Healthy Early Postmenopausal Women Research Articles

The Effectiveness of a Lactobacilli-Based Probiotic Food Supplement on Bone Mineral Density and Bone Metabolism in Australian Early Postmenopausal Women: Protocol for a Double-Blind Randomized Placebo-Controlled Trial.

Osteoporosis affects one in three women over the age of 50 and results in fragility fractures. Oestrogen deficiency during and after menopause exacerbates bone loss, accounting for higher prevalence of fragility fractures in women. The gut microbiota (GM) has been proposed as a key regulator of bone health, as it performs vital functions such as immune regulation and biosynthesis of vitamins. Therefore, GM modulation via probiotic supplementation has been proposed as a target for potential therapeutic intervention to reduce bone loss. While promising results have been observed in mouse model studies, translation into human trials is limited. Here, we present the study protocol for a double-blind randomized controlled trial that aims to examine the effectiveness of three lactobacilli strains on volumetric bone mineral density (vBMD), trabecular, and cortical microstructure, as measured using High Resolution peripheral Quantitative Computed Tomography (HR-pQCT). The trial will randomize 124 healthy early postmenopausal women (up to 8 years from menopause) to receive either probiotic or placebo administered once daily for 12 months. Secondary outcomes will investigate the probiotics' effects on areal BMD and specific mechanistic biomarkers, including bone metabolism and inflammatory markers. The trial is registered with Australian New Zealand Clinical Trials Registry (ACTRN12621000810819).

Differences in dietary intake in early postmenopausal women with different levels of areal and volumetric bone mineral density: a cross-sectional analysis of baseline data from an intervention study

Osteoporosis is a degenerative disease of the bone. The rate of bone loss is accelerated during the first postmenopausal years in women which results in their disproportionate prevalence of osteoporosis(2). Some of the factors contributing to the development and maintenance of bone mineral density (BMD) relate to diet, particularly the intake of protein, calcium and other micronutrients that play a crucial role in bone composition(3). The most common method of measuring BMD is dual-energy X-ray absorptiometry (DXA) which generates a two-dimensional image of the scan site (typically spine, hip and/or forearm) to determine areal BMD (aBMD). However, new methods have recently emerged, including High Resolution peripheral Quantitative Computed Tomography (HRpQCT), that offer more accurate three-dimensional measurements of volumetric BMD (vBMD) and microstructure of distal tibia and radius(4). The aim of this study was to examine the differences in the dietary intake of nutrients that represent organic or inorganic components of the bone, in early postmenopausal women with different spine aBMD and tibia and radius vBMD levels. One hundred and fourteen healthy early postmenopausal women with a lumbar spine or total hip BMD T score > −2.5 (measured by DXA) were recruited as part of a larger interventional study. Dietary intake was recorded using a 297-point self-reported validated food frequency questionnaire(5) for assessing the intake of energy, macro and micronutrients. Physical activity was self-reported using the validated Active Australia Questionnaire. Years since menopause were self-reported. DXA and HRpQCT scans measured L1-L4 spine, proximal femur aBMD, and distal tibia and radius vBMD respectively. Non-parametric statistical tests examined differences in dietary intake and physical activity levels between women at different levels of aBMD and vBMD. Data reported as median and interquartile ranges. There were no significant differences observed in the total sample between tertiles of aBMD and vBMD, regarding nutrient intake. However, for women with less than 3 years since menopause (i.e., the time-period of accelerated bone loss), lower dietary intakes of energy [8,658(3,324) vs 10,068(3,688) kJ/day; p = 0.047], protein [94(29) vs 103(32) g/day; (p = 0.044)], sodium [1,927(992) vs 2,625(2,185) mg/d; (p = 0.044)], potassium [4,064(1,373) vs 5,121(2,377) mg/d; (p = 0.041)], calcium [969(325) vs 1,214(652) mg/d; (p = 0.028)] and zinc [10(3) vs 12(4) mg/d; (p = 0.005)] were observed for women with osteopenia (−1< L1-L4 aBMD T-score <2.5) compared to those with normal L1-L4 aBMD (i.e., T-score > −1). No significant differences were observed for women with more than 3 years since menopause, with the only exception of alcohol intake (p = 0.033), which was found to be lower in women with osteopenia compared to those with normal aBMD. These findings highlight the importance of targeting osteopenic women within the first 3 years following menopause as candidates for tailored dietary intervention programs for preventing osteoporosis.

Menopausal stage differences in endothelial resistance to ischemia-reperfusion injury.

