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Luigi Gennari - One of the best experts on this subject based on the ideXlab platform.
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Lasofoxifene: Selective Estrogen Receptor Modulator for the Prevention and Treatment of Postmenopausal Osteoporosis
Annals of Pharmacotherapy, 2011Co-Authors: Gregory M. Peterson, L. Tichelaar, Mark Naunton, Luigi GennariAbstract:Objective:To review literature evaluating the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of Lasofoxifene (CP-336156), a selective estrogen receptor modulator (SERM) that is not approved for use in the US.Data Sources:Literature was accessed through the MEDLINE and EMBASE databases (1985-June 2010) using the terms Lasofoxifene and selective estrogen receptor modulators. Reference lists from retrieved articles were also manually reviewed. The Food and Drug Administration and Pfizer provided additional information.Study Selection and Data Extraction:All clinical trials evaluating Lasofoxifene were included in (his review. In addition, all articles evaluating the pharmacology, pharmacokinetics, and safety of Lasofoxifene in humans were reviewed. DATA SYNTHESIS: Lasofoxifene is a third-generation SERM with markedly higher in vitro and in vivo potency and oral bioavailability than other SERMs. The drug has produced significant improvements in bone density and biochemical markers of b...
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Lasofoxifene, from the preclinical drug discovery to the treatment of postmenopausal osteoporosis
Expert opinion on drug discovery, 2011Co-Authors: Luigi Gennari, Daniela Merlotti, Konstantinos Stolakis, Ranuccio NutiAbstract:Introduction: Estrogen replacement is traditionally seen as the gold standard for preventing osteoporotic fractures in postmenopausal women as well as for the management of menopausal symptoms. However, estrogen may lead to an increased risk of breast and, when unopposed by progestins, endometrial cancers. Alternative therapies include bisphosphonates and raloxifene, a selective estrogen receptor modulator (SERM). While the former have been associated with suboptimal adherence, the latter is considerably less potent than estrogen and its effect in the prevention of nonvertebral fractures remains uncertain. Hence, there is a need for additional effective medications to prevent fractures in postmenopausal women that provide additional benefits. Areas covered: This article reviews Lasofoxifene, a new SERM for the treatment of postmenopausal osteoporosis and urogenital atrophy. The medical literature is reviewed for articles containing the terms ‘Lasofoxifene’ and ‘SERMs’. The manuscript reviews the discovery...
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Lasofoxifene: Evidence of its therapeutic value in osteoporosis
Core evidence, 2010Co-Authors: Luigi Gennari, Daniela Merlotti, Vincenzo De Paola, Ranuccio NutiAbstract:Introduction: Osteoporosis is a skeletal disorder characterized by compromised bone strength and increased risk of fracture. It is a common disorder in elderly subjects and represents a major public health problem, affecting up to 40% postmenopausal women and 15% of men. Among the several therapeutical interventions, hormone replacement therapy (HRT) was traditionally seen as the gold standard for preventing osteoporotic fractures in postmenopausal women, as well as for the management of menopausal symptoms. However HRT, especially if administered long-term, may lead to an increased risk of breast and, when unopposed by progestins, endometrial cancers. Alternative therapies include bisphosphonates and raloxifene, a selective estrogen receptor modulator (SERM). While the former have been associated with suboptimal adherence, the latter was considerably less potent than estrogen and its effect in the prevention of nonvertebral fractures remain uncertain.
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Selective estrogen receptor modulator (SerM) for the treatment of osteoporosis in postmenopausal women: focus on Lasofoxifene
Clinical interventions in aging, 2010Co-Authors: Luigi Gennari, Daniela Merlotti, Ranuccio NutiAbstract:Selective estrogen receptor modulators (SERMs) represent a class with a growing number of compounds that act as either estrogen receptor agonists or antagonists in a tissue-specific manner. This article reviews Lasofoxifene, a new-generation SERM that has completed phase III development for the prevention and treatment of osteoporosis in postmenopausal women. Consistent with preclinical observations, this new SERM demonstrated improved skeletal efficacy over raloxifene and at an oral dose of 0.5 mg/day was effective in the prevention of both vertebral and nonvertebral fractures in postmenopausal women with osteoporosis. At the same dosage, Lasofoxifene treatment also reduced estrogen receptor-positive breast cancer risk and the occurrence of vaginal atrophy, but, like the other SERMs, was associated with hot flushes and an increased risk of venous thromboembolic events. With its increased efficacy on the prevention of nonvertebral fractures than current available SERMs and its positive effects on the vagina, this new compound may represent an alternative and cost-effective therapy for osteoporosis in postmenopausal women.
