Associations of menopausal vasomotor symptoms with fracture incidence.

ORIGINAL E n d o c r i n e

ARTICLE R e s e a r c h

Associations of Menopausal Vasomotor Symptoms with Fracture Incidence Carolyn J. Crandall, Aaron Aragaki, Jane A. Cauley, JoAnn E. Manson, Erin LeBlanc, Robert Wallace, Jean Wactawski-Wende, Andrea LaCroix, Mary Jo O’Sullivan, Mara Vitolins, and Nelson B. Watts Department of Internal Medicine (C.J.C.), David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California 90095; Women’s Health Initiative Clinical Coordinating Center (A.A.), Fred Hutchinson Cancer Research Center, Seattle, Washington 98109; Department of Epidemiology (J.A.C.), Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; Division of Preventive Medicine (J.E.M.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115; Center for Health Research NW (E.L.), Kaiser Permanente, Portland, Oregon 97227; Department of Epidemiology (R.W.), University of Iowa College of Public Health, Iowa City, Iowa 52242; Department of Epidemiology and Environmental Health (J.W.-W.), University at Buffalo, State University of New York, Buffalo, New York 14214; Public Health Sciences (A.L.), Fred Hutchinson Cancer Research Center, Seattle, Washington 98109; Department of Obstetrics and Gynecology (M.J.O’S.), Miller School of Medicine, University of Miami, Miami, Florida 33136; Department of Epidemiology and Prevention (M.V.), Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157; and Mercy Health Osteoporosis and Bone Health Services (N.B.W.), Cincinnati, Ohio 45236 Context: Vasomotor symptoms (VMS) are common. Whether VMS are associated with fracture incidence or bone mineral density (BMD) levels is unknown. Objective: This study aimed to examine associations of baseline VMS with fracture incidence and BMD. Design: This was a prospective observational study with mean (SD) followup of 8.2 (1.7) years (1993–2005). Setting: Forty United States clinical centers. Participants: We examined data from Women’s Health Initiative Clinical Trial participants (n ⫽ 23 573) age 50 –79 years not using menopausal hormone therapy, and 4,867 participants of the BMD sub-study. Interventions: None. Main Outcome Measures: We measured baseline VMS, incident adjudicated fractures, and BMD (baseline, annual visits 1, 3, 6, and 9). Results: After adjustment for baseline age, body mass index, race/ethnicity, smoking, and education, the hazard ratio for hip fracture among women with baseline moderate/severe VMS (vs no VMS) was 1.78 (95% confidence interval [CI], 1.20–2.64; P ⫽ .01). There was no association between VMS and vertebral fracture. VMS severity was inversely associated with BMD during followup (P ⫽ .004 for femoral neck, P ⫽ .045 for lumbar spine). In repeated measures models, compared with women who reported no VMS, women with moderate/severe VMS had 0.015 g/cm2 lower femoral neck BMD (95% CI, ⫺0.025–⫺0.005) and 0.016 g/cm2 lower lumbar spine BMD (95% CI, ⫺0.032–⫺0.004). Conclusions: Women with moderate/severe VMS have lower BMD and increased hip fracture rates. Elucidation of the biological mechanisms underlying these associations may inform the design of preventive strategies for at-risk women prior to occurrence of fracture. (J Clin Endocrinol Metab 100: 0000 – 0000, 2015) ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2015 by the Endocrine Society Received July 29, 2014. Accepted November 21, 2014.

doi: 10.1210/jc.2014-3062

Abbreviations: BMD, bone mineral density; BMI, body mass index; CI, confidence interval; HR, hazard ratio; HT, hormone therapy; VMS, Vasomotor symptom; WHI, Women’s Health Initiative, WHI-CT, Women’s Health Initiative Clinical Trial; WHI-OS, Women’s Health Initiative Observational Study.

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Crandall et al

Vasomotor Symptoms and Fracture Risk


with vertebral or nonvertebral fracture risk (14). To our knowledge, no prospective studies have examined these associations in a large cohort of postmenopausal women not selected for having osteoporosis at baseline. Our goal was to examine associations of baseline VMS with subsequent BMD and fracture incidence using data from the Women’s Health Initiative, a large cohort of United States postmenopausal women (15). We hypothesized that VMS would be associated with lower BMD and higher fracture rates. We also hypothesized that selective estrogen receptor modulator use, physical functioning, incident cancer, and sleep disruption (potentially leading to falls) may be potential mechanisms involved in associations between VMS and fracture risk.

