The effect of zoledronic acid incorporated in a poly(D,L‐lactide) implant coating on osteoblasts in vitro

Abstract

Bisphosphonates such as zoledronic acid (ZOL) are used in diseases associated with osteoclast-mediated bone loss. However, their antiresorptive activity is partly due to their effect on osteoblasts. Local application might increase the therapeutical fence and their local efficiency and reduce systemic side effects. Aim of the study was to investigate the effect of ZOL on human osteoblasts like cells in vitro with special focus on the synthesis of factors mediating osteoclast differentiation (RANKL, OPG). ZOL was incorporated in an implant coating based on poly(D,L-lactide) (PDLLA) in different concentrations (10-150 microM). Control groups were treated with uncoated implants, PDLLA-coated implants, and ZOL pure substance in corresponding concentrations. After an experimental period of 144 h, primary human osteoblasts were stained with alamar blue and cell viability was measured. Procollagen I synthesis, osteoprotegerin (OPG) secretion, and soluble receptor activator of nuclear factor-kappaB ligand (sRANKL) were analyzed. Results showed that cell viability was not affected when treated with doses equivalent up to 100 microM ZOL-coated implants (ZOL-CI). Procollagen I synthesis was highest when treated with 50 microM ZOL-CI. OPG increased significantly in the 10 microM ZOL-CI group, whereas sRANKL decreased significantly with different concentrations of ZOL-CI. Higher concentrations or exposure to the pure substance showed a decrease in cell viability, collagen I, OPG, and sRANKL synthesis. In conclusion, exposure to specific concentrations of ZOL-CI showed a beneficial effect on osteoblast differentiation and protein synthesis without influencing their proliferation. Changes in sRANKL and OPG production may contribute to the inhibition of osteoclastic bone resorption. This local antiresorptive effect might be clinically useful in osseous implant integration and fracture healing.

Does locally delivered Zoledronate influence peri-implant bone formation? – Spatio-temporal monitoring of bone remodeling in vivo

“…This finding supports the theory that Zoledronate can have a direct anabolic effect on bone formation. Published in vitro studies are not conclusive as they demonstrate that Zoledronate can have positive as well as negative results on osteoblasts, depending on the dose and study design [11,12,56]. Orriss et al showed that the Zoledronate dose has to be increased 10-to 100-fold to achieve the same inhibitory effect on osteoblasts when those are cultured on dentin slides, a finding that supports the theory that absorbed BPs are significantly less effective on osteoblasts [13].…”

“…However, effects of BPs on cells of the osteoblast lineage have also been described, which raises the question if BPs can also enhance bone formation activity [6,7]. In vitro experiments have shown that low concentrations of BPs can protect osteoblasts and osteocytes against apoptosis [8,9], stimulate mineralized bone nodule formation [10], and have a beneficial effect on osteoblast differentiation and protein synthesis [11]. Specifically for Zoledronate, the most potent bisphosphonate used in clinics today, an improved mineralization and proliferation of human osteoblast-like cells has been demonstrated [12].…”

High-Dose Zoledronic Acid Impacts Bone Remodeling with Effects on Osteoblastic Lineage and Bone Mechanical Properties

“…They also induce the intracellular production of Apppi [triphosphoric acid 1-adenosin-5-yl ester 3-(3-methylbut-3-enyl) ester], an ATP analogue (38) that induces cell apoptosis. However, the effects of bisphosphonate on osteoblast are not completely elucidated, and data from literature are controversial (39)(40)(41)(42).…”

In vivo local co-delivery of recombinant human bone morphogenetic protein-7 and pamidronate via poly-D, L-lactic acid

“…Poly-D,L-lactic-acid (PDLLA) is a common and inexpensive polymer that has been used as an implant coating material for growth factor delivery (Schmidmaier et al, 2001;Schmidmaier et al, 2004), and for BMP delivery in bone tissue engineering and defect repair (Zegzula et al, 1997;Saito et al, 1999;Saito et al, 2001a;Saito et al, 2001b;Kato et al, 2006a;Kato et al, 2006b;Yu et al, 2010). PDLLA also has the capacity to act as a local delivery system for bisphosphonates (Choi et al, 2007;Greiner et al, 2007a;Greiner et al, 2007b;Greiner et al, 2008). A local approach could overcome some of the adverse side-effects associated with systemic bisphosphonate dosing including stomach ulceration, low bioavailability of oral drugs and flu-like symptoms (Thiébaud et al, 1997;Mönkkönen et al, 1998).…”