Effects of Estrogen Plus Progestin on Risk of Fracture and Bone Mineral Density: The Women's Health Initiative Randomized Trial | Geriatrics | JAMA | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
Writing Group for the Women's Health Initiative Investigators.  Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial.  JAMA.2002;288:321-333.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12117397&dopt=AbstractGoogle Scholar
Women's Health Initiative Study Group.  Design of the Women's Health Initiative clinical trial and observational study.  Control Clin Trials.1998;19:61-109.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9492970&dopt=AbstractGoogle Scholar
Kristal AR, Shattuck AL, Williams AE. Food frequency questionnaires for diet intervention research. In: Proceedings of the 17th National Nutrient Databank Conference, June 7-10, 1992; Baltimore, Md. Washington, DC: International Life Sciences Institute Press; 1994:110-125.
Ensrud KE, Palermo L, Black DM.  et al.  Hip and calcaneal bone loss increase with advancing age: longitudinal results from the study of osteoporotic fractures.  J Bone Miner Res.1995;10:1778-1787.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8592956&dopt=AbstractGoogle Scholar
Expert Panel on the Identification, Evaluation, and Treatment of Overweight in Adults.  Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: executive summary.  Am J Clin Nutr.1998;68:899-917.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9771869&dopt=AbstractGoogle Scholar
Black DM, Steinbuch M, Palermo L.  et al.  An assessment tool for predicting fracture risk in postmenopausal women.  Osteoporos Int.2001;12:519-528.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11527048&dopt=AbstractGoogle Scholar
Kanis JA, Melton III LJ, Christiansen C, Johnston CC, Khaltaev N. The diagnosis of osteoporosis.  J Bone Miner Res.1994;9:1137-1141.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7976495&dopt=AbstractGoogle Scholar
Handa VL, Landerman R, Hanlon JT, Harris T, Cohen HJ. Do older women use estrogen replacement? data from the Duke Established Populations for Epidemiologic Studies of the Elderly (EPESE).  J Am Geriatr Soc.1996;44:1-6.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8537578&dopt=AbstractGoogle Scholar
Cauley JA, Seeley DG, Ensrud K, Ettinger B, Black D, Cummings SR. Estrogen replacement therapy and fractures in older women.  Ann Intern Med.1995;122:9-16.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7985914&dopt=AbstractGoogle Scholar
Weiss NS, Ure CL, Ballard JH, Williams AR, Daling JR. Decreased risk of fractures of hip and lower forearm with postmenopausal use of estrogen.  N Engl J Med.1980;303:1195-1198.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7421945&dopt=AbstractGoogle Scholar
Wells G, Tugwell P, Shea B.  et al.  Meta-analysis of the efficacy of hormone replacement therapy in treating and preventing osteoporosis in postmenopausal women.  Endocr Rev.2002;23:529-539.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12202468&dopt=AbstractGoogle Scholar
Torgerson DL, Bell-Syer SE. Hormone replacement therapy and prevention of nonvertebral fractures.  JAMA.2001;285:2891-2897.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11401611&dopt=AbstractGoogle Scholar
Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD. Postmenopausal hormone replacement therapy.  JAMA.2002;288:872-881.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12186605&dopt=AbstractGoogle Scholar
Grady D, Cummings SR. Postmenopausal hormone therapy for prevention of fractures: how good is the evidence?  JAMA.2001;285:2909-2011.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11401615&dopt=AbstractGoogle Scholar
Shumaker SA, Legault C, Rapp SR.  et al.  Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women.  JAMA.2003;289:2651-2662.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12771112&dopt=AbstractGoogle Scholar
Melton III LJ, Crowson CS, O'Fallon WM. Fracture incidence in Olmsted County, Minnesota: comparison of urban with rural rates and changes in urban rates overtime.  Osteoporos Int.1999;9:29-37.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10367027&dopt=AbstractGoogle Scholar
Black DM, Cummings SR, Karpf DB.  et al.  Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures.  Lancet.1996;348:1535-1541.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8950879&dopt=AbstractGoogle Scholar
Harris ST, Watts NB, Genant HK.  et al.  Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial.  JAMA.1999;282:1344-1352.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10527181&dopt=AbstractGoogle Scholar
McClung MR, Geusens P, Miller PD.  et al.  Effect of risedronate on the risk of hip fracture in elderly women.  N Engl J Med.2001;344:333-340.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11172164&dopt=AbstractGoogle Scholar
Cummings SR, Black DM, Thompson DE.  et al.  Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial.  JAMA.1998;280:2077-2082.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9875874&dopt=AbstractGoogle Scholar
Cauley JA, Petrini AM, LaPorte RE.  et al.  The decline of grip strength in the menopause: relationship to physical activity, estrogen use and anthropometric factors.  J Chronic Dis.1987;40:115-120.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3818864&dopt=AbstractGoogle Scholar
Brown BW, Birge SJ, Kohrt WM. Hormone replacement therapy does not augment gains in muscle strength or fat-free mass in response to weight-bearing exercise.  J Gerontol A Biol Sci Med Sci.1997;52:B166-B170.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9158551&dopt=AbstractGoogle Scholar
Seeley DG, Cauley JA, Grady D, Browner WS, Nevitt MC, Cummings SR. Is postmenopausal estrogen therapy associated with neuromuscular function or falling in elderly women?  Arch Intern Med.1995;155:293-299.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7832601&dopt=AbstractGoogle Scholar
Hulley SB, Grady D, Bush TL.  et al.  Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women.  JAMA.1998;280:605-613.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9718051&dopt=AbstractGoogle Scholar
Cauley JA, Black DM, Barrett-Connor E.  et al.  The effects of hormone replacement therapy on clinical fractures and height loss: the Heart and Estrogen/Progestin Replacement Study (HERS).  Am J Med.2001;110:442-450.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11331055&dopt=AbstractGoogle Scholar
Hulley SB, Furberg C, Barrett-Connor E.  et al.  Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/Progestin Replacement Study follow-up (HERS II).  JAMA.2002;288:58-66.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12090863&dopt=AbstractGoogle Scholar
Jamal S, Browner WS, Bauer DC, Cummings SR. Intermittent use of nitrates increases BMD: the Study of Osteoporotic Fractures.  J Bone Miner Res.1998;13:1755-1759.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9797485&dopt=AbstractGoogle Scholar
Meier CR, Schlienger RG, Kraenzlin ME, Schlegel B, Jick H. HMG-CoA reductase inhibitors and the risk of fractures.  JAMA.2000;283:3205-3210.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10866867&dopt=AbstractGoogle Scholar
Nelson HD, Helfano M, Wolf SH, Allan JD. Screening for postmenopausal osteoporosis: a review of the evidence from the US Preventive Services Task Force.  Ann Intern Med.2002;137:529-541.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12230356&dopt=AbstractGoogle Scholar
Black DM, Arden NK, Palermo L, Pearson J, Cummings SR. Prevalent vertebral deformities predict hip fractures and new vertebral deformities but not wrist fractures.  J Bone Miner Res.1999;14:821-828.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10320531&dopt=AbstractGoogle Scholar
Cooper C, O'Neill T, Silman AJ. The epidemiology of vertebral fractures.  Bone.1993;14:S89-S97.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8110529&dopt=AbstractGoogle Scholar
Jacobsen SJ, Goldberg J, Miles TP, Brody J, Stiers W, Rimm AA. Race and sex differences in mortality following fracture of the hip.  Am J Public Health.1992;82:1147-1150.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1636840&dopt=AbstractGoogle Scholar
Hannan EL, Magaziner J, Wang JJ.  et al.  Mortality and locomotion 6 months after hospitalization for hip fracture: risk factors and risk adjusted hospital outcomes.  JAMA.2001;285:2736-2742.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11386929&dopt=AbstractGoogle Scholar
Kado DM, Palermo WS, Nevitt MC, Genant HK, Cummings SR. Vertebral fractures and mortality in older women: a prospective study.  Arch Intern Med.1999;159:1215-1220.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10371229&dopt=AbstractGoogle Scholar
Nevitt MC, Ettinger B, Black DM.  et al.  The association of radiographically detected vertebral fractures with back pain and function: a prospective study.  Ann Intern Med.1998;128:793-800.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9599190&dopt=AbstractGoogle Scholar
Hays J, Ockene JK, Brunner RL.  et al.  Effects of estrogen plus progestin on health-related quality of life.  N Engl J Med.2003;348:1839-1854.Google Scholar
Original Contribution
October 1, 2003

