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. 2021 Jan 6;4(1):e2030405. doi: 10.1001/jamanetworkopen.2020.30405

Association of Female Reproductive Factors With Incidence of Fracture Among Postmenopausal Women in Korea

Jung Eun Yoo 1, Dong Wook Shin 2,3,✉, Kyungdo Han 4, Dahye Kim 5, Ji Won Yoon 6, Dong-Yun Lee 7
PMCID: PMC7788464  PMID: 33404618

Key Points

Question

Are female reproductive factors associated with bone health in postmenopausal women?

Findings

In this population-based cohort study of 1 272 115 postmenopausal Korean women, later menarche, earlier menopause, and shorter reproductive span were each independently associated with increased risk of fracture.

Meaning

This study’s findings suggest that female reproductive factors are independent risk factors for fracture incidence, with a higher risk associated with shorter lifetime endogenous estrogen exposure.

Abstract

Importance

Although estrogen level is positively associated with bone mineral density, there are limited data on the risk of fractures after menopause.

Objective

To investigate whether female reproductive factors are associated with fractures among postmenopausal women.

Design, Setting, and Participants

This population-based retrospective cohort study used data from the Korean National Health Insurance Service database on 1 272 115 postmenopausal women without previous fracture who underwent both cardiovascular and breast and/or cervical cancer screening from January 1 to December 31, 2009. Outcome data were obtained through December 31, 2018.

Exposures

Information was obtained about reproductive factors (age at menarche, age at menopause, parity, breastfeeding, and exogenous hormone use) by self-administered questionnaire.

Main Outcomes and Measures

Incidence of any fractures and site-specific fractures (vertebral, hip, and others).

Results

Among the 1 272 115 participants, mean (SD) age was 61.0 (8.1) years. Compared with earlier age at menarche (≤12 years), later age at menarche (≥17 years) was associated with a higher risk of any fracture (adjusted hazard ratio [aHR], 1.24; 95% CI, 1.17-1.31) and vertebral fracture (aHR, 1.42; 95% CI, 1.28-1.58). Compared with earlier age at menopause (<40 years), later age at menopause (≥55 years) was associated with a lower risk of any fracture (aHR, 0.89; 95% CI, 0.86-0.93), vertebral fracture (aHR, 0.77; 95% CI, 0.73-0.81), and hip fracture (aHR, 0.88; 95% CI, 0.78-1.00). Longer reproductive span (≥40 years) was associated with lower risk of fractures compared with shorter reproductive span (<30 years) (any fracture: aHR, 0.86; 95% CI, 0.84-0.88; vertebral fracture: aHR, 0.73; 95% CI, 0.71-0.76; and hip fracture: aHR, 0.87; 95% CI, 0.80-0.95). Parous women had a lower risk of any fracture than nulliparous women (aHR, 0.96; 95% CI, 0.92-0.99). Although breastfeeding for 12 months or longer was associated with a higher risk of any fractures (aHR, 1.05; 95% CI, 1.03-1.08) and vertebral fractures (aHR, 1.22; 95% CI, 1.17-1.27), it was associated with a lower risk of hip fracture (aHR, 0.84; 95% CI, 0.76-0.93). Hormone therapy for 5 years or longer was associated with lower risk of any factures (aHR, 0.85; 95% CI, 0.83-0.88), while use of oral contraceptives for 1 year or longer was associated with a higher risk of any fractures (aHR, 1.03; 95% CI, 1.01-1.05).

Conclusions and Relevance

The findings of this cohort study suggest that female reproductive factors are independent risk factors for fracture, with a higher risk associated with shorter lifetime endogenous estrogen exposure. Interventions to reduce fracture risk may be needed for women at high risk, including those without osteoporosis.

This cohort study uses data from the Korean National Health Insurance System database to investigate whether female reproductive factors are associated with fractures among postmenopausal women in Korea.

