospective Epidemiologic Risk Factor study. Baseline demographics and serum were collected at the time of registration. Follow up cancer diagnoses were obtained from the Danish Cancer Registry in 2014. Serum C1M, C4M, and VICM levels were measured by competitive ELISAs., Results: A total of 881 women were diagnosed with solid cancers after baseline. C1M, C4M, and VICM levels were significantly elevated in women diagnosed less than 1 year after baseline. C1M and VICM, but not C4M, were independent predictors of increased risk of cancer., Conclusion: C1M, C4M, and VICM are elevated prior to cancer diagnosis. C1M and VICM are both independent predictors of increased cancer risk., Impact: C1M and VICM are predictors for increased risk of cancer. Cancer Epidemiol Biomarkers Prev; 25(9); 1348-55. ©2016 AACR., (©2016 American Association for Cancer Research.)

Objective: The objective of this post hoc analysis was to investigate the effect of strontium ranelate on a cartilage degradation marker in postmenopausal women who participated in a randomized, placebo-controlled osteoporosis study. Women were stratified according to reported symptoms of osteoarthritis and to the baseline levels of a cartilage degradation marker., Methods: The analysis included the 2617 postmenopausal women (75 years old) with osteoporosis randomized to strontium ranelate or placebo for a 36-month period. Cartilage degradation was evaluated using a validated urinary marker adjusted for creatinine (CTX-II/cr), whereas bone resorption was assessed by serum CTX-I. The presence of osteoarthritis was determined by individual interviews., Results: CTX-II was significantly elevated at baseline in subjects with a history of osteoarthritis (OA+) compared to subjects who did not (OA-) (p < 0.0001), whereas CTX-I was unaffected by osteoarthritis status. Strontium ranelate caused a significant decrease from baseline in CTX-II over a 12-month period whatever the osteoarthritis status. Strontium ranelate-treated patients had a significant decrease in CTX-II compared to placebo in both OA+ and OA- groups up to 12 months, the difference remaining still significant at 36 months in patients from the OA- group (p < 0.001)., Conclusions: The CTX-II profile of changes over 3 years may reflect efficacy of strontium ranelate against cartilage degradation, with an enhanced beneficial effect in subjects with early or mild clinical osteoarthritis, probably exerting its putative chondroprotective influence in early stages of the disease. Carefully controlled studies in targeted populations with early osteoarthritis are warranted to assess the role of strontium ranelate halting osteoarthritis progression.

Background: Aortic calcification is a major risk factor for death from cardiovascular disease. We investigated the relationship between mortality and the composite markers of number, size, morphology and distribution of calcified plaques in the lumbar aorta., Methods: 308 postmenopausal women aged 48-76 were followed for 8.3 ± 0.3 years, with deaths related to cardiovascular disease, cancer, or other causes being recorded. From lumbar X-rays at baseline the number (NCD), size, morphology and distribution of aortic calcification lesions were scored and combined into one Morphological Atherosclerotic Calcification Distribution (MACD) index. The hazard ratio for mortality was calculated for the MACD and for three other commonly used predictors: the EU SCORE card, the Framingham Coronary Heart Disease Risk Score (Framingham score), and the gold standard Aortic Calcification Severity score (AC24) developed from the Framingham Heart Study cohorts., Results: All four scoring systems showed increasing age, smoking, and raised triglyceride levels were the main predictors of mortality after adjustment for all other metabolic and physical parameters. The SCORE card and the Framingham score resulted in a mortality hazard ratio increase per standard deviation (HR/SD) of 1.8 (1.51-2.13) and 2.6 (1.87-3.71), respectively. Of the morphological x-ray based measures, NCD revealed a HR/SD >2 adjusted for SCORE/Framingham. The MACD index scoring the distribution, size, morphology and number of lesions revealed the best predictive power for identification of patients at risk of mortality, with a hazard ratio of 15.6 (p < 0.001) for the 10% at greatest risk of death., Conclusions: This study shows that it is not just the extent of aortic calcification that predicts risk of mortality, but also the distribution, shape and size of calcified lesions. The MACD index may provide a more sensitive predictor of mortality from aortic calcification than the commonly used AC24 and SCORE/Framingham point card systems.

Objective: The aim of this study was to assess the impact of oral hormone therapy (HT) on breast density in postmenopausal women and to compare the use of computer-based automated approaches for the assessment of breast density with reference to traditional methods., Methods: Low-dose oral estrogen (1 mg) continuously combined with drospirenone (2 mg) was administered to postmenopausal women for up to 2 years (26 treatment cycles, 28 d/cycle) in a randomized, placebo-controlled trial. This post hoc analysis assessed the changes in breast density measured from digitized images by two radiologist-based approaches (Breast Imaging Reporting and Data System score and interactive threshold) and one computer-based technique (heterogeneity examination of radiographs). Correlations of temporal changes in breast density with changes in serum estradiol levels, biochemical markers of bone metabolism, and bone mineral density at the spine and femur were also assessed., Results: Breast density assessed by the radiologist-based approaches increased significantly from baseline in the HT group (P < 0.01), with significant divergence from placebo at 2 years (P < 0.01). Heterogeneity examination of radiograph score by computer-based technique was unchanged in the HT group and decreased significantly with placebo (P < 0.001) to produce a significant group divergence (P < 0.05). Changes in mammographic markers by radiologist- and computer-based approaches correlated with each other in the HT group (P < 0.01) but not in the placebo group., Conclusions: HT for 2 years in postmenopausal women significantly increased radiologist-assessed breast density compared with placebo, in addition to significant changes in estrogen levels, markers of bone metabolism, and bone mineral density. Computer-automated techniques may be comparable with and offer advantages over traditional methods.

We have previously shown that repeated dosing of glucagon-like peptide-2 (GLP-2) at 10 p.m. in postmenopausal women for 14 days results in a dose-dependent decrease in the nocturnal bone resorption, as assessed by s-CTX. In contrast, bone formation, as assessed by serum osteocalcin, appeared to be unaffected by treatment with exogenous GLP-2, at least over 14 days. The present study extends the observation period to four months. The study was a double-blind placebo-controlled dose-ranging trial comparing three different doses of GLP-2 (0.4 mg, 1.6 mg and 3.2 mg GLP-2, administered nightly) against a saline control injection. We examined safety and tolerability, and the effects on biochemical markers of bone turnover and the effect on bone mineral density. Injection of 0.4 mg, 1.6 mg and 3.2 mg GLP-2 resulted in similar reduction in the nocturnal rise of s-CTX, at Treatment Day 120 the mean difference to placebo was approximately -150%*h at AUC(0-10H) (P<0.01). Osteocalcin levels were unaffected in the 10-hour period after injection indicating that injections of 0.4 mg, 1.6 mg and 3.2 mg GLP-2 do not exert any acute stimulatory or inhibitory effect on bone formation. Treatment with GLP-2 resulted in a significant dose-dependent increase in total hip BMD over the course of the study that for the 3.2 mg GLP-2 group reached 1.1% (P=0.007) from baseline. The overall rates of adverse events in the 4 treatment groups were similar and there were no signs of tachyphylaxis or antibodies against GLP-2. The results indicate that GLP-2 produces a substantial decrease in bone resorption without suppression of bone formation thereby changing the bone remodeling balance in favor of bone formation, particularly at the hip.