In postmenopausal women, reduced ovarian function precedes endothelial dysfunction and attenuated endothelial resistance to ischemia-reperfusion (IR) injury. We hypothesized that IR injury would lower endothelial function, with premenopausal women demonstrating the greatest protection from injury, followed by early, then late postmenopausal women. Flow-mediated dilation (FMD) was assessed at baseline and following IR injury in premenopausal (n = 11), early (n = 11; 4 ± 1.6 years since menopause), and late (n = 11; 15 ± 5.5 years since menopause) postmenopausal women. There were significant group differences in baseline FMD (p = 0.007); post hoc analysis revealed a similar resting FMD between premenopausal (7.8% ± 2.1%) and early postmenopausal (7.1% ± 2.7%), but significantly lower FMD in late postmenopausal women (4.5% ± 2.3%). Results showed an overall decline in FMD after IR injury (p < 0.001), and a significant condition*time interaction (p = 0.048), with early postmenopausal women demonstrating the most significant decline in FMD following IR. Our findings indicate that endothelial resistance to IR injury is attenuated in healthy early postmenopausal women.

Short-Term Supplementation With Fermented Red Clover Extract Reduces Vascular Inflammation in Early Post-menopausal Women.

The decline in estrogen at menopause poses a critical challenge to cardiovascular and metabolic health. Recently, a growing interest in the role of phytoestrogens, with a particular focus on isoflavones, has emerged as they can bind to estrogen receptors and may mimic the roles of endogenous estrogen. Fermented red clover extract (RC) contains isoflavones with superior bioavailability compared to non-fermented isoflavones, however little is known regarding the impact of isoflavones on cardiovascular and metabolic health. We assessed markers of vascular health in plasma and skeletal muscle samples obtained from healthy but sedentary early post-menopausal women (n = 10; 54 ± 4 years) following 2 weeks of twice daily treatment with placebo (PLA) or RC (60 mg isoflavones per day). The two interventions were administered using a randomized, double-blind, crossover design with a two-week washout period. Plasma samples were utilized for assessment of markers of vascular inflammation. There was a statistically significant reduction (~5.4%) in vascular cell adhesion molecule 1 (VCAM-1) following 2 weeks of RC supplementation compared to PLA (p = 0.03). In contrast, there was no effect of RC supplementation compared to PLA on skeletal muscle estrogen receptor content and enzymes related to vascular function, and angiogenesis. Supplementation with RC reduces vascular inflammation in early post-menopausal women and future studies should address the long-term impact of daily supplementation with RC after menopause.

A 12-month continuous and intermittent high-impact exercise intervention and its effects on bone mineral density in early postmenopausal women: a feasibility randomized controlled trial.

Intermittent mechanical loading generates greater bone adaptations than continuous mechanical loading in rodents but has never been evaluated in humans. This study aimed to evaluate the feasibility of a continuous and intermittent countermovement jump (CMJ) intervention for attenuating early postmenopausal BMD loss. 41 healthy early postmenopausal women (age=54.6±3.4 years) were randomly assigned to a continuous countermovement jumping group, an intermittent countermovement jumping group or a control group for 12 months. Adherence and dropout rates were recorded along with bone mineral density (BMD) at lumbar spine, femoral neck and trochanter sites at baseline, 6 months and 12 months. 28 participants completed the study. Dropout rate during the intervention (from the initiation of exercise) was 36% from continuous and 38% from intermittent countermovement jumping groups. For the participants that completed the intervention, adherence was 60.0±46.8% for continuous and 68.5±32.3% for intermittent countermovement jumping. The control group lost significant lumbar spine BMD (% difference=-2.7 [95%CI: -3.9 to -1.4]) and femoral neck BMD (% difference=-3.0% [95%CI: -5.1 to -0.8]). There was no statistically significant change in BMD for either countermovement jumping group. There was no statistically significant difference in BMD change between continuous or intermittent countermovement jumping groups when compared with the control group. Adherence and dropout rates were in line with previous similar interventions. To evaluate the effect of continuous and intermittent exercise on BMD, future studies should focus on maintaining participant engagement and adherence to the exercise intervention.

Probiotic treatment using a mix of three Lactobacillus strains for lumbar spine bone loss in postmenopausal women: a randomised, double-blind, placebo-controlled, multicentre trial.