Introduction

Osteoporotic fractures are an important global health issue in aging societies. The combined lifetime risk for any type of fracture that receives clinical attention is around 40%, which is equivalent to the risk for cardiovascular disease.1 In particular, postmenopausal women disproportionately experience osteoporosis and its sequelae, such as fractures.2

Estrogen levels are positively associated with bone mineral density (BMD) and have been suggested to have protective effects against osteoporotic fractures. For example, epidemiologic studies have shown that late age at menarche is associated with a risk of reduced BMD3 and subsequent osteoporosis or osteoporotic fractures.3,4,5 In addition, earlier menopause4,6,7,8,9,10 and shorter reproductive span3,4,5,8,11 have all been suggested to be risk factors for osteoporotic fractures. However, some reported fracture data were based on questionnaires or interviews and thus may have been subject to recall bias.4,5,6,7,10 In addition, limitations of previous studies included assessment of only certain types of fractures (eg, hip fractures4,8,10 or vertebral fractures5) and failure to adjust for comorbidities that may act as potential confounders, such as diabetes or cancer.4,5,9,10 Although there is wide variation in BMD and fracture incidence across racial and ethnic groups,12 epidemiologic information regarding osteoporotic fractures in Asian women and its determinants is scarce, comprising 1 Japanese study involving 250 self-reported vertebral fractures among 43 652 women5 and 1 Chinese study with 1327 incident hip fractures among 125 336 women.8 Furthermore, BMD levels change during pregnancy and lactation, but the long-term associations of these events with postmenopausal BMD or fracture are controversial, with protective,13,14,15 negative,16,17,18 and null4,5 findings.

Hormone therapy (HT) reduces postmenopausal bone loss and decreases the incidence of all osteoporosis-related fractures19 even in women not at high risk of fractures.20 In a meta-analysis of randomized clinical trials, HT was associated with a 26% overall reduction in total fractures, a 37% reduction in vertebral fractures, and a 28% reduction in hip fractures.21 However, because all published randomized clinical trials have been conducted in Western countries, the associations of HT with the risk of fractures in Asian women is unclear. The associations of exogenous estrogen exposure from oral contraceptives (OCs) with fracture risk also remain inconclusive.22 Use of OCs was reported to be protective against low BMD in several studies,23,24,25 but null26,27,28 or even negative29 associations have also been reported. It is also unclear whether the associations of OC use with BMD during reproductive years continue into postmenopausal years when bone loss accelerates and if such changes in BMD alter the risk of fracture later in life.30,31 Therefore, in this retrospective cohort study of a large population of women identified from a population-based database, we investigated the associations between female reproductive factors and incident fractures.

Methods

Data Source and Study Setting

We analyzed data obtained from the Korean National Health Insurance Service (NHIS), which contains sociodemographic information. To reimburse medical providers, the NHIS collects all information about use of medical facilities as well as records of medical procedures and prescriptions with International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes. In addition, the NHIS recommends free biennial cardiovascular health screening for all Koreans 40 years or older and all employees regardless of age, as well as annual screening for workers in jobs requiring physical labor, enabling the NHIS to collect data from health check-ups (self-administered questionnaire on health behavior, anthropometric measurements, and laboratory test results).32,33 This study was designed and conducted according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.34 This study received institutional review board approval from Samsung Medical Center. Informed consent was waived because the data are public and anonymized under confidentiality guidelines.

The National Cancer Screening Program was implemented as part of the Korean National Cancer Control Plan and involves cancer screening of all individuals exceeding cancer-specific target ages.35 For instance, all Korean women older than 40 years are screened for breast cancer biennially and are required to fill out a self-administered questionnaire on reproductive factors.35

Study Population

Among 3 109 506 women 40 years or older who underwent both cardiovascular and breast and/or cervical cancer screening from January 1 to December 31, 2009, we identified 1 939 690 eligible postmenopausal women. We first excluded individuals who reported undergoing a hysterectomy procedure in general (n = 215 083), as most did not know whether they had a simultaneous oophorectomy. We also excluded people with any fracture history (n = 111 764) or registered disability status (n = 99 861) before the health screening date and those with at least 1 missing variable (n = 216 913). Last, those who had any fracture (n = 20 760) or died (n = 3194) within 1 year after the health screening date were excluded. A total of 1 272 115 individuals were included in the final analyses (eFigure in the Supplement). The cohort was followed up from baseline (health screening date) to the date of incident fracture, censoring (eg, death), or end of the study period (December 31, 2018), whichever came first.

