The anti-fracture efficacy of MHT has been assessed in observational studies, case-control studies, meta-analyses and randomized clinical trials: Women’s Health Initiative (WHI), Heart and Estrogen/progestin Replacement Study (HERS), Women’s Interventional Study of long Duration Oestrogen after Menopause (WISDOM). Overall, these analyses (except HERS) show that MHT decreases fragility fracture risk by 20-35% [3]Hulley, S., et al., Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA, 2002. 288(1): p. 58-66.

[4]Cauley, J.A., et al., Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial. JAMA, 2003. 290(13): p. 1729-38.

[5]Vickers, M.R., et al., Main morbidities recorded in the women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women. BMJ, 2007. 335(7613): p. 239.

Despite this anti-fracture efficacy, the original analyses of the WHI suggested that the overall long-term health risks generally outweighed the benefits due to a higher incidence of cardiovascular events (unstable angina, thromboembolic stroke, venous thromboembolism including pulmonary embolism) and increased incidence of endometrial and breast cancer [6]Rossouw, J.E., et al., Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA, 2002. 288(3): p. 321-33.

[7]Chlebowski, R.T., et al., Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA, 2003. 289(24): p. 3243-53.

[8]Wassertheil-Smoller, S., et al., Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial. JAMA, 2003. 289(20): p. 2673-84.

. However, in a recent re-analysis with a cumulative follow-up of 18 years and including all-cause mortality, MHT was not associated with risk of all-cause, cardiovascular or cancer mortality [9]Manson, J.E., et al., Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials. JAMA, 2017. 318(10): p. 927-938.

. Additionally, more recent studies show that even low doses of MHT may protect bone by decreasing bone turnover markers (BTM) levels and preventing bone loss [10]Lindsay, R., et al., Bone response to treatment with lower doses of conjugated estrogens with and without medroxyprogesterone acetate in early postmenopausal women. Osteoporos Int, 2005. 16(4): p. 372-9.

[11]Gambacciani, M., et al., Ultra low-dose hormone replacement therapy and bone protection in postmenopausal women. Maturitas, 2008. 59(1): p. 2-6.

. However, the anti-fracture efficacy of these regimens has not been studied yet.

MHT is effective and appropriate for the prevention of osteoporosis-related fractures in at risk women before age 60 years or within 10 years after menopause. Initiation of MHT after the age of 60 years for the indication of fracture prevention is considered second-line therapy and requires individually calculated benefit/risk, compared to other approved drugs. If MHT is elected, the lowest effective dose should be used [12]de Villiers, T.J., et al., Revised global consensus statement on menopausal hormone therapy. Maturitas, 2016. 91: p. 153-5.

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Discontinuation of MHT results in acceleration of bone turnover, decrease in BMD and eventual loss of anti-fracture efficacy [13]Sornay-Rendu, E., et al., Effect of withdrawal of hormone replacement therapy on bone mass and bone turnover: the OFELY study. Bone, 2003. 33(1): p. 159-66.

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Raloxifene decreases markers of bone turnover levels by 35% and increases BMD by 2-3% at the lumbar spine and femoral neck [14]Delmas, P.D., et al., Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med, 1997. 337(23): p. 1641-7.

[15]Delmas, P.D., 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): p. 3609-17.

It has also been shown to reduce the incidence of vertebral fractures by 40 to 50% after 3 years [16]Ettinger, B., et al., Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA, 1999. 282(7): p. 637-45.

[17]Barrett-Connor, E., et al., Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med, 2006. 355(2): p. 125-37.

[18]Ensrud, K.E., et al., Effects of raloxifene on fracture risk in postmenopausal women: the Raloxifene Use for the Heart Trial. J Bone Miner Res, 2008. 23(1): p. 112-20.

. However, no effect has been observed on the risk of non-vertebral fractures [19]Delmas, P.D., et al., Severity of prevalent vertebral fractures and the risk of subsequent vertebral and nonvertebral fractures: results from the MORE trial. Bone, 2003. 33(4): p. 522-32.

[20]Siris, E.S., et al., Skeletal effects of raloxifene after 8 years: results from the continuing outcomes relevant to Evista (CORE) study. J Bone Miner Res, 2005. 20(9): p. 1514-24.

, except a 22% decrease in the incidence of major osteoporotic fractures in women with prevalent vertebral fractures (mainly severe vertebral fractures at baseline) [19]Delmas, P.D., et al., Severity of prevalent vertebral fractures and the risk of subsequent vertebral and nonvertebral fractures: results from the MORE trial. Bone, 2003. 33(4): p. 522-32.

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Other effects of raloxifene include the significant reduction in risk of invasive oestrogen-receptor positive breast cancer[17]Barrett-Connor, E., et al., Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med, 2006. 355(2): p. 125-37.

[21]Cummings, S.R., et al., The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA, 1999. 281(23): p. 2189-97.

[22]Grady, D., et al., Reduced incidence of invasive breast cancer with raloxifene among women at increased coronary risk. J Natl Cancer Inst, 2008. 100(12): p. 854-61.

