Skip to main content
Log in

Effects of combined human parathyroid hormone (1–34) and menaquinone-4 treatment on the interface of hydroxyapatite-coated titanium implants in the femur of osteoporotic rats

  • Original Article
  • Published:
Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

The objective of this study was to investigate the effects of human parathyroid hormone (1–34) (PTH1–34; PTH) plus menaquinone-4 (vitamin K2; MK) on the osseous integration of hydroxyapatite (HA)-coated implants in osteoporotic rats. Ovariectomized female Sprague–Dawley rats were used for the study. Twelve weeks after bilateral ovariectomy, HA-coated titanium implants were inserted bilaterally in the femoral medullary canal of the remaining 40 ovariectomized rats. All animals were then randomly assigned to four groups: Control, MK, PTH and PTH + MK. The rats from groups MK, PTH and PTH + MK received vitamin K2 (30 mg/kg/day), PTH1–34 (60 μg/kg, three times a week), or both for 12 weeks. Thereafter, serum levels of γ-carboxylated osteocalcin (Gla-OC) were quantitated by ELISA and the bilateral femurs of rats were harvested for evaluation. The combination of PTH and MK clearly increased the serum levels of Gla-OC (a specific marker for bone formation) compared to PTH or MK alone. The results of our study indicated that all treated groups had increased new bone formation around the surface of implants and increased push-out force compared to Control. In addition, PTH + MK treatment showed the strongest effects in histological, micro-computed tomography and biomechanical tests. In summary, our results confirm that treatment with PTH1–34 and MK together may have a therapeutic advantage over PTH or MK monotherapy on bone healing around HA-coated implants in osteoporotic rats.

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
Fig. 4

Similar content being viewed by others

References

  1. Patel A, Pavlou G, Mújica-Mota RE, Toms AD (2015) The epidemiology of revision total knee and hip arthroplasty in England and Wales: a comparative analysis with projections for the United States. A study using the National Joint Registry dataset. Bone Joint J 97-B:1076–1081

    Article  CAS  Google Scholar 

  2. Tao ZS, Zhou WS, Bai BL, Cui W, Lv YX, Yu XB, Huang ZL, Tu KK, Zhou Q, Sun T (2016) The effects of combined human parathyroid hormone (1–34) and simvastatin treatment on the interface of hydroxyapatite-coated titanium rods implanted into osteopenic rats femurs. J Mater Sci Mater Med 27:43

    Article  Google Scholar 

  3. Duarte PM, César Neto JB, Gonçalves PF, Sallum EA, Jf N (2003) Estrogen deficiency affects bone healing around titanium implants: a histometric study in rats. Implant Dent 12:340

    Article  Google Scholar 

  4. Philip S, Cyrus C (2006) Osteoporosis. Lancet 367:2010–2018

    Article  Google Scholar 

  5. Jinno T, Kirk SS, Goldberg VM (2004) Effects of calcium ion implantation on osseointegration of surface-blasted titanium alloy femoral implants in a canine total hip arthroplasty model. J Arthroplast 19:102–109

    Article  Google Scholar 

  6. Sul YT, Johansson C, Byon E, Albrektsson T (2005) The bone response of oxidized bioactive and non-bioactive titanium implants. Biomaterials 26:6720–6730

    Article  CAS  Google Scholar 

  7. Tao ZS, Zhou WS, Tu KK, Huang ZL, Zhou Q, Sun T, Lv YX, Cui W, Yang L (2015) The effects of combined human parathyroid hormone (1–34) and simvastatin treatment on osseous integration of hydroxyapatite-coated titanium implants in the femur of ovariectomized rats. Injury 46:2164–2169

    Article  Google Scholar 

  8. Reikeras O, Gunderson RB (2003) Excellent results of HA coating on a grit-blasted stem: 245 patients followed for 8–12 years. Acta Orthop Scand 74:140

    Article  Google Scholar 

  9. Palm L, Jacobsson SA, Ivarsson I (2002) Hydroxyapatite coating improves 8- to 10-year performance of the link RS cementless femoral stem. J Arthroplast 17:172–175

    Article  Google Scholar 

  10. Hara T, Hayashi K, Nakashima Y, Kanemaru T, Iwamoto Y (1999) The effect of hydroxyapatite coating on the bonding of bone to titanium implants in the femora of ovariectomised rats. J Bone Joint Surg Br 81:705–709

    Article  CAS  Google Scholar 

  11. Hayashi K, Uenoyama K, Mashima T, Sugioka Y (1994) Remodelling of bone around hydroxyapatite and titanium in experimental osteoporosis. Biomaterials 15:11–16

    Article  CAS  Google Scholar 

  12. Mavrogenis AF, Dimitriou R, Parvizi J, Babis GC (2009) Biology of implant osseointegration. J Musculoskel Neuron 9:61

    CAS  Google Scholar 

  13. Fini M, Giavaresi G, Rimondini L, Giardino R (2002) Titanium alloy osseointegration in cancellous and cortical bone of ovariectomized animals: histomorphometric and bone hardness measurements. Int J Oral Maxillofac Implants 17:28–37

