Background Estrogen therapy prevents bone loss in postmenopausalwomen who take it early in the postmenopausal period. The riskof fracture is highest much later in life, however. We studiedwhether bone mass in elderly women was affected by earlier estrogenuse and how long women needed to take estrogen for it to havea beneficial effect on bone density later in life.
Methods In 1988 and 1989, we measured bone mineral density atthe femur, spine, shaft of the radius, and ultradistal radiusin 670 white women in the Framingham Study cohort (mean age,76 years; range, 68 to 96). These women had been followed prospectivelythrough menopause and had been asked repeatedly about estrogentherapy. After excluding women who began taking estrogen aftera fracture, we investigated whether postmenopausal estrogentherapy affected bone density; in these analyses we adjustedfor age, weight, height, cigarette smoking, physical activity,and age at menopause.
Results A total of 212 women (31.6 percent) had received estrogentherapy (mean estimated duration of treatment, 5 years). Onlywomen who had taken estrogen for 7 to 9 years or for 10 or moreyears had significantly higher bone mineral density than womenwho had not taken estrogen (7 to 9 years of treatment, P<0.05at sites in the femur and the spine; 10 years, P<0.05 atall sites except the spine).
In the women less than 75 years of age who had taken estrogenfor seven or more years, the bone density was, averaging allsites, 11.2 percent greater than in women who had never receivedestrogen. Among women 75 years of age and older in whom theduration of therapy was comparable, bone density was only 3.2percent higher than in women who had never taken estrogen.
Conclusions For long-term preservation of bone mineral density,women should take estrogen for at least seven years after menopause.Even this duration of therapy may have little residual effecton bone density among women 75 years of age and older, who havethe highest risk of fracture.
Estrogen therapy is most often received by women soon afterthe menopause, and the prevalence of use declines as women reachtheir 60s. On the other hand, the incidence of fractures relatedto bone fragility increases with age. The rate of hip fracture,for example, doubles with each 10-year increase in age1,2. Themedian age at hip fracture among women is either late in theeighth decade2,3 or in the ninth decade1 of life, and ratesof mortality after hip fracture are highest among elderly women4,5.The incidence of vertebral fractures6 and fractures of the proximalhumerus7 also increases with age.
Estrogen therapy begun soon after the menopause slows or evenreverses the loss of bone that occurs normally during thoseyears8,9. The long-term effect of postmenopausal estrogen therapyon bone density, however, is not known. Epidemiologic studies10,11,12have reported that postmenopausal estrogen therapy protectswomen against later hip fracture, suggesting a residual effectof estrogen on bone density, but there are few data on the effectsof early postmenopausal estrogen therapy on bone density inelderly women.
How long should women take estrogen to obtain a prolonged effecton bone density? Although five years of estrogen therapy hasbeen suggested, on the basis of epidemiologic studies of estrogentherapy and hip fracture in which women who had taken estrogenfor different periods of time were grouped together,11,12,13there are insufficient data to support this recommendation8.Women considering estrogen therapy and their physicians maywish to know the minimal duration of therapy necessary to achievea prolonged effect on bone density.
The long-term effect of estrogen on bone may be modified byother factors. Age, independent of estrogen loss, may contributeto bone loss in elderly women14; estrogen therapy may becomeincreasingly irrelevant as women approach the age at which therisk of fracture is highest. Other factors such as smoking15,16,17,18may affect the benefit conferred by long-term estrogen therapy.
In previous studies of women in Framingham, Massachusetts,10we documented that estrogen therapy protected women againsthip fracture. In this study, we examined whether postmenopausalestrogen therapy affected bone density in elderly women in thesame cohort.
Methods
The Framingham Study began in 1948 with the primary goal ofevaluating risk factors for heart disease. The participantshave been examined every two years since that time, and by 1988,over half the original cohort had died. The Framingham OsteoporosisStudy, a component of the biennial examination performed in1988 and 1989, involved 1164 surviving subjects (448 men and716 women), all of whom were white.