asomotor symptoms (VMS), ie, hot flashes and/or night sweats, are common in women during the menopause transition. VMS peak in late perimenopause, when women have had no menses for at least 3 months but not yet experienced 12 months of amenorrhea (1). During the late perimenopause, approximately 60% of women experience VMS (2). VMS may persist well past the final menstrual period. Four years after the final menstrual period, nearly 50% of women are still symptomatic, and 10% of women continue having VMS 12 years or more after the final menstrual period (2). The peak prevalence of VMS coincides with the time period of accelerated bone loss at the hip and spine (3). Given the high prevalence and potentially long exposure to VMS, it is clinically important to examine whether these symptoms are indicative of adverse bone health. A few studies examined associations between VMS and bone mineral density (BMD); they were cross sectional (4 – 8), brief (9, 10), or focused on premenopausal infertile women (11). Cross-sectional studies (4, 5, 7, 12), and a 30-month study (10) of peri- and postmenopausal women suggested that spine BMD is lower among women with VMS than among women without VMS. A longitudinal study of younger women progressing through the menopausal transition using repeated measures analysis found that the presence of VMS was inversely associated with spine and femoral neck BMD (13). Likewise, little is known about associations between VMS and fracture risk. A longitudinal study of women who had osteoporosis at baseline found no association of “bothersome” VMS

V

A

Materials and Methods Participants The Women’s Health Initiative (WHI) was conducted at 40 Unites States clinical centers (16, 17). The clinical trials (WHICT) and the observational study (WHI-OS) enrolled postmenopausal women age 50 –79 years at baseline who were free from serious medical conditions (15, 18). The three WHI-CTs evaluated menopausal hormone therapy (HT), calcium and vitamin D supplementation, and a low-fat eating pattern (15). For the current study, analyses of the associations between VMS and fracture were performed using data from participants of the WHI-CT (Figure 1). Of the 68 132 women enrolled onto the WHI-CT, we excluded data from 588 participants for whom we lacked data regarding VMS severity. Because HT use can influence fracture risk, data from 35 217 participants who re-

B

Figure 1. Flow diagram of analytic cohorts.


doi: 10.1210/jc.2014-3062

ported prior or current HT use, and 13 816 who were randomly assigned to receive HT (conjugated equine estrogens alone or conjugated equine estrogens ⫹ medroxyprogesterone acetate), were also excluded. Thus, our analytic sample size for incident fractures was 23 573 participants. Using data from the WHI BMD cohort, we analyzed associations between VMS and BMD. At the time of enrollment, participants at three of the 40 clinical centers (Tucson/Phoenix, Arizona; Pittsburgh, Pennsylvania; and Birmingham, Alabama; n ⫽ 10 833) underwent hip and anteroposterior lumbar dual-energy x-ray absorptiometry on a Hologic QDR2000 or 4500W machine (Hologic) using standard protocols for positioning and analysis (19 –21). Quality assurance methods included crossclinic calibration phantoms, further evaluation of scans with specific problems, and review of a random sample of scans (22). Of 10 833 CT and OS participants from the WHI BMD cohort, 10 358 had at least one BMD measurement at baseline and/or followup. Among these, 5419 participants were excluded because of current or prior use of HT. (Women who reported never having used HT at baseline tended not to initiate HT during followup). A further 72 were missing baseline VMS severity data. Thus, the sample size for our BMD analyses was 4867 participants (Figure 1). Postrandomization BMD measures were censored for participants who were assigned to either HT preparation (n ⫽ 626). Each institution obtained human subjects committee approval. All participants provided written informed consent.

Outcomes: Fracture incidence and BMD Information regarding incident fractures was self reported semiannually. Self-reported fractures were then confirmed based on medical record adjudication. The questionnaire item asked participants whether they had experienced fracture events since the previous visit: “Has a doctor told you for the first time that you have a new broken, crushed, or fractured bone?” Which bone did you break?” Response choices included: hip, upper leg (not hip), pelvis, knee (patella), lower leg or ankle, foot (not toe), spine or back (vertebra), lower arm or wrist, hand (not finger), elbow, and upper arm or shoulder. For this analysis, we classified fractures into the following categories: hip, spine, and nonvertebral (including hip). The BMD outcome was absolute BMD (g/cm2), measured at baseline, and annual followup visits 1, 3, 6, and 9 for the WHI-CT, and at baseline and annual followup visits 3, 6, and 9 for the WHIOS. If information was missing regarding one or more BMD measurements for a participant, the participant still contributed to the model the BMD measurements that were available.

Predictor: Vasomotor symptom assessment The primary exposure variable was VMS severity. Information regarding VMS at baseline was obtained on the baseline questionnaire. The questionnaire item stated, “Below is a list of symptoms people sometimes have. For each item, mark the one oval that best describes how bothersome the symptom was during the past 4 weeks for you.” Response choices were: symptom did not occur, mild (symptom did not interfere with usual activities), moderate (symptom interfered somewhat with usual activities), and severe (symptom was so bothersome that usual activities could not be performed). The symptom list included separate items for hot flashes and night sweats. As expected, the overlap between hot flashes and night sweats was high.


