The first large prospective cohort study to examine the relationship between menopausal symptoms and bone health in postmenopausal women has found that those who experience moderate to severe hot flashes and night sweats during menopause tend to have lower bone mineral density and higher rates of hip fracture than peers with no menopausal symptoms.

The study followed thousands of women for eight years. After adjusting for age, body mass index and demographic factors, it found that women who reported moderate to severe hot flashes at baseline enrollment showed a significant reduction in the bone density in the femoral neck region of their hips over time and were nearly twice as likely to have a hip fracture during the follow-up period.

This study employed data and study participants from the Women’s Health Initiative (WHI) initiated by the U.S. National Institutes of Health (NIH) in 1991 to address major health issues causing morbidity and mortality in postmenopausal women.

The WHI consisted of three clinical trials and an observational study undertaken at 40 clinical centers throughout the US, including the University at Buffalo Clinical Center directed by Wactawski-Wende.

She says the research team examined data from 23,573 clinical trial participants, aged 50 to 79, who were not then using menopausal hormone therapy nor assigned to use it during the trial. They conducted baseline and follow-up bone density examinations in 4,867 of these women.

Wactawski-Wende says, “We knew that during menopause, about 60 percent of women experience vasomotor symptoms (VMS), such as hot flashes and night sweats. They are among the most bothersome symptoms of menopause and can last for many years.

“It also was known that osteoporosis, a condition in which bones become structurally weak and more likely to break, afflicts 30 percent of all postmenopausal women in the United States and Europe, and that at least 40 percent of that group will sustain one or more fragility fractures in their remaining lifetime,” she says.

“What we did not know,” says Wactawski-Wende, “was whether VMS are associated with reductions in bone mineral density or increased fracture incidence.

“Women who experience vasomotor menopausal symptoms will lose bone density at a faster rate and nearly double their risk of hip fracture,” she says, “and the serious public health risk this poses is underscored by previous research that found an initial fracture poses an 86 percent risk for a second new fracture.”

Wactawski-Wende says, “Clearly more research is needed to understand the relationship between menopausal symptoms and bone health. In the meantime, women at risk of fracture may want to engage in behaviors that protect their bones including increasing their physical activity and ensuring they have adequate intakes of calcium and vitamin D.”

Novel bioidentical estradiol vaginal capsule shows promise in pilot study

A novel estradiol vaginal gel cap containing low doses of solubilized bioidentical estradiol improved vaginal cytology and pH in healthy postmenopausal women, according to a presentation at the 25th annual meeting of The North American Menopause Society.

About a half-inch in size, TX-004HR (TherapeuticsMD) capsules of 10 mcg and 25 mcg were safe and well tolerated, with less systemic exposure than with equivalent doses of an existing vaginal estradiol tablet, suggesting another local option for treating menopause-related vulvovaginal atrophy, the researchers said.

“The idea is for the vaginal estrogen to work locally, you really don’t want to get systemic absorption,” James H. Pickar, MD, of Columbia University Medical Center, New York, told Endocrine Today. “That’s exactly what happened. We saw blood levels that were roughly half to a third of those seen with the FDA-approved product at similar doses.”

Pickar and colleagues initially conducted two randomized, single-dose, two-way crossover pharmacokinetic trials comparing the bioavailability of TX-004HR with that of an existing vaginal estradiol tablet (Reference).

Each trial involved 36 healthy postmenopausal women (BMI, 19-30 kg/m2) aged 40 to 65 years. Single vaginal doses of TX-004HR or Reference were administered, followed by single vaginal doses of the alternate therapy after a 14-day washout; one trial used 10-mcg doses and the other 15 mcg.

The scientists sampled blood pre- and post-insertion at set intervals for 24 hours and analyzed for concentration-time curve (AUC0-24), peak concentration (Cmax) and time to peak concentration (tmax) for estradiol and estrone.

Safety and efficacy of TX-004HR was then tested in a pilot study that included 50 healthy postmenopausal women (BMI ≤34 kg/m2) aged 40 to 75 years with at least one moderate to severe vulvovaginal atrophy symptom, superficial cells ≤5% and a vaginal pH >5. The women were randomly assigned to a single vaginal gel cap containing 10 mcg of solubilized 17beta-estradiol or placebo for 14 days.

