What are the risks of bone fractures for women when using menopausal hormonal therapy and after cessation of treatment?

Problem

Older women are particularly at risk of developing osteoporosis and suffering fragility fractures as a consequence of reduced levels of oestrogen found in all women during and after menopause. Menopausal hormone therapy (MHT) treatments are known to have a protective effect on bone, and previous studies have confirmed that current use of MHT decreases the rate of fractures. It is also known that the protective effect of MHT diminishes or disappears after treatment is discontinued, but how long the effect lasts, whether duration of the treatment before discontinuation is a factor, and whether the patterns of decrease differ between specific hormonal treatments are all still unclear. Currently evidence for different treatments is not comprehensive and sometimes even contradictory.

Approach

From UK primary care data in the Clinical Practice Research Datalink, 204,135 women over 40 had a fracture record between 1998 and 2022. In a nested case-control study, each case was matched by general practice and year of birth to 5 female controls alive at the date of case diagnosis (index date). Exposure to MHT was based on prescriptions excluding one year prior to the index date. Compared to no MHT use, associations with treatment duration and recency were examined using conditional logistic regression, adjusted for indicators for MHT prescribing and osteoporosis risk factors (smoking, ethnicity, alcohol consumption, body-mass index, and relevant co-morbidities and other medicines), and treatment for osteoporosis.

Findings

49,713 (24%) cases and 217,707 (24%) controls had used MHT drugs in the exposure period. 31% of exposed cases and controls were prescribed oestrogen-only treatments, 69% prescribed oestrogen-progestogen. Current (within 5 years) use was associated with decreased fracture risk both for oestrogen-only (<5 to ≤ 10 years of use, odds ratio 0.84, 95% confidence interval 0.79-0.89; >10 years, OR 0.69, 0.64-0.74) and for oestrogen-progestogen (<5 to ≤10 years, OR 0.87, 0.83-0.91; >10 years, OR 0.76, 0.70-0.81) treatments. Past (>5 years prior) users of oestrogen-only therapy had reduced risk (<5 to ≤ 10 years of use, OR 0.90, 0.86-0.94; >10 years OR 0.86, 0.79 to 0.94). Past users of oestrogen-progestogen therapy, however, showed no residual protective association. Risk levels across all MHT treatments studied proved broadly similar.

Consequences

This very large, population-based study of fracture risks and MHT therapy has shown that, in general, increased duration of treatment decreased fracture risk for current users. After discontinuation, however, only oestrogen-only treatments showed longer-term risk reduction, most marked for longer prior exposures. Particularly for women suffering from, or at increased risk of developing, osteoporosis, our comprehensive findings will usefully inform decision-making of doctors, patients, healthcare professionals and policy makers regarding optimal MHT treatment regimens, and possibly stimulate further research.