Chairperson: Thomas E. Nolan, MD, MBA; Faculty: Robin K. Dore, MD; Lori Mosca, MD, MPH, PhD; Jane Cauley, DrPH; Susan Johnson, MD

Editorial Content produced by the Annenberg Center for Health Sciences.

Copyright © 2003 Quadrant HealthCom Inc.

This CME activity, "HRT and SERMs: New Guidelines for Patient Management," was originally offered as a supplement to the March 2002 Special Edition to The Female Patient, certified for CME. The original supplement was published prior to the early termination of the estrogen/progestin arm of the Women's Health Initiative (WHI) trial in July 2002 due to adverse outcomes. The companion estrogen-alone trial continues, with close monitoring by the data and safety monitoring board. The Women's International Study on long Duration Oestrogen after Menopause (WISDOM) trial was halted in October 2002 because the main funding body of WISDOM, the Medical Research Council (UK), withdrew funding for the study. More recent references discussing trial outcomes have been added below, and are recommended reading for completion of this CME activity.

Faculty affiliations and disclosures are at the end of this activity.

This activity is supported by an educational grant from Eli Lilly.

Legal Disclaimer
The material presented here does not necessarily reflect the views of Medscape, The Annenberg Center for Health Sciences, the companies providing educational grants or the authors and writers. These materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. All readers and continuing education participants should verify all information and consult a qualified healthcare professional before treating patients or utilizing any therapeutic product discussed in this educational activity.

Thomas E. Nolan, MD, MBA

 

 

The time for this program has never been better: Researchers are intensely exploring the role of female hormones in the development of age-related illnesses such as cardiovascular disease, osteoporosis, and cancer. Such investigation has unveiled estrogen's benefits in preserving bone mineral density (BMD) and preventing certain gynecologic cancers, and has provided evidence that combined estrogen and progesterone exert positive effects on serum lipid levels and, quite possibly, the risk of coronary artery disease. This investigation has also unveiled much controversy, which has complicated prevention and treatment protocols.

As diligent as many healthcare providers have been in communicating to patients about the various advantages of estrogen replacement therapy (ERT) and hormone replacement therapy (HRT), many postmenopausal women have been less enthusiastic about long-term use of these interventions. Although the many benefits of supplemental estrogen have been documented in numerous studies, several factors contribute to many patients' lack of interest in and compliance with ERT and HRT. These include real and perceived breast tenderness, weight gain, and skin changes, as well as the possible risks of breast and ovarian cancer.

Thomas E. Nolan, MD, MBA

 

 

Because of these limitations on ERT and HRT, a great emphasis has been placed on identifying estrogen-related therapies that postmenopausal women might perceive as less fraught with side effects and risks. These efforts have yielded selective estrogen receptor modulators (SERMs): compounds that act efficiently through the estrogen receptor but do not increase the amount of active hormone in the body. The first agent observed to act in this manner was tamoxifen, used for the prevention of breast cancer in women at high risk for the disease. Tamoxifen has also been widely observed to exert beneficial effects on bone,^[1] and, more recently, markers for cardiovascular health.^[2] However, tamoxifen has also been shown to incur some risk of ocular disorders and uterine cancer.^[3,4]

Further efforts to improve upon the prevention of age-related disease in postmenopausal women have led to the development of another SERM, raloxifene, designed for even higher selectivity in this population. Raloxifene is currently under investigation for the prevention of breast cancer and may actually hold promise in several therapeutic areas. Readers should note, however, that the risk of thromboembolism is the same in women using raloxifene as in those using exogenous estrogen, and identification of appropriate disease markers in at-risk patients is warranted. The areas in which SERMs are being explored for optimum benefit were discussed in a roundtable meeting entitled "HRT and SERMs: Evidence-Based Data to Guide Patient Management," the proceeds of which are presented here in the form of clinical articles and an additional dialogue section titled "The Faculty Speaks." Brief summaries of the clinical articles appear below.

Skeletal Activity.

Raloxifene decreases bone turnover in a manner similar to that seen with estrogen replacement. As discussed in the article, "Osteoporosis: Fractures and Key Risk Factors" by Robin K. Dore, MD, this agent has been extensively studied for its use in reducing osteoporotic fracture in the spine, hip, and total body.

Applications in Heart Health.

As cardiovascular disease (CVD) is the number-one killer of women (and men), healthcare providers are generally enthusiastic about the discovery of cardiovascular benefits in a new drug. Currently, there is good reason to believe that the SERMs offer some consistent and positive effects on low-density lipoprotein cholesterol, without increasing serum triglycerides or decreasing high-density lipoprotein cholesterol.^[2] The article, "Cardiovascular Disease: New Recommendations for Minimizing the Threat," by Lori Mosca, MD, MPH, PhD, provides thoughtful insight into these and other therapies to reduce the incidence of CVD among older women.

Thomas E. Nolan, MD, MBA

 

 

SERMs represent a very exciting option for disease prevention in certain postmenopausal women. In enthusiastic response to our readers, the articles in this program aim to "cut through the noise" that too often clouds the issue of postmenopausal hormone-related therapy. It is my hope that you, the reader, will be able to draw from the insights published here to enhance the overall well-being of our postmenopausal patient population.

Thomas E. Nolan, MD, MBA

 

 

1. Powles TJ, Hickish T, Kanis JA, Tidy A, Ashley S. Effect of tamoxifen on bone mineral density measured by dual energy x-ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol. 1996;14(1):78-84.
2. Love RR, Wiebe DA, Feyzi JM, Newcomb PA, Chappell RJ. Effects of tamoxifen on cardiovascular risk factors in postmenopausal women after 5 years of treatment. J Natl Cancer Inst. 1994; 86:1534-1539.
3. Nayfield SG, Gorin MB. Tamoxifen associated eye disease: a review. J Clin Oncol. 1996;14(3):1018-1026.
4. Dessole S, Cherchi PL, Ruiu GA, et al. Uterine metastases from breast cancer in a patient under tamoxifen therapy: case report. Eur J Gynaecol Oncol. 1999;20(5-6):416-417.
5. Cauley JA, Norton L, Lippman ME, et al. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Breast Cancer Res Treat. 2001;65(2):125-134.

Robin K. Dore, MD

 

 

Osteoporosis is a global public health problem associated with aging, but it is not an inevitable part of aging. Its diagnosis should be considered in all women who have had fractures as adults.

The United States, blessed with an aging population, has the dubious distinction of being a world leader in fractures caused by this disease.^[1]

Recognizing that osteoporosis and fractures are largely preventable, the National Institutes of Health (NIH) convened an NIH Development Consensus Panel on Osteoporosis Prevention, Diagnosis, and Therapy in March 2000 to address what it perceived as a "major health threat" affecting 28 million Americans, 80% of them women.^[2] (Table 1) Among other issues, the panel was asked to discuss the meaning of osteoporosis, the consequences of this disease, and the optimal evaluation and treatment of osteoporosis and fractures. Given the NIH view that osteoporosis is largely preventable and frequently not diagnosed, even after a fracture has occurred, it is not surprising that the panel concluded: "There is a need to determine the most effective method of educating healthcare professionals and the public about the prevention, diagnosis, and treatment of osteoporosis."^[2] It is hoped that this article will be a helpful step in that direction.