AUC0-24 values were 63% (10 mcg) and 69% (25 mcg) less for estradiol and 50% (10 mcg) and 70% (25 mcg) less for estrone with TX-004HR vs. Reference, after baseline adjustments. Similar decreases were seen in Cmax values at 29% (10 mcg) and 46% (25 mcg) less for estradiol and 26% (10 mcg) and 55% (25 mcg) less for estrone with TX-004HR vs. Reference. Systemic exposure was significantly reduced with both doses of TX-004HR compared with equivalent doses of Reference. No adverse events were seen in either trial.

At the end of the 2-week pilot, women had higher mean increases from baseline with TX-004HR compared with placebo for superficial cells (35% vs. 4%; P=.0002) and intermediate cells (13% vs. 4%; P=.0002). The mean decrease from baseline in parabasal cells was greater with TX-004HR than placebo (54% vs. 5%; P=.0001), as was the mean decrease in vaginal pH (0.97 vs. 0.34; P=.0002).

“The next thing you would hope to see over time would be relief from symptoms including pain during intercourse, bleeding with intercourse, vaginal itching and burning — the standard symptoms you would see with vaginal atrophy,” Pickar said.

Women treated with TX-004HR also achieved greater improvements in vaginal epithelial integrity and secretions than with placebo. Improvement in vaginal symptoms was similar between groups, which the researchers attribute to small size and short duration.

In 14 of 50 women (28%), 17 treatment-emergent adverse events were observed, although not all were treatment-related. Eye contusion, nephrolithiasis, blood pressure increase, vaginal discharge, dysplasia or pruritus, vulvovaginal pain or burning, hot flush and cervical dysplasia occurred with TX-004HR. Paresthesia, vaginal hemorrhage or vulvovaginal discomfort occurred with placebo. Most events were mild and none were serious, the researchers said.

TherapeuticsMD is running a phase 3 Rejoice Trial for the investigational therapy in doses of 4 mcg, 10 mcg and 25 mcg.

“Our trial includes 700 women with vulvovaginal atrophy and dyspareunia,” Sebastian Mirkin, MD, chief medical officer of TherapeuticsMD, told Endocrine Today. “We are evaluating the effect of this compound over 12 weeks, fulfilling the regulatory guidelines for this particular indication. We expect to have it completed in late 2015.” – by Allegra Tiver

Ospemifene benefited postmenopausal women with vulvar, vaginal atrophy

In postmenopausal women with vulvar and vaginal atrophy, ospemifene showed higher responder rates than placebo in two phase 3 randomized trials and offered relief from symptoms, according to data presented at the 25th annual meeting of The North American Menopause Society.

Responder rates

Rates were better with 60 mg daily than 30 mg daily, and the effect ofospemifene (Osphena, Shionogi Inc.) could be attributed to improvement in vaginal physiology, including maturation value and pH, according to Risa Kagan, MD, of Sutter East Bay Medical Foundation, Berkeley, Calif.

Risa Kagan

Risa Kagan

“Oral ospemifene 60 mg per day demonstrated significantly higher responder rates than placebo in both trials, as did oral ospemifene 30 mg per day, which was only studied in one,” Kagan said.

The analysis was based on two double blind, placebo-controlled trials evaluating the efficacy and safety of ospemifene, approved by the FDA in 2013 for the treatment of dyspareunia in postmenopausal women.

In both studies, women aged 40 to 80 years were diagnosed with vulvar and vaginal atrophy (VVA) based on vaginal pH, maturation index in the vaginal smear and VVA symptoms reported at baseline.

In study A, 826 women were randomly assigned 1:1:1 to ospemifene 30 mg per day, 60 mg per day or placebo and followed for 12 weeks based on most bothersome symptom (MBS). In study B, 919 participants were stratified into two categories by MBS — moderate to severe dyspareunia or vaginal dryness — reported at baseline, then randomly assigned, respectively, 1:1 to ospemifene 60 mg daily or placebo for 12 weeks. Lubricants could be used by all women in both trials.

