Presented in part at the 24th Annual Meeting of the American Society of Bone and Mineral Research, San Antonio, TX, September 20-24, 2002.
Article first published online: 1 MAY 2003
Copyright © 2003 ASBMR
Journal of Bone and Mineral Research
Volume 18, Issue 5, pages 900–905, May 2003
How to Cite
Melton, L. J., Khosla, S., Malkasian, G. D., Achenbach, S. J., Oberg, A. L. and Riggs, B. L. (2003), Fracture Risk After Bilateral Oophorectomy in Elderly Women. J Bone Miner Res, 18: 900–905. doi: 10.1359/jbmr.2003.18.5.900
The authors have no conflict of interest.
- Issue published online: 2 DEC 2009
- Article first published online: 1 MAY 2003
- Manuscript Accepted: 7 NOV 2002
- Manuscript Revised: 25 OCT 2002
- Manuscript Received: 25 JUL 2002
- hip fracture;
- vertebral fracture
Elderly women with the lowest serum estrogen levels are at the greatest risk of bone loss and fractures, but it is controversial whether the ovaries contribute to estrogen production after menopause, and therefore, whether bilateral oophorectomy in postmenopausal women might have adverse skeletal effects. To address this potential problem, we estimated long-term fracture risk among 340 postmenopausal Olmsted County, MN, women who underwent bilateral oophorectomy for a benign ovarian condition in 1950-1987. In over 5632 person-years of follow-up (median, 16 years per subject), 194 women experienced 516 fractures (72% from moderate trauma). Compared with expected rates, there was a significant increase in the risk of any osteoporotic fracture (moderate trauma fractures of the hip, spine, or distal forearm; standardized incidence ratio [SIR], 1.54; 95% CI, 1.29-1.82) but almost as large an increase in fractures at other sites (SIR, 1.35; 95% CI, 1.13-1.59). In multivariate analyses, the independent predictors of overall fracture risk were age, anticonvulsant or anticoagulant use for ≥6 months, and a history of alcoholism or prior osteoporotic fracture; obesity was protective. Estrogen replacement therapy was associated with a 10% reduction in overall fracture risk (hazard ratio [HR], 0.90; 95% CI, 0.64-1.28) and a 20% reduction in osteoporotic fractures (HR, 0.80; 95% CI, 0.52-1.23), but neither was statistically significant. The increase in fracture risk among women who underwent bilateral oophorectomy after natural menopause is consistent with the hypothesis that androgens produced by the postmenopausal ovary are important for endogenous estrogen production that protects against fractures.
It was shown over 50 years ago that menopause is associated with a period of rapid bone loss that is preventable by estrogen replacement therapy.(1) More recently, it became evident that this rapid phase of bone loss, which can last for up to 8-10 years, is followed by a slower phase of age-related bone loss that continues indefinitely.(2) Convincing evidence has now emerged that this continuing slow phase of bone loss is caused in large part by estrogen deficiency, through effects on the gut and kidney that impair intestinal calcium absorption and renal calcium conservation.(3) Because testosterone and androstenedione produced by the ovary can serve as substrate for extragonadal endogenous estrogen production after menopause,(3) there could be effects on the skeleton of bilateral oophorectomy later in life, even after the rapid phase of bone loss has ceased. Little attention has been given to this potential problem, and there is controversy of whether the postmenopausal ovary is(4–8) or is not(9) an important source of these androgens. However, population-based studies have shown that even slightly lower levels of circulating estrogens are associated with increased bone loss and fracture risk in postmenopausal women.(10–15) To the extent that ovarian androgens make a contribution to endogenous estrogen production after menopause, there may be unexpected adverse consequences of oophorectomy in elderly women. The purpose of this study was to assess the practical significance of this potential problem by estimating the long-term risk of fractures among an inception cohort of women who were already past menopause when they underwent bilateral oophorectomy for a benign ovarian condition.
