Advertisement

Current Osteoporosis Reports

, Volume 16, Issue 2, pp 182–197 | Cite as

Preclinical and Translational Studies in Small Ruminants (Sheep and Goat) as Models for Osteoporosis Research

  • Isabel R. Dias
  • José A. Camassa
  • João A. Bordelo
  • Pedro S. Babo
  • Carlos A. Viegas
  • Nuno Dourado
  • Rui L. Reis
  • Manuela E. Gomes
Regenerative Biology and Medicine in Osteoporosis (T Webster, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Regenerative Biology and Medicine in Osteoporosis

Abstract

Purpose of the Review

This review summarizes research on the use of sheep and goats as large animal models of human osteoporosis for preclinical and translational studies.

Recent Findings

The most frequent osteoporotic sheep model used is the ovariectomized sheep with 12 months post-operatively or more and the combined treatment of ovariectomized sheep associated to calcium/vitamin D-deficient diet and glucocorticoid applications for 6 months, but other methods are also described, like pinealectomy or hypothalamic-pituitary disconnection in ovariectomized sheep. The goat model for osteoporosis research has been used in a very limited number of studies in osteoporosis research relative to sheep. These osteoporotic small ruminant models are applied for biomaterial research, bone augmentation, efficacy of implant fixation, fragility fracture-healing process improvement, or bone-defect repair studies in the osteopenic or osteoporotic bone.

Summary

Sheep are a recognized large animal model for preclinical and translational studies in osteoporosis research and the goat to a lesser extent. Recently, the pathophysiological mechanism underlying induction of osteoporosis in glucocorticoid-treated ovariectomized aged sheep was clarified, being similar to what occurs in postmenopausal women with glucocorticoid-induced osteoporosis. It was also concluded that the receptor activator of NF-κB ligand was stimulated in the late progressive phase of the osteoporosis induced by steroids in sheep. The knowledge of the pathophysiological mechanisms at the cellular and molecular levels of the induction of osteoporosis in small ruminants, if identical to humans, will allow in the future, the use of these animal models with greater confidence in the preclinical and translational studies for osteoporosis research.

