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Systemically administered zoledronic acid activates locally implanted synthetic hydroxyapatite particles enhancing peri-implant bone formation : A regenerative medicine approach to improve fracture fixation

Markeviciute, Vetra LU ; Puthia, Manoj LU ; Arvidsson, Linnea LU ; Liu, Yang LU ; Törnquist, Elin LU ; Tengattini, Alessandro ; Huang, Jintian LU ; Bai, Yiguang ; Vater, Corina and Petrolis, Robertas , et al. (2024) In Acta Biomaterialia
Abstract

Fracture fixation in an ageing population is challenging and fixation failure increases mortality and societal costs. We report a novel fracture fixation treatment by applying a hydroxyapatite (HA) based biomaterial at the bone-implant interface and biologically activating the biomaterial by systemic administration of a bisphosphonate (zoledronic acid, ZA). We first used an animal model of implant integration and applied a calcium sulphate (CaS)/HA biomaterial around a metallic screw in the tibia of osteoporotic rats. Using systemic ZA administration at 2-weeks post-surgery, we demonstrated that the implant surrounded by HA particles showed significantly higher peri‑implant bone formation compared to the unaugmented implants at 6-weeks.... (More)

Fracture fixation in an ageing population is challenging and fixation failure increases mortality and societal costs. We report a novel fracture fixation treatment by applying a hydroxyapatite (HA) based biomaterial at the bone-implant interface and biologically activating the biomaterial by systemic administration of a bisphosphonate (zoledronic acid, ZA). We first used an animal model of implant integration and applied a calcium sulphate (CaS)/HA biomaterial around a metallic screw in the tibia of osteoporotic rats. Using systemic ZA administration at 2-weeks post-surgery, we demonstrated that the implant surrounded by HA particles showed significantly higher peri‑implant bone formation compared to the unaugmented implants at 6-weeks. We then evaluated the optimal timing (day 1, 3, 7 and 14) of ZA administration to achieve a robust effect on peri‑implant bone formation. Using fluorescent ZA, we demonstrated that the uptake of ZA in the CaS/HA material was the highest at 3- and 7-days post-implantation and the uptake kinetics had a profound effect on the eventual peri‑implant bone formation. We furthered our concept in a feasibility study on trochanteric fracture patients randomized to either CaS/HA augmentation or no augmentation followed by systemic ZA treatment. Radiographically, the CaS/HA group showed signs of increased peri‑implant bone formation compared with the controls. Finally, apart from HA, we demonstrated that the concept of biologically activating a ceramic material by ZA could also be applied to β-tricalcium phosphate. This novel approach for fracture treatment that enhances immediate and long-term fracture fixation in osteoporotic bone could potentially reduce reoperations, morbidity and mortality. Statement of significance: • Fracture fixation in an ageing population is challenging. Biomaterial-based augmentation of fracture fixation devices has been attempted but lack of satisfactory biological response limits their widespread use. • We report the biological activation of locally implanted microparticulate hydroxyapatite (HA) particles placed around an implant by systemic administration of the bisphosphonate zoledronic acid (ZA). The biological activation of HA by ZA enhances peri‑implant bone formation. •Timing of ZA administration after HA implantation is critical for optimal ZA uptake and consequently determines the extent of peri‑implant bone formation. • We translate the developed concept from small animal models of implant integration to a proof-of-concept clinical study on osteoporotic trochanteric fracture patients. • ZA based biological activation can also be applied to other calcium phosphate biomaterials.

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publication status
epub
subject
keywords
Bisphosphonate, Fracture fixation, Hydroxyapatite, Implant loosening
in
Acta Biomaterialia
publisher
Elsevier
external identifiers
  • pmid:38490481
  • scopus:85188602532
ISSN
1742-7061
DOI
10.1016/j.actbio.2024.03.005
language
English
LU publication?
yes
id
b54762b9-f225-4aa4-940d-11209da84a93
date added to LUP
2024-04-15 13:02:21
date last changed
2024-04-29 14:55:56
@article{b54762b9-f225-4aa4-940d-11209da84a93,
  abstract     = {{<p>Fracture fixation in an ageing population is challenging and fixation failure increases mortality and societal costs. We report a novel fracture fixation treatment by applying a hydroxyapatite (HA) based biomaterial at the bone-implant interface and biologically activating the biomaterial by systemic administration of a bisphosphonate (zoledronic acid, ZA). We first used an animal model of implant integration and applied a calcium sulphate (CaS)/HA biomaterial around a metallic screw in the tibia of osteoporotic rats. Using systemic ZA administration at 2-weeks post-surgery, we demonstrated that the implant surrounded by HA particles showed significantly higher peri‑implant bone formation compared to the unaugmented implants at 6-weeks. We then evaluated the optimal timing (day 1, 3, 7 and 14) of ZA administration to achieve a robust effect on peri‑implant bone formation. Using fluorescent ZA, we demonstrated that the uptake of ZA in the CaS/HA material was the highest at 3- and 7-days post-implantation and the uptake kinetics had a profound effect on the eventual peri‑implant bone formation. We furthered our concept in a feasibility study on trochanteric fracture patients randomized to either CaS/HA augmentation or no augmentation followed by systemic ZA treatment. Radiographically, the CaS/HA group showed signs of increased peri‑implant bone formation compared with the controls. Finally, apart from HA, we demonstrated that the concept of biologically activating a ceramic material by ZA could also be applied to β-tricalcium phosphate. This novel approach for fracture treatment that enhances immediate and long-term fracture fixation in osteoporotic bone could potentially reduce reoperations, morbidity and mortality. Statement of significance: • Fracture fixation in an ageing population is challenging. Biomaterial-based augmentation of fracture fixation devices has been attempted but lack of satisfactory biological response limits their widespread use. • We report the biological activation of locally implanted microparticulate hydroxyapatite (HA) particles placed around an implant by systemic administration of the bisphosphonate zoledronic acid (ZA). The biological activation of HA by ZA enhances peri‑implant bone formation. •Timing of ZA administration after HA implantation is critical for optimal ZA uptake and consequently determines the extent of peri‑implant bone formation. • We translate the developed concept from small animal models of implant integration to a proof-of-concept clinical study on osteoporotic trochanteric fracture patients. • ZA based biological activation can also be applied to other calcium phosphate biomaterials.</p>}},
  author       = {{Markeviciute, Vetra and Puthia, Manoj and Arvidsson, Linnea and Liu, Yang and Törnquist, Elin and Tengattini, Alessandro and Huang, Jintian and Bai, Yiguang and Vater, Corina and Petrolis, Robertas and Zwingenberger, Stefan and Krisciukaitis, Algimantas and Smailys, Alfredas and Lukosevicius, Saulius and Stravinskas, Mindaugas and Isaksson, Hanna and Tarasevicius, Sarunas and Lidgren, Lars and Tägil, Magnus and Raina, Deepak Bushan}},
  issn         = {{1742-7061}},
  keywords     = {{Bisphosphonate; Fracture fixation; Hydroxyapatite; Implant loosening}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Acta Biomaterialia}},
  title        = {{Systemically administered zoledronic acid activates locally implanted synthetic hydroxyapatite particles enhancing peri-implant bone formation : A regenerative medicine approach to improve fracture fixation}},
  url          = {{http://dx.doi.org/10.1016/j.actbio.2024.03.005}},
  doi          = {{10.1016/j.actbio.2024.03.005}},
  year         = {{2024}},
}