Changes in BMD, Bone Markers, and Reductions in Hot Flashes
Objective. A post hoc exploratory analysis was conducted to examine correlations between changes in bone density, bone markers, and hot flushes after the treatment of postmenopausal women with bazedoxifene (BZA)/conjugated estrogens (CE).
Methods. In a 2-year phase 3 study, 3,397 postmenopausal women were randomized to BZA 10 mg/CE 0.45 mg, BZA 20 mg/CE 0.45 mg, BZA 40 mg/CE 0.45 mg, BZA 10 mg/CE 0.625 mg, BZA 20 mg/CE 0.625 mg, BZA 40 mg/CE 0.625 mg, raloxifene 60 mg, or placebo. In this analysis, bone density changes at 2 years were compared with baseline levels of the bone markers serum C-telopeptide and osteocalcin. Correlations between changes in bone density and changes in 12-week hot flush composite scores in symptomatic women were also analyzed.
Results. Treatment with BZA 20 mg/CE 0.45 mg or BZA 20 mg/CE 0.625 mg increased lumbar spine bone density more in women with higher bone resorption and formation, categorized by baseline levels of C-telopeptide and osteocalcin (P < 0.001, both BZA/CE doses). With placebo, larger decreases in lumbar spine bone density were seen in the highest tertile of serum C-telopeptide. There was no correlation between changes in total hip bone density and baseline bone markers. There were significant correlations between percent change in hot flush score at week 12 and percent changes in lumbar spine (r = −0.31, P = 0.006) and total hip (r = −0.23, P = 0.044) bone densities at month 24.
Conclusions. With 2-year BZA/CE treatment, women with larger increases in lumbar spine and total hip densities also have higher baseline bone markers. Early reductions in hot flush score (12 wk) are predictive of long-term increases in bone density (24 mo).
According to the Study of Women's Health Across the Nation, approximately 60% to 85% of women in the United States experience vasomotor symptoms during menopause. These symptoms often cause sleep loss and mood changes and reduce quality of life in postmenopausal women. Reduced levels of endogenous estrogens in postmenopausal women also contribute to increased rate of bone loss and later risk of osteoporosis.
It has been reported that postmenopausal women who experience vasomotor symptoms have lower bone mineral density (BMD) at the spine, hip, and total body, and a higher risk of osteoporosis compared with women without vasomotor symptoms. Based on data from 5,600 women in the Eindhoven Perimenopausal Osteoporosis Study, mean spine BMD decreased with increasing frequency of hot flushes (P < 0.0001 for trend) and night sweats. Similar findings were reported from an analysis of 2,213 women in the Study of Women's Health Across the Nation; postmenopausal women with vasomotor symptoms had lower lumbar spine and total hip BMD than those without symptoms. In contrast to these findings, vasomotor symptoms were not associated with decreased BMD in older postmenopausal women in a study in which information was based on recall of symptoms many years earlier.
A selective estrogen receptor modulator (SERM), bazedoxifene (BZA), combined with conjugated estrogens (CE), has been used for the treatment of menopausal symptoms and the prevention of postmenopausal osteoporosis. In the 2-year Selective Estrogens, Menopause, and Response to Therapy (SMART)-1 trial, BZA 20 mg/CE 0.45 mg and BZA 20 mg/CE 0.625 mg significantly improved spine and total hip BMD and reduced levels of bone markers compared with placebo in postmenopausal women at risk for osteoporosis. BZA 20 mg/CE 0.45 mg and BZA 20 mg/CE 0.625 mg also significantly reduced the frequency and severity of hot flushes versus placebo in a subset of symptomatic women while ensuring endometrial and breast safety. In the SMART-2 trial that enrolled postmenopausal women with seven or more moderate to severe hot flushes per day, BZA 20 mg/CE 0.45 mg and BZA 20 mg/CE 0.625 mg significantly reduced the frequency and severity of hot flushes during 12 weeks of treatment.
The objective of this post hoc exploratory analysis of the SMART-1 trial was to correlate changes in BMD with baseline levels of bone markers and with reduction in hot flush severity in postmenopausal women treated with BZA/CE.
