Relugolix monotherapy and in combined therapy and its effects on bones: a systematic review

This project is a systematic review titled “Relugolix Monotherapy and in Combined Therapy and Its Effects on Bones: A Systematic Review”. The purpose of this review is to critically evaluate the impact of relugolix, both as a standalone treatment and in combination with estradiol and norethisterone acetate (NETA), on bone mineral density (BMD) in women of reproductive age diagnosed with uterine fibroids (UFs) and/or endometriosis. Uterine fibroids and endometriosis are common hormone-dependent gynecological disorders that cause significant morbidity and negatively affect the quality of life of millions of women globally. Traditional medical therapies, including GnRH agonists such as leuprolide, have shown efficacy but are limited by their hypoestrogenic side effects, particularly their detrimental effects on bone health. Relugolix, a novel non-peptide oral GnRH receptor antagonist, has emerged as a promising therapeutic option due to its rapid onset of action and avoidance of the initial hormonal flare typical of GnRH agonists. However, relugolix monotherapy is associated with estrogen suppression, which in turn may cause a decline in BMD and increase the risk of osteoporosis. To counteract these adverse effects, combination therapy with relugolix, estradiol (E2), and norethisterone acetate has been developed and approved in several regions. This combination therapy is designed to maintain the therapeutic benefits of relugolix while preserving bone health and minimizing vasomotor and urogenital symptoms. The present review was conducted following the PRISMA 2020 guidelines and includes a comprehensive search of PubMed, Medline, and the Cochrane Library. Additionally, clinical practice guidelines from major academic societies were consulted. Eligible studies included clinical trials and observational studies that assessed BMD outcomes in women treated with relugolix alone or in combination. Risk of bias was assessed using the Cochrane RoB 2 tool. Key findings were extracted and summarized in structured tables that address sample characteristics, treatment duration, BMD changes, and overall safety. Expected outcomes of this research include: - A detailed synthesis of the effects of relugolix monotherapy versus combination therapy on bone health; - A clearer understanding of how quickly and to what extent BMD declines during monotherapy, and how it stabilizes with the introduction of add-back therapy; - Practical implications for clinicians regarding the monitoring of BMD and the choice of therapeutic regimens for women with UFs or endometriosis; - Identification of gaps in the current literature, especially in relation to long-term (beyond two years) bone safety data.