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Published in: Journal of Bone and Mineral Metabolism 6/2013

01-11-2013 | Original Article

The SERM raloxifene improves diaphyseal fracture healing in mice

Authors: Alexander S. Spiro, Shahram Khadem, Anke Jeschke, Robert Percy Marshall, Pia Pogoda, Anita Ignatius, Michael Amling, Frank Timo Beil

Published in: Journal of Bone and Mineral Metabolism | Issue 6/2013

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Abstract

Although several studies reported that raloxifene treatment improves postmenopausal osteoporotic bone structure and reduces fracture risk, only a few animal and no human studies have examined its effects on the fracture healing process. Thus the aim of the present study was to determine, whether systemic application of the selective estrogen receptor modulator raloxifene promotes fracture healing compared to untreated control-, estrogen-deficient-, as well as estrogen-treated mice using a standardized femoral osteotomy model (n = 60 mice). Ten days after surgery, contact radiography and undecalcified histomorphometric analysis revealed that raloxifene administration significantly improved the early stage of fracture healing compared to all other groups. At day 20, raloxifene and estrogen treatment led to a significant increase in callus mineralization and trabecular thickness compared to control mice. μCT analyses revealed no evidence of complete bony bridging of the fracture site in any control-, nor estrogen-deficient mouse after 20 days, while all femoral fractures in the raloxifene and estrogen group already healed adequately at this time. These data indicate that raloxifene treatment significantly improves all phases of fracture healing at least in mice. Therefore, raloxifene could be a possible pharmaceutical to enhance fracture healing in women, without the known side effects of estrogen.
Literature
1.
2.
go back to reference Tu Z, Ma Y, Tian J, Li H, Akers W, Achilefu S, Gu Y (2012) Estrogen receptor β potentiates the antiproliferative effect of raloxifene and affects the cell migration and invasion in HCT-116 colon cancer cells. J Cancer Res Clin Oncol 138:1091–1103PubMedCrossRef Tu Z, Ma Y, Tian J, Li H, Akers W, Achilefu S, Gu Y (2012) Estrogen receptor β potentiates the antiproliferative effect of raloxifene and affects the cell migration and invasion in HCT-116 colon cancer cells. J Cancer Res Clin Oncol 138:1091–1103PubMedCrossRef
3.
go back to reference Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, Christiansen C, Delmas PD, Zanchetta JR, Stakkestad J, Gluer CC, Krueger K, Cohen FJ, Eckert S, Ensrud K, Avioli LV, Lips P, Cummings SR (1999) Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: Results from a 3-year randomized clinical trial. JAMA 282:637–645PubMedCrossRef Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, Christiansen C, Delmas PD, Zanchetta JR, Stakkestad J, Gluer CC, Krueger K, Cohen FJ, Eckert S, Ensrud K, Avioli LV, Lips P, Cummings SR (1999) Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: Results from a 3-year randomized clinical trial. JAMA 282:637–645PubMedCrossRef
4.
go back to reference Delmas PD, Ensrud KE, Adachi JD, Harper KD, Sarkar S, Gennari C, Reginster JY, Pols HA, Recker RR, Harris ST, Wu W, Genant HK, Black DM, Eastell R (2002) Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: Four-year results from a randomized clinical trial. J Clin Endocrinol Metab 87:3609–3617PubMedCrossRef Delmas PD, Ensrud KE, Adachi JD, Harper KD, Sarkar S, Gennari C, Reginster JY, Pols HA, Recker RR, Harris ST, Wu W, Genant HK, Black DM, Eastell R (2002) Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: Four-year results from a randomized clinical trial. J Clin Endocrinol Metab 87:3609–3617PubMedCrossRef
