Hormone Therapy - Protecting Your Bones: Osteoporosis
Content provided by the Faculty of the Harvard Medical School
Hormone therapy
Hormone therapy is the oldest treatment for osteoporosis. Once it was the most widely prescribed, but its use has fallen sharply as negative effects of the therapy have come to light.
In years past, the conventional wisdom on hormone therapy was that, in addition to easing menopausal symptoms and improving bone strength, it could help protect against heart disease. The glow of hormone therapy was dimmed by speculation that it might slightly increase the risk of developing breast cancer, but this remained a source of debate. But evidence of the negative effects of hormone therapy has mounted. A number of studies have documented a link between hormone therapy and breast cancer, and the once widely held belief that hormone therapy protected against heart disease has been turned on its head. Instead, hormone therapy appears to increase the risk for heart attack, as well as increase the number of strokes and blood clots in the legs and lungs.
Now, most doctors no longer recommend hormone therapy for treating bone loss; instead, it is primarily used as a short-term treatment for troublesome menopausal symptoms such as hot flashes. Interestingly, the study that led more doctors and patients to turn away from hormone therapy is the same one that demonstrated that hormone therapy reduces fractures.
Table 2: Medications approved for osteoporosis | ||||
| Medication | Brand name | Approved uses | Benefits | Comments |
| Alendronate | Fosamax | Prevention and treatment in postmenopausal women. Treatment in men. For men and women with glucocorticoid-induced osteoporosis. | Increases bone density at spine and hip. Reduces the risk for spine and hip fractures. Side effects uncommon. | Difficult to digest. May cause nausea, heartburn, or irritation of the esophagus if not taken properly. |
| Risedronate | Actonel | Prevention and treatment in postmenopausal women. For men and women with glucocorticoid-induced osteoporosis. | Increases bone density at spine and hip. Reduces the risk for spine and hip fractures. Side effects uncommon. | Difficult to digest. May cause nausea, heartburn, or irritation of the esophagus if not taken properly. |
| Ibandronate | Boniva | Prevention and treatment in postmenopausal women. | Increases bone mass. Reduces vertebral fractures. | Difficult to digest. May cause ulcers, nausea, heartburn, or irritation of the esophagus if not taken properly. This medication will not be available until a once-monthly formulation is approved. |
| Raloxifene | Evista | Prevention and treatment in postmenopausal women. | Increases bone density, although not as much as the bisphosphonates. Reduces the risk for spinal fractures. May reduce breast cancer risk. Lowers LDL (bad) cholesterol. | Side effects are uncommon, but can include hot flashes, leg cramps, and blood clots. |
| Hormone therapy | Many types, including Premarin, Ogen, Estrace, Estratab, Premphase, Prempro, FemHRT, Activella, Estraderm, and Climara | Prevention and treatment in women. | Increases bone density. Reduces the risk for fractures. Helps alleviate the symptoms of menopause, including hot flashes, vaginal dryness, and insomnia. Improves cholesterol levels. | Estrogen alone increases the risk for stroke and uterine cancer. Prempro, an estrogen plus progestin formula, increases the risk for heart attack, stroke, blood clots, and breast cancer; other estrogen plus progestin formulas have not been studied as extensively so it is unclear if they carry the same risks. |
| Calcitonin | Miacalcin; Calcimar | Treatment only. | Increases bone density but not as dramatically as any of the other approved medications. Reduces the risk for spinal fractures. | The injected form can cause flushing of the face and hands, nausea, increased urination, and rash. The nasal spray can cause a runny nose. |
| Teriparatide (parathyroid hormone, or PTH) | Forteo | Treatment only in men and postmenopausal women. | May double the rate of bone formation. Reduces vertebral and nonvertebral fractures. | Must be taken as an injection. Because effects appear to wane and long-term safety data are lacking, PTH should not be prescribed for more than two years. |
Hormone therapy: A brief history
Estrogen was the first drug to be approved by the FDA for the treatment of osteoporosis. In the 1970s, many women were taking estrogen in the menopausal years to relieve symptoms like hot flashes and vaginal dryness. In the 1980s, when research showed that women taking estrogen alone were at increased risk for endometrial cancer, doctors added progestins (synthetic versions of the hormone progesterone) as a preventive measure. While estrogen encourages the growth of the tissue lining the uterus, progestin curbs it. Estrogen-progestin therapy, also known as combined hormone therapy, became the hormone treatment of choice for women who hadn't had hysterectomies, while estrogen alone was commonly used among women who'd had hysterectomies.