Table 1. Osteoporosis Statistics

Robin K. Dore, MD

 

 

For many years, osteoporosis was viewed simply as a fracture: the outcome of a "silent" process that was not well understood. While the complex process leading to an excess of bone resorption over bone formation remains asymptomatic, major advances have been made in the understanding of the basic science underlying this process^[3,4] and the biomechanics of fracture.^[5]

Osteoporosis is now defined as a skeletal disorder characterized by compromised bone strength, which predisposes the patient to an increased risk of fracture.^[2] The elements of bone strength are bone density and bone quality. Bone density, as measured by bone densitometry, is expressed as grams of mineral per area and the patient's bone density is compared with a young adult peak bone mass value (called a T-score). Bone quality includes bone architecture, turnover, damage accumulation (eg, microfractures), and mineralization. A fracture is the outcome of the application of failure-inducing force to strength-compromised, or osteoporotic, bone.^[2]

Robin K. Dore, MD

 

 

Osteoporosis can be classified as either primary or secondary. Primary osteoporosis most often occurs in postmenopausal women and older men, although it can occur at any age. Secondary osteoporosis is a result of medications, other conditions, or diseases. Risk factors for primary and secondary osteoporosis are listed in Table 2.

Table 2. Risk Factors

While osteoporosis may be a silent disease, it is striking that the most important risk factors are apparent from a brief look at a patient and his or her chart. It is also apparent that ancillary medical personnel, and even the patient, can perform a rudimentary risk assessment. It is therefore essential to ensure that the osteoporosis "radar" is on as healthcare providers go about their daily clinical practice.

Robin K. Dore, MD

 

 

Osteoporosis and associated fractures are a major public health concern because of the cost, disability, decreased quality of life, and increased mortality associated with fractures.

Hip Fractures.

Hip fractures have traditionally been the focus of osteoporosis because they are easy to diagnose and result in costly hospitalizations and nursing home placements that are easy to quantify. In addition, there is a 10% to 20% excess mortality in the 6 months following a hip fracture. For those who survive, the picture is not encouraging: One year after a hip fracture, 40% of patients are still unable to walk unassisted, 60% have difficulty with at least one essential activity of daily living, and 80% are restricted in other activities, such as driving and shopping for groceries.^[7] Nearly one third of patients with hip fractures enter nursing homes within the year following a fracture.^[2]

Given the morbidity and mortality associated with hip fracture, it is important to remember that a very effective way to prevent a hip fracture in a given population may be to utilize hip protectors.^[8]

Hip fractures usually occur when women are in their late 70s and 80s.^[2] This is not surprising, because 50% of women in their 80s have osteoporosis (as measured by bone density studies) at one or both hips, a reflection of the impact of aging on bones.^[9]

Vertebral Fractures.

A key insight of the NIH Consensus Panel was that, while a great deal is known about the impact of hip fractures, the adverse effects of vertebral fractures on health, function, and quality of life are often underestimated.

Vertebral fractures lead to chronic pain and disability.^[2] They can result in height loss and kyphosis, with associated postural and height changes that erode self-esteem. Compression of the thoracic and abdominal cavities results from multiple vertebral fractures. Multiple thoracic fractures may result in restrictive lung disease, and lumbar fractures may alter abdominal anatomy, leading to constipation, abdominal pain, distention, reduced appetite, and premature satiety.^[10-12]

Vertebral fractures are also associated with an increase in mortality. In a population-based study of survival following osteoporotic fracture, Cooper and colleagues examined the survival rate of 335 patients who had initial radiologic diagnoses of vertebral fracture between 1985 and 1989 and compared them to survival rates of patients who had experienced hip fractures.^[13] They found that, while there was a much greater incidence of mortality among hip fracture patients within the first 6 months, the estimated survival rates at 5 years after diagnosis were comparable. Patients with vertebral fractures, however, had a worse survival rate than expected; that rate diverged steadily from expected values throughout the course of the study.

Kado and associates found an increased risk of death of 1.23 in patients who had experienced one or more vertebral fractures.^[14] In the case of severe vertebral fractures, the increased risk of death was 1.34, and there was an increased risk of death related to respiratory disorders as well. This study demonstrated that vertebral fractures contribute to comorbid conditions, such as pneumonia as the result of incomplete lung expansion, and consequently to mortality.

Cauley and colleagues examined the relative risks of dying following a clinically related fracture that was apparent to the examining physician, as reported in the Fracture Intervention Trial.^[15] The relative risk of death following any clinical fracture was 2.15. After a hip fracture, the risk was 6.68, but after a clinical vertebral fracture, the risk rose to 8.64 -- the highest risk associated with any clinical fractures.

Vertebral fractures are a bearer of bad tidings for the skeleton. They may reflect generalized loss of bone strength and increase the force on other vertebral bodies, making them more likely to fail. They may also weaken muscles, cause pain, and/or upset balance and thereby increase the risk of a fall. It is not surprising that there is an increased risk of subsequent fractures following an initial vertebral fracture.

In a study that was conducted to determine whether vertebral fractures predict subsequent fractures, the authors found that not only do vertebral fractures indicate an increased risk for subsequent fractures, but that the greatest risk of subsequent fracture was in the axial skeleton.^[16] After an initial vertebral fracture, the authors observed a 12.6-fold increase in additional vertebral fractures, a 2.3-fold increase in hip fractures, and a 1.6-fold increase in additional forearm fractures.

A study by Lindsay and associates analyzed data from four large 3-year osteoporosis treatment trials conducted at 373 study centers in the United States and abroad.^[17] Subjects were a mean age of 74 years, had a mean of 28 years since menopause, and were known to have had one or more vertebral fractures. Data analysis showed that patients who had one or more vertebral fractures at baseline had a 5-fold increased risk of having a fracture during the first 12 months of the study. Among patients who developed a vertebral fracture during the study, approximately 20% had a new vertebral fracture in the next 12 months.

Not every aging woman will develop vertebral fractures, but they are very common and underdiagnosed. If healthcare providers can prevent a vertebral fracture, then prevention of the morbidity and mortality associated with that fracture and the prevention of hip and other fractures may be achieved as well.

Robin K. Dore, MD

 

 

The National Institutes of Health Consensus Panel regards the assessment of bone mass, identification of fracture risk, and determination of who should be treated as the optimal goals when evaluating patients for osteoporosis.^[2] Until the late 1980s, it was difficult to identify the patients who were at risk for a fracture before it occurred. Since that time, bone mineral density (BMD) measurements have become fairly common. While BMD is not a true measurement of bone strength, it is the best surrogate measurement available at present.

Table 3. Defining Osteoporosis by BMD

The World Health Organization (WHO) operationally defines osteoporosis as bone density 2.5 SD below the mean for young white adult women (Table 3). Clinicians now use risk factors to help determine which patients should be evaluated for osteoporosis with a bone density test. Several important risk factors for osteoporosis have been identified; however, the list can be expanded to include the following:

• Adults with vertebral, rib, hip, or distal forearm fractures should be evaluated for the presence of osteoporosis. The National Osteoporosis Foundation (NOF) recommends that any woman who has had a fracture as an adult be evaluated for osteoporosis.^[18]
• Since osteoporosis increases with age, the NOF recommends that every woman aged 65 years and older have a bone density test.^[18]
• Corticosteroid (glucocorticoid) use is the major cause of secondary osteoporosis.
• Estrogen deficiency leads to osteoporosis, particularly in women who experience rapid bone loss following menopause or who have early menopause (ie, before age 40). Women with irregular periods prior to menopause may have osteoporosis due to estrogen deficiency. Also, female athletes who don't have regular menstrual periods may have osteoporosis at an early age, particularly if this behavior is accompanied by an eating disorder. The NOF recommends that every woman aged 65 years and older have a bone density test.
• Family history is very important, and should include both the mother's and the father's side of the family. The genetic tendency to develop osteoporosis is not exclusive to the female's side of the family, nor is it exclusively a female tendency. Patients who are diagnosed with osteoporosis should be encouraged to talk to their brothers and sons about osteoporosis screening and treatment.
• Older patients who lose a significant amount of body weight (ie, 5%) are at risk for bone mass loss as well.^[19]

Robin K. Dore, MD

 

 

A patient who has been diagnosed with osteoporosis should be treated promptly and aggressively. The NOF recommends initiating therapy to reduce fracture risk in women with BMD T-scores below -2.0 SD in the absence of risk factors and in women with T-scores below -1.5 SD if other risk factors are present. Women aged older than 70 years and who have multiple risk factors (especially those with previous fractures) are at enough of a risk for fracture to begin treatment without BMD testing.^[18]

Several options for prevention or treatment of osteoporosis are available, including therapies that enhance bone mass and reduce risk of fractures. All current options are antiresorptive therapies: They inhibit bone resorption by osteoclasts.