5.
go back to reference Beil FT, Barvencik F, Gebauer M, Seitz S, Rueger JM, Ignatius A, Pogoda P, Schinke T, Amling M (2010) Effects of estrogen on fracture healing in mice. J Trauma 69:1259–1265PubMedCrossRef Beil FT, Barvencik F, Gebauer M, Seitz S, Rueger JM, Ignatius A, Pogoda P, Schinke T, Amling M (2010) Effects of estrogen on fracture healing in mice. J Trauma 69:1259–1265PubMedCrossRef
6.
go back to reference He YX, Zhang G, Pan XH, Liu Z, Zheng LZ, Chan CW, Lee KM, Cao YP, Li G, Wei L, Hung LK, Leung KS, Qin L (2011) Impaired bone healing pattern in mice with ovariectomy-induced osteoporosis: a drill-hole defect model. Bone 48:1388–1400PubMedCrossRef He YX, Zhang G, Pan XH, Liu Z, Zheng LZ, Chan CW, Lee KM, Cao YP, Li G, Wei L, Hung LK, Leung KS, Qin L (2011) Impaired bone healing pattern in mice with ovariectomy-induced osteoporosis: a drill-hole defect model. Bone 48:1388–1400PubMedCrossRef
7.
go back to reference Boden SD, Joyce ME, Oliver B, Heydemann A, Bolander ME (1989) Estrogen receptor mRNA expression in callus during fracture healing in the rat. Calcif Tissue Int 45:324–325PubMedCrossRef Boden SD, Joyce ME, Oliver B, Heydemann A, Bolander ME (1989) Estrogen receptor mRNA expression in callus during fracture healing in the rat. Calcif Tissue Int 45:324–325PubMedCrossRef
8.
go back to reference Kolios L, Hoerster AK, Sehmisch S, Malcherek MC, Rack T, Tezval M, Seidlova-Wuttke D, Wuttke W, Stuermer KM, Stuermer EK (2010) Do estrogen and alendronate improve metaphyseal fracture healing when applied as osteoporosis prophylaxis? Calcif Tissue Int 86:23–32PubMedCrossRef Kolios L, Hoerster AK, Sehmisch S, Malcherek MC, Rack T, Tezval M, Seidlova-Wuttke D, Wuttke W, Stuermer KM, Stuermer EK (2010) Do estrogen and alendronate improve metaphyseal fracture healing when applied as osteoporosis prophylaxis? Calcif Tissue Int 86:23–32PubMedCrossRef
9.
go back to reference Namkung-Matthai H, Appleyard R, Jansen J, Hao Lin J, Maastricht S, Swain M, Mason RS, Murrell GA, Diwan AD, Diamond T (2001) Osteoporosis influences the early period of fracture healing in a rat osteoporotic model. Bone 28:80–86PubMedCrossRef Namkung-Matthai H, Appleyard R, Jansen J, Hao Lin J, Maastricht S, Swain M, Mason RS, Murrell GA, Diwan AD, Diamond T (2001) Osteoporosis influences the early period of fracture healing in a rat osteoporotic model. Bone 28:80–86PubMedCrossRef
10.
go back to reference Black LJ, Sato M, Rowley ER, Magee DE, Bekele A, Williams DC, Cullinan GJ, Bendele R, Kauffman RF, Bensch WR, Frolik CA, Termine JD, Bryant HU (1994) Raloxifene (LY139481 HCI) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovariectomized rats. J Clin Invest 93:63–69PubMedCrossRef Black LJ, Sato M, Rowley ER, Magee DE, Bekele A, Williams DC, Cullinan GJ, Bendele R, Kauffman RF, Bensch WR, Frolik CA, Termine JD, Bryant HU (1994) Raloxifene (LY139481 HCI) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovariectomized rats. J Clin Invest 93:63–69PubMedCrossRef
11.
go back to reference Sato M, Kim J, Short LL, Slemenda CW, Bryant HU (1995) Longitudinal and cross-sectional analysis of raloxifene effects on tibiae from ovariectomized aged rats. J Pharmacol Exp Ther 272:1252–1259PubMed Sato M, Kim J, Short LL, Slemenda CW, Bryant HU (1995) Longitudinal and cross-sectional analysis of raloxifene effects on tibiae from ovariectomized aged rats. J Pharmacol Exp Ther 272:1252–1259PubMed
12.