Keywords

Bone Goat Large animal models Orthopedics Osteoporosis Sheep 

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest. José A. Camassa reports and acknowledges the National Council for Scientific and Technological Development (CNPq-Brazil) for his PhD scholarship 202248/2015-1.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001;285:785–95.Google Scholar
  2. 2.
    Burge R, Dawson-Hughes B, Salomon DH, Wong JB, King A, Tosteson A. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res. 2007;22:465–75.CrossRefPubMedGoogle Scholar
  3. 3.
    Blume SW, Curtis JR. Medical costs of osteoporosis in the elderly Medicare population. Osteoporos Int. 2011;22:1835–44.CrossRefPubMedGoogle Scholar
  4. 4.
    Cauley JA. Osteoporosis: fracture epidemiology update 2016. Curr Opin Rheumatol. 2017;29:150–6.CrossRefPubMedGoogle Scholar
  5. 5.
    LaFleur J, Rillamas-Sun E, Colón-Emeric CS, Knippenberg KA, Ensrud KE, Gray SL, et al. Fracture rates and bone density among postmenopausal veteran and non-veteran women from the Women’s Health Initiative. Gerontologist. 2016;56:S78–90.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Turner AS. How to select your animal model for osteoporosis research. In: Duque G, Watanabe K, editors. Osteoporosis research—animal models. London, UK: Springer-Verlag; 2011. p. 1–12.Google Scholar
  7. 7.
    Oheim R, Schinke T, Amling M, Pogoda P. Can we induce osteoporosis in animals comparable to the human situation? Injury. 2016;47:S3–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Smith SY, Jolette J, Turner CH. Skeletal health: primate model of postmenopausal osteoporosis. Am J Primatol. 2009;71(9):752–65.CrossRefPubMedGoogle Scholar
  9. 9.
    Smith SY, Varela A, Jolette J. Nonhuman primate models of osteoporosis. In: Duque G, Watanabe K, editors. Osteoporosis research—animal models. London: Springer-Verlag; 2011. p. 135–57.Google Scholar
  10. 10.
    Quigley M. Non-human primates: the appropriate subjects of biomedical research? J Med Ethics. 2007;33:655–8.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Sophocleous A, Idris AI. Rodent models of osteoporosis. Bonekey Rep. 2014;3:614.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Bonjour JP, Ammann P, Rizzoli R. Importance of preclinical studies in the development of drugs for treatment of osteoporosis: a review related to the 1998 WHO guidelines. Osteoporos Int. 1999;9:379–93.CrossRefPubMedGoogle Scholar
  13. 13.
    Thompson DD, Simmons HA, Pirie CM, Ke HZ. FDA guidelines and animal models for osteoporosis. Bone. 1995;17:125S–33S.CrossRefPubMedGoogle Scholar
  14. 14.
    Lelovas PP, Xanthos TT, Thoma SE, Lyritis GP, Dontas IA. The laboratory rat as an animal model for osteoporosis research. Comp Med. 2008;58:424–30.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Leitner MM, Tami AE, Montavon PM, Ito K. Longitudinal as well as age-matched assessments of bone changes in the mature ovariectomized rat model. Lab Anim. 2009;43:266–71.CrossRefPubMedGoogle Scholar
  16. 16.
    Reinwald S, Burr D. Review of nonprimate, large animal models for osteoporosis research. J Bone Miner Res. 2008;23:1353–68.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Checa S, Prendergast PJ, Duda GN. Inter-species investigation of the mechano-regulation of bone healing: comparison of secondary bone healing in sheep and rat. J Biomech. 2011;44:1237–45.CrossRefPubMedGoogle Scholar
  18. 18.
    Aerssens J, Boonen S, Lowet G, Dequeker J. Interspecies differences in bone composition, density, and quality: potential implications for in vivo bone research. Endocrinology. 1998;139:663–70.CrossRefPubMedGoogle Scholar
  19. 19.
    Pearce AI, Richards RG, Milz S, Schneider E, Pearce SG. Animal models for implant biomaterial research in bone: a review. Eur Cell Mater. 2007;13:1–10.CrossRefPubMedGoogle Scholar
  20. 20.
    Turner AS. The sheep as a model for osteoporosis in humans. Vet J. 2002;163:232–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Egermann M, Goldhahn J, Schneider E. Animal models for fracture treatment in osteoporosis. Osteoporos Int. 2005;16:S129–38.CrossRefPubMedGoogle Scholar
  22. 22.
    • Reinwald S, Burr DB. Other large animal models. In: Duque G, Watanabe K, editors. Osteoporosis research—animal models. London, UK: Springer-Verlag; 2011. p. 159–74. This is an excellent and marvellous review that covers the relevance of the other large animal models, with the exception of the non-human primates, also reporting to the animal and veterinary sciences aspects of the use of these animals as experimental models for osteoporosis research (rabbits, dogs, sheep, goats, and pigs).Google Scholar
