Abstract
This presentation, developed from a symposium lecture at the 40th Annual Convention of the American College of Osteopathic Family Physicians on March 22, 2003, in Nashville, Tenn, highlights three pivotal studies that have altered the preferred option for the treatment and prevention of osteoporosis in postmenopausal women. The Heart Estrogen/progestin Replacement Study (HERS), the HERS II, and the Women's Health Initiative provide evidence that the benefits (fewer colorectal cancers and hip fractures) of using hormone replacement therapy—conjugated equine estrogens (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) specifically—did not outweigh the risks (more CHD-related deaths, strokes, venous thromboembolisms, and invasive breast cancer). Treatment and prevention options for osteoporosis now include modification of risk factors, calcium and vitamin D supplementation, bisphosphonates (alendronate sodium and risedronate sodium), selective estrogen receptor modulators, and synthetic parathyroid hormone.
The preferred treatment for osteoporosis after menopause has for years been hormone replacement therapy (HRT). This therapy was also used because there was the belief that hormones did many wonderful things. During the past year, however, sufficient evidence has been published that has determined that the blanket use of HRT in this patient population is unacceptable. Previously, observational data had established that combination hormone therapy protected women against coronary heart disease (CHD).
1
Three pivotal studies—the Heart Estrogen/progestin Replacement Study (HERS),
2 the HERS II,
3 and the Women's Health Initiative (WHI)
4—have demonstrated that hormones do not protect against heart disease and in fact may increase the risk. There also may be an increase in breast cancer. Thus, the dilemma in using hormones: Do the benefits of using these drugs outweigh the risks?
The HERS trial
2 was a randomized, double-blind, placebo-controlled trial that included 2763 postmenopausal women with an intact uterus and with established CHD. These women were randomly assigned to receive placebo or 0.625 mg of conjugated estrogen (CEE) plus 2.5 mg of medroxyprogesterone acetate (MPA) daily for 4.1 years. The primary outcome measure was CHD-related deaths or nonfatal myocardial infarctions (MIs).
The average age of these women was 67 years. The results showed primary CHD events (CHD-related deaths or nonfatal MIs) occurred in 172 women in the HRT group and 176 in the placebo group (
P = .91). None of these differences were statistically significant at 4 years (
Figure 1). The only outcomes that were statistically significant at 4 years were increased risks for venous thromboembolism (VTE) and gallbladder disease in the treatment group. There were no statistically significant increases in deaths due to cancer or any other causes.
Closer examination of the cardiac data revealed in a post hoc analysis a 52% increase in cardiovascular events in the first year of HRT versus placebo. Fewer events per year were observed toward the end of the study.
This evidence led researchers to question whether therapy continued for a longer time would confer a CHD prevention benefit. Consequently, the HERS II,
3 an open-label, observational follow-up study was established to continue the HERS trial for another 4 years. The primary outcome measure of the HERS II was also CHD-related deaths and nonfatal MI (
Figure 2).
3 The study was stopped after 2.7 years because no benefit was reported.
The HERS II data
3 are similar to the HERS data.
2 In the HERS II, the total number of CHD-related deaths was 71 in the HRT-treated group compared with 58 in the group receiving placebo. In the group receiving HRT, there was a threefold increase in deep vein thrombosis (DVT), a threefold increase in pulmonary emboli, and a slight increase in gallbladder disease.
The researchers concluded after both the HERS (a total of 6.8 years when considering the length of the HERS and HERS II together) that daily use of HRT (CEE plus MPA) does not reduce the overall risk for nonfatal MI, CHD, or any other cardiovascular event.
A much larger study than HERS conducted to evaluate the effect of HRT and estrogen replacement therapy (ERT) on various health outcomes including cardiac disease and fracture is the WHI
4 (
Table). This study is the nation's largest study of HRT.