go back to reference Spiro AS, Beil FT, Schinke T, Schilling AF, Eulenburg C, Rueger JM, Amling M (2010) Short-term application of dexamethasone enhances bone morphogenetic protein-7-induced ectopic bone formation in vivo. J Trauma 69:1473–1480PubMedCrossRef Spiro AS, Beil FT, Schinke T, Schilling AF, Eulenburg C, Rueger JM, Amling M (2010) Short-term application of dexamethasone enhances bone morphogenetic protein-7-induced ectopic bone formation in vivo. J Trauma 69:1473–1480PubMedCrossRef
13.
go back to reference Amling M, Priemel M, Holzmann T, Chapin K, Rueger JM, Baron R, Demay MB (1999) Rescue of the skeletal phenotype of vitamin D receptor-ablated mice in the setting of normal mineral ion homeostasis: formal histomorphometric and biomechanical analyses. Endocrinology 140:4982–4987PubMedCrossRef Amling M, Priemel M, Holzmann T, Chapin K, Rueger JM, Baron R, Demay MB (1999) Rescue of the skeletal phenotype of vitamin D receptor-ablated mice in the setting of normal mineral ion homeostasis: formal histomorphometric and biomechanical analyses. Endocrinology 140:4982–4987PubMedCrossRef
14.
go back to reference Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR (1987) Bone histomorphometry: standardization of nomenclature, symbols and units. J Bone Miner Res 6:595–610 Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR (1987) Bone histomorphometry: standardization of nomenclature, symbols and units. J Bone Miner Res 6:595–610
15.
go back to reference Spiro AS, Beil FT, Baranowsky A, Barvencik F, Schilling AF, Nguyen K, Khadem S, Seitz S, Rueger JM, Schinke T, Amling M (2010) BMP-7-induced ectopic bone formation and fracture healing is impaired by systemic NSAID application in C57BL/6-mice. J Orthop Res 28:785–791PubMed Spiro AS, Beil FT, Baranowsky A, Barvencik F, Schilling AF, Nguyen K, Khadem S, Seitz S, Rueger JM, Schinke T, Amling M (2010) BMP-7-induced ectopic bone formation and fracture healing is impaired by systemic NSAID application in C57BL/6-mice. J Orthop Res 28:785–791PubMed
16.
go back to reference Beil FT, Barvencik F, Gebauer M, Beil B, Pogoda P, Rueger JM, Ignatius A, Schinke T, Amling M (2011) Effects of increased bone formation on fracture healing in mice. J Trauma 70:857–862PubMedCrossRef Beil FT, Barvencik F, Gebauer M, Beil B, Pogoda P, Rueger JM, Ignatius A, Schinke T, Amling M (2011) Effects of increased bone formation on fracture healing in mice. J Trauma 70:857–862PubMedCrossRef
17.
go back to reference Stuermer EK, Sehmisch S, Rack T, Wenda E, Seidlova-Wuttke D, Tezval M, Wuttke W, Frosch KH, Stuermer KM (2010) Estrogen and raloxifene improve metaphyseal fracture healing in the early phase of osteoporosis. A new fracture-healing model at the tibia in rat. Langenbecks Arch Surg 395:163–172PubMedCrossRef Stuermer EK, Sehmisch S, Rack T, Wenda E, Seidlova-Wuttke D, Tezval M, Wuttke W, Frosch KH, Stuermer KM (2010) Estrogen and raloxifene improve metaphyseal fracture healing in the early phase of osteoporosis. A new fracture-healing model at the tibia in rat. Langenbecks Arch Surg 395:163–172PubMedCrossRef
18.
go back to reference Cao Y, Mori S, Mashiba T, Westmore MS, Ma L, Sato M, Akiyama T, Shi L, Komatsubara S, Miyamoto K, Norimatsu H (2002) Raloxifene, estrogen, and alendronate affect the processes of fracture repair differently in ovariectomized rats. J Bone Miner Res 17:2237–2246PubMedCrossRef Cao Y, Mori S, Mashiba T, Westmore MS, Ma L, Sato M, Akiyama T, Shi L, Komatsubara S, Miyamoto K, Norimatsu H (2002) Raloxifene, estrogen, and alendronate affect the processes of fracture repair differently in ovariectomized rats. J Bone Miner Res 17:2237–2246PubMedCrossRef
19.
