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Objective: Hormone therapy can positively impact bone mineral density after menopause. We explored bone mineral density change in postmenopausal women who discontinued hormone therapy after the Women's Health Initiative landmark 2002 trial results were published. We secondarily explored whether usual physical activity modified the results., Methods: Postmenopausal women participating in the Buffalo OsteoPerio study with information on hip bone density, hormone therapy use, and self-reported physical activity at two time points (1997-2001; 2002-2007) were included (N = 961). Hormone therapy included three groups according to use at baseline and year 5 (non/non; current/non; current/current)., Results: At baseline (mean age, 65.9 years; SD, 6.7 years), 480 women were not using hormone therapy, while 481 were current users. Between the baseline and 5-year visits, 336 women using hormone therapy discontinued. Baseline total hip bone density was highest in current users. After 5 years, those who continued hormone therapy exhibited no bone loss; those who discontinued exhibited the greatest loss at the total hip of -0.021 gm/cm2. Women who never used hormone therapy exhibited some loss of -0.012 gm/cm2. Usual physical activity did not appreciably impact change in bone density in any group., Conclusions: This prospective observational study explored the 5-year change in bone mineral density among older postmenopausal women after the landmark 2002 hormone therapy trial findings were released. We found bone density decreased in never-users and in women who discontinued use. Bone density was maintained in current users. Although usual physical activity did not mitigate bone loss, targeted physical activity regimens should be investigated., Competing Interests: Financial disclosure/conflicts of interest: None reported., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The Menopause Society.)

Objective: This study aimed to evaluate the associations of hormone preparations with lumbar spine bone mineral density (BMD), osteopenia, and osteoporosis in postmenopausal women, and whether these impacts persisted after hormone preparations were discontinued., Methods: A total of 6,031 postmenopausal women were enrolled and divided into seven groups based on the types of hormone preparations. Among them, 1,996 participants were further divided into a current users (CU) group and a past users (PU) group. Multivariable linear regression models or logistic regression models were used to evaluate the associations of hormone preparation with lumbar spine BMD, osteopenia, and osteoporosis., Results: Combined oral contraceptive pills, estrogen-only pills, estrogen/progestin combo pills, estrogen-only patches, or the use of more than two kinds of hormone preparations were positively associated with lumbar spine BMD (all P < 0.05). Except for estrogen-only patches, other hormone preparations also had a protective effect against osteopenia (all OR < 1, all P < 0.05), but none of them were associated with osteoporosis prevalence (all P > 0.05). The BMD increased by 0.10 and 0.04 g/cm 2 in the CU and PU groups, respectively, compared with the nonusers group (all P < 0.05). In both the CU and PU groups, the risk of osteopenia was reduced (OR, 0.34 and 0.57, respectively)., Conclusions: Hormone preparations increase lumbar spine BMD in postmenopausal women and exert a protective effect against osteopenia. These impacts persisted after hormone preparations were discontinued. Hormone preparations, however, were not associated with osteoporosis prevalence., Competing Interests: Financial disclosure/conflicts of interest: None reported., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The North American Menopause Society.)

Objective: Osteoporosis is a skeletal disease characterized by low bone mass, reduced bone strength, and increased fracture risk. We aimed to investigate the association between combined dietary antioxidant intake and the likelihood of osteoporosis in premenopausal and postmenopausal women, based on data from the National Health and Nutrition Examination Survey., Methods: Nutrient intake data were obtained using two 24-hour recalls. Composite dietary antioxidant index (CDAI), which refers to the intake amounts of β-carotene, vitamin A, vitamin C, vitamin E, selenium, zinc, copper, and iron, was then constructed. Prevalent osteoporosis was defined according to bone mineral density T scores of ≤ -2.5 and self-reports. Multiple logistic and Poisson regression models were used for association analyses., Results: A total of 3,418 participants (1,157 premenopausal and 2,261 postmenopausal women) 40 years or older were included, 776 (22.70%) of whom had prevalent osteoporosis. In terms of individual nutrients, postmenopausal women in the highest CDAI quartiles for dietary β-carotene, vitamin A, vitamin C, and iron intakes had a low likelihood of osteoporosis. Regarding the CDAI-osteoporosis association, postmenopausal women in the highest quartile were less likely to have osteoporosis (OR Q3 vs Q1 , 0.64; 95% CI, 0.43-0.96; OR Q4 vs Q1 , 0.56; 95% CI, 0.35-0.89; P for trend = 0.013), after controlling for covariates., Conclusions: CDAI was negatively associated with the likelihood of osteoporosis in postmenopausal women. Our findings suggest that the combined intake of antioxidant nutrients can help reduce the likelihood of osteoporosis in women., Competing Interests: Financial disclosure/conflicts of interest: None reported., (Copyright © 2023 by The North American Menopause Society.)

Objective: To review evidence regarding osteoporosis screening, prevention, diagnosis, and management in the past decade and update the position statement published by The North American Menopause Society (NAMS) in 2010 regarding the management of osteoporosis in postmenopausal women as new therapies and paradigms have become available., Design: NAMS enlisted a panel of clinician experts in the field of metabolic bone diseases and/or women's health to review and update the 2010 NAMS position statement and recommendations on the basis of new evidence and clinical judgement. The panel's recommendations were reviewed and approved by the NAMS Board of Trustees., Results: Osteoporosis, especially prevalent in older postmenopausal women, increases the risk of fractures that can be associated with significant morbidity and mortality. Postmenopausal bone loss, related to estrogen deficiency, is the primary contributor to osteoporosis. Other important risk factors for postmenopausal osteoporosis include advanced age, genetics, smoking, thinness, and many diseases and drugs that impair bone health. An evaluation of these risk factors to identify candidates for osteoporosis screening and recommending nonpharmacologic measures such as good nutrition (especially adequate intake of protein, calcium, and vitamin D), regular physical activity, and avoiding smoking and excessive alcohol consumption are appropriate for all postmenopausal women. For women at high risk for osteoporosis, especially perimenopausal women with low bone density and other risk factors, estrogen or other therapies are available to prevent bone loss. For women with osteoporosis and/or other risk factors for fracture, including advanced age and previous fractures, the primary goal of therapy is to prevent new fractures. This is accomplished by combining nonpharmacologic measures, drugs to increase bone density and to improve bone strength, and strategies to reduce fall risk. If pharmacologic therapy is indicated, government-approved options include estrogen agonists/antagonists, bisphosphonates, RANK ligand inhibitors, parathyroid hormone-receptor agonists, and inhibitors of sclerostin., Conclusions: Osteoporosis is a common disorder in postmenopausal women. Management of skeletal health in postmenopausal women involves assessing risk factors for fracture, reducing modifiable risk factors through dietary and lifestyle changes, and the use of pharmacologic therapy for patients at significant risk of osteoporosis or fracture. For women with osteoporosis, lifelong management is necessary. Treatment decisions occur continuously over the lifespan of a postmenopausal woman. Decisions must be individualized and should include the patient in the process of shared decision-making., (Copyright © 2021 by The North American Menopause Society.)

Objectives: Osteoporosis is a prevalent condition among postmenopausal women, and lacks satisfactory therapeutic options. Hydrogen (H2) has been shown to be effective in alleviating many diseases. This study aimed to investigate the effects of H2 on inhibiting osteoclastogenesis and bone loss in ovariectomized mice., Methods: Osteoclast differentiation from Raw264.7 cells was induced with receptor activator NF-κB ligand (RANKL) with or without 60% H2. The number and resorption activity of osteocalsts were assessed by tartrate-resistant acid phosphatase staining and pit formation assay, respectively. The expression of osteoclast markers and NF-κB phosphorylation were detected by western blot. NF-κB nuclear translocation was assessed by immunofluorescence. NF-κB transcriptional activity was analyzed by luciferase assay. Bone loss in mice was induced by ovariectomy (OVX). OVX mice were given either regular air or 60% H2. Bone structure was analyzed by micro-computed tomography and hematoxylin and eosin staining. Cytokine levels were measured by enzyme-linked immunosorbent assay. The data were analyzed with one-way or two-way ANOVA followed by Bonferroni post hoc tests., Results: H2 did not have any measurable effect on the proliferation of Raw264.7 cells. The number of osteoclasts and size of resorption pits of RANKL+H2-treated cells were 3 to 4 times less than RANKL treated cells. The expression of osteoclast marker genes of RANKL+H2-treated cells was 30% to 60% lower than RANKL-treated cells (P < 0.05). H2 markedly inhibited RANKL-induced activation, nuclear translocation, and transcriptional activity of NF-κB (P < 0.05, RANKL+H2 vs RANKL). The amount and density of trabecular bone and bone mineral density of ovariectomized mice were significantly less than sham-operated mice (P < 0.05 OVX vs sham). The amount of trabecular bone and bone mineral density of OVX mice that inhaled H2 were more than 40% higher, whereas the levels of serum proinflammatory cytokine interleukin 1β, IL-6, and tumor necrosis factor-α were more than 50% lower than those of OVX mice (P < 0.05)., Conclusions: These results demonstrated that H2 could be an effective therapeutic agent of postmenopausal osteoporosis.

