Do Estrogen or Selective Estrogen Receptor Modulators Improve Quality of Life for Women with Postmenopausal Osteoporosis? Deborah T. Gold, PhD, and Stuart L. Silverman, MD
Corresponding author Deborah T. Gold, PhD Departments of Psychiatry and Behavioral Sciences, Sociology, and Psychology; Center for the Study of Aging and Human Development, Box 3003, Duke University Medical Center, Durham, NC 27710, USA. E-mail:
[email protected] Current Osteoporosis Reports 2007, 5:3 –7 Current Medicine Group LLC ISSN 1544-1873 Copyright © 2007 by Current Medicine Group LLC
Osteoporotic fractures result in significant deficits in health-related quality of life (HRQOL). The accumulation of deficits resulting from osteoporosis and fractures is now recognized as a major cause of reduced HRQOL in women after the menopause and in later life. Some of these same postmenopausal women may also have deficits in HRQOL related to vasomotor symptoms during the menopausal transition. Although estrogen therapy has not been shown to improve overall HRQOL in late postmenopausal women in randomized, controlled trials, it may improve menopausal symptoms. In contrast, selective estrogen receptor modulators (SERMs) such as raloxifene may increase vasomotor symptoms. Although estrogen is not indicated for the primary prevention of osteoporosis, estrogen therapy may be considered for the postmenopausal woman at risk of osteoporotic fracture who is symptomatic and who is not at high risk of breast cancer or cardiovascular events. Raloxifene decreases risk of invasive breast cancer and may be considered in women at high risk of breast cancer. Decision making about osteoporosis treatment should also consider the impact of the treatment on HRQOL.
deficits in the health-related quality of life (HRQOL) of people who suffer from them. Osteoporosis is a disease that compromises overall skeletal health and can result in low-trauma fractures [1••]. Initially, many believed that osteoporosis was an unavoidable consequence of aging and that the deformity and pain associated with multiple fractures was to be expected, especially in older postmenopausal women. However, increases in knowledge about osteoporosis and improvements in diagnostic technology and pharmaceutical treatments have helped us recognize that this condition may be avoided in many cases. Thus, the accumulation of deficits resulting from osteoporosis is now recognized as a potential major cause of reduced HRQOL, along with menopausal symptoms, which start early in the menopausal transition but may persist into the seventh and eighth decade at much lower frequency [2]. Approximately 20% of women in the fifth decade have deficits in HRQOL related to menopausal symptoms. The literature on osteoporosis and quality of life (especially in the context of randomized controlled trials of osteoporosis medications) has grown substantially with data from randomized clinical trials of new classes of drugs to treat the disease (eg, bisphosphonates, parathyroid hormone). Yet little attention has been paid to the role of estrogen and selective estrogen receptor modulators (SERMs) in the discourse around HRQOL and osteoporosis. This article examines the role of osteoporosis in reduced HRQOL in postmenopausal women and considers whether pharmacotherapy with either estrogen or SERMs can mitigate the decrements in HRQOL caused by osteoporosis and fractures as well as the decrease in HRQOL related to menopausal symptoms.
Introduction
The Concept of Health-related Quality of Life and Osteoporosis
Osteoporosis has taken its place among the chronic diseases of later life (eg, hypertension, diabetes, chronic obstructive pulmonary disease) that cause substantial
In the medical literature, the term quality of life appears for the first time around 1975, in the midst of literature on older adults and euthanasia and on the ethics of letting grossly
Therapeutics
deformed children die. In those articles, the term was used to identify circumstances when extraordinary interventions should or should not be used to sustain life. Quality of life was used as the measure to determine whether continuing life was appropriate or would just perpetuate suffering. As the literature on the relationship between health and quality of life became more sophisticated, this discussion expanded, and the term was, in many cases, replaced by health-related quality of life (HRQOL). Whereas quality of life was usually defined as overall physical, financial, psychological, and social well-being, healthrelated quality of life referred specifically to the aggregate effects of disease on these life domains as perceived and evaluated by the individual. The study of the impact of osteoporosis on HRQOL presented some challenges. Early in the disease course, the disease is often asymptomatic, even when radiographic vertebral fractures are present. Without symptoms, disease impact is minimal and, if osteoporosis is undiagnosed, there is little or no effect on HRQOL [3]. As osteoporosis progresses, fractures and their cumulative outcomes quite obviously cause physical, social, and psychological distress. Therefore, it is important to measure HRQOL throughout the natural history of osteoporosis; this longitudinal perspective helps to identify when HRQOL begins to deteriorate and what specific factors are associated with this decline. Interestingly, only a few studies of HRQOL and osteoporosis identify a fifth domain, one that is especially important to a subgroup of those with postmenopausal osteoporosis: symptoms [4]. Despite a long list of instruments developed to measure disease-specific HRQOL in osteoporosis, only two explicitly address the impact of symptoms on HRQOL: the Osteoporosis Quality-of-Life Questionnaire (OQLQ) [5] and the Osteoporosis Assessment Questionnaire (OPAQ) [6]. The symptoms measured by these instruments include back pain and fatigue.