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Selective estrogen receptor modulator (SERM) for the treatment of osteoporosis in postmenopausal women: focus on Lasofoxifene
Dove Medical Press, 2010Co-Authors: Luigi Gennari, Daniela Merlotti, Ranuccio NutiAbstract:Luigi Gennari, Daniela Merlotti, Ranuccio NutiDepartment of Internal Medicine, Endocrine-Metabolic Sciences and Biochemistry, University of Siena, Siena, ItalyAbstract: Selective estrogen receptor modulators (SERMs) represent a class with a growing number of compounds that act as either estrogen receptor agonists or antagonists in a tissuespecific manner. This article reviews Lasofoxifene, a new-generation SERM that has completed phase III development for the prevention and treatment of osteoporosis in postmenopausal women. Consistent with preclinical observations, this new SERM demonstrated improved skeletal efficacy over raloxifene and at an oral dose of 0.5 mg/day was effective in the prevention of both vertebral and nonvertebral fractures in postmenopausal women with osteoporosis. At the same dosage, Lasofoxifene treatment also reduced estrogen receptor-positive breast cancer risk and the occurrence of vaginal atrophy, but, like the other SERMs, was associated with hot flushes and an increased risk of venous thromboembolic events. With its increased efficacy on the prevention of nonvertebral fractures than current available SERMs and its positive effects on the vagina, this new compound may represent an alternative and cost-effective therapy for osteoporosis in postmenopausal women.Keywords: SERM, Lasofoxifene, postmenopausal osteoporosis, fractures, bone density, menopaus
Ranuccio Nuti - One of the best experts on this subject based on the ideXlab platform.
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Lasofoxifene, from the preclinical drug discovery to the treatment of postmenopausal osteoporosis
Expert opinion on drug discovery, 2011Co-Authors: Luigi Gennari, Daniela Merlotti, Konstantinos Stolakis, Ranuccio NutiAbstract:Introduction: Estrogen replacement is traditionally seen as the gold standard for preventing osteoporotic fractures in postmenopausal women as well as for the management of menopausal symptoms. However, estrogen may lead to an increased risk of breast and, when unopposed by progestins, endometrial cancers. Alternative therapies include bisphosphonates and raloxifene, a selective estrogen receptor modulator (SERM). While the former have been associated with suboptimal adherence, the latter is considerably less potent than estrogen and its effect in the prevention of nonvertebral fractures remains uncertain. Hence, there is a need for additional effective medications to prevent fractures in postmenopausal women that provide additional benefits. Areas covered: This article reviews Lasofoxifene, a new SERM for the treatment of postmenopausal osteoporosis and urogenital atrophy. The medical literature is reviewed for articles containing the terms ‘Lasofoxifene’ and ‘SERMs’. The manuscript reviews the discovery...
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Lasofoxifene: Evidence of its therapeutic value in osteoporosis
Core evidence, 2010Co-Authors: Luigi Gennari, Daniela Merlotti, Vincenzo De Paola, Ranuccio NutiAbstract:Introduction: Osteoporosis is a skeletal disorder characterized by compromised bone strength and increased risk of fracture. It is a common disorder in elderly subjects and represents a major public health problem, affecting up to 40% postmenopausal women and 15% of men. Among the several therapeutical interventions, hormone replacement therapy (HRT) was traditionally seen as the gold standard for preventing osteoporotic fractures in postmenopausal women, as well as for the management of menopausal symptoms. However HRT, especially if administered long-term, may lead to an increased risk of breast and, when unopposed by progestins, endometrial cancers. Alternative therapies include bisphosphonates and raloxifene, a selective estrogen receptor modulator (SERM). While the former have been associated with suboptimal adherence, the latter was considerably less potent than estrogen and its effect in the prevention of nonvertebral fractures remain uncertain.
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Selective estrogen receptor modulator (SerM) for the treatment of osteoporosis in postmenopausal women: focus on Lasofoxifene
Clinical interventions in aging, 2010Co-Authors: Luigi Gennari, Daniela Merlotti, Ranuccio NutiAbstract:Selective estrogen receptor modulators (SERMs) represent a class with a growing number of compounds that act as either estrogen receptor agonists or antagonists in a tissue-specific manner. This article reviews Lasofoxifene, a new-generation SERM that has completed phase III development for the prevention and treatment of osteoporosis in postmenopausal women. Consistent with preclinical observations, this new SERM demonstrated improved skeletal efficacy over raloxifene and at an oral dose of 0.5 mg/day was effective in the prevention of both vertebral and nonvertebral fractures in postmenopausal women with osteoporosis. At the same dosage, Lasofoxifene treatment also reduced estrogen receptor-positive breast cancer risk and the occurrence of vaginal atrophy, but, like the other SERMs, was associated with hot flushes and an increased risk of venous thromboembolic events. With its increased efficacy on the prevention of nonvertebral fractures than current available SERMs and its positive effects on the vagina, this new compound may represent an alternative and cost-effective therapy for osteoporosis in postmenopausal women.
