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.
Similar content being viewed by others
References
Consensus Development Conference (1993) Diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med 94:646–650
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
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
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
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
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
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
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
Jahng JS, Kim HW (2000) Effect of intermittent administration of parathyroid hormone on fracture healing in ovariectomized rats. Orthopedics 23:1089–1094
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
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
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
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
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
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
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
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
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
Wang JW, Xu SW, Yang DS, Lv RK (2007) Locally applied simvastatin promotes fracture healing in ovariectomized rat. Osteoporos Int 18:1641–1650
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
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
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
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
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
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
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
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
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
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
Caverzasio J (2008) Strontium ranelate promotes osteoblastic cell replication through at least two different mechanisms. Bone 42:1131–1136
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
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
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
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
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
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
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
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
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
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
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
Acknowledgments
This study was supported by a grant from National Science Funds for Distinguished Young Scholars (No. 30825040).
Conflicts of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00198-009-1140-6