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Systemic treatment with strontium ranelate promotes tibial fracture healing in ovariectomized rats

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Abstract

Summary

Systemic treatment with strontium ranelate (SR) was performed on ovariectomized (OVX) rats with fractured tibiae. Callus quality was assessed by radiographic, histological, micro-computerized tomography, and biomechanical examinations at 4 and 8 weeks after fracture. Results revealed that systemic applied SR promoted osteoporotic fracture healing.

Introduction

Several studies have demonstrated the dual effect of SR on osteoporotic and undisturbed bone. However, reports of their effect on osteoporotic fracture healing are limited. This study was designed to investigate the effects of SR on bone regeneration in OVX rats with fractured tibiae.

Methods

Three months after being OVX, female Sprague–Dawley rats accepted bilateral osteotomy on proximal tibiae fixed with intramedullary wires and were divided into two groups: OVX and OVX + SR (625 mg/kg/day). Callus quality was evaluated at 4 and 8 weeks postfracture.

Results

Compared with OVX group, SR treatment significantly increased bone formation, BMD, biomechanical strength, and improved microstructural properties of the callus. The ultimate load was increased by 211.0% and 61.4% (p < 0.01), and the total bone volume of callus by 74.8% and 79.3% (p < 0.01) at 4 and 8 weeks postfracture, respectively. SR treatment also promoted healing progress with increased osteogenesis at 4 weeks; more mature and tightly arranged woven or lamellar bone at 8 weeks across the fracture gap in histological analysis.

Conclusion

This study suggests that systemic treatment with strontium ranelate could promote tibial fracture healing in OVX rats.

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References

  1. Consensus Development Conference (1993) Diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med 94:646–650

    Article  Google Scholar 

  2. Kubo T, Shiga T, Hashimoto J, Yoshioka M, Honjo H, Urabe M, Kitajima I, Semba I, Hirasawa Y (1999) Osteoporosis influences the late period of fracture healing in a rat model prepared by ovariectomy and low calcium diet. J Steroid Biochem Mol Biol 68:197–202

    Article  CAS  PubMed  Google Scholar 

  3. 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 28:80–86

    Article  CAS  PubMed  Google Scholar 

  4. McCann RM, Colleary G, Geddis C, Clarke SA, Jordan GR, Dickson GR, Marsh D (2008) Effect of osteoporosis on bone mineral density and fracture repair in a rat femoral fracture model. J Orthop Res 26:384–393

    Article  PubMed  Google Scholar 

  5. Hao YJ, Zhang G, Wang YS, Qin L, Hung WY, Leung K, Pei FX (2007) Changes of microstructure and mineralized tissue in the middle and late phase of osteoporotic fracture healing in rats. Bone 41:631–638

    Article  PubMed  Google Scholar 

  6. 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 17:2237–2246

    Article  CAS  PubMed  Google Scholar 

  7. Amanata N, He LH, Swain MV, Little DG (2008) The effect of zoledronic acid on the intrinsic material properties of healing bone: an indentation study. Med Eng Phys 30:843–847

    Article  PubMed  Google Scholar 

  8. Li X, Luo X, Yu N, Zeng B (2007) Effects of salmon calcitonin on fracture healing in ovariectomized rats. Saudi Med J 28:60–64

    PubMed  Google Scholar 

  9. Jahng JS, Kim HW (2000) Effect of intermittent administration of parathyroid hormone on fracture healing in ovariectomized rats. Orthopedics 23:1089–1094

    CAS  PubMed  Google Scholar 

  10. Nozaka K, Miyakoshi N, Kasukawa Y, Maekawa S, Noguchi H, Shimada Y (2008) Intermittent administration of human parathyroid hormone enhances bone formation and union at the site of cancellous bone osteotomy in normal and ovariectomized rats. Bone 42:90–97

    Article  CAS  PubMed  Google Scholar 

  11. Bonnelye E, Chabadel A, Saltel F, Jurdic P (2008) Dual effect of strontium ranelate: stimulation of osteoblast differentiation and inhibition of osteoclast formation and resorption in vitro. Bone 42:129–138

    Article  CAS  PubMed  Google Scholar 

  12. Bain SD, Jerome C, Shen V, Dupin-Roger I, Ammann P (2009) Strontium ranelate improves bone strength in ovariectomized rat by positively influencing bone resistance determinants. Osteoporos Int 20:1417–1428

    Article  CAS  PubMed  Google Scholar 

  13. Hott M, Deloffre P, Tsouderos Y, Marie PJ (2003) S12911–2 reduces bone loss induced by short-term immobilization in rats. Bone 33:115–123

    Article  CAS  PubMed  Google Scholar 

  14. Marquis P, Roux C, de la Loge C, Diaz-Curiel M, Cormier C, Isaia G, Badurski J, Wark J, Meunier PJ (2008) Strontium ranelate prevents quality of life impairment in post-menopausal women with established vertebral osteoporosis. Osteoporos Int 19:503–510

