Felicia Cosman, MD
Osteoporosis Specialist/ Endocrinologist
Helen Hays Hospital
Clinical Director
National Osteoporosis Foundation
Associate Professor of Clinical Medicine
Columbia University

Diane B. Ginsburg, MS, RPh, FASHP
Clinical Associate Professor
University of Texas at Austin
College of Pharmacy
Division of Pharmacy Practice and Administration

Enid Morales, PharmD, BCPS
Clinical Assistant Professor
Rutgers—The State University of New Jersey
College of Pharmacy
Department of Pharmacy Practice and Administration

Jerry E. Silverman, RPh
President
Bimark Healthcare Communications

Disclosure of Faculty Relationships
Felicia Cosman, MD, has disclosed that she is a member of the Eli Lilly & Company’s Speakers Bureau. None of the other faculty has any disclosures to report.

Photo of woman gardening

Foreword

Maintaining Postmenopausal Health is a series of professional education programs for pharmacists. This monograph, Management Options and Counseling Strategies for Pharmacists, explores ways pharmacists can improve patient outcomes through patient education and counseling intended to promote compliance with postmenopausal therapies. The primary focus is the pharmacist’s role as a critical member of the healthcare team, who can provide patients with balanced information about drug efficacy and safety, allowing patients to realize the full benefits of treatment.

This monograph addresses clinical and patient issues in the selection of an appropriate postmenopausal management plan and provides a summary of the counseling information and communication skills needed to help ensure patient compliance with various postmenopausal therapies. Module I in the series, entitled Patient Assessment and Health Education Strategies for Pharmacists, which consists of a monograph and accompanying videotape, explores the social and clinical impact of menopause, reviews the basic physiology and pathophysiology of menopause, and discusses the specific communication strategies and skills necessary to increase the pharmacist’s contribution to the healthcare team that cares for women after menopause.

Introduction

Based on average life expectancy and age at onset of menopause, women currently can expect to live about one-third of their lives after the cessation of menses.¹ After menopause, women face several distinct health risks related both to aging and to the specific consequences of long-term estrogen deficiency, in particular osteoporosis and cardiovascular disease. Although many women consider cancer to be the greatest health risk they face as they age, heart disease is actually the leading cause of death among older women following menopause.² Moreover, osteoporotic fractures are common and are responsible for considerable morbidity and mortality. In her lifetime, a 50-year-old woman has a 40% risk of experiencing an osteoporotic fracture, including a 17% risk of hip fracture.³ A woman’s risk of developing a hip fracture is equal to her combined risk of breast, uterine, and cervical cancer.⁴ In addition, approximately 25% of 80-year-old women have had at least one vertebral fracture.⁵

Although we are not yet able to eliminate postmenopausal health problems, advances in medical diagnosis and therapeutics have made it possible to better quantify and control them. For example, an older woman’s cardiovascular risk can be quantified through routine monitoring of blood pressure and a serum cholesterol profile. Similarly, osteoporosis—and the consequent risk of fracture—can be monitored noninvasively through radiographic assessment of a woman’s bone mineral density.

Several factors that influence the risk of fracture have been identified—including genetics, lifestyle factors, nutrition, medical disorders, and drugs—many of which can be eliminated or modified (see Table Factors Commonly Associated with Osteoporosis).⁶ Bone mineral density (BMD) is the major measurable determinant of the risk of fragility fractures. Recent prospective studies, however, have identified other factors that influence the risk of fracture, independent of those associated with low BMD.⁶ Skeletal factors other than BMD that may increase the risk of hip fracture in women include hip geometry and body height. Low body weight (secondary to poor appetite or poor health) has also been associated with increased fracture risk. Smoking, prior fracture occurrence during adulthood, and maternal history of hip fracture are also independent predictors of hip fracture risk. In addition, nutritional deficiencies and sedentary lifestyle may play a role in fracture pathogenesis. Other factors, some of which are potentially modifiable, operate through effects on the risk of trauma, including decreased visual acuity, neuromuscular impairment, cognitive impairment, residence in a long-term care facility, and use of medications that diminish alertness.

Factors in Osteoporosis

Factors In Osteoporosis

The evolving ability to define postmenopausal health risks is reflected in a growing interest in disease prevention strategies, including dietary modifications, lifestyle changes, and pharmacologic therapies that can help reduce these risks. Ongoing clinical research continues to further expand our understanding of women’s health issues. Notable examples are the 16-year Nurses’ Health Study of almost 60,000 female nurses, and the Women’s Health Initiative, which is designed to involve over 160,000 postmenopausal women.^8,9,10

Findings from these studies should continue to bridge the remaining gaps in our understanding of postmenopausal health. In the meantime, pharmacists must be prepared to counsel women about steps they can take to minimize their risks for osteoporosis and cardiovascular disease. These steps are valuable in enabling a woman to preserve her well-being during the postmenopausal years.

Pharmacists can play an important role in educating women of all ages about the prevention and treatment of osteoporosis so that they can make more informed decisions about their own health. For example, pharmacists should initiate discussions with women of all ages to help prevent, recognize, and treat osteoporosis.¹¹ In addition, pharmacists must be prepared to counsel women about both the positive effects of therapies such as hormone replacement therapy, or HRT (i.e., possible cardiovascular protection and decreased risk of osteoporosis), as well as potential negative effects. Many women are concerned with the possible increased risk of breast cancer related to HRT, a fear that can be a barrier to utilizing this therapy in the postmenopausal years. An increase in uterine cancer risk and benign uterine conditions increasing vaginal bleeding can also reduce the chances of initiation or adherence to HRT.

The pharmacist’s role in maintaining the health of older women is increasingly relevant given the expected increase in the postmenopausal population. More than 30 million women in the United States are now in or past menopause, and another 6 million or more will reach this stage of life in the next decade.¹² This trend is reflected globally: The number of postmenopausal women is expected to triple by the year 2030.¹³ Given the predicted increase in the postmenopausal population, the numbers of osteoporotic fractures are likely to increase in the future. For example, the number of hip fractures in the United States is projected to increase by 300% by the year 2040.³

Disease management frequently involves drug therapy. Accordingly, pharmacists are well positioned to participate in maintaining the health of women after menopause. Pharmacists are accessible to the community, have access to prescription records, and can make recommendations for both prescription and nonprescription medications.

