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Endocrine Care |
Department of Epidemiology (J.A.C., J.M.Z.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261; Department of Internal Medicine and Epidemiology (K.E.E.), University of Minnesota, Minneapolis, Minnesota 55417; Department of Epidemiology and Biostatistics (D.C.B.), University of California, San Francisco, San Francisco, California 94105; and Kaiser Permanente Medical Care Program (B.E.), Oakland, California 15261
Address all correspondence and requests for reprints to: Jane A. Cauley, Ph.D., University of Pittsburgh, Department of Epidemiology, Pittsburgh, Pennsylvania 15261.
Abstract
To determine whether estrogen initiated at age 60 yr or later reduces rates of bone loss and fracture incidence, we performed a prospective cohort study of 6910 nonosteoporotic women, 65 yr of age or older. Estrogen use, medical history, lifestyle, and anthropometric data were obtained by questionnaire, interview and examination. We identified five patterns of estrogen use: never users (67%); past early users (started under age 60 yr with no current use; 23%); past late users (started at age 60 or later with no current use; 2%); current early users (started under age 60 yr with use both at baseline and 6 yr later; 6.7%); and current late users (started at age 60 or later with use at baseline and 6 yr later; 1.5%). Bone mineral density was measured at the total hip twice, an average of 3.5 yr apart, and at the calcaneus, an average of 5.7 yr apart. Incident nonspine fractures were validated by radiographic report. Bone mineral density was significantly higher among current users, compared with never and past users. The annual rate of hip bone loss was significantly lower in current early users (-0.22%/yr) and current late users (-0.35%/yr) in comparison with never users (-0.6%/yr), past early users (-0.6%/yr), and past late users (-0.72%/yr). During an average of 11.0 yr of follow-up, 1953 nonspine fractures were confirmed. The multiple-adjusted relative risk of nonspine fracture was 0.63 (95% confidence interval 0.51–0.78) among current early users and 0.75 (0.50–1.12) among current late users, compared with never users. Early initiation and long-term continuation of estrogen is associated with a reduction in the risk of nonspine fractures, and initiation at or after age 60 yr with long-term continuation may also be associated with a reduced fracture risk.
OBSERVATIONAL STUDIES HAVE reported lower fracture rates in postmenopausal women who take estrogen than in women not receiving this therapy (1, 2, 3, 4, 5). Addition of a progestin has little effect on the observed fracture benefit (1). Previous analyses from the Study of Osteoporotic Fractures suggested that for optimal prevention of fractures, estrogen therapy should be initiated within 5 yr of menopause, even among women who had used estrogen for more than 10 yr (1). These data imply that women need to continue their estrogen initiated soon after menopause for their remaining lifetime to prevent osteoporosis, raising a concern about breast cancer and other risks associated with extended use of estrogen (6).
Schneider et al. (7) subsequently reported that women who initiated estrogen after age 60 yr and continued had similar bone mineral density (BMD) as women who started their estrogen before age 60. In addition, despite accelerated rates of bone loss among women over age 80 yr, elderly women taking estrogen experienced significantly slower rates of bone loss than women not on estrogen (8).
These results raise the possibility that women could delay initiation of estrogen for prevention of osteoporotic fractures. However, before such a recommendation can be made, information is needed on whether delaying initiation of estrogen will influence the risk of fractures. In the current report, we expanded our initial analyses of the Study of Osteoporotic Fractures (SOF) cohort to include an additional 6.5 yr of follow-up to test the hypothesis that estrogen initiated at age 60 yr or later will result in a reduced risk of fractures.
Materials and Methods
Subjects
All women were participants in the SOF, a prospective study of 9704 community-dwelling white women who were at least 65 yr of age. Women were recruited for SOF between 1986 and 1988 from population-based listings, such as voter registration lists, at four clinical centers in the United States: Baltimore, MD; Minneapolis, MN; Mon Valley, PA; and Portland, OR (9). Women were excluded from the study if they reported a bilateral hip replacement or were unable to walk unassisted. African-American women were excluded because of their low risk of hip fracture. The institutional review boards at each institution approved the study. All women provided written informed consent at entry into the study and at each clinical examination.
