title: Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1-34)] in postmenopausal osteoporosis. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. Premenopausal ovariectomy-related bone loss: a randomized, double-blind, one-year trial of conjugated estrogen or medroxyprogesterone acetate. Medroxyprogesterone and conjugated oestrogen are equivalent for hot flushes: a 1-year randomized double-blind trial following premenopausal ovariectomy. Progesterone Therapy, Endothelial Function and Cardiovascular Risk Factors: A 3-Month Randomized, Placebo-Controlled Trial in Healthy Early Postmenopausal Women Effect of progestin therapy on cortical and trabecular bone: comparison with estrogen. Oestrogen replacement therapy for prevention of osteoporosis after oophorectomy. A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone (1-34)] with alendronate in postmenopausal women with osteoporosis. Prevention of postmenopausal bone loss with minimal uterine bleeding using low dose continuous estrogen/progestin therapy: a 2-year prospective study. Progesterone or progestin as menopausal ovarian hormone therapy: recent physiology-based clinical evidence Cyclic medroxyprogesterone treatment increases bone density: a controlled trial in active women with menstrual cycle disturbances. Effects of hormone therapy on bone mineral density: results from the postmenopausal estrogen/progestin interventions (PEPI) trial. The Writing Group for the PEPI. Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. Esterified estrogen therapy in postmenopausal women. Relationships of bone marker changes and plasma estradiol to BMD changes: A two-year study Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial.
abstract: Clinical data suggest concomitant therapy with bisphosphonates and parathyroid hormone ( PTH ) may blunt the anabolic effect of PTH ; rodent models suggest that infrequently administered bisphosphonates may interact differently . To evaluate the effects of combination therapy with an intravenous infusion of zoledronic acid 5 mg and daily subcutaneous recombinant human (rh)PTH(1 - 34 ) ( teriparatide ) 20 µg versus either agent alone on bone mineral density ( BMD ) and bone turnover markers , we conducted a 1-year multicenter , multinational , r and omized , partial double-blinded , controlled trial . 412 postmenopausal women with osteoporosis ( mean age 65 ± 9 years ) were r and omized to a single infusion of zoledronic acid 5 mg plus daily subcutaneous teriparatide 20 µg ( n = 137 ) , zoledronic acid alone ( n = 137 ) , or teriparatide alone ( n = 138 ) . The primary endpoint was percentage increase in lumbar spine BMD ( assessed by dual-energy X-ray absorptiometry [ DXA ] ) at 52 weeks versus baseline . Secondary endpoints included change in BMD at the spine at earlier time points and at the total hip , trochanter , and femoral neck at all time points . At week 52 , lumbar spine BMD had increased 7.5 % , 7.0 % , and 4.4 % in the combination , teriparatide , and zoledronic acid groups , respectively ( p < .001 for combination and teriparatide versus zoledronic acid ) . In the combination group , spine BMD increased more rapidly than with either agent alone ( p < .001 versus both teriparatide and zoledronic acid at 13 and 26 weeks ) . Combination therapy increased total-hip BMD more than teriparatide alone at all times ( all p < .01 ) and more than zoledronic acid at 13 weeks ( p < .05 ) , with final 52-week increments of 2.3 % , 1.1 % , and 2.2 % in the combination , teriparatide , and zoledronic acid groups , respectively . With combination  therapy , bone formation ( assessed by serum N-terminal propeptide of type I collagen [ PINP ] ) increased from 0 to 4 weeks , declined minimally from 4 to 8 weeks , and then rose throughout the trial , with levels above baseline from 6 to 12 months . Bone resorption ( assessed by serum β-C-telopeptide of type I collagen [ β-CTX ] ) was markedly reduced with combination therapy from 0 to 8 weeks ( a reduction of similar magnitude to that seen with zoledronic acid alone ) , followed by a gradual increase after week 8 , with levels remaining above baseline for the latter half of the year . Levels for both markers were significantly lower with combination therapy versus