Section I

COMPLIANCE CHALLENGES WITH POSTMENOPAUSAL THERAPY

In the past, many women have not reaped the benefits of available postmenopausal therapies due to inadequate physician awareness and communication about the traditional treatment regimen—HRT—and poor patient compliance with this therapy.¹²

Although short-term HRT provides relief from such acute menopausal symptoms as hot flashes, vaginal atrophy, and urinary frequency and urgency, protection against the silent onset and progression of osteoporosis and cardiovascular disease requires compliance with long-term therapy.^13,14 As many as 20% to 30% of women who are advised by their physicians to begin HRT never fill their prescriptions.^13,14,15 Reasons for failure to initiate HRT range from fear of side effects to lack of information.^15,16

Common reasons for discontinuing HRT include fear of side effects, fear of cancer, loss or abatement of menopausal symptoms, weight gain, physician’s recommendation, breast pain and engorgement, and bleeding disturbances (see Table 1-1).^16,17,18 Monthly withdrawal bleeding is an important factor in some women’s decision to discontinue HRT.¹⁸ However, monthly bleeding occurs only with cyclical HRT, not with continuous HRT. Continuous HRT, however, also frequently causes irregular bleeding or spotting, at least in the first 6 to 9 months of therapy. Women may choose to discontinue HRT due to a lack of information regarding the different regimens. Cessation of HRT is also frequently associated with confusing diagnostic, prescribing, and monitoring practices by healthcare providers. Women who are uncertain about their changing health status and the merits of medication may be particularly affected by such confusing information.¹⁹ Some physicians tend to underestimate women’s desire for information about HRT and underrate their concerns about symptomatic conditions such as urinary incontinence.²⁰

^{Table
1-1}^{Common Reasons for Discontinuing HRT}

	Fear of side effects
	Fear of cancer
	Loss or abatement of menopausal symptoms
	Weight gain
	Physician’s recommendation
	Bleeding disturbances

Patients with contraindications to HRT or who do not wish to start HRT can be offered newer, alternative therapies. A number of pharmacologic agents—including new molecular entities—that target potentially debilitating postmenopausal conditions have been introduced in recent years or are currently in development.

Section II

NONPHARMACOLOGIC MANAGEMENT OF
OSTEOPOROSIS

Menopause is a time to reassess an individual woman’s health and risk status and to develop a personalized healthcare strategy. Protocols for the prevention of postmenopausal heart disease and osteoporosis are not yet precisely defined. Lifestyle modifications and pharmacologic intervention can modulate postmenopausal health risks, however.

Pharmacists who are well informed about current options for postmenopausal health management are in a unique position to enhance the well-being of older women. By increasing acceptance and promoting appropriate use of prescribed medications, pharmacists can help improve therapeutic outcomes and minimize the potential for adverse events. The ultimate goal is to give older women the tools to protect their long-term health so that they can remain active and independent during the decades that follow menopause.

Diet and exercise are important components of the management plan. It is important for patients to understand, however, that dietary supplements (eg, calcium and vitamin D) and exercise alone are insufficient preventive therapy for many women after menopause but should be part of a prevention program, even for women on medication.

Diet

The results of clinical trials suggest that calcium supplementation may help prevent hip and vertebral fractures in the elderly.²¹ Nutritional factors have a significant influence on the cause of osteoporosis.²¹ However, calcium supplementation alone cannot prevent or reverse all bone loss related to estrogen deficiency, and adequate calcium intake is vital to maintaining bone density.²²

Unfortunately, most women obtain insufficient calcium from their diet, especially if they are restricting calories to control weight. According to the National Institutes of Health (NIH), the average woman consumes one-half or less of the recommended daily allowance of calcium (see Supplemental Insert, Identifying Patients Who Need Calcium Supplementation).⁴ Responding to this challenge, in June 1994, a NIH Consensus Conference on Optimal Calcium Intake proposed the calcium intakes at various stages of life (see Table 2-1).^21,23,24

Table 2-1
Optimal Calcium Intake -- Recommended Dietary Allowances (RDA)

Table 2-1

Exercise

The bulk of bone mass is built in young adulthood, but regular, moderate weight-bearing exercise can help maintain or increase bone mass at any age.²² Even elderly, frail people may respond to exercise therapy. The type, duration, and style of exercise that yields such benefits is still being determined. Brisk walking is a particularly appropriate exercise that is well accepted by many older women. Walking more than 7.5 miles a week has been found to produce higher bone densities than walking less than 1 mile per week.⁷ Swimming has aerobic benefits that strengthen the heart, lungs, and major muscles of the body and promote overall fitness, but it does not provide the stress and gravitational force on long bones necessary to build bone mass. Still, the other effects of swimming can improve balance and coordination and therefore reduce falling risk, a major precipitant of osteoporotic fracture. Naturally, patients who undertake an exercise program must be cautioned to avoid activities with increased risk for falls or spinal stress that could result in fractures. Furthermore, healthcare professionals should not recommend exercise to women after menopause if the risk of such exercise to women with known or undiagnosed coronary artery disease (CAD) is unknown. Patients should always be evaluated by a physician before beginning any exercise program.

Nontraditional Measures

A variety of nontraditional measures, such as relaxation techniques, special diets, and herbal remedies, have been promoted for relief of menopausal symptoms. In particular, advocates assert that a soy-rich diet can relieve hot flashes during menopause, prevent osteoporosis, and improve the ratio of high-density lipoprotein to low-density lipoprotein cholesterol in the blood. These benefits are attributed to soy’s high levels of phytoestrogens, which are chemically very similar to estrogen.

Many phytoestrogens with mixed estrogen agonist and antagonist properties have been identified.²⁹ A wide variety of commonly consumed foods contain different phytoestrogens, including parsley, garlic, soybeans, wheat, dates, and coffee. Some of the isoflavonoids, a class of compounds derived from soybean-based foods, also produce estrogen-like activity. Additionally, many herbs have estrogen-receptor binding properties; the most common are soy, thyme, and red clover. Although these compounds have gained widespread use, optimal dose and potential adverse effects remain unknown. Long-term studies in a controlled setting are necessary to assess efficacy and risk. Thus, the pharmacist should not recommend these therapies until controlled studies assess their efficacy and risk.

Section III

HORMONE REPLACEMENT THERAPY

Until recently, pharmacologic options for the management of perimenopausal and postmenopausal signs and symptoms have been dominated by HRT, with either estrogen alone or estrogen plus a progestin.

The choice of type of HRT is determined primarily by whether or not a woman has undergone hysterectomy. Because of the risk of endometrial cancer, unopposed estrogen is recommended only for postmenopausal women without a uterus.^30,31 Women with an intact uterus may be given medroxyprogesterone acetate (5–10 mg daily) during the last 10 to 12 days of their cycle. Other progestins used in cyclic therapy (daily estrogen and progestin 12–14 days per month) include norethindrone (2.5 mg), norgestrel (150 µg), or micronized oral progesterone (300 mg). Such cyclic regimens can result in the return of regular periods, however, which may be objectionable to some women. These women may elect to follow an alternative regimen—standard continuous HRT—which does not cause menstrual bleeding. This regimen involves the daily administration of both estrogen and progestin.⁷

In recent years, several prospective trials of HRT in postmenopausal women have been carried out. For example, the multicenter, randomized, placebo-controlled Postmenopausal Estrogen/Progestin Interventions (PEPI) trial has assessed differences between placebo, unopposed estrogen, and estrogen/progestin regimens on selected heart disease risk factors and bone density in healthy postmenopausal women,³⁰ but was not large enough to assess cardiovascular outcomes or fractures. The Randomized Heart and Estrogen/Progestin Replacement Study (HERS) trial has examined whether estrogen plus progestin therapy alters the risk for coronary heart disease in women after menopause with established coronary artery disease (secondary prophylaxis).³² The ongoing Women’s Health Initiative, including a large, randomized trial of estrogen in healthy postmenopausal women, is likely to help answer many of the unanswered questions about estrogen therapy. These and other more recent studies will be discussed in more detail later on in this section.

