Hormone replacement therapy and the prevention of postmenopausal osteoporosis Reproductive hormones and skeletal health in young women. Bone Mineral Density and Endogenous Hormones and Risk of Breast Cancer in Postmenopausal Women (United States) Progesterone or progestin as menopausal ovarian hormone therapy: recent physiology-based clinical evidence Calcium Supplementation with and without Hormone Replacement Therapy To Prevent Postmenopausal Bone Loss Guidance for the management of breast cancer treatment-induced bone loss: a consensus position statement from a UK Expert Group. Bone mineral density among premenopausal women with early breast cancer in a randomized trial of adjuvant endocrine therapy. Comparison of the effects of estrogen alone and estrogen plus androgen on biochemical markers of bone formation and resorption in postmenopausal women. Postmenopausal bone loss is prevented by treatment with low-dosage estrogen with calcium. Effect of estrogen/gestagen and 24R,25-dihydroxyvitamin D3 therapy on bone formation in postmenopausal women. The effects of compounded bioidentical transdermal hormone therapy on hemostatic, inflammatory, immune factors; cardiovascular biomarkers; quality-of-life measures; and health outcomes in perimenopausal and postmenopausal women. Esterified estrogen therapy in postmenopausal women. Relationships of bone marker changes and plasma estradiol to BMD changes: A two-year study Comparison of Oral Estrogens and Estrogens Plus Androgen on Bone Mineral Density, Menopausal Symptoms, and Lipid‐Lipoprotein Profiles in Surgical Menopause Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause. Significant Differential Effects of Alendronate, Estrogen, or Combination Therapy on the Rate of Bone Loss after Discontinuation of Treatment of Postmenopausal Osteoporosis Testosterone addition during menopausal hormone therapy: effects on mammographic breast density Digitized mammography: a clinical trial of postmenopausal women randomly assigned to receive raloxifene, estrogen, or placebo.
Fracture prevention is one of the public health priorities worldwide . Estrogen deficiency is the major factor in the pathogenesis of postmenopausal osteoporosis , the most common metabolic bone disease . Different effective treatments for osteoporosis are available . Hormone replacement therapy ( HRT ) at different doses rapidly normalizes turnover , preserves bone mineral density ( BMD ) at all skeletal sites , leading to a significant , reduction in vertebral and non-vertebral fractures .  Tibolone , a selective tissue estrogenic activity regulator ( STEAR ) , is effective in the treatment of vasomotor symptoms , vaginal atrophy and prevention/treatment of osteoporosis with a clinical efficacy similar to that of conventional HRT . Selective estrogen receptor modulators ( SERMs ) such as raloxifene and bazedoxifene reduce turnover and maintain or increase vertebral and femoral BMD and reduce the risk of osteoporotic fractures . The combination of bazedoxifene and conjugated estrogens , defined as tissue selective estrogen complex ( TSEC ) , is able to reduce climacteric symptoms , reduce bone turnover and preserve BMD . In conclusion , osteoporosis prevention can actually be considered as a major additional benefit in climacteric women who use HRT for treatment of climacteric symptoms . The use of a st and ard dose of HRT for osteoporosis prevention is based on biology , epidemiology , animal and pre clinical data , observational studies and r and omized , clinical trials . The antifracture effect of a lower dose HRT or TSEC is supported by the data on BMD and turnover , with compelling scientific evidence In young women , low estrogen levels complicate a wide variety of diseases , including premature ovarian failure , anorexia nervosa , athletic amenorrhea , prolactinoma , hypopituitarism , and chronic kidney disease . Hypoestrogenemia may also result from therapy with GnRH agonists , glucocorticosteroids , chemotherapy , and especially aromatase inhibitors . All of these situations are associated with bone loss , because estrogen chronically suppresses bone resorption . Several mechanisms are involved : 1 ) estrogen increases osteoclast apoptosis ; 2 ) by suppressing interleukins and proinflammatory cytokine expression in bone marrow cells , estrogen decreases the number of osteoclasts ; 3 ) by inhibiting the production of receptor activator of nuclear factor-κB lig and , estrogen reduces the number and activity of osteoclasts ; and 4 ) by increasing stromal cell/osteoblast cell expression of TGFβ , estrogen inhibits osteoclast activity . Estrogen also has some positive effects on bone formation by acting as a mitogen to cells early in the osteoblast line , reducing apoptosis of osteoblasts , and increasing expression of TGFβ , bone morphogenetic proteins , and IGF-I ( 1 ) . In these pathological conditions , the cause of the bone loss is frequently multifactorial . For example , women with anorexia nervosa also have low IGF levels . Nonspecific factors such as poor diet , reduced exercise , or chronic inflammation may further increase bone resorption . Low estrogen levels are also seen in healthy young women who are using depo-medroxyprogesterone acetate ( DMPA ) for contraception .  Bone loss is a side effect of this medication ( 2 ) . The bone mineral density ( BMD ) decreases at a more rapid rate during the first years of therapy and then continues to decrease at a slower rate ( 3 ) . After 5 yr , the loss is about 6 % ( 0.5 sd ) . The  DMPA effects are worse in teenagers ; combined results from four prospect i ve studies found an average loss of spine BMD of 3.1 % over 2 yr in  DMPA  users compared with a gain of 7.2 % in untreated controls ( 4 ) . A cross-sectional study in this issue by Walsh and colleagues ( 5 ) focused on the age of starting DMPA .  