teriparatide alone ( p < .002 ) . Limitations of the study included its short duration , lack of endpoints beyond DXA-based BMD ( e.g. , quantitative computed tomography and finite-element modeling for bone strength ) , lack of teriparatide placebo , and insufficient power for fracture outcomes . We conclude that while teriparatide increases spine BMD more than zoledronic acid and zoledronic acid increases hip BMD more than teriparatide , combination therapy provides the largest , most rapid increments when both spine and hip sites are considered OBJECTIVE To report the histological findings of the endometrium of postmenopausal women who were r and omized to receive placebo , estrogen only , or one of three estrogen plus progestin ( E+P ) regimens in the Postmenopausal Estrogen/Progestin Interventions ( PEPI ) Trial . DESIGN A 3-year multicenter , r and omized , double-masked , placebo-controlled trial . PARTICIPANTS A total of 596 postmenopausal women aged 45 through 64 years without contraindication to hormone therapy . INTERVENTION Participants were r and omized and stratified in equal numbers to one of the following treatments in 28-day cycles : placebo , 0.625 mg/d of conjugated equine estrogens ( CEE ) , 0.625 mg/d of CEE plus 10 mg/d of medroxyprogesterone acetate ( MPA ) for the first 12 days , 0.625 mg/d of CEE plus 2.5 mg/d of MPA , or 0.625 mg/d of CEE plus 200 mg/d of micronized progesterone ( MP ) for the first 12 days . OUTCOME MEASURE Histology of endometrium collected at baseline , annual , or unscheduled visits by biopsy , curettage , or hysterectomy . ANALYSIS Intention to treat . RESULTS During follow-up women assigned to estrogen alone were more likely to develop simple ( cystic ) , complex ( adenomatous ) , or atypical hyperplasia than those given placebo ( 27.7 % vs 0.8 % , 22.7 % vs 0.8 % , and 11.8 % vs 0 % , respectively ) for the same types of hyperplasia ( P < .001 ) . Participants administered one of the three E+P regimens had similar rates of hyperplasia as those given placebo ( P = .16 ) . The occurrence of hyperplasia was distributed evenly across the 3 years of the trial . Women taking estrogens alone also had more unscheduled biopsies ( 66.4 % vs 8.4 % ; P < .001 ) and curettages ( 17.6 % vs 0.8 % ; P < .001 ) than women receiving placebo . The number of surgical procedures was similar for women receiving placebo and women receiving the E+P regimens ( P = .38 ) . Of the 45 women with complex ( adenomatous ) or atypical hyperplasia , study medications were discontinued in all , and the biopsy results of 34 ( 94 % ) of 36 women with hyperplasia reverted to normal with progestin therapy . The remainder had dilatation and curettage ( n = 2 ) or hysterectomy with ( n = 2 ) or without ( n = 6 ) prior medical therapy , or refused further biopsies ( n = 1 ) . One woman developed adenocarcinoma of the endometrium while receiving placebo . CONCLUSIONS At a dosage of 0.625 mg , the daily administration of CEE enhanced the development of endometrial hyperplasia . Combining CEE with cyclic or continuous MPA or cyclic MP protected the endometrium from hyperplastic changes associated with estrogen-only therapy The purpose of this study was to contrast the effects of conventional estrogen treatment with medroxyprogesterone on cancellous and cortical bone change in the first year following premenopausal ovariectomy .  This 1-year double-blind r and omized therapy trial was stratified by osteoporosis family history and performed in an academic medical center and community hospitals . Premenopausal women 45 + /- 5 years old , postovariectomy for benign diseases were provided 600 mg/day of calcium and r and omized to daily therapy with conjugated equine estrogen ( CEE , 0.6 mg ) or medroxyprogesterone ( MPA , 10 mg ) . The primary outcome variable was spinal quantitative computed tomography ( QCT ) bone density change over 1 year with additional outcomes of dual-energy X-ray absorptiometry ( DXA ) of proximal femur ( FN ) , whole body ( WB ) , and spine segment ( WBS ) and N-telopeptide , bone-specific alkaline phosphatase , and other bone marker , hormonal , and weight changes . Results in the 33 women completing the study , whose initial bone densities were normal ( QCT 133 mg/cm3 , femoral