Postmenopausal hormone therapy in the prevention and treatment of osteoporosis
- Harold N Rosen, MD
Harold N Rosen, MD
- Assistant Professor in Medicine
- Harvard Medical School
- Marc K Drezner, MD
Marc K Drezner, MD
- Section Editor — Bone Disease
- Professor of Medicine
- University of Wisconsin Medical School
- Section Editors
- Robert L Barbieri, MD
Robert L Barbieri, MD
- Editor-in-Chief — Obstetrics, Gynecology and Women's Health
- Section Editor — General Gynecology and Female Reproductive Endocrinology
- Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology
- Harvard Medical School
- William F Crowley, Jr, MD
William F Crowley, Jr, MD
- Section Editor — Female Reproductive Endocrinology
- Daniel K Podolsky Professor of Medicine
- Harvard Medical School
Normal women have menopause (ovarian failure) at a mean age of 51 years. The resulting lack of estrogen is associated with rapid bone loss due to increased bone resorption and often consequent osteoporosis (see "Pathogenesis of osteoporosis"). Many women also experience menopausal symptoms, including hot flashes, vaginal dryness, and urinary symptoms, all of which are relieved most effectively by estrogen therapy with or without a progestin.
For women with menopausal symptoms, estrogen is often given short-term (six months to five years), with the goal of eventual tapering and discontinuation (unless there is a compelling reason to continue long-term). (See "Menopausal hot flashes".)
Prior to the publication of the Women's Health Initiative, long-term (more than five years) estrogen and combined estrogen-progestin therapy were routinely prescribed for osteoporosis and coronary heart disease (CHD) based upon observational data demonstrating a protective antiresorptive effect of estrogen on bone and a positive effect on the heart.
However, currently available data from clinical trials do not confirm that estrogen prevents or delays cardiovascular disease. To the contrary, the Women's Health Initiative (WHI) and other trials suggest that combined estrogen-progestin is not cardioprotective and may slightly increase risk when used for either primary or secondary prevention of CHD. Moreover, combined therapy increases the risk of stroke, venous thromboembolism, and breast cancer , while unopposed estrogen therapy may increase stroke and venous thromboembolism, but not CHD or breast cancer risk. Of note, follow-up analyses suggest that older, but not younger, postmenopausal women have excess CHD risk. (See "Menopausal hormone therapy and cardiovascular risk" and "Menopausal hormone therapy and the risk of breast cancer".)
In light of the WHI data and the efficacy of other antiresorptive drugs, including bisphosphonates and raloxifene, estrogen-progestin therapy should no longer be used solely for the prevention or treatment of osteoporosis. Exceptions include women with persistent menopausal symptoms and those who cannot tolerate the other drugs. (See "Overview of the management of osteoporosis in postmenopausal women".)
- Rossouw JE, Anderson GL, Prentice RL, et al. 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.
- Effects of hormone therapy on bone mineral density: results from the postmenopausal estrogen/progestin interventions (PEPI) trial. The Writing Group for the PEPI. JAMA 1996; 276:1389.
- Riis B, Thomsen K, Christiansen C. Does calcium supplementation prevent postmenopausal bone loss? A double-blind, controlled clinical study. N Engl J Med 1987; 316:173.
- Prince RL, Smith M, Dick IM, et al. Prevention of postmenopausal osteoporosis. A comparative study of exercise, calcium supplementation, and hormone-replacement therapy. N Engl J Med 1991; 325:1189.
- Aloia JF, Vaswani A, Yeh JK, et al. Calcium supplementation with and without hormone replacement therapy to prevent postmenopausal bone loss. Ann Intern Med 1994; 120:97.
- Munk-Jensen N, Pors Nielsen S, Obel EB, Bonne Eriksen P. Reversal of postmenopausal vertebral bone loss by oestrogen and progestogen: a double blind placebo controlled study. Br Med J (Clin Res Ed) 1988; 296:1150.
- Field CS, Ory SJ, Wahner HW, et al. Preventive effects of transdermal 17 beta-estradiol on osteoporotic changes after surgical menopause: a two-year placebo-controlled trial. Am J Obstet Gynecol 1993; 168:114.
- Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004; 291:1701.
- Banks E, Beral V, Reeves G, et al. Fracture incidence in relation to the pattern of use of hormone therapy in postmenopausal women. JAMA 2004; 291:2212.
- Gallagher JC, Kable WT, Goldgar D. Effect of progestin therapy on cortical and trabecular bone: comparison with estrogen. Am J Med 1991; 90:171.
- Schneider DL, Barrett-Connor EL, Morton DJ. Timing of postmenopausal estrogen for optimal bone mineral density. The Rancho Bernardo Study. JAMA 1997; 277:543.