Exposure and Study Outcome

Information about age at menarche, age at menopause, parity, total lifetime breastfeeding history, and use of HT and/or OCs was collected by self-administered questionnaire (eMethods in the Supplement). The primary end point was newly diagnosed fractures during the follow-up period. We included fracture sites considered to be the most associated with osteoporosis.36 Fractures were defined by ICD-10 codes as vertebral, hip, or other fractures. Other fractures included clavicle, upper arm, wrist, and ankle (eMethods in the Supplement).37,38

Statistical Analysis

Continuous variables are presented as mean (SD) values, and categorical variables are presented as numbers and percentages. Incidence rates of fractures were calculated by dividing the number of incident cases by 1000 person-years. Three multivariable Cox proportional hazards regression models were evaluated. Model 1 was the crude model. Model 2 included age, age at menarche, age at menopause, parity, duration of breastfeeding, duration of HT, duration of OC use, lifestyle risk factors (alcohol consumption, smoking, and regular exercise), income, body mass index, and comorbidities (hypertension, diabetes, dyslipidemia, and cancer). Model 3 included reproductive span instead of age at menarche and the menopause variables in model 2. Model 3 also adjusted for other reproductive factors (parity, duration of breastfeeding, duration of HT, and duration of OC use) and covariates (age, lifestyle factors, income, body mass index, and comorbidities) included in model 2. Detailed information on the variables included in multivariable models is provided in the eMethods in the Supplement.

Statistical analyses were performed using SAS, version 9.4 (SAS Institute Inc). Statistical significance was defined as 2-sided P < .05.

Results

Baseline Characteristics of the Study Population

Characteristics of the 1 272 115 study participants are presented in the Table. The mean (SD) age of the total population was 61.0 (8.1) years. The overall mean (SD) age at menarche was 16.4 (1.8) years and at menopause was 50.1 (4.0) years. The mean (SD) reproductive span was 33.6 (4.4) years. Compared with women with no fractures (n = 1 082 232), women with incident fracture (n = 189 883) were likely to be older (mean [SD] age, 63.7 [8.1] vs 60.5 [8.1] years), multiparous (92.8% vs 91.0%), have later menarche (mean [SD] age at menarche, 16.7 [1.8] vs 16.4 [1.8] years), earlier menopause (mean [SD] age at menopause, 49.9 [4.2] vs 50.1 [4.0] years), a shorter reproductive span (mean [SD], 33.3 [4.6] vs 33.7 [4.3] years), and a duration of breastfeeding of 12 months or longer (74.0% vs 67.8%) and to have never used HT (82.6% vs 80.1%) or OC (80.0% vs 79.8%).

Table. Baseline Characteristics of the Study Participants.