Because this report focused on prevention of fractures, we excluded 1907 women who reported a history of physician-diagnosed osteoporosis or spine fracture at baseline and 175 women who had missing information on their history of osteoporosis. We excluded women who reported estrogen use more than 2 yr before the onset of menopause and women with missing information on age at menopause or estrogen use at baseline or at the follow-up visit. Because of accelerated bone loss after discontinuation of estrogen (10), we excluded 189 women who reported estrogen use at baseline but had discontinued use by the follow-up examination. Thus, the current analysis is based on 6910 women enrolled in the SOF cohort.
Estrogen/Progestin
Information on estrogen and progestin use was obtained during a clinic interview at baseline and 6 yr later. Participants were asked to bring all medications to the clinic for verification of use, preparation, and dosage. Information was collected about oral and parenteral (skin patches, injections, vaginal creams, and suppositories) and oral progestins. Our analyses are limited to oral preparations. Data were collected on age at initiation of use of hormone preparations and on whether a participant had used such preparations for the entire time period and, if not, when she had stopped. Duration of use was calculated by adding up the total number of years that a woman had used estrogen. Estrogen users included women who reported combination estrogen and progestin use.
We identified five patterns of estrogen use, adapted from the Rancho-Bernardo study (7). These five patterns of use included: never users; past early users (women who initiated estrogen use before age 60 yr but discontinued its use before baseline); past late users (women who initiated estrogen use at age 60 yr or greater but discontinued its use before baseline); current early users (women who initiated use before age 60 yr and were taking estrogen at both baseline and 6 yr later); current late users (women who initiated estrogen use at age 60 yr or greater and were taking estrogen at both baseline and 6 yr later).
BMD
Distal and proximal radial and calcaneal BMD was measured using single-photon absorptiometry using the Osteon Osteoanalyzer (Dove Medical Group, Los Angeles, CA). The measurement of calcaneal BMD was repeated an average of 5.7 yr later using single x-ray absorptiometry. Lumbar spine and total hip BMD (and subregions) were measured by dual-energy x-ray absorptiometry using the QDR 1000 (Hologic, Inc., Bedford, MA). The measurement of total hip subregion BMD was repeated an average of 3.5 yr later. Details of these methods and quality control procedures have been reported elsewhere (8, 11). Bone loss is expressed as an annualized percentage change in BMD.
Other measurements
Body weight was measured (after removal of shoes and heavy outer clothing) using a balance beam scale. Height was measured without shoes using a Harpenden stadiometer (Holtain Ltd., Dyved, UK). Height and weight were used to calculate the body mass index (BMI, kg/m2). Radial pulse rate was measured in the supine position after 5 min of rest. Reported health status, reproductive history, alcohol consumption, and physical activity were assessed by questionnaire that was reviewed with the participant by a trained interviewer. The measure of alcohol consumption was expressed as drinks per week adjusted for atypical drinking, especially heavy drinking during the previous 30 d. Dietary calcium intake was assessed by a food frequency questionnaire and by interview using standardized food models to estimate portion sizes (12). Total calcium intake included dietary and supplemental calcium. Women were asked whether they walk for exercise. Women were also asked about whether they were currently taking thiazide diuretics, thyroid hormones, or corticosteroids.
Ascertainment of fractures
Details of our method for identifying fractures have been published (13). Briefly, we contact participants every 4 months by postcard or telephone to ask whether they had sustained a fracture. More than 95% of these contracts were completed. All fractures are confirmed by radiographic report or by x-ray (hip fracture). We excluded fractures that occurred because of major trauma such as motor vehicle fractures as well as face and skull fractures. Most vertebral fractures do not come to medical attention. These fractures must be discovered by systematically obtaining radiographs from all participants and by comparing them with previous radiographs. Hence, self-reported vertebral fractures were not included.
Follow-up for fractures averaged 11 yr, range 0.02–13.9 yr. For women who died during the follow-up period, date of death was used as the end of follow-up.
Statistical analyses
We compared the characteristics of the women, BMD, and annual
percent change in BMD across patterns of estrogen use by ANOVA or
analysis of covariance for continuous variables and
2 tests for categorical variables. Incidence
rates of fracture were calculated for each pattern of estrogen use by
dividing the number of fractures by the number of person-years of
follow-up and multiplying by 1000. Cox proportional hazard models were
used to assess the relationship between pattern of estrogen use and
nonspine fractures first after adjusting for age and BMI and
subsequently after adjusting for multiple covariates including: age,
BMI, physical activity (walk for exercise), current use of steroids,
thyroid hormones and thiazide diuretics, total calcium intake, history
of bilateral oophorectomy, and alcohol consumption (three or more
drinks per week vs. not). Additional adjustment was made for
health status and pulse rate. We calculated the relative risk of
fracture and 95% confidence intervals. Women who had never used
estrogen formed the referent group. To test the hypothesis that bone
mass accounts for the effect of estrogen on fracture risk, we
subsequently added total hip BMD to the multivariate models.