Types and Formulations of Estrogens and Progestins

The three principal natural human estrogens are estradiol, estrone, and estriol (which is important only during pregnancy). Since these endogenous estrogens are rapidly inactivated in the liver, several forms of chemically modified natural estrogens (semisynthetic or conjugated estrogens) and synthetic estrogens have been developed for a variety of therapeutic uses (see Table 3-1).^33,34

Many different types and formulations of estrogens and progestins are available specifically for postmenopausal HRT. Oral preparations are the most commonly prescribed, but implants, vaginal suppositories, vaginal rings, transdermal patches, and vaginal creams may also be used. These non-oral preparations are especially useful in patients who do not tolerate oral therapy well or for whom the hepatic effects of HRT must be reduced (eg, patients with liver disease).^35,36 Although estrogen is well absorbed systemically through the vaginal mucosa or skin, non-oral formulations do not appear to confer the benefits of oral estrogen on LDL-cholesterol and HDL-cholesterol, presumably because they do not undergo first-pass hepatic metabolism, and they are usually not as well absorbed vaginally after keratinization occurs.^37,39 These benefits are realized for other symptoms of menopause (eg, hot flashes, vaginal atrophy), as exemplified by the patches that are FDA approved for these indications. Recent evidence suggests, however, that transdermal estrogen may equal oral estrogen in terms of cardioprotective benefits and is of particular benefit for women with hypertriglyceridemia.³⁹

Indications for HRT

In addition to its beneficial effects for acute menopausal symptoms, substantial evidence indicates that HRT prevents the development of osteoporosis and may reduce the risk of cardiovascular disease in women after menopause who do not have established CAD (primary prophylaxis).^8,30,40,41 HRT may be limited by side effects such as withdrawal vaginal bleeding if cyclical progestins are administered, as well as the potential risk of breast cancer. In recent years, a great deal of evidence has accumulated regarding the potential association between HRT and breast and endometrial cancer. A review published in 1998 of meta-analyses of clinical trials indicated an increased risk of breast cancer in current users, with relative risks ranging from 1.20 to 1.63.¹ At present, the debate continues among healthcare providers over whether HRT should be used on a short-term or long-term basis.⁴¹ Some studies have indicated that adding progestins to estrogen reduces the risk of endometrial cancer, although epidemiological evidence suggests that the risk is not completely eliminated.^7,42

Osteoporosis

HRT (estrogen alone or with progestin in women with an intact uterus) helps prevent osteoporosis through two mechanisms. First, it induces a transient increase in bone mass during the initial stage of therapy, most prominently at sites of high bone turnover, such as the spine. Second, it provides continuous protection against further bone loss.^43,44 Table 3-2 lists the minimum daily dose of various forms of estrogen for the prevention of postmenopausal bone loss.

A recent large clinical study showed that bone mineral density increased, on average, up to 5% in the spine and 1.7% in the hip in women taking postmenopausal HRT over 36 months.⁴⁵ Women who were assigned to active regimens had significantly greater changes of BMD than those assigned to placebo. Clinical trial data support the concept that prescribed estrogen reduces the risk of vertebral fractures;³⁵ however, there are no clinical trial data that prove that prescribed estrogen reduces the risk of hip or other non-spine fracture. Clinically, women who receive long-term HRT have about a 50% decreased incidence of arm and hip fracture.³⁷ Prevention of fractures, especially hip fractures, has a profound impact on public health in terms of decreased morbidity, mortality, and the economic costs of healthcare, as well as improved quality of life for patients.²⁵

The beneficial effects of estrogen on the skeleton are dose dependent and are seen only while therapy is continued (see Figure 3-1).¹³ Thus, treatment must be maintained long term in order to sustain estrogen’s positive metabolic effects on bone. In addition to its preventive role, HRT is effective in treating women with established osteoporosis.^25,37 HRT may increase spinal bone mass by more than 5% and decrease the incidence of vertebral fracture by 50%.²²

^{Figure 3.1

Rate of Bone Loss in Postmenopausal Women

When HRT is Discontinued}⁽⁴⁶⁾

Figure 3-1. Estimated bone density by age in women who never used estrogen (never-users: n), those who used continuously beginning at menopause (presumed to occur at age 50) (continuous-users: n), and those who began at menopause and stopped at age 65 (early-users: n).

Cardiovascular Disease

Heart disease represents the most frequent cause of death for women over the age of 60.⁴⁷ Factors that can contribute to the development of cardiovascular disease in women after menopause include hypertension, diabetes, and smoking, as well as age, family history, poor lipid profile, obesity, and hormonal changes (decreased endogenous estrogen levels). Surgical menopause (hysterectomy) increases the risk of cardiovascular disease, and it is thought that natural menopause may do so as well.⁴⁸

Numerous studies have demonstrated that postmenopausal estrogen replacement is associated with a reduced incidence of coronary heart disease.⁴⁷ Observational data provide substantial support for the magnitude of the cardioprotective effects of estrogen. Evidence from more than 30 epidemiological studies suggests a 35–50% decrease in the incidence of initial coronary events with HRT.⁴⁷

Estrogen acts on the cardiovascular system by at least two different mechanisms—positive effects on serum lipid profile, and direct actions on blood vessels.⁴⁷ Estrogen may protect against heart disease by modulating postmenopausal changes in the blood lipid profile which favor the development of atherosclerosis (see Figure 3-2). Estrogen promotes cholesterol turnover in the liver, raising serum levels of HDL-cholesterol while decreasing levels of LDL-cholesterol.⁴⁸ Approximately 25% of estrogen’s cardioprotective effect is a result of increasing HDL-cholesterol levels, decreasing LDL-cholesterol levels, and decreasing vascular uptake of LDL.^47,49 In addition, postmenopausal estrogen replacement therapy lowers serum levels of lipoprotein (a), a special class of LDL-related particles that are a strong independent risk factor for coronary heart disease.^38,47,50 Results from the large, multicenter, randomized PEPI trial support the claim that estrogen decreases LDL-cholesterol and raises HDL-cholesterol levels in postmenopausal women.³⁰

The remaining cardioprotective effect of estrogen is believed to result from lipid-independent effects on the heart and blood vessels, including benefits in vascular function, oxidative status, endothelial-dependent vasodilation, intimal hyperplasia, and insulin sensitivity.^47,51 Since transdermal estrogen bypasses the liver, it is believed to exert its cardioprotective effects through these non-lipid mechanisms.⁴⁷ There has been some concern that adding progestin to the HRT regimen might negate estrogen’s cardioprotective benefits, specifically by blunting its effects on blood lipids. Recent studies indicate, however, that both unopposed estrogen and combined estrogen plus progestin therapy have a favorable overall effect on lipid levels and cardiovascular risk.^8,30,52,53

The PEPI trial found that while concomitant use of medroxyprogesterone acetate (MPA) with estrogen blunted the increase in HDL-cholesterol, it did not effect the reduction in LDL-cholesterol.³⁰ Moreover, micronized progesterone exerted less of a negative effect on HDL than MPA. A follow-up to the Nurses Health Study reported a marked decrease in the risk of cardiovascular events with HRT, regardless of the presence of a progestin.⁸ It is important to recognize, however, that these are results of a retrospective, nonrandomized trial. Some studies have also shown that HRT protects against stroke,⁵³ but others have not shown this protective effect.^53,54 The public health implications of these findings are significant, especially considering the large number of women who do not receive postmenopausal HRT. The findings of the HERS trial, the only clinical trial of heart disease outcomes with estrogen therapy, however, do not show a protective effect of continuous combined HRT against heart disease in women with prior known heart disease.³²

Limitations of HRT

As noted earlier, women may prematurely discontinue use of HRT (estrogen-only and combined estrogen plus progestin regimens) because of side effects (see Table 3-3).^15,17,55 Some of these effects abate with continued therapy or may be reduced by changes in the dosing regimen, route of administration, or active components of therapy. Some women also complain of bloating, edema, and weight gain.

