Safety assessment of raloxifene over eight years in a clinical trial setting

Martino, Silvana; Disch, Damon; Dowsett, Sherie A.; Keech, Cheryl; Mershon, John L.

doi:10.1185/030079905x61839

Cited by 105 publications

(69 citation statements)

References 15 publications

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“…Raloxifene is a clinically-validated SERM, which has been shown to mimic the protective effect of estrogen on the skeletal system without triggering the proliferative effects of estrogen on the breast and endometrium of the uterus [4,5]. Many clinical studies have confirmed the therapeutic effectiveness of raloxifene in reducing the risk of vertebral fractures in postmenopausal osteoporosis patients by significantly slowing bone turnover, preventing bone loss, and maintaining the structural integrity of cancellous bone [6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Structural features underlying raloxifene’s biophysical interaction with bone matrix

Bivi

Balagopalakrishna

et al. 2016

Bioorganic & Medicinal Chemistry

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Raloxifene, a selective estrogen receptor modulator (SERM), reduces fracture risk at least in part by improving the mechanical properties of bone in a cell-and estrogen receptor-independent manner. In this study, we determined that raloxifene directly interacts with the bone tissue. Through the use of multiple and complementary biophysical techniques including nuclear magnetic resonance (NMR) and Fourier transform infrared spectroscopy (FTIR), we show that raloxifene interacts specifically with the organic component or the organic/mineral composite, and not with hydroxyapatite. Structure-activity studies reveal that the basic side chain of raloxifene is an instrumental determinant in the interaction with bone. Thus, truncation of portions of the side chain reduces bone binding and also diminishes the increase in mechanical properties. Our results support a model wherein the piperidine interacts with bone matrix through electrostatic interactions with the piperidine nitrogen and through hydrophobic interactions (van der Waals) with the aliphatic groups in the side chain and the benzothiopene core. Furthermore, in silico prediction of the potential binding sites on the surface of collagen revealed the presence of a groove with sufficient space to accommodate raloxifene analogs. The hydroxyl groups on the benzothiophene nucleus, which are necessary for binding of SERMs to the estrogen receptor, are not required for binding to the bone surface, but mediate a more robust binding of the compound to the bone powder. In conclusion, we report herein a novel property of raloxifene analogs that allows them to interact with the bone tissue through potential contacts with the organic matrix and in particular collagen.

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Section: Introductionmentioning

confidence: 99%

Structural features underlying raloxifene’s biophysical interaction with bone matrix

Bivi

Balagopalakrishna

et al. 2016

Bioorganic & Medicinal Chemistry

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“…[11,12] Raloxifene is known to be a safe agent. [13] In our study, it did not induce any appreciable nephrotoxicity in therapeutic doses. Many studies have shown that raloxifene has also a favorable impact on lipid metabolism.…”

mentioning

confidence: 73%

“…[11,12] Clinical data suggest that raloxifene has a safety profile. [13] Oral bisphosphonates are an effective alternative to hormone replacement therapy in the management of postmenopausal osteoporosis and are becoming widely used as first choice treatment. Both second-and third-generation bisphosphonates, like alendronate and risedronate, are available as weekly tablets, which have facilitated the patient compliance to treatment together with a decreased occurrence of gastrointestinal side effects.…”

Section: B Yanik Et Almentioning

confidence: 99%

The Effect of Alendronate, Risedronate, and Raloxifene on Renal Functions, Based on the Cockcroft and Gault Method, in Postmenopausal Women

et al. 2007

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Background. Oral alendronate, risedronate, and raloxifene are effective treatment options in the management of postmenopausal osteoporosis. There is little previously reported about the renal safety profiles of these three agents in osteoporosis. We aimed to assess the risk of renal toxicity associated with oral alendronate, risedronate, and raloxifene in the treatment of osteoporosis, prospectively. Methods. One hundred and twentyseven patients with osteoporosis and osteopenia according to lumbar or femoral-neck bone mineral density t score were enrolled in the study. The patients were randomized to alendronate 70 mg once weekly (n = 47), risedronate 35 mg once weekly (n = 44), or raloxifene 60 mg per day (n = 36) for one year. Preliminary screening included medical history, physical examination, lumbar and femoral bone mineral densitometry measurement, and blood biochemical tests, including renal function tests. The biochemical markers were then assessed at the end of 12 months. Results. There was no significant difference between basal and final renal function parameters of each group. Also these parameters did not differ between the three groups after 12 months of treatment period. Conclusions. These results demonstrate that alendronate, risedronate, and raloxifene are all safe drugs for renal functions in the treatment of osteoporosis.

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“…Goldstein et al (2000) reported that raloxifene was not increasing the incidence of endometrial cancer. Martino et al (2005) studied the safety of raloxifene over 8 years in a clinical trial setting. The authors reported that 8-year data support the known clinical safety profile of raloxifene.…”

Section: Raloxifenementioning

confidence: 99%

Genotoxicity of the some selective estrogen receptor modulators: a review

2014

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The objective of this article is to review genotoxicological profile of the major selective estrogen receptor modulators, including clomiphene, tamoxifen, toremifene, raloxifene. These drugs have been used for infertility treatment and breast cancer prevention in high risk-women. However, some studies reported that especially tamoxifen is a genotoxic agent and is related with endometrial cancer. Our review indicate that clomiphene and tamoxifen were found as genotoxic agent in majority of the tests. However published reports showed that toremifene is a weakly genotoxic agent. The genotoxic effects of raloxifene are still poorly known. Further genotoxicity studies should be conducted especially for raloxifene.

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Safety assessment of raloxifene over eight years in a clinical trial setting

Abstract: These 8-year data support the known clinical safety profile of raloxifene, established in the MORE trial.

Cited by 105 publications

References 15 publications

Structural features underlying raloxifene’s biophysical interaction with bone matrix

Structural features underlying raloxifene’s biophysical interaction with bone matrix

The Effect of Alendronate, Risedronate, and Raloxifene on Renal Functions, Based on the Cockcroft and Gault Method, in Postmenopausal Women

Genotoxicity of the some selective estrogen receptor modulators: a review

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