  23. 23.
    Beil FT, Oheim R, Barvencik F, Hissnauer TN, Pestka JM, Ignatius A, et al. Low turnover osteoporosis in sheep induced by hypothalamic-pituitary disconnection. J Orthop Res. 2012;30:1254–62.CrossRefPubMedGoogle Scholar
  24. 24.
    • Oheim R, Amling M, Ignatius A, Pogoda P. Large animal model for osteoporosis in humans: the ewe. Eur Cell Mater. 2012;24:372–85. This is an updated and an in-depth review that covers the relevance of the ewe as a large animal model for osteoporosis study and as a preclinical model for orthopaedic implant and biomaterial research CrossRefPubMedGoogle Scholar
  25. 25.
    • Zhang Z, Ren H, Shen G, Qiu T, Liang, Yang Z, et al. Animal models for glucocorticoid-induced postmenopausal osteoporosis: an updated review. Biomed Pharmacother. 2016;84:438–46. This is an updated and an in-depth review that covers the relevance of the creation of animal models (rat, rabbit, sheep) for glucocorticoid-induced postmenopausal osteoporosis and the underlying mechanism of osteoporosis induced by glucocorticoids in OVX animals CrossRefPubMedGoogle Scholar
  26. 26.
    Yu Z, Wang G, Tang T, Fu L, Yu X, Cao L, et al. Production and repair of implant-induced microdamage in the cortical bone of goats after long-term estrogen deficiency. Osteoporos Int. 2014;25:897–903.CrossRefPubMedGoogle Scholar
  27. 27.
    Newman E, Turner AS, Wark JD. The potential of sheep for the study of osteopenia: current status and comparison with other animal models. Bone. 1995;16:277–84.CrossRefGoogle Scholar
  28. 28.
    Turner AS. Experiences with sheep as an animal model for shoulder surgery: strengths and shortcomings. J Shoulder Elb Surg. 2007;16:S158–63.CrossRefGoogle Scholar
  29. 29.
    Johnson RB, Gilbert JA, Cooper RC, Parsell DE, Steward BA, Dai X, et al. Effect of estrogen deficiency on skeletal and alveolar bone density in sheep. J Periodontol. 2002;73:383–91.CrossRefPubMedGoogle Scholar
  30. 30.
    Arens D, Sigrist I, Alini M, Schawalder P, Schneider E, Egermann M. Seasonal changes in bone metabolism in sheep. Vet J. 2007;174:585–91.CrossRefPubMedGoogle Scholar
  31. 31.
    Healy C, Kennedy OD, Brennan O, Rackard SM, O’Brien FJ, Lee TC. Structural adaptation and intracortical bone turnover in an ovine model of osteoporosis. J Orthop Res. 2010;28:248–51.PubMedGoogle Scholar
  32. 32.
    Lans C, Khan TE, Curran MM, McCorkle CM. Plant chemistry in veterinary medicine: medicinal constituents and their mechanisms of action. In: Wynn SG, Fougere B, editors. Veterinary herbal medicine. St. Louis, Missouri: Elsevier Health Sciences, Mosby; 2007. p. 159–82.Google Scholar
  33. 33.
    Lill CA, Fluegel AK, Schneider E. Sheep model for fracture treatment in osteoporotic bone: a pilot study about different induction regimens. J Orthop Trauma. 2000;14:559–65.CrossRefPubMedGoogle Scholar
  34. 34.
    Lill CA, Fluegel AK, Schneider E. Effect of ovariectomy, malnutrition and glucocorticoid application on bone properties in sheep: a pilot study. Osteoporos Int. 2002;13:480–6.CrossRefPubMedGoogle Scholar
  35. 35.
    Lill CA, Gerlach UV, Eckhardt C, Goldhahn J, Schneider E. Bone changes due to glucocorticoid application in an ovariectomized animal model for fracture treatment in osteoporosis. Osteoporos Int. 2002;13:407–14.CrossRefPubMedGoogle Scholar
  36. 36.
    Goldhahn J, Jenet A, Schneider E, Lill CA. Slow rebound of cancellous bone after mainly steroid-induced osteoporosis in ovariectomized sheep. J Orthop Trauma. 2005;19:23–8.CrossRefPubMedGoogle Scholar
  37. 37.
    • Egermann M, Goldhahn J, Holz R, Schneider E, Lill CA. A sheep model for fracture treatment in osteoporosis: benefits of the model versus animal welfare. Lab Anim. 2008;42:453–64. This is a study that reports to the benefits and complications of the induction methods to obtain osteoporosis in sheep, namely about the combined treatment of ovariectomy, calcium/vitamin D-restricted diet and glucocorticoids as one of the most effective in view of the induction of severe osteoporosis in sheep CrossRefPubMedGoogle Scholar
  38. 38.
    Klopfenstein Bregger MD, Schawalder P, Rahn B, Eckhardt C, Schneider E, Lill C. Optimization of corticosteroid induced osteoporosis in ovariectomized sheep. A bone histomorphometric study. Vet Comp Orthop Traumatol. 2007;20:18–23.CrossRefPubMedGoogle Scholar
  39. 39.