The aim of this study was to assess the bioavailability and pharmacodynamic efficacy of synthetic salmon calcitonin (ssCT) and recombinant salmon calcitonin (rsCT) in healthy postmenopausal women. The study was a single-blind, randomized study. Participants were 36 postmenopausal women 62 to 74 years old, randomly assigned to a comparison of dosing with ssCT (n = 12) or rsCT (n = 24) given in the morning at 08:00. Study parameters were plasma CT levels measured up to 2 hours postdose and changes in the bone resorption marker serum CTX-I and the cartilage degradation marker urine CTX-II measured up to 4 hours postdose. For both formulations, peak plasma concentrations were obtained 15 minutes after dosage, and no statistically significant differences in the uptake of CT were observed. Measurement of bone resorption and cartilage degradation markers displayed comparable responses, with AUCs of relative change of serum CTX-I of -250% x hours and relative change of urine CTX-II of -180% x hours during the 4-hour observation period. In conclusion, oral synthetic and recombinant calcitonin displayed comparable pharmacodynamic and kinetic properties.

Introduction: Polymorphisms of genes encoding enzymes of the mevalonate pathway could modulate the response to amino-bisphosphonate treatment in postmenopausal osteoporosis., Research Design and Methods: A characterisation of 234 Danish osteoporotic postmenopausal women (as part of the Prospective Epidemiological Risk Factors study (PERF)), treated for at least 2 years with amino-bisphosphonates, with respect to the adenosine/cytosine (A/C) rs2297480 farnesyl pyrophosphate synthase (FDPS) gene polymorphism, was carried out by PCR-based enzymatic digestion and quantitative PCR allelic discrimination on genomic DNA extracted from blood leukocytes. The association between these polymorphism genotypes and the response of spine and femur bone mineral density (BMD) and of biochemical bone biomarkers to treatment with amino-bisphosphonates was statistically examined., Results: FDPS polymorphism did not show any relationship to baseline spinal and femoral BMD in Danish postmenopausal women. BMD response to treatment with amino-bisphosphonates was similar in the AA and the AC genotypes, while the CC genotype showed a lower BMD response to 2-year-treatment with amino-bisphosphonates at all examined skeletal sites (p=0.60 at the spine and p=0.59 at the femur). Interestingly, after 2 years of treatment the response of urinary Cross-laps to amino-bisphosphonates treatment was significantly (p<0.05) lower in the CC genotype when compared to both the AC and AA genotypes. Even the response of serum osteocalcin was lower in the CC genotype, but without reaching a statistical significance (p=0.65)., Conclusions: Danish postmenopausal women with osteoporosis bearing the homozygous CC genotype for rs2297480 FDPS polymorphism showed a decreased response of bone turnover markers to amino-bisphosphonate therapy, when compared to the heterozygous AC and to the homozygous AA genotypes. Further investigation on larger and different populations, together with polymorphism functional studies are required to confirm these data.

Unlabelled: Osteoporosis is an increasingly common health concern in postmenopausal women. In a 2-yr phase III study, bazedoxifene prevented bone loss, reduced bone turnover, and was well tolerated in early postmenopausal women with normal or low BMD., Introduction: Bazedoxifene is a novel selective estrogen receptor modulator that has increased BMD and bone strength in experimental models, without stimulating breast or uterus. This 24-mo, randomized, double-blind study assessed the efficacy and safety of three doses of bazedoxifene compared with placebo and raloxifene in the prevention of postmenopausal osteoporosis., Materials and Methods: Healthy postmenopausal women with a BMD T-score at the lumbar spine or femoral neck between -1.0 and -2.5 or clinical risk factors for osteoporosis were randomly assigned to one of five groups: bazedoxifene 10, 20, or 40 mg/d, placebo, or raloxifene 60 mg/d. All women received elemental calcium. Efficacy outcomes included changes from baseline through 24 mo in BMD of the lumbar spine, hip, femoral neck, and femoral trochanter and biomarkers of bone metabolism., Results: The intent-to-treat population included 1434 women (mean age, 58 yr; mean time from last menstrual period, 11 yr). All doses of bazedoxifene and raloxifene prevented bone loss, whereas in the placebo group, there was significant loss of BMD at all skeletal sites. Mean differences in percent change in lumbar spine BMD from baseline to 24 mo relative to placebo were 1.08 +/- 0.28%, 1.41 +/- 0.28%, 1.49 +/- 0.28%, and 1.49 +/- 0.28% for 10, 20, and 40 mg bazedoxifene and 60 mg raloxifene, respectively (p < 0.001 for all comparisons). Comparable BMD responses were observed at other body sites. Significant and comparable decreases in serum osteocalcin and C-telopeptide levels from baseline and relative to placebo with active treatment were observed as early as 3 mo and were sustained through study conclusion (p < 0.001). Overall incidences of adverse events, serious adverse events, and discontinuations caused by adverse events were similar between groups. The most common adverse events included headache, infection, arthralgia, pain, hot flush, and back pain., Conclusions: Treatment with bazedoxifene prevented bone loss and reduced bone turnover equally as well as raloxifene and was generally well tolerated in postmenopausal women with normal/low BMD.

Objective: To study the influence of smoking on uterine bleeding patterns during continuous and interrupted oral hormone therapy (HT)., Methods: Using a post-hoc strategy, we included five oral HT groups from three studies. The therapies consisted of continuous estrogen (estradiol, estradiol valerate or piperazine estrone sulfate) in combination with continuous progestogen (cyproterone acetate, gestodene or norethisterone acetate) or in combination with interrupted progestogen (norethisterone) given on days 4-6, 10-12, 16-18, 22-24 and 28-30. A total of 145 healthy postmenopausal women (54 smokers and 91 non-smokers), who had been followed for 2 years, were included in the analyses. Uterine bleeding data were collected from bleeding calendars., Results: In general, smoking women experienced significantly less days with uterine bleeding per cycle than non-smoking women during continuous and interrupted HT (0.53 +/- 0.1 vs. 1.6 +/- 0.1; p < 0.001). Smoking women were also more likely than non-smoking women to be amenorrheic during these therapies (48.2% vs. 29.7%; p < 0.05). Finally, more smoking than non-smoking women attained amenorrhea during HT (94.4% vs. 76.9%p < 0.01)., Conclusions: In healthy postmenopausal women, smoking may reduce uterine bleeding during interrupted and continuous HT regimens containing a broad selection of estrogens and progestogens. Further study with appropriate stratification for smoking status is warranted.