Meanwhile, it became clear that long-term hormone use had another effect besides curbing menopausal symptoms: It seemed to reduce hip fractures. Evidence mounted, and in 1991 the first International Consensus Development Conference on Osteoporosis concluded that hormone therapy was the only well-established measure that could significantly reduce the risk for fractures.
Many studies have demonstrated that hormone therapy can hamper bone loss and boost bone density. The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial found that women on hormone therapies — estrogen alone or an estrogen-progestin combination — gained bone density. Over a three-year period, the bone density of the women taking hormones rose, on average, 4% at the spine and 2% at the hip. But women who weren't taking hormones lost bone, to the tune of 1.8% at the spine and 1.7% at the hip.
But a number of questions remained. Could hormone therapy prevent hip fractures? How does long-term hormone use affect heart disease? Could it increase the risk for breast cancer? A variety of studies looked at the long-term effects of hormone use.
It appeared that hormone therapy reduced the risk for colon cancer, but increased the risk for breast cancer and blood clots. A number of studies further explored the relationship between breast cancer and hormone therapy. Many found that hormone therapy slightly increased the likelihood of developing breast cancer, and that the risk compounded over time. For example, a January 2000 study revealed that a woman's increased risk for breast cancer climbed by 8% a year for each year of estrogen-progestin use. For women using only estrogen, risk increased by 1% per year. A month later, a study published in the Journal of the National Cancer Institute found that breast cancer risk rose 24% for every five years of combined hormone therapy use, compared with a 6% jump for women on estrogen alone.
| Experimental treatments show promise In the last few decades, there has been great progress in the prevention and treatment of osteoporosis, and the coming years are likely to yield more advances. New varieties of existing treatments, such as bisphosphonates that are designed to be given just once a month or once a year or new SERMs, may be introduced to the market. And some experimental treatments may eventually offer even more help in shielding bones from osteoporosis. Researchers are currently studying several treatments — including statins, strontium ranelate, and agents that mimic osteoprotegerin. Experts hope that some of these new treatments will someday prove useful in curtailing bone loss or building new bone, giving people who have osteoporosis and those who are at risk for it even more therapeutic choices. Here's a look at some of the avenues of research being pursued. Statins. Researchers are trying to sort out whether statins — drugs taken by millions of Americans to lower cholesterol and prevent heart attacks — can build bone and reduce the risk for fractures. Statins first became linked to bone development when scientists discovered that these drugs stimulated bone morphogenic protein 2, a growth factor that spurs the development of bone-building osteoblasts. In testing the drugs on female rats, researchers found that bone volume increased dramatically — by 40% to 90% — in the thighbone and lumbar vertebrae. Two subsequent studies revealed that people taking statins were less likely to suffer fractures. The numbers were compelling: an 88% reduction in hip fractures and a 45% drop in all kinds of fractures in one study, and a 50% lower risk of breaking a hip in the other. But other studies have found that statins don't help bones, especially in doses commonly used to manage cholesterol levels and prevent heart disease. For example, the Women's Health Initiative found that participants taking statins were just as likely to lose bone tissue or break a bone as those who didn't take one of these drugs. More study is needed to determine whether these medications can protect bones against fracture. Strontium ranelate. Strontium ranelate is a compound that incorporates the element strontium, which is found in trace amounts throughout the skeleton. Results from trials conducted by French researchers suggest that strontium ranelate may reduce vertebral fractures about as well as bisphosphonates. The drug is believed to work by decreasing bone breakdown. More study is under way. Osteoprotegerin. An exciting development was the discovery of osteoprotegerin (OPG), a protein found naturally in the body that protects against bone loss. Researchers found that OPG stalls the production of osteoclasts, the cells that destroy bone. In mice with osteoporosis, OPG cut the number of osteoclasts and increased bone density. It's hoped that this discovery will lead to new treatments for osteoporosis. Integrin inhibitors. These medications work by preventing osteoclasts from attaching themselves to the surfaces of bone. Thus, these cells are unable to break down the bone. According to the Surgeon General's report on osteoporosis, early studies have yielded promising results. While current research suggests that integrin inhibitors are safe and effective, more study is needed. Sodium fluoride. Fluoride has been tested in many experiments over the last few decades, with contradictory results. While studies have shown that fluoride builds bone by prodding osteoblasts, the quality of that bone is