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Age of menopause and fracture risk in postmenopausal women randomized to calcium + vitamin D, hormone therapy, or the combination: results from the Women's Health Initiative Clinical Trials

Sullivan, Shannon D. MD, PhD; Lehman, Amy MAS; Nathan, Nisha K. MD; Thomson, Cynthia A. PhD, RDN; Howard, Barbara V. PhD

doi: 10.1097/GME.0000000000000775
Original Articles

Objective: We previously reported that in the absence of hormone therapy (HT) or calcium/vitamin D (Ca/D) supplementation, earlier menopause age was associated with decreased bone mineral density and increased fracture risk in healthy postmenopausal women. Treatment with HT and Ca/D is protective against fractures after menopause. In this analysis, we asked if the age of menopause onset alters fracture risk in healthy postmenopausal women receiving HT, Ca/D, or a combination.

Methods: Hazard ratios (HRs) for any fracture among 21,711 healthy postmenopausal women enrolled in the Women's Health Initiative Clinical Trial, who were treated with HT, Ca/D, or HT + Ca/D, and who reported age of nonsurgical menopause of <40, 40 to 49, and ≥50 years, were compared.

Results: Women with menopause <40 years had significantly higher HR for fracture than women with menopause 40 to 49 or ≥50 years, regardless of treatment intervention (HR [95% CI]: menopause <40 y vs ≥50 y, 1.36 [1.11-1.67]; menopause <40 y vs 40-49 y, 1.30 [1.06-1.60]).

Conclusions: In the overall Women's Health Initiative Clinical Trial cohort and within each treatment group, women with younger menopause age (<40 y) had a higher risk of any fracture than women reporting older menopause ages. The effect of menopause age on fracture risk was not altered by any of the treatment interventions (HT, Ca/D, HT + Ca/D), suggesting that early age of menopause is an independent contributor to postmenopausal fracture risk.

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1US Food and Drug Administration, Silver Spring, MD

2Center for Biostatistics, The Ohio State University, Columbus, OH

3Department of Medicine, Division of Endocrinology & Metabolism, George Washington University Medical Faculty Associates, Washington, DC

4Department of Health Promotion Sciences, Mel & Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ

5Medstar Health Research Institute and Georgetown/Howard Universities Center for Clinical and Translational Research, Hyattsville, MD.

Address correspondence to: Shannon D. Sullivan, MD, PhD, Medical Officer, US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993. E-mail:

Received 2 May, 2016

Revised 6 September, 2016

Accepted 6 September, 2016

Funding/support: The WHI program is funded by the National Heart, Lung, and Blood Institute, and by the United States Department of Health and Human Services.

Financial disclosure/conflicts of interest: None reported.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (

© 2017 by The North American Menopause Society.