Postmenopausal bone loss in the spine is associated with an increased risk of vertebral fractures. Certain probiotic treatment protects rodents from ovariectomy-induced bone loss. The aim of the present study was to determine if treatment with a combination of three bacterial strains protects against the rapid spine bone loss occurring in healthy early postmenopausal women. This randomised, double-blind, placebo-controlled, multicentre trial was done at four study centres in Sweden. Early postmenopausal women were randomly assigned in a 1:1 ratio to receive probiotic treatment consisting of three Lactobacillus strains (Lactobacillus paracasei DSM 13434, Lactobacillus plantarum DSM 15312, and Lactobacillus plantarum DSM 15313; 1 x 1010 colony-forming units per capsule) or placebo once daily for 12 months. The primary outcome was the percentage change from baseline in lumbar spine bone mineral density (LS-BMD) at 12 months. The primary analysis was done in all participants with BMD measurements available both at baseline and at 12 months. Analyses of adverse events and safety included all participants who had taken at least one capsule of placebo or Lactobacillus. This trial is registered with ClinicalTrials.gov, NCT02722980, and is completed. Between April 18 and Nov 11, 2016, 249 participants were randomly assigned to receive probiotic product or placebo, and 234 (94%) completed the analyses required for the primary outcome. Lactobacillus treatment reduced the LS-BMD loss compared with placebo (mean difference 0·71%, 95% CI 0·06 to 1·35). The LS-BMD loss was significant in the placebo group (-0·72%, -1·22 to -0·22), whereas no bone loss was observed in the Lactobacillus-treated group (-0·01%, -0·50 to 0·48). The adverse events were similar between the two groups. Probiotic treatment using a mix of three Lactobacillus strains protects against lumbar spine bone loss in healthy postmenopausal women. Probi.

Progesterone Therapy, Endothelial Function and Cardiovascular Risk Factors: A 3-Month Randomized, Placebo-Controlled Trial in Healthy Early Postmenopausal Women

BackgroundProgesterone is effective treatment for hot flushes/night sweats. The cardiovascular effects of progesterone therapy are unknown but evidence suggests that premenopausal normal estradiol with also normal progesterone levels may provide later cardiovascular protection. We compared the effects of progesterone to placebo on endothelial function, weight, blood pressure, metabolism, lipids, inflammation and coagulation.Methods and ResultsWe conducted a randomized, double-blind, 3-month placebo-controlled trial of progesterone (300 mg daily) among 133 healthy postmenopausal women in Vancouver, Canada from 2003–2009. Endothelial function by venous occlusion plethysmography was a planned primary outcome. Enrolled women were 1–11 y since last menstruation, not using hormones (for >6 months), non-smoking, without diabetes, hypertension, heart disease or their medications. Randomized (1∶1) women (55±4 years, body mass index 25±3) initially had normal blood pressure, fasting lipid, glucose and electrocardiogram results. Endothelial function (% forearm blood flow above saline) was not changed with progesterone (487±189%, n = 18) compared with placebo (408±278%, n = 16) (95% CI diff [−74 to 232], P = 0.30). Progesterone (n = 65) and placebo (n = 47) groups had similar changes in systolic and diastolic blood pressure, resting heart rate, weight, body mass index, waist circumference, total cholesterol, low-density lipoprotein cholesterol and triglyceride levels. High-density lipoprotein was lower (−0.14 mmol/L, P = 0.001) on progesterone compared with placebo. Fasting glucose, hs-C-reactive protein, albumin and D-dimer changes were all comparable to placebo. Framingham General Cardiovascular Risk Profile scores were initially low and remained low with progesterone therapy and not statistically different from placebo.ConclusionsResults indicate that progesterone has short-term cardiovascular safety. Endothelial function, weight, blood pressure, waist circumference, inflammation and coagulation were unchanged as were lipids except for HDL-C. The statistically significant decrease in HDL-C levels was not clinically important (based on lack of Cardiovascular Risk Profile change).Trial RegistrationClinicalTrials.gov NCT00152438

Hot flushes and night sweats differ in associations with cardiovascular markers in healthy early postmenopausal women