Objective: The purpose of this systematic review was to update and examine to what extent multicomponent training interventions could improve lean and bone mass at different anatomical regions of the body in postmenopausal and older women., Methods: A computerized literature search was performed in the following online databases: PubMed MEDLINE, Cochrane, and Web of Knowledge. The search was performed to include articles up until February 2017. The methodological quality of selected studies was evaluated using the Cochrane risk of bias tool., Results: Fifteen studies met the inclusion criteria. Studies examining the effects of combined training methods in postmenopausal and older women showed contrasting results, possibly due to the wide range of the participants' age, the evaluation of different regions, and the varying characteristics of the training methods between studies. Overall, it appears that exercise modes that combine resistance, weight-bearing training, and impact-aerobic activities can increase or prevent muscle and skeletal mass loss during the ageing process in women., Conclusions: Further studies are needed to identify the optimal multicomponent training protocols, specifically the training loads that will improve lean and bone mass at different anatomical locations, in postmenopausal and older women.

Objective: The aim of the study was to analyze the effects of endurance and high-impact training oriented toward preventing osteoporosis in postmenopausal women with calcium and vitamin D supplementation., Methods: This study was a randomized clinical trial. Thirty-six postmenopausal women were randomized to the control and experimental groups. Thirty-four women completed the 2-year interventions. The control group training involved walking at an intense pace. The experimental group conducted high-impact training specifically oriented to prevent osteoporosis. Dual-energy x-ray absorptiometry was used to estimate the T-scores of the lumbar spine and femoral neck., Results: The fast-walking group showed constant T-scores in the femoral neck and improved T-scores in the lumbar spine. High-impact exercises produced improvements in both anatomical levels. Significant differences were found in the femoral neck (ΔControl = -0.04, ΔExperimental = 0.28). The differences were not significant in the lumbar spine (ΔControl = 0.27, ΔExperimental = 0.47). Cohen's effect size (d = 0.52) suggested a medium practical significance of the trial. The power was 51%., Conclusions: Calcium plus vitamin D supplementation combined with specifically oriented exercises had a higher impact in the femoral neck than walking at an intense pace. As there were no differences at the lumbar spine level, the results were, however, inconclusive concerning which type of exercise was the most convenient. Importantly, the fact that the T-scores did not decrease after 2 years supports the belief that both proposed interventions can be conveniently used to prevent osteoporosis in postmenopausal women. A trial with a larger sample size would provide consistency to the findings and is warranted given the possible effects and benefits.

Objective: Orthosiphon stamineus (OS) or Misai Kucing (Java tea) is a popular herbal supplement from Southeast Asia for various metabolic, age-related diseases. This study investigated the potential use of OS leaf extracts to ameliorate osteoporosis in ovariectomized rats., Methods: Fifty-six female Sprague-Dawley rats were randomly allocated into eight groups (n = 7): SHAM (healthy sham control); OVX (ovarietomized) nontreated rats (negative control); OVX + Remifemin (100 mg/kg body weight), and 2% green tea extract (positive controls); OVX + OS 50% ethanolic and aqueous extracts, both at either 150 or 300 mg/kg. After 16 weeks, the rats' bones and blood were evaluated for osteoporosis indicators (protein and mRNA expressions), micro-computed tomography for bone histomorphometry, and three-point bending test for tibia mechanical strength., Results: The extracts dose-dependently and significantly (P < 0.05) improved bone strength and flexibility, bone mineral density, bone formation protein markers (P1NP), and bone histomorphometry. All extracts reduced the inflammation biomarker (interleukin-6). The extracts up-regulated osteoblastogenesis (bone morphogenetic protein-2) and collagen-1 synthesis (collagen type 1 alpha-1) mRNA expressions, and down-regulated bone resorption (TNFSF11 and nuclear factor-kappa B) mRNA expressions. Both the water and 50% ethanolic extract were effective. The effective dose is equivalent to 25 to 50 mg/kg extract for humans., Conclusions: The extract showed bone-protective and antiosteoporotic effects (improving bone strength, flexibility, bone density, and bone morphometry) by reducing inflammation and the bone resorption biomarkers, while enhancing bone formation biomarkers and collagen synthesis.

The 2017 Hormone Therapy Position Statement of The North American Menopause Society (NAMS) updates the 2012 Hormone Therapy Position Statement of The North American Menopause Society and identifies future research needs. An Advisory Panel of clinicians and researchers expert in the field of women's health and menopause was recruited by NAMS to review the 2012 Position Statement, evaluate new literature, assess the evidence, and reach consensus on recommendations, using the level of evidence to identify the strength of recommendations and the quality of the evidence. The Panel's recommendations were reviewed and approved by the NAMS Board of Trustees.Hormone therapy (HT) remains the most effective treatment for vasomotor symptoms (VMS) and the genitourinary syndrome of menopause (GSM) and has been shown to prevent bone loss and fracture. The risks of HT differ depending on type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used. Treatment should be individualized to identify the most appropriate HT type, dose, formulation, route of administration, and duration of use, using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of the benefits and risks of continuing or discontinuing HT.For women aged younger than 60 years or who are within 10 years of menopause onset and have no contraindications, the benefit-risk ratio is most favorable for treatment of bothersome VMS and for those at elevated risk for bone loss or fracture. For women who initiate HT more than 10 or 20 years from menopause onset or are aged 60 years or older, the benefit-risk ratio appears less favorable because of the greater absolute risks of coronary heart disease, stroke, venous thromboembolism, and dementia. Longer durations of therapy should be for documented indications such as persistent VMS or bone loss, with shared decision making and periodic reevaluation. For bothersome GSM symptoms not relieved with over-the-counter therapies and without indications for use of systemic HT, low-dose vaginal estrogen therapy or other therapies are recommended.This NAMS position statement has been endorsed by Academy of Women's Health, American Association of Clinical Endocrinologists, American Association of Nurse Practitioners, American Medical Women's Association, American Society for Reproductive Medicine, Asociación Mexicana para el Estudio del Climaterio, Association of Reproductive Health Professionals, Australasian Menopause Society, Chinese Menopause Society, Colegio Mexicano de Especialistas en Ginecologia y Obstetricia, Czech Menopause and Andropause Society, Dominican Menopause Society, European Menopause and Andropause Society, German Menopause Society, Groupe d'études de la ménopause et du vieillissement Hormonal, HealthyWomen, Indian Menopause Society, International Menopause Society, International Osteoporosis Foundation, International Society for the Study of Women's Sexual Health, Israeli Menopause Society, Japan Society of Menopause and Women's Health, Korean Society of Menopause, Menopause Research Society of Singapore, National Association of Nurse Practitioners in Women's Health, SOBRAC and FEBRASGO, SIGMA Canadian Menopause Society, Società Italiana della Menopausa, Society of Obstetricians and Gynaecologists of Canada, South African Menopause Society, Taiwanese Menopause Society, and the Thai Menopause Society. The American College of Obstetricians and Gynecologists supports the value of this clinical document as an educational tool, June 2017. The British Menopause Society supports this Position Statement.

Objective: Estetrol (E4) is an estrogen produced exclusively by the human fetal liver during pregnancy. In this study the pharmacodynamic effects of escalating doses of E4 in postmenopausal women were investigated., Methods: This was a partly randomized, open-label, multiple-rising-dose study in 49 postmenopausal women. Participants were randomized to receive either 2 mg E4 or 2 mg estradiol-valerate (E2 V) for 28 days. Subsequent dose-escalation groups were (non-randomized): 10, 20 and 40 mg E4. Blood samples were collected regularly for measuring endocrine and hemostasis variables, lipids and lipoproteins, fasting glucose and bone turnover markers., Results: Estetrol treatment resulted in a decrease of follicle-stimulating hormone and luteinizing hormone and an increase of sex-hormone binding globulin. Changes in hemostasis variables were small. A lowering effect on low-density lipoprotein cholesterol was accompanied with an increase in high-density lipoprotein cholesterol and no or minimal changes in triglycerides. The considerable decrease in osteocalcin levels in the three highest E4 dose groups and the small decrease in C-telopeptide levels were comparable to the E2 V control group and suggest a preventive effect on bone loss. All changes observed were dose-dependent., Conclusions: In this study, estetrol treatment showed dose-dependent estrogenic effects on endocrine parameters, bone turnover markers, and lipids and lipoproteins. The effect on triglycerides was small as were the effects on hemostatic variables. These results support the further investigation of estetrol as a candidate for hormone therapy. Quantitatively, the effects of 10 mg estetrol were similar to the study comparator 2 mg estradiol valerate.

