DEFINING MENOPAUSE — With the onset of menopause, a woman's body stops making estrogen and progesterone. Estrogen and progesterone are the female hormones produced by the ovaries that prepare the uterus for possible pregnancy. Prior to menopause, (which usually occurs between the ages of 45 and 55), many women notice that their periods start to occur more frequently (as often as every 21 days), although periods eventually become infrequent. This time of "transition," called perimenopause, can last for several years until menopause, when periods stop altogether.
The average age of menopause is between 50 and 51 years, although some women experience unusually early menopause (before age 40) due to surgical removal of the uterus or both ovaries, chemotherapy, or radiation therapy. However, most cases of early menopause are unexplained.
Hot flashes — Hot flashes (or hot flushes) occur because of a fall in estrogen levels. Hot flashes often begin several years before menopause and continue for several years after menopause. They are far more common at night, and can disrupt sleep. Therefore, many women also experience symptoms related to sleep-deprivation, such as fatigue, irritability, difficulty concentrating, and mood swings.
Vaginal and urinary symptoms — Many women begin to experience vaginal dryness or urinary symptoms, both of which are related to estrogen deficiency. Estrogen is the most effective treatment available for hot flashes, vaginal dryness, and urinary symptoms.
Estrogen has important effects on many other organs, such as the brain, skin, blood vessels, heart, bone, and breast. Of particular importance are the effects of estrogen on bone and possibly cardiovascular (heart) health. Without estrogen, the body is at greater risk of developing osteoporosis, a disease in which bones lose calcium and become more susceptible to fracture. In addition, the risk of heart disease in women increases after menopause, although taking estrogen (hormone replacement therapy) has not been shown to prevent heart disease.
HORMONE REPLACEMENT THERAPY — Estrogen replacement therapy, also called ERT, is a way for a postmenopausal woman to replace the estrogen her body is no longer making. While it does not make her fertile again, it does eliminate many of the symptoms of menopause. Women with a uterus who take estrogen must also take a progesterone-like hormone (called progestins) to eliminate the risk of uterine (endometrial) cancer. The term hormone replacement therapy (HRT) is used when estrogen and progestin are given together.
HISTORY OF HRT USE — Estrogen first became popular in the 1960's for the treatment of hot flushes. At that time, it was also thought that estrogen helped to preserve a woman's youthful appearance. Early on, high doses of estrogen were given (as an example, 2.5 mg of conjugated estrogens compared to the standard 0.625 mg dose that is currently used). Since then, the regimens and the reasons for taking it have changed. Taking estrogen alone results in an increased risk of endometrial cancer (also known as uterine cancer). Adding a progestin to estrogen can prevent the increased endometrial cancer risk. Therefore, by the mid-1980s, progestins were routinely added to estrogen replacement therapy (in any woman with an intact uterus, ie, women who had not undergone a hysterectomy). Many studies showed that taking ERT or HRT could prevent the bone loss that occurs after menopause, which can lead to osteoporosis and its fractures. Over 30 studies suggested that estrogen was an important therapy for preventing or reducing the risk of coronary heart disease (CHD). In fact, it appeared that women taking estrogen reduced their risk of a first heart attack by 50 percent. In addition, estrogen appeared to reduce recurrent events in women who already had coronary disease. Because of the osteoporosis and CHD studies, ERT and HRT began to be prescribed for the prevention of both diseases, which meant giving it long-term (more than five years). Breast cancer studies began to indicate that taking ERT more than 5 years increased the risk of breast cancer. Clinical trials, (studies in which women are randomly assigned to receive active treatment or placebo), did not agree with the earlier studies. The Women's Health Initiative (WHI) and the HERS trials (of combined estrogen-progestin therapy) demonstrated that HRT did not prevent heart disease, and in fact, might increase risk. The WHI trial of combined estrogen-progestin therapy did show an increased risk of breast cancer, but there was no increased risk of breast cancer in women who took estrogen alone [1].
One possible explanation for the conflicting results between the observational studies and clinical trials, is that the observational studies had a problem with "healthy user bias". This means that the healthiest women (ie. those who were less apt to have a heart attack), were more likely to be started on estrogen by their physicians. Therefore, it is possible that estrogen's beneficial effect on the heart was more related to the underlying health of the women taking it, rather than the medication itself.
WOMEN'S HEALTH INITIATIVE — The Women's Health Initiative (WHI) is a set of clinical trials that includes two HRT trials. The WHI studied healthy postmenopausal women aged 50 to 79 years, and the study was scheduled to be completed in 2005. However, one component of the WHI (continuous, combined conjugated estrogen (CEE 0.625 mg/day) and medroxyprogesterone acetate (MPA 2.5 mg/day) versus placebo in over 16,000 women) was discontinued in 2002 because of an increased risk of coronary heart disease, breast cancer, stroke, and venous thromboembolism (blood clots in the leg or lung) over an average follow-up of 5.2 years [2]. Although there was reduction in risk of osteoporotic fractures and colon cancer, there was concern that the risks of combined estrogen-progestin may outweigh the benefits.
The WHI trial of unopposed estrogen (CEE 0.625 mg/day) versus placebo in women who had undergone hysterectomy (and therefore did not require a progestin) was also discontinued (early 2004) because of a small increase in stroke risk (but no increase in CHD or breast cancer risk) [1].
Only one type of estrogen (CEE 0.625 mg) and one type of progestin (MPA 2.5 mg) treatment were studied in the WHI brand names Premarin (unopposed estrogen) and Prempro (estrogen combined with progestin). Although there are theoretical reasons to believe that other types of estrogen and progestin, different routes of administration (skin patch) or lower doses might be safer, to date, there are no studies to demonstrate that this is true.
The results of the WHI were as follows [2]:
Coronary heart disease — The rate of coronary events such as heart attacks was 24 percent higher in the women taking HRT compared to those taking placebo. This seems like a large increase in risk, but the increase for an individual woman is low. As an example, on average there were 39 CHD events per year per 10,000 women versus 33 events per 10,000 women taking placebo (ie, an additional 6 events per 10,000 women per year).
The difference in coronary events developed within the first year of the study. The risk persisted in years two through five of the study, but the highest risk was in the first year. Taking a daily aspirin did not seem to reduce the risk.
In contrast, the WHI trial of unopposed estrogen did not observe an increase in CHD risk. In the younger women in the trial (ages 50-59), a possible protective effect was seen with estrogen (although this was not significant).
The WHI investigators subsequently reported that women ages 50 to 59 years at baseline, who had been menopausal for less than 10 years, did not have an increased risk of heart disease. The excess risk was only seen in older women in the trial. This was true for both the combined estrogen-progestin trial and the unopposed estrogen trial.
Prevention of CHD after a heart attack was evaluated in the HERS trials with 2763 postmenopausal women [3]. After nearly 7 years of follow-up, continuous estrogen-progestin therapy did not reduce the risk of CHD events in women with established CHD.
Stroke — The rate of stroke was increased with combined estrogen-progestin. On average per year, there were 29 strokes in the treatment group versus 21 events in the placebo group per 10,000 women (8 additional cases per 10,000 women per year). Most of the increase in risk was due to nonfatal strokes, and the increase did not appear until year two of the study (but persisted through year five). A very similar pattern of risk was seen in the trial of unopposed estrogen [1]. (See "Patient information: Stroke").
Blood clots — The rate of blood clots (in the leg and lung) increased with combined estrogen-progestin (34 versus 16 per 10,000 women per year; or 18 additional cases per 10,000 women per year). Risk was also increased with unopposed estrogen. (See "Patient information: Venous thrombosis").
Breast cancer — The risk of breast cancer was increased in the WHI trial of combined estrogen-progestin. On average, per year there were 38 cases of breast cancer per 10,000 women versus 30 per 10,000 women (8 additional cases per year per 10,000 women). Similar findings have been noted in a number of observational studies, all of which suggest that the major increase in risk occurs after taking estrogen-progestin for four or five years. In addition, the WHI reported that women taking combined estrogen-progestin were more likely to have an abnormal mammogram. However, the majority of the abnormal mammograms were requests to return for additional views.
The results of the trial of unopposed estrogen were quite surprising, because no increase of breast cancer was seen. In fact, a possible lower risk was seen, but this was not quite significant. The fact that an increase in breast cancer risk was seen with combined hormone therapy, but not with unopposed estrogen, suggests that the progestin component is a very important factor in the risk of developing breast cancer. (See "Patient information: Postmenopausal hormone therapy and breast cancer").
Osteoporotic fracture — The risk of osteoporotic fracture was reduced at the hip and spine in both the trial of combined estrogen-progestin and the trial of unopposed estrogen. On average, per year there were 5 fewer hip fractures per 10,000 women in the HRT versus placebo group. (See "Patient information: Osteoporosis prevention and treatment").
Colorectal cancer — The risk of colorectal cancer was reduced (6 fewer colorectal cancers per 10,000 women per year) in the trial of combined estrogen-progestin versus placebo group. This benefit was not seen in the trial of unopposed estrogen. (See "Patient information: Screening for colon cancer").
Cognitive function and dementia — Although it was thought that estrogen could preserve cognitive function and prevent dementia, data from the WHI do not support this. No significant improvement in overall cognitive function was seen with combined estrogen-progestin therapy compared with placebo. It is still possible, however, that there are benefits for certain specific types of cognitive function, although this is not proven. The impact of unopposed estrogen, or taking HRT in the early postmenopausal years is not known.
In addition, combined estrogen-progestin therapy did not prevent dementia. To the contrary, an increased risk was seen (approximately 23 additional cases of dementia per 10,000 women per year). It is not known why dementia risk was higher with hormone therapy, but one possible explanation is an increased risk of multiple small strokes (which predisposes women to dementia). Similar results were reported in the unopposed estrogen trial. The effect of taking HRT in the early menopausal years on the risk of later dementia is not known, although many early studies suggest that it is early, rather than late, exposure to estrogen is important for later cognitive function.
Endometrial hyperplasia and cancer — Studies have found that postmenopausal women with a uterus who are treated with estrogen alone increase their risk of endometrial cancer and hyperplasia (a precursor to cancer). Within one year, endometrial hyperplasia can be found in 20 to 50 percent of women receiving estrogen alone. The risk can be even greater if very high doses are used or if the unopposed estrogen is continued for many years. Even when women discontinue the estrogen, the endometrial cancer risk persists for approximately five years.
In the WHI, only women without a uterus received unopposed estrogen. In women with a uterus who received combined estrogen-progestin therapy, there was no increased risk of endometrial hyperplasia or cancer.
Absolute risk of an adverse event — It should be emphasized that the absolute risk of an adverse event occurring in an individual on the estrogen-progestin regimen in the WHI was extremely low (19 additional events per year per 10,000 women with HRT compared to placebo).
In the trial of unopposed estrogen, it was calculated that overall risks and benefits would be equal (not taking into account the effect that estrogen has on hot flashes).
Most now agree that using either unopposed estrogen or combined estrogen-progestin therapy for symptom relief in young postmenopausal women in a safe and reasonable option.
OTHER RISKS — There are many HRT studies in addition to the WHI that provide other information about breast cancer. In addition, there are other known risks of HRT such as gallbladder disease that were not addressed in the WHI report.
Other breast cancer issues — The degree of increase in breast cancer risk due to estrogen is often misinterpreted. It is most important for a woman to understand the absolute risk that she will get breast cancer because she takes estrogen. It has been calculated that for a 50-year-old woman taking estrogen, there is a 1 in 100 chance that she will develop breast cancer over a 10-year period that would not have developed without estrogen. This estimate would be slightly higher (eg, 1.5 in 100) for a woman over 65 years of age.
Many studies have reported that if breast cancer does occur during estrogen therapy, it is biologically less aggressive, and survival rates are better than when breast cancer occurs in women who were not taking estrogen. However, in the WHI combined estrogen-progestin trial, women on hormones had tumors that were slightly larger and more likely to have spread to the lymph nodes. As mentioned above, no increase in breast cancer risk was seen in the trial of unopposed estrogen.
Gallbladder disease — There is considerable evidence that estrogen therapy, especially in pill form, is associated with an increased risk of gallbladder disease. The risk of cholecystectomy, (removal of the gallbladder), increases the longer a woman uses hormone therapy and the higher the dose of estrogen used. The risk decreases substantially within one to three years after a woman discontinues hormone therapy.
OTHER BENEFITS — In addition to easing the symptoms of menopause, ER/HRT has many other positive effects.
Menopausal symptoms — Estrogen is the most effective treatment available for symptoms such as hot flashes, urinary symptoms, and vaginal atrophy (atrophic vaginitis), a condition in which the vagina can become dry, resulting in pain with intercourse.
Quality of life — Women with severe menopausal symptoms often describe a dramatic improvement in their quality of life when they are treated with estrogen. This is due to relief of hot flushes and restoration of normal sleep.
Urinary tract infection — Estrogen has been found to decrease the frequency of urinary tract infections, possibly by normalizing the microorganisms present in the vagina. It does not help the symptoms of urinary incontinence. (See "Patient information: Urinary tract infection in adults").
Diabetes mellitus — The WHI reported that HRT appears to reduce the risk of type 2 diabetes mellitus (adult onset diabetes). However, because of the other risks of HRT, this effect is insufficient to recommend HRT for routine diabetes prevention in postmenopausal women. (See "Patient information: Diabetes mellitus, type 2").
Depression — Estrogen may improve mood and decrease depression in some menopausal women. One study showed that estrogen plus progestin was effective in perimenopausal women with depression. (See "Patient information: Depression in adults").
WHO SHOULD TAKE HRT?— Data from the WHI and the HERS trials have led to changes in our recommendations for hormone therapy [2,3]. Continuous estrogen-progestin therapy appears to increase the risk of cardiovascular events and breast cancer; in addition, other drugs (eg, bisphosphonates, raloxifene) can protect against osteoporosis. Unopposed estrogen increases the risk of stroke, but overall, its benefits seem equal to its risks. As a result, the main reason to take hormone therapy at present is to control menopausal symptoms.
Menopausal symptoms — Estrogen or combined estrogen-progestin therapy remains the gold standard for relief of menopausal symptoms, and therefore is a reasonable option for most postmenopausal women, with the exception of those with a history of breast cancer, CHD, a previous blood clot or stroke, or those at high risk for these complications. In otherwise healthy women, the absolute risk of an adverse event is extremely low. Most experts agree that hormone therapy is safe and reasonable for healthy postmenopausal women who need to take it to relieve symptoms. When it is used, is should be taken for the shortest period of time possible.
Administration of estrogen short-term is not associated with an increased risk of breast cancer, but endometrial hyperplasia and cancer can occur after as little as six months of unopposed estrogen therapy; as a result, a progestin must be added in those women who have not had a hysterectomy.
In women being treated for symptoms, the goal is to eventually taper and stop the estrogen (unless there is a compelling reason to continue it long-term). After the planned treatment interval, the estrogen should be discontinued gradually, as an example, by omitting one pill per week, to minimize recurrence of the menopausal symptoms.
Low-dose oral contraceptives — A low-estrogen oral contraceptive (20 µg of ethinyl estradiol) remains an appropriate treatment for perimenopausal women who seek relief of menopausal symptoms. Most of these women are between the ages of 40 and 50 years and are still candidates for oral contraception. For them, an oral contraceptive pill containing 20 µg of ethinyl estradiol provides symptomatic relief, contraception, and sometimes better bleeding control than conventional estrogen-progestin therapy. (See "Patient information: Hormonal methods of birth control").
Dose of estrogen — It is possible that lower doses of estrogen may be safer than estrogen, while still effectively treating menopausal symptoms. As an example, conjugated estrogens (0.3 mg) or the equivalent dose of other estrogens (estradiol, estrogen patch) have been shown in some, but not all studies to relieve symptoms and prevent bone loss. But it is not yet known whether lower doses of estrogen or different HRT preparations are safer with regards to breast cancer and cardiovascular risks. Therefore, it is safest to assume that other preparations carry the same risk.
Long-term estrogen therapy — Only a minority of women who are unable to successfully discontinue estrogen without persistent symptoms should consider long-term estrogen therapy. If HRT is resumed, the lowest dose possible should be used, and plans should be made to try another taper at a later date. It is important that the breast cancer and cardiovascular risks are discussed in detail with these women.
TYPES OF ESTROGEN — Estrogen can be taken as a pill (orally), or absorbed through the skin from a patch (transdermally), or inserted into the vagina.
Estrogen pill — There are many forms of estrogen pills. The most commonly used preparation, called Premarin, is made from pregnant mares' urine. Many other preparations are derived from plant sources, such as soy and yams. While there is no evidence that plant-derived estrogens work better or are safer than Premarin, many women prefer them.
Sometimes the dose of estrogen is large enough to protect bones, but not to completely eliminate menopausal symptoms. When these symptoms occur, a larger dose may be given for a year or two, but then the dose is usually reduced.
Besides Premarin, other brands of estrogen include: Cenestin, Estratab, Menest, Ogen, Estrace, and Gynediol. While these preparations vary in their potency and dose amounts, they are all effective.
Estrogen patch — There are many brands of estrogen patches. Those available in the United States include: Estraderm, Climara, Vivelle, FemPatch, and Alora. Some patches need to be replaced every few days, others once a week.
If an equivalent dose is given, transdermal estrogen is just as effective as oral estrogens in increasing bone density and in treating menopausal symptoms. But unlike oral estrogen, it has not been shown to have a beneficial effect on cholesterol levels.
Vaginal estrogen — Vaginal estrogen is available as a cream, vaginal ring, or vaginal tablet. Estrogen cream is inserted into the vagina using an applicator once a day for two to three weeks. After this, the frequency may be reduced to one or two times weekly. The estrogen vaginal tablet (Vagifem®) is given on a similar schedule.
The vaginal ring, called Estring, is a flexible plastic ring. It is inserted once every three months and does not need to be removed during intercourse or bathing. Estring may be preferred by women who have trouble using vaginal cream on a regular basis, or in women with reproductive organs that may be sagging, called prolapse, who would benefit from additional support.
Vaginal estrogen is an excellent choice for women who want to control vaginal dryness or prevent frequent urinary tract infections. Unlike the estrogen in pills and patches, very little vaginal estrogen is absorbed by the rest of the body. As a result, vaginal estrogen does not have the other positive or negative effects.
There is one vaginal estrogen product for postmenopausal women that contains a higher dose of estrogen (Femring®). This ring contains a higher dose of estrogen that is absorbed into the bloodstream to relieve hot flashes. We do not recommend Femring for women who need vaginal estrogen to relieve vaginal dryness or urinary symptoms.
TYPES OF PROGESTIN — As noted above, progestins are now routinely added to estrogen for any woman with a uterus. The most commonly prescribed progestin is medroxyprogesterone acetate, available in pill form under the brand names Provera, Cycrin, or Amen. There are other progestin preparations, like those used in oral contraceptives, but none have obvious advantages over medroxyprogesterone. A natural progesterone, called Prometrium®, may be a good alternative for women who cannot tolerate medroxyprogesterone. In addition, natural progesterone has no negative effect on lipids, and therefore is a good choice in women with underlying high cholesterol levels.