The aim of this study was to evaluate the associations between vasomotor symptoms ([VMS] hot flushes or flashes and night sweats) and markers of cardiovascular risk. Healthy postmenopausal women in a randomized controlled trial of progesterone for VMS recorded VMS frequency in the Daily Menopause Diary for 28 days at baseline. Accepted risks for cardiovascular disease were measured: body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), blood pressure (BP), endothelial function by venous occlusion plethysmography, fasting lipids, glucose, high-sensitivity C-reactive protein, albumin, and D-dimer. Relationships between risk variables and VMS frequency (24 h, day and night) were assessed by univariate and multivariate robust regressions with adjustment for age and WHtR. Data were available for 145 healthy, nonsmoking women without heart disease, hypertension, or diabetes who were 1 to 11 years past their final menstruation and were aged 43 to 65 years, with a mean (SD) BMI of 25.0 (2.9) kg/m and WC of 79.1 (7.1) cm. Anthropometric variables (BMI, WC, and WHtR) were significantly negatively associated with total (24-h day) VMS frequency and with day VMS but not with night VMS frequency. Systolic BP decreased with greater 24-hour VMS frequency, and both systolic and diastolic BPs were inversely related to day but not night VMS frequency. Albumin was positively associated with night VMS frequency but not with day or 24-hour VMS frequency. Other variables showed little association with VMS frequency. Hot flushes, but not night sweats, were associated with lower cardiovascular risk factors in these healthy postmenopausal women. Future research should differentiate night sweats from hot flushes.

Fat mass and obesity-associated gene polymorphisms do not affect metabolic response to hormone therapy in healthy postmenopausal women

To determine whether fat mass and obesity-associated gene polymorphisms rs9939609 T>A and rs8050136 A>C or their haplotypes influence anthropometric and metabolic variables in recently postmenopausal women receiving hormone therapy. In this randomized crossover study carried out in a university clinic, 86 postmenopausal women consulting for symptoms of estrogen deficiency were genotyped by real-time polymerase chain reaction for single nucleotide polymorphisms rs9939609 T>A and rs8050136 A>C of the fat mass and obesity-associated gene. Haplotypes were constructed from the combination of polymorphisms rs9939609 and rs8050136, and their frequencies were inferred using the PHASE 2.1.1 program. Participants were clinically evaluated before and after 6 months of hormone therapy to determine body mass index (current kg/m(2)) and waist circumference, blood pressure, lipid profile (total cholesterol, HDL cholesterol and triglycerides) plasma glucose (oral glucose tolerance test), and insulin. Blood samples were also drawn for ultra sensitive C reactive protein. The lipid accumulation product index was calculated as (waist [cm] - 58) × triglyceride concentration (mmol/L). Non-normally distributed parameters were log10 transformed before statistical analysis. Measurements at baseline and at follow-up were compared with ANOVA for repeated measures. Data were considered significant at P<0.05. In women with the homozygous polymorphic AA genotype of the single nucleotide polymorphisms rs9939609 and the wild AA genotype of the single nucleotide polymorphisms rs8050136, lipid accumulation product index and ultra sensitive C reactive protein were higher before hormone therapy in comparison with women with other genotypes from the same single nucleotide polymorphisms group. There was no worsening of any of the anthropometric or metabolic variables, and lipid accumulation product index improved slightly after hormone therapy in SNP rs9939609 (P=0.03) and haplotype AAAA. No changes were observed after hormone therapy in SNP rs8050136. The presence of fat mass and obesity-associated gene risk variants in healthy early postmenopausal women does not adversely affect their response to hormone therapy.

Progesterone for hot flush and night sweat treatment – effectiveness for severe vasomotor symptoms and lack of withdrawal rebound

A controlled trial recently showed that oral micronized progesterone (Progesterone, 300 mg at h.s. daily) was effective for vasomotor symptoms (VMS) in 133 healthy early postmenopausal women. Here, we present subgroup data in women with severe VMS (50 VMS of moderate–severe intensity/wk) and also 1-mo withdrawal study outcomes. Women with severe VMS (n = 46) resembled the full cohort but experienced 10 VMS/d of 3 of 4 intensity. On therapy, the progesterone VMS number (#) decreased significantly more than placebo # to 5.5/day (d) versus 8/d (ANCOVA −2.0 95% CI: −3.5 to −0.4). Just after trial mid-point, a withdrawal substudy (D/C) was added – 56 women were invited and 34 (61%) took part (progesterone 17; placebo 17). Those in the D/C cohort resembled the whole cohort. On stopping, VMS gradually increased – at D/C week 4, on progesterone, VMS daily # reached 78% and significantly less than baseline (−3.0 to −0.8) but placebo VMS # did not differ from run-in. In summary, progesterone is effective for severe VMS and does not cause a rebound increase in VMS when stopped. That progesterone may be used alone for severe VMS and unlike estrogen does not appear to cause a withdrawal rebound increases VMS treatment options.