Kagan and considered objective measures, including the percentage of parabasal cells and vaginal pH, along with subjective measures, including self-reported VVA symptoms, as parameters to assess efficacy.

A responder was defined by: more than 10-unit increase from baseline in maturation value; vaginal pH decrease of at least 0.5 from baseline; and decrease in severity of MBS by at least one point from baseline.

“The criteria of a responder for this specific trial was chosen by the sponsor when designing the phase 3 trials and was agreed to by the US FDA,” Kagan said.

Responder percentage, either at week 12 or last observation carried forward (LOCF), was compared between groups. The researchers used Cochran-Mantel-Haenszel (CMH) general association test, controlling for study center and uterine status, in study A, and CMH row mean score test, controlling for stratum, in study B.

In study A, the responder percentage at week 12/LOCF was 20.6% (58/282) with ospemifene 30 mg and 33.7% (93/276) with 60 mg vs. 3.4% (9/268) with placebo. Both ospemifene groups showed higher responder rates than placebo, with 60 mg better than 30 mg (P<.001 for both).

The researchers conducted an exploratory analysis to assess the percentage of women who met individual criteria in the responder definition; 20.9% in the placebo, 48.9% in the ospemifene 30-mg and 54% in 60-mg groups were maturation value responders, and 32.1% in the placebo, 56.7% in the ospemifene 30-mg and 70.7% in 60-mg groups were vaginal pH responders (P<.001 vs. placebo, for both).

In study B, the responder percentage at week 12/LOCF was significantly higher with ospemifene 60 mg (39.7%, 184/463) than placebo (5.5%, 25/456; P<.0001). The percentage of maturation value responders was 65.7% with ospemifene 60 mg vs. 23% with placebo, and the percentage of pH responders was 70.4% with ospemifene vs. 34.9% with placebo (P<.0001, for both).

“Interpretation of the most bothersome symptom results may be confounded by the use of lubricant in these two trials,” Kagan said.

Subjective symptoms

Besides its effects on objective measures of vaginal epithelium physiology, ospemifene 60 mg daily alleviated subjective VVA symptoms, whether they were reported as MBS, according to Ginger D. Constantine, MD, of EndoRheum consultants, Malvern, Pa.

Ginger Constantine

Ginger D. Constantine

“Oral ospemifene 60 mg per day demonstrated improvements in the severity of the most bothersome symptom of dyspareunia and vaginal dryness,” Constantine said. “In one trial, both symptoms were significantly improved, and in the second trial only dyspareunia was significantly improved.”

Based on the same phase 3 trials, Constantine and colleagues compared women treated with ospemifene 60 mg daily (n=276) vs. placebo (n=278) in study A and study B (n=463 and n=456, respectively) to evaluate subjective endpoints of VVA, looking at both patient-reported MBS and all moderate to severe VVA symptoms.

The trials assessed: vaginal dryness, dyspareunia, vulvar and/or vaginal irritation/itching, difficult and/or painful urination and vaginal bleeding associated with sexual activity. Symptoms were self-reported at baseline, week 4 and week 12; those reported at baseline as moderate to severe were included in the analysis. The researchers used CMH row mean scores test to analyze change in the severity of VVA symptoms from baseline to week 4 or 12.

In study A, ospemifene demonstrated superiority over placebo at week 12 for all endpoints, including mean change in severity of MBS of dyspareunia (–1.19 vs. –0.89; P=.023) or MBS of vaginal dryness (–1.26 vs. –0.84; P=.021). At week 4, the change in severity of MBS dyspareunia or MBS vaginal dryness was numerically but not statistically improved with treatment vs. placebo.

Ospemifene showed superiority compared with placebo in VVA symptoms, regardless of being reported as MBS, including vaginal dryness at week 4 (P<.05) and week 12 (P<.001) and dyspareunia at week 12 (P<.05). Difficult/painful urination was numerically improved with treatment vs. placebo at week 12 (P=.052).