One group aged 18–25 started DMPA before age 20 , and another group aged 35–45 started after age 34 . Each group had matched controls . Importantly , the average use was 37 months in both groups . This avoids the confounding between age and duration of use , which is encountered in other studies . The BMD was significantly lower than controls when DMPA was started in teenagers but not when it was started after age 34 . Estrogen levels were lower in the DMPA users than the non-hormone users and were also lower in the younger women than in the older women . The authors concluded that estrogen levels mediated the effect of DMPA on bone markers because adding DMPA to a regression model reduced the correlation between markers and estrogen . These correlations were not very strong ( r = −0.17 between N-telopeptide and estradiol-treated ) , so this is a tenuous conclusion , but it is bolstered by the findings from two other studies that adding estrogen to DMPA abolishes the negative effect on the skeleton ( 6,7 ) . The age range of the older group of women is underrepresented in most of the previous studies of skeletal effects of DMPA . These results lead to several questions about basic bone biology . How are adolescent bones different from mature bones ? How does DMPA use compare to the natural state of low estrogen seen in healthy lactating women ? Is bone completely restored in these situations ? There are also important clinical questions about potential risk of fractures and the skeletal risks from other forms of contraception Objective : This case – cohort study was design ed to examine whether total hip bone mineral density ( BMD ) is independently associated with breast cancer over and above its association with other determinants , including levels of total and bioavailable estradiol and testosterone and sex-hormone binding globulin . Methods : Our study population was selected from a cohort of 8203 postmenopausal women who were screened for the Fracture Intervention Trial in 1992 , at which time  BMD was assessed  , and  blood sample s were obtained . A total of 109 women developed breast cancer during four years of follow-up ; 173 other r and omly selected women from the larger cohort were also selected . Cox proportional hazards with robust variance adjustment was used for these analyses . Results : Relative to women in the lower fourth of the BMD distribution , the risk associated with being in the upper fourth was 2.6 ( 95 % confidence interval ( CI ) 1.1–5.8 ) . After adjusting for serum hormone levels , the corresponding relative risk was 2.5 ( 95 % CI 0.9–5.2 ) . With body mass index and number of years since menopause added to the multivariate analysis , the relative risk decreased to 1.4 ( 95 % CI 0.5–4.0 ) . Conclusions : BMD may not influence breast cancer risk independent of its relationship with endogenous hormones and measured covariates Purpose of review Provide evidence -based recent data on oral micronized progesterone ( OMP ) and progestins in menopausal hormonal therapy ( MHT ) . Recent findings Medroxyprogesterone acetate ( MPA ) increases breast cancer acting through the glucocorticoid receptor ; progestins in MHT increase thrombosis more than oral estrogens ; MPA , but not OMP or other progestins , increase monocyte cell endothelium adhesion ; MPA and estradiol (E2)/MPA have negative brain effects , whereas E2/progesterone ( P4 ) has neuroregenerative brain effects . The ‘ window of opportunity ’ cardiovascular disease hypothesis is not supported by a r and omized controlled trial showing that transdermal estradiol with sequential OMP in early menopause does not prevent increased carotid intimal media thickness ; P4 in the cardiac electrical system opposes E2 effects and prevents sudden death/long QT syndrome ;  transdermal estradiol/OMP does not increase venous thromboembolism in observational data . P4 decreases breast cell proliferation and improves prognosis through P4 receptor alteration of estrogen receptor & agr ; genetic effects ;  OMP with conjugated equine estrogen (CEE)/estrogen (E)/E2 does not increase breast cancer in two prospect i ve cohorts , one population -based . Endometrial cancer is increased in MHT of CEE/E/E2+cyclic OMP at 200 mg/day . Summary New data show CEE/E/E2+MPA/P mechanisms for negative breast cancer , venous thromboembolism , cardiovascular system , and brain effects .  OMP/P4 counterbalances CEE/E/E2-related negative effects on breast cancer and long QT syndrome .  OMP effectively treats vasomotor symptoms and sleep disturbances , and could safely be used alone for symptomatic menopause Postmenopausal bone loss is a major factor in the increasing prevalence of osteoporotic fractures . Evidence is abundant that hormonal replacement therapy prevents the bone loss that follows natural or surgical menopause and reduces the prevalence of osteoporotic fractures in later life [ 1 - 4 ] . However , only about 10 % of American women elect to receive replacement therapy because of attitudes of physicians and patients , the undesirability of menstrual bleeding , and unresolved questions about the relation of the use of estrogen to breast cancer [ 5 ] . Moreover , the duration of hormonal therapy may need to be prolonged because bone loss recurs when therapy is discontinued , yet the incidence of some adverse effects increases with the duration of estrogen use . Safer alternatives to estrogen use have been sought . Epidemiologic and cross-sectional studies have suggested that increasing calcium intake might prevent postmenopausal bone loss , and prospect i ve studies have yielded conflicting results [ 6 - 17 ] . Moreover , some investigators have suggested that effects differ on the various skeletal sites used to determine the rate of bone loss [ 18 ] . We compared the efficacy of calcium augmentation in early postmenopause with calcium augmentation plus hormonal replacement therapy and with placebo . The study had a three-arm , r and omized , parallel design . The patients receiving hormonal replacement therapy were obviously not blinded nor were their physicians , whereas the placebo and calcium groups were double blinded . Methods Healthy , white women between 6 months and 6 years after a natural menopause were recruited to participate in the study . The protocol was approved by the Human Investigation Review Committees of Winthrop-University Hospital and Brookhaven National Laboratory ; written informed consent was obtained from each participant . Participants were recruited by announcements in the local press and in hospital and university publications and through a direct mail campaign . All participants had a history and physical examination . Exclusion characteristics included any disorder known to affect bone metabolism such as glucocorticoid use , gastrointestinal disease , or any chronic illness . Previous or current malignancy was an exclusion characteristic as were absolute contraindications to estrogen replacement or calcium supplements . Absolute contraindications to estrogen replacement therapy included estrogen-dependent neoplasm ( breast or uterus ) , undiagnosed vaginal bleeding , thrombophlebitis or thromboembolism , and acute liver disease .  