neck 0.94 g/cm2 , whole body DXA 1.13 g/cm2 ) , showed annual QCT loss during CEE therapy of -11.5 mg/cm3 ( p < 0.0007 ) and MPA bone loss of -19.7 mg/cm3 ( p < 0.0001 ) . Losses were marginally greater on MPA than CEE ( p = 0.04 ) . Extremely high postovariectomy ( 5 days ) and pretreatment resorption markers ( > 3 SD above premenopausal normal levels ) were significantly related to bone loss . Across the year , resorption decreased during CEE but increased on MPA treatment . Significant DXA bone losses were prevented by CEE treatment ( -1.4 % FN , -.4 % WB , and -1.5 % WBS , all NS ) . However , DXA bone loss was not prevented by MPA treatment ( -5 % FN , -2.8 % WB , and -6.1 % WBS , all p < 0.03 ) . Average weight gain was significant ( + 3.2 + /- 4.0 kg ) and greater on CEE than MPA ( + 4.7 vs. + 2.0 kg , p = 0.049 ) . In conclusion , CEE therapy did not prevent significant 8 % cancellous spinal bone loss in the first year following premenopausal ovariectomy , despite supplementation with 600 mg/day of calcium , good control of vasomotor symptoms , and nearly 5 kg of gain in weight . Significant DXA bone loss , however , was prevented by CEE , but not by MPA therapy . These unexpected results were statistically related to high bone resorption following ovariectomy , which CEE suppressed but MPA did not . Bone formation markers increased during MPA therapy but were unchanged during CEE therapy Oestrogen therapy is the gold st and ard treatment for hot flushes/night sweats , but it and oestrogen/progestin are not suitable for all women . MPA ( medroxyprogesterone acetate ) reduces hot flushes , but its effectiveness compared with oestrogen is unknown . In the present study , oral oestrogen [ CEE ( conjugated equine oestrogen ) ] and MPA were compared for their effects on hot flushes in a planned analysis of a secondary outcome for a 1-year r and omized double-blind parallel group controlled trial in an urban academic medical centre . Participants were healthy menstruating women prior to hysterectomy/ovariectomy for benign disease . A total of 41 women { age , 45 ( 5 ) years [ value is mean ( S.D. ) ] } were enrolled ; 38 women were included in this analysis of daily identical capsules containing CEE ( 0.6 mg/day ) or MPA ( 10 mg/day ) . Demographic variables did not differ at baseline . Daily data provided the number of night and day flushes compared by group . The vasomotor symptom day-to-day intensity change was assessed by therapy assignment . Hot flushes/night sweats were well controlled in both groups , one occurred on average every third day and every fourth night . Mean/day daytime occurrences were 0.363 and 0.187 with CEE and MPA respectively , but were not significantly different ( P=0.156 ) . Night sweats also did not differ significantly ( P=0.766 ) . Therapies were statistically equivalent ( within one event/24 h ) in the control of vasomotor symptoms . Day-to-day hot flush intensity decreased with MPA and tended to remain stable with CEE ( P<0.001 ) . In conclusion , this analysis demonstrates that MPA and CEE are equivalent and effective in the control of the number of hot flushes/night sweats immediately following premenopausal ovariectomy Background Progesterone is effective treatment for hot flushes/night sweats . The cardiovascular effects of progesterone therapy are unknown but evidence suggests that premenopausal normal estradiol with also normal progesterone levels may provide later cardiovascular protection . We compared the effects of progesterone to placebo on endothelial function , weight , blood pressure , metabolism , lipids , inflammation and coagulation . Methods and Results We conducted a r and omized , double-blind , 3-month placebo-controlled trial of progesterone ( 300 mg daily ) among 133 healthy postmenopausal women in Vancouver , Canada from 2003–2009 . Endothelial function by venous occlusion plethysmography was a planned primary outcome . Enrolled women were 1–11 y since last menstruation , not using hormones ( for > 6 months ) , non-smoking , without diabetes , hypertension , heart disease or their medications . R and omized ( 1∶1 ) women ( 55±4 years , body mass index 25±3 ) initially had normal blood pressure , fasting lipid , glucose and electrocardiogram results . Endothelial function ( % forearm blood flow above saline ) was not changed with progesterone ( 487±189 % , n = 18 ) compared with placebo ( 408±278 % , n = 16 ) ( 95 % CI diff [ −74 to 232 ] , P = 0.30 ) .  