    PubMed  Google Scholar 

  14. Gabet Y, Müller R, Levy J, Dimarchi R, Chorev M, Bab I, Kohavi D (2006) Parathyroid hormone 1–34 enhances titanium implant anchorage in low-density trabecular bone: a correlative micro-computed tomographic and biomechanical analysis. Bone 39:276–282

    Article  CAS  Google Scholar 

  15. Tao ZS, Qiang Z, Tu KK, Huang ZL, Xu HM, Sun T, Lv YX, Cui W, Yang L (2015) Treatment study of distal femur for parathyroid hormone (1–34) and β-tricalcium phosphate on bone formation in critical-sized defects in rats. J Craniomaxillofac Surg 43:2136–2143

    Article  Google Scholar 

  16. Shirota T, Tashiro M, Ohno K, Yamaguchi A (2003) Effect of intermittent parathyroid hormone (1–34) treatment on the bone response after placement of titanium implants into the tibia of ovariectomized rats. J Oral Maxillofac Surg 61:471–480

    Article  Google Scholar 

  17. Shearer MJ (1995) Vitamin K. Lancet 345:229–234

    Article  CAS  Google Scholar 

  18. Shiraki M, Shiraki Y, Aoki C, Miura M (2000) Vitamin K2 (menatetrenone) effectively prevents fractures and sustains lumbar bone mineral density in osteoporosis. J Bone Miner Res 15:515–521

    Article  CAS  Google Scholar 

  19. Iwamoto I, Kosha S, Noguchi SI, Murakami M, Fujino T, Douchi T, Nagata Y (1999) A longitudinal study of the effect of vitamin K2 on bone mineral density in postmenopausal women; a comparative study with vitamin D3 and estrogen–progestin therapy. Maturitas 31:161–164

    Article  CAS  Google Scholar 

  20. Shimizu T, Takahata M, Kameda Y, Hamano H, Ito T, Kimura-Suda H, Todoh M, Tadano S, Iwasaki N (2014) Vitamin K-dependent carboxylation of osteocalcin affects the efficacy of teriparatide (PTH 1–34) for skeletal repair. Bone 64:95–101

    Article  CAS  Google Scholar 

  21. Kaneki M, Hedges SJ, Hosoi T, Fujiwara S, Lyons A, Crean SJ, Ishida N, Nakagawa M, Takechi M, Sano Y (2001) Japanese fermented soybean food as the major determinant of the large geographic difference in circulating levels of vitamin K2: possible implications for hip-fracture risk. Nutrition 17:315–321

    Article  CAS  Google Scholar 

  22. Yamaguchi M, Kakuda H, Ying HG, Tsukamoto Y (2000) Prolonged intake of fermented soybean (natto) diets containing vitamin K2 (menaquinone-7) prevents bone loss in ovariectomized rats. J Bone Miner Metab 18:71–76

    Article  CAS  Google Scholar 

  23. Mawatari T, Hiromasa MMD, Higaki H, Moro-Oka T, Kurata K, Murakami T, Iwamoto Y (2000) Effect of vitamin K2 on three-dimensional trabecular microarchitecture in ovariectomized rats. J Bone Miner Res 15:1810–1817

    Article  CAS  Google Scholar 

  24. Inoue T, Fujita T, Kishimoto H, Makino T, Nakamura T, Nakamura T, Sato T, Yamazaki K (2009) Randomized controlled study on the prevention of osteoporotic fractures (OF study): a phase IV clinical study of 15-mg menatetrenone capsules. J Bone Miner Metab 27:66–75

    Article  CAS  Google Scholar 

  25. Iwamoto J (2014) Vitamin K2 therapy for postmenopausal osteoporosis. Nutrients 6:1971–1980

    Article  Google Scholar 

  26. Nagura N, Komatsu J, Iwase H, Hosoda H, Ohbayashi O, Nagaoka I, Kaneko K (2015) Effects of the combination of vitamin K and teriparatide on the bone metabolism in ovariectomized rats. Biomed Rep 3:295–300

    Article  CAS  Google Scholar 

  27. Chen B, Li Y, Xie D, Yang X (2012) Low-magnitude high-frequency loading via whole body vibration enhances bone-implant osseointegration in ovariectomized rats. J Orthop Res 30:733–739

    Article  Google Scholar 

  28. Virdi AS, Liu M, Sena K, Maletich J, Mcnulty M, Ke HZ, Sumner DR (2012) Sclerostin antibody increases bone volume and enhances implant fixation in a rat model. J Bone Joint Surg Am 94:1670–1680

    Article  Google Scholar 

  29. Li YF, Zhou CC, Li JH, Luo E, Zhu SS, Feng G, Hu J (2012) The effects of combined human parathyroid hormone (1–34) and zoledronic acid treatment on fracture healing in osteoporotic rats. Osteoporos Int 23:1463–1474

    Article  CAS  Google Scholar 

  30. He F, Yang G, Wang X, Zhao S (2009) Effect of electrochemically deposited nanohydroxyapatite on bone bonding of sandblasted/dual acid-etched titanium implant. Int J Oral Maxillofac Implants 24:790