Table 3-3
Common Side Effects of HRT*^15,18,55

	Breakthrough bleeding (with continuous combined HRT for approximately 10 months of therapy)
	Monthly bleeding (with cyclical combined HRT)
	Vaginal irritation and secretions (other than bleeding)
	Breast tenderness
	Gastrointestinal effects (eg, nausea, vomiting, abdominal cramps)
	Local skin irritation (from estrogen patch or gel)
	Headaches * Other reported side effects that do not occur more frequently than with placebo include bloating, edema, and weight gain. More serious but rare complications of HRT include hepatic dysfunction, hypertension, thromboembolic complications, and gallbladder disease.

Endometrial Cancer

Because estrogen stimulates growth of the cells lining the uterus, prolonged exposure to exogenous estrogens is associated with an increased risk for endometrial hyperplasia, whereby the number and size of endometrial cells increase but their normal form and function are maintained. This overgrowth is often a precursor to endometrial cancer.^31,55

The PEPI trial that examined the effects of HRT on endometrial histology in postmenopausal women found that women assigned estrogen alone were more likely to develop simple (cystic), complex (adenomatous), or atypical hyperplasia than were those given placebo (27.7% vs. 0.8%, 22.7% vs. 0.8%, 11.8% vs. 0%, respectively) for the same type of hyperplasia (p < 0.001). The women in the study were randomized and stratified in equal numbers to one of the following treatments in 28-day cycles: placebo, 0.625 mg/d of conjugated equine estrogens (CEE), 0.625 mg/d of CEE plus 10 mg/d of medroxyprogesterone acetate (MPA) for the first 12 days, 0.625 mg/d of CEE plus 2.5 mg/d of MPA, or 0.625 mg/d of CEE plus 200 mg/d of micronized progesterone (MP) for the first 12 days. The study found that combining CEE with cyclic or continuous MPA or cyclic MP protected the endometrium from hyperplastic changes associated with estrogen only therapy.⁵⁶

Unopposed estrogen replacement therapy increases two to eight times the incidence of endometrial cancer in postmenopausal women who have not undergone hysterectomy.⁵⁷ Progestins counteract the proliferative effects of estrogen and substantially reduce the risk of endometrial cancer.³¹ Women who are receiving estrogen and have an intact uterus should also be prescribed some form of progestin.^57,58 The most common progestin regimens are continuous or cyclic. Continuous therapy is initiated first, since between 60 and 80% of women are amenorrheic 6 to 12 months after starting therapy, and fewer women will have hyperplasia.⁷ Until then, however, random spotting and bleeding are likely.⁷ Healthcare professionals should be sure to counsel their patients about these effects.

Breast Cancer

Some studies suggest that long-term exposure to exogenous postmenopausal estrogen may increase the risk of breast cancer, while others do not show an increased risk.⁵⁷ Among women who have ever used HRT, some analyses reveal no apparent increased risk of breast cancer.¹ One collaborative reanalysis published in 1997, however, reported an increased relative risk of breast cancer among women who currently use or who ceased use of HRT 1 to 4 years previously by a factor of 1.023 (95% CI 1.011–1.036) for each year of use. The relative risk was 1.35 (1.21–1.49) for women who had used HRT for 5 years or longer. The average use in this group was 11 years.⁵⁹ The collaborative reanalysis found that among current users of estrogens, the relative risk of diagnosis of breast cancer increased by 2.3% each year following 5 years of use of unopposed estrogen. The cumulative excess number of diagnosed breast cancers that would occur after 15 to 20 years of therapy would be 1 additional woman for every 100 receiving estrogen.⁵⁹

In the Nurse’s Health Study, a 16-year follow-up also showed that estrogen therapy (with or without progestin) increased the risk of breast cancer, particularly in older women who had been taking HRT for 5 years or more (relative risk is 1.71; 95% CI 1.34–2.18).⁶ Of course, it is important to remember that this study is an observational study, which was not developed with the objective of determining the risk of breast cancer with HRT. Results of this study still need to be confirmed with controlled studies.

While there is some conflicting evidence, overall, a review of meta-analyses of clinical trials suggests that current users of HRT or ERT have an increased risk of breast cancer, with relative risks ranging from 1.20 to 1.63.¹ Recent data from the Iowa Women’s Health Study show, however, that breast cancers occurring in women on HRT are of overall lower malignant potential than in those women not on HRT.⁶¹

Venous Thrombotic Disorders

There is a well-known association between oral contraceptives and venous thrombotic disorders, but until recently the risk was not believed to apply to postmenopausal estrogen replacement. Several reports published in 1996, however, suggest that the risk of venous thromboembolism is increased by two to four times with both unopposed estrogen and combination estrogen/progestin therapy.^62,63,64 Although the number of cases of venous thrombotic events attributable to HRT is likely to remain quite low, other risk factors for venous thrombosis (eg, previous history/family history, gross obesity, recent surgery, and thrombophitic disorders) should be considered in the individual risk-benefit assessment of HRT.^28,63 This association was proven in the HERS trial.

Refer to Important Patient Information about HRT for further points for pharmacists to consider during patient counseling.

Section IV

OSTEOPOROSIS-SPECIFIC THERAPY

Until 1997, HRT (either estrogen alone or estrogen plus progestin) was the only widely accepted therapy approved for the prevention and treatment of osteoporosis in the United States.⁶⁵

Non-HRT pharmacologic treatments used in the clinical management of osteoporosis can be broadly classified as either inhibitors of bone resorption or stimulators of bone formation (see Table 4-1).

Clinical Effects of Alendronate (Fosamax®)

Bone normally is in a state of equilibrium; it is constantly resorbed and synthesized in a continual process of repair and regeneration called remodeling, which occurs on bone surfaces. Osteoclasts and osteoblasts work in a synchronized fashion (coupling) and are responsible for the remodeling process.⁷ Bisphosphonates are synthetic pyrophosphate analogs that inhibit bone resorption by adhering to bone at activation sites, where they become embedded in bone matrix during remodeling.^67,68 Alendronate has been shown to increase bone mass significantly and to decrease the incidence of new spinal fractures (see Figure 4-1).^68,69 In a randomized placebo-controlled trial of alendronate (Fosamax®) in women between the ages of 55 and 81 who had been postmenopausal for at least 2 years and had low femoral neck BMD (0.68 g/cm2 or less) and the presence or absence of a vertebral fracture, the risk of new radiographic vertebral fractures was found to be 47% lower in women given alendronate compared with placebo.⁶⁹ These women were initially treated with alendronate 5 mg/d and were then increased to 10 mg/d at 24 months. Furthermore, alendronate treatment reduces the risk of hip, forearm, and other non-spine fractures by approximately 50%.⁶⁹

Direct chemical irritation of the esophagus with alendronate (Fosamax®) may result in severe esophagitis, which can progress to serious esophageal ulceration.⁷⁰ Patients receiving alendronate should be counseled to take it with 6 to 8 ounces of plain water (no carbonated water, milk, or juice) and to avoid lying down for at least 30 minutes afterwards to avoid esophageal irritation. In addition, since food and drink impair absorption of alendronate, it must be taken at least 30 minutes before the first meal of the day, which can be problematic for some patients.^69,71

Refer to Important Patient Information about Alendronate (Fosamax) for further issues for pharmacists to consider during patient counseling.

