A good-quality systematic review (SR) pooled data from 47 RCTs investigating oestrogen alone and/or oestrogen with opposed progesterone compared to placebo for postmenopausal women.5 Treatment was associated with a significant improvement in BMD at the lumbar spine (weighted mean difference [WMD]: 4.86, 95% confidence interval [CI]: 3.70–6.02), forearm (WMD: 3.01, 95% CI: 2.29–3.74) and femoral neck (FN) (WMD: 2.25, 95% CI: 0.80–3.69) at 12 months, with the effect increasing at 24 months. Sub-analysis indicated that after two years’ treatment there was a larger effect on BMD at all sites of high dose therapy (equivalent to 0.9 mg Premarin) compared to low-dose therapy (equivalent to 0.3 mg Premarin), but the difference was only significant for FN BMD. A second good-quality SR presented evidence from five RCTs on the effectiveness of oestrogen in reducing vertebral, non-vertebral and/or hip fracture in postmenopausal women.1 There was good evidence that compared to placebo, oestrogen is associated with decreased risk in vertebral, non-vertebral and hip fractures. This effect was observed in the analysis including all postmenopausal women (odds ratio [OR] not reported), as well as for groups at higher risk of fractures (relative risk [RR]: approximately 0.07).1 In two clinical trials conducted by the WHI, conjugated oestrogen in combination with progestin in postmenopausal women (n = 16,608) or conjugated equine oestrogen (CEE) alone in women after hysterectomy (n = 10,739) were shown to reduce risk of osteoporotic fractures.2,4 Participants taking CEE 0.625 mg and medroxyprogesterone acetate 2.5 mg per day in a combined tablet (opposed oestrogen therapy) for an average of five years had a significant reduction in total fractures (hazard ratio [HR]: 0.76, 95% CI: 0.69–0.85, P = 0.05) as well as hip fractures (HR: 0.66, 95% CI: 0.45–0.98, P = 0.05).4 Participants taking CEE 0.625 mg per day for an average of six years had a significant reduction in the rate of all osteoporotic fractures (HR: 0.70, 95% CI: 0.63–0.79, P = 0.01) and rate of hip fractures (HR: 0.61, 95% CI: 0.41–0.91, P = 0.01).2
In a good-quality RCT of Tibolone in 4500 women over three years, there was a decreased risk of vertebral fracture (HR: 0.55, 95% CI: 0.41–0.74) and non-vertebral fracture (HR: 0.74, 95% CI: 0.58–0.93).3
In a clinical trial of 7705 women randomised to two doses of raloxifene or placebo followed for up to four years there was a reduction of vertebral fractures (RR: 0.64, 95% CI: 0.53–0.76) for the approved dose of 60 mg.9 There was no significant reduction in non-vertebral fractures (RR: 0.93, 95% CI: 0.81–1.06). Similar results were found for another good-quality study of raloxifene in over 10,000 women at high risk of heart disease at baseline.8
A good-quality SR reported an increase in risk compared to placebo of thromboembolic events (OR: 1.36, 95% CI: 1.01–1.86) and CV accident (OR: 1.34, 95% CI: 1.07–1.68) associated with oestrogen therapy.1 Although populations treated with oestrogen only had a lower risk compared to placebo for breast cancer (OR: 0.79, 95% CI: 0.66–0.93), the risk was significantly increased for women taking oestrogen/progestin combination therapy (OR: 1.28, 95% CI: 1.03–1.60).1 These findings were consistent with those in the WHI trials, which were both ceased early due to the significant risk of serious side effects.2,4 In the moderate-quality oestrogen/ progestin trial,4 HT was associated with an increased risk of coronary artery disease (HR: 1.29, 95% CI: 1.02–1.63, P = 0.05), stroke (HR: 1.41, 95% CI: 1.07–1.85) and invasive breast cancer (HR: 1.26, 95% CI:
1.00–1.59, P = 0.05). Subsequent analyses found that the initially reported increase in coronary artery disease was no longer statistically significant (HR: 1.18, 95% CI: 0.95–1.45). In the good-quality oestrogen alone trial,2 HT was associated with an increased risk of stroke (HR: 1.39, 95% CI: 1.10–1.77) and venous thromboembolic disease (HR: 1.33, 95% CI: 0.99–1.79), but not coronary artery disease (HR: 0.91, 95% CI: 0.75–1.12) or breast cancer (HR: 0.77, 95% CI: 0.59–1.01). The increase in thromboembolic disease only reached borderline statistical significance for deep venous thrombosis (HR: 1.47, 95% CI: 1.04–2.08) but not pulmonary thromboembolism (HR: 1.34, 95% CI: 0.87–2.06). A small RCT of 1006 recently menopausal women (aged 45–58)10 of oestradiol plus 1 mg norethisterone acetate for 10 years versus placebo treated for 10 years reported a reduction in the primary composite outcome of death, admission to hospital for heart failure and myocardial infarction (HR: 0.48, 95% CI: 0.26–0.87, P = 0.015). There was no increased risk of cancer, venous thromboembolism or stroke. This is consistent with reanalyses of the WHI by 10-year age groups where the adverse effects of HT were less significant in those started on HT prior to 60 years of age.6
Another good-quality trial conducted in women older than 60 years of age reported a reduction in risk of invasive breast cancer (absolute risk reduction [ARR]: 1.9 per 1000 person years, 95% CI: 0.5–3.4, P = 0.02) and colon cancer (ARR: 1.3 per 1000 person years, 95% CI: 0.1–2.6, P = 0.04) associated with tibolone therapy.3 However, relative hazard for stroke was 2.19 (95% CI: 1.14–4.23) and the absolute risk increase was 2.3 per 1000 person years (95% CI: 0.4–4.2), leading to early cessation of the trial. Absolute risk increased more in participants aged over 70 years (absolute risk increase 3.1 per 1000 person years). There was no increased risk of heart disease or venous thromboembolic events.3 In a subsequent study of women already treated for breast cancer, tibolone was found to decrease vasomotor symptoms and maintain BMD, but there was an increased risk of breast cancer recurrence (HR: 1.40, 95% CI: 1.14–1.70).7 Similar to the above study, there was no increased risk of venous thromboembolic events or heart disease in this younger group.
In the four-year follow-up of the pivotal raloxifene Multiple Outcomes of Raloxifene Evalation (MORE) study,9,11 there was an increased risk of thromboembolic events, with an RR of 2.76 (95% CI: 1.30–5.86) for deep venous thrombosis and 2.76 (95% CI: 0.95–8.01) for pulmonary embolism. Unlike HT, there was a reduced risk of breast cancer (RR: 0.38, 95% CI: 0.24–0.58) and no increased risk of CV events.12 In a subsequent RCT of raloxifene in over 10,000 women with either established heart disease or risk factors for heart disease, there was a similar reduction in breast cancer (primarily oestrogen receptor positive) and no increased risk of primary coronary events, overall risk of stroke or overall deaths.8 However, there was an increased risk of fatal strokes (HR: 1.49, 95% CI: 1.00–2.24) and venous thromboembolism (HR: 1.44, 95% CI: 1.06–1.95).8