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Selective estrogen receptor modulator (SERM) for the treatment of osteoporosis in postmenopausal women: focus on Lasofoxifene
Dove Medical Press, 2010Co-Authors: Luigi Gennari, Daniela Merlotti, Ranuccio NutiAbstract:Luigi Gennari, Daniela Merlotti, Ranuccio NutiDepartment of Internal Medicine, Endocrine-Metabolic Sciences and Biochemistry, University of Siena, Siena, ItalyAbstract: Selective estrogen receptor modulators (SERMs) represent a class with a growing number of compounds that act as either estrogen receptor agonists or antagonists in a tissuespecific manner. This article reviews Lasofoxifene, a new-generation SERM that has completed phase III development for the prevention and treatment of osteoporosis in postmenopausal women. Consistent with preclinical observations, this new SERM demonstrated improved skeletal efficacy over raloxifene and at an oral dose of 0.5 mg/day was effective in the prevention of both vertebral and nonvertebral fractures in postmenopausal women with osteoporosis. At the same dosage, Lasofoxifene treatment also reduced estrogen receptor-positive breast cancer risk and the occurrence of vaginal atrophy, but, like the other SERMs, was associated with hot flushes and an increased risk of venous thromboembolic events. With its increased efficacy on the prevention of nonvertebral fractures than current available SERMs and its positive effects on the vagina, this new compound may represent an alternative and cost-effective therapy for osteoporosis in postmenopausal women.Keywords: SERM, Lasofoxifene, postmenopausal osteoporosis, fractures, bone density, menopaus
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Lasofoxifene: a new-generation SERM for the treatment of postmenopausal osteoporosis
Expert Review of Obstetrics & Gynecology, 2009Co-Authors: Luigi Gennari, Daniela Merlotti, Ranuccio NutiAbstract:Lasofoxifene is a new-generation selective estrogen receptor modulator that completed the Phase III development program for the prevention and treatment of osteoporosis in postmenopausal women. This compound has a remarkably improved oral bioavailability with respect to other selective estrogen receptor modulators owing to its increased resistance to intestinal wall glucuronidation. In both preclinical and short-term Phase II clinical studies, Lasofoxifene showed a favorable safety profile and demonstrated a proven efficacy in preventing bone loss and lowering cholesterol levels. The recent results from Phase III clinical trials demonstrated the clinical efficacy of this drug in the prevention of vertebral and nonvertebral fractures. The purpose of this article is to review the clinical evidence for the use of Lasofoxifene in women after menopause and to discuss how it will fit into the treatment of postmenopausal osteoporosis.
M. J. Gardner - One of the best experts on this subject based on the ideXlab platform.
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Effects of three cytochrome P450 inhibitors, ketoconazole, fluconazole, and paroxetine, on the pharmacokinetics of Lasofoxifene
British journal of clinical pharmacology, 2006Co-Authors: Daniele Ouellet, Candace Bramson, Doina Roman, Edward J. Randinitis, Ann E. Remmers, Ashley Milton, M. J. GardnerAbstract:Aims Two studies were conduced to assess the effects of ketoconazole, a CYP3A4/5 inhibitor; fluconazole, a CYP2C9 inhibitor; and paroxetine, a CYP2D6 inhibitor, on Lasofoxifene pharmacokinetics. Methods The first parallel group study was conducted in 45 healthy postmenopausal women (15 per group) to compare the pharmacokinetics of a single dose of Lasofoxifene (0.25 mg) administered alone and in combination with ketoconazole (400 mg daily × 20 days) or fluconazole (400 mg daily × 20 days). Lasofoxifene was administered on day 2 and blood samples were collected serially for up to 456 h postdose (20 days). The second study enrolled 20 healthy postmenopausal women (10 per group) to compare the pharmacokinetics of a single dose of Lasofoxifene (0.25 mg) alone and in combination with paroxetine (30 mg qd × 21 days). Lasofoxifene was given on day 8 of paroxetine treatment and blood samples were collected serially for up to 336 h postdose. Results All subjects completed the study and the treatments were well tolerated. Lasofoxifene Cmax and AUC ratios [90% confidence interval (CI)] with/without ketoconazole were 111% (98.4, 127) and 120% (105, 136), respectively, and were 91.3% (80.3, 104) and 104% (91.4, 118), respectively, with/without fluconazole. Lasofoxifene Cmax and AUC ratios (90% CI) with/without paroxetine were 118% (95.4, 146) and 135% (120, 152), respectively. Conclusions Coadministration of potent inhibitors of CYP3A4/5 and CYP2D6, but not CYP2C9, resulted in a moderate increase in Lasofoxifene exposure. No dosage adjustment should be required when Lasofoxifene is coadministered with ketoconazole, fluconazole, paroxetine or other agents that inhibit these CYP enzymes.
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A single-dose pharmacokinetic study of Lasofoxifene in healthy volunteers and subjects with mild and moderate hepatic impairment.
The Journal of Clinical Pharmacology, 2006Co-Authors: Candace Bramson, Daniele Ouellet, Doina Roman, Edward J. Randinitis, M. J. GardnerAbstract:Lasofoxifene, a selective estrogen receptor modulator for osteoporosis management, is metabolized primarily by hepatic oxidation and conjugation. This study compared the pharmacokinetics of 0.25 mg Lasofoxifene in subjects with mild (Child-Pugh grade A, n = 6) or moderate (Child-Pugh grade B, n = 6) hepatic impairment and healthy volunteers (n = 6). Analysis of variance was used to calculate 90% confidence intervals for the ratios (impaired/healthy) of least squares mean log maximum plasma concentration (C m a x ) and area under the curve (AUC) values. Lasofoxifene pharmacokinetics was similar between healthy and mild hepatic impairment subjects : ratios of C m a x and AUC from 0 to infinity (AUC | 0 - ∞ | ) were 101% (75.0-138) and 95.5% (77.9-117), respectively. In subjects with moderate hepatic impairment, ratios of C m a x and AUC [ 0 - ∞ ] were 121% (89.6-165) and 138% (112-169), respectively; mean terminal half-life was 252 hr compared to 193 hr in healthy subjects. Dose adjustment should not be required for subjects with mild to moderate hepatic impairment.