Women with the following problems considered by some investigators to be relative contraindications to estrogen therapy were also excluded : gallbladder disease , history of liver disease , first-degree relatives with breast cancer , and hypertension . Calcium urolithiasis was also an exclusion factor . Women with known osteoporosis or with a vertebral compression fracture were not eligible for the study . One hundred eighteen women entered the study . The women were r and omly assigned to three groups : 1 ) hormonal replacement [ estrogen-progesterone-calcium carbonate ] , 2 ) calcium carbonate , or 3 ) placebo . Assignment to the groups was based on computer-generated r and om numbers provided by the statistician , with stratification for years postmenopause . The women in the hormonal replacement group took conjugated equine estrogens ( Premarin , Wyeth-Ayerst Laboratories , Inc. ; Philadelphia , Pennsylvania ) , 0.625 mg daily for 25 days of the month along with medroxyprogesterone ( Provera , Upjohn ; Kalamazoo , Michigan ) , 10 mg from days 16 to 25 . All women received 400 IU of vitamin D daily in the form of a multivitamin , and calcium supplementation ( as Caltrate , Lederle ; Clifton , New Jersey ) was provided to the two treatment groups . The duration of the study was 2.9 1.1 years ( mean SD ) . A 7-day dietary history was review ed with a nutritionist every 2 months ; calcium was provided as calcium carbonate , 600 mg ( Caltrate ) , and used to supplement the diet to approximate a total daily intake of 1700 mg of elemental calcium ( the mean + 2 SD found by Heaney and colleagues [ 7 ] to result in zero calcium balance in estrogen-deprived women ) . The calcium supplements were taken with meals in divided doses . The placebo appeared identical to the calcium carbonate tablets . No patients took antacids or histamine-2 blockers . All women had a baseline mammogram . Measurements Routine laboratory studies included a complete blood count , urinalysis , and serum fasting calcium , phosphorus , urea nitrogen , creatinine , alkaline phosphatase , cholesterol , and aminotransferase measurements [ 19 , 20 ] . In addition , follicle-stimulating hormone , estradiol , parathyroid hormone , osteocalcin , free thyroxine , and bone alkaline phosphatase were measured , and a urine specimen was collected after an overnight fast for hydroxyproline , calcium , and creatinine determinations , following a 3-day low-hydroxyproline diet [ 21 - 23 ] . Total body calcium was measured annually in the participants , using the delayed neutron activation method at Brookhaven National Laboratory [ 24 , 25 ] . This method uses a whole-body counter to measure the characteristic rays emitted from the neutron capture of Calcium-48 ( natural abundance of 0.187 % ) in the body . The Brookhaven National Laboratory whole-body counter was up grade d in 1987 to use 32 NaI ( T1 ) detectors of 10 cm 10 cm 46 cm positioned symmetrically above and below the patient [ 25 ] . The activated isotope , Calcium-49 , decays with a half-life of 8.72 minutes , emitting a 3.08 MeV characteristic line . More than 99.5 % of the body calcium is contained in the bone [ 26 ] . The method provides total body calcium with a coefficient of variation of about 1.5 % when no substantial change in the body weight occurs during the period of repeated studies . The measurements were made annually . The bone mineral density of the distal radius site was measured using a Lunar Radiation ( Madison , Wisconsin ) single-photon absorptiometer ( SP2 ) .  Bone mineral density of the spine ( L2-L4 ) and femur ( neck , trochanter , and Ward triangle ) was measured using a Lunar Radiation DP4 dual-photon absorptiometer . The software version used for the analysis of scans was DP4 Lunar Corporation Version 1.1 . All scans were analyzed using the same software version , which corrects for source decay . Instruments were calibrated daily , and the radioactive source was changed annually . Each measurement was done every 6 months . The coefficient of variation of these measurements was 2 % , except for the Ward triangle ( 2.5 % ) . Activity was measured using  activity monitors  ( large-scale integrated monitors ) , which were worn about the waist [ 27 ] . The average of 2 weekdays and 1 weekend day was used as an activity score . Activity was measured at baseline and at one other point during the study to ensure that differences among the groups were not due to varied levels of exercise . Statistical Analysis Total body calcium was selected as the primary criterion for efficacy for the following reasons : It measures mass rather than density per unit area ; it measures calcium balance precisely and accurately in the free living state and may be better related to previous studies using the balance technique ; it is more precise than the other measurements ; and it avoids sampling error by measuring the entire skeleton rather than a specific region of the appendicular or axial skeleton . The rate of change in bone mineral was calculated for each woman at each of the sites used in the study . St and ard linear regression procedures were used to estimate the rate of bone mineral change for each woman , and the regression intercept was used as the best estimate of the baseline value . Because some women terminated their participation in the study before others , the rate-of-change data were weighted by the inverse variance to reflect the fit of the regression line for each woman [ 28 ] . Analyses of covariance were done using body mass index , activity scores , cigarette smoking , calcium intake , age , and years postmenopause as covariates . The data reported in this article are based on all women who provided at least three observations for a particular skeletal site . We considered other criteria , such as using data only from women who had participated in the study for at least 2 years , and all data analyses were done for this subgroup as well . The results of these analyses were invariably similar to those reported here and therefore are not presented separately . The mean rates of change in bone mineral for each condition at each site were characterized in terms of both raw units and percentages ; separate analyses were carried out for each . The two indices were similar . Evidence from recent research is substantial that estrogen replacement therapy is effective , whereas the efficacy of calcium supplements is question able . Our expectation was that our data would confirm the efficacy of estrogen-progesterone-calcium therapy , and the critical question was whether or not a beneficial effect of calcium supplements given alone could be shown . A separate one-way analysis of covariance was done for each of the bone mineral measurements to compare the mean rates of change in bone