Skip to main content

Advertisement

SpringerLink
Log in

Strontium ranelate stimulates trabecular bone formation in a rat tibial bone defect healing process

  • Original Article
  • Published:
Osteoporosis International Aims and scope Submit manuscript

Abstract

Summary

Strontium ranelate treatment is known to prevent fractures. Here, we showed that strontium ranelate treatment enhances bone healing and affects bone cellular activities differently in intact and healing bone compartments: Bone formation was increased only in healing compartment, while resorption was reduced in healing and normal bone compartments.

Introduction

Systemic administration of strontium ranelate (SrRan) accelerates the healing of bone defects; however, controversy about its action on bone formation remains. We hypothesize that SrRan could affect bone formation differently in normal mature bone or in the bone healing process.

Methods

Proximal tibia bone defects were created in 6-month-old female rats, which orally received SrRan (625 mg/kg/day, 5/7 days) or vehicle (control groups) for 4, 8, or 12 weeks. Bone samples were analyzed by micro-computed tomography and histomorphometry in various regions, i.e., metaphyseal 2nd spongiosa, a region close to the defect, within the healing defect and in cortical defect bridging region. Additionally, we evaluated the quality of the new bone formed by quantitative backscattered electron imaging and by red picosirius histology.

Results

Healing of the bone defect was characterized by a rapid onset of bone formation without cartilage formation. Cortical defect bridging was detected earlier compared with healing of trabecular defect. In the healing zone, SrRan stimulated bone formation early and laterly decreased bone resorption improving the healing of the cortical and trabecular compartment without deleterious effects on bone quality. By contrast, in the metaphyseal compartment, SrRan only decreased bone resorption from week 8 without any change in bone formation, leading to little progressive increase of the metaphyseal trabecular bone volume.

Conclusions

SrRan affects bone formation differently in normal mature bone or in the bone healing process. Despite this selective action, this led to similar increased bone volume in both compartments without deleterious effects on the newly bone-formed quality.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Curtis R, Goldhahn J, Schwyn R, Regazzoni P, Suhm N (2005) Fixation principles in metaphyseal bone—a patent based review. Osteoporos Int 16(Suppl 2):S54–S64

    Article  PubMed  Google Scholar 

  2. Claes L, Veeser A, Gockelmann M, Simon U, Ignatius A (2009) A novel model to study metaphyseal bone healing under defined biomechanical conditions. Arch Orthop Trauma Surg 129:923–928

    Article  PubMed  Google Scholar 

  3. Shapiro F (2008) Bone development and its relation to fracture repair. The role of mesenchymal osteoblasts and surface osteoblasts. Eur Cells Mater 15:53–76

    Article  CAS  Google Scholar 

  4. Aspenberg P (2005) Drugs and fracture repair. Acta Orthop 76:741–748

    Article  PubMed  Google Scholar 

  5. Goldhahn J, Feron 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 90:343–353

    Article  CAS  PubMed  Google Scholar 

  6. Zacchetti G, Dayer R, Rizzoli R, Ammann P (2014) Systemic treatment with strontium ranelate accelerates the filling of a bone defect and improves the material level properties of the healing bone. Biomed Res Int 2014:549785

    Article  PubMed  PubMed Central  Google Scholar 

  7. Tarantino U, Celi M, Saturnino L, Scialdoni A, Cerocchi I (2010) Strontium ranelate and bone healing: report of two cases. Clinical Cases Miner Bone Metab : Off Journal Ital Soc Osteoporos Miner Metab Skelet Dis 7:65–68

    Google Scholar 

  8. 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 32:439–443

    Article  PubMed  Google Scholar 

  9. Ozturan KE, Demir B, Yucel I, Cakici H, Yilmaz F, Haberal A (2011) Effect of strontium ranelate on fracture healing in the osteoporotic rats. J Orthop Res : Off Publ Orthop Res Soc 29:138–142

    Article  CAS  Google Scholar 

  10. 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 : J Established Result Coop Eur Found Osteoporos Natl Osteoporos Found USA 21:1889–1897