Bone-Mineral-Density Measurements
The bone mineral density of the lumbar spine, femur (neck, trochanter,and Ward's triangle), shaft of the radius, and ultradistal radiuswere measured during the 20th biennial examination in 1988 or1989. The bone density of the lumbar spine (L2 through L4) andfemur was measured by dual-photon absorptiometry (LUNAR DP3)and the bone density of the shaft of the radius and the ultradistalradius by single-photon absorptiometry (LUNAR SP2). The densityof the shaft of the radius was measured at the junction of theproximal two thirds and the distal one third of the radius,and the density of the ultradistal radius near the wrist wherethe radius and ulna meet. The coefficients of variation forthese measurements in young normal subjects ranged from 2.6percent at the femoral neck to 5.7 percent at the ultradistalradius19.
Estrogen Therapy
From the 7th biennial examination (performed in 1960 through1963) through the 16th examination (1979 through 1981), allwomen were asked about hormone use since the previous examination.Starting with the 17th examination (1981 through 1983), thewomen were asked specifically about estrogen therapy. We characterizedtherapy received for less than one year as one year of therapyand therapy for one year or more as two years of therapy. Menopausewas defined as occurring one year after the last menstrual periodor at the time of ovariectomy. Total estrogen therapy includedthe two years before menopause because symptoms of estrogendeficiency leading to the initiation of estrogen therapy maybegin at that time. Restricting the analyses to therapy receivedafter menopause did not alter the results.
To confirm that hormone use referred to estrogen therapy, toverify the women's reports that they were taking estrogen, toverify that at least one year of therapy usually reflected twoyears of therapy, and to identify women who started estrogentherapy after being given a diagnosis of osteoporosis, we reviewedthe charts of all the women in the cohort who were identifiedby computer as having taken estrogen for three or more years.These reviews led to the exclusion of three women in whom hormoneuse was identified as corticosteroid therapy. Almost all estrogentherapy was confirmed by the appearance of the medication namein the medical records. If the name of the medication was notrecorded, we accepted an appropriate time of therapy (for example,therapy for several years just after menopause), an appropriateindication (such as hot flashes), or the report of estrogentherapy at the 17th examination or later as evidence that thewomen had taken estrogen. All women who took estrogen for atleast five years had at least one examination during which itwas noted that they had had two years of therapy. All thosewho had taken estrogen for at least seven years had at leasttwo examinations during which two years of therapy were noted,and most had taken it continuously.
With respect to the type and dose of estrogen, almost all womentook oral conjugated estrogens at a dose of 0.625 mg or moredaily, without concomitant progestin therapy.
Other Variables
Other variables that affect bone density were also assessed.They included age, weight at the 20th examination, and heightat the first examination. Age at menopause was ascertained prospectively,and it was documented by a review of the operative notes inthe cases of women who had undergone ovariectomy. Cigarettesmoking was measured as the mean number of cigarettes smokedper day after menopause. Habitual physical activity was assessedwith use of the Framingham Physical Activity Index20 at the4th and 12th examinations, and the results were averaged.
Statistical Analysis
We used multiple regression analysis to assess the effect ofestrogen therapy on bone mineral density at different sites,adjusting for confounding factors including age (modeled asa quadratic function), age at menopause, weight, height, andcigarette smoking. Physical-activity assessments were missingfor some women, so that analyses reported here did not includethis variable; analyses including this variable did not changethe estimates of the effect of estrogen on bone. The least-squaresmeans from these linear models and their 95 percent confidenceintervals were used to measure the association between estrogentherapy and bone mineral density. These least-squares means,calculated with the PROC GLM program in SAS software, representthe mean bone mineral density for each estrogen-exposure group,assuming mean values for all other covariates (weight, height,and so on). All P values are two-tailed.
We tested the length of time since estrogen therapy was discontinuedas an independent factor predicting bone density at all sites.The analyses were limited by the strong inverse correlation(r = -0.60) between the duration of estrogen therapy and theyears since therapy was discontinued. Therefore, we analyzedthe time since therapy was discontinued as an independent variablein equations in which bone mineral density was the dependentvariable and other independent variables (such as age) wereincluded, but without terms for the duration of estrogen therapy.For the women who had taken estrogen for at least seven years,among whom the length of time since the discontinuation of therapywas more weakly correlated with the duration of therapy (r =-0.36), we carried out regression analyses including the durationof estrogen therapy.