Clinical Effects of Calcitonin

The peptide hormone calcitonin reduces the rate of bone loss after menopause and may reduce vertebral fracture risk by approximately 35% without affecting the risk of other fractures significantly.^25,72

Until recently, calcitonin could be administered only by injection. In the United States, injectable calcitonin was approved for use in the treatment of postmenopausal osteoporosis in 1984.⁷³ Delivery of calcitonin by nasal spray [calcitonin-salmon (Miacalcin®)] was subsequently approved in 1995. Troublesome side effects of parenteral calcitonin include hot flashes, vomiting, diarrhea, and pain at the injection site. The availability of calcitonin in a nasal spray formulation improves its acceptability and results in a great reduction in side effects. Because it has analgesic properties, calcitonin may be especially useful for osteoporotic patients with bone pain.²⁵ However, some trials with continuous administration over 2 years have found the bone density effect to plateau or decrease after 12 to 18 months (tachyphylaxis). To overcome such resistance, intermittent therapy—such as 50 IU intranasally 5 times per week for 3 months, followed by no treatment for 1 month—is being investigated.⁷

Each bottle of calcitonin-salmon nasal spray (Miacalcin®) contains enough active medication for 14 daily doses. The spray must be refrigerated until it is opened. Once opened, it may be stored at room temperature, capped, while in use, for up to 4 weeks. Only one spray should be administered each day, alternating nostrils daily to prevent nasal irritation.³³

Clinical Effects of Other Agents

At therapeutic concentrations, fluoride produces significant increases in skeletal mass by stimulating bone formation.^35,74 Fluoride has not won wide clinical acceptance as a treatment for osteoporosis, however, in part because of the potentially inferior quality of the bone it produces and the lack of consistent evidence that fluoride reduces the risk of vertebral or nonvertebral fractures.^22,75,76 Thus, fluoride is usually given together with calcium to minimize possible negative effects on mineralization and bone resorption. Side effects—including gastrointestinal disturbance and joint and bone pain—are common but usually transient. Many patients find it difficult to tolerate fluoride treatment due to high incidence of adverse effects.⁷⁶

Anabolic steroids also increase bone mass, especially at cortical sites, presumably by interacting with androgen receptors on bone cells, but it is not clear whether they reduce the incidence of fracture. Their adverse effects (eg, virilization, hepatotoxicity, increased muscle mass, adverse effects on blood lipids) have limited their clinical utility.²² Bone formation also may be stimulated by intermittent low doses of parathyroid hormone, which has been shown in clinical trials to moderately or dramatically increase spinal bone mineral density in postmenopausal women and may be associated with a reduction in vertebral fracture occurrence.²²

Section V

NEWER OPTIONS IN
MAINTAINING HEALTH AFTER MENOPAUSE

An understanding of estrogen’s beneficial effects has led to a search for drugs that turn on selected estrogen-regulated genes while turning off others (see Boxed Insert, Estrogens and Gene Expression). The goal of such targeted pharmacotherapy is to counteract the loss of the hormone’s positive effects in appropriate tissues without inducing undesirable estrogen-stimulated effects in other tissues. This research has led to the development of a class of drugs, the selective estrogen receptor modulators (SERMs) that show promise for treatment of postmenopausal conditions caused by estrogen deficiency.⁶⁷

Estrogens and Gene Expression

Understanding how estrogens and estrogen-like compounds affect gene expression is the first step in designing an ideal therapeutic strategy for the management of the adverse consequences of postmenopausal estrogen deficiency. The functional effects of estrogens are complex and are dictated by the type of target tissue. In certain tissues, they may increase the synthesis of some proteins while decreasing the synthesis of others, or they may enhance some cellular functions and suppress others. Consequently, estrogens may have completely different metabolic effects in different parts of the body.

Estrogen binds to receptor molecules to form estrogen/estrogen-receptor complexes. These complexes are attracted to specific sites within the DNA which are responsible for turning genes on or off, allowing the complexes to alter gene expression in the intracellular DNA. Thus, estrogen can affect protein synthesis by influencing the chemical processes of transcription (synthesis of a messenger RNA bearing the genetic information that defines a protein’s amino acid sequence) and translation (reading the messenger RNA’s genetic information to synthesize the polypeptide or protein it specifies).

As the name implies, SERMs have both agonistic and antagonistic effects on estrogen receptors.⁷⁷ Tamoxifen, which is available for the treatment of breast cancer, is considered a first-generation SERM. Although originally developed as a nonsteroidal antiestrogen, tamoxifen produces beneficial estrogen-like effects in bone and serum lipids.^77,78 Since it also acts on estrogen receptors in the uterus, however, tamoxifen’s potential for promoting uterine cancer is similar to that of unopposed estrogen.^77,78

The second-generation SERMs, exemplified by raloxifene hydrochloride (marketed by Eli Lilly and Company as Evista® and approved by the FDA for the prevention and treatment of osteoporosis in postmenopausal women), are designed to address this concern with greater selectivity of estrogenic effects in target tissues.⁶⁷ These second-generation SERMs appear to produce estrogen-like effects in one or more desired organ systems, such as bone or liver, without affecting reproductive tissues, such as the breast or uterus.

Clinical Effects of Raloxifene (Evista®)

The biological actions of raloxifene, like those of estrogen, are mediated through binding to estrogen receptors. Preclinical data demonstrate that raloxifene is an estrogen antagonist in uterine and breast tissue.⁷⁹ In bone tissue and serum lipids, however, it acts as an estrogen agonist.⁷⁷

Clinical trials with raloxifene indicate that it increases bone mineral density and improves the serum lipid profile by decreasing total and LDL cholesterol levels, though not to the same degree as estrogen.^80,81,82,83 Clinical data suggest, however, that raloxifene lacks antiproliferative effects on the breast and does not stimulate endometrial growth.⁸⁴ Thus, raloxifene provides an important new option for postmenopausal therapy.

Bone Turnover and Mineral Density

Like estrogen, raloxifene acts as a skeletal antiresorptive agent. Raloxifene decreases bone loss by reducing resorption of bone and thus decreasing overall bone turnover (ie, by decreasing osteoclastic activity in the bone remodeling process).⁸⁰ These effects on bone can be evaluated in clinical trials by measuring reductions in the serum and urine levels of markers of bone turnover (eg, serum bone alkaline phosphatase), by determining reduction of bone resorption in radiocalcium studies, and by measuring increases in BMD. These values, however, have little relevance clinically where the primary outcome for an osteoporosis study should be decreased fracture rate.