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Clinical pharmacology of multiple doses of Lasofoxifene in postmenopausal women.
Journal of clinical pharmacology, 2006Co-Authors: M. J. Gardner, Ann Taylor, Greg C. G. Wei, Albert Calcagni, Barbara A. Duncan, Ashley MiltonAbstract:Lasofoxifene, a next-generation selective estrogen receptor modulator, is undergoing phase 3 clinical development for osteoporosis. This study evaluated daily Lasofoxifene for 14 days in healthy postmenopausal women. A loading dose of 5 times the daily dose was followed by daily doses of 0.01 mg (n = 8), 0.03 mg (n =8), 0.1 mg(n = 16), 0.3 mg (n =9), 1 mg (n = 8), or placebo (n = 16). Samples were collected for pharmacokinetic and pharmacodynamic assessments. Lasofoxifene was well tolerated; study drug-associated adverse events were mild and unrelated to dose. There was a predictable increase in plasma concentrations of Lasofoxifene with dose. Pharmacokinetic parameters included mean half-life of 165 hours, mean area under the plasma concentration-time curve from time 0 to 24 hours ranging from 1.67 ng x h/mL to 137 ng x h/mL, and mean maximum observed plasma concentration ranging from 0.09 ng/mL to 6.43 ng/mL. Lasofoxifene partially suppressed luteinizing hormone, follicle-stimulating hormone, low-density lipoprotein, and N-telopeptide.
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Effects of Lasofoxifene on the pharmacokinetics and pharmacodynamics of single-dose warfarin.
British journal of clinical pharmacology, 2006Co-Authors: Daniele Ouellet, Candace Bramson, Doina Roman, Edward J. Randinitis, Ann E. Remmers, Santos Carvajal-gonzalez, M. J. GardnerAbstract:Aim To investigate the effect of steady-state Lasofoxifene on the pharmacokinetics and pharmacodynamics of warfarin. Methods Twelve healthy postmenopausal women received warfarin (single 20-mg dose) alone and during Lasofoxifene. R- and S-warfarin concentrations, prothrombin time (PT) and international normalized ratio (INR) were determined with each treatment. Results Lasofoxifene had no clinically meaningful effect on R- or S-warfarin pharmacokinetics. The S-warfarin area under the plasma concentration–time curve (AUC) was 23% and 67% larger in subjects with *1/*2 and *1/*3 heterozygous mutations, relative to *1/*1, respectively. The mean PT AUC and Cmax ratio (90% confidence interval) was 91.9 (89.6, 94.2) and 84.2 (80.6, 87.8), respectively. INR results were similar. Conclusions Lasofoxifene has no clinically meaningful effect on the pharmacokinetics of warfarin. Although the decrease in PT/INR may not be clinically meaningful, more frequent INR monitoring may be considered during Lasofoxifene introduction and discontinuation, consistent with warfarin’s label.
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Effects of Steady-State Lasofoxifene on CYP2D6- and CYP2E1-Mediated Metabolism
The Annals of pharmacotherapy, 2005Co-Authors: Robert A Moller, M. J. Gardner, Ann Taylor, Jeannine M Fisher, Sheela Kolluri, R. Scott Obach, Robert L. WalskyAbstract:Background:Lasofoxifene, a selective estrogen receptor modulator, may be coadministered with other drugs, raising the issue of drug–drug interactions.Objective:Using a 7-day, open-label, sequential study to determine whether Lasofoxifene at steady-state concentration affects cytochrome P450–mediated drug metabolism.Methods:Lasofoxifene was tested in 18 postmenopausal women with probe drugs for CYP2E1 and CYP2D6. Changes in CYP2E1 metabolism were measured by the formation clearance of 6-hydroxychlorzoxazone (6-OHCLZ; Clf,6-OHCLZ) following a 250 mg dose of chlorzoxazone in the absence (day 1) and presence (day 6) of Lasofoxifene. Changes in the dextromethorphan/dextrorphan urine metabolic ratio (MRDX) measured the effect on CYP2D6 metabolism following a 30 mg dose of dextromethorphan in the absence and presence of Lasofoxifene (days 2 and 7).Results:Steady-state Lasofoxifene did not affect the formation clearance of 6-OHCLZ or the urinary MRDX. For 6-OHCLZ, the lower boundary (87.12%) of the 90% confidence...
David D Thompson - One of the best experts on this subject based on the ideXlab platform.
