Hormone replacement therapy applied via the skin is the best way of protecting bone density in women whose periods have stopped due to anorexia or intense exercise, according to new research from Imperial College London and Imperial College Healthcare NHS Trust.
The study, a meta-analysis of all previous clinical trials, identifies the most effective way to treat women with Functional Hypothalamic Amenorrhoea (FHA), where periods stop because of anorexia nervosa or intense exercise. FHA is a common reproductive disorder, accounting for almost a third of cases of menstrual periods stopping. When periods cease, the resulting lack of natural oestrogen can lead to negative physical changes, particularly regarding bone mineral density.
Approximately half of affected women with FHA suffer from low bone mineral density, compared to only 1% of healthy women, and their risk of bone fractures is up to seven times higher than in the general population.
When women are diagnosed with FHA, doctors will first aim to restore menstrual periods through lifestyle changes, including psychological and dietary interventions, but these are frequently unsuccessful. International clinical guidelines then recommend giving hormone replacement therapy (HRT) containing oestrogen, but the evidence for which form is best has until now been unclear.
The team reviewed all previous randomised clinical trials involving a total of 692 individuals—the largest dataset of its kind—and examined the various therapies available, focusing on their impact on bone mineral density at different sites in the body. As well as looking at different formulations of HRT (oral and transdermal) they investigated teriparatide, a prescription bone-building agent that can be used to treat severe osteoporosis.
They found that:
• Transdermal HRT and teriparatide demonstrated clinically significant benefits on bone mineral density, with reported increases in density typically ranging between 2-13% over 1-2 years depending on patient characteristics, treatment choice and body site
• No significant benefit was observed for oral HRT or the combined oral contraceptive pill.
The study has immediate implications for frontline clinical care, since a recent UK audit found that around a quarter of women with anorexia-related FHA are prescribed the oral contraceptive pill to address bone loss. This study suggests such treatment is suboptimal and should be replaced by more effective alternatives like transdermal HRT.
"This study provides much-needed evidence to improve practice and underpin future bone guidelines for this common condition," the researchers noted, emphasizing that the results could drive immediate improvements in how a wide range of specialists—from endocrinologists, GPs, rheumatologists, gynaecologists to psychiatrists—treat the disorder. The researchers added that patients considering their treatment plan should speak to their GP or bone health specialist in the first instance and before making any decisions.
Dr Agathoklis Efthymiadis, Clinical Research Fellow at Imperial College London, said: "Our study provides robust data to improve the management of this condition and inform practice guidelines. Given the present fragmented management of women with amenorrhoea, we believe this will be of interest not just to GPs but to a wide range of specialists, from gynaecologists, rheumatologists and endocrinologists. Our goal is simple: to help women receive the right treatment sooner and to protect their bone health in the long-term."
Reflecting a modern approach to clinical research, the researchers shared the findings with women personally affected by FHA, from the Imperial Endocrine Bone Unit at St Mary's Hospital (part of Imperial College Healthcare NHS Trust), and their insights were also included in the paper.
Professor Alexander Comninos, Professor of Practice at Imperial College London and Consultant Endocrinologist at Imperial College Healthcare NHS Trust where he heads the Endocrine Bone Unit, is the senior author of the study. He said: "Bone density is lost very rapidly in FHA and so addressing bone health early is of paramount importance to reduce the lifelong risk of fractures. Our study provides much-needed comparisons of all the available treatments from all available studies.
"Clearly the best treatment is restoration of their normal menstrual cycles and therefore oestrogen levels through various psychological, nutritional or exercise interventions - but that is not always possible unfortunately. The foundation for bone health is good calcium and vitamin D intake (through diet and/or supplements) but we have additional more effective treatments."
'While teriparatide showed benefits at the spine only, we established that giving oestrogen through the skin, or transdermally, improved both bone density in the spine and at the neck of the femur."
The researchers say there are good scientific reasons why giving the oestrogen transdermally is better than orally and that it was reassuring to see this reflected in the overall results. For example, they say, oral oestrogens can reduce certain bone-forming hormones, whereas transdermal oestrogens do not. Oral oestrogens may typically result in lower 'active' oestrogens compared to transdermal oestrogen.
Professor Comninos added: "We hope this study provides clinicians with better evidence to choose transdermal oestrogen when prescribing oestrogen and so inform future practice guidelines. This is important as millions of women with FHA may not at present be receiving the best treatments for their bone health.".
Further large studies are needed in this area directly comparing different forms of oestrogen and progesterone, and in women with different causes of FHA, for example due to purely intense exercise or anorexia nervosa.
The researchers were supported by grants from the Medical Research Council (MRC) and National Institute for Health and Care Research (NIHR), with wider support from the NIHR Imperial Biomedical Research Centre (BRC).
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Pharmacological Interventions to Improve Bone Density in Functional Hypothalamic Amenorrhea: A Systematic Review and Network Meta-Analysis of Randomized Clinical Trials Open Access. Agathoklis Efthymiadis , Konstantinos Tsikopoulos , Edouard G Mills , Andrew Milne , Waljit S Dhillo , Ali Abbara , Alexander N Comninos (corresponding author).
The Journal of Clinical Endocrinology & Metabolism, February 2026 https://doi.org/10.1210/clinem/dgag005
