Osteoporosis prevention, diagnosis and management in postmenopausal women and men over 50 years of age


Hormone therapy

Evidence statement

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

Grade: A

Recommendation 20
Consider oestrogen replacement therapy to reduce the risk of fractures in postmenopausal women. The increase in risk of adverse events associated with treatment should be weighed carefully against benefits. Long-term use is not recommended.

Grade: A

Recommendation 21
Selective oestrogen receptor modulators (SERMs) should be considered as a treatment option for postmenopausal women with osteoporosis where vertebral fractures are considered to be the major osteoporosis risk (on the basis of low spine bone mineral density and/or an existing vertebral fracture) and where other agents are poorly tolerated. SERMs may be particularly useful in younger postmenopausal women at risk of vertebral fracture and who have a prior or family history of breast cancer.

Oestrogen is available on the Pharmaceutical Benefits Scheme (PBS) for the prevention and treatment of osteoporosis in postmenopausal women. Oestrogen acts to decrease bone resorption. Oestrogen replacement therapy is effective in preventing loss of bone mineral density (BMD) and reducing the risk of fractures when given at, or near, menopause (and is also useful for control of menopausal symptoms) and has a role in reducing the risk of fractures in postmenopausal women with osteoporosis.1,2-5 Ideally, therapy should be continuous (ie without a break in therapy). Adjuvant progestogens are necessary in women who still have a uterus to protect against endometrial cancer. They may be given cyclically for 10–14 days each month in perimenopausal women or as continuous therapy combined with oestrogen in postmenopausal women. The latter is more suitable for women more than two years postmenopause to avoid the initial irregular bleeding commonly seen with this regimen being unduly prolonged. The minimum effective dose of oestrogen therapy on bone loss has yet to be clearly established,5 but the beneficial effects of oestrogen therapy can be achieved by many routes of administration (including oral and transdermal). Patients who demonstrate ongoing bone loss with low-dose oestrogen replacement therapy may be considered for higher doses, with attention paid to calcium intake and vitamin D status, provided that the risk associated with oestrogen replacement therapy is not increased (eg clotting, cardiovascular [CV] disease or breast cancer).

Tibolone is a form of hormone therapy (HT) that has oestrogenic, progestogenic and androgenic effects and does not need to be given with a progestogen. It has similar efficacy to traditional HT in reducing fracture risk.

Raloxifene is a selective oestrogen receptor modulator (SERM) and is available on the PBS for treatment of postmenopausal osteoporosis. SERMs have evidence of breast cancer prevention, so their use can be tailored to suit an individual’s unique risk factor profile and may be particularly useful in the younger postmenopausal female with low spine BMD and a prior or family history of breast cancer.

While there is excellent evidence (Grade A) for raloxifene in reduction of vertebral fracture risk, there is minimal evidence for reduction in non-vertebral fractures. Therapy should be continuous and there is no need for concomitant progestogens.

The role of long-term postmenopausal HT in the prevention and management of osteoporosis remains controversial, following publication of the results of the Women’s Health Initiative (WHI) study of combined oestrogen and progestin therapy4 and its study of oestrogen-alone therapy.2 In the oestrogen-alone group, there was no increased risk of invasive breast cancer or CV disease, although the other outcomes were similar to the combined group. For the combined oestrogen/progesterone group, increased risk of invasive breast cancer has been reported, although the initial report of increased coronary heart disease was no longer significant in subsequent analyses.1,2-4,6 Increased risks of thromboembolic events and cerebrovascular accident are reported for both groups. Subsequent to the initial publication, there have been multiple reanalyses of the data, including by age of initiation of HT. The side effect profile is more favourable for those women starting HT within 10 years of the menopause (50–59 years) with low absolute risks of thromboembolic events and stroke.6

Tibolone has a different side effect profile from traditional HT. There is no randomised controlled trial (RCT) evidence for an increase in breast cancer, although there was a small increased risk in one large longitudinal study.7 However, tibolone does appear to increase breast cancer recurrence in those with treated breast cancer. There is no evidence for increased heart disease or thromboembolic events, but in older women there was an increased risk of stroke.7

Raloxifene may increase hot flushes and is likely to aggravate vasomotor symptoms. Like traditional HT, it is associated with increased thromboembolic events but has not been associated with heart disease or overall risk of stroke.8 In one study of women at high heart-disease risk it increased fatal but not overall stroke risk.9

  • General practitioners should discuss with patients the long-term risks and benefits of HT, especially breast cancer, thromboembolic and CV effects. Side effects of traditional HT are minimised, with absolute risk low if given within 10 years of the menopause. The side effect profiles of traditional HT, tibolone and raloxifene are different.
  • Individuals who require immobilisation for any period (eg hospitalisation or a long plane trip) should cease HT or raloxifene for a week before and afterward.
  • Postmenopausal women taking HT should maintain adequate calcium intake (from dietary sources or supplements) and vitamin D status.
  • Raloxifene should not be used in combination with oestrogen therapy.
  1. MacLean C, Newberry S, Maglione M, et al. Systematic review: Comparative effectiveness of treatments to prevent fractures in men and women with low bone mineral density or osteoporosis. Ann Intern Med 2008;148(3):197–213.
  2. Anderson G, Limacher M, Assaf A, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women’s Health Initiative randomised controlled trial. JAMA 2004;291(14):1701–12.
  3. Cummings S, Ettinger B, Delmas P, et al. The effects of tibolone in older postmenopausal women. N Engl J Med 2008;359(7):697– 708.
  4. Rossouw J, Anderson G, Prentice R, et al. Risks and benefits of oestrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomised controlled trial. JAMA 2002;288(3):321–30.
  5. Wells G, Tugwell P, Shea B, et al. Meta-analyses of therapies for postmenopausal osteoporosis. V. Meta-analysis of the efficacy of hormone replacement therapy in treating and preventing osteoporosis in postmenopausal women. Endocr Rev 2002;23(4):529–39.
  6. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomised trials. JAMA 2013;310(13):1353–68. doi:10.1001/ jama.2013.278040.
  7. Kenemans P, Bundred NJ, Foidart JM, et al. LIBERATE Study Group. Safety and efficacy of tibolone in breast-cancer patients with vasomotor symptoms: A double-blind, randomised, non-inferiority trial. Lancet Oncol 2009;10(2):135–46.
  8. Delmas PD, Ensrud KE, Adachi JD, et al. Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: Four-year results from a randomized clinical trial. J Clin Endocrinol Metab 2002;87(8):3609–17.
  9. Barrett-Connor E, Mosca L, Collins P, et al. Raloxifene Use for The Heart (RUTH) Trial Investigators. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 2006;355(2):125–37.
  10. Schierbeck LL, Rejnmark L, Tofteng CL, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: Randomised trial. BMJ. 2012;345:e6409.
  11. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: Results from a 3-year randomised clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999;282(7):637–45.
  12. Barrett-Connor E, Grady D, Sashegyi A, et al. Raloxifene and cardiovascular events in osteoporotic postmenopausal women: Fouryear results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomised trial. JAMA. 2002;287(7):847–57.

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