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Effects of 3 years of Lasofoxifene treatment on bone turnover markers in women with postmenopausal osteoporosis
Bone, 2012Co-Authors: Richard Eastell, Kristine E Ensrud, Andrea Z Lacroix, John R Thompson, David D Thompson, David M Reid, Slobodan Vukicevic, Steven R. CummingsAbstract:The aims of this study were to describe the changes in bone turnover markers (BTMs) in response to Lasofoxifene therapy; to describe the changes in BTMs in the individual; and to examine the relationships between BTM levels on treatment and treatment outcomes. Women (n=1126) aged 59-80years with femoral neck or spine bone mineral density T-scores ≤-2.5 were randomized to Lasofoxifene 0.25mg/d, 0.5mg/d, or placebo for 5years. We measured serum C-telopeptide of type I collagen (CTX) and serum procollagen I N-propeptide (PINP), osteocalcin, and bone alkaline phosphatase (ALP) at baseline and at 1, 3, 6, 12, 24, and 36months. Lasofoxifene therapy resulted in a decrease in the concentrations of bone resorption and bone formation markers compared with placebo; the decrease was maximal between 6 and 24months. The effect of Lasofoxifene 0.5mg/d was similar to that of Lasofoxifene 0.25mg/d. The decrease in bone ALP was less than the decreases in CTX, osteocalcin, and PINP. Lasofoxifene therapy 0.5mg/d resulted in BTM-defined response rates for CTX (decrease in concentration from baseline >60%), PINP (>50%), and bone ALP (>30%) of 35%, 45%, and 43% of women at month 12, respectively, compared with placebo responses of 4%, 4%, and 7%. In contrast, the increase in BMD took longer (50% responded after 36months of Lasofoxifene 0.5mg/d) and was not as specific (15% of placebo group responded). Bone density change was weakly inversely correlated with change in the concentrations of BTMs. BTMs may prove useful in the monitoring of the response to Lasofoxifene treatment for women with postmenopausal osteoporosis early in the course of treatment.
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Breast Cancer Incidence in the Randomized PEARL Trial of Lasofoxifene in Postmenopausal Osteoporotic Women
Journal of the National Cancer Institute, 2010Co-Authors: Andrea Z Lacroix, John R Thompson, David D Thompson, Roisin Armstrong, Trevor J. Powles, C. Kent Osborne, Kevin Wolter, D. Craig Allred, Steve Cummings, Richard EastellAbstract:Author(s): LaCroix, Andrea Z; Powles, Trevor; Osborne, C Kent; Wolter, Kevin; Thompson, John R; Thompson, David D; Allred, D Craig; Armstrong, Roisin; Cummings, Steve R; Eastell, Richard; Ensrud, Kristine E; Goss, Paul; Lee, Andrew; Neven, Patrick; Reid, David M; Curto, Madelyn; Vukicevic, Slobodan; PEARL Investigators | Abstract: BACKGROUND: Currently available selective estrogen receptor modulators reduce the risk of breast cancer, but they are not widely used. In the Postmenopausal Evaluation and Risk-Reduction with Lasofoxifene (PEARL) trial, Lasofoxifene was shown to reduce the risk of estrogen receptor-positive (ER+) breast cancer, nonvertebral and vertebral fractures, coronary artery disease, and stroke, but the effects on total breast cancer (invasive and ductal carcinoma in situ, ER+ and estrogen receptor-negative [ER-]) and ER+ invasive breast cancer are unknown. METHODS: Postmenopausal women (n = 8556) aged 59-80 years with low bone density and normal mammograms were randomly assigned to two doses of Lasofoxifene (0.25 and 0.5 mg) or placebo. The primary endpoints of the PEARL trial were incidence of ER+ breast cancer and nonvertebral fractures at 5 years. A nested case-control study of 49 incident breast cancer case patients and 156 unaffected control subjects from the PEARL trial was performed to evaluate treatment effects on risk of total and ER+ invasive breast cancer by baseline serum estradiol and sex hormone-binding globulin levels using logistic regression models. Cox proportional hazards models were used to evaluate risk of total breast cancer and ER+ invasive breast cancer using intention-to-treat analysis. All statistical tests were two-sided. RESULTS: Breast cancer was confirmed in 49 women. Compared with placebo, 0.5 mg of Lasofoxifene statistically significantly reduced the risk of total breast cancer by 79% (hazard ratio = 0.21; 95% confidence interval [CI] = 0.08 to 0.55) and ER+ invasive breast cancer by 83% (hazard ratio = 0.17; 95% CI = 0.05 to 0.57). The effects of 0.5 mg of Lasofoxifene on total breast cancer were similar regardless of Gail score, whereas the effects were markedly stronger for women with baseline estradiol levels greater than the median (odds ratio = 0.11; 95% CI = 0.02 to 0.51) vs those with levels less than the median (odds ratio = 0.78; 95% CI = 0.16 to 3.79; P(interaction) = .04). CONCLUSION: A 0.5-mg dose of Lasofoxifene appears to reduce the risks of both total and ER+ invasive breast cancer in postmenopausal women with osteoporosis.
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Lasofoxifene and cardiovascular events in postmenopausal women with osteoporosis five year results from the postmenopausal evaluation and risk reduction with Lasofoxifene pearl trial
Circulation, 2010Co-Authors: Kristine E Ensrud, Andrea Z Lacroix, John R Thompson, David D Thompson, Richard Eastell, David M Reid, Slobodan Vukicevic, Jane A Cauley, Elizabeth Barrettconnor, Roisin ArmstrongAbstract:Background—In the Postmenopausal Evaluation and Risk Reduction With Lasofoxifene (PEARL) trial, women assigned to Lasofoxifene 0.5 mg/d had a lower risk of major coronary heart disease (CHD) events and stroke, whereas women assigned to Lasofoxifene 0.25 mg/d had a lower risk of stroke. Both doses of Lasofoxifene increased the risk of venous thromboembolic events. In this report, we provide comprehensive cardiovascular end-point data, including component events comprising the composite end point of major CHD events, and evaluate whether the effect of Lasofoxifene 0.5 mg/d is consistent across different categories of CHD risk. Methods and Results—In this study, 8556 women 59 to 80 years of age with osteoporosis received Lasofoxifene 0.25 mg/d, Lasofoxifene 0.5 mg/d, or placebo for 5 years. Cardiovascular events, including major CHD events, were prespecified secondary end points. Compared with placebo, Lasofoxifene 0.5 mg/d reduced the risk of major CHD events 32% (hazard ratio, 0.68; 95% confidence interval...
