Effect of intermittent teriparatide (PTH 1-34) on the alveolar healing process in orchiectomized rats

  • Danila de OliveiraEmail author
  • Igor de Oliveira Puttini
  • Pedro Henrique Silva Gomes-Ferreira
  • Letícia Pitol Palin
  • Mariza Akemi Matsumoto
  • Roberta Okamoto
Original Article



To evaluate intermittent teriparatide therapy’s influence on the alveolar healing process in rats with induced osteoporosis.

Materials and methods

Fifty-four male rats were divided into three groups: fictitious surgery (SHAM), bilateral orchiectomy (ORQ NT), and bilateral orchiectomy treated with teriparatide (ORQ TERI). Right upper incisor extraction was performed. After 14 and 42 days, the rats were euthanized. Immunolabeling analysis was performed in order to characterize bone turnover through Wnt, alcaline phosphatase, osteocalcin, and TRAP presence in tissue; micro-CT analysis was performed in order to determine the bone volume fraction (BV/TV), trabecular thickness, separation, and number (Tb.Th, Tb.Sp, Tb.N). For the micro-CT data, statistical analysis was performed through one-way ANOVA and Tukey post-test, for parametrical data, with significance level adopted in p < 0.05. Days, Wnt, alkaline phosphatase, and osteocalcin revealed more labeling for ORQ TERI and less for TRAP. For the Tb.N in the ORQ NT group was 0.496 mm, a significant statistical difference was observed between the groups of ORQ NT and ORQ TERI (p < 0.05). For the BV/TV, Tb.Sp, and Tb.Th parameters, no significant statistical difference was observed among the three experimental groups (p > 0.05).


Treatment with intermittent teriparatide reverted impairment in the metabolism of repairing bone tissue in orchiectomized animals.

Clinical relevance

Cases of decreased bone density such as osteoporosis can lead to delayed alveolar repair process. PTH 1-34 has been shown to be a medication that improves this repair, making bone of low quality into one with normal features.


Osteoporosis Orchiectomy Teriparatide Men Wnt proteins Alkaline phosphatase 



The work was supported by the São Paulo Research Foundation (FAPESP), process number: 2015/14688-0 and 2015/20203-9.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed, process number: 706/2015 of the Brazilian College of Animal Experimentation – COBEA.

Informed consent

For this type of study, formal consent is not required.