Objective: The aim of this study was to demonstrate the efficacy of extract derived from Spinacia oleracea extract (SOE) in reversing bone loss induced by ovariectomy and bone healing properties in a drill-hole fracture model in rats., Methods: SOE was administered orally for 12 weeks in adult ovariectomized Sprague Dawley rats after inducing osteopenic condition. Bone micro-architecture, expressions of osteogenic and resorptive gene markers, biomechanical strength, new bone formation, and bone turnover markers were studied. Uterine histomorphometry was used to assess estrogenicity. Bone regeneration potential of SOE was assessed in a drill-hole fracture model. Fracture healing was assessed by calcein intensity and micro-CT analysis of callus at fracture region., Results: SOE prevented ovariectomy-induced bone loss as evident from 122% increase in bone volume/tissue volume (BV/TV) and 29% decline in Tb.Sp in femoral trabecular micro-architecture. This was corroborated by the more than twofold stimulation in the expression of osteogenic genes runt-related transcription factor 2, osterix, osteocalcin, bone morphogenetic protein 2, collagen-1. Furthermore in the fracture healing model, we observed a 25% increase in BV/TV and enhancement in calcein intensity at the fractured site. The extract when converted into dried deliverable Spinaceae oleracea granule (SOG) form accelerated bone regeneration at fracture site, which was more efficient as evident by a 39% increase in BV/TV. Transforming SOE into dried granules facilitated prolonged systemic availability, thus providing enhanced activity for a period of 14 days., Conclusions: SOE treatment effectively prevents ovariectomy-induced bone loss and stimulated fracture healing in adult rats. The dried granular form of the extract of Spinaceae oleracea was effective in fracture healing at the same dose.

Objective: Multimorbidity related to menopause and/or increased age will put healthcare systems in western nations under ever-greater strain. Effective strategies to prevent diseases are thus of high priority and should be started earlier in life. The purpose of the study was to evaluate the long-term effect of exercise on different important health parameters in initially early postmenopausal women over a 16-year period., Methods: In 1998, 137 early postmenopausal women with osteopenia living in Erlangen-Nürnberg were included in the study. Eighty-six women joined the exercise group (EG) and conducted two supervised group and two home training sessions per week, whereas the control group (CG: n = 51) maintained their physical activity level. Primary outcome parameters were clinical overall fractures incidence; secondary study endpoint was Framingham study-based 10-year risk of coronary death/myocardial infarction and low back pain., Results: In 2014, 59 women of the EG and 46 women of the CG were included in the 16-year follow-up analysis. Framingham study-based 10-year risk of myocardial infarction/coronary death increased significantly (P < 0.001) in both groups; however, changes were significantly more favorable in the EG (5.00% ± 2.94% vs CG: 6.90% ± 3.98%; P = 0.02). The ratio for clinical "overall" fractures was 0.47 (95% CI: 0.24-0.92; P = 0.03), and thus significantly lower in the EG. Although we focused on a high-intensity exercise strategy, low back pain was favorably affected in the EG., Conclusions: Multipurpose exercise programs demonstrated beneficial effects on various relevant risk factors and diseases of menopause or/and increased age, and should thus be preferentially applied for primary or secondary prevention in postmenopausal women.

Objective: Conjugated estrogens/bazedoxifene reduces vasomotor symptoms and prevents postmenopausal bone loss without stimulating the breast and endometrium. We analyzed changes in bone mineral density (BMD) and bone markers using pooled data from two phase-3 trials., Methods: Selective Estrogens, Menopause, and Response to Therapy (SMART)-1 and SMART-5 were randomized, double-blind, placebo- and active-controlled studies conducted in postmenopausal nonhysterectomized women. BMD and turnover marker data were pooled for women given conjugated estrogens (0.45 or 0.625 mg) plus bazedoxifene 20 mg or placebo over 12 months. Sensitivity analyses were conducted using baseline Fracture Risk Assessment Tool score, age, years since menopause, body mass index, race, and geographic region., Results: There were 1,172 women, mean age 54.9 years, mean 6.21 years since menopause, mean lumbar spine, and total hip T scores -1.05 and -0.58; 58.8% had a Fracture Risk Assessment Tool score less than 5% indicating low fracture risk. At 12 months, adjusted differences (vs placebo) in BMD change in the groups taking conjugated estrogens 0.45 or 0.625 mg plus bazedoxifene 20 mg were 2.3% and 2.4% for lumbar spine, 1.4% and 1.5% for total hip, and 1.1% and 1.5% for femoral neck (all P < 0.001 vs placebo). These increases were unrelated to baseline Fracture Risk Assessment Tool score, age, years since menopause, body mass index, or geographic region. Both doses reduced bone turnover markers (P < 0.001)., Conclusions: Conjugated estrogens/bazedoxifene significantly improved BMD and turnover in a large population of younger postmenopausal women at low fracture risk and is a promising therapy for preventing postmenopausal bone loss.

Objective: Recent studies have shown that immune system plays a major role in pathophysiology of postmenopausal osteoporosis. Previously we have shown that phytoestrogens like daidzein and medicarpin exhibit immunoprotective effects, by virtue of which they alleviate bone loss. With this background, methoxyisoflavones like formononetin (formo) and isoformononetin (isoformo) that have been studied for preventing bone loss in ovariectomized rats were tested for their immunomodulatory effects in estrogen-deficient bone loss mice model., Methods: Adult Balb/c mice (N = 8/group) were given oral dose of formo and isoformo at 10 mg/kg body weight, post ovariectomy (Ovx) daily for 6 weeks. Animals were autopsied and long bones were harvested to study bone microarchitecture. Peripheral blood mononuclear cells were isolated for fluorescence-activated cell sorting and RNA analysis. Serum was collected for enzyme-linked immunosorbent assay., Results: It was observed that formo and isoformo treatment to Ovx mice led to significant restoration of Ovx-induced deterioration of trabecular microarchitecture. Pro-osteoclastogenic subset Th17 and B cells were decreased in formo/isoformo-treated Ovx mice in comparison with vehicle-treated Ovx group. Formo and isoformo treatment to Ovx mice also led to decreased expression of Th17 diffentiation factors and promoted T-regulatory cell differentiation. Formo was more effective in enhancing the FOXP3 expression compared with isoformo. IL-17A-induced osteoclastogenesis and inhibition of osteoblast apoptosis were also suppressed by formo and isoformo treatment, with formo having a more potent effect., Conclusions: Our study demonstrates the immunomodulatory activity of methoxyisoflavones, formo, and isoformo, which translate into improved skeletal parameters, thereby preventing Ovx-induced bone loss.

Objective: We investigated whether long-term consumption of Korean mistletoe or Asian Ulmi cortex would prevent or delay menopausal symptoms and progression of osteoarthritis in estrogen-deficient obese rats., Methods: Ovariectomized (OVX) rats were provided a 45% fat diet containing either (1) 0.6% lyophilized water extract of Korean mistletoe (KME) + 1.4% dextrose (KME; n = 10), (2) 2% lyophilized water extract of Ulmi cortex (UCE; n = 10), (3) 30 μg/kg bw 17β-estradiol + 2% dextrose (positive control; n = 10), (4) 2% dextrose (placebo; OVX-control; n = 10), or (5) 2% dextrose (normal-control; n = 10) for 4 weeks. At the beginning of the 5th week, OVX rats, except in the normal-control group, were given articular injections of monoiodoacetate into the right knee and the assigned diets were provided for an additional 3 weeks. The rats in the normal-control had injections of saline into the right knee., Results: KME, but not UCE, partially prevented the insulin resistance and the loss of bone mineral density and lean mass. The limping scores were lower in the descending order of the OVX-control > KME and 17β-estradiol > UCE > normal-control at day 14 and 21 (P < 0.05). The scores for pain behaviors measured by weight distribution on the right leg, maximum running velocity on a treadmill and locomotive activity, were markedly decreased in the same order as limping scores. Monoiodoacetate increased the expression of matrix metalloprotinase-3 and metalloprotinase-13 in the articular cartilage and elevated the production of inflammatory markers such as tumor necrosis factor-α, interleukin-1β, and interleukin-6, but they were lower in the UCE than in the other groups (P < 0.05). Histology of the right knee revealed cartilage damage near the tidemark of the knee and proteoglycan loss was markedly less in UCE., Conclusions: UCE was an effective therapeutic agent for preventing osteoarthritis and KME prevented decreases in lean body mass, bone mineral density, and insulin sensitivity in estrogen-deficient rats.