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Therefore, in this analysis, we made the a priori decision to define VMS as hot flashes and/or night sweats. Because of the low prevalence of severe VMS, we combined the moderate and severe categories of VMS into a single category for purposes of statistical analysis.

Other questionnaire-based information We obtained information regarding age, race/ethnicity, education, family income, age at menopause, hysterectomy, oophorectomy, smoking, alcohol consumption, physical activity, previous fracture, sleep disturbance, incident falls, and medication use from baseline self-assessment questionnaires. Age at menopause was defined as previously described (23). Sleep disturbance was characterized using the validated WHI sleep disturbance construct (24). Participants were classified as never, past, or current users of HT based on questionnaire responses. Past HT use was defined as use of an estrogen or progestogen-containing pill or transdermal patch for 3 months or longer following menopause. Weight and height were measured using standardized protocols. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared.

Statistical analysis We examined baseline characteristics across categories of baseline VMS severity after adjustment for age, BMI, and smoking. We analyzed associations between baseline VMS and incident fractures in the WHI-CT cohort. We analyzed associations between baseline VMS severity (none, mild, moderate/severe) and time to fracture using Cox proportional hazards regression, adjusting for covariates chosen a priori: baseline age, BMI, race/ethnicity, smoking, and education, and stratified by age and prior history of fracture. Hip, spine, and nonvertebral fractures each served as outcomes of separate models, where statistical significance was based on a 2-degree-of-freedom test for association. In subgroup analyses, we tested for interactions between VMS and baseline characteristics chosen a priori: age, BMI, years since menopause, race/ethnicity, and physical activity. Statistical significance was based on a test of interaction. Twenty comparisons were made (5 outcomes ⫻ 4 subgroups); thus, one interaction was expected to be significant by chance alone. Additional post-hoc analyses investigated effect modification by baseline diabetes and history of cardiovascular disease. Additional analyses were carried out to elucidate potential mechanisms of associations between VMS and fracture risk. Time-dependent covariates (ie, tamoxifen/selective estrogen receptor modulator use, sleep disturbance, physical functioning, incident cancer, number of incident falls) were added one at a time to the Cox regression model in which hip fracture was the outcome. We analyzed associations between baseline VMS and BMD in the WHI BMD cohort. To do this, we examined associations between baseline VMS severity and longitudinal measures of BMD using repeated measures regression with an unstructured variance-covariance matrix, adjusting for baseline age, BMI, race/ethnicity, BMD scanner, smoking, and education. We compared mean BMD at baseline and during followup (averaged over followup visit) by baseline VMS severity categories using two 1-degree-of-freedom tests for trend. Femoral neck BMD and


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Crandall et al



interaction of VMS severity with BMD at baseline and followup; one interaction was expected to be statistically significant by chance alone. Because of the known influence of breast cancer therapy on both VMS and BMD, we performed a sensitivity analysis in

spine BMD each served as outcomes of separate regression models. Based on a priori hypotheses, we examined the associations of baseline VMS with BMD by subgroups of baseline age (50 – 59, 60 – 69, 70 –79 y) and BMI (⬍ 25, 25–⬍30, and ⱖ 30 kg/m2) (2, 25). Statistical significance was based on a test for trend of the

Table 1.

Baseline Characteristics of the Fracture Cohort (n ⫽ 23 573) by Severity of Baseline Vasomotor Symptoms Severity of Baseline Vasomotor Symptoms

Characteristic Age at screening, y 50 –54 55–59 60 – 69 70 –79 Race/ethnicity White Black Hispanic American Indian Asian/Pacific Islander Unknown Education ⱕHigh school/GED School after high school ⱖCollege degree Family income ⬍20K 20 –⬍35K 35–⬍50K 50 –⬍75K ⱖ75K US region Northeast South Midwest West Time since menopause, y ⬍5 5–⬍10 10 –⬍15 ⱖ15 Hysterectomy Bilateral oophorectomy Smoking status Never Past Current Treated diabetes (pills or shots) Alcohol consumption Non/past drinker ⬍1 drink/wk 1–14 drinks/wk ⬎14 drinks/wk Moderate-strenuous physical activity ⱖ20 min, episodes/wk No activity Some activity 2–⬍4 episodes/wk ⱖ4 episodes/wk Osteoporosis prescription medication

None (n ⴝ 15 418)

Mild (n ⴝ 5766)

Moderate/ Severe (n ⴝ 2389)