    Dvorak G, Reich KM, Tangl S, Goldhahn J, Haas R, Gruber R. Cortical porosity of the mandible in an osteoporotic sheep model. Clin Oral Implants Res. 2011;22:500–5.CrossRefPubMedGoogle Scholar
  40. 40.
    Veigel E, Moore RJ, Zarrinkalam MR, Schulze D, Sauerbier S, Schmelzeisen R, et al. Osteopenia in the maxillofacial area: a study in sheep. Osteoporos Int. 2011;22:1115–21.Google Scholar
  41. 41.
    Zarrinkalam MR, Mulaibrahimovic A, Atkins GJ, Moore RJ. Changes in osteocyte density correspond with changes in osteoblast and osteoclast activity in an osteoporotic sheep model. Osteoporos Int. 2012;23:1329–36.CrossRefPubMedGoogle Scholar
  42. 42.
    Zarrinkalam MR, Schultz CG, Parkinson IH, Moore RJ. Osteoporotic characteristics persist in the spine of ovariectomized sheep after withdrawal of corticosteroid administration. J Osteoporos. 2012;182509Google Scholar
  43. 43.
    Newton BI, Cooper RC, Gilbert JA, Johnson RB, Zardiackas LD. The ovariectomized sheep as a model for human bone loss. J Comp Pathol. 2004;130:323–6.CrossRefPubMedGoogle Scholar
  44. 44.
    Kennedy OD, Brennan O, Mahony NJ, Rackard SM, O’Brien FJ, Taylor D, et al. Effects of high bone turnover on the biomechanical properties of the L3 vertebra in an ovine model of early stage osteoporosis. Spine. 2008;33:2518–23.Google Scholar
  45. 45.
    Kennedy OD, Brennan O, Mahony NJ, Rackard SM, O’Brien FJ, Taylor D, et al. The behaviour of fatigue-induced microdamage in compact bone samples from control and ovariectomised sheep. Stud Health Technol Inform. 2008;133:148–55.Google Scholar
  46. 46.
    Wu ZX, Lei W, Hu YY, Wang HQ, Wan SY, Ma ZS, et al. Effect of ovariectomy on BMD, micro-architecture and biomechanics of cortical and cancellous bones in a sheep model. Med Eng Phys. 2008;30:1112–8.CrossRefPubMedGoogle Scholar
  47. 47.
    Kennedy OD, Brennan O, Rackard SM, Staines A, O’Brien FJ, Taylor D, et al. Effects of ovariectomy on bone turnover, porosity, and biomechanical properties in ovine compact bone 12 months postsurgery. J Orthop Res. 2009;27:303–9.Google Scholar
  48. 48.
    Zhang Y, Li Y, Gao Q, Shao B, Xiao J, Zhou H, et al. The variation of cancellous bones at lumbar vertebra, femoral neck, mandibular angle and rib in ovariectomized sheep. Arch Oral Biol. 2014;59:663–9.CrossRefPubMedGoogle Scholar
  49. 49.
    Kreipke TC, Rivera NC, Garrison JG, Easley JT, Turner AS, Niebur GL. Alterations in trabecular bone microarchitecture in the ovine spine and distal femur following ovariectomy. J Biomech. 2014;47:1918–21.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Kreipke TC, Garrison JG, Easley J, Turner AS, Niebur GL. The roles of architecture and estrogen depletion in microdamage risk in trabecular bone. J Biomech. 2016;49:3223–9.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Zarrinkalam MR, Beard H, Schultz CG, Moore RJ. Validation of the sheep as a large animal model for the study of vertebral osteoporosis. Eur Spine J. 2009;18:244–53.CrossRefPubMedGoogle Scholar
  52. 52.
    Egermann M, Gerhardt C, Barth A, Maestroni GJ, Schneider E, Alini M. Pinealectomy affects bone mineral density and structure—an experimental study in sheep. BMC Musculoskelet Disord. 2011;12:271.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Oheim R, Beil FT, Köhne T, Wehner T, Barvencik F, Ignatius A, et al. Sheep model for osteoporosis: sustainability and biomechanical relevance of low turnover osteoporosis induced by hypothalamic-pituitary disconnection. J Orthop Res. 2013;31:1067–74.CrossRefPubMedGoogle Scholar
  54. 54.
    Pogoda P, Egermann M, Schnell JC, Priemel M, Schilling AF, Alini M, et al. Leptin inhibits bone formation not only in rodents, but also in sheep. J Bone Miner Res. 2006;21:1591–9.CrossRefPubMedGoogle Scholar
  55. 55.
    Oheim R, Beil FT, Barvencik F, Egermann M, Amling M, Clarke IJ, et al. Targeting the lateral but not the third ventricle induces bone loss in ewe: an experimental approach to generate an improved large animal model of osteoporosis. J Trauma Acute Care Surg. 2012;72:720–6.Google Scholar
  56. 56.
    Oheim R, Simon MJK, Steiner M, Vettorazzi E, Barvencik F, Ignatius A, et al. Sheep model for osteoporosis: the effects of peripheral hormone therapy on centrally induced systemic bone loss in an osteoporotic sheep model. Injury. 2017;48:841–8.CrossRefPubMedGoogle Scholar
  57. 57.
    MacLeay JM, Olson JD, Enns RM, Les CM, Toth CA, Wheeler DL, et al. Dietary-induced metabolic acidosis decreases bone mineral density in mature ovariectomized ewes. Calcif Tissue Int. 2004;75:431–7.Google Scholar
  58. 58.