Objective: Previous data have suggested that Panax notoginseng saponins (PNS) can prevent estrogen deficiency-induced bone loss by dual action: stimulation of new bone formation and inhibition of bone resorption. Marrow adipogenesis has been identified as a negative indicator of skeletal strength and integrity. This study assessed the effects of early PNS supplementation on bone microarchitecture preservation and marrow fat content in an ovariectomized rat model., Methods: Forty adult female Sprague-Dawley rats were randomly assigned to four equal groups for 12 weeks of treatment: (1) sham operation (SHAM) + vehicle; (2) ovariectomy (OVX) + vehicle; (3) OVX + 17β-estradiol (25 μg/kg); (4) OVX + PNS (300 mg/kg/d, PO). Marrow fat content of the femur was determined, using fat/water magnetic resonance imaging (MRI), at baseline and 6 and 12 weeks after operation. At the end of the experiment, bone turnover, trabecular microarchitecture, and marrow adipocytes were assessed by serum biomarkers, micro-computed tomography (micro-CT), and histopathology, respectively. The effects of PNS on adipocytic differentiation were reflected by expression levels of the adipogenic genes PPARγ2 and C/EBPα, as determined by reverse transcription-polymerase chain reaction., Results: Ovariectomized rats experienced remarkable increases in marrow fat content across time points, which were accompanied by elevated rate of bone turnover, global volumetric bone density, and trabecular microarchitecture deterioration. These OVX-induced pathological changes are reversible in that most of them could be mostly corrected upon 17β-estradiol treatment. PNS treatment significantly reduced marrow adipogenesis (adipocyte density, -27.2%; size, -22.7%; adipocyte volume-to-tissue volume ratio, -53.3%; all P < 0.01) and adipocyte marker gene expression, and prevented bone mass loss and microarchitecture deterioration. Moreover, PNS enhanced osteoblast activity but suppressed osteoclast turnover, as evidenced by decreased levels of serum C-terminal telopeptides of type I collagen and elevated levels of alkaline phosphatase., Conclusions: PNS mitigates estrogen deficiency-induced deterioration of trabecular microarchitecture and suppresses marrow adipogenesis.

Objective: Dalbergiphenol (DGP) is a neoflavonoid isolated from heartwood of Dalbergia sissoo. Effects of DGP on skeletal health remain to be elucidated. The objective of the present study was to investigate the biological effects of DGP on bone loss in ovariectomized mice., Methods: Adult BALB/c mice were ovariectomized and administered DGP (1 and 5  mg/kg/d) or 17β-estradiol (E2) orally for 6 weeks. The sham group and the ovariectomy (OVX) + vehicle group served as controls. Eight female BALB/c mice were taken for each group. Uterine estrogenicity, bone microarchitecture, biomechanical strength, new bone formation (based on bone formation rate and mineral apposition rate), and skeletal expression of osteogenic and resorptive gene markers were studied., Results: OVX resulted in a marked increase in body weight and a decrease in femoral and vertebral trabecular bone volume that were prevented by DGP or E2 treatment. DGP treatment increased bone biomechanical strength and new bone formation rate in ovariectomized mice, comparable with E2 treatment. However, increase in uterine weight and estrogenicity were observed in E2-treated ovariectomized mice, but not in response to DGP treatment. Treatment with DGP increased messenger RNA expression of runt-related transcription factor 2, osterix, and collagen type I, and decreased messenger RNA expression of tartrate-resistant acid phosphatase and the osteoprotegerin-to-receptor activator of nuclear factor-κB ligand ratio in the femur of ovariectomized mice., Conclusions: Overall findings suggest that DGP treatment can effectively prevent OVX-induced increase in bone loss and decrease in bone strength possibly by increasing osteoblastic activities and by decreasing osteoclastic activities.

Objective: This study aims to estimate the incidence of first hip or clinical vertebral fracture or major osteoporotic (hip, clinical vertebral, proximal humerus, or wrist) fracture in postmenopausal women undergoing their first bone mineral density (BMD) test before age 65 years., Methods: We studied 4,068 postmenopausal women, aged 50 to 64 years without hip or clinical vertebral fracture or antifracture treatment at baseline, who were participating in the Women's Health Initiative BMD cohort study. BMD tests were performed between October 1993 and April 2005, with fracture follow-up through 2012. Outcomes were the time for 1% of women to sustain a hip or clinical vertebral fracture and the time for 3% of women to sustain a major osteoporotic fracture before initiating treatment, adjusting for clinical risk factors and accounting for competing risks. Women without osteoporosis and women with osteoporosis on their first BMD test were analyzed separately., Results: During a maximum of 11.2 years of concurrent BMD and fracture follow-up, the adjusted estimated time for 1% of women to have a hip or clinical vertebral fracture was 12.8 years (95% CI, 8.0-20.4) for women aged 50 to 54 years without baseline osteoporosis, 7.6 years (95% CI, 4.8-12.1) for women aged 60 to 64 years without baseline osteoporosis, and 3.0 years (95% CI, 1.3-7.1) for all women aged 50 to 64 years with baseline osteoporosis. Results for major osteoporotic fracture were similar., Conclusions: Because of very low rates of major osteoporotic fracture, postmenopausal women aged 50 to 64 years without osteoporosis on their first BMD test are unlikely to benefit from frequent rescreening before age 65 years.

Objective: This study aims to assess the overall safety and potential endometrium-stimulating effects of soy isoflavone tablets consumed (3 y) by postmenopausal women and to determine endometrial thickness response to treatment among compliant women, taking into account hormone concentrations and other hypothesized modifying factors., Methods: We randomized healthy postmenopausal women (aged 45.8-65.0 y) to placebo control or two doses (80 or 120 mg/d) of soy isoflavones at two sites. We used intent-to-treat analysis (N = 224) and compliant analysis (>95%; N = 208) to assess circulating hormone concentrations, adverse events, and endometrial thickness (via transvaginal ultrasound)., Results: Median values for endometrial thickness (mm) declined from baseline through 36 months. Nonparametric analysis of variance for treatment differences among groups showed no differences in absolute (or percentage of change) endometrial thickness (χ(2) P ranged from 0.12 to 0.69) or in circulating hormones at any time point. A greater number of adverse events in the genitourinary system (P = 0.005) were noted in the 80 mg/day group compared with the 120 mg/day group, whereas other systems showed no treatment effects. The model predicting endometrial thickness response (using natural logarithm) to treatment among compliant women across time points was significant (P ≤ 0.0001), indicating that estrogen exposure (P = 0.0013), plasma 17β-estradiol (P = 0.0086), and alcohol intake (P = 0.023) contributed significantly to the response. Neither the 80 mg/day dose (P = 0.57) nor the 120 mg/day dose (P = 0.43) exerted an effect on endometrial thickness across time., Conclusions: Our randomized controlled trial verifies the long-term overall safety of soy isoflavone tablet intake by postmenopausal women who display excellent compliance. We find no evidence of treatment effects on endometrial thickness, adverse events, or circulating hormone concentrations, most notably thyroid function, across a 3-year period.

Objective: Icariin prevents bone loss by stimulating new bone formation and by inhibiting bone resorption. However, less is known about how icariin affects marrow adiposity. This lack of information is a vital problem, as the degree of marrow adipogenesis may be an alternative indicator of the severity of osteoporosis in relation to the degree of osteogenesis and osteoblastogenesis. To explore this question, we tested the effects of icariin on bone mineral density (BMD) and marrow fat content in a rat model of postmenopausal osteoporosis., Methods: Thirty-six 3-month-old female Sprague-Dawley rats were randomly assigned to one of the following treatment groups: sham operation, ovariectomized controls, and ovariectomized rats treated orally with either 17β-estradiol or icariin for 12 weeks. BMD and marrow fat fraction were dynamically measured on weeks 0, 6, and 12. After 12 weeks of treatment, serum 17β-estradiol and bone biomarker levels were measured, and marrow adipocytes were quantitatively evaluated by histopathology., Results: Ovariectomized controls experienced a marked increase in fat fraction over time, with increases of 40% between weeks 0 and 6 and 69.4% between weeks 6 and 12 (P < 0.001). Marrow adiposity in ovariectomized controls was dramatically higher than that in sham rats on week 6; however, a reduction in BMD was detected in ovariectomized rats on week 12 (P < 0.001). Ovariectomized rats had levels of serum alkaline phosphatase and serum C-terminal telopeptide of type I collagen that were 49.4% and 67.2% higher, respectively, than those of sham rats (P < 0.001). The density, size, and volume of marrow adipocytes in ovariectomized controls were 57.3%, 29.5%, and 163% higher, respectively, than those in sham rats. Early icariin treatment decreased bone biomarker levels, inhibited bone degeneration, and restored marrow fat infiltration and adipocyte parameters to the levels observed in sham rats. Overall, the osteoprotective effect of icariin was comparable with that of 17β-estradiol; however, icariin did not produce uterine estrogenicity., Conclusions: Early icariin treatment restores marrow adiposity in the estrogen-deficient rat model.

