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Bryant, Henry U.

doi:10.1023/a:1010019410881

Cited by 45 publications

(9 citation statements)

References 65 publications

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“…The classical pathway of steroid hormone action was thought to involve high-affinity binding of the estrogen ligand to its receptor, movement of the ligand–receptor complex to the nucleus and subsequent transcriptional activation of nuclear genomic elements. Although the precise mechanism of action of estrogen and SERMs is still unknown, the pathways of estrogen action are clearly much more complex [13]. There appear to be multiple potential interactions for estrogen and its receptors (membrane-bound and nuclear) in the activation of genomic and non-genomic pathways, the subtype of the ER involved in nuclear transcription and multiple co-regulatory factors involved in nuclear responses.…”

Section: Raloxifenementioning

confidence: 99%

Treatment of osteoporosis and reduction in risk of invasive breast cancer in postmenopausal women with raloxifene

Jordan

2011

Expert Opinion on Pharmacotherapy

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Introduction Raloxifene, a non-steroidal selective estrogen receptor modulator (SERM), offers a new dimension for the treatment and prevention of osteoporosis and risk reduction of invasive breast cancer in postmenopausal populations at high risk. Both osteoporosis and breast cancer are important public health issues for postmenopausal women. It is well known that estrogen and estrogen receptors play an important role in the pathogenesis of both diseases. Initially, hormone replacement therapy (HRT) was used for the purpose of preventing and treating postmenopausal osteoporosis. However, HRT significantly contributed to an increase in breast cancer risk. The SERM, raloxifene, is used for the prevention and for the treatment of post-menopausal osteoporosis and reducing the risk of invasive breast cancer in postmenopausal women. Areas covered This article reviews the emerging evidence of the efficacy of raloxifene in postmenopausal women, summarizes the results and places in perspective their therapeutic uses for women having either a high risk of osteoporosis or breast cancer. Emerging clinical evidence suggests bisphosphonates, currently used as drugs for the treatment of osteoporosis, may also reduce breast cancer risk. The status of other SERMs and bisphosphonates are included for completeness. A Medline search of raloxifene, osteoporosis, breast cancer and SERMs was used to derive a database of 355 references. Expert opinion Readers will understand the value of raloxifene to prevent osteoporosis and breast cancer in postmenopausal women. Although most women do not require pharmacotherapy for menopausal symptoms, many are severely affected by osteoporosis or breast cancer at and beyond menopause and, for such women, pharmacologic intervention is important if they are to retain an acceptable quality of life. It is reasonable to use raloxifene or bisphosphonate as an appropriate drug that targets symptom-free postmenopausal women for treatment and prevention of osteoporosis but raloxifene is proven to reduce the incidence of invasive breast cancer.

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Section: Raloxifenementioning

confidence: 99%

Treatment of osteoporosis and reduction in risk of invasive breast cancer in postmenopausal women with raloxifene

Jordan

2011

Expert Opinion on Pharmacotherapy

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“…Raloxifene acts as an estrogen agonist in bone and reduces turnover by binding to estrogen receptors and acting through estrogen response elements and coregulator proteins (IL-6, IL-7, TGF-β, etc.) [37,86]. Turnover is reduced less with raloxifene than with zoledronate and other bisphosphonates both in women with osteoporosis and animals with replete estrogen levels [10,33].…”

Section: Discussionmentioning

confidence: 99%

“…As tissue age and the amount of turnover influence tissue properties [21, 22], Zoledronate was expected to alter these properties more markedly than raloxifene relative to the ovine model for osteoporosis because bisphosphonates reduce bone turnover to a greater degree than SERMs [33,36]. However, raloxifene treatment was expected to better restore cancellous tissue properties to those present in healthy, ovary intact female sheep, since SERMs act through natural estrogen receptor pathways [37]. …”

Section: Introductionmentioning

confidence: 99%

Variations in nanomechanical properties and tissue composition within trabeculae from an ovine model of osteoporosis and treatment

Burket

Brooks

MacLeay

et al. 2013

Bone

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Osteoporosis and treatment may affect both composition and nanomechanical properties and their spatial distributions within the individual trabeculae of cancellous bone at length scales that cannot be captured by bulk measurements. This study utilized 25 mature adult ewes divided into 5 treatment groups. Four treatment groups were given a dietary model for human high-turnover osteoporosis, and two of these were treated with antiresorptive drugs, either zoledronate (ZOL) or raloxifene (RAL), to examine their effects on bulk tissue properties and nanoscale tissue composition and mechanical properties within trabeculae. Treatment effects were most pronounced at the nanoscale, where RAL increased indentation modulus and hardness throughout trabeculae by 10% relative to the osteoporosis model. In comparison, ZOL increased these properties exclusively at the surfaces of trabeculae (indentation modulus + 12%, hardness +16%). Nanomechanical alterations correlated with changes in tissue mineralization, carbonate substitution, crystallinity, and aligned collagen. Despite only minimal changes in bulk tissue tBMD, the nanomechanical improvements within trabeculae with both treatments greatly improved the predicted theoretical bending stiffness of individual trabeculae when idealized as cylindrical struts. Hence, small tissue-level alterations in critical locations for resisting trabecular failure could account for some of the discrepancy between the large reductions in fracture risk and the only modest changes in BMD with antiresorptive treatments.

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“…Raloxifene suppresses osteoclast activity and bone remodeling in a manner similar to estrogen through high affinity interactions with ERα [4]. Compared to other anti-remodeling agents, such as bisphosphonates, raloxifene only modestly suppresses bone remodeling and induces little or no change in bone mineral density [5].…”

Section: Introductionmentioning

confidence: 99%

Bone cell-independent benefits of raloxifene on the skeleton: A novel mechanism for improving bone material properties

Gallant

Brown

Hammond

et al. 2014

Bone

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Raloxifene is an FDA approved agent used to treat bone loss and decrease fracture risk. In clinical trials and animal studies, raloxifene reduces fracture risk and improves bone mechanical properties, but the mechanisms of action remain unclear because these benefits occur largely independent of changes to bone mass. Using a novel experimental approach, machined bone beams, both from mature male canine and human male donors, were depleted of living cells and then exposed to raloxifene ex vivo. Our data show that ex vivo exposure of non-viable bone to raloxifene improves intrinsic toughness, both in canine and human cortical bone beams tested by 4-point bending. These effects are cell-independent and appear to be mediated by an increase in matrix bound water, assessed using basic gravimetric weighing and sophisticated ultrashort echo time magnetic resonance imaging. The hydroxyl groups (−OH) on raloxifene were shown to be important in both the water and toughness increases. Wide and small angle x-ray scattering patterns during 4-pt bending show that raloxifene alters the transfer of load between the collagen matrix and the mineral crystals, placing lower strains on the mineral, and allowing greater overall deformation prior to failure. Collectively, these findings provide a possible mechanistic explanation for the therapeutic effect of raloxifene and more importantly identify a cell-independent mechanism that can be utilized for novel pharmacological approaches for enhancing bone strength.

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Untitled

Cited by 45 publications

References 65 publications

Treatment of osteoporosis and reduction in risk of invasive breast cancer in postmenopausal women with raloxifene

Treatment of osteoporosis and reduction in risk of invasive breast cancer in postmenopausal women with raloxifene

Variations in nanomechanical properties and tissue composition within trabeculae from an ovine model of osteoporosis and treatment

Bone cell-independent benefits of raloxifene on the skeleton: A novel mechanism for improving bone material properties

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