MATERIALS AND METHODS
This study was possible because medical care for the residents of Rochester, Minnesota, is delivered almost exclusively by the Mayo Clinic and a small number of other providers. Most providers use a dossier (or unit) medical record system, wherein all data on each patient are contained in a single file. The unit records at Mayo, for example, contain the information recorded for outpatient office or clinic consultations, emergency room and nursing home care, inpatient hospitalizations, autopsy, and death certification. These records are accessible because Mayo Clinic maintains a master index to all diagnoses and surgical procedures recorded among its patients. The Rochester Epidemiology Project supports a similar index to the records of the other medical care providers serving the community.(16) The original medical records have been preserved and are easily retrieved for review. The result is documentation of the medical care provided to Rochester residents by Mayo Clinic or its two large affiliated hospitals (Saint Marys and Rochester Methodist), the Olmsted Medical Group and its affiliated Olmsted Community Hospital (Olmsted Medical Center), and other hospitals and practitioners in the vicinity. The potential of this data system for population-based studies has been described previously.(16)
After approval by Mayo's Institutional Review Board, all Rochester women who underwent an oophorectomy during the 38-year period, 1950-1987, were identified using the indexes described.(17) Oophorectomy was defined as complete removal of the ovary and was classified as unilateral or bilateral (including a second unilateral oophorectomy). Hysterectomy was recorded, if done, but women who had only a hysterectomy and no oophorectomy were excluded. The indication for oophorectomy was determined by review of each woman's complete inpatient and outpatient medical record, including the surgeon's narrative report of the operation. We previously reported on subsequent fracture risk among the 463 Rochester women who were still menstruating when they had their bilateral oophorectomy.(18) This study focuses on 545 postmenopausal women who underwent bilateral oophorectomy; 195 of them had ovarian cancer. This analysis was restricted to the 350 women who were already postmenopausal when they underwent bilateral (or second unilateral) oophorectomy for a benign ovarian condition. However, 10 of these women were excluded from further study because they had not provided an authorization for review of their medical records for research in accordance with Minnesota State law.(19)
After additional approval by Mayo's Institutional Review Board, the remaining 340 women were followed forward in time through their linked medical records in the community (retrospective cohort study). Each subject's complete inpatient and outpatient medical record at each local provider of medical care was searched by trained nurse abstractors for the occurrence of any fracture. Follow-up continued until death or the most recent clinical contact documented in community medical records. The records contained the clinical history and the radiologist's report of each fracture, but the original roentgenograms were not available for review. Consequently, the diagnosis of vertebral fracture was accepted based on a radiologist's report of compression or collapse of one or more thoracic or lumbar vertebra.(20) Fracture ascertainment is believed to be complete except for vertebral fractures, some of which are never diagnosed. Fractures were also classified according to the circumstances of the injury: by convention, falls from standing height or less were considered moderate trauma, whereas motor vehicle accidents and falls from greater heights were deemed severe trauma.
The influence of bilateral oophorectomy on fracture risk was evaluated using three basic methods of analysis. In the primary analysis, we calculated standardized incidence ratios (SIR), comparing the number of fractures that were observed at each skeletal site (based on the first fracture of a given type per person) to the number expected during follow-up in the community. Expected numbers of fractures were derived by applying age- and sex-specific incidence rates of these fractures in the Rochester population(20–24) to the age-specific person-years of follow-up among the oophorectomy cases. Ninety-five percent confidence intervals (95% CI) for the SIRs were calculated with the assumption that the expected rates are fixed and the observed fractures follow a Poisson distribution.(25)
In the second method of analysis, the cumulative incidence of a new fracture (1 − survival-free-of-fracture) was projected for up to 30 years after the index date, using product-limit life table methods.(26) Two approaches were used in this analysis. The customary analysis censored women who died and therefore estimated cumulative fracture incidence among survivors at each point in time. Alternatively, we estimated fracture risk with death as a competing event, thereby providing a cumulative incidence figure more concordant with that actually observed by the treating physician. The one-sample log-rank test was used to compare observed and expected cumulative fracture incidence curves.(27) Life-table methods were used to assess survival, and the observed and expected survival curves were also compared using the log-rank test statistic.
Finally, Cox proportional hazards models(28) were used to assess the impact of various covariates on the subsequent risk of fracture after bilateral oophorectomy. Univariate relationships between the risk of specific fractures and each clinical characteristic under consideration were first assessed. Stepwise methods with forward selection and backward elimination were then used to choose independent variables for the final models. The dependent variable was time until the first new fracture, and the independent variables were the clinical characteristics. For the final multiple models, as well as for the univariate models, the assumption of proportional hazards was examined and was not violated for the variables considered.
In the 38-year period, 1950-1987, 340 Rochester, Minnesota, women had a bilateral oophorectomy, which was unrelated to primary ovarian cancer (median age at surgery, 62 years; range, 37-86 years), after natural menopause (median age at menopause, 50 years). All but four of them were white, reflecting the racial composition of the community (98% white in 1980). The majority of operations, 292 (86%), were incidental in the course of total abdominal hysterectomy. Fifteen others (4%) were elective procedures with other types of surgery, whereas 31 women (9%) were operated for a variety of benign conditions (e.g., endometriosis). The final two women were castrated for management of breast cancer. Altogether, 314 (92%) of the women underwent hysterectomy at the time of bilateral oophorectomy, whereas 6 others had a hysterectomy previously and 4 had one afterward. The hysterectomy status of 16 women was uncertain.