Insulin sensitivity is associated with thigh adipose tissue distribution in healthy postmenopausal women

ObjectiveEvidence suggests intermuscular adipose tissue (IMAT) may be linked to insulin resistance, whereas thigh subcutaneous adipose tissue (SAT) may be related favorably with indices of metabolic health. However, whether adipose tissue depots of the thigh are differentially related to insulin sensitivity independent of total adiposity and other adipose tissue depots has not been determined. The objective of this study was to identify independent associations of the subcompartments of adipose tissue of the thigh with insulin sensitivity among 97 healthy early postmenopausal women. Materials and MethodsComputed tomography (CT) scans of the mid-thigh were used to assess Thigh-SAT, Thigh perimuscular adipose tissue (PMAT), and Thigh-IMAT. CT scans at the L4-L5 intervertebral space were used to assess intra-abdominal adipose tissue (IAAT) and Abdominal-SAT. Total body fat was measured by dual-energy X-ray absorptiometry (DXA). The insulin sensitivity index (SI) was assessed by using a frequently sampled intravenous glucose tolerance test with minimal model analysis. ResultsResults indicated SI was positively associated with Thigh-SAT independent of total fat mass and other adipose tissue compartments. Among all women combined, SI was inversely associated with Thigh-IMAT independent of total fat mass. However, the relationship between SI and Thigh-IMAT was independent of IAAT only among women with high levels of Thigh-IMAT and IAAT. ConclusionsThis is the first study to demonstrate independent, opposing relationships of Thigh-SAT and Thigh-IMAT with insulin sensitivity in healthy postmenopausal women. Further research is needed to determine if these associations are causal in nature.

Long-term consumption of isoflavone-enriched foods does not affect bone mineral density, bone metabolism, or hormonal status in early postmenopausal women: a randomized, double-blind, placebo controlled study

Background: Osteoporosis is a major health problem. It was hypothesized that isoflavone-containing products may be a potential alternative to hormone replacement therapy for preventing bone loss during the menopausal transition.Objective: The objective was to investigate whether the consumption of isoflavone-enriched foods for 1 y affects bone mineral density, bone metabolism, and hormonal status in early postmenopausal women.Design: This was a randomized, double-blind, placebo-controlled, parallel, multicenter trial. Two hundred thirty-seven healthy early postmenopausal women [mean (±SD) age of 53 ± 3 y and time since last menses of 33 ± 15 mo] consumed isoflavone-enriched foods providing a mean daily intake of 110 mg isoflavone aglycones or control products for 1 y while continuing their habitual diet and lifestyle. Outcome measures included bone mineral density of the lumbar spine and total body, markers of bone formation and bone resorption, hormones, isoflavones in plasma and urine, safety variables, and adverse events.Results: Consumption of isoflavone-enriched products did not alter bone mineral density of the lumbar spine and total body or markers of bone formation and bone resorption. Hormone concentrations did not differ between the isoflavone and control groups. Consumption of isoflavone-enriched products resulted in increased isoflavone concentrations in plasma and urine, whereas control products did not. This finding indicated good compliance with treatment. Subgroup analysis did not support an effect of equol phenotype on bone density. The intervention had no effect on a range of safety variables and reported adverse events.Conclusion: Consumption of foods containing 110 mg/d of soy isoflavone aglycone equivalents for 1 y did not prevent postmenopausal bone loss and did not affect bone turnover in apparently healthy early postmenopausal white women. This trial was registered at clinicaltrials.gov as NCT00301353.

First human exposure to exogenous single-dose oral estetrol in early postmenopausal women

Objective To evaluate the safety, tolerability, pharmacokinetics and effect on gonadotropins of a single escalating dose of estetrol (E4).Methods A first-in-human study with E4 was performed in healthy early postmenopausal women. Four single doses of 0.1, 1, 10 and 100 mg E4 were evaluated in study groups of eight subjects each, of whom six received active treatment and two placebo treatment. Safety and tolerability were documented and several pharmacokinetic parameters were determined, as were the plasma levels of the gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH) (pharmacodynamics). The next higher-dose group was enrolled after pharmacokinetic evaluation and confirmed safety of the previous group.Results After oral intake, the plasma concentrations of E4 showed a steep increase, followed by a sharp decline and a secondary increase at all dose levels. Estetrol was distributed and reabsorbed during the first 18 h after oral intake. The terminal elimination phase started at 24 h post-dose and half-life (t½) ranged in the 10 mg group between 19 and 40 h (mean 28.4 h, median 28.8 h) and in the 100 mg group between 18 and 60 h (mean 28.0 h, median 20 h), indicating a dose independency of the half-life.The pharmacokinetic parameters also demonstrated a high dose–response relationship and showed excellent consistency and low variability within the dose groups.The pharmacodynamic data showed a dose-dependent inhibition of plasma LH levels by E4. A profound and sustained inhibition of FSH levels, lasting over 168 h, was observed in the 100 mg dose group (FSH was not measured in the other dose groups).Estetrol was well tolerated at all dose levels and no safety problems were encountered.Conclusions Estetrol is orally absorbed and bioavailable with a strong dose–response relationship suggesting high oral bioavailability. Interindividual variations of plasma levels are low. The elimination half-life of 28 h suggests slow metabolism of E4. The pharmacodynamic pattern complies with enterohepatic recirculation. Estetrol has a profound central inhibitory and dose-dependent effect on gonadotropins, confirming its biological potency.

