TY - JOUR
T1 - 27-Hydroxycholesterol, an Endogenous SERM, and Risk of Fracture in Postmenopausal Women
T2 - A Nested Case-Cohort Study in the Women's Health Initiative
AU - Chang, Po Yin
AU - Feldman, David
AU - Stefanick, Marcia L.
AU - McDonnell, Donald P.
AU - Thompson, Bonne M.
AU - McDonald, Jeffrey G
AU - Lee, Jennifer S.
N1 - Funding Information:
This study received pilot feasibility contract funding from the NIH, National Heart, Lung and Blood Institute (NHLBI) subcontract HHSN268201100046C to JSL. The WHI program is funded by the U.S. Department of Health and Human Services, NIH, National Heart, Lung, and Blood Institute (NHLBI) through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C.
Funding Information:
This study received pilot feasibility contract funding from the NIH, National Heart, Lung and Blood Institute (NHLBI) subcontract HHSN268201100046C to JSL. The WHI program is funded by the U.S. Department of Health and Human Services, NIH, National Heart, Lung, and Blood Institute (NHLBI) through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. Authors? roles: Study design and conduct: PYC and JSL. Data collection: MLS. Data analysis: BMT and JGM. Statistical analysis: PYC. Data interpretation: PYC, DF, and JSL. Drafting manuscript: PYC. Revising manuscript content critically: PYC, DF, MLS, DPM, JGM, and JSL. Approving final version of manuscript: All authors. PYC and JSL have full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the statistical analysis.
Funding Information:
PYC was supported by the NIH, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant T32 DK007217. DPM received federal funding from the NIH, NIDDK grant DK48807. BMT and JGM were supported by the Center for Human Nutrition. JGM was supported by a Program Project Grant to Molecular Genetics (HL20948). All other authors declare that they have no conflicts of interest.
PY - 2019/1
Y1 - 2019/1
N2 - 27-Hydroxycholesterol (27HC) is a purported, novel endogenous SERM. In animal models, 27HC has an anti-estrogen effect in bone, and 17β-estradiol mitigates this effect. 27HC in relation to fracture risk has not been investigated in humans. Depending on the level of bioavailable 17β-estradiol (bioE 2 ), 27HC may increase fracture risk in postmenopausal women and modify the fracture risk reduction from menopausal hormone therapy (MHT). To test these a priori hypotheses, we conducted a nested case-cohort study of 868 postmenopausal women within the Women's Health Initiative Hormone Therapy (WHI-HT) trials. The WHI-HT tested conjugated equine estrogens versus placebo and separately conjugated equine estrogens plus progestin versus placebo. Fracture cases were 442 women who had an adjudicated incident hip or clinical vertebral fracture during the WHI-HT follow-up. The subcohort included 430 women randomly selected at WHI-HT baseline, four of whom had a subsequent fracture. Of the 868 women, 266 cases and 219 non-cases were assigned to the placebo arms. Cox models estimated hazard ratios for incident fracture in relation to pre-randomization circulating levels of 27HC and 27HC/bioE 2 molar ratio. Models adjusted for age, race/ethnicity, total cholesterol, bioE 2 , sex hormone-binding globulin, 25-hydroxyvitamin D, diabetes, osteoporosis, prior MHT use, BMI, falls history, and prior fracture. In women assigned to placebo arms, those in the middle and the highest tertiles of 27HC/bioE 2 had an up to 1.9-fold (95% confidence intervals, 1.25 to 2.99) greater risk of fracture than women in the lowest tertile. In women assigned to MHT arms, fracture risk increased with continuous 27HC/bioE 2 levels but not with categorical levels. 27HC levels alone were not associated with fracture risk. 27HC and 27HC/bioE 2 did not modify the fracture risk reduction from MHT. In postmenopausal women, circulating levels of 27HC relative to bioE 2 may identify those at increased risk of fracture.
AB - 27-Hydroxycholesterol (27HC) is a purported, novel endogenous SERM. In animal models, 27HC has an anti-estrogen effect in bone, and 17β-estradiol mitigates this effect. 27HC in relation to fracture risk has not been investigated in humans. Depending on the level of bioavailable 17β-estradiol (bioE 2 ), 27HC may increase fracture risk in postmenopausal women and modify the fracture risk reduction from menopausal hormone therapy (MHT). To test these a priori hypotheses, we conducted a nested case-cohort study of 868 postmenopausal women within the Women's Health Initiative Hormone Therapy (WHI-HT) trials. The WHI-HT tested conjugated equine estrogens versus placebo and separately conjugated equine estrogens plus progestin versus placebo. Fracture cases were 442 women who had an adjudicated incident hip or clinical vertebral fracture during the WHI-HT follow-up. The subcohort included 430 women randomly selected at WHI-HT baseline, four of whom had a subsequent fracture. Of the 868 women, 266 cases and 219 non-cases were assigned to the placebo arms. Cox models estimated hazard ratios for incident fracture in relation to pre-randomization circulating levels of 27HC and 27HC/bioE 2 molar ratio. Models adjusted for age, race/ethnicity, total cholesterol, bioE 2 , sex hormone-binding globulin, 25-hydroxyvitamin D, diabetes, osteoporosis, prior MHT use, BMI, falls history, and prior fracture. In women assigned to placebo arms, those in the middle and the highest tertiles of 27HC/bioE 2 had an up to 1.9-fold (95% confidence intervals, 1.25 to 2.99) greater risk of fracture than women in the lowest tertile. In women assigned to MHT arms, fracture risk increased with continuous 27HC/bioE 2 levels but not with categorical levels. 27HC levels alone were not associated with fracture risk. 27HC and 27HC/bioE 2 did not modify the fracture risk reduction from MHT. In postmenopausal women, circulating levels of 27HC relative to bioE 2 may identify those at increased risk of fracture.
KW - 27-HYDROXYCHOLESTEROL
KW - ESTRADIOL
KW - FRACTURE
KW - OXYSTEROL
KW - POSTMENOPAUSAL WOMEN
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UR - http://www.scopus.com/inward/citedby.url?scp=85058061634&partnerID=8YFLogxK
U2 - 10.1002/jbmr.3576
DO - 10.1002/jbmr.3576
M3 - Article
C2 - 30138538
AN - SCOPUS:85058061634
VL - 34
SP - 59
EP - 66
JO - Journal of Bone and Mineral Research
JF - Journal of Bone and Mineral Research
SN - 0884-0431
IS - 1
ER -