N

%

N

%

N

%

1093 2341 7911 4073

7.1 15.2 51.3 26.4

1036 1497 2481 752

18.0 26.0 43.0 13.0

612 662 844 271

25.6 27.7 35.3 11.3

12 746 1490 570 63 355 194

82.7 9.7 3.7 0.4 2.3 1.3

4202 1102 247 32 106 77

72.9 19.1 4.3 0.6 1.8 1.3

1363 735 208 13 28 42

57.1 30.8 8.7 0.5 1.2 1.8

3716 5805 5806

24.2 37.9 37.9

1503 2219 1998

26.3 38.8 34.9

815 946 606

34.4 40.0 25.6

2905 4016 3113 2528 1850

20.2 27.9 21.6 17.5 12.8

1025 1396 1147 1016 798

19.0 25.9 21.3 18.9 14.8

654 513 404 356 289

29.5 23.1 18.2 16.1 13.0

4825 3415 3560 3618

31.3 22.1 23.1 23.5

1728 1381 1423 1234

30.0 24.0 24.7 21.4

676 720 562 431

28.3 30.1 23.5 18.0

1102 1988 2750 6830 4129 1362

8.7 15.7 21.7 53.9 26.8 9.1

1254 1030 963 1728 1518 474

25.2 20.7 19.4 34.7 26.3 8.4

622 414 338 711 824 262

29.8 19.9 16.2 34.1 34.5 11.4

8097 5970 1164 851

53.2 39.2 7.6 5.5

2922 2246 535 326

51.2 39.4 9.4 5.7

1118 942 294 191

47.5 40.0 12.5 8.0

4687 5275 4869 470

30.6 34.5 31.8 3.1

1755 2037 1750 171

30.7 35.7 30.6 3.0

898 829 581 56

38.0 35.1 24.6 2.4

2665 6419 2229 2802 302

18.9 45.5 15.8 19.9 2.0

1099 2361 797 941 75

21.1 45.4 15.3 18.1 1.3

517 1000 297 393 26

23.4 45.3 13.5 17.8 1.1

P Valuea ⬍.001

⬍.001

⬍.001

⬍.001

.008

⬍.001

.53 .01 ⬍.001

.11 .002

.05

.43 (Continued)


doi: 10.1210/jc.2014-3062

Table 1.


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Continued Severity of Baseline Vasomotor Symptoms

Age at screening, y BMI, kg/m2 Total calcium intake, mg Total vitamin d intake, IU Physical functioning scale (RAND36) Total energy expenditure/wk from phys act, MET-h

None (n ⴝ 15 418)

Mild (n ⴝ 5766)

Moderate/ Severe (n ⴝ 2389)

Mean

SD

Mean

SD

Mean

SD

P Value

64.9 29.5 1104.1 339.4 80.9 10.4

6.7 6.2 674.4 260.7 19.5 12.5

61.2 29.6 1059.6 326.4 80.9 9.8

6.8 6.1 663.7 266.4 20.2 12.4

59.9 30.7 1029.2 305.4 75.2 9.4

6.9 6.3 745.0 251.5 23.6 12.8

⬍.001 ⬍.001 .37 .14 ⬍.001 .38

Abbreviations: GED, General Educational Diploma; MET-hrs, metabolic equivalent of task (hours/week); RAND36, 36-item Short-Form Health Survey. a

P values adjusted for age, BMI, race/ethnicity, and smoking.

which we repeated the regression models after excluding women with a history of breast cancer (n ⫽ 133). All analyses were conducted by using SAS software version 9.3 (SAS Institute) and R software version 2.15 (R Foundation for Statistical Computing). All P values were two-sided and P ⱕ .05 were regarded as statistically significant.

Results Characteristics of the participants Compared with excluded participants, participants in the analytic sample tended to be younger (mean age, 62.3 vs 63.5 y), thinner (mean BMI, 28.6 vs 29.6 kg/m2), and white (82 vs 78%) (data not shown). At baseline, 15 418 participants (65%) reported having no VMS, 5766 (24%) reported mild VMS, and 2378 (10%) reported moderate/severe VMS (Table 1). Mean (SD) age of the participants of the fracture sample at baseline was 63.5 (7.0) years. Women in the fracture cohort who had moderate/severe VMS at baseline tended to be younger, were more likely to be non-White, and were more likely to have undergone bilateral oophorectomy compared with women with no VMS or mild VMS (all P ⬍ 0.05). Likewise, women in the BMD cohort with moderate/ severe VMS tended to be younger and non-White (all P ⬍ 0.05; Table 2). Average (SD) followup was 8.2 (1.7) years. Associations between VMS and fracture incidence After adjusting for baseline age, BMI, race/ethnicity, smoking, and education, baseline VMS severity was associated with increased hazard ratio (HR) for fracture (Table 3). Among women reporting baseline moderate/severe VMS (compared with no VMS), the HR for hip fracture was 1.78 (95% confidence interval [CI], 1.20 –2.64, P ⫽ .01). Higher VMS severity was associated with increased HR for nonvertebral fractures (P ⫽ .04). However, VMS