Hormone Replacement.

Hormone replacement therapy (HRT) is indicated for the prevention of osteoporosis. Several short-term studies and a few longer-term studies using BMD as the primary outcome have shown significant efficacy. For example, the Postmenopausal Estrogen/ Progestin Interventions (PEPI) trial showed that HRT increases bone density in the spine and the hip and produces a reduction in bone turnover.^[20] There have not, however, been any large, randomized, controlled clinical trials showing fracture reduction with HRT. The Women's Health Initiative (initiated in 1992, with a planned completion date of 2007^[21]) may show that HRT prevents fractures, but at the present time, no data are available. As HRT may be associated with a modest increase in the risk of breast cancer with long-term use and is associated with increased risk of deep-vein thrombosis (DVT), the clinician is advised to seek alternative treatments for women diagnosed with or at risk for osteoporosis who also have a history of, or at significant risk for, breast cancer or DVT. HRT may have significant side effects in some individuals, including vaginal bleeding, breast tenderness, mood disturbances,^[18] and gallbladder disease.^[17]

SERMs.

The NIH Consensus Panel considered the development of selective estrogen receptor modulators (SERMs) "an important new thrust in osteoporosis research."^[2] The interest in developing a SERM for the prevention and treatment of osteoporosis was driven by the observation that tamoxifen, an effective adjuvant therapy for breast cancer, has estrogen-like effects on bone.^[22]

The SERM raloxifene, approved for the prevention of postmenopausal osteoporosis in 1997 and the treatment of postmenopausal osteoporosis in 1999, has estrogen-like effects on bone, but acts as an estrogen antagonist on breast and endometrial tissue.^[23]

Raloxifene has been shown to prevent bone loss at the spine, hip, and total body.^[23] More importantly, the 3-year randomized Multiple Outcomes of Raloxifene Evaluation (MORE) trial demonstrated that raloxifene significantly reduced the risks of vertebral fracture. At 1 year, therapy with raloxifene resulted in a 68% reduction in clinical vertebral fractures. At 3 years, raloxifene decreased vertebral fractures in women who had not had fractures at baseline by 55%. In women who had vertebral fractures entering the trial, raloxifene produced a 30% reduction.^[24] The MORE trial was continued into a fourth year, but because the data had not been analyzed and the significance of the reduction in vertebral fractures was not known at that point, women who continued the trial into the fourth year were allowed to add a bone-active agent, with the exception of estrogen. The investigators and participants remained blinded as to whether patients were taking raloxifene or placebo. At 4 years, raloxifene continued to provide fracture protection for a significant number of women. Among women who had no fractures at the start of the study 4 years earlier, raloxifene produced a 49% reduction in vertebral fractures. In the cohort with existing vertebral fractures at study entry, there was a 34% reduction.^[25]

Raloxifene increases the risk of DVT to a degree similar to that observed with estrogen. In addition, an increase in hot flashes is observed (approximately 6% more than with placebo). Thus, raloxifene should not be used to treat menopausal symptoms.^[18] However, for asymptomatic women who were taking estrogen for menopausal symptoms and wish to remain on preventive therapy, it is reasonable to change their therapy to raloxifene.

Calcitonin.

Salmon calcitonin is a synthetic hormone that inhibits bone resorption and is approved for the treatment of osteoporosis in women 5 years after menopause has occurred. It is available as an intranasal spray; a single daily dose provides 200 units (u) of the drug. In a 5-year, double-blind, randomized, placebo-controlled trial of 511 postmenopausal women with established osteoporosis, participants were randomized to receive 100, 200, or 400 u of intranasal calcitonin daily.^[26] Results showed that only the 200-u dose produced a significant (36%) reduction of vertebral fractures, with no reduction in hip fractures and no significant change in either bone density or bone turnover.

Bisphosphonates.

Alendronate sodium was the first bisphosphonate approved for use in osteoporosis. Alendronate 5 mg daily and 35 mg once weekly are approved by the US Food and Drug Administration for the prevention of osteoporosis. The dose for the treatment indication is 10 mg daily or 70 mg once weekly. Alendronate is also approved for the treatment of bone loss in both men and women as a result of prolonged glucocorticoid use and for the treatment of male osteoporosis.^[18] Large, randomized, controlled trials have shown that alendronate reduces the incidence of fracture at the spine, hip, and wrist by 50% in patients with osteoporosis.^[27]

Alendronate must be taken on an empty stomach, first thing in the morning, at least 30 minutes before having any food or beverage. It must be taken with a large glass of water, and patients are advised to sit upright or stand for 30 minutes after administration. In clinical trials, the incidence of side effects with alendronate was no different than placebo; however, in clinical experience, upper gastrointestinal disturbance, particularly esophageal symptoms (eg, chest pain, heartburn, painful or difficult swallowing) has been a problem with alendronate in some patients. A rare (probably <1%) reported complication of alendronate is esophageal ulceration.^[18]

Risedronate is a second bisphosphonate approved for use in osteoporosis. Data from the Vertebral Efficacy with Risedronate trial showed a 41% reduction in new x-ray-apparent vertebral fractures, and a 39% reduction in nonvertebral fractures.^[28] Risedronate also demonstrated a significant reduction in hip fracture in a population of postmenopausal women aged 70 to 79 years.^[29] Risedronate is also approved for the prevention and treatment of glucocorticoid-induced osteoporosis in women and men. Risedronate must be taken using the same regimen as alendronate: on an empty stomach with a full glass of water, remaining upright, and waiting 30 minutes before having any food or beverage.

Combination Therapy.

Studies have shown that increases in bone density with combination therapy are greater than those achieved by either agent alone, but without additive increases. Because there are no data regarding fracture reduction with combination therapy, and no bone biopsy data, many bone specialists are hesitant to recommend combination therapies until the data show greater fracture reduction. However, if a patient who takes estrogen for menopausal symptoms needs treatment for osteoporosis, most bone specialists will continue her on estrogen therapy and add a bisphosphonate. It is currently not advisable that estrogens and raloxifene be taken together; investigation is underway.

Robin K. Dore, MD

 

 

Risedronate is currently being evaluated to determine whether a once-weekly dose is as effective as the 5-mg daily dose presently approved. A study of nasal calcitonin is ongoing to determine the mechanism by which calcitonin prevents fractures. A 5-year trial comparing alendronate with raloxifene initiated enrollment in the fall of 2001. This is a very large study, with primary endpoints including vertebral and nonvertebral fractures that will give clinicians the first "head-to-head" comparison of the antifracture efficacy and safety of a SERM and a bisphosphonate. This trial may provide answers as to why, when compared to bisphosphonates in postmenopausal women, raloxifene has produced similar vertebral fracture reductions with small increases in BMD and small reductions in bone turnover.

Robin K. Dore, MD

 

 

In the near future, we hope to have anabolic therapies that will actually increase bone formation. The first of these, parathyroid hormone, which may be on the market within the year, demonstrated significant reduction in vertebral fractures.^[30] [Teriparatide therapy for osteoporosis was approved by the FDA at the end of November 2002. The teriparatide package insert includes a "black box" warning, acknowledging an increased risk of osteosarcoma in rats treated with relatively high doses of teriparatide. Treatment beyond 2 years is not currently recommended.] New SERMs are under development, as are oral formulations of salmon calcitonin. Intravenous bisphosphonates are also being evaluated for the treatment of osteoporosis.

