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Calcified Tissue International

, Volume 97, Issue 4, pp 391–401 | Cite as

The Impact of Strontium Ranelate on Metaphyseal Bone Healing in Ovariectomized Rats

  • Marina KomrakovaEmail author
  • Anna Weidemann
  • Christian Dullin
  • Joachim Ebert
  • Mohammad Tezval
  • Klaus Michael Stuermer
  • Stephan Sehmisch
Original Research

Abstract

The following questions were addressed: whether therapy with strontium ranelate (SR) should be continued or interrupted if the fractures occur during SR treatment and whether SR could be applied directly after fracture to improve bone healing. Sprague–Dawley rats (3 month old) were ovariectomized (Ovx, n = 48) or left intact (n = 12). After 8 weeks, a bilateral transverse osteotomy of the tibia metaphysis was created in all rats. Ovx rats were divided into four groups: Ovx; SR applied directly after Ovx until osteotomy (prophylaxis, SR pr, 8 weeks); SR applied after osteotomy (therapy, SR th, 5 weeks); SR applied during the whole experiment (pr + th, 13 weeks). SR dosage was 625 mg/kg body weight/day, administered in the feed. Five weeks later, tibiae were analyzed by biomechanical, histological, micro-CT, and gene expression analyses. The SR pr + th treatment increased total bone mineral density (BMD), bone volume fraction, cortical BMD and volume, callus area and density, serum alkaline phosphatase, tartrate-resistant acid phosphatase mRNA, accelerated osteotomy bridging, and callus formation at weeks 2 and 3 of healing and decreased the osteoprotegerin/receptor activator of nuclear factor kB ligand mRNA ratio. SR th enlarged callus area and improved callus formation during the 5th week of healing. SR pr improved cortical BMD preserving bone after SR discontinuation (5-week rest); the bone healing was not affected. SR content in the tibia metaphysis was the highest in SR pr + th group and was not different between SR pr and SR th. SR has a positive effect on osteoporotic bone healing in rat and SR treatment can be continued after the fracture occurs or applied directly after the fracture.

Keywords

Strontium ranelate Bone healing Osteoporosis Rat model 

Notes

Acknowledgments

The present study was supported by the Elsbeth–Bonhoff Foundation (N 70). We are thankful to R. Castro-Machguth and A. Witt for technical support.

Conflict of Interest

Authors declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

The animal study protocol was approved by the local regional government (G 11.560, Oldendurg, Germany) in accordance with German animal-protection laws prior to performing the study.