severity was not associated with the incidence of clinical spine fractures. VMS were not associated with lower arm/ wrist fractures (data not shown). Associations between VMS severity and fracture incidence did not vary across subgroups of baseline age or BMI (Table 3). In addition, there was no interaction of VMS with years since menopause, race/ethnicity, baseline cardiovascular disease, or physical activity (data not shown). The HR for hip fracture associated with moderate/severe VMS was attenuated by the inclusion of physical functioning in the Cox regression models, although VMS remained statistically significantly associated with hip fracture incidence; the HR (95% CI) changed from 1.78 (1.20 –2.64) to 1.64 (1.09 –2.46). None of the other potential confounders (tamoxifen/selective estrogen receptor modulator use, sleep disturbance, incident cancer, and incident number of falls) appreciably altered the HR for VMS (attenuation ranging between 0 and 6%), and VMS remained significantly associated with hip fracture incidence. There were insufficient hip fracture events to allow stratification of results according to presence of diabetes mellitus or prevalent cardiovascular disease. Of the 29 hip fracture cases with moderate/severe symptoms at baseline, only one occurred in a participant who was treated for diabetes at baseline. In the subset of women without diabetes, the HR (95% CI) for hip fracture among women with moderate/severe VMS, compared with women without VMS, was 1.88 (1.25–2.81). VMS were not associated with diabetes, and adding diabetes as a covariate did not appreciably change the results: hip fracture HR (95% CI) was 0.93 (0.69 –1.26) for mild VMS (vs none); and 1.77 (1.19 –2.63) for moderate/severe VMS (vs none; P ⫽ .01). In a sensitivity analysis, we excluded data from participants who reported use of selective estrogen receptor modulators (n ⫽ 1038) or prescription osteoporosis med-


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Crandall et al

Table 2.



Baseline Characteristics of the BMD Cohort (n ⫽ 4867) by Severity of Baseline Vasomotor Symptoms Severity of Baseline Vasomotor Symptoms None (n ⴝ 3161)

Characterisic Age at screening, y 50 –54 55–59 60 – 69 70 –79 Race/ethnicity White Black Hispanic American Indian Asian/Pacific Islander Unknown Education ⱕHigh school/GED School after high school ⱖCollege Degree Family income ⬍20K 20 –⬍35K 35–⬍50K 50 –⬍75K ⱖ75K US region Northeast South West Time since menopause, y ⬍5 5–⬍10 10 –⬍15 ⱖ15 Hysterectomy Bilateral oophorectomy Smoking status Never Past Current Treated diabetes (pills or shots) Alcohol consumption Non/past drinker ⬍1 drink/wk 1–14 drinks/wk ⬎14 drinks/wk Moderate-strenuous physical activity ⱖ20 min, episodes/wk No activity Some activity 2–⬍4 episodes/wk ⱖ4 episodes/wk Osteoporosis prescription medication Age at screening, y BMI, kg/m2 Total calcium intake, mg Total vitamin d intake, IU Physical functioning scale (RAND36) Total energy expenditure/wk from phys act, MET-h