    Article  CAS  PubMed  Google Scholar 

  15. Reginster JY, Seeman E, De Vernejoul MC, Adami S, Compston J, Phenekos C, Devogelaer JP, Curiel MD, Sawicki A, Goemaere S, Sorensen OH, Felsenberg D, Meunier PJ (2005) Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. J Clin Endocrinol Metab 90:2816–2822

    Article  CAS  PubMed  Google Scholar 

  16. Meunier PJ, Roux C, Ortolani S, Diaz-Curiel M, Compston J, Marquis P, Cormier C, Isaia G, Badurski J, Wark JD, Collette J, Reginster JY (2009) Effects of long-term strontium ranelate treatment on vertebral fracture risk in postmenopausal women with osteoporosis. Osteoporos Int 20:1663–1673

    Article  CAS  PubMed  Google Scholar 

  17. Cebesoy O, Tutar E, Kose KC, Baltaci Y, Bagci C (2007) Effect of strontium ranelate on fracture healing in rat tibia. Jt Bone Spine 74:590–593

    Article  Google Scholar 

  18. Varkey M, Kucharski C, Doschak MR, Winn SR, Brochmann EJ, Murray S, Matyas JR, Zernicke RF, Uludag H (2007) Osteogenic response of bone marrow stromal cells from normal and ovariectomized rats treated with a low dose of basic fibroblast growth factor. Tissue Eng 13:809–817

    Article  CAS  PubMed  Google Scholar 

  19. Wang JW, Xu SW, Yang DS, Lv RK (2007) Locally applied simvastatin promotes fracture healing in ovariectomized rat. Osteoporos Int 18:1641–1650

    Article  PubMed  Google Scholar 

  20. Ammann P, Shen V, Robin B, Mauras Y, Bonjour JP, Rizzoli R (2004) Strontium ranelate improves bone resistance by increasing bone mass and improving architecture in intact female rats. J Bone Miner Res 19:2012–2020

    Article  CAS  PubMed  Google Scholar 

  21. Marie PJ, Hott M, Modrowski D, De Pollak C, Guillemain J, Deloffre P, Tsouderos Y (1993) An uncoupling agent containing strontium prevents bone loss by depressing bone resorption and maintaining bone formation in estrogen-deficient rats. J Bone Miner Res 8:607–615

    Article  CAS  PubMed  Google Scholar 

  22. Goldberg VM, Powell A, Shaffer JW, Zika J, Bos GD, Heiple KG (1985) Bone grafting: role of histocompatibility in transplantation. J Orthop Res 3:389–404

    Article  CAS  PubMed  Google Scholar 

  23. Gerstenfeld LC, Sacks DJ, Pelis M, Mason ZD, Graves DT, Barrero M, Ominsky MS, Kostenuik PJ, Morgan EF, Einhorn TA (2009) Comparison of effects of the bisphosphonate alendronate versus the RANKL inhibitor denosumab on murine fracture healing. J Bone Miner Res 24:196–208

    Article  CAS  PubMed  Google Scholar 

  24. Kakar S, Einhorn TA, Vora S, Miara LJ, Hon G, Wigner NA, Toben D, Jacobsen KA, Al-Sebaei MO, Song M, Trackman PC, Morgan EF, Gerstenfeld LC, Barnes GL (2007) Enhanced chondrogenesis and Wnt signaling in PTH-treated fractures. J Bone Miner Res 22:1903–1912

    Article  CAS  PubMed  Google Scholar 

  25. Fu L, Tang T, Miao Y, Hao Y, Dai K (2009) Effect of 1, 25-dihydroxy vitamin D3 on fracture healing and bone remodeling in ovariectomized rat femora. Bone 44:893–898

    Article  CAS  PubMed  Google Scholar 

  26. Nagashima M, Sakai A, Uchida S, Tanaka S, Tanaka M, Nakamura T (2005) Bisphosphonate (YM529) delays the repair of cortical bone defect after drill-hole injury by reducing terminal differentiation of osteoblasts in the mouse femur. Bone 36:502–511

    Article  CAS  PubMed  Google Scholar 

  27. Stuermer EK, Sehmisch S, Rack T, Wenda E, Seidlova-Wuttke D, Tezval M, Wuttke W, Frosch KH, Stuermer KM (2008) 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 [Epub ahead of print], Dec 2

  28. Aspenberg P, Genant HK, Johansson T, Nino AJ, See K, Krohn K, García-Hernández PA, Recknor CP, Einhorn TA, Dalsky GP, Mitlak BH, Fierlinger A, Lakshmanan MC (2009) Teriparatide for acceleration of fracture repair in humans: a prospective, randomized, double-blind study of 102 postmenopausal women with distal radial fractures. J Bone Miner Res [Epub ahead of print], Jul 13