Characteristic No. (%) P value
Total (N = 1 272 115) No fractures (n = 1 082 232) Fractures (n = 189 883)
Age, mean (SD), y 61.0 (8.1) 60.5 (8.1) 63.7 (8.1) <.001
Income, quartile
Q1 (lowest) 291 625 (22.9) 249 802 (23.1) 41 823 (22.0) <.001
Q2 238 175 (18.7) 204 466 (18.9) 33 709 (17.8)
Q3 314 688 (24.7) 267 733 (24.7) 46 955 (24.7)
Q4 (highest) 427 627 (33.6) 360 231 (33.3) 67 396 (35.5)
Smoking status
Never 1 224 497 (96.3) 1 041 677 (96.3) 182 820 (96.3) <.001
Ex-smoker 13 511 (1.1) 11 652 (1.1) 1859 (1.0)
Current smoker 34 107 (2.7) 28 903 (2.7) 5204 (2.7)
Alcohol consumption
None 1 110 358 (87.3) 942 633 (87.1) 167 725 (88.3) <.001
Mild 155 185 (12.2) 134 031 (12.4) 21 154 (11.1)
Heavy 6572 (0.5) 5568 (0.5) 1004 (0.5)
Regular exercise 237 484 (18.7) 204 195 (18.9) 33 289 (17.5) <.001
BMI, mean (SD) 24.2 (3.1) 24.2 (3.1) 24.2 (3.1) .30
<18.5 26 156 (2.1) 21 883 (2.0) 4273 (2.3) <.001
18.5 to <23 439 792 (34.6) 375 698 (34.7) 64 094 (33.8)
23 to <25 338 511 (26.6) 287 749 (26.6) 50 762 (26.7)
25 to <30 415 412 (32.7) 352 228 (32.6) 63 184 (33.3)
≥30 52 244 (4.1) 44 674 (4.1) 7570 (4.0)
Blood pressure, mean (SD), mm Hg
Systolic 125.4 (16.1) 125.2 (16.1) 126.5 (16.2) <.001
Diastolic 76.8 (10.2) 76.8 (10.2) 77.1 (10.1) <.001
Fasting glucose level, mean (SD), mg/dL 99.6 (24.0) 99.4 (23.8) 100.2 (25.1) <.001
Total cholesterol level, mean (SD), mg/dL 208.3 (43.8) 208.5 (43.4) 207.4 (45.5) <.001
Comorbidities
Hypertension 530 378 (41.7) 443 850 (41.0) 86 528 (45.6) <.001
Diabetes 159 996 (12.6) 132 923 (12.3) 27 073 (14.3) <.001
Dyslipidemia 432 129 (34.0) 366 702 (33.9) 65 427 (34.5) <.001
Cancer 33 882 (2.7) 29 205 (2.7) 4677 (2.5) <.001
Age at menarche, mean (SD), y 16.4 (1.8) 16.4 (1.8) 16.7 (1.8) <.001
≤12 12 580 (1.0) 12 580 (1.0) 11 295 (1.0) <.001
13-14 159 722 (12.6) 159 722 (12.6) 140 472 (13.0)
15-16 500 445 (39.3) 500 445 (39.4) 430 429 (39.8)
≥17 599 368 (47.1) 599 368 (47.1) 500 036 (46.2)
Age at menopause, mean (SD), y 50.1 (4.0) 50.1 (4.0) 49.9 (4.2) <.001
<40 21 101 (1.7) 17 353 (1.6) 3748 (2.0)
40-44 71 142 (5.6) 59 281 (5.5) 11 861 (6.3) <.001
45-49 345 678 (27.2) 294 429 (27.2) 51 249 (27.0)
50-54 699 018 (55.0) 597 401 (55.2) 101 617 (53.5)
≥55 135 176 (10.6) 113 768 (10.5) 21 408 (11.3)
Reproductive span, mean (SD), y 33.6 (4.4) 33.7 (4.3) 33.3 (4.6) <.001
<30 170 474 (13.4) 140 756 (13.0) 29 718 (15.7) <.001
30-34 529 589 (41.6) 448 793 (41.5) 80 796 (42.6)
35-39 490 384 (38.6) 423 003 (39.1) 67 381 (35.5)
≥40 81 668 (6.4) 69 680 (6.4) 11 988 (6.3)
Parity
Nulliparity 32 006 (2.5) 27 764 (2.6) 4242 (2.2) <.001
1 79 411 (6.2) 69 965 (6.5) 9446 (5.0)
≥2 1 160 698 (91.2) 984 503 (91.0) 176 195 (92.8)
Duration of breastfeeding, mo
Never 86 477 (6.8) 76 028 (7.0) 10 449 (5.5) <.001
<6 86 290 (6.8) 76 446 (7.1) 9844 (5.2)
6-11 225 607 (17.7) 196 465 (18.2) 29 142 (15.4)
≥12 873 741 (68.7) 733 293 (67.8) 140 448 (74.0)
Duration of HT, y
Never 1 023 519 (80.5) 866 595 (80.1) 156 924 (82.6) <.001
<2 118 146 (9.3) 102 795 (9.5) 15 351 (8.1)
2-4 48 812 (3.8) 42 699 (4.0) 6113 (3.2)
≥5 37 581 (3.0) 32 858 (3.0) 4723 (2.5)
Unknown 44 057 (3.5) 37 285 (3.5) 6772 (3.6)
Duration of OC use, y
Never 1 015 265 (79.8) 863 407 (79.8) 151 858 (80.0) <.001
<1 116 384 (9.2) 99 781 (9.2) 16 603 (8.7)
≥1 77 581 (6.1) 65 718 (6.1) 11 863 (6.3)
Unknown 62 885 (4.9) 53 326 (4.9) 9559 (5.0)
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Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); HT, hormone therapy; OC, oral contraceptive.