In a separate analysis, we further excluded women who had osteoporosis at the total hip as defined by the World Health Organization: t score -2.5 or lower (14). We examined the relative risk of nonspine fracture across patterns of estrogen in these nonosteoporotic women, (n = 4517).
Results
Sixty-seven percent of the 6901 women included in this analysis
had never used estrogen; 23% were past early users; 2%, past late
users; 7%, current early users, and 1.5%, current late users (Table 1
). Never users were on average 2–3 yr
older than the E-using women. The average duration of estrogen use was
5 yr among past early users; 2 yr among past late users, 25 yr among
current early users, and 10 yr among current late users. The average
interval between onset of menopause and initiation of estrogen was
considerably shorter among the early users, averaging about 2 yr. In
contrast, initiation of estrogen in the late users was on average
16–19 yr after the onset of menopause.
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BMD
Multivariate adjusted BMD levels across pattern of estrogen use
are shown in Table 2. Women who started
estrogen before age 60 yr and continued (current early users) had the
highest BMD at every site, compared with all other groups.
Compared with never users, current early users had 13% higher
mean BMD at the total hip, 9% higher BMD at the femoral neck, 15%
higher at the lumbar spine, 13% higher BMD at the proximal radius,
17% higher BMD at the distal radius, and 15% higher BMD at the
calcaneus. Thus, in comparison with never users, their BMD was on
average 0.5–1.0 SD higher.
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BMD was significantly higher among current early users, compared with current late users. The percent difference in BMD between these two groups of estrogen users ranged from a low of 2% for the femoral neck to a high of 8% for the lumbar spine and distal radius.
In general, BMD was similar in both early and late past users and never users. At some sites, the difference was statistically significant, but the magnitude of the difference was quite small.
Bone loss
The annual percentage change in total hip BMD and calcaneal BMD by
pattern of estrogen use is shown in Fig. 1 and Fig. 2. The annual rate of bone loss was
significantly slower among women who reported current estrogen use in
comparison with past or never users. There was no difference in the
rate of bone loss among current users who initiated use at age 60 yr or
later and continued (-0.35% per year, total hip BMD) and women who
initiated use before age 60 and continued (-0.22% per year, total hip
BMD). Similar results were observed for calcaneal BMD. Additional
adjustment for health status and pulse rate had no effect on our
results (data not shown).
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There was no evidence that past use of estrogen was protective
against fractures, Table 3. Women who
started estrogen use before age 60 yr and continued had the lowest rate
of fracture. In multivariate analyses, their risk of any nonspine
fracture was reduced by 37% (20–49%) in comparison with never users.
Compared with never users, women who initiated estrogen use at age 60
or later had a statistically nonsignificant 25% reduction in the risk
of nonspine fractures. Additional adjustment for health status and
pulse rate had no effect on our results (data not shown). In analyses
limited to women without osteoporosis as defined by their total hip
BMD, our results were similar: The relative risk of nonspine fracture
among women who initiated use at age 60 or later and continued long
term was 0.61 (95% confidence interval, 0.37–1.02). Inclusion of
total hip BMD in the multivariate models attenuated the effect of
estrogen on fracture risk in both current early and late estrogen
users.
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Current estrogen users who initiated use before age 60, an average of 2 yr within menopause and had an average duration of use of 25 yr, had the highest average radial, calcaneal, hip, and lumbar spine BMD, experienced the lowest average rate of bone loss, compared with all other women, and had a 37% lower risk of experiencing a nonspine fracture, compared with women who had never used estrogen. These findings are consistent with our previous report, which demonstrated that for optimal prevention of fractures, estrogen should be initiated within 5 yr of menopause and continued (1).