mineral for each of the three conditions . We used two a priori contrasts : the first contrasting women taking estrogen with those receiving calcium and the second comparing women receiving calcium supplements with those on placebo . All P values reported are two-tailed . Results Baseline data for historical data and bone mineral measurements and chemical studies are given in Table 1 . Analysis of variance showed no significant differences in the baseline variables . The initial and final activity scores did not differ significantly . Table 1 . Baseline Values for Patient Characteristics , Bone Mineral Measurements , and Chemical Variables The range of initial daily calcium intake in the overall study group was 150 to 1263 mg ; in the calcium augmentation group , it was 222 to In postmenopausal women , the use of aromatase inhibitors increases bone turnover and induces bone loss at sites rich in trabecular bone at an average rate of 1 - 3 % per year leading to an increase in fracture incidence compared to that seen during tamoxifen use . The bone loss is much more marked in young women with treatment-induced ovarian suppression followed by aromatase inhibitor therapy ( average 7 - 8 % per annum ) . Pre-treatment with tamoxifen for 2 - 5 years may reduce the clinical significance of the adverse bone effects associated with aromatase inhibitors , particularly if this leads to a shortening in the duration of exposure to an aromatase inhibitor . However , skeletal status should still be assessed at the commencement of aromatase inhibitor therapy . The rate of bone loss in women who experience a premature menopause before the age of 45 or are receiving ovarian suppression therapy is accelerated by the concomitant use of aromatase inhibitors . These patients are considered to be at high risk of clinical ly important bone loss and should have a baseline dual energy X-ray absorptiometry ( DXA ) assessment of bone mineral density ( BMD ) . R and omised clinical trials in postmenopausal women indicate that bisphosphonates prevent the bone loss and accelerated bone turnover associated with aromatase inhibitor therapy and are a promising strategy for the prevention and treatment of osteoporosis in this setting . Treatment initiation recommendations are based on a combination of risk factors for osteoporotic fracture and BMD levels .  Bisphosphonates , along with a healthy lifestyle and adequate intake of calcium and vitamin D are the treatments of choice to prevent bone loss . Due to the rate of bone loss associated with breast cancer treatments , and uncertainties about the interaction between aromatase inhibitor use and BMD for fracture risk , the threshold for intervention has been set at a higher level than that generally recommended for postmenopausal osteoporosis . Management recommendations have been summarised in two algorithms , one for women experiencing a premature menopause and the other for postmenopausal women requiring adjuvant aromatase inhibitor therapy PURPOSE To examine the effects on bone mineral density of 2 years of treatment with a luteinizing hormone-releasing hormone ( LHRH ) agonist alone or in combination with tamoxifen or tamoxifen alone in premenopausal breast cancer . PATIENTS AND METHODS We recruited 89 women from two centers in Stockholm participating in a r and omized multicenter trial of three different endocrine approaches in the adjuvant setting ( Zoladex in Premenopausal Patients Trial ) . The women were assigned to receive the LHRH agonist goserelin with or without tamoxifen , tamoxifen alone , or no endocrine therapy . The treatment was given for 2 years . We measured total-body bone density before start of treatment and at 12 , 24 , and 36 months . RESULTS After 2 years of treatment , there was a significant loss of bone mineral density ( mean change , -5 % ; P < .001 ) in the women receiving goserelin alone . The combined goserelin and tamoxifen treatment , as well as tamoxifen alone , result ed in a lesser but statistically significant decline in bone mineral density ( mean change , -1.4 % ; P = .02 ; and -1.5 % ; P < .001 ) . One year after cessation of treatment , the goserelin group alone showed a partial recovery from bone loss ( mean change , 1.5 % ; P = .02 ) . CONCLUSION Two years of ovarian ablation from goserelin treatment caused a significant reduction in bone mineral density but there was a partial recovery from the bone loss 1 year after cessation of treatment . The addition of tamoxifen seems to partially counteract the demineralizing effects of goserelin The present study was undertaken to determine whether the addition of an and rogen to estrogen therapy in postmenopausal women would alter the skeletal response as determined by measurements of markers of bone formation and resorption .  Postmenopausal women were treated for 9 weeks with either a combination of 1.25 mg esterified estrogen and 2.5 mg methyltestosterone ( E+A ) or 1.25 mg conjugated equine estrogen ( CEE ) . Both groups showed a similar decrease in urinary excretion of the bone resorption markers , deoxypyridinoline , pyridinoline , and hydroxyproline . Patients treated with CEE showed decreases in the serum markers of bone formation , bone-specific alkaline phosphatase , osteocalcin , and C-terminal procollagen peptide . In contrast , subjects treated with E+A showed increases in these markers of bone formation . CEE increased , and E+A decreased serum levels of sex hormone-binding globulin as well as triglycerides and high density lipoprotein levels . Only CEE significantly reduced low density lipoproteins . Both regimens were effective in reducing postmenopausal somatic symptoms , but only E+A had a significant effect on psychological symptoms . We conclude that short term administration of and rogen with estrogen may reverse the inhibitory effects of estrogen on bone formation . Long term studies are needed to determine the relative benefits and risks of the combination of estrogen and and rogen and whether this results in greater increases in bone mass and strength Bone mass was measured prospect ively in 73 women during the period immediately after menopause . By comparing the rates of loss at three skeletal sites , we assessed the protective effects of calcium supplements given alone or combined with low-dosage estrogen therapy . After 2 years of follow-up , spinal trabecular mineral content , measured by quantitative computed tomography , decreased by a mean of 9.0 % ( p = 0.002 compared with baseline ) in untreated women and a mean of 10.5 % ( p = 0.0001 ) in women given calcium supplements alone . By contrast , women given conjugated estrogens , 0.3 mg/d , with calcium supplements showed an insignificant increase of 2.3 % . Significant losses of a lesser magnitude were seen in the appendicular cortical skeleton of women not receiving therapy and in those receiving calcium alone , but no significant changes were observed in women receiving estrogen with calcium The effect of two different estrogen/gestagen regimens and 24R,25-(OH)2-cholecalciferol on bone formation was studied in a r and omized trial with 144 healthy postmenopausal women .  