Menopausal women with an intact uterus treated for a year with a daily, oral, single-pill formulation of estradiol and progesterone for the primary goal of reducing moderate to severe vasomotor symptoms showed evidence of reduced bone turnover in a post hoc, subgroup analysis of 157 women enrolled in the REPLENISH trial.
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These findings “provide support for a potential skeletal benefit” when menopausal women with an intact uterus regularly used the tested estradiol plus progesterone formulation to treat moderate to severe vasomotor symptoms (VMS), Risa Kagan, MD, and associates wrote in an abstract released ahead of the study’s scheduled presentation at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. ACOG canceled the meeting, and released abstracts for press coverage.
The reductions reported for three different markers of bone turnover compared with placebo control after 6 and 12 months on treatment with a U.S.-marketed estradiol plus progesterone formulation were ”reassuring and in line with expectations” said Lubna Pal, MBBS, professor of obstetrics, gynecology, and reproductive sciences at Yale University, New Haven, Conn., who was not involved with the study. But the findings fell short of addressing the more clinically relevant issue of whether the tested regimen reduces the rate of bone fractures.
Dr. Lubna Pal
“Only longer-term data can tell us whether this magnitude of effect is sustainable,” which would need to happen to cut fracture incidence, said Dr. Pal, who directs the menopause program at her center. “The reduction in bone-turnover markers is adequate, but magnitude alone doesn’t entirely explain a reduction in fractures.”
The bone-marker findings came from a post hoc analysis of data collected in REPLENISH (Safety and Efficacy Study of the Combination Estradiol and Progesterone to Treat Vasomotor Symptoms in Postmenopausal Women With an Intact Uterus), a phase 3 randomized trial run at 119 U.S. sites that during 2013-2015 enrolled 1,845 menopausal women aged 65 years with an intact uterus and with moderate to severe VMS. The researchers randomized women to alternative daily treatment regimens with a single, oral pill that combined a bioidentical form of 17 beta-estradiol at dosages of 1.0 mg/day, 0.50 mg/day, or 0.25 mg/day, and dosages of bioidentical progesterone at dosages of 100 mg/day or 50 mg/day, or to a placebo control arm; not every possible dosage combination underwent testing.
The original study’s primary safety endpoint was the incidence of endometrial hyperplasia after 12 months on treatment, and the results showed no such events in any dosage arm. The primary efficacy endpoints assessed the frequency and severity of VMS after 4 and 12 weeks on treatment, and the results showed that all four tested formulations of estradiol plus progesterone had similar, statistically significant effects on decreasing VMS frequency, and the four formulations reduced severity in a dose-dependent way (Obstet Gynecol. 2018 Jul;132[1]:161-70). Based in part on results from this pivotal trial, the 1-mg estradiol/100 mg progesterone formulation (Bijuva) received Food and Drug Administration marketing approval in late 2018.
The new analysis of bone-turnover markers focused on a subgroup of women selected from two of the drug-treated arms and control patients who had at least 50 moderate to severe VMS events per week at baseline, were at least 5 years out from their last menstrual period, and had data recorded for three markers of bone turnover at baseline, and after 6 and 12 months on treatment, according to the abstract published in Obstetrics and Gynecology.
The analysis included 56 women treated with 1.0 mg estradiol and 100 mg progesterone daily, 56 who received 0.5 mg estradiol and 100 mg progesterone daily, and 45 women in the placebo arm. It assessed changes from baseline in the on-treatment compared with placebo groups using immunoassays for bone-specific alkaline phosphatase (BSAP), C-terminal telopeptide of type 1 collagen (CTX-1), and N-terminal propeptide of type 1 procollagen (PINP). For this analysis, the researchers combined the two active-treatment arms, and found that all three markers showed statistically significant drops from baseline with treatment, compared with placebo at both 6- and 12-month follow-up. For all three markers, the declines on active treatment grew larger with time, and after 12 months the mean drops from baseline compared with placebo were an 18% relative reduction in BSAP, a 41% relative reduction in CTX-1, and a 29% relative reduction in PINP, reported Dr. Kagan, a gynecologist based in Berkeley, Calif., who is affiliated with the University of California San Francisco.
In addition to not yet providing more clinically meaningful results on bone fracture rates, Dr. Pal cited additional issues that limit interpretation of both these findings and the broader REPLENISH results. First, the new analysis of bone-turnover markers as reported in the abstract does not allow assessment of a possible dose-dependent effect on bone turnover. More importantly, while the full REPLENISH trial provided reassuring data on endometrial protection, it has not yet reported data on the other major safety concern of hormone replacement: the effects of treatment on breast cancer rates. “They need to show no harm” in breast tissue, Dr. Pal said in an interview. In addition, the positive effect reported on markers of bone turnover is not unique to this formulation. Other formulations with estrogen at similar dosages would have similar effects, she said.
Other considerations when using an oral formulation include the reduced risk for prothrombotic effects from estradiol when delivered transdermally instead of orally, although some women have trouble getting insurance coverage for transdermal formulations, Dr. Pal said. Oral estrogen is appropriate only for women without an elevated clotting risk. Daily progesterone treatment also is more problematic than a cyclical dosage regimen, but noncontinuous progesterone results in monthly bleeding, something that some women prefer to avoid. “I’m not convinced that continuous progesterone is a physiologic approach,” said Dr. Pal, a member of the Ob.Gyn. News editorial advisory board. In addition, some women may find the formulation attractive because both the estradiol and progesterone are bioidentical and not synthetic molecules.
In short, the oral estradiol plus progesterone formulation tested in REPLENISH “is another tool” that’s an option for selected menopausal women with a uterus. “The bone findings are in line with expectations and are reassuring. Long-term data are keenly awaited to understand whether the bone marker changes lead to fewer fractures. The impact of the treatment on breast safety will be especially important.” For women who want a bioidentical, oral option and to not have bleeding, the tested formulation can be an effective option providing both symptom benefit and endometrial protection, Dr. Pal said.
REPLENISH was funded by TherapeuticsMD, the company that markets the tested estradiol plus progesterone formulation (Bijuva). Dr. Kagan has been a consultant and adviser to and speaker on behalf of Therapeutics MD, and she has also been a consultant or adviser to or has spoken on behalf of AMAG, Amgen, Astellas, Lupin, Radius, and Warner Chilcott/Allergan, and she has received research funding from Endoceutics. Dr. Pal has been a consultant to Flow Health.
SOURCE: Kagan R et al. Obstet Gynecol. 2020 May;135:62S. doi: 10.1097/01.AOG.0000665076.20231.a8.