Mild (n ⴝ 1157) %

%

20.6 22.8 39 17.6

142 127 199 81

25.9 23.1 36.2 14.8

759 276 91 17 3 11

65.6 23.9 7.9 1.5 0.3 1

252 213 66 10 3 5

45.9 38.8 12 1.8 0.5 0.9

34.4 36 29.5

395 414 338

34.4 36.1 29.5

251 181 111

46.2 33.3 20.4

946 880 503 360 243

32.3 30 17.2 12.3 8.3

343 305 177 138 87

32.7 29 16.9 13.1 8.3

234 125 65 50 27

46.7 25 13 10 5.4

1277 801 1083

40.4 25.3 34.3

406 403 348

35.1 34.8 30.1

143 246 160

26 44.8 29.1

183 308 487 1427 1029 315

7.6 12.8 20.2 59.3 32.6 10.3

215 183 167 383 405 117

22.7 19.3 17.6 40.4 35 10.6

115 71 75 195 245 67

25.2 15.6 16.4 42.8 44.7 12.8

1797 1072 251 215

57.6 34.4 8 6.8

638 408 98 75

55.8 35.7 8.6 6.5

272 201 66 75

50.5 37.3 12.2 13.7

1276 1027 749 85

40.7 32.7 23.9 2.7

495 372 249 30

43.2 32.5 21.7 2.6

290 146 84 19

53.8 27.1 15.6 3.5

523 1234 420 643 55

18.5 43.8 14.9 22.8 1.7

226 446 128 215 10

22.3 43.9 12.6 21.2 0.9

125 219 65 78 5

25.7 45 13.3 16 0.9

%

251 437 1507 966

7.9 13.8 47.7 30.6

238 264 451 204

2517 381 180 54 7 22

79.6 12.1 5.7 1.7 0.2 0.7

1083 1134 929

Mean

Moderate/Severe (n ⴝ 549) N

Mean

N

N

SD

SD

Mean

SD

P Valuea ⬍.001

⬍.001

⬍.001

.002

.08b

⬍.001

.18 .07 .01

.22 .13

.26

65.3 28.5 1085.5 313.4 80 11.5

7 6.1 672.4 252.9 20 14.5

61.8 29.1 1055.6 298.2 78 10.4

7.5 6 691.4 288.5 20.9 13.2

60.6 30.7 942.2 272.4 69.9 9.1

7.6 6.7 592.8 259 25.7 13

.51 ⬍.001 .02 .49 .96 ⬍.001 .34

Abbreviations: GED, General Educational Diploma; MET-h, metabolic equivalent of task (hours/week); RAND36, 36-item Short-Form Health Survey. a

P adjusted for age, BMI, race/ethnicity, BMD scanner, and smoking.

b

Region and BMD scanner are confounded so P was not adjusted for scanner.

ications (n ⫽ 3621) at baseline or any time during the followup period. Results were similar to the results of the primary analyses (data not shown). Associations between VMS and BMD The baseline severity of VMS was not associated with baseline femoral neck or spine BMD. Associations between baseline VMS severity and baseline BMD did not significantly differ across categories of BMI, age, or years

since menopause (interaction P ⬎ 0.05), except that associations of VMS severity with baseline lumbar spine BMD differed according to BMI category (interaction P ⫽ 0.04). In the subgroup of women with BMI ⱖ 30 kg/m2, compared with women who reported no VMS, women with moderate/severe VMS had lower baseline femoral neck BMD (⫺0.015 g/cm2; 95% CI, ⫺0.029 –⫺0.001 g/cm2) and baseline lumbar spine BMD (⫺0.024 g/cm2; 95% CI, ⫺0.045–⫺0.002 g/cm2).


doi: 10.1210/jc.2014-3062


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Table 3. Multivariablea-Adjusted Risk of Fracture Associated with Severity of Baseline Vasomotor Symptoms in the Fracture Study Population (n ⫽ 23 573), Stratified by Age and BMI Severity of Baseline Vasomotor Symptoms

Fracture Site Hip

Spine

Otherc

a

None

Mild

Moderate/Severe

Subgroup

N

%

N

%

HR

(95% CI)

N

%

HR

(95% CI)

P Valueb

Overall Age, y 50 –59 60 – 69 70 –79 BMI Normal (⬍25) Overweight (25–30) Obese (ⱖ30) Overall Age, y 50 –59 60 – 69 70 –79 BMI Normal (⬍25) Overweight (25–30) Obese (ⱖ30) Overall Age, y 50 –59 60 – 69 70 –79 BMI Normal (⬍25) Overweight (25–30) Obese (ⱖ30)

265

0.21

53

0.11

0.93

(0.69 –1.27)

29

0.15

1.78

(1.20 –2.64)

.01 .90

13 85 167

0.04 0.13 0.53

8 21 24

0.04 0.11 0.41

1.08 0.92 0.90

(0.43–2.70) (0.57–1.49) (0.57–1.41)

5 10 14

0.05 0.15 0.69

1.76 1.63 1.93

(0.61–5.11) (0.84 –3.16) (1.11–3.34)

88 120 57 226

0.28 0.28 0.11 0.18

21 21 11 66

0.19 0.13 0.06 0.14

1.26 0.79 0.75 1.16

(0.76 –2.09) (0.50 –1.27) (0.38 –1.48) (0.87–1.54)

7 12 10 21

0.19 0.19 0.11 0.11

1.53 1.90 1.95 1.09

(0.70 –3.35) (1.03–3.50) (0.98 –3.87) (0.68 –1.75)

29 84 113

0.10 0.13 0.36

13 31 22

0.06 0.16 0.38

0.71 1.34 1.20

(0.37–1.37) (0.88 –2.02) (0.75–1.91)

3 7 11

0.03 0.11 0.54

0.39 1.12 1.74

(0.12–1.28) (0.52–2.42) (0.91–3.34)

76 75 74 2240

0.24 0.17 0.15 1.94

15 24 27 673

0.13 0.15 0.14 1.51

0.82 1.27 1.38 0.93

(0.46 –1.48) (0.79 –2.02) (0.88 –2.18) (0.85–1.02)

7 7 7 289

0.19 0.11 0.07 1.57

1.40 1.45 0.75 1.12

(0.63–3.10) (0.65–3.19) (0.32–1.74) (0.98 –1.27)

387 1115 738

1.41 1.88 2.55

253 295 125

1.23 1.57 2.32

0.91 0.92 1.00

(0.78 –1.07) (0.80 –1.04) (0.82–1.22)

133 109 47

1.30 1.75 2.52

1.07 1.15 1.14

(0.87–1.31) (0.95–1.41) (0.84 –1.55)

647 798 785

2.26 2.00 1.68

169 266 236

1.61 1.73 1.27

0.89 1.03 0.88

(0.74 –1.06) (0.89 –1.19) (0.76 –1.02)

54 101 130

1.58 1.72 1.46

0.92 1.21 1.15

(0.69 –1.23) (0.97–1.50) (0.95–1.40)

.33

.59 .07

.17

.04 .77

.49

Adjusted for baseline age, BMI, race/ethnicity, smoking, education, and stratified by age group and prior history of fracture.

b

P corresponds to a 2-degree-of-freedom test of association for the 3-level nominal categorical predictor.

c

Includes hip fracture.