In study B strata, the mean changes in MBS of dyspareunia (n=605) were significantly different between groups at week 12 (P=.0001) and numerically different at week 4 (P=.1698); the mean change in MBS of vaginal dryness was not significant at week 12 (P=.0803) or week 4 (P=.1886).

Ospemifene was better than placebo in reducing the severity of dryness at both weeks 4 and 12 (P<.0001) for VVA symptoms reported as moderate or severe at baseline, regardless of being reported as MBS.

Severity of dyspareunia and vulvar and/or vaginal irritation/itching were significantly reduced with ospemifene (P=.0003) vs. placebo (P=.0421) at week 12. Numerical improvements were seen in severity of dyspareunia at week 4 (P=.2614) and vaginal bleeding associated with sexual activity at week 12 (P=.0691).

“The severity of VVA symptoms, when most bothersome symptom was not a construct, that were reported as moderate to severe at baseline was improved with regard to dyspareunia, vaginal dryness and itching and irritation.” – by Allegra Tiver



Study Highlights

  • Older women who eat foods with higher amounts of potassium may be at lower risk of stroke and death than women who consume less potassium-rich foods.
  • The health benefits from potassium-rich foods are greater among older women who do not have high blood pressure.
  • Most older American women do not eat the recommended amounts of potassium from foods.

Postmenopausal women who eat foods higher in potassium are less likely to have strokes and die than women who eat less potassium-rich foods, according to new research in the American Heart Association’s journal Stroke.

“Previous studies have shown that potassium consumption may lower blood pressure. But whether potassium intake could prevent stroke or death wasn’t clear,” said Sylvia Wassertheil-Smoller, Ph.D., study senior author and distinguished university professor emerita, department of epidemiology and population health at Albert Einstein College of Medicine, Bronx, NY.

“Our findings give women another reason to eat their fruits and vegetables. Fruits and vegetables are good sources of potassium, and potassium not only lowers postmenopausal women’s risk of stroke, but also death.”

Researchers studied 90,137 postmenopausal women, ages 50 to 79, for an average 11 years. They looked at how much potassium the women consumed, as well as if they had strokes, including ischemic and hemorrhagic strokes, or died during the study period. Women in the study were stroke-free at the start and their average dietary potassium intake was 2,611 mg/day. Results of this study are based on potassium from food, not supplements.

The researchers found:

    • Women who ate the most potassium were 12 percent less likely to suffer stroke in general and 16 percent less likely to suffer an ischemic stroke than women who ate the least.
    • Women who ate the most potassium were 10 percent less likely to die than those who ate the least.
    • Among women who did not have hypertension (whose blood pressure was normal and they were not on any medications for high blood pressure),  those who ate the most potassium had a 27 percent lower ischemic stroke risk and 21 percent reduced risk for all stroke types, compared to women who ate the least potassium in their daily diets.
  • Among women with hypertension (whose blood pressure was high or they were taking drugs for high blood pressure), those who ate the most potassium had a lower risk of death, but potassium intake did not lower their stroke risk.

Researchers suggested that higher dietary potassium intake may be more beneficial before high blood pressure develops. They also said there was no evidence of any association between potassium intake and hemorrhagic stroke, which could be related to the low number of hemorrhagic strokes in the study.

The U.S. Department of Agriculture recommends that women eat at least 4,700 mg of potassium daily. “Only 2.8 percent of women in our study met or exceeded this level. The World Health Organization’s daily potassium recommendation for women is lower, at 3,510 mg or more. Still, only 16.6 percent of women we studied met or exceeded that,” said Wassertheil-Smoller.

“Our findings suggest that women need to eat more potassium-rich foods. You won’t find high potassium in junk food. Some foods high in potassium include white and sweet potatoes, bananas and white beans.”

While increasing potassium intake is probably a good idea for most older women, there are some people who have too much potassium in their blood, which can be dangerous to the heart. “People should check with their doctor about how much potassium they should eat,” she said.

The study was observational and included only postmenopausal women. Researchers also did not take sodium intake into consideration, so the potential importance of a balance between sodium and potassium is not among the findings. Researchers said more studies are needed to determine whether potassium has the same effects on men and younger people.