Objective: To investigate the effect of pulsed estrogen therapy S21400 (intranasal 17 beta-estradiol) on different quality of life (QoL) dimensions in early postmenopausal women treated with S21400 150 microg per day, S21400 300 microg per day, or placebo in a double blind, randomized, controlled 2-year study., Study Design: QoL was assessed based on the validated Women's Health Questionnaire designed for peri- and post-menopausal women. Three hundred and thirty-five healthy, early postmenopausal Danish women, 53 years of age in average, who completed one questionnaire at baseline and one under study treatment were included in the analysis set. All analyses were performed on an intention-to-treat basis., Results: QoL improved significantly in both S21400 groups compared to placebo in the dimensions 'memory/concentration', 'vasomotor symptoms', 'sleep problems' and 'sexual behavior' (difference in mean change scores being respectively +7.9, +28.3, +9.9 and +10.8%, p < 0.001, between the S21400 300 microg and placebo group). There were no significant differences between actively treated groups and placebo in the dimensions 'anxiety/depressed mood' and 'well-being'., Conclusion: Pulsed estradiol therapy had a pronounced effect not only on vasomotor symptoms but also a significant and clinically relevant improvement in several other QoL dimensions.

Objective: To investigate how variation in the dose of the progestogen influence the impact of 17beta-oestradiol plus drospirenone (DRSP) treatment on adipose tissue and its secretor function with direct implications for atherogenic metabolites., Design: Randomized, double-blind, placebo-controlled trial., Setting: Primary care, single study site., Subjects: A total of 240 healthy postmenopausal women 53-65 years old, 178 completer., Intervention: Daily treatment with 1 mg 17beta-oestradiol plus 1, 2, or 3 mg DRSP, or placebo for 2 years., Main Outcome Measures: Absolute changes in central (CFM) and peripheral fat mass (PFM; dual-energy X-ray absorptiometry, DEXA), adipokines [interleukin (IL)-6 and adiponectin], atherogenic metabolites [triglycerides, high-density lipoprotein cholesterol (HDL-C), glucose] and blood pressure., Results: Oestradiol plus 1 mg DRSP evoked significant decreases in CFM and the CFM/PFM ratio from baseline. These benefits virtually decreased with increasing dose of DRSP confounded by dose-dependent increases in CFM and PFM in smokers (P-value for trends <0.001), in whom the increases in bioavailable oestradiol were half of that in nonsmokers (P < 0.001). Treatment with 3 mg DRSP induced decreases in serum adiponectin by month 6 (P < 0.05), which persisted in nonsmokers only and led to significant increases in glucose and triglycerides and decreases in HDL-C (P < 0.05). Adiponectin in smokers normalized by the end of the study parallel with the increases in body fat mass., Conclusions: Interactions of the sex steroids with adipose tissue and its secretor function are important determinants of the overall impact of hormone therapy on cardiovascular risk. A DRSP dose up to 2 mg does not seem to exert adverse effects when combined with 1 mg 17beta-oestradiol.

Unlabelled: In the placebo group of the MORE study, including 2576 postmenopausal women (mean age, 66.5 years), the authors describe a strong linear association between the severity grade of osteoporosis (from low BMD to presence of severe vertebral fractures) and the future risk of cardiovascular events. Accordingly, treatment of postmenopausal osteoporosis should include consideration of measures to prevent adverse cardiovascular outcomes., Introduction: Observations indicate an inverse association between BMD and the severity of peripheral atherosclerosis in postmenopausal women. The predictive value of osteoporosis and its different severity stages for the risk of acute cardiovascular events remains unknown., Materials and Methods: Participants were 2576 women (mean age, 66.5 years) assigned to placebo and followed for 4 years in an osteoporosis treatment trial. Those with at least one vertebral fracture or total hip BMD T score < or = -2.5 at baseline were defined as having osteoporosis, whereas those without vertebral fracture and total hip BMD T score between -2.5 and -1 were defined as having low bone mass. The primary outcome for these posthoc analyses was the incidence of adjudicated fatal or nonfatal cardiovascular events., Results: After adjustment for potential confounders, women with osteoporosis had a 3.9-fold (95% CI, 2.0-7.7; p < 0.001) increased risk for cardiovascular events compared with women with low bone mass. Under the same boundaries, a total hip BMD T score < or = -2.5 versus a T score between -2.5 and -1 was associated with a 2.1-fold (95% CI, 1.2-3.6; p < 0.01) increase in risk, whereas presence of at least one vertebral fracture versus no vertebral fracture at baseline was associated with a 3.0-fold (95% CI, 1.8-5.1; p < 0.001) increase in risk. The risk of cardiovascular events increased incrementally with the number and increasing severity of baseline vertebral fractures (both p < 0.001)., Conclusions: Postmenopausal women with osteoporosis are at an increased risk for cardiovascular events that is proportional to the severity of osteoporosis at the time of the diagnosis. Treatment of postmenopausal osteoporosis should include consideration of measures to prevent cardiovascular outcomes.

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.

Objective: To investigate whether radiologic spine disc degeneration is associated with increased type II collagen (CII) degradation products in the urine of postmenopausal women, independently of radiologic knee osteoarthritis (OA) and clinical hand OA., Methods: The study group comprised 324 postmenopausal women ages 58-94 years who had no treatment or disease that could alter bone metabolism. Lateral radiographs of the thoracic and lumbar spine were obtained in each woman and scored for disc space narrowing (DSN) and osteophytes. Fixed-flexion posteroanterior radiographs of the knee were obtained to assess femorotibial knee OA. In all women, hand OA was assessed by clinical examination, and the level of urinary C-terminal crosslinking telopeptide of CII (CTX-II), a biologic marker of CII degradation, was measured., Results: The prevalences of radiographic lumbar and thoracic spine disc degeneration, knee OA, and clinical hand OA were 84%, 88%, 35%, and 58%, respectively. After adjustment for age and body mass index (BMI), patients with lumbar spine DSN grade > or = 1 had, on average, 34% higher CTX-II levels compared with the other women (P = 0.0005), whereas no association was observed with lumbar spine osteophytes. No significant association between thoracic spine DSN or osteophytes and urinary CTX-II levels was observed. Multivariate analysis of variance showed that, after adjustment for age and BMI, lumbar spine DSN (P = 0.0049), knee OA (P = 0.0055), and clinical hand OA (P = 0.0060) were, independently of each other, associated with CTX-II levels. Thus, patients with lumbar spine DSN, knee OA, and clinical hand OA had CTX-II levels 80% higher (P < 0.0001 after adjustment for age and BMI) than those of patients with no lumbar spine DSN, no radiologic knee OA, and no clinical hand OA., Conclusion: Postmenopausal women with lumbar spine disc degeneration are characterized by increased CII degradation. The contribution of lumbar spine DSN to CII degradation was similar to, and independent of, the contribution of radiologic knee OA or clinical hand OA. Lumbar spine disc degeneration in elderly patients should be assessed when analyzing levels of CTX-II in studies of knee, hip, and hand OA., (Copyright 2004 American College of Rheumatology)

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.