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Lasofoxifene and Cardiovascular Events in Postmenopausal Women With Osteoporosis Five-Year Results From the Postmenopausal Evaluation and Risk Reduction With Lasofoxifene (PEARL) Trial
Circulation, 2010Co-Authors: Kristine E Ensrud, Andrea Z Lacroix, John R Thompson, David D Thompson, Richard Eastell, David M Reid, Slobodan Vukicevic, Jane A Cauley, Elizabeth Barrett-connor, Roisin ArmstrongAbstract:Background— In the Postmenopausal Evaluation and Risk Reduction With Lasofoxifene (PEARL) trial, women assigned to Lasofoxifene 0.5 mg/d had a lower risk of major coronary heart disease (CHD) events and stroke, whereas women assigned to Lasofoxifene 0.25 mg/d had a lower risk of stroke. Both doses of Lasofoxifene increased the risk of venous thromboembolic events. In this report, we provide comprehensive cardiovascular end-point data, including component events comprising the composite end point of major CHD events, and evaluate whether the effect of Lasofoxifene 0.5 mg/d is consistent across different categories of CHD risk. Methods and Results— In this study, 8556 women 59 to 80 years of age with osteoporosis received Lasofoxifene 0.25 mg/d, Lasofoxifene 0.5 mg/d, or placebo for 5 years. Cardiovascular events, including major CHD events, were prespecified secondary end points. Compared with placebo, Lasofoxifene 0.5 mg/d reduced the risk of major CHD events 32% (hazard ratio, 0.68; 95% confidence interval, 0.50 to 0.93), including the risk of coronary revascularization (hazard ratio, 0.56, 95% confidence interval, 0.32 to 0.98). Reductions in risk of hospitalization for unstable angina (hazard ratio, 0.55; 95% confidence interval, 0.29 to 1.04) and diagnosis of new ischemic heart disease (hazard ratio, 0.52; 95% confidence interval, 0.26 to 1.04) nearly reached significance ( P =0.06 for both comparisons). Although both hazard ratios were
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Lasofoxifene enhances vaginal mucus formation without causing hypertrophy and increases estrogen receptor β and androgen receptor in rats
Menopause (New York N.Y.), 2006Co-Authors: Xiao-ning Wang, H.a. Simmons, Christopher T. Salatto, Patricia G. Cosgrove, David D ThompsonAbstract:OBJECTIVE Lasofoxifene, a new selective estrogen-receptor modulator (SERM), shows efficacy in vaginal and vulvar atrophy in postmenopausal women. Here, we sought to explore the possible mechanisms of action for this effect in comparison with other SERMs using an immature ovariectomized rat model. DESIGN SERMs (Lasofoxifene, raloxifene, and tamoxifen) and 17alpha-ethinyl estradiol were administered orally to immature ovariectomized rats daily for 1 or 4 days. Vaginal and uterine tissues were weighed and processed for histomorphometric measurements, vaginal mucopolysaccharide staining, and immunohistochemistry of 5-bromo-2'-deoxyuridine and steroid receptors. Receptor quantification was determined by a novel ultrasensitive enzyme-linked immunosorbent assay method. RESULTS Lasofoxifene and raloxifene showed a minimal increase in vaginal and uterine weight, epithelial cell proliferation, and epithelial thickness in comparison with estradiol and tamoxifen. Lasofoxifene significantly enhanced vaginal mucus formation in a dose-dependent manner. Vaginal progesterone receptor protein was increased fivefold by estradiol and all three SERMs tested. 17alpha-Ethinyl estradiol caused a significant decrease in estrogen receptor alpha, but no change with other treatments. Only Lasofoxifene significantly increased vaginal estrogen receptor beta and androgen receptor protein levels. CONCLUSIONS These results demonstrated that Lasofoxifene stimulated vaginal mucus formation without causing cell proliferation in the rat reproductive tract. These effects may be due to the increased vaginal estrogen receptor beta and androgen receptor levels. This cellular and molecular profile of Lasofoxifene in the vagina may account for its efficacy in the treatment of vaginal and vulvar atrophy in postmenopausal women.
Richard Eastell - One of the best experts on this subject based on the ideXlab platform.
