For women who have stopped menstruating due to anorexia and/or excessive exercise — a condition known as functional hypothalamic amenorrhea (FHA) — the use of transdermal hormone replacement therapy (HRT) with estrogen shows significantly greater efficacy in preventing the bone loss compared with oral HRT, according to a new meta-analysis.

“This is important as millions of women with FHA may not at present be receiving the best treatments for their bone health,” said senior author Alexander Comninos, PhD, professor of practice at Imperial College London and head of the Endocrine Bone Unit at Imperial College Healthcare NHS Trust, London, England, in a press statement for the study, which was published in The Journal of Clinical Endocrinology & Metabolism.

“We hope this study provides clinicians with better evidence to choose transdermal estrogen when prescribing estrogen and so inform future practice guidelines,” he said.

FHA accounts for roughly 30% of early-onset amenorrhea and the characteristic drop in estrogen levels poses a high risk for bone loss and fractures.

As many as 44% of women with FHA reportedly have low bone mineral density (BMD) vs only about 1% of healthy women, the authors noted, and the risk for bone fracture is increased by up to sevenfold compared with the general population.

While lifestyle and exercise modification and psychological stress reduction are first-line treatments, research shows that up to 68% of women do not recover menstruation after 1 year of those interventions and approximately 30% remain amenorrheic after 9 years of follow-up.

In such cases, hormonal options are recommended, including HRT containing estrogen, and the combined oral contraceptive pill (COCP), and as well as osteoporosis drugs including off-label teriparatide.

Of note, while transdermal is the route of estrogen recommended as first-line pharmacotherapy, in guidelines such as those of the Endocrine Society, the recommendation is said to represent “very low” certainty due to weak evidence, and recommendations for COCP use are also with a “low” level of evidence.

A Meta-Analysis of 13 Randomized Controlled Trials (RCTs)

To better understand those strategies, the authors conducted a network meta-analysis of 13 RCTs involving 897 women with FHA.

The trials evaluated interventions for lumbar spine BMD (n = 897), femoral neck BMD (n = 370), or total hip BMD (n = 750).

For the primary outcome of lumbar spine BMD changes, transdermal HRT provided significantly greater improvement over placebo or no intervention (standardized mean difference [SMD], 0.34), with benefits also observed in femoral neck BMD (SMD, 0.57).

In contrast, no significant benefit was observed for oral HRT (SMD, 0.13) or for COCP (SMD, 0.07) in lumbar spine or any other BMD site.

Meanwhile, the osteoporosis drug teriparatide was superior to transdermal HRT and COCP for lumbar spine BMD (hazard ratio [HR], 1.48) and (HR, 1.75), respectively, but not for femoral neck or total hip BMD.

“To our knowledge, this is the first network meta-analysis evaluating this clinical conundrum by providing direct and indirect comparisons between available pharmacological interventions for women with persistent FHA,” the authors reported.

Differences Between Transdermal and Oral HRT

Key reasons why transdermal HRT has a more favorable effect on BMD include the fact that, unlike oral estrogens, the transdermal formulation does not suppress bone-anabolic IGF-1 or free estrogen, both of which are important for bone metabolism.

The findings are “potentially immediately practice-changing” in light of evidence that oral contraceptives are often used in FHA for bone loss, the authors stated. A recent UK audit showed that about a quarter of women with anorexia-related FHA were prescribed the oral contraceptive pill to address bone loss.

While teriparatide showed superiority to the other interventions in lumber spine improvements to BMD, the authors noted that “HRT may still be preferable for most women with FHA, given its additional clinical benefits, [including] endometrial and cardiovascular health, and quality of life.”

Of note, “teriparatide is generally reserved for adult FHA cases as an option in the setting of delayed fracture healing and very low BMD,” they added.

Importantly, teriparatide cessation after 2 years could result in the loss of the BMD gained while on treatment if menstruation is not restored.

In contrast, transdermal HRT can be used for an extended time frames, “providing longer-term bone protection, potentially for many years,” the study authors wrote.

The research underscores the need to “really take bone health seriously in FHA and consider treatment promptly if periods have not restarted after 6-12 months of lifestyle, psychological, and nutritional interventions,” Comninos told Medscape Medical News.

“We now provide better evidence that transdermal HRT is most effective mode of estrogen delivery for bone health in these women,” he added.

A ‘Reassuring and Robust Signal’

Commenting on the issue, Hannah Olivia Davies, MRCGP, MBBS, of Mid and South Essex NHS Foundation Trust, Leigh-on-Sea, England, who was lead author of the UK audit showing the high use of oral contraceptives for FHA bone loss, underscored that recovery of menstruation from FHA can be challenging.

“Unfortunately, full clinical and biochemical recovery from FHA is uncommon,” she explained to Medscape Medical News.

“Some individuals may experience the return of menses without normalization of hormonal profiles, others demonstrate biochemical recovery without menstrual resumption, and a proportion do not recover at all.”

Regarding the new analysis, Davies noted that “it is encouraging to see further research in this area, which remains significantly under-researched.”

“We still lack a clear consensus on the optimal estrogen regimen for managing bone loss in FHA, so any high-quality data are very welcome,” she added.

The findings importantly align with the existing evidence on the superiority of transdermal estradiol vs oral estradiol and COCP, she noted. “When evidence from multiple sources converges, this provides a reassuring and robust signal.”

Davies said she “fully agreed” that current guidelines should be updated to reflect the mounting data supporting transdermal HRT.

“Osteoporosis carries substantial morbidity and mortality, and the risks in this cohort are entirely predictable,” Davies added. “We therefore need to be far more proactive in mitigating long-term skeletal harm, including earlier intervention with estrogen therapy — the only intervention shown to meaningfully protect bone health in this population.”

Need Consistency in Practice Guidelines Across Specialties

Further commenting, Madhusmita Misra, MD, the Benjamin Armistead Shepherd Chair and professor of pediatrics at the University of Virginia, and Physician-in-Chief of UVA Health Children’s, in Charlottesville, noted that many recent guidelines include recommendations to use transdermal HRT (17-beta estradiol) rather than the COCP for bone health in FHA; however, she told Medscape Medical News, “we need practice guidelines across specialties to be consistent with these recommendations.”

“Particularly for adolescents with FHA, given that the teenage years are such a critical and narrow window in time to optimize bone accrual, and given that deficits incurred during this time may well have longstanding and permanent effects on bone health, there should be a low threshold to initiate replacement therapy with transdermal estradiol and cyclic progestin in these young women,” Misra said.

Ultimately, “at this time, it is important for practitioners to stop prescribing the combined oral contraceptive pill for the purpose of improving bone health in this population,” she said.

Comninos and Davies reported having no disclosures. Misra’s disclosures included that she has been a co-author on numerous FHA studies and has consulted for Regeneron.