Less frequent bisphosphonate dosing in women with postmenopausal osteoporosis has the potential to promote therapy adherence through improved convenience. Ibandronate is a highly potent nitrogen-containing bisphosphonate, proven to significantly increase vertebral and nonvertebral bone mineral density (BMD) when administered as a convenient intravenous injection. A recent double-blind, placebo-controlled, randomized phase III study explored the antifracture efficacy and safety of 1 and 0.5 mg iv ibandronate injections, given once every 3 months, in 2862 women (55-76 years) with postmenopausal osteoporosis [one to four prevalent vertebral fractures and lumbar spine (L1-L4) BMD T score of less than -2.0 and greater than -5.0 in >or=1 vertebra]. All participants received daily vitamin D (400 IU) and calcium (500 mg) supplementation. The primary endpoint was the incidence of new morphometric vertebral fractures after 3 years. However, although a consistent trend toward a reduction in the incidence of new morphometric vertebral fracture was observed in the active treatment arms compared with placebo (9.2% vs. 8.7% vs. 10.7% in the 1 mg, 0.5 mg and placebo groups, respectively), as well as in the incidence of nonvertebral and hip fractures, the magnitude of fracture reduction was suboptimal and was insufficient to achieve statistical significance. At the studied doses, intravenous ibandronate injections also produced dose-dependent, but comparatively small, increases in lumbar spine BMD (4.0% and 2.9%, respectively) and decreases in biochemical markers of bone resorption and formation, relative to placebo. Optimal fracture efficacy likely requires more substantial increases in BMD and more pronounced suppression of bone turnover. In light of the clear dose-response relationship observed in this and other studies, this is likely to be achieved with higher intravenous doses of ibandronate. The results of a recent phase II/III study (Intermittent Regimen Intravenous Ibandronate Study: the IRIS study) provide support for this hypothesis.

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.

Objective: The purpose of this study was to investigate the influence of body mass index and body composition on endometrial thickness and bone mass., Study Design: This was a cross-sectional study that included 531 healthy postmenopausal women aged 48 to 65 years. Endometrial thickness was measured as double-layer thickness. Body composition was measured by dual energy x-ray absorptiometry, which divides the body into fat mass, lean mass, and bone mass, both for the total body and regional body compartments. An abdominal region was inserted manually. Statistics were Pearson correlations and analysis of variance., Results: Endometrial thickness and total body bone mass were correlated, respectively, to body mass index (r = 0.14, P <.01; r = 0.35, P <.001), total body fat mass (r = 0.14, P <.01; r = 0.38, P <.001), abdominal fat mass (r = 0.16, P <.001; r = 0.33, P <.001), peripheral fat mass (r = 0.10, P <.05; r = 0.41, P <.001), and abdominal/peripheral fat mass (r = 0.12, P <.01; r = 0.11, P <.01)., Conclusion: High body mass index and abdominal fat distribution correlate with increased endometrial thickness and bone mass.

Objectives: The aim of this study was to examine the endometrial thickness (ET) in an asymptomatic postmenopausal population, and to assess the long-term variability., Design: A total of 1182 asymptomatic generally healthy postmenopausal women were enrolled into this cross-sectional evaluation of the ET. Measurements were performed by transvaginal ultrasound. A subset of the women (n = 178) was examined twice 3 months to 2 years apart to assess the long-term variability., Results: Cross-sectionally, ET varied with length of menopause. During the first 5 years after menopause (YSM) the mean ET was 2.3 mm but it decreased by 0.03 mm/year (P < 0.01). From 5 to 13 YSM the ET remained stable at a mean of 1.8 mm with no significant changes (P = 0.13). Thereafter there was a minimal increase of 0.01 mm/year (P < 0.05). In order to minimize the influence of natural changes on ET, only women who had reached the menopause more than 5 years earlier were entered into the subsequent long-term study. The mean ET was 2.0 mm +/- 1.0 mm with no significant differences within or between the observers' measurements. The precision errors were less than 1 mm., Conclusions: The normal range of the thickness of the postmenopausal endometrium in asymptomatic women varies with YSM. There is a high long-term agreement within and between observers in measuring the ET.

Based on data from 153 early postmenopausal women who completed a double-blind, randomized 3 year study of graded hormone replacement therapy (HRT) doses or placebo, we investigated the value of bone markers to predict prevention of bone loss. Absolute values of serum and urinary CrossLaps (S-CTX and U-CTX) after 2 weeks of treatment were significantly correlated to 3 year bone mass response (r = -0. 28/-0.35; p < 0.001). These associations were fully expressed at 6 months (r = -0.61/-0.64; p < 0.001). Receiver operating characteristic analyses revealed that the predictive capacity of one measurement of a resorption marker after 6 months' treatment performed similarly as assessment of hip bone mass over 3 years in predicting preservation of spinal bone mass over 3 years. Comparable results were obtained using percent change from baseline in resorption markers at both 6 and 12 months, whereas for formation markers percent change was superior to absolute value at 6 months but not at 12 months. Values of accuracy for S-CTX for a cutoff of 1881 pmol/L at 6 months were 85.2% (sensitivity), 74.3% (specificity), 90.5% (positive predictive value), and 63.4% (negative predictive value); U-CTX performed similarly, whereas the values for the formation markers were slightly lower. A cutoff for S-CTX of 1245 pmol/L eliminated false-positive individuals (those who had a decrease below the cutoff but lost bone). In the false-negative group, which was composed of individuals whose S-CTX did not decrease below the cutoff but had preserved bone mass, S-CTX was significantly associated with spinal bone mass response (r = -0. 41; p < 0.01), indicating these women had been treated with a dose that was not at its optimum for their individual bone turnover. For this cutoff, the values were 49.5% (sensitivity), 97.1% (specificity), 98% (positive predictive value), and 40% (negative predictive value). In conclusion, early bone marker measurements predict long-term preservation of bone mass during HRT. Resorption markers seem superior to formation markers, which reflects that the primary effect of HRT is on bone resorption. A strategy with two cutoff levels may optimize the use of bone markers to predict bone mass response. Whether resorption markers can be used to guide individualized treatment remains to be investigated.

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.