    Article  CAS  Google Scholar 

  11. 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 86:82–89

    Article  CAS  PubMed  Google Scholar 

  12. Wang J, Zhu X, Liu L, Shi X, Yin L, Zhang Y, Li X, Wang Z, Liu G (2013) Effects of strontium on collagen content and expression of related genes in rat chondrocytes cultured in vitro. Biol Trace Elem Res 153:212–219

    Article  CAS  PubMed  Google Scholar 

  13. Henrotin Y, Labasse A, Zheng SX, Galais P, Tsouderos Y, Crielaard JM, Reginster JY (2001) Strontium ranelate increases cartilage matrix formation. J Bone Miner Res : Off J Am Soc Bone Miner Res 16:299–308

    Article  CAS  Google Scholar 

  14. 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 : J Established Result Coop Eur Found Osteoporos Natl Osteoporos Found USA 20:1417–1428

    Article  CAS  Google Scholar 

  15. 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. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 2:595–610

    Article  CAS  PubMed  Google Scholar 

  16. Junqueira LC, Bignolas G, Brentani RR (1979) Picrosirius staining plus polarization microscopy, a specific method for collagen detection in tissue sections. Histochem J 11:447–455

    Article  CAS  PubMed  Google Scholar 

  17. Dayan D, Hiss Y, Hirshberg A, Bubis JJ, Wolman M (1989) Are the polarization colors of picrosirius red-stained collagen determined only by the diameter of the fibers? Histochemistry 93:27–29

    Article  CAS  PubMed  Google Scholar 

  18. Roschger P, Fratzl P, Eschberger J, Klaushofer K (1998) Validation of quantitative backscattered electron imaging for the measurement of mineral density distribution in human bone biopsies. Bone 23:319–326

    Article  CAS  PubMed  Google Scholar 

  19. Gaudin-Audrain C, Irwin N, Mansur S, Flatt PR, Thorens B, Basle M, Chappard D, Mabilleau G (2013) Glucose-dependent insulinotropic polypeptide receptor deficiency leads to modifications of trabecular bone volume and quality in mice. Bone 53:221–230

    Article  CAS  PubMed  Google Scholar 

  20. Beuvelot J, Mauras Y, Mabilleau G, Marchand-Libouban H, Chappard D (2013) Adsorption and release of strontium from hydroxyapatite crystals developed in simulated body fluid (SBF) on poly (2-hydroxyethyl) methacrylate substrates. Dig J Nanomater Biostruct 207–217

  21. Lloyd GE (1987) Atomic number and crystallographic contrast images with SEM: a review of backscattered electron techniques. Mineralog Mag 51:3–19

    Article  CAS  Google Scholar 

  22. Lavet C, Martin A, Linossier MT et al (2016) Fat and sucrose intake induces obesity-related bone metabolism disturbances: kinetic and reversibility studies in growing and adult rats. J Bone Miner Res : Off J Am Soc Bone Miner Res 31:98–115

    Article  CAS  Google Scholar 

  23. Hadjiargyrou M, Lombardo 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 

  24. Schmidmaier G, Wildemann B, Melis B, Krummrey G, Einhorn A, Haas NP, 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 

  25. Fisher M, Hyzy S, Guldberg RE, Schwartz Z, Boyan BD (2010) Regeneration of bone marrow after tibial ablation in immunocompromised rats is age dependent. Bone 46:396–401

    Article  PubMed  Google Scholar 

  26. Monfoulet L, Rabier B, Chassande O, Fricain JC (2010) Drilled hole defects in mouse femur as models of intramembranous cortical and cancellous bone regeneration. Calcif Tissue Int 86:72–81

    Article  CAS  PubMed  Google Scholar 

  27. Raisz LG, Seeman E (2001) Causes of age-related bone loss and bone fragility: an alternative view. J Bone Miner Res : Off J Am Soc Bone Miner Res 16:1948–1952

    Article  CAS  Google Scholar 

  28. McNulty MA, Virdi AS, Christopherson KW, Sena K, Frank RR, Sumner DR (2012) Adult stem cell mobilization enhances intramembranous bone regeneration: a pilot study. Clin Orthop Relat Res 470:2503–2512