  1. 1.
    Drake MT, Khosla S (2012) Male osteoporosis. Endocrinol Metab Clin N Am 41(3):629–641. CrossRefGoogle Scholar
  2. 2.
    Cauley JA, Robbins J, Chen Z, Cummings SR, Jackson RD, LaCroix AZ, LeBoff M, Lewis CE, McGowan J, Neuner J, Pettinger M, Stefanick ML, Wactawski-Wende J, Watts NB (2003) Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomized trial. Jama 290(13):1729–1738. CrossRefPubMedGoogle Scholar
  3. 3.
    Liberman UA, Hochberg MC, Geusens P, Shah A, Lin J, Chattopadhyay A, Ross PD (2006) Hip and non-spine fracture risk reductions differ among antiresorptive agents: evidence from randomised controlled trials. Int J Clin Pract 60(11):1394–1400. CrossRefPubMedGoogle Scholar
  4. 4.
    Miller PD, Derman RJ (2010) What is the best balance of benefits and risks among anti-resorptive therapies for postmenopausal osteoporosis? Osteoporosis International 21(11):1793–1802. CrossRefPubMedGoogle Scholar
  5. 5.
    Khosla S, Amin S, Orwoll E (2008) Osteoporosis in men. Endocr Rev 29(4):441–464. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Giusti A, Bianchi G (2015) Treatment of primary osteoporosis in men. Clin Interv Aging 10:105–115. CrossRefPubMedGoogle Scholar
  7. 7.
    Kaufman JM, Goemaere S (2008) Osteoporosis in men. Best Pract Res Clin Endocrinol Metab 22(5):787–812. CrossRefPubMedGoogle Scholar
  8. 8.
    Kaufman JM, Lapauw B, Goemaere S (2014) Current and future treatments of osteoporosis in men. Best Pract Res Clin Endocrinol Metab 28(6):871–884. CrossRefPubMedGoogle Scholar
  9. 9.
    Mittan D, Lee S, Miller E, Perez RC, Basler JW, Bruder JM (2002) Bone loss following hypogonadism in men with prostate cancer treated with GnRH analogs. J Clin Endocrinol Metab 87(8):3656–3661. CrossRefPubMedGoogle Scholar
  10. 10.
    Riggs BL, Khosla S, Melton LJ 3rd (2002) Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 23(3):279–302. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Van Pottelbergh I, Goemaere S, Kaufman JM (2003) Bioavailable estradiol and an aromatase gene polymorphism are determinants of bone mineral density changes in men over 70 years of age. J Clin Endocrinol Metab 88(7):3075–3081. CrossRefPubMedGoogle Scholar
  12. 12.
    Gennari L, Nuti R, Bilezikian JP (2004) Aromatase activity and bone homeostasis in men. J Clin Endocrinol Metab 89(12):5898–5907. CrossRefPubMedGoogle Scholar
  13. 13.
    Vanderschueren D, Vandenput L, Boonen S, Lindberg MK, Bouillon R, Ohlsson C (2004) Androgens and bone. Endocr Rev 25(3):389–425. CrossRefPubMedGoogle Scholar
  14. 14.
    Niimi R, Kono T, Nishihara A, Hasegawa M, Matsumine A, Kono T, Sudo A (2015) Analysis of daily teriparatide treatment for osteoporosis in men. Osteoporos Int 26(4):1303–1309. CrossRefPubMedGoogle Scholar
  15. 15.
    Jilka RL (2007) Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. Bone 40(6):1434–1446. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Hodsman AB, Bauer DC, Dempster DW, Dian L, Hanley DA, Harris ST, Kendler DL, McClung MR, Miller PD, Olszynski WP, Orwoll E, Yuen CK (2005) Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use. Endocr Rev 26(5):688–703. CrossRefPubMedGoogle Scholar
  17. 17.
    Komrakova M, Stuermer EK, Werner C, Wicke M, Kolios L, Sehmisch S, Tezval M, Daub F, Martens T, Witzenhausen P, Dullin C, Stuermer KM (2010) Effect of human parathyroid hormone hPTH (1-34) applied at different regimes on fracture healing and muscle in ovariectomized and healthy rats. Bone 47(3):480–492. CrossRefPubMedGoogle Scholar
  18. 18.
    Kuroshima S, Entezami P, McCauley LK, Yamashita J (2014) Early effects of parathyroid hormone on bisphosphonate/steroid-associated compromised osseous wound healing. Osteoporos Int 25(3):1141–1150. CrossRefPubMedGoogle Scholar
  19. 19.
    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(1):82–89. CrossRefPubMedGoogle Scholar
  20. 20.
    Naruse K, Uchino M, Hirakawa N, Toyama M, Miyajima G, Mukai M, Urabe K, Uchida K, Itoman M (2016) The low-intensity pulsed ultrasound (LIPUS) mechanism and the effect of teriparatide on fracture healing. J Orthop Trauma 30(8):S3. CrossRefPubMedGoogle Scholar
  21. 21.
    Okamoto T, de Russo MC (1973) Wound healing following tooth extraction. Histochemical study in rats. Rev Fac Odontol Aracatuba 2(2):153–169PubMedGoogle Scholar
  22. 22.
    Teofilo JM, Brentegani LG, Lamano-Carvalho TL (2004) Bone healing in osteoporotic female rats following intra-alveolar grafting of bioactive glass. Arch Oral Biol 49(9):755–762. CrossRefPubMedGoogle Scholar
  23. 23.