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Effects of 3 years of Lasofoxifene treatment on bone turnover markers in women with postmenopausal osteoporosis
Bone, 2012Co-Authors: Richard Eastell, Kristine E Ensrud, Andrea Z Lacroix, John R Thompson, David D Thompson, David M Reid, Slobodan Vukicevic, Steven R. CummingsAbstract:The aims of this study were to describe the changes in bone turnover markers (BTMs) in response to Lasofoxifene therapy; to describe the changes in BTMs in the individual; and to examine the relationships between BTM levels on treatment and treatment outcomes. Women (n=1126) aged 59-80years with femoral neck or spine bone mineral density T-scores ≤-2.5 were randomized to Lasofoxifene 0.25mg/d, 0.5mg/d, or placebo for 5years. We measured serum C-telopeptide of type I collagen (CTX) and serum procollagen I N-propeptide (PINP), osteocalcin, and bone alkaline phosphatase (ALP) at baseline and at 1, 3, 6, 12, 24, and 36months. Lasofoxifene therapy resulted in a decrease in the concentrations of bone resorption and bone formation markers compared with placebo; the decrease was maximal between 6 and 24months. The effect of Lasofoxifene 0.5mg/d was similar to that of Lasofoxifene 0.25mg/d. The decrease in bone ALP was less than the decreases in CTX, osteocalcin, and PINP. Lasofoxifene therapy 0.5mg/d resulted in BTM-defined response rates for CTX (decrease in concentration from baseline >60%), PINP (>50%), and bone ALP (>30%) of 35%, 45%, and 43% of women at month 12, respectively, compared with placebo responses of 4%, 4%, and 7%. In contrast, the increase in BMD took longer (50% responded after 36months of Lasofoxifene 0.5mg/d) and was not as specific (15% of placebo group responded). Bone density change was weakly inversely correlated with change in the concentrations of BTMs. BTMs may prove useful in the monitoring of the response to Lasofoxifene treatment for women with postmenopausal osteoporosis early in the course of treatment.
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Breast Cancer Incidence in the Randomized PEARL Trial of Lasofoxifene in Postmenopausal Osteoporotic Women
Journal of the National Cancer Institute, 2010Co-Authors: Andrea Z Lacroix, John R Thompson, David D Thompson, Roisin Armstrong, Trevor J. Powles, C. Kent Osborne, Kevin Wolter, D. Craig Allred, Steve Cummings, Richard EastellAbstract:Author(s): LaCroix, Andrea Z; Powles, Trevor; Osborne, C Kent; Wolter, Kevin; Thompson, John R; Thompson, David D; Allred, D Craig; Armstrong, Roisin; Cummings, Steve R; Eastell, Richard; Ensrud, Kristine E; Goss, Paul; Lee, Andrew; Neven, Patrick; Reid, David M; Curto, Madelyn; Vukicevic, Slobodan; PEARL Investigators | Abstract: BACKGROUND: Currently available selective estrogen receptor modulators reduce the risk of breast cancer, but they are not widely used. In the Postmenopausal Evaluation and Risk-Reduction with Lasofoxifene (PEARL) trial, Lasofoxifene was shown to reduce the risk of estrogen receptor-positive (ER+) breast cancer, nonvertebral and vertebral fractures, coronary artery disease, and stroke, but the effects on total breast cancer (invasive and ductal carcinoma in situ, ER+ and estrogen receptor-negative [ER-]) and ER+ invasive breast cancer are unknown. METHODS: Postmenopausal women (n = 8556) aged 59-80 years with low bone density and normal mammograms were randomly assigned to two doses of Lasofoxifene (0.25 and 0.5 mg) or placebo. The primary endpoints of the PEARL trial were incidence of ER+ breast cancer and nonvertebral fractures at 5 years. A nested case-control study of 49 incident breast cancer case patients and 156 unaffected control subjects from the PEARL trial was performed to evaluate treatment effects on risk of total and ER+ invasive breast cancer by baseline serum estradiol and sex hormone-binding globulin levels using logistic regression models. Cox proportional hazards models were used to evaluate risk of total breast cancer and ER+ invasive breast cancer using intention-to-treat analysis. All statistical tests were two-sided. RESULTS: Breast cancer was confirmed in 49 women. Compared with placebo, 0.5 mg of Lasofoxifene statistically significantly reduced the risk of total breast cancer by 79% (hazard ratio = 0.21; 95% confidence interval [CI] = 0.08 to 0.55) and ER+ invasive breast cancer by 83% (hazard ratio = 0.17; 95% CI = 0.05 to 0.57). The effects of 0.5 mg of Lasofoxifene on total breast cancer were similar regardless of Gail score, whereas the effects were markedly stronger for women with baseline estradiol levels greater than the median (odds ratio = 0.11; 95% CI = 0.02 to 0.51) vs those with levels less than the median (odds ratio = 0.78; 95% CI = 0.16 to 3.79; P(interaction) = .04). CONCLUSION: A 0.5-mg dose of Lasofoxifene appears to reduce the risks of both total and ER+ invasive breast cancer in postmenopausal women with osteoporosis.
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Lasofoxifene and cardiovascular events in postmenopausal women with osteoporosis five year results from the postmenopausal evaluation and risk reduction with Lasofoxifene pearl trial
Circulation, 2010Co-Authors: Kristine E Ensrud, Andrea Z Lacroix, John R Thompson, David D Thompson, Richard Eastell, David M Reid, Slobodan Vukicevic, Jane A Cauley, Elizabeth Barrettconnor, Roisin ArmstrongAbstract:Background—In the Postmenopausal Evaluation and Risk Reduction With Lasofoxifene (PEARL) trial, women assigned to Lasofoxifene 0.5 mg/d had a lower risk of major coronary heart disease (CHD) events and stroke, whereas women assigned to Lasofoxifene 0.25 mg/d had a lower risk of stroke. Both doses of Lasofoxifene increased the risk of venous thromboembolic events. In this report, we provide comprehensive cardiovascular end-point data, including component events comprising the composite end point of major CHD events, and evaluate whether the effect of Lasofoxifene 0.5 mg/d is consistent across different categories of CHD risk. Methods and Results—In this study, 8556 women 59 to 80 years of age with osteoporosis received Lasofoxifene 0.25 mg/d, Lasofoxifene 0.5 mg/d, or placebo for 5 years. Cardiovascular events, including major CHD events, were prespecified secondary end points. Compared with placebo, Lasofoxifene 0.5 mg/d reduced the risk of major CHD events 32% (hazard ratio, 0.68; 95% confidence interval...