    Article  PubMed  PubMed Central  Google Scholar 

  29. Wise JK, Sena K, Vranizan K, Pollock JF, Healy KE, Hughes WF, Sumner DR, Virdi AS (2010) Temporal gene expression profiling during rat femoral marrow ablation-induced intramembranous bone regeneration. PloS one:5

  30. Chavassieux P, Meunier PJ, Roux JP, Portero-Muzy N, Pierre M, Chapurlat R (2014) Bone histomorphometry of transiliac paired bone biopsies after 6 or 12 months of treatment with oral strontium ranelate in 387 osteoporotic women: randomized comparison to alendronate. J Bone Miner Res : Off J Am Soc Bone Miner Res 29:618–628

    Article  CAS  Google Scholar 

  31. Recker RR, Marin F, Ish-Shalom S et al (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 : Off J Am Soc Bone Miner Res 24:1358–1368

    Article  CAS  Google Scholar 

  32. Fournier C, Perrier A, Thomas M, Laroche N, Dumas V, Rattner A, Vico L, Guignandon A (2012) Reduction by strontium of the bone marrow adiposity in mice and repression of the adipogenic commitment of multipotent C3H10T1/2 cells. Bone 50:499–509

    Article  CAS  PubMed  Google Scholar 

  33. Peng S, Liu XS, Wang T, Li Z, Zhou G, Luk KD, Guo XE, Lu WW (2010) In vivo anabolic effect of strontium on trabecular bone was associated with increased osteoblastogenesis of bone marrow stromal cells. J Orthop Res 28:1208–1214

    Article  CAS  PubMed  Google Scholar 

  34. Komrakova M, Weidemann A, Dullin C, Ebert J, Tezval M, Stuermer KM, Sehmisch S (2015) The impact of strontium ranelate on metaphyseal bone healing in ovariectomized rats. Calcif Tissue Int

  35. Kates SL, Ackert-Bicknell CL (2016) How do bisphosphonates affect fracture healing? Injury Suppl 1:S65–8

  36. Stathopoulos KD, Giannitsioti E, Fragkou AN, Zoubos AB, Papaggelopoulos PJ, Skarantavos G (2014) Strontium ranelate improves delayed healing of osteolytic lesions of the jaw in a man with chronic osteomyelitis. Case report. Clin Cases Miner Bone Metab : Off J Ital Soc Osteoporos Miner Metab Skelet Dis 11:77–81

    Google Scholar 

  37. Doublier A, Farlay D, Bala Y, Boivin G (2014) Strontium does not affect the intrinsic bone quality at tissue and BSU levels in iliac samples from Macaca fascicularis monkeys. Bone 64:18–24

    Article  CAS  PubMed  Google Scholar 

  38. Boivin G, Farlay D, Khebbab MT, Jaurand X, Delmas PD, Meunier PJ (2010) In osteoporotic women treated with strontium ranelate, strontium is located in bone formed during treatment with a maintained degree of mineralization. Osteoporos Int : J Established Result Coop Eur Found Osteoporos Natl Osteoporos Found USA 21:667–677

    Article  CAS  Google Scholar 

  39. Cattani-Lorente M, Rizzoli R, Ammann P (2013) In vitro bone exposure to strontium improves bone material level properties. Acta Biomater 9:7005–7013

    Article  CAS  PubMed  Google Scholar 

  40. Heiner DE, Meyer MH, Frick SL, Kellam JF, Fiechtl J, Meyer RA Jr (2006) Gene expression during fracture healing in rats comparing intramedullary fixation to plate fixation by DNA microarray. J Orthop Trauma 20:27–38

    Article  PubMed  Google Scholar 

  41. Brennan TC, Rizzoli R, Ammann P (2009) The mode of action of strontium ranelate involves the stimulation of IGF-I production and a decrease in signals for osteoclastogenesis in vivo. Bone 44:S236

    Article  Google Scholar 

  42. Jiang J, Lichtler AC, Gronowicz GA, Adams DJ, Clark SH, Rosen CJ, Kream BE (2006) Transgenic mice with osteoblast-targeted insulin-like growth factor-I show increased bone remodeling. Bone 39:494–504

    Article  CAS  PubMed  Google Scholar 

  43. Zhang M, Xuan S, Bouxsein ML et al (2002) Osteoblast-specific knockout of the insulin-like growth factor (IGF) receptor gene reveals an essential role of IGF signaling in bone matrix mineralization. J Biol Chem 277:44005–44012

