Skip to main content

Advertisement

Log in

Strontium Ranelate Enhances Callus Strength More Than PTH 1-34 in an Osteoporotic Rat Model of Fracture Healing

  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

Treatment of an underlying disease is often initiated after the occurrence of an osteoporotic fracture. Our aim was to investigate whether teriparatide (PTH 1-34) and strontium ranelate affect fracture healing in ovariectomized (OVX) rats when provided for the first time after the occurrence of an osteoporotic fracture. We combined the model of an OVX rat with a closed diaphyseal fracture. Sixty Sprague Dawley rats were randomly assigned to four groups. Fracture healing in OVX rats after treatment with pharmacological doses of strontium ranelate and PTH 1-34 was compared with OVX and sham-treated control groups. After 28 days, the femur was excised and scanned by micro computed tomography and the callus evaluated, after which biomechanical torsional testing was performed and torque and toughness until reaching the yield point were analyzed. Only treatment with strontium ranelate led to a significant increase in callus resistance compared to the OVX control rats, whereas both PTH 1-34 and strontium ranelate increased the bone volume/tissue volume ratio of the callus. The PTH 1-34–increased trabecular bone volume within the callus was even higher compared to sham. As for the callus tissue volume, the increase induced by strontium ranelate was significant, contrary to the changes induced by PTH. Callus in strontium ranelate–treated animals is more resistant to torsion compared with OVX control rats. To our knowledge, this is the first report of the enhancement of fracture healing by strontium ranelate. Because both treatments enhance bone and tissue volume within the callus, there may be a qualitative difference between the calluses of PTH 1-34– and strontium ranelate–treated OVX rats. The superior results obtained with strontium ranelate compared to PTH in terms of callus resistance could be the consequence of a better quality of the new bone formed within the callus.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. 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 

  2. Meunier PF, 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 

  3. Roux C, Reginster JY, Fechtenbaum J, Kolta S, Sawicki A, Tulassay Z, Luisetto G, Padrino JM, Doyle D, Prince R, Fardellone P, Sorensen OH, Meunier PJ (2006) Vertebral fracture risk reduction with strontium ranelate in women with postmenopausal osteoporosis is independent of baseline risk factors. J Bone Miner Res 21:536–542

    Article  CAS  PubMed  Google Scholar 

  4. 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 

  5. Réginster JY, Bruyère O, Sawicki A, Roces-Varela A, Fardellone P, Roberts A, Devogelaer JP (2009) Long-term treatment of postmenopausal osteoporosis with strontium ranelate: results at 8 years. Bone 45:1059–1064

    Article  PubMed  CAS  Google Scholar 

  6. Marie PJ (2005) Strontium ranelate: a novel mode of action optimizing bone formation and resorption. Osteoporos Int 16(suppl 1):S7–S10

    Article  CAS  PubMed  Google Scholar 

  7. Marie PJ (2006) Strontium ranelate: a physiological approach for optimizing bone formation and resorption. Bone 38:S10–S14

    Article  CAS  PubMed  Google Scholar 

  8. 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 18:517–523

    Article  CAS  PubMed  Google Scholar 

  9. Zhu LL, Zaidi S, Peng Y, Zhou H, Moonga BS, Blesius A, Dupin-Roger I, Zaidi M, Sun L (2007) Induction of a program gene expression during osteoblast differentiation with strontium ranelate. Biochem Biophys Res Commun 355:307–311

    Article  CAS  PubMed  Google Scholar 

  10. 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 

  11. 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 

  12. Takahashi N, Sasaki T, Tsouderos Y, Suda T (2003) S 12911–2 inhibits osteoclastic bone resorption in vitro. J Bone Miner Res 18:1082–1087

    Article  CAS  PubMed  Google Scholar 

  13. Hurtel AS, Mentaverri R, Caudrillier A, Cournarie F, Wattel A, Kamel S, Terwilliger EF, Brown EM, Brazier M (2008) The calcium-sensing receptor is involved in strontium ranelate-induced osteoclast apoptosis: new insights into the associated signalling pathways. J Biol Chem 284:575–584

    Article  CAS  Google Scholar 

  14. Ammann P, Badoud I, Barraud S, Dayer R, Rizzoli R (2007) Strontium ranelate treatment improves trabecular and cortical intrinsic bone tissue quality, a determinant of bone strength. J Bone Miner Res 22:1419–1425

