In this issue of Climacteric, Yoon et al. report results of a clinical trial comparing the use of menopause hormone therapy (MHT) and risedronate for prevention of fracture recurrence in older postmenopausal women [Citation1]. The International Menopause Society (IMS) recommendations advise against the initiation of MHT in elderly women for fracture protection [Citation2]. This editorial serves to place the above study and current IMS recommendations in perspective.
The beneficial effect of MHT on bone mineral density (BMD) is well known [Citation3]. The Women’s Health Initiative (WHI) randomized clinical trials provided proof of fracture protection in postmenopausal women [Citation4] when using conjugated equine estrogen (CEE) with or without medroxyprogesterone acetate (MPA). The initial reaction to the WHI trials was that the overall unfavorable risk/benefit profile mitigated against the use of MHT for fracture protection [Citation4], but re-analysis, long-term follow up [Citation5] and later studies [Citation6] suggested a favorable risk/benefit profile amongst younger women, especially when MHT was initiated in the window of opportunity (<60 years old or <10 years since menopause).
IMS Guidelines caution against initiation of MHT after the age of 60 or more than 10 years from menopause, mainly because of a less favorable risk/benefit profile [Citation2]. In large part, this reasoning is based on possible adverse effects on the cardiovascular system (CVS) particularly regarding proinflammatory and prothrombotic events seen with some forms of MHT [Citation7]. Data from the WHI Memory Study [Citation8], showing deficits in global and domain-specific cognitive function when MHT was administered to women over age 65, added to this overall change in risk/benefit profile.
However, it is important to understand that, whilst CVS protection from MHT declines after age 60 (pre-existing coronary arterial disease), there is no reason to believe that the effect of MHT on bone is affected by increasing age.
Yoon et al. [Citation1] argue that the unfavorable risk/benefit profile of MHT in elderly woman is a specific consequence of the use of oral CEE and MPA and that this can be overcome by using transdermal estradiol (E2) and oral micronized progesterone (P4). Elderly women at high risk of fracture (recent hip fracture) were randomized to receive standard of care (oral risedronate) or MHT (transdermal E2 plus oral P4). The study set out to prove equivalence of efficacy for MHT compared to standard of care in terms of fracture prevention (significance level p ≤ 0.5) and non-inferiority in terms of safety profile (breast cancer, cardiovascular events and mortality). There was no placebo group as risedronate therapy had proven efficacy and an acceptable safety profile.
It should be noted that the study used combined MHT even in patients without a uterus, in order to gain maximum bone benefit. This is also contrary to current IMS recommendations as there is evidence that some progestogens may dilute the beneficial effect of estrogen alone on possible cardiovascular benefits and may increase the risk of breast cancer and cognitive decline compared to estrogen alone.
It should also be noted that, amongst 281 participants who were randomized, only 45 in the risedronate group and 29 in the MHT group completed the study. These are very small numbers. The mean age of participants was 74.7 years. After 48 months, the incidence of new fractures per 100 person-years was not significantly different between the two groups (any new fracture, clinical fractures or asymptomatic vertebral fractures). In addition, safety data were also not different between the two groups (mortality, non-gynecological adverse events, CVS and cerebrovascular events). There were no cases of deep vein thrombosis and one case of breast cancer in the risedronate group. Increase in BMD was similar between the groups in terms of the spine but better at the hip with MHT. There was no difference shown in the suppression of markers of bone turnover.
The authors conclude that the effects of MHT using percutaneous E2 gel and oral micronized P4 might not differ from those of risedronate in preventing the incidence of new fractures and death among postmenopausal Korean women with recent hip fractures. Furthermore, MHT was not associated with an increased incidence of overall serious adverse events compared with risedronate.
The IMS recommendations regarding the use of MHT for fracture protection regard it as first-line therapy in women initiating therapy at age younger than 60 years or within 10 years of menopause and at risk of fracture [Citation2]. In older women, MHT is only recommended as second-line therapy if other bone-active medications are inappropriate.
It is our opinion that these recommendations should remain in place. Although the present study reports encouraging results, the numbers involved in both efficacy and safety analyses are very small. It reaffirms IMS recommendations of a preference for the transdermal application of estrogen and the use of natural progesterone in the older patient. We are not convinced that the use of P4 in the absence of a uterus would have made a difference to outcomes and stand by the present recommendation of using unopposed estrogen whenever the uterus is absent.
The study under discussion adds to our knowledge of the use of MHT for fracture protection but should be seen in perspective. It is important to understand that the IMS recommendations pertain only to the age at initiation of MHT. Continuation after the age of 60 years is allowed as long as the initial indication is valid.
References
- Park C-W, Lim S-Y, Moon Y-W, et al. Fracture recurrence in hip fracture with menopausal hormone therapy versus risedronate: a clinical trial. Climacteric. 2021;24(4):408–414.
- Baber RJ, Panay N, Fenton A, IMS Writing Group2016 2016 IMS Recommendations on women's midlife health and menopause hormone therapy. Climacteric. 2016;19(2):109–150.
- De Villiers TJ. The role of menopause hormone therapy in the management of osteoporosis. Climacteric. 2015;18(sup2):19–31.
- Cauley JA, Robbins J, Chen Z, 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):1729–1738.
- Manson JE, Chlebowski RT, Stefanick ML, et al. Menopause hormone therapy and health outcomes during the intervention and extended post stopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353–1368.
- Hodis HN, Mack WJ, Henderson VW, et al. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med. 2016;374(13):1221–1231.
- El Khoudary SR, Aggarwal B, Beckie TM, et al. Menopause transition and cardiovascular risk: implications for timing of early prevention. Circulation. 2020;22:e506–e532.
- Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in post-menopausal women: Women’s Health Initiative Memory Study. JAMA. 2004;291(24):2947–2958.