Objective: This study aims to assess the current status of shared decision-making on instituting postmenopausal hormone therapy (HT)., Methods: Two cross-sectional nationwide surveys of postmenopausal women and primary care physicians in the Republic of Korea were conducted in 2012 via face-to-face interviews. A total of 685 women (aged 50-69 y) who with natural menopause and 250 primary care physicians were included., Results: Only 56.8% of primary care physicians reported that they explain the benefits and risks of HT and leave the decision to postmenopausal women. The others usually recommended using or not using HT. Of those postmenopausal women who had discussed such therapy with physicians (147 of 685; 21.5%), not all were aware of breast cancer or cardiovascular risks (only 65.3% and 38.8% were informed, respectively). Although most physicians perceived HT as beneficial for menopausal symptom control (99.6%) and acknowledged the related risk of breast cancer (84.8%), nearly half had the impression that HT was preventive of cardiovascular diseases. The interviewed women were less informed of the benefits and risks of HT than were the physician respondents. The awareness levels of the treated and untreated women did not differ., Conclusions: Participation of postmenopausal women in deciding whether to use HT is not prevalent. Physician-woman information transfer is suboptimal, and treatment decisions often are not based on the best available evidence. The current status of shared decision-making in this setting is clearly in need of improvement.

Objective: A post hoc exploratory analysis was conducted to examine correlations between changes in bone density, bone markers, and hot flushes after the treatment of postmenopausal women with bazedoxifene (BZA)/conjugated estrogens (CE)., Methods: In a 2-year phase 3 study, 3,397 postmenopausal women were randomized to BZA 10 mg/CE 0.45 mg, BZA 20 mg/CE 0.45 mg, BZA 40 mg/CE 0.45 mg, BZA 10 mg/CE 0.625 mg, BZA 20 mg/CE 0.625 mg, BZA 40 mg/CE 0.625 mg, raloxifene 60 mg, or placebo. In this analysis, bone density changes at 2 years were compared with baseline levels of the bone markers serum C-telopeptide and osteocalcin. Correlations between changes in bone density and changes in 12-week hot flush composite scores in symptomatic women were also analyzed., Results: Treatment with BZA 20 mg/CE 0.45 mg or BZA 20 mg/CE 0.625 mg increased lumbar spine bone density more in women with higher bone resorption and formation, categorized by baseline levels of C-telopeptide and osteocalcin (P < 0.001, both BZA/CE doses). With placebo, larger decreases in lumbar spine bone density were seen in the highest tertile of serum C-telopeptide. There was no correlation between changes in total hip bone density and baseline bone markers. There were significant correlations between percent change in hot flush score at week 12 and percent changes in lumbar spine (r = -0.31, P = 0.006) and total hip (r = -0.23, P = 0.044) bone densities at month 24., Conclusions: With 2-year BZA/CE treatment, women with larger increases in lumbar spine and total hip densities also have higher baseline bone markers. Early reductions in hot flush score (12 wk) are predictive of long-term increases in bone density (24 mo).

Objective: This study aims to critically evaluate the effects of a walking intervention on bone mineral density (BMD) in perimenopausal and postmenopausal women and to identify the optimal duration of this walking exercise intervention., Methods: Two independent reviewers assessed for eligibility randomized and nonrandomized controlled trials evaluating the effects of walking on BMD in perimenopausal and postmenopausal women. Heterogeneity, potential publication bias, and the quality of the included trials were assessed., Results: Ten trials were eligible for inclusion. A meta-analysis of trials assessing lumbar spine BMD showed no significant effects (weighted mean difference [WMD] [fixed effects], 0.01 g/cm(2); 95% CI, -0.00 to 0.02; P = 0.05) regardless of the length of the intervention duration. BMD at the femoral neck increased after long intervention durations (6 mo to 1-2 y), although no significant effect could be seen when all trials assessing femoral neck BMD were taken into account (WMD [fixed effects], 0.01 g/cm(2); 95% CI, -0.00 to 0.01; P = 0.07). The effects of walking on the radius and whole body were not significant (WMD [random effects], -0.01 g/cm; 95% CI, -0.06 to 0.04; P = 0.71; and WMD [fixed effects], 0.04 g/cm(2); 95% CI, -0.00 to 0.08; P = 0.06, respectively)., Conclusions: Walking as a singular exercise therapy has no significant effects on BMD at the lumbar spine, at the radius, or for the whole body in perimenopausal and postmenopausal women, although significant and positive effects on femoral neck BMD in this population are evident with interventions more than 6 months in duration.

Objective: In this study, we have investigated the role of zinc supplementation (a nutritional antioxidant) in an ovariectomized osteopenic rat model., Methods: Forty-eight female Wistar rats were assigned to four groups: control, zinc, ovariectomy (OVX), and OVX + zinc. Analysis was performed to compare the study groups on bone metabolism markers, bone antioxidant enzymes, and zinc and copper levels in serum and bone tissues. Electron microscopy was also performed to assess morphological changes., Results: Estradiol levels decreased and tartarate-resistant acid phosphatase 5b levels increased in the OVX group. In the OVX + zinc group, these levels were regulated; however, estradiol levels were still significantly lower than those in controls. The OVX group showed significantly higher urinary excretion of hydroxyproline, which recovered upon zinc supplementation but was higher than normal levels. The activities of catalase and superoxide dismutase decreased in ovariectomized animals and up-regulated upon zinc supplementation. Zinc supplementation in the OVX group revoked reduced glutathione levels and elevated malondialdehyde levels. Reduction in zinc and copper levels was observed in the bone tissues and serum of the OVX group. Zinc administration restored these levels to normal. Electron microscopic studies revealed a looser structure and resorbed areas in ovariectomized rat cortical bone. Zinc administration restored bone tissue morphology., Conclusions: These findings suggest that changes in cortical bone attributed to estrogen deficiency are arrested by zinc supplementation, which can be a sustainable approach to improving bone health.

Tibolone is a drug with complex tissue-specific action that exhibits a combination of estrogenic, progestogenic, and slight androgenic activity. Its variable profile explains its clinical effects, depending on the target tissue where it is metabolized, its metabolites' affinity for and potency in hormone receptors, and probable enzymatic activity modulation.In recent reviews and clinical trials, the effectiveness of tibolone in alleviating different hot flush menopause symptoms, mainly in mood and sexuality disorders, has been noted. In Spain, tibolone is the most prescribed hormonal treatment, and one of the most common complaints among postmenopausal women is change in sexual drive. For such reason, a panel of experts from the Spanish Menopause Society met to develop usage recommendations based on the best evidence available.

Objective: Estrogen deficiency after menopause results in rapid bone loss, predisposing women to osteoporotic fractures. Genistein, a phytoestrogen present in high concentrations in soy, is an ingredient in dietary supplements aggressively marketed for bone health. However, in a recent long-duration clinical trial in postmenopausal women, the efficacy of soy extracts in reducing bone loss was disappointing. To better understand the failure of soy extracts to consistently induce a robust skeletal response in women, we investigated the long-term (5 mo) efficacy of genistein, administered as a daily oral supplement, (1) in preventing cancellous bone loss in skeletally mature virgin Long-Evans rats ovariectomized at 7 months of age and (2) in improving cancellous bone mass and architecture in aged retired-breeder rats ovariectomized at 16 or 22 months of age., Methods: Rats within each age group were randomly assigned into one of three treatment groups (n = 7-12 rats/group): (1) vehicle control, (2) genistein 485 μg/day, or (3) genistein 970 μg/day, resulting in mean (SE) serum genistein levels of 0.18 (0.10), 0.76 (0.15), and 1.48 (0.31) μM, respectively. Total tibia bone mass and density were evaluated using dual-energy x-ray absorptiometry, whereas cancellous bone mass and architecture in the tibial metaphysis, as well as cortical bone mass and architecture in the tibial diaphysis, were evaluated by micro-CT., Results: Oral genistein administered as a dietary supplement did not influence the cumulative effects of ovariectomy, aging, and/or reproductive history on cancellous and cortical bone mass and architecture., Conclusions: Serum levels of genistein similar to those in women consuming a high-soy diet are ineffective in preventing or treating bone loss in rat models for postmenopausal osteoporosis.