decrements associated with osteoporosis report impaired HRQOL when compared with those without physical outcomes. Fractures play a major role in this reduction in HRQOL [5,12], as does the deformity that results from multiple fractures [9•,13].
Studies of HRQOL with Osteoporosis
Virtually every study of the prevalence of osteoporosis among white women notes that postmenopausal women are at the highest risk of developing this disease and experiencing a fracture [30]. It is estimated that 40% of white women age 50 or older will experience an osteoporotic fracture during her lifetime. For many of these women, whose bone density diminishes in the years directly after the menopause, the impact of osteoporosis and fractures is profound. In a recent study using data from the National Osteoporosis Risk Assessment (NORA) database, Brenneman et al. [31•] examined SF-12 data and found that among women without fractures, the physical component score (PCS) was significantly higher for older women (P < 0.0001), and the mental component score (MCS) was significantly higher for women closer to the menopause. Specifically, women aged 50 to 64 years with fractures of the spine and ribs had significantly lower MCS
Physical outcomes
As noted, the early asymptomatic stage of osteoporosis has little or no impact on HRQOL. In fact, there appears to be no impact on HRQOL of low BMD in the absence of fractures. However, for many people, HRQOL deteriorates once disease-specific outcomes emerge. Silverman et al. [7] found that deterioration in HRQOL among postmenopausal women was strongly associated with worsening back pain. Other physical symptoms that accompany worsening postmenopausal osteoporosis, in addition to chronic pain, include deformity and height loss [8]. Such symptoms can and do occur regardless of the age of the person with osteoporosis. Studies examining the physical deterioration associated with osteoporosis are plentiful [9•,10,11]. In virtually all, participants with physical and functional
Social outcomes Deteriorating HRQOL goes far beyond the physical domain in patients with osteoporosis. The financial, social, and psychological domains deteriorate as well [14,15]. The financial costs of vertebral [16] and hip [17] fractures are enormous; the costs in terms of morbidity and mortality are even greater [18]. Social outcomes include isolation, role loss, and dependence [14,19,20], as well as loss of social support [6]. There are undoubtedly more social consequences of osteoporosis and fractures that have not yet been studied.
Psychological outcomes The psychological injuries imposed by osteoporosis and fractures can also be devastating. General anxiety often accompanies the diagnosis of osteoporosis, even before more specific information is presented [14,21,22]. Individuals with osteoporosis also have disease-specific anxieties such as fear of falling, fear of fracture, and fear of loss of independence [23]. Deformity and pain can lead to diminished self-esteem or self-image [23–25]. Several studies have provided evidence that depression is associated with osteoporosis and fractures [7,26–29]. In summary, we have illustrated some of the negative consequences of osteoporosis that interfere with HRQOL on many different levels. The outcomes discussed here are not experienced by everyone with this disease but certainly are seen frequently in patients with both primary and secondary osteoporosis.
Prevalence of Osteoporosis in Postmenopausal Women
Do Estrogen or SERMs Improve Quality of Life? Gold and Silverman
scores than comparably aged women without fractures (P < 0.004). The authors suggest that early postmenopausal women may have their HRQOL reduced more by osteoporosis and fractures than older women because, in the older group, fractures are only one of the factors contributing to reduced HRQOL. However, for a subgroup of women in the menopause transition, HRQOL may also be reduced by the presence of vasomotor symptoms.
