A systematic review and network meta analysis of pharmacological approaches to enhance bone mineral density in functional hypothalamic amenorrhoea

Agathoklis Efthymiadis; Konstantinos Tsikopoulos; Edouard Mills; Andrew Milne; Waljit Dhillo; Ali Abbara; Alexander Comninos

doi:10.1530/endoabs.117.P262

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Endocrine Abstracts (2026) 117 P262 | DOI: 10.1530/endoabs.117.P262

SFEBES2026 Poster Presentations Late Breaking (54 abstracts)

A systematic review and network meta analysis of pharmacological approaches to enhance bone mineral density in functional hypothalamic amenorrhoea

Agathoklis Efthymiadis ¹ , Konstantinos Tsikopoulos ² , Edouard Mills ¹ , Andrew Milne ³ , Waljit Dhillo ¹ , Ali Abbara ¹ & Alexander Comninos ¹

Author affiliations

¹Imperial College London, London, United Kingdom; ²Department of Orthopaedics, University Hospitals Bristol, Bristol, United Kingdom; ³Hammersmith Campus Library, Imperial College London, London, United Kingdom

Background: In Functional Hypothalamic Amenorrhoea (FHA), sustained low oestrogen together with nutritional deficiency leads to significant deterioration in bone health. When psychological and nutritional interventions fail to restore menses within 6-12 months, pharmacological treatment is usually introduced to preserve bone health. Nevertheless, the relative efficacy of available pharmacotherapies remains unclear.

Aim: To compare the efficacy of available pharmacological treatments for bone mineral density (BMD) in women with FHA using network meta-analysis (NMA) for the first time.

Methods: Medline/Embase/Emcare/Cochrane/CENTRAL/ISRCTN/ClinicalTrials.gov were searched until 20-September-2025. Eligible randomised-controlled trials (RCTs) examining pharmacotherapies for lumbar spine (LS), femoral neck (FN), or total hip (TH) BMD were considered and synthesised according to PRISMA-NMA recommendations. Outcomes were reported as standardised mean differences (SMDs) with 95% confidence intervals (CIs).

Results: Thirteen RCTs were included (LS-BMD: n = 897; FN-BMD: n = 370; TH-BMD: n = 750). Transdermal hormone replacement therapy (HRT) was better than control (placebo or no intervention) in increasing LS-BMD with SMD 0.34 (95% CI 0.03, 0.64) and FN-BMD with SMD 0.57 (0.04, 1.10) over 12-18 months. By comparison, oral HRT and the combined oral contraceptive pill (COCP) did not increase BMD at any skeletal site over 12-24 months. Finally, teriparatide was superior to transdermal HRT, oral HRT and COCP for LS-BMD with SMDs 1.48 (0.38, 2.59), 1.69 (0.48, 2.91) and 1.75 (0.66, 2.83), but not FN or TH-BMD.

Conclusions: Transdermal HRT and teriparatide both produce significant LS-BMD improvements in women with FHA, while transdermal HRT also increases FN-BMD. By contrast, oral HRT and COCP show no benefit at any skeletal site.The difference in the effect of transdermal vs oral oestrogens may be partly explained by differential effects on IGF-1. This is the first NMA comparing all pharmacological treatments for bone health in FHA, offering key new evidence to shape clinical guidelines.

Study registration: PROSPERO (CRD42024576872).