However, we also found that women who initiated estrogen use at age 60 or later, an average of almost 20 yr after the onset of menopause and who continued for an average of 10 yr, tended to have nonspine fracture rates lower than never or past users. Failure to reach statistical significance may have reflected the smaller sample of women who initiated estrogen many years after menopause. However, these results suggest that initiation of estrogen well beyond the menopause transition can still be effective in reducing fracture risk. This conclusion differs from our previous results that were based on a considerably shorter period of follow-up for fracture. In our earlier report, we found no fracture benefit among women who had used estrogen for at least 10 yr but had initiated use more than 5 yr after menopause (1). The current report extends follow-up for an additional 6.5 yr, increasing our power to detect a benefit among these women.
Later initiation would reduce the overall duration of estrogen use, lowering other health-related consequences of long-term use of estrogen. This could impact on the risk-benefit equation when evaluating estrogen replacement therapy in older women.
Our results are consistent with the findings of the Rancho-Bernardo cohort, which first reported that women who initiated use at age 60 yr or later and continued use had higher BMD than women who had used estrogen in the past or had never used estrogen. Our results extend these findings to include slower rates of bone loss and possibly fracture benefits among these late initiators of estrogen. Our results are also consistent with the model developed by Ettinger and Grady (15) that initiation of estrogen at age 65 would result in an improvement in bone mass and a reduction in fractures.
The relative risk of nonspine fracture was attenuated when we adjusted for total hip bone mass, which is consistent with the hypothesis that estrogen prevents fractures by preserving bone mass.
The major limitation to our study is its observational design. Observational studies may be biased because women who use estrogen therapy are healthier, of a higher social class, have access to medical care, and are more compliant and maintain healthier lifestyles than women who do not use estrogen (16). We controlled for many factors that differ markedly across the patterns of estrogen use, but there may be residual confounding by other factors we did not measure. Only a randomized trial can provide conclusive evidence that estrogen causes a reduction in fractures.
There have been few controlled, randomized trials of estrogen with fracture as an end point. A recent metaanalysis of hormone replacement therapy and the prevention of nonvertebral fractures concluded that hormone therapy was effective in reducing fractures among women under age 60 yr but not among older women (17). However, an accompanying editorial noted that this conclusion was based on essentially one study among younger subjects and one study, among older subjects, the Heart and E/progestin Replacement Study (HERS) (18).
HERS was the largest randomized trial of hormone replacement therapy. Results showed that 4 yr of treatment with hormone replacement therapy did not reduce the incidence of fractures among these 2763 women, mean age 67 yr, with heart disease (19). The difference between results of the current report and the HERS trial may reflect the much longer duration of use in our study, even among women who initiated use after age 60 (average duration of use, 10 yr). Results from the Framingham study suggested that women need to take estrogen for at least 7 yr after menopause (20).
There were also important differences between the characteristics of the women in HERS and SOF that also may have contributed. Most notably, the HERS women all had coronary heart disease. Hysterectomized women were excluded from HERS, so our results are not directly comparable, especially because hysterectomy status was a major selection factor for estrogen use (16). In addition, the women in HERS were on average more obese than the women in the SOF cohort.
We found that estrogen was effective in preventing bone loss, irrespective of when it was initiated. These results are consistent with observational studies (10, 21) and clinical trials (19, 22) that antiresorptive agents are effective in reducing bone loss in elderly women.
Our study confirms that previous use of estrogen does not have long-standing effects on BMD, bone loss, or fractures (1, 7). Women who initiated use an average of 1.6 yr after the onset of menopause and continued use for about 5 yr had similar BMD, rates of bone loss, and fracture risk as women who never used estrogen. Failure to see any benefit among these women may reflect accelerated loss of bone following discontinuation of therapy (10). The small group of past-late estrogen users took estrogen for less than 2 yr about 16 yr ago on average and it is not surprising that such short-term use decades ago had no impact on fractures. Many women initiate therapy around menopause for relief of menopausal symptoms and discontinue its use once the symptoms have abated. It will be important to evaluate whether these women achieve fracture benefits if they restart their estrogen later in life.
The focus of our study was osteoporosis prevention. To this end, we relied on a self-report of a physician diagnosis of osteoporosis or spine fracture to exclude women who may have been prescribed estrogen for treatment of their osteoporosis. We have shown previously that women with a self-report of osteoporosis were more likely to take estrogen (16), but our study may have included some women with osteoporosis, defined by more objective criteria. However, in a subanalysis, we excluded women who had a total hip BMD t score less than or equal to -2.5, and our results were similar.