- Cauley JA, Seeley DG, Ensrud K, et al. Estrogen replacement therapy and fractures in older women. Study of Osteoporotic Fractures Research Group. Ann Intern Med 1995; 122:9.
- Cauley JA, Zmuda JM, Ensrud KE, et al. Timing of estrogen replacement therapy for optimal osteoporosis prevention. J Clin Endocrinol Metab 2001; 86:5700.
- Felson DT, Zhang Y, Hannan MT, et al. The effect of postmenopausal estrogen therapy on bone density in elderly women. N Engl J Med 1993; 329:1141.
- Michaëlsson K, Baron JA, Farahmand BY, et al. Hormone replacement therapy and risk of hip fracture: population based case-control study. The Swedish Hip Fracture Study Group. BMJ 1998; 316:1858.
- Lindsay R, Hart DM, MacLean A, et al. Bone response to termination of oestrogen treatment. Lancet 1978; 1:1325.
- Christiansen C, Christensen MS, Transbøl I. Bone mass in postmenopausal women after withdrawal of oestrogen/gestagen replacement therapy. Lancet 1981; 1:459.
- Greendale GA, Espeland M, Slone S, et al. Bone mass response to discontinuation of long-term hormone replacement therapy: results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) Safety Follow-up Study. Arch Intern Med 2002; 162:665.
- Greenspan SL, Emkey RD, Bone HG, et al. Significant differential effects of alendronate, estrogen, or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2002; 137:875.
- Lufkin EG, Wahner HW, O'Fallon WM, et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med 1992; 117:1.
- Villareal DT, Binder EF, Williams DB, et al. Bone mineral density response to estrogen replacement in frail elderly women: a randomized controlled trial. JAMA 2001; 286:815.
- Ettinger B, Genant HK, Steiger P, Madvig P. Low-dosage micronized 17 beta-estradiol prevents bone loss in postmenopausal women. Am J Obstet Gynecol 1992; 166:479.
- Stevenson JC, Cust MP, Gangar KF, et al. Effects of transdermal versus oral hormone replacement therapy on bone density in spine and proximal femur in postmenopausal women. Lancet 1990; 336:265.
- Speroff L, Rowan J, Symons J, et al. The comparative effect on bone density, endometrium, and lipids of continuous hormones as replacement therapy (CHART study). A randomized controlled trial. JAMA 1996; 276:1397.
- Ettinger B, Pressman A, Sklarin P, et al. Associations between low levels of serum estradiol, bone density, and fractures among elderly women: the study of osteoporotic fractures. J Clin Endocrinol Metab 1998; 83:2239.
- Lindsay R, Gallagher JC, Kleerekoper M, Pickar JH. Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women. JAMA 2002; 287:2668.
- Genant HK, Lucas J, Weiss S, et al. Low-dose esterified estrogen therapy: effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Estratab/Osteoporosis Study Group. Arch Intern Med 1997; 157:2609.
- Ettinger B, Ensrud KE, Wallace R, et al. Effects of ultralow-dose transdermal estradiol on bone mineral density: a randomized clinical trial. Obstet Gynecol 2004; 104:443.
- Prestwood KM, Kenny AM, Kleppinger A, Kulldorff M. Ultralow-dose micronized 17beta-estradiol and bone density and bone metabolism in older women: a randomized controlled trial. JAMA 2003; 290:1042.
- Ravn P, Bidstrup M, Wasnich RD, et al. Alendronate and estrogen-progestin in the long-term prevention of bone loss: four-year results from the early postmenopausal intervention cohort study. A randomized, controlled trial. Ann Intern Med 1999; 131:935.
- Eviö S, Tiitinen A, Laitinen K, et al. Effects of alendronate and hormone replacement therapy, alone and in combination, on bone mass and markers of bone turnover in elderly women with osteoporosis. J Clin Endocrinol Metab 2004; 89:626.
- Greenspan SL, Resnick NM, Parker RA. Combination therapy with hormone replacement and alendronate for prevention of bone loss in elderly women: a randomized controlled trial. JAMA 2003; 289:2525.
- Wimalawansa SJ. A four-year randomized controlled trial of hormone replacement and bisphosphonate, alone or in combination, in women with postmenopausal osteoporosis. Am J Med 1998; 104:219.
- Odvina CV, Zerwekh JE, Rao DS, et al. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 2005; 90:1294.
- Prior JC. Progesterone as a bone-trophic hormone. Endocr Rev 1990; 11:386.
- Horowitz M, Wishart J, Need AG, et al. Treatment of postmenopausal hyperparathyroidism with norethindrone. Effects on biochemistry and forearm mineral density. Arch Intern Med 1987; 147:681.
- Abdalla HI, Hart DM, Lindsay R, et al. Prevention of bone mineral loss in postmenopausal women by norethisterone. Obstet Gynecol 1985; 66:789.