  29. Atkins GJ, Welldon KJ, Halbout P, Findlay DM (2009) Strontium ranelate treatment of human primary osteoblasts promotes an osteocyte-like phenotype while eliciting an osteoprotegerin response. Osteoporos Int 20:653–664

    Article  CAS  PubMed  Google Scholar 

  30. Caverzasio J (2008) Strontium ranelate promotes osteoblastic cell replication through at least two different mechanisms. Bone 42:1131–1136

    Article  CAS  PubMed  Google Scholar 

  31. Sila-Asna M, Bunyaratvej A, Maeda S, Kitaguchi H, Bunyaratavej N (2007) Osteoblast differentiation and bone formation gene expression in strontium-inducing bone marrow mesenchymal stem cell. Kobe J Med Sci 53:25–35

    CAS  PubMed  Google Scholar 

  32. Baron R, Tsouderos Y (2002) In vitro effects of S12911–2 on osteoclast function and bone marrow macrophage differentiation. Eur J Pharmacol 450:11–17

    Article  CAS  PubMed  Google Scholar 

  33. Boivin G, Farlay D, Khebbab MT, Jaurand X, Delmas PD, Meunier PJ (2009) In osteoporotic women treated with strontium ranelate, strontium is located in bone formed during treatment with a maintained degree of mineralization. Osteoporos Int [Epub ahead of print], Jul 14

  34. Collette J, Bruyère O, Kaufman JM, Lorenc R, Felsenberg D, Spector TD, Diaz-Curiel M, Boonen S, Reginster JY (2009) Vertebral anti-fracture efficacy of strontium ranelate according to pre-treatment bone turnover. Osteoporos Int [Epub ahead of print], May 13

  35. Shirley D, Marsh D, Jordan G, McQuaid S, Li G (2005) Systemic recruitment of osteoblastic cells in fracture healing. J Orthop Res 23:1013–1021

    Article  PubMed  Google Scholar 

  36. Meunier PJ, Roux C, Seeman E, Ortolani S, Badurski JE, Spector TD, Cannata J, Balogh A, Lemmel EM, Pors-Nielsen S, Rizzoli R, Genant HK, Reginster JY (2004) The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 350:459–468

    Article  CAS  PubMed  Google Scholar 

  37. Brennan T, Rybchyn M, Green W, Atwa S, Conigrave A, Mason R (2009) Osteoblasts play key roles in the mechanisms of action of strontium ranelate. Br J Pharmacol 157:1291–1300

    Article  CAS  PubMed  Google Scholar 

  38. Van Beek ER, Löwik CW, Papapoulos SE (2002) Bisphosphonates suppress bone resorption by a direct effect on early osteoclast precursors without affecting the osteoclastogenic capacity of osteogenic cells: the role of protein geranylgeranylation in the action of nitrogen-containing bisphosphonates on osteoclast precursors. Bone 30:64–70

    Article  PubMed  Google Scholar 

  39. Kwak HB, Kim JY, Kim KJ, Choi MK, Kim JJ, Kim KM, Shin YI, Lee MS, Kim HS, Kim JW, Chun CH, Cho HJ, Hong GY, Juhng SK, Yoon KH, Park BH, Bae JM, Han JK, Oh J (2009) Risedronate directly inhibits osteoclast differentiation and inflammatory bone loss. Biol Pharm Bull 32:1193–1198

    Article  CAS  PubMed  Google Scholar 

  40. Recker RR, Marin F, Ish-Shalom S, Möricke R, Hawkins F, Kapetanos G, de la Peña MP, Kekow J, Farrerons J, Sanz B, Oertel H, Stepan J (2009) Comparative effects of teriparatide and strontium ranelate on bone biopsies and biochemical markers of bone turnover in postmenopausal women with osteoporosis. J Bone Miner Res 24:1358–1368

    Article  CAS  PubMed  Google Scholar 

  41. Boivin G, Deloffre P, Perrat B, Panczer G, Boudeulle M, Mauras Y, Allain P, Tsouderos Y, Meunier PJ (1996) Strontium distribution and interactions with bone mineral in monkey iliac bone after strontium salt (S12911) administration. J Bone Miner Res 11:1302–1311

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by a grant from National Science Funds for Distinguished Young Scholars (No. 30825040).

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Correspondence to J. Hu.

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Li, Y.F., Luo, E., Feng, G. et al. Systemic treatment with strontium ranelate promotes tibial fracture healing in ovariectomized rats. Osteoporos Int 21, 1889–1897 (2010). https://doi.org/10.1007/s00198-009-1140-6

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  • DOI: https://doi.org/10.1007/s00198-009-1140-6

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