Estetrol Reduces Bone Turnover Markers in Postmenopause

CHICAGO — Two bone turnover markers were significantly lower at 3 months and 1 year in postmenopausal women who received estetrol (E4) compared with patients who received placebo, according to a study presented September 12 at the annual meeting of The Menopause Society.
The findings suggest that “E4 has a potentially beneficial effect on maintenance of bone and therefore prevention of osteoporosis in postmenopausal women,” Amanda Black, MD, of the University of Ottawa in Canada, told attendees in her presentation. 
Women lose an estimated 10%-12% of hip and spine bone across the full menopause transition, with up to 0.5% reductions in bone per year after menopause. Among the bone markers that can be used to track bone remodeling are the bone resorption marker type 1 collagen C-terminal peptide (CTX-1) and the bone formation markers osteocalcin and procollagen type 1 N-terminal propeptide (P1NP).
“CTX-1 and P1NP are the bone turnover markers that the International Osteoporosis Foundation has identified as the most promising for clinical use, and reductions of CTX-1 and P1NP seem to be predictive of improvement in bone mineral density and a decrease in fracture risk,” Black said. 
Estetrol is a native estrogen produced by the fetal liver during pregnancy with agonistic actions on the bone, vagina, brain, and vascular system but antagonistic or neutral actions on the liver and breast. James Simon, MD, a clinical professor of obstetrics and gynecology at The George Washington University School of Medicine and medical director of IntimMedicine in Washington, DC, was not involved in the study but offered additional perspectives on the potential of E4. 
“It’s a very weak estrogen that seems to have different activity in different tissues — estrogen agonist–like activity in some, estrogen-antagonist activities in others — and it happens to be that the distribution of estrogen-agonist activity and estrogen-antagonist activity are just what we would want: anti-estrogenic in the breast, estrogenic in bone, the brain, and the uterus.” But that also feels a little too good to be true without additional evidence, Simon suggested. “It requires bigger, longer clinical investigations to prove.” 
E4 has been shown in previous studies to significantly reduce the frequency and severity of menopausal vasomotor symptoms with minimal impact on metabolic and hemostasis parameters and potential benefits on lipids and glucose metabolism, Black told attendees. Currently, the only E4 approved by the US Food and Drug Administration is an oral contraceptive made of 15 mg of E4 and 3 mg of drospirenone, but there’s hope that it will be approved for treatment of moderate to severe vasomotor symptoms, she said. 
Data from a phase 2 study suggest that E4 could be beneficial for bone health, with decreased osteocalcin and CTX-1 compared with placebo. In this phase 3 study, the researchers assessed bone turnover markers after 12 weeks and 52 weeks of E4 treatment. 
The trial enrolled 579 postmenopausal women, aged 40-65, at 122 sites throughout the United States and Canada. The women reported at least seven moderate to severe daily vasomotor symptoms or at least 50 in the week before randomization, and they needed to have stable blood pressure below 130/80 mm Hg. Participants were excluded if they had a history of any malignancy, thromboembolism or coagulopathy, breast cancer, or uncontrolled diabetes. Non-hysterectomized participants were excluded if they had a history of uterine cancer, endometrial hyperplasia, polyp, or abnormal cervical smear, and they received a 14-day consecutive dose of 200 mg micronized progesterone at the end of the 52 weeks. 
Two groups received E4 — 192 women received 15 mg and 193 women received 20 mg — while the remaining 194 women received placebo. Blood samples taken at 12 and 52 weeks assessed calcium, vitamin D, CTX-1, and P1NP. 
At week 12, the least-squares mean change from baseline for CTX-1 was -0.15 µg/L in both the 15 mg and 20 mg groups, compared with -0.02 µg/L in the placebo group (P < .0001 for both comparisons). At 52 weeks, the placebo group remained stable at -0.02 µg/L while the 15 mg group was at -0.19 and the 20 mg group was at -0.16 (P < .001). 
The least-squares mean change from baseline at 12 weeks for P1NP was -8.45 µg/L in the 15 mg group and -13.84 in the 20 mg group, compared with -2.22 in the placebo group (P = .022 and P < .0001, respectively). At 52 weeks, the 15 mg group was -16.08 µg/L and the 20 mg group was -13.83 µg/L, compared with -0.15 µg/L in the placebo group (P < .0001). 
“Calcium and vitamin D were also measured, and calcium decreased significantly in both E4 groups at week 12 and at week 52” while vitamin D levels remained the same, Black said. “Remember, with calcium, the goal is to avoid a high bone turnover, which leads to bone loss, and estrogen can actually increase calcium absorption directly. So, a reduction in calcium levels is actually a good thing from a bone perspective.” 
The study was limited by looking only at bone turnover markers with no bone mineral density assessments performed. In addition, no head-to-head studies exist of E4 against other types of estrogen. 
Simon said the study suggests that E4 looks good in terms of its effects on bone, “but until we see whether or not there are fracture reductions, it’s very difficult to say that the surrogate endpoint is meaningful and has relevance to humans,” he said. 
Fracture studies are expensive and can take nearly a decade to conduct, so researchers need to rely instead on fracture studies in animals with shorter lifespans and on intermediate markers as surrogate endpoints, he said. While E4 currently looks positive in terms of hot flashes, vaginal dryness, and bone turnover, Simon noted that past agents have been developed for osteoporosis which dramatically increased bone density but were then problematic because they resulted in brittle bones instead of strong ones. 
Seeing data on fractures from animal studies would help support the surrogate markers seen in this study. Until then, Simon remains cautiously optimistic. “We’ve been faked out on bones before,” he said. “We just need all of the stars to align before we can see the whole picture.”
The research was funded by Estetra SRL, an affiliate company of Mithra Pharmaceuticals. Dr Black reported consulting or serving on the advisory board for Organon, Bayer, Pfizer, Searchlight, and Estetra SRL. Dr Simon has grant/research support, consulting/advisory board participation, and/or speaking disclosures with AbbVie, Bayer Healthcare, Besins Healthcare, California Institute of Integral Studies, Camargo Pharmaceutical Services, Covance, Daré Bioscience, DEKA M.E.L.A S.r.l., Femasys, Ipsen, KaNDy/NeRRe Therapeutics, Khyria, Madorra, Mayne Pharma, Mitsubishi Tanabe Pharma Development America, Mylan/Viatris Inc., Myovant Sciences, ObsEva SA, Pfizer, Pharmavite, QUE Oncology, Scynexis, Sebela Pharmaceuticals, Sprout Pharmaceuticals, TherapeuticsMD, Vella Bioscience and Viveve Medical, and he is a stockholder in Sermonix Pharmaceuticals. 
Tara Haelle is a Dallas-based medical journalist. 
 
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