These 340 women were followed subsequently for 5632 person-years (range, 1 day to 42 years per subject). Survival was unimpaired in this cohort (at 30 years, 30% remained alive compared with an expected 27%; p = 0.826), and follow-up was complete to death in 59% of the subjects (median, 14 years of follow-up per subject). Among survivors, the median duration of follow-up was 17 years. During this entire period of observation, 194 subjects experienced 516 different fractures (Table 1). Eighty-two women had a single fracture, whereas 39 had two different fractures, 25 had three fractures, and 48 had four or more fractures. After 30 years of follow-up, the cumulative incidence of a new fracture was 67% compared with an expected 60% (p < 0.001). Among 30-year survivors, an actuarially estimated 86% of the women had experienced at least one new fracture compared with 76% expected (p < 0.001). Eighty-two of the fractures (16%) were caused by severe trauma (26 motor vehicle accidents, 24 falls from a height, and 32 miscellaneous causes, e.g., hand crushed in car door), but the majority of fractures (369, 72%) were attributed to minimal or moderate trauma (Table 1). Excluding hands and feet, 77% of the limb fractures were caused by a fall from standing height or less, which accounted for 44% of all fractures/observed. Three-fourths of all vertebral fractures occurred “spontaneously” in the course of everyday activities. Twenty-two fractures (4%) were the result of a specific pathological lesion (e.g., metastatic malignancy), and the etiology of the remaining 43 fractures was uncertain.
Skeletal site-specific data are delineated in Table 2. Compared with expected rates among community women generally, statistically significant increases were seen for fractures at most sites in the axial skeleton, such as the vertebrae (SIR, 3.01; 95% CI, 2.46-3.64) and ribs (SIR, 2.24; 95% CI, 1.69-2.92), as well as the proximal femur (SIR, 1.54; 95% CI, 1.17-1.99) and distal forearm (SIR, 1.47; 95% CI, 1.06-1.98). As shown in Fig. 1, the increase in vertebral fracture risk seemed to accelerate over follow-up, but the ratio of observed to expected cumulative incidence did not actually change. In contrast, the excess of proximal femur and distal forearm fractures was relatively constant over time (Fig. 1). Overall, there was a significant increase in the risk of any of the traditional osteoporotic fractures (moderate trauma fractures of the hip, spine, or distal forearm ≥35 years of age: SIR, 1.54; 95% CI, 1.29-1.82), but almost as large an increase was seen in the likelihood of a fracture at any of the remaining skeletal sites (SIR, 1.35; 95% CI, 1.13-1.59).
In multivariate analyses, advancing age was the strongest risk factor for any fracture (hazard ratio [HR] per 10-year increase, 1.60; 95% CI, 1.35-1.89) or for any osteoporotic fracture (HR, 1.85; 95% CI, 1.48-2.31). There was no suggestion of an association with earlier age or shorter duration since menopause nor any significant relation to the indication for oophorectomy (ovarian pathology vs. incidental), or in the latter group, to the indication for concomitant hysterectomy (uterine descensus vs. endometrial cancer vs. other vaginal bleeding vs. fibroids vs. other indications). The other independent predictors of any subsequent fracture were use of anticonvulsants or anticoagulants for more than 6 months and a history of alcoholism or prior osteoporotic fractures, while obesity was protective (Table 3). As also shown in Table 3, the other risk factors for any osteoporotic fracture included anticonvulsant use, a history of prior osteoporotic fracture or kyphosis, and more recent year of oophorectomy, while thiazide use was protective. Fifty-one women (15%) had been on hormone replacement therapy (80% of them for at least 6 months) before the oophorectomy and over one-half continued this treatment after surgery. An additional 61 women (14%) were put on hormone replacement for the first time after their oophorectomy, but the median delay to initiating treatment was 5.7 years; only 13 women (4%) were started within 6 months of surgery. In a univariate model, hormone replacement therapy, when handled as a time-dependent variable, was associated with a 10% reduction in overall fracture risk (HR, 0.90; 95% CI, 0.64-1.28) and a 20% reduction in osteoporotic fractures (HR, 0.80; 95% CI, 0.52-1.23), but neither difference was statistically significant.
In this population-based study, women who had a bilateral oophorectomy on average 14 years after natural menopause experienced a 32% increase in subsequent overall fracture risk and a 54% increase in the fractures traditionally associated with osteoporosis. This finding is consistent with the notion that postmenopausal women experience reductions in circulating testosterone and androstenedione levels after the removal of their ovaries.(4–8) The androgen reductions themselves could have an independent adverse effect on bone,(3) but more importantly, they are aromatized to estrogens systemically in fat and locally in bone tissue.(29, 30) To the extent that endogenous estrogen production is reduced even slightly,(31) postmenopausal bone turnover might be exacerbated and fracture risk increased.(32, 33) Although most authors have concluded that circulating estrogen levels are not lowered after oophorectomy, in fact, small reductions are typically observed, though the differences may not be statistically significant.(5–8, 34) Similarly, in an age-stratified sample of 213 postmenopausal Rochester women, we found that those who had undergone bilateral oophorectomy but were not on estrogen replacement therapy, when compared with untreated women with intact ovaries, had lower serum total estradiol (13.6 vs. 24.1 pg/ml) and estrone (25.9 vs. 32.7 pg/ml) levels (LJ Melton, III, unpublished data, 2002). These reductions were not statistically significant given the relatively small number of subjects, but differences of this magnitude in otherwise low circulating estrogen levels seem to adversely influence bone metabolism in most,(10–15) if not all,(35, 36) recent studies of postmenopausal women.