Objective: The aim of this study was to demonstrate clinical equivalence between a novel intranasal estradiol formulation and a reference oral drug., Study Design: In this multinational, double-blind, parallel-group study 659 postmenopausal women with moderate to severe postmenopausal symptoms were randomly assigned to receive either 300 microg/d intranasal 17beta-estradiol (S21400) or 2 mg/d oral micronized estradiol, plus the appropriate placebo, for 24 weeks. All patients also received 10 mg/d dydrogesterone for 14 days per 28-day cycle. Adjustment of intranasal dosage was permitted from week 14 on. The primary efficacy criterion was the Kupperman index at week 14, with a predefined limit of equivalence of 4., Results: Kupperman index scores improved similarly in the 2 groups, from 28.4 +/- 6.2 to 10.0 +/- 8.6 (mean +/- SD) for S21400 and from 28.1 +/- 6.0 to 8.9 +/- 8.0 for oral therapy, with a difference between groups at week 14 of 1.1 +/- 0.6 (90% confidence interval, 0. 0 to 2.2). This was below the predefined equivalence limit of +4 for statistical noninferiority (P <.001). The daily number and intensity of hot flushes decreased similarly in the two treatment groups. Withdrawal bleeding was 20% less frequent with intranasal therapy (90% confidence interval, 12.5 to 27.6). Severe mastalgia was less frequent in the S21400 group (1.0%) than in the group with oral therapy (5.2%; P <.01). Triglyceride and angiotensinogen levels increased significantly with oral therapy but not with S21400. The same number of patients required dose adaptation in the 2 groups (approximately 20%)., Conclusion: Intranasal administration of 300 microg/d estradiol was at least as effective as oral administration of 2 mg/d estradiol in alleviating postmenopausal symptoms, with less frequent mastalgia and uterine bleeding and without the metabolic consequences of the first-pass effect.

Sodium fluoride stimulates bone formation and has been used to treat osteoporosis for decades despite debate about the antifracture efficacy. Hormone replacement therapy (HRT) results in only modest increases in bone mineral density (BMD). However, for women with low bone mass, the ideal therapy should not only inhibit bone resorption but simultaneously stimulate bone formation to increase bone mass above the fracture threshold. We thus performed a randomized, double-blind, placebo-controlled intervention study to prospectively investigate the effect of a low dose of fluoride, in combination with HRT, on BMD and biochemical markers of bone turnover. One hundred healthy postmenopausal women (60-70 yr old) were thus randomly assigned to: 1) HRT [transdermal 17beta-estradiol, releasing 50 microg/day; plus oral norethisterone acetate (NETA), 1 mg/day]; or 2) oral monofluorophosphate (MFP; equivalent to fluoride, 20 mg/day); or 3) HRT+MFP; or 4) placebo, for 96 weeks. All participants received a calcium supplement of 1000 mg/day. Sixty-eight women completed the study. We found a pronounced, linear increase in spinal BMD during treatment with HRT+MFP [11.8% (1.7% SEM)], which was significantly greater than the increase in the HRT group [4.0% (0.5% per yr); P < 0.05]. MFP produced a smaller increase [2.4% (0.6% per yr)], whereas there was no change in the placebo group [0.0% (0.5% SEM)]. Similar changes were found at the other skeletal sites (distal forearm, hip, and total body). Markers of bone formation showed a fall in the HRT group, which was significantly more pronounced than in the combined HRT+MFP group. A nonsignificant increase was found in the MFP group, whereas the placebo group showed a decrease caused by calcium treatment. The marker of bone resorption decreased significantly more in the HRT and the HRT+MFP groups than in the placebo group but tended to increase in the MFP group. In conclusion, this study shows, by use of biochemical markers of bone turnover, that bone resorption and formation may be dissociated, as a result of actions of two compounds with diverging effects on bone turnover. Furthermore, the synergistic effects of relatively low doses of the compounds suggested statistically and clinically significant increases in trabecular and probably also cortical bone. Adverse effects were relatively rare and mild.

Objective: The aim of the study was to assess the dose-response effects on the postmenopausal endometrium of 3 sequential combined hormone replacement regimens and 1 continuous combined hormone replacement regimen of estradiol and gestodene., Study Design: In this 2-year double-blind, placebo-controlled study, 278 healthy postmenopausal women received either 2 mg estradiol sequentially combined with 50 microg or 25 microg gestodene, 1 mg estradiol sequentially or continuously combined with 25 microg gestodene, or placebo., Results: All 4 hormone treatment regimens produced a safe endometrial histologic appearance. The regimens that were based on the lower dose of 1 mg estradiol was associated with less uterine bleeding than were those that were based on 2 mg estradiol. For sequentially opposing the 2 mg dose of estradiol, the dose of 25 microg gestodene was less efficient in producing secretory activity than was the dose of 50 microg gestodene. The measurement of placental protein 14 in serum reflected the secretory transformation of the endometrial buildup., Conclusion: The reduction in bleeding episodes associated with regimens with lower estradiol doses may lead to improved long-term therapy compliance by menopausal women. The potency of progestogens can be assessed by measuring the serum concentration of placental protein 14.

Osteoporosis is a serious, frequently occurring disease. Sensitive, specific and precise biochemical measures of bone remodelling, thus, are important tools in the evaluation of bone loss, fracture risk and treatment response. Bone turnover is predictive of the subsequent rate of loss. A high bone turnover documented by increased levels of biochemical markers predicts an increased rate of loss in bone mass. Additionally, as a high bone turnover leads to an increase in the extent of bone resorption as well as an increase of the erosion depth, this may also cause deterioration of the bone structure, thereby leading to an increased risk of fracture. That the predictive values of bone mass and markers of bone turnover are additive suggests that these measures describe different properties of bone. Hormone replacement induces a reduction in postmenopausal bone turnover, arrests loss of bone mass and decreases fracture risk. The skeletal response to therapy is reflected by bone markers and these may be used for monitoring purposes. Those who are in most need of treatment can be identified by a combination of bone mass and bone marker measurement. Furthermore, those who need the treatment most will demonstrate the best response in terms of bone mass. Concern has arisen because of a relatively large day-to-day variation, especially in urinary markers; however, this seems to be resolved through use of the new serum markers.

Objective: To examine the effect of diet with exercise on serum leptin and whether leptin is associated with the metabolic syndrome X in a high risk population such as overweight postmenopausal women., Study Design and Subjects: 121 healthy overweight, postmenopausal women (aged 49-58y, body mass index (BMI) 25-42 kg/m2) were randomized to: A low-energy-diet, 4.2 MJ/d (n = 51), low-energy-diet + standardized physical exercise (n=49) or no intervention (control: n=21) for 12 weeks, followed by 6 months follow-up without intervention., Measurements: S-leptin was measured by Radio Immuno Assay (RIA), body composition and fat distribution by dual energy X-ray absorptiometry (DEXA) and anthropometry. Factors associated with the metabolic syndrome X and sex hormones were measured., Results: S-leptin was two-fold higher than in normal-weight postmenopausal women and S-leptin was normalized after weight loss induced by the 12-week low-energy-diet, without any additive effect of the exercise. Of the factors associated with the metabolic syndrome X, serum-leptin correlated significantly only with sex-hormone-binding-globulin and plasminogen-activator-inhibitor-1, whereas factors associated with obesity per se correlated significantly with leptin. Changes in S-leptin correlated with changes in fat tissue mass during the follow-up, but not during the intervention. S-leptin at baseline did not correlate with either short term or long term weight loss., Conclusion: There is no effect of exercise added to diet on S-leptin in overweight postmenopausal women. Leptin does not seem to be associated with the metabolic syndrome X, but rather with fatness. S-leptin is probably associated with both dynamic and static effects of adipose tissue. S-leptin did not predict weight loss.