    Manrique N, Pereira CC, Luvizuto ER, Sanchez Mdel P, Okamoto T, Okamoto R, Sumida DH, Antoniali C (2015) Hypertension modifies OPG, RANK, and RANKL expression during the dental socket bone healing process in spontaneously hypertensive rats. Clin Oral Investig 19(6):1319–1327. CrossRefPubMedGoogle Scholar
  24. 24.
    Ramalho-Ferreira G, Faverani LP, Momesso GAC, Luvizuto ER, de Oliveira Puttini I, Okamoto R (2017) Effect of antiresorptive drugs in the alveolar bone healing. A histometric and immunohistochemical study in ovariectomized rats. Clin Oral Investig 21(5):1485–1494. CrossRefPubMedGoogle Scholar
  25. 25.
    Al-Shahat AR, Shaikh MA, Elmansy RA, Shehzad K, Kaimkhani ZA (2011) Prostatic assessment in rats after bilateral orchidectomy and calcitonin treatment. Endocr Regul 45(1):29–36PubMedGoogle Scholar
  26. 26.
    Ersan N, van Ruijven LJ, Bronckers AL, Olgac V, Ilguy D, Everts V (2014) Teriparatide and the treatment of bisphosphonate-related osteonecrosis of the jaw: a rat model. Dentomaxillofac Radiol 43(1):20130144. CrossRefPubMedGoogle Scholar
  27. 27.
    Pedrosa WF Jr, Okamoto R, Faria PE, Arnez MF, Xavier SP, Salata LA (2009) Immunohistochemical, tomographic and histological study on onlay bone graft remodeling. Part II: calvarial bone. Clin Oral Implants Res 20(11):1254–1264. CrossRefPubMedGoogle Scholar
  28. 28.
    Day TF, Guo X, Garrett-Beal L, Yang Y (2005) Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell 8(5):739–750. CrossRefPubMedGoogle Scholar
  29. 29.
    Chung YE, Lee SH, Lee SY, Kim SY, Kim HH, Mirza FS, Lee SK, Lorenzo JA, Kim GS, Koh JM (2012) Long-term treatment with raloxifene, but not bisphosphonates, reduces circulating sclerostin levels in postmenopausal women. Osteoporos Int 23(4):1235–1243. CrossRefPubMedGoogle Scholar
  30. 30.
    Whyte MP (1994) Hypophosphatasia and the role of alkaline phosphatase in skeletal mineralization. Endocr Rev 15(4):439–461. CrossRefPubMedGoogle Scholar
  31. 31.
    Ducy P, Schinke T, Karsenty G (2000) The osteoblast: a sophisticated fibroblast under central surveillance. Science (New York, NY) 289(5484):1501–1504CrossRefGoogle Scholar
  32. 32.
    Luvizuto ER, Queiroz TP, Dias SM, Okamoto T, Dornelles RC, Garcia IR Jr, Okamoto R (2010) Histomorphometric analysis and immunolocalization of RANKL and OPG during the alveolar healing process in female ovariectomized rats treated with oestrogen or raloxifene. Arch Oral Biol 55(1):52–59. CrossRefPubMedGoogle Scholar
  33. 33.
    Bouxsein ML, Boyd SK, Christiansen BA, Guldberg RE, Jepsen KJ, Muller R (2010) Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J Bone Miner Res 25(7):1468–1486. CrossRefPubMedGoogle Scholar
  34. 34.
    Ibrahim MR, Singh S, Merican AM, Raghavendran HR, Murali MR, Naveen SV, Kamarul T (2016) The effect of strontium ranelate on the healing of a fractured ulna with bone gap in rabbit. BMC Vet Res 12(1):112. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Luvizuto ER, Dias SM, Queiroz TP, Okamoto T, Garcia IR Jr, Okamoto R, Dornelles RC (2010) Osteocalcin immunolabeling during the alveolar healing process in ovariectomized rats treated with estrogen or raloxifene. Bone 46(4):1021–1029. CrossRefPubMedGoogle Scholar
  36. 36.
    Luvizuto ER, Dias SS, Okamoto T, Dornelles RC, Okamoto R (2011) Raloxifene therapy inhibits osteoclastogenesis during the alveolar healing process in rats. Arch Oral Biol 56(10):984–990. CrossRefPubMedGoogle Scholar
  37. 37.
    Seifi M, Ezzati B, Saedi S, Hedayati M (2015) The effect of ovariectomy and orchiectomy on orthodontic tooth movement and root resorption in Wistar rats. J Dent (Shiraz, Iran) 16(4):302–309Google Scholar
  38. 38.
    Shirakawa J, Harada H, Noda M, Ezura Y (2016) PTH-induced osteoblast proliferation requires upregulation of the ubiquitin-specific peptidase 2 (Usp2) expression. Calcif Tissue Int 98(3):306–315. CrossRefPubMedGoogle Scholar
  39. 39.
    Phelps E, Bezouglaia O, Tetradis S, Nervina JM (2005) Parathyroid hormone induces receptor activity modifying protein-3 (RAMP3) expression primarily via 3′,5′-cyclic adenosine monophosphate signaling in osteoblasts. Calcif Tissue Int 77(2):96–103. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Danila de Oliveira
    • 1
    Email author
  • Igor de Oliveira Puttini
    • 2
  • Pedro Henrique Silva Gomes-Ferreira
    • 2
  • Letícia Pitol Palin
    • 1
  • Mariza Akemi Matsumoto
    • 1
  • Roberta Okamoto
    • 1
  1. 1.Department of Basic Sciences, Aracatuba Dental SchoolUniv. Estadual Paulista – UNESPAracatubaBrazil
  2. 2.Department of Surgery and Integrated Clinic, Aracatuba Dental SchoolUniv. Estadual Paulista – UNESPAracatubaBrazil

Personalised recommendations