Osteoporosis in 2000 - NIH Consensus Development Program

Clin Geriatr Med 19 (2003) 361 – 370

Hormone replacement therapy for postmenopausal osteoporosis Ann Cranney, MD, MSca,*, George A. Wells, PhDb a

Division of Rheumatology, Department of Medicine, Queen’s University, Etherington Hall, Room 2004, 94 Stuart Street, Kingston, Ontario, Canada, K7L 3N4 b Department of Epidemiology and Community Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada, K1H 8M5

Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength, predisposing to an increased risk of fracture. Hip fractures, in particular, are associated with increased mortality and morbidity, and constitute an important socioeconomic burden [1]. Therefore, it is essential to find effective treatments to prevent osteoporotic fractures. It is clear that estrogen deficiency places postmenopausal women at an increased risk of fracture, and for many years, clinical experts have recommended hormone replacement therapy (HRT) as the first-line therapy for both the prevention and treatment of osteoporosis. Several randomized controlled trials (RCTs) have provided strong evidence that HRT prevents bone loss at both cortical and trabecular sites. Recommendations have challenged the use of HRT as the first-line therapy for reduction of hip fractures, however, given that the results of randomized trials have confirmed the efficacy of bisphosphonates for vertebral and hip fracture reduction [2,3]. Guidelines from the American Association of Endocrinologists [4] do not recommend HRT over other forms of therapy. The US Food and Drug Administration (FDA) rescinded estrogen as a treatment option for osteoporosis, but estrogen replacement therapy (ERT) has been retained as an option for prevention. This article reviews the evidence for the use of HRT for the prevention of postmenopausal osteoporosis and highlights the recent results of the Women’s Health Initiative (WHI) trial [5]. Whenever possible, when discussing the

* Corresponding author. E-mail address: [email protected] (A. Cranney). 0749-0690/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved. PII: S 0 7 4 9 - 0 6 9 0 ( 0 2 ) 0 0 0 7 8 - 2

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A. Cranney, G.A. Wells / Clin Geriatr Med 19 (2003) 361–370

magnitude of efficacy of HRT, the highest level of evidence available has been used.

Pathophysiology of estrogen deficiency on bone metabolism Bone loss during and after menopause occurs in both the endocortical and trabecular bone. Estrogen deficiency results in an increased rate of bone remodeling and is an important factor in the pathogenesis of osteoporosis [6]. Estrogen deficiency triggers increased levels of IL-1, IL-6, and tumor necrosis factor, which are cytokines that cause increased activity of osteoclastic bone resorption [7]. The increased remodeling that occurs after menopause results in an increased renal loss of calcium and an overall negative calcium balance. Estrogen deprivation has been demonstrated to reduce the resistance to resorbing effect of parathyroid hormone (PTH) and estrogen therapy restores the resistance to PTH [8]. There is evidence from cohort studies that higher circulating levels of estradiol have been associated with reduced fracture risk [9].

Efficacy of HRT Bone mineral density Bone mineral density (BMD) is used as a proxy measure of bone strength and is believed to account for 70% of bone strength [10]. Earlier trials have used BMD as a surrogate outcome for fracture and have chosen to select BMD as the primary outcome measure. Observational studies have shown that the optimal benefit of HRT appears to be obtained if started early after menopause and continued indefinitely [11]. A recent meta-analysis of HRT by Wells et al [12] evaluated 57 studies that included an estrogen arm compared with a control arm. Of the 57 studies, 47 were prevention studies and 10 were treatment studies. Treatment trials were defined as those studies that included women with prevalent fractures at baseline. Wells et al combined the prevention and treatment trials for both unopposed and opposed estrogen preparations. When the results of these studies were pooled, the authors found a percentage change in bone density that was statistically in favor of the HRT arm. For example, when the results of 21 trials that assessed the efficacy of HRT (equivalent to 0.625 mg CEE) on the lumbar spine were pooled, the difference in the percentage change in bone density at 2 years between HRT and control arms was 6.8 (95% confidence interval [CI] = 5.83 –7.89). Similar effects were noted at the forearm and femoral neck, with increases of 4.5% and 4.1%, respectively. The difference between the prevention and treatment groups at each bone density site was not statistically significant. Larger increases were seen with the opposed estrogen preparation versus the unopposed (5.1% versus 3.9%, respectively, at the lumbar spine). When the doses of estrogen were grouped according to low,