Effects of Estrogen on HRQOL In some women, estrogen deficiency after menopause is associated with vasomotor symptoms, sleep disruption, vaginal atrophy, changes in sexual functioning, and depression. Recent studies using both generic HRQOL instruments and instruments targeting menopausal symptoms have addressed the effects of these symptoms on HRQOL and the effects of intervention with estrogen therapy [32–34]. Two major randomized, controlled trials have studied the effects of estrogen therapy on HRQOL in postmenopausal women. The Heart and Estrogen/Progestin Replacement Study (HERS) used four generic instruments in postmenopausal women who were being given estrogen and progestin for secondary cardiovascular protection [32]. Physical function was measured using the Duke Activity Status Index, energy and fatigue using the Rand SF36 Scale, mental health using the Rand Mental Health Inventory 5, and depressive symptoms using the Burnham Screening Scale. The HERS trial showed no benefits of estrogen therapy on HRQOL except in women who were experiencing flushes. In these women, hormone therapy improved QOL by improving mental health (P = 0.04) and reducing depressive symptoms (P = 0.01) However, in this trial, many of the other symptoms of the menopausal transition (eg, changes in sexual functioning and urogenital problems) were not addressed. Furthermore, the mean age in the study was 67, and few vasomotor symptoms are likely to be seen this late after the menopause for most women. In the estrogen and progestin arm of the Women’s Health Initiative (WHI), 16,608 nonhysterectomized postmenopausal women aged 50 to 79 years (mean, 63.2) were randomized to estrogen plus progestin or a placebo [33]. HRQOL assessments were made at baseline and 1 year in the entire group and at 3 years in 1511 women, using the SF-36 to measure health status, the CES-D to measure depression, the WHI Insomnia Rating Scale to measure sleep quality, a single item to measure sexual functioning, and the Modified Mini-Mental State Examination to assess cognitive function. A checklist of five items measured menopausal symptoms. The presence of moderate or severe vasomotor symptoms was seen in approximately 12% of both the estrogen/progestin group and the placebo group. Therefore, this population was mainly asymptomatic, healthy women; 63% were more than 10 years postmeno-
pausal. There were no significant QOL benefits on any of the outcomes, including general health, vitality, mental health, or sexual satisfaction, for the treatment group as a whole. A statistically (P = 0.02) but not clinically significant improvement in sleep disturbances was found in women 50 to 54 years old who reported moderate-to-severe vasomotor symptoms. In summary, generic HRQOL instruments found no significant improvement in quality of life with the use of hormonal therapy in older, asymptomatic postmenopausal women, a finding similar to that of the HERS trial.
Benefits and risks of estrogen therapy in postmenopausal women at risk for osteoporotic fracture In the WHI, estrogen was found to significantly reduce the risk of vertebral and hip fracture by approximately one third. However, during the first 1 to 2 years of treatment with conjugated equine estrogen alone or combined with medroxyprogesterone acetate, women experienced an elevated risk of coronary heart disease, stroke, and deep venous thrombosis or pulmonary embolus. Increased breast cancer risk appeared only after 4 to 5 years of use of estrogen and progesterone and after up to 7 years of treatment with estrogen alone. The pattern of risks and benefits was similar in women who were in their 50s and women who had had a hysterectomy, with or without intact ovaries [34]. The primary indication for therapy with systemic estrogen or estrogen and progestin is to treat moderate to severe menopausal symptoms such as vasomotor symptoms. Estrogen should be used at the lowest effective dose for the shortest period consistent with treatment goals. When menopausal symptoms are controlled or cease, the continued benefits and risks of estrogen must be compared against those of all the other therapies [35]. Estrogen should not be considered as a first-line therapy for the prevention of any chronic disease, including osteoporosis. However, the symptomatic postmenopausal woman who is at risk for osteoporotic fracture and who is not at high risk for breast cancer or cardiovascular events may have a positive benefit/risk ratio for use of estrogen therapy. She may have benefits of vasomotor symptom relief and decreased vulvovaginal atrophy (which may also be treated with topical estrogen) [36]. Hormone therapy may also benefit mood, sexual function, and sleep [37]. Decisions on the use of estrogen or hormone therapy must be made on a patient-by-patient basis [36,37]. In symptomatic patients, hormone therapy may provide benefits by reducing menopausal symptoms and also by reducing risk of both vertebral and hip fractures. The knowledge of these possible outcomes of hormone replacement may, in fact, improve HRQOL, although this idea has not yet been tested empirically.
