Protecting Bone Health With GnRH Antagonist Treatment for Endometriosis

Key Takeaways:

• GnRH antagonists induce estrogen suppression, creating a dose-dependent risk for bone mineral density (BMD) loss.
• Baseline risk stratification and ongoing monitoring are essential to identify patients susceptible to accelerated bone loss.
• Fixed-dose combination therapy incorporates add-back hormones to preserve BMD, allowing for extended treatment durations compared to monotherapy.

Gonadotropin-releasing hormone (GnRH) antagonists represent a significant advancement in managing endometriosis-associated pain.¹

Unlike GnRH agonists, which initially stimulate the pituitary gland before causing downregulation, GnRH antagonists competitively bind to pituitary GnRH receptors, resulting in a rapid, dose-dependent suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This suppression reduces ovarian estrogen production, effectively managing the estrogen-dependent pathophysiology of endometriosis. GnRH antagonists do not cause the same flare in endometriosis symptoms during the initial pituitary gland stimulation as agonists do, which could be a benefit for patients.¹

However, the resulting hypoestrogenic state presents a clinical challenge: the preservation of bone mineral density (BMD). Because estrogen is critical for inhibiting bone resorption, prolonged suppression can lead to accelerated bone loss and increased fracture risk. For healthcare providers, optimizing patient outcomes requires balancing the efficacy of pain relief with the mitigation of hypoestrogenic side effects, particularly regarding long-term bone health.^1,2

Mitigating bone loss with combination therapy

To address the limitations imposed by hypoestrogenism, "add-back" therapy – the co-administration of low-dose estrogen and progestin – has become a standard approach.¹

The goal is to maintain estradiol levels within a "therapeutic window" (typically 30 to 50 pg/mL) that is sufficient to protect bone density and minimize vasomotor symptoms, yet low enough to suppress endometriotic tissue growth.¹

Comparative profiles of GnRH antagonists

Two primary oral GnRH antagonists are currently available for endometriosis management: elagolix and relugolix. Their effect on bone health differs significantly based on formulation and dosing strategies.¹

Elagolix (Orilissa)

Elagolix is available as a monotherapy in 2 dosages: 150 mg once daily and 200 mg twice daily.^1,2

• Bone safety – In clinical trials (Elaris EM-I and EM-II), elagolix demonstrated a dose-dependent decrease in BMD. At week 52, the 200 mg twice-daily dose was associated with a greater than 3.5 percent decrease in lumbar spine BMD, compared to approximately 1 percent for the lower dose.
• Duration limits – Due to these risks, the FDA limits the duration of use. The 150 mg dose is limited to 24 months, while the 200 mg dose is limited to 6 months.
• Add-back status – Elagolix for endometriosis is approved as a monotherapy, although clinicians may prescribe add-back therapy off-label to mitigate side effects. (This is not combination therapy.)

Relugolix combination therapy (Myfembree)

Relugolix is available as a once-daily fixed-dose combination tablet containing relugolix (40 mg), estradiol (1 mg), and norethindrone acetate (0.5 mg). This formulation integrates add-back therapy directly into the treatment regimen.^1,3

• Bone safety data – The pivotal Phase 3 SPIRIT 1 and SPIRIT 2 trials evaluated the safety and efficacy of relugolix combination therapy over 24 weeks. It showed that Relugolix does not worsen bone health. Study results demonstrated a mean BMD loss of less than 1 percent at the lumbar spine, which was not clinically meaningful compared to placebo.
• Long-term maintenance – Data from the SPIRIT long-term extension study showed that BMD remained stable through 52 weeks and up to 104 weeks of treatment. This suggests that the add-back component effectively mitigates the hypoestrogenic bone loss typically associated with GnRH antagonism.
• Duration – Supported by this safety profile, relugolix combination therapy is FDA-approved for use for up to 24 months.

Monitoring bone health

The impact of GnRH antagonists on BMD is dose- and duration-dependent. Therefore, baseline risk stratification is essential before initiating therapy.^1,2

• Baseline assessment – FDA prescribing information for elagolix recommends considering a baseline BMD assessment in patients with a history of low-trauma fracture or other risk factors for osteoporosis. For relugolix combination therapy, DXA scans are recommended at baseline for patients with known risk factors for bone loss./li>
• Contraindications – Use of GnRH antagonists is generally contraindicated in women with known osteoporosis due to the risk of further bone loss./li>
• Ongoing monitoring – Periodic BMD assessment is recommended for patients on long-term therapy or those with coexisting risk factors./li>

Providers should also encourage lifestyle changes to support bone health, including weight-bearing exercise, smoking cessation, and adequate intake of calcium and Vitamin D.

Minimizing long-term risks to patients’ bone health

Preserving bone health is a critical component of long-term endometriosis management. While GnRH antagonists offer pain reduction, their mechanism of action necessitates careful attention to skeletal integrity.^1-3

Current clinical data indicates that fixed-dose combination therapies, such as relugolix with estradiol and norethindrone acetate, successfully uncouple efficacy from adverse bone events, maintaining BMD stability over 2 years of treatment. By utilizing these regimens and adhering to monitoring guidelines, healthcare providers can deliver effective symptom relief while minimizing long-term risks to patient health.^1-3