From the Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, MN.
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ABSTRACT |
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hip fractures; menstrual cycle; osteoporosis, postmenopausal; prospective studies
Abbreviations: CI, confidence interval; RR, relative risk
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INTRODUCTION |
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Premenopausal female athletes with menstrual disturbances have been extensively studied. Female athletes with amenorrhea and oligomenorrhea have been found to have lower plasma estradiol and progesterone levels than either eumenorrhagic female athletes or eumenorrhagic female nonathletes (1618
). In addition, many studies have found that female athletes with menstrual irregularities show lower bone mineral density in both trabecular (17
, 19
) and cortical (17
, 18
) bone relative to eumenorrhagic female athletes or eumenorrhagic controls. Another study also found that women with nonexercise-related amenorrhea had significantly lower bone density compared with normally menstruating women (20
).
Few studies have focused on menstrual history and the clinical outcomes of osteoporosis, such as hip fracture. One study found a slightly increased risk of hip, wrist, and vertebral fracture among women who always had irregular menses compared with those women who sometimes or never had irregular menses (10). This same study found that later age at menopause and increased menstrual cycle length increased the risk of hip, wrist, and hip fractures combined. However, no significant association of hip, wrist, and vertebral fracture with menstrual cycle variability or mean menstrual bleeding duration was observed (10
). Paganini-Hill et al. (21
) reported that a later age at menopause and a long menstrual cycle length both increased the risk of hip fracture. However, a case-control study of postmenopausal women showed no significant association of hip and wrist fractures with age at menarche or menopause, length of menstrual cycles, amount of menstrual blood loss, or variation in cycle length (22
).
Because the relation between osteoporotic hip fractures and menstrual history has not been fully explored, the present study examined the association of self-reported recall of variations in menstrual cycles and in the length of menstrual bleeding time with the incidence of hip fracture in a cohort of postmenopausal women. We also examined the relation of infertility with risk of hip fracture because of a recent report suggesting a possible inverse association (23).
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MATERIALS AND METHODS |
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To assess menstrual irregularities, women were asked to self-report their lifetime history of menstrual cycle regularity (never, usually, always), with "regular" being defined as periods being predictable within 5 days. Women also reported variation in menstrual bleeding length (usually lasted same number of days, did not usually last same number of days). Infertility history was assessed by the question, "Did you ever try for one straight year or more to become pregnant and, during that time, not become pregnant?" Other questions were asked about menarche, menopause (including both natural and surgical menopause), gynecologic surgery, and lifestyle; weight and height were reported and waist and hip circumferences were measured (24). Body mass index was calculated as the participant's weight in kilograms divided by her height in meters, squared; the waist/hip ratio was calculated as the waist measurement (in inches) divided by the hip measurement (in inches).
Women were followed for self-reported hip fracture by mail surveys in 1987 (91 percent response), 1989 (89 percent response), 1992 (83 percent response), and 1997 (79 percent response). Deaths were identified via the mail survey and by linkage to Iowa death certificate files and the National Death Index.
We hypothesized that women with more menstrual irregularities (always had irregular menses, generally had variation in length of menstrual bleeding) would have a higher risk of hip fracture than did those who reported no menstrual irregularities. Those who reported occasional menstrual irregularities we predicted would have a risk of hip fracture midway between those with regular cycles and those who always had irregular cycles.
Women were excluded who were premenopausal at baseline (n = 508), who had cancer (other than skin cancer) at baseline (n = 2,676), who had implausible energy intake (less than 500 calories or greater than 5,000 calories per day) (n = 536), who failed to complete a significant proportion of the food frequency questionnaire (n = 2,560), or who reported never having menstruated or failed to respond to any of the questions regarding menstrual cycles, menstrual bleeding, or any of the covariates (n = 1,222). After all exclusions, the number of participants under study was 33,434.
For cases, person-years of follow-up were calculated as the number of years since completion of the baseline questionnaire until the midpoint between the date of the questionnaire where first hip fracture was reported and the person's previous questionnaire. For noncases, person-years were calculated from completion of the baseline questionnaire to the date of the last follow-up questionnaire. Participants contributed 9.5 (standard deviation, 3.4) years of follow-up, on average.
For descriptive purposes, analysis of variance was performed to test differences between means and chi-square tests to test differences between proportions. Cox proportional hazards regression was used to derive both age- and mulitvariate-adjusted relative risks and 95 percent confidence intervals. After the elimination of all covariates in table 1 not found to be associated with both menstrual history and hip fracture, model building was accomplished in forward stepwise fashion. For each variable added to the model, a likelihood ratio chi-square test was performed to test the fit of the model to the data. Variables that did not improve model fit were eliminated from the final model. The covariates used in the final multivariate model were age, smoking status, estrogen use, body mass index, and waist/hip ratio.
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RESULTS |
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The covariates in table 1 tended to be associated in a similar direction with regularity of menstrual bleeding (data not shown).
