Lasofoxifene for the prevention and treatment of postmenopausal osteoporosis

Lewiecki, E. Michael

doi:10.2147/tcrm.s5645

Cited by 21 publications

(17 citation statements)

References 67 publications

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“…It is unclear which chemical structural features are responsible for such an action profile. As pointed out above, lasofoxifene belongs to the naphthalene class of SERMs, and an account of its structure-activity relationship and other pharmacological properties has been reported recently [48].…”

Section: New Sermsmentioning

confidence: 97%

Enhancing Endothelial Progenitor Cell Function Through Selective Estrogen Receptor Modulation: A Potential Approach to Cardiovascular Risk Reduction

Cignarella

Fadini

2010

CHAMC

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Estrogen receptors (ER) have been targets of pharmacological intervention for decades. The use of menopausal hormone therapy (MHT) for improving cardiovascular health is associated with serious adverse effects and therefore cannot be recommended as a first-line strategy. While recently menopausal women in good cardiovascular health may be more likely to benefit from MHT than older women with worse risk profiles, adverse MHT effects such as increased risk for stroke have been consistently shown. Selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene have been developed to avoid such negative aspects of MHT. Based on available evidence, however, SERMs are not endowed with greater cardiovascular efficacy and safety than conventional MHT. By contrast, the newly developed SERM lasofoxifene has been shown to reduce cardiovascular events in post-menopausal women, although it also increased venous thromboembolic events in line with other ER-targeting agents. Fundamental research has shown that endothelial progenitor cells are important targets of estrogen actions in the cardiovascular system. This indicates that preferential targeting of specific cells and tissues is likely to enhance safety over nonselective hormone agents. Similarly, increased ER-isoform selectivity along with deeper understanding of ER biology should assist in designing novel ER modulators that are more effective and safer than currently used agents. In this article, we summarize the potential connections between SERMs and EPC biology, uncovering novel possible routes to cardiovascular risk reduction.

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Section: New Sermsmentioning

confidence: 97%

Enhancing Endothelial Progenitor Cell Function Through Selective Estrogen Receptor Modulation: A Potential Approach to Cardiovascular Risk Reduction

Cignarella

Fadini

2010

CHAMC

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“…Lasofoxifene demonstrates high-affinity selective binding to both ER and ER receptors [59]. Unlike bazedoxifene, it is characterized by a remarkable oral bioavailability, which is attributed to increased resistance in intestinal wall glucuronidation [60,61]. Lasofoxifene has demonstrated linear pharmacokinetics over a wide dose range (from 0.01 to 100 mg/d), and interestingly a Cmax of ~ 6 hours.…”

Section: Selective Estrogen Receptor Modulators (Serms)mentioning

confidence: 99%

“…Dosing regimens were compared in a phase II RCT were BMD increase was measured as a biomarker with both doses of lasofoxifene, compared with baseline ( increases of 1.8% and 2.2% for 0.25 mg and 1.0 mg/day, respectively, p ≤ 0.05), and with placebo (3.6% and 3.9% for 0.25 mg and 1.0 mg/day, respectively, p ≤ 0.05) [61]. Lasofoxifene has been evaluated in multiple phase To date, the FDA has yet to approve the use of lasofoxifene following the last rejection in January 2009.…”

Section: Selective Estrogen Receptor Modulators (Serms)mentioning

confidence: 99%

Current and emerging osteoporosis pharmacotherapy for women: state of the art therapies for preventing bone loss

Fontalis

Kenanidis

Kotronias

et al. 2019

Expert Opinion on Pharmacotherapy

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Introduction: Pharmacological options to address the imbalance between bone resorption and accrual in osteoporosis include anti-resorptive and osteoanabolic agents. Unique biologic pathways such as Wnt/-catenin pathway have been targeted in the quest for new emerging therapeutic strategies. Areas Covered: This review aims to provide an overview of existing pharmacotherapy for osteoporosis in women and explore state-of-the-art and emerging therapies to prevent bone loss, with an emphasis on the mechanism of action, indications and side effects. Expert Opinion: Bisphosphonates appear to be a reliable and cost-effective option, whereas denosumab has introduced a simpler dosing regimen and may achieve a linear increase in BMD with no plateau being observed, along with continuous anti-fracture efficacy. Selective estrogen receptor modulators (SERMs) are synthetic non-steroidal agents which have varying estrogen agonist and antagonist activities in different tissues and antifracture efficacy. Abaloparatide, a parathyroid-hormone-related peptide (PTHrP)-analogue, approved by the FDA in April 2017, constitutes the first new anabolic osteoporosis drug in the US for nearly 15 years and has also proven its anti-fracture efficacy. Romosozumab, a sclerostin inhibitor, which induces bone formation and suppresses bone resorption, has also been developed and shown anti-fracture efficacy; however, concerns have arisen with regard to increased cardiovascular risk.

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“…5, 11-13 Although it has not received FDA approval in the US, 14 LAS was approved by the European Commission for the treatment of osteoporosis in postmenopausal women at increased risk for fracture in March, 2009. 15 …”

Section: Introductionmentioning

confidence: 99%

Selective Estrogen Receptor Modulator (SERM) Lasofoxifene Forms Reactive Quinones Similar to Estradiol

Michalsen

Gherezghiher

Choi

et al. 2012

Chem. Res. Toxicol.

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The bioactivation of both endogenous and equine estrogens to electrophilic quinoid metabolites has been postulated as a contributing factor in carcinogenic initiation and/or promotion in hormone sensitive tissues. Bearing structural resemblance to estrogens, extensive studies have shown that many selective estrogen receptor modulators (SERMs) are subject to similar bioactivation pathways. Lasofoxifene (LAS), a third generation SERM which has completed Phase III clinical trials for the prevention and treatment of osteoporosis, is currently approved in the European Union for this indication. Previously, Prakash et al. (Drug Metab. Dispos. 2008, 36, 1218-26) reported that similar to estradiol, two catechol regioisomers of LAS are formed as primary oxidative metabolites, accounting for roughly half of total LAS metabolism. However, the potential for further oxidation of these catechols to electrophilic o-quinones has not been reported. In the present study, LAS was synthesized and its oxidative metabolism investigated in vitro under various conditions. Incubation of LAS with tyrosinase, human liver microsomes, or rat liver microsomes in the presence of GSH as a trapping reagent resulted in formation of two mono-GSH and two di-GSH catechol conjugates which were characterized by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Similar conjugates were also detected in incubations with P450 3A4, P450 2D6, and P450 1B1 supersomes. Interestingly, these conjugates were also detected as major metabolites when compared to competing detoxification pathways such as glucuronidation and methylation. The 7-hydroxylasofoxifene (7-OHLAS) catechol regioisomer was also synthesized and oxidized either chemically or enzymatically to an o-quinone that was shown to form depurinating adducts with DNA. Collectively, these data show that analogous to estrogens, LAS is oxidized to catechols and o-quinones which could potentially contribute to in vivo toxicity for this SERM.

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Lasofoxifene for the prevention and treatment of postmenopausal osteoporosis

Cited by 21 publications

References 67 publications

Enhancing Endothelial Progenitor Cell Function Through Selective Estrogen Receptor Modulation: A Potential Approach to Cardiovascular Risk Reduction

Enhancing Endothelial Progenitor Cell Function Through Selective Estrogen Receptor Modulation: A Potential Approach to Cardiovascular Risk Reduction

Current and emerging osteoporosis pharmacotherapy for women: state of the art therapies for preventing bone loss

Selective Estrogen Receptor Modulator (SERM) Lasofoxifene Forms Reactive Quinones Similar to Estradiol

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