Progesterone ( n = 65 ) and placebo ( n = 47 ) groups had similar changes in systolic and diastolic blood pressure , resting heart rate , weight , body mass index , waist circumference , total cholesterol , low-density lipoprotein cholesterol and triglyceride levels . High-density lipoprotein was lower ( −0.14 mmol/L , P = 0.001 ) on progesterone compared with placebo . Fasting glucose , hs-C-reactive protein , albumin and D-dimer changes were all comparable to  placebo . Framingham General Cardiovascular Risk Profile scores were initially low and remained low with progesterone therapy and not statistically different from placebo . Conclusions Results indicate that progesterone has short-term cardiovascular safety . Endothelial function , weight , blood pressure , waist circumference , inflammation and coagulation were unchanged as were lipids except for HDL-C. The statistically significant decrease in HDL-C levels was not clinical ly important ( based on lack of Cardiovascular Risk Profile change ) . Trial Registration Clinical Trials.gov PURPOSE To determine the effect of progestin therapy on bone mineral density in postmenopausal women and to compare its effects to those of estrogen . SUBJECTS AND METHODS A prospect i ve , r and omized clinical trial was performed in 81 postmenopausal women aged 51.7 + /- 4.4 years ( mean + /- SD ) . They were assigned to one of four groups : Provera 20 mg , Premarin 0.6 mg , Premarin 0.3 mg plus Provera 10 mg , and a placebo . In addition , all women received calcium supplementation , if necessary , to a calcium intake of 1,000 mg/day . We used single- and dual-photon absorpiometry , metacarpal radiogrammetry , and computed axial tomography to measure bone mineral density in the total skeleton , spine , radius , and metacarpal . RESULTS Women receiving placebo  lost bone at all sites ( p less than 0.01 ) . The Provera-treated group showed no change in total body calcium , but there were decreases in radial density ( p less than 0.01 ) , metacarpal cortex ( p less than 0.01 ) , and spine density ( p less than 0.01 ) . The Premarin-treated group had an increase in spine density and total body density ( p less than 0.05 ) , but a decrease in radial density ( p less than 0.05 ) . The Premarin-plus-Provera group showed no change in spine density , total body calcium , or radial density but had a decrease in metacarpal cortex ( p less than 0.01 ) . CONCLUSIONS Compared to placebo , Provera reduced the rate of loss in cortical areas of the skeleton , but not in the spine , which contains more trabecular bone . In contrast , Premarin reduced the rate of loss in both cortical and trabecular areas of the skeleton . The low-dose combination of Premarin plus Provera was similar in its effect on bone to that of Premarin alone , suggesting that there may be a synergistic effect of this hormone combination on bone . Serum cholesterol levels decreased with Provera , Premarin , and the combination of both , whereas levels of serum triglycerides increased with Premarin treatment , decreased with the Provera regimen , and were unchanged with the combination therapy . Provera does not adversely affect the lipid profile The value of oestrogen therapy in the prevention of osteoporosis  after oophorectomy was assessed in 114 middle-aged women who participated in a double-blind controlled trial of mestranol in an average daily dose of 23 mug . The skeletal response to treatment was measured by a photon absorption technique . Where treatment was started within two months of operation subsequent bone mineral loss was prevented . Treatment started three years after oophorectomy caused a highly significant increase in bone mineral content . When treatment was delayed for six years mestranol failed to prevent subsequent bone mineral loss with age . These effects occurred independently of the associated humoral changes in calcium and phosphorus homoeostasis . Mestranol in this dosage appeared to be relatively safe , but it is too early to evaluate the long-term hazards of such