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medium, and high dose, there was a clear dose – response relationship at each site at 2 years. At the lumbar spine and femoral neck sites, there was a significant difference in bone density at 2 years, (3.9% and 2.0% for dose equivalent to 0.3 mg of conjugated estrogen, and 8.0% and 4.7% for dose equivalent to 0.9 mg). The results of this meta-analysis revealed a consistent efficacy of HRT on bone density at both cortical and trabecular sites after both 1 and 2 years of therapy. The majority of the trials were of short duration; further evidence from longer duration trials is needed to support a sustained effect of HRT on bone density. The Women’s Health, Osteoporosis, Progestin, Estrogen (HOPE) study was a 2-year RCT that was designed to evaluate the impact of lower doses of conjugated estrogen on BMD [13]. This study was not included in the Wells et al [12] meta-analysis. This trial randomized 822 postmenopausal women, age 40 to 60 years, to different doses of conjugated equine estrogens (CEE) (0.625, 0.45, and 0.3 mg) and medroxyprogesterone acetate (MPA) (2.5 and 1.5 mg). Women assigned to all the treatment groups had a significant increase in BMD relative to placebo. The authors found that lower doses of CEE were effective in preventing bone loss, with larger increases in bone density in the CEE/MPA group in comparison with CEE alone. Impact of estrogen on bone density in elderly women The incidence of osteoporotic fractures increases in elderly women. In the past, it was believed that bone turnover slowed in elderly women. Observational trials indicate that bone loss continues in elderly women and may even accelerate [14,15]. There is increased evidence that even low-dose ERT may have a positive impact on the bone density of elderly women [16,17]. A 9-month RCT of frail elderly women by Villareal et al [18] showed that compared with placebo, the BMD of the lumbar spine increased by 3.9% (95% CI = 3.5 –4.3) in the HRT group. Effect of progestogens in combination with estrogen Randomized trials have suggested that C21 derivatives such as MPA and progesterone do not interact with the effect of estrogen on bone [19]. The 19-nortesterone derivatives, such as norethindrone, have been shown to reduce bone remodeling, and there is some evidence that norethindrone enhances the effect of estrogen on bone [20]. It is not clear whether this effect is anabolic or antiresorptive. Previous RCTs that have included continuous MPA at a dose of 2.5 mg have not shown an additive effect with CEE [19]. Gallagher et al [21] demonstrated that use of a higher dose of MPA (10 mg, with 0.3 mg of CEE) resulted in a similar maintenance of bone mass to that seen with 0.625 mg of CEE. The Womens’ HOPE trial [13] demonstrated a significant difference between lumbar spine BMD at 2 years in the group taking 0.625 mg of CEE and 2.5 mg of MPA relative to the group taking 0.625 mg of CEE (3.36% versus 2.43%, respectively). There was no difference between the group taking 0.45 mg of CEE and 1.5 mg of MPA versus the group taking 0.45 mg of CEE.