SI conversion factors: To convert cholesterol to millimoles per liter, multiply by 0.0259; glucose to millimoles per liter, multiply by 0.0555.

Association of Reproductive Factors With Incidence of Fractures

The median follow-up duration was 8.3 years (interquartile range, 8.0-8.6 years). There were 189 883 new cases of any fractures (14.9%), which consisted of vertebral fractures (n = 72 732), hip fractures (n = 11 153), and others (n = 106 895).

Menstrual History

In model 2, compared with women who experienced menarche at age 12 years or younger, age at menarche showed a significant dose-response association with any fracture (age, 13-14 years; adjusted hazard ratio [aHR], 1.10; 95% CI, 1.04-1.16; 15-16 years: aHR, 1.16; 95% CI, 1.10-1.23; and ≥17 years: aHR, 1.24; 95% CI, 1.17-1.31) (eTable 1 in the Supplement). However, compared with women who experienced menopause before age 40 years, the risk of any fracture decreased with age at menopause (age, 40-44 years: aHR, 0.97; 95% CI, 0.93-1.01; 45-49 years: aHR, 0.94; 95% CI, 0.91-0.97; 50-54 years: aHR, 0.90; 95% CI, 0.88-0.93; and ≥55 years: aHR, 0.89; 95% CI, 0.86-0.93). Furthermore, in model 3, when compared with a reproductive span of less than 30 years, the risk of any fracture also decreased with reproductive span (length of span, 30-34 years: aHR, 0.94; 95% CI, 0.93-0.95; 35-39 years: aHR, 0.89; 95% CI, 0.88-0.90; and ≥40 years: aHR, 0.86; 95% CI, 0.84-0.88). Similar patterns were noted for vertebral fractures (age of menarche, ≥17 years: aHR, 1.42; 95% CI, 1.28-1.58; age at menopause, ≥55 years: aHR, 0.77; 95% CI, 0.73-0.81; and reproductive span, ≥40 years: aHR, 0.73; 95% CI, 0.71-0.76) and hip fractures (age at menopause, ≥55 years: aHR, 0.88; 95% CI, 0.78-1.00; reproductive span, ≥40 years: aHR, 0.87; 95% CI, 0.80-0.95) (eTables 2 and 3 in the Supplement, Figure 1, and Figure 2). Other fracture risk was associated only with age at menarche (eTable 4 in the Supplement).

Figure 1. Hazard Ratios (HRs) for Vertebral Fractures According to Menstrual History.

Figure 1.

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NA indicates not applicable.

aModel 2: the full model included age, age at menarche, age at menopause, parity, duration of breastfeeding, duration of hormone therapy, duration of oral contraceptive use, alcohol consumption, smoking, regular exercise, income, body mass index, hypertension, diabetes, dyslipidemia, and cancer.

bModel 3: the full model included reproductive span instead of age at menarche and the menopause variables in model 2.

Figure 2. Hazard Ratios (HRs) for Hip Fractures According to Menstrual History.

Figure 2.

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NA indicates not applicable.

aModel 2: the full model included age, age at menarche, age at menopause, parity, duration of breastfeeding, duration of hormone therapy, duration of oral contraceptive use, alcohol consumption, smoking, regular exercise, income, body mass index, hypertension, diabetes, dyslipidemia, and cancer.

bModel 3: the full model included reproductive span instead of age at menarche and the menopause variables in model 2.

Parity and Breastfeeding

In model 2, primiparous women were found to have a lower fracture risk (any fracture: aHR, 0.96; 95% CI, 0.92-0.99; vertebral fracture: aHR, 0.90; 95% CI, 0.84-0.97) than nulliparous women, whereas there was no significant association between fracture risk and multiparity (eTables 1 and 2 in the Supplement and Figure 3). There was no association between parity and hip fracture (eTable 3 in the Supplement and Figure 4). Other fracture risk was negatively associated with parity (primiparous women: aHR, 0.94; 95% CI, 0.89-0.98; multiparous women: aHR, 0.93; 95% CI, 0.89-0.97) (eTable 4 in the Supplement).

Figure 3. Hazard Ratios (HRs) for Vertebral Fractures According to Parity, Breastfeeding, and Exogenous Hormone Use.

Figure 3.