    MacLeay JM, Olson JD, Turner AS. Effect of dietary-induced metabolic acidosis and ovariectomy on bone mineral density and markers of bone turnover. J Bone Miner Metab. 2004;22:561–8.CrossRefPubMedGoogle Scholar
  59. 59.
    Ding M, Cheng L, Bollen P, Schwarz P, Overgaard S. Glucocorticoid induced osteopenia in cancellous bone of sheep: validation of large animal model for spine fusion and biomaterial research. Spine. 2010;35:363–70.CrossRefPubMedGoogle Scholar
  60. 60.
    Sigrist IM, Gerhardt C, Alini M, Schneider E, Egermann M. The long-term effects of ovariectomy on bone metabolism in sheep. J Bone Miner Metab. 2007;25:28–35.CrossRefPubMedGoogle Scholar
  61. 61.
    Jainudeen MR, Wahid H, Hafez ESE. Sheep and goats. In: Hafez B, Hafez ESE, editors. Reproduction in farm animals. 7th ed. Baltimore: Lippincott Williams & Wilkins; 2000. p. 172–81.Google Scholar
  62. 62.
    Fabre-Nys C, Gelez H. Sexual behavior of ewes and other domestic ruminants. Horm Behav. 2007;52:18–25.CrossRefPubMedGoogle Scholar
  63. 63.
    Wilkinson JM. Silage and animal health. Nat Toxins. 1999;7:221–32.CrossRefPubMedGoogle Scholar
  64. 64.
    Giavaresi G, Fini M, Torricelli P, Martini L, Giardino R. The ovariectomized ewe model in the evaluation of biomaterials for prosthetic devices in spinal fixation. Int J Artif Organs. 2001;24:814–20.CrossRefPubMedGoogle Scholar
  65. 65.
    Brennan MA, Gleeson JP, Browne M, O’Brien FJ, Thurner PJ, McNamara LM. Site specific increase in heterogeneity of trabecular bone tissue mineral during oestrogen deficiency. Eur Cell Mater. 2011;15:396–406.CrossRefGoogle Scholar
  66. 66.
    Brennan O, Kuliwaba JS, Lee TC, Parkinson IH, Fazzalari NL, McNamara LM, et al. Temporal changes in bone composition, architecture, and strength following estrogen deficiency in osteoporosis. Calcif Tissue Int. 2012;91:440–9.Google Scholar
  67. 67.
    Leung KS, Siu WS, Cheung NM, Lui PY, Chow DH, James A, et al. Goats as an osteopenic animal model. J Bone Miner Res. 2001;16:2348–55.Google Scholar
  68. 68.
    Siu WS, Qin L, Cheung WH, Leung KS. A study of trabecular bones in ovariectomized goats with micro-computed tomography and peripheral quantitative computed tomography. Bone. 2004;35:21–6.CrossRefPubMedGoogle Scholar
  69. 69.
    Tam KF, Cheung WH, Lee KM, Qin L, Leung KS. Shockwave exerts osteogenic effect on osteoporotic bone in an ovariectomized goat model. Ultrasound Med Biol. 2009;35:1109–18.CrossRefPubMedGoogle Scholar
  70. 70.
    Yu Z, Wang G, Tang T, Fu L, Yu X, Zhu Z, et al. Long-term effects of ovariectomy on the properties of bone in goats. Exp Ther Med. 2015;9:1967–73.Google Scholar
  71. 71.
    Aldini NN, Fini M, Giavaresi G, Giardino R, Greggi T, Parisini P. Pedicular fixation in the osteoporotic spine: a pilot in vivo study on long-term ovariectomized sheep. J Orthop Res. 2002;20:1217–24.CrossRefPubMedGoogle Scholar
  72. 72.
    Goldhahn J, Neuhoff D, Schaeren S, Steiner B, Linke B, Aebi M, et al. Osseointegration of hollow cylinder based spinal implants in normal and osteoporotic vertebrae: a sheep study. Arch Orthop Trauma Surg. 2006;126:554–61.Google Scholar
  73. 73.
    Li Y, Cheng H, Liu ZC, Wu JW, Yu L, Zang Y, et al. In vivo study of pedicle screw augmentation using bioactive glass in osteoporosis sheep. J Spinal Disord Tech. 2013;26:E118–23.CrossRefPubMedGoogle Scholar
  74. 74.
    Galovich LA, Perez-Higueras A, Altonaga JR, Orden JM, Barba ML, Morillo MT. Biomechanical, histological and histomorphometric analyses of calcium phosphate cement compared to PMMA for vertebral augmentation in a validated animal model. Eur Spine J. 2011;20:376–82.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Fini M, Pierini G, Giavaresi G, Biagini G, Mattioli Belmonte MM, Nicoli Aldini N, et al. The ovariectomised sheep as a model for testing biomaterials and prosthetic devices in osteopenic bone: a preliminary study on iliac crest biopsies. Int J Artif Organs. 2000;23:275–81.CrossRefPubMedGoogle Scholar
  76. 76.
    Fini M, Giavaresi G, Rimondini L, Giardino R. Titanium alloy osseointegration in cancellous and cortical bone of ovariectomized animals: histomorphometric and bone hardness measurements. Int J Oral Maxillofac Implants. 2002;17:28–37.PubMedGoogle Scholar
  77. 77.
    Rocca M, Fini M, Giavaresi G, Aldini NN, Giardino R. Osteointegration of hydroxyapatite-coated and uncoated titanium screws in long-term ovariectomized sheep. Biomaterials. 2002;23:1017–23.CrossRefPubMedGoogle Scholar
  78. 78.