Robin K. Dore, MD

 

 

For now, our most effective means of treating osteoporosis remains identifying patients, starting them on antiresorptive therapy, if appropriate, and sending-them out into the world as "ambassadors for bone health." Healthcare providers must also remember the basics: counseling all patients to take adequate calcium and vitamin D, reviewing and encouraging appropriate exercise activities, and discussing fall prevention. In addition, clinicians must be mindful that hip protectors may be the most effective way to prevent hip fractures in a given population.

Many postmenopausal women with existing osteoporotic fractures are not diagnosed and treated. Only 22.9% of women with Colles fractures were treated for osteoporosis in a large retrospective study of more than 3 million patients in 30 states.^[31]

Excellent therapies are available now, and it is hoped that better ones will be available in the near future. With bone density studies, clinicians have the tool to diagnose osteoporosis. By reviewing patients' charts, looking for previous fracture, identifying a positive family history of the disease and medications that could contribute to it, and examining patients for height loss and kyphosis and other risk factors, clinicians can diagnose and treat patients before a fracture occurs.

Robin K. Dore, MD

 

 

1. Osteoporosis: both health organizations and individuals must act now to avoid an impending epidemic. Press Release WHO/58. October 11, 1999. Available at http://www.who.int/infpr-1999/en/pr99-58.html. Accessed January 4, 2002.
2. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis and Therapy. JAMA. 2001;285:785-795. Available at http://consensus.nih.gov/cons/111/111_statement.htm#introduction. Accessed January 4, 2002.
3. Ducy P, Schinke T, Karsenty G. The osteoblast: a sophisticated fibroblast under central surveillance. Science. 2000;289:1501-1504.
4. Teitelbaum S. Bone resorption by osteoclasts. Science. 2000;289: 1504-1508.
5. Van Der Linden JC, Verhaar JA, Weinans H. Mechanical consequences of bone loss in cancellous bone. J Bone Miner Res. 2001;16: 457-465.
6. Osteoporosis Overview. Fact Sheets. National Institutes of Health Osteoporosis and Related Bone Diseases, National Resource Center. Available at http://www.osteo.org/docs/30.464633275.html. Accessed January 4, 2002.
7. Kannus P, Parkkari J, Niemi S, et al. Prevention of hip fracture in elderly people with use of a hip protector. N Engl J Med. 2000;343:1506-1513.
8. Leech JA, Dulberg C, Kellie S, et al. Relationship of lung function to severity of osteoporosis in women. Am Rev Respir Dis. 1990;141(1):68-71.
9. Melton LJ. How many women have osteoporosis now? J Bone Miner Res. 1995;10:175-177.
10. Schlaich C, Minne HW, Bruckner T, et al. Reduced pulmonary function in patients with spinal osteoporotic fractures. Osteoporos Int. 1998;8(3):261-267.
11. Silverman SL. The clinical consequences of vertebral compression fracture. Bone. 1992;13 Suppl (2): S27-S31.
12. Cooper C. The crippling consequences of fractures and their impact on quality of life. Am J Med 1997; 103(2A):12S-17S.
13. Cooper C, Atkinson EJ, Jacobsen SJ, et al. Population-based study of survival after osteoporotic fractures. Am J Epidemiol. 1993;137(9):1001-1005.
14. Kado DM, Browner WS, Palermo L, et al. Vertebral fractures and mortality in older women: a prospective study. Study of Osteoporotic Fractures Research Group. Arch Int Med. 1999;159:1215-1229.
15. Cauley JA, Thompson DE, Ensrud KC, et al. Risk of mortality following clinical fracture. Osteoporos Int. 2000;11:556-561.
16. Melton J. Vertebral fractures predict subsequent fractures. Osteoporos Int. 1999;213-221.
17. Lindsay R, Silverman SL, Cooper C, et al. Risk of new vertebral fracture in the year following a fracture. JAMA. 2001;285(3):320-323.
18. National Osteoporosis Foundation. Physician's Guide to Prevention and Treatment of Osteoporosis, 1998. Available at: http://www.nof.org. physguide.htm. Accessed January 11, 2002.
19. Hannan MT, Felson DT, Dawson-Hughes B, et al. Risk factors for longitudinal bone loss in elderly men and women: the Framingham Osteoporosis Study. J Bone Miner Res. 2000;15:710-720.
20. The Writing Group for the PEPI. Effects of hormone therapy on bone mineral density: results from the postmenopausal estrogen/progestin interventions (PEPI) trial. JAMA. 1996;276(17):1389-1396.
21. The Women's Health Initiative Study Group. Design of the Women's Health Initiative clinical trial and observational study. Control Clin Trials. 1998;19(1):61-109.
22. Fontana A, Delmas PD. Clinical use of selective estrogen receptor modulators. Curr Opin Rheumatol. 2001; 13(4):303-309.
23. Johnston CC, Bjarnason NH, Cohen FJ, et al. Long-term effects of raloxifene on bone mineral density, bone turnover, and serum lipid levels in early postmenopausal women: three-year data from 2 double-blind, randomized, placebo-controlled trials. Arch Intern Med. 2000;160(22):3444-3450.
24. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple outcomes of raloxifene evaluation (MORE) investigators. JAMA. 1999;282(7):637-645.
25. Eastell R, Mallinak N, Weiss S, et al. Biological variability of serum and urinary N-telopeptides of type I collagen in postmenopausal women. J Bone Miner Res. 2000;15(1):522-529.
26. Chestnut CH, Silverman S, Andriano K, et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. PROOF Study Group. Am J Med. 2000;109(4):267-276.
27. Black DM, Thompson DE, Bauer DC, et al. Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. FIT Research Group. J Clin Endocrinol Metab. 2000;85 (11):4118-4124.
28. Harris ST, Watts, NJ, Genant HK, et al. Effects of risedronate treatment on vertebral and on vertebral factures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. JAMA. 1999;282(14):1244-1252.
29. McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women: Hip Intervention Program Study Group. N Engl J Med. 2001;344 (5):333-340.
30. Neer R, Arnaud CD, Zanchetta JR, et al. Recombinant human PTH (rhPTH 1-34] reduces the risk of spine and non-spine fractures in women with postmenopausal osteoporosis. N Engl J Med. 2001; 344(19):1434-1441.
31. Freedman KB, Kaplan FS, Bilker WB, et al. Treatment of osteoporosis: are physicians missing an opportunity? J Bone Joint Surg Am. 2000;82A(8):1063-1070.

Lori Mosca, MD, MPH, PhD

 

 

The successful assessment and management of woman's cardiovascular health after menopause is reliant on several factors.

Clinicians treating postmenopausal patients must be well versed on an increasing number of cardiovascular disease (CVD) markers and risk factors. The benefits and risks of hormone replacement therapy (HRT) must be weighed with extreme care; familiarity with emerging therapies and new indications is crucial for the optimal treatment of CVD in postmenopausal women.

This program outlines the important markers of CVD, with attention to several new markers that likely are not familiar to most primary care physicians and OB/GYNs. The role of HRT in cardioprotection is addressed, based on findings from three major clinical trials of HRT in CVD. Additionally, new recommendations recently issued by the American Heart Association (AHA) concerning HRT use in CVD are summarized, as well as updated guidelines for cholesterol testing and management from the third Adult Treatment Panel (ATP III) of the National Cholesterol Education Program (NCEP). Finally, the roles of statins and selective estrogen receptor modulators (SERMs) in treating and preventing CVD are reviewed.

Lori Mosca, MD, MPH, PhD

 

 

Traditional.

The traditional markers of CVD risk in postmenopausal women include elevated levels of low-density lipoproteins (LDL), low levels of high-density lipoproteins (HDL), high triglycerides, family history of heart disease, diabetes, hypertension, obesity, physical inactivity, and smoking. These markers for CVD have been well established over many years and remain the most important markers to emphasize to patients.

Novel.