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The full model (model 2) included age, age at menarche, age at menopause, parity, duration of breastfeeding, duration of hormone therapy (HT), duration of oral contraceptive (OC) use, alcohol consumption, smoking, regular exercise, income, body mass index, hypertension, diabetes, dyslipidemia, and cancer. NA indicates not applicable.

Figure 4. Hazard Ratios (HRs) for Hip Fractures According to Parity, Breastfeeding, and Exogenous Hormone Use.

Figure 4.

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The full model (model 2) included age, age at menarche, age at menopause, parity, duration of breastfeeding, duration of hormone therapy (HT), duration of oral contraceptive (OC) use, alcohol consumption, smoking, regular exercise, income, body mass index, hypertension, diabetes, dyslipidemia, and cancer. NA indicates not applicable.

Although women who breastfed for less than 6 months had a lower fracture risk than those who never breastfed (any fracture: aHR, 0.97; 95% CI, 0.94-0.99; vertebral fracture: aHR, 0.97; 95% CI, 0.92-1.03), women who breastfed for 12 months or longer had a higher fracture risk (any fracture: aHR, 1.05; 95% CI, 1.03-1.08; vertebral fracture: aHR, 1.22; 95% CI, 1.17-1.27) (eTables 1 and 2 in the Supplement and Figure 3). Hip fracture risk was negatively associated with duration of breastfeeding (<6 months: aHR, 0.84; 95% CI, 0.73-0.97; 6-11 months: aHR, 0.85; 95% CI, 0.76-0.95; and ≥12 months: aHR, 0.84; 95% CI, 0.76-0.93) (eTable 3 in the Supplement and Figure 4).

HT and OC Use

Hormone therapy for 5 years or longer was associated with a lower risk of any fracture (aHR, 0.85; 95% CI, 0.83-0.88) (eTable 1 in the Supplement). In model 2, when compared with the never-HT group, HT users had a lower risk of vertebral fracture (HT for <2 years: aHR, 0.95; 95% CI, 0.92-0.98; HT for 2-4 years: aHR, 0.88; 95% CI, 0.84-0.92; and HT for ≥5 years: aHR, 0.82; 95% CI, 0.78-0.86) (eTable 2 in the Supplement and Figure 3). The results were largely consistent across various types of fracture (eTables 1, 3, and 4 in the Supplement and Figure 4). Fracture risk tended to increase with OC use for 1 year or longer (any fracture: aHR, 1.03; 95% CI, 1.01-1.05; vertebral fracture: aHR, 1.06; 95% CI, 1.03-1.09; hip fracture: aHR, 1.06; 95% CI, 0.97-1.15; and other fracture: aHR, 1.03; 95% CI, 1.00-1.02).

Other Fracture Risk Factors

Current smokers (aHR, 1.06; 95% CI, 1.03-1.09), heavy drinkers (alcohol consumption, ≥30 g/d; aHR, 1.26; 95% CI, 1.19-1.35), and patients with diabetes (aHR, 1.05; 95% CI, 1.03-1.06) were at higher risk of any fracture (eTable 5 in the Supplement). Those who engaged in regular exercise (aHR, 0.98; 95% CI, 0.97-0.99) and were severely obese (defined as a body mass index ≥30 [calculated as weight in kilograms divided by height in meters squared]) (aHR, 0.94; 95% CI, 0.92-0.96) were at lower risk of any fracture.

Discussion

This study found that female reproductive factors were independently associated with the incidence of fractures among postmenopausal women. Later menarche, earlier menopause, and shorter reproductive span were each independently associated with fracture risk in postmenopausal women. Parous women were found to have a lower risk of any fracture than nulliparous women. Although a breastfeeding duration of 12 months or longer was associated with a higher risk of any fractures and vertebral fractures, breastfeeding was associated with a lower risk of hip fracture. The use of HT was independently associated with a lower risk of fracture in postmenopausal women, but the use of OCs for 1 year or longer was associated with a higher risk of fracture.