    Fini M, Giavaresi G, Greggi T, Martini L, Aldini NN, Parisini P, et al. Biological assessment of the bone-screw interface after insertion of uncoated and hydroxyapatite-coated pedicular screws in the osteopenic sheep. J Biomed Mater Res A. 2003;66:176–83.Google Scholar
  79. 79.
    Lill CA, Hesseln J, Schlegel U, Eckhardt C, Goldhahn J, Schneider E. Biomechanical evaluation of healing in a non-critical defect in a large animal model of osteoporosis. J Orthop Res. 2003;21:836–42.CrossRefPubMedGoogle Scholar
  80. 80.
    Sachse A, Wagner A, Keller M, Wagner O, Wetzel WD, Layher F, et al. Osteointegration of hydroxyapatite-titanium implants coated with nonglycosylated recombinant human bone morphogenetic protein-2 (BMP-2) in aged sheep. Bone. 2005;37:699–710.CrossRefPubMedGoogle Scholar
  81. 81.
    Egermann M, Baltzer AW, Adamaszek S, Evans C, Robbins P, Schneider E, et al. Direct adenoviral transfer of bone morphogenetic protein-2 cDNA enhances fracture healing in osteoporotic sheep. Hum Gene Ther. 2006;17:507–17.Google Scholar
  82. 82.
    Phillips FM, Turner AS, Seim HB 3rd, MacLeay J, Toth CA, Pierce AR, et al. In vivo BMP-7 (OP-1) enhancement of osteoporotic vertebral bodies in an ovine model. Spine J. 2006;6:500–6.Google Scholar
  83. 83.
    Borsari V, Fini M, Giavaresi G, Rimondini L, Chiesa R, Chiusoli L, et al. Sandblasted titanium osteointegration in young, aged and ovariectomized sheep. Int J Artif Organs. 2007;30:163–72.Google Scholar
  84. 84.
    Borsari V, Fini M, Giavaresi G, Rimondini L, Consolo U, Chiusoli L, et al. Osteointegration of titanium and hydroxyapatite rough surfaces in healthy and compromised cortical and trabecular bone: in vivo comparative study on young, aged, and estrogen-deficient sheep. J Orthop Res. 2007;25:1250–60.CrossRefPubMedGoogle Scholar
  85. 85.
    Stadelmann VA, Gauthier O, Terrier A, Bouler JM, Pioletti DP. Implants delivering bisphosphonate locally increase periprosthetic bone density in an osteoporotic sheep model. A pilot study. Eur Cell Mater. 2008;16:10–6.Google Scholar
  86. 86.
    Verron E, Gauthier O, Janvier P, Pilet P, Lesoeur J, Bujoli B, et al. In vivo bone augmentation in an osteoporotic environment using bisphosphonate-loaded calcium deficient apatite. Biomaterials. 2010;31:7776–84.CrossRefPubMedGoogle Scholar
  87. 87.
    Wan S, Lei W, Wu Z, Liu D, Gao M, Fu S. Biomechanical and histological evaluation of an expandable pedicle screw in osteoporotic spine in sheep. Eur Spine J. 2010;19:2122–9.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Giavaresi G, Fini M, Giardino R, Salamanna F, Sartori M, Borsari V, et al. In vivo preclinical evaluation of the influence of osteoporosis on the anchorage of different pedicle screw designs. Eur Spine J. 2011;20:1289–96.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Liu D, Lei W, Wu ZX, Gao MX, Wan SY, Fu SC, et al. Augmentation of pedicle screw stability with calcium sulfate cement in osteoporotic sheep: biomechanical and screw-bone interfacial evaluation. J Spinal Disord Tech. 2011;24:235–41.Google Scholar
  90. 90.
    Wu ZX, Liu D, Wan SY, Cui G, Zhang Y, Lei W. Sustained-release rhBMP-2 increased bone mass and bone strength in an ovine model of postmenopausal osteoporosis. J Orthop Sci. 2011;16:99–104.CrossRefPubMedGoogle Scholar
  91. 91.
    Shi L, Wang L, Guo Z, Wu ZX, Liu D, Gao MX, et al. A study of low elastic modulus expandable pedicle screws in osteoporotic sheep. J Spinal Disord Tech. 2012;25:123–8.CrossRefPubMedGoogle Scholar
  92. 92.
    Shi L, Wang L, Zhang Y, Guo Z, Wu ZX, Liu D, et al. Improving fixation strength of pedicle screw by microarc oxidation treatment: an experimental study of osteoporotic spine in sheep. J Orthop Res. 2012;30:1296–303.CrossRefPubMedGoogle Scholar
  93. 93.
    Bindl R, Oheim R, Pogoda P, Beil FT, Gruchenberg K, Reitmaier S, et al. Metaphyseal fracture healing in a sheep model of low turnover osteoporosis induced by hypothalamic-pituitary disconnection (HPD). J Orthop Res. 2013;31:1851–7.PubMedGoogle Scholar
  94. 94.
    Liu D, Zhang Y, Zhang B, Xie QY, Wang CR, Liu JB, et al. Comparison of expansive pedicle screw and polymethylmethacrylate-augmented pedicle screw in osteoporotic sheep lumbar vertebrae: biomechanical and interfacial evaluations. PLoS One. 2013;8:e74827.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Xiao JR, Li DH, Chen YX, Chen SJ, Guan SM, Kong L. Evaluation of fixation of expandable implants in the mandibles of ovariectomized sheep. J Oral Maxillofac Surg. 2013;71:682–8.CrossRefPubMedGoogle Scholar
  96. 96.