A 1-year prospective, randomized, double-blind trial of raloxifene in 143 postmenopausal osteoporotic women with vertebral fractures and low BMD found significant improvement in several markers of bone turnover (see Figure 5-1).⁸⁴ Compared with controls (no drug), women receiving raloxifene 60 mg daily had a significant decrease in the levels of serum bone alkaline phosphatase (-14.9%), serum osteocalcin (-20.7%), and urinary C-telopeptide fragment of type I collagen/creatinine (-24.9%). All of the women in the study received supplemental calcium and vitamin D. The study concluded that raloxifene is well tolerated, reduces serum lipids, and does not stimulate the uterus or breasts. The study also found a relationship between raloxifene and beneficial effects on bone.⁸⁴

Similarly, results published in 1999 from the 3-year randomized Multiple Outcomes of Raloxifene Evaluation (MORE) trial in over 7,700 postmenopausal osteoporotic women indicated that serum osteocalcin concentrations decreased by a median of 26.3%, and urinary C-telopeptide excretion decreased by 34.0% in patients receiving raloxifene 60 mg/day.⁸⁵ All participants also received supplemental calcium (500 mg/day) and cholecalciferol (400 to 600 IU/day).

Interim reports (at 24 months) of three large double-blind, placebo-controlled trials enrolling a total of more than 1,764 postmenopausal women have demonstrated that daily raloxifene preserves bone mass and increases BMD relative to calcium alone (see Figure 5-2).⁷⁹ In the 1-year randomized trial described above, BMD increased significantly in the total hip (1.66%) for women receiving raloxifene 60 mg/day compared to control, and in the ultradistal radius (2.92%) for those receiving 60 mg/day.⁸⁴ Nonsignificant trends toward increased BMD for lumbar spine, total body, and total hip were also apparent. Similarly, the MORE trial found that raloxifene 60 mg/day, significantly increased BMD in the femoral neck by 2.1% and in the spine by 2.6%.⁸⁵ Together, these trials suggest that raloxifene is of value in the treatment of osteoporosis in women after menopause.

Lipid Metabolism and Clotting Factors

Raloxifene has also been shown to exert a beneficial effect on lipid profiles in both animal and human studies.^77,80 Specifically, raloxifene has been shown to reduce total and LDL-cholesterol concentrations similar to that of estrogen therapy, although HDL-cholesterol and triglyceride concentrations do not increase during raloxifene therapy. Raloxifene had a smaller effect than estrogen on lipoprotein (a), however.⁸⁶

A 6-month study of 390 postmenopausal women comparing raloxifene (60 mg once daily) with oral continuous combined estrogen/ progestin HRT (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) and placebo demonstrated a variety of favorable effects on selected lipid fractions and clotting factors.⁸⁷ Raloxifene decreased serum total and LDL-cholesterol without effects on serum total HDL-cholesterol or triglycerides. In addition, raloxifene significantly decreased serum fibrinogen and lipoprotein (a) when compared to placebo.⁸⁷

Serum total cholesterol and LDL-cholesterol decreased significantly in patients receiving raloxifene 60 mg/day compared to controls.⁸⁴ The LDL/HDL ratio also decreased significantly. Specifically, there was a 7.0% decrease in serum total cholesterol in patients given raloxifene 60 mg/day compared to controls, and a 13.2% decrease in the LDL/HDL cholesterol ratio in patients receiving raloxifene 60 mg/day. The HDL-cholesterol and triglyceride levels were not significantly altered.

In another trial, similar favorable effects on the lipid profile were observed after 24 months of treatment.⁸² Raloxifene significantly decreased serum total and LDL cholesterol by approximately 5% and 8%, respectively, without adversely affecting HDL cholesterol or triglycerides.⁷⁹ While these effects are expected to reduce the occurrence of atherosclerotic disease, no outcome data are yet available. In addition, the effects of raloxifene on coronary artery disease prevention and mortality have not yet been studied.

Refer to Important Patient Information About Raloxifene for specific points to consider during patient counseling.

Treatment of Osteoporosis

Overall, the results from recent prospective randomized trials indicate that treatment with raloxifene preserves bone density, reduces bone turnover, and reduces the incidence of vertebral fractures in women with osteoporosis following menopause.^84,85

Recent prospective randomized trials have confirmed that raloxifene has a beneficial effect on fracture risk.^84,85 The 1-year randomized trial described earlier found a significant dose-related reduction in incident (new) vertebral fractures (defined as >30% decrease in vertical height in same vertebra between baseline and 1 year).⁸⁴ Similarly, the 3-year MORE trial, which included 7,705 women who were at least 2 years postmenopausal and had no severe or long-term disabling conditions but had osteoporosis, defined as low BMD or radiographically apparent vertebral fractures, showed that the risk of vertebral fracture was reduced in patients receiving 60 mg/day raloxifene.⁸⁵ For those receiving raloxifene 60 mg/day, the relative risk was 0.7 (95% CI, 0.5–0.8), indicating a 30% reduction in the risk of vertebral fracture in those women with preexisting fractures. The relative risk was 0.5, indicating a 50% reduction in the risk of vertebral fracture in those women without preexisting fractures. This study also showed that women receiving raloxifene had fewer new vertebral fractures, regardless of whether they had existing fractures at the beginning of the study (Figure 5-3).⁸⁵

Pharmacokinetics ⁸⁵

No differences in raloxifene pharmacokinetics have been detected with regard to the woman’s age (range 42 to 84 years) or race. Raloxifene is absorbed rapidly after oral administration and can be given without regard to meals. Concurrent administration of calcium carbonate or aluminum and magnesium hydroxide-containing antacids does not affect the systemic exposure of raloxifene. Raloxifene undergoes extensive first-pass metabolism to glucuronide conjugates, but no other metabolites have been detected, indicating that it is not metabolized by cytochrome P450 pathways. Its plasma elimination half-life is 27.7 hours after oral dosing. Clearance ranges from 40 to 60 L/kg-hr following chronic dosing. Raloxifene is primarily excreted in feces, and less than 0.2% is excreted unchanged in urine. Less than 6% of the raloxifene dose is eliminated in urine as glucuronide conjugates. Raloxifene exhibits high within-subject variability of most pharmacokinetic parameters. For example, increased plasma raloxifene concentrations (approximately 2.5 higher than in controls) have been found in patients with mild hepatic dysfunction, but safety and efficacy have not been evaluated further in patients with hepatic insufficiency.

Safety and Tolerability

Raloxifene has been shown to be well tolerated in a variety of clinical trials lasting from 2 to 30 months.^80,82 The majority of adverse events occurring during the clinical trials of raloxifene were mild and tolerable; they generally did not require discontinuation of therapy. Overall, 11.4% of 581 women treated with raloxifene and 12.2% of 584 women treated with placebo discontinued therapy due to an adverse event.⁷⁹

Common adverse events considered to be drug-related were hot flashes (24.6% for raloxifene; 18.3% for placebo) and leg cramps (5.9% for raloxifene; 1.9% for placebo). When hot flashes were experienced, they typically occurred shortly after the initiation of therapy (ie, during the first 6 months of treatment). Discontinuation rates due to hot flashes did not differ significantly between raloxifene and placebo groups (1.7% and 2.2%, respectively).⁷⁹

A study published in 1999, which pooled data from 8 randomized clinical trials (6–30 months’ duration) of raloxifene in women following menopause, found a significant increase in hot flashes with raloxifene, but this event did not increase discontinuation rates.⁸⁸ The increased incidence of new hot flashes among raloxifene-treated patients in the placebo-controlled studies was observed during the first 6 months. After 6 months, however, the incidence of new hot flashes was not significantly different. Furthermore, the increase was small (about 7 of 100 women treated) compared with the placebo group, and the hot flashes were mild to moderate.⁸⁸

No stimulatory effect of raloxifene on the endometrium has been detected even when given at more than twice the recommended dose.^80,82 Raloxifene is indistinguishable from placebo with regard to frequency or severity of breast pain and tenderness. The incidence of estrogen-dependent cancers of the endometrium and breast is being evaluated across all completed and ongoing raloxifene clinical trials.