Over the 318,522 person-years of follow-up, 523 hip fractures were reported. Women who reported always having irregular menstrual cycles had a 36 percent (95 percent confidence interval (CI): 1.03, 1.78) higher multivariate-adjusted incidence of hip fracture than did women who reported never having irregular cycles (table 2). Those women who indicated that they sometimes had irregular menstrual cycles had no greater risk of hip fracture than those who never had irregular cycles (relative risk (RR) = 1.04, 95 percent CI: 0.87, 1.25). Participants who reported having variations in the duration of menstrual bleeding had a 40 percent increased multivariate-adjusted risk of hip fracture (95 percent CI: 1.10, 1.78) compared with women reporting regular bleeding duration. There was no relation of age at menopause or lifetime duration of menstruation with risk of hip fracture (data not shown).
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Because a high proportion of women whose menstrual cycles were never regular reported either hysterectomy and/or oophorectomy, the analyses were rerun restricting the population at risk to women who had undergone natural menopause. In this subset, hip fracture incidence was associated with menstrual bleeding regularity and menstrual cycle regularity in a similar direction as the full cohort, although p values were larger because of loss of power, and the estimates of relative risk were slightly weaker (data not shown). For example, among this subset the relative risk of hip fracture for women who reported always having irregular menstrual cycles and irregular duration of menstruation was 1.38 (95 percent CI: 1.00, 1.92) versus women reporting neither abnormality.
We also examined the relation between reported infertility and hip fracture risk. Women who indicated that they had tried for a year or more to become pregnant without success had no higher risk of hip fracture than those who did not have problems becoming pregnant (multivariate-adjusted RR = 1.00, 95 percent CI: 0.78, 1.27) (data not shown).
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DISCUSSION |
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Studies focusing on female athletes with menstrual irregularities have consistently shown that irregular menses are associated with a loss of bone density (1620
). Increasing severity of menstrual dysfunction, defined by either cessation of menses altogether or by duration of irregularity, has also been found to decrease bone loss (17
, 19
, 20
). Since exercise increases bone mass, it is difficult to generalize findings from athletes to persons with normal activity levels. However, even among women athletes, those who are eumenorrhagic have higher plasma levels of estradiol and progesterone and higher bone density than female athletes who have menstrual disturbances. In addition, one study has shown that spinal bone density was related to disturbances in ovulation but not to level of physical activity (8
).
Our findings are consistent with the bulk of the literature focusing on bone density among women with normal levels of physical activity (7, 8
, 10
13
). The findings add to the small and inconsistent literature on menstrual history and clinical outcomes of osteoporosis, although our conclusions are in conflict with those of Cooper and Sandler (10
) who found no association of menstrual cycle variability with risk of hip fracture. However, the number of hip fractures in that study was very small (n = 18), and the study focused on only 5 years (when participants were aged 2832 years) of menstrual history, which may not have been indicative of overall menstrual history.
The strengths of the Iowa Women's Health Study are its large size and prospective design. However, information on hip fracture was self-reported and, therefore, is subject to misclassification. Bush et al. (25) reported a 91 percent agreement between self-reported fracture and medical record review, although self-reported fractures were overreported. Munger et al. (26
) reported a high validity of hip fracture self-reports in our cohort. We could not differentiate between osteoporotic and trauma-related hip fractures. In addition, since the original response rate was 42 percent, the generalizability of our findings could be threatened. From information gathered through the 1980 US Census and the Iowa driver's license list, women who were nonparticipants were found to be slightly older, had 0.4 kg/m2 lower body mass, and were less likely to live in urban or more affluent counties than were participants (27
). Given the lower body mass and older age of nonrespondents, it is possible that non-respondents would have had higher rates of hip fracture. However, the differences in body mass and age were small, and we assume that the longitudinal associations observed would not be affected significantly.
We excluded women who were pre- and perimenopausal, so the results should only be generalized to women who are postmenopausal. In addition, women who reported implausible energy intake or who did not answer 30 or more questions on the food frequency questionnaire were removed from the analysis. It is possible that these women represented women with disordered eating patterns or chronic illness who may be at increased risk of hip fractures. However, the number of women excluded for missing or implausible dietary information was small. Exclusions also included women who were missing information on menstrual history. These women may have declined to answer questions pertaining to menstrual history because they had irregular menses but felt the available responses were not applicable to them, perhaps because they had underlying medical problems or eating disorders or were athletic. If women who refrained from answering questions regarding menstrual history were among those who had irregular menses, this would limit generalizability somewhat.
Little information exists on within- and between-woman variation in menstrual cycles or bleeding duration (28). Women thus may have had difficulty recalling or judging how regular their cycles and menstrual bleeding duration were. Misclassification of menstrual history variables would tend to attenuate the observed relation between menstrual history and hip fracture.
To summarize, we found that women who reported always having irregular menstrual cycles and who had irregular menstrual bleeding duration were at increased risk of hip fracture.
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ACKNOWLEDGMENTS |
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NOTES |
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REFERENCES |
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