Background: Long-term estrogen therapy can reduce the risk of osteoporotic fracture and cardiovascular disease in postmenopausal women. At present, however, these beneficial effects are not separable from undesirable stimulation of breast and endometrial tissues., Methods: We studied the effect of raloxifene, a nonsteroidal benzothiophene, on bone mineral density, serum lipid concentrations, and endometrial thickness in 601 postmenopausal women. The women were randomly assigned to receive 30, 60, or 150 mg of raloxifene or placebo daily for 24 months., Results: The women receiving each dose of raloxifene had significant increases from base-line values in bone mineral density of the lumbar spine, hip, and total body, whereas those receiving placebo had decreases in bone mineral density. For example, at 24 months, the mean (+/-SE) difference in the change in bone mineral density between the women receiving 60 mg of raloxifene per day and those receiving placebo was 2.4+/-0.4 percent for the lumbar spine, 2.4+/-0.4 percent for the total hip, and 2.0+/-0.4 percent for the total body (P<0.001 for all comparisons). Serum concentrations of total cholesterol and low-density lipoprotein cholesterol decreased in all the raloxifene groups, whereas serum concentrations of high-density lipoprotein cholesterol and triglycerides did not change. Endometrial thickness was similar in the raloxifene and placebo groups at all times during the study. The proportion of women receiving raloxifene who reported hot flashes or vaginal bleeding was not different from that of the women receiving placebo., Conclusions: Daily therapy with raloxifene increases bone mineral density, lowers serum concentrations of total and low-density lipoprotein cholesterol, and does not stimulate the endometrium.

In 979 healthy women, aged 30-75 years, bone mass was measured by DXA in the lumbar spine and proximal femur, and by SXA in the distal forearm. Bone turnover was assessed by urinary CrossLaps (CrossLaps ELISA), a new assay which measures type I collagen degradation products in urine and by osteocalcin (two-site N-Mid hOsteocalcin ELISA), a new assay which measures the N-terminal-mid fragment (1-43) as well as the intact (1-49) osteocalcin (OCN-Mid) in serum. For comparison data on urinary hydroxyproline (fU Hpr/Cr) and serum, total alkaline phosphatase were included (AP). In premenopausal women below 50 years of age, the concentrations of the biochemical markers were stable with age. At menopause CrossLaps and OCN-Mid increased abruptly to a level 60% and 35% above the premenopausal mean values (p < 0.001). Premenopausal women in the highest quartiles, stratified according to the concentration of CrossLaps and OCN-Mid corrected for height and weight, had 6%-11% lower bone mass in all regions (p < 0.01) as compared to women in the lowest quartiles. CrossLaps and OCN-Mid corrected for height and weight correlated with bone mass in the spine and proximal femur, r = -0.13 to r = -0.28, p < 0.05. In postmenopausal women, the difference in bone mass between the highest and lowest quartiles was 8%-14% (p < 0.001). CrossLaps and OCN-Mid correlated with bone mass measured in all regions, r = -0.14 to r = -0.32, p < 0.05. The correlation between bone mass and AP and Fu Hpr/Cr was lower; r = -0.06 to r = -0.20 for premenopausal women, NS to p < 0.01, and r = -0.01 to r = -0.23, NS to p < 0.001 for postmenopausal women. In conclusion, the present data indicate that high bone turnover is associated with a significantly lower bone mass in not only postmenopausal, but interestingly also in premenopausal women. In consistence with previous results, we found that bone turnover increased perimenopausally and in the early menopause.

The main aim of this study was to investigate the effect of an energy-restrictive, high-protein diet with or without exercise on muscle morphology and biochemistry. Moderately overweight postmenopausal women (49-58 yr, body mass index: 25-42 kg/m2) were randomly assigned to three groups for 12 wk of intervention; namely, a control group, a group on a 4.2 MJ/day diet, and a group on 4.2 MJ/day diet combined with aerobic and anaerobic exercise. Muscle morphology and biochemistry analysis were performed in 69 and 58 women, respectively. In contrast to the diet-only group, the die-plus- exercise group significantly increased the muscle fiber areas by 20-25%, the number of capillaries per muscle fiber type I by approximately 20%, and the activities of citrate synthase by approximately 35% and hexokinase by approximately 20% (P < 0.05). There were no statistically significant changes in any other muscle variable (P < 0.05). The respiratory exchange ratio decreased in both intervention groups by 2-4% (P < 0.01). It is concluded that 12-wk period of an energy-restrictive high-protein diet was not associated with major changes in muscle morphology or biochemistry. The addition of exercise to the die led to an adaptive increase in muscle fiber areas and in the oxidative capacity of the muscles.

This study assessed the short- and long-term effects of an energy-restrictive diet with or without exercise on plasminogen activator inhibitor-1 antigen (PAI-1 Ag) and PAI-1 activity, tissue-type plasminogen activator antigen (TPA Ag), and fibrinogen serum levels. Healthy, overweight postmenopausal women (age, 53.8+/-2.5 years; body mass index, 25 to 42 kg/m2; n=121) were randomly assigned to one of three groups: control, 4200-kJ/d diet, or 4200-kJ/d diet with combined aerobic and anaerobic exercise. PAI-1 activity and PAI-1 Ag, TPA Ag, and fibrinogen levels were measured at baseline, after a 12-week intervention, and after a further 6-month follow-up. PAI-1 Ag and activity and TPA Ag were positively correlated with serum triglyceride levels, the abdominal-to-total-body fat ratio (as assessed by total-body dual-energy x-ray absorptiometry), fasting blood glucose, and systolic BP and negatively with HDL cholesterol and sex hormone-binding globulin. The diet led to profound decreases and normalization of PAI-1 activity (approximately 50%), PAI-1 Ag (approximately 30%) and TPA Ag (approximately (29%), but exercise conferred no additional effect. Fibrinogen did not change. At follow-up there were no longer any significant changes (P>.05). In conclusion, PAI-1 Ag and activity as well as TPA Ag seem to be part of the metabolic syndrome X. The diet made the blood less thrombogenic in the short term with no effect of the added exercise.