The recently published MORE trial indicated that raloxifene reduced the risk of invasive breast cancer by 76% during 3 years of treatment of women with osteoporosis following menopause.⁸⁹ To prevent one case of breast cancer, 126 women would need to be treated. This benefit was attributable to a 90% reduction in the risk of estrogen receptor-positive breast cancer. There was no apparent decrease in the risk of estrogen receptor-negative invasive breast cancer. These results support the concept that raloxifene acts by interacting with estrogen receptors in the breast to competitively inhibit estrogen-induced DNA transcription. The study was not designed or powered to examine the effects of raloxifene on endometrial cancer.⁸⁵

Placebo-controlled clinical trials of raloxifene have indicated an increased risk of venous thromboembolic events (ie, deep vein thrombosis, pulmonary embolism, retinal vein thrombosis) versus placebo.⁸⁵ In the MORE trial, a higher rate of deep venous thrombosis (0.7%) and pulmonary embolism (0.3%) was shown in the combined raloxifene groups than in the placebo group (0.2% and 0.1%, respectively) at 40 months follow-up.⁸⁹ One case of venous thromboembolism occurred per 155 women treated with raloxifene for 3 years. Although the risk of venous thromboembolic disease was 3.1 times higher in women assigned raloxifene than placebo, this risk compares favorably to the relative risk reported for oral contraceptives (4 to 11 for deep vein thrombosis or pulmonary embolism compared to oral contraceptive nonusers).²⁸

Drug Interactions ⁷⁹

Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with it. Concurrent use of raloxifene and other agents that lower serum lipid levels has not been studied, but the lipid-lowering effects of raloxifene should be taken into account for patients receiving therapy for hyperlipidemia. Prothrombin time should be monitored if raloxifene is given concurrently with warfarin. Single-dose studies have shown 10% decreases in prothrombin time, although the coadministration of raloxifene and warfarin has not been assessed under chronic conditions.

The concurrent use of raloxifene and systemic estrogen or estrogen plus progestin has not been studied in prospective clinical trials; therefore, concomitant use of raloxifene with systemic estrogen is not recommended. Raloxifene is more than 95% bound to plasma proteins.⁷⁹ Therefore, caution should be used when raloxifene is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, ibuprofen, diazepam, and diazoxide.

Section VI

COUNSELING STRATEGIES TO IMPROVE PATIENT COMPLIANCE

In order to counsel patients effectively about health after menopause, pharmacists must be well-informed about the pathophysiologic effects of menopausal estrogen depletion as well as the strategies used for management of postmenopausal health problems.

In addition, pharmacists must have excellent communication skills and be able to implement a strategy for providing patients with balanced information about the efficacy and safety of specific therapeutic regimens.⁹⁰

Effective pharmaceutical care has two primary goals:⁹⁰

	reduction of disease-related morbidity and mortality; and
	reduction of drug-related morbidity and mortality.

These goals can be achieved through the implementation of a medication counseling strategy that balances efficacy and safety—the BES method.⁹⁰ The core of this approach is the application of key communication skills, including active listening and evaluation of the patient’s understanding and acceptance of health information (see Boxed Insert, Key Communication Skills for Patient Counseling). The implementation of a balanced counseling strategy is based on the premise that providing patients with information about both the benefits and risks of the prescribed medication enhances patient outcomes.

Key Communication Skills
for Patient Counseling

Effective medication counseling demands the mastery of key communication skills, including:

• asking open-ended questions to determine what the patient knows about the condition and her beliefs about the relative risks and benefits of treatment;

• listening empathetically while the patient identifies her concerns and describes her knowledge and understanding of treatment information; and

• delivering a balanced counseling presentation that includes the benefits and risks of treatment and promotes appropriate therapeutic compliance.

An appropriate emphasis on efficacy motivates the patient to adhere to the treatment plan. At the same time, balancing the counseling session by providing the patient with information on potential adverse effects prepares her to manage them appropriately. If the possibility of adverse effects is overemphasized, the patient may decide to take less medication or fewer doses—or perhaps to abstain from taking the medication altogether. Thus, pharmacists must give fair weight to both sides of the efficacy and safety scale (see Figure 6-1).⁹⁰

^{Figure 6-1}

Five Elements of a Balanced Counseling Approach90

Effective counseling typically involves five major communication elements:

	pharmacist’s introduction
	probing and listening
	medication/drug therapy
	presentation;
	addressing patient concerns; and
	closing the counseling session.

Each of these communication elements may not be emphasized equally during each counseling session. Furthermore, although these elements may occur more or less in sequence, they may overlap or repeat.

Pharmacist’s Introduction

All effective counseling sessions begin with an appropriate introduction that involves identifying who the medication is for, establishing the purpose of the counseling session, and demonstrating the pharmacist’s credibility and empathy. Establishing the objective of counseling early in the encounter lets the patient know that the pharmacist is prepared to answer her questions and ensure that the medication is taken properly.

Probing and Listening

This portion of the counseling session should include an open-ended question to determine what the patient knows about the medication and whether she has any significant concerns that might contribute to noncompliance. By responding to any questions promptly, the pharmacist can ensure that the patient remains receptive and attentive throughout the session.

Medication/Drug Therapy Presentation

While the opening of the counseling session introduces the pharmacist to the patient, the medication/drug therapy presentation introduces the medication. At this point the pharmacist provides the name and a description of the drug. The value of this portion of the session cannot
be overemphasized.

A persuasive message about the potential therapeutic benefits of the medication is important for enhancing patient compliance. The pharmacist should be careful not to overstate product efficacy or understate the potential for side effects and drug interactions. The patient needs to understand that any drug’s therapeutic promise must be weighed against its potential risks. A balanced counseling approach also gives the pharmacist confidence about the patient’s understanding of the medication and her motivation to adhere to the therapeutic regimen.

Addressing Patient Concerns

The use of open-ended questions and active listening facilitates the dialogue between the patient and the pharmacist. By integrating probing and listening into a balanced presentation of the product’s risks and benefits, the pharmacist is able to address patient concerns as they arise. The pharmacist should respond thoughtfully to the patient’s worries. Instead of ignoring or dismissing the patient’s fears as “irrational,” the pharmacist can acknowledge their subjective validity and provide reliable information about the product’s objective risks and benefits.

Closing the Counseling Session

Once the patient’s concerns are addressed, closure allows the pharmacist to review relevant product information, such as the indication, dosage, length of treatment, refills, and storage requirements. Like the rest of the elements of the counseling encounter, the closing communication technique should be informative, supportive, and designed to influence adherence to the prescribed regimen. For example, it may be helpful to write down the refill date for the patient to reinforce the importance of compliance. This action can also demonstrate the pharmacist’s commitment to a long-term relationship with the patient.