therapy Teriparatide ( rDNA origin ) injection [ recombinant human PTH ( 1 - 34 ) ] stimulates bone formation , increases bone mineral density ( BMD ) , and restores bone architecture and integrity . In contrast , bisphosphonates reduce bone resorption and increase BMD . We compared the effects of teriparatide and alendronate sodium on BMD , nonvertebral fracture incidence , and bone turnover in 146 postmenopausal women with osteoporosis . Women were r and omized to either once-daily sc injections of teriparatide 40 micro g plus oral placebo ( n = 73 ) or oral alendronate 10 mg plus placebo injection ( n = 73 ) . Median duration of treatment was 14 months . At 3 months , teriparatide increased lumbar spine BMD significantly more than did alendronate ( P < 0.001 ) . Lumbar spine-BMD increased by 12.2 % in the teriparatide group and 5.6 % in the alendronate group ( P < 0.001 teriparatide vs. alendronate ) . Teriparatide increased femoral neck BMD and total body bone mineral significantly more than did alendronate , but BMD at the one third distal radius decreased , compared with alendronate ( P < or = 0.05 ) . Nonvertebral fracture incidence was significantly lower in the teriparatide group than in the alendronate group ( P < 0.05 ) . Both treatments were well tolerated despite transient mild asymptomatic hypercalcemia with teriparatide treatment . In conclusion , teriparatide , a bone formation agent , increased BMD at most sites and decreased nonvertebral fractures more than alendronate OBJECTIVE To re-examine the minimal effective dose of conjugated estrogen (CEE)-progestin hormone replacement on postmenopausal bone loss . DESIGN A 2-year , prospect i ve , open label , r and omized study . SETTING Department of Obstetrics and Gynecology of a university hospital . PARTICIPANTS Fifty-two postmenopausal or oophorectomized women . INTERVENTION One of the following regimens was continuously administered for 2 years : ( 1 ) CEE 0.625 mg/day , ( 2 ) CEE 0.625 mg + medroxyprogesterone ( MPA ) 2.5 mg/day , ( 3 ) CEE 0.31 mg + MPA 2.5 mg/day and ( 4 ) control . MEASUREMENTS Lumbar spine and femoral BMD by dual energy X-ray absorptiometry ( DXA ) , a monthly based incidence of bleeding , serum lipids , PTH , calcitonin . A1-p , and osteocalcin . RESULTS Of the 52 patients enrolled in this study , 49 patients completed the 1 year of therapy and 36 completed the 2- year study . The control group showed a significant decrease in lumbar BMD over the 2 years ( P < 0.05 ) . The % changes in lumbar BMD at 2 years of CEE alone , CEE 0.625 + MPA and CEE 0.31 + MPA were 8.52 % ( 95 % confidence intervals ; 4.61 approximately 12.4 % ) , 7.4 % ( 0.60 approximately 14.2 % ) and 3.20 % ( 0.61 approximately 5.84 % ) , respectively , and were significantly higher than pretreatment values . The incidence of bleeding was significantly lower in women taking CEE 0.31 mg + MPA . HDL cholesterol increased in women taking CEE 0.625 mg alone or with MPA . No significant changes in lipid profiles were seen in the control or in the group of women taking CEE 0.31 mg + MPA . CONCLUSIONS Continuous hormone replacement therapy ( HRT ) using 0.31 mg of CEE and 2.5 mg of MPA is effective in increasing lumbar BMD in postmenopausal or oophorectomized women and can be an appropriate option for women with a normal lipid profile or those women wishing to eliminate unscheduled bleeding 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 OBJECTIVE Bone loss occurs in young women who experience amenorrhea or ovulatory disturbances . The purpose of this study was to determine whether bone loss could be prevented by simulating a more normal hormonal pattern , using treatment with cyclic medroxyprogesterone , with or without calcium supplementation , in physically active women with disturbed menstruation . DESIGN This study was a 1-year r and omized , double-blind , placebo-controlled trial . Women who were stratified by menstrual cycle disturbance were r and omized into four groups . The outcome variable was the change in spinal bone density measured by dual energy techniques . SETTING A large metropolitan area . PARTICIPANTS Sixty-one healthy , normal-weight physically active premenopausal women aged 21 to 45 years who experienced amenorrhea , oligomenorrhea , anovulation , or short luteal phase cycles completed the study . INTERVENTION Therapies were cyclic medroxyprogesterone ( 10 mg/day for 10 days per month ) and calcium carbonate ( 1,000 mg/day of calcium ) in four groups : ( A ) ( n = 16 ) cyclic medroxyprogesterone plus calcium carbonate ; ( B ) ( n = 16 ) cyclic medroxyprogesterone with calcium placebo ; ( C ) ( n = 15 ) placebo medroxyprogesterone with active calcium ; or ( D ) ( n = 14 ) both medroxyprogesterone and calcium placebos . RESULTS The initial bone density ( mean = 1.12 g/cm2 ) did not differ by group ( P = 0.85 ) . The 1-year bone density change was strongly related to treatment with medroxyprogesterone ( P = 0.0001 ) and weakly to calcium ( P = 0.072 ) treatment . Bone density increased significantly ( + 1.7 % + /- 0.5 % , + /- SEM , P = 0.004 ) in the medroxyprogesterone-treated groups ( A and B ) , did not change in the calcium-treated group ( C ) ( -0.7 % + /- 0.6 % , P = 0.28 ) , and decreased on both placebos ( D ) ( -2.0 % + /- 0.6 % , P = 0.005 ) . CONCLUSIONS Cyclic medroxyprogesterone increased spinal bone density in physically active women experiencing amenorrhea or ovulatory disturbances . POTENTIAL CLINICAL SIGNIFICANCE : Amenorrhea , oligomenorrhea , anovulation , and short luteal phase cycles are common in premenopausal women and associated with  spinal bone loss occurring at a stage of life when bone density would normally be stable or increasing . This controlled trial shows a significant gain in bone in women in the cyclic medroxyprogesterone intervention group , whereas those subjects in the placebo group  lost bone .  Calcium supplementation appeared to be helpful but did not reach statistical significance . The implication s of these findings for the prevention of osteoporosis warrant further investigation OBJECTIVE To assess the effects of hormone therapy on bone mineral density ( BMD ) in the spine and hip of postmenopausal women . DESIGN A 3-year , multicenter , r and omized , double-blinded , placebo-controlled clinical trial . PARTICIPANTS A total of 875 healthy women aged 45 to 64 years recruited at 7 clinical centers . INTERVENTIONS Treatments were ( 1 ) placebo ; ( 2 ) conjugated equine estrogens ( CEE ) , 0.625 mg/d ; ( 3 ) CEE , 0.625 mg/d plus medroxyprogesterone acetate ( MPA ) , 10 mg/d for 12 d/mo ; ( 4 ) CEE , 0.625 mg/d plus MPA , 2.5 mg/d daily ; or ( 5 ) CEE , 0.625 mg/d plus micronized progesterone ( MP ) , 200 mg/d for 12 d/mo . MAIN OUTCOME MEASURES Bone mineral density at baseline , 12 months , and 36 months . RESULTS Participants assigned to the placebo group lost an average of 1.8 % of spine BMD and 1.7 % of hip BMD by the 36-month visit , while those assigned to active regimens gained BMD at both sites , ranging from 3.5 % to 5.0 % mean total increases in spinal BMD and a mean total increase of 1.7 % of BMD in the hip . Changes in BMD for women assigned to active regimens were significantly greater than those assigned to placebo . Women assigned to CEE plus continuous MPA had significantly greater increases in spinal BMD ( increase of 5 % ) than those assigned to the other 3 active regimens ( average increase , 3.8 % ) . Findings were similar among those adhering to assigned therapy , although , among adherent participants , there were no significant differences in BMD changes among the 4 active treatment groups . Older women , women with low initial BMD , and those with no previous hormone use gained significantly more bone than younger women , women with higher initial BMD , and those who had used hormones previously . CONCLUSIONS Postmenopausal women assigned to placebo demonstrated decreased BMD at the spine and hip , whereas women assigned to estrogen therapy increased BMD during a 36-month period . These findings demonstrate that estrogen replacement therapy increases BMD at clinical ly important sites CONTEXT Lower-than-commonly-prescribed doses of conjugated equine estrogens ( CEEs ) with medroxyprogesterone acetate ( MPA ) improve vasomotor symptoms and vaginal atrophy , provide acceptable bleeding and lipid profiles , and afford endometrial protection . This lower-dose therapy 's protection against loss of bone mineral density ( BMD ) associated with menopause