ALTERNATIVES TO ERT/HRT — Not all women are able or willing to take estrogen replacement, and alternative therapies are available. These are discussed in detail elsewhere (See "Patient information: Alternatives to postmenopausal hormone therapy").
BREAST CANCER AND ESTROGEN — Although women with breast cancer often experience early menopause due to adjuvant chemotherapy, and may have vasomotor symptoms due to tamoxifen therapy, estrogen therapy (by mouth or patch) is generally not recommended.
In a study called the HABITS trial, 434 women with breast cancer were randomly assigned to receive two years of HRT (estrogen alone or with progestin depending upon hysterectomy status) or no hormones [4]. After 2 years of follow-up, women in the estrogen groups were at least three times more likely to have a recurrence than women who did not take hormones. Based upon the excessive risk in the hormone group, the study was terminated in December 2003.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
The Hormone Foundation
(www.hormone.org/public/menopause.cfm, available in English and Spanish)
[1-4]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. 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.
2. 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.
3. Grady, D, Herrington, D, Bittner, V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002; 288:49.
4. Holmberg, L, Anderson, H. HABITS (hormonal replacement therapy after breast cancer--is it safe?), a randomised comparison: trial stopped. Lancet 2004; 363:453.
Monday, October 15, 2007
Postmenopausal hormone therapy
DEFINING MENOPAUSE — With the onset of menopause, a woman's body stops making estrogen and progesterone. Estrogen and progesterone are the female hormones produced by the ovaries that prepare the uterus for possible pregnancy. Prior to menopause, (which usually occurs between the ages of 45 and 55), many women notice that their periods start to occur more frequently (as often as every 21 days), although periods eventually become infrequent. This time of "transition," called perimenopause, can last for several years until menopause, when periods stop altogether.
The average age of menopause is between 50 and 51 years, although some women experience unusually early menopause (before age 40) due to surgical removal of the uterus or both ovaries, chemotherapy, or radiation therapy. However, most cases of early menopause are unexplained.
Hot flashes — Hot flashes (or hot flushes) occur because of a fall in estrogen levels. Hot flashes often begin several years before menopause and continue for several years after menopause. They are far more common at night, and can disrupt sleep. Therefore, many women also experience symptoms related to sleep-deprivation, such as fatigue, irritability, difficulty concentrating, and mood swings.
Vaginal and urinary symptoms — Many women begin to experience vaginal dryness or urinary symptoms, both of which are related to estrogen deficiency. Estrogen is the most effective treatment available for hot flashes, vaginal dryness, and urinary symptoms.
Estrogen has important effects on many other organs, such as the brain, skin, blood vessels, heart, bone, and breast. Of particular importance are the effects of estrogen on bone and possibly cardiovascular (heart) health. Without estrogen, the body is at greater risk of developing osteoporosis, a disease in which bones lose calcium and become more susceptible to fracture. In addition, the risk of heart disease in women increases after menopause, although taking estrogen (hormone replacement therapy) has not been shown to prevent heart disease.
HORMONE REPLACEMENT THERAPY — Estrogen replacement therapy, also called ERT, is a way for a postmenopausal woman to replace the estrogen her body is no longer making. While it does not make her fertile again, it does eliminate many of the symptoms of menopause. Women with a uterus who take estrogen must also take a progesterone-like hormone (called progestins) to eliminate the risk of uterine (endometrial) cancer. The term hormone replacement therapy (HRT) is used when estrogen and progestin are given together.
HISTORY OF HRT USE — Estrogen first became popular in the 1960's for the treatment of hot flushes. At that time, it was also thought that estrogen helped to preserve a woman's youthful appearance. Early on, high doses of estrogen were given (as an example, 2.5 mg of conjugated estrogens compared to the standard 0.625 mg dose that is currently used). Since then, the regimens and the reasons for taking it have changed. Taking estrogen alone results in an increased risk of endometrial cancer (also known as uterine cancer). Adding a progestin to estrogen can prevent the increased endometrial cancer risk. Therefore, by the mid-1980s, progestins were routinely added to estrogen replacement therapy (in any woman with an intact uterus, ie, women who had not undergone a hysterectomy). Many studies showed that taking ERT or HRT could prevent the bone loss that occurs after menopause, which can lead to osteoporosis and its fractures. Over 30 studies suggested that estrogen was an important therapy for preventing or reducing the risk of coronary heart disease (CHD). In fact, it appeared that women taking estrogen reduced their risk of a first heart attack by 50 percent. In addition, estrogen appeared to reduce recurrent events in women who already had coronary disease. Because of the osteoporosis and CHD studies, ERT and HRT began to be prescribed for the prevention of both diseases, which meant giving it long-term (more than five years). Breast cancer studies began to indicate that taking ERT more than 5 years increased the risk of breast cancer. Clinical trials, (studies in which women are randomly assigned to receive active treatment or placebo), did not agree with the earlier studies. The Women's Health Initiative (WHI) and the HERS trials (of combined estrogen-progestin therapy) demonstrated that HRT did not prevent heart disease, and in fact, might increase risk. The WHI trial of combined estrogen-progestin therapy did show an increased risk of breast cancer, but there was no increased risk of breast cancer in women who took estrogen alone [1].
One possible explanation for the conflicting results between the observational studies and clinical trials, is that the observational studies had a problem with "healthy user bias". This means that the healthiest women (ie. those who were less apt to have a heart attack), were more likely to be started on estrogen by their physicians. Therefore, it is possible that estrogen's beneficial effect on the heart was more related to the underlying health of the women taking it, rather than the medication itself.
WOMEN'S HEALTH INITIATIVE — The Women's Health Initiative (WHI) is a set of clinical trials that includes two HRT trials. The WHI studied healthy postmenopausal women aged 50 to 79 years, and the study was scheduled to be completed in 2005. However, one component of the WHI (continuous, combined conjugated estrogen (CEE 0.625 mg/day) and medroxyprogesterone acetate (MPA 2.5 mg/day) versus placebo in over 16,000 women) was discontinued in 2002 because of an increased risk of coronary heart disease, breast cancer, stroke, and venous thromboembolism (blood clots in the leg or lung) over an average follow-up of 5.2 years [2]. Although there was reduction in risk of osteoporotic fractures and colon cancer, there was concern that the risks of combined estrogen-progestin may outweigh the benefits.
The WHI trial of unopposed estrogen (CEE 0.625 mg/day) versus placebo in women who had undergone hysterectomy (and therefore did not require a progestin) was also discontinued (early 2004) because of a small increase in stroke risk (but no increase in CHD or breast cancer risk) [1].
Only one type of estrogen (CEE 0.625 mg) and one type of progestin (MPA 2.5 mg) treatment were studied in the WHI brand names Premarin (unopposed estrogen) and Prempro (estrogen combined with progestin). Although there are theoretical reasons to believe that other types of estrogen and progestin, different routes of administration (skin patch) or lower doses might be safer, to date, there are no studies to demonstrate that this is true.
The results of the WHI were as follows [2]:
Coronary heart disease — The rate of coronary events such as heart attacks was 24 percent higher in the women taking HRT compared to those taking placebo. This seems like a large increase in risk, but the increase for an individual woman is low. As an example, on average there were 39 CHD events per year per 10,000 women versus 33 events per 10,000 women taking placebo (ie, an additional 6 events per 10,000 women per year).
The difference in coronary events developed within the first year of the study. The risk persisted in years two through five of the study, but the highest risk was in the first year. Taking a daily aspirin did not seem to reduce the risk.
In contrast, the WHI trial of unopposed estrogen did not observe an increase in CHD risk. In the younger women in the trial (ages 50-59), a possible protective effect was seen with estrogen (although this was not significant).
The WHI investigators subsequently reported that women ages 50 to 59 years at baseline, who had been menopausal for less than 10 years, did not have an increased risk of heart disease. The excess risk was only seen in older women in the trial. This was true for both the combined estrogen-progestin trial and the unopposed estrogen trial.
Prevention of CHD after a heart attack was evaluated in the HERS trials with 2763 postmenopausal women [3]. After nearly 7 years of follow-up, continuous estrogen-progestin therapy did not reduce the risk of CHD events in women with established CHD.
Stroke — The rate of stroke was increased with combined estrogen-progestin. On average per year, there were 29 strokes in the treatment group versus 21 events in the placebo group per 10,000 women (8 additional cases per 10,000 women per year). Most of the increase in risk was due to nonfatal strokes, and the increase did not appear until year two of the study (but persisted through year five). A very similar pattern of risk was seen in the trial of unopposed estrogen [1]. (See "Patient information: Stroke").
Blood clots — The rate of blood clots (in the leg and lung) increased with combined estrogen-progestin (34 versus 16 per 10,000 women per year; or 18 additional cases per 10,000 women per year). Risk was also increased with unopposed estrogen. (See "Patient information: Venous thrombosis").
Breast cancer — The risk of breast cancer was increased in the WHI trial of combined estrogen-progestin. On average, per year there were 38 cases of breast cancer per 10,000 women versus 30 per 10,000 women (8 additional cases per year per 10,000 women). Similar findings have been noted in a number of observational studies, all of which suggest that the major increase in risk occurs after taking estrogen-progestin for four or five years. In addition, the WHI reported that women taking combined estrogen-progestin were more likely to have an abnormal mammogram. However, the majority of the abnormal mammograms were requests to return for additional views.
The results of the trial of unopposed estrogen were quite surprising, because no increase of breast cancer was seen. In fact, a possible lower risk was seen, but this was not quite significant. The fact that an increase in breast cancer risk was seen with combined hormone therapy, but not with unopposed estrogen, suggests that the progestin component is a very important factor in the risk of developing breast cancer. (See "Patient information: Postmenopausal hormone therapy and breast cancer").
Osteoporotic fracture — The risk of osteoporotic fracture was reduced at the hip and spine in both the trial of combined estrogen-progestin and the trial of unopposed estrogen. On average, per year there were 5 fewer hip fractures per 10,000 women in the HRT versus placebo group. (See "Patient information: Osteoporosis prevention and treatment").
Colorectal cancer — The risk of colorectal cancer was reduced (6 fewer colorectal cancers per 10,000 women per year) in the trial of combined estrogen-progestin versus placebo group. This benefit was not seen in the trial of unopposed estrogen. (See "Patient information: Screening for colon cancer").
Cognitive function and dementia — Although it was thought that estrogen could preserve cognitive function and prevent dementia, data from the WHI do not support this. No significant improvement in overall cognitive function was seen with combined estrogen-progestin therapy compared with placebo. It is still possible, however, that there are benefits for certain specific types of cognitive function, although this is not proven. The impact of unopposed estrogen, or taking HRT in the early postmenopausal years is not known.
In addition, combined estrogen-progestin therapy did not prevent dementia. To the contrary, an increased risk was seen (approximately 23 additional cases of dementia per 10,000 women per year). It is not known why dementia risk was higher with hormone therapy, but one possible explanation is an increased risk of multiple small strokes (which predisposes women to dementia). Similar results were reported in the unopposed estrogen trial. The effect of taking HRT in the early menopausal years on the risk of later dementia is not known, although many early studies suggest that it is early, rather than late, exposure to estrogen is important for later cognitive function.
Endometrial hyperplasia and cancer — Studies have found that postmenopausal women with a uterus who are treated with estrogen alone increase their risk of endometrial cancer and hyperplasia (a precursor to cancer). Within one year, endometrial hyperplasia can be found in 20 to 50 percent of women receiving estrogen alone. The risk can be even greater if very high doses are used or if the unopposed estrogen is continued for many years. Even when women discontinue the estrogen, the endometrial cancer risk persists for approximately five years.
In the WHI, only women without a uterus received unopposed estrogen. In women with a uterus who received combined estrogen-progestin therapy, there was no increased risk of endometrial hyperplasia or cancer.
Absolute risk of an adverse event — It should be emphasized that the absolute risk of an adverse event occurring in an individual on the estrogen-progestin regimen in the WHI was extremely low (19 additional events per year per 10,000 women with HRT compared to placebo).
In the trial of unopposed estrogen, it was calculated that overall risks and benefits would be equal (not taking into account the effect that estrogen has on hot flashes).
Most now agree that using either unopposed estrogen or combined estrogen-progestin therapy for symptom relief in young postmenopausal women in a safe and reasonable option.
OTHER RISKS — There are many HRT studies in addition to the WHI that provide other information about breast cancer. In addition, there are other known risks of HRT such as gallbladder disease that were not addressed in the WHI report.
Other breast cancer issues — The degree of increase in breast cancer risk due to estrogen is often misinterpreted. It is most important for a woman to understand the absolute risk that she will get breast cancer because she takes estrogen. It has been calculated that for a 50-year-old woman taking estrogen, there is a 1 in 100 chance that she will develop breast cancer over a 10-year period that would not have developed without estrogen. This estimate would be slightly higher (eg, 1.5 in 100) for a woman over 65 years of age.
Many studies have reported that if breast cancer does occur during estrogen therapy, it is biologically less aggressive, and survival rates are better than when breast cancer occurs in women who were not taking estrogen. However, in the WHI combined estrogen-progestin trial, women on hormones had tumors that were slightly larger and more likely to have spread to the lymph nodes. As mentioned above, no increase in breast cancer risk was seen in the trial of unopposed estrogen.
Gallbladder disease — There is considerable evidence that estrogen therapy, especially in pill form, is associated with an increased risk of gallbladder disease. The risk of cholecystectomy, (removal of the gallbladder), increases the longer a woman uses hormone therapy and the higher the dose of estrogen used. The risk decreases substantially within one to three years after a woman discontinues hormone therapy.
OTHER BENEFITS — In addition to easing the symptoms of menopause, ER/HRT has many other positive effects.
Menopausal symptoms — Estrogen is the most effective treatment available for symptoms such as hot flashes, urinary symptoms, and vaginal atrophy (atrophic vaginitis), a condition in which the vagina can become dry, resulting in pain with intercourse.
Quality of life — Women with severe menopausal symptoms often describe a dramatic improvement in their quality of life when they are treated with estrogen. This is due to relief of hot flushes and restoration of normal sleep.
Urinary tract infection — Estrogen has been found to decrease the frequency of urinary tract infections, possibly by normalizing the microorganisms present in the vagina. It does not help the symptoms of urinary incontinence. (See "Patient information: Urinary tract infection in adults").
Diabetes mellitus — The WHI reported that HRT appears to reduce the risk of type 2 diabetes mellitus (adult onset diabetes). However, because of the other risks of HRT, this effect is insufficient to recommend HRT for routine diabetes prevention in postmenopausal women. (See "Patient information: Diabetes mellitus, type 2").
Depression — Estrogen may improve mood and decrease depression in some menopausal women. One study showed that estrogen plus progestin was effective in perimenopausal women with depression. (See "Patient information: Depression in adults").
WHO SHOULD TAKE HRT?— Data from the WHI and the HERS trials have led to changes in our recommendations for hormone therapy [2,3]. Continuous estrogen-progestin therapy appears to increase the risk of cardiovascular events and breast cancer; in addition, other drugs (eg, bisphosphonates, raloxifene) can protect against osteoporosis. Unopposed estrogen increases the risk of stroke, but overall, its benefits seem equal to its risks. As a result, the main reason to take hormone therapy at present is to control menopausal symptoms.
Menopausal symptoms — Estrogen or combined estrogen-progestin therapy remains the gold standard for relief of menopausal symptoms, and therefore is a reasonable option for most postmenopausal women, with the exception of those with a history of breast cancer, CHD, a previous blood clot or stroke, or those at high risk for these complications. In otherwise healthy women, the absolute risk of an adverse event is extremely low. Most experts agree that hormone therapy is safe and reasonable for healthy postmenopausal women who need to take it to relieve symptoms. When it is used, is should be taken for the shortest period of time possible.
Administration of estrogen short-term is not associated with an increased risk of breast cancer, but endometrial hyperplasia and cancer can occur after as little as six months of unopposed estrogen therapy; as a result, a progestin must be added in those women who have not had a hysterectomy.
In women being treated for symptoms, the goal is to eventually taper and stop the estrogen (unless there is a compelling reason to continue it long-term). After the planned treatment interval, the estrogen should be discontinued gradually, as an example, by omitting one pill per week, to minimize recurrence of the menopausal symptoms.
Low-dose oral contraceptives — A low-estrogen oral contraceptive (20 µg of ethinyl estradiol) remains an appropriate treatment for perimenopausal women who seek relief of menopausal symptoms. Most of these women are between the ages of 40 and 50 years and are still candidates for oral contraception. For them, an oral contraceptive pill containing 20 µg of ethinyl estradiol provides symptomatic relief, contraception, and sometimes better bleeding control than conventional estrogen-progestin therapy. (See "Patient information: Hormonal methods of birth control").
Dose of estrogen — It is possible that lower doses of estrogen may be safer than estrogen, while still effectively treating menopausal symptoms. As an example, conjugated estrogens (0.3 mg) or the equivalent dose of other estrogens (estradiol, estrogen patch) have been shown in some, but not all studies to relieve symptoms and prevent bone loss. But it is not yet known whether lower doses of estrogen or different HRT preparations are safer with regards to breast cancer and cardiovascular risks. Therefore, it is safest to assume that other preparations carry the same risk.
Long-term estrogen therapy — Only a minority of women who are unable to successfully discontinue estrogen without persistent symptoms should consider long-term estrogen therapy. If HRT is resumed, the lowest dose possible should be used, and plans should be made to try another taper at a later date. It is important that the breast cancer and cardiovascular risks are discussed in detail with these women.
TYPES OF ESTROGEN — Estrogen can be taken as a pill (orally), or absorbed through the skin from a patch (transdermally), or inserted into the vagina.
Estrogen pill — There are many forms of estrogen pills. The most commonly used preparation, called Premarin, is made from pregnant mares' urine. Many other preparations are derived from plant sources, such as soy and yams. While there is no evidence that plant-derived estrogens work better or are safer than Premarin, many women prefer them.
Sometimes the dose of estrogen is large enough to protect bones, but not to completely eliminate menopausal symptoms. When these symptoms occur, a larger dose may be given for a year or two, but then the dose is usually reduced.
Besides Premarin, other brands of estrogen include: Cenestin, Estratab, Menest, Ogen, Estrace, and Gynediol. While these preparations vary in their potency and dose amounts, they are all effective.
Estrogen patch — There are many brands of estrogen patches. Those available in the United States include: Estraderm, Climara, Vivelle, FemPatch, and Alora. Some patches need to be replaced every few days, others once a week.
If an equivalent dose is given, transdermal estrogen is just as effective as oral estrogens in increasing bone density and in treating menopausal symptoms. But unlike oral estrogen, it has not been shown to have a beneficial effect on cholesterol levels.