Effects of Estrogen Plus Progestin on Risk of Fracture and Bone Mineral Density: The Women's Health Initiative Randomized Trial

Author Affiliations

Author Affiliations: Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pa (Dr Cauley); Department of Internal Medicine, University of California, Davis, School of Medicine, Sacramento (Dr Robbins); Division of Epidemiology and Biostatistics, Mel and Enid Zuckerman Arizona College of Public Health, University of Arizona, Tucson (Dr Chen); Research Institute at California Pacific Medical Center and Department of Epidemiology, University of California, San Francisco (Dr Cummings); Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Ohio State University, Columbus (Dr Jackson); Women's Health Initiative Clinical Coordinating Center, Fred Hutchinson Cancer Research Center, Seattle, Wash (Dr LaCroix and Ms Pettinger), Endocrine-Hypertension Division, Brigham and Women's Hospital, Boston, Mass (Dr LeBoff); Division of Preventive Medicine, University of Alabama at Birmingham (Dr Lewis); National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Md (Dr McGowan); Department of Medicine and Center for Patient Care and Outcomes Research, Medical College of Wisconsin, Milwaukee (Dr Neuner); Stanford Center for Research in Disease Prevention, Department of Medicine, Stanford University, Palo Alto, Calif (Dr Stefanick); University at Buffalo, State University of New York, Buffalo (Dr Wactawski-Wende); and University of Cincinnati College of Medicine, Cincinnati, Ohio (Dr Watts).

JAMA. 2003;290(13):1729-1738. doi:10.1001/jama.290.13.1729

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 16 608 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 subgroups 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.