After adjusting for baseline age, BMI, race/ethnicity, smoking, and education, VMS severity was inversely associated with mean followup BMD both at the femoral neck and at the spine BMD (P for test of trend ⫽ .004 for femoral neck and .045 for spine). Compared with women who reported no VMS, women with moderate/severe VMS had 0.015 g/cm2 lower femoral neck BMD (95% CI, ⫺0.025–⫺0.005, g/cm2) and 0.016 g/cm2 lower lumbar spine BMD (95% CI, ⫺0.032–⫺0.004, g/cm2). Associations between VMS severity and BMD during followup did not differ by baseline age, years since menopause, or baseline BMI category (P ⬎ .05 for trend test). We show the trajectories of femoral neck BMD (Figure 2) and lumbar spine BMD (Figure 3) over time for each category of VMS severity (no VMS, mild VMS, moderate/severe VMS). Compared with participants without VMS, participants with moderate/severe VMS, had a steeper decline in femoral neck BMD and blunted increase in spine BMD. In a sensitivity analysis that excluded women with a history of breast cancer at baseline (n ⫽ 133), associations between VMS and BMD were similar. Compared with women who reported no VMS, women with moderate/ severe VMS had 0.013 g/cm2 lower femoral neck BMD (95% CI, ⫺0.024 –⫺0.003, g/cm2, P ⫽ .01) and 0.017

g/cm2 lower lumbar spine BMD (95% CI, ⫺0.033– ⫺0.007, g/cm2, P ⫽ .04).

Discussion In this prospective study, compared with women who did not have VMS, women with moderate/severe VMS had lower BMD over time at the femoral neck and lumbar spine, and increased rates of hip fractures during an average (SD) of 8.2 years of followup. These associations did not differ by baseline age or BMI category. Despite being younger and heavier than asymptomatic women, characteristics associated with higher BMD, women with moderate/severe VMS had a higher risk of hip fractures that was also independent of other established risk factors for fractures. To our knowledge, only one study has examined associations of VMS with subsequent fracture rates. That study included postmenopausal women with osteoporosis by BMD or prevalent fractures and found no association between hot flashes “that bothered them or interfered with their lives” in the previous 6 months with vertebral or nonvertebral fractures (14). However, followup duration


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Figure 2. Femoral neck BMD by baseline vasomotor symptoms.

was only 3 years and information regarding fracture locations was not analyzed. Two thirds of participants were randomly assigned to receive raloxifene, which is known to cause hot flashes in some women. The etiology of these hot flashes may be different than menopause-related VMS and may explain the discrepancy between results of the prior study and ours. Other longitudinal studies have found that postmenopausal women with VMS had lower BMD than those without VMS (13, 14). An additional longitudinal study found an association between “sweating” frequency and more rapid rates of loss in forearm BMD (9). Lower estradiol levels in women with hot flashes may partly explain the associations we found between VMS and decreased bone density. We and others have previously found that higher estradiol levels are associated with

lower rates of bone loss over the menopausal transition (26 –28), and some longitudinal studies have found lower estradiol levels among women with VMS (29 –31). Associations of estrogen level with VMS are likely complex, and may also depend on whether women have residual intermittent ovulatory activity (32). Information on estrogen levels is not available for the present study. A possible explanation for our findings may be related to balance. However, moderate/severe VMS were not associated with increased risk for lower arm/wrist fracture. Moreover, including incident falls as a covariate did not attenuate the VMS HR for hip fracture. Our analysis does suggest that impaired physical functioning may partially explain the association between moderate/severe VMS and hip fracture. Falls are multifactorial and it is likely that


doi: 10.1210/jc.2014-3062


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Figure 3. Lumbar spine (L2–L4) BMD by baseline vasomotor symptoms.