Vaginal estrogen — Vaginal estrogen is available as a cream, vaginal ring, or vaginal tablet. Estrogen cream is inserted into the vagina using an applicator once a day for two to three weeks. After this, the frequency may be reduced to one or two times weekly. The estrogen vaginal tablet (Vagifem®) is given on a similar schedule.
The vaginal ring, called Estring, is a flexible plastic ring. It is inserted once every three months and does not need to be removed during intercourse or bathing. Estring may be preferred by women who have trouble using vaginal cream on a regular basis, or in women with reproductive organs that may be sagging, called prolapse, who would benefit from additional support.
Vaginal estrogen is an excellent choice for women who want to control vaginal dryness or prevent frequent urinary tract infections. Unlike the estrogen in pills and patches, very little vaginal estrogen is absorbed by the rest of the body. As a result, vaginal estrogen does not have the other positive or negative effects.
There is one vaginal estrogen product for postmenopausal women that contains a higher dose of estrogen (Femring®). This ring contains a higher dose of estrogen that is absorbed into the bloodstream to relieve hot flashes. We do not recommend Femring for women who need vaginal estrogen to relieve vaginal dryness or urinary symptoms.
TYPES OF PROGESTIN — As noted above, progestins are now routinely added to estrogen for any woman with a uterus. The most commonly prescribed progestin is medroxyprogesterone acetate, available in pill form under the brand names Provera, Cycrin, or Amen. There are other progestin preparations, like those used in oral contraceptives, but none have obvious advantages over medroxyprogesterone. A natural progesterone, called Prometrium®, may be a good alternative for women who cannot tolerate medroxyprogesterone. In addition, natural progesterone has no negative effect on lipids, and therefore is a good choice in women with underlying high cholesterol levels.
ALTERNATIVES TO ERT/HRT — Not all women are able or willing to take estrogen replacement, and alternative therapies are available. These are discussed in detail elsewhere (See "Patient information: Alternatives to postmenopausal hormone therapy").
BREAST CANCER AND ESTROGEN — Although women with breast cancer often experience early menopause due to adjuvant chemotherapy, and may have vasomotor symptoms due to tamoxifen therapy, estrogen therapy (by mouth or patch) is generally not recommended.
In a study called the HABITS trial, 434 women with breast cancer were randomly assigned to receive two years of HRT (estrogen alone or with progestin depending upon hysterectomy status) or no hormones [4]. After 2 years of follow-up, women in the estrogen groups were at least three times more likely to have a recurrence than women who did not take hormones. Based upon the excessive risk in the hormone group, the study was terminated in December 2003.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
The Hormone Foundation
(www.hormone.org/public/menopause.cfm, available in English and Spanish)
[1-4]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. 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.
2. 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.
3. Grady, D, Herrington, D, Bittner, V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002; 288:49.
4. Holmberg, L, Anderson, H. HABITS (hormonal replacement therapy after breast cancer--is it safe?), a randomised comparison: trial stopped. Lancet 2004; 363:453.
The average age of menopause is between 50 and 51 years, although some women experience unusually early menopause (before age 40) due to surgical removal of the uterus or both ovaries, chemotherapy, or radiation therapy. However, most cases of early menopause are unexplained.
Hot flashes — Hot flashes (or hot flushes) occur because of a fall in estrogen levels. Hot flashes often begin several years before menopause and continue for several years after menopause. They are far more common at night, and can disrupt sleep. Therefore, many women also experience symptoms related to sleep-deprivation, such as fatigue, irritability, difficulty concentrating, and mood swings.
Vaginal and urinary symptoms — Many women begin to experience vaginal dryness or urinary symptoms, both of which are related to estrogen deficiency. Estrogen is the most effective treatment available for hot flashes, vaginal dryness, and urinary symptoms.
Estrogen has important effects on many other organs, such as the brain, skin, blood vessels, heart, bone, and breast. Of particular importance are the effects of estrogen on bone and possibly cardiovascular (heart) health. Without estrogen, the body is at greater risk of developing osteoporosis, a disease in which bones lose calcium and become more susceptible to fracture. In addition, the risk of heart disease in women increases after menopause, although taking estrogen (hormone replacement therapy) has not been shown to prevent heart disease.
HORMONE REPLACEMENT THERAPY — Estrogen replacement therapy, also called ERT, is a way for a postmenopausal woman to replace the estrogen her body is no longer making. While it does not make her fertile again, it does eliminate many of the symptoms of menopause. Women with a uterus who take estrogen must also take a progesterone-like hormone (called progestins) to eliminate the risk of uterine (endometrial) cancer. The term hormone replacement therapy (HRT) is used when estrogen and progestin are given together.
HISTORY OF HRT USE — Estrogen first became popular in the 1960's for the treatment of hot flushes. At that time, it was also thought that estrogen helped to preserve a woman's youthful appearance. Early on, high doses of estrogen were given (as an example, 2.5 mg of conjugated estrogens compared to the standard 0.625 mg dose that is currently used). Since then, the regimens and the reasons for taking it have changed. Taking estrogen alone results in an increased risk of endometrial cancer (also known as uterine cancer). Adding a progestin to estrogen can prevent the increased endometrial cancer risk. Therefore, by the mid-1980s, progestins were routinely added to estrogen replacement therapy (in any woman with an intact uterus, ie, women who had not undergone a hysterectomy). Many studies showed that taking ERT or HRT could prevent the bone loss that occurs after menopause, which can lead to osteoporosis and its fractures. Over 30 studies suggested that estrogen was an important therapy for preventing or reducing the risk of coronary heart disease (CHD). In fact, it appeared that women taking estrogen reduced their risk of a first heart attack by 50 percent. In addition, estrogen appeared to reduce recurrent events in women who already had coronary disease. Because of the osteoporosis and CHD studies, ERT and HRT began to be prescribed for the prevention of both diseases, which meant giving it long-term (more than five years). Breast cancer studies began to indicate that taking ERT more than 5 years increased the risk of breast cancer. Clinical trials, (studies in which women are randomly assigned to receive active treatment or placebo), did not agree with the earlier studies. The Women's Health Initiative (WHI) and the HERS trials (of combined estrogen-progestin therapy) demonstrated that HRT did not prevent heart disease, and in fact, might increase risk. The WHI trial of combined estrogen-progestin therapy did show an increased risk of breast cancer, but there was no increased risk of breast cancer in women who took estrogen alone [1].
One possible explanation for the conflicting results between the observational studies and clinical trials, is that the observational studies had a problem with "healthy user bias". This means that the healthiest women (ie. those who were less apt to have a heart attack), were more likely to be started on estrogen by their physicians. Therefore, it is possible that estrogen's beneficial effect on the heart was more related to the underlying health of the women taking it, rather than the medication itself.
WOMEN'S HEALTH INITIATIVE — The Women's Health Initiative (WHI) is a set of clinical trials that includes two HRT trials. The WHI studied healthy postmenopausal women aged 50 to 79 years, and the study was scheduled to be completed in 2005. However, one component of the WHI (continuous, combined conjugated estrogen (CEE 0.625 mg/day) and medroxyprogesterone acetate (MPA 2.5 mg/day) versus placebo in over 16,000 women) was discontinued in 2002 because of an increased risk of coronary heart disease, breast cancer, stroke, and venous thromboembolism (blood clots in the leg or lung) over an average follow-up of 5.2 years [2]. Although there was reduction in risk of osteoporotic fractures and colon cancer, there was concern that the risks of combined estrogen-progestin may outweigh the benefits.
The WHI trial of unopposed estrogen (CEE 0.625 mg/day) versus placebo in women who had undergone hysterectomy (and therefore did not require a progestin) was also discontinued (early 2004) because of a small increase in stroke risk (but no increase in CHD or breast cancer risk) [1].
Only one type of estrogen (CEE 0.625 mg) and one type of progestin (MPA 2.5 mg) treatment were studied in the WHI brand names Premarin (unopposed estrogen) and Prempro (estrogen combined with progestin). Although there are theoretical reasons to believe that other types of estrogen and progestin, different routes of administration (skin patch) or lower doses might be safer, to date, there are no studies to demonstrate that this is true.
The results of the WHI were as follows [2]:
Coronary heart disease — The rate of coronary events such as heart attacks was 24 percent higher in the women taking HRT compared to those taking placebo. This seems like a large increase in risk, but the increase for an individual woman is low. As an example, on average there were 39 CHD events per year per 10,000 women versus 33 events per 10,000 women taking placebo (ie, an additional 6 events per 10,000 women per year).
The difference in coronary events developed within the first year of the study. The risk persisted in years two through five of the study, but the highest risk was in the first year. Taking a daily aspirin did not seem to reduce the risk.
In contrast, the WHI trial of unopposed estrogen did not observe an increase in CHD risk. In the younger women in the trial (ages 50-59), a possible protective effect was seen with estrogen (although this was not significant).
The WHI investigators subsequently reported that women ages 50 to 59 years at baseline, who had been menopausal for less than 10 years, did not have an increased risk of heart disease. The excess risk was only seen in older women in the trial. This was true for both the combined estrogen-progestin trial and the unopposed estrogen trial.
Prevention of CHD after a heart attack was evaluated in the HERS trials with 2763 postmenopausal women [3]. After nearly 7 years of follow-up, continuous estrogen-progestin therapy did not reduce the risk of CHD events in women with established CHD.
Stroke — The rate of stroke was increased with combined estrogen-progestin. On average per year, there were 29 strokes in the treatment group versus 21 events in the placebo group per 10,000 women (8 additional cases per 10,000 women per year). Most of the increase in risk was due to nonfatal strokes, and the increase did not appear until year two of the study (but persisted through year five). A very similar pattern of risk was seen in the trial of unopposed estrogen [1]. (See "Patient information: Stroke").
Blood clots — The rate of blood clots (in the leg and lung) increased with combined estrogen-progestin (34 versus 16 per 10,000 women per year; or 18 additional cases per 10,000 women per year). Risk was also increased with unopposed estrogen. (See "Patient information: Venous thrombosis").
Breast cancer — The risk of breast cancer was increased in the WHI trial of combined estrogen-progestin. On average, per year there were 38 cases of breast cancer per 10,000 women versus 30 per 10,000 women (8 additional cases per year per 10,000 women). Similar findings have been noted in a number of observational studies, all of which suggest that the major increase in risk occurs after taking estrogen-progestin for four or five years. In addition, the WHI reported that women taking combined estrogen-progestin were more likely to have an abnormal mammogram. However, the majority of the abnormal mammograms were requests to return for additional views.
The results of the trial of unopposed estrogen were quite surprising, because no increase of breast cancer was seen. In fact, a possible lower risk was seen, but this was not quite significant. The fact that an increase in breast cancer risk was seen with combined hormone therapy, but not with unopposed estrogen, suggests that the progestin component is a very important factor in the risk of developing breast cancer. (See "Patient information: Postmenopausal hormone therapy and breast cancer").
Osteoporotic fracture — The risk of osteoporotic fracture was reduced at the hip and spine in both the trial of combined estrogen-progestin and the trial of unopposed estrogen. On average, per year there were 5 fewer hip fractures per 10,000 women in the HRT versus placebo group. (See "Patient information: Osteoporosis prevention and treatment").
Colorectal cancer — The risk of colorectal cancer was reduced (6 fewer colorectal cancers per 10,000 women per year) in the trial of combined estrogen-progestin versus placebo group. This benefit was not seen in the trial of unopposed estrogen. (See "Patient information: Screening for colon cancer").
Cognitive function and dementia — Although it was thought that estrogen could preserve cognitive function and prevent dementia, data from the WHI do not support this. No significant improvement in overall cognitive function was seen with combined estrogen-progestin therapy compared with placebo. It is still possible, however, that there are benefits for certain specific types of cognitive function, although this is not proven. The impact of unopposed estrogen, or taking HRT in the early postmenopausal years is not known.
In addition, combined estrogen-progestin therapy did not prevent dementia. To the contrary, an increased risk was seen (approximately 23 additional cases of dementia per 10,000 women per year). It is not known why dementia risk was higher with hormone therapy, but one possible explanation is an increased risk of multiple small strokes (which predisposes women to dementia). Similar results were reported in the unopposed estrogen trial. The effect of taking HRT in the early menopausal years on the risk of later dementia is not known, although many early studies suggest that it is early, rather than late, exposure to estrogen is important for later cognitive function.
Endometrial hyperplasia and cancer — Studies have found that postmenopausal women with a uterus who are treated with estrogen alone increase their risk of endometrial cancer and hyperplasia (a precursor to cancer). Within one year, endometrial hyperplasia can be found in 20 to 50 percent of women receiving estrogen alone. The risk can be even greater if very high doses are used or if the unopposed estrogen is continued for many years. Even when women discontinue the estrogen, the endometrial cancer risk persists for approximately five years.
In the WHI, only women without a uterus received unopposed estrogen. In women with a uterus who received combined estrogen-progestin therapy, there was no increased risk of endometrial hyperplasia or cancer.
Absolute risk of an adverse event — It should be emphasized that the absolute risk of an adverse event occurring in an individual on the estrogen-progestin regimen in the WHI was extremely low (19 additional events per year per 10,000 women with HRT compared to placebo).
In the trial of unopposed estrogen, it was calculated that overall risks and benefits would be equal (not taking into account the effect that estrogen has on hot flashes).
Most now agree that using either unopposed estrogen or combined estrogen-progestin therapy for symptom relief in young postmenopausal women in a safe and reasonable option.
OTHER RISKS — There are many HRT studies in addition to the WHI that provide other information about breast cancer. In addition, there are other known risks of HRT such as gallbladder disease that were not addressed in the WHI report.
Other breast cancer issues — The degree of increase in breast cancer risk due to estrogen is often misinterpreted. It is most important for a woman to understand the absolute risk that she will get breast cancer because she takes estrogen. It has been calculated that for a 50-year-old woman taking estrogen, there is a 1 in 100 chance that she will develop breast cancer over a 10-year period that would not have developed without estrogen. This estimate would be slightly higher (eg, 1.5 in 100) for a woman over 65 years of age.
Many studies have reported that if breast cancer does occur during estrogen therapy, it is biologically less aggressive, and survival rates are better than when breast cancer occurs in women who were not taking estrogen. However, in the WHI combined estrogen-progestin trial, women on hormones had tumors that were slightly larger and more likely to have spread to the lymph nodes. As mentioned above, no increase in breast cancer risk was seen in the trial of unopposed estrogen.
Gallbladder disease — There is considerable evidence that estrogen therapy, especially in pill form, is associated with an increased risk of gallbladder disease. The risk of cholecystectomy, (removal of the gallbladder), increases the longer a woman uses hormone therapy and the higher the dose of estrogen used. The risk decreases substantially within one to three years after a woman discontinues hormone therapy.
OTHER BENEFITS — In addition to easing the symptoms of menopause, ER/HRT has many other positive effects.
Menopausal symptoms — Estrogen is the most effective treatment available for symptoms such as hot flashes, urinary symptoms, and vaginal atrophy (atrophic vaginitis), a condition in which the vagina can become dry, resulting in pain with intercourse.
Quality of life — Women with severe menopausal symptoms often describe a dramatic improvement in their quality of life when they are treated with estrogen. This is due to relief of hot flushes and restoration of normal sleep.
Urinary tract infection — Estrogen has been found to decrease the frequency of urinary tract infections, possibly by normalizing the microorganisms present in the vagina. It does not help the symptoms of urinary incontinence. (See "Patient information: Urinary tract infection in adults").
Diabetes mellitus — The WHI reported that HRT appears to reduce the risk of type 2 diabetes mellitus (adult onset diabetes). However, because of the other risks of HRT, this effect is insufficient to recommend HRT for routine diabetes prevention in postmenopausal women. (See "Patient information: Diabetes mellitus, type 2").
Depression — Estrogen may improve mood and decrease depression in some menopausal women. One study showed that estrogen plus progestin was effective in perimenopausal women with depression. (See "Patient information: Depression in adults").
WHO SHOULD TAKE HRT?— Data from the WHI and the HERS trials have led to changes in our recommendations for hormone therapy [2,3]. Continuous estrogen-progestin therapy appears to increase the risk of cardiovascular events and breast cancer; in addition, other drugs (eg, bisphosphonates, raloxifene) can protect against osteoporosis. Unopposed estrogen increases the risk of stroke, but overall, its benefits seem equal to its risks. As a result, the main reason to take hormone therapy at present is to control menopausal symptoms.
Menopausal symptoms — Estrogen or combined estrogen-progestin therapy remains the gold standard for relief of menopausal symptoms, and therefore is a reasonable option for most postmenopausal women, with the exception of those with a history of breast cancer, CHD, a previous blood clot or stroke, or those at high risk for these complications. In otherwise healthy women, the absolute risk of an adverse event is extremely low. Most experts agree that hormone therapy is safe and reasonable for healthy postmenopausal women who need to take it to relieve symptoms. When it is used, is should be taken for the shortest period of time possible.
Administration of estrogen short-term is not associated with an increased risk of breast cancer, but endometrial hyperplasia and cancer can occur after as little as six months of unopposed estrogen therapy; as a result, a progestin must be added in those women who have not had a hysterectomy.
In women being treated for symptoms, the goal is to eventually taper and stop the estrogen (unless there is a compelling reason to continue it long-term). After the planned treatment interval, the estrogen should be discontinued gradually, as an example, by omitting one pill per week, to minimize recurrence of the menopausal symptoms.
Low-dose oral contraceptives — A low-estrogen oral contraceptive (20 µg of ethinyl estradiol) remains an appropriate treatment for perimenopausal women who seek relief of menopausal symptoms. Most of these women are between the ages of 40 and 50 years and are still candidates for oral contraception. For them, an oral contraceptive pill containing 20 µg of ethinyl estradiol provides symptomatic relief, contraception, and sometimes better bleeding control than conventional estrogen-progestin therapy. (See "Patient information: Hormonal methods of birth control").
Dose of estrogen — It is possible that lower doses of estrogen may be safer than estrogen, while still effectively treating menopausal symptoms. As an example, conjugated estrogens (0.3 mg) or the equivalent dose of other estrogens (estradiol, estrogen patch) have been shown in some, but not all studies to relieve symptoms and prevent bone loss. But it is not yet known whether lower doses of estrogen or different HRT preparations are safer with regards to breast cancer and cardiovascular risks. Therefore, it is safest to assume that other preparations carry the same risk.
Long-term estrogen therapy — Only a minority of women who are unable to successfully discontinue estrogen without persistent symptoms should consider long-term estrogen therapy. If HRT is resumed, the lowest dose possible should be used, and plans should be made to try another taper at a later date. It is important that the breast cancer and cardiovascular risks are discussed in detail with these women.
TYPES OF ESTROGEN — Estrogen can be taken as a pill (orally), or absorbed through the skin from a patch (transdermally), or inserted into the vagina.
Estrogen pill — There are many forms of estrogen pills. The most commonly used preparation, called Premarin, is made from pregnant mares' urine. Many other preparations are derived from plant sources, such as soy and yams. While there is no evidence that plant-derived estrogens work better or are safer than Premarin, many women prefer them.