Objective: Epidemiological studies indicate that higher bone mass is associated with moderate alcohol consumption in postmenopausal women. However, the underlying cellular mechanisms responsible for the putative beneficial effects of alcohol on bone are unknown. Excessive bone turnover, combined with an imbalance whereby bone resorption exceeds bone formation, is the principal cause of postmenopausal bone loss. This study investigated the hypothesis that moderate alcohol intake attenuates bone turnover after menopause., Methods: Bone mineral density was determined by dual-energy x-ray absorptiometry in 40 healthy postmenopausal women (mean ± SE age, 56.3 ± 0.5 y) who consumed alcohol at 19 ± 1 g/day. Serum levels of the bone formation marker osteocalcin and the resorption marker C-terminal telopeptide (CTx) were measured by immunoassay at baseline (day 0) and after alcohol withdrawal for 14 days. Participants then consumed alcohol and were assayed on the following morning., Results: Bone mineral density at the trochanter and total hip were positively correlated to the level of alcohol consumption. Serum osteocalcin and CTx increased after abstinence (4.1 ± 1.6%, P = 0.01 and 5.8 ± 2.6%, P = 0.02 compared with baseline, respectively). Osteocalcin and CTx decreased after alcohol readministration, compared with the previous day (-3.4 ± 1.4%, P = 0.01 and -3.5 ± 2.1%, P = 0.05, respectively), to values that did not differ from baseline (P > 0.05)., Conclusions: Abstinence from alcohol results in increased markers of bone turnover, whereas resumption of alcohol reduces bone turnover markers. These results suggest a cellular mechanism for the increased bone density observed in postmenopausal moderate alcohol consumers. Specifically, the inhibitory effect of alcohol on bone turnover attenuates the detrimental skeletal consequences of excessive bone turnover associated with menopause.

Objective: The aims of this study were to evaluate the compliance with antiresorptive therapy (ART) and supplements in Spain and to analyze the validity of the different treatment compliance assessment methods., Methods: A cross-sectional study with retrospective data collection was carried out in women starting ART, evaluating indirect objective compliance, self-reported compliance, and the Morisky-Green questionnaire., Results: A total of 480 women with a mean (SD) age of 65.8 (9.2) years were studied. Of these women, 62.9% received calcium and/or vitamin D supplements in addition to ART. According to the objective compliance method, 76.9% of the women were compliers (≥80%) with bisphosphonates; 69.4%, with selective estrogen receptor modulators; and 61.8%, with supplements (P < 0.01). Using the self-reported compliance, we identified 91% compliers with antiresorptive drugs and 75% with supplements. Using the Morisky-Green test, we classified 60.8% of the women as compliers with antiresorptive drugs and 48.4% with supplements. Combining the objective and self-reported compliance, 29.5% of the women did not adequately comply with ART and 56% with the drug supplements., Conclusions: With all three compliance measures, supplements were the treatment yielding the lowest percentage of compliers. Bisphosphonates constituted the treatment offering the best objective compliance: 38.2% of the women with drug supplements and between 23.1% and 30.6% of the women with ART failed to exceed the theoretical value of 80% regarded as representing good compliance.

Objective: Millions of women in the United States and across the globe abruptly discontinued postmenopausal hormone therapy (HT) after the initial Women's Health Initiative trial publication. Few data describing the effects of HT cessation on hip fracture incidence in the general population are available. We evaluated the impact of HT cessation on hip fracture incidence in a large cohort from the Southern California Kaiser Permanente health management organization., Methods: In this longitudinal observational study, 80,955 postmenopausal women using HT as of July 2002 were followed up through December 2008. Data on HT use after July 2002, antiosteoporotic medication use, and occurrence of hip fracture were collected from the electronic medical record system. Bone mineral density (BMD) was assessed in 54,209 women once during the study period using the dual-energy x-ray absorptiometry scan., Results: After 6.5 years of follow-up, age- and race-adjusted Cox proportional hazard models showed that women who discontinued HT were at 55% greater risk of hip fracture compared with those who continued using HT (hazard ratio, 1.55; 95% CI, 1.36-1.77). Hip fracture risk increased as early as 2 years after cessation of HT (hazard ratio, 1.52; 95% CI, 1.26-1.84), and the risk incrementally increased with longer duration of cessation (P for trend < 0.0001). Longer duration of HT cessation was linearly correlated with lower BMD (β estimate [SE]) = -0.13 [0.003] T-score SD unit per year of HT cessation; P < 0.0001)., Conclusions: Women who discontinued postmenopausal HT had significantly increased risk of hip fracture and lower BMD compared with women who continued taking HT. The protective association of HT with hip fracture disappeared within 2 years of cessation of HT. These results have public health implications with regard to morbidity and mortality from hip fracture.

Objective: The aim of this study was to examine the utilization of mammography and bone mineral density (BMD) screenings and factors associated with compliance according to the recommended clinical practice guidelines., Methods: Mammography and BMD were assessed using employer's administrative claims data for eligible women identified between January 2004 and December 2006. Women were categorized into five cohorts based on mammography- and BMD-recommended screening guidelines. Logistic regression modeling was used to examine the covariates associated with compliance., Results: Mammography and BMD screening utilization were low in relation to recommendations, with 21%, 27%, and 16% of women complying with mammography, age-motivated BMD, and fracture-motivated BMD screening guidelines, respectively. BMD screening use (odds ratio [OR], 7.19; 95% CI, 7.08-7.31) was associated with compliance in the mammogram cohort. Mammogram use was associated with compliance in both the age-motivated BMD cohort (OR, 6.01; 95% CI, 5.28-6.85) and the fracture-motivated BMD cohort (OR, 2.20; 95% CI, 2.07-2.33). Having a Papanicolaou test was strongly associated with compliance in the combined mammogram plus age-motivated BMD cohort (OR, 16.83; 95% CI, 14.01-20.22) and the combined mammogram plus fracture-motivated BMD cohort (OR, 10.46; 95% CI 9.26-11.81)., Conclusions: Postmenopausal women with employer-sponsored health insurance had low utilization of mammography and BMD screening relative to clinical guidelines. Use of other health screening services was associated with compliance with guidelines. Methods to improve adherence to mammography and BMD screening guidelines should be explored, which could possibly leverage the increased likelihood that women who receive one screening service will receive another.

Osteoporosis is a common postmenopausal disease that has a substantial impact on the quality of life of older women and is associated with significant morbidity and mortality. There are various options for preventing osteoporosis in postmenopausal women, and all are associated with differing benefit-risk profiles. Estrogen therapy (in hysterectomized women) and estrogen/progestogen therapy (in nonhysterectomized women) are the most effective treatments available for the relief of vasomotor and urogenital symptoms in postmenopausal women and provide significant protection against osteoporotic fractures. Selective estrogen receptor modulators reduce bone loss and prevent vertebral fractures without endometrial or breast stimulation. Raloxifene, the only selective estrogen receptor modulator approved for osteoporosis prevention and treatment, significantly reduces vertebral but not nonvertebral or hip fractures. Bisphosphonates prevent bone loss and vertebral fractures; however, not all bisphosphonates have been shown to prevent nonvertebral fractures. Selective estrogen receptor modulators and bisphosphonates are not effective for menopausal symptoms. Hormone therapy should be considered as first-line therapy for preventing bone loss and fractures in early postmenopausal women who are symptomatic; other options include selective estrogen receptor modulators and bisphosphonates, especially in older, nonsymptomatic women. Future therapies are likely to include newer selective estrogen receptor modulators, combinations of estrogen with selective estrogen receptor modulators, and denosumab.

Objective: Basic science data, animal studies, and observational human studies suggest that the lipid-lowering cardiovascular family of statin medications might decrease fractures, increase bone density, and have a positive effect on bone turnover markers. The primary purpose of our review was to determine whether statins can prevent fractures in postmenopausal women; as secondary and explanatory factors, bone density and bone biomarker data were also evaluated., Methods: All randomized controlled trials assessing the effect of statins on bone mineral density were included; bone turnover markers and fractures in postmenopausal women were considered., Results: We identified six randomized trials involving 3,022 participants. Statins had no association with decreasing incidence of fracture. There was no statistical difference in the reduction in lumbar spine or total hip bone density. Other predictors of osteoporosis-related fracture risk, including markers relating to bone resorption (c-telopeptide of type I collagen and n-telopeptide of type I collagen) and bone formation (osteocalcin and bone-specific alkaline phosphates), did not show any significant changes., Conclusions: The trials included in our review, which included data on 3,022 women (mean age, >62.7 y), do not indicate that statin use prevents fractures or increases bone density.

Objective: Part of the risks for coronary heart disease (CHD) and osteoporosis in women are established by their lifestyle in the premenopausal period. Therefore, we assessed the risk of women aged 45 to 49 years for CHD and osteoporosis and its relation with socioeconomic status (SES) and access to general practitioners (GPs) to provide clues for prevention., Methods: The health interview data used for this study originated from the second Dutch National Survey of General Practice, a study with a response rate of 64.5%. We studied SES, risk factors for CHD and osteoporosis, and access to GPs in women aged 45 to 49 years., Results: The data of 571 women aged 45 to 49 years were included. A total of 39% had an increased risk for developing CHD in the next 10 years, and 3% had a high risk. A total of 22% had an increased risk for osteoporosis. We found a significant relation between SES and unhealthy lifestyle. An unhealthy lifestyle led to an increased or high risk for CHD, and a high osteoporosis risk. We did not find a significant relation between SES and GP consultation frequency., Conclusions: Special attention is required for women with the lowest SES because they have an unhealthier lifestyle than do women with middle or the highest SES. The group of women at higher risk for CHD and osteoporosis consulted their GP with the same frequency as did women at lower risk. The Dutch GP seems to be in an ideal position to play a role in the prevention of CHD and osteoporosis in premenopausal women because access to GPs is not influenced by SES.