    Verron E, Pissonnier ML, Lesoeur J, Schnitzler V, Fellah BH, Pascal-Moussellard H, et al. Vertebroplasty using bisphosphonate-loaded calcium phosphate cement in a standardized vertebral body bone defect in an osteoporotic sheep model. Acta Biomater. 2014;10:4887–95.CrossRefPubMedGoogle Scholar
  97. 97.
    Eschler A, Roepenack P, Herlyn PK, Roesner J, Martin H, Vollmar B, et al. Intrabody application of eptotermin alpha enhances bone formation in osteoporotic fractures of the lumbar spine; however, fails to increase biomechanical stability—results of an experimental sheep model. Growth Factors. 2015;33:290–7.CrossRefPubMedGoogle Scholar
  98. 98.
    Eschler A, Röpenack P, Herlyn PK, Roesner J, Pille K, Büsing K, et al. The standardized creation of a lumbar spine vertebral compression fracture in a sheep osteoporosis model induced by ovariectomy, corticosteroid therapy and calcium/phosphorus/vitamin D-deficient diet. Injury. 2015;46:S17–23.CrossRefPubMedGoogle Scholar
  99. 99.
    Eschler A, Roepenack P, Roesner J, Herlyn PK, Martin H, Reichel M, et al. Cementless titanium mesh fixation of osteoporotic burst fractures of the lumbar spine leads to bony healing: results of an experimental sheep model. Biomed Res Int. 2016;4094161Google Scholar
  100. 100.
    James AW, Chiang M, Asatrian G, Shen J, Goyal R, Chung CG, et al. Vertebral implantation of NELL-1 enhances bone formation in an osteoporotic sheep model. Tissue Eng A. 2016;22:840–9.CrossRefGoogle Scholar
  101. 101.
    Liu D, Wu ZX, Zhang Y, Wang CR, Xie QY, Gong K, et al. Local treatment of osteoporotic sheep vertebral body with calcium sulfate for decreasing the potential fracture risk: microstructural and biomechanical evaluations. Clin Spine Surg. 2016;29:E358–64.PubMedGoogle Scholar
  102. 102.
    Andreasen CM, Ding M, Andersen TL, Overgaard S. Effects of substitute coated with hyaluronic acid or poly-lactic acid on implant fixation: experimental study in ovariectomized and glucocorticoid-treated sheep. J Tissue Eng Regen Med. 2017;  https://doi.org/10.1002/term.2447.
  103. 103.
    Bungartz M, Kunisch E, Maenz S, Horbert V, Xin L, Gunnella F, et al. GDF5 significantly augments the bone formation induced by an injectable, PLGA fiber-reinforced, brushite-forming cement in a sheep defect model of lumbar osteopenia. Spine J. 2017;17:1685–98.CrossRefPubMedGoogle Scholar
  104. 104.
    Gunnella F, Kunisch E, Bungartz M, Maenz S, Horbert V, Xin L, et al. Low-dose BMP-2 is sufficient to enhance the bone formation induced by an injectable, PLGA fiber-reinforced, brushite-forming cement in sheep defect model of lumbar osteopenia. Spine J. 2017;17:1699–711.CrossRefPubMedGoogle Scholar
  105. 105.
    Gunnella F, Kunisch E, Maenz S, Horbert V, Xin L, Mika J, et al. The GDF5 mutant BB-1 enhances the bone formation induced by an injectable, poly(l-lactide-co-glycolide) acid (PLGA) fiber-reinforced, brushite-forming cement in a sheep defect model of lumbar osteopenia. Spine J. 2017;  https://doi.org/10.1016/j.spinee.2017.10.002.
  106. 106.
    Maenz S, Brinkmann O, Kunisch E, Horbert V, Gunnella F, Bischoff S, et al. Enhanced bone formation in sheep vertebral bodies after minimally invasive treatment with a novel, PLGA fiber-reinforced brushite cement. Spine J. 2017;17:709–19.CrossRefPubMedGoogle Scholar
  107. 107.
    Bungartz M, Maenz S, Kunisch E, Horbert V, Xin L, Gunnella F, et al. First-time systematic postoperative clinical assessment of a minimally invasive approach for lumbar ventrolateral vertebroplasty in the large animal model sheep. Spine J. 2016;16:1263–75.CrossRefPubMedGoogle Scholar
  108. 108.
    Zara JN, Siu RK, Zhang X, Shen J, Ngo R, Lee M, et al. High doses of bone morphogenetic protein 2 induce structurally abnormal bone and inflammation in vivo. Tissue Eng A. 2011;17:1389–99.CrossRefGoogle Scholar
  109. 109.
    Chavassieux P, Garnero P, Duboeuf F, Vergnaud P, Brunner-Ferber F, Delmas PD, et al. Effects of a new selective estrogen receptor modulator (MDL 103,323) on cancellous and cortical bone in ovariectomized ewes: a biochemical, histomorphometric, and densitometric study. J Bone Miner Res. 2001;16:89–96.Google Scholar
  110. 110.
    Thomas T, Skerry TM, Vico L, Caulin F, Lanyon LE, Alexandre C. Ineffectiveness of calcitonin on a local-disuse osteoporosis in the sheep: a histomorphometric study. Calcif Tissue Int. 1995;57:224–8.CrossRefPubMedGoogle Scholar
  111. 111.
    Jiang Y, Zhao J, Geusens P, Liao EY, Adriaensens P, Gelan J, et al. Femoral neck trabecular microstructure in ovariectomized ewes treated with calcitonin: MRI microscopic evaluation. J Bone Miner Res. 2005;20:125–30.CrossRefPubMedGoogle Scholar