Table
Estimated Hazard Ratios of Major Clinical Outcomes in the Women's Health Initiative Study (Through April 30, 2002) *
| Outcome | No. of Cases | Hazard Ratio (Adjusted CI † ) |
|---|
| □ Coronary heart disease | 286 | 1.29 (0.85–1.97) |
| □ Stroke | 212 | 1.41 (0.86–2.31) |
| □ Deep venous thrombosis | | 2.07 (1.14–3.74) |
| □ Pulmonary embolism | 101 | 2.13 (0.99–4.45) |
| □ Invasive breast cancer | 290 | 1.26 (0.83–1.92) |
| □ Colorectal cancer | 112 | 0.63 (0.43–0.92) |
| □ Hip fracture | 106 | 0.66 (0.45–0.98) |
Table
Estimated Hazard Ratios of Major Clinical Outcomes in the Women's Health Initiative Study (Through April 30, 2002) *
| Outcome | No. of Cases | Hazard Ratio (Adjusted CI † ) |
|---|
| □ Coronary heart disease | 286 | 1.29 (0.85–1.97) |
| □ Stroke | 212 | 1.41 (0.86–2.31) |
| □ Deep venous thrombosis | | 2.07 (1.14–3.74) |
| □ Pulmonary embolism | 101 | 2.13 (0.99–4.45) |
| □ Invasive breast cancer | 290 | 1.26 (0.83–1.92) |
| □ Colorectal cancer | 112 | 0.63 (0.43–0.92) |
| □ Hip fracture | 106 | 0.66 (0.45–0.98) |
×
The WHI, initiated in 1992 and planned to be completed in 2007, was designed to examine the effects of a low-calcium diet, calcium and vitamin D (Ca/D) supplementation, ERT, and HRT, as well as counseling on the risks of cardiovascular disease and cancer and the effect of osteoporosis on women's health. Each of these arms of the study has been treated separately.
The WHI is a randomized, double-blind, placebo-controlled study with an enrollment of 16,608 women (average age, 65 years). On entering the study, all subjects had an intact uterus and no known CHD. (The latter clinical characteristic is in contrast to both HERS trials, in which all women had known CHD.)
The primary endpoints of the studies are the following:
the HRT study, CHD;
the Ca/D supplementation arm, hip fracture; and
the dietary modification study, breast and colorectal cancer;
The secondary endpoints of the studies are as follows:
The HRT study, hip and other fractures;
the Ca/D supplementation arm, colorectal cancer, combined fractures; and
the dietary arm, CHD.
Each arm of the study has been examined separately. The estrogen/progestin arm was abruptly stopped July 2002 after 5.2 years because a predetermined level of breast cancer was reached (but not a statistically significant increased risk). The CEE only arm of the study did not meet the cut-off point for increased risk, and it is continuing, as are the low-fat diet arm, the Ca/D supplementation arm, and the observational arm.
In the estrogen plus progestin component of the WHI that ended early,
4 the primary outcome measure was CHD (nonfatal MI and CHD-related death), and the primary adverse outcome was invasive breast cancer in healthy postmenopausal women.
In the HRT-treated group, CHD events increased significantly (
P=.05) within the first 5.2 years (
Figure 3). Preliminary data from the first 2 years (found in WHI HRT update on the National Heart, Lung, and Blood Institute Web site at
http://www.nhlbi.nih.gov/whi/index.html) suggest a small increase in the number of MIs, strokes, and blood clots in subjects receiving ERT or HRT versus placebo. Over time, the differences seemed to become smaller and disappear. Overall CHD events were low during the whole trial. The rate of women having CHD was increased by 29% for women taking estrogen plus progestin relative to placebo (37 vs 30 per 10,000 person-years), reaching nominal statistical significance (but not adjusted statistical significance). Most of the excess was in nonfatal MI. No significant differences were observed in CHD-related deaths or revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty).
Stroke rates were also higher in women receiving estrogen plus progestin (41% increase, 29 vs 21 per 10,000 person-years), with most of the elevation occurring in nonfatal events.
Women in the group treated with estrogen plus progestin had twofold greater rates of VTE (34 vs 16 per 10,000 person-years), as well as DVT and pulmonary embolism individually.
The total rate of cardiovascular disease, including other events requiring hospitalization, was increased by 22% in the group treated with estrogen plus progestin.
Results of the ongoing ERT arm of the study (in women who have had hysterectomies) are still being reviewed internally by the study group every 6 months. The study group has not stopped that arm of the study, so it is not known whether the benefits of ERT in women who have had hysterectomies outweigh the risks.
The HRT-treated group had a significant increase (26%,
P ≤ .05) in invasive breast cancer compared with the group receiving placebo (
Figure 4). The 26% increase (38 vs 30 per 10,000 person-years) observed in the group receiving estrogen plus progestin almost reached nominal significance, and the weighted test statistic used for monitoring reached a prespecified value. However, the adjusted rate did not reach statistical significance. No statistical significance was noted for in situ breast cancer. This means that there was a number of cases of breast cancer that was prespecified before the trial began above which the risks of HRT would outweigh the benefits. The trial was stopped because this number was reached. However, it was not a statistically significant number of cases.