To test whether age or other factors (such as smoking) affecteda woman's response to estrogen, we added interaction terms tothe regression models. In addition, we assessed the effect ofperimenopausal and postmenopausal estrogen therapy in womenabove and below the age of 75 years, the median age of the studysubjects at the 20th examination.
We reviewed the records of women who had clinically recognizedfractures of the forearm, humerus, pelvis, hip, and vertebralbodies to determine whether estrogen therapy was begun afterthe fracture, suggesting preexisting osteoporosis. We also identifiedwomen with a diagnosis of osteoporosis by chart reviews. Weexcluded from the analyses women in whom fractures or a diagnosisof osteoporosis preceded estrogen therapy.
Results
Of the 684 women in whom bone mineral density was measured andfor whom information about estrogen therapy was available, 14had fractures or had been given a diagnosis of osteoporosisat one of the two examinations before they began estrogen therapyand were therefore excluded. The mean age of the remaining 670women was 76 years (range, 68 to 96). The 212 women (31.6 percent)who had been treated with estrogen were younger than the restof the group and, since many started estrogen therapy aftersurgical menopause, they had a younger average age at menopause(Table 1). The mean duration of therapy was five years.
Table 1. Characteristics of the Women According to the Duration of Estrogen Therapy.
Bone Mineral Density and Duration of Estrogen Therapy
The density of the shaft of the radius and the ultradistal radiusincreased with an increasing duration of estrogen therapy andwas significantly higher among women who had taken estrogenfor at least 10 years than among those who had never taken estrogen(Figure 1). The women who had taken estrogen for 7 to 9 yearsor 10 or more years generally had higher values for femoralbone density than the untreated women (Figure 2). The resultswere similar for the spine (Figure 3), where the bone mineraldensity was significantly increased only among women who hadtaken estrogen for seven to nine years.
Figure 1. Bone Mineral Density in the Radius, According to the Duration of Estrogen Therapy in Postmenopausal Women in the Framingham Study.
The results, shown in grams per square centimeter, have been adjusted for age, age at menopause, weight, height, and cigarette smoking. The number of women in each group is shown within each bar. These numbers do not total 670 because bone assessments were not obtained at all sites in some women. The asterisks indicate P<0.05 for the comparison with women not treated with estrogen. The I bars show the 95 percent confidence intervals.
Figure 2. Bone Mineral Density at the Proximal Femur, According to the Duration of Estrogen Therapy in Postmenopausal Women in the Framingham Study.
The results, shown in grams per square centimeter, have been adjusted for age, age at menopause, weight, height, and cigarette smoking. The number of women in each group is shown within each bar. These numbers do not total 670 because bone assessments were not obtained at all sites in some women. The asterisks indicate P<0.05 for the comparison with women not treated with estrogen. The I bars show the 95 percent confidence intervals.
Figure 3. Bone Mineral Density in the Lumbar Spine, According to the Duration of Estrogen Therapy in Postmenopausal Women in the Framingham Study.
The results, shown in grams per square centimeter, have been adjusted for age, age at menopause, weight, height, and cigarette smoking. The number of women in each group is shown within each bar. These numbers do not total 670 because bone assessments were not obtained at all sites in some women. The asterisk indicates P<0.05 for the comparison with women not treated with estrogen. The I bars show the 95 percent confidence intervals.
Among the women treated for three to four years, the mean bonemineral density was similar to that of untreated women at everysite. Among the women treated for five to six years, the meanbone density was marginally, but not significantly, higher atmost sites (Figure 1, 2, and 3).
More than two thirds of the women who had taken estrogen (67.5percent) had not been treated long enough (at least seven years)to have long-term preservation of bone density. Of the entirecohort, only 69 women (10.3 percent) had been treated for atleast seven years.