In recent years, several new markers have been found that may prove critical in the assessment of CVD risk. While not commonly used by the primary care physician or OB/GYN, these markers are often used by cardiologists to assess CVD risk in women who appear to be at high risk or have already experienced a CVD-related event.

C-reactive protein: As a marker for systemic inflammation, C-reactive protein (CRP) is considered an important component in determining the risk for CVD. Researchers have known that CRP levels are higher in people with heart disease, and they have long speculated that atherosclerosis is an inflammatory process. With a simple but highly sensitive blood test that measures CRP levels, the extent of underlying atherosclerosis can be determined and the risk of future heart attack and stroke predicted. In a 3-year study of more than 28,000 healthy postmenopausal women, CRP was the strongest single predictor of future cardiac events, such as heart attacks.^[1] Women with the highest levels of CRP had a fivefold increase in the risk of developing CVD and a sevenfold increase in the risk of having a heart attack or stroke, compared with those who had the lowest levels of CRP. Levels of CRP predicted these events even among apparently low-risk women, such as those who did not smoke, had no evidence of high cholesterol, and had no family history of heart disease. The investigators cautioned that standard laboratory tests are not sufficient for determining CVD risk. Only high-sensitivity or ultrasensitive tests for CRP are capable of predicting CVD risk.

Homocysteine: Elevated levels of this amino acid have been correlated with artery damage, blood clotting, myocardial infarction, stroke, and other manifestations of CVD. Inadequate intake of folic acid and B6 and B12 vitamins is thought to cause increases in homocysteine. Plasma homocysteine levels increase dramatically when a woman reaches menopause, and this is thought to play a role in the increased incidence of vascular disease, cancer, and possibly osteoporosis in postmenopausal women.^[2,3] However, the strength of the association between homocysteine and CVD is not certain, and controversy exists about whether lowering homocysteine levels will reduce Coronary Heart Disease (CHD) risk.

Fibrinogen: The body depends on this protein for proper blood clotting. However, high levels of fibrinogen can restrict blood flow and lead to hardened arteries and accumulation of plaque. Increased production of fibrinogen is associated with traditional CVD risk factors (eg, obesity, smoking, physical inactivity, diabetes).^[4] Aging also has been linked to high fibrinogen levels.^[5] In healthy volunteers, fibrinogen levels were markedly higher in those aged more than 50 years compared with younger participants. Moreover, higher fibrinogen levels in older adults corresponded with a 60% drop in dilation ability, whereas other markers, such as HDL, LDL, and total cholesterol did not significantly correlate with age or dilation ability. As such, the investigators noted that fibrinogen is a highly predictive marker for reduced elasticity of the endothelium.

Lipoprotein(a): Lipoprotein(a) [Lp(a)] is composed of an LDL-like particle and apolipoprotein A. An elevated blood concentration of Lp(a) is associated with an increased risk of atherosclerosis and coronary artery disease.^[6] However, Lp(a) is not considered as great a risk for CHD as are the traditional risk factors. Moreover, measurement of Lp(a) is not standardized, nor is it widely available in clinical practice. It has been suggested that measurement of Lp(a) be reserved for those with a strong family history of early CHD or with genetic predisposition to hypercholesterolemia, such as familial hypercholesterolemia.^[7,8]

Lori Mosca, MD, MPH, PhD

 

 

Although HRT has an established role in the prevention of osteoporosis and relief of vasomotor symptoms, controversy remains regarding the role of HRT in CVD. Data from observational studies largely support the use of HRT in postmenopausal women for a reduced risk of CVD; however, recent randomized, controlled clinical trials have found no overall benefit of HRT in CVD risk reduction or prevention.

The Heart and Estrogen/progestin Replacement Study (HERS) was the first large-scale randomized trial of HRT for prevention of coronary heart disease (CHD) in postmenopausal women.^[9] After an average of 4.1 years of follow-up, there was no overall benefit of HRT on secondary prevention of CHD. In fact, during the first year of treatment, a significant (52%) increase in cardiovascular events was noted in the HRT group compared with placebo. Fewer events occurred as the study progressed, and benefit with HRT was seen by year 4. Based on these findings, the investigators recommended that HRT not be started for secondary prevention of CHD. A 3-year follow-up study, HERS-II, is currently underway to evaluate the longer term effects of HRT in secondary prevention of CHD.^[10]

In the Estrogen Replacement and Atherosclerosis (ERA) trial, no benefit was seen after 3 years of treatment with HRT or with estrogen alone on the progression of atherosclerosis in postmenopausal women with established disease.^[11] These results support those of HERS and consequently lend more support to the recommendation that HRT not be initiated for secondary prevention of CHD.

Several ongoing prospective angiographic trials should offer more insight into the effect of HRT on the progression of coronary disease. Angiographic endpoint trials include the Estrogen and Bypass Graft Atherosclerosis Regression trial (EAGER), the Women's Lipid Lowering Heart Atherosclerosis Trial (WELLHART), and the Women's Atherosclerosis Vitamin/Estrogen trial (WAVE). In primary prevention, trials include the Women's Health Initiative (WHI; of which the combination HRT arm has been discontinued as of July 2002) and the Women's International Study of Long-Duration Oestrogen after Menopause (WISDOM). In secondary prevention, trials include the Heart and Estrogen/progestin Replacement Study follow-up (HERS II) and the Estrogen in the Prevention of Reinfarction Trial (ESPRIT).^[10]

One of these ongoing trials is the Women's Health Initiative (WHI), which includes a large-scale randomized trial to assess the effects of HRT on primary prevention of CHD over an 8- to 12-year period.^[12] The latest update from the WHI indicates an early increased risk of CVD events among healthy women randomized to estrogen alone or HRT compared with placebo. Fewer than 1% of women taking estrogen only or HRT experienced early CVD events. Future updates are awaited for further information regarding the long-term effects of estrogen or HRT on primary prevention of CVD.

Lori Mosca, MD, MPH, PhD

 

 

An extensive analysis of the evidence from these current and ongoing clinical trials led to the development of new guidelines by the AHA for the role of HRT in CVD.^[10] The new guidelines consider the use of HRT in both secondary and primary prevention. In summary, the AHA recommends that HRT not be initiated for the purpose of secondary prevention. This is based on the lack of definitive evidence that HRT will prevent coronary events, particularly among women with established coronary disease. For primary prevention, the AHA states that decisive clinical recommendations for HRT use must await the results of ongoing randomized clinical trials. However, possible coronary benefits and risks can be factored into the treatment decision for primary prevention.

The AHA emphasizes that the driving factor of whether HRT should be used in primary prevention should be based mainly on established noncoronary benefits, such as osteoporosis prevention, relief of vasomotor symptoms, and patient preference. The decision to use HRT in secondary prevention should be driven by noncoronary factors as well. For women who have an acute coronary event or are immobile, the AHA suggests discontinuation of HRT.

Lori Mosca, MD, MPH, PhD

 

 

Clinicians should also be familiar with the Third Report of the NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III).^[13] This report, issued in 2001, describes in great depth the NCEP updated clinical guidelines for cholesterol testing and management. These guidelines are outlined in the table below.

Table. (click to enlarge) Adult Treatment Panel III Guidelines: A Quick Reference

The updated guidelines share many features with previous ATP recommendations for the management of CVD in women with hypercholesterolemia, but emphasize more aggressive lowering of elevated LDL levels. For example, the ATP III guidelines recommend a target LDL of less than 100 in women who have greater than a 20% 10-year risk for CHD. This includes women with peripheral vascular disease, coronary artery disease, abdominal aortic aneurysms, or diabetes.

Another advancement in the ATP III guidelines is the classification of the metabolic syndrome, a very common problem in postmenopausal women. By definition, metabolic syndrome can be diagnosed in women with at least three of the following factors: a waist circumference greater than 35 inches, triglycerides at least 150 mg/dL, HDL cholesterol lower than 50 mg/dL, blood pressure at least 130/85 mm Hg, or a fasting glucose at least 110 mg/dL.