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Lasofoxifene and Cardiovascular Events in Postmenopausal Women With Osteoporosis Five-Year Results From the Postmenopausal Evaluation and Risk Reduction With Lasofoxifene (PEARL) Trial
Circulation, 2010Co-Authors: Kristine E Ensrud, Andrea Z Lacroix, John R Thompson, David D Thompson, Richard Eastell, David M Reid, Slobodan Vukicevic, Jane A Cauley, Elizabeth Barrett-connor, Roisin ArmstrongAbstract:Background— In the Postmenopausal Evaluation and Risk Reduction With Lasofoxifene (PEARL) trial, women assigned to Lasofoxifene 0.5 mg/d had a lower risk of major coronary heart disease (CHD) events and stroke, whereas women assigned to Lasofoxifene 0.25 mg/d had a lower risk of stroke. Both doses of Lasofoxifene increased the risk of venous thromboembolic events. In this report, we provide comprehensive cardiovascular end-point data, including component events comprising the composite end point of major CHD events, and evaluate whether the effect of Lasofoxifene 0.5 mg/d is consistent across different categories of CHD risk. Methods and Results— In this study, 8556 women 59 to 80 years of age with osteoporosis received Lasofoxifene 0.25 mg/d, Lasofoxifene 0.5 mg/d, or placebo for 5 years. Cardiovascular events, including major CHD events, were prespecified secondary end points. Compared with placebo, Lasofoxifene 0.5 mg/d reduced the risk of major CHD events 32% (hazard ratio, 0.68; 95% confidence interval, 0.50 to 0.93), including the risk of coronary revascularization (hazard ratio, 0.56, 95% confidence interval, 0.32 to 0.98). Reductions in risk of hospitalization for unstable angina (hazard ratio, 0.55; 95% confidence interval, 0.29 to 1.04) and diagnosis of new ischemic heart disease (hazard ratio, 0.52; 95% confidence interval, 0.26 to 1.04) nearly reached significance ( P =0.06 for both comparisons). Although both hazard ratios were
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A randomised, double-blinded, placebo-controlled, trial to determine the individual response in bone turnover markers to Lasofoxifene therapy.
Bone, 2009Co-Authors: Angela Rogers, Sarah J Glover, Richard EastellAbstract:Abstract Lasofoxifene is a novel selective estrogen receptor modulator that is being developed for the treatment of postmenopausal osteoporosis. Bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) is currently used to diagnose osteoporosis. BMD response to therapy, however, is often not apparent until at least one year following start of treatment. Biochemical markers of bone turnover may provide an early indication of BMD response in individual patients. The aims of the study were: 1) to determine the variability in bone turnover markers (BTM) to estimate a value for least significant change (LSC); 2) to determine the number of subjects with a response to Lasofoxifene greater than LSC; 3) to determine the number of subjects whose bone turnover is decreased to the lower half of the reference range and 4) to evaluate the use of bone turnover markers to predict the change in bone density in response to Lasofoxifene. Fifty-one postmenopausal osteopenic women, ages 55 to 77 (mean 63.7) years, were recruited with 44 women completing the 2 year follow up. Participants received either Lasofoxifene (0.25 mg/d) or placebo, in a 1:1 ratio. Duplicate measurements of BTM (bone alkaline phosphatase (bone ALP), N-terminal propeptide of type I collagen (PINP), serum β crosslinked C-telopeptides of type I collagen (sβ-CTX), urinary crosslinked N-telopeptides of type I collagen (U-NTX)) were made at baseline and 6 months with single measurements at 4, 8 and 12 weeks. Duplicate measurements of BMD at the lumbar spine (LS), total hip (TH) and distal forearm (DF) were made by DXA at baseline, one and two years in all subjects. Almost all women (92 to 96%), treated with Lasofoxifene, had a reduction in serum-based bone turnover markers greater than LSC, and 52 to 80% had serum-based bone turnover markers in the lower half of the reference range, by six months of Lasofoxifene therapy. The change in mean LSBMD from baseline, was significantly greater in the Lasofoxifene group compared to placebo at 1 and 2 years (+ 2.5% and + 3.4%, respectively, P The use of Lasofoxifene therapy leads to significant decreases in bone turnover by 4 weeks of Lasofoxifene therapy as a group, with a decrease in BTM greater than LSC occurring in almost all women taking Lasofoxifene by 6 months. By this time, in over half of women taking Lasofoxifene, BTM reached the lower half of the reference range. Our results suggest that bone turnover markers are useful for monitoring response to Lasofoxifene. Changes occur early and relate to the BMD response.