Objective: This study aimed to determine the skeletal effects of total ethanolic extract (TEE) and its butanolic fraction (BF) from the stem-bark of Ulmus wallichiana, which is rich in C-glycosylated flavonoids, in growing rats (for peak bone [PB] achievement) and in ovariectomized (OVx) rats (for menopausal bone loss)., Methods: TEE (750 mg kg(-1) d(-1)) and BF (50 mg kg(-1) d(-1)) were given orally for 10 weeks to weaning female Sprague-Dawley rats and for 12 weeks to adult OVx rats of the same strain, respectively. In studies with OVx rats, sham operated + vehicle, OVx + 17beta-estradiol, and OVx + vehicle groups served as various controls. Bone mineral density (BMD), biomechanical strength, bone histology, formations of osteoprogenitor cells, osteoid formation, and bone turnover/resorption markers were studied. Bioactive marker compounds in TEE and BF were analyzed by high-performance liquid chromatography. One-way analysis of variance was used to test significance of effects., Results: In growing rats, both TEE and BF increased BMD, bone strength, and bone formation rate, suggesting higher PB achievement. OVx rats treated with either TEE or BF exhibited increased BMD at various anatomical positions and improved bone strength and trabecular architecture compared with the OVx + vehicle group. Serum osteocalcin and urinary type 1 collagen degradation product levels in OVx rats treated with either TEE or BF were significantly lower than those of the OVx + vehicle group. Neither TEE nor BF exhibited uterine estrogenicity. Analysis of marker compounds revealed significant enrichment of two bioactive markers in BF over TEE., Conclusions: Derived from U wallichiana, BF at much a lower dose than TEE was effective in PB achievement and prevention of OVx-induced bone loss.

Objective: To update the evidence-based position statement published by The North American Menopause Society (NAMS) in 2006 regarding the management of osteoporosis in postmenopausal women., Methods: NAMS followed the general principles established for evidence-based guidelines to create this updated document. A panel of clinicians and researchers expert in the field of metabolic bone diseases and/or women's health was enlisted to review the 2006 NAMS position statement, compile supporting statements, and reach consensus on recommendations. The panel's recommendations were reviewed and approved by the NAMS Board of Trustees., Results: Osteoporosis, which is especially prevalent among older postmenopausal women, increases the risk of fractures. Hip and spine fractures are associated with particularly high morbidity and mortality in this population. Given the health implications of osteoporotic fractures, the primary goal of osteoporosis therapy is to prevent fractures, which is accomplished by slowing or stopping bone loss, maintaining bone strength, and minimizing or eliminating factors that may contribute to fractures. The evaluation of postmenopausal women for osteoporosis risk requires a medical history, physical examination, and diagnostic tests. Major risk factors for postmenopausal osteoporosis (as defined by bone mineral density) include advanced age, genetics, lifestyle factors (such as low calcium and vitamin D intake, smoking), thinness, and menopause status. The most common risk factors for osteoporotic fracture are advanced age, low bone mineral density, and previous fracture as an adult. Management focuses first on nonpharmacologic measures, such as a balanced diet, adequate calcium and vitamin D intake, adequate exercise, smoking cessation, avoidance of excessive alcohol intake, and fall prevention. If pharmacologic therapy is indicated, government-approved options are bisphosphonates, selective estrogen-receptor modulators, parathyroid hormone, estrogens, and calcitonin., Conclusions: Management strategies for postmenopausal women involve identifying those at risk for fracture, followed by instituting measures that focus on reducing modifiable risk factors through dietary and lifestyle changes and, if indicated, pharmacologic therapy.

Objective: The aim of this study was to examine the endometrial, ovarian, and breast safety of bazedoxifene, a novel selective estrogen-receptor modulator, in postmenopausal women at risk for osteoporosis., Methods: Healthy postmenopausal women (N = 1,583; mean age, 57.6 y) with lumbar spine or femoral neck bone mineral density T scores between -1 and -2.5 and/or other clinical risk factors for osteoporosis were enrolled in a 24-month, phase 3, randomized, double-blind, placebo- and active-controlled trial. They received daily treatment with bazedoxifene 10, 20, or 40 mg; placebo; or raloxifene 60 mg. Reproductive safety assessments included periodic transvaginal ultrasound measurements of endometrial thickness, ovarian volume, and presence of ovarian cysts; periodic endometrial biopsies; and adverse event reporting., Results: Bazedoxifene was not associated with a significant change from baseline in mean endometrial thickness at month 24. The percentage of participants with a change from baseline in endometrial thickness or endometrial thickness greater than 5 mm at month 24 was similar among groups. There was no consensus diagnosis of endometrial hyperplasia or malignancy in the bazedoxifene or raloxifene groups; the rates of other histologic findings, including endometrial polyps, were low (<5%) and similar among groups. No significant between-group differences were found in the change from baseline in ovarian volume, number or size of ovarian cysts, or incidence of ovarian cancer. Reports of breast pain (<4%) and breast cancer (<1%) were low and evenly distributed among groups., Conclusion: A favorable endometrial, ovarian, and breast safety profile was found after 2 years of treatment with bazedoxifene in healthy, recently postmenopausal women at risk for osteoporosis.

Objective: The aim of this study was to determine whether frequent onion consumption is associated with increased bone density in perimenopausal and postmenopausal non-Hispanic white women 50 years and older., Methods: An analysis of the National Health and Nutrition Examination Survey 2003-2004 was performed. Perimenopausal and postmenopausal non-Hispanic white female participants (unweighted N = 507; weighted N = 35.7 million) were divided into those who consumed onions less than once a month, twice a month to twice a week, three to six times a week, and once a day or more based on self-reported dietary history. All study participants underwent total body dual-energy x-ray absorptiometry., Results: After controlling for age, body mass index, daily calcium intake, serum vitamin D, serum parathyroid hormone, estrogen use, smoking status, and exercise status, bone density increased as the frequency of onion consumption increased. Individuals who consumed onions once a day or more had an overall bone density that was 5% greater than individuals who consumed onions once a month or less (P < 0.03)., Conclusions: Onion consumption seems to have a beneficial effect on bone density in perimenopausal and postmenopausal non-Hispanic white women 50 years and older. Furthermore, older women who consume onions most frequently may decrease their risk of hip fracture by more than 20% versus those who never consume onions.

Objective: Phytoestrogens and phytoestrogen-containing plants are currently being explored as potential candidates for the treatment of estrogen-related disorders. The aim of this study was to evaluate the anti-osteoporotic effect of the phytoestrogen-rich plant Phaseolus vulgaris L, commonly known as French beans., Methods: Adult Sprague-Dawley rats were either bilaterally ovariectomized (OVX) or sham operated. OVX and sham control groups were administered vehicle, whereas the other two OVX groups were given 0.15 mg/kg estradiol and 1 g/kg methanolic extract of P vulgaris L seeds (MPV) orally for 10 weeks (10 rats per group). At autopsy, blood, urine, bones, and uteri of the animals were collected. Serum was evaluated for estradiol, calcium (Ca), phosphorus, alkaline phosphatase, tartarate resistant acid phosphatase, and urine for Ca. The bone density, ash density, mineral content, and mechanical strength of bones was evaluated. Scanning electron microscopic analysis of bones (tibia) was performed. Results were analyzed using analysis of variance and Tukey's multiple comparison test., Results: Compared with the OVX control, MPV (1 g/kg PO) significantly decreased serum alkaline phosphatase and reduced serum tartarate resistant acid phosphatase and urinary Ca levels. It caused an increase in bone density, ash density, and bone mechanical strength and significantly increased bone Ca. Improvement in bone microarchitecture was indicated by image analysis of scanning electron microscopic photomicrographs. No increase in weight of atrophic uterus in OVX animals was observed with MPV treatment., Conclusions: Treatment with MPV prevented estrogen deficiency-induced osteopenia without affecting the uterine mass. The promising results of the study warrant further investigation of French beans as a potential candidate for the treatment of postmenopausal osteoporosis.

