Discontinuation of menopausal hormone therapy and risk of fracture: nested case–control studies using routinely collected primary care data

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BACKGROUND: Women benefit from reduced fracture risk while using menopausal hormone therapy. However, information on risks after stopping menopausal hormone therapy is scarce and inconsistent, with no information on longer-term fracture risk as women age. We aimed to produce robust estimates of fracture risk among past users for the longest possible period after discontinuing therapy. METHODS: We did a nested case-control study using UK primary and secondary care data from the Clinical Practice Research Datalink, with the underlying cohorts CPRD GOLD and Aurum. Women, aged 40 years and older, registered with a primary care practice between Jan 1, 1998, and Feb 28, 2023, and with a first record for any fracture, were matched at the fracture index date with up to five female controls with no fracture history, who were of the same age and registered at the same general practice. Menopausal hormone therapy-related fracture risks were assessed using conditional logistic regression adjusted for demographics, family history, menopausal symptoms, comorbidities, and other medications. FINDINGS: In total, 648 747 women (500 692 from Aurum and 148 055 from GOLD databases) with a first fracture record during the study period were matched to 2 357 125 women with no previous or contemporaneous fracture record. Age of average fracture cases was 68·5 years (SD 14·0), 3·2% were recorded as being from minority ethnic populations, and about a quarter of patients were older than 80 years. 140 410 (21·6%) cases used menopausal hormone therapy for a median of 3·6 years (IQR 1·3-6·8) and 515 917 (21·9%) controls used it for a median of 3·9 years (1·4-7·3). Compared with never-use, overall fracture risk was reduced for current use (oestrogen-only odds ratio [OR] 0·76 [95% CI 0·74-0·78], oestrogen-progestogen OR 0·75 [0·73-0·76]), became higher 1-10 years after discontinuation (oestrogen-only OR 0·99 [0·98-1·01], oestrogen-progestogen OR 1·06 [1·05-1·08]), but was again lower for more than 10 years post-cessation (oestrogen-only OR 0·93 [0·91-0·94], oestrogen-progestogen OR 0·95 [0·94-0·96]). Risk levels varied by menopausal hormone therapy type and by duration of treatment. Estimated extra fracture cases per 10 000 women-years 1-10 years after oestrogen-progestogen treatment were equivalent to 14 cases for less than 5 years menopausal hormone therapy exposure and five cases for 5 or more years of exposure. However, for more than 10 years after discontinuation, we estimated three fewer fracture cases for those on oestrogen-progestogen therapy for less than 5 years exposure and 13 fewer fracture cases for those with 5 or more years of exposure. INTERPRETATION: We have observed an attenuation of fracture risk after discontinuing menopausal hormone therapy, which manifests after an initial sharp rise. Fracture risk generally increases with age, but after discontinuation of menopausal hormone therapy, fracture risk increases steeply, usually to above the levels of comparable never-users, and then rises less quickly relative to never-users to become again notably reduced by comparison in older age. Our findings provide information for researchers looking to improve fracture risk outcomes for women after discontinuing menopausal hormone therapy, and for doctors and their patients to consider before commencing or stopping menopausal hormone therapy, especially regarding expected steep post-discontinuation rises in fracture risk and periods of enhanced fracture risk. FUNDING: National Institute for Health & Care Research.

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