Changes in Hemostatic Variables Induced by Estrogen Replacement Therapy: Comparison of Transdermal and Oral Administration in a Crossover-Designed Study

Aim: The purpose of this study was to determine the changes of biochemical risk factors for thromboembolisms using different administration routes of early estrogen replacement therapy. Methods: In a 12-week prospective, randomized crossover trial, estradiol was administered orally (2 mg daily) or transdermally (0.05 mg daily). Forty-five healthy early postmenopausal women were included into the study within 12 weeks after hysterectomy and oophorectomy. Forty-one women (age 49 ± 6 years) completed the study, and their data were analyzed. The hemocoagulation parameters were determined prior to beginning of the study and at the end of each treatment period, separated by a 1-week washout period. Results: After oral therapy, the average tissue factor pathway inhibitor levels decreased statistically significantly (p < 0.0001) from 87.5 ± 39.1 to 68 ± 37.49 ng/ml. The plaminogen activator inhibitor-1 levels also decreased statistically significantly (p = 0.001) after the oral estrogen therapy from 11.39 ± 12.02 to 5.0 ± 5.27 IU/l. These changes were also significant when compared with the nonsignificant changes after the transdermal therapy. No significant changes occurred in the levels of D-dimers. After both treatment methods, the antithrombin III and fibrinogen levels decreased, but within their physiological ranges. Conclusions: Oral administration of estrogen statistically significantly reduced the tissue factor pathway inhibitor and plasminogen activator inhibitor-1 levels when compared with the transdermal route. These changes cannot be unambiguously considered risky, and the zero change of D-dimers suggests that there was no activation of the coagulation cascade. We consider the neutral effect of the transdermal therapy more beneficial.

Peripheral quantitative computed tomography (pQCT) is useful for monitoring bone mineral density of the patients who receive hormone replacement therapy

Objective A forearm fracture (Colles’ fracture) is often the first sign of osteoporosis and should alert the patient and physician to the possibility of underlying skeletal fragility. Therefore, the establishment of a more accurate and reliable method for the measurement of bone mineral density (BMD) at the distal radius would be beneficial for the patients who suffer from osteoporosis. The objective of the present study was to evaluate the usefulness of peripheral quantitative computed tomography (pQCT) to assess the change of BMD at the distal radius in early postmenopausal women who receive hormone replacement therapy (HRT). Methods Twenty healthy early postmenopausal women who were diagnosed as osteoporosis or osteopenia were randomized to either HRT or placebo treatment. We analyzed BMD of the distal radius by pQCT, lumbar spine by dual-energy X-ray absorptiometry (DXA) and the biochemical markers of bone turn over (osteocalcin, deoxypyridinoline) every 6 months. Results The placebo group showed a significant decrease from the baseline in the trabecular BMD of the radius at 12 months (7.4 ± 2.5%) ( p < 0.05), whereas the HRT group showed a slight increase (0.7 ± 2.2%). The changes in the trabecular BMD of the radius between the HRT and placebo groups were statistically different at 12 months ( p < 0.05). On the other hand, in the cortical BMD of the radius, no significant differences were seen between the changes of bone densities in the HRT and control groups after 1 year of treatment. pQCT could detect a significant loss of BMD of the radius in early postmenopausal women after 1 year and HRT prevented its loss. Conclusion Our preliminary clinical trial showed that pQCT might be useful for the early detection of bone loss in early postmenopausal women and for the monitoring BMD of the patients who receive HRT.