The pharmacist’s closing comments should seal an informal behavioral contract with the patient which will lead to improved compliance. By asking the patient to confirm that she accepts the information provided in the counseling session, the pharmacist empowers the patient as a decision-maker in a healthcare partnership.

Counseling Tips for Patients on HRT

Patient counseling by pharmacists is now widely accepted as essential to promoting appropriate drug utilization in virtually every therapeutic class of medication. This is particularly true in the case of HRT, since the rate of nonadherence and discontinuation is high.¹⁴ Many women have little contact with their healthcare provider at the time of menopause, and therefore lack reliable information about the potential health risks from estrogen decline.

As previously discussed, a balanced counseling strategy is essential to improving patient compliance with any therapy. Several points are particularly relevant to counseling patients about HRT. One of the major problems with postmenopausal HRT is the patient’s fears about the perceived risks of treatment. In order to forestall compliance problems, the pharmacist should ensure that the patient understands the goals of treatment, especially the long-term benefits in terms of protection from osteoporosis and cardiovascular disease.

It is especially important to ask open-ended questions that allow the patient to air her concerns about HRT. Patients may have exaggerated fears about the risks associated with treatment based on incomplete or sensationalist media reports. A clear understanding of the relative risks based on reliable information can help the patient accurately weigh the risks and benefits for herself.

Finally, the pharmacist should encourage the patient to consult with her primary healthcare provider about any lingering questions or concerns regarding her HRT regimen. Her physician may try another approach to postmenopausal risk reduction if the patient remains uncomfortable about the use of HRT.

Counseling Tips for Patients on Alendronate (Fosamax®) and Calcitonin

Once osteoporosis has been diagnosed, several therapeutic options are available, including alendronate (Fosamax®) and calcitonin. Alendronate has emerged as an important option for the management of osteoporosis. However, dosing restrictions can make it inconvenient for some women to take, which may increase the likelihood of noncompliance. For this reason, it is especially important to balance efficacy and safety in patient counseling with alendronate so that patients adhere to a long-term treatment of osteoporosis.

During the medication presentation, the pharmacist should explain the efficacy of alendronate in reversing bone loss due to osteoporosis, pointing out that it also may help protect against future spinal fractures if taken as prescribed. The pharmacist should carefully balance this information with a discussion about the importance of taking bisphosphonates with 8 ounces of plain water (not carbonated water or beverages, juice, or milk) while standing upright to avoid esophageal irritation and to avoid ingesting any food or beverages for at least 30 minutes after administration to minimize the risk of gastrointestinal irritation.

Throughout the counseling encounter, the pharmacist should employ probing and listening techniques to elicit and address patient concerns. He or she can help the patient balance the potential inconvenience of the product’s dosing restrictions with its clinical benefits. The pharmacist should also reinforce the importance of long-term compliance by specifically stressing the need for patients to refill their medication as directed by the physician.

Several important facts related to calcitonin-salmon nasal spray (Miacalcin®) should be conveyed to patients before beginning this therapy. When putting the nasal spray pump together, first allow it to reach room temperature and do not depress the pump when it is not attached to the bottle. To ensure proper delivery of the medication, a newly opened and assembled bottle must be primed before the first use. The patient should alternate nostrils daily and wipe the nozzle with a clean, damp cloth once or twice a week. Finally, once the pump is primed, the unit must be kept at room temperature. Bottles left at room temperature (opened or unopened) for more than 30 days must be discarded.

Counseling Tips for Patients on Raloxifene (Evista®)

One of the greatest challenges to pharmacists can be providing patients with balanced information about a promising new product that represents a novel therapeutic category. In such situations, pharmacists must exercise particular caution to avoid overstating the benefits while explaining the therapeutic approach in a manner that promotes compliance. In the case of raloxifene, patients should be informed about the possibility of hot flashes during the first months of therapy. If such vasomotor symptoms occur, it may be easier for the patient to accept them if she is able to weigh the small inconvenience and discomfort they may cause against the overall safety and efficacy of the agent.

Some patients state that they are not comfortable being on HRT long-term and seek their physician’s advice on whether to continue therapy. When a physician changes a patient’s treatment from HRT to raloxifene, the pharmacist should be sure to spend extra time explaining the differences and similarities between the actions of traditional exogenous estrogen replacement and those of selective estrogen receptor modulators. It is critical to keep this conversation simple and fairly brief, based upon the patient’s level of understanding and interest.

The pharmacist should always reinforce the patient’s awareness of the value of postmenopausal preventive and treatment therapies since a patient may have been regularly using HRT for many years. The pharmacist always needs to provide a balanced evaluation of the efficacy and safety profile of raloxifene, paying particular attention to the potential for venous blood clot formation, such as stopping medication prior to any prolonged immobilization.

When ending any counseling session, the pharmacist should provide supplemental written information that can reinforce specific instructions for dosing and special precautions to ensure that the patient takes her medication appropriately. The pharmacist’s concluding comments should also seal an informal behavioral contract with the patient, helping to improve long-term patient compliance.

Section VII

SUMMARY

This is an era of rapidly increasing knowledge and understanding of health issues in general and women’s health issues in particular. Nevertheless, many women are unaware of specific health risks associated with postmenopausal estrogen deficiency.

They may attribute declines in their well-being to the inevitable consequence of aging and fail to seek therapy that could prevent disability and preserve quality of life. Other women may be offered treatment but fail to comply because they do not fully appreciate its benefits.

As medical knowledge advances, we come closer to fulfilling the ultimate goal of postmenopausal therapy: to provide optimal therapeutic benefits while minimizing the potential for adverse effects, thus allowing women to enjoy continued good health long after menopause. The growing number of options now available makes it increasingly possible to tailor treatment to the individual’s specific risk factors and health concerns.

Hormone replacement therapy has been well established for many decades as an effective treatment for acute menopausal symptoms. It also has proven benefits in prevention of two major postmenopausal health risks — osteoporosis and heart disease, although the latter has been derived primarily from observational studies and from surrogate markers. The introduction of the bisphosphonate alendronate (Fosamax®) provided an additional therapeutic option for women with established osteoporosis as well as a preventive measure for women at risk for osteoporosis. Now, the availability of selective estrogen receptor modulators, such as raloxifene (Evista®), provides a further advance in menopausal treatment. These agents may make it possible to address serious health consequences of long-term postmenopausal estrogen deficiency in target tissues, without the potential risks of long-term stimulation of reproductive tissues in the breast and uterus.

In conclusion, pharmacists have a critical opportunity to provide their patients with educational information about postmenopausal health promotion, disease prevention, and medication counseling. This information can help make the difference between optimal health and progressive disability. The frequent interactions between pharmacists and their customers provide a strong foundation for a long-term relationship of mutual trust and respect.

Since pharmacy is a service profession, there is clearly a professional benefit for pharmacists who forge a special relationship with postmenopausal patients. Through appropriate patient education and counseling, pharmacists can help protect women’s continued good health, vitality, and independence during the decades after menopause.

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[Introduction] [References]

Maintaining Postmenopausal Health