Urinary excretion ( UE ) of 99m-technetium-diphosphonate and serum alkaline phosphatase ( AP ) was determined before and then once a year for 2 years of treatment . Both estimates of bone formation showed highly significant decreases ( p less than .001 ) to normal premenopausal levels in women receiving unopposed 17 beta-estradiol or in a sequential combination with progestagen , whereas unchanged high values were found in the groups receiving 24R,25-(OH)2D3 and placebo . The data show that bone turnover increases in early postmenopausal women concomitantly with the loss of bone mass , and that hormonal substitutional therapy normalizes the total skeletal turnover as well as preventing bone loss Menopause impacts 25 million women world wide each year , and the World Health Organization estimates 1.2 billion women will be postmenopausal by 2030 . Menopause has been associated with symptoms of hot flashes , night sweats , dysphoric mood , sleep disturbance , and conditions of cardiovascular disease , depression , osteoporosis , osteoarthritis , depression , dementia , and frailty . Conventional hormone replacement therapy results in increased thrombotic events , and an increased risk of breast cancer and dementia as evidence d in large prospect i ve clinical trials including Heart and Estrogen/Progestin Replacement Study I and the Women 's Health Initiative . A possible mechanism for these adverse events is the unfavorable net effects of conjugated equine estrogens and medroxyprogesterone acetate on the hemostatic balance and inflammatory and immune factors . Physiologic sex steroid therapy with transdermal delivery for peri/postmenopausal women may offer a different risk/benefit profile , yet long-term studies of this treatment model are lacking . The objective of this study was to examine the long-term effects of compounded bioidentical transdermal sex steroid therapy including estriol , estradiol , progesterone , DHEA , and testosterone on cardiovascular biomarkers , hemostatic , inflammatory , immune signaling factors ; quality -of-life measures ; and health outcomes in peri/postmenopausal women within the context of a hormone restoration model of care . A prospect i ve , cohort , closed-label study received approval from the Human Subjects Committee . Recruitment from outpatient clinics at an academic medical center and the community at large result ed in three hundred women giving signed consent . Seventy-five women who met strict inclusion /exclusion criteria were enrolled .  Baseline hormone evaluation was performed along with baseline experimental measures . Following this , women received compounded transdermal bioidentical hormone therapy of BiEst ( 80%Estriol/20%Estradiol ) , and /or Progesterone for eight weeks to meet established physiologic reference ranges for the luteal phase in premenopausal women . The luteal phase hormone ratios were selected based on animal and epidemiologic studies demonstrating favorable outcomes related to traumatic , ischemic , or neuronal injury . Follow-up testing was performed at eight weeks and adjustment to hormone regimens were made including addition of and rogens of DHEA and Testosterone if indicated . Experimental subjects were monitored for 36 months . Baseline , 2-month , and annual values were obtained for : blood pressure , body mass index , fasting glucose , Homeostasis Metabolic Assessment of Insulin Resistance ( HOMA-IR ) , fasting triglycerides , total Factor VII , Factor VIII , fibrinogen , Antithrombin III , Plasminogen Activator Inhibitor1(PAL-1 ) , C-reactive protein ( CRP ) , Interleukin-6 ( IL-6 ) , Matrix Metalloproteinase-9 ( MMP-9 ) , Tumor Necrosis Factor-alpha ( TNF ) , Insulin-like Growth Factor ( IGF-1 ) , and sex steroid levels . Psychosocial measures included : Greene Climacteric Scale , Visual Analog Pain Scale , Hamilton Anxiety Scale , Hamilton Depression Scale , Holmes Rahe Stress Scale , Job Strain , and Home Strain . Health outcome measures included the number of prescribed medications used , number of co-morbidities , and endometrial thickness in postmenopausal women with intact uteri . Subjects receiving  compounded transdermal bioidentical hormone therapy showed significant favorable changes in : Greene Climacteric Scale scores , Hamilton Anxiety Scale , Hamilton Depression Scale , Visual Analog Pain Scale , fasting glucose , fasting triglycerides , MMP-9 , C-reactive Protein , fibrinogen , Factor VII , Factor VIII , Insulin-Like Growth Factor 1 , and health outcomes of co-morbidities and a number of prescribed medications . Antithrombin III levels were significantly decreased at 36 months . All other measures did not exhibit significant effects . Administration of compounded transdermal bioidentical hormone therapy in doses targeted to physiologic reference ranges administered in a daily dose significantly relieved menopausal symptoms in peri/postmenopausal women . Cardiovascular biomarkers , inflammatory factors , immune signaling factors , and health outcomes were favorably impacted , despite very high life stress , and home and work strain in study subjects . The therapy did not adversely alter the net prothrombotic potential , and there were no associated adverse events . This model of care warrants consideration as an effective and safe clinical therapy for peri/postmenopausal women especially in population s with high perceived stress and a history of stressful life events prior to , or during the menopausal transition Objective To determine the relationships among bone mineral density changes , bone marker changes , and plasma estrogens in postmenopausal women receiving estrogen replacement therapy .  