Bone Mineral Density and Age
Among the women less than 75 years old, the 45 who had takenestrogen for at least 7 years (mean [±SD], 11 ±3)had significantly higher bone mineral density than the 209 womenwho had never taken estrogen, after adjustment for age, weight,and other factors that might affect bone mineral density (Table 2).The bone-mineral-density values among women with seven ormore years of treatment were higher at every site; the meanbone-density values were 7.6 to 18.8 percent higher than inthe never-treated women.
Table 2. Adjusted Bone Mineral Density in Postmenopausal Women, According to the Presence or Absence and Duration of Estrogen Therapy.
Among women 75 years of age or older, the differences in bonedensity between the 24 women who had taken estrogen for at least7 years (mean, 11 ±3) and the 249 women who had nevertaken estrogen ranged from 0.1 percent to 8.5 percent (Table 2).The only site at which the former group had significantlyhigher bone mineral density was the shaft of the radius. Theresults were similar when the 16 women who had taken estrogenfor at least 10 years were compared with those who were nevertreated. Most women in the cohort had begun estrogen therapyaround the time of menopause, and even those who had taken estrogenfor 10 years had often ceased therapy by the time they were60 to 65 years old. Thus, of the 24 women 75 years old or olderwho had taken estrogen for at least 7 years, only 2 had beguntherapy at 60 years of age or later and only 3 were still takingestrogen when their bone density was measured. The majorityof these women had discontinued estrogen therapy many yearsbefore the bone assessment. In regression analyses evaluatingall women, the statistical significance (or near-significance)of age-estrogen interaction terms corroborated the differenteffect of estrogen depending on a woman's age, as follows: ultradistalradius (P = 0.02), trochanter (P = 0.04), and femoral neck (P= 0.07).
Among women less than 75 years old, the bone mineral densitywas positively correlated with the duration of estrogen therapy.Considering the mean values at all sites, the mean bone densitywas 5.3 percent higher among the women treated for five to sixyears than among the women who had never taken estrogen. Thecomparable values for the women treated for 7 to 9 years andthe women treated for 10 or more years were 8.0 percent and13.4 percent, respectively. Among the women 75 years old andolder, the effect of prolonged therapy was slight. As comparedwith the women who were never treated, the mean bone densityamong the women treated for 5 to 6 years was 3.8 percent higher,that among the women treated for 7 to 9 years was 8.0 percenthigher, and that among women treated for 10 years or more was2.7 percent higher. Among the women who received estrogen forat least 7 years, therapy was discontinued 10 ±4 yearsbefore this study began in the women less than 75 years oldand 12 ±6 years before the study began in those 75 yearsold or older (P = 0.04). After adjustment for variables affectingbone density, the length of time since the discontinuation oftherapy was not an independent predictor of bone density atany site either among all women or among those treated for atleast seven years. Nonetheless, among the women who had takenestrogen for at least 10 years, those in the highest third ofthe group in terms of the time since therapy was discontinued( 14 years) had a lower average bone density than the womenin the lowest third, a group of women who had discontinued therapyless than 9 years earlier. The differences in mean bone densitybetween these groups ranged from 13.0 percent at the femoralneck to 23.0 percent at the ultradistal radius.
Effects of Smoking
Among the nonsmokers, the average difference in bone densitybetween estrogen-treated women and women who had never receivedestrogen was 9.1 to 24.5 percent, depending on the site; thewomen treated with estrogen had higher bone density at all sites.Among smokers the differences ranged from only 5.6 percent to14.3 percent, with the estrogen-treated women again having higherbone densities. Although these results suggest a weaker effectof estrogen among smokers, the interaction between smoking andestrogen was not statistically significant at any site.
Discussion
The results of this cross-sectional study of bone density inpostmenopausal women suggest that at least seven years of estrogentherapy is necessary for a persistent long-term effect on bonedensity. Only 10.3 percent of all the women we studied and only32.5 percent of those treated with estrogen actually took estrogenthis long. Thus, for many women treatment may be too short tohave a long-term effect on bone mineral density. The long-termbenefit of at least seven years of estrogen therapy extendedto the age of 75 years, but it may not persist after that age.A strength of this study is that information about estrogentherapy was obtained repeatedly and prospectively, minimizingthe likelihood of recall bias.