    Article  CAS  PubMed  Google Scholar 

  15. 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 

  16. Ejersted C, Andreassen TT, Oxlund H, Jørgensen PH, Bak B, Häggblad J, Tørring O, Nilsson MHL (1993) Human parathyroid hormone (1–34) and (1–84) increase the mechanical strength and thickness of cortical bone in rats. J Bone Miner Res 8:1097–1101

    Article  CAS  PubMed  Google Scholar 

  17. Wronski TJ, Yen CF, Qi H, Dann LM (1993) Parathyroid hormone is more effective than estrogen or bisphosphonates for restoration of lost bone mass in ovariectomized rats. Endocrinology 132:823–831

    Article  CAS  PubMed  Google Scholar 

  18. Mosekilde L, Danielsen CC, Søgaard CH, McOsker JE, Wronski TJ (1995) The anabolic effects of parathyroid hormone on cortical bone mass, dimensions and strengthassessed in a sexually mature, ovariectomized rat model. Bone 16:223–230

    Article  CAS  PubMed  Google Scholar 

  19. Andreassen TT, Oxlund H (2000) The influence of combined parathyroid hormone and growth hormone treatment on cortical bone in aged ovariectomized rats. J Bone Miner Res 15:2266–2275

    Article  CAS  PubMed  Google Scholar 

  20. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH (2001) Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344:1434–1441

    Article  CAS  PubMed  Google Scholar 

  21. Skripitz R, Aspenberg P (2004) Parathyroid hormone—a drug for orthopedic surgery? Acta Orthop Scand 75:654–662

    PubMed  Google Scholar 

  22. Andreassen TT, Ejersted C, Oxlund H (1999) Intermittent parathyroid hormone (1–34) treatment increases callus formation and mechanical strength of healing rat fractures. J Bone Miner Res 14:960–968

    Article  CAS  PubMed  Google Scholar 

  23. Holzer G, Majeska RJ, Lundy MW, Hartke JR, Einhorn TA (1999) Parathyroid hormone enhances fracture healing. A preliminary report. Clin Orthop 366:258–263

    Article  PubMed  Google Scholar 

  24. Kim HW, Jahng JS (1999) Effect of intermittent administration of parathyroid hormone on fracture healing in ovariectomized rats. Iowa Orthop J 19:71–77

    CAS  PubMed  Google Scholar 

  25. Andreassen TT, Fledlius C, Ejersted C, Oxlund H (2001) Increases in callus formation and mechanical strength of healing fractures in old rats treated with parathyroid hormone. Acta Orthop Scand 72:304–307

    Article  CAS  PubMed  Google Scholar 

  26. Bonnarens F, Einhorn TA (1984) Production of a standard closed fracture in laboratory animal bone. J Orthop Res 2:97–101

    Article  CAS  PubMed  Google Scholar 

  27. Waynforth HB (1980) Experimental and surgical techniques in the rat. Academic Press, New York, pp 161–163

    Google Scholar 

  28. Müller W (1975) A method for the comparison of morphometrical data on skeletal muscles in young rats of different ages and body weights. Histochemistry 43:241–248

    Article  PubMed  Google Scholar 

  29. Giannoudis P, Tzioupis C, Almali T, Buckley R (2007) Fracture healing in osteoporotic fractures: is it really different? A basic science perspective. Injury 38(suppl 1):S90–S99

    Article  PubMed  Google Scholar 

  30. Melhus G, Solberg LB, Dimmen S, Madsen JE, Nordsletten L, Reinholt FP (2007) Experimental osteoporosis induced by ovariectomy and vitamin D deficiency does not markedly affect fracture healing in rats. Acta Orthop 78:393–403

    Article  PubMed  Google Scholar 

  31. 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 

  32. Yingje H, Ge Z, Yishen W, Ling Q, Hung WY, Kwoksui L, Fuxing P (2007) Changes of microstructure and mineralized tissue in the middle and late phase of osteoporotic fracture healing in rats. Bone 41:631–638

    Article  Google Scholar 

  33. Wang JW, Li W, Xu SW, Yang DS, Wang Y, Lin M, Zhao GF (2005) Osteoporosis influences the middle and late periods of fracture healing in a rat osteoporotic model. Chin J Traumatol 8:111–116