[23]Martino, S., et al., Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst, 2004. 96(23): p. 1751-61.

. Additionally, in most studies, raloxifene did not influence the risk of cardiovascular (coronary) events [17]Barrett-Connor, E., et al., Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med, 2006. 355(2): p. 125-37.

[24]Collins, P., et al., Effects of the selective estrogen receptor modulator raloxifene on coronary outcomes in the Raloxifene Use for The Heart trial: results of subgroup analyses by age and other factors. Circulation, 2009. 119(7): p. 922-30.

and, in some groups, may have even decreased the risk of myocardial infarction or unstable angina [25]Barrett-Connor, E., et al., Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA, 2002. 287(7): p. 847-57.

. However, it increased the risk of deep venous thromboembolism to the same extent as MHT and increases the risk of fatal stroke mainly in women with a high baseline stroke risk baseline [17]Barrett-Connor, E., et al., Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med, 2006. 355(2): p. 125-37.

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Overall risk-benefit ratio is favourable and raloxifene is approved for the prevention and treatment of postmenopausal osteoporosis widely throughout the world. 

Another SERM, bazedoxifene, decreases bone turnover marker (BTM) levels to a similar extent as raloxifene daily, has been shown to increase BMD of the lumbar spine by 2% and to prevent bone loss at the total hip [26]Miller, P.D., et al., Effects of bazedoxifene on BMD and bone turnover in postmenopausal women: 2-yr results of a randomized, double-blind, placebo-, and active-controlled study. J Bone Miner Res, 2008. 23(4): p. 525-35.

[27]Silverman, S.L., et al., Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: results from a 3-year, randomized, placebo-, and active-controlled clinical trial. J Bone Miner Res, 2008. 23(12): p. 1923-34.

. However, bazedoxifene, like other SERMS, does not prevent hip BMD loss beyond the first couple of years of therapy, due to its relative weak anti-resorptive potency [28]Silverman, S.L., et al., Sustained efficacy and safety of bazedoxifene in preventing fractures in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled study. Osteoporos Int, 2012. 23(1): p. 351-63.

. It has also been observed to decrease the risk of vertebral fracture by 40% (similar to raloxifene) [27]Silverman, S.L., et al., Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: results from a 3-year, randomized, placebo-, and active-controlled clinical trial. J Bone Miner Res, 2008. 23(12): p. 1923-34.

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In postmenopausal osteoporotic women at high risk of fracture assessed by FRAX®, bazedoxifene decreased the risk of morphometric vertebral fracture by 50% and the risk of all clinical fractures by 30% [29]Kanis, J.A., et al., Bazedoxifene reduces vertebral and clinical fractures in postmenopausal women at high risk assessed with FRAX. Bone, 2009. 44(6): p. 1049-54.

. In these studies, the risk of cardiovascular events, cerebrovascular events, thromboembolism and of cancer was shown to be similar when comparing women treated with bazedoxifene, raloxifene or placebo. Similar to raloxifene, bazedoxifene increased the risk of deep venous thromboembolism, leg cramps and hot flushes. 

Tibolone is a synthetic steroid with weak oestrogenic, progestogenic, and androgenic activity. Tibolone is used in the treatment of menopausal symptoms like hot flushes and vaginal atrophy. Tibolone preserves bone mineral density [30]Kanis, J.A., et al., Bazedoxifene reduces vertebral and clinical fractures in postmenopausal women at high risk assessed with FRAX. Bone, 2009. 44(6): p. 1049-54.

and increases BMD both at the lumbar spine and hip more than raloxifene [31]Delmas, P.D., et al., Effects of tibolone and raloxifene on bone mineral density in osteopenic postmenopausal women. Osteoporos Int, 2008. 19(8): p. 1153-60.

. In older women with osteoporosis, tibolone, compared to placebo, significantly decreases the risk of vertebral fracture and nonvertebral fracture by 45% and 25% respectively. Tibolone also decreases the risk of invasive breast cancer, whereas it increases the risk of stroke by more than 2-fold [32]Cummings, S.R., et al., The effects of tibolone in older postmenopausal women. N Engl J Med, 2008. 359(7): p. 697-708.

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Tibolone is available widely throughout the world.

The combination of bazedoxifene (BZA) with conjugated equine oestrogen (CEE) to create a tissue selective oestrogen complex (TSEC) has been developed for the management of vasomotor, vaginal symptoms and the prevention of postmenopausal osteoporosis. This combination CEE/BZA is effective in the prevention of bone loss in postmenopausal women and has been approved by the FDA (US Food and Drug Administration) and EMA (European Medicines Agency) [33]Umland, E.M., L. Karel, and N. Santoro, Bazedoxifene and Conjugated Equine Estrogen: A Combination Product for the Management of Vasomotor Symptoms and Osteoporosis Prevention Associated with Menopause. Pharmacotherapy, 2016. 36(5): p. 548-61.

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Bazedoxifene is approved for the treatment of postmenopausal osteoporosis in Europe and Japan.