Abstract and Introduction
Abstract
Objective. A post hoc exploratory analysis was conducted to examine correlations between changes in bone density, bone markers, and hot flushes after the treatment of postmenopausal women with bazedoxifene (BZA)/conjugated estrogens (CE).
Methods. In a 2-year phase 3 study, 3,397 postmenopausal women were randomized to BZA 10 mg/CE 0.45 mg, BZA 20 mg/CE 0.45 mg, BZA 40 mg/CE 0.45 mg, BZA 10 mg/CE 0.625 mg, BZA 20 mg/CE 0.625 mg, BZA 40 mg/CE 0.625 mg, raloxifene 60 mg, or placebo. In this analysis, bone density changes at 2 years were compared with baseline levels of the bone markers serum C-telopeptide and osteocalcin. Correlations between changes in bone density and changes in 12-week hot flush composite scores in symptomatic women were also analyzed.
Results. Treatment with BZA 20 mg/CE 0.45 mg or BZA 20 mg/CE 0.625 mg increased lumbar spine bone density more in women with higher bone resorption and formation, categorized by baseline levels of C-telopeptide and osteocalcin (P < 0.001, both BZA/CE doses). With placebo, larger decreases in lumbar spine bone density were seen in the highest tertile of serum C-telopeptide. There was no correlation between changes in total hip bone density and baseline bone markers. There were significant correlations between percent change in hot flush score at week 12 and percent changes in lumbar spine (r = −0.31, P = 0.006) and total hip (r = −0.23, P = 0.044) bone densities at month 24.
Conclusions. With 2-year BZA/CE treatment, women with larger increases in lumbar spine and total hip densities also have higher baseline bone markers. Early reductions in hot flush score (12 wk) are predictive of long-term increases in bone density (24 mo).
Introduction
According to the Study of Women's Health Across the Nation, approximately 60% to 85% of women in the United States experience vasomotor symptoms during menopause. These symptoms often cause sleep loss and mood changes and reduce quality of life in postmenopausal women. Reduced levels of endogenous estrogens in postmenopausal women also contribute to increased rate of bone loss and later risk of osteoporosis.
It has been reported that postmenopausal women who experience vasomotor symptoms have lower bone mineral density (BMD) at the spine, hip, and total body, and a higher risk of osteoporosis compared with women without vasomotor symptoms. Based on data from 5,600 women in the Eindhoven Perimenopausal Osteoporosis Study, mean spine BMD decreased with increasing frequency of hot flushes (P < 0.0001 for trend) and night sweats. Similar findings were reported from an analysis of 2,213 women in the Study of Women's Health Across the Nation; postmenopausal women with vasomotor symptoms had lower lumbar spine and total hip BMD than those without symptoms. In contrast to these findings, vasomotor symptoms were not associated with decreased BMD in older postmenopausal women in a study in which information was based on recall of symptoms many years earlier.
A selective estrogen receptor modulator (SERM), bazedoxifene (BZA), combined with conjugated estrogens (CE), has been used for the treatment of menopausal symptoms and the prevention of postmenopausal osteoporosis. In the 2-year Selective Estrogens, Menopause, and Response to Therapy (SMART)-1 trial, BZA 20 mg/CE 0.45 mg and BZA 20 mg/CE 0.625 mg significantly improved spine and total hip BMD and reduced levels of bone markers compared with placebo in postmenopausal women at risk for osteoporosis. BZA 20 mg/CE 0.45 mg and BZA 20 mg/CE 0.625 mg also significantly reduced the frequency and severity of hot flushes versus placebo in a subset of symptomatic women while ensuring endometrial and breast safety. In the SMART-2 trial that enrolled postmenopausal women with seven or more moderate to severe hot flushes per day, BZA 20 mg/CE 0.45 mg and BZA 20 mg/CE 0.625 mg significantly reduced the frequency and severity of hot flushes during 12 weeks of treatment.
The objective of this post hoc exploratory analysis of the SMART-1 trial was to correlate changes in BMD with baseline levels of bone markers and with reduction in hot flush severity in postmenopausal women treated with BZA/CE.
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