go back to reference Takada J, Miki T, Imanishi Y, Nakatsuka K, Wada H, Naka H, Yoshizaki T, Iba K, Beck TJ, Yamashita T (2010) Effects of raloxifene treatment on the structural geometry of the proximal femur in Japanese women with osteoporosis. J Bone Miner Metab 28:561–567PubMedCrossRef Takada J, Miki T, Imanishi Y, Nakatsuka K, Wada H, Naka H, Yoshizaki T, Iba K, Beck TJ, Yamashita T (2010) Effects of raloxifene treatment on the structural geometry of the proximal femur in Japanese women with osteoporosis. J Bone Miner Metab 28:561–567PubMedCrossRef
20.
go back to reference Gorai I, Hattori S, Tanaka Y, Iwaoki Y (2012) Alfacalcidol-supplemented raloxifene therapy has greater bone-sparing effect than raloxifene-alone therapy in postmenopausal Japanese women with osteoporosis or osteopenia. J Bone Miner Metab 30:349–358PubMedCrossRef Gorai I, Hattori S, Tanaka Y, Iwaoki Y (2012) Alfacalcidol-supplemented raloxifene therapy has greater bone-sparing effect than raloxifene-alone therapy in postmenopausal Japanese women with osteoporosis or osteopenia. J Bone Miner Metab 30:349–358PubMedCrossRef
21.
go back to reference Hatano H, Siegel HJ, Yamagiwa H, Bronk JT, Turner RT, Bolander ME, Sarkar G (2004) Identification of estrogen-regulated genes during fracture healing, using DNA microarray. J Bone Miner Metab 22:224–235PubMedCrossRef Hatano H, Siegel HJ, Yamagiwa H, Bronk JT, Turner RT, Bolander ME, Sarkar G (2004) Identification of estrogen-regulated genes during fracture healing, using DNA microarray. J Bone Miner Metab 22:224–235PubMedCrossRef
22.
go back to reference Zhou S, Zilberman Y, Wassermann K, Bain SD, Sadovsky Y, Gazit D (2001) Estrogen modulates estrogen receptor alpha and beta expression, osteogenic activity, and apoptosis in mesenchymal stem cells (MSCs) of osteoporotic mice. J Cell Biochem 36:144–155CrossRef Zhou S, Zilberman Y, Wassermann K, Bain SD, Sadovsky Y, Gazit D (2001) Estrogen modulates estrogen receptor alpha and beta expression, osteogenic activity, and apoptosis in mesenchymal stem cells (MSCs) of osteoporotic mice. J Cell Biochem 36:144–155CrossRef
23.
go back to reference He YX, Liu Z, Pan XH, Tang T, Guo BS, Zheng LZ et al (2012) Deletion of estrogen receptor beta accelerates early stage of bone healing in a mouse osteotomy model. Osteoporos Int 23:377–389PubMedCrossRef He YX, Liu Z, Pan XH, Tang T, Guo BS, Zheng LZ et al (2012) Deletion of estrogen receptor beta accelerates early stage of bone healing in a mouse osteotomy model. Osteoporos Int 23:377–389PubMedCrossRef
24.
go back to reference Yang NN, Bryant HU, Hardikar S, Sato M, Galvin RJ, Glasebrook AL, Termine JD (1996) Estrogen and raloxifene stimulate transforming growth factor-beta 3 gene expression in rat bone: a potential mechanism for estrogen- or raloxifene-mediated bone maintenance. Endocrinology 137:2075–2084PubMedCrossRef Yang NN, Bryant HU, Hardikar S, Sato M, Galvin RJ, Glasebrook AL, Termine JD (1996) Estrogen and raloxifene stimulate transforming growth factor-beta 3 gene expression in rat bone: a potential mechanism for estrogen- or raloxifene-mediated bone maintenance. Endocrinology 137:2075–2084PubMedCrossRef
25.
go back to reference Glasebrook AL, Phillips DL, Sluka JP (1993) Multiple binding sites for the anti-estrogen raloxifene. J Bone Miner Res 8(Suppl 1):268 Glasebrook AL, Phillips DL, Sluka JP (1993) Multiple binding sites for the anti-estrogen raloxifene. J Bone Miner Res 8(Suppl 1):268
Metadata
Title
The SERM raloxifene improves diaphyseal fracture healing in mice
Authors
Alexander S. Spiro
Shahram Khadem
Anke Jeschke
Robert Percy Marshall
Pia Pogoda
Anita Ignatius
Michael Amling
Frank Timo Beil
Publication date
01-11-2013
Publisher
Springer Japan
Published in
Journal of Bone and Mineral Metabolism / Issue 6/2013
Print ISSN: 0914-8779
Electronic ISSN: 1435-5604
DOI
https://doi.org/10.1007/s00774-013-0461-x

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