Effects of Estrogen Plus Progestin on Risk of Fracture and Bone Mineral Density

The Women's Health Initiative Randomized Trial

Jane A. Cauley, John Robbins, Zhao Chen, Steven R. Cummings, Rebecca D. Jackson, Andrea Z. LaCroix, Meryl LeBoff, Cora E. Lewis, Joan McGowan, Joan Neuner, Mary Pettinger, Marcia L. Stefanick, Jean Wactawski-Wende, Nelson B. Watts

Research output: Contribution to journalArticle

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Abstract

Context: In the Women's Health Initiative trial of estrogen-plus-progestin therapy, women assigned to active treatment had fewer fractures. Objective: To test the hypothesis that the relative risk reduction of estrogen plus progestin on fractures differs according to risk factors for fractures. Design, Setting, and Participants: Randomized controlled trial (September 1993-July 2002) in which 16608 postmenopausal women aged 50 to 79 years with an intact uterus at baseline were recruited at 40 US clinical centers and followed up for an average of 5.6 years. Intervention: Women were randomly assigned to receive conjugated equine estrogen, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102). Main Outcome Measures: All confirmed osteoporotic fracture events that occurred from enrollment to discontinuation of the trial (July 7, 2002); bone mineral density (BMD), measured in a subset of women (n = 1024) at baseline and years 1 and 3; and a global index, developed to summarize the balance of risks and benefits to test whether the risk-benefit profile differed across tertiles of fracture risk. Results: Seven hundred thirty-three women (8.6%) in the estrogen-plus-progestin group and 896 women (11.1%) in the placebo group experienced a fracture (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.69-0.83). The effect did not differ in women stratified by age, body mass index, smoking status, history of falls, personal and family history of fracture, total calcium intake, past use of hormone therapy, BMD, or summary fracture risk score. Total hip BMD increased 3.7% after 3 years of treatment with estrogen plus progestin compared with 0.14% in the placebo group (P<.001). The HR for the global index was similar across tertiles of the fracture risk scale (lowest fracture risk tertile, HR, 1.20; 95% CI, 0.93-1.58; middle tertile, HR, 1.23; 95% CI, 1.04-1.46; highest tertile, HR, 1.03; 95% CI, 0.88-1.24) (P for interaction = .54). Conclusions: This study demonstrates that estrogen plus progestin increases BMD and reduces the risk of fracture in healthy postmenopausal women. The decreased risk of fracture attributed to estrogen plus progestin appeared to be present in all sub-groups of women examined. When considering the effects of hormone therapy on other important disease outcomes in a global model, there was no net benefit, even in women considered to be at high risk of fracture.

Original languageEnglish (US)
Pages (from-to)1729-1738
Number of pages10
JournalJournal of the American Medical Association
Volume290
Issue number13
DOIs
StatePublished - Oct 1 2003

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Women's Health
Progestins
Bone Density
Estrogens
Confidence Intervals
Placebos
Pelvic Bones
Hormones
Therapeutics
Conjugated (USP) Estrogens
Medroxyprogesterone Acetate
Osteoporotic Fractures
Risk Reduction Behavior
Tablets
Uterus
Body Mass Index
Randomized Controlled Trials
Smoking
Outcome Assessment (Health Care)
Calcium

ASJC Scopus subject areas

  • Medicine(all)

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Effects of Estrogen Plus Progestin on Risk of Fracture and Bone Mineral Density : The Women's Health Initiative Randomized Trial. / Cauley, Jane A.; Robbins, John; Chen, Zhao; Cummings, Steven R.; Jackson, Rebecca D.; LaCroix, Andrea Z.; LeBoff, Meryl; Lewis, Cora E.; McGowan, Joan; Neuner, Joan; Pettinger, Mary; Stefanick, Marcia L.; Wactawski-Wende, Jean; Watts, Nelson B.

In: Journal of the American Medical Association, Vol. 290, No. 13, 01.10.2003, p. 1729-1738.