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Fractures Although numerous small trials have evaluated the efficacy of HRT on bone density, few of these trials collected data on fractures and very few controlled trials have examined fractures as a primary outcome [22 – 24]. There have been no RCTS of HRT with hip fracture as a primary outcome, although the WHI [5] has obtained evidence that HRT reduces hip fractures (discussed below). Unlike recent osteoporosis therapies, such as the bisphosphonates and selective estrogen receptor modulators, the FDA did not demand fracture data for HRT. As a result, for years the evidence to support the use of HRT to reduce fractures has been based on the results of observational studies [24]. Observational studies (case control and cohort) suggested an approximate 25% to 50% reduction in hip fractures and a 50% reduction in vertebral fractures, in HRT users versus nonusers [25]. Grady and Cummings [26], in a systematic review of 11 observational studies, concluded that the pooled relative risk (RR) for hip fractures was 0.75 (95% CI = 0.68– 0.84), which is consistent with a 25% risk reduction. The risk of nonvertebral fractures was evaluated in a prospective cohort study of women 65 years or older—the Study for Osteoporotic Fractures—and the RR for all nonvertebral fractures was 0.66 (95% CI = 0.54 – 0.80) in HRT users compared with nonusers. Subgroup analysis indicated that estrogen was more effective in preventing hip fractures for those older than 75 years and for those who commenced estrogen within 5 years of menopause [27]. In another prospective cohort study of early postmenopausal women in Finland [28], the adjusted RR was 0.67 (95% CI = 0.55 –0.81) for any fracture and 0.53 (95% CI = 0.26– 0.67) for distal forearm fracture in HRT users compared with never users. Results from observational studies must be interpreted with caution because observational studies are subject to confounding and selection bias and may therefore overestimate the degree of RR reduction. Randomized trials minimize bias through the use of concealment of treatment allocation and by blinding of outcome assessment. A good example of how the findings of an RCT can contradict findings of observational studies is the Heart and Estrogen/Progestin Replacement Study (HERS), which was designed to evaluate the efficacy of HRT for secondary prevention of coronary heart disease. This large RCT showed no effect of HRT on the reduction of coronary events [29,30], and, in fact, demonstrated an increase in cardiovascular events that contradicted the beneficial effects of earlier observational studies. A potential explanation for this discrepancy between RCT and observational results is selection and adherence bias [31]. Prior to the WHI results, systematic reviews of both nonvertebral and vertebral fractures have been used to determine whether there is adequate evidence from all available trials to state that HRT reduces the risk of vertebral and nonvertebral fractures. In a recent meta-analysis of HRT and the prevention of nonvertebral fractures, Torgerson and Bell-Syer [32] pooled results from 22 trials. The pooled RR was consistent with a 27% reduction in nonvertebral fractures (RR = 0.73; 95% CI = 0.56 – 0.94). The results were not significant for women over 60 years. Only one of the included trials [30] was actually designed to evaluate fractures as an