There was no significant change in rates of endometrial cancer (
Figure 4), and the rate of colorectal cancer decreased 37% (
P ≤ .05). The development of both vertebral and hip fractures was also decreased by 33.3% (
Figure 5).
4
In summary, HRT (CEE plus MPA) does not confer any benefit in the prevention of CHD in patients with an intact uterus. Hormone replacement therapy does increase the risk of CHD after initiation of treatment. The WHI finding of a 41% increase in stroke is similar to the findings in the HERS trials. The development of VTE in the HERS trial was twofold and in the WHI, the increase was twofold.
The WHI is the first randomized, controlled study to confirm that HRT increases the risk of invasive breast cancer. In the past, the only available data that pointed to an increased risk were observational.
Overall, from the WHI, it is possible to conclude that among patients treated with HRT (as compared with subjects receiving placebo), 7 more CHD-related deaths, 8 more strokes, 18 more VTEs, and 8 more cases of invasive breast cancer will occur per 10,000 person-years. There will be 6 fewer colorectal cancers and 5 fewer hip fractures per 10,000 person-years.
4
Although the numbers may seem small, they reflect a calculation per 10,000 patient years, and when projected over the many millions of patients who take the drug, the numbers become significant. Clearly, the advantages of using HRT (including use for control of menopausal symptoms, prevention—not treatment—of osteoporosis, and prevention of colon cancer) simply do not outweigh the risks of VTE, menstrual bleeding, breast cancer, and development of cardiovascular disease associated with use of HRT.
Prevention of osteoporosis and heart disease in postmenopausal women has been in the spotlight lately. Years ago, physicians thought hormones did everything from improving hot flashes and vaginal dryness to reducing the risk for heart disease, osteoporosis, and even wrinkles. This thinking had been based on observational data. Now that three major randomized trials show the same results, physicians have to change their thinking. They can no longer safely say that combination CEE and MPA prevents heart disease. Does this also apply to other estrogen and progestin combinations, or estrogen itself? Data that answer these questions are yet to be published. For now, the only recommended use of combination hormone therapy is for hot flashes and menopausal symptoms and for the shortest amount of time possible. If clinicians want to treat or prevent osteoporosis, they need to use other agents such as the bisphosphonates. If they want to prevent heart disease, they need to address the risk factors separately.
Dr Shoemaker is medical director of the Ormond Medical Arts Osteoporosis Center in Ormond Beach, Fla. Dr Klemes is senior regional medical director, South Region, Procter & Gamble Pharmaceuticals, in Tallahassee, FL 32317-3767.
This manuscript was developed from a presentation at the 40th Annual Convention of the American College of Osteopathic Family Physicians on March 22, 2003, in Nashville, Tenn.
Barrett-Connor E. Estrogen and coronary heart disease in women. JAMA. . 1991;265:1861-1867.
Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. .(1998). ;280:605-613.
Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, et al; HERS Research Group. Cardiovascular outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study Follow-up (HERS II). JAMA. .(2002). ;288:49-57.
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al; 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.
Khan AA, Brown J, Faulkner K, Kendler D, Lentle B, Leslie W, et al; Canadian Panel of International Society for Clinical Densitometry. Standards and guidelines for performing central dual X-ray densitometry from the Canadian Panel of International Society for Clinical Densitometry. J Clin Densitom. .(2002). ;5:435-445.
Leib ES, Lenchik L, Bilezikian JP, Maricic MJ, Watts NB. Position statements of the International Society for Clinical Densitometry: methodology. J Clin Densitom. .(2002). ;5(Suppl):S5-S10.
Lenchik L, Leib ES, Hamdy RC, Binkley NC, Miller PD, Watts NB; International Society for Clinical Densitometry Position Development Panel and Scientific Advisory Committee. Executive summary, International Society for Clinical Densitometry, position development conference, Denver, Colorado, July 20-22, 2001. J Clin Densitom. .(2002). ;5(Suppl):S1-S3.
Fulton JP. New guidelines for the prevention and treatment of osteoporosis. National Osteoporosis Foundation. Med Health RI. . 1999;82(3):110-111.
Heinemann DF. Osteoporosis. An overview of the National Osteoporosis Foundation clinical practice guide. Geriatrics. .(2000). ;55(5):31-36.