Nordin et al.14. have suggested that there are estrogen-dependentand age-dependent components of bone loss and that, by the ageof 70, the age-dependent component predominates. Even so, onecould theoretically prevent the estrogen-dependent componentof bone loss if women took estrogen for long enough after themenopause. In one study,13 women whose average age was 73 yearswho had taken estrogen almost continuously since menopause hadhigher bone-mineral-density values than those who were nevertreated, suggesting that the estrogen-dependent component ofbone loss may be delayed as long as estrogen is taken. Unfortunately,the effect of estrogen does not persist long after the discontinuationof therapy. Even 10 or more years of past estrogen therapy amongwomen 75 years old or older did not have a significant effecton bone density. Our findings confirm the predictions of Heaney,21who suggested that 5 or even 10 years of early postmenopausalestrogen therapy would have a trivial residual effect on bonemineral density at age 75. It is also possible that women maybe able to reverse some of their estrogen-dependent bone lossor prevent further loss by starting estrogen therapy late inlife22.
These results extend and confirm our previous findings thatestrogen therapy protects against hip fracture10. Our earlierstudy was structured differently from this one and involvedwomen whose mean age was in the lower 70s; in it we examinedthe effect of recent and past estrogen therapy on the risk ofhip fracture in the subsequent two years. We found a strongerprotective effect against hip fracture among women less than75 years of age than among those 75 or older. Other studiesthat found that estrogen therapy protects against hip fractureincluded only women 75 years of age or younger11 or women upto the age of 8012,23,24. Among women older than 75 or 80, theprotective effect of estrogen (usually taken earlier in life)is negligible25,26.
In our study, among women under the age of 75, bone densitywas higher in the women treated with estrogen. How is that likelyto affect the risk of fracture? Cummings et al.27. reportedthat the risk of hip fracture was 2.6 times higher for everydecrease of 1 SD in the density of the femoral neck and 2.7times higher for every decrease of 1 SD in the density of thetrochanter. On the basis of these results, women less than 75years old in the Framingham Study who took estrogen for 10 ormore years would have an approximate reduction of 44 percentin the risk of hip fracture at the femoral neck or of 52 percentat the trochanter. This reduction in risk is similar to thatreported in epidemiologic studies of the effect of estrogenin protecting against hip fracture. Because the precision ofthe measurements obtained by dual-photon absorptiometry in thisstudy was less than the precision of currently used machinesfor dual-energy x-ray absorptiometry, our estimate of the riskreduction is conservative.
We had difficulty distinguishing the effect of the durationof estrogen therapy from that of the number of years since therapywas discontinued, because the two were strongly inversely correlated.Although our multivariate analyses did not reveal an independenteffect on bone density of the length of time since therapy wasdiscontinued, a small number of women who had received long-termestrogen therapy but discontinued it many years earlier hadmuch lower average bone density than women who had taken estrogenrecently.
In conclusion, at least seven years of estrogen therapy aftermenopause are necessary for a long-term protective effect onbone mineral density. Even therapy of this duration may be insufficientto protect women 75 years old and older from fracture.
Supported by grants (Multipurpose Arthritis Center grant AR20613and R01AG09300) from the National Institutes of Health.
We are indebted to Ms. Gaynell Walker, Ms. Nilsa Carrasquillo,and Ms. Karen Neuhauser for their assistance and to Ms. CherlynMercier and Ms. Mimi Brodsky for the measurements of bone density.
Source Information
From the Boston University Arthritis Center, Boston (D.T.F., Y.Z., M.T.H., J.J.A.); the Departments of Medicine, Boston City Hospital and University Hospital, Boston (D.T.F.); Hebrew Rehabilitation Center for Aged, Boston (D.P.K.); and the Framingham Study, Framingham, Mass. (P.W.F.W.).
Address reprint requests to Dr. Felson at A203, Boston University School of Medicine, Arthritis Center, 80 E. Concord St., Boston, MA 02118.
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10 years, P<0.05 at all sites except the spine). 