Design A total of 406 postmenopausal women received 1,000 mg calcium and continuous esterified estrogens ( 0.3 mg , 0.625 mg , or 1.25 mg ) or placebo daily for up to 24 months . Bone mineral density and bone marker measurements were determined at 6-month intervals ; plasma estrogens were measured in a subset after 12 , 18 , and 24 months . Results Esterified estrogens produced significant increases in bone mineral density ( lumbar spine , hip ) compared with baseline and placebo at 6 , 12 , 18 , and 24 months . Bone markers decreased from baseline with all esterified estrogen doses relative to placebo . Bone marker changes at 6 months correlated negatively with bone mineral density changes at 24 months ( correlation coefficient range = −0.122 to −0.439 ) . The strongest correlation was noted for spine bone mineral density changes and serum osteocalcin . Mean plasma estrogen levels increased with esterified estrogen dose , and bone mineral density changes correlated positively with plasma estrogen levels . Positive bone mineral density changes were noted in treatment groups with plasma estradiol levels at and above 25 pg/mL. Conclusions Esterified estrogens , at doses from 0.3 mg to 1.25 mg/day , unopposed by progestin , increase bone mineral density of the spine and hip in postmenopausal women .  These bone mineral density changes correlated significantly with bone marker changes at 6 months and with plasma estrogens at 12 , 18 , or 24 months . Data variability minimizes the predictive value of the bone marker changes in monitoring individual therapy Objective To compare an oral estrogen- and rogen combination with estrogens alone on bone , menopausal symptoms , and lipoprotein profiles in postmenopausal women . Methods Surgically menopausal women received oral esterified estrogens ( 1.25 mg ) , or esterified estrogens ( 1.25 mg ) and methyltestosterone ( 2.5 mg ) daily , for 2 years . Bone mineral density of the lumbar spine and hip , menopausal symptoms , lipoprotein profiles , and biochemical and hematologic indices were evaluated . Results Sixty-six patients were enrolled in the study . Both treatment regimens prevented bone loss at the spine and hip ; combined estrogen- and rogen therapy was associated with a significant increase in spinal bone mineral density compared with baseline ( n = 24 ; mean score ± st and ard error 3.4 ± 1.2 % , P < .01 ) . In the estrogen group , high-density lipoprotein ( HDL ) cholesterol increased significantly and low-density lipoprotein cholesterol decreased significantly . Cholesterol , HDL cholesterol , and triglycerides decreased significantly in the estrogen- and rogen  group . Menopausal symptoms of somatic origin ( hot flashes , vaginal dryness , and insomnia ) were improved significantly by both treatments . Neither adverse hepatic effects nor significant safety or tolerance problems were reported in either group . Conclusion Oral estrogen- and rogen  increased vertebral bone mineral density compared with pre-treatment values and relieved somatic symptoms . Safety indices , including lipoprotein levels , indicated that the combination was well tolerated over the 2 years of treatment The authors further analyzed results from the Women 's Health Initiative r and omized trials ( 1993 - 2004 ) of conjugated equine estrogens , with or without medroxyprogesterone acetate , focusing on health benefits versus risks among women who initiated hormone therapy soon after menopause . Data from the Women 's Health Initiative observational study ( 1993 - 2004 ) were included in some analyses for additional precision . Results are presented here for incident coronary heart disease , stroke , venous thromboembolism , breast cancer , colorectal cancer , endometrial cancer , or hip fracture ; death from other causes ; a summary global index ; total cancer ; and total mortality . Hazard ratios for breast cancer and total cancer were comparatively higher ( P < 0.05 ) among women who initiated hormone therapy soon after menopause , for both regimens . Among these women , use of conjugated equine estrogens appeared to produce elevations in venous thromboembolism and stroke and a reduction in hip fracture .  Estrogen plus progestin results among women who initiated use soon after menopause were similar for venous thromboembolism , stroke , and hip fracture but also included evidence of longer-term elevations in breast cancer , total cancer , and the global index . These analyses provide little support for the hypothesis of favorable effects among women who initiate postmenopausal estrogen use soon after menopause , either for coronary heart disease or for health benefits versus risk indices considered Context Alendronate and conjugated estrogen therapy both increase bone mineral density in postmenopausal women , but is the rate of bone loss greater when alendronate or estrogen therapy is discontinued ? Contribution The discontinuation phase of this double-blind , placebo-controlled trial showed loss of spine and trochanter bone mass in postmenopausal women 1 year after withdrawal of estrogen and no such loss after withdrawal of either alendronate or combination therapy with alendronate and estrogen therapy . Caution s The study was not large or long enough to show whether discontinuation of estrogen therapy is associated with more fractures than discontinuation of either alendronate or combination therapy . The Editors Several antiresorptive agents have been shown to increase bone mass and reduce osteoporotic fractures ( 1 - 3 ) . Because greater improvements in bone mass in women using therapy are associated with greater reductions in fracture ( 4 , 5 ) , investigators have begun to examine combinations of antiresorptive therapies to achieve more substantial gains in bone mass . Lindsay and colleagues demonstrated that addition of alendronate to hormone replacement therapy in postmenopausal women result ed in greater increases in bone mass than did maintenance of estrogen therapy alone ( 6 ) . We previously showed that administration of alendronate and estrogen for 2 years in postmenopausal women with low bone mass result ed in statistically significantly greater increases in bone mass at the lumbar spine and femoral neck than those seen in women taking either agent alone ( 7 ) . Furthermore , combination therapy was safe and result ed in normal findings on histologic examination of bone . In clinical practice , a key concern is the potential for accelerated bone loss when antiresorptive therapy is discontinued . Approximately one third of women discontinue hormone replacement therapy within 1 year of initiation ( 8) . Older studies have demonstrated significant losses in bone mass after discontinuation of hormone replacement therapy ( 9 - 11 ) . In contrast , when therapy with oral alendronate , 10 mg/d , is discontinued after osteoporosis treatment , bone mass at the hip and spine are maintained for 1 year ( 12 ) . However , no head-to-head comparison of hormone replacement therapy and alendronate or the combination of