Objective: To investigate whether fat distribution or sex hormone status in overweight postmenopausal women do influence the response to treatment of overweight., Design: Longitudinal, clinical intervention study of a 4.2 MJ diet daily with or without exercise., Subjects: 98 healthy, overweight, postmenopausal women (age: 49-58 y, BMI: 25-42 kg/m2)., Measurements: Various fatness and fat distribution parameters (by dual-energy x-ray absorptiometry and anthropometry), sex hormone-binding globulin (SHBG), sex hormones, and the resting energy expenditure (REE) at baseline and after 3 months., Results: Reductions in weight and fat were independent of the initial fat distribution and the REE, but were significantly associated with high initial SHBG levels. Furthermore, loss of fat was significantly and independently associated with increases in SHBG and reductions in central fat distribution., Conclusion: Postmenopausal women with an android and gynoid fat distribution respond with similar weight loss to treatment of overweight. Furthermore, a more healthy, less android, fat distribution and sex hormone status may be achieved with increasing weight loss.

Diminution of bone mineral density (BMD) in the spine and forearm was studied cross-sectionally in 363 women who were 6 months to 10 years postmenopausal. BMD was determined by dual-energy X-ray absorptiometry (DXA) (Hologic QDR-2000) in the lumbar spine, in both the supine lateral (LAT) and anteroposterior (AP) projections, and in the distal third of the forearm. The postmenopausal diminution of BMD was best described by an exponential fit. The initial rate of postmenopausal diminution of BMD was highest in the most trabecular sites (LAT > AP > forearm), but 10-year diminution was similar at all sites (12%-13%, corresponding to about 1.0-1.5 SD), and extrapolation suggested reverse order of the rates of diminution thereafter (forearm > AP > LAT). When bone mineral content of the entire L3 vertebra (tBMC) was measured in vivo, AP tBMC could account for only 67% of the variation in LAT tBMC, compared with r2 = 0.997 in vitro. This observation suggests an accuracy problem in vivo in one of the spine measurement methods. We conclude that the initial rate of BMD diminution after the menopause seems to be highest in the spine, especially when measured laterally, but that this rate levels off within the first decade. The lower precision error of a forearm measurement (0.8% v 1.6 for AP and 3.1 for LAT) therefore implies that this method may require a shorter observation period than spine measurements for the detection of bone loss 5-10 years after menopause. Long-term longitudinal spine and forearm measurements are, however, needed to confirm these conclusions.

A circadian rhythm in the serum concentration of the procollagen type I carboxyl-terminal propeptide (sPICP) has previously been demonstrated in premenopausal women. This study was performed to investigate the circadian rhythm in sPICP in healthy and osteopenic postmenopausal women. Blood samples were taken every third hour for 27 h from three groups of women: 12 early postmenopausal women (aged 55 +/- 2 years; mean +/- SD); 12 late postmenopausal women (aged 73 +/- 1 years); and 12 osteopenic but otherwise healthy late postmenopausal women (aged 73 +/- 1 years). A circadian rhythm in sPICP was found in all three groups, as shown by cosinor analysis (p = 0.000003-0.03). The circadian rhythm in sPICP was significantly different between the osteopenic group and the age-matched healthy group (p < 0.008). The amplitude of the circadian rhythm in sPICP was about twice as high in the osteopenic group, and the time of the maximum tended to be about 3 h later, as compared with the age-matched healthy group. The plasma concentration of osteocalcin, as measured by a recently developed two-site enzyme-linked immunosorbent assay, also showed a circadian rhythm in all three groups (p = 0.0001-0.05), with no significant differences between groups. In conclusion, we have found a significant circadian rhythm in sPICP in both early and late postmenopausal women. In osteopenic women the nightly peak in sPICP is larger and persists later into the night as compared with non-osteopenic women.

Total and regional body composition were measured in 373 early postmenopausal women aged 49-60 y by dual-energy x-ray absorptiometry to evaluate whether the changes in body composition in the early postmenopausal years are related to menopause itself or merely to age. Both fat mass and fat distribution correlated with age (r = 0.12-0.21, P < 0.05-P < 0.001), but not with years since menopause (YSM). Lean tissue mass, on the other hand, decreased with YSM (r = -0.17, P < 0.001) but was not related significantly to age. Total body bone mineral density decreased with both YSM (r = -0.30, P < 0.001) and age (r = -0.21, P < 0.001). Our study suggests that postmenopausal changes in body fat and fat distribution are more dependent on age than on menopause, but we cannot exclude a separate effect of the menopause. Changes in fat-free mass, including a postmenopausal decline in both soft lean tissue mass and bone mass, are, however, mainly menopause-related

This study was performed to investigate whether the circadian variation in urinary pyridinium crosslinks is related to physical activity, age, the menopause, and asymptomatic osteopenia. We measured urinary pyridinoline/creatinine (Pyr/Cr) and deoxypyridinoline/creatinine (D-Pyr/Cr) in 9 healthy premenopausal women in two 27 h studies, before and at the end of 5 days of total bed rest. Both Pyr/Cr and D-Pyr/Cr showed highly significant circadian variations, with the peak at night and the nadir during the day (p < 0.001). The 5 days of complete bed rest produced no changes in the circadian pattern, but a general increase of 28% was observed in pyridinium crosslinks. A group of 12 healthy, early postmenopausal women (aged 55 +/- 2 years), 12 healthy, elderly postmenopausal women (aged 73 +/- 1 years), and 12 elderly osteopenic but otherwise healthy women (aged 73 +/- 1 years) were also studied for 27 h. All three groups showed highly significant (p < or = 0.001) circadian variations in the urinary excretion of pyridinium crosslinks. As expected, both Pyr/Cr (p < 0.05) and D-Pyr/Cr (p < 0.001) increased at the time of menopause, but the circadian variations in Pyr/Cr and D-Pyr/Cr were similar in all groups studied. We conclude that the circadian variation in the urinary excretion of pyridinium crosslinks is independent of physical factors. Furthermore, the circadian variation in pyridinium crosslinks was not related to age, menopausal status, or asymptomatic osteopenia.

Total and regional bone mineral density (BMD) of the proximal femur was measured by DXA in 1238 healthy white women. In the 389 premenopausal women, aged 21-54 years, no bone loss was observed before the menopause, except in the femoral neck and Ward's triangle, in which BMD decreased by 0.3%/year (SEE 0.2-0.9%/year, p < 0.001) and 0.6%/year (SEE 0.4-0.8%/year, p < 0.001), respectively. In the postmenopausal women aged 48-75 years, there was a highly significant exponential decay in BMD with age and years since menopause (YSM) in all regions (-0.58 < r < -0.48, p < 0.001). However, YSM was a better predictor of BMD than age. The decrease in BMD in the first 5 years postmenopause reached values of 9-13%. The estimated bone loss after 20 years was 17-30%, greatest in Ward's triangle and smallest in the intertrochanteric region. BMD correlated highly significantly with BMI (0.26 < r < 0.48, p < 0.001). In conclusion, the present study indicates a stable premenopausal bone mass of the proximal femur and a postmenopausal bone loss, which is influenced mainly by YSM within the first 10-15 years after menopause. BMD correlated with body mass index (BMI) in the postmenopausal years, confirming that low BMI constitutes a potential risk factor for osteoporosis.