    PubMed  Google Scholar 

  31. Li YF, Li XD, Bao CY, Chen QM, Zhang H, Hu J (2013) Promotion of peri-implant bone healing by systemically administered parathyroid hormone (1–34) and zoledronic acid adsorbed onto the implant surface. Osteoporos Int 24:1063–1071

    Article  CAS  Google Scholar 

  32. Gabet Y, Kohavi D, Kohler T, Baras M, Müller R, Bab I (2008) Trabecular bone gradient in rat long bone metaphyses: mathematical modeling and application to morphometric measurements and correction of implant positioning. J Bone Miner Res 23:48–57

    Article  Google Scholar 

  33. Li Y, Li Q, Zhu S, Luo E, Li J, Feng G, Liao Y, Hu J (2010) The effect of strontium-substituted hydroxyapatite coating on implant fixation in ovariectomized rats. Biomaterials 31:9006–9014

    Article  CAS  Google Scholar 

  34. Tao ZS, Zhou WS, He XW, Liu W, Bai BL, Zhou Q, Huang ZL, Tu KK, Li H, Sun T (2016) A comparative study of zinc, magnesium, strontium-incorporated hydroxyapatite-coated titanium implants for osseointegration of osteopenic rats. Mater Sci Eng C Mater Biol Appl 62:226

    Article  CAS  Google Scholar 

  35. Turner RT, Vandersteenhoven JJ, Bell NH (2010) The effects of ovariectomy and 17 beta-estradiol on cortical bone histomorphometry in growing rats. J Bone Miner Res 2:115–122

    Article  Google Scholar 

  36. Koshihara Y, Hoshi K (1997) Vitamin K2 enhances osteocalcin accumulation in the extracellular matrix of human osteoblasts in vitro. J Bone Miner Res 12:431–438

    Article  CAS  Google Scholar 

  37. Vermeer C, Jie KS, Knapen MH (1995) Role of vitamin K in bone metabolism. Annu Rev Nutr 15:1–22

    Article  CAS  Google Scholar 

  38. Hara K, Akiyama Y, Nakamura T, Murota S, Morita I (1995) The inhibitory effect of vitamin K2 (menatetrenone) on bone resorption may be related to its side chain. Bone 16:179–184

    Article  CAS  Google Scholar 

  39. Iwasaki Y, Yamato H, Murayama H, Takahashi T, Ezawa I, Kurokawa K, Fukagawa M (2002) Menatetrenone prevents osteoblast dysfunction in unilateral sciatic neurectomized rats. Jpn J Pharmacol 90:88–93

    Article  CAS  Google Scholar 

  40. Matsumoto T, Miyakawa T, Yamamoto D (2012) Effects of vitamin K on the morphometric and material properties of bone in the tibiae of growing rats. Metabolism 61:407–414

    Article  CAS  Google Scholar 

  41. Saito M, Marumo K (2010) Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. Osteoporos Int 21:195–214

    Article  CAS  Google Scholar 

  42. Saito M, Fujii K, Soshi S, Tanaka T (2005) Effects of vitamin B6 and vitamin K2 on bone mechanical properties and collagen crosslinks in spontaneously diabetic WBN/Kob rats. J Bone Miner Res Suppl SU420

  43. Roy ME, Nishimoto SK, Rho JY, Bhattacharya SK, Lin JS, Pharr GM (2001) Correlations between osteocalcin content, degree of mineralization, and mechanical properties of C. carpio rib bone. J Biomed Mater Res 54:547–553

    Article  CAS  Google Scholar 

  44. Dayer R, Brennan TC, Rizzoli R, Ammann P (2010) PTH improves titanium implant fixation more than pamidronate or renutrition in osteopenic rats chronically fed a low protein diet. Osteoporos Int 21:957–967

    Article  CAS  Google Scholar 

  45. Dayer R, Badoud I, Rizzoli R, Ammann P (2007) Defective implant osseointegration under protein undernutrition: prevention by PTH or pamidronate. J Bone Miner Res 22:1526–1533

    Article  CAS  Google Scholar 

  46. Ichikawa T, Horieinoue K, Ikeda K, Blumberg B, Inoue S (2007) Vitamin K2 induces phosphorylation of protein kinase a and expression of novel target genes in osteoblastic cells. J Mol Endocrinol 39:4–239

    Article  Google Scholar 

Download references

Acknowledgements

This work was funded by a research grant to Natural Science Foundation of Zhejiang Province (Grant No.: LY16H250002).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lei Yang.

Ethics declarations

Conflict of interest

All authors have no conflict of interest.

Ethical approval

Statement of ethical approval: Animals were handled with the approval of the Animal Experimentation Ethics Committee of Second Affiliated Hospital of Wenzhou Medical University.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, H., Zhou, Q., Bai, BL. et al. Effects of combined human parathyroid hormone (1–34) and menaquinone-4 treatment on the interface of hydroxyapatite-coated titanium implants in the femur of osteoporotic rats. J Bone Miner Metab 36, 691–699 (2018). https://doi.org/10.1007/s00774-017-0893-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00774-017-0893-9

Keywords

Navigation