antiresorptive therapy after discontinuation has been done . In addition , future losses in bone mass when patients discontinue therapy must be considered in management of osteoporosis in postmenopausal women . We therefore sought to examine the rate of bone loss after discontinuation of 2 years of alendronate therapy , hormone replacement therapy , or combination therapy . A subset of participants continued to take combination therapy for a third year to determine whether prolonged therapy remained beneficial . Methods Study Participants Four hundred twenty-five postmenopausal women 42 to 82 years of age who had low bone mass were enrolled in a 2-year r and omized , double-blind , placebo-controlled clinical trial conducted at 18 centers in the United States ( 7 ) . Participants were recruited from clinics , private practice s , newspaper advertisements , and targeted mailings . All participants who completed the initial study were asked to enroll in the 1-year extension . Participants were told that if they were taking active treatment , they might be r and omly allocated to receive placebo or treatment for the third year and that if they were taking placebo , they would continue to do so . Entry criteria for the initial study are described elsewhere ( 7 ) . All women had had hysterectomy and had a bone mineral density at the lumbar spine that was less than or equal to a T score of 2.0 SDs below the peak bone mass in young adults . Data on presence or absence of ovaries were not collected . Exclusion criteria were metabolic bone disease , a low serum 25-hydroxyvitamin D level , use of medications known to affect bone turnover , renal insufficiency , severe cardiac disease , and recent major upper gastrointestinal disease . The institutional review board at each clinical site approved the extension protocol . After signing the extension consent form and undergoing baseline evaluation for the extension , participants were allocated to blinded treatment on the basis of their original treatment in the first 2 years of the study . The r and omization process was central ly determined by a statistician ; as in the initial study , treatment allocation was concealed . Design As described for the initial study at each center , patients were r and omly allocated to one of four treatment groups : placebo ( n = 50 ) ; alendronate , 10 mg/d ( n = 92 ) ; conjugated estrogen , 0.625 mg/d ( n = 143 ) ; or alendronate , 10 mg/d , plus conjugated estrogen , 0.625 mg/d ( n = 140 ) ( Figure 1 ) . The conjugated estrogen used was Premarin ( Wyeth-Ayerst , Philadelphia , Pennsylvania ) . All women received calcium carbonate to provide 500 mg of elemental calcium daily . Figure 1 . Design of original 2-year study and reallocation to extension phase for year 3 . At the end of the second year , 244 of the 425 women ( 57 % ) continued in a 1-year extension of the study ( Figure 1 ) . Of these women , 28 who previously received placebo continued to do so . Women who were taking combination therapy  were reallocated to continue taking combination therapy ( n = 44 ) or switch to placebo ( n = 41 ) . In addition , 50 participants taking alendronate alone and 81 participants taking conjugated estrogen alone for the first 2 years were assigned to placebo for the third year . All patients and investigators remained blinded to medication allocation . Patients continued to receive calcium supplementation during the third year . Outcome Measures Women were examined at month 24 ( baseline of the 1-year extension ) , month 30 , and month 36 . Bone mineral density of the lumbar spine , hip ( femoral neck , trochanter , total hip ) , and total body were assessed by using dual-energy x-ray absorptiometry with QDR-1000W , QDR-1500 , or QDR-2000 series bone densitometers ( Hologic , Inc. , Bedford , Massachusetts ) . A st and ard phantom was used for cross-calibration at all sites . Serum and urine sample s were also obtained at months 24 , 30 , and 36 for assessment of biochemical markers of bone turnover , namely bone-specific alkaline phosphatase and urinary N-telopeptide cross-links of collagen type I , corrected for creatinine . Statistical Analysis We used SAS software , version 6.12 , TSLevel 0060 , PROCedureGLM ( SAS Institute , Inc. , Cary , North Carolina ) to analyze the data . The primary efficacy end point was the mean difference between groups in the percentage change in bone mineral density at the lumbar spine from month 24 to month 36 . Secondary efficacy end points were the mean percentage changes in bone mineral density of the hip and total body and biochemical markers of bone turnover . Overall percentage changes from month 0 to 36 in spine , hip , and total-body bone mineral density were also analyzed . The prespecified analysis was based on an intention-to-treat approach . At study design , we prespecified that all patients who had a baseline measurement and at least one measurement during treatment would be included in the analysis according to the group to which they were r and omly allocated . The missing data were approximated by carrying forward the last available value on treatment forward to the missing time point . No data from the original 2-year study were carried forward to the extension period for any assessment of change . Women who violated the protocol were excluded from analysis of biochemical markers , as previously reported ( 7 ) . Between-group comparisons of bone mineral density and biochemical measures were made by using analysis of variance techniques , with treatment , center , and treatment-by-center as factors . The assumption of homoscedasticity for the analysis of variance model was assessed by using the Levene test , and the normality assumption was assessed by using the ShapiroWilk test ( 13 ) . If the assumptions were violated , a nonparametric method was used to corroborate the parametric results . The Fisher exact test was used to compare treatment groups for the proportion of participants who exceeded predefined limits of change in laboratory safety variables ( 13 ) . Power calculations based on estimated sample sizes of 56 and 84 participants in the alendronate/placebo and estrogen/placebo treatment groups , respectively , yielded an estimate of 92 % power to detect a 1.5 % difference between mean percentage changes from month 24 to month 36 in bone mineral density at the lumbar spine ( = 0.05 , two-tailed test ) . As requested by the journal editors , data on bone mineral density were also analyzed by using a mixed-model analysis , and results of this analysis are presented . An appropriate curvilinear function was