  112. 112.
    Brennan O, Kennedy OD, Lee TC, Rackard SM, O’Brien FJ. Effects of estrogen deficiency and bisphosphonate therapy on osteocyte viability and microdamage accumulation in an ovine model of osteoporosis. J Orthop Res. 2011;29:419–24.CrossRefPubMedGoogle Scholar
  113. 113.
    Brennan O, Kennedy OD, Lee TC, Rackard SM, O’Brien FJ, McNamara LM. The effects of estrogen deficiency and bisphosphonate treatment on tissue mineralisation and stiffness in an ovine model of osteoporosis. J Biomech. 2011;44:386–90.CrossRefPubMedGoogle Scholar
  114. 114.
    Brennan MA, Gleeson JP, O’Brien FJ, McNamara LM. Effects of ageing, prolonged estrogen deficiency and zoledronate on bone tissue mineral distribution. J Mech Behav Biomed Mater. 2014;29:161–70.CrossRefPubMedGoogle Scholar
  115. 115.
    Burket JC, Brooks DJ, MacLeay JM, Baker SP, Boskey AL, van der Meulen MC. Variations in nanomechanical properties and tissue composition within trabeculae from an ovine model of osteoporosis and treatment. Bone. 2013;52:326–36.CrossRefPubMedGoogle Scholar
  116. 116.
    Leung KS, Siu WS, Li SF, Qin L, Cheung WH, Tam KF, et al. An in vitro optimized injectable calcium phosphate cement for augmenting screw fixation in osteopenic goats. J Biomed Mater Res B Appl Biomater. 2006;78:153–60.Google Scholar
  117. 117.
    Cao L, Liu G, Gan Y, Fan Q, Yang F, Zhang X, et al. The use of autologous enriched bone marrow MSCs to enhance osteoporotic bone defect repair in long-term estrogen deficient goats. Biomaterials. 2012;33:5076–84.CrossRefPubMedGoogle Scholar
  118. 118.
    Alt V, Cheung WH, Chow SK, Thormann U, Cheung EN, Lips KS, et al. Bone formation and degradation behavior of nanocrystalline hydroxyapatite with or without collagen-type 1 in osteoporotic bone defects—an experimental study in osteoporotic goats. Injury. 2016;47:S58–65.CrossRefPubMedGoogle Scholar
  119. 119.
    Li Z, Lu WW, Chiu PK, Lam RW, Xu B, Cheung KM, et al. Strontium-calcium coadministration stimulates bone matrix osteogenic factor expression and new bone formation in a large animal model. J Orthop Res. 2009;27:758–62.CrossRefPubMedGoogle Scholar
  120. 120.
    •• Andreasen CM, Ding M, Overgaard S, Bollen P, Andersen TL. A reversal phase arrest uncoupling the bone formation and resorption contributes to the bone loss in glucocorticoid treated ovariectomised aged sheep. Bone. 2015;75:32–9. This a study showing that glucocorticoid treatment of OVX sheep induces a significant bone loss, promoted by an arrest of the reversal phase, resulting in an uncoupling of the bone formation and resorption during the reversal phase, like in postmenopausal women with glucocorticoid-induced osteoporosis, supporting the importance of this large animal model for the study of the pathophysiology of this disorder and as a preclinical model for orthopedic implant and biomaterial research CrossRefPubMedGoogle Scholar
  121. 121.
    Jensen PR, Andersen TL, Abdallah BM, Hauge E, Bollerslev J, Delaisse JM. Arrest of the reversal phase in postmenopausal and glucocorticoid-induced osteoporosis. J Bone Miner Res. 2011;26:S57.Google Scholar
  122. 122.
    Andersen TL, Abdelgawad ME, Kristensen HB, Hauge EM, Rolighed L, Bollerslev J, et al. Understanding coupling between bone resorption and formation: are reversal cells the missing link? Am J Pathol. 2013;183:235–46.CrossRefPubMedGoogle Scholar
  123. 123.
    El Khassawna T, Merboth F, Malhan D, Böcker W, Daghma DES, Stoetzel S, et al. Osteocyte regulation of receptor activator of NF-κB ligand/osteoprotegerin in a sheep model of osteoporosis. Am J Pathol. 2017;187:1686–99.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Isabel R. Dias
    • 1
    • 2
    • 3
  • José A. Camassa
    • 1
  • João A. Bordelo
    • 1
  • Pedro S. Babo
    • 2
    • 3
  • Carlos A. Viegas
    • 1
    • 2
    • 3
  • Nuno Dourado
    • 4
  • Rui L. Reis
    • 2
    • 3
  • Manuela E. Gomes
    • 2
    • 3
  1. 1.Department of Veterinary Sciences, Agricultural and Veterinary Sciences SchoolUniversity of Trás-os-Montes e Alto Douro (UTAD)Vila RealPortugal
  2. 2.3B’s Research Group-Biomaterials, Biodegradables and Biomimetics, Department of Polymer EngineeringUniversity of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative MedicineGuimarãesPortugal
  3. 3.ICVS/3B’s-PT Government Associate LaboratoryGuimarãesPortugal
  4. 4.CMEMS-UMinho, Department of Mechanical EngineeringUniversity of MinhoGuimarãesPortugal

Personalised recommendations