we saw no attenuation because of our inability to directly control for balance. In this study, increases in spine BMD over time were more pronounced among women without VMS than among women with moderate/severe VMS, yet spine BMD increased over time in all groups. A previous crosssectional study found that age and BMD were strongly inversely related at the hip, but not at the lumbar spine (33). This may be because typical anteroposterior projection used in dual-energy x-ray absorptiometry to measure spine BMD is confounded by degenerative changes due to aging. For example, spinal degeneration and hyperostosis (osteophytes), vertebral fracture, and aortic calcification can spuriously increase bone density (34). It is also possible that increases in spine BMD are driven by the sub-

group of WHI participants who received calcium and vitamin D in the WHI Calcium ⫹ Vitamin D trial (35). Our study has limitations. Participants of WHI were healthier than similarly aged women in the general population, and the incidence of fractures in this cohort was low. Also, VMS were self reported and assessed at a single baseline visit. However, we suspect that this means of assessing VMS reflects what occurs in routine clinical practice. We cannot rule out residual confounding. The associations among age, VMS, BMD, fracture, and HT use in an observational setting are complex. However, in the current study, it is unlikely that HT use confounded our results because we included only women who reported that they had never used HT at baseline, and the overwhelming majority of these women did not initiate HT


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during followup. Because BMD was available only in a subset of participants (n ⫽ 4867), we were unable to adjust for BMD in the fracture models. Insufficient numbers of hip fracture events precluded a more detailed investigation into the joint effects of hot flash severity and night sweat severity and their corresponding interactions. Finally, information regarding serum levels of estrogen, vitamin D, and bone turnover markers was not available. Strengths of our study include the large number of participants, the long followup duration, the collection of information regarding both hot flashes and night sweats, the direct measurement of BMI (which is associated with both VMS and BMD), the adjudication of fracture endpoints, and the detailed information regarding fracture risk factors and anatomical locations of fractures. In conclusion, we found that women with moderate/ severe VMS have lower BMD and increased hip fracture rates over followup. VMS are common, experienced by at least 60% of women (2). Information regarding VMS is easily assessable by clinicians. Women with VMS may benefit from greater attention to healthy lifestyle habits to maintain bone health. Elucidation of the biological mechanisms underlying these associations may inform the design of preventive strategies for at-risk women prior to occurrence of fracture.

Acknowledgments Address all correspondence and requests for reprints to: Carolyn Janet Crandall, MD, MS, David Geffen School of Medicine at University of California, Los Angeles, 911 Broxton Avenue, 1st floor, Los Angeles, CA 90049. E-mail: [email protected]. Program Office: (National Heart, Lung, and Blood Institute, Bethesda, Maryland) Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan, Leslie Ford, and Nancy Geller. Clinical Coordinating Center: (Fred Hutchinson Cancer, Research Center, Seattle, Washington) Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles, Kooperberg. Investigators and Academic Centers: (Brigham and Women’s Hospital, Harvard Medical, School, Boston, Massachusetts) JoAnn E. Manson; (MedStar Health Research Institute/Howard University, Washington, DC) Barbara V. Howard; (Stanford Prevention Research Center, Stanford, California), Marcia L. Stefanick; (The Ohio State University, Columbus, Ohio) Rebecca Jackson; (University of Arizona, Tucson/Phoenix, Arizona) Cynthia A. Thomson; (University at Buffalo, Buffalo, New York), Jean WactawskiWende; (University of Florida, Gainesville/Jacksonville, Florida) Marian Limacher; (University of Iowa, Iowa/Davenport, Iowa) Robert Wallace; (University of Pittsburgh, Pittsburgh, Pennsylvania) Lewis Kuller; (Wake Forest University School of Medicine, Winston-Salem, North Carolina) Sally Shumaker, Women’s Health Initiative Memory Study: (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker.


The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through Contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN 268201100004C, and HHSN271201100004C. Disclosure Summary: C.J.C., E.L., M.J.O’S., A.L., J.C., J.M., M.V., J.W.-W., and A.A. have nothing to discolse. R.W. is a consultant to Merck and Novartis to perform safety monitoring of antiosteoporotic clinical trials. N.W. is cofounder, stockholder, and director of Osteodynamics. He has received honoraria for lectures from Amgen and Merck in the past year. He has received consulting fees from the following companies in the past year: AbbVie, Amarin, Amgen, Bristol-Myers Squibb, Corcept, Endo, Imagepace, Janssen, Lilly, Merck, Novartis, Noven, Pfizer/Wyeth, Radius, and Sanfo-Aventis. Through his health system, he has received research support from Merck and NPS.

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Exercise for vasomotor menopausal symptoms.

Early severe vasomotor menopausal symptoms are associated with diabetes.

EMAS position statement: Non-hormonal management of menopausal vasomotor symptoms.

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Vasomotor menopausal symptoms and risk of stroke among mid-aged women.

Estrogen receptor beta and its selective ligands: an option for treatment of menopausal vasomotor symptoms?

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Combined Red Clover isoflavones and probiotics potently reduce menopausal vasomotor symptoms.

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Association of Vasomotor and Other Menopausal Symptoms with Risk of Cardiovascular Disease: A Systematic Review and Meta-Analysis.

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