Sometimes the dose of estrogen is large enough to protect bones, but not to completely eliminate menopausal symptoms. When these symptoms occur, a larger dose may be given for a year or two, but then the dose is usually reduced.
Besides Premarin, other brands of estrogen include: Cenestin, Estratab, Menest, Ogen, Estrace, and Gynediol. While these preparations vary in their potency and dose amounts, they are all effective.
Estrogen patch — There are many brands of estrogen patches. Those available in the United States include: Estraderm, Climara, Vivelle, FemPatch, and Alora. Some patches need to be replaced every few days, others once a week.
If an equivalent dose is given, transdermal estrogen is just as effective as oral estrogens in increasing bone density and in treating menopausal symptoms. But unlike oral estrogen, it has not been shown to have a beneficial effect on cholesterol levels.
Vaginal estrogen — Vaginal estrogen is available as a cream, vaginal ring, or vaginal tablet. Estrogen cream is inserted into the vagina using an applicator once a day for two to three weeks. After this, the frequency may be reduced to one or two times weekly. The estrogen vaginal tablet (Vagifem®) is given on a similar schedule.
The vaginal ring, called Estring, is a flexible plastic ring. It is inserted once every three months and does not need to be removed during intercourse or bathing. Estring may be preferred by women who have trouble using vaginal cream on a regular basis, or in women with reproductive organs that may be sagging, called prolapse, who would benefit from additional support.
Vaginal estrogen is an excellent choice for women who want to control vaginal dryness or prevent frequent urinary tract infections. Unlike the estrogen in pills and patches, very little vaginal estrogen is absorbed by the rest of the body. As a result, vaginal estrogen does not have the other positive or negative effects.
There is one vaginal estrogen product for postmenopausal women that contains a higher dose of estrogen (Femring®). This ring contains a higher dose of estrogen that is absorbed into the bloodstream to relieve hot flashes. We do not recommend Femring for women who need vaginal estrogen to relieve vaginal dryness or urinary symptoms.
TYPES OF PROGESTIN — As noted above, progestins are now routinely added to estrogen for any woman with a uterus. The most commonly prescribed progestin is medroxyprogesterone acetate, available in pill form under the brand names Provera, Cycrin, or Amen. There are other progestin preparations, like those used in oral contraceptives, but none have obvious advantages over medroxyprogesterone. A natural progesterone, called Prometrium®, may be a good alternative for women who cannot tolerate medroxyprogesterone. In addition, natural progesterone has no negative effect on lipids, and therefore is a good choice in women with underlying high cholesterol levels.
ALTERNATIVES TO ERT/HRT — Not all women are able or willing to take estrogen replacement, and alternative therapies are available. These are discussed in detail elsewhere (See "Patient information: Alternatives to postmenopausal hormone therapy").
BREAST CANCER AND ESTROGEN — Although women with breast cancer often experience early menopause due to adjuvant chemotherapy, and may have vasomotor symptoms due to tamoxifen therapy, estrogen therapy (by mouth or patch) is generally not recommended.
In a study called the HABITS trial, 434 women with breast cancer were randomly assigned to receive two years of HRT (estrogen alone or with progestin depending upon hysterectomy status) or no hormones [4]. After 2 years of follow-up, women in the estrogen groups were at least three times more likely to have a recurrence than women who did not take hormones. Based upon the excessive risk in the hormone group, the study was terminated in December 2003.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
The Hormone Foundation
(www.hormone.org/public/menopause.cfm, available in English and Spanish)
[1-4]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. 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.
2. 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.
3. Grady, D, Herrington, D, Bittner, V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002; 288:49.
4. Holmberg, L, Anderson, H. HABITS (hormonal replacement therapy after breast cancer--is it safe?), a randomised comparison: trial stopped. Lancet 2004; 363:453.
Osteoporosis prevention and treatment
INTRODUCTION — Osteoporosis is a common skeletal disorder that causes a decrease in bone mass and density, causing bones to become abnormally thin (osteopenic), weakened, and easily broken (fractured). Women are at a higher risk for osteoporosis after menopause due to lower levels of estrogen, a female hormone that helps to maintain bone mass.
Fortunately, preventive treatments are available that can help to maintain or increase bone density. For those already affected by osteoporosis, prompt diagnosis of bone loss and fracture risk are essential because therapies are available that can slow further loss of bone or increase bone density.
This topic review discusses the therapies available for the prevention and treatment of osteoporosis. A separate topic review is available about the causes, diagnosis, and screening measures for osteoporosis. (See "Patient information: Osteoporosis causes, diagnosis, and screening").
NON-DRUG PREVENTION AND TREATMENT — The non-drug therapy of osteoporosis includes three major components: diet, exercise, and smoking cessation. These recommendations apply to men and women.
Diet — An optimal diet for the prevention or treatment of osteoporosis includes an adequate intake of calories as well as calcium and vitamin D, both of which are essential in helping to maintain proper bone formation and density.
Calcium intake — Experts recommend that daily elemental calcium intake (total of diet plus supplement) be at least 1000 mg for premenopausal women and men, and 1500 mg in postmenopausal women who do not take estrogen. However, the total daily calcium intake should not routinely exceed 2000 mg due to the possibility of adverse effects. (See "Patient information: Calcium for bone health").
The main dietary sources of calcium include milk and other dairy products, such as cottage cheese, yogurt, or hard cheese, and green vegetables, such as spinach and broccoli (show table 1). A rough method of estimating dietary calcium intake is to multiply the number of dairy servings consumed each day by 300 mg. One serving is 8 oz of milk or yogurt, 1 oz of hard cheese, or 16 oz of cottage cheese.
Calcium supplements (calcium carbonate or calcium citrate) may be suggested if a person cannot get enough calcium in their diet (show figure 1). Calcium doses greater than 500 mg/day should be taken in divided doses (eg, once in morning and evening). The daily intake recommendations given above always apply to "elemental calcium". Use caution when reading the labels of calcium supplements and be sure to note the amount of elemental calcium contained per serving, as many products give the calcium content per two pills.
Vitamin D intake — Experts also recommend 800 International Units (IU) of vitamin D each day. This dose appears to reduce bone loss and fracture rate in older women and men when there is adequate calcium intake (described above).
Milk is the primary dietary source of dietary vitamin D, containing approximately 100 IU per cup. Experts recommend vitamin D supplementation for all patients with osteoporosis whose intake of vitamin D is below 400 IU per day. This can be found in a daily multivitamin or a calcium/vitamin D supplement. Vitamin D is available separately in 400 IU supplements.
Protein supplements — Protein supplements may also be recommended for some patients to ensure sufficient protein intake. This may be particularly important for those who have already had osteoporotic fractures.
Alcohol, caffeine, and salt intake — A healthcare provider may also recommend limiting alcohol consumption, since high alcohol intake may increase the risk of fracture due to an increased risk of falling, poor nutrition, etc. It is not clear if restricting caffeine or salt is helpful; these measures have not been proven to prevent bone loss in those who have a sufficient intake of calcium.
Exercise — A person who has or wants to prevent osteoporosis should exercise for at least 30 minutes three times per week. Any weight-bearing exercise regimen is appropriate (eg, walking). However, exercises that could increase the risk of falling should be avoided.
Weight-bearing exercises can improve bone mass in premenopausal women and help to maintain bone density for women after menopause. Physical activity reduces the risk of hip fracture in older women as a result of increased muscle strength.
The benefits of exercise are quickly lost if a person stop exercising. A regular, weight-bearing exercise regimen that a person genuinely enjoys improves the chances of continuing to follow the routine over the long term. (See "Patient information: Exercise").
Smoking cessation — Smoking cessation is strongly recommended for patients at risk for osteoporosis because smoking cigarettes is known to accelerate bone loss. One study suggested that women who smoke one pack per day throughout adulthood have a 5 to 10 percent reduction in bone density by menopause, resulting in an increased risk of fracture. (See "Patient information: Smoking cessation").
Preventing falls — Repeated falling may significantly increase the risk of osteoporotic fractures in the elderly. Taking measures to prevent falls can decrease the risk of fractures. Such measures may include the following: Remove loose rugs and electrical cords or any other loose items in your home that could lead to tripping, slipping, and falling. Ensure that there is adequate lighting in all areas inside and around the home, including stairwells and entrance ways. Avoid walking on ice, wet or polished floors, or other potentially slippery surfaces. Avoid walking in unfamiliar areas outside.
Because certain drugs may increase the risk of falls, drug regimens should be reviewed on a regular basis. In some cases, the healthcare provider may decide to substitute one medication with an alternative that has a lower risk of causing falls. In addition, people with poor vision should see an eye specialist (eg, optomotrist or ophthamologist) for corrective lenses (glasses).
Hip pads — A person with osteoporosis who falls on their hip but has a substantial amount of muscle or fat padding over the hips has a lower risk of fracture than a person who has little padding. Hip pads (external hip protectors) are designed to reduce the risk of fracture when an elderly person falls. Results of studies that used hip pads have shown mixed results. For people who are willing to wear them on a consistent basis, hip pads may be of benefit in preventing fractures related to an accidental fall.
Medication monitoring — Prolonged therapy with and/or high doses of certain medications that increase bone loss should be monitored closely by a healthcare provider and decreased or discontinued when possible. Such medications include the following: Glucocorticoid medications (eg, prednisone) Heparin, a medication used to prevent and treat abnormal blood clotting (ie, anticoagulant) Vitamin A and certain synthetic retinoids (eg, etretinate) Certain antiepileptic drugs (eg, phenytoin, carbamazepine, primidone, phenobarbital, and valproate)
MEDICATIONS — The non-drug measures discussed above can help to reduce bone loss. For certain men and for premenopausal women who have or who are at risk for osteoporosis, drug or hormonal therapies may also be recommended.
However, the relationship between bone density and fracture risk in premenopausal women is not well defined. A premenopausal woman with low bone density may have no increased risk of fracture. Thus, bone density alone should not be used to define osteoporosis in a premenopausal woman, but instead indicates the need for further evaluation. (See "Patient information: Osteoporosis causes, diagnosis, and screening").
Bisphosphonates — Bisphosphonates inhibit the breakdown and removal of bone (ie, resorption). They are widely used for the prevention and treatment of osteoporosis in postmenopausal women.
These drugs need to be taken first thing in the morning on an empty stomach with a full 8 oz glass of water. The person must then wait at least half an hour (with alendronate (Fosamax®) and risedronate (Actonel®)) or one hour (with ibandronate (Boniva®)) before eating or taking any other medications. These dosing instructions help to reduce the risk of side effects and potential complications.
Side effects of bisphosphonates — Most people who take bisphosphonates for prevention or treatment of osteoporosis do not have any serious side effects related to the medication. However, it is important to closely follow the instructions for taking the medication; lying down or eating sooner than 30 minutes after a dose increases the risk of stomach upset.
There has been concern about a risk of bisphosphonates in people who require invasive dental work. A problem known as avascular necrosis or osteonecrosis of the jaw has rarely developed in a small number of people who used bisphosphonates. The risk of this problem is small in people who take bisphosphonates for osteoporosis prevention and treatment. However, there is a slightly higher risk of this problem when higher doses of bisphosphonates are given into vein during cancer treatment.
Most experts do not think that it is necessary to stop bisphosphonates before invasive dental work (eg, tooth extraction or implant) unless the treatment has been given into a vein. In this case, the patient should consult their healthcare provider for a specific recommendation.
Bisphosphonates are not recommended for premenopausal women who could become pregnant because of the unknown effects on a developing fetus.
Alendronate — Alendronate (Fosamax®) reduces vertebral and nonvertebral fractures, and decreases the loss of height associated with vertebral fractures. The dose for treatment is 10 mg per day, and the dose for prevention is 5 mg per day. Alendronate is usually taken as a weekly 70 or 35 mg pill.
Risedronate — Risedronate (Actonel®) is also approved for both prevention and treatment of osteoporosis at a dose of 5 mg/day (or as a single 35 mg once-weekly pill). Like alendronate, it reduces the risk of both vertebral and hip fractures.
Ibandronate — Ibandronate (Boniva®) can be used for prevention and treatment of osteoporosis at a dose of 150 mg once monthly. A monthly reminder can be sent by phone, mail, or email from the manufacturer. Although Boniva reduces the risk of bone loss and spine fractures, there is no proof that it reduces the risk of hip fractures.
Other new bisphosphonates are being studied, including single yearly intravenous infusions of zoledronic acid, which might be an effective treatment for postmenopausal osteoporosis.
"Estrogen-like" medications — Certain medications, known as selective estrogen receptor modulators (SERMs) produce some estrogen-like effects in the bone that provides protection against postmenopausal bone loss. In addition, SERMS also decrease the risk of breast cancer in women who are at high risk. Currently available SERMs include raloxifene (Evista®) and tamoxifen. Raloxifene (Evista) can be used for the prevention and treatment of osteoporosis in postmenopausal women, although it may be less effective in preventing bone loss than bisphosphonates or estrogen. (See "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer").
SERMs are not recommended for premenopausal women.
Estrogen/progestin therapy — In the past, estrogen or estrogen-progestin therapy was considered the best way to prevent postmenopausal osteoporosis and was often used for treatment. Data from the Women's Health Initiative (WHI), a large clinical trial, found that combined estrogen-progestin treatment reduced hip and vertebral fracture risk by 34 percent. A similar reduction in fracture risk was seen in the WHI trial of estrogen alone.
Estrogen had the additional advantages of controlling menopausal symptoms. However, the WHI found that estrogen plus progestin does not reduce the risk of coronary heart disease, and slightly increases the risk of breast cancer, stroke, and blood clots. The details of the WHI are discussed elsewhere. (See "Patient information: Postmenopausal hormone therapy").
Thus, estrogen is not recommended for the treatment or prevention of osteoporosis in postmenopausal women. However, some postmenopausal women continue to use estrogen, including women with persistent menopausal symptoms and those who cannot tolerate other types of osteoporosis treatment.
Estrogen may be an appropriate treatment for prevention of osteoporosis in young women with amenorrhea (absence of menses). This is often accomplished with a birth control pill. (See "Patient information: Menstrual cycle disorders (Absent and irregular periods)").
Calcitonin — Calcitonin is a hormone produced by the thyroid gland that, together with parathyroid hormone, helps to regulate calcium concentrations in the body. Synthetic calcitonin is sometimes recommended as a treatment for osteoporosis. Calcitonin may be administered via nasal spray or injection (subcutaneous salmon calcitonin). Nasal administration is typically preferred due to ease of use and because the injections tend to cause more nausea and flushing.
Other drugs are usually recommended before calcitonin because it is not clear if calcitonin increases bone density and decreases the fracture rate outside the spine. However, due to its pain-relieving (analgesic) effects, calcitonin may be suggested as a first-line therapy for those who have a sudden, intense (acute) onset of pain due to vertebral fractures. The treatment regimen is typically changed once the acute pain subsides or if the pain fails to subside over a prolonged period (eg, four weeks).
Parathyroid hormone (PTH) — PTH is produced by the parathyroid glands and stimulates both bone resorption and new bone formation. Intermittent administration stimulates formation more than resorption. Clinical trials suggest that PTH therapy is effective in both the prevention and treatment of osteoporosis in postmenopausal women and in men.
A PTH preparation called Forteo®, given by daily injection for two years, is approved for the treatment of severe osteoporosis. It is more effective at building spine bone density than any other treatment, although it is unclear if it also prevents fracture better than other treatments (specifically, the bisphosphonates). Because it requires daily injection and is expensive, it is usually reserved for patients with very severe hip or spine osteoporosis. It is not recommended for premenopausal women.
Monitoring response to hormonal or drug therapy — Testing may be recommended to monitor a patient's response to osteoporosis therapy. This may include measurement of bone mineral density or laboratory tests that indicate bone turnover (ie, rate of new bone formation and breakdown).
Testing is typically done before treatment begins to get a baseline measurement. Laboratory testing may be repeated three months after treatment begins, while bone density testing may be repeated after two years.
SUMMARY Osteoporosis causes bones to become abnormally thin (osteopenic), weakened, and easily broken. This condition can be treated and prevented with diet, exercise, and stopping smoking. Calcium and vitamin D can prevent and treat thinning bones. The main dietary sources of calcium include milk and other dairy products, such as cottage cheese, yogurt, or hard cheese, and green vegetables, such as spinach and broccoli (show table 1). Milk is the primary source of dietary vitamin D, containing approximately 100 IU per cup. Calcium and vitamin D can also be taken as a supplement (eg, in a pill, show figure 1). A total of at least 1000 mg of calcium per day is recommended for premenopausal women and men. Women after menopause should consume 1500 mg calcium per day if they do not take estrogen. Experts also recommend 800 International Units (IU) of vitamin D each day. Exercise can help to prevent and treat thinning bones. Exercise should be done for at least 30 minutes three times per week. Any weight-bearing exercise regimen is appropriate (eg, walking). Smoking cigarettes can cause bones to become thinner and weaker. Stopping smoking can reduce this risk. Falling can cause fractures in the elderly. Preventing falls can lower the risk of fractures. Some medications can cause bone thinning. Such medications include glucocorticoid medications (eg, prednisone), heparin, vitamin A and certain synthetic retinoids (eg, etretinate), and certain antiepileptic drugs (eg, phenytoin, carbamazepine, primidone, phenobarbital, and valproate). You should talk to your provider about the risk of bone thinning if you take one of these medications (see "Medication monitoring" above). There are several medications that help prevent osteoporosis in women after menopause. We think alendronate (Fosamax®), risedronate (Actonel®), or raloxifene (Evista) are the best medications for prevention (see "Bisphosphonates" above). Alendronate (Fosamax®) or risedronate (Actonel®) are recommended to treat women after menopause who have osteoporosis (see "Bisphosphonates" above). Parathyroid hormone (Forteo®) is another medication that can be used to treat osteoporosis. We recommend this medication for men or postmenopausal women with severe hip or spine osteoporosis (see "Parathyroid hormone (PTH)" above). Hormone replacement (eg, estrogen, progesterone) is not usually recommended to prevent osteoporosis in women after menopause. Hormone therapy is recommended for some young women who do not have a monthly menstrual period (see "Estrogen/progestin therapy" above). A bone density test may be recommend to monitor how the bones respond to osteoporosis treatment. For postmenopausal women, a bone density test is usually done two years after treatment starts.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
Osteoporosis and Related Bone Diseases National Resource Center (ORBD-NRC)
Toll-free: (800) 624-BONE (2663)
TTY: (202) 466-4315
E-mail: orbdnrc@nof.org
(www.osteo.org)
National Osteoporosis Foundation
Phone: (202) 223-2226
E-mail: patientinfo@nof.org
(www.nof.org)
National Women's Health Resource Center (NWHRC)
Toll-free: (877) 986-9472
E-mail: ddiamant@healthywomen.org
(www.healthywomen.org)
Osteoporosis Society of Canada
Phone: (416) 696-2663 x 294
(www.osteoporosis.ca/)
The Hormone Foundation
(www.hormone.org/public/osteoporosis.cfm, available in English, Spanish, French, Italian, German, and Portuguese)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Delmas, PD, Bjarnason, NH, Mitlak, BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997; 337:1641.