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outcome, however, and this trial dominated the over 60 age subgroup. In addition, there were methodological quality issues with some of the trials included in this meta-analysis [26]. For example, two trials did not make a clear distinction between vertebral and nonvertebral fractures [33 –35]. In two of the included trials, the randomness of the allocation to study arms was unclear [24,36]. One of the trials reported the number of fractures and not the number of women with fractures [19]. Two of the trials were a continuation of a previous RCT, which raises concerns regarding selection bias that devalued the original RCT design [13,36]. HERS [30] was a large RCT that included fracture as a secondary outcome. HERS was the first randomized controlled trial to evaluate the impact of HRT on the risk of coronary artery disease in postmenopausal women (n = 2763) with pre-existing coronary disease. Women in the HRT arm (conjugated estrogen, 0.625 mg, and medroxyprogesterone, 2.5 mg) did not have a lower risk of nonvertebral or hip fractures compared with placebo (12 in the HRT group versus 11 in the placebo group (RR = 1.10; 95% CI = 0.49 – 2.50). In HERS, 262 women—35 women on placebo and 127 on HRT—had nonvertebral fractures, which results in an RR of 0.95 (95% CI = 0.75 –1.21). The lack of a beneficial effect of HRT on fractures may have been due to the fact that less than 20% of these women were osteoporotic [30,37]. In another meta-analysis, Wells et al [12] pooled six trials [22,37 – 41] that measured the efficacy of HRT on nonvertebral fractures and the results indicated a nonsignificant reduction in RR of 13% (RR = 0.87; 95% CI = 0.71– 1.08). One of the included trials that evaluated the effect of HRT on nonvertebral fractures was the trial by Komulainen et al [22]. This 5-year RCT was a subgroup of the Kupio Osteoporosis Study, which randomized 464 early postmenopausal women to one of four arms: HRT (estradiol valerate, 2 mg/d, and cyproterone acetate, 1 mg/d), vitamin D3, HRT and vitamin D, or placebo. The pooled results of the two HRT arms showed a statistically significant RR reduction of 0.29 (95% CI = 0.1 – 0.9) for nonvertebral fractures with HRT [22]. The RR reduction was not significant for the HRT and vitamin D group compared with the placebo group (RR = 0.44; 95% CI = 0.17 – 1.15). In addition, there were only 39 fractures in the entire study. One of the limitations of this trial was that there was a large loss to follow-up in the HRT arms and the authors found a significant result by a post hoc pooling of two HRT treatment groups. The results of the large HERS trial had substantial impact on the results of the Wells [12] and Torgerson [43] meta-analyses of nonvertebral fractures. Until the WHI and HERS, there hade been few trials that evaluated the outcome of fracture, with the most frequently quoted trial being a small RCT by Lufkin et al [42]. This trial was a 1-year treatment trial of transdermal estrogen in postmenopausal women, the results of which demonstrated an RR of 0.39 (95% CI = 0.16– 0.95) for radiographic vertebral fractures. These results were based on the number of fractures and not the number of women with fractures; when reanalyzed, the results were no longer significant. Torgerson and Bell-Syer [43] also reviewed the efficacy of HRT for the prevention of vertebral fractures. They included 13 trials in their meta-analysis

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and the pooled results were consistent with a 33% reduction in vertebral fractures (95% CI = 0.45– 0.98), although the upper boundary of the CI was close to 1. The pooled RR of fracture for women over age 60 years was 0.63 (95% CI = 0.41– 0.96). There were some methodological concerns with some of the included trials with respect to the reporting of vertebral fractures. In addition, the majority of the trials were not designed to assess vertebral fractures as the primary outcome. In the HRT meta-analysis, Wells et al [12] reviewed studies that included data on vertebral fracture. The authors pooled five trials that assessed vertebral fractures [37 –39,41,42] and the results indicated a trend toward a reduced incidence of vertebral fractures with a pooled RR of 0.66 (95% CI = 0.41 –1.07). This result was consistent with a 34% reduction; however, the results were nonsignificant with the upper level of the CI overlapping 1.

Duration of treatment and the impact of withdrawal of HRT on BMD Observational studies have suggested that the impact of HRT on fracture reduction is not sustained in women who discontinue therapy [27]. One potential explanation for this is an accelerated loss of bone density when estrogen is discontinued; however, few studies have evaluated this [44 –46]. The results of a recent study [46] have challenged the theory of accelerated bone loss after discontinuation of HRT. The Postmenopausal Estrogen/Progestin Intervention (PEPI) randomized controlled trial was a 3-year RCT. The PEPI Safety Followup Study (PSFS; 57% of the original cohort, 495 women) monitored safety end points that included bone density testing 4 years after completion of the PEPI trial [46]. The results indicated that women who continued HRT after the initial 3 years did not demonstrate any further gains in BMD. In addition, women who discontinued HRT lost bone, but their rate of loss was not different from that found in women who were treated with placebo, thereby arguing against the accelerated loss hypothesis.

Adverse effects When a clinician prescribes HRT for a postmenopausal woman, the benefit to risk ratio is considered. Observational data has suggested that HRT needs to be taken for at least 10 years to have an impact on fracture reduction. Meta-analyses, however, have suggested that after 5 years of HRT, the risk of breast cancer is increased, with an RR of 1.35. The Collaborative Group on Hormonal Factors in Breast Cancer assembled about 90% of the evidence on the relationship between risk of breast cancer and HRT and found that the RR of having breast cancer was 1.023 for each year of HRT use [47]. Another concern with estrogen use based on results of observational studies is the increased risk of venous thromboembolic events and stroke [48 – 50]. A recent


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systematic review [50] indicated that current estrogen use was associated with an increased RR of 2.14 (95% CI = 1.64 –2.81), and the risk may be highest during the initial year of use. The concern about these adverse effects has been confirmed by results of the WHI trial and HERS [30,51].