Research output: Contribution to journalArticle

Cauley, JA, Robbins, J, Chen, Z, Cummings, SR, Jackson, RD, LaCroix, AZ, LeBoff, M, Lewis, CE, McGowan, J, Neuner, J, Pettinger, M, Stefanick, ML, Wactawski-Wende, J & Watts, NB 2003, 'Effects of Estrogen Plus Progestin on Risk of Fracture and Bone Mineral Density: The Women's Health Initiative Randomized Trial', Journal of the American Medical Association, vol. 290, no. 13, pp. 1729-1738. https://doi.org/10.1001/jama.290.13.1729
Cauley, Jane A. ; Robbins, John ; Chen, Zhao ; Cummings, Steven R. ; Jackson, Rebecca D. ; LaCroix, Andrea Z. ; LeBoff, Meryl ; Lewis, Cora E. ; McGowan, Joan ; Neuner, Joan ; Pettinger, Mary ; Stefanick, Marcia L. ; Wactawski-Wende, Jean ; Watts, Nelson B. / Effects of Estrogen Plus Progestin on Risk of Fracture and Bone Mineral Density : The Women's Health Initiative Randomized Trial. In: Journal of the American Medical Association. 2003 ; Vol. 290, No. 13. pp. 1729-1738.
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abstract = "Context: In the Women's Health Initiative trial of estrogen-plus-progestin therapy, women assigned to active treatment had fewer fractures. Objective: To test the hypothesis that the relative risk reduction of estrogen plus progestin on fractures differs according to risk factors for fractures. Design, Setting, and Participants: Randomized controlled trial (September 1993-July 2002) in which 16608 postmenopausal women aged 50 to 79 years with an intact uterus at baseline were recruited at 40 US clinical centers and followed up for an average of 5.6 years. Intervention: Women were randomly assigned to receive conjugated equine estrogen, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102). Main Outcome Measures: All confirmed osteoporotic fracture events that occurred from enrollment to discontinuation of the trial (July 7, 2002); bone mineral density (BMD), measured in a subset of women (n = 1024) at baseline and years 1 and 3; and a global index, developed to summarize the balance of risks and benefits to test whether the risk-benefit profile differed across tertiles of fracture risk. Results: Seven hundred thirty-three women (8.6{\%}) in the estrogen-plus-progestin group and 896 women (11.1{\%}) in the placebo group experienced a fracture (hazard ratio [HR], 0.76; 95{\%} confidence interval [CI], 0.69-0.83). The effect did not differ in women stratified by age, body mass index, smoking status, history of falls, personal and family history of fracture, total calcium intake, past use of hormone therapy, BMD, or summary fracture risk score. Total hip BMD increased 3.7{\%} after 3 years of treatment with estrogen plus progestin compared with 0.14{\%} in the placebo group (P<.001). The HR for the global index was similar across tertiles of the fracture risk scale (lowest fracture risk tertile, HR, 1.20; 95{\%} CI, 0.93-1.58; middle tertile, HR, 1.23; 95{\%} CI, 1.04-1.46; highest tertile, HR, 1.03; 95{\%} CI, 0.88-1.24) (P for interaction = .54). Conclusions: This study demonstrates that estrogen plus progestin increases BMD and reduces the risk of fracture in healthy postmenopausal women. The decreased risk of fracture attributed to estrogen plus progestin appeared to be present in all sub-groups of women examined. When considering the effects of hormone therapy on other important disease outcomes in a global model, there was no net benefit, even in women considered to be at high risk of fracture.",
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T1 - Effects of Estrogen Plus Progestin on Risk of Fracture and Bone Mineral Density

T2 - The Women's Health Initiative Randomized Trial

AU - Cauley, Jane A.

AU - Robbins, John

AU - Chen, Zhao

AU - Cummings, Steven R.

AU - Jackson, Rebecca D.

AU - LaCroix, Andrea Z.

AU - LeBoff, Meryl

AU - Lewis, Cora E.

AU - McGowan, Joan

AU - Neuner, Joan

AU - Pettinger, Mary

AU - Stefanick, Marcia L.

AU - Wactawski-Wende, Jean

AU - Watts, Nelson B.