There are a number of strengths to our study. The sample size was large enough to facilitate defining several important patterns of estrogen use and to link these patterns with a fracture outcome. All fractures were validated by radiographic report. Follow-up for fracture is more than 95% complete, so it is very unlikely that there could be differential reporting of fractures across patterns of estrogen use. Finally, we adjusted for many confounding factors that could have influenced our results.
There are, however, a number of limitations. Our results are limited to older white women, but it is this population that appears to have the greatest risk of osteoporosis and who may benefit most from preventive efforts. The design was observational; randomized trials of hormone therapy that are designed with longer follow-up, such as the Women’s Health Initiative may be useful in addressing the question of whether initiation of use at older ages prevent fractures. Our power to detect fracture risk reduction was limited among women who initiated use at age 60 yr or later and continued. Finally, our primary outcome includes a heterogeneous combination of fractures. Information on specific types of fractures is needed, although most of the fractures are, indeed, related to low bone mass and are osteoporotic in nature (23).
In summary, women who initiated estrogen before age 60 yr and continued had the greatest BMD, lost less bone, and experienced a 37% lower risk of fracture. Of importance, initiation of use at age 60 or later is also effective in maintaining BMD, slowing bone loss and appears to reduce fracture risk. If estrogen can effectively be postponed until a woman is older, we may be able to reduce the overall costs and risks associated with its extended use.
Acknowledgments
Investigators in the Study of Osteoporotic Fractures Research Group— University of California, San Francisco (Coordinating Center): S. R. Cummings (principal investigator), M. C. Nevitt (coinvestigator), D. C. Bauer, (coinvestigator), K. Stone (project director), D. M. Black (study statistician), H. K. Genant (director, central radiology laboratory), P. Mannen (research associate), T. Blackwell, W. S. Browner, M. Dockrell, T. Duong, C. Fox, S. Harvey, M. Jaime-Chavez, L. Y. Lui, G. Milani, L. Nusgarten, L. Palermo, E. Williams, D. Tanaka, C. Yeung. University of Maryland: M. Hochberg (principal investigator), J. C. Lewis (project director), D. Wright (clinic coordinator), R. Nichols, C. Boehm, L. Finazzo, B. Hohman, T. Page, S. Trusty, H. Kelm, T. Lewis, B. Whitkop.
University of Minnesota: K. Ensrud (principal investigator), K. Margolis (coinvestigator), P. Schreiner (coinvestigator), K. Worzala (coinvestigator), M Oberdorfer (project director), E. Mitson (clinic coordinator), C. Bird, D. Blanks, F. Imker-Witte, K. Jacobson, K. Knauth, N. Nelson, E. Penland-Miller, G. Saecker. University of Pittsburgh: J. A. Cauley (principal investigator), L. H. Kuller (co-principal investigator), M. Vogt (coinvestigator), L. Harper (project director), L. Buck (clinic coordinator), C. Bashada, D. Cusick, G. Engleka, A. Flaugh, A. Githens, M. Gorecki, D. Medve, M. Nasim, C. Newman, S. Rudovsky, N. Watson, D. Lee.
The Kaiser Permanente Center for Health Research, Portland, Oregon: T. Hillier (principal investigator), E. Harris (co-principal investigator), E. Orwoll (coinvestigator), H. Nelson (coinvestigator), Mikel Aiken (biostatistician), Marge Erwin (project administrator), Mary Rix (clinic coordinator), Jane Wallace, Kathy Snider, Kathy Canova, Kathy Pedula, JoAnne Rizzo.
Footnotes
This work was supported by in part by Public Health Service research grants from the NIH: AR35582, AM35584, AG05407, AG05395 and AR35583.
Abbreviations: BMD, Bone mineral density; BMI, body mass index; HERS, Heart and E/progestin Replacement Study; SOF, Study of Osteoporotic Fractures.
Received May 31, 2001.
Accepted August 23, 2001.
References
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 H. D. Nelson, J. Rizzo, E. Harris, J. Cauley, K. Ensrud, D. C. Bauer, E. Orwoll, and for the Study of Osteoporotic Fractures Research G Osteoporosis and Fractures in Postmenopausal Women Using Estrogen Arch Intern Med, November 11, 2002; 162(20): 2278 - 2284. [Abstract] [Full Text] [PDF]
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