Lori Mosca, MD, MPH, PhD

 

 

Statins -- First-line therapy for CVD: Based on the AHA recommendations and the ATP III guidelines, the general consensus for CVD prevention and management in postmenopausal women is modification of lifestyle supplemented with pharmacotherapy when indicated. Statins are currently considered the most effective therapy for lowering LDL cholesterol levels.^{[14, 15]} Statins block the synthesis of cholesterol in the liver, which effects a decrease in plasma LDL levels. These agents have been shown to dramatically reduce levels of total serum cholesterol, thus demonstrating their beneficial effect in reducing CHD events.^[14] Studies among postmenopausal women with hypercholesterolemia have reported that statins reduced LDL levels by 25.4% to 45%.^[15-20] Statins are also more effective than ERT/HRT in reducing LDL levels,^{[16, 17, 19, 20]} and have demonstrated significant triglyceride-lowering effects compared with HRT.^[20] Thus, for women with elevated LDL cholesterol, statins are now considered first-line therapy instead of ERT/HRT.

SERMs -- Emerging cardioprotective effects: SERMs are drugs with mixed agonist/antagonist action on estrogen receptors in different tissues. Raloxifene is a SERM indicated for both the prevention and treatment of osteoporosis. Tamoxifen also belongs to the SERM class of drugs, and has been shown to reduce the incidence of breast cancer in healthy women at high risk of developing the disease. Studies of SERMs in CHD have shown that they are capable of reducing LDL levels without affecting HDL or triglyceride levels significantly in postmenopausal women.^[21-25]

Studies in postmenopausal women also have demonstrated beneficial effects of SERMs on several new markers of CVD. Both tamoxifen and raloxifene have been shown to decrease levels of Lp(a),^{[23, 26]} with tamoxifen having a greater effect than that seen with conjugated equine estrogen.^[26] SERMs also have a greater ability to lower fibrinogen levels compared with HRT.^{[23, 27]} In a recent study of tamoxifen, fibrinogen levels were reduced by 22%, and the drug was effective in reducing levels of CRP by 26%.^[28]

These trials offer encouraging evidence for a potential role of SERMs in CVD prevention; however, further research is needed to confirm the clinical relevance of the beneficial effect on many markers of CVD. The Raloxifene Use for the Heart (RUTH) Study is underway to examine more than 10,000 perimenopausal women for CVD and breast cancer.^[29] Future decisions regarding SERM use will likely be influenced by the effects of compounds on more than one organ system.

Lori Mosca, MD, MPH, PhD

 

 

Because CVD is the leading cause of death and an important cause of disability in postmenopausal women, it is imperative that clinicians are familiar with its emerging markers. It is also important that clinicians understand all of the agents available to help women achieve lipid targets and optimize risk-reducing strategies.

Lori Mosca, MD, MPH, PhD

 

 

1. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. New Engl J Med. 2000;342: 836-843.
2. Anker G, Lonning PE, Ueland PM, et al. Plasma levels of the atherogenic amino acid homocysteine in postmenopausal women with breast cancer treated with tamoxifen. Int J Cancer. 1995;60:365-368.
3. Boers GH, Smals AG, Trijbels FJ, et al. Unique efficiency of methionine metabolism in premenopausal women may protect against vascular disease in the reproductive years. J Clin Invest. 1983;72:1971-1976.
4. Stec JJ, Silbershatz H, Tofler GH, et al. Association of fibrinogen with cardiovascular risk factors and cardiovascular disease in the Framingham Offspring Population. Circulation. 2000; 102:1634-1638.
5. Allen JD, Wilson JB, Tulley RT, et al. Influence of age and normal plasma fibrinogen levels on flow-mediated dilation in healthy adults. Am J Cardiol. 2000; 86:703-705.
6. Zenker G, Koltringer P, Bone G, et al. Lipoprotein(a) as a strong indicator for cerebrovascular disease. Stroke. 1986;17:942-945.
7. Marcovina SM, Koschinsky ML. Lipoprotein(a) as a risk factor for coronary artery disease. Am J Cardiol. 1998;82:57U-66U; discussion 86U.
8. Marcovina SM, Hegele RA, Koschinsky ML. Lipoprotein(a) and coronary heart disease risk. Curr Cardiol Rep. 1999;1:105-111.
9. Hulley S, Grady D, Bush T, et al, for the Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998; 280:605-613.
10. Mosca L, Collins R, Herrington DM, et al. Hormone replacement therapy and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation. 2001;104:499-503.
11. Herrington DM, Reboussin DM, Brosnihan KB, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med. 2000;343:522-529.
12. The Women's Health Initiative Study Group. Design of the Women's Health Initiative clinical trial and observational study. Control Clin Trials. 1998;19:61-109.
13. National Cholesterol Education Program. Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). National Heart, Lung and Blood Institute Web site. Available at http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.htm. Accessed January 7, 2002.
14. Gould AL, Rossouw JE, Santanello NC, et al. Cholesterol reduction yields clinical benefit: impact of statin trials. Circulation. 1998;97:946-952.
15. Gotto AM, Jr. Cholesterol management in theory and practice. Circulation. 1997;96:4424-4430.
16. Davidson MH, Testolin LM, Maki KC, et al. A comparison of estrogen replacement, pravastatin, and combined treatment for the management of hypercholesterolemia in postmenopausal women. Arch Intern Med. 1997;157:1186-1192.
17. Herrington DM, Werbel BL, Riley WA, et al. Individual and combined effects of estrogen/progestin therapy and lovastatin on lipids and flow-mediated vasodilation in postmenopausal women with coronary artery disease. J Am Coll Cardiol. 1999;33:2030-2037.
18. Ushiroyama T, Ikeda A, Ueki M, Sugimoto O. Efficacy and short-term effects of pravastatin, a potent inhibitor of HMG-Co A reductase, on hypercholesterolemia in climacteric women. J Med. 1994;25:319-331.
19. Darling GM, Johns JA, McCloud PI, Davis SR. Estrogen and progestin compared with simvastatin for hypercholesterolemia in postmenopausal women. N Engl J Med. 1997;337:595-601.
20. Sbarouni E, Kyriakides ZS, Kremastinos DT. The effect of hormone replacement therapy alone and in combination with simvastatin on plasma lipids of hypercholesterolemic postmenopausal women with coronary artery disease. J Am Coll Cardiol. 1998;32:1244-1250.
21. Love RR, Wiebe DA, Newcomb PA, et al. Effects of tamoxifen on cardiovascular risk factors in postmenopausal women. Ann Intern Med. 1991; 115:860-864.
22. Love RR, Wiebe DA, Feyzi JM, et al. Effects of tamoxifen on cardiovascular risk factors in postmenopausal women after 5 years of treatment. J Natl Cancer Inst. 1994;86:1534-1539.
23. Walsh BW, Kuller LH, Wild RA, et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA. 1998; 279:1445-1451.
24. Draper MW, Flowers DE, Huster WJ, et al. A controlled trial of raloxifene (LY139481) HCl: impact on bone turnover and serum lipid profile in healthy postmenopausal women. J Bone Miner Res. 1996;11:835-842.
25. 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;337:1641-1647.
26. Shewmon DA, Stock JL, Rosen CJ, et al. Tamoxifen and estrogen lower circulating lipoprotein(a) concentrations in healthy postmenopausal women. Arterioscler Thromb. 1994;14:1586-1593.
27. Grey AB, Stapleton JP, Evans MC, et al. The effect of the antiestrogen tamoxifen on bone mineral density in normal late postmenopausal women. Am J Med. 1995;99:636-641.
28. Cushman M, Costantino JP, Tracy RP, et al. Tamoxifen and cardiac risk factors in healthy women: suggestion of an anti-inflammatory effect. Arterioscler Thromb Vasc Biol. 2001;21:255-261.
29. Mosca L, Barrett-Connor E, Wenger NK, et al. Design and methods of the Raloxifene Use for The Heart (RUTH) study. Am J Cardiol. 2001;88:392-395.