References

  1. 1.
    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 28:80–86CrossRefPubMedGoogle Scholar
  2. 2.
    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 41:631–638CrossRefPubMedGoogle Scholar
  3. 3.
    Riggs BL, Parfitt AM (2005) Drugs used to treat osteoporosis: the critical need for a uniform nomenclature based on their action on bone remodeling. J Bone Miner Res 20:437–440CrossRefGoogle Scholar
  4. 4.
    Goldhahn J, Féron JM, Kanis J, Papapoulos S, Reginster JY, Rizzoli R, Dere W, Mitlak B, Tsouderos Y, Boonen S (2012) Implications for fracture healing of current and new osteoporosis treatments: an ESCEO consensus paper. Calcif Tissue Int 90:343–353CrossRefPubMedGoogle Scholar
  5. 5.
    Larsson S, Fazzalari NL (2014) Anti-osteoporosis therapy and fracture healing. Arch Orthop Trauma Surg 134:291–297CrossRefPubMedGoogle Scholar
  6. 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 17:2237–2246CrossRefPubMedGoogle Scholar
  7. 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 30:843–847CrossRefPubMedGoogle Scholar
  8. 8.
    Marie PJ (2006) Strontium ranelate: a physiological approach for optimizing bone formation and resorption. Bone 38:S10–S14CrossRefPubMedGoogle Scholar
  9. 9.
    Deeks ED, Dhillon S (2010) Strontium ranelate: a review of its use in the treatment of postmenopausal osteoporosis. Drugs 70:733–759CrossRefPubMedGoogle Scholar
  10. 10.
  11. 11.
    Alegre DN, Ribeiro C, Sousa C, Correia J, Silva L, de Almeida L (2012) Possible benefits of strontium ranelate in complicated long bone fractures. Rheumatol Int 32:439–443CrossRefPubMedGoogle Scholar
  12. 12.
    Tarantino U, Celi M, Saturnino L, Scialdoni A, Cerocchi I (2010) Strontium ranelate and bone healing: report of two cases. Clin Cases Miner Bone Metab 7:65–68PubMedCentralPubMedGoogle Scholar
  13. 13.
    Cebesoy O, Tutar E, Kose KC, Baltaci Y, Bagci C (2007) Effect of strontium ranelate on fracture healing in rat tibia. Joint Bone Spine 74:590–593CrossRefPubMedGoogle Scholar
  14. 14.
    Brüel A, Olsen J, Birkedal H, Risager M, Andreassen TT, Raffalt AC, Andersen JE, Thomsen JS (2011) Strontium is incorporated into the fracture callus but does not influence the mechanical strength of healing rat fractures. Calcif Tissue Int 88:142–152CrossRefPubMedGoogle Scholar
  15. 15.
    Li YF, Luo E, Feng G, Zhu SS, Li JH, Hu J (2010) Systemic treatment with strontium ranelate promotes tibial fracture healing in ovariectomized rats. Osteoporos Int 21:1889–1897CrossRefPubMedGoogle Scholar
  16. 16.
    Habermann B, Kafchitsas K, Olender G, Augat P, Kurth A (2010) Strontium ranelate enhances callus strength more than PTH 1-34 in an osteoporotic rat model of fracture healing. Calcif Tissue Int 86:82–89CrossRefPubMedGoogle Scholar
  17. 17.
    Ozturan KE, Demir B, Yucel I, Cakıcı H, Yilmaz F, Haberal A (2011) Effect of strontium ranelate on fracture healing in the osteoporotic rats. J Orthop Res 29:138–142CrossRefPubMedGoogle Scholar
  18. 18.
    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 395:163–172PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Eriksen EF, Hodgson SF, Eastell R, Cedel SL, O’Fallon WM, Riggs BL (1990) Cancellous bone remodeling in type I (postmenopausal) osteoporosis: quantitative assessment of rates of formation, resorption, and bone loss at tissue and cellular levels. JBMS 5:311–319Google Scholar
  20. 20.
    Komrakova M, Werner C, Wicke M, Nguyen BT, Tezval M, Semisch S, Stuermer KM, Stuermer EK (2009) Effect of daidzein, 4-methylbenzylidene camphor or estrogen on gastrocnemius muscle of osteoporotic rats undergoing tibia healing period. J Endocrinol 201:253–262CrossRefPubMedGoogle Scholar
  21. 21.
    Sturmer EK, Seidlova-Wuttke D, Sehmisch S, Rack T, Wille J, Frosch KH, Wuttke W, Sturmer KM (2006) Standardized bending and breaking test for the normal and osteoporotic metaphyseal tibias of the rat: effect of estradiol, testosterone, and raloxifene. J Bone Miner Res 21:89–96CrossRefPubMedGoogle Scholar
  22. 22.
    Stuermer EK, Komrakova M, Sehmisch S, Tezval M, Dullin C, Schaefer N, Hallecker J, Stuermer KM (2014) Whole body vibration during fracture healing intensifies the effects of estradiol and raloxifene in estrogen-deficient rats. Bone 64:187–194CrossRefPubMedGoogle Scholar
  23. 23.
    Bouxsein ML, Boyd SK, Christiansen BA, Guldberg RE, Jepsen KJ, Müller R (2010) Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. JBMR 25:1468–1486CrossRefGoogle Scholar
  24. 24.
    Dempster DW, Compston JE, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR, Parfitt AM (2012) Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR histomorphometry nomenclature committee. JBMR 28:1–16Google Scholar
  25. 25.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods 25:402–408CrossRefPubMedGoogle Scholar
  26. 26.
    CEN (2002) European committee for standardization. Determination of Calcium and Magnesium. EN ISO 7980Google Scholar
  27. 27.
    Dahl SG, Allain P, Marie PJ, Mauras Y, Boivin G, Ammann P, Tsouderos Y, Delmas PD, Christiansen C (2001) Incorporation and distribution of strontium in bone. Bone 28:446–453CrossRefPubMedGoogle Scholar
  28. 28.
    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. JBMR 19:2012–2020CrossRefGoogle Scholar
  29. 29.
    Rizzoli R, Laroche M, Krieg M-A, Frieling I, Thomas T, Delmas P, Felsenberg D (2010) Strontium ranelate and alendronate have differing effects on distal bone microstructure in women with osteoporosis. Rheumatol Int 30:1341–1348PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Canalis E, Hott M, Deloffre P, Tsouderos Y, Marie PJ (1996) The divalent strontium salt S12911 enhances bone cell replication and bone formation in vitro. Bone 18:517–523CrossRefPubMedGoogle Scholar
  31. 31.
    Baron R, Tsouderos Y (2002) In vitro effects of S12911-2 on osteoclast function and bone marrow macrophage differentiation. Eur J Pharmacol 450:11–17CrossRefPubMedGoogle Scholar
  32. 32.
    Henricson A, Hulth A, Johnell O (1987) The cartilaginous fracture callus in rats. Acta Orthop Scand 58:244–248CrossRefPubMedGoogle Scholar
  33. 33.
    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(8):1417–1428CrossRefPubMedGoogle Scholar
  34. 34.
    Meyer RA, Meyer MH, Tenholder M, Wondracek S, Wasserman R, Garges P (2003) Gene expression in older rats with delayed union of femoral fractures. J Bone Joint Surg Am 85:1243–1254PubMedGoogle Scholar
  35. 35.
    Vogel C, Marcotte EM (2012) Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet 13:227–232PubMedCentralPubMedGoogle Scholar
  36. 36.
    Manigrasso MB, O’Connor JP (2004) Characterization of a closed femur fracture model in mice. J Orthop Trauma 18:687–695CrossRefPubMedGoogle Scholar
  37. 37.
    Kalu DN (1991) The ovariectomized rat model of postmenopausal bone loss. Bone Miner 15:175–192CrossRefPubMedGoogle Scholar
  38. 38.
    Lei Z, Xiaoying Z, Xingguo L (2009) Ovariectomy-associated changes in bone mineral density and bone marrow haematopoiesis in rats. Int J Exp Pathol 90:512–519PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Marina Komrakova
    • 1
    Email author
  • Anna Weidemann
    • 1
  • Christian Dullin
    • 2
  • Joachim Ebert
    • 3
  • Mohammad Tezval
    • 1
  • Klaus Michael Stuermer
    • 1
  • Stephan Sehmisch
    • 1
  1. 1.Department of Trauma Surgery and Reconstructive SurgeryUniversity Medical Center GöttingenGöttingenGermany
  2. 2.Department of RadiologyUniversity of GöttingenGöttingenGermany
  3. 3.Department of Medical Microbiology, Subdivision of General Hygiene and Environmental HealthUniversity of GöttingenGöttingenGermany

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