2. 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.
3. Fulton, JP. New guidelines for the prevention and treatment of osteoporosis. National Osteoporosis Foundation. Med Health R I 1999; 82:110.
4. Gregg, EW, Cauley, JA, Seeley, DG, et al. Physical activity and osteoporotic fracture risk in older women. Ann Intern Med 1998; 129:81.
5. NIH Consensus Development Panel on Optimal Calcium Intake. Optimal calcium intake. JAMA 1994; 272:1942.
Fortunately, preventive treatments are available that can help to maintain or increase bone density. For those already affected by osteoporosis, prompt diagnosis of bone loss and fracture risk are essential because therapies are available that can slow further loss of bone or increase bone density.
This topic review discusses the therapies available for the prevention and treatment of osteoporosis. A separate topic review is available about the causes, diagnosis, and screening measures for osteoporosis. (See "Patient information: Osteoporosis causes, diagnosis, and screening").
NON-DRUG PREVENTION AND TREATMENT — The non-drug therapy of osteoporosis includes three major components: diet, exercise, and smoking cessation. These recommendations apply to men and women.
Diet — An optimal diet for the prevention or treatment of osteoporosis includes an adequate intake of calories as well as calcium and vitamin D, both of which are essential in helping to maintain proper bone formation and density.
Calcium intake — Experts recommend that daily elemental calcium intake (total of diet plus supplement) be at least 1000 mg for premenopausal women and men, and 1500 mg in postmenopausal women who do not take estrogen. However, the total daily calcium intake should not routinely exceed 2000 mg due to the possibility of adverse effects. (See "Patient information: Calcium for bone health").
The main dietary sources of calcium include milk and other dairy products, such as cottage cheese, yogurt, or hard cheese, and green vegetables, such as spinach and broccoli (show table 1). A rough method of estimating dietary calcium intake is to multiply the number of dairy servings consumed each day by 300 mg. One serving is 8 oz of milk or yogurt, 1 oz of hard cheese, or 16 oz of cottage cheese.
Calcium supplements (calcium carbonate or calcium citrate) may be suggested if a person cannot get enough calcium in their diet (show figure 1). Calcium doses greater than 500 mg/day should be taken in divided doses (eg, once in morning and evening). The daily intake recommendations given above always apply to "elemental calcium". Use caution when reading the labels of calcium supplements and be sure to note the amount of elemental calcium contained per serving, as many products give the calcium content per two pills.
Vitamin D intake — Experts also recommend 800 International Units (IU) of vitamin D each day. This dose appears to reduce bone loss and fracture rate in older women and men when there is adequate calcium intake (described above).
Milk is the primary dietary source of dietary vitamin D, containing approximately 100 IU per cup. Experts recommend vitamin D supplementation for all patients with osteoporosis whose intake of vitamin D is below 400 IU per day. This can be found in a daily multivitamin or a calcium/vitamin D supplement. Vitamin D is available separately in 400 IU supplements.
Protein supplements — Protein supplements may also be recommended for some patients to ensure sufficient protein intake. This may be particularly important for those who have already had osteoporotic fractures.
Alcohol, caffeine, and salt intake — A healthcare provider may also recommend limiting alcohol consumption, since high alcohol intake may increase the risk of fracture due to an increased risk of falling, poor nutrition, etc. It is not clear if restricting caffeine or salt is helpful; these measures have not been proven to prevent bone loss in those who have a sufficient intake of calcium.
Exercise — A person who has or wants to prevent osteoporosis should exercise for at least 30 minutes three times per week. Any weight-bearing exercise regimen is appropriate (eg, walking). However, exercises that could increase the risk of falling should be avoided.
Weight-bearing exercises can improve bone mass in premenopausal women and help to maintain bone density for women after menopause. Physical activity reduces the risk of hip fracture in older women as a result of increased muscle strength.
The benefits of exercise are quickly lost if a person stop exercising. A regular, weight-bearing exercise regimen that a person genuinely enjoys improves the chances of continuing to follow the routine over the long term. (See "Patient information: Exercise").
Smoking cessation — Smoking cessation is strongly recommended for patients at risk for osteoporosis because smoking cigarettes is known to accelerate bone loss. One study suggested that women who smoke one pack per day throughout adulthood have a 5 to 10 percent reduction in bone density by menopause, resulting in an increased risk of fracture. (See "Patient information: Smoking cessation").
Preventing falls — Repeated falling may significantly increase the risk of osteoporotic fractures in the elderly. Taking measures to prevent falls can decrease the risk of fractures. Such measures may include the following: Remove loose rugs and electrical cords or any other loose items in your home that could lead to tripping, slipping, and falling. Ensure that there is adequate lighting in all areas inside and around the home, including stairwells and entrance ways. Avoid walking on ice, wet or polished floors, or other potentially slippery surfaces. Avoid walking in unfamiliar areas outside.
Because certain drugs may increase the risk of falls, drug regimens should be reviewed on a regular basis. In some cases, the healthcare provider may decide to substitute one medication with an alternative that has a lower risk of causing falls. In addition, people with poor vision should see an eye specialist (eg, optomotrist or ophthamologist) for corrective lenses (glasses).
Hip pads — A person with osteoporosis who falls on their hip but has a substantial amount of muscle or fat padding over the hips has a lower risk of fracture than a person who has little padding. Hip pads (external hip protectors) are designed to reduce the risk of fracture when an elderly person falls. Results of studies that used hip pads have shown mixed results. For people who are willing to wear them on a consistent basis, hip pads may be of benefit in preventing fractures related to an accidental fall.
Medication monitoring — Prolonged therapy with and/or high doses of certain medications that increase bone loss should be monitored closely by a healthcare provider and decreased or discontinued when possible. Such medications include the following: Glucocorticoid medications (eg, prednisone) Heparin, a medication used to prevent and treat abnormal blood clotting (ie, anticoagulant) Vitamin A and certain synthetic retinoids (eg, etretinate) Certain antiepileptic drugs (eg, phenytoin, carbamazepine, primidone, phenobarbital, and valproate)
MEDICATIONS — The non-drug measures discussed above can help to reduce bone loss. For certain men and for premenopausal women who have or who are at risk for osteoporosis, drug or hormonal therapies may also be recommended.
However, the relationship between bone density and fracture risk in premenopausal women is not well defined. A premenopausal woman with low bone density may have no increased risk of fracture. Thus, bone density alone should not be used to define osteoporosis in a premenopausal woman, but instead indicates the need for further evaluation. (See "Patient information: Osteoporosis causes, diagnosis, and screening").
Bisphosphonates — Bisphosphonates inhibit the breakdown and removal of bone (ie, resorption). They are widely used for the prevention and treatment of osteoporosis in postmenopausal women.
These drugs need to be taken first thing in the morning on an empty stomach with a full 8 oz glass of water. The person must then wait at least half an hour (with alendronate (Fosamax®) and risedronate (Actonel®)) or one hour (with ibandronate (Boniva®)) before eating or taking any other medications. These dosing instructions help to reduce the risk of side effects and potential complications.
Side effects of bisphosphonates — Most people who take bisphosphonates for prevention or treatment of osteoporosis do not have any serious side effects related to the medication. However, it is important to closely follow the instructions for taking the medication; lying down or eating sooner than 30 minutes after a dose increases the risk of stomach upset.
There has been concern about a risk of bisphosphonates in people who require invasive dental work. A problem known as avascular necrosis or osteonecrosis of the jaw has rarely developed in a small number of people who used bisphosphonates. The risk of this problem is small in people who take bisphosphonates for osteoporosis prevention and treatment. However, there is a slightly higher risk of this problem when higher doses of bisphosphonates are given into vein during cancer treatment.
Most experts do not think that it is necessary to stop bisphosphonates before invasive dental work (eg, tooth extraction or implant) unless the treatment has been given into a vein. In this case, the patient should consult their healthcare provider for a specific recommendation.
Bisphosphonates are not recommended for premenopausal women who could become pregnant because of the unknown effects on a developing fetus.
Alendronate — Alendronate (Fosamax®) reduces vertebral and nonvertebral fractures, and decreases the loss of height associated with vertebral fractures. The dose for treatment is 10 mg per day, and the dose for prevention is 5 mg per day. Alendronate is usually taken as a weekly 70 or 35 mg pill.
Risedronate — Risedronate (Actonel®) is also approved for both prevention and treatment of osteoporosis at a dose of 5 mg/day (or as a single 35 mg once-weekly pill). Like alendronate, it reduces the risk of both vertebral and hip fractures.
Ibandronate — Ibandronate (Boniva®) can be used for prevention and treatment of osteoporosis at a dose of 150 mg once monthly. A monthly reminder can be sent by phone, mail, or email from the manufacturer. Although Boniva reduces the risk of bone loss and spine fractures, there is no proof that it reduces the risk of hip fractures.
Other new bisphosphonates are being studied, including single yearly intravenous infusions of zoledronic acid, which might be an effective treatment for postmenopausal osteoporosis.
"Estrogen-like" medications — Certain medications, known as selective estrogen receptor modulators (SERMs) produce some estrogen-like effects in the bone that provides protection against postmenopausal bone loss. In addition, SERMS also decrease the risk of breast cancer in women who are at high risk. Currently available SERMs include raloxifene (Evista®) and tamoxifen. Raloxifene (Evista) can be used for the prevention and treatment of osteoporosis in postmenopausal women, although it may be less effective in preventing bone loss than bisphosphonates or estrogen. (See "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer").
SERMs are not recommended for premenopausal women.
Estrogen/progestin therapy — In the past, estrogen or estrogen-progestin therapy was considered the best way to prevent postmenopausal osteoporosis and was often used for treatment. Data from the Women's Health Initiative (WHI), a large clinical trial, found that combined estrogen-progestin treatment reduced hip and vertebral fracture risk by 34 percent. A similar reduction in fracture risk was seen in the WHI trial of estrogen alone.
Estrogen had the additional advantages of controlling menopausal symptoms. However, the WHI found that estrogen plus progestin does not reduce the risk of coronary heart disease, and slightly increases the risk of breast cancer, stroke, and blood clots. The details of the WHI are discussed elsewhere. (See "Patient information: Postmenopausal hormone therapy").
Thus, estrogen is not recommended for the treatment or prevention of osteoporosis in postmenopausal women. However, some postmenopausal women continue to use estrogen, including women with persistent menopausal symptoms and those who cannot tolerate other types of osteoporosis treatment.
Estrogen may be an appropriate treatment for prevention of osteoporosis in young women with amenorrhea (absence of menses). This is often accomplished with a birth control pill. (See "Patient information: Menstrual cycle disorders (Absent and irregular periods)").
Calcitonin — Calcitonin is a hormone produced by the thyroid gland that, together with parathyroid hormone, helps to regulate calcium concentrations in the body. Synthetic calcitonin is sometimes recommended as a treatment for osteoporosis. Calcitonin may be administered via nasal spray or injection (subcutaneous salmon calcitonin). Nasal administration is typically preferred due to ease of use and because the injections tend to cause more nausea and flushing.
Other drugs are usually recommended before calcitonin because it is not clear if calcitonin increases bone density and decreases the fracture rate outside the spine. However, due to its pain-relieving (analgesic) effects, calcitonin may be suggested as a first-line therapy for those who have a sudden, intense (acute) onset of pain due to vertebral fractures. The treatment regimen is typically changed once the acute pain subsides or if the pain fails to subside over a prolonged period (eg, four weeks).
Parathyroid hormone (PTH) — PTH is produced by the parathyroid glands and stimulates both bone resorption and new bone formation. Intermittent administration stimulates formation more than resorption. Clinical trials suggest that PTH therapy is effective in both the prevention and treatment of osteoporosis in postmenopausal women and in men.
A PTH preparation called Forteo®, given by daily injection for two years, is approved for the treatment of severe osteoporosis. It is more effective at building spine bone density than any other treatment, although it is unclear if it also prevents fracture better than other treatments (specifically, the bisphosphonates). Because it requires daily injection and is expensive, it is usually reserved for patients with very severe hip or spine osteoporosis. It is not recommended for premenopausal women.
Monitoring response to hormonal or drug therapy — Testing may be recommended to monitor a patient's response to osteoporosis therapy. This may include measurement of bone mineral density or laboratory tests that indicate bone turnover (ie, rate of new bone formation and breakdown).
Testing is typically done before treatment begins to get a baseline measurement. Laboratory testing may be repeated three months after treatment begins, while bone density testing may be repeated after two years.
SUMMARY Osteoporosis causes bones to become abnormally thin (osteopenic), weakened, and easily broken. This condition can be treated and prevented with diet, exercise, and stopping smoking. Calcium and vitamin D can prevent and treat thinning bones. The main dietary sources of calcium include milk and other dairy products, such as cottage cheese, yogurt, or hard cheese, and green vegetables, such as spinach and broccoli (show table 1). Milk is the primary source of dietary vitamin D, containing approximately 100 IU per cup. Calcium and vitamin D can also be taken as a supplement (eg, in a pill, show figure 1). A total of at least 1000 mg of calcium per day is recommended for premenopausal women and men. Women after menopause should consume 1500 mg calcium per day if they do not take estrogen. Experts also recommend 800 International Units (IU) of vitamin D each day. Exercise can help to prevent and treat thinning bones. Exercise should be done for at least 30 minutes three times per week. Any weight-bearing exercise regimen is appropriate (eg, walking). Smoking cigarettes can cause bones to become thinner and weaker. Stopping smoking can reduce this risk. Falling can cause fractures in the elderly. Preventing falls can lower the risk of fractures. Some medications can cause bone thinning. Such medications include glucocorticoid medications (eg, prednisone), heparin, vitamin A and certain synthetic retinoids (eg, etretinate), and certain antiepileptic drugs (eg, phenytoin, carbamazepine, primidone, phenobarbital, and valproate). You should talk to your provider about the risk of bone thinning if you take one of these medications (see "Medication monitoring" above). There are several medications that help prevent osteoporosis in women after menopause. We think alendronate (Fosamax®), risedronate (Actonel®), or raloxifene (Evista) are the best medications for prevention (see "Bisphosphonates" above). Alendronate (Fosamax®) or risedronate (Actonel®) are recommended to treat women after menopause who have osteoporosis (see "Bisphosphonates" above). Parathyroid hormone (Forteo®) is another medication that can be used to treat osteoporosis. We recommend this medication for men or postmenopausal women with severe hip or spine osteoporosis (see "Parathyroid hormone (PTH)" above). Hormone replacement (eg, estrogen, progesterone) is not usually recommended to prevent osteoporosis in women after menopause. Hormone therapy is recommended for some young women who do not have a monthly menstrual period (see "Estrogen/progestin therapy" above). A bone density test may be recommend to monitor how the bones respond to osteoporosis treatment. For postmenopausal women, a bone density test is usually done two years after treatment starts.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
Osteoporosis and Related Bone Diseases National Resource Center (ORBD-NRC)
Toll-free: (800) 624-BONE (2663)
TTY: (202) 466-4315
E-mail: orbdnrc@nof.org
(www.osteo.org)
National Osteoporosis Foundation
Phone: (202) 223-2226
E-mail: patientinfo@nof.org
(www.nof.org)
National Women's Health Resource Center (NWHRC)
Toll-free: (877) 986-9472
E-mail: ddiamant@healthywomen.org
(www.healthywomen.org)
Osteoporosis Society of Canada
Phone: (416) 696-2663 x 294
(www.osteoporosis.ca/)
The Hormone Foundation
(www.hormone.org/public/osteoporosis.cfm, available in English, Spanish, French, Italian, German, and Portuguese)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Delmas, PD, Bjarnason, NH, Mitlak, BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997; 337:1641.
2. 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.
3. Fulton, JP. New guidelines for the prevention and treatment of osteoporosis. National Osteoporosis Foundation. Med Health R I 1999; 82:110.
4. Gregg, EW, Cauley, JA, Seeley, DG, et al. Physical activity and osteoporotic fracture risk in older women. Ann Intern Med 1998; 129:81.
5. NIH Consensus Development Panel on Optimal Calcium Intake. Optimal calcium intake. JAMA 1994; 272:1942.
Osteoporosis prevention and treatment
INTRODUCTION — Osteoporosis is a common skeletal disorder that causes a decrease in bone mass and density, causing bones to become abnormally thin (osteopenic), weakened, and easily broken (fractured). Women are at a higher risk for osteoporosis after menopause due to lower levels of estrogen, a female hormone that helps to maintain bone mass.
Fortunately, preventive treatments are available that can help to maintain or increase bone density. For those already affected by osteoporosis, prompt diagnosis of bone loss and fracture risk are essential because therapies are available that can slow further loss of bone or increase bone density.
This topic review discusses the therapies available for the prevention and treatment of osteoporosis. A separate topic review is available about the causes, diagnosis, and screening measures for osteoporosis. (See "Patient information: Osteoporosis causes, diagnosis, and screening").
NON-DRUG PREVENTION AND TREATMENT — The non-drug therapy of osteoporosis includes three major components: diet, exercise, and smoking cessation. These recommendations apply to men and women.
Diet — An optimal diet for the prevention or treatment of osteoporosis includes an adequate intake of calories as well as calcium and vitamin D, both of which are essential in helping to maintain proper bone formation and density.
Calcium intake — Experts recommend that daily elemental calcium intake (total of diet plus supplement) be at least 1000 mg for premenopausal women and men, and 1500 mg in postmenopausal women who do not take estrogen. However, the total daily calcium intake should not routinely exceed 2000 mg due to the possibility of adverse effects. (See "Patient information: Calcium for bone health").
The main dietary sources of calcium include milk and other dairy products, such as cottage cheese, yogurt, or hard cheese, and green vegetables, such as spinach and broccoli (show table 1). A rough method of estimating dietary calcium intake is to multiply the number of dairy servings consumed each day by 300 mg. One serving is 8 oz of milk or yogurt, 1 oz of hard cheese, or 16 oz of cottage cheese.
Calcium supplements (calcium carbonate or calcium citrate) may be suggested if a person cannot get enough calcium in their diet (show figure 1). Calcium doses greater than 500 mg/day should be taken in divided doses (eg, once in morning and evening). The daily intake recommendations given above always apply to "elemental calcium". Use caution when reading the labels of calcium supplements and be sure to note the amount of elemental calcium contained per serving, as many products give the calcium content per two pills.
Vitamin D intake — Experts also recommend 800 International Units (IU) of vitamin D each day. This dose appears to reduce bone loss and fracture rate in older women and men when there is adequate calcium intake (described above).
