New analysis suggests bone mineral density loss over time differs by medication.
GnRH antagonists were associated with the greatest decrease in bone mineral density, according to new meta-anaylsis, followed by agonist leuprolide/leuprorelin (Lucrin, Eligard), synthetic progestin dienogest (Visanne, Dinasane), and agonist goserelin (Zoladex).
Endometriosis, which affects up to 10% of women and people assigned female at birth, is commonly managed with hormonal suppression therapies which reduce circulating oestrogen levels and help control symptoms.
However, given oestrogen’s central role in maintaining bone mineral density (BMD), this course of action has consequences for bone health which require consideration when deciding what to prescribe.
A systematic review and meta-analysis of 37 studies – including 28 randomised controlled trials, six prospective cohort studies, and three retrospective cohort studies – assessed mean percentage change in BMD at six and 12 months across commonly used endometriosis therapies. Studies were identified from 1153 screened records from international cohorts across Europe, Asia, and North America. The lumbar spine was the most frequently assessed site for BMD measurement across all studies.
Pooled analysis of gonadotropin-releasing hormone (GnRH) agonists with add-back therapy showed a mean reduction in lumbar spine BMD of 0.89% at six months (11 studies, n=348), with higher heterogeneity observed (I² = 20.3%).
At 12 months, the reduction in BMD was greater at 1.50% (four studies, n=215). Overall, the included add-back therapies such as tibolone, combined oestrogen–progestin, and progestin-only regimens, appeared similarly protective of BMD across the studies, researchers said.
Subgroup analysis of GnRH agonists found that leuprolide was associated with a statistically significant reduction in BMD at six months (1.33%, six studies, n=279), whereas goserelin demonstrated a smaller, non-significant reduction (0.42%, five studies, n=69).
Dienogest was also associated with reductions in BMD, with pooled data showing a 0.83% decrease at 6 months (six studies, n=273) and 1.91% at 12 months (four studies, n=241). However, heterogeneity was high across analyses (I² > 75%), meaning significant variability in study design, population characteristics, and dosing regimens.
Despite this, all individual studies reported small declines in BMD over time. Longer-term observational data suggested that BMD loss was primarily seen within the first six months and stabilised with ongoing therapy.
GnRH antagonists were associated with a larger early reduction in bone density. Pooled analysis of five studies demonstrated a 2.17% decrease in BMD at six months (n=1311), with very high heterogeneity (I² = 97.3%).
Notably, none of the included studies used add-back therapy, which researchers said may partially explain the greater BMD loss associated with antagonists in the study.
Therapies included were elagolix (150mg daily and 200mg twice daily), linzagolix (100mg and 200mg daily), and relugolix (40mg daily). Limited 12-month data suggested dose-dependent effects, with higher-dose elagolix associated with greater BMD reduction (up to 3.6% compared with 0.63% for lower-dose therapy).
Among the therapies included in the meta-analysis, dienogest and relugolix (as the combination product Ryeqo) are listed on the Pharmaceutical Benefits Scheme for the management of endometriosis. Goserelin is also PBS-listed for endometriosis, although the 3.6mg formulation is due to be withdrawn from the Australian market later this year. In contrast, leuprolide, elagolix and linzagolix are not included on the PBS.
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The study also looked at depot medroxyprogesterone acetate (Depo-Provera), another synthetic progestin, for which there was data from four studies. However, researchers explained that the variability in reporting precluded meta-analysis.
DMPA showed consistent but modest reductions in BMD at six months, ranging from 0.99% to 1.1%. Longer-term data, which were limited to small samples, suggested greater reductions over extended use (e.g., 1.66% over 36 months in a small cohort of 10 patients). Existing broader contraceptive literature suggests that BMD loss with DMPA is generally reversible following discontinuation.
Across all hormonal suppression strategies used in endometriosis management, small but measurable reductions in BMD were observed within the first 6-12 months of treatment.
However, the long-term skeletal impact and fracture risk remains uncertain and requires the context of symptom severity, duration of therapy, and individual patient risk factors, researchers concluded.