Endogenous estrogen exposure occurs mainly during the reproductive phase, which is bounded by menarche and menopause. Lack of estrogen increases bone resorption and decreases the deposition of new bone that normally takes place in weight-bearing bones.39 The present study showed significant inverse associations between increased endogenous estrogen exposure and risk of all fracture sites combined, as well as vertebral and hip fractures specifically. Consistent with our findings, one study suggested that earlier menopausal age may be a risk factor associated with decreased whole-body, total-spine, and hip BMD.10 In a systematic review of anatomical sites associated with osteoporotic fractures, femoral neck and vertebral fractures were found to be the fracture types most strongly associated with osteoporosis.36 The present study provides further evidence that female reproductive factors may be associated with osteoporosis-related fractures.

According to a meta-analysis, increasing parity is associated with a linear reduction in osteoporotic fracture risk among postmenopausal women.40 Serum estrogen levels increase during pregnancy to levels approximately 20 to 30 times above their peak during the normal menstrual cycle. Such markedly increased estrogen exposure during each pregnancy may reduce a woman’s fracture risk. Some nulliparous women could be subfertile, producing less estrogen during the menstrual cycle than more fertile women and hence be at greater risk of fracture.41 In the present study, primiparous women had a lower risk of any fracture and vertebral fracture than nulliparous women, but multiparity failed to show a significant association with risk of any fracture or vertebral fracture. We also failed to find any significant association between parity and hip fracture. In addition to parity, a shorter interpregnancy interval may have a detrimental association with BMD in postmenopausal age.42 In the case of multiparity, it is more likely for age at last childbirth to be older, and postmenopausal women of older age at last childbirth are at increased risk of osteoporosis.43 However, this information was not available in the NHIS database.

Although it is believed that bone loss during lactation is restored 6 to 12 months after weaning through mechanisms that remain unclear, we found that prolonged breastfeeding duration increased the risk of any fracture as well as vertebral fracture. In support of our finding, 1 study reported that breastfeeding for only 6 months resulted in a reduction in bone density that stopped after 6 months and returned to previous levels after another 6 months, whereas bone density did not return to original levels when breastfeeding lasted 12 months or longer.44 However, a reduced risk of hip fracture in women who breastfed was also noted. Consistent with these findings, a recent meta-analysis reported that the incidence of osteoporotic hip fracture decreased with the extension of breastfeeding time.14 Other researchers have reported an association between longer duration of lactation and lower BMD in the lumbar spine but not in the femoral neck or the total hip.45,46 Skeletal loss is more profound from trabecular bone than from cortical bone during lactation: the vertebra is primarily trabecular bone, whereas hip bones are largely cortical bone.47 Trabecular bone is more metabolically active than cortical bone48,49 and possibly more susceptible than cortical bone to hormonal influences and reductions in calcium reserve.45 In an animal model, mechanical properties in cortical bone of the femur were substantially improved during the postlactation period compared with those observed at the end of lactation,50 and these gains during the postlactation period were also greater than the normal growth observed in control rats, indicating that the postlactation period is an “anabolic” phase for the accumulation of bone mass.51 Furthermore, our results suggest that there is something unique about breastfeeding that protects against future fracture at weight-bearing sites because breastfeeding had the greatest association with reducing hip fractures.

We also showed that exogenous hormonal exposure, in particular HT, was associated with a lower risk of fractures. Based on available evidence, the benefits of postmenopausal estrogen therapy for fracture risk are well established.20,21 Hormone therapy is associated with a reduced risk of total, hip, and vertebral fractures; however, it may also have adverse effects.21 Although the mechanism underlying the association of HT with reduced fracture risk is unclear, it is thought to involve the inhibition of osteoclasts,52,53 resulting in decreased bone turnover and improved balance between bone formation and resorption.52 Hormone therapy also improves calcium retention through increased intestinal calcium absorption and renal calcium reabsorption.54 Our findings support the hypothesis that exogenous female hormone use may protect against future fracture through the beneficial effects of estrogen on bone metabolism.

Oral contraceptives may also improve bone density by biologically plausible mechanisms, but considerable controversy exists as to whether OCs have a positive association with bone density. Furthermore, relatively few studies have investigated the association between prior OC use and fracture in postmenopausal women. In those studies, fracture risk among women who used OCs after 35 to 40 years of age was decreased, suggesting that the association of OC use with later fracture risk depends on a woman’s age at the time of OC use.55,56 Our finding of a small but statistically significantly increased risk of fracture among those who had previously used OCs for 1 year or more was unexpected. Similarly, a cohort study of postmenopausal women reported that past OC use for 5 years led to a 15% increased risk of self-reported fracture.57 However, because exposure to OCs was determined by participant recall, an apparent decrease in previous use of OCs among older women in our study may have been a result of poor recall. In fact, women with unknown OC use accounted for approximately 5% of the total population, and this segment of the population had a 6% increased risk of vertebral fracture. The exact mechanism underlying this finding needs further investigation.