Thomas E. Nolan, MD, MBA; Susan Johnson, MD; Robin Dore, MD; Jane Cauley, DrPH; Lori Mosca, MD, MPH, PhD

 

 

The following are excerpts from a closed roundtable discussion that took place in October, 2001, entitled "HRT and SERMs: Evidence-Based Data to Guide Patient Management." Dr Thomas E. Nolan acted as moderator.

As noted in "Cardiovascular Disease: New Recommendations for Minimizing the Threat," by Lori Mosca, MD, MPH, PhD, a great need exists for education, screening, and intervention for cardiovascular illness in postmenopausal patients.

Dr Nolan: When it comes to the prevention and management of cardiovascular disease (CVD), for many years we've segregated male and female patients. However, data are beginning to show that women have some of the same problems with coronary arteries as men do. Also, many OB/GYNs are not well attuned to the difference between primary and secondary prevention; in many cases, by the time secondary prevention is needed, they have already lost control of that patient.

Dr Johnson: What should be the approach in treating women who don't have proven coronary heart disease but are at very high risk, because of such conditions as diabetes and hyperlipidemia? Should we be giving them estrogen?

Dr Mosca: The question you are raising is one of risk equivalence. The American Heart Association guidelines do not recommend estrogen for secondary prevention. For nearly all postmenopausal women, there's some degree of atherosclerosis. At some point, when it becomes clinically evident, we call its management "secondary prevention." The problem with that way of thinking is that the first time a woman manifests coronary heart disease, two thirds of the time it's with sudden death. There are no prior symptoms. The OB/GYN is in a unique position to treat women more aggressively and to not wait until there is a diagnosis.

Even in women who are 55 or recently postmenopausal and have one or more risk factors, I am aggressive in the prevention of CVD.

Dr Nolan: I try to intervene with patients early in menopause as well. I'm not always successful, because patients are often not yet willing to accept menopause-related interventions.

Pharmacotherapy.

Dr Mosca: As for hormone replacement therapy (HRT), it's generally not being used now as a mechanism for the prevention of heart disease. In the cardiovascular community, the data appear to be insufficient to use it when there are many other methods [eg, physical activity, smoking cessation, nutrition, lipid lowering via statin therapy, blood pressure medication] of controlling CVD.

Dr Dore: What about primary versus secondary prevention and low dose aspirin in women?

Dr Mosca: For secondary prevention, aspirin is well accepted. For primary prevention, there's an ongoing trial right now. We do not generally recommend aspirin in the setting of primary prevention.

Even though a benefit has been seen on an epidemiological level, mainly among women with risk factors, aspirin therapy may increase risk of hemorrhagic stroke.^[1] Stroke accounts for nearly one third of all cardiovascular events in women. Therefore, until we really have an evidence base to suggest that aspirin lowers overall cardiovascular mortality, there isn't a lot of enthusiasm to use it right now.

Dr Cauley: The Women's Health Initiative and the Heart and Estrogen /Progesterone Replacement (HERS) studies both use conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA). What about some of the other forms of HRT? My understanding is that they're now being used more frequently.

Dr Mosca: The world literature still largely pertains to CEE and MPA. One school of thought exists that different estrogens and progestins may exert different cardiovascular effects. In particular, there is a lot of enthusiasm in Europe over 17-beta estradiol. Last year, Hodis presented an estradiol study showing a reduction in the progression of corroded intima-media thickness.^[2]

In terms of progestins, there is a lot of controversy surrounding whether or not one progestin might be better than another. The literature is quite mixed. The take-home message is that we don't know whether or not one form of estrogen and/or progestin is better. It's worth pursuing these studies to see if we can develop a database that qualifies for a larger-scale critical outcome study.

Unfortunately, the long-term epidemiologic studies of secondary prevention have been minimal. So, in this case, epidemiology data seem to be consistent with the randomized trials. And there is no primary prevention outcome study yet.

Depression and CVD.

Dr Nolan: I see a lot of symptomatic depression in postmenopausal women, which is also a considerable risk factor.

Dr Mosca: Indeed. Although the Enhancing Recovery in Coronary Heart Disease [ENRICHD] trial, the first major randomized, clinical trial to test treating depression and low social support with psychosocial intervention, did not show a reduction in cardiovascular endpoints, there was a statistical improvement in depression and social isolation.^[3] There is great opportunity for us to make sure that women get appropriate treatment for these problems. I suspect that depression, anxiety, and social isolation are major contributors to CVD for women.

Dr Nolan: Our community is now really looking for depression and treating it. Dr Johnson, you and I were talking about using selective serotonin reuptake inhibitors (SSRIs) for chronic pelvic pain and premenstrual dysmorphic disorder several years ago.

Dr Johnson: Yes, and at present, a lot more practitioners are now prescribing SSRIs for these and other hormone-related psychological mood disorders.

Dr Dore: Thanks to the higher level of social acceptance than these agents once had, patients as well as clinicians are now more willing to discuss and use these therapies.

Dr Nolan: Indeed, and over the years, I'm finding less and less reluctance. Twenty years ago, a colleague of mine said CVD was related to chronic stress causing damage to the arterial walls. I thought it was an interesting theory, and I still think there may be an element in there somewhere.

Dr Mosca: Absolutely. The role of psychosocial markers in CVD is now very prominent. A number of studies have examined, for example, type A personality as a risk factor for cardiovascular events. Unfortunately, most of this research has been conducted in men. Only in recent years have even the major studies begun to collect information about how personality traits and reactions to environmental stress affect heart health. We all suspect that these factors are major contributors to CVD in women.

Another issue is the multiplicity of the family and societal roles women now have. For many years, women have been the caretakers of their spouse and children; now, they are often also in the "sandwich role" of caregiver for a parent, while also working outside the home. How the psychosocial environment contributes to CVD remains to be determined. Common sense tells us that it doesn't bode well to have competing priorities. Because of these responsibilities, many women tell us that they don't have time to exercise or to go to cardiac rehabilitation, for example. They feel their need to care for others is greater than that to care for themselves.

When the World Trade Center disaster occurred, we set up a heart attack prevention center downtown. We did it because severe emotional stress leads to a host of responses from the body: Viscosity is increased, fibrinogen levels are increased, blood pressure is increased, and cholesterol is even increased in some studies. All of these markers can acutely affect risk among individuals who have unstable plaque.

Here is another example: There tends to be about an eight fold increase in the risk of cardiovascular events in the 2 weeks following earthquakes and other natural disasters. For about 6 months, cardiovascular mortality rates remain doubled.

Hormone Alternatives.

Dr Dore: Nutraceuticals are very important to my patients. Have any trials looked at soy or red clover?

Dr Mosca: The soy data have been mixed, also. Some surrogate endpoint studies, such as those on endothelial function, have been positive.^[4] Others have been neutral.^[5] Many women like the idea of using a natural form of estrogen rather than a pharmaceutical compound. I have concerns about that, because I don't know exactly what they're getting or what it's doing to their blood vessels. There's evidence that soy, when it's replacing animal protein, can lower cholesterol.^[4] Again, whether these intermediate endpoint data are going to translate into beneficial clinical outcomes remains to be determined. It would be very nice if we could see a well-conducted trial of soy in postmenopausal women. In terms of our recommendations, it's premature right now to say that soy has a cardiovascular benefit.

Thomas E. Nolan, MD, MBA; Susan Johnson, MD; Robin Dore, MD; Jane Cauley, DrPH; Lori Mosca, MD, MPH, PhD

 

 

Awareness is the key to preventing osteoporosis. Here, Robin Dore, MD, author of "Osteoporosis: Focusing on Fracture and Key Risk Factors," discusses this disease with the other faculty

members, offering critical information on monitoring, prevention, and treatment.

