Advertisement

Clinical Oral Investigations

, Volume 22, Issue 1, pp 255–265 | Cite as

Raloxifene but not alendronate can compensate the impaired osseointegration in osteoporotic rats

  • Leonardo Perez Faverani
  • Tárik Ocon Braga Polo
  • Gabriel Ramalho-Ferreira
  • Gustavo Antonio Correa Momesso
  • Jaqueline Suemi Hassumi
  • Ana Cláudia Rossi
  • Alexandre Rodrigues Freire
  • Felippe Bevilacqua Prado
  • Eloá Rodrigues Luvizuto
  • Reinhard Gruber
  • Roberta Okamoto
Original Article

Abstract

Objectives

Alendronate and raloxifene, a bisphosphonate and a selective estrogen modulator, respectively, are established osteoporosis therapies. Current evidence suggests that simultaneous application of osteoporosis therapies modulates osseointegration. However, alendronate shows inconsistent findings and raloxifene has not been studied comprehensively. This study aimed to evaluate the bone dynamics and molecular and microstructural features at the peri-implant bone interface in osteoporotic rats.

Materials and methods

Thirty female rats underwent ovariectomy and were fed a diet low in calcium and phosphate and treated with alendronate or raloxifene for 30 days or underwent fictional ovariectomy surgery (SHAM) prior to implant insertion in the tibia; osteoporosis therapies continued thereafter. After 42 days, peri-implant bone was evaluated by histometric and micro-CT analysis. Fluorochrome incorporation and gene expression was determined to evaluate bone turnover.

Results

We report here that alendronate had no impact on bone-to-implant contacts and the mineral apposition rate. The RANKL/OPG ratio and local bone volume, however, were increased compared to the untreated osteoporotic rats. Even though signaling to bone resorption activity through RANKL production was observed in the alendronate group, the blockade of bone resorption activity that occurs in decorrence to alendronate activity took place and resulted in an increase in bone volume. Raloxifene significantly increased osseointegration in osteoporotic rats, as indicated by bone-to-implant contacts, mineral apposition, and local bone volume. Raloxifene, however, had no considerable impact on the RANKL/OPG ratio compared to untreated osteoporotic rats. As expected, the SH group showed higher bone-to-implant contacts and mineral apposition rates than the untreated osteoporotic rats.

Conclusions

These findings suggest that raloxifene but not alendronate can compensate for the impaired osseointegration in osteoporotic rats.

Clinical relevance

Regarding the superiority of raloxifene observed in the improvement of bone dynamics response, this statement suggests that raloxifene could be a good option for osteoporosis patients in oral rehabilitation procedures.

Keywords

Osteoporosis Dental implants Alendronate Raloxifene Microscopy 

Notes

Acknowledgments

The authors would like to thank the São Paulo Research Foundation—FAPESP (2012/15748-8 and 2012/15912-2), for financial support; Marcia Sirlene Zardin Graeff, from Bauru Dental School—USP, for help in obtaining confocal microscopy images, and Prof. Dr. Elcio Marcantonio Junior and laboratory technician Ana Claudia Gregolin Costa Miranda, from UNESP—Araraquara, for facilitating the laboratory processing of specimens with EXAKT. Also, we would like to thank the Implalife Biotechnology for providing the implants.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Funding

This study was supported by the São Paulo Research Foundation—FAPESP (2012/15748-8 and 2012/15912-2).

Ethical approval

The procedures and protocol design described here were approved by the Ethics Committee in Animal Experimentation of Aracatuba Dental School, UNESP—Univ Estadual Paulista, Brazil (approval no. 2012-01096).