Milk is the primary dietary source of dietary vitamin D, containing approximately 100 IU per cup. Experts recommend vitamin D supplementation for all patients with osteoporosis whose intake of vitamin D is below 400 IU per day. This can be found in a daily multivitamin or a calcium/vitamin D supplement. Vitamin D is available separately in 400 IU supplements.
Protein supplements — Protein supplements may also be recommended for some patients to ensure sufficient protein intake. This may be particularly important for those who have already had osteoporotic fractures.
Alcohol, caffeine, and salt intake — A healthcare provider may also recommend limiting alcohol consumption, since high alcohol intake may increase the risk of fracture due to an increased risk of falling, poor nutrition, etc. It is not clear if restricting caffeine or salt is helpful; these measures have not been proven to prevent bone loss in those who have a sufficient intake of calcium.
Exercise — A person who has or wants to prevent osteoporosis should exercise for at least 30 minutes three times per week. Any weight-bearing exercise regimen is appropriate (eg, walking). However, exercises that could increase the risk of falling should be avoided.
Weight-bearing exercises can improve bone mass in premenopausal women and help to maintain bone density for women after menopause. Physical activity reduces the risk of hip fracture in older women as a result of increased muscle strength.
The benefits of exercise are quickly lost if a person stop exercising. A regular, weight-bearing exercise regimen that a person genuinely enjoys improves the chances of continuing to follow the routine over the long term. (See "Patient information: Exercise").
Smoking cessation — Smoking cessation is strongly recommended for patients at risk for osteoporosis because smoking cigarettes is known to accelerate bone loss. One study suggested that women who smoke one pack per day throughout adulthood have a 5 to 10 percent reduction in bone density by menopause, resulting in an increased risk of fracture. (See "Patient information: Smoking cessation").
Preventing falls — Repeated falling may significantly increase the risk of osteoporotic fractures in the elderly. Taking measures to prevent falls can decrease the risk of fractures. Such measures may include the following: Remove loose rugs and electrical cords or any other loose items in your home that could lead to tripping, slipping, and falling. Ensure that there is adequate lighting in all areas inside and around the home, including stairwells and entrance ways. Avoid walking on ice, wet or polished floors, or other potentially slippery surfaces. Avoid walking in unfamiliar areas outside.
Because certain drugs may increase the risk of falls, drug regimens should be reviewed on a regular basis. In some cases, the healthcare provider may decide to substitute one medication with an alternative that has a lower risk of causing falls. In addition, people with poor vision should see an eye specialist (eg, optomotrist or ophthamologist) for corrective lenses (glasses).
Hip pads — A person with osteoporosis who falls on their hip but has a substantial amount of muscle or fat padding over the hips has a lower risk of fracture than a person who has little padding. Hip pads (external hip protectors) are designed to reduce the risk of fracture when an elderly person falls. Results of studies that used hip pads have shown mixed results. For people who are willing to wear them on a consistent basis, hip pads may be of benefit in preventing fractures related to an accidental fall.
Medication monitoring — Prolonged therapy with and/or high doses of certain medications that increase bone loss should be monitored closely by a healthcare provider and decreased or discontinued when possible. Such medications include the following: Glucocorticoid medications (eg, prednisone) Heparin, a medication used to prevent and treat abnormal blood clotting (ie, anticoagulant) Vitamin A and certain synthetic retinoids (eg, etretinate) Certain antiepileptic drugs (eg, phenytoin, carbamazepine, primidone, phenobarbital, and valproate)
MEDICATIONS — The non-drug measures discussed above can help to reduce bone loss. For certain men and for premenopausal women who have or who are at risk for osteoporosis, drug or hormonal therapies may also be recommended.
However, the relationship between bone density and fracture risk in premenopausal women is not well defined. A premenopausal woman with low bone density may have no increased risk of fracture. Thus, bone density alone should not be used to define osteoporosis in a premenopausal woman, but instead indicates the need for further evaluation. (See "Patient information: Osteoporosis causes, diagnosis, and screening").
Bisphosphonates — Bisphosphonates inhibit the breakdown and removal of bone (ie, resorption). They are widely used for the prevention and treatment of osteoporosis in postmenopausal women.
These drugs need to be taken first thing in the morning on an empty stomach with a full 8 oz glass of water. The person must then wait at least half an hour (with alendronate (Fosamax®) and risedronate (Actonel®)) or one hour (with ibandronate (Boniva®)) before eating or taking any other medications. These dosing instructions help to reduce the risk of side effects and potential complications.
Side effects of bisphosphonates — Most people who take bisphosphonates for prevention or treatment of osteoporosis do not have any serious side effects related to the medication. However, it is important to closely follow the instructions for taking the medication; lying down or eating sooner than 30 minutes after a dose increases the risk of stomach upset.
There has been concern about a risk of bisphosphonates in people who require invasive dental work. A problem known as avascular necrosis or osteonecrosis of the jaw has rarely developed in a small number of people who used bisphosphonates. The risk of this problem is small in people who take bisphosphonates for osteoporosis prevention and treatment. However, there is a slightly higher risk of this problem when higher doses of bisphosphonates are given into vein during cancer treatment.
Most experts do not think that it is necessary to stop bisphosphonates before invasive dental work (eg, tooth extraction or implant) unless the treatment has been given into a vein. In this case, the patient should consult their healthcare provider for a specific recommendation.
Bisphosphonates are not recommended for premenopausal women who could become pregnant because of the unknown effects on a developing fetus.
Alendronate — Alendronate (Fosamax®) reduces vertebral and nonvertebral fractures, and decreases the loss of height associated with vertebral fractures. The dose for treatment is 10 mg per day, and the dose for prevention is 5 mg per day. Alendronate is usually taken as a weekly 70 or 35 mg pill.
Risedronate — Risedronate (Actonel®) is also approved for both prevention and treatment of osteoporosis at a dose of 5 mg/day (or as a single 35 mg once-weekly pill). Like alendronate, it reduces the risk of both vertebral and hip fractures.
Ibandronate — Ibandronate (Boniva®) can be used for prevention and treatment of osteoporosis at a dose of 150 mg once monthly. A monthly reminder can be sent by phone, mail, or email from the manufacturer. Although Boniva reduces the risk of bone loss and spine fractures, there is no proof that it reduces the risk of hip fractures.
Other new bisphosphonates are being studied, including single yearly intravenous infusions of zoledronic acid, which might be an effective treatment for postmenopausal osteoporosis.
"Estrogen-like" medications — Certain medications, known as selective estrogen receptor modulators (SERMs) produce some estrogen-like effects in the bone that provides protection against postmenopausal bone loss. In addition, SERMS also decrease the risk of breast cancer in women who are at high risk. Currently available SERMs include raloxifene (Evista®) and tamoxifen. Raloxifene (Evista) can be used for the prevention and treatment of osteoporosis in postmenopausal women, although it may be less effective in preventing bone loss than bisphosphonates or estrogen. (See "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer").
SERMs are not recommended for premenopausal women.
Estrogen/progestin therapy — In the past, estrogen or estrogen-progestin therapy was considered the best way to prevent postmenopausal osteoporosis and was often used for treatment. Data from the Women's Health Initiative (WHI), a large clinical trial, found that combined estrogen-progestin treatment reduced hip and vertebral fracture risk by 34 percent. A similar reduction in fracture risk was seen in the WHI trial of estrogen alone.
Estrogen had the additional advantages of controlling menopausal symptoms. However, the WHI found that estrogen plus progestin does not reduce the risk of coronary heart disease, and slightly increases the risk of breast cancer, stroke, and blood clots. The details of the WHI are discussed elsewhere. (See "Patient information: Postmenopausal hormone therapy").
Thus, estrogen is not recommended for the treatment or prevention of osteoporosis in postmenopausal women. However, some postmenopausal women continue to use estrogen, including women with persistent menopausal symptoms and those who cannot tolerate other types of osteoporosis treatment.
Estrogen may be an appropriate treatment for prevention of osteoporosis in young women with amenorrhea (absence of menses). This is often accomplished with a birth control pill. (See "Patient information: Menstrual cycle disorders (Absent and irregular periods)").
Calcitonin — Calcitonin is a hormone produced by the thyroid gland that, together with parathyroid hormone, helps to regulate calcium concentrations in the body. Synthetic calcitonin is sometimes recommended as a treatment for osteoporosis. Calcitonin may be administered via nasal spray or injection (subcutaneous salmon calcitonin). Nasal administration is typically preferred due to ease of use and because the injections tend to cause more nausea and flushing.
Other drugs are usually recommended before calcitonin because it is not clear if calcitonin increases bone density and decreases the fracture rate outside the spine. However, due to its pain-relieving (analgesic) effects, calcitonin may be suggested as a first-line therapy for those who have a sudden, intense (acute) onset of pain due to vertebral fractures. The treatment regimen is typically changed once the acute pain subsides or if the pain fails to subside over a prolonged period (eg, four weeks).
Parathyroid hormone (PTH) — PTH is produced by the parathyroid glands and stimulates both bone resorption and new bone formation. Intermittent administration stimulates formation more than resorption. Clinical trials suggest that PTH therapy is effective in both the prevention and treatment of osteoporosis in postmenopausal women and in men.
A PTH preparation called Forteo®, given by daily injection for two years, is approved for the treatment of severe osteoporosis. It is more effective at building spine bone density than any other treatment, although it is unclear if it also prevents fracture better than other treatments (specifically, the bisphosphonates). Because it requires daily injection and is expensive, it is usually reserved for patients with very severe hip or spine osteoporosis. It is not recommended for premenopausal women.
Monitoring response to hormonal or drug therapy — Testing may be recommended to monitor a patient's response to osteoporosis therapy. This may include measurement of bone mineral density or laboratory tests that indicate bone turnover (ie, rate of new bone formation and breakdown).
Testing is typically done before treatment begins to get a baseline measurement. Laboratory testing may be repeated three months after treatment begins, while bone density testing may be repeated after two years.
SUMMARY Osteoporosis causes bones to become abnormally thin (osteopenic), weakened, and easily broken. This condition can be treated and prevented with diet, exercise, and stopping smoking. Calcium and vitamin D can prevent and treat thinning bones. The main dietary sources of calcium include milk and other dairy products, such as cottage cheese, yogurt, or hard cheese, and green vegetables, such as spinach and broccoli (show table 1). Milk is the primary source of dietary vitamin D, containing approximately 100 IU per cup. Calcium and vitamin D can also be taken as a supplement (eg, in a pill, show figure 1). A total of at least 1000 mg of calcium per day is recommended for premenopausal women and men. Women after menopause should consume 1500 mg calcium per day if they do not take estrogen. Experts also recommend 800 International Units (IU) of vitamin D each day. Exercise can help to prevent and treat thinning bones. Exercise should be done for at least 30 minutes three times per week. Any weight-bearing exercise regimen is appropriate (eg, walking). Smoking cigarettes can cause bones to become thinner and weaker. Stopping smoking can reduce this risk. Falling can cause fractures in the elderly. Preventing falls can lower the risk of fractures. Some medications can cause bone thinning. Such medications include glucocorticoid medications (eg, prednisone), heparin, vitamin A and certain synthetic retinoids (eg, etretinate), and certain antiepileptic drugs (eg, phenytoin, carbamazepine, primidone, phenobarbital, and valproate). You should talk to your provider about the risk of bone thinning if you take one of these medications (see "Medication monitoring" above). There are several medications that help prevent osteoporosis in women after menopause. We think alendronate (Fosamax®), risedronate (Actonel®), or raloxifene (Evista) are the best medications for prevention (see "Bisphosphonates" above). Alendronate (Fosamax®) or risedronate (Actonel®) are recommended to treat women after menopause who have osteoporosis (see "Bisphosphonates" above). Parathyroid hormone (Forteo®) is another medication that can be used to treat osteoporosis. We recommend this medication for men or postmenopausal women with severe hip or spine osteoporosis (see "Parathyroid hormone (PTH)" above). Hormone replacement (eg, estrogen, progesterone) is not usually recommended to prevent osteoporosis in women after menopause. Hormone therapy is recommended for some young women who do not have a monthly menstrual period (see "Estrogen/progestin therapy" above). A bone density test may be recommend to monitor how the bones respond to osteoporosis treatment. For postmenopausal women, a bone density test is usually done two years after treatment starts.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
Osteoporosis and Related Bone Diseases National Resource Center (ORBD-NRC)
Toll-free: (800) 624-BONE (2663)
TTY: (202) 466-4315
E-mail: orbdnrc@nof.org
(www.osteo.org)
National Osteoporosis Foundation
Phone: (202) 223-2226
E-mail: patientinfo@nof.org
(www.nof.org)
National Women's Health Resource Center (NWHRC)
Toll-free: (877) 986-9472
E-mail: ddiamant@healthywomen.org
(www.healthywomen.org)
Osteoporosis Society of Canada
Phone: (416) 696-2663 x 294
(www.osteoporosis.ca/)
The Hormone Foundation
(www.hormone.org/public/osteoporosis.cfm, available in English, Spanish, French, Italian, German, and Portuguese)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Delmas, PD, Bjarnason, NH, Mitlak, BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997; 337:1641.
2. 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.
3. Fulton, JP. New guidelines for the prevention and treatment of osteoporosis. National Osteoporosis Foundation. Med Health R I 1999; 82:110.
4. Gregg, EW, Cauley, JA, Seeley, DG, et al. Physical activity and osteoporotic fracture risk in older women. Ann Intern Med 1998; 129:81.
5. NIH Consensus Development Panel on Optimal Calcium Intake. Optimal calcium intake. JAMA 1994; 272:1942.
Fortunately, preventive treatments are available that can help to maintain or increase bone density. For those already affected by osteoporosis, prompt diagnosis of bone loss and fracture risk are essential because therapies are available that can slow further loss of bone or increase bone density.
This topic review discusses the therapies available for the prevention and treatment of osteoporosis. A separate topic review is available about the causes, diagnosis, and screening measures for osteoporosis. (See "Patient information: Osteoporosis causes, diagnosis, and screening").
NON-DRUG PREVENTION AND TREATMENT — The non-drug therapy of osteoporosis includes three major components: diet, exercise, and smoking cessation. These recommendations apply to men and women.
Diet — An optimal diet for the prevention or treatment of osteoporosis includes an adequate intake of calories as well as calcium and vitamin D, both of which are essential in helping to maintain proper bone formation and density.
Calcium intake — Experts recommend that daily elemental calcium intake (total of diet plus supplement) be at least 1000 mg for premenopausal women and men, and 1500 mg in postmenopausal women who do not take estrogen. However, the total daily calcium intake should not routinely exceed 2000 mg due to the possibility of adverse effects. (See "Patient information: Calcium for bone health").
The main dietary sources of calcium include milk and other dairy products, such as cottage cheese, yogurt, or hard cheese, and green vegetables, such as spinach and broccoli (show table 1). A rough method of estimating dietary calcium intake is to multiply the number of dairy servings consumed each day by 300 mg. One serving is 8 oz of milk or yogurt, 1 oz of hard cheese, or 16 oz of cottage cheese.
Calcium supplements (calcium carbonate or calcium citrate) may be suggested if a person cannot get enough calcium in their diet (show figure 1). Calcium doses greater than 500 mg/day should be taken in divided doses (eg, once in morning and evening). The daily intake recommendations given above always apply to "elemental calcium". Use caution when reading the labels of calcium supplements and be sure to note the amount of elemental calcium contained per serving, as many products give the calcium content per two pills.
Vitamin D intake — Experts also recommend 800 International Units (IU) of vitamin D each day. This dose appears to reduce bone loss and fracture rate in older women and men when there is adequate calcium intake (described above).
Milk is the primary dietary source of dietary vitamin D, containing approximately 100 IU per cup. Experts recommend vitamin D supplementation for all patients with osteoporosis whose intake of vitamin D is below 400 IU per day. This can be found in a daily multivitamin or a calcium/vitamin D supplement. Vitamin D is available separately in 400 IU supplements.
Protein supplements — Protein supplements may also be recommended for some patients to ensure sufficient protein intake. This may be particularly important for those who have already had osteoporotic fractures.
Alcohol, caffeine, and salt intake — A healthcare provider may also recommend limiting alcohol consumption, since high alcohol intake may increase the risk of fracture due to an increased risk of falling, poor nutrition, etc. It is not clear if restricting caffeine or salt is helpful; these measures have not been proven to prevent bone loss in those who have a sufficient intake of calcium.
Exercise — A person who has or wants to prevent osteoporosis should exercise for at least 30 minutes three times per week. Any weight-bearing exercise regimen is appropriate (eg, walking). However, exercises that could increase the risk of falling should be avoided.
Weight-bearing exercises can improve bone mass in premenopausal women and help to maintain bone density for women after menopause. Physical activity reduces the risk of hip fracture in older women as a result of increased muscle strength.
The benefits of exercise are quickly lost if a person stop exercising. A regular, weight-bearing exercise regimen that a person genuinely enjoys improves the chances of continuing to follow the routine over the long term. (See "Patient information: Exercise").
Smoking cessation — Smoking cessation is strongly recommended for patients at risk for osteoporosis because smoking cigarettes is known to accelerate bone loss. One study suggested that women who smoke one pack per day throughout adulthood have a 5 to 10 percent reduction in bone density by menopause, resulting in an increased risk of fracture. (See "Patient information: Smoking cessation").
Preventing falls — Repeated falling may significantly increase the risk of osteoporotic fractures in the elderly. Taking measures to prevent falls can decrease the risk of fractures. Such measures may include the following: Remove loose rugs and electrical cords or any other loose items in your home that could lead to tripping, slipping, and falling. Ensure that there is adequate lighting in all areas inside and around the home, including stairwells and entrance ways. Avoid walking on ice, wet or polished floors, or other potentially slippery surfaces. Avoid walking in unfamiliar areas outside.
Because certain drugs may increase the risk of falls, drug regimens should be reviewed on a regular basis. In some cases, the healthcare provider may decide to substitute one medication with an alternative that has a lower risk of causing falls. In addition, people with poor vision should see an eye specialist (eg, optomotrist or ophthamologist) for corrective lenses (glasses).
Hip pads — A person with osteoporosis who falls on their hip but has a substantial amount of muscle or fat padding over the hips has a lower risk of fracture than a person who has little padding. Hip pads (external hip protectors) are designed to reduce the risk of fracture when an elderly person falls. Results of studies that used hip pads have shown mixed results. For people who are willing to wear them on a consistent basis, hip pads may be of benefit in preventing fractures related to an accidental fall.
Medication monitoring — Prolonged therapy with and/or high doses of certain medications that increase bone loss should be monitored closely by a healthcare provider and decreased or discontinued when possible. Such medications include the following: Glucocorticoid medications (eg, prednisone) Heparin, a medication used to prevent and treat abnormal blood clotting (ie, anticoagulant) Vitamin A and certain synthetic retinoids (eg, etretinate) Certain antiepileptic drugs (eg, phenytoin, carbamazepine, primidone, phenobarbital, and valproate)
MEDICATIONS — The non-drug measures discussed above can help to reduce bone loss. For certain men and for premenopausal women who have or who are at risk for osteoporosis, drug or hormonal therapies may also be recommended.