has not been thoroughly investigated . OBJECTIVE To determine the effects of lower doses of CEEs only or CEEs-MPA on spine and hip BMD , total body bone mineral content ( BMC ) , and biochemical markers of bone turnover in postmenopausal women . DESIGN AND SETTING Two-year r and omized , double-blind , placebo-controlled sub study of the Women 's Health , Osteoporosis , Progestin , Estrogen trial , conducted at 19 US centers between August 1995 and October 2000 . PARTICIPANTS Eight hundred twenty-two healthy postmenopausal women aged 40 to 65 years who were within 4 years of their last menstrual period . INTERVENTIONS Patients were r and omly assigned to receive CEEs , 0.625 ; CEEs , 0.625 and MPA , 2.5 ; CEEs , 0.45 ; CEEs , 0.45 and MPA , 2.5 ; CEEs , 0.45 and MPA , 1.5 ; CEEs , 0.3 ; CEEs 0.3 and MPA , 1.5 ( all doses in mg/d ) ; or placebo for 2 years . All participants also received elemental calcium at 600 mg/d . MAIN OUTCOME MEASURES Changes from baseline in spine and total hip BMD , total body BMC , and biochemical markers of bone turnover ( serum osteocalcin and urinary cross-linked N-telopeptides of type I collagen ) , assessed at 6-month intervals and compared among treatment groups with a modified intention-to-treat approach . RESULTS At 24 months , women assigned to all of the active treatment groups had significant gains from baseline ( P<.001 ) in spine and hip BMD and total body BMC ( except total body BMC in the group receiving CEEs , 0.3 mg/d ) . These changes were significantly different from those in the placebo group , in which losses of bone mass in spine and total body were evident over the course of the study ( P<.001 ) . The loss in hip BMD from baseline in the placebo group was significant at 18 ( P = .02 ) but not at 24 months ( P = .06 ) . Osteocalcin and N-telopeptides of type I collagen were significantly reduced from baseline ( P<.001 ) for all active treatment groups at all time points ; no changes were found for the placebo group . For women treated with CEEs alone , the gains in spine BMD for the group taking CEEs , 0.625 mg/d , were significantly higher than those of the group taking CEEs , 0.3 mg/d ( P = .02 ) , but not the group treated with CEEs , 0.45 mg/d ( P = .48 ) . CONCLUSIONS Doses of CEEs or CEEs-MPA lower than 0.625 mg/d effectively increase BMD and BMC in early postmenopausal women CONTEXT Despite decades of use and considerable research , the role of estrogen alone in preventing chronic diseases in postmenopausal women remains uncertain . OBJECTIVE To assess the effects on major disease incidence rates of the most commonly used postmenopausal hormone therapy in the United States . DESIGN , SETTING , AND PARTICIPANTS A r and omized , double-blind , placebo-controlled disease prevention trial ( the estrogen-alone component of the Women 's Health Initiative [ WHI ] ) conducted in 40 US clinical centers beginning in 1993 . Enrolled were 10 739 postmenopausal women , aged 50 - 79 years , with prior hysterectomy , including 23 % of minority race/ethnicity . INTERVENTION Women were r and omly assigned to receive either 0.625 mg/d of conjugated equine estrogen ( CEE ) or placebo . MAIN OUTCOME MEASURES The primary outcome was coronary heart disease ( CHD ) incidence ( nonfatal myocardial infa rct ion or CHD death ) . Invasive breast cancer incidence was the primary safety outcome . A global index of risks and benefits , including these primary outcomes plus stroke , pulmonary embolism ( PE ) , colorectal cancer , hip fracture , and deaths from other causes , was used for summarizing overall effects . RESULTS In February 2004 , after review ing data through November 30 , 2003 , the National Institutes of Health ( NIH ) decided to end the intervention phase of the trial early . Estimated hazard ratios ( HRs ) ( 95 % confidence intervals [ CIs ] ) for CEE vs placebo for the major clinical outcomes available through February 29 , 2004 ( average follow-up 6.8 years ) , were : CHD , 0.91 ( 0.75 - 1.12 ) with 376 cases ; breast cancer , 0.77 ( 0.59 - 1.01 ) with 218 cases ; stroke , 1.39 ( 1.10 - 1.77 ) with 276 cases ; PE , 1.34 ( 0.87 - 2.06 ) with 85 cases ; colorectal cancer , 1.08 ( 0.75 - 1.55 ) with 119 cases ; and hip fracture , 0.61 ( 0.41 - 0.91 ) with 102 