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N2 - Context: In the Women's Health Initiative trial of estrogen-plus-progestin therapy, women assigned to active treatment had fewer fractures. Objective: To test the hypothesis that the relative risk reduction of estrogen plus progestin on fractures differs according to risk factors for fractures. Design, Setting, and Participants: Randomized controlled trial (September 1993-July 2002) in which 16608 postmenopausal women aged 50 to 79 years with an intact uterus at baseline were recruited at 40 US clinical centers and followed up for an average of 5.6 years. Intervention: Women were randomly assigned to receive conjugated equine estrogen, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102). Main Outcome Measures: All confirmed osteoporotic fracture events that occurred from enrollment to discontinuation of the trial (July 7, 2002); bone mineral density (BMD), measured in a subset of women (n = 1024) at baseline and years 1 and 3; and a global index, developed to summarize the balance of risks and benefits to test whether the risk-benefit profile differed across tertiles of fracture risk. Results: Seven hundred thirty-three women (8.6%) in the estrogen-plus-progestin group and 896 women (11.1%) in the placebo group experienced a fracture (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.69-0.83). The effect did not differ in women stratified by age, body mass index, smoking status, history of falls, personal and family history of fracture, total calcium intake, past use of hormone therapy, BMD, or summary fracture risk score. Total hip BMD increased 3.7% after 3 years of treatment with estrogen plus progestin compared with 0.14% in the placebo group (P<.001). The HR for the global index was similar across tertiles of the fracture risk scale (lowest fracture risk tertile, HR, 1.20; 95% CI, 0.93-1.58; middle tertile, HR, 1.23; 95% CI, 1.04-1.46; highest tertile, HR, 1.03; 95% CI, 0.88-1.24) (P for interaction = .54). Conclusions: This study demonstrates that estrogen plus progestin increases BMD and reduces the risk of fracture in healthy postmenopausal women. The decreased risk of fracture attributed to estrogen plus progestin appeared to be present in all sub-groups of women examined. When considering the effects of hormone therapy on other important disease outcomes in a global model, there was no net benefit, even in women considered to be at high risk of fracture.

AB - Context: In the Women's Health Initiative trial of estrogen-plus-progestin therapy, women assigned to active treatment had fewer fractures. Objective: To test the hypothesis that the relative risk reduction of estrogen plus progestin on fractures differs according to risk factors for fractures. Design, Setting, and Participants: Randomized controlled trial (September 1993-July 2002) in which 16608 postmenopausal women aged 50 to 79 years with an intact uterus at baseline were recruited at 40 US clinical centers and followed up for an average of 5.6 years. Intervention: Women were randomly assigned to receive conjugated equine estrogen, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102). Main Outcome Measures: All confirmed osteoporotic fracture events that occurred from enrollment to discontinuation of the trial (July 7, 2002); bone mineral density (BMD), measured in a subset of women (n = 1024) at baseline and years 1 and 3; and a global index, developed to summarize the balance of risks and benefits to test whether the risk-benefit profile differed across tertiles of fracture risk. Results: Seven hundred thirty-three women (8.6%) in the estrogen-plus-progestin group and 896 women (11.1%) in the placebo group experienced a fracture (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.69-0.83). The effect did not differ in women stratified by age, body mass index, smoking status, history of falls, personal and family history of fracture, total calcium intake, past use of hormone therapy, BMD, or summary fracture risk score. Total hip BMD increased 3.7% after 3 years of treatment with estrogen plus progestin compared with 0.14% in the placebo group (P<.001). The HR for the global index was similar across tertiles of the fracture risk scale (lowest fracture risk tertile, HR, 1.20; 95% CI, 0.93-1.58; middle tertile, HR, 1.23; 95% CI, 1.04-1.46; highest tertile, HR, 1.03; 95% CI, 0.88-1.24) (P for interaction = .54). Conclusions: This study demonstrates that estrogen plus progestin increases BMD and reduces the risk of fracture in healthy postmenopausal women. The decreased risk of fracture attributed to estrogen plus progestin appeared to be present in all sub-groups of women examined. When considering the effects of hormone therapy on other important disease outcomes in a global model, there was no net benefit, even in women considered to be at high risk of fracture.

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