Informed consent

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

References

  1. 1.
    Yoshimura N et al (2009) Prevalence of knee osteoarthritis, lumbar spondylosis, and osteoporosis in Japanese men and women: the research on osteoarthritis/osteoporosis against disability study. J Bone Miner Metab 27(5):620–628CrossRefPubMedGoogle Scholar
  2. 2.
    Tanaka S et al (2016) Real-world evidence of raloxifene versus alendronate in preventing non-vertebral fractures in Japanese women with osteoporosis: retrospective analysis of a hospital claims database. J Bone Miner Metab. doi: 10.1007/s00774-016-0809-0
  3. 3.
    Chen H et al (2013) Smoking, radiotherapy, diabetes and osteoporosis as risk factors for dental implant failure: a meta-analysis. PLoS One 8(8):e71955CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Busenlechner D et al (2014) Long-term implant success at the academy for oral implantology: 8-year follow-up and risk factor analysis. J Periodontal Implant Sci 44(3):102–108CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Khan M, Cheung AM, Khan AA (2017) Drug-related adverse events of osteoporosis therapy. Endocrinol Metab Clin N Am 46(1):181–192CrossRefGoogle Scholar
  6. 6.
    Giro G et al (2011) The effect of oestrogen and alendronate therapies on postmenopausal bone loss around osseointegrated titanium implants. Clin Oral Implants Res 22(3):259–264CrossRefPubMedGoogle Scholar
  7. 7.
    Tsurushima H et al (2013) Bacterial promotion of bisphosphonate-induced osteonecrosis in Wistar rats. Int J Oral Maxillofac Surg 42(11):1481–1487CrossRefPubMedGoogle Scholar
  8. 8.
    Gossiel F et al (2016) The effect of bisphosphonate treatment on osteoclast precursor cells in postmenopausal osteoporosis: the TRIO study. Bone 92:94–99CrossRefPubMedGoogle Scholar
  9. 9.
    Russell RG (2011) Bisphosphonates: the first 40 years. Bone 49(1):2–19CrossRefPubMedGoogle Scholar
  10. 10.
    Ramalho-Ferreira G et al (2015) Raloxifene enhances peri-implant bone healing in osteoporotic rats. Int J Oral Maxillofac Surg 44(6):798–805CrossRefPubMedGoogle Scholar
  11. 11.
    Lama A et al (2017) Extracorporeal shock waves alone or combined with raloxifene promote bone formation and suppress resorption in ovariectomized rats. PLoS One 12(2):e0171276CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Urano T et al (2017) Preventive effects of raloxifene treatment on agerelated weight loss in postmenopausal women. J Bone Miner Metab 35(1):108–113CrossRefPubMedGoogle Scholar
  13. 13.
    Narai S, Nagahata S (2003) Effects of alendronate on the removal torque of implants in rats with induced osteoporosis. Int J Oral Maxillofac Implants 18(2):218–223PubMedGoogle Scholar
  14. 14.
    Skripitz R et al (2009) Effect of alendronate and intermittent parathyroid hormone on implant fixation in ovariectomized rats. J Orthop Sci 14(2):138–143CrossRefPubMedGoogle Scholar
  15. 15.
    Dikicier E et al (2014) Effect of systemic administered zoledronic acid on osseointegration of a titanium implant in ovariectomized rats. J Craniomaxillofac Surg 42(7):1106–1111CrossRefPubMedGoogle Scholar
  16. 16.
    Chen B et al (2013) Zoledronic acid enhances bone-implant osseointegration more than alendronate and strontium ranelate in ovariectomized rats. Osteoporos Int 24(7):2115–2121CrossRefPubMedGoogle Scholar
  17. 17.
    de Oliveira MA et al (2015) The effects of zoledronic acid and dexamethasone on osseointegration of endosseous implants: histological and histomorphometrical evaluation in rats. Clin Oral Implants Res 26(4):e17–e21CrossRefPubMedGoogle Scholar
  18. 18.
    Vohra F et al (2014) Efficacy of systemic bisphosphonate delivery on osseointegration of implants under osteoporotic conditions: lessons from animal studies. Arch Oral Biol 59(9):912–920CrossRefPubMedGoogle Scholar
  19. 19.
    Evans HM, Long JA (1922) Characteristic effects upon growth, oestrus and ovulation induced by the Intraperitoneal Administration of Fresh Anterior Hypophyseal Substance. Proc Natl Acad Sci U S A 8(3):38–39CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Teofilo JM et al (2003) Comparison between two experimental protocols to promote osteoporosis in the maxilla and proximal tibia of female rats. In Pesqui Odontol Bras Brazil p 302–6Google Scholar
  21. 21.
    Ramalho-Ferreira G et al (2015) Alveolar bone dynamics in osteoporotic rats treated with raloxifene or alendronate: confocal microscopy analysis. J Biomed Optics 20(3)Google Scholar
  22. 22.
    da Paz LH et al (2001) Effect of 17beta-estradiol or alendronate on the bone densitometry, bone histomorphometry and bone metabolism of ovariectomized rats. In Braz J Med Biol Res Brazil p 1015–22Google Scholar
  23. 23.
    Luvizuto ER et al (2010) Histomorphometric analysis and immunolocalization of RANKL and OPG during the alveolar healing process in female ovariectomized rats treated with oestrogen or raloxifene. In Arch Oral Biol 2009 Elsevier Ltd: England p 52–9Google Scholar
  24. 24.
    Luvizuto ER et al (2010) Osteocalcin immunolabeling during the alveolar healing process in ovariectomized rats treated with estrogen or raloxifene. In Bone 2009 Elsevier Inc: United States p 1021–9Google Scholar
  25. 25.
    Ramalho-Ferreira G et al (2015) Alveolar bone dynamics in osteoporotic rats treated with raloxifene or alendronate: confocal microscopy analysis. J Biomed Opt p 038003–1 - 038003-7Google Scholar
  26. 26.
    Dempster DW et al (2013) Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 28(1):2–17CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Blackledge NP, Rose NR, Klose RJ (2015) Targeting polycomb systems to regulate gene expression: modifications to a complex story. Nat Rev Mol Cell Biol 16(11):643–649CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Giro G et al (2011) Influence of estrogen deficiency on bone around osseointegrated dental implants: an experimental study in the rat jaw model. J Oral Maxillofac Surg 69(7):1911–1918CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Cardemil C et al (2013) The effects of a systemic single dose of zoledronic acid on post-implantation bone remodelling and inflammation in an ovariectomised rat model. Biomaterials 34(5):1546–1561CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Leonardo Perez Faverani
    • 1
  • Tárik Ocon Braga Polo
    • 1
  • Gabriel Ramalho-Ferreira
    • 1
  • Gustavo Antonio Correa Momesso
    • 1
  • Jaqueline Suemi Hassumi
    • 1
    • 2
  • Ana Cláudia Rossi
    • 3
  • Alexandre Rodrigues Freire
    • 3
  • Felippe Bevilacqua Prado
    • 3
  • Eloá Rodrigues Luvizuto
    • 4
  • Reinhard Gruber
    • 5
  • Roberta Okamoto
    • 2
  1. 1.Department of Surgery and Integrated Clinic, Division of Oral and Maxillofacial SurgerySão Paulo State University (UNESP), School of DentistryAraçatubaBrazil
  2. 2.Department of Basic SciencesSão Paulo State University (UNESP), School of DentistryAraçatubaBrazil
  3. 3.Department of Morphology, Piracicaba Dental SchoolUniversity of Campinas (UNICAMP)PiracicabaBrazil
  4. 4.Department of Surgery and Integrated Clinic, Division of Integrated ClinicSão Paulo State University UNESP), School of DentistryAraçatubaBrazil
  5. 5.Department of Oral BiologyMedical University of ViennaWienAustria

Personalised recommendations