    Article  CAS  PubMed  Google Scholar 

  44. Kusumbe AP, Ramasamy SK, Adams RH (2014) Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature 507:323–328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Street J, Bao M, deGuzman L et al (2002) Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci U S A 99:9656–9661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Tatsuyama K, Maezawa Y, Baba H, Imamura Y, Fukuda M (2000) Expression of various growth factors for cell proliferation and cytodifferentiation during fracture repair of bone. Eur J Histochem : EJH 44:269–278

    CAS  PubMed  Google Scholar 

  47. Gu Z, Xie H, Li L, Zhang X, Liu F, Yu X (2013) Application of strontium-doped calcium polyphosphate scaffold on angiogenesis for bone tissue engineering. J Mater Sci Mater Med 24:1251–1260

    Article  CAS  PubMed  Google Scholar 

  48. Liu F, Zhang X, Yu X, Xu Y, Feng T, Ren D (2011) In vitro study in stimulating the secretion of angiogenic growth factors of strontium-doped calcium polyphosphate for bone tissue engineering. J Mater Sci Mater Med 22:683–692

    Article  CAS  PubMed  Google Scholar 

  49. 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 28:446–453

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital, 4, rue Gabrielle-Perret-Gentil, CH-1211, Geneva 14, Switzerland

    C. Lavet, R. Rizzoli & P. Ammann

  2. GEROM-LHEA, Institut de Biologie en Santé, University of Angers, Angers, France

    G. Mabilleau & D. Chappard

  3. SCIAM, Institut de Biologie en Santé, University of Angers, Angers, France

    G. Mabilleau & D. Chappard

Authors
  1. C. Lavet
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. Mabilleau
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. Chappard
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. Rizzoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. Ammann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. Lavet.

Ethics declarations

Conflicts of interest

Lavet C, Mabilleau G, Chappard D, Rizzoli R, and Ammann P declare that they received funding from Servier Laboratory to complete this project.

Electronic supplementary material

Supplementary data 1

A-Experimental design. Seventy 6 month-old Sprague-Dawley female rats were randomly assigned to seven groups of 10 animals each. After surgery, three groups were respectively submitted to SrRan or vehicle treatment by gavage 5 days a week. The healing process was followed over time at weeks 4, 8 and 12 after surgery in one group of SrRan and control. B-Investigated compartments. In order to evaluate if SrRan could differently alter bone cellular activities in healing bone compartment (modeling and remodeling) as compared to normal bone (remodeling), we used a metaphyseal drill hole defect model in a mature animal model. Three regions of interest were investigated at the trabecular compartment: i) in the metaphyseal compartment far from the defect characterized by a normal bone remodeling (MC), ii) within the defect defined as the healing zone and submitted to both modeling and remodeling (DC) and iii) in an area close to the defect considered as a transition zone between the two first compartments potentially influenced by factor diffusion (CDC). At the cortical level the cortical shell bridging the defect (DC) was analyzed. (GIF 97 kb)

High resolution image (TIFF 52861 kb)

Supplementary data 2

Red picosirius staining under polarized lightning of the healing compartment. A- Outer bone zone. B- Cortical shell bridging the defect zone. C- Metaphyseal healing zone. Red picosirius staining used in combination with polarized microscopy is particularly useful to observe collagen network abnormalities as the large and better aligned collagen fibers appear in bright red and the thinner and/or not organized one in green or yellow. From week-4, large collagen and well organized fibers already appeared in bright red and were predominant at the cortical and trabecular compartment of the healing zone of both SrRan and control animals. Note that area A included collagen appearing in green with polarized microscopy. This area corresponded to a fibrin network at the periosteal in relation to the healing process after local surgery. (GIF 340 kb)

High resolution image (TIFF 49785 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lavet, C., Mabilleau, G., Chappard, D. et al. Strontium ranelate stimulates trabecular bone formation in a rat tibial bone defect healing process. Osteoporos Int 28, 3475–3487 (2017). https://doi.org/10.1007/s00198-017-4156-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-017-4156-3

Keywords

Search

Navigation