fitted to the actual data , and the function was estimated by using all data available across time points for each participant . A model that regressed bone mineral density versus log ( month + 1 ) provided the appropriate fit for the 3-year data and was used to analyze these data . The variable log ( month + 1 ) was used because log ( month ) is undefined when month is 0 , and log ( month + 1 ) yields the value 0 at baseline . The fitted values from the model were used to obtain the percentage change during the period of interest . Data on bone mineral density from the mixed-model analyses are presented unless otherwise specified . Role of the Funding Source Data were collected by investigators at each study site with the support of Merck Research Laboratories , Rahway , New Jersey . Analyses were performed by statisticians at Merck & Co. , Inc. Data were interpreted by the authors , who su bmi tted the manuscript for publication . Results Patient Characteristics and Retention Baseline r and omization characteristics did not differ between participants who entered the extension phase and those who did not . Baseline demographic characteristics of the 244 women who entered the extension phase were Objective To study the effect on mammographic breast density of testosterone addition during combined estrogen/progestogen therapy in postmenopausal women . Methods A prospect i ve , r and omized , double-blind , placebo-controlled trial . A total of 99 women were given 2 mg 17β-estradiol and 1 mg norethisterone acetate in combination with either a testosterone patch ( 300 μg/24 h ) or a placebo patch . Mammographic breast density at baseline and after 6 months was assessed by visual classification scales and by digitized quantification . A st and ardized question naire was used to quantify subjective breast symptoms . Results Visual classifications showed an increase in mammographic density in 18–30 % of the women , with no significant differences between the treatment groups . The mean increase of the area of dense breast during treatment according to digitized assessment was 7.4 % in the placebo group and 5.4 % in the testosterone group . Breast symptoms showed a positive association with the increase in density ( rs = 0.34 ; p < 0.01 ) . Symptoms were most pronounced at 2 months of treatment . Density , both at baseline ( rs = −0.35 ; p < 0.01 ) and change during treatment ( rs = −0.28 ; p < 0.01 ) showed a negative association with free testosterone levels . Conclusion The addition of testosterone does not appear to influence mammographic breast density in women concurrently treated with a common oral estrogen/progestogen regimen for a period of 6 months BACKGROUND High mammographic density is associated with increased breast cancer risk . Previous studies have shown that estrogens increase breast density on mammograms , but the effect on mammographic density of selective estrogen receptor modulators , such as raloxifene , is unknown . We assessed changes in mammographic density among women receiving placebo , raloxifene , or conjugated equine estrogens in an osteoporosis prevention trial . METHODS In a 5-year multicenter , double-blind , r and omized , placebo-controlled osteoporosis prevention trial , healthy postmenopausal women who had undergone hysterectomy less than 15 years before the study and had no history of breast cancer received placebo , raloxifene ( at one of two doses ) , or conjugated estrogens ( ERT ) .  Women from English-speaking investigative sites who had baseline and 2-year craniocaudal mammograms with comparable positioning ( n = 168 ) were eligible for this analysis . Changes in mammographic density were determined by digital scanning and computer-assisted segmentation of mammograms and were analyzed with the use of analysis of variance . All statistical tests were two-sided . RESULTS Among the four treatment groups after 2 years on study , the mean breast density ( craniocaudal view ) was statistically significantly greater in the ERT group than it was in the other three groups ( P<0.01 for all three comparisons ) . Within treatment groups , the mean breast density from baseline to 2 years decreased statistically significantly in women receiving the placebo or either the higher or lower raloxifene dose ( P = 0.003 , P = 0.002 , and P<0.001 , respectively ) and showed a nonstatistically significant increase in women receiving ERT . CONCLUSIONS In an osteoporosis prevention trial , raloxifene did not increase breast density after 2 years of treatment . Raloxifene administration should not interfere with , and could even enhance , mammographic detection of new breast cancers
Results of systematic review s and meta-analyses of r and omized controlled trials have shown that both systemic estrogen therapy or hormone therapy ( estrogen combined with a progestin ) are useful to prevent bone loss , and they are the most effective treatment for such climacteric symptoms as hot flushes , sweating , vaginal dryness , and dyspareunia .
The combination of a SERM with estrogen as a tissue selective estrogen complex ( TSEC ) is a new strategy for the prevention of bone loss and the treatment of climacteric symptoms .
This combination is particularly interesting from a clinical point of view , taking into account that estrogen alone did not increase breast cancer risk by the Women 's Health Initiative .
TSEC is hypothesized to provide the benefits of estrogen-alone therapy , with an improved tolerability profile because the SERM component can make possible the elimination of progestin .
The conclusion is that effectively , the combination of bazedoxifene and conjugated estrogens may be a promising alternative to hormone therapy for the prevention of osteoporosis and the treatment of postmenopausal symptoms in non-hysterectomized postmenopausal women
Decreasing levels of estrogens during menopause are associated with reduced bone density and an increased risk of osteoporosis .
Many women also experience bothersome vasomotor and vaginal symptoms during the menopausal transition .
Unfortunately , estrogen therapy and hormone therapy increase the risk of endometrial and breast cancer , respectively .
The selective estrogen receptor modulators ( SERMs ) result in positive estrogenic effects on bone , with no negative effects on the endometrium and breast but do not provide relief from postmenopausal symptoms .
The objective of this review was to critically evaluate the evidence from the reports published to date on the use of bazedoxifene ( a third-generation SERM ) in combination with conjugated estrogens in postmenopausal women .