Effect of SERMs on HRQOL SERMs such as raloxifene have been found to significantly reduce the risk of vertebral (but not nonvertebral) fracture [38]. In the Multiple Outcomes of Raloxifene Evaluation
Therapeutics
(MORE) study, incident vertebral fracture was reduced by 55% over 3 years in postmenopausal women with no history of prevalent vertebral fracture and by 30% in postmenopausal women with a history of prevalent vertebral fracture [39,40]. However, raloxifene also increased vasomotor symptoms and incidence of deep venous thrombosis. Several randomized, controlled trials have examined the impact of SERMs such as tamoxifen and raloxifene on HRQOL. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial [41], 11,064 women were randomized to tamoxifen versus placebo and followed for 36 months. There were no significant differences between the groups in the SF-36 physical score summary or mental score summary or in the number of patients scoring above a clinically significant level of depressive symptoms on the CES-D. However, the mean number of vasomotor and gynecologic symptoms from a symptom checklist was higher with tamoxifen. Although the overall rate of sexual activity was similar between groups, there was also a significant increase in the proportion of individuals reporting serious problems with sexual functioning in the tamoxifen group [41]. In the NSABP study of tamoxifen versus raloxifene for breast cancer prevention [42], HRQOL was studied in a subset of 1983 participants with a median follow-up of 5.4 years. Instruments used included a symptom checklist to measure HRQOL, the SF-36 physical and mental component summary scores, the CES-D to measure depression, and a sexual activity questionnaire; all were measured every 6 months for 60 months. No significant differences between the tamoxifen and raloxifene groups were noted in patient-reported outcomes in physical health, mental health, and depression (P > 0.2), although the tamoxifen group reported better sexual functioning. The mean symptom severity was low in both groups, but there were differences in the type of symptoms for each agent. Women taking tamoxifen reported significantly more gynecologic problems, vasomotor symptoms, leg cramps, and bladder problems (P < 0.001), whereas the women on raloxifene had significantly more musculoskeletal problems, dyspareunia, and weight gain (P < 0.002). In another study on the effects of raloxifene versus placebo on menopausal QOL measured by the Utian Quality of Life Score, a questionnaire targeted at menopausal symptoms, there were improvements from baseline in multiple domains but no significant difference between groups in any of the domains. This was a randomized, double-blind, placebo-controlled trial including 74 women with a mean age of 55.6 years [43].
Conclusions As health care providers, we need to work with each patient to make correct therapeutic decisions for the treatment of osteoporosis. We must recognize that patients are unique individuals who have different health and disease profiles
and, therefore, have different needs for bone health. When we assess a postmenopausal woman who is at risk for osteoporotic fracture based on bone mineral density and clinical risk factors [44], we should not consider only her bone health; we should also assess whether she has moderate or severe vasomotor symptoms that negatively affect her quality of life. If she does have significant vasomotor symptoms and reports impaired HRQOL as a result, a SERM would be likely to increase those symptoms and would be contraindicated. Instead, we should consider estrogen therapy. But this decision-making process is never straightforward. We would also need to assess her personal risks for breast cancer and cardiovascular events and ask about concomitant illnesses such as diabetes and hypertension. If she has substantial risks for these diseases, estrogen therapy may be contraindicated as well. Ultimately, for the woman with risk for fractures, breast cancer, and/or cardiovascular events, we may need to consider other antiresorptive therapies such as bisphosphonates or an anabolic therapy such as teriparatide. Similarly, if she is a postmenopausal woman who does not have vasomotor symptoms but who is at risk for breast cancer owing to clinical risk factors, she may be a candidate for a SERM such as raloxifene, which has been shown to reduce the risk of invasive breast cancer in multiple trials [45,46] and to reduce risk of vertebral fractures. Although breast cancer prevention is not currently an indication for raloxifene use, an application has been filed with the US Food and Drug Administration (FDA).
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