questionable. Several trials in the 1980s indicated that fluoride treatment did not reduce spinal fractures and may even have increased hip fractures. There were other drawbacks. Fluoride had to be taken at least two hours after the previous meal and two hours before the next one, and was often associated with nausea, vomiting, and diarrhea. However, studies have shown that a slow-release fluoride may be a marked improvement over the fluorides used in the 1980s. This kind of fluoride is encased in a wax coating, allowing it to pass through the stomach intact and eliminating most of the digestive problems associated with the older version. Some studies have shown that, when taken with calcium citrate, the newer fluoride increases bone density and reduces spinal fractures. But more study is needed. For now, the issue of how fluoride that's been added to drinking water affects bone fractures remains controversial and unclear. The hypothalamus. Scientists found that mice that don't have enough leptin — a hormone produced in fat cells — or that lack a hypothalamic receptor for leptin have more osteoblasts and higher bone density. The leptin itself does not seem to affect the osteoblasts; instead it appears that the osteoblast activity is influenced by signals from the hypothalamus (a region of the brain). This preliminary research may eventually lead to a new approach in treating osteoporosis. |
Researchers also looked closely at the effects of hormone therapy on heart disease. At first, the news on heart disease was encouraging. The Nurses' Health Study found that women taking hormone therapy were at lower risk for cardiovascular disease, although there was some speculation that this was because, compared with women in general, the participants in this study led healthier lifestyles and were more apt to seek medical care. And a 1995 report from the PEPI trial found that hormone therapy improved HDL (good) cholesterol and lowered LDL (bad) cholesterol and clotting factors that contribute to heart disease and strokes. But the study didn't last long enough to determine whether these improvements paid off in fewer actual heart attacks, strokes, or blood clots. The picture began to darken in 1998, when the Heart and Estrogen/Progestin Replacement Study found that hormone therapy did not prevent heart attacks in women who already had heart disease. Moreover, women taking hormones had 50% more heart attacks during the study's first year. The women on hormones were also more likely to develop blood clots. The results shocked estrogen enthusiasts.
Hormone therapy takes another blow
But the debate was far from over. The links between hormone use and breast cancer and heart disease remained controversial. Enter the Women's Health Initiative. This landmark study was designed to help answer lingering questions about the long-term effects of hormone therapy. The two arms of the study examined the effects of estrogen-only and combined hormone therapy. Both trials came to abrupt ends when the health risks of taking the hormone therapies emerged.
In July 2002, the trial of Prempro, an estrogen and progestin formula, was closed after researchers found significant increases in breast cancer (29%), heart disease (24%), stroke (31%), and blood clots in the veins (107%) and lungs (113%). The trial did establish, however, that the combined hormone therapy reduces the risk for hip fractures (34%), spinal fractures (34%), and colorectal cancer (37%). The 16,000 women in the study were told to stop taking the medication. Similarly, women in the estrogen-only portion of the study were told to stop taking their pills in 2004 because of a nearly 40% increase in stroke risk. Like the estrogen-progestin combination, the estrogen-only formulation (Premarin) was found to raise the risk for stroke and decrease the risk for hip fracture. On the other hand, it didn't appear to affect heart disease risk in any way. At the time the study was halted, there wasn't an increase in breast cancer risk either.
While both of these studies established that hormone therapy could indeed reduce hip fractures, they led many women to abandon using this treatment for osteoporosis. For these women, the increased risk for breast cancer and heart disease wasn't an acceptable tradeoff for the reduced fracture risk, especially since other drugs can effectively prevent and treat osteoporosis.
Hormone therapy is certainly down, but it may not be out. Critics of these studies point out that only one hormone preparation was used in each arm of the Women's Health Initiative and that other formulas may not carry the same risks and benefits. Others note that the women in the study began taking the hormones long after the start of menopause and question whether the results may be different for women who take hormones earlier.
It's likely that hormone therapy will continue to make headlines in years to come. In the meantime, if you are considering hormone therapy, it's wise to weigh the potential risks carefully, identify your own health risks and concerns, and discuss the issue with your doctor.
| Last updated: | January 23, 2007 |
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Medical content reviewed by the Faculty of the Harvard Medical School. Harvard Health Publications, Copyright © 2007 by President and Fellows of Harvard College. All rights reserved. Used with permission of StayWell.
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