    PubMed  Google Scholar 

  34. 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 3:384–393

    Article  Google Scholar 

  35. Stürmer EK, Seidlová-Wuttke D, Sehmisch S, Rack T, Wille J, Frosch KH, Wuttke W, Stürmer 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 21:89–96

    Article  PubMed  CAS  Google Scholar 

  36. Tezval M, Stuermer EK, Sehmisch S, Rack T, Stary A, Stebener M, Konietschke F, Stuermer KM (2009) Improvement of trochanteric bone quality in an osteoporosis model after short-term treatment with parathyroid hormone: a new mechanical test for trochanteric region of rat femur. Osteoporos Int. [Epub ahead of print]. doi:10.1007/s00198-009-0941-y

  37. Kubo T, Shiga T, Hashimoto J (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 

  38. Schmidmaier G, Wildemann B, Melis B, Krummrey G, Einhorn A, Haas N, Raschke M (2004) Development and characterization of a standard closed tibial fracture model in the rat. Eur J Trauma 30:35–42

    Article  Google Scholar 

  39. Hadjiargyrou M, Lambardo F, Zhao S, Ahrens W, Joo J, Ahn H, Jurman M, White DW, Rubin CT (2002) Transcriptional profiling of bone regeneration: insight into the molecular complexity of wound repair. J Biol Chem 277:30177–30182

    Article  CAS  PubMed  Google Scholar 

  40. Drosse I, Volkmer E, Seitz S, Seitz H, Penzkofer R, Zahn K, Matis U, Mutschler W, Augat P, Schieker M (2008) Validation of a femoral critical size defect model for orthotopic evaluation of bone healing: a biomechanical, veterinary and trauma surgical perspective. Tissue Eng Part C Methods 1:79–88

    Article  Google Scholar 

  41. Mark H, Rydevik B (2005) Torsional stiffness in healing fractures: influence of ossification: an experimental study in rats. Acta Orthop 3:428–433

    Google Scholar 

  42. Hill EL, Kraus K, Labierre KP (1995) Ovariectomy impairs fracture healing after 21 days in rat. Trans Orthop Res Soc 20:230

    Google Scholar 

  43. Tsahakis PJ, Martin DF, Harrow ME, Kiebzak GM, Meyer RA Jr (1996) Ovariectomy impairs femoral fracture healing in adult female rats. Trans Orthop Res Soc 21:264

    Google Scholar 

  44. Walsh WR, Sherman P, Howlet CR, Sonnabend DH, Ehrlich MG (1997) Fracture healing in a rat osteopenia model. Clin Orthop 342:218–227

    PubMed  Google Scholar 

  45. Barnes GL, Kakar S, Vora S, Morgan EF, Gerstenfeld LC, Einhorn TA (2008) Stimulation of fracture-healing with systemic intermittent parathyroid hormone treatment. J Bone Joint Surg Am 90(suppl 1):120–127

    Article  PubMed  Google Scholar 

  46. Komatsu DE, Brune KA, Liu H, Schmidt AL, Han B, Zeng QQ, Yang X, Nunes JS, Lu Y, Geiser AG, Ma YL, Wolos JA, Westmore MS, Sato M (2009) Longitudinal in vivo analysis of the region-specific efficacy of parathyroid hormone in a rat cortical defect model. Endocrinology 4:1570–1579

    Google Scholar 

  47. Nakajima A, Shimoji N, Shiomi K, Shimizu S, Moriya H, Einhorn TA, Yamazaki M (2002) Mechanisms for the enhancement of fracture healing in rats treated with intermittent low-dose human parathyroid hormone (1–34). J Bone Miner Res 11:2038–2047

    Article  Google Scholar 

  48. Brennan TC, Rizzoli R, Ammann P (2009) Selective modification of bone quality by PTH, pamidronate or raloxifene. J Bone Miner Res 24:800–808

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The study was supported by Elsbeth Bonhoff Stiftung. No direct funding from any pharmaceutical company was received.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bjoern Habermann.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Habermann, B., Kafchitsas, K., Olender, G. et al. Strontium Ranelate Enhances Callus Strength More Than PTH 1-34 in an Osteoporotic Rat Model of Fracture Healing. Calcif Tissue Int 86, 82–89 (2010). https://doi.org/10.1007/s00223-009-9317-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-009-9317-8

Keywords

Navigation