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AS537 - A novel endogenous SERM and cholesterol metabolite, 27-hydroxcholesterol, and fracture risk in postmenopausal women

AS537 - A novel endogenous SERM and cholesterol metabolite, 27-hydroxcholesterol, and fracture risk in postmenopausal women

[This page is intended to provide a study summary, the sections of which are below. Please complete these sections, as applicable. The headings below are suggested headings. You can remove inapplicable sections, or add new ones relevant to your study]

Investigator Names and Contact Information

Jennifer Lee [ ]



Estrogens, including menopausal estrogen hormone therapies (MHT), prevent fractures and improve cholesterol levels, such as LDL-cholesterol, in postmenopausal women but have other well documented, and adverse health effects. Selective estrogen receptor modulators (SERMs) are ER ligands whose relative agonist/antagonist activity depends on their siteof action. Thus, SERMs can increase or decrease the risks of outcomes including fractures, cancers of breast and endometrium, cardiovascular disease, thromboembolism, cognition, and menopausal symptoms. Although a weaker agonist than estradiol (E2) or other estrogens used as MHT, drugs with SERM properties such as raloxifene also are used medically to prevent vertebral fractures, but also with adverse effects (Ettinger 1999).

Ideally, a SERM provides an optimally favorable outcomes profile across all estrogen influenced conditions.

The oxysterol 27-hydroxycholesterol (27HC), a major circulating cholesterol metabolite in humans, recently has been discovered to function as an endogenous SERM (DuSell 2010). Notably, unlike SERM drugs such as raloxifene and tamoxifen, this endogenous SERM acts as an estrogen antagonist in bone and adversely increases bone turnover in animal models (DuSell 2010). It also acts in bone to activate the liver X receptor(LXR), which in turn increases production of pro-osteoclastic cytokine, TNF-alpha (Nelson 2011, Nelson 2013).  With dual action as a SERM and LXR activator in bone, 27HC causes uncoupled osteoblastogenesis and osteoclastogenesis, above and beyond its SERM action alone (Nelson, 2011). Considering what is known pharmacologically, 27HC is expected to increase fracture risk and might attenuate estrogen benefit in bone.

Hypercholesterolemia is a risk factor for osteoporosis in postmenopausal women, independent of body mass index (BMI) (Tanko 2003, Orozco 2004, Tarakida 2011). Statins lower total cholesterol and LDL-C levels; although still debated (LaCroix 2003, Pena 2014), statins have been associated with both increased BMD and decreased fracture risk (Bauer 2004, Lupattelli 2004, Gotoh 2011). These findings put in context theobservations in preclinical animal studies that the negative impact of cholesterol on bone quality requires cholesterol's conversion to 27HC (Nelson, 2013). This abundant oxysterol is produced stoichiometrically from cholesterol, via the CYP27A1 enzyme in macrophages and other cell types (Su 2004). The mechanism for such a link could be that statins, by reducing the cholesterol substrate, lessen 27HC synthesis, thereby improving bone health. Thus it is possible that putative bone protection by statin is ascribed to their ability to reduce 27HC, secondary to lowering LDL-cholesterol.

Preclinical studies suggest that 27HC might be a predictor of such multiple outcomes and a drug target to improve such outcomes; 27HC also promotes breast cancer (as an estrogen agonist) and cardiovascular disease (as an estrogen antagonist) (Umetani 2011). Yet 27HC's effects on fractures and other health outcomes in aging women are unknown. Our goal here is to begin to determine the relationship between 27HC and fracture in postmenopausal women. Using an efficient approach, new collaborations, and unique WHI resources, we propose to test the hypotheses that: (a) elevated circulating 27HC increases susceptibility to fractures and (b) 27HC is a mechanistic link between cholesterol metabolism and bone health (Nelson, 2011).


Specific Aims

Aim 1: To describe the relationships between circulating 27-hydroxycholesterol (27HC) levels and

cholesterol levels and endogenous circulating estradiol (E2) levels.

Aim2: To assess the relationship of circulating 27HC levels to the risk of subsequent fracture.