However, the relationship between bone density and fracture risk in premenopausal women is not well defined. A premenopausal woman with low bone density may have no increased risk of fracture. Thus, bone density alone should not be used to define osteoporosis in a premenopausal woman, but instead indicates the need for further evaluation. (See "Patient information: Osteoporosis causes, diagnosis, and screening").
Bisphosphonates — Bisphosphonates inhibit the breakdown and removal of bone (ie, resorption). They are widely used for the prevention and treatment of osteoporosis in postmenopausal women.
These drugs need to be taken first thing in the morning on an empty stomach with a full 8 oz glass of water. The person must then wait at least half an hour (with alendronate (Fosamax®) and risedronate (Actonel®)) or one hour (with ibandronate (Boniva®)) before eating or taking any other medications. These dosing instructions help to reduce the risk of side effects and potential complications.
Side effects of bisphosphonates — Most people who take bisphosphonates for prevention or treatment of osteoporosis do not have any serious side effects related to the medication. However, it is important to closely follow the instructions for taking the medication; lying down or eating sooner than 30 minutes after a dose increases the risk of stomach upset.
There has been concern about a risk of bisphosphonates in people who require invasive dental work. A problem known as avascular necrosis or osteonecrosis of the jaw has rarely developed in a small number of people who used bisphosphonates. The risk of this problem is small in people who take bisphosphonates for osteoporosis prevention and treatment. However, there is a slightly higher risk of this problem when higher doses of bisphosphonates are given into vein during cancer treatment.
Most experts do not think that it is necessary to stop bisphosphonates before invasive dental work (eg, tooth extraction or implant) unless the treatment has been given into a vein. In this case, the patient should consult their healthcare provider for a specific recommendation.
Bisphosphonates are not recommended for premenopausal women who could become pregnant because of the unknown effects on a developing fetus.
Alendronate — Alendronate (Fosamax®) reduces vertebral and nonvertebral fractures, and decreases the loss of height associated with vertebral fractures. The dose for treatment is 10 mg per day, and the dose for prevention is 5 mg per day. Alendronate is usually taken as a weekly 70 or 35 mg pill.
Risedronate — Risedronate (Actonel®) is also approved for both prevention and treatment of osteoporosis at a dose of 5 mg/day (or as a single 35 mg once-weekly pill). Like alendronate, it reduces the risk of both vertebral and hip fractures.
Ibandronate — Ibandronate (Boniva®) can be used for prevention and treatment of osteoporosis at a dose of 150 mg once monthly. A monthly reminder can be sent by phone, mail, or email from the manufacturer. Although Boniva reduces the risk of bone loss and spine fractures, there is no proof that it reduces the risk of hip fractures.
Other new bisphosphonates are being studied, including single yearly intravenous infusions of zoledronic acid, which might be an effective treatment for postmenopausal osteoporosis.
"Estrogen-like" medications — Certain medications, known as selective estrogen receptor modulators (SERMs) produce some estrogen-like effects in the bone that provides protection against postmenopausal bone loss. In addition, SERMS also decrease the risk of breast cancer in women who are at high risk. Currently available SERMs include raloxifene (Evista®) and tamoxifen. Raloxifene (Evista) can be used for the prevention and treatment of osteoporosis in postmenopausal women, although it may be less effective in preventing bone loss than bisphosphonates or estrogen. (See "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer").
SERMs are not recommended for premenopausal women.
Estrogen/progestin therapy — In the past, estrogen or estrogen-progestin therapy was considered the best way to prevent postmenopausal osteoporosis and was often used for treatment. Data from the Women's Health Initiative (WHI), a large clinical trial, found that combined estrogen-progestin treatment reduced hip and vertebral fracture risk by 34 percent. A similar reduction in fracture risk was seen in the WHI trial of estrogen alone.
Estrogen had the additional advantages of controlling menopausal symptoms. However, the WHI found that estrogen plus progestin does not reduce the risk of coronary heart disease, and slightly increases the risk of breast cancer, stroke, and blood clots. The details of the WHI are discussed elsewhere. (See "Patient information: Postmenopausal hormone therapy").
Thus, estrogen is not recommended for the treatment or prevention of osteoporosis in postmenopausal women. However, some postmenopausal women continue to use estrogen, including women with persistent menopausal symptoms and those who cannot tolerate other types of osteoporosis treatment.
Estrogen may be an appropriate treatment for prevention of osteoporosis in young women with amenorrhea (absence of menses). This is often accomplished with a birth control pill. (See "Patient information: Menstrual cycle disorders (Absent and irregular periods)").
Calcitonin — Calcitonin is a hormone produced by the thyroid gland that, together with parathyroid hormone, helps to regulate calcium concentrations in the body. Synthetic calcitonin is sometimes recommended as a treatment for osteoporosis. Calcitonin may be administered via nasal spray or injection (subcutaneous salmon calcitonin). Nasal administration is typically preferred due to ease of use and because the injections tend to cause more nausea and flushing.
Other drugs are usually recommended before calcitonin because it is not clear if calcitonin increases bone density and decreases the fracture rate outside the spine. However, due to its pain-relieving (analgesic) effects, calcitonin may be suggested as a first-line therapy for those who have a sudden, intense (acute) onset of pain due to vertebral fractures. The treatment regimen is typically changed once the acute pain subsides or if the pain fails to subside over a prolonged period (eg, four weeks).
Parathyroid hormone (PTH) — PTH is produced by the parathyroid glands and stimulates both bone resorption and new bone formation. Intermittent administration stimulates formation more than resorption. Clinical trials suggest that PTH therapy is effective in both the prevention and treatment of osteoporosis in postmenopausal women and in men.
A PTH preparation called Forteo®, given by daily injection for two years, is approved for the treatment of severe osteoporosis. It is more effective at building spine bone density than any other treatment, although it is unclear if it also prevents fracture better than other treatments (specifically, the bisphosphonates). Because it requires daily injection and is expensive, it is usually reserved for patients with very severe hip or spine osteoporosis. It is not recommended for premenopausal women.
Monitoring response to hormonal or drug therapy — Testing may be recommended to monitor a patient's response to osteoporosis therapy. This may include measurement of bone mineral density or laboratory tests that indicate bone turnover (ie, rate of new bone formation and breakdown).
Testing is typically done before treatment begins to get a baseline measurement. Laboratory testing may be repeated three months after treatment begins, while bone density testing may be repeated after two years.
SUMMARY Osteoporosis causes bones to become abnormally thin (osteopenic), weakened, and easily broken. This condition can be treated and prevented with diet, exercise, and stopping smoking. Calcium and vitamin D can prevent and treat thinning bones. The main dietary sources of calcium include milk and other dairy products, such as cottage cheese, yogurt, or hard cheese, and green vegetables, such as spinach and broccoli (show table 1). Milk is the primary source of dietary vitamin D, containing approximately 100 IU per cup. Calcium and vitamin D can also be taken as a supplement (eg, in a pill, show figure 1). A total of at least 1000 mg of calcium per day is recommended for premenopausal women and men. Women after menopause should consume 1500 mg calcium per day if they do not take estrogen. Experts also recommend 800 International Units (IU) of vitamin D each day. Exercise can help to prevent and treat thinning bones. Exercise should be done for at least 30 minutes three times per week. Any weight-bearing exercise regimen is appropriate (eg, walking). Smoking cigarettes can cause bones to become thinner and weaker. Stopping smoking can reduce this risk. Falling can cause fractures in the elderly. Preventing falls can lower the risk of fractures. Some medications can cause bone thinning. Such medications include glucocorticoid medications (eg, prednisone), heparin, vitamin A and certain synthetic retinoids (eg, etretinate), and certain antiepileptic drugs (eg, phenytoin, carbamazepine, primidone, phenobarbital, and valproate). You should talk to your provider about the risk of bone thinning if you take one of these medications (see "Medication monitoring" above). There are several medications that help prevent osteoporosis in women after menopause. We think alendronate (Fosamax®), risedronate (Actonel®), or raloxifene (Evista) are the best medications for prevention (see "Bisphosphonates" above). Alendronate (Fosamax®) or risedronate (Actonel®) are recommended to treat women after menopause who have osteoporosis (see "Bisphosphonates" above). Parathyroid hormone (Forteo®) is another medication that can be used to treat osteoporosis. We recommend this medication for men or postmenopausal women with severe hip or spine osteoporosis (see "Parathyroid hormone (PTH)" above). Hormone replacement (eg, estrogen, progesterone) is not usually recommended to prevent osteoporosis in women after menopause. Hormone therapy is recommended for some young women who do not have a monthly menstrual period (see "Estrogen/progestin therapy" above). A bone density test may be recommend to monitor how the bones respond to osteoporosis treatment. For postmenopausal women, a bone density test is usually done two years after treatment starts.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
Osteoporosis and Related Bone Diseases National Resource Center (ORBD-NRC)
Toll-free: (800) 624-BONE (2663)
TTY: (202) 466-4315
E-mail: orbdnrc@nof.org
(www.osteo.org)
National Osteoporosis Foundation
Phone: (202) 223-2226
E-mail: patientinfo@nof.org
(www.nof.org)
National Women's Health Resource Center (NWHRC)
Toll-free: (877) 986-9472
E-mail: ddiamant@healthywomen.org
(www.healthywomen.org)
Osteoporosis Society of Canada
Phone: (416) 696-2663 x 294
(www.osteoporosis.ca/)
The Hormone Foundation
(www.hormone.org/public/osteoporosis.cfm, available in English, Spanish, French, Italian, German, and Portuguese)
[1-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Delmas, PD, Bjarnason, NH, Mitlak, BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997; 337:1641.
2. 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.
3. Fulton, JP. New guidelines for the prevention and treatment of osteoporosis. National Osteoporosis Foundation. Med Health R I 1999; 82:110.
4. Gregg, EW, Cauley, JA, Seeley, DG, et al. Physical activity and osteoporotic fracture risk in older women. Ann Intern Med 1998; 129:81.
5. NIH Consensus Development Panel on Optimal Calcium Intake. Optimal calcium intake. JAMA 1994; 272:1942.
Osteoporosis causes, diagnosis, and screening
INTRODUCTION — Osteoporosis is characterized by a progressive decrease in bone density, causing bones to become brittle, weakened, and fracture easily. Osteoporosis and the fractures that result are a major public health concern; more than 1.3 million osteoporotic fractures occur annually in the United States. Early diagnosis of bone loss can reduce or eliminate the risk of fractures.
This topic review discusses the causes, risk factors, signs, and symptoms of osteoporosis, as well as the ways that it can be diagnosed. For information about ways to prevent and treat osteoporosis, see "Patient information: Osteoporosis prevention and treatment".
BONE METABOLISM — To maintain bone density and strength, the body needs a sufficient supply of calcium and phosphorus, normal production of hormones that help to regulate bone cell function (eg, the calcium-regulating hormones, parathyroid hormone, calcitriol, and calcitonin; thyroid hormone; glucocorticoids; the sex hormones estrogen and testosterone), and an adequate supply of vitamin D, which is essential for normal bone formation and calcium absorption.
Bone is constantly being turned over and replaced as a result of cells that break down and remove bone (osteoclasts) and cells that replace and rebuild bone (osteoblasts). The resorption and formation of bone are essential to repair tiny breaks (microfractures) and to "remodel" bone (ie, remove and replace bone) in response to stress, including injury.
Osteoporosis is the result of years of bone loss, due to a "mismatch" between bone formation and resorption. Osteoporosis may also be related to years of inadequate bone formation, especially during the teens and 20s, which are the most important years of bone building. When bone becomes abnormally thin (known as osteopenia) and porous, the risk of fracture increases. Osteopenia is
Cortical bone, the normally dense, compact bone that forms the outer part of skeletal structures, provides strength and protection. Trabecular bone is found inside the long bones, particularly at the ends, and helps to provide mechanical support, particularly within the vertebrae. In patients with osteoporosis, both cortical and trabecular bone may be affected (show figure 1).
The processes of bone resorption and formation vary with age. Although 95 to 100 percent of expected peak bone mass develops by the late teen years, the body continues to form more bone than it breaks down until approximately 30 years of age. Maximum bone density is attained between 20 years (hip) and 30 years of age (spine and forearm). Thereafter, bone mass is slowly lost in the spine and hip; the loss occurs more rapidly during perimenopause.
SIGNS AND SYMPTOMS — Osteoporosis usually causes no symptoms until a fracture occurs, but it can cause back pain or loss of height.
Vertebral fractures — Vertebrae are the bones that make up the spine, and vertebral fractures are the most common sign of osteoporosis. About two-thirds of these fractures occur without symptoms. In these cases, the fracture is found during a chest or abdominal x-ray done for other reasons. In some patients, vertebral fractures may lead to a sudden onset of back pain, usually when performing routine activities, such as bending or lifting. This pain usually resolves over several weeks and is replaced by a chronic dull ache or pain. However, the pain may sometimes persist for many months. Successive compression or crush fractures, in which there is collapse of affected bone, may lead to increased curvature of the spine (thoracic kyphosis). As a result, there is typically an abnormal rounding of the upper back, known as a "dowager's hump," and loss of height (show figure 2). Due to vertebral fractures and associated height loss, the abdomen may be compressed, causing it to bulge forward. Such patients may note that their abdomens appear larger than before, their clothes no longer fit, and their waists seem to have "disappeared" even though they have not gained weight. Patients with multiple vertebral compression fractures may also have hip discomfort. The pain may be due to a decrease in the distance between the bottom of the rib cage and the uppermost portion of the pelvis. This change may also result in difficulty breathing or digestive abnormalities, such as constipation or an early feeling of fullness while eating.
Other fractures — Hip fractures are relatively common in patients with osteoporosis, affecting 15 percent of women and 5 percent of men by age 80. Such fractures are a major cause of disability in the elderly and increase the risk of death, although conditions other than the fracture (such as surgical complications) may be responsible for this increase.
Osteoporosis may also lead to fractures near the wrist in the lower end of the radius (the bone on the thumb side of the forearm), causing backward displacement of the wrist and hand. This type of break is known as a Colles' fracture, and often results when the hand is outstretched to stop a fall.
CAUSES — As mentioned above, osteoporosis results from either accelerated bone loss or inadequate bone formation. The imbalance between the rate of new bone formation and breakdown may occur due to several underlying conditions, including the following:
Menopause-related loss of estrogen — Estrogen is a hormone that plays an important role in regulating bone formation. The rate of bone loss increases soon after the menopause, particularly in trabecular bone; this increased rate of loss lasts for approximately 10 years. At this point, the rate of bone loss slows to near the premenopausal rate, but the premenopausal rate of bone formation is absent.
Hyperthyroidism — Hyperthyroidism is a condition in which the thyroid gland is overactive in its production of thyroid hormones. It is associated with increased bone turnover, potentially leading to bone loss. (See "Patient information: Hyperthyroidism").
Hyperparathyroidism — Hyperparathyroidism refers to overactivity of the parathyroid glands. These glands produce parathyroid hormone, which helps to regulate calcium concentrations in the body. Increased secretion of parathyroid hormone increases the removal of calcium from bone, raising blood calcium levels (hypercalcemia) and potentially leading to osteoporosis. (See "Patient information: Primary hyperparathyroidism").
Age-related bone loss — This may result from decreased calcium absorption, which typically begins in the fourth or fifth decade of life. It is associated with a slow loss of cortical and trabecular bone in both women and men.
Hypogonadism — Hypogonadism is a decrease in activity of the ovaries or testes resulting in low amounts of estrogen or testosterone, respectively. This may be a result of aging, but it can also occur in younger men and women due to medications that cause hypogonadism (eg, chemotherapy agents), block estrogen synthesis (aromatase inhibitors), or induce testosterone/estrogen deficiency (GnRH agonists). It may also occur as a result of low body weight, excessive exercise, or pituitary abnormalities.
Men who have low or absent levels of the hormone testosterone are at increased risk of osteoporosis, and women who have a low level of estrogen are also at risk. Symptoms of hypogonadism in men include a decreased sexual drive (libido) or impotence. In young women, signs of hypogonadism include loss of menstrual periods, which may or may not be associated with hot flashes, night sweats, or vaginal dryness.
Medications — Prolonged therapy with certain medications, including glucocorticoids (also called corticosteroids), heparin, certain medications for seizure disorders (eg, phenytoin, carbamazepine, primidone, and phenobarbital), cyclosporine, medroxyprogesterone acetate and vitamin A may result in accelerated bone resorption as well as slowed bone formation, leading to bone loss.
Pregnancy and breastfeeding — Bone loss occurs during pregnancy and breastfeeding, although the loss is temporary and has no long term effect on a woman's bone density. In women who become pregnant and breastfeed, there is no increased risk of fracture after menopause. Using a calcium supplement while breastfeeding has no effect on the amount of bone lost.
Vitamin B12 deficiency — Vitamin B12 deficiency (also known as pernicious anemia) appears to increase the risk of osteoporosis, which can lead to an increased risk of hip and spine fractures.
RISK FACTORS FOR FRACTURE — Several factors are associated with an increased risk of osteoporotic fractures, including the following:
Age — In people aged 90 years or more, approximately one-third of women and 15 percent of men will have a hip fracture.
Sex — Osteoporosis is a serious problem in men, although women are affected more commonly. Women have a lower average peak bone mass and lose more bone after menopause. About 30 percent of women over age 50 have osteoporosis, and this percentage increases with age.
Race — Whites have a considerably higher risk of hip fractures than blacks. Blacks generally have a higher peak bone mass and a lower rate of bone loss after menopause.
Falls — Repeated falling can be a significant problem for older people with osteoporosis. Over 90 percent of hip fractures occur after a fall. Certain factors contribute to the risk of falls, including poor vision, certain medications (eg, tranquilizers, some anxiety medications, sleeping pills), and neurologic disorders such as dementia (confusion).
Other factors — A number of other factors increase the risk of fractures, some of which include the following: Previous fracture between the ages of 20 and 50 years History of fracture in a first degree relative Cigarette smoking (men and women) Inflammatory bowel disease Celiac disease Cystic fibrosis Sedentary life style Drinking large amounts of caffeine Medications for anxiety or seizures Low body weight or weight loss Above average height Type 1 or 2 diabetes mellitus
DIAGNOSIS — Osteoporosis is diagnosed based upon the patient and family history, physical examination, laboratory studies, and bone mineral density (BMD) testing. It is important to exclude other conditions that can cause bone thinning (osteopenia), such as osteomalacia (softening and weakening of bone) as well as other potentially treatable conditions (eg, hyperparathyroidism, hyperthyroidism, kidney disease).
History and physical examination — During a medical history, a healthcare provider will ask about life events (pregnancies, age at first menstrual period and menopause), past or present medical conditions, medications, calcium intake, exercise, and alcohol/tobacco use.