Objective: Declining estrogen levels after menopause result in bone loss and increased fracture risk. This study investigated whether transdermal microdose 17beta-estradiol (E2) has efficacy and safety comparable to those of raloxifene, a selective estrogen-receptor modulator approved for the prevention and treatment of postmenopausal osteoporosis., Methods: This study involved a multicenter, randomized, double-blind, active-controlled, noninferiority trial in 500 osteopenic postmenopausal women comparing transdermal microdose E2 (0.014 mg/d) versus oral raloxifene (60 mg/d), administered for 2 years. Percent change from baseline in bone mineral density at the lumbar spine was measured after 2 years of treatment. Secondary endpoints included proportion of women with no loss of bone mineral density in lumbar spine, change in bone mineral density at hip, biochemical markers of bone turnover, and safety parameters., Results: In the per protocol set, lumbar spine bone mineral density increased by 2.4% (95% CI, 1.9-2.9) with microdose E2 versus 3.0% (95% CI, 2.5-3.5) with raloxifene after 2 years; 77.3% of E2 recipients and 80.5% of those taking raloxifene had no bone loss in the lumbar spine. Both treatments were well tolerated. Most women (99% in the E2 group and 100% in the raloxifene group) showed no histological evidence of endometrial stimulation after 2 years. Mean dense area in breast mammograms was 19.8% in the E2 group versus 19.0% in the raloxifene group after 2 years., Conclusions: Transdermal microdose E2 was similarly effective as raloxifene in preventing bone loss at the lumbar spine. Both treatments were well tolerated, with no clinically significant effect on endometrium or breast density.

Objective: Flaxseed is rich in lignans and alpha-linolenic acid, compounds that may promote healthy skeletons. Many postmenopausal women consume complementary health products such as flaxseed or its components in addition to pharmacological agents such as low-dose estrogen therapy for additional support for menopausal symptoms and related conditions. However, their combined effect on bone health is unknown. The aim of this study was to determine the effects of 10% dietary flaxseed, low-dose estrogen therapy, or their combination on bone mineral density, biomechanical strength, and skeletal fatty acid composition in an ovariectomized rat model of postmenopausal osteoporosis., Methods: Ovariectomized rats received (1) basal diet (negative control), (2) 10% flaxseed, (3) low-dose estrogen implant (13 microg, 90 day release), or (4) flaxseed + low-dose estrogen implant for 12 weeks. A sham-operated group was included as a positive control. Bone mineral density, biomechanical strength, and fatty acid composition were measured at multiple skeletal sites., Results: Flaxseed + low-dose estrogen therapy resulted in the highest bone mineral density and peak load at the lumbar vertebrae, with no effect on bone mineral density or strength in the tibia and femur. Flaxseed and flaxseed + low-dose estrogen therapy resulted in significantly higher relative levels of alpha-linolenic acid and eicosapentaenoic acid and lower levels of linoleic acid, arachidonic acid, and n-6/n-3 ratio in the lumbar vertebrae and tibia compared with all other groups., Conclusion: Flaxseed + low-dose estrogen therapy provides the greatest protection against ovariectomy-induced bone loss at the lumbar vertebrae. Moreover, this study is the first to demonstrate that flaxseed, rich in alpha-linolenic acid, alters fatty acid composition in the ovariectomized rat skeleton.

Objective: Most fractures occur in elderly individuals without osteoporosis, and more than 90% of all hip fractures are associated with a fall. It is unclear whether hormone therapy (HT) can improve postural balance when initiated in elderly women and the effect of endogenous estradiol (E2) levels., Design: Forty healthy women (33 assessable), age 60 years or older, were recruited through advertising in the local media. They were randomly and blindly assigned to receive either estradiol patches (50 microg/24 h) combined with oral medroxyprogesterone acetate (2.5 mg/d) or placebo for 6 months. Postural balance was assessed as sway velocity using a force platform., Results: Low serum E2 levels were associated with greater impairment of sway velocity during the study in the placebo group. After 6 months sway velocity had improved (decreased) in the HT group by 4.3% from baseline and increased in the placebo group by 6.2%. The difference was not significant (1.30 cm/s, 95% CI: -3.0 to 0.4; P = 0.13). However, among women with low serum E2 levels at baseline (less than the median, 35 pmol/L), sway velocity improved in the HT group and deteriorated in the placebo group with a difference of 23% (2.9 cm/s, 95% CI: 0.6-5.1; P = 0.013). There were similar results after adjustment for baseline sway velocity (P = 0.003) and in the intention-to-treat analysis (P = 0.023). There was also a significant interaction between the study group and baseline serum E2 levels with regard to changes in sway velocity (P = 0.014)., Conclusions: In elderly women low endogenous serum E2 levels were associated with greater impairment of postural balance function during the study, whereas HT, as compared with placebo, improved postural balance in women with low serum E2 levels.

Objective: Findings from the Women's Health Initiative (WHI) failed to confirm previous expectations about the net benefits of menopausal hormone therapy and have resulted in reduced use of these medications. The aim of this study was to evaluate women's awareness and knowledge concerning the risks and benefits of hormone therapy., Design: A nationally representative survey was completed for a sample of 781 women (ages 40-60 y, mean 49 y) drawn from the Knowledge Networks Internet panel 24 months after publication of the first WHI findings, in June 2004. Responses were weighted to reflect the demographics of the US population. The main outcome measures were awareness of WHI and knowledge of its findings. An aggregate score was constructed to assess women's knowledge of the impact of hormone therapy on seven key disease outcomes. Logistic regression determined the independent predictors of (1) WHI awareness and (2) a positive aggregate knowledge score, reflecting appropriate responses about risks and benefits., Results: Only 29% of women were aware of the WHI results. Only 40% of women had a positive aggregate knowledge score. Aside from awareness of WHI and independent of other factors, knowledge scores were lower for African American women (odds ratio, 0.4; 95% CI: 0.2-0.6) and among women with less education (odds ratio, 0.5; 95% CI: 0.3-0.9). Knowledge was greatest for breast cancer and osteoporosis outcomes and most limited for colorectal cancer and memory loss., Conclusion: Surveyed women had limited awareness and knowledge of the WHI results, suggesting limited diffusion. Targeting younger, less educated, and African American women is warranted.

Objective: Equol is more biologically active than its precursor daidzein, which is the principal isoflavone found in soybean. There are interindividual differences in the ability to produce equol; these may lead to differences in the effects of isoflavone intervention on human health. This study aimed to investigate whether the effects of soy isoflavones on bone and fat mass are related to an individual's equol status., Design: We performed a 1-year double-blind, randomized trial to compare the effects of isoflavone (75 mg of isoflavone conjugates/day) with those of placebo on bone mineral density, fat mass, and serum isoflavone concentrations in early postmenopausal Japanese women who were classified based on their equol-producer phenotype., Results: After 1 year, the isoflavone intervention significantly increased the serum equol concentration in the equol producers but not in the nonproducers. In the isoflavone group, the annualized changes in the bone mineral density of the total hip and intertrochanteric regions were -0.46% and -0.04%, respectively, in the equol producers and -2.28% and -2.61%, respectively, in the nonproducers; these values were significantly different (P<0.05 for both the regions). Significant differences were observed between the equol producers and nonproducers in the isoflavone group with regard to the annualized changes in the fat mass. No significant difference in the annualized changes in bone mineral density and fat mass was observed between the equol producers and nonproducers in the placebo group., Conclusions: Our data suggest that the preventive effects of isoflavones on bone loss and fat accumulation in early postmenopausal women depend on an individual's equol-producing capacity.

Objective: Long-term effects of soy-derived isoflavones on lipids remain uncertain, and few data are available on their effects on glycemic control. We examined the effects of isolated soy germ isoflavones on the changes in fasting glucose (FG) and lipids., Design: A double-blind, randomized, placebo-controlled trial was conducted in 203 postmenopausal Chinese women aged 48 to 62 years. They were randomly assigned to receive daily doses of 500 mg calcium, and 0 mg isoflavones (placebo, n=67), 40 mg isoflavones (n=68), and 80 mg isoflavones (n=68). Serum FG, triglycerides, high-density lipoprotein, low-density lipoprotein, total cholesterol, and lipoprotein cholesterol were measured at baseline and 1 year after treatment. The primary data analysis was performed on the 203 randomized women according to the intent-to-treat principle. The last value carried forward was used for any missing data at follow-up., Results: We observed moderate but significant favorable effects of soy isoflavones on the changes (P=0.012) and percentage of changes (P=0.031) in FG (analysis of variance). The 1-year mean (SD) differences of FG changes were -5.2 (-9.4 to -1.0) mg/dL (P=0.010) and -3.3 (-7.5 to 0.9) mg/dL (P=0.18) in the 40- and 80-mg isoflavone groups compared with the placebo group. We also noted a significant interaction between the treatment and baseline FG on the changes in FG (P=0.004). The isoflavone effects were much more significant in women with baseline FG 100 mg/dL or more than in those with FG less than 90 mg/dL. We observed little effect of soy isoflavones on changes in serum lipids among the treatment groups., Conclusions: One-year of soy isoflavone supplementation might have a favorable effect on FG in women, but has no significant effect on serum lipids.