cases . Corresponding results for composite outcomes were : total cardiovascular disease , 1.12 ( 1.01 - 1.24 ) ; total cancer , 0.93 ( 0.81 - 1.07 ) ; total fractures , 0.70 ( 0.63 - 0.79 ) ; total mortality , 1.04 ( 0.88 - 1.22 ) , and the global index , 1.01 ( 0.91 - 1.12 ) . For the outcomes significantly affected by CEE , there was an absolute excess risk of 12 additional strokes per 10 000 person-years and an absolute risk reduction of 6 fewer hip fractures per 10 000 person-years . The estimated excess risk for all monitored events in the global index was a nonsignificant 2 events per 10 000 person-years . CONCLUSIONS The use of CEE increases the risk of stroke , decreases the risk of hip fracture , and does not affect CHD incidence in postmenopausal women with prior hysterectomy over an average of 6.8 years . A possible reduction in breast cancer risk requires further investigation . The burden of incident disease events was equivalent in the CEE and placebo groups , indicating no overall benefit . Thus , CEE should not be recommended for chronic disease prevention in postmenopausal women 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 CONTEXT In the Women 's Health Initiative trial of estrogen-plus-progestin therapy , women assigned to active treatment had fewer fractures . OBJECTIVE To test the hypothesis that the relative risk reduction of estrogen plus progestin on fractures differs according to risk factors for fractures . DESIGN , SETTING , AND PARTICIPANTS R and omized controlled trial ( September 1993-July 2002 ) in which 16 608 postmenopausal women aged 50 to 79 years with an intact uterus at baseline were recruited at 40 US clinical centers and followed up for an average of 5.6 years . INTERVENTION Women were r and omly assigned to receive conjugated equine estrogen , 0.625 mg/d , plus medroxyprogesterone acetate , 2.5 mg/d , in 1 tablet ( n = 8506 ) or placebo ( n = 8102 ) . MAIN OUTCOME MEASURES All confirmed osteoporotic fracture events that occurred from enrollment to discontinuation of the trial ( July 7 , 2002 ) ; bone mineral density ( BMD ) , measured in a subset of women ( n = 1024 ) at baseline and years 1 and 3 ; and a global index , developed to summarize the balance of risks and benefits to test whether the risk-benefit profile differed across tertiles of fracture risk . RESULTS Seven hundred thirty-three women ( 8.6 % ) in the estrogen-plus-progestin group and 896 women ( 11.1 % ) in the placebo group experienced a fracture ( hazard ratio [ HR ] , 0.76 ; 95 % confidence interval [ CI ] , 0.69 - 0.83 ) . The effect did not differ in women stratified by age , body mass index , smoking status , history of falls , personal and family history of fracture , total calcium intake , past use of hormone therapy , BMD , or summary fracture risk score . Total hip BMD increased 3.7 % after 3 years of treatment with estrogen plus progestin compared with 0.14 % in the placebo group ( P<.001 ) . The HR for the global index was similar across tertiles of the fracture risk scale ( lowest fracture risk tertile , HR , 1.20 ; 95 % CI , 0.93 - 1.58 ; middle tertile , HR , 1.23 ; 95 % CI , 1.04 - 1.46 ; highest tertile , HR , 1.03 ; 95 % CI , 0.88 - 1.24 ) ( P for interaction = .54 ) . CONCLUSIONS This study demonstrates that estrogen plus progestin increases BMD and reduces the risk of fracture in healthy postmenopausal women . The decreased risk of fracture attributed to estrogen plus progestin appeared to be present in all subgroups of women examined . When considering the effects of hormone therapy on other important disease outcomes in a global model , there was no net benefit , even in women considered to be at high risk of fracture
target: CONCLUSION Estrogen with an osteoblast P4R-acting progestin ( EPT ) in these five published RCT provides Level 1 evidence that MPA caused significantly greater annual percent spinal BMD gains than the same dose of ET .
background: OBJECTIVE To assess whether progesterone ( P4 ) or osteoblast P4 receptor-acting progestin ( P ) contributed to estrogen ( E ) therapy-related  increased areal bone mineral density ( BMD ) in r and omized controlled trials ( RCT ) with direct r and omization to estrogen ( ET ) or estrogen-progestin ( EPT ) therapy .