Conversely, 50% of the women with a history of bilateral oophorectomy in the Rochester population sample were on estrogen replacement compared with only 14% of the unoperated women, an association observed previously,(37) and estrogen levels among the treated women were practically identical. In the present study, 27% of the women were on estrogen replacement therapy after bilateral oophorectomy, and the effect on fracture risk was generally positive (a 20% reduction in osteoporotic fractures and a 10% reduction in fractures overall), although not statistically significant. Randomized controlled clinical trials, on the other hand, have shown that bone loss can be slowed in elderly women(38, 39) and fracture risk reduced(40) by hormone replacement therapy.
In addition to the well-known effects of age,(41) the other risk factors identified here have been associated with fracture risk in previous studies. Thus, a prior history of fractures has been shown to be a strong predictor of future osteoporotic fracture risk,(42) while anticonvulsant use has been associated with an increased risk of fractures generally,(43) probably through a relationship with seizure disorders and falling. Anticoagulants also had an effect on overall fracture risk in this study, but other investigators have not found associations except with vertebral and rib fractures.(44, 45) Alcoholism has been linked to an increase in all sorts of fractures as we also/observed.(46) The use of thiazide diuretics was linked with a 40% reduction in osteoporotic fractures, but we saw no independent protective effect of thiazides on specific fractures or on overall fracture risk in accordance with most other work on the subject.(47) Obesity was protective for fractures in general as shown in a host of earlier studies,(47) and this may relate to the role of fat mass as a site for aromatization of androgens to estrogens in postmenopausal women.(3)
The present investigation has a number of strengths. The population-based retrospective cohort design allowed us to rapidly estimate long-term fracture outcomes among un-selected community women undergoing bilateral oophorectomy after the menopause. The clinical characteristics of these women were recorded before any knowledge of resultant fractures, and a large number of such fractures were documented during extensive follow-up in the detailed medical records that spanned each subject's entire period of residency in the community. Because the vast majority of fractures come to medical attention,(24) ascertainment should be nearly complete with the possible exception of vertebral fractures.(20) Although our results are not generalizable to non-whites, because the Rochester population is largely white,(16) age-adjusted hip fracture incidence rates from Rochester are comparable with those for United States whites in general.(22) There are also corresponding limitations of an observational study based on medical records. Risk factors for falls could not be fully assessed, and measurements of the variables of special interest (e.g., bone density, circulating estrogen levels) were not routinely performed. Moreover, these data do not allow direct assessment of any pathophysiologic mechanism for the increase in fracture risk, such as elevated bone resorption caused by secondary hyperparathyroidism.(3)
As in most populations in this country,(48) the great majority of bilateral oophorectomies in Rochester were performed incidentally in the course of hysterectomy. Concurrent oophorectomy is technically simple, does not increase short-term morbidity, and limits the risk of ovarian cancer, although only 2.6 ovarian cancers would have been expected in this cohort, given the incidence rates in this community.(49) Consequently, this practice is recommended routinely for women undergoing hysterectomy after 50 years of age,(50) although some have argued that incidental oophorectomy should be re-evaluated based on the observation that androgen levels are reduced in these women.(8, 51) On the other hand, highly detailed studies of a small number of women suggest that the androgens in postmenopausal women are not ovarian but rather adrenal in origin and that prophylactic oophorectomy need not be abandoned.(9) Regardless of the underlying pathophysiology involved, we have documented a significant increase in fracture risk among these women, which may be reduced somewhat by estrogen replacement therapy. Although recent results from the Women's Health Initiative cast doubt on the wisdom of using combined estrogen and progestin therapy for this purpose,(40) the estrogen-only arm of that trial continues, and it is the latter results that are relevant to these women, almost all of whom are without a uterus. Further research will be needed to define the impact of postmenopausal oophorectomy on androgen and estrogen metabolism and its effects on bone pathophysiology and to devise the most suitable strategies for the care of women who have undergone bilateral oophorectomy at an older age.
The authors thank Leona Bellrichard, RN, Barbara Nolte, RN, and Kristine Otto-Higgins, RN for their help with data collection, and Mary Roberts for preparing the manuscript. This work was supported in part by Grants AG-04875 and AR-30582 from the National Institutes of Health, U.S. Public Health Service.
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