Osteoporosis in otherwise healthy perimenopausal and early postmenopausal women: Physical and biochemical characteristics

Population studies have shown that about 3-5% of perimenopausal women already have osteoporosis according to the WHO definition of osteoporosis for postmenopausal women ( t -score<or=-2.5). In general, this bone loss arises from well-characterized diseases or conditions that affect acquisition of peak bone mass and/or the rate of bone loss after peak bone mass has been attained. However, there often remains a subset of these women, with no identifiable cause of bone loss. This group has so far been little studied. We prospectively evaluated a group of 60 perimenopausal and early postmenopausal women (mean age 52.2+/-2.5 years) who were found to have apparently unexplained low bone mass, and we compared them to 120 controls matched for age and menopausal status. These women were extensively investigated, including by detailed questionnaire and laboratory testing. Of the 60 women with osteoporosis, only three were found to have previously undiagnosed disorders (two with subclinical hyperthyroidism and one with elevated serum PTH levels) that might have contributed to their low bone mass. On the other hand, osteoporotic patients were characterized by a significantly lower body weight, higher prevalence of personal and parental histories of fractures and a higher level of bone turnover as assessed by increased serum osteocalcin and bone alkaline phosphatase levels and urinary type I collagen C-telopeptide (CTX) excretion, as compared to controls. These findings support theories of a genetic contribution to osteoporosis and underline the predictive value of a previous history of personal and familial fracture in the identification of osteoporosis in early postmenopausal women.

Monitoring bone effect of transdermal hormone replacement therapy by ultrasound investigation at the phalanx: a four-year follow-up study.

A controlled 4-year follow-up study was conducted on a population composed of 112 healthy early postmenopausal women to evaluate the ability of ultrasound technology in detecting the effects of hormone replacement therapy (HRT) on bone. At the end of the study, 47 untreated and 25 treated women had been evaluated. Cyclic sequential estrogen/progestogen therapy, 50 microg/day of transdermal 17beta-estradiol (Rotta Research Laboratorium) plus 5 mg/day of medrogestone (Wyeth-Ayerst) was used. Ultrasound transmission through the distal metaphysis of hand phalanxes was measured by DBM Sonic. Beside amplitude-dependent speed of sound (AD-SoS), three new parameters could be calculated: pure speed of sound (pSOS), bone transmission time (BTT), and ultrasound bone profile index (UBPI). Ultrasound measurements were taken at baseline and after 1, 2, and 4 years. Among untreated women a significant decrease of all ultrasound parameters was observed at follow-up measurements. In the HRT-treated group we observed a significant increase of AD-SoS, pSoS, and BTT. We qualified as "responders" women in the treated group for whom AD-SoS, pSoS, and BTT increased by more than 2.77 times the coefficient of variation of the measurement, i.e., 95% variability. Women in the treated group were identified as responders at 4 years of follow-up by AD-SoS (56%), pSOS (56%), and BTT (60%). Ultrasound bone profile index declined in both groups, although to a lower extent among HRT-treated subjects. The 4-year data confirm the results obtained at 1 and 2 years of follow-up. This study demonstrates that bone tissue investigation by ultrasound at the phalanx can be used to monitor the effect of HRT, and thus it should be considered a potential technology for the management of menopause by gynecologists.

Annual skeletal balance and metabolic bone marker changes in healthy early postmenopausal women: results of a prospective study

The aim of this study was to establish the duration and annual rate of menopause-related bone loss and to investigate the relationship between bone turnover and bone loss in early healthy postmenopausal women. The rate of change in bone mineral density (BMD) at the lumbar spine and in bone turnover was measured twice at the exact interval of 12 months by dual-energy X-ray absorptiometry (DXA) and by the determination of plasma alkaline phosphatase levels (ALP) and fasting urinary hydroxyproline/creatinine ratio (OHPr/Cr), respectively, in 123 healthy premenopausal and postmenopausal women 45–60 years of age. The subjects were divided into nine groups according to their menstrual status and years since menopause (YSM). Annual bone loss at the lumbar spine of women who were menopausal for 1, 2, 3, 4, and 5 years was −2.62 ± 0.37 (95% confidence interval −3.66, −1.58), −3.87 ± 0.96 (−6.02, −1.73), −2.50 ± 0.37 (−3.29, −1.70), −2.86 ± 0.73 (−4.44, −1.27), and −1.54 ± 0.41 (−2.42, −0.66), respectively, and was significantly less than zero. But, the annual bone loss of women who were premenopausal or menopausal for 6, 7, and 8 years was −0.76 ± 0.60 (−2.04, +0.53), −1.16 ± 0.68 (−2.61, +0.29), 0.24 ± 0.48 (−0.78, +1.26), and 0.16 ± 0.63 (−1.18, −1.49), respectively, and was not significantly different from zero. These results demonstrate that the early hormone-dependent bone loss commences in the first year after menopause and is arrested within 6 years after the onset of menopause. The overall bone loss for this phase is estimated to be approximately 15%. Annual change in ALP and OHPr/Cr seems to indicate that bone resorption prevails on bone formation in the first 2 YSM, whereas osteoblastic activity relatively prevails from YSM 3 to YSM 5, which explains the progressive repairing of the imbalance between bone resorption and formation.

