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

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


Menopause. 2017;24(4):371-378. 

In This Article

Abstract and Introduction


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.


Osteoporotic fractures are a significant cause of morbidity and mortality in postmenopausal women.[1–7] The Women's Health Initiative Clinical Trial (WHI CT) was composed of three prospective, randomized, controlled trials investigating the effects of (1) hormone therapy (HT), (2) calcium and vitamin D (Ca/D) supplementation, and (3) a low fat, high fruit/vegetable/grain diet on morbidity and mortality in postmenopausal women. Eligible women were able to participate in one, two, or all three trials. Among the WHI CTs, primary outcome measures were the occurrence of osteoporotic fractures and modification of fracture rate by intervention with HT, Ca/D supplementation, or both (HT + Ca/D). Results from the WHI CT showed that HT reduced the risk for osteoporotic fractures compared with placebo.[8–10] Ca/D treatment alone significantly decreased risk for hip fracture in women aged 60 or older, suggesting a longer duration of menopause may be associated with greater efficacy of treatment.[8] On the contrary, all participants treated with HT experienced a decrease in fracture rate compared with women taking placebo, and this effect was independent of participants' age or baseline risk for fracture.[9,10]

We recently reported that age of nonsurgical menopause onset is a risk factor for fracture among healthy postmenopausal women in the WHI Observational Study (WHI OS), in which there was no treatment intervention.[11] In the absence of HT or Ca/D supplementation, and after adjusting for known risk factors for fracture, women in the WHI OS who experienced early menopause (<40 y) had higher fracture rates than women who experienced menopause between ages 40 to 49 and ≥50 years.[11] Building on these findings, here we sought to examine the effect of age of nonsurgical menopause on fracture risk in women randomized within the WHI CT to HT, Ca/D, or HT + Ca/D, understanding that these exposures might attenuate fracture risk related to age of menopause and thus offer a therapeutic intervention to reduce fracture risk in women who experience younger age of natural menopause.