Results of the HRT arm of the WHI The WHI [5] is a 15-year, national health study (United States) investigating strategies for the prevention and control of common causes of morbidity and mortality in postmenopausal women. The clinical trial component of the WHI is a randomized controlled trial to evaluate HRT/estrogen, low-fat diets, and calcium/ vitamin D administration, with the completion date planned for 2007. The estrogen (0.625 mg of conjugated estrogen) and progestin (2.5 mg of MPA) primary prevention trial of the WHI involved 16,608 women, aged 50 to 79 years, with an intact uterus. Hip fracture was a secondary outcome of the WHI. Women were not selected based on their risk for osteoporosis, and bone density data was not collected. The mean age of participants was 63 years, and the mean body mass index was 28.5 kg/m2 in both the HRT and placebo groups. The history of previous fracture was comparable in both arms (13.5 versus 13.6, respectively). In May 2002, the Data and Safety Monitoring Board recommended that the HRT arm of the WHI be stopped early (after 5.2 years of follow-up) due to concerns that the risks outweighed the benefits (global index 1.15, 95% CI 1.03 – 1.28). In the HRT arm, there was a statistically significant increased risk of invasive breast cancer (hazard ratio [HR] = 1.26; unadjusted 95% CI = 1.00 – 1.59) [51]. The results also indicated an increased risk of coronary heart disease (HR = 1.29; unadjusted 95% CI = 1.02 – 1.63), stroke (HR = 1.41; 95% unadjusted CI = 1.07 – 1.85), and deep vein thrombosis/pulmonary embolism (HR = 2.3; 95% CI = 1.39 –3.25) in the HRT arm. The absolute risk of these adverse events in a woman on HRT is very low, because the baseline risk of each event is low. The results of the WHI did demonstrate a beneficial effect of HRT on reduction of osteoporotic fractures. The HRT arm had a reduced RR of hip fractures (HR = 0.66; unadjusted 95% CI = 0.45 – 0.98) with 44 out of 8506 in the HRT arm and 62 out of 8102 in the placebo arm. This translates into five fewer hip fractures per 10,000 person years. There was also a reduction in vertebral fractures (HR = 0.66; 95% unadjusted CI = 0.44 – 0.98) and other osteoporotic fractures. In addition, there was a significant reduction in colorectal cancer. When the HRs are adjusted for multiple outcomes, the upper limit of the confidence interval overlaps 1.0 for outcomes of hip and vertebral fracture. The smaller unopposed estrogen arm versus placebo in women with a previous hysterectomy of the WHI continues. In Europe, the Womens’ International Study of Long Duration Estrogen after Menopause (WISDOM) has included fractures as an outcome; this trial was recently discontinued. Large RCTs have demonstrated the efficacy of bisphosphonates for the reduction of vertebral and nonvertebral fractures in women with osteoporosis

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and the efficacy of raloxifene (HR) for the reduction of vertebral fractures [2]. Given the recent results of the WHI, it is difficult to recommend HRT as a longterm therapy for the prevention of osteoporotic fractures.

Summary The role of HRT for the prevention of osteoporosis has been clarified by the recent results of the WHI. There is consistent and favorable data from RCTs supporting the efficacy of HRT on the surrogate outcome of bone density at both cortical and trabecular sites, including a dose – response relationship. Both observational and RCT data provide support that HRT has a positive impact on the reduction of vertebral and hip fractures. The unfavorable risk/benefit profile of HRT, however, strongly limits its use for prevention of osteoporosis, given that there are other medications that have demonstrated fracture efficacy.

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