Cytokine RNA levels in transiliac bone biopsies from healthy early postmenopausal women

The cytokines interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6 induce osteoclast formation and may contribute to the development of postmenopausal osteoporosis. Cross-sectional studies have suggested that both IL-1 and IL-1ra secretion increase on estrogen withdrawal, and that postmenopausal osteoporosis is associated with an inadequate increase in monocyte IL-1ra secretion with age. We measured cytokine mRNA (IL-1β, IL-1ra, IL-6, and TNF-α) directly in bone biopsies from early postmenopausal women to determine if a lower compensatory increase in IL-1ra mRNA could be demonstrated in women with rapid bone loss after the menopause. Biopsies were obtained from 23 early postmenopausal women (mean age 53.9 years) who participated in a randomized study of hormone replacement therapy (HRT) and risk factors for osteoporosis. Bone mineral density was assessed by duel energy X-ray absorptiometry at 0, 1, 2, and 5 years. Women in the control group were recruited to the biopsy study based on their observed rate of bone loss (upper or lower tertile). Consent was also obtained from 11 participants receiving HRT. Biopsies were taken at 2 years, frozen in nitrogen, and homogenized. Cytokine mRNA was measured by competitive reverse transcriptase polymerase chain reaction. The IL-1ra/IL-1β mRNA slope for the slow-loss group was steeper (ΔF = 23.3, p < 0.01) than that observed in the fast-loss group, indicating that slower bone loss was associated with higher IL-1ra mRNA levels relative to IL-1β. During HRT, the IL-1β mRNA level was inversely correlated with serum estradiol (log r 2 = 0.77, p < 0.01), and women with a serum estradiol below 200 pmol/L during HRT had IL-1β mRNA levels identical to the control group. In contrast, IL-1ra mRNA was independent of serum estradiol. Histomorphometric analysis revealed weak correlations between IL-1β mRNA and activation frequency (r 2 = 0.26, p = 0.06) and between IL-1ra and volume referent bone resorption rate (r 2 = 0.19, p = 0.11). TNF-α was not associated with the bone loss rates or with serum estradiol, and only three samples were positive for IL-6 mRNA. The findings support the hypothesis that IL-1β production within bone increases with declining estrogen levels, and that an increase in IL-1ra protects against accelerated bone loss.

Cytokines and T-lymphocyte subsets in healthy post-menopausal women: Estrogen retards bone loss without affecting the release of IL-1 or IL-1ra

Interleukin (IL)-1 is a potent inducer of bone resorption, and an increased secretion of the IL-1 agonists IL-1α and IL-1β relative to the IL-1 receptor antagonist (IL-1ra) has been proposed as a mechanism leading to post-menopausal osteoporosis. T-lymphocytes are capable of secreting bone resorptive cytokines and have also been linked with bone metabolism and the development of osteoporosis. Cytokine secretion from whole blood cell cultures was compared between two randomized groups of healthy early post-menopausal women (mean age 52.5 yrs, N = 91) and lymphocyte subsets were quantitated by flow cytometry. One group received cyclic estrogen-gestagen replacement therapy (ERT) while the other group was untreated. In spite of a significant bone maintaining effect of ERT, the basal and LPS-stimulated secretion of IL-1α, IL-1β, and IL-1ra was identical in the two groups. There was no association between cytokine release and bone mass or loss assessed over 2 yrs. The only exception was a weak estrogen-independent correlation between basal IL-1ra secretion and bone loss ( r = −0.21, p < 0.05). Flow cytometry did not confirm a relationship between CD4/CD8 T-cell ratios and bone density or loss, and there was no effect of ERT on lymphocyte subsets. The number of CD3+ CD56+ T-cells showed a highly significant negative correlation with femoral and lumbar bone density in untreated women ( r = −0.42, p < 0.01) similar to that found in patients with established osteoporosis, indicating that these adherent mononuclear cells may be important in the pathophysiology of post-menopausal bone loss. The possibility that IL-1ra acts as an independent bone-sparing factor unrelated to estrogen withdrawal warrants further investigation. In conclusion, ERT maintains bone without affecting the release of the IL-1 family of cytokines in whole blood cultures.