Dr Dore: My primary goal in speaking to patients and physicians is to increase their awareness of osteoporosis prior to the fracture so we can prevent those fractures from occurring. Luckily, we have many therapies for preventing and/or treating these patients, including alendronate, raloxifene, risedronate, and calcitonin. Estrogens no longer have the indication for the treatment of osteoporosis as there has been no clinical evidence indicating that estrogen reduces the risk of fractures. In the future, maybe next year, we will have therapies that are anabolic and actually increase bone formation. So what we can do today is identify the patients who are at risk, start them on therapy, and have them be ambassadors of bone health.

We need to constantly emphasize to adolescents the importance of building peak bone density -- through calcium intake, weightbearing exercise, and not smoking.

Screening.

Dr Cauley: The National Osteoporosis Society guidelines do not recommend follow-up bone mineral density (BMD) measurement once a woman is on therapy. Why wouldn't you need them?

Dr Dore: The National Osteoporosis Foundation guidelines on vertebral fractures assume that the patient has osteoporosis. But a malignancy [eg, multiple myeloma, primary malignancies of bone] can cause those vertebral fractures as well. A patient could have a trauma as a child and not remember having a vertebral fracture.

One of my patients had a vertebral compression fracture at T10. She was on long-term thyroid replacement, had never taken estrogen, was at risk of falling, and had a positive family history of osteoporosis. If I had treated her, she would have taken therapy needlessly, because she had a normal BMD. As it turns out, she had fallen down a flight of stairs when she was 12 -- that was when the fracture occurred.

Dr Cauley: Bone mineral density is a good screening tool. It identifies people at risk for fracture. But it's not perfect. A patient with a BMD higher than -2.5 SD can still have a hip fracture.

Dr Dore: Indeed, the problem with the World Health Organization criteria for osteoporosis is that age and prior fracture are not taken into account. I put age first, fracture history second, and then T-score. So, if a person has a T-score of -1.8 but has a hip fracture, I would certainly treat her. I advise that these guidelines not be used too strictly.

Unfortunately, I've had many patients referred to me for treatment of osteoporosis because they've had a fracture, and it turns out to be a malignancy. I always evaluate a patient for malignancy if she's had a fracture and the assumption has been that it's osteoporotic.

Dr Johnson: Do we know what the prevalence is of morphometric fractures in women based on their BMD? For example, in women with BMD above -2.5 SD and who are 70 years old?

Dr Dore: In 80-year-old patients, the prevalence is 44%.^[6] With regard to BMD measurements, a great disparity exists among different machine manufacturers. Therefore, I always recommend using the same machine every time if possible. If that's not possible, the next best thing is to use a machine from the same manufacturer.

Troubleshooting.

Dr Nolan: What about hyperthyroidism and overuse of thyroid replacements?

Dr Dore: Three abstracts at the World Congress of Osteoporosis last year looked at these data. They showed that between 4 and 9 years of having a normal ultrasensitive thyroid-stimulating hormone level, some bone loss occurred. Other recent data showed that one of the greatest risks for hip fractures was longterm thyroid replacement.^[7] Thus, it appears that the endogenous thyroid hormone acts differently than taking either exogenous thyroid or exogenous corticosteroids in this regard.

The issue of frozen bone also came up, surrounding the fact that there was increased

tetracycline labeling along the surface of the bone in patients who were taking both alendronate and estrogen. This was not the case in patients taking residronate and estrogen. Also, alendronate has a half-life of about 10 years in bone and residronate is about 400 days.

Thomas E. Nolan, MD, MBA; Susan Johnson, MD; Robin Dore, MD; Jane Cauley, DrPH; Lori Mosca, MD, MPH, PhD

 

 

Any discussion of postmenopausal health interventions warrants the inclusion of their respective safety issues. In this section, the participants focus on the use of SERMs and estrogen replacement in a variety of health scenarios.

Dr Cauley: Between 2005 and 2007, we can expect a large amount of data to surface regarding breast cancer prevention, SERMs, and HRT. We will then have a lot more information on the safety of these interventions.

Dr Dore: If a woman does have some vaginal dryness and is on raloxifene, there are studies demonstrating that topical estrogen use is safe. Do you agree?

Dr Johnson: That's an important point. I believe that vaginal estrogen can be used in those women reasonably safely, now that we have available two forms of delivery systems that don't lead to systemic absorption and therefore don't lead to receptor competition. The estradiol ring (Estring) and estradiol vagina tablet (Vagifem) are not absorbed systemically and can be used safely in almost any patient if vaginal atrophy symptoms are present.

Dr Cauley: I just want to emphasize that raloxifene is not approved by the US Food and Drug Administration for breast cancer prevention. The data from the Multiple Outcomes of Raloxifene (MORE) study is, however, very exciting; it didn't demonstrate simulation of the endometrium with raloxifene. Other trials showed an increased risk of endometrial cancer with tamoxifen use, particularly in patients older than 50. Therefore, in women with a uterus, raloxifene has potential as an attractive therapy. Of course, we need more data before we can recommend it for breast cancer.

Dr Dore: Raloxifene is not recommended to control vasomotor symptoms, such as hot flashes, associated with menopause. However, it is a good option for asymptomatic women who want to remain on preventive therapy.

If a 70-year-old patient is using HRT and her BMD is high, would you recommend that she stop estrogen at that point because she's at increased risk for breast cancer?

Dr Cauley: The American College of Obstetrics and Gynecology recently recommended that after 5 years of HRT use, it is important to weigh the benefits and risks of HRT for an individual woman. Use of the Gail Model for Estimating Breast Cancer Risk can be helpful (Table). The major benefits of HRT are symptom relief and prevention of bone loss; and risks include possibly breast cancer, especially after long-term use and deep vein thrombosis. In other words, I think she needs to reconsider why she is taking the HRT.

Table 1. (click to enlarge) The Gail Model

Dr Johnson: For what reason is this 70-year-old patient continuing HRT? She clearly doesn't need it for bones. Perhaps it will help with Alzheimer's disease. She needs to understand that she is at somewhat increased risk for breast cancer, merely by being on the hormones for 20 years, let alone her high BMD. We have to be careful about how we explain those risks and benefits to patients.

As I understand it, the Alzheimer's-estrogen connection began about 10 years ago with a few very small open trials. Patients with Alzheimer's disease were given estrogen in an uncontrolled fashion and, after a few weeks, were observed by clinicians to be thinking better. Later, epidemiologic studies showed that women who had taken estrogen seemed to have about a 50% lower rate of developing Alzheimer's disease. Mechanistic studies in the lab showed that estrogen stimulated dendrite development. In theory, these factors explained why estrogen might help to prevent Alzheimer's disease in women. Two years ago, however, the first large, 1-year, randomized trial of estrogen vs placebo in a group of women with early Alzheimer's disease was conducted and showed no difference between the two groups. This study raised caution about the extent to which we should believe those epidemiologic studies; after all, they have the same kinds of biases with this disease as they do with others.

Dr Nolan: I've begun to focus more on study design and process, and when higher cortical function is observed, to examine the tests that are used and their reproducibility.

Dr Dore: Raloxifene is also being studied in the prevention and progression of Alzheimer's disease. One group looked at five different tests of cognitive functioning and showed that, using two of them, a significant improvement was seen.

Thomas E. Nolan, MD, MBA; Susan Johnson, MD; Robin Dore, MD; Jane Cauley, DrPH; Lori Mosca, MD, MPH, PhD

 

 

Dr Nolan: I'd like to extend my thanks to everyone for joining me today and sharing your thoughts about postmenopausal health. This lively conversation is sure to have value to our readers in their pursuit of optimal patient care.

Thomas E. Nolan, MD, MBA; Susan Johnson, MD; Robin Dore, MD; Jane Cauley, DrPH; Lori Mosca, MD, MPH, PhD

 

 

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