The physical examination will include measurement of height and weight and may include laboratory tests. Such studies may include a complete blood count, measurement of calcium, phosphorus, vitamin D, bicarbonate, creatinine, and hormones such as thyroid-stimulating hormone (TSH). The testosterone level may be measured in men, particularly if the man has decreased libido or impotence. (See "Patient information: Sexual problems in men").
Bone density measurement — Measurement of bone mineral density is the most common method to determine if a person is at risk for or already has osteoporosis. The goal is to recognize people who are at risk before a fracture occurs. Several methods are available to measure bone density.
Dual x-ray absorptiometry (DXA) — DXA testing is the most popular method for measuring BMD because it provides precise measurements at important bone sites (eg, spine, hip, forearm) with minimal radiation.
During DXA, the patient lies on an examination table. An x-ray detector scans a bone region, and the amount of x-rays that pass through bone are measured and displayed as an image that is interpreted by a radiologist. The test causes no discomfort, and usually takes only 5 to 10 minutes. The bone mineral density is then compared with the normal range for the patient's sex and race.
Other Quantitative computerized tomography — This is a type of CT that provides accurate measures of bone density in the spine. Although this test may be a good alternative to DXA, it is seldom used because it is expensive, less precise for following measurements over time, and requires a higher radiation dose. Ultrasonography — Ultrasound can be used to measure the bone density of the heel. This may be useful to determine a person's fracture risk. However, it is used less frequently than DXA because there are no guidelines that use ultrasound measurements to diagnose osteoporosis or predict fracture risk. In areas that do not have access to DXA, ultrasound is an acceptable way to measure bone density.
We recommend DXA of the hip and spine because measurements at these sites are effective for predicting osteoporotic fracture at any site.
Interpreting BMD results — The World Health Organization (WHO) has defined normal bone density as a value within one standard deviation (SD) from average peak bone mass. Standard deviation is a statistical measure that defines how much a patient's result vary from the "average" young adult. Normal bone density — Bone density that is between 0 and 1 standard deviation below the mean is considered to be normal. This may be reported as a T-score of 0 to -1. Treatment is not usually recommended for people with normal bone density, although preventive measures (eg, calcium supplementation, weight-bearing exercise) are recommended to prevent osteopenia and osteoporosis. (See "Patient information: Osteoporosis prevention and treatment"). Osteopenia — Bone density that is between 1 and 2.5 standard deviations below the mean is called osteopenia. This may be reported as a T-score of -1 to -2.4. A person with osteopenia does not yet have osteoporosis, but is at risk to develop it if not treated. Osteoporosis — Osteoporosis is defined as BMD more than 2.5 standard deviations (SD) below the mean of normal young women. This is reported as a T-score of -2.5 or less. The lower the bone density, the greater the risk of fracture.
When to measure BMD — Bone density testing can be used to diagnose osteoporosis, as well as to screen for it. The National Osteoporosis Foundation has issued recommendations for bone density testing that primarily apply to white women after menopause. Bone density should be measured in women: Greater than 65 years of age Under age 65 who have one or more risk factors for osteoporotic fracture in addition to menopause.
In addition to the recommendations above, the International Society for Clinical Densitometry (ISCD) recommends bone density testing for men over 70 years of age and for adults (including premenopausal women): With fragility fracture (a bone fracture that occurs after a fall from standing height or less) With disease associated with low bone mass (Cushing's syndrome, hyperthyroidism, hyperparathyroidism, rheumatoid arthritis, gastrointestinal diseases associated with malabsorption) Taking drugs associated with low bone mass (glucocorticoids, GnRH agonists, some chemotherapy drugs)
PREVENTION AND TREATMENT — All women should be educated about the risk factors for osteoporotic fractures. A provider may recommend certain lifestyle changes that can help to reduce fracture risk, such as stopping smoking, limiting alcohol consumption, and participating in regular weight-bearing and muscle-strengthening exercises. A full discussion of osteoporosis prevention and treatment is available separately. (See "Patient information: Osteoporosis prevention and treatment").
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
Osteoporosis and Related Bone Diseases National Resource Center (ORBD-NRC)
Toll-free: (800) 624-BONE (2663)
TTY: (202) 466-4315
(www.osteo.org)
National Osteoporosis Foundation
Phone: (202) 223-2226
(www.nof.org)
International Society for Clinical Densitometry (ISCD)
(www.ISCD.org)
National Women's Health Resource Center (NWHRC)
Toll-free: (877) 986-9472
(www.healthywomen.org)
Osteoporosis Society of Canada
Phone: (416) 696-2663 x 294
(www.osteoporosis.ca/)
The Hormone Foundation
(www.hormone.org/public/osteoporosis.cfm, available in English, Spanish, French, Italian, German, and Portuguese)
[1-4]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Johnell, O, Kanis, JA, Black, DM, et al. Associations between baseline risk factors and vertebral fracture risk in the Multiple Outcomes of Raloxifene Evaluation (MORE) Study. J Bone Miner Res 2004; 19:764.
2. Raisz, LG. Clinical practice. Screening for osteoporosis. N Engl J Med 2005; 353:164.
3. Marshall, D, Johnell, O, Wedel, H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 1996; 312:1254.
4. Bainbridge, KE, Sowers, MF, Crutchfield, M, et al. Natural history of bone loss over 6 years among premenopausal and early postmenopausal women. Am J Epidemiol 2002; 156:410.
This topic review discusses the causes, risk factors, signs, and symptoms of osteoporosis, as well as the ways that it can be diagnosed. For information about ways to prevent and treat osteoporosis, see "Patient information: Osteoporosis prevention and treatment".
BONE METABOLISM — To maintain bone density and strength, the body needs a sufficient supply of calcium and phosphorus, normal production of hormones that help to regulate bone cell function (eg, the calcium-regulating hormones, parathyroid hormone, calcitriol, and calcitonin; thyroid hormone; glucocorticoids; the sex hormones estrogen and testosterone), and an adequate supply of vitamin D, which is essential for normal bone formation and calcium absorption.
Bone is constantly being turned over and replaced as a result of cells that break down and remove bone (osteoclasts) and cells that replace and rebuild bone (osteoblasts). The resorption and formation of bone are essential to repair tiny breaks (microfractures) and to "remodel" bone (ie, remove and replace bone) in response to stress, including injury.
Osteoporosis is the result of years of bone loss, due to a "mismatch" between bone formation and resorption. Osteoporosis may also be related to years of inadequate bone formation, especially during the teens and 20s, which are the most important years of bone building. When bone becomes abnormally thin (known as osteopenia) and porous, the risk of fracture increases. Osteopenia is
Cortical bone, the normally dense, compact bone that forms the outer part of skeletal structures, provides strength and protection. Trabecular bone is found inside the long bones, particularly at the ends, and helps to provide mechanical support, particularly within the vertebrae. In patients with osteoporosis, both cortical and trabecular bone may be affected (show figure 1).
The processes of bone resorption and formation vary with age. Although 95 to 100 percent of expected peak bone mass develops by the late teen years, the body continues to form more bone than it breaks down until approximately 30 years of age. Maximum bone density is attained between 20 years (hip) and 30 years of age (spine and forearm). Thereafter, bone mass is slowly lost in the spine and hip; the loss occurs more rapidly during perimenopause.
SIGNS AND SYMPTOMS — Osteoporosis usually causes no symptoms until a fracture occurs, but it can cause back pain or loss of height.
Vertebral fractures — Vertebrae are the bones that make up the spine, and vertebral fractures are the most common sign of osteoporosis. About two-thirds of these fractures occur without symptoms. In these cases, the fracture is found during a chest or abdominal x-ray done for other reasons. In some patients, vertebral fractures may lead to a sudden onset of back pain, usually when performing routine activities, such as bending or lifting. This pain usually resolves over several weeks and is replaced by a chronic dull ache or pain. However, the pain may sometimes persist for many months. Successive compression or crush fractures, in which there is collapse of affected bone, may lead to increased curvature of the spine (thoracic kyphosis). As a result, there is typically an abnormal rounding of the upper back, known as a "dowager's hump," and loss of height (show figure 2). Due to vertebral fractures and associated height loss, the abdomen may be compressed, causing it to bulge forward. Such patients may note that their abdomens appear larger than before, their clothes no longer fit, and their waists seem to have "disappeared" even though they have not gained weight. Patients with multiple vertebral compression fractures may also have hip discomfort. The pain may be due to a decrease in the distance between the bottom of the rib cage and the uppermost portion of the pelvis. This change may also result in difficulty breathing or digestive abnormalities, such as constipation or an early feeling of fullness while eating.
Other fractures — Hip fractures are relatively common in patients with osteoporosis, affecting 15 percent of women and 5 percent of men by age 80. Such fractures are a major cause of disability in the elderly and increase the risk of death, although conditions other than the fracture (such as surgical complications) may be responsible for this increase.
Osteoporosis may also lead to fractures near the wrist in the lower end of the radius (the bone on the thumb side of the forearm), causing backward displacement of the wrist and hand. This type of break is known as a Colles' fracture, and often results when the hand is outstretched to stop a fall.
CAUSES — As mentioned above, osteoporosis results from either accelerated bone loss or inadequate bone formation. The imbalance between the rate of new bone formation and breakdown may occur due to several underlying conditions, including the following:
Menopause-related loss of estrogen — Estrogen is a hormone that plays an important role in regulating bone formation. The rate of bone loss increases soon after the menopause, particularly in trabecular bone; this increased rate of loss lasts for approximately 10 years. At this point, the rate of bone loss slows to near the premenopausal rate, but the premenopausal rate of bone formation is absent.
Hyperthyroidism — Hyperthyroidism is a condition in which the thyroid gland is overactive in its production of thyroid hormones. It is associated with increased bone turnover, potentially leading to bone loss. (See "Patient information: Hyperthyroidism").
Hyperparathyroidism — Hyperparathyroidism refers to overactivity of the parathyroid glands. These glands produce parathyroid hormone, which helps to regulate calcium concentrations in the body. Increased secretion of parathyroid hormone increases the removal of calcium from bone, raising blood calcium levels (hypercalcemia) and potentially leading to osteoporosis. (See "Patient information: Primary hyperparathyroidism").
Age-related bone loss — This may result from decreased calcium absorption, which typically begins in the fourth or fifth decade of life. It is associated with a slow loss of cortical and trabecular bone in both women and men.
Hypogonadism — Hypogonadism is a decrease in activity of the ovaries or testes resulting in low amounts of estrogen or testosterone, respectively. This may be a result of aging, but it can also occur in younger men and women due to medications that cause hypogonadism (eg, chemotherapy agents), block estrogen synthesis (aromatase inhibitors), or induce testosterone/estrogen deficiency (GnRH agonists). It may also occur as a result of low body weight, excessive exercise, or pituitary abnormalities.
Men who have low or absent levels of the hormone testosterone are at increased risk of osteoporosis, and women who have a low level of estrogen are also at risk. Symptoms of hypogonadism in men include a decreased sexual drive (libido) or impotence. In young women, signs of hypogonadism include loss of menstrual periods, which may or may not be associated with hot flashes, night sweats, or vaginal dryness.
Medications — Prolonged therapy with certain medications, including glucocorticoids (also called corticosteroids), heparin, certain medications for seizure disorders (eg, phenytoin, carbamazepine, primidone, and phenobarbital), cyclosporine, medroxyprogesterone acetate and vitamin A may result in accelerated bone resorption as well as slowed bone formation, leading to bone loss.
Pregnancy and breastfeeding — Bone loss occurs during pregnancy and breastfeeding, although the loss is temporary and has no long term effect on a woman's bone density. In women who become pregnant and breastfeed, there is no increased risk of fracture after menopause. Using a calcium supplement while breastfeeding has no effect on the amount of bone lost.
Vitamin B12 deficiency — Vitamin B12 deficiency (also known as pernicious anemia) appears to increase the risk of osteoporosis, which can lead to an increased risk of hip and spine fractures.
RISK FACTORS FOR FRACTURE — Several factors are associated with an increased risk of osteoporotic fractures, including the following:
Age — In people aged 90 years or more, approximately one-third of women and 15 percent of men will have a hip fracture.
Sex — Osteoporosis is a serious problem in men, although women are affected more commonly. Women have a lower average peak bone mass and lose more bone after menopause. About 30 percent of women over age 50 have osteoporosis, and this percentage increases with age.
Race — Whites have a considerably higher risk of hip fractures than blacks. Blacks generally have a higher peak bone mass and a lower rate of bone loss after menopause.
Falls — Repeated falling can be a significant problem for older people with osteoporosis. Over 90 percent of hip fractures occur after a fall. Certain factors contribute to the risk of falls, including poor vision, certain medications (eg, tranquilizers, some anxiety medications, sleeping pills), and neurologic disorders such as dementia (confusion).
Other factors — A number of other factors increase the risk of fractures, some of which include the following: Previous fracture between the ages of 20 and 50 years History of fracture in a first degree relative Cigarette smoking (men and women) Inflammatory bowel disease Celiac disease Cystic fibrosis Sedentary life style Drinking large amounts of caffeine Medications for anxiety or seizures Low body weight or weight loss Above average height Type 1 or 2 diabetes mellitus
DIAGNOSIS — Osteoporosis is diagnosed based upon the patient and family history, physical examination, laboratory studies, and bone mineral density (BMD) testing. It is important to exclude other conditions that can cause bone thinning (osteopenia), such as osteomalacia (softening and weakening of bone) as well as other potentially treatable conditions (eg, hyperparathyroidism, hyperthyroidism, kidney disease).
History and physical examination — During a medical history, a healthcare provider will ask about life events (pregnancies, age at first menstrual period and menopause), past or present medical conditions, medications, calcium intake, exercise, and alcohol/tobacco use.
The physical examination will include measurement of height and weight and may include laboratory tests. Such studies may include a complete blood count, measurement of calcium, phosphorus, vitamin D, bicarbonate, creatinine, and hormones such as thyroid-stimulating hormone (TSH). The testosterone level may be measured in men, particularly if the man has decreased libido or impotence. (See "Patient information: Sexual problems in men").
Bone density measurement — Measurement of bone mineral density is the most common method to determine if a person is at risk for or already has osteoporosis. The goal is to recognize people who are at risk before a fracture occurs. Several methods are available to measure bone density.
Dual x-ray absorptiometry (DXA) — DXA testing is the most popular method for measuring BMD because it provides precise measurements at important bone sites (eg, spine, hip, forearm) with minimal radiation.
During DXA, the patient lies on an examination table. An x-ray detector scans a bone region, and the amount of x-rays that pass through bone are measured and displayed as an image that is interpreted by a radiologist. The test causes no discomfort, and usually takes only 5 to 10 minutes. The bone mineral density is then compared with the normal range for the patient's sex and race.
Other Quantitative computerized tomography — This is a type of CT that provides accurate measures of bone density in the spine. Although this test may be a good alternative to DXA, it is seldom used because it is expensive, less precise for following measurements over time, and requires a higher radiation dose. Ultrasonography — Ultrasound can be used to measure the bone density of the heel. This may be useful to determine a person's fracture risk. However, it is used less frequently than DXA because there are no guidelines that use ultrasound measurements to diagnose osteoporosis or predict fracture risk. In areas that do not have access to DXA, ultrasound is an acceptable way to measure bone density.
We recommend DXA of the hip and spine because measurements at these sites are effective for predicting osteoporotic fracture at any site.
Interpreting BMD results — The World Health Organization (WHO) has defined normal bone density as a value within one standard deviation (SD) from average peak bone mass. Standard deviation is a statistical measure that defines how much a patient's result vary from the "average" young adult. Normal bone density — Bone density that is between 0 and 1 standard deviation below the mean is considered to be normal. This may be reported as a T-score of 0 to -1. Treatment is not usually recommended for people with normal bone density, although preventive measures (eg, calcium supplementation, weight-bearing exercise) are recommended to prevent osteopenia and osteoporosis. (See "Patient information: Osteoporosis prevention and treatment"). Osteopenia — Bone density that is between 1 and 2.5 standard deviations below the mean is called osteopenia. This may be reported as a T-score of -1 to -2.4. A person with osteopenia does not yet have osteoporosis, but is at risk to develop it if not treated. Osteoporosis — Osteoporosis is defined as BMD more than 2.5 standard deviations (SD) below the mean of normal young women. This is reported as a T-score of -2.5 or less. The lower the bone density, the greater the risk of fracture.
When to measure BMD — Bone density testing can be used to diagnose osteoporosis, as well as to screen for it. The National Osteoporosis Foundation has issued recommendations for bone density testing that primarily apply to white women after menopause. Bone density should be measured in women: Greater than 65 years of age Under age 65 who have one or more risk factors for osteoporotic fracture in addition to menopause.
In addition to the recommendations above, the International Society for Clinical Densitometry (ISCD) recommends bone density testing for men over 70 years of age and for adults (including premenopausal women): With fragility fracture (a bone fracture that occurs after a fall from standing height or less) With disease associated with low bone mass (Cushing's syndrome, hyperthyroidism, hyperparathyroidism, rheumatoid arthritis, gastrointestinal diseases associated with malabsorption) Taking drugs associated with low bone mass (glucocorticoids, GnRH agonists, some chemotherapy drugs)
PREVENTION AND TREATMENT — All women should be educated about the risk factors for osteoporotic fractures. A provider may recommend certain lifestyle changes that can help to reduce fracture risk, such as stopping smoking, limiting alcohol consumption, and participating in regular weight-bearing and muscle-strengthening exercises. A full discussion of osteoporosis prevention and treatment is available separately. (See "Patient information: Osteoporosis prevention and treatment").
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
Osteoporosis and Related Bone Diseases National Resource Center (ORBD-NRC)
Toll-free: (800) 624-BONE (2663)
TTY: (202) 466-4315
(www.osteo.org)
National Osteoporosis Foundation
Phone: (202) 223-2226
(www.nof.org)
International Society for Clinical Densitometry (ISCD)
(www.ISCD.org)
National Women's Health Resource Center (NWHRC)
Toll-free: (877) 986-9472
(www.healthywomen.org)
Osteoporosis Society of Canada
Phone: (416) 696-2663 x 294
(www.osteoporosis.ca/)
The Hormone Foundation
(www.hormone.org/public/osteoporosis.cfm, available in English, Spanish, French, Italian, German, and Portuguese)
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Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Johnell, O, Kanis, JA, Black, DM, et al. Associations between baseline risk factors and vertebral fracture risk in the Multiple Outcomes of Raloxifene Evaluation (MORE) Study. J Bone Miner Res 2004; 19:764.
2. Raisz, LG. Clinical practice. Screening for osteoporosis. N Engl J Med 2005; 353:164.
3. Marshall, D, Johnell, O, Wedel, H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 1996; 312:1254.
4. Bainbridge, KE, Sowers, MF, Crutchfield, M, et al. Natural history of bone loss over 6 years among premenopausal and early postmenopausal women. Am J Epidemiol 2002; 156:410.
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