To our knowledge, this is the largest study performed to date to assess the association between female reproductive factors and fracture, especially according to skeletal site. We directly assessed fracture risk as a clinical outcome rather than BMD, which is a surrogate marker. Furthermore, we examined various reproductive factors comprehensively. The clinical implications of our study are that menstrual and reproductive factors associated with reproductive hormonal disturbances, in particular late menarche, early menopause, and longer reproductive span, are potential risk factors for osteoporosis-related fractures. The World Health Organization fracture-risk (FRAX) tool58 is widely used to estimate osteoporotic fractures by integrating clinical risk factors. Currently, the FRAX algorithm does not include reproductive factors, but it is hoped that these factors will be incorporated into existing algorithms as additional supporting data become available in the future.

Limitations

Our study had several limitations. First, the exposure variables of interest were based on a self-administered questionnaire; therefore, we cannot exclude the possibility of bias caused by inaccurate recall. Second, detailed information about female hormone use, such as age at use or dose, was not available. Further detailed information about female hormone use and users’ potential risk factors for fracture is required to clarify the possible association between exogenous female hormone use and risk of fracture. Third, we were unable to obtain information on the cause of fractures. However, we limited our analysis to common sites of osteoporotic fracture. In addition, our data did not include fractures from traffic accidents, violence, or self-injury, which are not included in NHIS claims data. There is also no reason to believe that traumatic fractures selectively occur by reproductive factors. Fourth, other potential confounders, such as nutritional factors (eg, calcium intake or vitamin D level) or osteoporosis-related factors (eg, osteoporosis treatment or causes of secondary osteoporosis), may have been present. Fifth, there might have been a birth cohort effect owing to improvements in health status and economic growth and rapid assimilation of a Western lifestyle. In Korea, mean age at menarche decreased from 16.9 years for women born between 1920 and 1925 to 13.8 years for those born between 1980 and 1985,59 whereas the mean age at menopause increased from 47.9 years for women born in 1929 or earlier to 50.0 years for those born between 1945 and 1949.60 As a result, the short reproductive span observed in this study may primarily reflect the characteristics of the older participants in the cohort. The association of age with reproductive factors, however, was minimized by controlling for age. Sixth, this was a retrospective study, and the findings should be interpreted as associations, not as causality.

Conclusions

The findings of this large, population-based cohort study suggest that female reproductive factors are independently associated with fracture development. An association was also noted between lower lifetime endogenous estrogen exposure and increased fracture incidence.

Supplement.

eMethods. Supplemental Methods

eTable 1. Hazard Ratios and 95% Confidence Intervals of Any Fracture According to Reproductive Factors

eTable 2. Hazard Ratios and 95% Confidence Intervals of Vertebral Fracture According to Reproductive Factors

eTable 3. Hazard Ratios and 95% Confidence Intervals of Hip Fracture According to Reproductive Factors

eTable 4. Hazard Ratios and 95% Confidence Intervals of Other Fractures According to Reproductive Factors

eTable 5. Hazard Ratios and 95% Confidence Intervals of Fractures

eFigure. Flow Chart of the Study Population

Click here for additional data file. (576.5KB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement.

eMethods. Supplemental Methods

eTable 1. Hazard Ratios and 95% Confidence Intervals of Any Fracture According to Reproductive Factors

eTable 2. Hazard Ratios and 95% Confidence Intervals of Vertebral Fracture According to Reproductive Factors

eTable 3. Hazard Ratios and 95% Confidence Intervals of Hip Fracture According to Reproductive Factors

eTable 4. Hazard Ratios and 95% Confidence Intervals of Other Fractures According to Reproductive Factors

eTable 5. Hazard Ratios and 95% Confidence Intervals of Fractures

eFigure. Flow Chart of the Study Population

Click here for additional data file. (576.5KB, pdf)

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