The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial was administered and primarily funded by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH). Four other NIH institutes, including the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), provided technical and financial support for the study.
The PEPI trial found that participants assigned to estrogen with or without a progestin experienced between a 3 1/2 and 5 percent increase in spinal bone mineral density (BMD) after 36 months. By comparison, women on placebo lost an average of nearly 2 percent in spinal BMD after 3 years. Similarly, women assigned to any of the HRT regimens gained nearly 2 percent in hip bone density while women on placebo lost nearly 2 percent of hip bone at the 36-month point.
Older women, women with low initial bone mineral density, and those with no previous hormone use gained the most bone among the women studied. Race, smoking, alcohol, calcium intake, physical activity and body weight did not alter HRT's effect on bone.
"The PEPI study answers key questions about the effects of hormone therapy on bone mineral density. Combined with PEPI's earlier findings on heart disease risk factors and on endometrial changes, this study is one of the best current sources of information on the risks and benefits of hormone replacement therapy," said Dr. Claude Lenfant, NHLBI director.
Physicians are increasingly prescribing replacement therapies for the treatment and prevention of osteoporosis. About 25 million people in the U.S. have or are at risk of developing osteoporosis, including 20 percent of women over 50. The increased prevalence of the condition among postmenopausal women is tied to estrogen loss. The hallmark symptom of osteoporosis is low bone mineral density, which leads to an increased risk of fracture. Fractures can result in serious complications including pain, loss of mobility, and death.
Although the PEPI study was not designed to determine fracture rates, other studies (not clinical trials) have shown a strong association between bone mineral density and fracture risk.
"The PEPI study is an important step. It confirms in a rigorous trial the positive effect of a variety of HRT regimens on bone density," said Dr. Joan McGowan, director of the NIAMS Bone Diseases Program, and a member of the PEPI trial writing group.
According to Dr. McGowan, the impact of hormone replacement therapies on fractures will be assessed by the NIH Women's Health Initiative, a large clinical trial involving 27, 500 postmenopausal women.
The PEPI trial involved 875 healthy postmenopausal women aged 45 to 64 years at seven clinical centers in the U.S. The women were randomly assigned to one of five treatment groups: (1) a placebo, (2) 0.625 mg of estrogen per day, (3) 0.625 mg of estrogen per day plus 10 mg of a synthetic progestin taken daily for 12 days, (4) 0.625 mg of estrogen daily plus 2.5 mg of synthetic progestin taken daily, or (5) 0.625 mg of estrogen daily plus 200 mg of a natural (micronized) progesterone (MP) taken daily for 12 days per month.
The investigators used dual-energy x-ray absorptiometry (DXA) to measure changes in bone mineral density in the patients' spine and hip at baseline, at 12 months, and at 36 months.
Although women assigned to the daily continuous progestin estrogen regimen had higher BMD in the spine, there were no significant differences in BMD at the hip among women assigned to any of the active therapies.
The PEPI trial also found that among those patients who stayed on their therapy for 3 years, combining progestin with estrogen offered no greater benefit in terms of bone mass than taking estrogen alone. Previous research suggested that progestin therapy alone increased BMD.
Among the patients who adhered to their treatment, between 70 and 90 percent of the increase in BMD occurred during the first year of the study. The remaining 10 to 30 percent increase in bone occurred during the final 2 years. The investigators report that the first-year surge in increased bone mass is likely to be related to estrogen's effect on the bone remodeling process that occurs during menopause.
Bone is constantly being removed and replaced by new bone throughout the skeleton. After menopause, this process accelerates and there are many more sites where bone removal takes place. Estrogen replacement slows down this process, and the increase in bone mineral during the first year reflects the filling in of these "bone construction" sites. The continued increase in BMD after the first year of the study may reflect a further slowing of this same process or may indicate another mechanism. Longer-term studies are needed to answer this question.
According to the investigators, the accelerated bone loss that occurs in early menopause also accounted for the finding that younger patients (45 to 54) who were on placebo lost significantly more bone than older women (55 to 64) on placebo.
A comparison of PEPI participants on active therapy revealed that older women taking any of the active regimens gained significant amounts of bone.
"These results are very encouraging for older women," said Trudy Bush, Ph.D., chair of the bone paper writing group and Professor of Epidemiology at the University of Maryland School of Medicine and at the Johns Hopkins University. "Estrogen therapy not only delays the accelerated rate of bone loss in early menopause, it also can increase bone density in women age 60 and above. This age group still has a lot to gain in terms of increased bone from hormone replacement therapy," she added.
Women who smoked and didn't use HRT lost significantly more bone from their hip (3 1/2 percent) than did non-smokers (2 percent). Previous research has suggested that smoking may interfere with the positive effect of estrogen on bone. However, the PEPI study found that smokers on estrogen gained BMD in the hip at about the same rate as non-smokers.
In addition to the NIAMS, PEPI was supported by the National Institute of Child Health and Human Development, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institute on Aging.