We investigated the effect of the menopause and postmenopausal hormone replacement therapy (HRT) on the serum concentration of carboxy-terminal pyridinoline cross-linked telopeptide of type I collagen (ICTP), a potential new biochemical marker of bone resorption. A group of 44 healthy postmenopausal women, aged 45-54 years, had about 19% higher serum ICTP than did a group of 42 healthy premenopausal women aged 35-50 years (3.6 +/- 0.8 micrograms/l v 3.0 +/- 0.7 micrograms/l (mean +/- SD); p < 0.01), although there was a large overlap in the values. The 44 postmenopausal women also participated in a longitudinal clinical study, in which 20 received HRT and 24 received a placebo. Compared with the placebo group, those who received HRT had a significant (p < 0.05) decrease in ICTP of about 12% at the end of 1 year of treatment, but again there was considerable overlap in the values. The menopause- and HRT-induced changes in ICTP were less than those seen in serum osteocalcin, serum total alkaline phosphatase, and fasting urinary excretion of hydroxyproline, calcium, pyridinoline and deoxypyridinoline. We conclude that the menopause increases and HRT decreases ICTP, although these changes are less pronounced than those seen in other biochemical markers of bone turnover.

One hundred and twenty-one healthy, overweight, postmenopausal women were randomly assigned to three groups: controls (no intervention), a 4200 kJ/day diet, or 4200 kJ/day diet with combined aerobic and anaerobic exercise, for 12 weeks. One hundred and eighteen women completed the study. The loss of weight was similar in the two intervention groups, but compared with the diet-only group, the diet-plus-exercise group lost significantly more fat (7.8 vs 9.6 kg) and no lean tissue mass (1.2 vs 0.0 kg). The resting metabolic rate was increased in the diet-plus-exercise group as compared to the controls (11% vs 4%, p < 0.009). The cardiovascular risk factors (serum lipids and lipoproteins (except high density lipoprotein), systolic blood pressure, and the waist-to-hip ratio) decreased significantly in both intervention groups, as compared to the controls. There were no consistent, major differences between groups in changes in total body, spinal, or forearm bone mineral density. In conclusion, overweight postmenopausal women benefit from addition of combined aerobic and anaerobic exercise to an energy-restrictive diet.

The independent impact of regional and total body composition and sex and thyroid hormone levels on resting energy expenditure (REE) was assessed in 121 healthy, overweight (body mass index [BMI], 25 to 42 kg/m2), postmenopausal women (aged 49 to 58 years). REE was measured by indirect calorimetry with a ventilated hood, and the total, trunk, and peripheral body composition by dual-energy x-ray absorptiometry (DXA). Sex and thyroid hormone levels were also measured. REE correlated significantly (P < .05) better with trunk lean tissue mass ([LTM] r = .61) than with total-body (r = .53) or peripheral LTM (r = .30). Trunk LTM (R2 = .37), total-body fat tissue mass ([FTM] R2 = .04), androstenedione (R2 = .03), and total triiodothyronine ([T3] R2 = .02) were all significantly independently associated with REE. Together they explained 46% (model R2) of the interindividual variation in REE, with a standard error of estimate (SEE) of 549 kJ/d. We conclude that the interindividual variation in REE is explained mainly by differences in the visceral component of LTM, with additional minor information from the total-body FTM, androstenedione, and T3.

Aim We aimed to study 2-h estrogen kinetics in smoking versus non-smoking postmenopausal women receiving estrogen therapy. Moreover, we wished to study estrogen concentrations over 2 years in smokers using ten or fewer cigarettes daily versus non-smokers in postmenopausal women on estrogen treatment. Method We used post-hoc analyses from two randomized trials. In study I, we included 150 women from three groups receiving therapies containing 1 or 2 mg 17β-estradiol, where trough and 2-h blood samples was collected in cycles 1, 7 and 13. In study II, we included 94 completing women who had received either placebo or a regimen containing 1 mg 17β-estradiol. Results In study I, 35% were smokers. At 2 h post tablet intake, serum estrone and estradiol concentrations were significantly lower in smokers as compared to non-smokers, i.e. mean serum estrone was 212 pg/ml (95% confidence interval (CI) 177-247 pg/ml) in smokers as opposed to 318 pg/ml (95% CI 278-359 pg/ml) in non-smokers on 1 mg estradiol ( p = 0.0002). In study II, 19% were smokers. In the estrogen group, smoking lead to significantly lower levels of both serum estrone and serum estradiol at all post-randomization time points. No differences between smokers and non-smokers were seen on placebo. Conclusion We conclude that smoking reduces serum estrogens at both trough and after 2 h in postmenopausal women on estrogen treatment. The effect of smoking on estrogen concentrations is fully expressed in women smoking ten or less cigarettes daily. These findings indicate that the influence of smoking upon the metabolism of estrogen therapy is constant and without dose-response for standard smoking intensities. [ABSTRACT FROM AUTHOR]

Summary: Early prognosis of osteoporosis risk is not only important to individual patients but is also a key factor when screening for osteoporosis drug trial populations. We present an osteoporosis fracture risk score based on vertebral heights. The score separated individuals who sustained fractures (by follow-up after 6.3 years) from healthy controls at baseline. Introduction: This case-control study was designed to assess the ability of three novel fracture risk scoring methods to predict first incident lumbar vertebral fractures in postmenopausal women matched for classical risk factors such as BMD, BMI, and age. Methods: This was a case-control study of 126 postmenopausal women, 25 of whom sustained at least one incident lumbar fracture and 101 controls that maintained skeletal integrity over a 6.3-year period. Three methods for fracture risk assessment were developed and tested. They are based on anterior, middle, and posterior vertebral heights measured from vertebrae T12-L5 in lumbar radiographs at baseline. Each score's fracture prediction potential was investigated in two variants using (1) measurements from the single most deformed vertebra or (2) average measurements across vertebrae T12-L5. Emphasis was given to the vertebral fracture risk (VFR) score. Results: All scoring methods demonstrated significant separation of cases from controls at baseline. Specifically, for the VFR score, cases and controls were significantly different (0.67 ± 0.04 vs. 0.35 ± 0.03, p < 10 ) with an AUC of 0.82. Dividing the VFR scores into tertiles, the fracture odds ratio for the highest versus lowest tertile was 35 ( p < 0.001). Sorting the combined case-control group according to VFR score resulted in 90% of cases in the top half. Conclusion: At baseline, the three scores separated cases from controls and, especially, the VFR score appears to be predictive of fractures. Control experiments, however also, indicate that VFR-based fracture prediction is operator/annotator dependent and high-quality annotations are needed for good fracture prediction [ABSTRACT FROM AUTHOR]